How the central domain of dystrophin acts to bridge F-actin to sarcolemmal lipids

Dystrophin is a large intracellular protein that prevents sarcolemmal ruptures by providing a mechanical link between the intracellular actin cytoskeleton and the transmembrane dystroglycan complex. Dystrophin deficiency leads to the severe muscle wasting disease Duchenne Muscular Dystrophy and the milder allelic variant, Becker Muscular Dystrophy (DMD and BMD). Previous work has shown that concomitant interaction of the actin binding domain 2 (ABD2) comprising spectrin like repeats 11 to 15 (R11-15) of the central domain of dystrophin, with both actin and membrane lipids, can greatly increase membrane stiffness. Based on a combination of SAXS and SANS measurements, mass spectrometry analysis of cross-linked complexes and interactive low-resolution simulations, we explored in vitro the molecular properties of dystrophin that allow the formation of ABD2-F-actin and ABD2-membrane model complexes. In dystrophin we identified two subdomains interacting with F-actin, one located in R11 and a neighbouring region in R12 and another one in R15, while a single lipid binding domain was identified at the C-terminal end of R12. Relative orientations of the dystrophin central domain with F-actin and a membrane model were obtained from docking simulation under experimental constraints. SAXS-based models were then built for an extended central subdomain from R4 to R19, including ABD2. Overall results are compatible with a potential F-actin/dystrophin/membrane lipids ternary complex. Our description of this selected part of the dystrophin associated complex bridging muscle cell membrane and cytoskeleton opens the way to a better understanding of how cell muscle scaffolding is maintained through this essential protein

Early incidence of occupational asthma is not accelerated by atopy in the bakery/pastry and hairdressing sectors.

International audienceSETTING: Occupational asthma (OA) is most likely to develop in the very early years of exposure. OBJECTIVE: To describe the early incidence of OA among bakers/pastry-makers (BP) and hairdressers and to explore the role of atopy. DESIGN: Following a retrospective follow-up design, subjects were invited to undergo telephone interviews. Those who declared work-related respiratory or rhinitis symptoms and a sample group of others were offered a medical visit for OA investigations. Data from interviews and from medical visits were used to estimate the incidence of OA according to increasing durations of exposure. RESULTS: A total of 866 subjects were interviewed (mean age 25.3 years, 43.8% females), of whom 282 underwent a medical visit. Total estimated incidence rates of 'confirmed or probable' OA during the first 12 years of exposure were high in BP (2.63 per 100 person-years [py]) and in hairdressers (0.58/100 py), particularly in the first 4 years. Atopy is a strong risk factor for incidence among BP but, irrespective of the occupational sector, it does not influence the timing of OA symptoms. CONCLUSION: OA symptoms occur soon after the start of exposure. Our results suggest that atopy does not precipitate the occurrence of symptoms in two different allergen exposure settings

Diagnostic approach to lower airway dysfunction in athletes: a systematic review and meta-analysis by a subgroup of the IOC consensus on ‘acute respiratory illness in the athlete’

Objectives To compare the performance of various diagnostic bronchoprovocation tests (BPT) in the assessment of lower airway dysfunction (LAD) in athletes and inform best clinical practice. Design Systematic review with sensitivity and specificity meta-analyses. Data sources PubMed, EBSCOhost and Web of Science (1 January 1990–31 December 2021). Eligibility criteria Original full-text studies, including athletes/physically active individuals (15–65 years) who underwent assessment for LAD by symptom-based questionnaires/history and/or direct and/or indirect BPTs. Results In 26 studies containing data for quantitative meta-analyses on BPT diagnostic performance (n=2624 participants; 33% female); 22% had physician diagnosed asthma and 51% reported LAD symptoms. In athletes with symptoms of LAD, eucapnic voluntary hyperpnoea (EVH) and exercise challenge tests (ECTs) confirmed the diagnosis with a 46% sensitivity and 74% specificity, and 51% sensitivity and 84% specificity, respectively, while methacholine BPTs were 55% sensitive and 56% specific. If EVH was the reference standard, the presence of LAD symptoms was 78% sensitive and 45% specific for a positive EVH, while ECTs were 42% sensitive and 82% specific. If ECTs were the reference standard, the presence of LAD symptoms was 80% sensitive and 56% specific for a positive ECT, while EVH demonstrated 65% sensitivity and 65% specificity for a positive ECT. Conclusion In the assessment of LAD in athletes, EVH and field-based ECTs offer similar and moderate diagnostic test performance. In contrast, methacholine BPTs have lower overall test performance

Prevalence of lower airway dysfunction in athletes: a systematic review and meta-analysis by a subgroup of the IOC consensus group on ‘acute respiratory illness in the athlete’

Objective To report the prevalence of lower airway dysfunction in athletes and highlight risk factors and susceptible groups. Design Systematic review and meta-analysis. Data sources PubMed, EBSCOhost and Web of Science (1 January 1990 to 31 July 2020). Eligibility criteria Original full-text studies, including male or female athletes/physically active individuals/military personnel (aged 15–65 years) who had a prior asthma diagnosis and/or underwent screening for lower airway dysfunction via self-report (ie, patient recall or questionnaires) or objective testing (ie, direct or indirect bronchial provocation challenge). Results In total, 1284 studies were identified. Of these, 64 studies (n=37 643 athletes) from over 21 countries (81.3% European and North America) were included. The prevalence of lower airway dysfunction was 21.8% (95% CI 18.8% to 25.0%) and has remained stable over the past 30 years. The highest prevalence was observed in elite endurance athletes at 25.1% (95% CI 20.0% to 30.5%) (Q=293, I2=91%), those participating in aquatic (39.9%) (95% CI 23.4% to 57.1%) and winter-based sports (29.5%) (95% CI 22.5% to 36.8%). In studies that employed objective testing, the highest prevalence was observed in studies using direct bronchial provocation (32.8%) (95% CI 19.3% to 47.2%). A high degree of heterogeneity was observed between studies (I2=98%). Conclusion Lower airway dysfunction affects approximately one in five athletes, with the highest prevalence observed in those participating in elite endurance, aquatic and winter-based sporting disciplines. Further longitudinal, multicentre studies addressing causality (ie, training status/dose–response relationship) and evaluating preventative strategies to mitigate against the development of lower airway dysfunction remain an important priority for future research

Utilisation des valeurs de référence GLI pour l’interprétation des résultats d’EFR : prise de position du groupe « Fonction Respiratoire » de la SPLF

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Recommandations pour le test de provocation bronchique à la méthacholine en pratique clinique, à partir de l’âge scolaire

International audienceBronchial challenge with the direct bronchoconstrictor agent methacholine is commonly used for the diagnosis of asthma. The “Lung Function” thematic group of the French Pulmonology Society (SPLF) elaborated a series of guidelines for the performance and the interpretation of methacholine challenge testing, based on French clinical guideline methodology. Specifically, guidelines are provided with regard to the choice of judgment criteria, the management of deep inspirations, and the role of methacholine bronchial challenge in the care of asthma, exercise-induced asthma, and professional asthma.Le test de provocation bronchique à la méthacholine est couramment utilisé pour la prise en charge de l’asthme. Le groupe de travail « Fonction Respiratoire » de la SPLF propose ici une série de recommandations concernant la réalisation et l’interprétation de ce test, élaborées dans l’esprit de la méthodologie proposée par la Haute Autorité de santé. Les thèmes abordés sont le choix des critères de jugement, la gestion des inspirations profondes, ainsi que la place du test dans la prise en charge de l’asthme, de l’asthme induit par l’exercice et de l’asthme professionnel