L’adhésion au traitement : Ce que devrait faire un physiothérapeute face à un patient mal-adhérent

Travail d'intégration présenté à la Faculté de Médecine en vue de l’obtention du grade de Maîtrise Science en PhysiothérapieIntroduction : La mal-adhésion au traitement est fréquente chez les patients en physiothérapie, ce qui constitue un impact majeur sur les résultats de traitement et sur les coûts de santé. La définition du concept d’adhésion ne fait pas consensus dans la littérature, mais peut être définie comme le fait de respecter le plan de traitement et les recommandations établis en collaboration avec le patient. Objectifs et Méthodologie : L’objectif de ce travail est de fournir des recommandations aux physiothérapeutes sur la prise en charge d’un patient mal-adhérent. Pour ce faire, une revue de la littérature sur l’adhésion au traitement dans différents domaines de la santé a été effectuée afin d’identifier les facteurs influençant l’adhésion, les outils la mesurant et les stratégies l’optimisant. Résultats : Le physiothérapeute doit détecter les signes de mal-adhésion et identifier les principaux facteurs personnels (éléments psychologiques) et environnementaux (support social et relation patient-thérapeute) pouvant nuire à l’adhésion. Ensuite, le physiothérapeute devrait prendre une mesure de l’adhésion grâce au SIRAS, la seule échelle validée et fidèle disponible actuellement. Le but de ces recommandations est finalement d’appliquer une stratégie éducationnelle, motivationnelle ou de développer une relation thérapeutique adéquate, tout en adaptant ces stratégies en fonction des facteurs responsables de la mal-adhésion spécifiques au patient. Conclusion : La mal-adhésion au traitement est un enjeu important en physiothérapie et pourrait être prise en charge selon des étapes présentées dans l’affiche, de la détection de la mal-adhésion à l’application de stratégies pour l’améliorer

Higher Sensitivity of Female Cells to Ethanol: Methylation of DNA Lowers Cyp2e1, Generating more ROS

Background: Cells taken from mouse embryos before sex differentiation respond to insults according to their chromosomal sex, a difference traceable to differential methylation. We evaluated the mechanism for this difference in the controlled situation of their response to ethanol. Methods: We evaluated the expression of mRNA for alcohol dehydrogenase (ADH), aldehyde dehyrogenases (ALDH), and a cytochrome P450 isoenzyme (Cyp2e1) in male and female mice, comparing the expressions to toxicity under several experimental conditions evaluating redox and other states. Results: Females are more sensitive to ethanol. Disulfiram, which inhibits alcohol dehydrogenase (ADH), increases cell death in males, eliminating the sex dimorphism. The expressions ADH Class 1 to 4 and ALDH Class 1 and 2 do not differ by sex. However, females express approximately 8X more message for Cyp2e1, an enzyme in the noncanonical pathway. Female cells produce approximately 15% more ROS (reactive oxygen species) than male cells, but male cells contain approximately double the concentration of GSH, a ROS scavenger. Scavenging ROS with Nacetyl cysteine reduces cell death and eliminates sex dimorphism. Finally, since many of the differences in gene expression derive from methylation of DNA, we exposed cells to the methyltransferase inhibitor 5-aza- 2- deoxycytidine; blocking methylation eliminates both the difference in expression of Cyp2e1 and cell death. Conclusion: We conclude that the sex-differential cell death caused by ethanol derives from sex dimorphic methylation of Cyp2e1 gene, resulting in generation of more ROS. Keywords: Sex differences, Cyp450, ROS, Cell death, Methylatio

Transposon mutagenesis in Mycobacterium kansasii links a small RNA gene to colony morphology and biofilm formation and identifies 9,885 intragenic insertions that do not compromise colony outgrowth

Mycobacterium kansasii (Mk) is a resilient opportunistic human pathogen that causes tuberculosis-like chronic pulmonary disease and mortality stemming from comorbidities and treatment failure. The standard treatment of Mk infections requires costly, long-term, multidrug courses with adverse side effects. The emergence of drug-resistant isolates further complicates the already challenging drug therapy regimens and threatens to compromise the future control of Mk infections. Despite the increasingly recognized global burden of Mk infections, the biology of this opportunistic pathogen remains essentially unexplored. In particular, studies reporting gene function or generation of defined mutants are scarce. Moreover, no transposon (Tn) mutagenesis tool has been validated for use in Mk, a situation limiting the repertoire of genetic approaches available to accelerate the dissection of gene function and the generation of gene knockout mutants in this poorly characterized pathogen. In this study, we validated the functionality of a powerful Tn mutagenesis tool in Mk and used this tool in conjunction with a forward genetic screen to establish a previously unrecognized role of a conserved mycobacterial small RNA gene of unknown function in colony morphology features and biofilm formation. We also combined Tn mutagenesis with next-generation sequencing to identify 12,071 Tn insertions that do not compromise viability in vitro. Finally, we demonstrated the susceptibility of the Galleria mellonella larva to Mk, setting the stage for further exploration of this simple and economical infection model system to the study of this pathogen

Detection of Intra-Tumor Self Antigen Recognition during Melanoma Tumor Progression in Mice Using Advanced Multimode Confocal/Two Photon Microscope

Determining how tumor immunity is regulated requires understanding the extent to which the anti-tumor immune response “functions” in vivo without therapeutic intervention. To better understand this question, we developed advanced multimodal reflectance confocal/two photon fluorescence intra-vital imaging techniques to use in combination with traditional ex vivo analysis of tumor specific T cells. By transferring small numbers of melanoma-specific CD8+ T cells (Pmel-1), in an attempt to mimic physiologic conditions, we found that B16 tumor growth alone was sufficient to induce naive Pmel-1 T cell proliferation and acquisition of effector phenotype. Tumor -primed Pmel-1 T cells, are capable of killing target cells in the periphery and secrete IFNγ, but are unable to mediate tumor regression. Within the tumor, Pmel-1 T cells have highly confined mobility, displaying long term interactions with tumor cells. In contrast, adoptively transferred non tumor-specific OT-I T cells show neither confined mobility, nor long term interaction with B16 tumor cells, suggesting that intra-tumor recognition of cognate self antigen by Pmel-1 T cells occurs during tumor growth. Together, these data indicate that lack of anti-tumor efficacy is not solely due to ignorance of self antigen in the tumor microenvironment but rather to active immunosuppressive influences preventing a protective immune response

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Adaptations cinématographiques d'Alice au pays des merveilles et de De l’autre côté du miroir de Lewis Carroll

Adaptations cinématographiques d’Alice au pays des merveilles et De l’autre côté du miroir de Lewis Carroll: Analyse des transécritures de Walt Disney, Jan Švankmajer et Tim Burton observe comment trois versions cinématographiques différentes, provenant d’un même texte source, peuvent être singulières les unes par rapport aux autres. Le but de ce mémoire est d’analyser les transécritures de Walt Disney (1951), de Jan Švankmajer (1989) et de Tim Burton (2010) autant dans les changements narratifs que dans les ajouts faits par les réalisateurs qui personnalisent l’adaptation. Pour ce faire, nous nous appuierons sur la notion d’idée de Deleuze. Chacune des analyses est divisée selon: les idées de roman et de cinéma qui se « rencontrent », les ajouts et modifications des idées de roman, ainsi que les idées ayant été rejetés par l’adaptateur-cinéaste.Adaptations cinématographiques d’Alice au pays des merveilles et De l’autre côté du miroir de Lewis Carroll: Analyse des transécritures de Walt Disney, Jan Švankmajer et Tim Burton observes how three different cinematographical versions, of the same source text, are singular from one another. The goal of this essay is to analyze the adaptations of Walt Disney (1951), Jan Švankmajer (1989) and Tim Burton (2010) from the narrative choices to what directors added in order to personalize the adaptation. To do so, we rely on Deleuze’s notion of ideas. Every analyze is being divided by: the meeting of the novel’s ideas and the film’s ideas, by ideas that have been added or modified, and by ideas that were eliminated by the adaptor-filmmaker

Generation of \u3ci\u3eMycobacterium smegmatis\u3c/i\u3e Model Systems for Testing Inhibitors of the Mycobactin Siderophore of \u3ci\u3eMycobacterium tuberculosis\u3c/i\u3e

