43 research outputs found

    RÎle des canaux Orai et TRPC dans le développement de l'hypertension artérielle pulmonaire

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    Pulmonary arterial hypertension (PAH) is a rare and severe disease resulting from intense remodeling of the pulmonary arterial wall leading to progressive obstruction of the small pulmonary arteries, mainly due to pathological accumulation of pulmonary artery smooth muscle cells (PASMC). The pulmonary arterial obstruction leads to right heart failure and ultimately to the patient's death.During my thesis, I focused on the deregulation of calcium homeostasis in PASMC. Calcium homeostasis is mainly regulated by the Orai and TRPC calcium channels, which are activated upon endoplasmic reticulum calcium depletion. Altogether, my work revealed an increased protein expression and function Orai1, TRPC3 and TRPC6 channels in PASMC from PAH patients. I also demonstrated, in vitro, that inhibition of these channels attenuates the pathological phenotype of PASMCs isolated from PAH patients, in particular, by restoring the proliferation/apoptosis balance at the origin of the pathological accumulation of PASMC. In vivo, I found that pharmacological inhibition of Orai1 or TRPC3 channel reduced the development of PAH by reducing pulmonary vascular and cardiac remodeling.Taken together, these results provide new insights into the pathophysiology of PAH, and allow us to consider the Orai1 and TRPC channels as innovative therapeutic targets for PAH.L'hypertension artérielle pulmonaire (HTAP) est une maladie rare et sévÚre résultant d'un intense remodelage de la paroi vasculaire conduisant à une obstruction progressive des petites artÚres pulmonaires, notamment provoquée par l'accumulation pathologique des cellules musculaires lisses des artÚres pulmonaires (CML-AP). L'obstruction des artÚres pulmonaires entraßne, à terme, une insuffisance cardiaque droite et le décÚs du patient. Lors de ma thÚse, je me suis intéressé à la dérégulation de l'homéostasie calcique dans les CML-AP. Cette homéostasie calcique est notamment maintenue par les canaux calciques Orai et TRPC, qui sont activés lors d'une déplétion en calcium du réticulum endoplasmique. L'ensemble de mes travaux a mis en évidence une augmentation protéique et fonctionnelle des canaux Orai1, TRPC3 et TRPC6 dans les CML-AP de patients atteints d'HTAP. J'ai également démontré, in vitro, que l'inhibition de ces canaux atténue le phénotype pathologique des CML-AP isolées de patients atteints d'HTAP. Cela s'effectue notamment grùce à un rééquilibre de la balance prolifération/apoptose à l'origine de l'accumulation pathologique des CML-AP. In vivo, j'ai confirmé que l'inhibition pharmacologique du canal Orai1 ou TRPC3 a un effet bénéfique sur le développement de l'HTAP grùce à une diminution du remodelage vasculaire pulmonaire. Conjointement, ces résultats apportent de nouvelles connaissances sur la pathophysiologie de l'HTAP et permettent de considérer les canaux Orai1 et TRPC comme de nouvelles cibles pour une thérapie innovante contre l'HTAP

    Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

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    Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies are not curative, and therapeutic approaches mostly target endothelial dysfunction, while PASMC dysfunction is under investigation. In PAH, modifications in intracellular Ca2+ homoeostasis could partly explain PASMC dysfunction. One of the most crucial actors regulating Ca2+ homeostasis is store-operated Ca2+ channels, which mediate store-operated Ca2+ entry (SOCE). This review focuses on the main actors of SOCE in human and experimental PASMC, their contribution to PAH pathogenesis, and their therapeutic potential in PAH

    Impacts of Indian Ocean SST biases on the Indian Monsoon: as simulated in a global coupled model

