Nicole Fabien

Hospices Civils de Lyon, Lyons, Rhône-Alpes, France

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Publications (94)291.33 Total impact

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    ABSTRACT: To describe the clinical spectrum associated with aminoacyl-transfer RNA synthetase (ARS) autoantibodies in patients with idiopathic inflammatory myositis defined according to Peter and Bohan's criteria. Cohort studies were selected from MEDLINE and Embase up to August 2013. Two investigators independently extracted data on study design, patient characteristics, and clinical features (interstitial lung disease [ILD], fever, mechanic's hands [MH], Raynaud's phenomenon [RPh], arthralgia, sclerodactyly, cancer and dermatomyositis-specific rash) according to the presence of myositis-specific (anti-aminoacyl-transfer RNA synthetase [ARS], anti-signal recognition particle [anti-SRP] and anti-Mi2) and myositis-associated (anti-PM/Scl, anti-U1-RNP and anti-Ku) autoantibodies. 27 studies (3487 patients) were included in the meta-analysis. Arthralgia (75%, CI 67-81) and ILD (69%, CI 63-74) were the most prevalent clinical signs associated with anti-ARS autoantibodies. Anti-Mi2 and anti-SRP autoantibodies were associated with few extramuscular signs. ARS autoantibodies were identified in 13% of patients with cancer-associated myositis (5-25). Patients with non-anti-Jo1 ARS had greater odds of presenting fever (RR 0.63, CI 0.52-0.90) and ILD (RR 0.87, CI 0.81-0.93) compared to those with anti-Jo1 autoantibodies. The frequencies of myositis (RR 1.60, CI 1.38-1.85), arthralgia (RR 1.52, CI 1.32-1.76) and MH (RR 1.47, CI 1.11-1.94) were almost 50% higher in patients with anti-Jo1 compared to non-anti-Jo1 ARS autoantibodies. Patients with anti-PM/Scl differed from those with anti-ARS autoantibodies by a greater prevalence of RPh (RR 0.70, CI 0.53-0.94) and sclerodactyly (RR 0.47, CI 0.25-0.89). ILD was less frequent in patients with anti-U1-RNP autoantibodies (RR 3.35, CI 1.07-10.43). No difference was observed between anti-ARS and myositis-associated autoantibodies for other outcomes. The presence of anti-ARS autoantibodies delimits a heterogeneous subset of patients with a high prevalence of myositis, MH, arthralgia in anti-Jo1 patients, and RPh and fever in non-anti-Jo1 patients. The clinical signs of populations positive for anti-PM/Scl and anti-ARS autoantibodies largely overlap, especially with regard to ILD, challenging the clinical delimitation of the antisynthetase syndrome.
    Autoimmunity reviews 04/2014; · 6.37 Impact Factor
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    ABSTRACT: Introduction Amyopathic dermatomyositis associated with anti-MDA5 autoantibodies is a rare and very recently described clinical entity. Case report A 58-year-old woman was admitted with subacute onset of dyspnea (NYHA class IV) associated with cough, oligoarthritis of the wrists, myalgia and intermittent fever. Examination demonstrated skin lesions with heliotrope rash, Gottron's papules, “mechanics hands”, and basal inspiratory crackles on lung auscultation. Pulmonary function tests showed a restrictive ventilatory defect, with decreased carbon monoxide diffusion capacity and marked hypoxemia (PaO2 61 mmHg). The chest high-resolution computed tomography appearances were consistent with organizing pneumonia. Bronchoalveolar lavage differential cell count demonstrated 22 % neutrophils. Serum creatine kinase and electromyography were normal ; the serum ferritin level was elevated. Antinuclear antibodies were present and anti-MDA5 autoantibodies were identified. Significant improvement was obtained with systemic corticosteroids, later converted to mycophenolate mofetil as a steroid-sparing agent. Conclusion Amyopathic dermatomyositis associated with anti-MDA5 autoantibodies shares some characteristics with those associated with anti-synthetase antibodies. Muscular involvement may be mild or absent. Early diagnosis and treatment may improve outcome.
    Revue des Maladies Respiratoires 03/2014; · 0.50 Impact Factor
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    ABSTRACT: A reduction of ADA2 activity due to autosomal recessive loss of function mutations in CECR1 results in a newly described vasculopathic phenotype reminiscent of polyarteritis nodosa, with manifestations ranging from fatal systemic vasculitis with multiple strokes in children to limited cutaneous disease in middle-aged individuals. Evidence indicates that ADA2 is essential for the endothelial integrity of small vessels. However, CECR1 is not expressed, nor is the ADA2 protein detectable, in cultured human endothelial cells, thus implicating additional cell types or circulating factors in disease pathogenesis.
