Moreau C.,University of Lille Nord de France |
Delval A.,University of Lille Nord de France |
Defebvre L.,University of Lille Nord de France |
Dujardin K.,University of Lille Nord de France |
And 28 more authors.
The Lancet Neurology | Year: 2012
Background: Despite optimum medical management, many patients with Parkinson's disease are incapacitated by gait disorders including freezing of gait. We aimed to assess whether methylphenidate-through its combined action on dopamine and noradrenaline reuptake-would improve gait disorders and freezing of gate in patients with advanced Parkinson's disease without dementia who also received subthalamic nucleus stimulation. Methods: This multicentre, parallel, double-blind, placebo-controlled, randomised trial was done in 13 movement disorders departments in France between October, 2009, and December, 2011. Eligible patients were younger than 80 years and had Parkinson's disease, severe gait disorders, and freezing of gate despite optimised treatment of motor fluctuations with dopaminergic drugs and subthalamic stimulation. We randomly assigned patients (1:1 with a computer random-number generator in blocks of four) to receive methylphenidate (1 mg/kg per day) or placebo capsules for 90 days. Patients, their carers, study staff, investigators, and data analysts were masked to treatment allocation. To control for confounding effects of levodopa we assessed patients under standardised conditions with an acute levodopa challenge. Our primary outcome was a change in the number of steps during the stand-walk-sit (SWS) test without levodopa. We compared the respective mean numbers of steps at day 90 in the methylphenidate and placebo groups in a covariance analysis and adjusted for baseline differences. This trial is registered with ClinicalTrials.gov, number NCT00914095. Findings: We screened 81 patients and randomly assigned 35 to receive methylphenidate and 34 to receive placebo. 33 patients in the methylphenidate group and 32 patients in the placebo group completed the study. Efficacy outcomes were assessed in the patients who completed the study. Compared with patients in the placebo group (median 33 steps [IQR 26-45]), the patients in the methylphenidate group made fewer steps at 90 days (31 [26-42], F(1, 62)=6·1, p=0·017, adjusted size effect 0·61). Adverse events were analysed in all randomly assigned patients. There were significantly more adverse events in the methylphenidate group compared with placebo. Patients on methylphenidate had a significant increase in heart rate (mean 3·6 [SD 7·2] beats per min) and decrease in weight (mean 2·2 [SD 1·8] kg) compared with the placebo group. Interpretation: Methylphenidate improved gait hypokinesia and freezing in patients with advanced Parkinson's disease receiving subthalamic nucleus stimulation. Methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stage of Parkinson's disease. The long term risk-benefit balance should be further studied. Funding: French Ministry of Health and Novartis Pharma. © 2012 Elsevier Ltd.
Fouret R.,Telecom ParisTech |
Laffaire J.,Programme Carte dIdentite des Tumeurs |
Hofman P.,Nice University Hospital Center |
Beau-Faller M.,CHU Strasbourg |
And 10 more authors.
Clinical Cancer Research | Year: 2012
Purpose: To identify genetic changes that could drive cancer pathogenesis in never and ever smokers with lung adenocarcinoma. Experimental Design: We analyzed the copy number and gene expression profiles of lung adenocarcinomas in 165 patients and related the alterations to smoking status. Having found differences in the tumor profiles, we integrated copy number and gene expression data from 80 paired samples. Results: Amplifications at 8q24.12 overlapping MYC and ATAD2 were more frequent in ever smokers. Unsupervised analysis of gene expression revealed two groups: in the group with mainly never smokers, the tumors expressed genes common to normal lung; in the group with more ever smokers, the tumors expressed "proliferative" and "invasive" gene clusters. Integration of copy number and gene expression data identified one module enriched in mitotic genes and MYC targets. Its main associated modulator was ATAD2, a cofactor of MYC. A strong dose-response relationship between ATAD2 and proliferation-related gene expression was noted in both never and ever smokers, which was verified in two independent cohorts. Both ATAD2 and MYC expression correlated with 8q24.12 amplification and were higher in ever smokers. However, only ATAD2, and not MYC, overexpression explained the behavior of proliferation-related genes and predicted a worse prognosis independently of disease stage in a large validation cohort. Conclusions: The likely driving force behind MYC contribution to uncontrolled cell proliferation in lung adenocarcinoma is ATAD2. Deregulation of ATAD2 is mainly related to gene amplification and is more frequent in ever smokers. ©2012 AACR.
Servais A.,Hopital Necker Enfan |
Servais A.,University of Paris Descartes |
Noel L.-H.,Hopital Necker Enfants Malades AP HP |
Noel L.-H.,French Institute of Health and Medical Research |
And 15 more authors.
Kidney International | Year: 2012
Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex-mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression. © 2012 International Society of Nephrology.
Gilard M.,Brest University Hospital Center |
Eltchaninoff H.,University of Rouen |
Iung B.,Bichat Hospital |
Donzeau-Gouge P.,Institute Jacques Cartier |
And 38 more authors.
