1,720,974 research outputs found
Managing cardio-renal-metabolic risk in patients with type 2 diabetes: the role of finerenone
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Benefits of the mineralocorticoid receptor antagonist finerenone in the cardiovascular consequences of a metabolic syndrome in postmenopausal mice or after weight loss of obese male mice.
No full textLes patients obèses et les femmes en post-ménopause montrent une prévalence plus élevée de dysfonction diastolique ventriculaire gauche, pouvant évoluer en insuffisance cardiaque à fraction d’éjection préservée. A ce jour, aucune stratégie thérapeutique n’est adaptée à ces patients. Néanmoins, il a été montré que le système rénine-angiotensine-aldostérone était pathologiquement suractivé dans un contexte d’insuffisance cardiaque. C’est pourquoi nous avons testé l’efficacité de la finérenone, un antagoniste du récepteur minéralocorticoïde non-stéroïdien, dans deux modèles murins d’insuffisance cardiaque à fraction d’éjection préservée.La première étude porte sur des souris mâles nourries par un régime riche en graisses pendant 16 semaines. Au terme de ces 16 semaines, le régime alimentaire est normalisé pour deux groupes de souris, dont un reçoit le traitement par la finérénone pendant 8 semaines. Les résultats obtenus montrent que l’amaigrissement conduit à une amélioration des paramètres métaboliques, mais que seul l’ajout du traitement par la finérénone permet une amélioration franche de la dysfonction diastolique et de la capacité d’exercice.La seconde étude porte sur des souris ovariectomisées à l’âge de 4 mois puis traitées par la finérénone pendant 1 mois à l’âge de 7 mois. Les résultats obtenus montrent une amélioration de la dysfonction diastolique, soutenue par une amélioration de la fonction coronaire et de la capacité d’exercice.En conclusion, la finérénone améliore la dysfonction cardiovasculaire, la fonction coronaire et la capacité d’exercice dans ces deux modèles murins de dysfonction diastolique associée à une altération des paramètres métaboliques. Ces études soulignent l’intérêt du récepteur minéralocorticoïde comme cible pharmacologique dans le traitement de l’insuffisance cardiaque à fraction d’éjection préservée.Obese patients and postmenopausal women show a higher prevalence of left ventricular diastolic dysfunction, which may progress to heart failure with preserved ejection fraction. To date, no therapeutic strategy is adapted to these patients. Nevertheless, it has been shown that the renin-angiotensin-aldosterone system is pathologically overactivated in the context of heart failure. In this context, we tested the efficacy of finerenone, a non-steroidal mineralocorticoid receptor antagonist, in two mouse models of heart failure with preserved ejection fraction.The first study involved mice fed a high-fat diet for 16 weeks. At the end of 16 weeks, the diet was normalized in two groups of mice, one of which received treatment with finerenone for 8 weeks. The results show that normalization of the diet shows an improvement of the metabolic parameters, but only the addition of the finerenone treatment allows a clear improvement of the diastolic dysfunction and of the exercise capacity.The second study involved ovariectomized mice at 4 months of age and then treated with finerenone for 1 month at 7 months of age. The results show an improvement in diastolic dysfunction, supported by an improvement in coronary function and exercise capacity.In conclusion, finerenone improves cardiovascular dysfunction, coronary function, and exercise capacity in these two mouse models of diastolic dysfunction associated with altered metabolic parameters. These studies highlight the interest of the mineralocorticoid receptor as a pharmaceutical target in the treatment of heart failure with preserved ejection fraction
Early nongenomic events in aldosterone action in renal collecting duct cells: PKCalpha activation, mineralocorticoid receptor phosphorylation, and cross-talk with the genomic response
Get PDFEffects of aldosterone on its target cells have long been considered to be mediated exclusively through the genomic pathway; however, evidence has been provided for rapid effects of the hormone that may involve nongenomic mechanisms. Whether an interaction exists between these two signaling pathways is not yet established. In this study, the authors show that aldosterone triggers both early nongenomic and late genomic increase in sodium transport in the RCCD(2) rat cortical collecting duct cell line. In these cells, the early (up to 2.5 h) aldosterone-induced increase in short-circuit current (Isc) is not blocked by the mineralocorticoid receptor (MR) antagonist RU26752, it does not require mRNA or protein synthesis, and it involves the PKCalpha signaling pathway. In addition, this early response is reproduced by aldosterone-BSA, which acts at the cell surface and presumably does not enter the cells (aldo-BSA is unable to trigger the late response). The authors also show that MR is rapidly phosphorylated on serine and threonine residues by aldosterone or aldosterone-BSA. In contrast, the late (4 to 24 h) aldosterone-induced increase in ion transport occurs through activation of the MR and requires mRNA and protein synthesis. Interestingly, nongenomic and genomic aldosterone actions appear to be interdependent. Blocking the PKCalpha pathway results in the inhibition of the late genomic response to aldosterone, as demonstrated by the suppression of aldosterone-induced increase in MR transactivation activity, alpha1 Na(+)/K(+)/ATPase mRNA, and Isc. These data suggest cross-talk between the nongenomic and genomic responses to aldosterone in renal cells and suggest that the aldosterone-MR mediated increase in mRNA/protein synthesis and ion transport depends, at least in part, upon PKCalpha activation.Fil: Le Moëllic, Cathy. Inserm; FranciaFil: Ouvrard Pascaud, Antoine. Inserm; FranciaFil: Capurro, Claudia Graciela. Inserm; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cluzeaud, Francoise. Inserm; FranciaFil: Fay, Michel. Inserm; FranciaFil: Jaisser, Frederic. Inserm; FranciaFil: Farman, Nicolette. Inserm; FranciaFil: Blot Chabaud, Marcel. Inserm; Franci
Rôle physiopathologique du récepteur minéralocorticoïde dans le rein et dans le coeur (approches utilisant des modèles conditionnels cellulaires et animaux)
No full textLe récepteur minéralocorticoïde est un facteur de transcription dépendant de sa liaison à l'hormone, l'aldostérone, qui régule la réabsorption terminale de sodium dans le néphron distal (tubule collecteur cortical), participant au contrôle de la volémie et de la pression artérielle. Les cibles moléculaires et voies de signalisation impliquées dans ce processus n'ont pas toutes été déterminées. De plus ce récepteur s'exprime dans d'autres tissus, dont le cœur, où sa fonction reste largement inconnue. A partir d'une lignée cellulaire de rat, nous avons établi un clone permettant l'expression inductible (Cre-lox) d'une protéine de fusion entre le récepteur minéralocorticoïde humain et un marqueur eGFP fluorescent (Ouvrard-Pascaud et al. 2004), qui a été utilisé dans une étude proposant que la translocation nucléaire du récepteur ne soit pas requise pour stimuler la réabsorption du sodium au cours de la phase précoce de la réponse hormonale (1 à 2 heures) (Le Moellic et al. 2004). Nous avons développé des souris transgéniques pour l'expression inductible (tet-OFF) du récepteur minéralocorticoïde humain spécifiquement dans les cardiomyocytes. 50% de ces animaux meurent au cours du développement embryonnaire sans défaut de cardiogenèse. L'histologie cardiaque adulte est normale. Des études d'électrophysiologie sur cellules isolées montrent un allongement du potentiel d'action. Des électrocardiogrammes montrent des extrasystoles et tachycardies ventriculaires. Ce phénotype évoque la survenue de morts subites par troubles du rythme, suggérant une fonction du récepteur dans la signalisation électrique cardiaque et sa possible implication dans des pathologies intégrant des arythmies.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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