Filtrer sans s'appauvrir : inférer les paramètres constants des modèles réactifs probabilistes

National audienceProbZelus étend le langage synchrone Zelus pour permettre de décrire des modèles probabilistes synchrones. Là où la programmation synchrone implémente des fonctions de suites, un langage probabiliste synchrone permet de décrire des modèles qui calculent des suites de distributions. On peut par exemple estimer la position d'un objet en mouvement à partir d'observations bruitées ou estimer l'incertitude d'un capteur à partir d'une suite d'observations. Ces problèmes mêlent des flots de variables aléatoires -- les paramètres d'état qui changent au cours du temps -- et des variables aléatoires constantes -- les paramètres constants. Pour estimer les paramètres d'état, les algorithmes d'inférence bayésienne de Monte Carlo séquentiels reposent sur des techniques de filtrage. Le filtrage est une méthode approchée qui consiste à perdre volontairement de l'information sur l'approximation actuelle pour recentrer les estimations futures autour de l'information la plus significative. Malheureusement, cette perte d'information est dommageable pour l'estimation des paramètres constants qui n'évoluent pas au cours du temps. Ce phénomène s'appelle l'appauvrissement. Inspirés de la méthode d'inférence Assumed Parameter Filter (APF), nous proposons (1) une analyse statique, (2) une passe de compilation et (3) une nouvelle méthode d'inférence modulaire pour ProbZelus qui évite l'appauvrissement pour les paramètres constants tout en gardant les performances des algorithmes de Monte Carlo séquentiels pour les paramètres d'états

Identification of new autoantibody specificities directed at proteins involved in the transforming growth factor β pathway in patients with systemic sclerosis

International audienceABSTRACT: INTRODUCTION: Antinuclear antibodies (ANA), usually detected by indirect immunofluorescence on HEp-2 cells, are identified in 90% of patients with systemic sclerosis (SSc). Thus, approximately 10% of SSc patients have no routinely detectable autoantibodies, and for 20% to 40% of those with detectable ANA, the ANA do not have identified specificity (non-identified ANA). In this work, we aimed to identify new target autoantigens in SSc patients. METHODS: Using a proteomic approach combining 2-D electrophoresis and immunoblotting with HEp-2 cell total and enriched nuclear protein extracts as sources of autoantigens, we systematically analysed autoantibodies in SSc patients. Sera from 45 SSc patients were tested in 15 pools from groups of 3 patients with the same phenotype. A sera pool from 12 healthy individuals was used as a control. Proteins of interest were identified by mass spectrometry and analysed using Pathway Studio software. RESULTS: We identified 974 and 832 protein spots in HEp-2 cell total and enriched nuclear protein extracts, respectively. Interestingly, alpha-enolase was recognised by immunoglobulin-G (IgG) from all pools of patients in both extracts. Fourteen and 4 proteins were recognised by IgG from at least 75% of the 15 pools in total and enriched nuclear protein extracts, respectively, whereas 15 protein spots were specifically recognised by IgG from at least 4 of the 10 pools from patients with non-identified ANA. The IgG intensity for a number of antigens was higher in sera from patients than in those from healthy controls; these antigens included triosephosphate isomerase, superoxide dismutase mitochondrial precursor, heterogeneous nuclear ribonucleoprotein L and lamin A/C. In addition, peroxiredoxin-2, cofilin-1 and calreticulin were specifically recognised by sera from phenotypic subsets of patients with non-identified ANA. Interestingly, several identified target antigens were involved in the transforming growth factor-beta pathway. CONCLUSIONS: We identified several new target antigens shared among patients with SSc or specific to a given phenotype. The specification of new autoantibodies could help in understanding the pathophysiology of SSc. Moreover, these autoantibodies could represent new diagnostic and/or prognostic markers for SSc

Efficacité et tolérance du rituximab dans le traitement des anémies hémolytiques auto-immunes à anticorps chauds de l adulte (étude rétrospective portant sur 27 cas)

L intérêt du rituximab dans le traitement des anémies hémolytiques auto-immunes (AHAI) à anticorps chauds a été essentiellement évalué chez l enfant. Afin de mieux évaluer l efficacité et la tolérance du rituximab au cours des AHAI à anticorps chauds de l adulte, nous avons conduit une étude rétrospective multicentrique incluant 27 patients (16F/11H, âge moyen 49,7 ans) atteints d une AHAI primaire (n=17) ou secondaire (n=10). En moyenne, les patients avaient reçu 2,1 lignes de traitement avant le rituximab et 6 avaient subi une splénectomie. L indication du rituximab était une cortico-résistance de l AHAI dans 5 cas, une cortico-dépendance dans 16 cas, et une rechute à l arrêt du traitement après une rémission initiale dans 6 cas. Au total, une réponse initiale au rituximab a été observée chez 25/27 patients (8 réponses complètes et 17 réponses partielles). La corticothérapie a pu être interrompue chez 11 patients. Après un suivi moyen de 20,9 mois après le rituximab, 5 parmi les patients initialement répondeurs ont rechuté et 3 d entre eux ont été retraités avec succès par le rituximab. Deux événements indésirables graves ont été observés : un patient a développé une neutropénie sévère rattachée au rituximab ; un autre patient, par ailleurs très immunodéprimé, a développé une pneumocystose au cours du suivi sans que le rituximab puisse être directement incriminé. En conclusion, le rituximab semble être un traitement particulièrement efficace et relativement bien toléré dans les AHAI cortico-résistantes ou cortico-dépendantes de l adulte. L intérêt du rituximab à une phase plus précoce de la maladie mérite d être évalué de façon prospective et contrôlée.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Caractérisation des cibles antigéniques des auto-anticorps au cours de la sclérodermie systémique et de l'hypertension artérielle pulmonaire

PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Scleroderma Renal Crisis: A Rare but Severe Complication of Systemic Sclerosis

Scleroderma renal crisis (SRC) is a major complication in patients with systemic sclerosis (SSc). It is characterized by malignant hypertension and oligo/anuric acute renal failure. SRC occurs in 5% of patients with SSc, particularly in the first years of disease evolution and in the diffuse form. The occurrence of SRC is more common in patients treated with glucocorticoids, the risk increasing with increasing dose. Left ventricular insufficiency and hypertensive encephalopathy are typical clinical features. Thrombotic microangiopathy is detected in 43% of the cases. Anti-RNA-polymerase III antibodies are present in one third of patients who develop SRC. Renal biopsy is not necessary if SRC presents with classical features. However, it can help to define prognosis and guide treatment in atypical forms. The prognosis of SRC has dramatically improved with the introduction of angiotensin-converting enzyme inhibitors (ACEi). However, 5 years survival in SSc patients who develop the full picture of SRC remains low (65%). SRC is often triggered by nephrotoxic drugs and/or intravascular volume depletion. The treatment of SRC relies on aggressive control of blood pressure with ACEi, if needed in combination with other types of antihypertensive drugs. Dialysis is frequently indicated, but can be stopped in approximately half of patients, mainly in those for whom a perfect control of blood pressure is obtained. Patients who need dialysis for more than 2 years qualify for renal transplantation

Unmasking Leprosy: An Unusual Immune Reconstitution Inflammatory Syndrome in a Patient Infected with Human Immunodeficiency Virus

Immune reconstitution inflammatory syndrome (IRIS) has become a frequent and potentially severe complication after initiation of following antiretroviral therapy (ART) in patients infected with human immunodeficiency virus (HIV). IRIS can unmask a previously clinically silent infection, such as tuberculosis, as recently described for Mycobacterium infections. We describe a case in a patient from Côte d'Ivoire living in France in whom skin papular lesions developed after initiation of ART. These lesions were associated with microbiologically proven leprosy. Thus, latent leprosy can appear as IRIS, and leprosy-associated IRIS should be considered in HIV-infected patients from areas endemic for leprosy

IgG from patients with pulmonary arterial hypertension and/or systemic sclerosis binds to vascular smooth muscle cells and induces cell contraction.

International audienceOBJECTIVES: Pulmonary arterial hypertension (PAH) is characterised by remodelling of pulmonary arteries with enhanced vascular smooth muscle cell (VSMC) contraction, migration and proliferation. The authors investigated the presence of antibodies to human VSMCs in the serum of patients with systemic sclerosis with or without PAH and idiopathic PAH (iPAH). METHODS AND RESULTS: Antibodies to VSMCs were detected by immunofluorescence in sera from healthy controls and patients with scleroderma without PAH, scleroderma-associated PAH and iPAH. Serum IgG from these patients induced contraction of VSMCs in a collagen matrix in contrast with IgG from healthy controls. Several protein spots of interest and target antigens were identified by two-dimensional immunoblotting and MS, including stress-induced phosphoprotein 1 and α-enolase. Finally, antibodies to stress-induced phosphoprotein 1 were detected by ELISA in sera from 84%, 76% and 24% of patients with scleroderma without PAH, scleroderma-associated PAH and iPAH, respectively, compared with only 3% of healthy controls. CONCLUSION: The authors have identified IgG that binds to VSMCs in the serum of patients with scleroderma and iPAH. These antibodies may be pathogenic by modulating vascular contraction. The target antigens of these antibodies are stress-induced phosphoprotein 1 and α-enolase

Factors associated with hospital admission and adverse outcome for COVID-19: Role of social factors and medical care

International audienceBackground: Beyond sex, age, and various comorbidities, geographical origin and socioeconomic deprivation are associated with Coronavirus Disease (COVID-19) morbidity and mortality in the general population. We aimed to assess factors associated with severe forms of COVID-19 after a hospital emergency department visit, focusing on socioeconomic factors. Methods: Patients with laboratory-confirmed COVID-19 attending the emergency department of Béclère Hospital (France) in March–April 2020 were included. Postal addresses were used to obtain two geographical deprivation indices at the neighborhood level. Factors associated with hospitalization and factors associated with adverse outcomes, i.e. mechanical ventilation or death, were studied using logistic and Cox analyses, respectively. Results: Among 399 included patients, 321 were hospitalized. Neither geographical origin nor socioeconomic deprivation was associated with any of the outcomes. Being male, older, overweight or obese, diabetic, or having a neuropsychiatric disorder were independent risk factors for hospitalization. Among 296 patients hospitalized at Béclère Hospital, 91 experienced an adverse outcome. Older age, being overweight or obese, desaturation and extent of chest CT scan lesions > 25% at admission (aHR: 2.2 [95% CI: 1.3–3.5]) and higher peak CRP levels and acute kidney failure (aHR: 2.0 [1.2–3.3]) during follow-up were independently associated with adverse outcomes, whereas treatment with hydrocortisone reduced the risk of mechanical ventilation or death by half (aHR: 0.5 [0.3–0.8]). Conclusion: No association between geographical origin or socioeconomic deprivation and the occurrence of a severe form of COVID-19 was observed in our population after arrival to the emergency department. Empirical corticosteroid use with hydrocortisone had a strong protective impact