15 research outputs found
Caractérisation neuro-immunitaire d'un modÚle d'encéphalomyélite auto-immune expérimentale spontanée
La sclérose en plaques est une maladie neuroinflammatoire idiopathique caractérisée
par la formation de lĂ©sions focales de dĂ©myĂ©linisation, qui apparaissent suite Ă lâinfiltration pĂ©rivasculaire de cellules immunitaires et Ă lâaugmentation de la permĂ©abilitĂ© de la barriĂšre hĂ©mato-encĂ©phalique. LâencĂ©phalomyĂ©lite auto-immune expĂ©rimentale (EAE) est le modĂšle animal de cette maladie. Cependant, ce modĂšle prĂ©sente des diffĂ©rences importantes avec la sclĂ©rose en plaques.
Lâobjectif de ce projet de maĂźtrise Ă©tait dâapprofondir la caractĂ©risation dâun nouveau
modĂšle transgĂ©nique dâencĂ©phalomyĂ©lite auto-immune expĂ©rimentale spontanĂ©e, le modĂšle TCR1640, afin de valider celui-ci pour lâĂ©tude des phĂ©nomĂšnes physiopathologiques qui surviennent Ă diffĂ©rents stades de la sclĂ©rose en plaques, ainsi que pour le dĂ©veloppement de nouveaux traitements de la maladie. La souris TCR1640 porte un rĂ©cepteur des cellules T (TCR) transgĂ©nique autorĂ©actif, qui reconnaĂźt un peptide de la myĂ©line et dĂ©clenche une rĂ©action auto-immune contre la myĂ©line endogĂšne au sein du systĂšme nerveux central (SNC).
Des observations faites in situ et in vitro ont permis dâidentifier des changements qui
surviennent de façon trĂšs prĂ©coce dans lâunitĂ© neurovasculaire chez les animaux TCR1640 prĂ©symptomatiques, et qui sont liĂ©s Ă la prĂ©sence dâun profil immunitaire pĂ©riphĂ©rique proinflammatoire. Lors des phases actives de lâEAE spontanĂ©e, les animaux TCR1640 au stade chronique prĂ©sentent une inflammation accrue du systĂšme nerveux central associĂ©e Ă une infiltration leucocytaire massive, par rapport aux animaux au stade aigu de la maladie.
Une étude in vivo a également permis de moduler la maladie développée par des
animaux ayant subi une immunisation passive avec des cellules T auxiliaires en provenance de souris TCR1640. Enfin, lâimplication de nouvelles molĂ©cules dâadhĂ©sion cellulaire dans le dĂ©veloppement et le maintien de lâEAE spontanĂ©e a Ă©tĂ© suggĂ©rĂ©e par des observations in vitro.
Lâensemble de ces rĂ©sultats suggĂšre que le modĂšle TCR1640 prĂ©sente plusieurs
avantages pour lâĂ©tude de la physiopathologie de maladies neuroinflammatoires telles que la sclĂ©rose en plaques, et servira dâoutil afin de valider de nouvelles stratĂ©gies thĂ©rapeutiques.Multiple sclerosis is an idiopathic inflammatory disease of the central nervous system.
It is characterized by the formation of focal perivascular lesions and demyelination of the
surrounding area, which appear concomitantly to a massive immune cell infiltration and
disruption of the blood brain barrier. Experimental autoimmune encephalomyelitis is the
animal model most extensively used for the study of multiple sclerosis. Unfortunately, this
model does not mimic many aspects of the human disease.
The goal of this project is to further the characterization of a new transgenic model of
spontaneous experimental autoimmune encephalomyelitis, the TCR1640 model, and to
validate it as a relevant tool for the study of multiple sclerosis physiopathology and treatment.
The TCR1640 mouse possesses a transgenic T cell receptor which recognizes a myelin peptide
and triggers an autoimmune response against endogenous myelin in the central nervous
system.
In situ and in vitro observations have led to the identification of early changes which
appear at the neurovascular unit in presymptomatic TCR1640 animals. This early disruption of
blood brain barrier homeostasis is linked to the establishment of a proinflammatory immune
profile in the periphery. Animals at the chronic stage show sustained inflammation of the
central nervous system parenchyma and massive leukocyte infiltration, compared to animals in
acute phase of disease.
