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Guilleminault L.,French Institute of Health and Medical Research | Just J.,University Paris Est Creteil | Just J.,Paris-Sorbonne University | Humbert M.,University Paris - Sud | And 5 more authors.
Presse Medicale | Year: 2016

The role of seasons should be taken into account in the management of asthma. The environment varies between seasons and it is well documented that asthma is modulated by environment. Viruses cause asthma exacerbations peak, in winter, in adults while the peak is present in September in children. Allergens are probably a less powerful source of asthma exacerbation than viruses but pollen involvement in spring and summer and dust mites in autumn are indisputable. Air pollutants, present in summer during the hottest periods, are also highly involved in asthma exacerbations. Indoor air pollution, in winter, is also implicated in asthma disease. All these environmental factors are synergistic and increase the risk of asthma exacerbation. Therapies should be adapted to each season depending on environmental factors potentially involved in the asthma disease. © 2016 Elsevier Masson SAS.

Perros F.,University Paris - Sud | Perros F.,Laval University | Gunther S.,University Paris - Sud | Ranchoux B.,University Paris - Sud | And 17 more authors.
Circulation | Year: 2015

Background - Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD. Methods and Results - We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats. Conclusions - MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease. © 2015 American Heart Association, Inc.

Ranchoux B.,University of Sfax | Ranchoux B.,French Institute of Health and Medical Research | Gunther S.,University of Sfax | Gunther S.,University Paris - Sud | And 41 more authors.
American Journal of Pathology | Year: 2014

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents. Copyright © 2015 American Society for Investigative Pathology.

Germain M.,University Pierre and Marie Curie | Germain M.,Institut Universitaire de France | Eyries M.,Institut Universitaire de France | Eyries M.,French Institute of Health and Medical Research | And 46 more authors.
Nature Genetics | Year: 2013

Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; P = 7.47 × 10-10). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs. © 2013 Nature America, Inc. All rights reserved.

Chaumais M.-C.,University Paris - Sud | Chaumais M.-C.,French Institute of Health and Medical Research | Chaumais M.-C.,Departement Hospitalo University Thorax Innovation | Guignabert C.,French Institute of Health and Medical Research | And 18 more authors.
American Journal of Cardiovascular Drugs | Year: 2015

Pulmonary arterial hypertension (PAH) is a devastating life-threatening disorder characterized by elevated pulmonary vascular resistance leading to elevated pulmonary arterial pressures, right ventricular failure, and ultimately death. Vascular endothelial cells mainly produce and secrete endothelin (ET-1) in vessels that lead to a potent and long-lasting vasoconstrictive effect in pulmonary arterial smooth muscle cells. Along with its strong vasoconstrictive action, ET-1 can promote smooth muscle cell proliferation. Thus, ET-1 blockers have attracted attention as an antihypertensive drug, and the ET-1 signaling system has paved a new therapeutic avenue for the treatment of PAH. We outline the current understanding of not only the pathogenic role played by ET-1 signaling systems in the pathogenesis of PH but also the clinical pharmacology of endothelin receptor antagonists (ERA) used in the treatment of PAH. © 2014, Springer International Publishing Switzerland.

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