Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings

Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure

Prise en charge des syndromes myélodysplasiques en 2019 : mise au point

International audienceMyelodysplastic syndromes are a heterogeneous group of clonal myeloid disorders characterized by peripheral cytopenias and an increased risk of progression to acute myeloid leukemia. Inflammatory, auto-immune or syndromic symptoms can make the diagnosis difficult. Diagnosis is currently based on bone marrow cytology but cytogenetics and molecular features are currently overpassing their initial prognostic function (allowing early diagnosis and prediction of therapeutic response). The prognostic classification is based on the Revised International Prognostic Scoring System, which also provides guidance for therapeutic management. The treatment of low-risk myelodysplastic syndromes is based on the correction of cytopenias (erythropoiesis stimulating agents, transfusions, lenalidomide, etc.), whereas in high-risk group, the goal is the control of the leukemic clone (hypomethylating agents, allograft of hematopoietic stem cell transplantation). Other molecules are used to manage complications of cytopenias or transfusion (anti-infectious prophylaxis and treatments, martial chelation). New molecules are being studied with some interesting results (luspatercept, venetoclax). This article aims to provide an update on the knowledge that an internist should know for the practical management of myelodysplastic syndromes in 2019

Toxicités immunologiques induites par les inhibiteurs de checkpoint en 2019 : mise au point

International audienceUse of checkpoint inhibitors to treat cancer was one of the most important revolution these last years and an increasing number of new types of tumors is currently under investigation with these new treatments. However, immune-related adverse events associated with these agents frequently affect various organs, mimicking auto-immune or inflammatory diseases. Some of these effects can be severe, often requiring hospitalization and specialized treatment (immunosuppression). Most known agents are ipilimumab (anti-CTLA-4 antibody) nivolumab and pembrolizumab (anti-PD-1 antibodies). New molecules are now approved or in development as anti-PD-L1 antibodies, anti-LAG-3 or anti-TIM-3 antibodies, increasing the probability and new description of immune-related adverse events. With his experience in auto-immune diseases, the immunologist/internal medicine specialist has an important role in the management of these toxicities. The goal of this review is to focus on the incidence, diagnostic assessment and recommended management of the most relevant immune-related adverse events.Les inhibiteurs de points de contrôle immunitaire ont révolutionné la prise en charge thérapeutique de nombreux cancers permettant des gains de survie globale jamais atteints auparavant. Leur champ de prescription ne cesse de croître. Malgré leur efficacité, ces traitements sont responsables d’effets indésirables immunologiques touchant l’ensemble des organes et mimant des pathologies auto-immunes et inflammatoires connues. Non seulement ces manifestations peuvent être sévères, menacer le pronostic vital et nécessiter une prise en charge spécialisée rapide mais en plus la chronologie de leur apparition est très variable d’un cas à l’autre et leur symptomatologie initiale est souvent fruste et trompeuse. Elles peuvent également remettre en question la reprise du traitement anti-cancéreux en raison du risque de récidives. Les molécules les plus connues ciblent CTLA-4, PD-1 ou PD-L1 et les indications de ces traitements se multiplient (nouvelles tumeurs, administration adjuvante aux stades précoces, combinaisons). De plus, de nouvelles molécules sont en développement ciblant d’autres antigènes d’intérêt (LAG-3, TIM-3…). Il faut donc s’attendre à une incidence accrue d’effets indésirables immunologiques et à l’apparition de nouvelles manifestations. Le pleiotropisme des manifestations indésirables associées aux inhibiteurs de checkpoint immunitaire place l’interniste et son approche médicale transversale au poste de régulation du nécessaire réseau multidisciplinaire organisé autour de ces molécules. Cet article a pour but de faire une mise au point sur les connaissances utiles à la prise en charge des patients exposés à des toxicités immunologiques liées aux inhibiteurs de point de contrôle immunitaire