Extracellular chloride is required for efficient platelet aggregation.

Anion channels perform a diverse range of functions and have been implicated in ATP release, volume regulation, and phosphatidylserine exposure. Platelets have been shown to express several anion channels but their function is incompletely understood. Due to a paucity of specific pharmacological blockers, we investigated the effect of extracellular chloride substitution on platelet activation using aggregometry and flow cytometry. In the absence of extracellular chloride, we observed a modest reduction of the maximum aggregation response to thrombin or collagen-related peptide. However, the rate of aggregation was substantially reduced in a manner that was dependent on the extracellular chloride concentration and aggregation in the absence of chloride was noticeably biphasic, indicative of impaired secondary signaling. This was further investigated by targeting secondary agonists with aspirin and apyrase or by blockade of the ADP receptor P2Y12. Under these conditions, the rates of aggregation were comparable to those recorded in the absence of extracellular chloride. Finally, we assessed platelet granule release by flow cytometry and report a chloride-dependent element of alpha, but not dense, granule secretion. Taken together these data support a role for anion channels in the efficient induction of platelet activation, likely via enhancement of secondary signaling pathways

Long-term tracking of neurological complications of encephalopathy and myopathy in a patient with nephropathic cystinosis: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Cystinosis is a hereditary storage disease resulting in intracellular accumulation of cystine and crystal formation that causes deterioration of the function of many organs. The major clinical symptom is renal failure, which progresses and necessitates renal transplantation at the beginning of the second decade of life. Encephalopathy and distal myopathy are important neurological long-term complications with a major impact on the quality of life of these patients. Application of cysteamine is the only specific therapy available; it decreases the intracellular cystine level and delays or may even prevent the failure of organ functions.</p> <p>Case presentation</p> <p>We present the case of a 38-year-old woman with cystinosis and the long-term tracking of her neurological symptoms under cysteamine treatment.</p> <p>Conclusion</p> <p>This case report describes a long observation period of neurological complications in a person with cystinosis who had strikingly different courses of encephalopathy and myopathy while on cysteamine treatment. Although encephalopathy was initially suspected, this did not develop, but distal myopathy progressed continuously despite specific therapy.</p

A model to predict cardiovascular events in patients with newly diagnosed Wegener's granulomatosis and microscopic polyangiitis

Objective To create a prognostic tool to quantify the 5-year cardiovascular (CV) risk in patients with newly diagnosed Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) without premorbid CV disease. Methods We reviewed CV outcomes during the long-term followup of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as CV death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener's Granulomatosis Etanercept Trial (WGET) cohort. Results Seventy-four (13.8%) of 535 patients with 5 years of followup from the EUVAS trials had at least 1 CV event: 33 (11.7%) of 281 WG versus 41 (16.1%) of 254 MPA. The independent determinants of CV outcomes were older age (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.11–1.90), diastolic hypertension (OR 1.97, 95% CI 0.98–3.95), and positive proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) status (OR 0.39, 95% CI 0.20–0.74). The model was validated using the WGET cohort (area under the receiver operating characteristic curve of 0.80). Conclusion Within 5 years of diagnosis of WG or MPA, 14% of patients will have a CV event. We have constructed and validated a tool to quantify the risk of a CV event based on age, diastolic hypertension, and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with a reduced CV risk compared to myeloperoxidase ANCA or negative ANCA status.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83751/1/20433_ftp.pd

Optimized DNA isolation from marine sponges for natural sampler DNA metabarcoding

