Étude comparative de l'impact de la simvastatine et de l'atorvastatine, deux inhibiteurs de l'HMG-COA réductase, sur la cinétique in vivo de l'apolipoprotéine A-I chez l'homme

Le projet de recherche qui constitue ce mémoire de maîtrise avait pour but d’investiguer les mécanismes physiologiques responsables de l’effet divergent de deux statines [inhibiteurs de la 3-hydroxy-3-méthylglutaryl coenzyme A (HMG-CoA) réductase] largement utilisées en clinique, la simvastatine et l’atorvastatine, sur les concentrations de cholestérol associées aux lipoprotéines de haute densité (HDL-C). Pour ce faire, nous avons comparé l’impact de ces deux médicaments hypocholestérolémiants sur la cinétique de l’apolipoprotéine A-I, la protéine majeure des lipoprotéines de haute densité, chez 7 sujets hypercholestérolémiques avec des concentrations relativement faibles de cholestérol HDL. Tous les sujets étaient soumis à chacun des deux traitements à l’étude, soit simvastatine 80 mg/jour et atorvastatine 40 mg/jour, selon un devis expérimental randomisé, en chassé-croisé et à double insu. Chaque phase de traitement durait 8 semaines. Des analyses de cinétique étaient réalisées à la fin de chacune des phases de traitement. Celles-ci ont démontré qu’un traitement de 8 semaines sous simvastatine 80 mg/jour était associé à une concentration d’apolipoprotéine A-I en circulation significativement plus élevée de 8% que sous traitement à l’atorvastatine 40 mg/jour. La concentration supérieure d’apolipoprotéine A-I sous traitement à la simvastatine était attribuable à un taux de production de d’apolipoprotéine A-I significativement plus élevé (15%) comparativement au traitement à l’atorvastatine.The purpose of the following study was to investigate the physiological mechanisms underlying the diverging impact of two statins (HMG-CoA reductase inhibitors) widely used in clinic, simvastatin and atorvastatin, on high density lipoprotein cholesterol (HDL-C). To do so, we compared the impact of the two lipid-lowering agents on apoA-I kinetics, the protein moiety of HDL, in 7 hypercholesterolemic men with low HDL levels. All subjects were assigned two both treatments, simvastatin 80 mg/day and atorvastatin 40mg/day, in a randomized, cross-over, double-blind fashion. Each treatment phase last 8 weeks and kinetic studies were performed at the end of each treatment phase. Our analysis has demonstrated that simvastatin 80 mg/day was associated with a significant 8% greater apoA-I concentration in circulation compared to atorvastatin 40 mg/day. The higher apoA-I conentration observed with simvastatin 80 mg/day was explained by a significant 15% greater aspoA-I production rate with simvastatin 80 mg/day compared to atorvastatin 40 mg/day

Apolipoptotéine C-III, taille des LDL et protéine C-réactive

Le syndrome métabolique est un regroupement de facteurs de nsque de maladie cardiovasculaire (MCV) étroitement liés à l'obésité. L 'hypertriglycéridémie, la présence en circulation de lipoprotéines de faible densité (LDL) de diamètre réduit et une condition proinflammatoire représentent trois de ces facteurs. L' apoliprotéine (apo) C-III, présente sous 3 isoformes en circulation, inhibe la lipase lipoprotéique. et serait impliquée dans le développement de l 'hypertriglycéridémie. Les LDL petites et denses seraient métabolisées moins rapidement et seraient ' ainsi plus susceptibles de participer au processus athérosclérotique. Les concentrations plasmatiques élevées de protéine C-réactive (CRP) sont utilisées en clinique dans l'évaluation de la condition inflammatoire et dans l'estimation du profil de risque de MCV. La compréhension du métabolisme intravasculair-e de l'apoC-III, des différentes classes de LDL et de la CRP en rapport avec le syndrome métabolique est incomplète. Utilisant des techniques de traçage in vivo, les mécanismes physiologiques (taux de production et de catabolisme) responsables des variations de concentrations plasmatiques des différents isoformes de l'apoC-III, de la CRP et des LDL petites et denses furent étudiés. Les études sur le métabolisme intravasculaire de l' apoC-III ont démontré que le taux de production de l'ensemble des isoformes de l' apoC-III était positivement associé aux concentrations plasmatiques de triglycérides et que le taux de production de l'isoforme doublement sialylée était fortement associé à la proportion de petites LDL en circulation. L'étude de la cinétique intravasculaire de différentes sousclasses de LDL a révélé que les LDL de moindres densités, malgré ' leur métabolisme intravasculaire rapide, sont les principaux précurseurs des LDL de plus hautes densités. Finalement, l'étude de la CRP révéla que les concentrations plasmatiques de ce marqueur inflammatoire sont déterminées principalement par son taux de production, et que ce dernier serait positivement associé au tour de taille et aux concentrations plasmatiques d'apoB-lOOet de triglycérides, et négativement associé aux concentrations plasmatiques de lipoprotéines de haute densité et d'adiponectine. Dans l'ensemble, ces études in vivo auront permis de mieux situer le rôle métabolique des isoformes de l'apoC-III, des LDL et de la CRP dans le développement du syndrome métabolique et appellent à la réalisation d'études dans divers contextes métaboliques afin de valider les conclusions ici présentées

