: Gender differences in STEMI

International audienceBACKGROUND: Gender differences in presentation, management and outcome in patients with ST-segment elevation myocardial infarction (STEMI) have been reported. AIM: To determine whether female gender is associated with higher inhospital mortality. METHODS: Data from ORBI, a regional STEMI registry of 5 years' standing, were analysed. The main data on presentation, management, inhospital outcome and prescription at discharge were compared between genders. Various adjusted hazard ratios were then calculated for inhospital mortality (women versus men). RESULTS: The analysis included 5000 patients (mean age 62.6±13 years), with 1174 women (23.5%). Women were on average 8 years older than men, with more frequent co-morbidities. Median ischaemia time was 215 minutes (26 minutes longer in women; P<0.05). Reperfusion strategies in women less frequently involved fibrinolysis, coronary angiography, radial access and thrombo-aspiration. Female gender, especially in patients aged<60 years, was associated with poorer inhospital prognosis (including higher inhospital mortality: 9% vs. 4% in men; P<0.0001), and underutilization of recommended treatments at discharge. Moreover, excess female inhospital mortality was independent of presentation, revascularization time and reperfusion strategy (hazard ratio for women 1.33, 95% confidence interval 1.01-1.76; P=0.04). CONCLUSIONS: One in four patients admitted for STEMI was female, with significant differences in presentation. Female gender was associated with less-optimal treatment, both in the acute-phase and at discharge. Efforts should be made to reduce these differences, especially as female gender was independently associated with an elevated risk of inhospital mortality

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Rôle des collagènes XV et XVIII dans le développement de vertébrés (étude préliminaire chez le poisson zèbre (Danio rerio))

Les collagènes sont des protéines multimodulaires dont la fonction principale est de maintenir la cohésion des tissus et des organes. Depuis les dernières années, un nombre croissant de données mettent en évidence la multifonctionnalité de ces molécules qui ont un rôle actif dans le comportement cellulaire. Les collagènes XV et XVIII possèdent des domaines respectifs restine et endostatine qui ont des propriétés anti-angiogéniques et anti-tumorales et dont la fonction reste encore inconnue. Aussi, l'objectif de cette thèse a été d'obtenir les outils et les concepts nécessaires afin de débuter l'étude fonctionnelle de ces collagènes et de leurs domaines respectifs, dans le modèle de développement du poisson zèbre dont les caractéristiques rendent les études plus aisées par rapport aux autres vertébrés. Ainsi, une seule forme de 1(XV) a été identifiée et l'étude de l'expression spatio-temporelle de col15a1, par hybridation in situ, a montré une expression restreinte à la notochorde. Trois isoformes du collagène XVIII, qui diffèrent par leur séquence N-terminale (courte, intermédiaire et longue), ont été isolées : elles présentent les caractéristiques conservées de leurs orthologues. Le collagène XVIII montre des singularités d'expression spatio-temporelle comparé à ses orthologues vertébrés. Les études par RT-PCR et hybridation in situ, avec une sonde C-terminale commune aux trois isoformes, ont permis d'observer son expression, dès le stade 5 somites, dans la plaque neurale antérieure, dans les cellules adaxiales. Pendant la période de segmentation, il est localisé dans l'épiderme, le rein et le cerveau. A 30 hpf, un gradient d'expression de col18a1 apparaît le long de la notochorde et du tube neural. L'expression spatio-temporelle différentielle des trois isoformes a été réalisée afin d'étudier l'expression précise de chacune d'elles (qui s'est avérée différente) et ainsi compléter l'étude globale réalisée avec la partie commune du collagène XVIII. Les résultats suggèrent que le collagène XVIII joue certainement un rôle important dans l'organogenèse de différents organes comme la peau, le cerveau et le rein. Aucune expression n'a été déterminée dans les cellules endothéliales. L'étude de la fonction par surexpression du NC1 et de l'endostatine ainsi que l'invalidation du gène de collagène XVIII utilisant les morpholinos a débuté. Les résultats préliminaires suggèrent que COL18A1 est particulièrement requis au développement précoce du cerveau. La fonction exacte reste, cependant, à être élucidéeLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Le collagène XV, un nouvel acteur de la différenciation de la chorde et du développement musculaire (une étude in vivo chez le poisson zèbre)

