Impact du diabète sur le travail et usage des antidiabétiques oraux chez les travailleurs au Québec

Ce mémoire a deux volets. L'objectif du premier était d'évaluer l'impact du diabète de type 2 sur la productivité au travail. Les objectifs du deuxième étaient de décrire la persistance et l'observance aux traitements antidiabétiques et de déterminer les facteurs y étant associés chez des travailleurs atteints de diabète de type 2. Au premier volet, nous avons effectué une synthèse systématique des connaissances. Au deuxième, nous avons réalisé une étude de cohorte à l'aide des données administratives de la Régie de l'assurance maladie du Québec. Selon notre synthèse, le diabète a un impact négatif significatif sur la productivité au travail. Parmi les 41006 sujets de la cohorte, 81,1% prenaient leur traitement un an après son début et de ceux-ci 69,7% avaient eu en leur possession des médicaments antidiabétiques pendant au moins 80% des jours de cette première année. La persistance et l'observance aux traitements antidiabétiques sont affectées par plusieurs déterminants

Peptides thérapeutiques à fleur de peau de grenouille

La recherche de nouvelles molécules bioactives utilisables en thérapeutique est un enjeu majeur de santé publique, en particulier dans le traitement de certaines maladies comme le cancer. Dans cette optique, l’exploration du venin des animaux (serpents, amphibiens, cônes, scorpions, insectes...), qui produisent des molécules de structures et d’activités biologiques diverses, est une piste très prometteuse. La recherche dans ce domaine a conduit à la découverte de neuropeptides, d’hormones, de toxines, de peptides antimicrobiens et d’autres médiateurs extrêmement puissants. Ceux-ci sont maintenant utilisés dans de nombreux domaines aussi bien en recherche fondamentale pour la compréhension des mécanismes biochimiques et physiologiques, qu’en recherche translationnelle comme outil de diagnostic médical ou à des fins thérapeutiques. Le Pr. V. Erspamer est le premier à avoir montré, dès les années 1930, qu’en plus des amines biogènes et des alcaloïdes, les glandes granulaires de la peau des amphibiens produisaient également d’énormes quantités de peptides de structures et d’activités biologiques diverses. Il a montré aussi que ces peptides se retrouvaient, le plus souvent, sous forme de peptides identiques ou similaires dans le système nerveux central et le tractus gastro-intestinal des mammifères. Ces observations sont résumées sous forme d’un concept de triangle « peau-cerveau-intestin » qui stipule que tout peptide trouvé dans un compartiment devrait se retrouver dans les deux autres. De plus, l’abondance, la facilité d’extraction et d’identification des peptides de la peau des amphibiens font de ce modèle un moyen pour la recherche de leurs équivalents chez les mammifères où ils sont présents en quantités infimes. Cette approche présente deux avantages : (i) au plan fondamental, la grande diversité peptidique, l’ubiquité et la multiplicité des fonctions auxquelles ils participent constituent une véritable chimiothèque pour comprendre les mécanismes fondamentaux de reconnaissance et de transduction des signaux et étudier les bases physico-chimiques de leur spécificit;é (ii) au plan des applications, la relative simplicité de ces molécules et l’essor des techniques de production massive par synthèse chimique ou par recombinaison offrent un potentiel novateur pour le développement d’agents à visée pharmacologique ou thérapeutique

