Accès à la thrombolyse lors d'AVC: rôle des secours préhospitaliers et des médecins de premier recours [Access to thrombolysis in stroke: place of the rescue system and of the primary care physician].

Thrombolysis is the most effective treatment improving the outcome of patients suffering from acute stroke. Moreover, its effectiveness increases when administrated as quick as possible after the onset of the first symptoms. Prehospital selection of patients and their immediate transfer to stroke center are the principal factors allowing the practice of thrombolysis within the authorized time frame. On the basis of regional Swiss French data, it seems that patients evaluated by emergency physician and their direct transfer in an acute stroke unit reduces delays and allows for a higher thrombolysis rate.

Effective continuing professional development for translating shared decision making in primary care: A study protocol.

Background: Shared decision making (SDM) is a process by which a healthcare choice is made jointly by the healthcare professional and the patient. SDM is the essential element of patient-centered care, a core concept of primary care. However, SDM is seldom translated into primary practice. Continuing professional development (CPD) is the principal means by which healthcare professionals continue to gain, improve, and broaden the knowledge and skills required for patient-centered care. Our international collaboration seeks to improve the knowledge base of CPD that targets translating SDM into the clinical practice of primary care in diverse healthcare systems. Methods: Funded by the Canadian Institutes of Health Research (CIHR), our project is to form an international, interdisciplinary research team composed of health services researchers, physicians, nurses, psychologists, dietitians, CPD decision makers and others who will study how CPD causes SDM to be practiced in primary care. We will perform an environmental scan to create an inventory of CPD programs and related activities for translating SDM into clinical practice. These programs will be critically assessed and compared according to their strengths and limitations. We will use the empirical data that results from the environmental scan and the critical appraisal to identify knowledge gaps and generate a research agenda during a two-day workshop to be held in Quebec City. We will ask CPD stakeholders to validate these knowledge gaps and the research agenda. Discussion: This project will analyse existing CPD programs and related activities for translating SDM into the practice of primary care. Because this international collaboration will develop and identify various factors influencing SDM, the project could shed new light on how SDM is implemented in primary care.

Prediction of myocardial infarction size using the SYNTAX score in patients treated with primary percutaneous coronary intervention for acute ST- segment elevation myocardial infarction

Objectives The relevance of the SYNTAX score for the particular case of patients with acute ST- segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI)  has previously only been studied in the setting of post hoc analysis of large prospective randomized clinical trials. A "real-life" population approach has never been explored before. The aim of this study was to evaluate the impact of the SYNTAX score for the prediction of the myocardial infarction size, estimated by the creatin-kinase (CK) peak value, using the SYNTAX score in patients treated with primary coronary intervention for acute ST-segment elevation myocardial infarction. Methods The primary endpoint of the study was myocardial infarction size as measured by the CK peak value. The SYNTAX score was calculated retrospectively in 253 consecutive patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) in a large tertiary referral center in Switzerland, between January 2009 and June 2010. Linear regression analysis was performed to compare myocardial infarction size with the SYNTAX score. This same endpoint was then stratified according to SYNTAX score tertiles: low <22 (n=178), intermediate [22-32] (n=60), and high >=33 (n=15). Results There were no significant differences in terms of clinical characteristics between the three groups. When stratified according to the SYNTAX score tertiles, average CK peak values of 1985 (low<22), 3336 (intermediate [22-32]) and 3684 (high>=33) were obtained with a p-value <0.0001. Bartlett's test for equal variances between the three groups was 9.999 (p-value <0.0067). A moderate Pearson product-moment correlation coefficient (r=0.4074) with a high statistical significance level (p-value <0.0001) was found. The coefficient of determination (R^2=0.1660) showed that approximately 17% of the variation of CK peak value (myocardial infarction size) could be explained by the SYNTAX score, i.e. by the coronary disease complexity. Conclusion In an all-comers population, the SYNTAX score is an additional tool in predicting myocardial infarction size in patients treated with primary percutaneous coronary intervention (PPCI). The stratification of patients in different risk groups according to SYNTAX enables to identify a high-risk population that may warrant particular patient care.