Mycobacterium tuberculosis (Mtb) is the pathogenic bacterium causative of tuberculosis. According to the 2021 World Health Organization (WHO) Global Tuberculosis (TB) Report, there were approximately 5.8 million TB cases in 2020, and 1.3 million TB deaths among HIV negative people in that year. The rise of multi-drug resistant Mtb strains has increased the need for more potent microbials against this pathogen. Biosynthesis of iron scavenging molecules, known as siderophores (e.g., mycobactin and carboxymycobactin), has been identified as a potential drug target candidate since iron acquisition has been directly linked to the survival and virulence of Mtb. Salicyl-AMS (Sal-AMS) is an antibiotic that targets the enzyme MbtA, responsible for initiating mycobactin/carboxymycobactin scaffold biosynthesis. This antibiotic has been found to inhibit the growth of Mtb in iron-limiting conditions by inhibiting MbtA’s ability to catalyze the first reaction in the biosynthetic pathway of mycobactin. Using a M. smegmatis (Msm) model system, we aimed to further investigate the mycobacterial susceptibility to Sal-AMS and analogues in iron-limiting conditions. Considering Msm produces an additional siderophore type (exochelin), our Msm model were engineered to lack the ability to produce exochelin, depending solely on the mycobactins/carboxymycobactins for iron acquisition under iron-limiting conditions, mirroring Mtb. Further generation of a siderophore deficient strain of Msm allowed for examination of mycobactin/carboxymycobactin dependent growth in iron-limiting medium and susceptibility to MbtA inhibitors. It also served as a host strain for expression of the potentially clinically relevant target, MbtA from Mtb (MbtAtb) and the generation of strains expressing MbtAtb with mutations hypothesized to result in resistance to specific Sal-AMS analogues. Lastly, our Msm model strain allowed for further exploration of the relationship between production of salicylic acid (SA) (which is the acyl substrate of MbtA) and Sal-AMS susceptibility via the generation of Msm mbtIsm deletion strains deficient in SA production necessary to produce mycobactin/carboxymycobactin. Overall, due to its fast-doubling time in liquid culture and non-pathogenicity, our findings demonstrate the usefulness of a Msm model system for exploring inhibition of not only MbtA by Sal-AMS and analogues, but for the examination of other mycobactin/carboxymycobactin inhibitors such as MbtI inhibitors

<i>Mycobacterium abscessus</i> Mutants with a Compromised Functional Link between the Type VII ESX-3 System and an Iron Uptake Mechanism Reliant on an Unusual Mycobactin Siderophore

The opportunistic pathogen Mycobacterium abscessus subsp. abscessus (Mab) has become an emerging public health threat due to the increasing number of Mab-associated chronic pulmonary disease cases. Treatment requires multiple drug courses and is often combined with surgical resection. Cure rates are only ~50% due to treatment failure and comorbidities. Deeper understanding of the biology of Mab is required to illuminate potential avenues for the development of better therapeutics against Mab infections. The ESX-3 type VII protein secretion system of Mab has an important role in host inflammatory and pathological responses during infection. In this work, we demonstrate a functional link between ESX-3 and an iron uptake system based on an unusual mycobactin-type siderophore (designated MBT Ab) and exploit this link to implement a large screen for transposon mutants with an impaired ESX-3. Most mutants we identified carry insertions in genes encoding predicted ESX-3 secretion machinery components or potential ESX-3 substrates. The mutants overproduce MBT Ab, a trait consistent with an iron uptake defect. Our characterization of MBT Ab revealed structural features reminiscent of nocardial mycobactin-like compounds with cytotoxicity. This finding raises the possibility that MBT Ab may play roles in pathogenesis unlinked to iron homeostasis. The mutants generated herein will facilitate research to better understand the role of ESX-3 and its interplay with the siderophore system

KIF20A mRNA and Its Product MKlp2 Are Increased During Hepatocyte Proliferation and Hepatocarcinogenesis

International audienceMitotic kinesin-like protein 2 (MKlp2), a microtubule-associated motor, is required during mitosis exit for the final step of cytokine;is. It also contributes to retrograde vesicular trafficking from the Golgi apparatus to the endoplasmic reticulum in interphase. The KIF20A gene encoding MKlp2 is controlled by the E2F-retinoblastoma protein-p16 pathway, and its widely expressed mRNA is found in fetal and proliferating adult tissues. The expression pattern and function of MKlp2 in the adult liver, however, have not been investigated. We report herein that MKlp2 transiently accumulates in vivo during mouse liver regeneration after partial hepatectomy and is strongly overexpressed in preneoplastic and neoplastic mouse liver. In vitro in mitogen-stimulated primary hepatocytes, MKlp2 accumulated in the nucleus during the G2 phase of the cell cycle coincident with the mitotic kinase Aurora B. Human hepatoma cell lines exhibited high levels of MKlp2; however, it was undetectable in normal human hepatocytes. RNAi-mediated MKlp2 knockdown in hepatoma cells induced polyploidization consistent with its essential function in promoting cytokinesis and inhibited cell proliferation without inducing apoptosis. KIF20A mRNA was strongly accumulated in a large series of human hepatocellular carcinomas, with the highest expression observed in tumors with genomic instability. Accumulation of MKlp2 in normal proliferating, preneoplastic, and transformed hepatocytes suggests that MKlp2 contributes to both normal and pathologic hepatocyte proliferation and is linked to tumor aggressiveness in human hepatocellular carcinomas