Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes

Aim: In cardiomyocytes, transverse tubules (T-tubules) associate with the sarcoplasmic reticulum (SR), forming junctional membrane complexes (JMCs) where L-type calcium channels (LTCCs) are juxtaposed to Ryanodine receptors (RyR). Junctophilin-2 (JPH2) supports the assembly of JMCs by tethering T-tubules to the SR membrane. T-tubule remodeling in cardiac diseases is associated with down-regulation of JPH2 expression suggesting that JPH2 plays a crucial role in T-tubule stability. Furthermore, increasing evidence indicate that JPH2 might additionally act as a modulator of calcium signaling by directly regulating RyR and LTCCs. This study aimed at determining whether JPH2 overexpression restores normal T-tubule structure and LTCC function in cultured cardiomyocytes. Methods and results: Rat ventricular myocytes kept in culture for 4 days showed extensive T-tubule remodeling with impaired JPH2 localization and relocation of the scaffolding protein Caveolin3 (Cav3) from the T-tubules to the outer membrane. Overexpression of JPH2 restored T-tubule structure and Cav3 relocation. Depletion of membrane cholesterol by chronic treatment with Methyl-β-cyclodextrin (MβCD) countered the stabilizing effect of JPH2 overexpression on T-tubules and Cav3. Super-resolution scanning patch-clamp showed that JPH2 overexpression greatly increased the number of functional LTCCs at the plasma membrane. Treatment with MβCD reduced LTCC open probability and activity. Proximity ligation assays showed that MβCD did not affect JPH2 interaction with RyR and the pore-forming LTCC subunit Cav1.2, but strongly impaired JPH2 association with Cav3 and the accessory LTCC subunit Cavβ2. Conclusions: JPH2 promotes T-tubule structural stability and recruits functional LTCCs to the membrane, most likely by directly binding to the channel. Cholesterol is involved in the binding of JPH2 to T-tubules as well as in the modulation of LTCC activity. We propose a model where cholesterol and Cav3 support the assembly of lipid rafts which provide an anchor for JPH2 to form JMCs and a platform for signaling complexes to regulate LTCC activity

How do surgeons decide? Conduit choice in coronary artery bypass graft surgery in the UK

OBJECTIVES Conduits used in coronary artery bypass grafting may have significant impact on outcomes, but evidence is mixed and there is large variation in practice. This study provides insights into the opinions of the UK surgeons on conduit use and their decision-making processes. METHODS A questionnaire was created using the Ottawa Decision Support Framework to elicit the importance that surgeons placed on bilateral internal mammary artery grafting, skeletonization, total arterial revascularization and sequential anastomoses on a scale of 1–10. Scores ≥8 were deemed ‘important’ and ≤3 ‘not important’. Surgeons were asked to specify changes to practice in frail patients or emergencies. Additional questions included conduit type used, factors affecting decision-making and vein harvesting methods. Questionnaires were administered in person with data analysed centrally. RESULTS Ninety-seven consultant cardiac surgeons from 25 centres responded. Thirty-two percent surgeons routinely used radial arteries and 36% used right internal mammary artery. High-quality evidence contributed most to decision-making receiving a total of 328/960 points, with consultant experience being the second (255/960 points). There was a bimodal distribution of perceived importance of bilateral internal mammary artery use, with 29 (30%) ‘important’ and ‘not important’ scores each. 23% of surgeons found total arterial revascularization important. Most surgeons (64%) preferred pedicled mammary arteries. Twenty-six percent of surgeons considered sequential grafting to be important. CONCLUSIONS Low uptake of total arterial revascularization and bilateral internal mammary artery among the UK consultants may be due to the lack of high-quality evidence demonstrating a significant benefit. It is also possible that reluctance to use certain conduits may stem from low levels of exposure to conduits or inadequate training, particularly given the importance of consultant experience on decision-making

Long-term outcomes in patients with polyarticular juvenile idiopathic arthritis receiving adalimumab with or without methotrexate

Objectives Long-term safety and efficacy of adalimumab among patients with juvenile idiopathic arthritis (JIA) was evaluated through 6 years of treatment. Methods Children aged 4-17 years with polyarticular JIA were enrolled in a phase III, randomised-withdrawal, double-blind, placebo-controlled trial consisting of a 16-week open-label lead-in period, 32-week randomised double-blind period and 360-week long-term extension. Patients were stratified by baseline methotrexate use. Adverse events (AEs) were monitored, and efficacy assessments included JIA American College of Rheumatology (JIA ACR) 30%, 50%, 70% or 90% responses and the proportions of patients achieving 27-joint Juvenile Arthritis Disease Activity Score (JADAS27) low disease activity (LDA, = 6 continuous months) during the study. Attainment of JIA ACR 50 or higher and JADAS27 LDA or ID in the initial weeks were the best predictors of clinical remission. Mean JADAS27 decreased from baseline, 22.5 (n=170), to 2.5 (n=30) at week 312 (observed analysis). Conclusions Through 6 years of exposure, adalimumab was well tolerated with significant clinical response (up to clinical remission) and a relatively low retention rate