Bourdieusian Reflections on Language: Unavoidable Conditions of the Real Speech Situation

The main purpose of this paper is to shed light on Pierre Bourdieu’s conception of language. Although he has dedicated a significant part of his work to the study of language and even though his analysis of language has been extensively discussed in the literature, almost no attention has been paid to the factthat Bourdieu’s account of language is based on a number of ontological presuppositions, that is, on a set of universal assumptions about the very nature of language. This article aims to fill this gap in the literature by offering a detailed overview of 10 key features which, from a Bourdieusian point of view, can be regarded as inherent in language. On the basis of this enquiry,the study seeks todemonstrate that——contraryto commonbelief——there is not only a Bourdieusian sociology of language but also a Bourdieusian philosophy of language, which provides a useful theoretical framework for examining the unavoidable conditions of the real speech situation. The paper draws to a close by reflecting on the flaws and limitations of Bourdieu’s approach to language

Ethnographie du travail social (une économie des biens symboliques)

Comment font les travailleurs sociaux (très majoritairement des femmes), pour tenir , dans l'exercice de métiers éprouvants, mais peu valorisés socialement et économiquement, peu reconnus académiquement et scientifiquement? Menée dans une ville de moyenne importance marquée par la désindustrialisation dans un des anciens bassins miniers wallons, une enquête ethnographique a permis de mettre en évidence des principes propres à l'économie des biens symboliques dans l'univers du travail social. Prendre au sérieux leurs raisons d'être conduit à s'intéresser à leurs pratiques (souvent tacites parce que jugées triviales), à leurs attentes, à leurs rétributions symboliques sous toutes leurs formes. Trois pôles ont été identifiés dans l'espace du travail social. Dans leur présentation d'eux-mêmes comme dans leurs pratiques, les travailleurs sociaux cliniques mettent en avant leur volonté de travailler au-delà de la demande de l'usager pour le soulager de sa souffrance . Ils apparaissent ainsi comme des agents de première ligne de ce que Didier Fassin nomme le traitement compassionnel de la question sociale . Les travailleurs sociaux militants mettent en avant leur lecture humaniste ou politique du monde et leur volonté de changement social qu'ils tentent de rapporter à leurs pratiques et discours face aux situations sociales particulières des usagers. Les travailleurs sociaux normatifs considèrent leur travail comme un travail comme un autre : de leur point de vue, le respect des règles, des lois, des normes, des hiérarchies et des contrats est un facteur d'intégration sinon d'insertion.How make the social workers (very mainly women), ''to like", in the exercise of testing professions, but little valued socially and economically, little recognized academically and scientifically? Led in a city of average importance marked by the deindustrialization in one of the former Walloon mineral fields, an ethnographical inquiry allowed to bring to light principles appropriate for the symbolic economy in the universe of the social work. Take seriously "their reasons for being" led to be interested in their practices (often tacit because considered coarse), in their expectations, in their symbolic remunerations under ail their forms. Three poles were identified in the space of the social work. ln their presentation of themselves as in their practices, the clinical social workers advance their "will" to work "beyond the demand of the user" "to relieve of his suffering". They so appear as first-line agents of what Didier Fassin names "the compassionnel treatment of the social question". The militant social workers advance their humanist or political reading of the world and their "will of social change" that they try to relate to their practices and talk in front of particular social situations of the users. The normative social workers consider their work as "a work as the other one": from their point of view, the respect for rules, laws, standards, hierarchies and contracts is a factor of integration otherwise of insertion.PARIS3-BU (751052102) / SudocSudocFranceF

CYP1A1, VEGFA and Adipokine Responses of Human Adipocytes Co-exposed to PCB126 and Hypoxia

