Perspectives in Molecular Imaging Using Staging Biomarkers and Immunotherapies in Alzheimer’s Disease

Sporadic Alzheimer’s disease (AD) is an emerging chronic illness characterized by a progressive pleiotropic pathophysiological mode of actions triggered during the senescence process and affecting the elderly worldwide. The complex molecular mechanisms of AD not only are supported by cholinergic, beta-amyloid, and tau theories but also have a genetic basis that accounts for the difference in symptomatology processes activation among human population which will evolve into divergent neuropathological features underlying cognitive and behaviour alterations. Distinct immune system tolerance could also influence divergent responses among AD patients treated by immunotherapy. The complexity in nature increases when taken together the genetic/immune tolerance with the patient’s brain reserve and with neuropathological evolution from early till advance AD clinical stages. The most promising diagnostic strategies in today’s world would consist in performing high diagnostic accuracy of combined modality imaging technologies using beta-amyloid 42 peptide-cerebrospinal fluid (CSF) positron emission tomography (PET), Pittsburgh compound B-PET, fluorodeoxyglucose-PET, total and phosphorylated tau-CSF, and volumetric magnetic resonance imaging hippocampus biomarkers for criteria evaluation and validation. Early diagnosis is the challenge task that needs to look first at plausible mechanisms of actions behind therapies, and combining them would allow for the development of efficient AD treatment in a near future

Drogues, sexe et risques dans la communauté gaie montréalaise : 1997-2003

Cet article décrit l’évolution de la consommation de drogues entre 1997 et 2003 chez des hommes gais et bisexuels séronégatifs de la grande région montréalaise, selon l’âge et selon les comportements sexuels à risque pour le VIH. Les données proviennent d’Oméga, une étude longitudinale sur l’incidence et les déterminants psychosociaux de l’infection au VIH chez ces hommes. Les participants ont rempli un questionnaire tous les six mois, et les données sont celles de leur première visite de suivi. Des analyses de tendance par période de calendrier ont été réalisées et un modèle de régression logistique utilisant une estimation par équations généralisées a été généré pour chaque type de drogues. Les résultats révèlent une augmentation de la consommation de cocaïne, de l’ecstasy, des hallucinogènes, du speed et du GHB entre 1997 et 2003. En revanche, la consommation de marijuana, de poppers et d’héroïne ne semble pas avoir changé de façon significative. Les moins de 30 ans et ceux qui ont eu des relations anales à risque semblent avoir été plus enclins à consommer certaines drogues pendant cette même période. Indices de transformations possibles dans les modes de vie de ces hommes, ces résultats soulèvent de nouveaux défis pour la prévention du VIH dans la communauté gaie.This article describes the evolution of drug use between 1997 and 2003 in HIV-negative men who have sex with men living in the Montreal region, according to age and HIV risk-taking behaviours. Data come from Omega, a longitudinal study on the incidence and on the psychosocial determinants of HIV infection among these men. Participants completed a questionnaire every six months and data are from the first follow-up visit. Trends analyses by calendar period were done and a logistic regression model using generalised equations for parameter estimation was generated for each type of drug. Results reveal an increase in cocaine, ecstasy, hallucinogen, speed and GHB use between 1997 and 2003. On the other hand, marijuana, poppers and heroin use do not seem to have change significantly. Men who are younger than 30 years old and who had risky anal intercourse seem to be more likely to have used specific drugs in the same period. This indicates possible transformations in the way of life of these men and these results suggest new challenges for HIV prevention in the gay community.Este artículo describe la evolución del consumo de drogas entre 1997 y 2003 entre los hombres gay y bisexuales seronegativos de la gran región montrealesa, según la edad y los comportamientos sexuales de riesgo con respecto al VIH. Los datos provienen de Oméga, un estudio longitudinal sobre la incidencia y los determinantes psicosociales de la infección de VIH en los hombres. Los participantes respondieron un cuestionario cada seis meses y los datos son los de su primera visita de seguimiento. Se realizaron análisis de tendencia por período de calendario y se generó un modelo de regresión logística, utilizando una estimación por ecuaciones generalizadas para cada tipo de droga. Los resultados revelan un aumento del consumo de cocaína, éxtasis, alucinógenos, speed y GHB entre 1997 y 2003. Por el contrario, el consumo de marihuana, poppers y heroína no parece haber cambiado de manera significativa. Los menores de 30 años y quienes tienen relaciones sexuales anales a riesgo parecen haber tenido una mayor tendencia a consumir ciertas drogas durante este mismo período. Estos resultados, índices de transformaciones posibles en los modos de vida de estos hombres, plantean nuevos desafíos en la prevención del VIH en la comunidad gay

