How ecosystem services are changing: an accounting application at the EU level.
Ecosystem services accounts are a useful tool that provides relevant information on the role of ecosystems in delivering services, and the society benefiting from them. This paper presents the accounting workflow for ecosystem services at the European Union level adopted by the Knowledge Innovation Project on an Integrated system for Natural Capital and ecosystem services Accounting (KIP INCA) - a European Commission initiative. The workflow includes: 1) biophysical assessment of ecosystem services; 2) monetary valuation; and 3) compilation of accounting tables. Supply and use tables are presented for six ecosystem services assessed so far. The supply table shows woodland and forest, followed by wetlands, as the ecosystem types with the highest monetary value per unit area. Analyses of changes between 2000 and 2012 show an overall increase of the monetary value of ecosystem services, mainly due to an increase in demand for them. We also discuss advantages and disadvantages of adopting a fast-track approach, based on official statistics, in comparison to an accounting strategy based on spatial models. We propose a novel workflow for ecosystem services accounts, focused on assessment of the actual flow of ecosystem services, making a significant contribution to further development of the technical recommendations for ecosystem services accounts.


Serum tartrate-resistant acid phosphatase 5b activity as a prognostic marker of survival in breast cancer with bone metastasis.
Serum tartrate-resistant acid phosphatase 5b (TRACP 5b) activity is a marker of osteoclast number and is elevated in breast cancer (BC) patients with extensive bone metastasis, which might in turn reflect the tumour burden. We tested the hypothesis that baseline serum TRACP 5b activity and its interval change are potential prognostic markers of survival in BC patients with bone metastasis. We analyzed the data from previous prospective studies. A total of 100 patients with newly diagnosed bone metastasis were included. Cox proportional regression model was used to evaluate the correlation between the overall survival time (OS) and baseline serum TRACP 5b activity and its interval changes. The least significant change (LSC) of TRACP 5b was calculated from data obtained from 15 patients with early BC. Estrogen receptor status (Hazard Ratio (HR) = 0.397; p = 0.003) and visceral metastasis (HR = 0.492; p = 0.0045) were significantly correlated with OS. The OS was significantly shorter in those patients with higher baseline TRACP 5b activity based on a cut-off value to delineate the highest tertile (HR = 3.524; p < 0.0001). Further analysis demonstrated that among patients in the highest tertile, OS was significantly longer in those patients who had achieved a decrease of serum TRACP 5b activity greater than the LSC (38.59%) (p = 0.0015). We found that TRACP 5b activity and its interval change after treatment bore a prognostic role in BC patients with bone metastasis and a high baseline serum TRACP 5b activity. Further prospective phase II study is necessary to confirm these results.


Mechanisms of Cannabinoids and Potential Applicability to Skin Diseases.
The legalisation of cannabis in a growing number of jurisdictions has led to increasing interest in its potential therapeutic effects in a range of disorders, including cutaneous conditions. Cannabinoids have been used as natural medicines for centuries; however, their biological activity in the skin is a new area of study. Recent data suggest that cannabinoids are involved in neuro-immuno-endocrine modulation of skin functioning, yet their effect on the features of dermatologic conditions is unclear. This article sought to review the mechanisms by which cannabinoids regulate skin functioning through the lens of relevance to treatment of dermatologic diseases looking at the effects of cannabinoids on a range of cellular activities and dermatologic conditions both in vitro and in vivo. We identified studies demonstrating an inhibitory effect of cannabinoids on skin inflammation, proliferation, fibrosis, pain, and itch-biological mechanisms involved in the pathogenesis of many dermatologic conditions. Cannabinoids have the potential to expand the therapeutic repertoire of a wide spectrum of skin disorders. Given their widespread unregulated use by the general public, basic and clinical studies are required to elucidate the effectiveness and long-term effects of topical and systemic cannabinoids in cutaneous disorders.


Using Chinese natural products for diabetes mellitus drug discovery and development.
This paper provides a review of natural Chinese drug products, including phytochemic compounds, medicinal herbs and multi-component herbal formulae, that have been reported to possess hypoglycemic activity with mechanisms for antidiabetic action. Along with a great number of combination formulae, ∼ 187 different Chinese medicinal herbs are clinically applied to treat diabetes mellitus and its complications in China, most of which have achieved reasonably good clinical outcomes. These valuable data and practical experience provide a promising opportunity for the discovery and development of drug candidates with good therapeutic efficacy and low toxicity. The concept of treating complex, multifactorial metabolic diseases, such as diabetes, using multi-component therapeutics, including single-herb formulae and combination herbal formulae, shall be regarded as a concerted pharmacologic intervention of multiple compounds interacting with multiple targets and possessing interdependent activities that are required for a synergistic or optimal effect. The conventional approach for the discovery and development of antidiabetic drug products from natural products involving a high-throughput, bioactivity guided drug screening of single compounds obtained from thousands of herbs has proven to be a costly and non-productive effort. Hence, an alternative way of developing new drug candidates, as suggested in this review, is to reduce and simplify a well-established combination herbal formula, along with the pharmacologic evaluation of a small group of phytochemic compounds, which are therapeutically effective as the original formula and have known chemical structures, compositions and mechanisms of action that are similar to chemical drugs.


Expression of active murine granulocyte-macrophage colony-stimulating factor in an Escherichia coli cell-free system.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important cytokine in the mammalian immune system. It has been expressed in Escherichia coli with the same biological activity as the native protein. Here, we report the synthesis of a murine recombinant GM-CSF in an E. coli cell-free protein synthesis system with a high yield. Since there are two disulfide bonds in the native structure of GM-CSF, an oxidizing redox potential of the reaction mixture was required. By pretreating the cell extract with iodoacetamide (IAM), the reducing activity of the cell extract was inactivated, and upon further application of an oxidized glutathione buffer, most of the synthesized GM-CSF was found in its oxidized form. However, the GM-CSF thus formed showed low activity because of poor folding. With the addition of DsbC, the periplasmic disulfide isomerase from E. coli, a high yield of active GM-CSF was produced in the cell-free reaction. Finally, successful folding of the cell-free synthesized GM-CSF-his6 was confirmed by its cell-proliferation activity after purification with a Ni2+ chelating column.


Imbalance of angiopoietin-1 and angiopoetin-2 in severe dengue and relationship with thrombocytopenia, endothelial activation, and vascular stability.
The pathogenesis of plasma leakage during dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is largely unknown. Angiopoietins are key regulators of vascular integrity: Angiopoietin-1 is stored in platelets and maintains vascular integrity, and endothelium-derived angiopoietin-2 promotes vascular leakage. We determined angiopoietin-1 and angiopoietin-2 levels in a cohort of children in Indonesia with DHF/DSS and related them to plasma leakage markers. Patients with DHF/DSS had reduced angiopoietin-1 and increased angiopoietin-2 plasma levels on the day of admission when compared with levels at discharge and in healthy controls. There was an inverse correlation between angiopoietin-1 and markers of plasma leakage and a positive correlation between angiopoietin-2 and markers of plasma leakage. Angiopoietin-1 levels followed the same trend as the soluble platelet activation marker P-selectin and correlated with platelet counts. Dengue-associated thrombocytopenia and endothelial activation are associated with an imbalance in angiopoietin-2: angiopoietin-1 plasma levels. This imbalance may contribute to the transient plasma leakage in DHF/DSS.


Highly selective synthesis of substituted (E)-alkenylsilatranes via catalytic trans-silylation and mechanistic implications.
A new route for the synthesis of functionalized alkenylsilatranes has been developed based on ruthenium-catalyzed trans-silylation with olefins. This transformation allowed for the synthesis of new (E)-alkenylsilatranes in good yields and excellent selectivity. Experimental studies concerning the reaction mechanism were carried out and the intermediate ruthenium-silatranyl complex was isolated and characterized. Moreover, detailed DFT calculations regarding the mechanism of the silylative coupling catalytic cycle of silatranes catalyzed by [Ru]-H complexes were also performed.


Soil temperature and diapause maintenance in eggs of the spittlebug, Deois flavopicta (Hemiptera: Cercopidae).
Diapausing eggs of the neotropical pasture pest, Deois flavopicta (Stal) (Hemiptera: Cercopidae), were exposed to low overnight temperatures that simulated field conditions during the dry season (23/12, 23/15 and 23/18 degrees C day/night), for different periods (0-60 days). After treatment, eggs were kept at 28 degrees C and contact water (100% humidity) until hatching. A group of diapausing eggs were kept all the time under this last condition as a control treatment. Time for hatching (in degree-days) was reduced with decrease in low overnight temperature and increase of exposure time to these cold shocks, although there was no interaction between the factors. Regression of exposure time to cold shock influencing the expected mean hatching time produced independent equations for temperatures below 18 degrees C and 15 degrees C. We constructed a model that simulates the expected proportion of the population hatching after the beginning of rainy season based on regression equations to mean hatching time and associated standard deviation. The simulation generated for the model correlated significantly with nymphal population observed in the field. These results showed that overnight soil temperatures below 18 degrees C, as occurs in Central and South-eastern Brazil between May and August, shorten the period of diapause, increase quiescent eggs in the soil, and may have synchronize population hatching.


The role of antioxidant activity in the prevention and treatment of infertility caused by Cisplatin in rats.
To investigate the importance of antioxidant activity in infertility caused by cisplatin in rats. Rats in cisplatin control (CG), Vitamin E + cisplatin (ECG), Vitamin C + cisplatin (CCG), Hippophae rhamnoides extract (HRE) + cisplatin (HRECG), and thiamine pyrophosphate (TPP) + cisplatin (TPPCG) groups were injected intraperitoneally (ip) with (100 mg/kg) Vitamin E, Vitamin C, HRE, and TPP, respectively. One hour later, ip cisplatin was administered (5 mg/kg), and then antioxidant medications were continued for 10 days. Cisplatin + Vitamin E (CEG-1), cisplatin + Vitamin C (CCG-1), cisplatin + HRE (CHREG-1), and cisplatin + TPP (TPPCG-1) rats received cisplatin (5 mg/kg, ip) and were kept for 10 days. At the end of that period, rats received antioxidant medications for 10 days. (n = 12, for each group). Six rats from each group were sacrificed. Ovaries were removed to measure malondialdehyde, total glutathione, glutathione S-transferase, and glutathione reductase levels. The remaining rats were kept in a suitable laboratory environment. Cisplatin-induced oxidative stress was best prevented by HRE, Vitamin E, Vitamin C, and TPP, in that order. However, infertility caused by cisplatin was only prevented and treated by TPP. Oxidative stress is not a major component in the pathogenesis of cisplatin-associated infertility.