It is increasingly recognized that hypoxia may develop in adipose tissue as its mass expands. Adipose tissue is also the main reservoir of lipophilic pollutants, including polychlorinated biphenyls (PCBs). Both hypoxia and PCBs have been shown to alter adipose tissue functions. The signaling pathways induced by hypoxia and pollutants may crosstalk, as they share a common transcription factor: aryl hydrocarbon receptor nuclear translocator (ARNT). Whether hypoxia and PCBs crosstalk and affect adipokine secretion in human adipocytes remains to be explored. Using primary human adipocytes acutely co-exposed to different levels of hypoxia (24 h) and PCB126 (48 h), we observed that hypoxia significantly inhibits the PCB126 induction of cytochrome P450 (CYP1A1) transcription in a dose-response manner, and that Acriflavine (ACF)—an HIF1α inhibitor—partially restores the PCB126 induction of CYP1A1 under hypoxia. On the other hand, exposure to PCB126 did not affect the transcription of the vascular endothelial growth factor-A (VEGFA) under hypoxia. Exposure to hypoxia increased leptin and interleukin-6 (IL-6), and decreased adiponectin levels dose-dependently, while PCB126 increased IL-6 and IL-8 secretion in a dose-dependent manner. Co-exposure to PCB126 and hypoxia did not alter the adipokine secretion pattern observed under hypoxia and PCB126 exposure alone. In conclusion, our results indicate that (1) hypoxia inhibits PCB126-induced CYP1A1 expression at least partly through ARNT-dependent means, suggesting that hypoxia could affect PCB metabolism and toxicity in adipose tissue, and (2) hypoxia and PCB126 affect leptin, adiponectin, IL-6 and IL-8 secretion differently, with no apparent crosstalk between the two factors

Human Preadipocytes Differentiated under Hypoxia following PCB126 Exposure during Proliferation: Effects on Differentiation, Glucose Uptake and Adipokine Profile

Persistent organic pollutants (POPs) accumulation and hypoxia are two factors proposed to adversely alter adipose tissue (AT) functions in the context of excess adiposity. Studies have shown that preadipocytes exposure to dioxin and dioxin-like POPs have the greatest deleterious impact on rodent and immortalized human preadipocyte differentiation, but evidence on human preadipocytes is lacking. Additionally, hypoxia is known to strongly interfere with the dioxin-response pathway. Therefore, we tested the effects of pre-differentiation polychlorinated biphenyl (PCB)126 exposure at 10 µM for 3 days and subsequent differentiation under hypoxia on human subcutaneous adipocytes (hSA) differentiation, glucose uptake and expression of selected metabolism- and inflammation-related genes. Pre-differentiation PCB126 exposure lowered the adenosine triphosphate (ATP) content, glucose uptake and leptin expression of mature adipocytes but had limited effects on differentiation under normoxia (21% O2). Under hypoxia (3% O2), preadipocytes ability to differentiate was significantly reduced as reflected by significant decreased lipid accumulation and downregulation of key adipocyte genes such as peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin. Hypoxia increased glucose uptake and glucose transporter 1 (GLUT1) expression but abolished the adipocytes insulin response and GLUT4 expression. The expression of pro-inflammatory adipokine interleukin-6 (IL-6) was slightly increased by both PCB126 and hypoxia, while IL-8 expression was significantly increased only following the PCB126-hypoxia sequence. These observations suggest that PCB126 does not affect human preadipocyte differentiation, but does affect the subsequent adipocytes population, as reflected by lower ATP levels and absolute glucose uptake. On the other hand, PCB126 and hypoxia exert additive effects on AT inflammation, an important player in the development of chronic diseases such as type 2 diabetes and cardiovascular diseases

PINTMF: PENALIZED INTEGRATIVE MATRIX FACTORIZATION METHOD FOR MULTI-OMICS DATA

It is more and more common to explore the genome at diverse levels and not only at a single omic level. Through integrative statistical methods, omics data have the power to reveal new biological processes, potential biomarkers, and subgroups of a cohort. The matrix factorization (MF) is a unsupervised statistical method that allows giving a clustering of individuals, but also revealing relevant omic variables from the various blocks. Here, we present PIntMF (Penalized Integrative Matrix Factorization), a model of MF with sparsity, positivity and equality constraints.To induce sparsity in the model, we use a classical Lasso penalization on variable and individual matrices. For the matrix of samples, sparsity helps for the clustering, and normalization (matching an equality constraint) of inferred coefficients is added for a better interpretation. Besides, we add an automatic tuning of the sparsity parameters using the famous glmnet package. We also proposed three criteria to help the user to choose the number of latent variables. PIntMF was compared to other state-of-the-art integrative methods including feature selection techniques in both synthetic and real data. PIntMF succeeds in finding relevant clusters as well as variables in two types of simulated data (correlated and uncorrelated). Then, PIntMF was applied to two real datasets (Diet and cancer), and it reveals interpretable clusters linked to available clinical data. Our method outperforms the existing ones on two criteria (clustering and variable selection). We show that PIntMF is an easy, fast, and powerful tool to extract patterns and cluster samples from multi-omics data