La matrice extracellulaire entoure chaque muscle et joue un rôle clé dans la migration, la prolifération et la différenciation des cellules musculaires. Le collagène XV est exprimé principalement à proximité des lames basales des muscles squelettiques et cardiaques. Son invalidation entraîne, chez la souris, une myopathie légère, ce qui suggère un rôle de ce collagène dans la morphogenèse et la fonction musculaire. Le projet de recherche qui m a été confié a visé à définir le rôle exact du collagène XV dans le développement musculaire. L originalité du projet a été l utilisation du modèle du poisson zèbre. Pendant la période de segmentation, l expression du collagène XV est restreinte à la chorde, et la protéine est déposée exclusivement dans la membrane péri-chordale. La fonction du collagène XV a été appréhendée en utilisant une double approche combinant une stratégie antisens, utilisant des oligonucléotides modifiés appelés morpholinos, et une surexpression in vivo de domaines spécifiques du collagène XV. La perte de fonction du collagène XV entraîne une désorganisation importante du manchon péri-chordal dont la conséquence est l inhibition de la différenciation de la chorde. La seconde conséquence est une inhibition à distance de la maturation des cellules musculaires comme l atteste le faible nombre et le mauvais arrangement des myofibrilles chez les morphants. Le résultat marquant est que le nombre d un type particulier de cellules musculaires dites fibres rapides médianes, augmente substantiellement. Ce résultat suggère fortement une interaction directe ou indirecte du collagène XV avec la voie de signalisation Shh pour laquelle un modèle est proposé. Ce travail de thèse a également permis de mettre en évidence un rôle du collagène XV dans la croissance et le guidage axonal. Par ailleurs, le rôle de deux éléments du collagène XV, le domaine NC1 et la restine, a été appréhendé par la surexpression de chacun d eux. Les résultats soulignent le rôle inhibiteur de ces domaines dans la migration cellulaire. Enfin, un paralogue du collagène XV a pu être mis en évidence. Son patron d expression, qui diffère du premier Collagène XV, permet de supposer qu il a un rôle spécifique qu il reste à déterminerEach muscle cell is surrounded by extracellular matrix whose components play a key role in the signaling mechanisms, which govern muscle development. Collagen XV is mainly expressed close to the basement membrane of skeletal and cardiac muscle and its lack results in a mild skeletal myopathy in mice, suggesting a role of collagen XV in muscle morphogenesis and function. The aim of my research project was to elucidate the precise role of collagen XV in muscle development using zebrafish as model of development. During the segmentation period, collagen XV mRNA expression is restricted to the notochord and the protein is deposited exclusively in the peri-notochordal basement membrane. The function of collagen XV was studied with knock-down assays and by over expressing specific domains of collagen XV. The knock-down of collagen XV was performed with an antisense strategy ( morpholino ). It led to an important disorganisation of the peri-notochordal basement membrane, and as a consequence, to an inhibition of the differentiation of the notochord. A second consequence was observed at a distance from the expression site of collagen XV: the maintenance of muscles cells was affected. The number of myofibrils was reduced and furthermore, their arrangement was disturbed. In contrast, the number of medial fast-twitch muscle fibers was substantially increased. This strongly suggests that the signaling by notochord derived Hh proteins was enhanced upon collagen XV knock-down. A model to explain the action of collagen XV is proposed. This thesis work also allowed to highlight on the role that collagen XV plays in axonal growth and guidance. Moreover, the role of two domains of collagen XV, the NC1 domain and restin, was analysed by over expression assays. The results showed that these domains inhibit cell migration. Finally, a collagen XV paralog was discovered. Its expression pattern, which differs from the first collagen XV, indicates that it has a different function which has yet to be elucidatedLYON1-BU.Sciences (692662101) / SudocSudocFranceF

The development of the myotendinous junction. A review

The myotendinous junction (MTJ) is a complex specialized region located at the muscle-tendon interface that represents the primary site of force transmission. Despite their different embryologic origins, muscle and tendon morphogenesis occurs in close spatial and temporal association. After muscle attachment, muscle and tendon constitute a dynamic and functional integrated unit that transduces muscle contraction force to the skeletal system. We review here the current understanding of MTJ formation describing changes during morphogenesis and focusing on the crosstalk between muscle and tendon cells that leads to the development of a functional MTJ. Molecules involved in the formation of the linkage, both at the tendon side and at the muscle side of the junction are described. Much of this knowledge comes from studies using different animal models such as mice, zebrafish and Drosophila where powerful methods for in vivo imaging and genetic manipulations can be used to enlighten this developmental proces