    Pediatric rheumatology online journal. 01/2014; 12:44.
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    ABSTRACT: Objective The aim of our study was to compare in a cohort of 705 patients the diagnostic performance of two tests to detect autoantibodies to cyclic citrullinated peptides (CCP) and to determine whether a bead-based assay within a multiplex flow immunoassay (MFA) can be used instead of an enzyme linked immunosorbent assay (ELISA) technique in routine practice. Design and methods Six hundred and thirty patients with rheumatic symptoms and 75 patients with systemic lupus erythematosus (SLE) were tested for anti-CCP autoantibodies using two techniques: ELISA (Inova) and MFA (BioPlex®, Bio-Rad). Results Using kappa coefficient, there was an excellent agreement between ELISA and MFA when comparing 630 patients with rheumatic symptoms (κ coefficient, 0.82). In this cohort 174 patients were identified as suffering from RA, while 456 patients suffered from other diseases. Sensitivity and specificity of anti-CCP autoantibodies for RA was 70.7% and 92.3% for ELISA and 64.4% and 92.8% for MFA. The positive and negative predictive values were 77.4% and 89.2% for ELISA and 77.2% and 87.2% for MFA, respectively. There were no differences in the diagnostic performances between the two assays (Z = 0.67). The specificity of anti-CCP autoantibodies analysing patients with SLE was 97.3% with MFA and 96% with ELISA with an excellent agreement between the methods (98.7%; κ coefficient, 0.79). Conclusions Concordance between ELISA and MFA is high in routine practice. Overall, MFA is a powerful tool for rapid assessment of anti-CCP autoantibodies and can replace the ELISA technique, which could be used as a second-line test in some cases.
    Clinical biochemistry 01/2014; · 2.02 Impact Factor
  • Nicole Fabien
    Revue Francophone des Laboratoires 01/2014; 2014(464):45–47.
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    ABSTRACT: Objective: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease, assumed to occur due to a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. Here, our objective was to identify the cause of an autosomal recessive form of SLE. Methods: We investigated three siblings from one consanguineous kindred with juvenile-onset SLE and used next generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunological and functional assays to assess the impact of the identified mutations on B cell biology. Results: We identified a homozygous missense mutation in PRKCD, encoding protein kinase delta (PKCδ) in all three affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ, involved in the deletion of autoreactive B cells, leading to a resistance to BCR- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increase of immature B cells in affected patients, and a developmental shift toward an immature phenotype of naïve B cells. Conclusion: Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 05/2013; · 7.48 Impact Factor
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    ABSTRACT: To assess the performance of commercial anti-ganglioside antibody assays, we determined anti-ganglioside antibody IgG and IgM isotype profiles of patients with acute and chronic well-characterized immune-mediated peripheral neuropathies by one immunodot assays (Zentec/Ingen: Dotzen Ganglio Profile Ab, Euroimmun/BioAdvance: Euroline ganglioprofile), two line-immuno assay (GA Generic Assays/Labodia: Anti-Gangli osid Dot, Euroimmun/BioAdvance: Euroline ganglioprofile), and one enzyme-linked immunosorbent assay (ELISA) (Bühlmann: GanglioCombi). Specific antibody profiles were compared with those obtained by our validated standard in-house immunodot assay (IDA). We selected 33 sera with high levels of IgG and IgM anti-ganglioside antibodies from 15 patients with Guillain-Barre syndrome (GBS) subtypes and variants, 12 patients with CANOMAD syndrome (chronic ataxic neuropathy with ophthalmoplegia, M-paraprotein, cold agglutinins, disialosyl antibodies), 5 patients with chronic motor peripheral neuropathies, and 1 patient with sensory neuropathy and a control group composed of 10 patients with non-autoimmune neuropathy. The 3 commercial IDAs employing hydrophobic membranes and the ELISA demonstrated different carbohydrate epitopes on 6 to 12 glycolipid antigens used for anti-ganglioside antibody detection. Comparison with the validated in-house IDA showed large variations in sensitivity between tests and a more diverse reactivity to gangliosides than expected. The test with the largest panel of glycolipids detecting 11 anti-ganglioside antibody reactivities (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b, and sulfatide) revealed the best concordance with our in-house assay. However, even with this test, differences were observed in the immunoreactivity against some gangliosides and weakly stained bands were not easy to interpret. Our data suggest an urgent need for standardization of commercial anti-ganglioside assays and the introduction of international anti-ganglioside antibody reference standards.
