A pH responsive fluorescent probe based on dye modified i-motif nucleic acids.
A new DNA-based fluorescent probe, which is a hybrid molecule of an i-motif forming sequence (IFS) and mono-functionalized tetraphenylethene (TPE), has been synthesized and investigated. A distinct pH-responsive aggregation-induced emission (AIE) effect has been observed from this hybrid molecule, i.e. the fluorescence of TPE will be turned on when the IFS part folds up under acidic conditions. According to the fact that a hybrid molecule with a relatively rigid structure shows a more obvious AIE effect, and whose nano-sized aggregates are formed at a high concentration, we assume that the solubility of the hybrid molecule in water will be reduced due to IFS folding, resulting in aggregation and the resultant AIE effect. Finally, due to its excellent pH responsiveness, this DNA-based probe employing an AIEgen has been applied in monitoring intracellular pH.


The acidic tail of HMGB1 regulates its secondary structure and conformational flexibility: A circular dichroism and molecular dynamics simulation study.
High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule that triggers the progression of several pro-inflammatory diseases such as diabetes, Alzheimer's disease and cancer, by inducing signals upon interaction with the receptors such as the receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs). The acidic C-terminal tail of HMGB1 is an intrinsically disordered region of the protein which is known to determine the interaction of HMGB1 to DNA and histones. This study characterizes its structural properties using a combination of circular dichroism (CD) and molecular dynamics (MD) simulations. The full-length and tail-less forms of HMGB1 were compared to rationalise the role of the acidic tail in maintaining the stability of the entire structure of HMGB1 in atomistic detail. Consistent with experimental data, the acidic tail was predicted to adopt an extended conformation that allows it to make a range of hydrogen-bonding and electrostatic interactions with the box-like domains that stabilize the overall structure of HMGB1. Absence of the acidic tail was predicted to increase structural fluctuations of all amino acids, leading to changes in secondary structure from α-helical to more hydrophilic turns along with increased exposure of multiple amino acids to the surrounding solvent. These structural changes reveal the intrinsic conformational dynamics of HMGB1 that are likely to affect the accessibility of its receptors.


Effect of beta-blockers on survival of lung cancer patients: a systematic review and meta-analysis.
The recent interest in beta-blockers as possible agents for drug repurposing in oncology arises from many pre-clinical and epidemiologic studies suggesting a possible clinically relevant antitumour effect. In lung cancer, given the contradictory results obtained, it is crucial to further study its effects. A systematic review of the literature was planned to evaluate a possible beneficial effect of beta-blocker on overall survival in lung cancer patients. Medline and Embase databases were searched from inception until 1 May 2018 to identify published studies that assessed the effect beta-blocker use on overall survival in lung cancer patients. Risk of bias was evaluated by Newcastle-Ottawa scale. Hazard ratios and 95% confidence intervals for overall survival were estimated using a random-effects model. Of 920 studies, seven (all retrospective and observational, six cohort and one case-control), including 7448 patients, met the inclusion criteria. Beta-blocker users with lung cancer had no increased overall survival compared to non-users (hazard ratio = 1.00; 95% confidence interval = 0.91-1.10; I = 45%). Similarly, beta-blocker users with non-small cell lung cancer had no increased overall survival compared to beta-blocker non-users (hazard ratio = 0.96; 95% confidence interval = 0.80-1.17; I = 56%). Our findings do not suggest an overall survival advantage in patients with lung cancer using beta-blocker therapy when compared to non-users. Further prospective cohort studies, designed to overcome the intrinsic limitations of retrospective observational studies are warranted to definitively clarify any possible beneficial effect of beta-blockers on lung cancer overall survival.


Optimization of a two-plasmid system for the identification of promoters recognized by RNA polymerase containing Staphylococcus aureus alternative sigma factor sigmaB.
We optimized a previously established two-plasmid system for the identification of Staphylococcus aureus promoters that are recognized by the alternative transcription factor sigma(B). The method allowed the identification of 18 S. aureus sigma(B)-dependent promoters, 12 of which are reported here for the first time to be sigma(B)-dependent. S1-nuclease mapping of the respective transcriptional start points revealed that all the promoters contained sequences exhibiting high similarity to the consensus sequence of Bacillus subtilis sigma(B)-dependent promoters. The promoters governed expression of genes encoding proteins proposed to be involved in various cellular functions, including the stress response genes and virulence-associated clfA gene for fibrinogen-binding clumping factor. Comparison of the nucleotide sequences upstream of the identified transcription start points identified a sigma(B) consensus promoter (GttTaa-N(12-15)-gGGTAt) that is highly homologous to that of sigma(B) of B. subtilis.


Introduction of a quality management system and outcome after hematopoietic stem-cell transplantation.
A comprehensive quality management system called JACIE (Joint Accreditation Committee International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation), was introduced to improve quality of care in hematopoietic stem-cell transplantation (HSCT). We therefore tested the hypothesis that the introduction of JACIE improved patient survival. Data on 41,623 allogeneic (39%) and 66,281 autologous (61%) HSCTs for an acquired hematologic disorder performed between 1999 and 2007 by 421 teams in Europe were used to assess the outcomes of patients who received a transplantation at baseline (> 3 years before application or no application), during preparation (3 years before application), during application (time from application to accreditation), and after JACIE accreditation. The analysis was clustered by team and stratified for year of HSCT, donor type, disease, conditioning, and gross national income per capita of the respective country. Patient's risks were adjusted for by their European Group for Blood and Marrow Transplantation score. Patient outcome was systematically better when the transplantation center was at a more advanced phase of JACIE accreditation, independent of year of transplantation and other risk factors. Improvement was robust as quantified for relapse-free survival after allogeneic HSCT compared with baseline by a hazard ratio (HR) of 0.96 (95% CI, 0.90 to 1.03; P = .22) for preparation, 0.95 (95% CI, 0.88 to 1.03; P = .20) for application, and 0.86 (95% CI, 0.78 to 0.95; P = .01) for the accreditation (test for trend P = .01). Improvement from baseline was similar after autologous HSCT (HR for accreditation, 0.83; 95% CI, 0.74 to 0.93; P < .01). Even with all the limitations of an observational study, these findings support the hypothesis that introduction of a comprehensive clinical quality management system is associated with improved outcome of patients after HSCT.


Health literacy and public health: a systematic review and integration of definitions and models.
Health literacy concerns the knowledge and competences of persons to meet the complex demands of health in modern society. Although its importance is increasingly recognised, there is no consensus about the definition of health literacy or about its conceptual dimensions, which limits the possibilities for measurement and comparison. The aim of the study is to review definitions and models on health literacy to develop an integrated definition and conceptual model capturing the most comprehensive evidence-based dimensions of health literacy. A systematic literature review was performed to identify definitions and conceptual frameworks of health literacy. A content analysis of the definitions and conceptual frameworks was carried out to identify the central dimensions of health literacy and develop an integrated model. The review resulted in 17 definitions of health literacy and 12 conceptual models. Based on the content analysis, an integrative conceptual model was developed containing 12 dimensions referring to the knowledge, motivation and competencies of accessing, understanding, appraising and applying health-related information within the healthcare, disease prevention and health promotion setting, respectively. Based upon this review, a model is proposed integrating medical and public health views of health literacy. The model can serve as a basis for developing health literacy enhancing interventions and provide a conceptual basis for the development and validation of measurement tools, capturing the different dimensions of health literacy within the healthcare, disease prevention and health promotion settings.


Failure to detect xenotropic murine leukemia virus-related virus in blood of individuals at high risk of blood-borne viral infections.
A xenotropic murine leukemia virus-related virus (XMRV) has recently been reported in association with prostate cancer and chronic fatigue syndrome, with a prevalence of up to 3.7% in the healthy population. We looked for XMRV in 230 patients with human immunodeficiency virus type 1 or hepatitis C infection. XMRV was undetectable in plasma or peripheral blood mononuclear cells by polymerase chain reaction targeting XMRV gag or env. T cell responses to XMRV Gag were undetectable in peripheral blood mononuclear cells by ex vivo gamma interferon enzyme-linked immunospot assay. In our cohorts, XMRV was not enriched in patients with blood-borne or sexually transmitted infections from the United Kingdom and Western Europe.


Critical Care Performance in a Simulated Military Aircraft Cabin Environment.
Critical Care Air Transport Teams care for 5% to 10% of injured patients who are transported on military aircraft to definitive treatment facilities. Little is known about how the aeromedical evacuation environment affects care. To determine the effects of 2 stressors of flight, altitude-induced hypoxia and aircraft noise, and to examine the contributions of fatigue and clinical experience on cognitive and physiological performance of the Critical Care Air Transport Team. This repeated measures 2 × 2 × 4 factorial study included 60 military nurses. The participants completed a simulated patient care scenario under aircraft cabin noise and altitude conditions. Differences in cognitive and physiological performance were analyzed using repeated measures analysis of variance. A multiple regression model was developed to determine the independent contributions of fatigue and clinical experience. Critical care scores (P = .02) and errors and omissions (P = .047) were negatively affected by noise. Noise was associated with increased respiratory rate (P = .02). Critical care scores (P < .001) and errors and omissions (P = .002) worsened with altitude-induced hypoxemia. Heart rate and respiratory rate increased with altitude-induced hypoxemia; oxygen saturation decreased (P < .001 for all 3 variables). In a simulated military aircraft environment, the care of critically ill patients was significantly affected by noise and altitude-induced hypoxemia. The participants did not report much fatigue and experience did not play a role, contrary to most findings in the literature.


Diketopiperazines from Costa Rican endolichenic fungus Colpoma sp. CR1465A.
Three new diketopiperazines (1-3), cyclo(l-Pro-d-trans-Hyp) (1), cyclo(l-Pro-d-Glu) (2), and cyclo(d-Pro-d-Glu) (3) and five known diketopiperazines (4-8) were isolated from the endolichenic fungus Colpoma sp. CR1465A identified from the Costa Rican plant Henriettea tuberculosa (Melatomataceae). The structures of the new compounds 1-3 were elucidated using a combination of extensive spectroscopic analyses, including 2D NMR and HR-MS, and their absolute configurations were determined by a combination of NOESY analysis and Marfey's method. Cyclo(l-Pro-d-allo-Thr) (4) was recently isolated from a South China Sea marine sponge Callyspongia sp., but its NMR spectroscopic data were not reported, and cyclo(l-Pro-l-Asp) (5) was previously reported but only as a synthetic product. The NMR data assignments of compounds 4 and 5 are reported for the first time. All of the isolated compounds were tested for antifungal and antimicrobial properties.


Drug advertisements in two dermatology journals: a critical comparison of IJDVL and JAAD.
Though drug promotion regulations exist worldwide, low quality of journal drug advertising is a global issue. Medical journals are regarded as a leading source of information for new drugs. They may also modulate prescribing behavior of physicians without their knowledge. A comparative analysis of advertisements from different countries may provide insights regarding strengths and weaknesses of different regulating systems. Prescription drug advertisements from the Indian Journal of Dermatology, Venereology, and Leprology (IJDVL) and Journal of American Academy of Dermatology (JAAD) were compared to check their compliance with criteria of World Health Organization (WHO) and International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). All the prescription drug advertisements of at least one page length appearing in all the issues of IJDVL and JAAD from January 2012 till December 2012 were included in this study. The contents of both advertisements were compared for compliance regarding different criteria of ethical codes for drug advertising of WHO and IFPMA. Statistical analysis was done using Fisher's exact test. Compared to IJDVL, more advertisements in JAAD complied with WHO and IFPMA codes. On the whole, advertisements in IJDVL had significantly less information regarding the approved usage, dosage, abbreviated prescribing information (API), summary of scientific information, safety information regarding the drug, and references to the scientific literature to support various claims. However, JAAD had more advertisements with multiple claims than IJDVL, and many advertisements interspersed between scientific articles while IJDVL had none. The complex issue of ethical drug advertising in dermatology journals requires constant review and discussion. Dermatologists should be cautious in assessing any advertisement or claim even if it seems evidence-based. The results from our study highlight the need for a global, proactive and effective regulatory system to ensure ethical medicinal drug advertising in medical journals.


Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity.
In this Review we focus on the initiation of autoantibody production and autoantibody pathogenicity, with a special emphasis on the targeted antigens. Release of intracellular antigens due to excessive cell death or to ineffective clearance of apoptotic debris, modification of self-antigens during inflammatory responses, and molecular mimicry contribute to the initiation of autoantibody production. We hypothesize that those autoreactive B cells that survive and produce pathogenic autoantibodies have specificity for self-antigens that are TLR ligands. Such B cells experience both B cell receptor (BCR) activation and TLR engagement, leading to an escape from tolerance. Moreover, the autoantibodies they produce form immune complexes that can activate myeloid cells and thereby establish the proinflammatory milieu that further negates tolerance mechanisms of both B and T cells.


Partial ablation versus radical prostatectomy in intermediate-risk prostate cancer: the PART feasibility RCT.
Prostate cancer (PCa) is the most common cancer in men in the UK. Patients with intermediate-risk, clinically localised disease are offered radical treatments such as surgery or radiotherapy, which can result in severe side effects. A number of alternative partial ablation (PA) technologies that may reduce treatment burden are available; however the comparative effectiveness of these techniques has never been evaluated in a randomised controlled trial (RCT). To assess the feasibility of a RCT of PA using high-intensity focused ultrasound (HIFU) versus radical prostatectomy (RP) for intermediate-risk PCa and to test and optimise methods of data capture. We carried out a prospective, multicentre, open-label feasibility study to inform the design and conduct of a future RCT, involving a QuinteT Recruitment Intervention (QRI) to understand barriers to participation. Five NHS hospitals in England. Men with unilateral, intermediate-risk, clinically localised PCa. Radical prostatectomy compared with HIFU. The randomisation of 80 men. Findings of the QRI and assessment of data capture methods. Eighty-seven patients consented to participate by 31 March 2017 and 82 men were randomised by 4 May 2017 (41 men to the RP arm and 41 to the HIFU arm). The QRI was conducted in two iterative phases: phase I identified a number of barriers to recruitment, including organisational challenges, lack of recruiter equipoise and difficulties communicating with patients about the study, and phase II comprised the development and delivery of tailored strategies to optimise recruitment, including group training, individual feedback and 'tips' documents. At the time of data extraction, on 10 October 2017, treatment data were available for 71 patients. Patient characteristics were similar at baseline and the rate of return of all clinical case report forms (CRFs) was 95%; the return rate of the patient-reported outcome measures (PROMs) questionnaire pack was 90.5%. Centres with specific long-standing expertise in offering HIFU as a routine NHS treatment option had lower recruitment rates (Basingstoke and Southampton) - with University College Hospital failing to enrol any participants - than centres offering HIFU in the trial context only. Randomisation of men to a RCT comparing PA with radical treatments of the prostate is feasible. The QRI provided insights into the complexities of recruiting to this surgical trial and has highlighted a number of key lessons that are likely to be important if the study progresses to a main trial. A full RCT comparing clinical effectiveness, cost-effectiveness and quality-of-life outcomes between radical treatments and PA is now warranted. Men recruited to the feasibility study will be followed up for 36 months in accordance with the protocol. We will design a full RCT, taking into account the lessons learnt from this study. CRFs will be streamlined, and the length and frequency of PROMs and resource use diaries will be reviewed to reduce the burden on patients and research nurses and to optimise data completeness. Current Controlled Trials ISRCTN99760303. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 52. See the NIHR Journals Library website for further project information.


WWW mesothelioma information: Surfing on unreliable waters. A cross-sectional study into the content and quality of online informational resources for mesothelioma patients.
Malignant Mesothelioma (MM) is a rare asbestos related disease mostly diagnosed in low-skilled patients. The decision-making process for MM treatment is complicated, making an adequate provision of information necessary. The objective of this study is to assess the content and quality of online informational resources available for Dutch MM patients. The first 100 hits of a Google search were studied using the JAMA benchmarks, the Modified Information Score (MIS) and the International Patient Decision Aid Standard Scoring (IPDAS). A total of 37 sources were included. Six of the 37 resources were published by hospitals. On average, the informational resources scored 37 points on the MIS (scale 0-100). The resources from a (bio)medical sources scored the best on this scale. However, on the domain of use of language, these resources scored the worst. The current level of medical content and quality of online informational resources for patient with MM is below average and cannot be used as decision-aids for patients. The criteria used in this article could be used for future improvements of online informational resources for patients, both online, offline and through health education in the care path.


K13-Propeller Polymorphisms in Plasmodium falciparum Isolates from Patients in Mayotte in 2013 and 2014.
Plasmodium falciparum isolates were collected from 29 malaria patients treated with artemether-lumefantrine in Mayotte in 2013 and 2014. Twenty-four cases (83%) consisted of imported malaria. Seventeen percent of the isolates presented mutations in one of the six K13-propeller blades (N490H, F495L, N554H/K, and E596G). A total of 23.8% of the isolates from the Union of Comoros showed K13-propeller polymorphisms. Three of the 18 isolates (16.7%) from Grande Comore showed polymorphisms (N490H, N554K, and E596G).


Clinical consequences of asbestos-related diffuse pleural thickening: A review.
Asbestos-related diffuse pleural thickening (DPT), or extensive fibrosis of the visceral pleura secondary to asbestos exposure, is increasingly common due to the large number of workers previously exposed to asbestos. It may coexist with asbestos related pleural plaques but has a distinctly different pathology. The pathogenesis of this condition as distinct from pleural plaques is gradually becoming understood. Generation of reactive oxygen and nitrogen species, profibrotic cytokines and growth factors in response to asbestos is likely to play a role in the formation of a fibrinous intrapleural matrix. Benign asbestos related pleural effusions commonly antedate the development of diffuse pleural thickening. Environmental as well as occupational exposure to asbestos may also result in pleural fibrosis, particularly in geographic areas with naturally occurring asbestiform soil minerals. Pleural disorders may also occur after household exposure. High resolution computed tomography (CT) is more sensitive and specific than chest radiography for the diagnosis of diffuse pleural thickening, and several classification systems for asbestos-related disorders have been devised. Magnetic resonance imaging and fluorodeoxyglucose positron emission tomography (PET) scanning may be useful in distinguishing between DPT and malignant mesothelioma. DPT may be associated with symptoms such as dyspnoea and chest pain. It causes a restrictive defect on lung function and may rarely result in respiratory failure and death. Treatment is primarily supportive.


Next generation sequencing reads comparison with an alignment-free distance.
Next Generation Sequencing (NGS) machines extract from a biological sample a large number of short DNA fragments (reads). These reads are then used for several applications, e.g., sequence reconstruction, DNA assembly, gene expression profiling, mutation analysis. We propose a method to evaluate the similarity between reads. This method does not rely on the alignment of the reads and it is based on the distance between the frequencies of their substrings of fixed dimensions (k-mers). We compare this alignment-free distance with the similarity measures derived from two alignment methods: Needleman-Wunsch and Blast. The comparison is based on a simple assumption: the most correct distance is obtained by knowing in advance the reference sequence. Therefore, we first align the reads on the original DNA sequence, compute the overlap between the aligned reads, and use this overlap as an ideal distance. We then verify how the alignment-free and the alignment-based distances reproduce this ideal distance. The ability of correctly reproducing the ideal distance is evaluated over samples of read pairs from Saccharomyces cerevisiae, Escherichia coli, and Homo sapiens. The comparison is based on the correctness of threshold predictors cross-validated over different samples. We exhibit experimental evidence that the proposed alignment-free distance is a potentially useful read-to-read distance measure and performs better than the more time consuming distances based on alignment. Alignment-free distances may be used effectively for reads comparison, and may provide a significant speed-up in several processes based on NGS sequencing (e.g., DNA assembly, reads classification).