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    International audienceIn this study, the impact of the ocean-atmosphere coupling on the atmospheric mean state over the Indian Ocean and the Indian Summer Monsoon (ISM) is examined in the framework of the SINTEX-F2 coupled model through forced and coupled control simulations and several sensitivity coupled experiments. During boreal winter and spring, most of the Indian Ocean biases are common in forced and coupled simulations, suggesting that the errors originate from the atmospheric model, especially a dry islands bias in the Maritime Continent. During boreal summer, the air-sea coupling decreases the ISM rainfall over South India and the monsoon strength to realistic amplitude, but at the expense of important degradations of the rainfall and Sea Surface Temperature (SST) mean states in the Indian Ocean. Strong SST biases of opposite sign are observed over the western (WIO) and eastern (EIO) tropical Indian Ocean. Rainfall amounts over the ocean (land) are systematically higher (lower) in the northern hemisphere and the south equatorial Indian Ocean rainfall band is missing in the control coupled simulation. During boreal fall, positive dipole-like errors emerge in the mean state of the coupled model, with warm and wet (cold and dry) biases in the WIO (EIO), suggesting again a significant impact of the SST errors. The exact contributions and the distinct roles of these SST errors in the seasonal mean atmospheric state of the coupled model have been further assessed with two sensitivity coupled experiments, in which the SST biases are replaced by observed climatology either in the WIO (warm bias) or EIO (cold bias). The correction of the WIO warm bias leads to a global decrease of rainfall in the monsoon region, which confirms that the WIO is an important source of moisture for the ISM. On the other hand, the correction of the EIO cold bias leads to a global improvement of precipitation and circulation mean state during summer and fall. Nevertheless, all these improvements due to SST corrections seem drastically limited by the atmosphere intrinsic biases, including prominently the unimodal oceanic position of the ITCZ (Inter Tropical Convergence Zone) during summer and the enhanced westward wind stress along the equator during fall

    Airbag Jacket for Motorcyclists: Evaluation of Real Effectiveness

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    IRCOBI 2019, International Conference on the Biomechanics of Injury, Florence, ITALIE, 11-/09/2019 - 13/09/2019This paper aims to evaluate the level of protection offered by airbag jackets for Powered Two Wheeler users. This research is based on a double approach which combines real accident data collected with a field survey and experimental data obtained in laboratory. The accident study shows that the airbag is globally well perceived by their users who highlight their protective effects. But these cases have mainly fallen from the motorcycles at low speeds and less direct impacts against an obstacle. However, some specific cases show that a direct impact at 40km/h or falling at 60km/h with an airbag jackets cannot avoid serious injuries on the trunk (AIS3+). Experimental tests consist on performing crash-tests with PMHS motorcyclists thrown at about 40km/h against passenger cars. Results show differences between the type of airbag jacket in terms of pressure and trigger time. The airbag jackets seem to offer limited protection from a threshold speed which can be estimated to an impact around to 30-40km/h but these speeds differ with the impact configuration

    Etude «EFFIGAM» - Rapport final - Gilets Airbags Pour Motocyclistes: Quelle Efficacité Réelle Pour Quelle Vitesse?

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    This research aims to evaluate the level of protection offered by airbag jackets for Power Two Wheelers users. It is based on a double approach which combines real accident data collected with a field survey and experimental data obtained in laboratory. The accident study shows that the airbag is globally well perceived by their users who highlight their protect effects. But these cases are mainly falling from the motorcycles at low speeds and less direct impacts against an obstacle. However, some specific cases show that a direct impact at 40km/h or a falling at 60km/h with an airbag jackets cannot avoid serious injuries on the trunk (AIS3+). Experimental tests show that an airbag jacket has a protection level superior to a classical back protector. But they highlight that an airbag jacket has a limited protection for impact speeds upper than 40km/h. Crash- tests show also differences between the type of airbag jacket in terms of pressure and trigger time. The airbag jackets seem to have a limited protection from a threshold speed which can be estimated to an impact around to 30-40km/h but these speeds differ with the impact configuration.Il existe aujourd'hui sur le marchĂ© diffĂ©rents modĂšles de gilet airbag qui permettent d'amĂ©liorer la protection des usagers de deux-roues motorisĂ©s (2RM). Ils sont conçus sur trois principes de dĂ©clenchement: Le systĂšme filaire: il s'agit d'un cĂąble fixĂ© sur le gilet et reliĂ© au 2RM qui se dĂ©tache lors de l'Ă©jection du conducteur et dĂ©clenche le gonflage du gilet. Le systĂšme radio: un calculateur et des capteurs positionnĂ©s sur le 2RM dĂ©tectent la chute ou le choc et dĂ©clenchent le gonflage de l'airbag. Le systĂšme «autonome» oĂč le calculateur et les capteurs sont intĂ©grĂ©s dans le gilet ce qui permet un dĂ©clenchement intrinsĂšque du gonflage. L'objectif de cette Ă©tude Ă©tait d'Ă©valuer la protection apportĂ©e au motocycliste par le port de tels gilets. L'approche adoptĂ©e combine une analyse de terrain couplĂ©e Ă  des reconstructions numĂ©riques et des expĂ©rimentations biomĂ©caniques en laboratoire. L'Ă©tude de terrain a montrĂ© que le gilet airbag est globalement bien perçu par les usagers et que la plupart de ceux qui ont eu un accident relĂšvent son effet protecteur. La majoritĂ© d'entre eux considĂšre que le port du gilet leur a Ă©vitĂ© des lĂ©sions ou qu'ils ont Ă©tĂ© indemnes grĂące Ă  lui. Ces cas correspondent principalement Ă  des chutes avec glissade mais peu avec des impacts directs contre un obstacle. Toutefois, des reconstructions numĂ©riques d'accidents ont permis de montrer qu'une chute Ă  60 km/h ou qu'un impact Ă  40km/h peuvent provoquer des lĂ©sions graves au niveau du tronc mĂȘme avec le port du gilet airbag. Les essais expĂ©rimentaux ont montrĂ© que les gilets airbags semblent avoir un effet protecteur supĂ©rieur Ă  celui d'une protection dorsale classique mais au-delĂ  de 50 Joules, la limite de protection est trĂšs rapidement atteinte pour les gilets dont la pression de gonflage est la plus faible. Les essais crash-test montrent une diffĂ©rence entre les gilets filaires et les dĂ©clenchements radios. Les seconds ayant une capacitĂ© Ă  dĂ©tecter le choc plus tĂŽt et donc Ă  se gonfler plus rapidement