A CRTC1 deficient mouse line study : relevance to mood disorders

Summary Mood disorders are among the most prevalent, psychosocial^ debilitating, chronic and relapsing forms of psychiatric illnesses. Despite considerable advances in their characterization, the heterogeneous nature of susceptibility factors and patient's symptoms could account for the lack of totally effective and remissive treatment. The neurobiological hypothesis of mood disorders etiology has evolved since the monoamine and neurotrophin theories and current evidence is pointing toward their integration in a broader polygenic epistatic model resulting in defective neuroplasticity of circuitries involved in emotion processing. Consequently, the unraveling of molecular underpinning pathways involved in neuronal plasticity, commonly altered among mood disorder syndromes and symptoms, should shed light on their etiology and provide new drug target. The transcription factor CREB has been critically involved in the long-lasting forms of neuronal plasticity and in the regulation of several mood disorders susceptibility genes. In addition, altered CREB activity has been associated with mood disorders pathophysiology and pharmacotherapy. Interestingly, the newly-identified protein CREB-regulated transcription coactivator 1 (CRTC1) was shown by previous studies in the laboratory to be a neuroactivity- dependent cAMP and calcium sensor, a potent activator of CREB-dependent transcription and involved in neuroplasticity mechanisms associated with long-term synaptic potentiation. Furthermore, the major mood disorder susceptibility gene Bdnf was suggested to be transcriptional regulated by CRTC1. Therefore, we aimed to investigate a role for CRTC1 in mood disorders by generating and characterizing a Crtcl deficient mouse model at the behavioral and molecular levels. Interestingly, their comprehensive characterization revealed a behavioral profile mirroring several major symptoms comorbid in mood disorders, including altered social interactions, aggressive behaviors, obesity, psychomotor retardation, increased emotional response to stress, decreased sexual drive and depression-like behaviors. To investigate the molecular mechanisms underlying these pathological behaviors and the implication of CRTC1 in the regulation of CREB-regulated genes in vivo, we also quantified transcript levels of several relevant CREB-regulated susceptibility genes in brain structures involved in the pathophysiology of mood disorders. Strikingly, we found the underexpression of primary components of the neurotrophin system: Bdnf and its cognate receptor TrkB, a marked decrease in the Nr4a family of transcription factors, implicated in neuroplasticity and associated with dopamine-related disorders, as well as in several other relevant CREB regulated genes. Moreover, neurochemical analysis revealed that Crtcl null mice presented alteration in prefrontal cortical monoamine turnover as well as in hippocampal and accumbal serotonin levels, similarly associated with mood disorders etiology and pharmacotherapy. Together, the present thesis supports the involvement of CRTC1 pathway hypofunction in the pathogenesis of mood disorders and specifically in pathological aggression, obesity and depression-related behavior comorbidities. Ultimately, CRTC1 may represent an interesting antidepressant, antiaggressive or mood stabilizer drug target candidate through the modulation of major CREB regulated susceptibility genes. Les troubles de l'humeur comptent parmi les maladies psychiatriques les plus prévalentes, psychosocialement débilitantes, chroniques et avec le plus grand risque de rechute. Malgré de considérable avancées dans leur caractérisation, la nature hétérogène des facteurs de susceptibilité et des symptômes présentés par les patients, semble justifier l'absence de traitement entraînant une rémission complète de la maladie. L'hypothèse de l'étiologie neurobiologique des troubles de l'humeur a évolué depuis la théorie des monoamines et des neurotrophines. Actuellement, elle tend à les englober dans un modèle polygénique épistatique induisant une déficience de la neuroplasticité des circuits impliqué dans la régulation des émotions. Par conséquent, il apparaît particulièrement relevant de caractériser des voies moléculaires impliquées dans la plasticité neuronale, communément altérées parmi les différents syndromes et symptômes des maladies de l'humeur, afin d'améliorer leur compréhension ainsi que de proposer de nouvelles cibles thérapeutiques potentielles. Le facteur de transcription CREB a été de façon répétée et cohérente impliqué dans les mécanismes à long terme de la plasticité neuronale, ainsi que dans la régulation de plusieurs gènes de susceptibilité aux maladies de l'humeur. De plus, une altération dans l'activité de CREB a été impliqué dans leur étiologie et pharmacothérapie. De façon intéressante, des résultats préliminaires sur la protéine récemment découverte CREB-regulated transcription coactivator 1 (CRTC1) ont indiqué que son activation était dépendante de l'activité neuronale, qu'il était un senseur du calcium et de l'AMPc, ainsi qu'un coactivateur de CREB requis et puissant impliqué dans les mécanismes de plasticité neuronale associés à la potentialisation à long terme. En outre, des résultats ont suggéré que le gène majeur de susceptibilité Bdnf est régulé par CRTC1. Ainsi, notre objectif a été d'investiguer un rôle éventuel de CRTC1 dans les maladies de l'humeur en générant et caractérisant une lignée de souris déficiente pour Crtcl, tant au niveau comportemental que moléculaire. De façon intéressante, leur caractérisation détaillée a révélé un profil comportemental reflétant de nombreux aspects des maladies de l'humeur incluant une altération des interactions sociales, une agression pathologique, l'obésité, un retard psychomoteur, une réponse émotionnelle au stress accrue, une diminution de la motivation sexuelle, et des comportements reliés à la dépression. Afin d'investiguer les mécanismes moléculaires sous- jacents cette altération du comportement, ainsi que l'implication de CRTC1 dans l'expression des gènes régulés par CREB in vivo, nous avons quantifié les niveaux de transcrits de plusieurs gènes de susceptibilité régulés par CREB et impliqués dans la physiopathologie des maladies de l'humeur. Remarquablement, nous avons trouvé la sous-expression de composants primordiaux du système neurotrophique: Bdnf et son récepteur TrkB, une diminution majeure de la famille des facteurs de transcription Nr4a, impliqués dans la neuroplasticité et associés à des désordres liés à la dopamine, ainsi que de nombreux autres gènes relevants régulés par CREB. De plus, une analyse neurochimique a révélé que les souris déficientes pour Crtcî présentent une altération du turn-over des monoamines du cortex préfrontal ainsi que des niveaux hippocampaux et accumbaux de sérotonine, associés de façon similaire dans l'étiologie et la pharmacothérapie des maladies de l'humeur. Vue dans son ensemble, la présente thèse supporte l'implication d'une sous-régulation de la voie de CRTCI dans la pathogenèse des maladies de l'humeur ainsi que dans la comorbidité de l'agression pathologique, l'obésité et la dépression. En conclusion, CRTCI pourrait représenter une cible médicamenteuse intéressante aux propriétés antidépressante, antiagressive ou stabilisatrice de l'humeur au travers de la modulation de gènes de susceptibilité majeurs régulés par CREB.

