Marc Humbert

Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud), Lutetia Parisorum, Île-de-France, France

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Publications (394)2261.96 Total impact

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    ABSTRACT: Comité de la ESC para la elaboración de Guías de Práctica Clínica (CPG): José Luis Zamorano (Presidente) (España), Stephan Achenbach (Alemania), Helmut Baumgartner (Alemania), Jeroen J. Bax (Países Bajos), Héctor Bueno (España), Veronica Dean (Francia), Christi Deaton (Reino Unido), Çetin Erol (Turquía), Robert Fagard (Bélgica), Roberto Ferrari (Italia), David Hasdai (Israel), Arno Hoes (Países Bajos), Paulus Kirchhof (Alemania/Reino Unido), Juhani Knuuti (Finlandia), Philippe Kolh (Bélgica), Patrizio Lancellotti (Bélgica), Ales Linhart (República Checa), Petros Nihoyannopoulos (Reino Unido), Massimo F. Piepoli (Italia), Piotr Ponikowski (Polonia), Per Anton Sirnes (Noruega), Juan Luis Tamargo (España), Michal Tendera (Polonia), Adam Torbicki (Polonia), William Wijns (Bélgica), Stephan Windecker (Suiza)
    Revista Espa de Cardiologia 01/2015; · 3.34 Impact Factor
  • European Respiratory Journal 01/2015; 45(1):1-6. · 7.13 Impact Factor
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    ABSTRACT: Right ventricle ejection fraction (RVEF) evaluated with magnetic resonance imaging is a strong determinant of patient outcomes in pulmonary arterial hypertension. We evaluated the prognostic value of RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change 3-6 months after initiating pulmonary arterial hypertension-specific therapy. In a prospective cohort of newly diagnosed patients with idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension, RVEF was measured at baseline (n=100) and 3-6 months after initiation of therapy (n=78). After a median follow-up of 4.1 years, 41 deaths occurred, including 35 from cardiovascular causes. Patients with a (median) baseline RVEF >25% had better survival than those with a RVEF <25% using Kaplan-Meier analysis (p=0.010). RVEF at baseline was an independent predictor of all-cause and cardiovascular mortality in adjusted Cox regression model (p=0.002 and p=0.007, respectively; HR 0.93 for both). Patients with stable or increased RVEF at 3-6 months had a trend for improved all-cause survival (HR 2.43, p=0.086) and had less cardiovascular mortality (HR 3.25, p=0.034) than those in whom RVEF decreased despite therapy. RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change in RVEF 3-6 months after therapy initiation independently predict outcomes in patients with pulmonary arterial hypertension. Copyright ©ERS 2015.
    European Respiratory Journal 12/2014; · 7.13 Impact Factor
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    ABSTRACT: Right ventricular (RV) response to exercise or pharmacological stress is not well documented in pulmonary hypertension (PH). We investigated the relationship between RV reserve and ventricular-arterial coupling. Surgical ligation of the left pulmonary artery was performed in 13 Large White piglets (PH group), thereafter weekly embolisations of the right lower lobe were performed for 5 weeks. A control group of six piglets underwent sham procedures. Right heart catheterisation and echocardiography were performed at week 6. Pressure-volume loops were recorded before and after dobutamine infusion. Induction of experimental PH resulted in a higher mean±sd pulmonary artery pressure (34±9 versus 14±2 mmHg; p<0.01) and in a lower ventricular-arterial coupling efficiency (0.66±0.18 versus 1.24±0.17; p<0.01) compared with controls at 6 weeks. Dobutamine-induced relative changes in RV stroke volume index (SVI) and end-systolic elastance were lower in the PH group (mean±sd 47±5% versus 20±5%, p<0.01, and 81±37% versus 32±14%, p<0.01, respectively). Change in SVI was strongly associated with resting ventricular-arterial coupling (R(2)=0.74; p<0.01). RV reserve was associated with ventricular-arterial coupling in a porcine model of chronic pressure overload. Copyright ©ERS 2014.