Oral Glucocorticoids: Fracture Risk and Benefit of Osteoporosis Pharmacotherapy

Oral glucocorticoids are potent anti-inflammatory and immunosuppressant agents used to treat and control several conditions. However, oral glucocorticoid exposure leads to an osteoporotic state characterized by increased bone loss and fracture risk. Bone loss is rapid upon oral glucocorticoid exposure, particularly in the vertebra. Osteoporosis treatment are often recommended for patients receiving oral glucocorticoids to prevent fracture. However, osteoporosis drug benefit in randomized controlled trials and observational studies is not yet established among oral glucocorticoid users. This research aimed to estimate fracture rates among new and ongoing oral glucocorticoid users and assess the benefit of osteoporosis drugs. First, meta-analytic methods were leveraged to pool fracture data from randomized clinical trials and examine fracture rates by oral glucocorticoid exposure history. Second, network meta-analysis was used to estimate the relative efficacy of osteoporosis drugs among oral glucocorticoid users. Third, using Ontario administrative healthcare data, three cohort analyses were conducted to assess the effectiveness of alendronate, etidronate, and risedronate in reducing fracture risk among chronic oral glucocorticoid users. Results of the meta-analytic analyses (study 1) showed that vertebral and non-vertebral fracture rates are higher among patients starting a new oral glucocorticoid treatment course than patients with ongoing use. These findings are consistent with higher bone loss among glucocorticoid initiators than ongoing users. The network meta-analysis (study 2) showed etidronate, risedronate, and teriparatide as efficacious in preventing vertebral fracture; teriparatide was identified as the most efficacious treatment followed by risedronate. No treatment was associated with a reduction in hip fracture risk, yet the data were limited to small pooled samples of heterogeneous patients in clinical trials. Results of the large population-based observational research (study 3) support the effectiveness of alendronate and risedronate to reduce hip fracture risk, and all three oral bisphosphonates to reduce vertebral fracture risk. The findings of this dissertation draw attention to the high fracture risk among new oral glucocorticoid users and provide evidence of the benefit of osteoporosis drugs early upon oral glucocorticoid exposure to reduce fracture risk. Further research is required to examine fracture risk by different glucocorticoid exposure patterns and estimate the comparative effectiveness between osteoporosis drugs.Ph.D

Etude du mécanisme d'action d'une peptide cationique antibactérien, la dermaseptine B2

L objet de cette thèse est l étude du mécanisme antibactérien de la dermaseptine B2 (Drs B2), peptide isolé de la peau de grenouille amazonienne du genre Phyllomedusa. Nous avons montré qu elle induit une courbure positive de la membrane du fait de sa forte charge positive lors de son insertion, laissant présager la formation de pores toroïdaux. De plus, la flexibilité de la région N-terminale du peptide ainsi que le caractère hydrophobe, réparti en deux domaines séparés par un coeur hydrophile, sont indispensables à son adaptabilité et à son insertion dans le corps hydrophobe de la bicouche. Une étude comparative entre les PAM et les CPP a montré que ces deux familles peptidiques recrutaient préférentiellement des lipides membranaires chargés négativement à chaînes acyles courtes et insaturées. Par ailleurs, nous avons observé que la Drs B2 ne possédait pas la capacité à franchir les membranes des cellules de mammifère. La frontière entre ces deux familles peptidiques est à élucider.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Analyse évolutive, moléculaire et fonctionnelle des peptides antimicrobiens des amphibiens

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Dermaseptins, Multifunctional Antimicrobial Peptides: A Review of Their Pharmacology, Effectivity, Mechanism of Action, and Possible Future Directions

International audienceDermaseptins are a group of α-helical shaped polycationic peptides isolated from the Hylid frogs, with antimicrobial effects against bacteria, parasites, protozoa, viruses in vitro. Besides, anti-tumor effects have been demonstrated. However, few animal experiments and no clinical trials have been conducted thus far. This review summarizes the current knowledge on the pharmacology, ethno pharmacology, effectivity against infectious pathogens and tumors cells and the mechanism of action of the Dermaseptins. Future research should focus on further clarification of the mechanisms of action, the effectivity of Dermaseptins against several cancer cell lines and their applicability in humans

Recent Advances in Multifunctional Antimicrobial Peptides as Immunomodulatory and Anticancer Therapy: Chromogranin A-Derived Peptides and Dermaseptins as Endogenous versus Exogenous Actors