The chemokine receptor CXCR4 strongly promotes neuroblastoma primary tumour and metastatic growth, but not invasion.

Neuroblastoma (NB) is a heterogeneous, and particularly malignant childhood neoplasm in its higher stages, with a propensity to form metastasis in selected organs, in particular liver and bone marrow, and for which there is still no efficient treatment available beyond surgery. Recent evidence indicates that the CXCR4/CXCL12 chemokine/receptor axis may be involved in promoting NB invasion and metastasis. In this study, we explored the potential role of CXCR4 in the malignant behaviour of NB, using a combination of in vitro functional analyses and in vivo growth and metastasis assessment in an orthotopic NB mouse model. We show here that CXCR4 overexpression in non-metastatic CXCR4-negative NB cells IGR-NB8 and in moderately metastatic, CXCR4 expressing NB cells IGR-N91, strongly increased tumour growth of primary tumours and liver metastases, without altering the frequency or the pattern of metastasis. Moreover shRNA-mediated knock-down experiments confirmed our observations by showing that silencing CXCR4 in NB cells impairs in vitro and almost abrogates in vivo growth. High levels of CXCL12 were detected in the mouse adrenal gland (the primary tumour site), and in the liver suggesting a paracrine effect of host-derived CXCL12 on NB growth. In conclusion, this study reveals a yet unreported NB-specific predominant growth and survival-promoting role of CXCR4, which warrants a critical reconsideration of the role of CXCR4 in the malignant behaviour of NB and other cancers.