Video Game Rehabilitation for Outpatient Stroke (VIGoROUS): protocol for a multi-center comparative effectiveness trial of in-home gamified constraint-induced movement therapy for rehabilitation of chronic upper extremity hemiparesis.
Constraint-Induced Movement therapy (CI therapy) is shown to reduce disability, increase use of the more affected arm/hand, and promote brain plasticity for individuals with upper extremity hemiparesis post-stroke. Randomized controlled trials consistently demonstrate that CI therapy is superior to other rehabilitation paradigms, yet it is available to only a small minority of the estimated 1.2 million chronic stroke survivors with upper extremity disability. The current study aims to establish the comparative effectiveness of a novel, patient-centered approach to rehabilitation utilizing newly developed, inexpensive, and commercially available gaming technology to disseminate CI therapy to underserved individuals. Video game delivery of CI therapy will be compared against traditional clinic-based CI therapy and standard upper extremity rehabilitation. Additionally, individual factors that differentially influence response to one treatment versus another will be examined. This protocol outlines a multi-site, randomized controlled trial with parallel group design. Two hundred twenty four adults with chronic hemiparesis post-stroke will be recruited at four sites. Participants are randomized to one of four study groups: (1) traditional clinic-based CI therapy, (2) therapist-as-consultant video game CI therapy, (3) therapist-as-consultant video game CI therapy with additional therapist contact via telerehabilitation/video consultation, and (4) standard upper extremity rehabilitation. After 6-month follow-up, individuals assigned to the standard upper extremity rehabilitation condition crossover to stand-alone video game CI therapy preceded by a therapist consultation. All interventions are delivered over a period of three weeks. Primary outcome measures include motor improvement as measured by the Wolf Motor Function Test (WMFT), quality of arm use for daily activities as measured by Motor Activity Log (MAL), and quality of life as measured by the Quality of Life in Neurological Disorders (NeuroQOL). This multi-site RCT is designed to determine comparative effectiveness of in-home technology-based delivery of CI therapy versus standard upper extremity rehabilitation and in-clinic CI therapy. The study design also enables evaluation of the effect of therapist contact time on treatment outcomes within a therapist-as-consultant model of gaming and technology-based rehabilitation. Clinicaltrials.gov, NCT02631850 .


A Liquid Chromatography with Tandem Mass Spectrometry-Based Proteomic Analysis of Primary Cultured Cells and Subcultured Cells Using Mouse Adipose-Derived Mesenchymal Stem Cells.
Adipose-derived mesenchymal stem cells (MSC-ATs) are representative cell sources for cell therapy. However, how cell stress resulting from passage influences the MSC-AT protein expression has been unclear. In this study, a protein expression analysis was performed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) using mouse primary cultured cells (P0) and cells passaged three times (P3) as samples. A total of 256 proteins were classified as cellular process-related proteins, while 179 were classified as metabolic process-related proteins in P0. These were considered to be adaptive responses of the cells to an in vitro environment. However, seven proteins of growth were identified (Csf1, App, Adam15, Alcam, Tbl1xr1, Ninj1, and Sbds) in P0. In addition, four proteins of antioxidant activity were also identified (Srxn1, Txndc17, Fam213b, and Apoe) in P0. We identified 1139 proteins expressed in both P0 and P3 cells that had their expression decreased to 69.4% in P3 cells compared with P0 cells, but 1139 proteins are very likely proteins that are derived from MSC-AT. The function of MSC-ATs was maintained after three passages. However, the LC-MS/MS analysis data showed that the protein expression was degraded after three passages. MSC-ATs retained about 70% of their protein expression ability in P3 cells.


INVESTIGATING THE IMPORTANCE OF ANATOMICAL HOMOLOGY FOR CROSS-SPECIES PHENOTYPE COMPARISONS USING SEMANTIC SIMILARITY. Accepted at Pacific Symposium on Biocomputing, 2016.
There is growing use of ontologies for the measurement of cross-species phenotype similarity. Such similarity measurements contribute to diverse applications, such as identifying genetic models for human diseases, transferring knowledge among model organisms, and studying the genetic basis of evolutionary innovations. Two organismal features, whether genes, anatomical parts, or any other inherited feature, are considered to be homologous when they are evolutionarily derived from a single feature in a common ancestor. A classic example is the homology between the paired fins of fishes and vertebrate limbs. Anatomical ontologies that model the structural relations among parts may fail to include some known anatomical homologies unless they are deliberately added as separate axioms. The consequences of neglecting known homologies for applications that rely on such ontologies has not been well studied. Here, we examine how semantic similarity is affected when external homology knowledge is included. We measure phenotypic similarity between orthologous and non-orthologous gene pairs between humans and either mouse or zebrafish, and compare the inclusion of real with faux homology axioms. Semantic similarity was preferentially increased for orthologs when using real homology axioms, but only in the more divergent of the two species comparisons (human to zebrafish, not human to mouse), and the relative increase was less than 1% to non-orthologs. By contrast, inclusion of both real and faux random homology axioms preferentially increased similarities between genes that were initially more dissimilar in the other comparisons. Biologically meaningful increases in semantic similarity were seen for a select subset of gene pairs. Overall, the effect of including homology axioms on cross-species semantic similarity was modest at the levels of divergence examined here, but our results hint that it may be greater for more distant species comparisons.


A prospective study comparing incisional labial to incisional parotid biopsies in the detection and confirmation of sarcoidosis, Sjögren's disease, sialosis and lymphoma.
Simultaneous incisional biopsies of labial minor salivary glands and the superficial lobe of the parotid were accomplished in patients suspicious for sarcoidosis, Sjögren's disease, sialosis and lymphomatous changes in Sjögren's disease. Labial minor salivary gland biopsies identified sarcoidosis in 11 of 31 (36%) patients, compared to 29 of 31 (93%) patients using the parotid biopsy (p = 0.005). Similarly, the labial minor salivary gland biopsy confirmed 21 of 36 (58%) patients to have Sjögren's disease, compared to 36 of 36 (100%) (p = 0.005) patients confirmed using the parotid biopsy. Five patients with normal labial salivary gland biopsies were shown to have idiopathic hypertrophic sialosis with enlarged parotids identified by the parotid biopsy. Five additional patients were diagnosed with lymphoma occurring within the parotid glands of patients with Sjögren's disease, via the parotid biopsies, that were not identifiable with the labial minor salivary gland biopsy. The parotid biopsy consistently identified each disease entity in an earlier stage, and with more evident histopathology. Neither technique showed appreciable morbidity. Three of 77 patients showed a sensory loss related to labial salivary gland biopsy. No sensory or motor nerve loss was associated with the parotid biopsy.


From genomic data analysis to drug development: a new generation of trials using molecular marker assessment in breast cance.
With the advent of molecular subtypes in breast cancer, the landscape of clinical trials and drug development is rapidly changing. Molecular screening identifies numerous mutations but actually druggable targets are few and far between. Thus, new clinical trial concepts are needed which are feasible in clinical practice and successful from the point of view of drug development. This article highlights the evolution of the sequencing technologies, the current molecular screening efforts and their impact on drug development as well as novel successful trial designs, focusing on the hormone receptor (HR) positive breast cancer patients. The range of mutations to identify in order to adapt the treatment to each patient and limit the resistance mechanisms is quite wide already, but theoretical or practical restriction may have to be considered to optimize the development of such adaptive combinations of targeted therapies.


Barriers and motivators to exercise for older adults: a focus on those living in rural and remote areas of Australia.
To identify the barriers and facilitators for exercise in older adults (50 years or over) specific to those living in rural and remote areas in Australia and to identify how this relates to falls prevention exercise programs in these areas. Literature review. Search of the databases of Medline, Scopus and Social Sciences Citation Index. Rural and remote areas. Searching identified 56 articles relating to barriers or facilitators to exercise in older adults in general, of which 25 are discussed in the article. Five of these articles specifically related to rural and remote areas, of which all were from studies in the United States. No literature specifically relating to rural and remote Australia was identified. Therefore, articles included in the final review were from three different domains - world literature (excluding those specific to rural and remote areas of Australia), rural and remote literature (note not Australian), and Australian literature to enable a comparison between the different populations to occur. There are similarities and differences between the barriers and facilitators in various populations, and no one factor alone will enable exercise in older adults. Research needs to be conducted on the barriers and facilitators to exercise in older adults living in rural and remote areas in Australia. Falls prevention exercise programs need to be tailored to suit the unique needs of the rural and remote older population.


Water fluoridation, bone mass and fracture: a quantitative overview of the literature.
To use the technique of meta-analysis to address the following research questions: Is water fluoridation associated with altered fracture risk at a population level and are the differences between studies consistent with confounding or chance variation between studies? The data sources utilised were Medline 1966-97, reviews and bibliographies. The search terms were fluoridation, bone mass and/or fracture. We included all observational studies published in English relating water fluoridation to bone mass and/or fracture in the initial assessment. Water fluoridation had no evident effect on fracture risk (RR 1.02, 95% CI 0.96-1.09, n = 18 studies). There was marked heterogeneity between studies which could be explained, in part, by the combination of gender, urbanicity and study quality (R2 0.25, p = 0.05, weighted analysis). Water fluoridation both at levels aimed at preventing dental caries and, possibly, at higher naturally occurring levels appears to have little effect on fracture risk, either protective or deleterious, at a population level. The small effect on bone mass seen in studies performed at the individual level is consistent with this finding. Variation between studies is also likely to be due to differences in the distribution of other recognised fracture risk factors between different populations. Confirmation of these findings is required in large studies performed at the individual level.


