Influence du diabète de type 2 sur l’activité et l’expression des cytochromes P450

Mon projet de doctorat a pour objet l'étude des facteurs pouvant influencer le métabolisme des médicaments et la variabilité interindividuelle dans la réponse aux médicaments. Mon projet cible plus précisément les Cytochromes P450 (CYP450), le système enzymatique majeur impliqué dans la biotransformation des médicaments. Mes travaux de recherche évaluent l'impact d’une condition pathologique, le diabète de type 2 (DT2), sur l'activité métabolique des CYP450s. Mes études comprennent un volet de métabolisme systémique chez le patient et un volet de métabolisme in vitro. Dans cette thèse, les résultats de mes recherches sont rapportés sous forme de présentation par articles. Le volet in vivo consistait en une étude de pharmacocinétique qui visait à évaluer l’impact du diabète sur l’activité métabolique de différentes isoformes des CYP450s en utilisant un cocktail de substrats-marqueurs. Des patients avec le DT2 et des sujets non diabétiques ont reçu une dose orale de notre cocktail VM/JT de substrats-marqueurs composé de caféine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), oméprazole (CYP2C19), dextrométhorphane (CYP2D6) et midazolam (CYP3A4/5) suivi d'une administration de chlorzoxazone (CYP2E1). Le protocole pour cette étude est détaillé dans l’article disponible à la section 2.1; manuscrit 1. Les concentrations plasmatiques et urinaires des médicaments marqueurs et de leurs métabolites spécifiques ont été quantifiées par LC-MS/MS suivant la méthode publiée dont l’article est disponible à l’annexe 1. Cette étude m’a permis de montrer que les patients avec le DT2 présenteraient une clairance systémique réduite via les isoformes CYP2B6, CYP2C19 et CYP3A. L’article présentant ces résultats se trouve à la section 2.1; manuscrit 2. Au cours de cette étude clinique, nous avons aussi évalué l’utilisation du 4-hydroxycholestérol comme biomarqueur endogène de l’activité du CYP3A dans une population avec le DT2 (objectif secondaire). Les conclusions démontrant la validité de ce biomarqueur sont disponibles dans l’article qui se trouve à la section 2.2; manuscrit 3. Le volet in vitro de mes travaux a permis d’évaluer au niveau du duodénum l’influence du DT2 sur l’expression de plusieurs CYP450s et transporteurs, ainsi que sur l’activité des CYP2B6, CYP2C9, CYP2J2 et CYP3A. Aucun impact significatif du DT2 n’a été mesuré sur l’expression d’ARNm des CYP450s et transporteurs testés exprimés dans des biopsies duodénales. Les niveaux d’activité mesurés à l’aide d’incubations avec des substrats-marqueurs des CYP450s dans des fractions S9 de biopsies duodénales étaient semblables chez des sujets avec le DT2 et des non diabétiques. L’article sur les résultats de ce volet in vitro est disponible à la section 2.3; manuscrit 4. Ces résultats suggèrent que les effets du diabète sur le métabolisme des substrat-marqueurs observés dans l’étude clinique peuvent s’expliquer par une modulation au niveau hépatique ou dans différentes sections de l’intestin. En accord avec ces résultats chez l’humain, notre groupe avait déjà rapporté que l’effet du diabète sur les CYP450s était isoforme et tissu spécifique chez la souris (annexe 