    European Respiratory Journal 12/2014; · 7.13 Impact Factor
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    ABSTRACT: 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 © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    The American journal of pathology. 12/2014;
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    ABSTRACT: Palliative Potts shunt has been proposed in children with suprasystemic pulmonary arterial hypertension (PAH). A retrospective multicentre study was performed to assess short- and long-term outcomes after Potts shunt. From 2003 to 2014, 24 children underwent a Potts shunt [19 surgical, median age: 7.7 years (1.5-17 years), median weight: 19.5 kg (10.2-47 kg) and 5 transcatheter, median age: 8.1 years (2.3-9.7 years), median weight: 22 kg (12.5-31 kg)] for drug-refractory PAH. For the first time in humans, we performed an unidirectional valved Potts anastomosis in a child with infrasystemic PAH on intravenous epoprostenol who experienced repeated central line infections. Severe postoperative complications occurred in 6 patients (25.0%, all from the surgical group) including 3 early deaths (12.5%) related to low cardiac output. After a median follow-up (FU) of 2.1 years (range, 3 months to 14.3 years, ≥8 years in 7 patients), World Health Organization (WHO) functional class was dramatically improved in the 21 survivors, all being in WHO-functional class 1 or 2 (P < 0.05); none experienced syncope during the FU; none had overt right ventricular failure; mean 6-min walk distance improved from 42.3 ± 10.0% to 81.2 ± 9.7% of adjusted values for age and sex (P < 0.001), BNP/NT-proBNP levels normalized in all; and weaning of intravenous epoprostenol was obtained in all patients who received triple combination as pre-Potts anastomosis therapy. Finally, all survivors caught up to normal growth curves. Arterial oxygen saturation gradient between upper and lower limbs persisted at the last FU (94.7 ± 3.6% vs 81.6 ± 5.1%, P < 0.001). One patient required double lung transplantation 6 years after a surgical Potts shunt. Palliative Potts shunt allows prolonged survival and dramatic, long-lasting improvement in functional capacities in children with severe, drug-refractory PAH. The Potts shunt might be considered as a first surgical or interventional step in the management of children with severe, drug-refractory PAH, leaving the door open for further lung transplantation, if needed. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 12/2014; · 2.40 Impact Factor
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    ABSTRACT: To investigate the usefulness of a self-reported respiratory health transition question over 10 years through reliability, ability to capture long-term asthma trajectory and predictive ability. In two 20-year cohorts (Asthma-E3N, n = 16,371, 61-88 years; EGEA, n = 1254, 27-82 years), perceived 10-year change in respiratory health ("Overall, in the last 10 years, do you think that your bronchial or respiratory health has changed?" if yes: "Has it improved/deteriorated?") was studied in relation with change in respiratory medication dispensation and lung function, with change in asthma status measured over the same period of time, and with subsequent asthma-related outcomes. Perceived deterioration (14% in Asthma-E3N) was associated with increased dispensations of respiratory medications over time (from 17% with >2 dispensations in 2004 to 26% in 2010). Report of perceived deterioration (13% in EGEA) was related to a lung function decline steeper by 9.3 mL/year as compared to perceived improvement. In both cohorts, change (improvement or deterioration) was more often perceived by participants with than without asthma (>45% vs <20%) and was dominant among participants with persistent current asthma (77%). Perceived deterioration was related to poorer asthma control 7 years later and to higher use of oral corticosteroids in the following 18 months. The proposed simple self-reported respiratory health transition question over 10 years allows predicting part of the long-term trajectory of asthma. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Respiratory Medicine 12/2014; · 2.92 Impact Factor
  • European Respiratory Review 12/2014; 23(134):469-475.
  • Pascal Chanez, Marc Humbert
    European Respiratory Review 12/2014; 23(134):405-7.
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    ABSTRACT: Mutations in the BMPR2 gene encoding bone morphogenetic protein receptor type II (BMPRII) is the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The suspected mechanism is considered to be a defect of BMP signaling. The BMPRII receptor exists in a short isoform without a cytoplasmic tail, which has preserved BMP signaling. A cohort-study compared age at PAH diagnosis and severity between patients carrying a BMPR2 mutation affecting the cytoplasmic tail of BMPRII and affected carriers of a mutation upstream of this domain. We identified 171 PAH affected carriers with a mutatedBMPR2 gene. Twenty-three were carriers of a point mutation located on the cytoplasmic tail of BMPRII. This population was characterized by having an older age at diagnosis compared to other BMPR2mutation carriers (43.2±12.1 and 35.7±14.6 years; p=0.040), a lower pulmonary vascular resistance (13.3±3.5 and 17.4±6.7; p=0.023) and a higher proportion of acute vasodilator responders with a long-term response to calcium channel blockers (8.7% and 0%, p=0.02). No statistically differences were observed in survival. An in vitro assay showed that mutations located in the cytoplasmic tail led to normal activation of the Smad pathway, whereas activation was abolished in the presence of mutations located in the kinase domain. Patients carrying a mutation affecting the cytoplasmic tail of BMPRII were characterized by an older age at diagnosis compared to other BMPR2 mutation carriers, less severe hemodynamic characteristics, and a greater chance of being a long-term responder to calcium channel blockers. Further investigations are needed to better understand the consequences of theseBMPR2 mutations in BMPRII signaling pathways, and their possible role in pulmonary arterial remodeling.
    Chest 11/2014; · 7.13 Impact Factor
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    ABSTRACT: Background:Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic and T cells (DC and LT), key driver and effector cells respectively of the immune system, may allow the identification of immunopathological approaches to PAH management. Methods:We performed immunophenotyping of monocyte-derived DC (MoDC) and circulating lymphocytes from idiopathic PAH (iPAH) and control patients by flow-cytometry. Using the same technique, we performed cytokine profiling of both populations following stimulation and/or coculture. We tested the immunomudulatory effects of the glucocorticoid (dexamethasone/Dex) on this immunophenotype and cytokine profile. We confirmed, the immune polarization of PAH patients in blood DNA, by an epigenetic approach. Results:The profile of membrane costimulatory molecules of PAH-MoDCs was similar to controls. However, PAH-MoDCs retained higher levels of the T cell activating molecules CD86 and CD40 after Dex pretreatment than controls. This was associated with an increased expression of IL-12p40 and a reduced migration toward CCL21. Moreover, both with and without Dex, PAH-MoDCs induced a higher activation and proliferation of CD4+ T cells, associated with a reduced expression of IL-4 (Th2 response) and a higher expression of IL-17 (Th17 response). Purified PAH CD4+ T cells expressed higher level of IL-17 after activation than controls. Lastly, there was significant hypomethylation of the IL-17 promoter in the PAH blood DNA as compared to controls. Conclusions:As previously demonstrated in other chronic inflammatory and autoimmune conditions, we have highlighted Th17 immune polarization in PAH patients for the first time. Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic and T cells (DC and LT), key driver and effector cells respectively of the immune system, may allow the identification of immunopathological approaches to PAH management. We performed immunophenotyping of monocyte-derived DC (MoDC) and circulating lymphocytes from idiopathic PAH (iPAH) and control patients by flow-cytometry. Using the same technique, we performed cytokine profiling of both populations following stimulation and/or coculture. We tested the immunomudulatory effects of the glucocorticoid (dexamethasone/Dex) on this immunophenotype and cytokine profile. We confirmed, the immune polarization of PAH patients in blood DNA, by an epigenetic approach. The profile of membrane costimulatory molecules of PAH-MoDCs was similar to controls. However, PAH-MoDCs retained higher levels of the T cell activating molecules CD86 and CD40 after Dex pretreatment than controls. This was associated with an increased expression of IL-12p40 and a reduced migration toward CCL21. Moreover, both with and without Dex, PAH-MoDCs induced a higher activation and proliferation of CD4+ T cells, associated with a reduced expression of IL-4 (Th2 response) and a higher expression of IL-17 (Th17 response). Purified PAH CD4+ T cells expressed higher level of IL-17 after activation than controls. Lastly, there was significant hypomethylation of the IL-17 promoter in the PAH blood DNA as compared to controls. As previously demonstrated in other chronic inflammatory and autoimmune conditions, we have highlighted Th17 immune polarization in PAH patients for the first time.