Clinical characteristics and outcome of isolated extracerebral relapses of primary central nervous system lymphoma: a case series.

There is very limited data on isolated systemic relapses of primary central nervous system lymphomas (PCNSL). We retrospectively reviewed the clinical characteristics and outcome of 10 patients with isolated systemic disease among 209 patients with PCNSL mainly treated with methotrexate-based chemotherapy (CT) with or without radiation therapy (RT). Isolated systemic relapse remained rare (4.8%, 10/209 patients). Median time from initial diagnosis to relapse was 33 months (range, 3-94). Sites of relapse were mostly extranodal. Three patients presented with early extra-cerebral (EC) relapse 3, 5 and 8 months from the beginning of initial treatment, respectively, and 7 patients had later relapses (range, 17-94 months). Treatment at relapse included surgery alone, RT alone, CT with or without radiotherapy, or CT with autologous stem cell transplantation (ASCT). Median overall survival (OS) after relapse was 15.5 months (range, 5.8-24.5) compared to 4.6 months (range, 3.6-6.5) for patients with central nervous system (CNS) relapse (p = 0.35). In conclusion, isolated systemic relapses exist but are infrequent. Early EC relapse suggests the presence of systemic disease undetectable by conventional evaluation at initial diagnosis. Patient follow-up must be prolonged because systemic relapse can occur as late as 10 years after initial diagnosis. Whether EC relapses of PCNSL have a better prognosis than CNS relapses needs to be assessed in a larger cohort. Copyright © 2010 John Wiley & Sons, Ltd.

Early Stage Primary Bone Lymphoma: A Retrospective, Multicenter Rare Cancer Network Study

Purpose/Objective(s): Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas, and 4-5% of all extranodal lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with stage I and II PBL.Materials/Methods: Between 1987 and 2008, 116 consecutive patients with PBL treated in 13 RCNinstitutions were included in this study. Inclusion criteriawere: age.17 yrs, PBLin stage I and II, andminimum6months follow-up. The median agewas 51 yrs (range: 17-93).Diagnosticwork-up included plain boneXray (74%of patients), scintigraphy (62%), CT-scan (65%),MRI (58%), PET (18%), and bone-marrow biopsy (84%).All patients had biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). The histopathological type was predominantly diffuse large B-cell lymphoma (78%) and follicular lymphoma (6%), according to theWHOclassification. One hundred patients had a high-grade, 7 intermediate and 9 low-gradeNHL. Ninety-three patients had anAnn-Arbor stage I, and 23 had a stage II. Seventy-seven patients underwent chemoradiotherapy (CXRT), 12 radiotherapy (RT) alone, 10 chemotherapy alone (CXT), 9 surgery followed by CXRT, 5 surgery followed by CXT, and 2 surgery followed by RT. One patient died before treatment.Median RT dosewas 40Gy (range: 4-60).Themedian number ofCXTcycleswas 6 (range, : 2-8).Median follow-upwas 41months (range: 6-242).Results: Following treatment, the overall response rate was 91% (CR 74%, PR 17%). Local recurrence was observed in 12 (10%) patients, and systemic recurrence in 17 (15%) patients. Causes of death included disease progression in 16, unrelated disease in 6, CXT-related toxicity in 1, and secondary cancer in 2 patients. The 5-yr overall survival (OS), disease-free survival (DFS), lymphoma- specific survival (LSS), and local control (LC) were 76%, 69%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for survival were: age\50 years (p = 0.008), IPI score #1 (p = 0.009), complete response (p\0.001), CXT (p = 0.008), number of CXT cycles $6 (p = 0.007), and RT dose . 40 Gy (p = 0.005). In multivariate analysis age, RT dose, complete response, and absence of B symptoms were independent factors influencing the outcome. There were 3 patients developing grade 3 or more (CTCAE.V3.0) toxicities.Conclusions: This large multicenter study, confirms the relatively good prognosis of early stage PBL, treated with combined CXRT. Local control was excellent, and systemic failure occurred infrequently. A sufficient dose of RT (. 40 Gy) and completeCXT regime (. 6 cycles) were associated with a better outcome. Combined modality appears to be the treatment of choice.Author Disclosure: L. Cai, None; M.C. Stauder, None; Y.J. Zhang, None; P. Poortmans, None; Y.X. Li, None; N. Constantinou, None; J. Thariat, None; S. Kadish, None; M. Ozsahin, None; R.O. Mirimanoff, None.