2). L'objectif de ma thèse était de mieux comprendre les mécanismes sous-jacents à la variabilité dans la réponse aux médicaments observés chez les patients diabétiques, lesquels nécessitent fréquemment une polypharmacie. Les résultats de ces travaux permettront éventuellement d’optimiser la pharmacothérapie chez ces patients.My PhD project evaluates factors that can influence drug metabolism and interindividual variability in drug response. More precisely, my thesis focuses on the major drug metabolizing enzymes, the cytochromes P450 (CYP450). My researches evaluated the impact of a pathological condition, namely type 2 diabetes (T2D), on CYP450 metabolic activities in two parts. First, the effect of diabetes on systemic metabolism was evaluated in patients. Then, in vitro experiments enabled us to measure the impact of T2D on organ-specific or metabolism. In this thesis, my research results are presented in 4 scientific papers. The in vivo part of my PhD research consisted of a pharmacokinetic study assessing metabolic activity of different isoforms of the CYP450s using a cocktail of probe drugs in T2D patients and non-diabetic subjects. All participants of both study groups received a dose of our oral VM/JT probe drugs cocktail consisting of caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6) and midazolam (CYP3A4/5) followed by a dose of chlorzoxazone (CYP2E1), alone. Study procedures are detailed in the protocol article (manuscrit 1) presented in section 2.1. Plasma and urine concentrations for all probe drugs and specific metabolites were quantified using a published LC-MS/MS method that is available in annexe 1. This study showed that patients with T2D exhibited reduced systemic clearances for the isoforms CYP2B6, CYP2C19 and CYP3A. Results of this pharmacokinetic research are presented in manuscrit 2 of section 2.1. As a secondary objective, this in vivo part of my PhD project enabled us to verify the validity of 4-hydroxycholesterol as an endogenous biomarker of CYP3A activity in a population with T2D. Conclusions showing its validity as an endogenous biomarker in such population are presented in section 2.2 (manuscrit 3). The in vitro part of my doctoral project evaluated in the intestines the influence of T2D on the mRNA expression of numerous CYP450 isozymes and drug transporters, as well as on metabolic activity of CYP2B6, CYP2C9, CYP2J2 and CYP3A. Using duodenal biopsies, no significant impact of T2D was detected on the mRNA expression levels of all tested CYP450s and transporters. Activity levels measured following incubations of probe-substrates in S9 fractions of duodenal biopsies obtained from patients with T2D and non-diabetic patients were similar. Results from this in vitro study are reported in section 2.3 (manuscrit 4) of this thesis. These results obtained in human subjects are in agreement with our previously published results showing isoform- and tissue-specific effects of T2D on CYP450s in mice (annexe 2). Overall, the central theme of this thesis is to better understand the underlying mechanisms of drug response variability observed in diabetic patients, whom often require polypharmacy, in order to eventually optimize drug therapy in those patients