AS1411-conjugated gold nanoparticles affect cell proliferation through a mechanism that seems independent of nucleolin

International audienceG-rich oligonucleotide, AS1411, has been shown to interact with nucleolin and to inhibit cancer cell proliferation and tumor growth. This antiproliferative action is increased when AS1411 is conjugated to different types of nanoparticles. However, the molecular mechanisms are not known. In this work, we show in several cell lines that optimized AS1411-conjugated gold nanoparticles (GNS-AS1411) inhibit nucleolin expression at the RNA and protein levels. We observed an alteration of the nucleolar structure with a decrease of ribosomal RNA accumulation comparable to what is observed upon nucleolin knock down. However, the expression of genes involved in cell cycle and the cell cycle blockage by GNS-AS1411 are not regulated in the same way that in cells where nucleolin has been knocked down. These data suggest that the anti-proliferative activity of GNS-AS1411 is not the only consequence of nucleolin targeting and down-regulation

Specific and Efficient Uptake of Surfactant-Free Poly(Lactic Acid) Nanovaccine Vehicles by Mucosal Dendritic Cells in Adult Zebrafish after Bath Immersion

Activation of mucosal immunity is a key milestone for next-generation vaccine development. Biocompatible polymer-based nanoparticles (NPs) are promising vectors and adjuvants for mucosal vaccination. However, their in vivo uptake by mucosae and their biodistribution in antigen-presenting cells (APCs) need to be better understood to optimize mucosal nanovaccine designs. Here, we assessed if APCs are efficiently targeted in a spontaneous manner by surfactant-free poly(lactic acid) nanoparticles (PLA-NPs) after mucosal administration. Combining histology and flow imaging approaches, we describe and quantify the mucosal uptake of 200 nm PLA-NPs in adult zebrafish. Following bath administration, PLA-NPs penetrated and crossed epithelial barriers from all exposed mucosae. In mucosae, PLA-NPs accumulated in APCs, which were identified as dendritic cells (DCs), macrophages, and IgZ(+) B cells in gills and skin. PLA-NP uptake by phagocytes was specific to these cell types, as PLA-NPs were not detected in neutrophils. Importantly, quantitative analyses in gills revealed that DCs take up PLA-NPs with specifically high efficiency. This study shows that surfactant-free PLA-NPs, which display optimal biocompatibility, can spontaneously target DCs with high efficiency in vivo following mucosal administration, and highlights PLA-NPs as powerful platforms for mucosal vaccine delivery in the medical and veterinary fields, and particularly in aquaculture

Biodistribution of surfactant-free poly(lactic-acid) nanoparticles and uptake by endothelial cells and phagocytes in zebrafish: Evidence for endothelium to macrophage transfer.

International audienceIn the development of therapeutic nanoparticles (NP), there is a large gap between in vitro testing and in vivo experimentation. Despite its prominence as a model, the mouse shows severe limitations for imaging NP and the cells with which they interact. Recently, the transparent zebrafish larva, which is well suited for high-resolution live-imaging, has emerged as a powerful alternative model to investigate the in vivo behavior of NP. Poly(D,L lactic acid) (PLA) is widely accepted as a safe polymer to prepare therapeutic NP. However, to prevent aggregation, many NP require surfactants, which may have undesirable biological effects. Here, we evaluate ‘safe-by-design’, surfactant-free PLA-NP that were injected intravenously into zebrafish larvae. Interaction of fluorescent NPs with different cell types labelled in reporter animals could be followed in real-time at high resolution; furthermore, by encapsulating colloidal gold into the matrix of PLA-NP we could follow their fate in more detail by electron microscopy, from uptake to degradation. The rapid clearance of fluorescent PLA-NP from the circulation coincided with internalization by endothelial cells lining the whole vasculature and macrophages. After 30 min, when no NP remained in circulation, we observed that macrophages continued to internalize significant amounts of NP. More detailed video-imaging revealed a new mechanism of NP transfer where NP are transmitted along with parts of the cytoplasm from endothelial cells to macrophages