An in vivo experiment has allowed modulating the disease by treatment with a multiple
sclerosis-approved therapy, in wild type mice which had received reactivated CD4+ T cells
from TCR1640 animals. Finally, the implication of new cell adhesion molecules in the
development and maintenance of spontaneous experimental autoimmune encephalomyelitis
has been suggested by in vitro study of melanoma cell adhesion molecule (CD146) and
activated leucocyte cell adhesion molecule (CD166).
The results obtained in this study suggest that the TCR1640 model is a valuable asset
in the study of neuroimmune diseases such as multiple sclerosis. It could also be used to
validate new therapeutic strategies for the treatment of this disease
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
Trémery, Moselle, ZAC de la Fontaine des Saints, site 19 : rapport de fouille
Le NĂ©olithique ancien est marquĂ© par la prĂ©sence de fosses allongĂ©es. La cĂ©ramique issue de leur remplissage montre des dĂ©cors rĂ©alisĂ©s selon la technique du pointillĂ©-sillonnĂ© ainsi que l'utilisation du peigne Ă deux dents et la forte proportion du motif en chevron simple ou double, permettant d'attribuer l'ensemble du mobilier cĂ©ramique des fosses Ă l'horizon IIc du RubanĂ© de la chronologie du Rhin moyen ou de la phase 5 rĂ©gionale. Si du point de vue de la cĂ©ramique, les fosses appartiennent au mĂȘme horizon chronologique, en revanche il n'est pas Ă©tabli qu'elles aient Ă©tĂ© associĂ©es au mĂȘme habitat qui n'a d'ailleurs pas Ă©tĂ© conservĂ©. Au regard du nombre de vestiges, on peut penser que le site ne comportait pas plus d'une ou deux habitations. Trois sĂ©pultures campaniformes ont Ă©tĂ© dĂ©couvertes dans lâemprise, dont la premiĂšre dĂ©couverte au cours du diagnostic. Lâune dâelle a livrĂ© un vase qui s'intĂšgre tout Ă fait au style maritime/mixte du Campaniforme occidental : gobelet (Ă profil en S ?), teinte orangĂ©e, impressions conjointes d'outils Ă dents multiples et de cordelette pour la rĂ©alisation du dĂ©cor. Le premier Ăąge du Fer, marquĂ© par des Ă©lĂ©ments cĂ©ramiques, provient principalement dâun petit groupe de silos et de fosses. La plupart des vases rencontrĂ©s ici trouvent des comparaisons directes essentiellement en Lorraine mais aussi en Alsace et en Allemagne. La plupart des formes de vases et leur dĂ©cor montrent des parallĂšles dans des ensembles du Hallstatt C alors que certaines formes Ă©voquent dĂ©jĂ le Hallstatt D. La datation proposĂ©e pour ce site est la fin du Hallstatt C voire le Hallstatt D1. Trois plans de bĂątiments lisibles dans lâemprise sud du dĂ©capage prĂ©sentent tous un plan rectangulaire Ce type de plan est connu en Lorraine, il apparaĂźt dĂšs lâĂge du Bronze final et perdure Ă la pĂ©riode hallstattienne, et de façon plus sporadique durant le second Ăge du fer. Un plan formant un quadrilatĂšre est constituĂ© de quatre poteaux porteurs dâune superficie de 27 m2 environ. Ce type de bĂątisse peut ĂȘtre interprĂ©tĂ© comme un grenier surĂ©levĂ©, trĂšs rĂ©pandu aux deux Ăąges du Fer. Un chemin 2075 trĂšs arasĂ©e, orientĂ©e est-ouest et sâincurve vers le nord-ouest. Son parcours a Ă©tĂ© suivi sur lâemprise dĂ©capĂ©e sur une petite centaine de mĂštres linĂ©aire. Cinq fossĂ©s ont Ă©tĂ© repĂ©rĂ©s dans lâemprise fouillĂ©e, quatre ont un tracĂ© identique, parallĂšle, orientĂ© nord-ouest-sud-est. On retrouve leur tracĂ© sur lâemprise du site 30 fouillĂ© par Marie-Pierre Petitdidier
French national diagnosis and care protocol (PNDS, protocole national de diagnostic et de soins): cystic lymphatic malformations
Abstract Cystic lymphatic malformations (LMs) are rare chronic conditions which management differs according to the type (macrocystic LMs, microcystic LMs or both). Studies are lacking due to rarity of the pathology. We aimed to establish a French National Diagnosis and Care Protocol (PNDS: Protocole National de Diagnostic et de Soins), to provide health professionals with free open access synthesis on optimal management and care of patients with LMs ( https://www.has-sante.fr/upload/docs/application/pdf/2021-03/malformations_lymphatiques_kystiques_-_pnds.pdf ). The process included a critical review of the literature and multidisciplinary expert consensus. LMs are congenital but are not always discovered at birth. Nearly 75% of them are located in the head and neck because of the highly dense lymphatic system in this region. Physical examination (showing painless masses with normal skin color and depressible consistency, or cutaneous/mucosal lymphangiectasia) and color Doppler ultrasonography, usually