    Clinical laboratory 01/2013; 59(11-12):1277-87. · 0.92 Impact Factor
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    Muscle & Nerve 10/2011; 44(4):611. · 2.31 Impact Factor
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    Muscle & Nerve 10/2011; 44(4):612. · 2.31 Impact Factor
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    ABSTRACT: Autoantibodies detected after kidney transplantation may contribute to chronic rejection. We and others have previously described the organization of immune effectors into functional intragraft tertiary lymphoid tissue, a site where breakdown of B-cell tolerance may occur. To test this, we performed a comprehensive analysis of 26 chronically rejected kidney grafts. Antibodies were screened by indirect immunofluorescence on HEp2 cells, a procedure that detects antibodies to intracellular antigens, and monkey kidney sections, which detects kidney tissue autoantigens. The incidence of anti-HEp2 autoantibodies was significantly higher in graft explant culture supernatants than in patient sera. Reactivity against monkey kidney sections was detected in almost half of culture supernatants with anti-HEp2 autoantibodies. A local enrichment in T helper 17 and B-cell-activating factor (CD257) correlated with intragraft production of anti-HEp2 antibodies. A decrease in Tregs and a symmetric increase of activated OX40 (CD134)-expressing CD4+ T cells were found in grafts in which anti-kidney autoantibodies were produced. Thus, a stepwise breakdown of B-cell tolerance occurs within the graft during chronic rejection. Hence, the intragraft microenvironment interferes with peripheral deletion of autoreactive immature B cells that, in turn, produce antibodies against intracellular autoantigens. When intragraft immune regulation is insufficient, spreading of the local response against kidney autoantigens is favored.
    Kidney International 09/2011; 81(2):207-19. · 8.52 Impact Factor
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    ABSTRACT: The usefulness of immumoglobulin (Ig) A antibodies to gliadin (AGA-IgA) in addition to IgA anti-endomysium and tissue transglutaminase antibodies was evaluated in 4122 children younger than 2 years with a suspicion of coeliac disease (CD). Eight percent (312/4122) displayed IgA anti-endomysium and/or IgA anti-tissue transglutaminase, whereas 2.1% (85/4122) displayed only AGA-IgA. Clinical data were obtained for 62 of 85 children with isolated AGA-IgA, and 33 children underwent a duodenal biopsy. Histologically proven CD was established for 5 patients, whereas 57 children were diagnosed to experience other diseases. The systematic detection of AGA-IgA using native gliadin conferred no additional diagnostic benefit for the diagnosis of CD in children younger than 2 years of age, except for rare cases.
    Journal of pediatric gastroenterology and nutrition 08/2011; 54(1):110-2. · 2.18 Impact Factor
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    ABSTRACT: Thrombotic events may occur in celiac disease. In this study, we analyzed clinical features and risk factors for thrombosis in seven patients who had celiac disease and thrombosis. We retrospectively studied 87 patients with adult celiac disease and identified seven cases of thrombosis. We searched if risk factors for thrombosis were identified and tested retrospectively antiphospholipid antibodies on the serum. In our study, the global prevalence of thrombosis was 8 %, and 5.7 % for spontaneous thrombosis, with venous thrombosis (n=5) or arterial thrombosis (n=1) or both (n=2). The seven patients consisted in six women and one man with a mean age of 44.8 years at time of thrombosis. Thrombotic events occurred before the diagnosis of celiac disease in four cases. In three cases, venous thrombosis was in unusual sites: portal (n=2), splenic vein thrombosis (n=1). In six cases, we identified risk factors for thrombosis, which could be linked to celiac disease: hyperhomocysteinemia (n=1), protein C and S deficiency due to vitamin K deficiency (n=3) and antiphospholipid antibodies (n=2). Such risk factors for thrombosis should be identified in patients in adult celiac disease in order to correct them and add a thromboembolic prophylaxis.
    La Revue de Médecine Interne 03/2011; 32(10):600-4. · 0.90 Impact Factor
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    ABSTRACT: The efficacy of anti-TNF-α therapies highlights the role of TNF-α in the pathogenesis of rheumatoid arthritis (RA). However, the mechanism of action of these agents is poorly understood at the molecular level. The aim of this study was to characterize the effects of anti-TNF-α treatment on the global gene expression profile in peripheral blood mononuclear cells (PBMCs) of responder RA patients. Changes in gene expression were determined using oligonucleotide microarrays (25,341 genes) in PBMCs obtained before and after 12 wk of treatment with either etanercept or adalimumab from responder RA patients. Two hundred fifty-one genes displayed significant changes (false discovery rate < 0.1%) in expression level (178 upregulations with mean fold change = 1.5 and 73 downregulations with mean fold change = -1.50) after 12 wk of treatment. Importantly, the expression of several genes, including those coding for the calcium binding proteins S100A12 and A8, CD14 antigen, Selectin P, or ribosomal protein L39, reported to be upregulated in RA patients, were found to be decreased after anti-TNF-α treatment. Globally, inflammation, immune response, apoptosis, protein synthesis, and mitochondrial oxido-reduction were the most affected pathways in response to anti-TNF-α treatment. The obtained gene expression signature in PBMCs provides new information to better understand the mechanisms of action of anti-TNF-α treatment in RA patients.
    Physiological Genomics 01/2011; 43(7):365-71. · 2.81 Impact Factor
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    ABSTRACT: The association of positive cytoplasmic antineutrophil antibody (ANCA) necrotizing crescentic glomerulonephritis with endocarditis raises diagnostic issues. Indeed, it is often difficult to determine if the kidney injury is either secondary to an infectious disease or caused by an ANCA-associated small vessel vasculitis. We report a 59-year-old man admitted in nephrology for acute glomerular syndrome in whom the renal biopsy showed a crescentic necrotizing glomerulonephritis. A diagnosis of vasculitis was initially considered in the presence of high titer of ANCA (anti-proteinase 3). Because of associated Staphyloccocus aureus endocarditis the patient received both corticosteroids and antibiotics that allowed remission of both kidney injury and endocarditis. The renal presentation and the disappearance of ANCA support the infectious etiology of this glomerulonephritis rather than an ANCA-associated small vessel vasculitis. It is important to be cautious in the presence of ANCA positive extracapillary glomerulonephritis and endocarditis should be ruled out before initiation of corticosteroids that may be nevertheless necessary in severe acute glomerulonephritis.
    La Revue de Médecine Interne 01/2011; 32(12):e116-8. · 0.90 Impact Factor
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    ABSTRACT: PurposeThrombotic events may occur in celiac disease. In this study, we analyzed clinical features and risk factors for thrombosis in seven patients who had celiac disease and thrombosis.
    Revue De Medecine Interne - REV MED INTERNE. 01/2011; 32(10):600-604.
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    ABSTRACT: Esophageal involvement occurs in about 80% of patients with systemic sclerosis, with a marked diminution of peristaltic pressures in the distal two-thirds of the esophagus. Our aims were to more fully characterize esophageal motility disorders in systemic sclerosis using high-resolution manometry (HRM) and to determine predictive factors of esophageal involvement. Fifty-one patients (46 females) with systemic sclerosis were included in this retrospective study. Esophageal motility was characterized with HRM. The demographic data, esophageal symptoms, presence of other organ involvement, and autoantibody profile (anti-Scl70 antibodies [Scl70], anticentromere antibodies [ACA]) were recorded for all patients. Esophageal body dysmotility was present in 33 patients (67.3%) and was associated with hypotensive esophagogastric junction in 27 patients (55.1%). The velocity of proximal contractions was higher in patients with esophageal body dysmotility compared to patients with normal peristalsis (median 10.8 cm/s vs. 5.5, P = 0.04). The amplitude of middle esophageal contraction but not of distal esophageal contraction was reduced in patients with hypoperistalsis. Diffuse esophageal skin involvement, presence of Scl70 and absence of ACA were associated with esophageal involvement. Esophageal symptoms encountered in 87.5% of patients were not predictive of esophageal dysmotility. This HRM series confirms the high prevalence of esophageal body dysmotility in systemic sclerosis. Diffuse skin involvement, positive Scl70 and negative ACA, but not esophageal symptoms, may predict esophageal body dysmotility.
    Diseases of the Esophagus 12/2010; · 1.64 Impact Factor
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    ABSTRACT: Clinical difficulties in predicting systemic lupus erythematosus (SLE) renal flares are still encountered. Biological markers such as autoantibodies (aAbs) may be of major interest for clinicians in the follow-up of SLE patients. The aim of our study was to investigate the clinical utility of one of these biological markers, anti-C1q aAbs, in predicting renal flares of SLE nephritis in comparison with the 'gold standard' anti-double stranded DNA (anti-dsDNA) aAbs. Anti-C1q aAbs and anti-dsDNA aAbs were analysed through a longitudinal retrospective study of 23 SLE patients presenting with one or more renal flares. Anti-C1q and/or anti-dsDNA aAbs were found in 20 (87%) of 23 patients, of whom 16 (69%) displayed both. Thirty-three renal flares occurred during the course of the study, and anti-C1q aAbs and anti-dsDNA aAbs were positive in 25 (76%) and 24 (73%) of these flares respectively. The sensitivity of anti-C1q and/or anti-dsDNA aAbs in predicting renal flares reached 85%. The specificity of anti-C1q aAbs was 84%, of anti-dsDNA aAbs 77% and of both aAbs 97%. Positive and negative predictive values were as follows: 56% and 70% for anti-C1q aAbs, 53% and 72% for anti-dsDNA aAbs. The combination of both aAbs had the highest positive predictive value (69%), whereas absence of both aAbs was associated with the highest negative predictive value (74%). In conclusion, our results confirm that anti-C1q aAbs are present in a significant percentage of SLE patients with active renal involvement, suggesting that these aAbs could be a useful additional marker. The presence of anti-C1q and anti-dsDNA aAbs was associated with a high risk of renal flare, whereas the absence of both aAbs excluded such an event. These data confirm that systematic detection of anti-C1q and anti-dsDNA aAbs is of interest for the follow-up in SLE patients with renal involvement.
    Lupus 10/2010; 20(1):28-34. · 2.78 Impact Factor
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    ABSTRACT: Protein microarray technology provides a useful approach for the simultaneous serodetection of various antibodies in low sample volumes. To implement functional protein microarrays, appropriate surface chemistry must be designed so that both the protein structure and the biological activity can be retained. In the current study, two surface chemistries for protein microarrays and immunofluorescent assays were developed. Glass slides were functionalized with N-hydroxysuccinimide (NHS) ester via a monofunctional silane or maleic anhydride-alt-methyl vinyl ether (MAMVE) copolymer to allow covalent grafting of histone proteins. Analytical performance of these microarrays was then evaluated for the detection of anti-histone autoantibodies present in the sera of patients suffering from a systemic autoimmune disease, namely systemic lupus erythematosus (SLE), and the results were compared with those of the classical enzyme-linked immunosorbent assay (ELISA) and Western blot. The detection limit of our MAMVE copolymer microarrays was 50-fold lower than that of the classical ELISA. Furthermore, 100-fold less volume of biological samples was required with these miniaturized immunoassays.
    Analytical Biochemistry 05/2010; 400(1):10-8. · 2.58 Impact Factor
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    ABSTRACT: To compare anti-PM/Scl autoantibody-associated interstitial lung disease (ILD) with anti-aminoacyl-tRNA synthetases (anti-ARS) autoantibody-associated ILD. We retrospectively studied 21 patients with ILD from a department of respiratory medicine, including 9 with anti-PM/Scl autoantibodies (6 women, median age 55 yrs, followup 5.5 yrs) and 12 with anti-ARS autoantibodies (6 women, median age 59 yrs, followup 2.3 yrs). Pulmonary manifestations in patients with anti-PM/Scl autoantibody-associated ILD usually followed the extrapulmonary manifestations of the connective tissue disease (CTD) (7/9 cases). The predominant imaging features on initial high resolution computed tomography were ground-glass attenuation and reticular opacities, and mainly suggested nonspecific interstitial pneumonia in both groups. CTD was classified as dermatomyositis (DM; 2), undifferentiated CTD (2), cutaneous limited systemic sclerosis (2), rheumatoid arthritis (RA; 1), and overlap syndrome (1) in the anti-PM/Scl group; and polymyositis (4), undifferentiated CTD (5), DM (1), amyopathic DM (1), and RA (1) in the anti-ARS group. Frequencies of arthralgia, Raynaud phenomenon, cutaneous rash, and mechanic's hands were comparable in both groups. Myalgia or muscle weakness was present in 0/9 PM/Scl and 5/12 ARS patients (p < 0.05). More than 1 autoantibody was present in 11 patients. ILD worsened despite treatment in 4 patients with anti-PM/Scl autoantibodies and 2 with anti-ARS autoantibodies, and included 1 death. Anti-PM/Scl and anti-ARS antibodies are associated with similar clinical manifestations, with the exception only of more overt myositis in the latter, therefore challenging the clinical specificity of the antisynthetase syndrome.
    The Journal of Rheumatology 03/2010; 37(5):1000-9. · 3.26 Impact Factor

Publication Stats

1k Citations
291.33 Total Impact Points

Institutions

  • 2005–2014
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2011
    • University of Lyon
      Lyons, Rhône-Alpes, France
    • Cliniques Universitaires Saint-Luc
      • Division of Neurology
      Brussels, BRU, Belgium
  • 1998–2009
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France
  • 2004
    • HCL
      Noida, Uttar Pradesh, India
  • 1999
    • CHU de Lyon - Hôpital Gériatrique Antoine Charial 
      Lyons, Rhône-Alpes, France
  • 1996
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Unité Inserm U1077
      Caen, Lower Normandy, France