Marine sponges have recently been recognized as natural samplers of environmental DNA (eDNA) due to their effective water filtration and their ubiquitous, sessile, and regenerative nature. However, laboratory workflows for metabarcoding of sponge tissue have not been optimized to ensure that these natural samplers achieve their full potential for community survey. We used a phased approach to investigate the influence of DNA isolation procedures on the biodiversity information recovered from sponges. In Phase 1, we compared three treatments of residual ethanol preservative in sponge tissue alongside five DNA extraction protocols. The results of Phase 1 informed which ethanol treatment and DNA extraction protocol should be used in Phase 2, where we assessed the effect of starting tissue mass on extraction success and whether homogenization of sponge tissue is required. Phase 1 results indicated that ethanol preservative may contain unique and/or additional biodiversity information to that present in sponge tissue, but blotting tissue dry generally recovered more taxa and generated more sequence reads from the wild sponge species. Tissue extraction protocols performed best in terms of DNA concentration, taxon richness, and proportional read counts, but the non-commercial tissue protocol was selected for Phase 2 due to cost-efficiency and greater recovery of target taxa. In Phase 2 overall, we found that homogenization may not be required for sponge tissue and more starting material does not necessarily improve taxon detection. These results combined provide an optimized DNA isolation procedure for sponges to enhance marine biodiversity assessment using natural sampler DNA metabarcoding

Impact of asthma on educational attainment in a socioeconomically deprived population: a study linking health, education and social care datasets

BACKGROUND: Asthma has the potential to adversely affect children's school examination performance, and hence longer term life chances. Asthma morbidity is especially high amongst UK ethnic minority children and those experiencing social adversity, populations which also have poor educational outcomes. We tested the hypothesis that asthma adversely affects performance in national school examinations in a large cohort from an area of ethnic diversity and social deprivation. METHODS AND FINDINGS: With a novel method (using patient and address-matching algorithms) we linked administrative and clinical data for 2002-2005 for children in east London aged 5-14 years to contemporaneous education and social care datasets. We modelled children's performance in school examinations in relation to socio-demographic and clinical variables. The dataset captured examination performance for 12,136 children who sat at least one national examination at Key Stages 1-3. For illustration, estimates are presented as percentage changes in Key Stage 2 results. Having asthma was associated with a 1.1% increase in examination scores (95%CI 0.4 to 1.7)%,p = 0.02. Worse scores were associated with Bangladeshi ethnicity -1.3%(-2.5 to -0.1)%,p = 0.03; special educational need -14.6%(-15.7 to -13.5)%,p = 0.02; mental health problems -2.5%(-4.1 to -0.9)%,p = 0.003, and social adversity: living in a smoking household -1.2(-1.7 to -0.6)%,p<0.001; living in social housing -0.8%(-1.3 to -0.2)% p = 0.01, and entitlement to free school meals -0.8%(-1.5 to -0.1)%,p<0.001. CONCLUSIONS: Social adversity and ethnicity, but not asthma, are associated with poorer performance in national school examinations. Policies to improve educational attainment in socially deprived areas should focus on these factors

Alcohol-related brain damage in humans

Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann’s area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin β II, and α- and β-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in α-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in β-spectrin protein levels, and a significant increase in transmembranous α3 (catalytic) subunit of the Na+,K+-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of α-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic α- and β-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics

Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism

Dietary supplement use among health care professionals enrolled in an online curriculum on herbs and dietary supplements

BACKGROUND: Although many health care professionals (HCPs) in the United States have been educated about and recommend dietary supplements, little is known about their personal use of dietary supplements and factors associated with their use. METHODS: We surveyed HCPs at the point of their enrollment in an on-line course about dietary supplements between September, 2004 and May, 2005. We used multivariable logistic regression to analyze demographic and practice factors associated with use of dietary supplements. RESULTS: Of the 1249 health care professionals surveyed, 81 % reported having used a vitamin, mineral, or other non-herbal dietary supplements in the last week. Use varied by profession with highest rates among nurses (88%), physician assistants or nurse practitioners (84 %) and the lowest rates among pharmacists (66%) and trainees (72%). The most frequently used supplements were multivitamins (60%), calcium (40%), vitamin B (31%), vitamin C (30%), and fish oil (24%). Factors associated with higher supplement use were older age, female, high knowledge of dietary supplements, and discussing dietary supplements with patients. In our adjusted model, nurses were more likely than other professionals to use a multivitamin and students were more likely to use calcium. CONCLUSION: Among HCPs enrolled in an on-line course about dietary supplements, women, older clinicians, those with higher knowledge and those who talk with patients about dietary supplements had higher use of dietary supplements. Additional research is necessary to understand the impact of professionals' personal use of dietary supplements on communication with patients about them

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal