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Biomedical subjects

Jean-Robert Harlé

Publications and source records attributed to Jean-Robert Harlé.

11 recordsLinked to original sources
PubMed2006

IL13RA2 gene polymorphisms are associated with systemic sclerosis.

OBJECTIVE: To investigate the influence of genetic variability on the phenotypic expression of systemic sclerosis (SSc), by testing possible associations between single nucleotide polymorphisms (SNP) in IL13RA1 and IL13RA2 genes and SSc in a Caucasian population. METHODS: As IL13RA1 and IL13RA2 are located on the X chromosome and SSc occurs far more frequently in women than in men, only women were genotyped. The study group comprised 97 women with SSc, 36 with diffuse (dcSSc) and 61 with limited (lcSSc) cutaneous forms of disease, and 109 healthy controls. Patients and controls were Caucasian. We investigated 4 SNP in IL13RA1 and 3 in IL13RA2 by polymerase chain reaction amplifications and enzymatic digestion or primer extension reactions and denaturing high-performance liquid chromatography. RESULTS: We detected an association between IL13RA2 rs638376 and patients with SSc [p = 0.004, odds ratio (OR) = 1.85, confidence interval (CI) 1.22-2.74, p corr = 0.02], as well as with dcSSc in that subgroup of patients (p = 0.01, OR 2.22, 95% CI 1.27-3.89, p corr = 0.05). The IL13RA2 rs638376G allele frequency was higher in patients with SSc (51.6%) than in controls (36.4%, p = 0.003, OR 1.86, 95% CI 1.24-2.79, p corr = 0.015) and in the subgroup with dcSSc (57.6%) than in controls (36.4%, p = 0.003, OR 2.37, 95% CI 1.35-4.15, p corr = 0.015). One other IL13RA2 SNP was only associated with the dcSSc subgroup: the IL13RA2 rs5946040G allele was more common in patients with dcSSc (33.8%) than in controls (17%, p = 0.004, OR 2.5, 95% CI 1.36-4.60, p corr = 0.02). CONCLUSION: Our data suggest that IL13RA2 gene polymorphisms may be involved in susceptibility to SSc. Further studies are under way to show that they contribute to disease.

Adult↗
PubMed2006

Evaluation of interleukin 13 polymorphisms in systemic sclerosis.

Systemic sclerosis (SSc) is a multisystem disease of unknown etiology. It is characterized by excessive cutaneous and visceral fibrosis, damage to small blood vessels, and production of autoantibodies. Interleukin-13 (IL-13) has been shown to be involved in abnormal fibrosis in other diseases. Therefore, we have evaluated its possible involvement in SSc. We analyzed four IL13 gene polymorphisms, rs1800925 (IL13-1055), rs20541 (Arg130Gln), rs847, and rs2243204 in 107 unrelated SSc patients (40 patients having diffuse cutaneous form and 67 patients having limited cutaneous form) and in 170 controls. All subjects were Caucasians. In the total patient population and in the diffuse cutaneous subset, we observed an association between two IL13 polymorphisms, IL13 rs1800925 (IL13-1055), and IL13 rs2243204, and disease (p=0.03-0.04). The IL13 rs2243204T allele was more common in SSc patients (p=0.01, OR=2.3 CI 1.21-4.38) and in the diffuse cutaneous form (p=0.01, OR=2.95, CI 1.35-6.49) than in control subjects. Our result supports the suggestion that polymorphisms in IL13 are associated to SSc and skin fibrosis process. However, further studies on larger and independent population and functional analyses are needed to confirm these findings.

Aged↗
PubMed2005

Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome.

Hemophagocytic syndrome (HPS) is characterized by an uncontrolled and poorly understood activation of T-helper 1 (Th-1) lymphocytes and macrophages. We studied 20 patients with HPS secondary to infections, autoimmune disease, lymphoma, or cancer and observed that the concentrations of serum interleukin 18 (IL-18), a strong inducer of Th-1 responses, interferon gamma (IFN-gamma) production, and stimulation of macrophages and natural killer (NK) cells were highly increased in HPS but not in control patients. In contrast, concentrations of its natural inhibitor, the IL-18 binding protein (IL-18BP), were only moderately elevated, resulting in a high level of biologically active free IL-18 in HPS (4.6-fold increase compared with controls; P < .001). Free IL-18 but not IL-12 concentrations significantly correlated with clinical status and the biologic markers of HPS such as anemia (P < .001), hypertriglyceridemia, and hyperferritinemia (P < .01) and also with markers of Th-1 lymphocyte or macrophage activation, such as elevated concentrations of IFN-gamma and soluble IL-2 and tumor necrosis factor alpha (TNF-alpha) receptor concentrations. Despite high IL-18 elevation, in vitro NK-cell cytotoxicity was severely impaired in HPS patients, in part due to NK-cell lymphopenia that was observed in a majority of patients but also secondary to an intrinsic NK-cell functional deficiency. We concluded that a severe IL-18/IL-18BP imbalance results in Th-1 lymphocyte and macrophage activation, which escapes control by NK-cell cytotoxicity and may allow for secondary HPS in patients with underlying diseases.