Self-regulation of local brain activity using real-time functional magnetic resonance imaging (fMRI).
Functional magnetic resonance imaging (fMRI) measures the blood oxygen level-dependent (BOLD) signal related to neuronal activity. So far, this technique has been limited by time-consuming data analysis impeding on-line analysis. In particular, no brain-computer interface (BCI) was available which provided on-line feedback to learn physiological self-regulation of the BOLD signal. Recently, studies have shown that fMRI feedback is feasible and facilitates voluntary control of brain activity. Here we review these studies to make the fMRI feedback methodology accessible to a broader scientific community such as researchers concerned with functional brain imaging and the neurobiology of learning. Methodological and conceptual limitations were substantially reduced by artefact control, sensitivity improvements, real-time algorithms, and adapted experimental designs. Physiological self-regulation of the local BOLD response is a new paradigm for cognitive neuroscience to study brain plasticity and the functional relevance of regulated brain areas by modification of behaviour. Voluntary control of abnormal activity in circumscribed brain areas may even be applied as psychophysiological treatment.


Data-driven strategies for optimal bicycle network growth.
Urban transportation networks, from pavements and bicycle paths to streets and railways, provide the backbone for movement and socioeconomic life in cities. To make urban transport sustainable, cities are increasingly investing to develop their bicycle networks. However, it is yet unclear how to extend them comprehensively and effectively given a limited budget. Here we investigate the structure of bicycle networks in cities around the world, and find that they consist of hundreds of disconnected patches, even in cycling-friendly cities like Copenhagen. To connect these patches, we develop and apply data-driven, algorithmic network growth strategies, showing that small but focused investments allow to significantly increase the connectedness and directness of urban bicycle networks. We introduce two greedy algorithms to add the most critical missing links in the bicycle network focusing on connectedness, and show that they outmatch both a random approach and a baseline minimum investment strategy. Our computational approach outlines novel pathways from car-centric towards sustainable cities by taking advantage of urban data available on a city-wide scale. It is a first step towards a quantitative consolidation of bicycle infrastructure development that can become valuable for urban planners and stakeholders.


Natural acquired group B Streptococcus capsular polysaccharide and surface protein antibodies in HIV-infected and HIV-uninfected children.
Group B Streptococcus (GBS) is a major cause of invasive disease in young infants and also in older immunocompromised individuals, including HIV-infected persons. We compared naturally acquired antibody titres to GBS polysaccharide and surface protein antigens in HIV-uninfected and HIV-infected children aged 4-7 years. A multiplex Luminex immunoassay was used to measure IgG concentrations against GBS capsular polysaccharides (CPS) for serotypes Ia, Ib, III and V; and also extracellular localizing proteins which included cell-wall anchored proteins: Fibrinogen binding surface Antigen (FbsA), GBS Immunogenic Bacterial Adhesin (BibA), Surface immunogenic protein (Sip), gbs0393, gbs1356, gbs1539, gbs0392; and lipoproteins gbs0233, gbs2106 and Foldase PsrA. HIV-infected children (n=68) had significantly lower IgG GMT compared to HIV-uninfected (n=77) children against CPS of serotype Ib (p=0.012) and V (p=0.0045), and surface proteins Sip (p<0.001) and gbs2106 (p=0.0014). IgG GMT against GBS surface proteins: FbsA, gbs1539, gbs1356, gbs0392, gbs0393 and Foldase PsrA were significantly higher in HIV-infected children (p<0.004). Moreover, amongst HIV infected children, IgG GMT to GBS surface proteins were higher in those with CD4+ lymphocyte counts <500cell/μL compared to those who had CD4+ lymphocyte count ⩾500cell/μL with the exception of Sip. The increased susceptibility to invasive GBS disease in HIV-infected individuals could be due to the lower serotype specific capsular antibody and possibly due to lower antibody to some of the GBS proteins such as Sip and gbs2106.


Physical Activity Differentially Affects the Cecal Microbiota of Ovariectomized Female Rats Selectively Bred for High and Low Aerobic Capacity.
The gut microbiota is considered a relevant factor in obesity and associated metabolic diseases, for which postmenopausal women are particularly at risk. Increasing physical activity has been recognized as an efficacious approach to prevent or treat obesity, yet the impact of physical activity on the microbiota remains under-investigated. We examined the impacts of voluntary exercise on host metabolism and gut microbiota in ovariectomized (OVX) high capacity (HCR) and low capacity running (LCR) rats. HCR and LCR rats (age = 27 wk) were OVX and fed a high-fat diet (45% kcal fat) ad libitum and housed in cages equipped with (exercise, EX) or without (sedentary, SED) running wheels for 11 wk (n = 7-8/group). We hypothesized that increased physical activity would hinder weight gain, increase metabolic health and shift the microbiota of LCR rats, resulting in populations more similar to that of HCR rats. Animals were compared for characteristic metabolic parameters including body composition, lipid profile and energy expenditure; whereas cecal digesta were collected for DNA extraction. 16S rRNA gene-based amplicon Illumina MiSeq sequencing was performed, followed by analysis using QIIME 1.8.0 to assess cecal microbiota. Voluntary exercise decreased body and fat mass, and normalized fasting NEFA concentrations of LCR rats, despite only running one-third the distance of HCR rats. Exercise, however, increased food intake, weight gain and fat mass of HCR rats. Exercise clustered the gut microbial community of LCR rats, which separated them from the other groups. Assessments of specific taxa revealed significant (p<0.05) line by exercise interactions including shifts in the abundances of Firmicutes, Proteobacteria, and Cyanobacteria. Relative abundance of Christensenellaceae family was higher (p = 0.026) in HCR than LCR rats, and positively correlated (p<0.05) with food intake, body weight and running distance. These findings demonstrate that exercise differentially impacts host metabolism and gut microbial communities of female HCR and LCR rats without ovarian function.


A systematic review of preventive health educational videos targeting infectious diseases in schoolchildren.
We conducted a systematic review of preventive health educational videos targeting infectious diseases in schoolchildren to formulate recommendations for establishing an evidence base for future studies. We included studies that evaluated interventions involving video-based health education in schools to improve knowledge and attitudes and to change behavior regarding different infections. The majority of the 11 studies we reviewed concluded that videos were well received by schools, teachers, and children, and are promising and effective health education tools, having a positive impact on knowledge and attitudes. However, there is a pressing need for more standardized, high-quality studies to draw evidence-based conclusions on the value of educational videos targeting infectious diseases. Therefore, we provide a descriptive summary of the results and make recommendations for studies using preventive educational videos targeting infectious diseases in schoolchildren on the basis of our experiences gained in a video-based cluster randomized trial.


[Use of complementary therapies by mothers in their children: study at an university hospital].
The objective of this article is to evaluate the use of complementary therapies by mothers in their children. A cross-sectional and descriptive study with 202 mothers of children that attended an University Hospital were interviewed. The variables analyzed were: use of complementary therapies/reasons, therapies used its purpose, effects, doctor's revelation/reasons and doctor's reaction. The prevalence of complementary therapies use was of 87.6%. Among the 177 mothers that used complementary therapies, many mentioned more than one kind, as follow: teas (72.8%), blessings (41%), sympathies (12.9%), homemade remedies/syrups (8.4%), prayer/promises (7.4%), homeopathy (4.0%), spiritual/parapsychological treatment (4.0%), mixture of unknown substances/"garrafada" (bottled) (3%), massage (2%) and reiki/floral (1.5%). The most used herbs were anise (16.7%), chamomile (14.8%) and mint (10.9%); 57.6% of the mothers did not inform its use to the doctor. Out of 499 treatments employed, there was a perception of improvement in 429 (86%) and 2 reports of adverse effects. The prevalence of complementary therapies utilization was high, being teas the most utilized therapy and anise, chamomile and mint the most used herbs. There was perception of improvement in most of the used therapies.


Increasing Cervical Cancer Screening Among US Hispanics/Latinas: A Qualitative Systematic Review.
Hispanic/Latina women experience the highest cervical cancer incidence rates of any racial/ethnic group in the USA and tend to present with more severe cases and experience higher mortality compared to most other populations. The goals of this qualitative systematic review were to explore existing interventions to increase cervical cancer screening among US Hispanics/Latinas and to identify characteristics of effective interventions and research gaps. Six online databases were searched from their inception through June 30, 2013, using designated search terms and keywords. Peer-reviewed articles that documented an intervention designed to improve screening for cervical cancer among Hispanics/Latinas ages 18 years and older living in the USA were reviewed. Data were abstracted using a standardized form to document intervention characteristics and results. Forty-five articles, describing 32 unique interventions, met inclusion criteria. Identified interventions consisted primarily of educational programs and/or provision of screening. Interventions used lay health advisors (LHAs), clinic-based outreach/delivery strategies, partnerships with churches, and mass media campaigns. Twelve interventions resulted in significant increases in cervical cancer screening rates. Interventions developed utilizing theory, applying community-based participatory research approaches, and using LHAs were identified as having the greatest potential for improving cervical cancer screening among Hispanics/Latinas. There continues to be a need for the development of interventions in geographic areas with new and emerging Hispanic/Latino populations and that are comprehensive, follow participants for longer periods of time, and broaden the roles and build the capacities of LHAs.


The Curious Acoustic Behavior of Estuarine Snapping Shrimp: Temporal Patterns of Snapping Shrimp Sound in Sub-Tidal Oyster Reef Habitat.
Ocean soundscapes convey important sensory information to marine life. Like many mid-to-low latitude coastal areas worldwide, the high-frequency (>1.5 kHz) soundscape of oyster reef habitat within the West Bay Marine Reserve (36°N, 76°W) is dominated by the impulsive, short-duration signals generated by snapping shrimp. Between June 2011 and July 2012, a single hydrophone deployed within West Bay was programmed to record 60 or 30 seconds of acoustic data every 15 or 30 minutes. Envelope correlation and amplitude information were then used to count shrimp snaps within these recordings. The observed snap rates vary from 1500-2000 snaps per minute during summer to <100 snaps per minute during winter. Sound pressure levels are positively correlated with snap rate (r = 0.71-0.92) and vary seasonally by ~15 decibels in the 1.5-20 kHz range. Snap rates are positively correlated with water temperatures (r = 0.81-0.93), as well as potentially influenced by climate-driven changes in water quality. Light availability modulates snap rate on diurnal time scales, with most days exhibiting a significant preference for either nighttime or daytime snapping, and many showing additional crepuscular increases. During mid-summer, the number of snaps occurring at night is 5-10% more than predicted by a random model; however, this pattern is reversed between August and April, with an excess of up to 25% more snaps recorded during the day in the mid-winter. Diurnal variability in sound pressure levels is largest in the mid-winter, when the overall rate of snapping is at its lowest, and the percentage difference between daytime and nighttime activity is at its highest. This work highlights our lack of knowledge regarding the ecology and acoustic behavior of one of the most dominant soniforous invertebrate species in coastal systems. It also underscores the necessity of long-duration, high-temporal-resolution sampling in efforts to understand the bioacoustics of animal behaviors and associated changes within the marine soundscape.