Leçons de Gillian (Scénario)

Cette recherche-création effectuée dans le cadre d’études de deuxième cycle présente une analyse de l’adaptation télévisuelle récente de meurtriers fictifs notoires. Dans la première partie, un essai retrace la façon dont ont été transposés pour la télévision les personnages de Norman Bates (Psycho, 1960) et d’Hannibal Lecter (The Silence of the Lambs, 1991) ainsi que les mécanismes qui ont été déployés afin d’étoffer ces protagonistes et leurs forces d’action. Dans la deuxième partie, on présente la création d’une série télévisée librement inspirée du personnage de John Doe (Seven, 1995). Cette section décrit les différentes étapes du processus d’élaboration d’une œuvre télévisuelle, incluant la démarche d’adaptation, le sujet de la saison, la description des personnages, la structure narrative et les milieux de l’action, les résumés et synopsis des épisodes. Par la suite, un des épisodes a été scénarisé

Inclusion of relatives in stroke rehabilitation : Perception of quality of services they received in the context of early supported discharged (ESD), in- and out-patient services

Background Relatives of stroke patients should be an integral part of the continuum of rehabilitation services. Objective The objective was to describe their perception of the quality of the services they received in the context of early supported discharged (ESD), in- and out-patient rehabilitation services. Methods Descriptive study using the Quality of Services Questionnaire for Relatives post-stroke (QSQR) completed online by relatives after the patient’s discharge. It consists of 22 statements with respect to three subscales: 1) the training/instructions, 2) the information provision and 3) the organizational process of the service offer. Space is allowed for free comments and two open-ended questions. Quantitative data were analyzed descriptively, and we used a content analysis for qualitative data. Results One-third (30/90; 33.3%) of the sample are composed of relatives aged 55 and under, with a majority (81%) of women and 51.3% of spouses. The training/instructions and information provision were perceived positively with a mean % agreement at 85.0 ± 29.6 and 84.8 ± 22.4, respectively. The mean % agreement was 91.4 ± 17.8 for the organizational process subscale. A significantly higher score (p = 0,03; Kruskal Wallis test) was found for out-patient services (n = 20) as compared to ESD (n = 29) or in-patient rehabilitation (n = 41). Qualitatively, a lack of involvement of relatives was mentioned as well as a lack of personalized information about stroke and its consequences and provision of resources available. However, communication between professionals, their availability, and their professionalism were appreciated. Conclusion Despite quantitative high scores, qualitative data allowed the identification of concrete avenues for improvement to truly and systematically include relatives in stroke rehabilitation

‘‘Healthy,’’ ‘‘diet,’’ or ‘‘hedonic’’ : how nutrition claims affect food-related perceptions and intake?

The main purpose of this study was to investigate the impact of nutrition claims on food perceptions and intake among adult men and women, during ad libitum snacks. In a three (healthy vs. diet vs. hedonic) by two (normal-weight vs. overweight/obese) by two (unrestrained vs. restrained eaters) factorial design, 164 men and 188 women were invited to taste and rate oatmeal-raisin cookies. Despite the fact that the cookies were the same in all conditions, they were perceived as being healthier in the “healthy” condition than in the “diet” and “hedonic” conditions. The caloric content was estimated as higher by participants in the “hedonic” than in the “healthy” condition, by women than by men, and by restrained than by unrestrained eaters. Although measured ad libitum cookie intake did not differ as a function of experimental condition, overweight restrained men ate more than did women from each BMI and restraint category. Conversely, overweight restrained women ate less than did men from each BMI and restraint category. In conclusion, our manipulations of healthiness and “fatteningness” of food were effective in changing perceptions, but were not in changing behavior

Promoting healthy eating in early pregnancy in individuals at risk of gestational diabetes mellitus: does it improve glucose homeostasis? A study protocol for a randomized control trial

BackgroundHealthy eating during pregnancy has favorable effects on glycemic control and is associated with a lower risk of gestational diabetes mellitus (GDM). According to Diabetes Canada, there is a need for an effective and acceptable intervention that could improve glucose homeostasis and support pregnant individuals at risk for GDM.AimsThis unicentric randomized controlled trial (RCT) aims to evaluate the effects of a nutritional intervention initiated early in pregnancy, on glucose homeostasis in 150 pregnant individuals at risk for GDM, compared to usual care.MethodsPopulation: 150 pregnant individuals ≥18 years old, at ≤14 weeks of pregnancy, and presenting ≥1 risk factor for GDM according to Diabetes Canada guidelines. Intervention: The nutritional intervention initiated in the first trimester is based on the health behavior change theory during pregnancy and on Canada’s Food Guide recommendations. It includes (1) four individual counseling sessions with a registered dietitian using motivational interviewing (12, 18, 24, and 30 weeks), with post-interview phone call follow-ups, aiming to develop and achieve S.M.A.R.T. nutritional objectives (specific, measurable, attainable, relevant, and time-bound); (2) 10 informative video clips on healthy eating during pregnancy developed by our team and based on national guidelines, and (3) a virtual support community via a Facebook group. Control: Usual prenatal care. Protocol: This RCT includes three on-site visits (10–14, 24–26, and 34–36 weeks) during which a 2-h oral glucose tolerance test is done and blood samples are taken. At each trimester and 3 months postpartum, participants complete web-based questionnaires, including three validated 24-h dietary recalls to assess their diet quality using the Healthy Eating Food Index 2019. Primary outcome: Difference in the change in fasting blood glucose (from the first to the third trimester) between groups. This study has been approved by the Ethics Committee of the Centre de recherche du CHU de Québec-Université Laval.DiscussionThis RCT will determine whether a nutritional intervention initiated early in pregnancy can improve glucose homeostasis in individuals at risk for GDM and inform Canadian stakeholders on improving care trajectories and policies for pregnant individuals at risk for GDM.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05299502, NCT0529950