Primary cutaneous posttransplant lymphoproliferative disorders in solid organ transplant recipients: a multicenter European case series.

Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)-classified according to the WHO-EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty-seven percent of patients had a kidney transplant. Twenty-four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV-associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV-negative. Sixteen (45.7%) patients died after a median follow-up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30(+) lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30(+) LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30(+) LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV-associated cutaneous B cell LPD predominates in OTR.

Troubles emotionnels en médecine de famille ou le visage caché d'une souffrance [Mental disorders in primary care].

Mental disorders (depression, anxiety and somatization) are frequent in Primary care and are often associated to physical complaints and to psychosocial stressors. Mental disorders have in this way a specific presentation and in addition patients may present different associations of them. Sometimes it is difficult to recognize them, but it is important to do so and to take rapidly care of these patients. Specific screening questions exist and have been used in a research of the Institute of General Medicine and the Department of Ambulatory Care and Community Medicine (PMU), University of Lausanne, Switzerland.

Severe primary cytomegalovirus infection in the immunocompetent adult patient: A case series.

Abstract Primary cytomegalovirus (CMV) infection is rare in immunocompetent adults, even rarer in elderly patients. Little is known about the severity of symptoms and the clinical course in this patient group. In children and younger adults, CMV mostly presents as an asymptomatic disease or a self-limiting mild mononucleosis-like syndrome. We describe the clinical course of an unusually severe primary CMV infection in a 69-y-old otherwise healthy man, as well as 6 other severe cases in immunocompetent adults at our institution, and compare them to adult cases from the literature. CMV primary infection and antiviral treatment should be considered in immunocompetent elderly persons presenting with a severe mononucleosis-like syndrome.

Intérêt du bleu de méthylène dans la chirurgie de l'hyperparathyroïdism primaire [Methylene blue in surgery of primary hyperparathyroidism]

Is surgery for primary hyperparathyroidism easier when methylene blue (MB) is given preoperatively? This retrospective study compares the durations of interventions for primary hyperparathyroidism carried out after i.v. MB administration to those when no MB was given. Over a period of 20 years (June 1976 to December 1996), 175 consecutive patients (56 men and 119 women, with ages ranging from 16 to 92, mean 59.6) were operated upon for primary hyperparathyrodism; 55 were operated before February 1986--the period when BM was introduced routinely, and 120 after. Thirty-two other patients were excluded from the study: 14 had had a previous cervicotomy and 18 another procedure in addition to the parathyroidectomy (usually on the thyroid gland), two conditions which prolonged the time devoted to parathyroid identification and excision. Preoperative calcemia averaged 2.97 mmol/L (2.34 to 4.59) and mean preoperative PTH was equal to 2.6 times the upper normal limit (0.5 to 24.1). Both groups were similar for as age, sex, preoperative calcium and PTH, and histologies. Methylene blue was administered intravenously (5 mg/kg diluted in 500 cc of 5% glucose) over a period of time of one hour starting two hours prior to surgery. All 175 procedures were performed by two surgeons and duration of surgery was recorded from the anesthesiologist's notes. There were 149 adenomas (85%), 24 hyperplasias (14%), a combination of both in two, and unspecified in two others. Except for a case of acute lower back pain synchronous to the injection of the dye (which was immediately stopped), MB was well tolerated. Mean duration for the 55 interventions performed without MB was 68 minutes (35 to 140, median 60), compared to 49 minutes for the 120 procedures carried out after MB had been given (20 to 155, median 45). Differences in operative, times were highly significant (p < 10(-6) and represented a gain of time of 27%. Surgery for primary hyperparathyroidism was significantly shorter when it was preceded by the administration of MB, a dye which facilitates the identification of pathologic parathyroid gland(s).