Targeting the AMPK pathway for the treatment of Type 2 diabetes.

International audienceType 2 diabetes is one of the fastest growing public health problems worldwide, resulting from both genetic factors and inadequate adaptation to environmental changes. It is characterized by abnormal glucose and lipid metabolism due in part to resistance to the actions of insulin in skeletal muscle, liver and fat. AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, acts as an integrator of regulatory signals monitoring systemic and cellular energy status. The growing realization that AMPK regulates the coordination of anabolic and catabolic metabolic processes represents an attractive concept for type 2 diabetes therapy. Recent findings showing that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile and blood pressure in insulin-resistant rodents suggest that this kinase could be a novel therapeutic target in the treatment of type 2 diabetes. Consistent with these results, physical exercise and major classes of antidiabetic drugs have recently been reported to activate AMPK. In the present review, we update these topics and discuss the concept of targeting the AMPK pathway for the treatment of type 2 diabetes

Divergent CD4+ T-cell profiles are associated with anti-HLA alloimmunization status in platelet-transfused AML patients

IntroductionAcute myeloid leukemia (AML) is one of the commonest hematologic disorders. Due to the high frequency of disease- or treatment-related thrombocytopenia, AML requires treatment with multiple platelet transfusions, which can trigger a humoral response directed against platelets. Some, but not all, AML patients develop an anti-HLA immune response after multiple transfusions. We therefore hypothesized that different immune activation profiles might be associated with anti-HLA alloimmunization status.MethodsWe tested this hypothesis, by analyzing CD4+ T lymphocyte (TL) subsets and their immune control molecules in flow cytometry and single-cell multi-omics.ResultsA comparison of immunological status between anti-HLA alloimmunized and non-alloimmunized AML patients identified differences in the phenotype and function of CD4+ TLs. CD4+ TLs from alloimmunized patients displayed features of immune activation, with higher levels of CD40 and OX40 than the cells of healthy donors. However, the most notable differences were observed in non-alloimmunized patients. These patients had lower levels of CD40 and OX40 than alloimmunized patients and higher levels of PD1. Moreover, the Treg compartment of non-alloimmunized patients was larger and more functional than that in alloimmunized patients. These results were supported by a multi-omics analysis of immune response molecules in conventional CD4+ TLs, Tfh circulating cells, and Tregs.DiscussionOur results thus reveal divergent CD4+ TL characteristics correlated with anti-HLA alloimmunization status in transfused AML patients. These differences, characterizing CD4+ TLs independently of any specific antigen, should be taken into account when considering the immune responses of patients to infections, vaccinations, or transplantations

SRH and HrQOL: does social position impact differently on their link with health status?