    Chest 11/2014; · 7.13 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) remains an incurable disease associated with an unacceptably high early mortality, despite advances in therapeutic options. The disease is clinically silent untillate in its natural history, when most of the distal pulmonary arteries have been obliterated. Early diagnosis of PAH is associated with improved long-term survival, and screening of at-risk populations is, therefore, a rational strategy to improve outcomes in this condition. Doppler echocardiography is the most widely used screening tool in current clinical practice. The role of evidence-based screening strategies has been clarified by research such as the DETECT study in patients with systemic sclerosis. A multimodal approach, using a range of noninvasive tests, improves the performance of screening algorithms. Right heart catheterization is mandatory to confirm a diagnosis of PAH. Uncertainties exist about the definition and prognostic relevance of pulmonary hypertension during exercise, but accumulating evidence suggests that stress testing of the pulmonary circulation can unmask clinically important early disease. Novel tools for the early detection of pulmonary vascular disease are urgently needed, given the substantial limitations ofcurrently availabletechniques.
    Nature Reviews Cardiology 11/2014; doi. · 10.40 Impact Factor
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    ABSTRACT: 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.
    American Journal of Cardiovascular Drugs 11/2014; · 2.20 Impact Factor
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    ABSTRACT: End-stage chronic respiratory diseases (CRD) have systemic consequences, such as weight loss and susceptibility to infection. However the mechanisms of such dysfunctions are as yet poorly explained. We hypothesized that the genes putatively involved in these mechanisms would emerge from a systematic analysis of blood mRNA profiles from pre-transplant patients with cystic fibrosis (CF), pulmonary hypertension (PAH), and chronic obstructive pulmonary disease (COPD).
    PLoS ONE 10/2014; 9(10):e109291. · 3.53 Impact Factor
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    ABSTRACT: Isolated cases of pulmonary arterial hypertension (PAH) in patients treated with interferon (IFN) α or β have been reported in the literature. The aim of this study was to describe all consecutive cases of PAH patients with a history of IFN exposure identified in the French reference centre for severe pulmonary hypertension between 1998 and 2012. A total of 53 patients with PAH and a history of IFN therapy were identified. 48 patients had been treated with IFNα for chronic hepatitis C. Most of them had portal hypertension (85%) and 56% had HIV co-infection. Five additional patients had been treated with IFNβ for multiple sclerosis. The diagnosis of PAH was made within 3 years after IFN therapy in 66% of patients. Repeated haemodynamic assessment was available in 13 out of 16 patients exposed to IFN after the diagnosis of PAH. Increased pulmonary vascular resistance >20% was observed in 11 out of 13 cases (median 43% increase; IQR 32-67%). In five of these patients, IFN withdrawal resulted in spontaneous haemodynamic improvement. This retrospective analysis suggests that IFN therapy may trigger PAH. However, most of these patients had other risk factors for PAH. A prospective case-control study is necessary to definitively establish a link between IFN exposure and PAH.
    European Respiratory Journal 10/2014; · 7.13 Impact Factor
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    ABSTRACT: Background:Pulmonary arterial hypertension (PAH) is a rare and ultimately fatal disorder of the pulmonary vasculature. There is increasing interest in the worldwide characteristics of PAH patients, although data coming from the southern hemisphere remain scarce. The objective of this study was to describe a cohort of incident PAH patients from a large reference center in Brazil. Methods:All consecutive patients diagnosed with PAH by right heart catheterization between 2008 and 2013 were included in the study. Results:A total of 178 newly diagnosed PAH patients were enrolled in the study (mean age of 46 yr, female/male ratio of 3.3:1 and 45.5% in functional class III or IV). IPAH, CTD and Sch-PAH accounted for 28.7, 25.8 and 19.7% of all cases, respectively. The patients were treated with PDE5 inhibitors (66%), ERAs (27%) or a combination of both (5%). For the PAH group as a whole, the estimated survival rate 3 years after diagnosis was 73.9%. The prognosis for the CTD patients was worse than that for the IPAH and Sch-PAH patients (p=0.03). Conclusions:The distribution of PAH etiologies and the baseline characteristics in our registry clearly differ from the previously published European and USA-based registries. These differences highlight the importance of regional registries and also raise questions regarding the need to better account for such differences in future clinical trials.