Generation of the primary hair follicle pattern.

Hair follicles are spaced apart from one another at regular intervals through the skin. Although follicles are predominantly epidermal structures, classical tissue recombination experiments indicated that the underlying dermis defines their location during development. Although many molecules involved in hair follicle formation have been identified, the molecular interactions that determine the emergent property of pattern formation have remained elusive. We have used embryonic skin cultures to dissect signaling responses and patterning outcomes as the skin spatially organizes itself. We find that ectodysplasin receptor (Edar)-bone morphogenetic protein (BMP) signaling and transcriptional interactions are central to generation of the primary hair follicle pattern, with restriction of responsiveness, rather than localization of an inducing ligand, being the key driver in this process. The crux of this patterning mechanism is rapid Edar-positive feedback in the epidermis coupled with induction of dermal BMP4/7. The BMPs in turn repress epidermal Edar and hence follicle fate. Edar activation also induces connective tissue growth factor, an inhibitor of BMP signaling, allowing BMP action only at a distance from their site of synthesis. Consistent with this model, transgenic hyperactivation of Edar signaling leads to widespread overproduction of hair follicles. This Edar-BMP activation-inhibition mechanism appears to operate alongside a labile prepattern, suggesting that Edar-mediated stabilization of beta-catenin active foci is a key event in determining definitive follicle locations.