Recording the rate of the cranial rhythmic impulse.
The rate of the cranial rhythmic impulse can be obtained by both palpation and instrumentation. However, the literature has reported higher rates obtained by instrumentation compared with palpation. The cranial rhythmic impulse has been demonstrated to be synchronous with the Traube-Hering oscillation, measured in blood flow velocity. The current study demonstrates that physicians tend to palpate the cranial rhythmic impulse and Traube-Hering oscillation in a 1:2 ratio. This finding provides an explanation for the difference between palpated and instrumentally recorded rates for the cranial rhythmic impulse.


Phlebitis risk varies by peripheral venous catheter site and increases after 96 hours: a large multi-centre prospective study.
This multi-centre prospective field study evaluated whether peripheral venous catheter site of insertion influences the risk of catheter-related phlebitis. Potential predictors of phlebitis were also investigated. Millions of patients worldwide use peripheral venous catheters, which frequently cause local complications including phlebitis, infection and obstruction. Although phlebitis predictors have been broadly investigated, uncertainties remain on the potential effect of cannulation anatomical site, duration and the appropriate time for catheter removal. A prospective cohort design was carried out from January-June 2012. The clinical course of each patient who received a new peripheral venous catheter for any cause in five Italian hospitals was followed by trained nurses until catheter removal. The presence of phlebitis was assessed every 24 hours using the Visual Infusion Phlebitis score. Analyses were based upon multilevel mixed-effects regression. The final sample consisted of 1498 patients. The average time for catheters in situ was 65·6 hours and 23·6% of the catheters were in place beyond 96 hours. Overall phlebitis incidence was 15·4%, 94·4% of which were grade 1. The likelihood of phlebitis independently increased with increasing catheter duration, being highest after 96 hours. Compared with patients with catheter placed in the dorsum of the hand (22·8% of the sample), those with the catheter located in the antecubital fossa (34·1%) or forearm were less likely to have a phlebitis of any grade. Antecubital fossa and forearm veins may be preferential sites for peripheral venous cannulation. Our results support Centers for Disease Control and Prevention recommendations to replace catheters in adults no later than 96 hours. A relevant proportion of healthcare personnel did not adhere to such guidelines - more attention to this issue is required.


The role of calcium in ABA-induced gene expression and stomatal movements.
There is much interest in the transduction pathways by which abscisic acid (ABA) regulates stomatal movements (ABA-turgor signalling) and by which this phytohormone regulates the pattern of gene expression in plant cells (ABA-nuclear signalling). A number of second messengers have been identified in both the ABA-turgor and ABA-nuclear signalling pathways. A major challenge is to understand the architecture of ABA-signalling pathways and to determine how the ABA signal is coupled to the appropriate response. We have investigated whether separate Ca2+-dependent and -independent ABA-signalling pathways are present in guard cells. Our data suggest that increases in [Ca2+]i are a common component of the guard cell ABA-turgor and ABA-nuclear signalling pathways. The effects of Ca2+ antagonists on ABA-induced stomatal closure and the ABA-responsive CDeT6-19 gene promoter suggest that Ca2+ is involved in both ABA-turgor signalling and ABA-nuclear signalling in guard cells. However, the sensitivity of these pathways to alterations in the external calcium concentration differ, suggesting that the ABA-nuclear and ABA-turgor signalling pathways are not completely convergent. Our data suggest that whilst Ca2+-independent signalling elements are present in the guard cell, they do not form a completely separate Ca2+-independent ABA-signalling pathway.


Stroke rehabilitation outcome: impact of coronary artery disease.
The frequency of clinically significant coronary artery disease (CAD) among stroke patients and the impact of CAD on stroke rehabilitation were studied in 132 patients with first thrombotic or embolic stroke who participated in comprehensive rehabilitation. Sixty-one patients (46%) had a history of CAD, and 16 of the 61 also had congestive heart failure (CAD-CHF). Patients with CAD, and especially those with CAD-CHF, had significantly longer intervals from stroke onset to rehabilitation admission (p less than 0.001), and once in rehabilitation they experienced three times as many cardiac complications (p less than 0.001). While all patient groups improved function during rehabilitation, those with CAD and CAD-CHF improved significantly less than did those without CAD (p less than 0.01). Patients with CAD did least well with rolling, moving in bed, transferring from a wheelchair to bed, and walking. CHF not only adversely influenced overall function and mobility task performance but also affected the potential for achieving functional gains. These data suggest that specific measures of function and rehabilitation are affected by CAD and that the levels of achievement for patients with CAD-CHF are limited.


The Influence of an Environmental Cue and Exercise on Food Consumption in College Students.
The purpose of this study was to determine the effect of an environmental cue (bowl size) on food consumption and to examine the influence of exercise on that relationship. This cross-sectional study included 286 college students attending a large Midwestern University. Upon arrival at an ice cream social for university students, participants were randomly given a small (8 oz) or large (12 oz) bowl and a 4-page survey addressing exercise and eating habits. At the social, participants were invited to dish themselves as much ice cream as they wanted and the amount consumed was determined by weighing the bowl with ice cream before and after consumption using a scale that measured to the nearest tenth of a gram. Participants who were provided the 12 oz bowl scooped and consumed significantly more ice cream than the participants provided the 8 oz bowl. Regular exercisers consumed more ice cream than non-regular exercisers regardless of statistical control for bowl size and body weight. Those participants who reported exercising previously that day also consumed significantly more ice cream than those not previously exercising; however, the difference was no longer significant after controlling for bowl size and body weight. Environment cues significantly influence food consumption and exercise may also influence subsequent food consumption but further research is needed.


Use of somatic cell genetics to study chromosomes contributing to antigen plus I recognition by T cell hybridomas.
Keyhole limpet hemocyanin (KLH)/I region-specific T cell hybridomas have been prepared by fusing KLH/I-specific T cell blasts from mice with single pairs of metacentric chromosomes to the inducible, interleukin 2 (IL-2)-secreting T cell hybridoma FS6-14.13.AG2.1. T cell hybridomas with KLH/I receptors were identified by their ability to secrete IL-2 in response to KLH and the appropriate antigen-presenting cells. After cloning and subcloning, KLH/I reactivity was correlated with the presence or absence of metacentric chromosomes derived from the KLH/I-specific T cell blast parent. Hybridomas were identified that had lost all chromosomes 4 and 6 or 16 and 17 derived from their normal T cell parent, but retained the ability to respond to KLH/I. This suggested that products of genes on these chromosomes did not contribute to the specific portions of T cell Ag/I receptors. These gene products would include, of course, kappa and lambda chains and H-2. We did not obtain any T cell hybridomas that had lost both metacentric (8.12) chromosomes derived from T cells of the Robertsonian mouse strain Rb(8.12)5, so we could not draw any conclusions about the contributions of products of genes on these chromosomes. T cell hybridomas with KLH/I reactivity were found that contained only one metacentric (8.12) chromosome derived from this strain. Moreover, a T cell hybridoma was found that retained both metacentric (8.12) chromosomes from its normal T cell parent, but had lost KLH/I reactivity. These results suggested that neither two chromosomes 8 nor two chromosomes 12 were required for antigen/I reactivity in normal T cells and that antigen/I reactivity was controlled, at least in part, by genes mapping on chromosomes other than 8 or 12.


Vaccination coverage among medical residents in Paris, France.
Medical residents are particularly exposed to the risk of occupational infection. We aimed to determine the vaccination coverage in residents with an anonymous self-reporting electronic questionnaire. A total of 250 residents took part in this survey. Vaccination rates were particularly high for mandatory vaccinations (diphtheria, tetanus, poliomyelitis, hepatitis B virus and tuberculosis). Regarding recommended vaccinations (influenza, 45.6%; pertussis, 65.2%; measles, 62.8%; varicella, 62.8%), rates were insufficient to prevent hospital epidemics, but higher than those reported in other healthcare workers. Further immunization programmes should target residents, and not only senior healthcare workers, with a critical role for occupational medicine departments.


Biochemical and functional characterization of the actin-binding activity of the B subunit of yeast vacuolar H+-ATPase.
Vacuolar H+-ATPase (V-ATPase) is a fundamentally important enzyme in eukaryotic cells that is responsible for acidification of endocytic compartments. The B subunits of V-ATPases from mammals and tobacco hornworm have been shown to bind actin filaments. Actin-binding activity by the B subunit is required for targeting V-ATPases to the plasma membrane of osteoclasts. Bacterially expressed B subunit from the yeast Saccharomyces cerevisiae bound actin filaments with a Kd of 195 nmol l(-1). The actin-binding domain of the B subunit was altered by mutations that reduced or eliminated the actin-binding activity. Mutants assembled properly with endogenous yeast subunits when expressed in B subunit-null yeast and bafilomycin-sensitive ATPase activity was not significantly different from yeast transformed with wild-type B subunit. Yeast containing the mutant subunits grew as well at pH 7.5 as wild-type. Screening null yeast or null yeast transformed with wild-type or mutant B subunits with sub-lethal doses of various drugs revealed that yeast containing the mutant B subunits were more sensitive to cycloheximide and wortmannin than those transformed with wild-type B subunits. These results suggest that actin-binding activity confers on the B subunit of yeast a function that is distinct from its role in the enzymatic activity of the proton pump.