Stronger and More Vulnerable: A Balanced View of the Impacts of the NICU Experience on Parents

For parents, the experience of having an infant in the NICU is often psychologically traumatic. No parent can be fully prepared for the extreme stress and range of emotions of caring for a critically ill newborn. As health care providers familiar with the NICU, we thought that we understood the impact of the NICU on parents. But we were not prepared to see the children in our own families as NICU patients. Here are some of the lessons our NICU experience has taught us. We offer these lessons in the hope of helping health professionals consider a balanced view of the NICU's impact on families

La conciliation travail-famille chez les employés universitaires ayant des enfants de 11 ans et moins dans le contexte de la pandémie de la COVID-19

Cadre de la recherche : Bien que tous les résidents du Québec aient été affectés par la pandémie de la COVID-19 et par les mesures sanitaires et sociales mises en place depuis le 13 mars 2020, les parents occupant un emploi rémunéré ont été particulièrement affectés par les différents stresseurs engendrés par cette crise, et ce, tant dans leur vie familiale que professionnelle. Dans un tel contexte, il apparaît pertinent de se pencher sur les conséquences engendrées par la pandémie sur la conciliation travail-famille, et plus particulièrement sur les facteurs qui y sont associés. Objectifs : La présente étude vise à documenter les caractéristiques personnelles, familiales et professionnelles associées à la conciliation travail-famille chez les employés universitaires ayant des enfants âgés de 11 ans ou moins dans le contexte de la pandémie. Méthodologie : Les données utilisées pour la présente étude ont été collectées entre le 24 avril et le 5 juin 2020 par le biais d’un sondage en ligne. Au total, 217 membres du personnel de dix établissements du Réseau de l’Université du Québec (RUQ) ont rempli le questionnaire, comprenant notamment des questions liées à la conciliation travail-famille. Des régressions linéaires multiples ont permis de déterminer l’influence respective des facteurs associés à la conciliation travail-famille. Résultats : De façon générale, cette étude indique que les employés universitaires ayant des enfants âgés de 11 ans ou moins présentent majoritairement un conflit travail-famille modéré ou élevé dans le contexte de la pandémie. Elle permet également de mettre en lumière certains facteurs susceptibles de favoriser ou de faire obstacle à la conciliation travail-famille dans cette population de parents, à savoir : le niveau de pression dans l’exercice du rôle parental, la satisfaction du partage des tâches liées aux soins et à l’éducation des enfants, la catégorie d’emploi, la stabilité du rendement au travail et le nombre de jeunes enfants d’âge scolaire. Conclusions : Ces résultats soulignent l’importance de mettre en œuvre des programmes de soutien professionnels et familiaux ainsi que des mesures de répit pour les parents ayant de jeunes enfants d’âge scolaire, afin de les aider à concilier leurs responsabilités familiales et professionnelles en temps de crise. Contribution : Bien que certaines études aient permis de documenter des facteurs associés à la conciliation travail-famille en temps de pandémie, ces dernières demeurent peu nombreuses et une seule a été réalisée en contexte québécois. Or, la conciliation travail-famille est susceptible d’être vécue différemment au Québec, qui se distingue des autres pays en ce qui a trait à sa politique familiale. De plus, cette étude est la première à s’intéresser aux employés universitaires, un groupe de travailleurs faisant partie des premiers à avoir été affectés par les fermetures des établissements scolaires au printemps 2020. Research Framework : Although all Quebec residents have been affected by the COVID-19 pandemic and by the health and social measures put in place since March 2020, working parents have been particularly affected by the various stressors caused by this crisis, in both their family and professional life. In such a context, it seems relevant to examine the consequences of the pandemic on work-family balance, and more specifically on the factors associated with it. Objectives : The purpose of this study is to document the personal, family and work characteristics associated with work-family balance among university employees with children aged 11 or younger in the context of the pandemic. Methodology : The data used for this study were collected between April 24 and June 5, 2020, through an online survey. A total of 217 staff members from ten institutions of the Quebec University Network completed the survey, which included questions related to work-family balance. Multiple linear regressions were used to determine the respective influence of factors associated with the work-family balance. Results : Overall, this study shows that university employees having children aged 11 or younger present a majority of moderate to high work-family conflict in the context of the pandemic. It also highlights some of the factors that may help or hinder work-family balance in this population of parents, namely level of parenting strain, satisfaction with sharing childcare and parenting duties, job category, stability of job performance, and number of young school-aged children. Conclusions : These findings underscore the importance of implementing work and family support programs and respite measures for parents with young school-aged children to help them balance their family and work responsibilities in times of crisis. Contribution : Although some studies have documented factors associated with work-family balance in times of pandemic, they remain few and only one has been conducted in the Quebec context. Work-family balance is likely to be experienced differently in Quebec, which is different from other countries in terms of its family policy. In addition, this study is the first to look at university employees, a group of workers who were among the first to be affected by the school closures in the spring of 2020