Deficiency of beta1 integrins results in increased myocardial dysfunction after myocardial infarction.
To study the role of beta1 integrins in left ventricular (LV) remodelling after myocardial infarction (MI). LV structural and functional alterations were determined in wild-type (WT) and beta1 integrin heterozygous knockout (hKO) mice one month after MI. MI increased beta1 integrin expression in both groups; however, the increase was lower in hKO. Infarct size was similar in WT and hKO mice, whereas lung wet weight to dry weight ratio was increased in the hKO-MI mice (5.17 (SE 0.13) v 4.60 (0.15) in WT-MI, p < 0.01). LV end systolic and end diastolic diameters were significantly higher and percentage fractional shortening was significantly lower in hKO-MI. The ratio of peak velocity of early LV filling (E wave) to that of the late LV filling (A wave) and the isovolumic relaxation time (IVRT) were increased in both MI groups but the increase in IVRT was significantly higher in hKO-MI group than in WT-MI mice. Langendorff perfusion analysis indicated reduced peak LV developed pressure and increased LV end diastolic pressure in both MI groups. The reduction in peak LV developed pressure (36.7 (2.2) v 53.4 (1.9) mm Hg, p < 0.05) and increase in LV end diastolic pressure was higher in hKO-MI than in WT-MI. Increase in fibrosis was not different between the two MI groups. The increase in myocyte circumference was higher in the hKO-MI group (p < 0.001 v WT-MI). The number of apoptotic myocytes was significantly higher in hKO-MI than in WT-MI mice (p < 0.005) three days after MI. The number of necrotic myocytes was not different between the two MI groups. beta1 integrins are crucial in post-MI remodelling with effects on LV function, hypertrophy and apoptosis.


EGFR and EGFRvIII undergo stress- and EGFR kinase inhibitor-induced mitochondrial translocalization: a potential mechanism of EGFR-driven antagonism of apoptosis.
Epidermal growth factor receptor (EGFR) plays an essential role in normal development, tumorigenesis and malignant biology of human cancers, and is known to undergo intracellular trafficking to subcellular organelles. Although several studies have shown that EGFR translocates into the mitochondria in cancer cells, it remains unclear whether mitochondrially localized EGFR has an impact on the cells and whether EGFRvIII, a constitutively activated variant of EGFR, undergoes mitochondrial transport similar to EGFR. We report that both receptors translocate into the mitochondria of human glioblastoma and breast cancer cells, following treatments with the apoptosis inducers, staurosporine and anisomycin, and with an EGFR kinase inhibitor. Using mutant EGFR/EGFRvIII receptors engineered to undergo enriched intracellular trafficking into the mitochondria, we showed that glioblastoma cells expressing the mitochondrially enriched EGFRvIII were more resistant to staurosporine- and anisomycin-induced growth suppression and apoptosis and were highly resistant to EGFR kinase inhibitor-mediated growth inhibition. These findings indicate that apoptosis inducers and EGFR-targeted inhibitors enhance mitochondrial translocalization of both EGFR and EGFRvIII and that mitochondrial accumulation of these receptors contributes to tumor drug resistance. The findings also provide evidence for a potential link between the mitochondrial EGFR pathway and apoptosis.


Gatekeeping and legitimization: how informal carers' relationship with health care workers is revealed in their everyday interactions.
This study explores the relationship between informal carers of older people, and health care workers within the context of a hospital ward. Through an analysis of their language-based encounters the purpose of the study was to identify the discursive processes involved in face-to-face informal carer-health care worker interactions, during the course of carers' visits to one elderly care rehabilitation hospital ward. An ethnomethodological research design, which encompassed the concerns of conversation analysis and the study of institutional interaction, was used. The study involved videotape recording informal carers naturally occurring spontaneous interactions with a range of health care workers on the ward. Data collection was carried out for between 1 and 3 hours, two to three times a week over a period of 3 months. The data comprised: 30 dyadic and group interactions involving 19 different carers and 25 different health care workers, including nurses (qualified and unqualified), physiotherapists, occupational therapists, dieticians, ambulance personnel, housekeepers and nursing auxiliaries. Detailed transcriptions of the data were produced and analysis was undertaken using a modified conversation analysis approach. Analysis revealed that a central aspect of the way the relationship between informal carers and health care workers is framed is by the way information and access to information is obtained. This paper examines some of the aspects of informal carer-health care worker discourse, which denote both parties as gatekeepers. In doing so it considers the roles that legitimatization of competence and knowledgeability have in facilitating informal carers interactions with health care workers. We conclude that the accomplishment of legitimacy is largely a collaborative undertaking on behalf of health care workers and informal carers. The implications of these findings for carers, health care workers, policy and future research are discussed.


Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation.
Costello syndrome is a rare developmental disorder characterized by coarse face, postnatal growth retardation, skin and musculoskeletal anomalies, cardiovascular abnormalities, mental retardation, and tumor predisposition. Dermatological manifestations usually include redundant, soft and thickened skin. Loose skin is especially present over the neck, hands, and feet. Heterozygous missense mutations in HRAS are causative for Costello syndrome, with the c.34G > A (p.G12S) mutation as the most commonly found alteration. In the majority of affected individuals pathogenic sequence changes appeared de novo, however, two individuals with somatic mosaicism for the HRAS mutation have been reported. Here, we describe a boy with somatic mosaicism for the c.34G > A mutation in HRAS. Allelic quantitation revealed the mutation in approximately 58% of his lymphocytes; however, in DNA derived from buccal cells we could not detect the sequence change. The patient presented with the typical clinical findings of Costello syndrome such as increased birth weight, severe failure to thrive, characteristic facial appearance, and skin abnormalities. The dermatological anomalies were remarkable as he showed severe skin laxity with wrinkling of skin on all parts of the body due to loss of subcutaneous fat that decreased significantly by age 13 months. This case further adds to the phenotypic variability seen in patients with somatic mosaicism for an HRAS mutation and highlights the awareness of mosaic mutations in Costello syndrome when molecular testing is performed.


Mössbauer spectroscopic studies of the terminal dioxygenase protein of benzene dioxygenase from Pseudomonas putida.
Mössbauer spectra obtained from the terminal dioxygenase protein of the benzene dioxygenase system from Pseudomonas putida show that it contains [2Fe--2S] centres similar to those of the two-iron plant-type ferredoxins. In the oxidized form the two iron atoms within the centre are high-spin ferric but with considerable inequivalence. In the reduced form the centre contains one extra electron, and this is localized on one of the iron atoms, which becomes high-spin ferrous.


The changing face of cancer care in the UK: can nurses help to structure new services?
The concept of the lead cancer nurse is relatively new; no models of practice are available. An evaluation of lead cancer nurses was undertaken to identify core elements of success associated with this role. A two-stage multiple case study was used. In stage one, information was collected about post holders, working contexts, strategic aims and evidence of achievements from lead nurses, lead clinicians and senior nurses. Stage two explored the processes that enhanced and inhibited development of the lead nurse role. Site-visits were made to 12 Macmillan lead cancer nurses throughout the UK. Detailed information from interviews, observations and documentary materials were analysed using a framework that emphasized four key areas: assessment of current service, promotion of evidence-based practice, contribution to strategic decision making and consumer perspectives. Enhancing factors important to the lead cancer nurses were the ability to: utilize decision-making power, build alliances and accommodate to a changing environment. Factors found to hinder achievement were: major changes in service and policy, restricted resources and the cancer site-specific structure of health service provisions. Further and greater contributions to cancer care from lead nurses require influential partnerships within local health care organizations and wider networks.


Screening mammography with special reference to guidelines in South Africa.
Screening mammography is known to reduce mortality from breast cancer. Controversy regarding screening has led to much confusion in the medical fraternity. The purpose of this review is to point out the 'pros and cons' of screening. The benefits and perceived harms of screening will be discussed using evidence-based literature from the past 30 years. The literature was obtained from various journals sourced from the Internet. General findings are that screening mammography from the age of 40 saves lives, but that the problem of overdiagnosis and overtreatment of certain breast cancers overrides the benefit of screening. The article also covers the debate on what age to begin screening. Screening in the South African context is discussed. Screening in the future will need to be more selective of patients and of which cancers to treat less aggressively, if at all.


Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity.
Dizocilpine (MK-801), an extensively investigated drug possessing secondary amine and benzenoid functions, displays a wide array of biological properties, including anticonvulsant and anesthetic. There is scant discussion of biomechanism. A relevant, important finding is formation of oxidative metabolites in the hydroxylamine and phenolic categories. Analogy to cocaine metabolites suggests participation of redox entities, such as, hydroxylamine, nitroxide and nitrosonium, which can lead to electron transfer and radical formation. There is also similarity to metabolism by 3,3'-iminodipropionitrile and phencyclidine. Alternatively, the phenolic metabolites are well-known precursors of ET quinones. The review documents various physiological effects, mainly involving the central nervous system. Also of interest are the pro- and ant-oxidant properties. Considerable attention has been paid to MK-801 as an antagonist of the N-methyl-D-aspartate receptor in the glutamate category. This aspect is often associated with effects on the central nervous system. The review also provides recent literature dealing with MK-801/NMDA receptor in various areas of bioactivity. Studies were made of MK-801 involvement in working memory processing. Deficits in behavior were noted after administration of the drug. Treatment of mice with dizocilpine induced learning impairment. The influence of MK-801 on fear has been investigated. The substance is known to exert an analgesic effect in pain control. A number of reports deal with anesthetic properties.


Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis.
Several studies found association between vitamin D levels and hypertension, coronary artery calcification, and heart disease. The aim of this study was to summarize the evidence on the effect of vitamin D on cardiovascular outcomes. We searched electronic databases from inception through August 2010 for randomized trials. Reviewers working in duplicate and independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta-analysis was used to pool the relative risks (RR) and the weighted mean differences across trials. We found 51 eligible trials with moderate quality. Vitamin D was associated with nonsignificant effects on the patient-important outcomes of death [RR, 0.96; 95% confidence interval (CI), 0.93, 1.00; P = 0.08], myocardial infarction (RR, 1.02; 95% CI, 0.93, 1.13; P = 0.64), and stroke (RR, 1.05; 95% CI, 0.88, 1.25; P = 0.59). These analyses were associated with minimal heterogeneity. There were no significant changes in the surrogate outcomes of lipid fractions, glucose, or diastolic or systolic blood pressure. The latter analyses were associated with significant heterogeneity, and the pooled estimates were trivial in absolute terms. Trial data available to date are unable to demonstrate a statistically significant reduction in mortality and cardiovascular risk associated with vitamin D. The quality of the available evidence is low to moderate at best.


Chronic oxidative DNA damage due to DNA repair defects causes chromosomal instability in Saccharomyces cerevisiae.
Oxidative DNA damage is likely to be involved in the etiology of cancer and is thought to accelerate tumorigenesis via increased mutation rates. However, the majority of malignant cells acquire a specific type of genomic instability characterized by large-scale genomic rearrangements, referred to as chromosomal instability (CIN). The molecular mechanisms underlying CIN are not entirely understood. We utilized Saccharomyces cerevisiae as a model system to delineate the relationship between genotoxic stress and CIN. It was found that elevated levels of chronic, unrepaired oxidative DNA damage caused chromosomal aberrations at remarkably high frequencies under both selective and nonselective growth conditions. In this system, exceeding the cellular capacity to appropriately manage oxidative DNA damage resulted in a "gain-of-CIN" phenotype and led to profound karyotypic instability. These results illustrate a novel mechanism for genome destabilization that is likely to be relevant to human carcinogenesis.


Parathyroid hormone and its receptor gene polymorphisms: implications in osteoporosis and in fracture healing.
Parathyroid glands secrete parathyroid hormone (PTH) which plays multiple roles in calcium homeostasis and in bone remodeling. Secretion of PTH is regulated by extracellular calcium levels and other humoral factors including 1α,25(OH)2D3. PTH regulates gene expression and induces biological effects directly and indirectly. The human gene encoding PTH is located on chromosome 11. In this review, we study the diverse PTH along with its receptor gene polymorphisms and their association with osteoporosis and fracture healing. Genetic factors are associated with osteoporosis by influencing bone mineral density (BMD), bone turnover, calcium homeostasis, and susceptibility to osteoporotic fractures. Polymorphisms in genes encoding PTH may contribute to genetic regulation of BMD and thus susceptibility to fracture risk. PTH stimulates the proliferation of osteoprogenitor cells, production of alkaline phosphatise, and bone matrix proteins that contribute to hard callus formation and increases strength at the site of fractured bone. During remodeling, PTH promotes osteoclastogenesis restoring the original shape, structure, and mechanical strength of the bone. Some PTH polymorphisms have shown an association with fracture risk. Further research is needed to elucidate the relative importance of PTH genetics and the mechanisms of genetic contributions to gene-gene interactions in the pathogenesis of osteoporosis and in fracture healing.


Factors affecting excitatory amino acid release following severe human head injury.
Recent animal studies demonstrate that excitatory amino acids (EAAs) play a major role in neuronal damage after brain trauma and ischemia. However, the role of EAAs in patients who have suffered severe head injury is not understood. Excess quantities of glutamate in the extracellular space may lead to uncontrolled shifts of sodium, potassium, and calcium, disrupting ionic homeostasis, which may lead to severe cell swelling and cell death. The authors evaluated the role of EEAs in human traumatic brain injury. In 80 consecutive severely head injured patients, a microdialysis probe was placed into the gray matter along with a ventriculostomy catheter or an intracranial pressure (ICP) monitor for 4 days. Levels of EAAs and structural amino acids were analyzed using high-performance liquid chromatography. Multifactorial analysis of the amino acid pattern was performed and its correlations with clinical parameters and outcome were tested. The levels of EAAs were increased up to 50 times normal in 30% of the patients and were significantly correlated to levels of structural amino acids both in each patient and across the whole group (p < 0.01). Secondary ischemic brain injury and focal contusions were most strongly associated with high EAA levels (27+/-22 micromol/L). Sustained high ICP and poor outcome were significantly correlated to high levels of EAAs (glutamate > 20 micromol/L; p < 0.01). The release of EAAs is closely linked to the release of structural amino acids and may thus reflect nonspecific development of membrane micropores, rather than presynaptic neuronal vesicular exocytosis. The magnitude of EAA release in patients with focal contusions and ischemic events may be sufficient to exacerbate neuronal damage, and these patients may be the best candidates for treatment with glutamate antagonists in the future.


Feasibility of filamentous fungi for biofuel production using hydrolysate from dilute sulfuric acid pretreatment of wheat straw.
Lipids produced from filamentous fungi show great promise for biofuel production, but a major limiting factor is the high production cost attributed to feedstock. Lignocellulosic biomass is a suitable feedstock for biofuel production due to its abundance and low value. However, very limited study has been performed on lipid production by culturing oleaginous fungi with lignocellulosic materials. Thus, identification of filamentous fungal strains capable of utilizing lignocellulosic hydrolysates for lipid accumulation is critical to improve the process and reduce the production cost. The growth performances of eleven filamentous fungi were investigated when cultured on glucose and xylose. Their dry cell weights, lipid contents and fatty acid profiles were determined. Six fungal strains with high lipid contents were selected to culture with the hydrolysate from dilute sulfuric acid pretreatment of wheat straw. The results showed that all the selected fungal strains were able to grow on both detoxified liquid hydrolysate (DLH) and non-detoxified liquid hydrolysate (NDLH). The highest lipid content of 39.4% was obtained by Mortierella isabellina on NDLH. In addition, NDLH with some precipitate could help M. isabellina form pellets with an average diameter of 0.11 mm. This study demonstrated the possibility of fungal lipid production from lignocellulosic biomass. M. isabellina was the best lipid producer grown on lignocellulosic hydrolysates among the tested filamentous fungi, because it could not only accumulate oils with a high content by directly utilizing NDLH to simplify the fermentation process, but also form proper pellets to benefit the downstream harvesting. Considering the yield and cost, fungal lipids from lignocellulosic biomass are promising alternative sources for biodiesel production.


Abnormal origin of the vertebral artery from the common carotid artery.
An abnormal origin of the vertebral artery from the common carotid artery (VA-CC) may occur on the right or left side with different embryonic mechanisms. We describe a patient with a double developmental anomaly, a right VA-CC and a right aortic arch. The rotation of the aortic arch caused a "twist" of the embryonic mechanisms of VA-CC and misdirected the differential diagnosis of the embryonic mechanisms at first glance. We discuss the pivotal points in differentiating the embryonic mechanisms of VA-CC.


A simple quinolone Schiff-base containing CHEF based fluorescence 'turn-on' chemosensor for distinguishing Zn2+ and Hg2+ with high sensitivity, selectivity and reversibility.
A new simple 'dual' chemosensor MQA ((E)-2-methoxy-N-((quinolin-2-yl)methylene)aniline) for distinguishing Zn2+ and Hg2+ has been designed, synthesized and characterized. The sensor showed excellent selectivity and sensitivity with a fluorescence enhancement to Zn2+/Hg2+ over other commonly coexisting cations (such as Na+, Mg2+, Al3+, K+, Mn2+, Fe2+, Fe3+, Co2+, Ni2+, Cu2+, Ga3+, Cd2+, In3+ and Pb2+) in DMSO-H2O solution (1/99 v/v), which was reversible with the addition of ethylenediaminetetraacetic acid (EDTA). The detection limit for Zn2+/Hg2+ by MQA both reached the 10-8 M level. The 1 : 1 ligand-to-metal coordination patterns of the MQA-Zn2+ and MQA-Hg2+ were calculated through a Job's plot and ESI-MS spectra, and were further confirmed by X-ray crystal structures of complexes MQA-Zn2+ and MQA-Hg2+. This chemosensor can recognize similar metal ions by coherently utilizing intramolecular charge transfer (ICT) and different electronic affinities of various metal ions. DFT calculations have revealed that the energy gap between the HOMO and LUMO of MQA has decreased upon coordination with Zn(ii)/Hg(ii).


Predictors of seropositivity to human papillomavirus type 53: one of the most prevalent high risk-related cervical human papillomaviruses.
Persistent cervicovaginal infection with high-risk types of HPV is the major risk factor for subsequent cervical neoplasia. HPV53, part of the alpha 6 species group along with HPV types 30, 56, and 66, is one of the most prevalent high risk-related HPV types, yet little is known about the molecular basis of its benign behavior. We generated and utilized HPV53 virus-like particles (VLPs) to investigate risk factors for its seroprevalence in a population of young college women. Seropositivity to HPV53 VLPs was determined using a polymer-based ELISA to measure IgG reactive antibodies. Cervicovaginal cells were collected for HPV DNA detection and typing by MY09/11 PCR. A questionnaire queried for HPV risk factors to estimate odds ratios (ORs). Prevalence of cervicovaginal HPV DNA was 26% (n = 148); 3% of women (n = 17) had HPV53 DNA and 7% (n = 40) were seropositive to HPV53. Seroprevalence of IgG to HPV53 VLPs in women with cervicovaginal HPV53, HPV53-related types (HPV30, 55, and 66), other HPV types, and no HPV was 41%, 11%, 7%, and 6%, respectively (p(trend) < 0.001). Risk factors independently associated with HPV53 VLP seropositivity included use of oral contraceptive pills (OCPs) (OR: 4; 95% CI: 1.8, 9), having >or=2 regular partners in the last 6 months (OR: 2.5; 95 % CI: 1.1, 5.8), having a regular male partner with >or=4 lifetime sex partners (OR: 2.6; 95% CI: 1.1 6), seropositivity to HPV16 (OR: 6.7; 95% CI: 3.1, 14.5), and isolation of HPV53 DNA from cervicovaginal lavage (OR: 17.3; 95% CI: 5.3, 55.9). In conclusion, host serological responses to HPV53 VLPs are strongly type-specific, and subjects' risk for HPV53 seropositivity is independently associated with sexual behavior and OCP use.


What Is a Cognitive Map? Organizing Knowledge for Flexible Behavior.
It is proposed that a cognitive map encoding the relationships between entities in the world supports flexible behavior, but the majority of the neural evidence for such a system comes from studies of spatial navigation. Recent work describing neuronal parallels between spatial and non-spatial behaviors has rekindled the notion of a systematic organization of knowledge across multiple domains. We review experimental evidence and theoretical frameworks that point to principles unifying these apparently disparate functions. These principles describe how to learn and use abstract, generalizable knowledge and suggest that map-like representations observed in a spatial context may be an instance of general coding mechanisms capable of organizing knowledge of all kinds. We highlight how artificial agents endowed with such principles exhibit flexible behavior and learn map-like representations observed in the brain. Finally, we speculate on how these principles may offer insight into the extreme generalizations, abstractions, and inferences that characterize human cognition.


Donor-anion interactions at the charge localization and charge ordering transitions of (TMTTF)2AsF6 probed by NEXAFS.
High-resolution near-edge X-ray absorption fine structure (NEXAFS) measurements at the As M-edge, F K-edge and S L-edge of the Fabre salt (TMTTF)2AsF6 were performed from room temperature (RT) to 90 K, allowing to reach the charge localization regime below Tρ ≈ 230 K and to cross the charge ordering (CO) transition at TCO ≈ 102 K. The F K-edge and S L-edge spectra exhibit several transitions which have been indexed on the basis of first-principles DFT calculations. Upon cooling from RT significant energy shifts up to +0.8 eV and -0.4 eV were observed in transitions exhibited by the F 1s and S 2p spectra respectively, while the As 3p doublet does not show a significant shift. Opposite energy shifts found in the F 1s and S 2p spectra reflect substantial thermal changes in the electronic environment of F atoms of the anion and S atoms of TMTTF. The changes found around the charge localization crossover suggest an increase of the participation of the S d orbitals in the empty states of TMTTF as well as an increase of the strength of donoranion interactions. A new F 1s pre-edge signal detected upon entry into the CO phase is a clear fingerprint of the symmetry breaking occurring at TCO. We propose that this new transition is caused by a substantial mixing between the HOMO of the AsF6(-) anion and the unoccupied part of the TMTTF HOMO conduction band. Analysis of the whole spectra also suggests that the loss of the inversion symmetry associated with the CO is due to an anion displacement increasing the strength of SF interactions. Our data show unambiguously that anions are not, as previously assumed, innocent spectators during the electronic modifications experienced by the Fabre salts upon cooling. In particular the interpretation of the spectra pointing out a thermally dependent mixing of anion wave functions with those of the TMTTF chains demonstrates for the first time the importance of anion-donor interactions.


Psychopathology and offense types in detained male juveniles.
A substantial proportion of violent crime is committed by juveniles. In detained juveniles, high rates of psychopathology have been found. The objective of this study was to determine psychopathology associated with offense characteristics in detained male adolescents. The Mini International Neuropsychiatric Interview was used to assess juvenile detainees. The final sample included 275 males (mean age=16.45, S.D.=1.27 years). Multivariate logistic regressions yielded significant associations between psychopathology and specific offense types: The presence of substance use disorders (without alcohol) (SUD) was found to predict drug-related crimes, and the presence of alcohol use disorders (AUD) without further SUD were a predictor of violent crime, especially in older juveniles. The absence of anxiety disorder, especially in younger juveniles, was found to be relevant for the prediction of robbery. The results of the study suggest that the use and abuse of legal and illegal substances might be a trigger for serious violent and drug-related crimes in juveniles. In particular, the presence of AUD is presumed to have a pivotal role in the development of impulsive aggression. These findings are important when considering the serious social impact of violent behaviors in adolescents.


Awareness of hypertension and factors associated with uncontrolled hypertension in Sudanese adults.
The incidence of hypertension (HTN) has increased rapidly in the Sudan in the last few years. The aim of this study was to determine the prevalence of uncontrolled HTN and the risk factors associated with it in Sudanese adults. This study was cross sectional. Data were collected using structured questionnaires filled in during interviews with subjects visiting referral clinics in Khartoum, the capital city of Sudan. Blood pressure (BP) was measured using a digital sphygmomanometer. A digital balance was used for determination of body weight and a traditional cloth tape measure was used for measuring height, for calculation of body mass index. This study included 200 subjects, 46% male and 54% female. In the whole study, 82% of subjects (p < 0.001) were on hypertension drug treatment. Of these, 64% had their BP controlled to normal standards set by the World Health Organistion (< 140/90 mmHg). The prevalence of uncontrolled BP was significantly (p < 0.001) higher in males (61%) compared to females (15%). When the risk factors of HTN were considered, 54% of the subjects had a positive family history of HTN and 52% were smokers. Uncontrolled BP was found to be significantly (p < 0.001) higher in smoking males (43%) compared to females (4%). It was also high in people with higher education (55%) and workers (41%). In these groups, when genders were considered separately, uncontrolled hypertension was significantly (p < 0.01) higher in males than females with higher education (67 and 40%, respectively), and in workers (86 and 10%, respectively). Uncontrolled HTN was associated with overweight and obesity in 45 and 29% of the subjects, respectively. Most of the interviewed subjects were not aware of the consequences of HTN and its associated risk factors. Uncontrolled HTN was associated with risk factors of HTN and lifestyle, and was more prominent in the male gender. The ignorance of the interviewed subjects about HTN, its associated risk factors, changes in lifestyle and adherence to taking the medication may have been a major factor in the prevalence of uncontrolled HTN.


Value-cell bar charts for visualizing large transaction data sets.
One of the common problems businesses need to solve is how to use large volumes of sales histories, Web transactions, and other data to understand the behavior of their customers and increase their revenues. Bar charts are widely used for daily analysis, but only show highly aggregated data. Users often need to visualize detailed multidimensional information reflecting the health of their businesses. In this paper, we propose an innovative visualization solution based on the use of value cells within bar charts to represent business metrics. The value of a transaction can be discretized into one or multiple cells: high-value transactions are mapped to multiple value cells, whereas many small-value transactions are combined into one cell. With value-cell bar charts, users can 1) visualize transaction value distributions and correlations, 2) identify high-value transactions and outliers at a glance, and 3) instantly display values at the transaction record level. Value-Cell Bar Charts have been applied with success to different sales and IT service usage applications, demonstrating the benefits of the technique over traditional charting techniques. A comparison with two variants of the well-known Treemap technique and our earlier work on Pixel Bar Charts is also included.


Adults with polio are at risk of hip fracture from middle age: A nationwide population-based cohort study.
Having motor impairment since childhood and being at risk of osteoporosis and falls, adults with polio would be more likely to suffer a hip fracture (HF) and may experience different epidemiological characteristics from the general population. To estimate the risk and incidence of HF in adults with polio. Using a national database, we conducted a population-based cohort study. We identified patients with polio using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 138. For each patient with polio, we randomly selected five age- and sex-matched control subjects. Those subjects aged <40 years were excluded. We analyzed participants aged 40˜64 years (middle-aged) and subjects aged ≥65 years (elderly) separately and recognized subjects who had an HF (ICD-9-CM code, 820) only when they received hospitalization to care for the illness from January 1, 2003 to December 31, 2008. We identified 403 adults with polio (mean age ± standard deviation, 47.2 ± 8.6 years). Compared to the controls, patients with polio had a higher incidence of HF (all, 4.1 vs. 1.1/1000 person-years, p = 0.002; middle-aged, 2.3 vs. 0.3/1000 person-years, p < 0.001; male, 6.2 vs. 0.9/1000 person-years, p < 0.001); had a younger mean age (±standard deviation) of fracturing a hip (61.0±14.9 vs. 74.4±9.3 years, p = 0.015); had a lower cumulative HF-free probability (±standard error) before the age of 65 years (0.970±0.017 vs. 0.988±0.007, p<0.001) and throughout the study duration (0.415 ± 0.296 vs. 0.682 ± 0.158, p<0.001); and had a higher risk of HF, yielding an adjusted hazard ratio (95% confidence interval) of 3.58 (1.45˜8.79, p = 0.006). Patients with polio aged >48.2 years were likely to experience an HF. Adults with polio are at risk of HF. A customized HF prevention program is important for people with polio. The program should be started early in middle-age and should include men.


p53 is upregulated in Alzheimer's disease and induces tau phosphorylation in HEK293a cells.
p53 and tau are both associated with neurodegenerative disorders. Here, we show by Western blotting that p53 is upregulated approximately 2-fold in the superior temporal gyrus of Alzheimer's patients compared to healthy elderly control subjects. Moreover, p53 was found to induce phosphorylation of human 2N4R tau at the tau-1/AT8 epitope in HEK293a cells. Confocal microscopy revealed that tau and p53 were spatially separated intracellularly. Tau was found in the cytoskeletal compartment, whilst p53 was located in the nucleus, indicating that the effects of p53 on tau phosphorylation are indirect. Collectively, these findings have ramifications for neuronal death associated with Alzheimer's disease and other tauopathies.


Heat probe thermocoagulation as a substitute for surgical intervention to arrest massive peptic ulcer hemorrhage: an experience in 153 cases.
In a period of 2 years 7 months, we performed heat probe (HP) thermocoagulation in 153 cases of massive peptic ulcer hemorrhage. The male/female sex ratio was 125/28. The average age was 57.6 +/- 1.3 years (mean +/- SEM; range, 17 to 88). There were 69 cases (45.1%) of spurting hemorrhage, 50 cases (32.7%) of oozing hemorrhage, and 34 cases (22.2%) of nonbleeding visible vessels. Seventy-seven patients (50.3%) were in shock before therapy. After therapy we obtained initial success in 147 cases (96.1%). Rebleeding episodes occurred in 23 patients (15.6%) within 1 month after therapy. Nineteen patients received a second therapy, and treatment in 15 of these cases (78.9%) was ultimately successful. Finally, treatment in 142 cases (92.8%) was ultimately successful. The duration of hospitalization was 6.3 +/- 0.4 days (mean +/- SEM). After discharge all patients were followed at the outpatient department for at least 1 month. Sixty-seven patients were followed endoscopically for at least 2 to 3 months after therapy. Fifty-six patients (83.6%) had a healed scar at the previous bleeding site 2 months after therapy, and 62 patients (92.5%) had a healed scar 3 months after therapy. We conclude that HP thermocoagulation is an ideal and reliable modality of therapeutic endoscopy in arrest of massive peptic ulcer hemorrhage. HP thermocoagulation may become the first choice of therapy for massive peptic ulcer bleeding in the near future.


Cintredekin besudotox in treatment of malignant glioma.
Interleukin-13 (IL-13) receptors are overexpressed in glioblastoma multiforme (GBM). The presence of IL-13 binding sites in GBM and their absence in normal brain tissue validates IL-13 receptor as an important target in human GBM. This review discusses the bench-to-bedside experience with a recombinant cytotoxin composed of human IL-13 and a truncated form of Pseudomonas exotoxin A (PE38QQR), delivered via convection-enhanced delivery (CED), in GBM treatment. The authors review publications regarding the laboratory research and clinical development of IL-13-directed therapies and summarize the future of IL-13-targeted cytotoxin. The IL-13 receptor remains an important potential target in GBM, and preliminary experience with the IL-13-PE38QQR cytotoxin (also called cintredekin besudotox) has helped to pave the way for study of CED as an important means of drug delivery to malignant gliomas. Ongoing analysis of recently completed clinical trials will determine the future of this agent and its potential therapeutic targets.


Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia.
DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Knockdown of ATM or of its obligate activating factor NBS1 (Nijmegen breakage syndrome 1 protein), as well as pharmacological inhibition of ATM with KU-55933, inhibited H2AX phosphorylation and prevented Env-elicited syncytia from undergoing apoptosis. ATM was found indispensable for the activation of MAP kinase p38, which catalyzes the activating phosphorylation of p53 on serine 46, thereby causing p53 dependent apoptosis. Both wild type HIV-1 and an HIV-1 mutant lacking integrase activity induced syncytial apoptosis, which could be suppressed by inhibiting ATM. HIV-1-infected T lymphoblasts from patients with inactivating ATM or NBS1 mutations also exhibited reduced syncytial apoptosis. Altogether these results indicate that apoptosis induced by a fusogenic HIV-1 Env follows a pro-apoptotic pathway involving the sequential activation of ATM, p38MAPK and p53.


Effects of haloperidol and clozapine administration on oxidative stress in rat brain, liver and serum.
Antipsychotics remain the standard of care for individuals with schizophrenia, despite their association with adverse effects including extrapyramidal symptoms, metabolic syndrome and agranulocytosis. While the biological mechanisms underlying these side effects remain unresolved, it has been proposed that oxidative stress may play a role in their development. The aim of this study was to evaluate markers of oxidative stress associated with first- and second-generation antipsychotics, focusing on protein and lipid oxidation and expression of the antioxidant proteins peroxiredoxin-2 and peroxiredoxin-6. Following 28-day administration of haloperidol, clozapine or saline to adult rats, brain grey matter, white matter, serum and liver samples were obtained and lipid peroxidation, protein oxidation, peroxiredoxin-2 and peroxiredoxin-6 levels quantified. In grey matter, peroxiredoxin-6 was significantly increased in the haloperidol-exposed animals, with a trend towards increased lipid peroxidation also observed in this group. In liver, lipid peroxidation was increased in the clozapine-exposed animals, with a similar trend noted in the haloperidol group. Antipsychotics did not produce significant changes in serum or white matter. Our results suggest that haloperidol and clozapine may induce oxidative stress in brain and liver, respectively, consistent with the documented adverse effects of these agents.


Detection of anti-Candida albicans IgE antibodies in vaginal washes from patients with acute vulvovaginal candidiasis.
Vaginal washes from 55 women were investigated by means of an ELISA method for the presence of IgE antibodies against Candida albicans. These antibodies were detected in 87.1% of patients with clinical acute vulvovaginal candidiasis (group I), 100% of patients with suspected vulvovaginal candidiasis but negative by microscopy and culture (group II), 0% of asymptomatic carriers (group III) and 33.3% of uninfected controls (group IV). Statistically significant differences were observed comparing groups I and II vs. groups III and IV. The highest IgE vaginal antibody titers were mostly at the expense of serotype A C. albicans strains, which represented 83.3% of the C. albicans isolates. Non-C. albicans species also showed very low IgE levels. No correlation between serum and vaginal IgE was found. Furthermore, a second determination of vaginal IgE levels was performed in 3 patients. A decrease in IgE levels concomitant to a decline in clinical symptoms was observed in all of them after treatment.


Oncogenicity of L-type amino-acid transporter 1 (LAT1) revealed by targeted gene disruption in chicken DT40 cells: LAT1 is a promising molecular target for human cancer therapy.
L-type amino-acid transporter 1 (LAT1) is the first identified light chain of CD98 molecule, disulfide-linked to a heavy chain of CD98. Following cDNA cloning of chicken full-length LAT1, we have constructed targeting vectors for the disruption of chicken LAT1 gene from genomic DNA of chicken LAT1 consisting of 5.4kb. We established five homozygous LAT1-disrupted (LAT1(-/-)) cell clones, derived from a heterozygous LAT1(+/-) clone of DT40 chicken B cell line. Reactivity of anti-chicken CD98hc monoclonal antibody (mAb) with LAT1(-/-) DT40 cells was markedly decreased compared with that of wild-type DT40 cells. All LAT1(-/-) cells were deficient in L-type amino-acid transporting activity, although alternative-splice variant but not full-length mRNA of LAT1 was detected in these cells. LAT1(-/-) DT40 clones showed outstandingly slow growth in liquid culture and decreased colony-formation capacity in soft agar compared with wild-type DT40 cells. Cell-cycle analyses indicated that LAT1(-/-) DT40 clones have prolonged cell-cycle phases compared with wild-type or LAT1(+/-) DT40 cells. Knockdown of human LAT1 by small interfering RNAs resulted in marked in vitro cell-growth inhibition of human cancer cells, and in vivo tumor growth of HeLa cells in athymic mice was significantly inhibited by anti-human LAT1 mAb. All these results indicate essential roles of LAT1 in the cell proliferation and occurrence of malignant phenotypes and that LAT1 is a promising candidate as a molecular target of human cancer therapy.


AVONET: morphological, ecological and geographical data for all birds.
Functional traits offer a rich quantitative framework for developing and testing theories in evolutionary biology, ecology and ecosystem science. However, the potential of functional traits to drive theoretical advances and refine models of global change can only be fully realised when species-level information is complete. Here we present the AVONET dataset containing comprehensive functional trait data for all birds, including six ecological variables, 11 continuous morphological traits, and information on range size and location. Raw morphological measurements are presented from 90,020 individuals of 11,009 extant bird species sampled from 181 countries. These data are also summarised as species averages in three taxonomic formats, allowing integration with a global phylogeny, geographical range maps, IUCN Red List data and the eBird citizen science database. The AVONET dataset provides the most detailed picture of continuous trait variation for any major radiation of organisms, offering a global template for testing hypotheses and exploring the evolutionary origins, structure and functioning of biodiversity.


Evaluating the risk of patient re-identification from adverse drug event reports.
Our objective was to develop a model for measuring re-identification risk that more closely mimics the behaviour of an adversary by accounting for repeated attempts at matching and verification of matches, and apply it to evaluate the risk of re-identification for Canada's post-marketing adverse drug event database (ADE).Re-identification is only demonstrably plausible for deaths in ADE. A matching experiment between ADE records and virtual obituaries constructed from Statistics Canada vital statistics was simulated. A new re-identification risk is considered, it assumes that after gathering all the potential matches for a patient record (all records in the obituaries that are potential matches for an ADE record), an adversary tries to verify these potential matches. Two adversary scenarios were considered: (a) a mildly motivated adversary who will stop after one verification attempt, and (b) a highly motivated adversary who will attempt to verify all the potential matches and is only limited by practical or financial considerations. The mean percentage of records in ADE that had a high probability of being re-identified was computed. Under scenario (a), the risk of re-identification from disclosing the province, age at death, gender, and exact date of the report is quite high, but the removal of province brings down the risk significantly. By only generalizing the date of reporting to month and year and including all other variables, the risk is always low. All ADE records have a high risk of re-identification under scenario (b), but the plausibility of that scenario is limited because of the financial and practical deterrent even for highly motivated adversaries. It is possible to disclose Canada's adverse drug event database while ensuring that plausible re-identification risks are acceptably low. Our new re-identification risk model is suitable for such risk assessments.


The Role of Aphid Abundance, Species Diversity, and Virus Titer in the Spread of Sweetpotato Potyviruses in Louisiana and Mississippi.
Sweet potato feathery mottle virus (SPFMV), Sweet potato virus G (SPVG), and Sweet potato virus 2 (SPV2) are sweetpotato (Ipomoea batatas) potyviruses nonpersistently transmitted by aphids. Our objective was to determine how aphid abundance, aphid species diversity, and virus titers relate to the spread of SPFMV, SPVG, and SPV2 in Louisiana and Mississippi sweetpotato fields. The most abundant aphid species were Aphis gossypii, Myzus persicae, Rhopalosiphum padi, and Therioaphis trifolii. Aphids were captured during the entire crop cycle but virus infection of sentinel plants occurred mainly during the months of June to August. SPFMV was more commonly detected than SPVG or SPV2 in sentinel plants. Virus titers for SPFMV were higher in samples beginning in late June. Because significant aphid populations were present during April to June when virus titers were low in sweetpotato and there was very little virus infection of sentinel plants, low virus titers may have limited aphid acquisition and transmission opportunities. This is the first study to comprehensively examine aphid transmission of potyviruses in sweetpotato crops in the United States and includes the first report of R. maidis and R. padi as vectors of SPFMV, though they were less efficient than A. gossypii or M. persicae.


Life expectancy of HIV-positive individuals on combination antiretroviral therapy in Canada.
We sought to evaluate life expectancy and mortality of HIV-positive individuals initiating combination antiretroviral therapy (ART) across Canada, and to consider the potential error introduced by participant loss to follow-up (LTFU). Our study used data from the Canadian Observational Cohort (CANOC) collaboration, including HIV-positive individuals aged ≥18 years who initiated ART on or after January 1, 2000. The CANOC collaboration collates data from eight sites in British Columbia, Ontario, and Quebec. We computed abridged life-tables and remaining life expectancies at age 20 and compared outcomes by calendar period and patient characteristics at treatment initiation. To correct for potential underreporting of mortality due to participant LTFU, we conservatively estimated 30% mortality among participants lost to follow-up. 9997 individuals contributed 49,589 person-years and 830 deaths for a crude mortality rate of 16.7 [standard error (SE) 0.6] per 1000 person-years. When assigning death to 30% of participants lost to follow-up, we estimated 1170 deaths and a mortality rate of 23.6 [SE 0.7] per 1000 person-years. The crude overall life expectancy at age 20 was 45.2 [SE 0.7] and 37.5 [SE 0.6] years after adjusting for LTFU. In the LTFU-adjusted analysis, lower life expectancy at age 20 was observed for women compared to men (32.4 [SE 1.1] vs. 39.2 [SE 0.7] years), for participants with injection drug use (IDU) history compared to those without IDU history (23.9 [SE 1.0] vs. 52.3 [SE 0.8] years), for participants reporting Aboriginal ancestry compared to those with no Aboriginal ancestry (17.7 [SE 1.5] vs. 51.2 [SE 1.0] years), and for participants with CD4 count <350 cells/μL compared to CD4 count ≥350 cells/μL at treatment initiation (36.3 [SE 0.7] vs. 43.5 [SE 1.3] years). Life expectancy at age 20 in the calendar period 2000-2003 was lower than in periods 2004-2007 and 2008-2012 in the LTFU-adjusted analyses (30.8 [SE 0.9] vs. 38.6 [SE 1.0] and 54.2 [SE 1.4]). Life expectancy and mortality for HIV-positive individuals receiving ART differ by calendar period and patient characteristics at treatment initiation. Failure to consider LTFU may result in underestimation of mortality rates and overestimation of life expectancy.


Diagnostic accuracy of intracoronary optical coherence tomography-derived fractional flow reserve for assessment of coronary stenosis severity.
A novel method for computation of fractional flow reserve (FFR) from optical coherence tomography (OCT) was developed recently. This study aimed to evaluate the diagnostic accuracy of a new OCT-based FFR (OFR) computational approach, using wire-based FFR as the reference standard. Patients who underwent both OCT and FFR prior to intervention were analysed. The lumen of the interrogated vessel and the ostia of the side branches were automatically delineated and used to compute OFR. Bifurcation fractal laws were applied to correct the change in reference lumen size due to the step-down phenomenon. OFR was compared with FFR, both using a cut-off value of 0.80 to define ischaemia. Computational analysis was performed in 125 vessels from 118 patients. Average FFR was 0.80±0.09. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for OFR to identify FFR ≤0.80 was 90% (95% CI: 84-95), 87% (95% CI: 77-94), 92% (95% CI: 82-97), 92% (95% CI: 82-97), and 88% (95% CI: 77-95), respectively. The AUC was higher for OFR than minimal lumen area (0.93 [95% CI: 0.87-0.97] versus 0.80 [95% CI: 0.72-0.86], p=0.002). Average OFR analysis time was 55±23 seconds for each OCT pullback. Intra- and inter-observer variability in OFR analysis was 0.00±0.02 and 0.00±0.03, respectively. OFR is a novel and fast method allowing assessment of flow-limiting coronary stenosis without pressure wire and induced hyperaemia. The good diagnostic accuracy and low observer variability bear the potential of improved integration of intracoronary imaging and physiological assessment.


Pemphigus Autoantibodies Induce Blistering in Human Conjunctiva.
The autoimmune blistering skin disease pemphigus vulgaris (PV) is caused by autoantibodies against desmosomal adhesion molecules. Patients may suffer conjunctival involvement, yet the underlying mechanisms are largely unclear. We characterized human and murine conjunctiva with respect to the PV autoantigens, and evaluated the effects and mechanisms of PV autoantibodies applied to human conjunctiva ex vivo. We obtained human conjunctiva specimens from surgical explants and established a short-term culture model to study the alterations induced by antibody fractions of PV patients (PV-IgG). Furthermore, we applied a mouse model depleted of the desmosomal cadherin desmoglein 3 (Dsg3), the primary autoantigen in PV. Murine and human conjunctiva also was used to analyze the expression pattern of desmosomal proteins by immunostaining and Western blotting. Human and murine conjunctiva samples expressed the majority of desmosomal molecules with an expression pattern similar to the epidermis. Interestingly, Dsg3 knock out animals frequently suffer eye lesions, histologically evident as microblisters in the eyelid epidermis and conjunctiva. Incubation of human specimens with PV-IgG for 12 hours caused blistering in the suprabasal layers of the conjunctiva as well as reduction of Dsg1 and Dsg3 protein levels. Furthermore, PV-IgG prompted activation of p38MAPK in the conjunctiva, which is a central pathomechanism leading to blistering in the epidermis. PV-IgG leads to blister formation and p38MAPK activation in the conjunctiva and, thus, resembles the effects found in the epidermis. Our data indicate that the ocular involvement observed in PV patients is mainly based on conjunctival blistering.


Alveolar type II cell responses to chronic inhalation of chrysotile asbestos in rats.
The effects of chronic exposure to chrysotile asbestos on alveolar type II cells were examined in the lungs of Fischer 344 rats. Morphometric and three-dimensional analyses were used to characterize the alveolar type II cell and to determine the relationship of asbestos fiber localization to ultrastructural change in these cells. During the 2-yr period of study, type II cell number and volume increased to values more than 4 times those seen in controls. Ultrastructurally, cisternal dilations of the rough endoplasmic reticulum (RER) composed 12% of the total cell volume after 12 mo of exposure to asbestos and was still 15% of the total cell volume 1 yr after fiber exposure had ended compared to less than 1% in control cells. Asbestos fiber density surrounding these cells was directly proportional to the degree of cisternal dilatation in the cell; however, lamellar body volume and number in these cells were not different from that found in control type II cells. The incidence of a subset of type II cells with large lamellated inclusions was 10-fold greater in regions near bronchiolar-alveolar duct junctions, compared to more distal gas exchange regions of the lungs. Normal-sized lamellar bodies were fused to these large lamellated inclusions. These cells also contained significantly greater numbers of lamellar bodies and multivesicular bodies than those type II cells in more distal lung regions. These ultrastructural changes observed in type II cells may be a simple dose response to inhaled asbestos or the manifestation of two distinct populations of cells in the lungs that respond to asbestos in different ways. Asbestos fiber dose, cellular microenvironment, and aberrations of the cell plasma membrane and/or cell cytoskeleton (i.e., microtubules and filaments) are discussed as potential factors in the changes noted in type II cells.


Changes in U.S. hospitalization and mortality rates following smoking bans.
U.S. state and local governments have increasingly adopted restrictions on smoking in public places. This paper analyzes nationally representative databases, including the Nationwide Inpatient Sample, to compare short-term changes in mortality and hospitalization rates in smoking-restricted regions with control regions. In contrast with smaller regional studies, we find that smoking bans are not associated with statistically significant short-term declines in mortality or hospital admissions for myocardial infarction or other diseases. An analysis simulating smaller studies using subsamples reveals that large short-term increases in myocardial infarction incidence following a smoking ban are as common as the large decreases reported in the published literature.


Myosin VI reduces proliferation, but not differentiation, in pluripotent P19 cells.
We have previously shown marked upregulation of the mRNA and corresponding protein for the cellular motor molecule myosin VI (Myo6) after an extremely traumatic stress experience, along with a delayed decrease in 5-bromo-2'-deoxyuridine incorporation in the murine hippocampus, a brain structure believed to undergo adult neurogenesis. In this study, we investigated the role of Myo6 in both proliferation and differentiation in pluripotent P19 cells by using stable transfection and RNA interference techniques. Stable overexpression of Myo6 not only led to significant inhibition of the reducing activity of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and the size of clustered aggregates in P19 cells, but also resulted in selectively decreased mRNA expression of the repressor type proneural gene Hes5 without affecting the expression of neuronal and astroglial marker proteins. In P19 cells transfected with Myo6 siRNA, by contrast, a significant increase was found in the size of aggregate and MTT reduction along with increased Sox2 protein levels, in addition to marked depletion of the endogenous Myo6 protein. In C6 glioma cells, however, introduction of Myo6 siRNA induced a drastic decrease in endogenous Myo6 protein levels without significantly affecting MTT reduction. The Ca(2+) ionophore A23187 drastically increased the luciferase activity in P19 cells transfected with a Myo6 promoter reporter plasmid, but not in HEK293, Neuro2A and C6 glioma cells transfected with the same reporter. These results suggest that Myo6 may play a predominant pivotal role in the mechanism underlying proliferation without affecting differentiation to progeny lineages in pluripotent P19 cells.


The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5-lipoxygenase-activating protein (FLAP).
Leukotrienes (LTs) are inflammatory mediators produced via the 5-lipoxygenase (5-LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP-7 as chemotype for anti-LT agents by virtual screening targeting 5-LOX-activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP-7 as an inhibitor of LT biosynthesis. We analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell-free assays. The effectiveness of BRP-7 in vivo was evaluated in rat carrageenan-induced pleurisy and mouse zymosan-induced peritonitis. BRP-7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5-LOX co-localization with FLAP. Neither the cellular viability nor the activity of 5-LOX in cell-free assays was affected by BRP-7, indicating that a functional FLAP is needed for BRP-7 to inhibit LTs, and FLAP bound to BRP-7 linked to a solid matrix. Compared with the FLAP inhibitor MK-886, BRP-7 did not significantly inhibit COX-1 or microsomal prostaglandin E2 synthase-1, implying the selectivity of BRP-7 for FLAP. Finally, BRP-7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels. BRP-7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti-inflammatory effectiveness in vivo, with promising potential for further development.