Long-term efficacy of a double-blind, placebo-controlled, randomized study for repetitive sphenopalatine blockade with bupivacaine vs. saline with the Tx360 device for treatment of chronic migraine.
This study aims to determine if repetitive sphenopalatine ganglion (SPG) blockades with 0.5% bupivacaine delivered with the Tx360 device results in long-term improvement in chronic migraine (CM). The SPG is a small concentrated structure of neuronal tissue that resides within the pterygopalatine fossa in close proximity to the sphenopalatine foramen and is innervated by the maxillary division of the trigeminal nerve. In a previous article, these authors reported repetitive SPG blockades with 0.5% bupivacaine delivered by the Tx360 device, which was an effective and well-tolerated intervention to incrementally decrease baseline headache intensity of subjects with CM. This was a double-blind, parallel-arm, placebo-controlled, randomized pilot study using a novel intervention for acute treatment in CM. A total of 41 subjects were enrolled at two headache specialty clinics in the USA. Eligible subjects were between 18 and 80 years of age and had a history of CM defined by International Classification of Headache Disorders-II definition. Subjects were allowed a stable dose of migraine preventive medications that was maintained throughout the study. Following a 28-day baseline period, subjects were randomized by computer-generated lists 2:1 to receive 0.3 cc of 0.5% bupivacaine or saline, respectively, delivered with the Tx360 twice a week for 6 weeks. Secondary end-points reported in this manuscript include post-treatment measures including number of headache days and quality of life measures. The final data set included 38 subjects: 26 in the bupivacaine group and 12 in the saline group. Our primary end-point for the study, difference in numeric pain rating scale scores, was met and reported in a previous article. The supplemental secondary end-points reported in this manuscript did not reach statistical significance. When looking collectively at these end-points, trends were noticed and worthy of reporting. Subjects receiving bupivacaine reported a decrease in the number of headache days 1 month post-treatment (Mdiff = -5.71), whereas those receiving saline only saw a slight improvement (Mdiff = -1.93). Headache Impact Test 6 scores were decreased in the bupivacaine group at 1 month (Mdiff = -5.13) and 6 months (Mdiff = -4.78) post-treatment, but only a modest reduction was seen for those receiving saline at 1 and 6 months, respectively (Mdiff = -2.08, Mdiff = -1.58). Furthermore, subjects receiving bupivacaine reported a reduction in acute medication usage and improved quality of life measures (average pain in the previous 24 hours, mood, normal work, and general activity) up to 6 months post-treatment. The changes in these measures for the saline group were minimal. Data from this exploratory pilot study suggest that there may be long-term clinical benefits with the use of repetitive SPG blockades with bupivacaine delivered with the simple to use Tx360 device. These include a sustained reduction of headache days and improvement in several important quality of life assessments. The SPG blockades were not associated with any significant or lasting adverse events. Further research on SPG blockade is warranted.


The effect of short-term, high-dose oral N-acetylcysteine treatment on oxidative stress markers in cystic fibrosis patients with chronic P. aeruginosa infection -- a pilot study.
Patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa lung infection have increased oxidative stress as a result of an imbalance between the production of reactive oxygen species caused by inflammation and their inactivation by the impaired antioxidant systems. Supplementation with anti-oxidants is potentially beneficial for CF patients. The effect of 4 weeks of oral N-acetylcysteine (NAC) treatment (2400 mg/day divided into two doses) on biochemical parameters of oxidative stress was investigated in an open-label, controlled, randomized trial on 21 patients; 11 patients in the NAC group and 10 in the control group. Biochemical parameters of oxidative burden and plasma levels of antioxidants were assessed at the end of the study and compared to the baseline values in the two groups. A significant increase in the plasma levels of the antioxidant ascorbic acid (p=0.037) and a significant decrease in the levels of the oxidized form of ascorbic acid (dehydroascorbate) (p=0.004) compared to baseline were achieved after NAC treatment. No significant differences were observed in the control group. The parameters of oxidative burden did not change significantly compared to baseline in either of the groups. A better lung function was observed in the NAC treated group with a mean (SD) change compared to baseline of FEV1% predicted of 2.11 (4.6), while a decrease was observed in the control group (change -1.4 (4.6)), though not statistically significant. Treatment with N-acetylcysteine 1200 mg×2/day for 30 days significantly decreased the level of oxidized vitamin C and increased the level of vitamin C (primary end-points) and a not statistically significant improvement of lung function was observed in this group of patients.


Identification of the putative intestinal stem cell marker doublecortin and CaM kinase-like-1 in Barrett's esophagus and esophageal adenocarcinoma.
In Barrett's esophagus (BE), the normal esophageal squamous epithelium is replaced with a specialized metaplastic columnar epithelium. BE is a premalignant lesion that can progress to esophageal adenocarcinoma (EAC). Currently, there are no early molecular indicators that would predict progression from BE to EAC. As the only permanent residents of the epithelium, stem cells have been implicated in this metaplastic progression. The aim of the present study was to determine the expression of doublecortin and CaM kinase-like-1 (DCAMKL-1) and other putative gastrointestinal stem cell markers in normal esophageal mucosa (NEM), BE, and EAC. Human NEM, BE, EAC, and multitissue microarrays were analyzed for DCAMKL-1, and immunohistochemically scored based on staining intensity and tissue involvement, with epithelia and stroma scored separately. Total RNA isolated from BE and paired NEM was subjected to real-time reverse-transcription-polymerase chain reaction analysis for DCAMKL-1, leucine-rich repeat-containing G-protein-coupled receptor (LGR5), and Musashi-1 (Msi-1) mRNA expression. DCAMKL-1 was minimally expressed in squamous NEM, but increased in BE (with and without dysplasia) and EAC tissues. In EAC, we found increased stromal DCAMKL-1 staining compared to adjacent epithelia. Within the submucosa of dysplastic BE tissues, an increase in the endothelial cell expression of DCAMKL-1 was observed. Finally, an upregulation of DCAMKL-1, LGR5, and Msi-1 mRNA was seen in BE compared to squamous NEM. In the present study, we report the progressive increase of DCAMKL-1 expression in BE from dysplasia to EAC. Furthermore, there was an increase in putative stem cell markers DCAMKL-1, LGR5, and Msi-1 mRNA. Taken together, these data suggest that the regulation of resident stem cells might play an important role in the progression of BE to EAC.


[Mechanisms of action of hyperbaric oxygenation in ischemic stroke].
A comprehensive clinico-polygraphic study (EEG, ECG, REG, sphygmography of the temporal arteries, phlebography of the jugular veins) of 60 patients with ischemic stroke before, during and after hyperbaric oxygenation (HBO) was carried out to investigate the mechanisms of action of HBO in ischemic stroke and to develop the most effective schedules of HBO. Acid-base balance was determined in all patients. The authors elucidated that the effect of HBO on the functional status of the vessels of the intact and impaired hemisphere in hemispherical ischemic stroke was phasic and nonunitary. The authors describe the most effective schedules of HBO and the optimum duration of the therapeutic course. The pathogenetic orientation of the suggested schedules of HBO in ischemic cerebral stroke was shown. The basis of the therapeutic effect of HBO is the liquidation of metabolic acidosis in the ischemic focus in the brain and normalization of the functional status of the cerebral vessels and brain.


Transforming growth factor-alpha induces neurogenesis and behavioral improvement in a chronic stroke model.
Transforming growth factor-alpha (TGFalpha) is a powerful endogenous mitogen and neurotrophic factor, which has previously been shown to induce a massive proliferative response in the brains of Parkinson's disease model rats injured by an acute neurotoxic lesion. We now show that TGFalpha can also produce a massive proliferative response in rat brains subjected to stroke caused by a middle cerebral artery occlusion (MCAO), even when the growth factor is administered as late as 4 weeks after injury. This combination of stimuli provokes DNA synthesis, shown by 5'-bromo-2-deoxyuridine incorporation, throughout the ependymal layer and subventricular zone (SVZ) of the forebrain during the 4 weeks of growth factor administration. The newly generated cells migrate preferentially along and ventral to the corpus callosum (CC) and external capsule to the site of the injury where many of them differentiate into several site-appropriate neuronal phenotypes in association with near complete (99%) behavioral recovery. We conclude that the injury response of endogenous neural stem cells as well as behavioral recovery can be significantly enhanced by application of TGFalpha, and that this approach represents a potential therapeutic strategy for chronic stroke and other neurological damage in human patients.


A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults.
Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres.


Ethnic stereotypes and the underachievement of UK medical students from ethnic minorities: qualitative study.
To explore ethnic stereotypes of UK medical students in the context of academic underachievement of medical students from ethnic minorities. Qualitative study using semistructured one to one interviews and focus groups. A London medical school. 27 year 3 medical students and 25 clinical teachers, purposively sampled for ethnicity and sex. Data were analysed using the theory of stereotype threat (a psychological phenomenon thought to negatively affect the performance of people from ethnic minorities in educational contexts) and the constant comparative method. Participants believed the student-teacher relationship was vital for clinical learning. Teachers had strong perceptions about "good" clinical students (interactive, keen, respectful), and some described being aggressive towards students whom they perceived as quiet, unmotivated, and unwilling. Students had equally strong perceptions about "good" clinical teachers (encouraging, interested, interactive, non-aggressive). Students and teachers had concordant and well developed perceptions of the "typical" Asian clinical medical student who was considered over-reliant on books, poor at communicating with patients, too quiet during clinical teaching sessions, and unmotivated owing to being pushed into studying medicine by ambitious parents. Stereotypes of the "typical" white student were less well developed: autonomous, confident, and outgoing team player. Direct discrimination was not reported. Asian clinical medical students may be more likely than white students to be perceived stereotypically and negatively, which may reduce their learning by jeopardising their relationships with teachers. The existence of a negative stereotype about their group also raises the possibility that underperformance of medical students from ethnic minorities may be partly due to stereotype threat. It is recommended that clinical teachers be given opportunities and training to encourage them to get to know their students as individuals and thus foster positive educational relationships with them.


Evaluation of optical ZP-OFDM transmission performance in multimode fiber links.
In this paper, the performance of Zero Padding Orthogonal Frequency Division Multiplexing (ZP-OFDM) on intensity modulation-direct detection (IM-DD) multimode fiber (MMF) links is assessed by means of numerical simulations. The performance of ZP-OFDM is compared to classical Cyclic Prefixed form of OFDM (CP-OFDM) which is known to offer a limited performance in terms of symbol recovery in subcarriers suffering severe fading. Simulations results show that ZP-OFDM is able to reach 29 Gbps in 99.5% of all installed MMF links up to 600 meters compared to 14 Gbps for CP-OFDM when a 64 points fast Fourier transform (FFT) size is used. The use of ZP-OFDM makes it possible to increase the link length up to 1200 and 2400 m with a 25 Gbps data rate if the FFT sizes are increased to 128 and 256 points, respectively; whereas the CP-OFDM scheme will offer a maximum data rate of 10 Gbps in both cases. ZP-OFDM can be an alternative to adaptive loading OFDM schemes without the need of a negotiation between transmitter and receiver, reducing the system deployment complexity and increasing the flexibility in scenarios with multiple receivers.


Metabolism as a key to histone deacetylase inhibition.
There is growing interest in the epigenetic mechanisms that are dysregulated in cancer and other human pathologies. Under this broad umbrella, modulators of histone deacetylase (HDAC) activity have gained interest as both cancer chemopreventive and therapeutic agents. Of the first generation, FDA-approved HDAC inhibitors to have progressed to clinical trials, vorinostat represents a "direct acting" compound with structural features suitable for docking into the HDAC pocket, whereas romidepsin can be considered a prodrug that undergoes reductive metabolism to generate the active intermediate (a zinc-binding thiol). It is now evident that other agents, including those in the human diet, can be converted by metabolism to intermediates that affect HDAC activity. Examples are cited of short-chain fatty acids, seleno-α-keto acids, small molecule thiols, mercapturic acid metabolites, indoles, and polyphenols. The findings are discussed in the context of putative endogenous HDAC inhibitors generated by intermediary metabolism (e.g. pyruvate), the yin-yang of HDAC inhibition versus HDAC activation, and the screening assays that might be most appropriate for discovery of novel HDAC inhibitors in the future.


Integrated system for combined Raman spectroscopy-spectral domain optical coherence tomography.
Raman spectroscopy (RS) and optical coherence tomography (OCT) are powerful tools for optical analysis of tissues with mutually complementary strengths and limitations. OCT excels at visualizing tissue microstructure but lacks molecular specificity, while RS can relay tissue biochemical composition but typically cannot relate microstructure. Previous implementations of combined RS-OCT have utilized a common sample arm while maintaining independent RS and OCT detection arms. We present the design and application of an integrated RS-OCT instrument with a common detection arm for both RS and OCT. The detector is a spectrograph capable of sequential detection of the 855-nm OCT signal and the Raman scatter generated by a 785-nm source. The capabilities of the instrument are demonstrated ex vivo in the calvaria and retina of rodents, as well as in vivo in human skin.


The effect of augmentation of labour with syntocinon on the fetal CTG using objective computerised analysis: a nested case-control study.
To investigate the effect of syntocinon augmentation on the fetal cardiotocogram (CTG) using computerised analysis. We hypothesised that syntocinon will have no direct effects on the fetal heart rate if used correctly. A retrospective, nested case-control study. Intrapartum CTG records from the digital archive at the John Radcliffe Hospital, Oxford, UK. 110 women with singleton pregnancies of >36 weeks gestation, no known congenital abnormality, spontaneous onset of labour and syntocinon augmentation for failure to progress, with start time of syntocinon recorded, from between August 1998 and December 1999, extensively matched to 110 controls who had normally progressing labours. Eight different CTG features were measured during four time points with OxSys, a computerised numerical analysis system. Differences in the CTG features over time in cases and controls using ANOVA and Friedman's ANOVA and at each time point between case-control pairs using Student's t-test and the Wilcoxon signed rank test. After administration, syntocinon increased the frequency, decreased the duration and decreased the resting time between contractions (p<0.001), resulting in no significant difference between normally progressing labours and those requiring augmentation. The case group had a significantly higher signal stability index (SSI) and fewer decelerations compared to the control group - differences which disappeared after augmentation was commenced (p=0.025 and 0.033 respectively). Syntocinon did not affect the baseline heart rate, short term variability (STV) or phase rectified signal averaging (PRSA) (p=0.518, 0.215 and 0.138) in comparison with controls. There was a significant increase in the PRSA in babies born with acidaemia (arterial pH≤7.05) 60-120min after syntocinon was commenced that was not seen with in babies with a normal pH (p=0.002). Syntocinon "normalises" ineffective uterine activity without any direct effect on the fetal heart rate. Therefore its administration does not confound objective computerised analysis. There may be a specific response in PRSA shortly after commencing syntocinon augmentation in the fetus which is subsequently born acidaemic which requires further investigation.


Effects of fluticasone propionate on methacholine dose-response curves in nonsmoking atopic asthmatics.
Methacholine is frequently used to determine bronchial hyperresponsiveness (BHR) and to generate dose-response curves. These curves are characterized by a threshold (provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20) = sensitivity), slope (reactivity) and maximal response (plateau). We investigated the efficacy of 12 weeks of treatment with 1,000 microg fluticasone propionate in a double-blind, placebo-controlled study in 33 atopic asthmatics. The outcome measures used were the influence on BHR and the different indices of the methacholine dose-response (MDR) curve. After 2 weeks run-in, baseline lung function data were obtained and a MDR curve was measured with doubling concentrations of the methacholine from 0.03 to 256 mg x mL(-1). MDR curves were repeated after 6 and 12 weeks. A recently developed, sigmoid cumulative Gaussian distribution function was fitted to the data. Although sensitivity was obtained by linear interpolation of two successive log2 concentrations, reactivity, plateau and the effective concentration at 50% of the plateau value (EC50) were obtained as best fit parameters. In the fluticasone group, significant changes occurred after 6 weeks with respect to means of PC20 (an increase of 3.4 doubling doses), plateau value fall in forced expiratory volume in one second (FEV1) (from 58% at randomization to 41% at 6 weeks) and baseline FEV1 (from 3.46 to 3.75 L) in contrast to the placebo group. Stabilization occurred after 12 weeks. Changes for reactivity were less marked, whereas changes in log, EC50 were not significantly different between the groups. We conclude that fluticasone is very effective in decreasing the maximal airway narrowing response and in increasing PC20. However, it is likely that part of this increase is related to the decrease of the plateau of maximal response.


Frontal dysconnectivity in 22q11.2 deletion syndrome: an atlas-based functional connectivity analysis.
22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental syndrome associated with deficits in cognitive and emotional processing. This syndrome represents one of the highest risk factors for the development of schizophrenia. Previous studies of functional connectivity (FC) in 22q11DS report aberrant connectivity patterns in large-scale networks that are associated with the development of psychotic symptoms. In this study, we performed a functional connectivity analysis using the CONN toolbox to test for differential connectivity patterns between 54 individuals with 22q11DS and 30 healthy controls, between the ages of 17-25 years old. We mapped resting-state fMRI data onto 68 atlas-based regions of interest (ROIs) generated by the Desikan-Killany atlas in FreeSurfer, resulting in 2278 ROI-to-ROI connections for which we determined total linear temporal associations between each. Within the group with 22q11DS only, we further tested the association between prodromal symptoms of psychosis and FC. We observed that relative to controls, individuals with 22q11DS displayed increased FC in lobar networks involving the frontal-frontal, frontal-parietal, and frontal-occipital ROIs. In contrast, FC between ROIs in the parietal-temporal and occipital lobes was reduced in the 22q11DS group relative to healthy controls. Moreover, positive psychotic symptoms were positively associated with increased functional connections between the left precuneus and right superior frontal gyrus, as well as reduced functional connectivity between the bilateral pericalcarine. Positive symptoms were negatively associated with increased functional connectivity between the right pericalcarine and right postcentral gyrus. Our results suggest that functional organization may be altered in 22q11DS, leading to disruption in connectivity between frontal and other lobar substructures, and potentially increasing risk for prodromal psychosis.


Adrenergic regulation of intercellular communications between cultured striatal astrocytes from the mouse.
The permeability of gap junctions in cultured striatal astrocytes was investigated by the scrape-loading/dyetransfer technique. Prolonged application of norepinephrine (NE) (10 microM) reduced by half the extent of dye (Lucifer yellow) spread. This effect was linked to the activation of alpha 1-adrenergic receptors since it was mimicked by methoxamine and antagonized by prazosin. The adenosine agonist 2-chloroadenosine (10 microM), which potentiates the NE-evoked activation of phospholipase C (PLC) in striatal astrocytes, also potentiated the NE-evoked closure of gap junctions, the effect being as important as that observed with the uncoupling agent octanol. Measurements of inositol phospholipid turnover performed in identical experimental conditions revealed a close relationship between the extent of PLC activation and the magnitude of the uncoupling process. The effect of NE was mimicked by both phorbol ester and arachidonic acid, suggesting that biochemical events linked to PLC stimulation such as protein kinase C activation and/or eicosanoid production are likely involved in the NE-induced uncoupling. In addition, in the presence of a cAMP phosphodiesterase inhibitor, the stimulation of beta-adrenergic receptors by isoproterenol (10 microM) led to a large increase in cAMP accumulation correlated with an extension of dye diffusion. This observation suggests that junctional permeability could also be controlled by a cAMP-dependent mechanism. Altogether these results indicate that intercellular communication between cultured astrocytes can be regulated by different second messenger pathways as a result of the action of neurotransmitters on their receptors.


Physical activity and the incidence of multiple sclerosis.
To study whether physical activity during adulthood or early life is associated with multiple sclerosis (MS) incidence in 2 prospective cohorts of women. Women in the Nurses' Health Study (NHS) (n = 81,723; 1986-2004) and NHS II (n = 111,804; 1989-2009) reported recent physical activity at baseline and in selected follow-up questionnaires. Using this information, we calculated total metabolic equivalent hours of physical activity per week, a measure of energy expenditure. There were 341 confirmed MS cases with first symptoms after baseline. Participants also reported early-life activity. To estimate relative rates (RRs) and 95% confidence intervals (CIs), we used Cox proportional hazards models, adjusting for age, latitude of residence at age 15, ethnicity, smoking, supplemental vitamin D, and body mass index at age 18. Compared with women in the lowest baseline physical activity quartile, women in the highest quartile had a 27% reduced rate of MS (RRpooled = 0.73, 95% CI 0.55-0.98; p-trend 0.08); this trend was not present in 6-year lagged analyses. Change in physical activity analyses suggested that women reduced activity before onset of MS symptoms. In NHS and NHS II, higher strenuous activity at ages 18-22 years was weakly associated with a decreased MS rate. However, in NHS II, total early-life activity at ages 12-22 was not associated with MS. Though higher physical activity at baseline was weakly associated with lower MS risk, this may have been due to women reducing physical activity in response to subclinical MS.