Prognostic significance of nonischaemic myocardial fibrosis in patients with normal left ventricular volumes and ejection-fraction

Objectives: This study aims to investigate the prognostic significance of late gadolinium enhancement (LGE) in patients without coronary artery disease and with normal range left ventricular (LV) volumes and ejection fraction. Background: Nonischemic patterns of LGE with normal LV volumes and ejection fraction are increasingly detected on cardiovascular magnetic resonance, but their prognostic significance, and consequently management, is uncertain. Methods: Patients with midwall/subepicardial LGE and normal LV volumes, wall thickness, and ejection fraction on cardiovascular magnetic resonance were enrolled and compared to a control group without LGE. The primary outcome was actual or aborted sudden cardiac death (SCD). Results: Of 748 patients enrolled, 401 had LGE and 347 did not. The median age was 50 years (interquartile range: 38-61 years), LV ejection fraction 66% (interquartile range: 62%-70%), and 287 (38%) were women. Scan indications included chest pain (40%), palpitation (33%) and breathlessness (13%). No patient experienced SCD and only 1 LGE+ patient (0.13%) had an aborted SCD in the 11th follow-up year. Over a median of 4.3 years, 30 patients (4.0%) died. All-cause mortality was similar for LGE+/- patients (3.7% vs 4.3%; P = 0.71) and was associated with age (HR: 2.04 per 10 years; 95% CI: 1.46-2.79; P < 0.001). Twenty-one LGE+ and 4 LGE- patients had an unplanned cardiovascular hospital admission (HR: 7.22; 95% CI: 4.26-21.17; P < 0.0001). Conclusions: There was a low SCD risk during long-term follow-up in patients with LGE but otherwise normal LV volumes and ejection fraction. Mortality was driven by age and not LGE presence, location, or extent, although the latter was associated with greater cardiovascular hospitalization for suspected myocarditis and symptomatic ventricular tachycardia

Th17 Cytokines and the Gut Mucosal Barrier

Local immune responses serve to contain infections by pathogens to the gut while preventing pathogen dissemination to systemic sites. Several subsets of T cells in the gut (T-helper 17 cells, γδ T cells, natural killer (NK), and NK-T cells) contribute to the mucosal response to pathogens by secreting a subset of cytokines including interleukin (IL)-17A, IL-17F, IL-22, and IL-26. These cytokines induce the secretion of chemokines and antimicrobial proteins, thereby orchestrating the mucosal barrier against gastrointestinal pathogens. While the mucosal barrier prevents bacterial dissemination from the gut, it also promotes colonization by pathogens that are resistant to some of the inducible antimicrobial responses. In this review, we describe the contribution of Th17 cytokines to the gut mucosal barrier during bacterial infections

200436.april

ABSTRACT. Objective. Chronic arthritis in children represents a nonhomogeneous group of diseases with unknown etiology. To classify these patients in well defined diagnostic categories, a task force of the International League Against Rheumatism proposed a new classification with precise criteria. We analyzed the new criteria in children with chronic arthritis. Methods. A cohort of children was prospectively and sequentially examined in a pediatric rheumatology clinic from April to June 1997. Results. One hundred ninety-four children fulfilled the criteria of juvenile idiopathic arthritis and 80% of them (155 children) were classified in one of the 6 diagnostic categories. Seventeen children (9%) did not fit any other category and 22 (11%) could be classified in more than one category. The proportion of children fitting only one category was much lower for psoriatic arthritis and enthesitis related arthritis than for the other categories. Conclusion. Based on the results, we propose some modifications to the classification criteria. This new classification is an important tool for the diagnosis of chronic arthritis in children, but the criteria need further adjustments to improve the percentage of patients classified in one defined category. (J Rheumatol 2001;28:1083-90

Prevalence of extended-spectrum beta-lactamase producing Escherichia coli in community-onset urinary tract infections in France in 2013

International audienceObjectives : We sought to assess the importance of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae in urinary tract infections in outpatients in France.Methods : Retrospective laboratory based survey analysing susceptibility patterns of Escherichia coli and Klebsiella pneumoniae isolates providing from urines collected from outpatients during three months in 2013.Results : 499 laboratories collected data on 51,643 E. coli and 3,495 K. pneumoniae isolates. The overall proportion of ESBL-producing E. coli was 3.3%. The proportion was higher for males (4.8%) than for females (3.0%) and increased with age: 2% for patients 80 years. More than 95% of isolates we susceptible to cefixime, fosfomycin, and nitrofurantoin. In nursing homes, the ESBL-producing E. coli proportion was 12.1%. For K. pneumoniae, the proportion of ESBL-positive isolates was 6.6%, and this proportion increased with age. Data from 2010 collected from a subset of the network showed that the ESBL-producing E. coli proportion was 2.0%.Conclusion : ESBL-producing isolates were rather frequent in urines in French outpatients in 2013. Males and persons residing in nursing homes were at higher risk of ESBL-positive infection. Despite the increase in ESBL-positive isolates, the susceptibility to antibiotics used to treat cystitis remains high