    Gilets airbags pour motocyclistes : analyse d'accidents et crash-tests

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    Colloque COSMOS - Connaissances Scientifiques sur les Motocycles, Marne-la-VallĂ©e, FRANCE, 04-/11/2019 - 05/11/2019Objectifs : Il existe aujourd'hui sur le marchĂ© diffĂ©rents modĂšles de gilets airbags qui permettent d'amĂ©liorer la protection des usagers de deux-roues motorisĂ©s (2RM). Ils sont conçus sur trois principes de dĂ©clenchement: « filaire » (un cĂąble fixĂ© au gilet et au 2RM se dĂ©tache lors de l'Ă©jection du motocycliste et dĂ©clenche le gonflage), « radio » (les capteurs placĂ©s sur le 2RM dĂ©tectent la chute ou le choc et lancent le gonflage) et « autonome » (les capteurs sont intĂ©grĂ©s dans le gilet). L'objectif de cette Ă©tude Ă©tait d'Ă©valuer la protection apportĂ©e au motocycliste par le port de tels gilets en essayant notamment d'identifier jusqu'Ă  quelle vitesse d'impact ces gilets sont capables de protĂ©ger l'individu. MĂ©thode : L'approche adoptĂ©e combine une analyse de terrain couplĂ©e Ă  des reconstructions numĂ©riques et des expĂ©rimentations biomĂ©caniques en laboratoire. Concernant l'analyse de terrain, l'objectif Ă©tait de recueillir des donnĂ©es sur des accidents rĂ©els d'usagers de 2RM Ă©quipĂ©s de gilets airbag puis de les analyser en dĂ©tail afin d'en dĂ©gager des conclusions sur leurs effets protecteurs. L'Ă©tude biomĂ©canique s'est attachĂ©e Ă  rĂ©aliser quatre essais expĂ©rimentaux de chocs (crash-tests) avec des gilets airbags de marques diffĂ©rentes. Ces essais consistent Ă  reproduire un impact frontal pour le motocycliste contre une voiture placĂ©e perpendiculairement Ă  la trajectoire du 2RM. La vitesse de la moto est d'environ 40 km/h et l'impact sur le vĂ©hicule se situe sur son cĂŽtĂ© latĂ©ral au niveau du pied milieu. Le temps de dĂ©tection, le temps de gonflage et la durĂ©e de gonflage de chaque type de gilet sont Ă©valuĂ©s ainsi que les pressions Ă  droite et Ă  gauche du gilet. Les essais sont rĂ©alisĂ©s avec des corps donnĂ©s Ă  la science qui sont prĂ©alablement Ă©quipĂ©s de capteurs accĂ©lĂ©romĂ©triques. RĂ©sultats : L'analyse terrain a permis le recueil d'une trentaine d'accidents et montre que la majoritĂ© des accidentĂ©s portant un gilet airbag considĂšre qu'il leur a Ă©vitĂ© des lĂ©sions. Ces cas sont principalement des chutes avec glissade mais peu avec des impacts directs contre un obstacle. Des reconstructions numĂ©riques d'accidents ont montrĂ© qu'une chute Ă  60 km/h ou un impact Ă  40km/h peuvent provoquer des lĂ©sions graves au tronc mĂȘme avec le port du gilet airbag. Les essais crash-test montrent une diffĂ©rence notable entre les gilets filaires et les dĂ©clenchements radios. Les deuxiĂšmes ayant une capacitĂ© Ă  dĂ©tecter le choc bien plus tĂŽt et Ă  se gonfler plus rapidement afin d'ĂȘtre opĂ©rationnel lors du choc du motocycliste contre l'obstacle. Il est Ă  noter Ă©galement des diffĂ©rences de pressions dans les gilets testĂ©s qui peuvent s'interprĂ©ter par une protection offerte lĂ©gĂšrement diffĂ©rente suivant les produits. En effet, pour certains gilets cela peut se traduire par une tendance Ă  plutĂŽt absorber de l'Ă©nergie alors que d'autres produits auraient tendance Ă  rĂ©partir l'effort appliquĂ©. Conclusion : Cette recherche a permis une Ă©valuation rĂ©elle de l'efficacitĂ© protectrice de plusieurs gilets airbags commercialisĂ©s de nos jours. Il en ressort que le gilet airbag est globalement bien perçu par les usagers et que la plupart de ceux qui ont eu un accident relĂšvent son effet protecteur. Toutefois, des cas ont Ă©tĂ© recueillis oĂč les configurations de choc montrent que les gilets ont un effet protecteur limitĂ© aussi bien en cas de choc contre un obstacle qu'en cas de chute puis glissade. Des essais crash-test ont montrĂ© une diffĂ©rence notable entre les gilets filaires et les dĂ©clenchements radios notamment en termes de temps de dĂ©clenchement. Il apparaĂźt donc important de bien Ă©valuer cette valeur dans le but de dĂ©terminer les produits les plus efficaces. D'une maniĂšre gĂ©nĂ©rale, le gilet airbag assure, pour l'ensemble du tronc, le mĂȘme niveau de protection qu'un casque pour la tĂȘte