Epithelial cell division in the Xenopus laevis embryo during gastrulation.
How vertebrate epithelial cells divide in vivo and how the cellular environment influences cell division is currently poorly understood. A sine qua non condition to study cell division in situ is the ease of observation of cell division. This is fulfilled in the Xenopus embryo at the gastrula stage where polarized epithelial cells divide with a high frequency at the surface of the organism. Recently, using this model system, we have shown that epithelial cells divide by asymmetric furrowing and that the mode of cell division is regulated during development. Here, we further characterize epithelial cell division in situ. To this end, we used confocal microscopy to study epithelial cell division in the ectoderm of the Xenopus laevis gastrula. Cell division was followed either by indirect immunofluorescence in fixed embryos or by live imaging of embryos transiently expressing diverse fluorescent proteins. Here, we show that during cytokinesis, the plasma membranes of the two daughter cells are usually separated by a gap. For most divisions, daughter cells make contacts basally at a distance from the furrow tip which creates an inverted teardrop-like shaped volume tightly associated with the furrow. At the end of cytokinesis, the inverted teardrop is resorbed; thus it is a transient structure. Several proteins involved in cytokinesis are localized at the tip of the inverted teardrop suggesting that the formation of the gap could be an active process. We also show that intercalation of neighboring cells between daughter cells occasionally occurs during cytokinesis. Our results reveal an additional level of complexity in the relationship between dividing cells and also with their neighboring cells during cytokinesis in the Xenopus embryo epithelium.


Imipramine affects autonomic control of sinoatrial rate in isolated right atrial preparations.
The effects of imipramine on sinoatrial rate and chronotropic responses to transmural stimulation (TS) were studied in the isolated guinea-pig right atrial preparation. The negative chronotropic response (cholinergically mediated rate decrease) to TS was progressively inhibited by imipramine (5 x 10(-6) M). This inhibition can be attributed directly to an "atropine-like" effect of this drug. The positive chronotropic response (adrenergically mediated rate increase) to TS was markedly potentiated by imipramine at similar therapeutic doses; higher doses (5 x 10(-5) M) substantially depressed this rate response. This depression of the adrenergic response to TS does not appear to be the result of a blockade of beta adrenergic receptors since imipramine still potentiated the rate increase in response to exogenous norepinephrine at doses where no TS response remained. Basal spontaneous rate was also depressed by imipramine at high doses (5 x 10(-5) M), both in the absence and presence of autonomic blockers.


Heterospecific aggression bias towards a rarer colour morph.
Colour polymorphisms are a striking example of phenotypic diversity, yet the sources of selection that allow different morphs to persist within populations remain poorly understood. In particular, despite the importance of aggression in mediating social dominance, few studies have considered how heterospecific aggression might contribute to the maintenance or divergence of different colour morphs. To redress this gap, we carried out a field-based study in a Nicaraguan crater lake to investigate patterns of heterospecific aggression directed by the cichlid fish, Hypsophrys nicaraguensis, towards colour polymorphic cichlids in the genus Amphilophus. We found that H. nicaraguensis was the most frequent territorial neighbour of the colour polymorphic A. sagittae. Furthermore, when manipulating territorial intrusions using models, H. nicaraguensis were more aggressive towards the gold than dark colour morph of the sympatric Amphilophus species, including A. sagittae. Such a pattern of heterospecific aggression should be costly to the gold colour morph, potentially accounting for its lower than expected frequency and, more generally, highlighting the importance of considering heterospecific aggression in the context of morph frequencies and coexistence in the wild.


Borneo and Indochina are major evolutionary hotspots for Southeast Asian biodiversity.
Tropical Southeast (SE) Asia harbors extraordinary species richness and in its entirety comprises four of the Earth's 34 biodiversity hotspots. Here, we examine the assembly of the SE Asian biota through time and space. We conduct meta-analyses of geological, climatic, and biological (including 61 phylogenetic) data sets to test which areas have been the sources of long-term biological diversity in SE Asia, particularly in the pre-Miocene, Miocene, and Plio-Pleistocene, and whether the respective biota have been dominated by in situ diversification, immigration and/or emigration, or equilibrium dynamics. We identify Borneo and Indochina, in particular, as major "evolutionary hotspots" for a diverse range of fauna and flora. Although most of the region's biodiversity is a result of both the accumulation of immigrants and in situ diversification, within-area diversification and subsequent emigration have been the predominant signals characterizing Indochina and Borneo's biota since at least the early Miocene. In contrast, colonization events are comparatively rare from younger volcanically active emergent islands such as Java, which show increased levels of immigration events. Few dispersal events were observed across the major biogeographic barrier of Wallace's Line. Accelerated efforts to conserve Borneo's flora and fauna in particular, currently housing the highest levels of SE Asian plant and mammal species richness, are critically required.


Genome-wide linkage analysis for loci affecting pulse pressure: the Family Blood Pressure Program.
Pulse pressure, the difference between systolic and diastolic blood pressure, is an independent risk factor for cardiovascular disease. Increased pulse pressure reflects reduced compliance of arteries and is a marker of atherosclerosis. To locate genes that affect pulse pressure, a genome-wide linkage scan for quantitative trait loci influencing pulse pressure was performed using variance components methods as implemented in sequential oligogenic linkage analysis routines. The analysis sample included 10 798 participants in 3320 families who were recruited as part of the Family Blood Pressure Program and were phenotyped with an oscillometric blood pressure measurement device using a consistent protocol across centers. Pulse pressure was adjusted for the effects of sex, age, age2, age-by-sex interaction, age2-by-sex interaction, body mass index, and field center to remove sources of variation other than the genetic effects related to pulse pressure. Significant linkage was observed on chromosome 18 (logarithm of odds [LOD]=3.2) in a combined racial sample, chromosome 20 (LOD=4.4), and 17 (LOD=3.6) in Hispanics, chromosome 21 (LOD=4.3) in whites, chromosome 19 (LOD=3.1) in a combined sample of blacks and whites, and chromosome 7 (logarithm of odds [LOD]=3.1) in blacks from the GenNet Network. Our genome scan shows significant evidence for linkage for pulse pressure in multiple areas of the genome, supporting previous published linkage studies. The identification of these loci for pulse pressure and the apparent congruence with other blood pressure phenotypes provide increased support that these regions contain genes influencing blood pressure phenotypes.


Improving Model Transferability for Clinical Note Section Classification Models Using Continued Pretraining.
The classification of clinical note sections is a critical step before doing more fine-grained natural language processing tasks such as social determinants of health extraction and temporal information extraction. Often, clinical note section classification models that achieve high accuracy for one institution experience a large drop of accuracy when transferred to another institution. The objective of this study is to develop methods that classify clinical note sections under the SOAP ("Subjective", "Object", "Assessment" and "Plan") framework with improved transferability. We trained the baseline models by fine-tuning BERT-based models, and enhanced their transferability with continued pretraining, including domain adaptive pretraining (DAPT) and task adaptive pretraining (TAPT). We added out-of-domain annotated samples during fine-tuning and observed model performance over a varying number of annotated sample size. Finally, we quantified the impact of continued pretraining in equivalence of the number of in-domain annotated samples added. We found continued pretraining improved models only when combined with in-domain annotated samples, improving the F1 score from 0.756 to 0.808, averaged across three datasets. This improvement was equivalent to adding 50.2 in-domain annotated samples. Although considered a straightforward task when performing in-domain, section classification is still a considerably difficult task when performing cross-domain, even using highly sophisticated neural network-based methods. Continued pretraining improved model transferability for cross-domain clinical note section classification in the presence of a small amount of in-domain labeled samples.


Proton NMR and structural features of a 24-nucleotide RNA hairpin.
The three-dimensional conformation of a 24-nucleotide variant of the RNA binding sequence for the coat protein of bacteriophage R17 has been analyzed using NMR, molecular dynamics, and energy minimization. The imino proton spectrum is consistent with base pairing requirements for coat protein binding known from biochemical studies. All 185 of the nonexchangeable protons were assigned using a variety of homonuclear 2D and 3D NMR methods. Measurements of nuclear Overhauser enhancements and two-quantum correlations were made at 500 MHz. New procedures were developed to characterize as many resonances as possible, including deconvolution and path analysis methods. An average of 21 distance constraints per residue were used in molecular dynamics calculations to obtain preliminary folded structures for residues 3-21. The unpaired A8 residue is stacked in the stem, and the entire region from G7 to C15 in the upper stem and loop appears to be flexible. Several of these residues have a large fraction of S-puckered ribose rings, rather than the N-forms characteristic of RNA duplexes. There is considerable variation in the low-energy loop conformations that satisfy the distance constraints at this preliminary level of refinement. The Shine-Dalgarno ribosome binding site is exposed, and only two apparently weak base pairs would have to break for the 16S ribosomal RNA to bind and the ribosome to initiate translation of the replicase gene. Although the loop form must be regarded as tentative, the known interaction sites with the coat protein are easily accessible from the major groove side of the loop.


Independent Regulation of Type VI Secretion in Vibrio cholerae by TfoX and TfoY.
Type VI secretion systems (T6SSs) are nanomachines used for interbacterial killing and intoxication of eukaryotes. Although Vibrio cholerae is a model organism for structural studies on T6SSs, the underlying regulatory network is less understood. A recent study showed that the T6SS is part of the natural competence regulon in V. cholerae and is activated by the regulator TfoX. Here, we identify the TfoX homolog TfoY as a second activator of the T6SS. Importantly, despite inducing the same T6SS core machinery, the overall regulons differ significantly for TfoX and TfoY. We show that TfoY does not contribute to competence induction. Instead, TfoY drives the production of T6SS-dependent and T6SS-independent toxins, together with an increased motility phenotype. Hence, we conclude that V. cholerae uses its sole T6SS in response to diverse cues and for distinctive outcomes: either to kill for the prey's DNA, leading to horizontal gene transfer, or as part of a defensive escape reaction.