<p>Abstract</p> <p>Background</p> <p>Self-rated Health (SRH) and health-related quality of life (HRQoL) are used to evaluate health disparities. Like all subjective measures of health, they are dependent on health expectations that are associated with socioeconomic characteristics. It is thus needed to analyse the influence played by socioeconomic position (SEP) on the relationship between these two indicators and health conditions if we aim to use them to study health disparities. Our objective is to assess the influence of SEP on the relationship between physical health status and subjective health status, measured by SRH and HRQoL using the SF-36 scale.</p> <p>Methods</p> <p>We used data from the French National Health Survey. SEP was assessed by years of education and household annual income. Physical health status was measured by functional limitations and chronic low back pain.</p> <p>Results</p> <p>Regardless of their health status, people with lower SEP were more likely than their more socially advantaged counterparts to report poor SRH and poorer HRQoL, using any of the indicators of SEP. The negative impact of chronic low back pain on SRH was relatively greater in people with a high SEP than in those with a low SEP. In contrast, chronic low back pain and functional limitations had less impact on physical and mental component scores of quality of life for socially advantaged men and women.</p> <p>Conclusions</p> <p>Both SRH and HRQoL were lower among those reporting functional limitations or chronic low back pain. However, the change varied according SEP and the measure. In relative term, the negative impact of a given health condition seems to be greater on SRH and lower on HRQoL for people with higher SEP in comparison with people with low SEP. Using SRH could thus decrease socioeconomic differences. In contrast using HRQoL could increase these differences, suggesting being cautious when using these indicators for analyzing health disparities.</p

G protein-coupled receptors: what a difference a 'partner' makes

G protein-coupled receptors (GPCRs) are important cell signaling mediators, involved in essential physiological processes. GPCRs respond to a wide variety of ligands from light to large macromolecules, including hormones and small peptides. Unfortunately, mutations and dysregulation of GPCRs that induce a loss of function or alter expression can lead to disorders that are sometimes lethal. Therefore, the expression, trafficking, signaling and desensitization of GPCRs must be tightly regulated by different cellular systems to prevent disease. Although there is substantial knowledge regarding the mechanisms that regulate the desensitization and down-regulation of GPCRs, less is known about the mechanisms that regulate the trafficking and cell-surface expression of newly synthesized GPCRs. More recently, there is accumulating evidence that suggests certain GPCRs are able to interact with specific proteins that can completely change their fate and function. These interactions add on another level of regulation and flexibility between different tissue/cell-types. Here, we review some of the main interacting proteins of GPCRs. A greater understanding of the mechanisms regulating their interactions may lead to the discovery of new drug targets for therapy

Crowdsourcing hypothesis tests: Making transparent how design choices shape research results

To what extent are research results influenced by subjective decisions that scientists make as they design studies? Fifteen research teams independently designed studies to answer fiveoriginal research questions related to moral judgments, negotiations, and implicit cognition. Participants from two separate large samples (total N > 15,000) were then randomly assigned to complete one version of each study. Effect sizes varied dramatically across different sets of materials designed to test the same hypothesis: materials from different teams renderedstatistically significant effects in opposite directions for four out of five hypotheses, with the narrowest range in estimates being d = -0.37 to +0.26. Meta-analysis and a Bayesian perspective on the results revealed overall support for two hypotheses, and a lack of support for three hypotheses. Overall, practically none of the variability in effect sizes was attributable to the skill of the research team in designing materials, while considerable variability was attributable to the hypothesis being tested. In a forecasting survey, predictions of other scientists were significantly correlated with study results, both across and within hypotheses. Crowdsourced testing of research hypotheses helps reveal the true consistency of empirical support for a scientific claim.</div

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Évaluation de la capacité adhésive des isolats d'Escherichia coli associés à la cellulite aviaire

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

Chapitre 10. Le mode opératoire des adolescents abuseurs sexuels d’enfants, l’événement criminel et la prévention situationnelle en criminologie

Dans ce chapitre, nous désirons mettre en valeur l’approche de la prévention situationnelle en criminologie afin de mieux comprendre et prévenir les abus sexuels d’enfants commis par des adolescents. Tout d’abord, nous présentons les principaux résultats des études portant sur le mode opératoire des adolescents abuseurs sexuels d’enfants. Ensuite, nous décrivons brièvement l’approche de la prévention situationnelle. Enfin, à partir de la classification de mesures de prévention situationnelle ..