    The SOCE Machinery: An Unbalanced Knowledge between Left and Right Ventricular Pathophysiology

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    Right ventricular failure (RVF) is the most important prognostic factor for morbidity and mortality in pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) caused by left heart diseases. However, right ventricle (RV) remodeling is understudied and not targeted by specific therapies. This can be partly explained by the lack of basic knowledge of RV remodeling. Since the physiology and hemodynamic function of the RV differ from those of the left ventricle (LV), the mechanisms of LV dysfunction cannot be generalized to that of the RV, albeit a knowledge of these being helpful to understanding RV remodeling and dysfunction. Store-operated Ca2+ entry (SOCE) has recently emerged to participate in the LV cardiomyocyte Ca2+ homeostasis and as a critical player in Ca2+ mishandling in a pathological context. In this paper, we highlight the current knowledge on the SOCE contribution to the LV and RV dysfunctions, as SOCE molecules are present in both compartments. he relative lack of studies on RV dysfunction indicates the necessity of further investigations, a significant challenge over the coming years

    Discordancia lipĂ­dica y placa carotĂ­dea en pacientes obesos en prevenciĂłn primaria

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    El texto completo de este trabajo no estĂĄ disponible en el Repositorio AcadĂ©mico UPC por restricciones de la casa editorial donde ha sido publicado.Introduction Obese patients with lipid discordance (non-HDL cholesterol levels 30mg/dL above the LDL-c value) may have a greater prevalence of carotid atherosclerotic plaque (CAP). Our study objectives were: 1) To assess the prevalence of lipid discordance in a primary prevention population of obese patients; 2) To investigate the association between lipid discordance and presence of CAP. Methods Obese subjects aged >18 years (BMI ≄30kg/m2) with no cardiovascular disease, diabetes, or lipid-lowering treatment from six cardiology centers were included. Lipid discordance was defined when, regardless of the LDL-c level, the non-HDL cholesterol value exceeded the LDL-c value by 30mg/dL. Presence of CAP was identified by ultrasonography. Univariate and multivariate analyses were performed to explore the association between lipid discordance and presence of CAP. Results The study simple consisted of 325 obese patients (57.2% men; mean age, 52.3 years). Prevalence of lipid discordance was 57.9%. CAP was found in 38.6% of patients, but the proportion was higher in subjects with lipid discordance as compared to those without this lipid pattern (44.4% vs. 30.7%, P=.01). In both the univariate (OR: 1.80; 95% CI: 1.14-2.87; P=.01) and the multivariate analysis (OR: 2.07; 95% CI: 1.22-3.54; P=.007), presence of lipid discordance was associated to an increased probability of CAP. Conclusion In these obese patients, lipid discordance was associated to greater prevalence of CAP. Evaluation of obese patients with this strategy could help identify subjects with higher residual cardiovascular risk.RevisiĂłn por pare
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