Oxidative Damage of Biomolecules by the Environmental Pollutants NO2• and NO3•.
Air pollution is responsible for the premature death of about 7 million people every year. Ozone (O3) and nitrogen dioxide (NO2•) are the key gaseous pollutants in the troposphere, which predominantly result from combustion processes. Their inhalation leads to reactions with constituents in the airway surface fluids (ASF) of the respiratory tract and/or lungs. ASF contain small molecular-weight antioxidants, which protect the underlying epithelial cells against oxidative damage. When this defense system is overwhelmed, proteins and lipids present on cell surfaces or within the ASF become vulnerable to attack. The resulting highly reactive protein and lipid oxidation products could subsequently damage the epithelial cells through secondary reactions, thereby causing inflammation. While reactions of NO2• with biological molecules are considered to proceed through radical pathways, the biological effect of O3 is attributed to its high reactivity with π systems. Because O3 and NO2• always coexist in the polluted ambient atmosphere, synergistic effects resulting from in situ formed strongly oxidizing nitrate radicals (NO3•) may also require consideration. For example, in vitro product studies revealed that phenylalanine, which is inert not only to oxidants produced through biochemical processes, but also to NO2• or O3 in isolation, is damaged by NO3•. The reaction is initiated by oxidation of the aromatic ring and, depending on the availability of NO2•, leads to formation of nitrophenylalanine or β-nitrooxyphenylalanine, which could serve as marker for NO3•-induced oxidative damage in peptides. More easily oxidizable aromatic amino acids are directly attacked by NO2• and are converted to the same products independent of whether O3 is also present. Remarkably, NO2•-induced oxidative damage in peptides occurs not only through the well-established radical oxidation of peptide side chains, but also through an unprecedented fragmentation/rearrangement of the peptide backbone. This process is initiated by a nonradical N-nitrosation of a peptide bond involving the dimer of NO2•, i.e., N2O4, and contracts the peptide chain in the N → C direction by expelling one amino acid residue with simultaneous fusion of the remaining molecular termini, thereby forming a new peptide bond. This peptide cleavage could potentially be highly relevant for peptide segments with "nonvulnerable" side chains closer to the terminus that are not tied up in complex secondary and tertiary structures and therefore accessible for environmental oxidants. Likewise, NO2• reacts with cholesterol at the C═C moiety through an ionic mechanism, which leads to formation of 6-nitrocholesterol in the presence of moisture. Contrary to common belief, this clearly shows that ionic chemistry, in particular nitrosation reactions by intermediately formed NO+, requires consideration when assessing NO2• toxicity. This conclusion is supported by recent work by Colussi et al. (Enami, S.; Hoffmann, M. R.; Colussi, A. J. Absorption of inhaled NO2. J. Phys. Chem. B. 2009, 113, 7977-7981), who showed that anions in the airway surfaces fluids mediate NO2• absorption by catalyzing its hydrolytic disproportionation into NO2-/HNO2 and NO3-. These findings could be the key to our understanding why NO2•, despite its low water solubility, has such pronounced biological effects in vivo.


Epidemiology of peritoneal mesothelioma: a review.
The epidemiology of peritoneal mesothelioma is complicated by possible geographic and temporal variations in diagnostic practices. The incidence rates in industrialized countries range between 0.5 and three cases per million in men and between 0.2 and two cases per million in women. Exposure to asbestos is the main known cause of peritoneal mesothelioma. Results on peritoneal mesothelioma have been reported for 34 cohorts exposed to asbestos, among which a strong correlation was present between the percentages of deaths from pleural and peritoneal mesothelioma (correlation coefficient 0.8, P < 0.0001). Studies of workers exposed only or predominantly to chrysotile asbestos resulted in a lower proportion of total deaths from peritoneal mesothelioma than studies of workers exposed to amphibole or mixed type of asbestos. Cases of peritoneal mesothelioma have also been reported following exposure to erionite and Thorotrast, providing further evidence of common etiological factors with the pleural form of the disease. The role of other suspected risk factors, such as simian virus 40 infection and genetic predisposition, is unclear at present. Control of asbestos exposure remains the main approach to prevent peritoneal mesothelioma.


A clustered ground-glass hepatocyte pattern represents a new prognostic marker for the recurrence of hepatocellular carcinoma after surgery.
The recurrence of hepatocellular carcinoma (HCC) after hepatectomy is a serious event. It has been demonstrated that different ground-glass hepatocyte (GGH) patterns harbor specific hepatitis B virus (HBV) pre-S deletion mutants and represent preneoplastic lesions in chronic HBV infection. In the current study, the authors investigated whether a specific GGH pattern in nontumorous liver tissues was associated with the recurrence of HBV-related HCC after surgery. Clinicopathologic data from 82 patients with HBV-related HCC were reviewed. GGH patterns were assessed on hematoxylin and eosin-stained sections. Tissue hepatitis B surface antigen (HBsAg) expression was evaluated by immunohistochemical staining. Serum profiles of pre-S status, viral load, and HBV genotype were determined and correlated with clinical recurrence and survival after surgery. The results indicated that the clustered pattern of GGHs or HBsAg expression was associated significantly with decreased local recurrence-free survival (LRFS) during a mean follow-up of 46.4 months (P<.001). This biomarker was comparable to or better than the prognostic value of other parameters, such as multifocal tumors (P = .022), satellite nodules (P = .005), small cell dysplasia (P = .045), or elevated viral load (P = .027), to predict recurrent HCC. Multivariate analysis also revealed that type II GGHs, which expressed marginal HBsAg and consistently clustered in nodules, were independent variables associated with LRFS (P<.001) and overall survival (P = .003). The current results indicated that the assessment of GGH patterns or HBsAg expression in nontumorous liver tissues provides an easily recognized, new risk marker for the recurrence of HBV-related HCC after hepatic resection.


Lung function changes before and after pulmonary exacerbation antimicrobial treatment in cystic fibrosis.
In cystic fibrosis, observation of a lung function drop (as percent predicted forced expiratory volume in 1 s [FEV1 ]; ppFEV1 ) frequently precedes pulmonary exacerbation (PEx) diagnosis. Recovery of ppFEV1 to a previous "baseline" is commonly used to assess antimicrobial treatment response. However, not all diagnosed PEx are associated with a ppFEV1 drop, and it is unclear whether these are a different type of PEx from those associated with a ppFEV1 drop. We analyzed pre- and posttreatment ppFEV1 for PEx recorded in the Epidemiologic Study of Cystic Fibrosis from 2003 through 2005. Baseline, pretreatment, and follow-up ppFEV1 were the best recorded within 12-months pre-PEx, the lowest recorded -30 to +3 days of treatment, and the best recorded during 6-month follow-up, respectively. Logistic regression models for return of ppFEV1 to baseline during follow-up were developed separately for PEx with ≥10%, <10%, and no ppFEV1 drop before treatment. Of 15 147 PEx, 10 166 (67.1%), 3479 (23.0%), and 1502 (9.9%) presented with a ≥10%, <10%, or no ppFEV1 drop at diagnosis, respectively. 19.5%, 35.2%, and 65.6% of PEx, respectively, had follow-up ppFEV1 equal to or exceeding baseline; overall 27.7% of all PEx treatments resulted in complete recovery of baseline ppFEV1 . Significant predictors of ppFEV1 recovery at follow-up were younger patient age, absence of Aspergillus, lower baseline ppFEV1 , fewer visits during the baseline, lower frequency of prior-year PEx, shorter elapsed time from baseline measure to treatment, smaller relative ppFEV1 drop before treatment, and non intravenous (ie, oral or inhaled antibiotic) treatment. PEx with ≥10%, <10%, and no ppFEV1 drop before treatment had only modest differences in covariate odds ratios associated with complete ppFEV1 recovery. Among the 10% of PEx presenting with no apparent ppFEV1 drop, more than one-third resulted in a decreased ppFEV1 during follow-up. Risk factors for this outcome were the same as those associated with lack of ppFEV1 recovery among PEx with pretreatment ppFEV1 drops. These results suggest that inherent FEV1 variability, baseline and follow-up sampling methodologies, ppFEV1 regression to the mean, and underlying lung disease progression complicate this approach for assessing effects of PEx and treatment response.


Physiological and behavioural responses to noxious stimuli in the Atlantic cod (Gadus morhua).
In the present study, our aim was to compare physiological and behavioural responses to different noxious stimuli to those of a standardized innocuous stimulus, to possibly identify aversive responses indicative of injury detection in a commercially important marine teleost fish, the Atlantic cod. Individual fish were administered with a noxious stimulus to the lip under short-term general anaesthesia (MS-222). The noxious treatments included injection of 0.1% or 2% acetic acid, 0.005% or 0.1% capsaicin, or piercing the lip with a commercial fishing hook. Counts of opercular beat rate (OBR) at 10, 30, 60, 90 and 120 min and observations of behaviour at 30 and 90 min post-treatment were compared with pre-treatment values and with control fish injected with physiological saline, an innocuous stimulus. Circulatory levels of physiological stress indicators were determined in all fish at 120 minutes post-treatment. All treatments evoked temporarily increased OBR that returned to pre-treatment levels at 60 minutes (saline, 0.005% capsaicin, hook), 90 minutes (0.1% acetic acid, 0.1% capsaicin), or 120 minutes (2% acetic acid), but with no significant differences from the control group at any time point. Fish treated with 0.1% and 2% acetic acid and 0.1% capsaicin displayed increased hovering close to the bottom of the aquaria and fish given 2% acetic acid and 0.1% capsaicin also displayed a reduced use of shelter. The only effect seen in hooked fish was brief episodes of lateral head shaking which were not seen pre-treatment or in the other groups, possibly reflecting a resiliency to tissue damage in the mouth area related to the tough nature of the Atlantic cod diet. There were no differences between groups in circulatory stress indicators two hours after treatment. This study provides novel data on behavioural indicators that could be used to assess potentially aversive events in Atlantic cod.