New England Journal of Medicine | Year: 2012
Background: Transcatheter aortic-valve implantation (TAVI) is an emerging intervention for the treatment of high-risk patients with severe aortic stenosis and coexisting illnesses. We report the results of a prospective multicenter study of the French national transcatheter aortic-valve implantation registry, FRANCE 2. Methods: All TAVIs performed in France, as listed in the FRANCE 2 registry, were prospectively included in the study. The primary end point was death from any cause. Results: A total of 3195 patients were enrolled between January 2010 and October 2011 at 34 centers. The mean (±SD) age was 82.7±7.2 years; 49% of the patients were women. All patients were highly symptomatic and were at high surgical risk for aortic-valve replacement. Edwards SAPIEN and Medtronic CoreValve devices were implanted in 66.9% and 33.1% of patients, respectively. Approaches were either transarterial (transfemoral, 74.6%; subclavian, 5.8%; and other, 1.8%) or transapical (17.8%). The procedural success rate was 96.9%. Rates of death at 30 days and 1 year were 9.7% and 24.0%, respectively. At 1 year, the incidence of stroke was 4.1%, and the incidence of periprosthetic aortic regurgitation was 64.5%. In a multivariate model, a higher logistic risk score on the European System for Cardiac Operative Risk Evaluation (EuroSCORE), New York Heart Association functional class III or IV symptoms, the use of a transapical TAVI approach, and a higher amount of periprosthetic regurgitation were significantly associated with reduced survival. Conclusions: This prospective registry study reflected real-life TAVI experience in high-risk elderly patients with aortic stenosis, in whom TAVI appeared to be a reasonable option. (Funded by Edwards Lifesciences and Medtronic.) Copyright © 2012 Massachusetts Medical Society.
Piroth L.,University of Burgundy |
Pol S.,CHU Cochin |
Lacombe K.,French Institute of Health and Medical Research |
Miailhes P.,Lyon University Hospital Center |
And 9 more authors.
Journal of Hepatology | Year: 2010
Background & Aims: To compare the management and the virological and serological efficacy of treatments for chronic hepatitis B (CHB) in HIV positive and negative patients. Methods: Two hundred and forty-six HIV positive and 205 HIV negative consecutive patients with past or present CHB, seen in October 2008 in participating departments, were included in a multicenter study. All the data were retrospectively collected from the first visit to October 2008 through a standardized questionnaire. Results: Compared to HIV negative patients, HIV positive patients more often presented positive HBeAg (46.4% vs. 32.8%, p = 0.01), HBV genotype A (54.8% vs. 17.1%, p <0.0001), co-infection with HCV (12.4% vs. 5.9%, p = 0.0002) or HDV (12.6% vs. 2.9%, p = 0.04). HIV positive patients were more often on HBV therapy (92.7% vs. 57.1%, p <0.0001), leading to undetectable serum HBV DNA levels (71.0% vs. 44.1%, p <0.0001). In HIV positive patients, multivariate analysis showed that older age, lower initial HBV DNA levels, and longer time on HBV therapy significantly correlated with undetectable HBV DNA. No difference in efficacy was observed between tenofovir used alone or in combination. HBsAg (but not HBe) loss was more often observed in HIV positive patients, sometimes followed by HBsAg re-appearance after withdrawal of HBV treatment. Excluding the 37 HBV-HCV-co-infected patients, the last clinical presentation and liver fibrosis scores were similar in HIV positive and negative patients. Conclusions: The assessment of CHB and the efficacy of HBV therapy have improved in HIV positive patients. HIV infection did not have a negative impact on the likelihood of HBV therapeutic success. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study
Emery P.,University of Leeds |
Gottenberg J.E.,CHU Strasbourg |
Rubbert-Roth A.,University of Cologne |
Sarzi-Puttini P.,University of Milan |
And 11 more authors.
Annals of the Rheumatic Diseases | Year: 2014
Objectives: To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. Methods: SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patient's global health component (DAS28-3)-erythrocyte sedimentation rate (ESR) over 6 months. Results: 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3-ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3-ESR at 6 months was significantly greater in rituximab than TNFi patients: -1.5 (0.2) vs -1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (-1.7 vs -1.3; p=0.017) but not intolerance (-0.7 vs -0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3-ESR with rituximab than with TNFi (-1.6 (0.3) vs -1.2 (0.3); p=0.011), particularly those switching because of inefficacy (-1.9 (0.3) vs -1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. Conclusions: These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.
Kaltenbach S.,French Institute of Health and Medical Research |
Soler G.,Laboratoire Of Cytogenetique |
Soler G.,University of Paris Descartes |
Barin C.,University of Tours |
And 5 more authors.
Blood | Year: 2010
Posttranscriptional modifications of histones play important roles in the control of chromatin structure and transcription. H3K4 (histone H3 lysine 4) methylation by the SET domain of the trithorax-group protein MLL (mixed-lineage leukemia) is important for the control of homeobox (HOX) gene expression during development. MLL is tethered to the HOXA locus through interaction of its amino-terminus with menin. MLL fusion proteins associated with human leukemia contain the menin interaction peptide and frequently recruit H3K79 (histone H3 lysine 79) methylation activity. This allows sustained expression of HOXA genes important for cellular transformation. We have characterized a novel recurrent chromosomal aberration, inv(11)(p15q23), as an isolated chromosomal abnormality in 2 patients with acute myeloid leukemia. This aberration is predicted to result in the expression of an NUP98 (nucleoporin 98 kDa)-MLL fusion protein that is unable to interact with menin. As expected, low levels of HOXA gene expression were observed in the patients' samples. This fusion protein is predicted to participate in cellular transformation by activating MLL targets other than HOXA genes. © 2010 by The American Society of Hematology.
Nisand I.,CHU Strasbourg
Medecine Therapeutique Medecine de la Reproduction, Gynecologie et Endocrinologie | Year: 2013
This opinion column provides grounds for initiating debate involving the public on new problems created by advances in Reproductive Medicine such as gamete donation, homosexual parenting and surrogacy.
Boursault L.,Bordeaux University Hospital Center |
Haddad V.,Bordeaux University Hospital Center |
Vergier B.,Bordeaux University Hospital Center |
Cappellen D.,Bordeaux University Hospital Center |
And 4 more authors.
PLoS ONE | Year: 2013
BRAF inhibitors have demonstrated improvement of overall survival in patients with metastatic melanoma and BRAFV600 mutations. In order to evaluate BRAF tumor heterogeneity between primary and metastatic site, we have evaluated the performance of immunohistochemistry (IHC) with an anti-BRAFV600E antibody in both localization by comparison with high resolution melting analysis followed by Sanger sequencing in a parallel blinded study. A total of 230 samples distributed as primary melanoma (n = 88) and different types of metastatic samples (n = 142) were studied in 99 patients with advanced or metastatic melanoma (stage III or IV). The prevalence of each BRAF mutation was c.1799T>A, BRAFV600E (45.2%), c.1799_1800TG>AA, BRAFV600E2 (3.0%), c.1798_1799GT>AA, BRAFV600K (3.0%), c.1801 A>G, BRAFK601E (1.3%), c.1789_1790CT>TC, BRAFL597S (0.4%), c.1780G>A, BRAFD594N (0.9%) respectively. IHC was positive in 109/112 samples harboring BRAFV600E/E2 mutations and negative in other cases. The cytoplasmic staining was either strongly positive in tumor cells of BRAFV600E mutated cases. It appeared strong brown, different from the vesicular grey cytoplasmic pigmentation of melanophages. Concordance between the two techniques was 96.4%. Sensitivity of IHC for detecting the BRAFV600E/E2 mutations was 97.3%, while specificity was 100%. Both our IHC and molecular study demonstrated homogeneity between primary and metastatic sites for BRAF status in melanoma. This study also provides evidence that IHC may be a cost-effective first-line method for BRAFV600E detection. Thereafter, molecular techniques should be used in negative, ambiguous or non-contributive cases. © 2013 Boursault et al.
Bernard A.,CHU Dijon |
Rivera C.,Bordeaux University Hospital Center |
Pages P.B.,CHU Dijon |
Falcoz P.E.,CHU Strasbourg |
And 2 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2011
Objectives: The estimation of risk-adjusted in-hospital mortality is essential to allow each thoracic surgery team to be compared with national benchmarks. The objective of this study is to develop and validate a risk model of mortality after pulmonary resection. Methods: A total of 18,049 lung resections for non-small cell lung cancer were entered into the French national database Epithor. The primary outcome was in-hospital mortality. Two independent analyses were performed with comorbidity variables. The first analysis included variables as independent predictive binary comorbidities (model 1). The second analysis included the number of comorbidities per patient (model 2). Results: In model 1 predictors for mortality were age, sex, American Society of Anesthesiologists score, performance status, forced expiratory volume (as a percentage), body mass index (in kilograms per meter squared), side, type of lung resection,extended resection, stage, chronic bronchitis, cardiac arrhythmia, coronary artery disease, congestive heart failure, alcoholism, history of malignant disease, and prior thoracic surgery. In model 2 predictors were age, sex, American Society of Anesthesiologists score, performance status, forced expiratory volume, body mass index, side, type of lung resection, extended resection, stage, and number of comorbidities per patient. Models 1 and 2 were well calibrated, with a slope correction factor of 0.96 and of 0.972, respectively. The area under the receiver operating characteristic curve was 0.784 (95% confidence interval, 0.76-0.8) in model 1 and 0.78 (95% confidence interval, 0.76-0.797) in model 2. Conclusions: Our preference is for the well-calibrated model 2 because it is easier to use in practice to estimate the adjusted postoperative mortality of lung resections for cancer. Copyright © 2011 by The American Association for Thoracic Surgery.