Analysis of antiviral immunity in primary and chronic infections

Several evidences in humans underscored the contribution of CD4 and CD8 T-cell responses in controlling viral and bacterial infections. However, CD4 and CD8 Τ cells have distinct and specific effector functions leading to a hierarchical importance in responding to different types of pathogens. In this context, the present work aimed to investigate distinct CD8 T-cell features potentially influencing T-cell efficacy against viral infection. To achieve this-objective, CD8 Τ cells derived from HIV-infected patients and healthy donors harbouring virus-specific immune responses or immunized with an HTV vaccine candidate were studied. In particular, we performed a comprehensive cross-sectional and longitudinal analysis to characterize the function, the phenotype and the functional avidity of HIV-specific CD8 Τ cells during acute (PHI) and chronic infection and, in particular, we investigated immunological parameters potentially associated with the functional avidity of HIV-specific CD8 Τ cells. In addition, we studied the expression pattern of co-inhibitory molecules and the influence of CD 160 on the functions of CD8 Τ cells in absence of chronic infections. From these analyses we observed that the functional avidity of HIV-specific CD8 T- cell responses was significantly lower in acute than in chronic infection, but was not different between chronic progressive and non-progressive patients. Functional avidity remained low after several years of antiretroviral therapy in PHI patients, but increased in patients experiencing a virus rebound following treatment interruption in association with a massive renewal of the global CD8 complementarity-determining region 3 of the TCR. The functional avidity was also directly associated to T-cell exhaustion. In individuals with no sign of HIV or Hepatitis A, Β or C virus infection, CD8 Τ cells expressed higher levels of co-inhibitory molecules than CD4 Τ cells and this was dependent on the stage of T-cell differentiation and activation. The expression of CD 160 impaired the proliferation capacity and IL-2 production of CD8 Τ cells and was reduced upon CD8 T-cell activation, entitling CD 160 as unique marker of CD8 T-cell exhaustion. The CD 160 blockade restored the proliferation capacity of virus-specific CD8 Τ cells providing a potential new target for immunotherapy. All together, these results expand our knowledge regarding the interplay between the immune system and the viruses. - De nombreuses études chez l'Homme ont mis en évidence la contribution des réponses cellulaires Τ CD4 et CD8 dans le contrôle des infections virales et bactériennes. En particulier, les lymphocytes Τ ont différentes fonctions effectrices spécifiques qui leur confèrent un rôle clé lors d'infections par différents pathogènes. Ce travail vise à étudier différentes caractéristiques des cellules Τ CD8 affectant l'efficacité des réponses cellulaires contre les virus. Pour atteindre cet objectif nous avons étudié les cellules Τ CD8 provenant de patients infectés par le VIH et de donneurs sains avec des réponses immunitaires naturelles ou vaccinales contre des virus. Nous avons effectué plusieurs analyses transversales et longitudinales des fonctions, du phénotype et de l'avidité fonctionnelle des lymphocytes Τ CD8 spécifiques au VIH au cours d'infections aiguës et chroniques; en particulier, nous avons étudié les paramètres immunologiques qui pourraient être associés à l'avidité fonctionnelle. De plus, nous avons investigué le profil d'expression des principales molécules co-inhibitrices et en particulier le rôle du CD 160 dans les fonctions des lymphocytes Τ CD8. Sur la base de ces analyses, nous avons constaté que l'avidité fonctionnelle des cellules Τ CD8 spécifiques au VIH était significativement plus faible lors infections aiguës que lors d'infections chroniques, mais n'était, par contre, pas différente entre les patients avec des infections chroniques progressives et non progressives. L'avidité fonctionnelle reste faible après plusieurs années de traitement antirétroviral, mais augmente chez les patients subissant un rebond viral, et donc exposés à des hautes virémies, suite à l'interruption du traitement. Cette augmentation d'avidité des lymphocytes Τ CD8, liée à un épuisement fonctionnel accru, était quantitativement directement associée à un renouvellement massif du TCR. Indépendamment de l'infection par le VIH, les cellules Τ CD8 expriment des niveaux plus élevés de molécules co-inhibitrices (PD-1, 2B4 et CD 160) par rapport aux cellules Τ CD4 et ceci dépend de leur stade de différenciation et d'activation. En particulier, CD 160 semble être un marqueur clé d'épuisement cellulaire des cellules Τ CD8, et donc une nouvelle cible potentielle pour l'immunothérapie, car a) son expression réduit la capacité proliférative et la production d'IL-2 b) CD 160 diminue suite à 1'activation et c) le blocage de CD 160 redonne la capacité proliférative aux cellules Τ CD8 spécifiques aux virus. - Le système immunitaire est un ensemble de cellules, tissus et organes indispensables pour limiter l'entrée des pathogènes à travers la peau et les muqueuses. Parmi les différentes cellules composant le système immunitaire, les cellules Τ CD4 et CD8 sont fondamentales pour le contrôle des infections virales et bactériennes. Les moyens pour combattre les différents pathogènes peuvent être cependant très variables. Les cellules Τ CD8, qui sont indispensables pour la lutte contre les virus, peuvent avoir différents niveaux de sensibilité; les cellules qui répondent à de faibles quantités d'antigène ont une forte sensibilité. Suite à une première infection virale, les cellules Τ CD8 ont une sensibilité plus faible que lors d'expositions répétées au même virus. En effet, la réexposition au pathogène induit une augmentation de sensibilité, grâce au recrutement et/ou à l'expansion de cellules Τ dotées d'une sensibilité plus élevée. Les cellules Τ CD8 avec une plus haute sensibilité semblent être caractérisées par une perte de fonctionnalité (épuisement fonctionnel associé à une haute expression de molécules dites inhibitrices). En absence d'infection, la fonction des molécules inhibitrices n'est pas encore clairement définie. Les cellules Τ CD8 montrent un niveau d'expression plus élevé de ces molécules par rapport aux cellules Τ CD4. Ceci dépend de l'état des cellules. Parmi ces molécules, le CD160 est associé à l'incapacité des cellules à proliférer et à produire de l'IL-2, une protéine importante pour la prolifération et la survie cellulaire. L'incapacité des cellules exprimant le CD 160 à proliférer en réponse à des virus peut être restaurée par le blocage fonctionnel du récepteur CD 160. Cette étude étoffe notre connaissance du rôle des cellules Τ CD8 ainsi que des conséquences induites par leur épuisement fonctionnel. Ces informations sont fondamentales pour le développement de nouvelles stratégies thérapeutiques et vaccinales.