Immune focusing and enhanced neutralization induced by HIV-1 gp140 chemical cross-linking.
Experimental vaccine antigens based upon the HIV-1 envelope glycoproteins (Env) have failed to induce neutralizing antibodies (NAbs) against the majority of circulating viral strains as a result of antibody evasion mechanisms, including amino acid variability and conformational instability. A potential vaccine design strategy is to stabilize Env, thereby focusing antibody responses on constitutively exposed, conserved surfaces, such as the CD4 binding site (CD4bs). Here, we show that a largely trimeric form of soluble Env can be stably cross-linked with glutaraldehyde (GLA) without global modification of antigenicity. Cross-linking largely conserved binding of all potent broadly neutralizing antibodies (bNAbs) tested, including CD4bs-specific VRC01 and HJ16, but reduced binding of several non- or weakly neutralizing antibodies and soluble CD4 (sCD4). Adjuvanted administration of cross-linked or unmodified gp140 to rabbits generated indistinguishable total gp140-specific serum IgG binding titers. However, sera from animals receiving cross-linked gp140 showed significantly increased CD4bs-specific antibody binding compared to animals receiving unmodified gp140. Moreover, peptide mapping of sera from animals receiving cross-linked gp140 revealed increased binding to gp120 C1 and V1V2 regions. Finally, neutralization titers were significantly elevated in sera from animals receiving cross-linked gp140 rather than unmodified gp140. We conclude that cross-linking favors antigen stability, imparts antigenic modifications that selectively refocus antibody specificity and improves induction of NAbs, and might be a useful strategy for future vaccine design.


Protective effects of standardized pomegranate (Punica granatum L.) polyphenolic extract in ultraviolet-irradiated human skin fibroblasts.
Exposure to ultraviolet (UV) radiation has been associated with several acute and chronic conditions, including sunburn, edema, hyperplasia, immunosuppression, photoaging, and skin cancer. The role of naturally occurring phytochemicals in the prevention of such UV-related conditions has captured increased interest. Pomegranate ( Punica granatum L.) is a rich source of polyphenolics, which have been shown to exert anti-inflammatory, antioxidant, and anticarcinogenic activity in numerous in vivo and in vitro studies. This work investigated potential protective effects of a pomegranate fruit extract standardized to punicalagins against UVA- and UVB-induced damage in SKU-1064 human skin fibroblast cells. Pomegranate extract (PE), in a range from 5 to 60 mg/L, was effective at protecting human skin fibroblasts from cell death following UV exposure, likely related to a reduced activation of the pro-inflammatory transcription factor NF-kappaB, a downregulation of proapoptotic caspase-3, and an increased G0/G1 phase, associated with DNA repair. Higher polyphenolic concentrations (500-10000 mg/L) were needed to achieve a significant reduction in UV-induced reactive oxygen species levels and increased intracellular antioxidant capacity (from 1.9 to 8.6 muM Trolox equivalents/mL). Results from this study demonstrate the protective effects of PE against UVA- and UVB-induced cell damage and the potential use of pomegranate polyphenolics in topical applications.


Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.
Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.


Greater T Regulatory Cells in Females Attenuate DOCA-Salt-Induced Increases in Blood Pressure Versus Males.
Hypertension is the most common risk factor for cardiovascular disease, causing over 18 million deaths a year. Although the mechanisms controlling blood pressure (BP) in either sex remain largely unknown, T cells play a critical role in the development of hypertension. Further evidence supports a role for the immune system in contributing to sex differences in hypertension. The goal of the current study was to first, determine the impact of sex on the renal T-cell profiles in DOCA-salt hypertensive males and females and second, test the hypothesis that greater numbers of T regulatory cells (Tregs) in females protect against DOCA-salt-induced increases in BP and kidney injury. Male rats displayed greater increases in BP than females following 3 weeks of DOCA-salt treatment, although increases in renal injury were comparable between the sexes. DOCA-salt treatment resulted in an increase in proinflammatory T cells in both sexes; however, females had more anti-inflammatory Tregs than males. Additional male and female DOCA-salt rats were treated with anti-CD25 to decrease Tregs. Decreasing Tregs significantly increased BP only in females, thereby abolishing the sex difference in the BP response to DOCA-salt. This data supports the hypothesis that Tregs protect against the development of hypertension and are particularly important for the control of BP in females.


Who's at The Door? - Surface Contamination of Door Frames in a Single-Bedded In-Patient Adult Cystic Fibrosis (CF) Unit.
The Gram-negative bacterium, Pseudomonas aeruginosa, is a major respiratory pathogen in patients with cystic fibrosis (CF), with an associated increase in morbidity and mortality. Consequently, infection prevention and control (IPC) plays an important role within health care in order to minimize the risk of cross-infection of this organism amongst patients and the hospital environment. It was the aim of this study to examine bacterial contamination of the health estate of CF in-patients' single-bedded rooms and related environments (n=40). Twelve bacterial genera were identified, six being Gram-positive (Brevibacterium, Dermacoccus, Micrococcus, Rothia, Staphylococcus and Streptococcus), and six being Gram-negative (Acinetobacter, Citrobacter, Klebsiella, Moraxella, Pantoea and Pseudoxanthomonas). None of the organisms identified were considered of particular clinical significance to CF patients. The CF lung and associated sputa may be important reservoirs of Pseudomonas aeruginosa, with potential for spill-over into the health care estate. In the aftermath of the Pseudomonas neonatal outbreak at Altnagelvin and the Royal Jubilee Maternity Hospitals, where there was heightened IPC awareness regarding the presence of this bacterium, it is encouraging to note its absence from the CF-health care estate examined.


Efficacy of fesoterodine compared with extended-release tolterodine in men and women with overactive bladder.
To assess the efficacy of fesoterodine 8 mg vs extended-release (ER) tolterodine 4 mg for overactive bladder (OAB) symptoms in terms of patient-reported outcomes in women and in men. Pooled data from two 12-week, randomized, double-blind, double-dummy studies were analysed. Participants eligible for the studies were ≥18 years old, had self-reported OAB symptoms for ≥3 months in 3-day baseline diaries and had ≥8 micturitions and ≥1 urgency urinary incontinence (UUI) episode per 24 h. Individuals were randomized to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks), ER tolterodine (4 mg), or placebo. Changes from baseline in 3-day bladder diary variables and scores from the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q), were assessed, as was the 'diary-dry' rate (the proportion of subjects with >0 UUI episodes according to baseline diary and no UUI episodes according to post-baseline diary). The primary endpoint was the change from baseline to week 12 in UUI episodes. At week 12, women showed significantly greater improvement with fesoterodine 8 mg (n = 1374) than with ER tolterodine 4 mg (n = 1382) and placebo (n = 679) in UUI episodes (primary endpoint), micturition frequency, urgency episodes, and all other diary endpoints (except nocturnal micturitions versus ER tolterodine), and also in scores on the PPBC, UPS, and all OAB-q scales and domains (all P < 0.005). Diary-dry rates in women were significantly greater with fesoterodine (63%) than with tolterodine (57%; P = 0.002) or placebo (48%; P < 0.0001). In men, there were no significant differences in improvement in UUI episodes between any treatment groups at week 12. Improvements in men were significantly greater with fesoterodine 8 mg (n = 265) than with ER tolterodine (n = 275) for severe urgency and the OAB-q Symptom Bother domain and were also significantly greater with fesoterodine than with placebo (n = 133) for micturition frequency, urgency episodes, severe urgency episodes, PPBC responses and scores on all OAB-q scales and domains at week 12 (all P < 0.04). The most frequently reported treatment-emergent adverse events in both genders were dry mouth (women: fesoterodine, 29%; ER tolterodine, 15%; placebo, 6%; men: fesoterodine, 21%; ER tolterodine, 13%; placebo, 5%) and constipation (women: fesoterodine, 5%; ER tolterodine, 4%; placebo, 2%; men: fesoterodine, 5%; ER tolterodine, 3%; placebo, 1%). Urinary retention rates were low in women (fesoterodine, <1%; ER tolterodine, <1%; placebo, 0%) and men (fesoterodine, 2%; ER tolterodine <1%; placebo, 2%). This analysis supports the superiority of fesoterodine 8 mg over ER tolterodine 4 mg on diary endpoints, including UUI, symptom bother and health-related quality of life in women. In men, fesoterodine 8 mg was superior to ER tolterodine 4 mg for improving severe urgency and symptom bother.


Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels.
Debate exists as to whether the higher hemoglobin A1c (HbA1c) levels observed in black persons than in white persons are due to worse glycemic control or racial differences in the glycation of hemoglobin. To determine whether a racial difference exists in the relationship of mean glucose and HbA1c. Prospective, 12-week observational study. 10 diabetes centers in the United States. 104 black persons and 104 white persons aged 8 years or older who had had type 1 diabetes for at least 2 years and had an HbA1c level of 6.0% to 12.0%. Mean glucose concentration, measured by using continuous glucose monitoring and compared by race with HbA1c, glycated albumin, and fructosamine values. The mean HbA1c level was 9.1% in black persons and 8.3% in white persons. For a given HbA1c level, the mean glucose concentration was significantly lower in black persons than in white persons (P = 0.013), which was reflected in mean HbA1c values in black persons being 0.4 percentage points (95% CI, 0.2 to 0.6 percentage points) higher than those in white persons for a given mean glucose concentration. In contrast, no significant racial differences were found in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.20 for both comparisons). There were too few participants with HbA1c levels less than 6.5% to generalize the results to such individuals. On average, HbA1c levels overestimate the mean glucose concentration in black persons compared with white persons, possibly owing to racial differences in the glycation of hemoglobin. However, because race only partially explains the observed HbA1c differences between black persons and white persons, future research should focus on identifying and modifying barriers impeding improved glycemic control in black persons with diabetes. Helmsley Charitable Trust.