    Chest 10/2014; · 7.13 Impact Factor
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    ABSTRACT: Systemic sclerosis per se should not be considered as an a priori contraindication for a pre-transplantation assessment in patients with advanced interstitial lung disease and/or pulmonary hypertension. For lung or heart-lung transplantation, a multidisciplinary approach, adapting the pre-transplant assessment to systemic sclerosis and optimizing systemic sclerosis patient management before, during and after surgery should improved the short- and long-term prognosis. Indications and contraindications for transplantation have to be adapted to the specificities of systemic sclerosis. A special focus on the digestive tract involvement and its thorough evaluation are mandatory before transplantation in systemic sclerosis. As the esophagus is almost always involved, isolated gastro-oesophageal reflux disease, pH metry and/or manometry abnormalities should not be a systematic per se contraindication for pre-transplantation assessment. Corticosteroids may be harmful in systemic sclerosis as they are associated with acute renal crisis. A low dose corticosteroids protocol for immunosuppression is therefore advisable in systemic sclerosis.
    La Presse Médicale 10/2014; · 1.17 Impact Factor
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    ABSTRACT: Identifying patients at risk of future severe asthma exacerbations, those whose asthma might be less treatment responsive, or both might guide treatment selection.
    Journal of Allergy and Clinical Immunology 09/2014; · 11.25 Impact Factor

Publication Stats

11k Citations
2,261.96 Total Impact Points

Institutions

  • 2008–2014
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      • Service de Pneumologie
      Lutetia Parisorum, Île-de-France, France
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Paris, Ile-de-France, France
    • University of Geneva
      • Division of Paediatrics
      Genève, GE, Switzerland
  • 2002–2014
    • Université Paris-Sud 11
      • • Faculty of Pharmaceutical Sciences
      • • Faculté de Médecine
      • • Service de Pneumologie
      Orsay, Île-de-France, France
    • Centre Chirurgical Marie Lannelongue
      Plessis-Robinson, Île-de-France, France
  • 2013
    • Catholic University of Louvain
      Walloon Region, Belgium
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
    • University of Grenoble
      Grenoble, Rhône-Alpes, France
    • Mater Misericordiae University Hospital
      • Department of Respiratory Medicine
      Dublin, Leinster, Ireland
  • 2006–2013
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2012
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Université du Droit et de la Santé Lille 2
      Lille, Nord-Pas-de-Calais, France
    • University of Michigan
      Ann Arbor, Michigan, United States
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
    • Icon Clinical Research Inc
      North Wales, Pennsylvania, United States
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 2011
    • Universitair Ziekenhuis Ghent
      Gand, Flanders, Belgium
    • Institut Cochin
      Lutetia Parisorum, Île-de-France, France
    • University College London
      • Centre for Rheumatology
      London, ENG, United Kingdom
  • 2008–2011
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 2006–2011
    • Centre Hospitalier Régional Universitaire de Lille
      • Division of Internal Medicine
      Lille, Nord-Pas-de-Calais, France
  • 2010
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
    • Université de Bretagne Occidentale
      Brest, Brittany, France
    • University of São Paulo
      • Department of Cardio-Pulmonary
      São Paulo, Estado de Sao Paulo, Brazil
    • University of California, Los Angeles
      • Division of Rheumatology
      Los Angeles, CA, United States
  • 2009
    • Palmelit Francia
      Montferrier, Languedoc-Roussillon, France
    • Lille Catholic University
      Lille, Nord-Pas-de-Calais, France
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, MD, United States
    • Medical University of Bialystok
      Belostok, Podlasie, Poland
  • 2007–2009
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2002–2009
    • University of Bologna
      • Institute of Cardiology
      Bologna, Emilia-Romagna, Italy
  • 2001
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 1997
    • National Heart, Lung, and Blood Institute
      Maryland, United States