Implementing shared decision-making in nutrition clinical practice: A theory-based approach and feasibility study

<p>Abstract</p> <p>Background</p> <p>There are a growing number of dietary treatment options to choose from for the management of many chronic diseases. Shared decision making represents a promising approach to improve the quality of the decision making process needed for dietary choices that are informed by the best evidence and value-based. However, there are no studies reporting on theory-based approaches that foster the implementation of shared decision making in health professions allied to medicine. The objectives of this study are to explore the integration of shared decision making within real nutritional consultations, and to design questionnaires to assess dieticians' intention to adopt two specific behaviors related to shared decision making using the Theory of Planned Behavior.</p> <p>Methods</p> <p>Forty dieticians will audiotape one clinical encounter to explore the presence of shared decision making within the consultation. They will also participate to one of five to six focus groups that aim to identify the salient beliefs underlying the determinants of their intention to present evidence-based dietary treatment options to their patients, and clarify the values related to dietary choices that are important to their patients. These salient beliefs will be used to elaborate the items of two questionnaires. The internal consistency of theoretical constructs and the temporal stability of their measurement will be checked using the test-retest method by asking 35 dieticians to complete the questionnaire twice within a two-week interval.</p> <p>Discussion</p> <p>The proposed research project will be the first study to: provide preliminary data about the adoption of shared decision making by dieticians and theirs patients; elicit dieticians' salient beliefs regarding the intention to adopt shared decision making behaviors, report on the development of a specific questionnaire; explore dieticians' views on the implementation of shared decision making; and compare their views regarding the implementation of shared decision making in different clinical settings.</p> <p>It is anticipated that the results generated by the proposed research project will significantly contribute to the emergence of shared decision making in nutrition through a theory-based approach.</p

A Pilot Study towards the Impact of Type 2 Diabetes on the Expression and Activities of Drug Metabolizing Enzymes and Transporters in Human Duodenum

To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein&minus;1 min&minus;1) determined by LC-MS/MS for CYP2C9 (0.48 &plusmn; 0.26 vs. 0.41 &plusmn; 0.12), CYP2J2 (2.16 &plusmn; 1.70 vs. 1.69 &plusmn; 0.93), and CYP3A (5.25 &plusmn; 3.72 vs. 5.02 &plusmn; 4.76) were not different between biopsies obtained from individuals with or without T2D (p &gt; 0.05). No CYP2B6 specific activity was measured. TNF-&alpha; levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines