Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in human monocytes

In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNFα), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNFα and adalimumab, a human anti-TNFα monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNFα or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)γ in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNFα inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPARγ activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNFα and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis

Reproducibility and sensitivity to change of various methods to measure joint space width in osteoarthritis of the hip: a double reading of three different radiographic views taken with a three-year interval

Joint space width (JSW) and narrowing (JSN) measurements on radiographs are currently the best way to assess disease severity or progression in hip osteoarthritis, yet we lack data regarding the most accurate and sensitive measurement technique. This study was conducted to determine the optimal radiograph and number of readers for measuring JSW and JSN. Fifty pairs of radiographs taken three years apart were obtained from patients included in a structure modification trial in hip osteoarthritis. Three radiographs were taken with the patient standing: pelvis, target hip anteroposterior (AP) and oblique views. Two trained readers, blinded to each other's findings, time sequence and treatment, each read the six radiographs gathered for each patient twice (time interval ≥15 days), using a 0.1 mm graduated magnifying glass. Radiographs were randomly coded for each reading. The interobserver and intraobserver cross-sectional (M0 and M36) and longitudinal (M0–M36) reproducibilities were assessed using the intraclass coefficient (ICC) and Bland–Altman method for readers 1 and 2 and their mean. Sensitivity to change was estimated using the standardized response mean (SRM = change/standard deviation of change) for M0–M36 changes. For interobserver reliability on M0–M36 changes, the ICCs (95% confidence interval [CI]) were 0.79 (0.65–0.88) for pelvic view, 0.87 (0.78–0.93) for hip AP view and 0.86 (0.76–0.92) for oblique view. Intraobserver reliability ICCs were 0.81 (0.69–0.89) for observer 1 and 0.97 (0.95–0.98) for observer 2 for the pelvic view; 0.87 (0.78–0.92) and 0.97 (0.96–0.99) for the hip AP view; and 0.73 (0.57–0.84) and 0.93 (0.88–0.96) for the oblique view. SRMs were 0.61 (observer 1) and 0.82 (observer 2) for pelvic view; 0.64 and 0.75 for hip AP view; and 0.77 and 0.70 for oblique view. All three views yielded accurate JSW and JSN. According to the best reader, the pelvic view performed slightly better. Both readers exhibited high precision, with SRMs of 0.6 or greater for assessing JSN over three years. Selecting a single reader was the most accurate method, with 0.3 mm precision. Using this cutoff, 50% of patients were classified as 'progressors'

A new classification of HLA-DRB1 alleles differentiates predisposing and protective alleles for autoantibody production in rheumatoid arthritis

The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity

Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients.

International audienceBackground: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2–10·7] vs 7·1 months [6·1–7·9]; p<0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5]; p<0·0001) compared with absence of a genetic alteration. Interpretation Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit

Don de sang : une approche territoriale

International audienc

Le don de sang dans les populations afrodescendantes : une approche territoriale

International audienc

Analyse rétrospective des effets indésirables de l'infliximab dans un service hospitalier de rhumatologie

L'infliximab (Rémicade®) est un anticorps monoclonal chimérique dirigé contre le TNFα (tumour necrosis factor-α) indiqué dans le traitement de la polyarthrite rhumatoïde (PR) et des formes actives ou fistulisées de la maladie de Crohn. Notre travail évalue les effets indésirables de l'infliximab chez des patients traités pour PR sur une période de 2 ans. Cette étude rétrospective du 1/01/2000–31/12/2001 réalisée dans un service de Rhumatologie du CHU de Toulouse (Hôpital Rangueil) inclut 32 patients d'âge moyen de 51,4 ans. Nous avons relevé 43 effets indésirables de type A "attendus" chez 21 patients (65,6 %) dont quatre (12,5 %) classés comme "graves". Dans cinq cas, l'effet indésirable a nécessité l'arrêt du traitement. Nous avons relevé essentiellement des atteintes infectieuses (n = 21), des manifestations allergiques (n = 3) et des effets cardiovasculaires (n = 3). Les atteintes infectieuses concernent une infection urinaire dans sept cas (dont cinq avec une réadministration positive [R+]), une infection respiratoire dans neuf cas (dont cinq avec R+) et une infection cutanée dans cinq cas. Nous avons noté trois cas de poussées hypertensives chez des patients traités par les antihypertenseurs. L'incidence des effets indésirables infectieux s'élève à 28 % pour les infections respiratoires, 22 % pour les infections urinaires et 15,6 % pour les infections cutanéo-muqueuses. L'incidence des manifestations allergiques comme celle des effets cardiovasculaires est de 9,4 %. Cette étude a permis de déterminer le profil qualitatif et quantitatif des effets indésirables de l'infliximab chez un nombre limité de patients traités pour une pathologie rhumatoïde sur une période de 2 ans. L'élargissement du nombre de patients ainsi que le suivi au long cours permettrait d'affiner les connaissances sur le profil d'effets indésirables de ce médicament

Subtle adjustments of the glucose-6-phosphate dehydrogenase (G6PD) mutation database and reference sequence.

International audienceReference sequences and mutation databases are essential for the development of molecular-based methods in human genetics. Lately, Minucci et al. [1] revised the glucose-6-phosphate dehydrogenase (G6PD) reference material from 131 bibliographic references, three previous databases, and the genomic reference sequence (GenBank accession number X55448.1). Deficiency in G6PD is the most common enzymatic insufficiency in human populations and clinical manifestations range from mild to severe: neonatal jaundice, acute hemolysis and chronic non-spherocytic hemolytic anemia prompted by infections or sudden onset of oxidative agents from for instance the ingestion of fava beans (Vicia faba) or anti-malarial treatments [2]. Given the clinical consequences, numerous studies and international projects are being carried out about the mechanisms leading to the numerous G6PD enzymatic variants, and in this context, the updated G6PD database provided in [1] is a precious substratum for lab protocols. Nonetheless, while setting our strategy from this material, we encountered two main hurdles that we would like to address