International audienceAntimicrobial peptides (AMPs) are produced by all living organisms exhibiting antimicrobial activities and representing the first line of innate defense against pathogens. In this context, AMPs are suggested as an alternative to classical antibiotics. However, several researchers reported their involvement in different processes defining them as Multifunctional AMPs (MF-AMPs). Interestingly, these agents act as the endogenous responses of the human organism against several dangerous stimuli. Still, they are identified in other organisms and evaluated for their anticancer therapy. Chromogranin A (CgA) is a glyco-phosphoprotein discovered for the first time in the adrenal medulla but also produced in several cells. CgA can generate different derived AMPs influencing numerous physiological processes. Dermaseptins (DRSs) are a family of α-helical-shaped polycationic peptides isolated from the skin secretions of several leaf frogs from the Phyllomedusidae family. Several DRSs were identified as AMPs and, until now, more than 65 DRSs have been classified. Recently, these exogenous molecules were characterized for their anticancer activity. In this review, we summarize the role of these two classes of MF-AMPs as an example of endogenous molecules for CgA-derived peptides, able to modulate inflammation but also as exogenous molecules for DRSs, exerting anticancer activities

Evaluation des effets de la lactoferrine sur la microflore gastro-intestinale, sur l'utilisation digestive des nutriments et sur les performances zootechniques du porcelet, et étude microbiologique avec quelques peptides antimicrobiens

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

The aspartic acid in deltorphin I and dermenkephalin promotes targeting to δ-opioid receptor independently of receptor binding

International audienceRecent studies on the highly potent and selective δ-opioid agonists demenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) and deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) suggested that key structural features necessary for specific targetting to the δ-opioid receptor are located within the C-terminal halves of these naturally occurring heptapeptides. To investigate the contribution of aspartic acid 4 residue in deltorphin I and aspartic acid 7 residue in dermenkephalin to the δ-addressing ability of the C-terminal ends, fourteen analogs were synthesized and assessed for their ability to bind to μ and δ-opioid receptors in rat brain membrane homogenates. Results showed that i/ although the tetrapeptide C-terminus of dermenkephalin and deltorphin I differ in amino acid composition, they play a similar role in specifying correct addressing of these peptides to the δ-receptor, ii/ the negatively charged side chain of aspartic acid 4 residue in deltorphin I and aspartic acid 7 residue in dermenkephalin is not involved in binding contact at the δ-receptor site, nor in maintaining a δ-bioactive folding of the peptides, iii/ these side chains are, in contrast, functionnally or structurally required to confer high δ-selectivity by preventing μ-site recognition and / or binding

Post-translational amino acid racemization in the frog skin peptide deltorphin I in the secretion granules of cutaneous serous glands.

International audienceThe dermal glands of the South American hylid frog Phyllomedusa bicolor synthesize and expel huge amounts of cationic, alpha-helical, 24- to 33-residue antimicrobial peptides, the dermaseptins B. These glands also produce a wide array of peptides that are similar to mammalian hormones and neuropeptides, including a heptapeptide opioid containing a D-amino acid, deltorphin I (Tyr-DAla-Phe-Asp-Val-Val-Gly NH2). Its biological activity is due to the racemization of L-Ala2 to D-Ala. The dermaseptins B and deltorphins are all derived from a single family of precursor polypeptides that have an N-terminal preprosequence that is remarkably well conserved, although the progenitor sequences giving rise to mature opioid or antimicrobial peptides are markedly different. Monoclonal and polyclonal antibodies were used to examine the cellular and ultrastructural distributions of deltorphin I and dermaseptin B in the serous glands by immunofluoresence confocal microscopy and immunogold-electron microscopy. Preprodeltorphin I and preprodermaseptins B are sorted into the regulated pathway of secretion, where they are processed to give the mature products. Deltorphin I, [l-Ala2]-deltorphin I and dermaseptin B are all stored together in secretion granules which accumulate in the cytoplasm of all serous glands. We conclude that the L- to D-amino acid isomerization of the deltorphin I occurs in the secretory granules as a post-translational event. Thus the specificity of isomerization depends on the presence of structural and/or conformational determinants in the peptide N-terminus surrounding the isomerization site