allow for diagnosis. MRI (involving T2 sequences with fat saturation in at least two spatial planes) is the tool of choice for evaluating anatomical extension, characterizing lesions (microcystic and macrocystic), and before considering therapeutic management. A biopsy, coupled to a blood sample, can also be used for molecular biology analyses, to search for activating mutations of the PIK3CA gene, particularly with LM integrating in a syndromic form (CLOVES or Klippel-Trenaunay syndrome) but also in certain isolated (or common) LMs. The spontaneous evolution of LMs, in particular microcystic forms, is often toward progressive aggravation, with an increase in the number of vesicles, thickening, increased oozing and bleeding, while pure macrocystic LMs may regress due to ânatural sclerosisâ, i.e. fibrosis secondary to an inflammatory reorganization after common infantile infections. In case of voluminous LMs or syndromic forms, functional and psychological repercussions can be major, deteriorating the patientâs quality of life. LMs must be treated by physicians integrated in multidisciplinary teams, and be personalized. Management is a life-long process that involves one or several of these therapies: conservative management, physical therapy (compression), sclerotherapy, surgery, drugs such as mTOR inhibitors (sirolimus), that has shown efficacy in decreasing the volume of LMs, and, more recently, PI3K-inhibitors in syndromic forms. Psychological and social support is necessary, taking into account the patient and his family
Dual role of ALCAM in neuroinflammation and blood-brain barrier homeostasis.
Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule found on blood-brain barrier endothelial cells (BBB-ECs) that was previously shown to be involved in leukocyte transmigration across the endothelium. In the present study, we found that ALCAM knockout (KO) mice developed a more severe myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE). The exacerbated disease was associated with a significant increase in the number of CNS-infiltrating proinflammatory leukocytes compared with WT controls. Passive EAE transfer experiments suggested that the pathophysiology observed in active EAE was linked to the absence of ALCAM on BBB-ECs. In addition, phenotypic characterization of unimmunized ALCAM KO mice revealed a reduced expression of BBB junctional proteins. Further in vivo, in vitro, and molecular analysis confirmed that ALCAM is associated with tight junction molecule assembly at the BBB, explaining the increased permeability of CNS blood vessels in ALCAM KO animals. Collectively, our data point to a biologically important function of ALCAM in maintaining BBB integrity
Treatment, outcome, and prognostic factors in non-metastatic anal cancer: The French nationwide cohort study FFCD-ANABASE
International audienceIntroduction: International guidelines regarding the treatment of squamous cell carcinoma of the anus (SCCA) recommend intensity-modulated radiotherapy (IMRT) combined with mitomycin-based chemotherapy (CT). The French FFCD-ANABASE cohort aimed at evaluating clinical practices, treatment, and outcomes of SCCA patients.Methods: This prospective multicentric observational cohort included all non-metastatic SCCA patients treated in 60 French centers from January 2015 to April 2020. Patients and treatment characteristics, colostomy-free survival (CFS), disease-free survival (DFS), overall survival (OS), and prognostic factors were analyzed.Results: Among 1015 patients (male: 24.4 %; female: 75.6 %; median age: 65 years), 43.3 %presented with early-stage(T1-2, N0) and 56.7 % with locally advanced stage (T3-4 or N + ) tumors. IMRT was used for 815 patients (80.3 %) and a concurrent CT was administered in 781 patients, consisting of mitomycin-based CT for 80 %. The median follow-up was 35.5 months. DFS, CFS, and OS at 3 years were 84.3 %, 85.6 %, and 91.7 % respectively in the early-stage group compared to 64.4 %, 66.9 %, and 78.2 % in the locally-advanced group (p < 0.001). In multivariate analyses, male gender, locally-advanced stage, and ECOG PS â„ 1 were associated with poorer DFS, CFS, and OS. IMRT was significantly associated with a better CFS in the whole cohort and almost reached significance in the locally-advanced group.Conclusion: Treatment of SCCA patients showed good respect for current guidelines. Significant differences in outcomes advocate for personalized strategies by either de-escalation for early-stage tumors or treatment intensification for locally-advanced tumors