Adolescent↗
PubMed2005

Role of reactive oxygen species and p38 MAPK in the induction of the pro-adhesive endothelial state mediated by IgG from patients with anti-phospholipid syndrome.

The association of the presence of anti-phospholipid antibodies (aPL) with thrombosis characterizes the anti-phospholipid syndrome (APS). The activation of the endothelium is a key event in the establishment of the thrombophilic state. However, the intracellular mechanisms leading to endothelial dysfunction are not fully elucidated. We investigated the role of reactive oxygen species (ROS) in the pro-adhesive state elicited by aPL and studied ROS-dependent downstream signaling pathways. Independent incubation of human umbilical vein endothelial cells (HUVEC) with IgG (IgG-APS) from 12 APS patients caused a large and sustained increase in ROS, which was prevented by the antioxidants vitamin C and N-acetyl-L-cysteine. ROS inhibition observed in the presence of diphenylene iodonium and rotenone indicated an involvement of a membrane-bound oxidase and the mitochondrial transport chain as sources of ROS. ROS acted as a second messenger by activating the p38 mitogen-activated protein kinase and its subsequent target, the stress-related transcription factor activating transcription factor-2 (ATF-2). ROS controlled the up-regulation of vascular cell adhesion molecule-1 expression by IgG-APS-stimulated HUVEC and the increase in THP-1 monocytic cells adhesion. The IgG-APS-mediated oxidative stress was observed irrespective of the clinical and biological criterions of the patients studied here. Taken together, these data indicate that the oxidative stress induced by IgG-APS is a key intracellular event that might contribute to the thrombotic complications of APS by controlling the endothelial adhesive phenotype.

Antioxidants↗
PubMed2005

Vascular cell adhesion molecule-1 (VCAM-1) plays a central role in the pathogenesis of severe forms of vasculitis due to hepatitis C-associated mixed cryoglobulinemia.

BACKGROUND/AIMS: To better characterize the molecules involved in leukocyte tissue infiltration during hepatitis C-mixed cryoglobulinemia (HCV-MC)-associated vasculitis. METHODS: The involvement of ELAM, ICAM-1 and VCAM-1 was evaluated in 36 patients with HCV-MC vasculitis using three different approaches: concentrations of soluble forms by specific ELISA, tissue expression by immunohistochemistry on patients nerve biopsies, endothelial expression by FACS analysis, on cells activated in vitro by cryoprecipitates purified from HCV-MC patients. RESULTS: Concentrations of sVCAM-1 were significantly elevated in the serum of HCV-MC patients compared to HCV patients without MC, the highest concentrations being found in severe vasculitis. VCAM-1 expression was detected on blood vessels from nerve biopsies performed in patients with severe vasculitis. When added to endothelial cells in vitro, HCV-MC patients cryoprecipitate induced VCAM-1 but also ELAM and ICAM-1 expression possibly through a mechanism due to the C1q complement fraction interaction with endothelial cells, since C1q was consistently present in the cryoprecipitates. CONCLUSIONS: VCAM-1 is mainly involved in the pathogenesis of HCV-MC-associated severe vasculitis and may be a potential interesting therapeutic target.

Adult↗
PubMed2005

Applicability of textual clinical practice guidelines: impact of physician interpretation.

OBJECTIVES: 1) Determine whether textual Clinical Practice Guidelines (CPGs) are interpreted accurately and unequivocally by targeted physicians. 2) Specify audience and perception of the CPGs. METHOD: Comparative analysis of answers given by a panel of general practitioners to a series of questions and clinical case studies related to three textual CPGs produced and published by the French National Agency for Accreditation and Evaluation in Health (ANAES). RESULTS: 68 to 96% of physicians are aware of the existence of the CPGs studied. Less than 50% state having read them. On average, 38% of physician interpretations of CPGs are incorrect (i.e., not in agreement with expert interpretation). Furthermore, there is disagreement among physicians responses. CONCLUSION: This study credits the argument of disparities in practice which derive from inaccurate and discordant CPGs' interpretations. The results should prompt those responsible for producing such decision-making support to design documents that are better structured, less ambiguous, and more precise. In a model which facilitates their computerisation the expression of CPGs provides a solution that should be included upstream in the publication process.

Awareness↗