M Roth

Universitätsspital Basel, Bâle, Basel-City, Switzerland

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Publications (64)367.43 Total impact

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    ABSTRACT: Background Airway wall remodelling is a key pathology of asthma. It includes thickening of the airway wall, hypertrophy and hyperplasia of bronchial smooth muscle cells (BSMC), as well as an increased vascularity of the sub-epithelial cell layer. BSMC are known to be the effector cells of bronchoconstriction, but they are increasingly recognized as an important source of inflammatory mediators and angiogenic factors. Objective To compare the angiogenic potential of BSMC of asthmatic and non-asthmatic patients and to identify asthma-specific angiogenic factors. Methods Primary BSMC were isolated from human airway tissue of asthmatic and non-asthmatic patients. Conditioned medium (CM) collected from BSMC isolates was tested for angiogenic capacity using the endothelial cell (EC)-spheroid in vitro angiogenesis assay. Angiogenic factors in CM were quantified using a human angiogenesis antibody array and enzyme linked immunosorbent assay. Results Induction of sprout outgrowth from EC-spheroids by CM of BSMC obtained from asthma patients was increased compared with CM of control BSMC (twofold, p < 0.001). Levels of ENA-78, GRO-α and IL-8 were significantly elevated in CM of BSMC from asthma patients (p < 0.05 vs. non-asthmatic patients). SB 265610, a competitive antagonist of chemokine (CXC-motif) receptor 2 (CXCR2), attenuated the increased sprout outgrowth induced by CM of asthma patient-derived BSMC. Conclusions ASMC isolated from asthma patients exhibit increased angiogenic potential. This effect is mediated through the CXCR2 ligands (ENA78, GRO-α and IL-8) produced by BSMC. Implications CXCR2 ligands may play a decisive role in directing the neovascularization in the sub-epithelial cell layers of the lungs of asthma patients. Counteracting the CXCR2-mediated neovascularization by pharmaceutical compounds may represent a novel strategy to reduce airway remodelling in asthma.
    Full-text · Article · Nov 2012 · Pneumologie
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    ABSTRACT: Cigarette smoke is a major cause of chronic obstructive pulmonary disease (COPD) and emphysema. Although cigarette smoke represses cellular proliferation, the molecular mechanisms underlying this phenomenon are unknown. CCAAT/enhancer-binding proteins (C/EBPs) are key regulators of cell cycle progression, differentiation and pro-inflammatory gene expression, are regulated predominantly at the translational level and may be involved in the pathogenesis of COPD. The aim of this study was to assess the effect of cigarette smoke on proliferation and the expression and translational regulation of C/EBPα and C/EBPβ in nondiseased primary human lung fibroblasts. Fibroblasts were exposed to cigarette smoke-conditioned medium (10% and 20% for 24 h). Proliferation was determined by [(3)H]thymidine incorporation. Protein expression levels were determined by immunoblotting and translation was monitored using a translation control reporter system. Cigarette smoke significantly reduced fibroblast proliferation and significantly upregulated full-length C/EBPα and C/EBPβ proteins due to a shift in the translational control of CEBPA and CEBPB mRNAs. This shift involved the re-initiation of mRNA translation via the regulatory upstream open reading frame, which coincided with increased interleukin-8 release and a decrease in functional elastin level. These findings provide a novel mechanism to understanding the tissue remodelling observed in the lungs of COPD patients.
    Full-text · Article · Aug 2011 · European Respiratory Journal
  • P Seidel · M Roth · Q Ge · I Merfort · C T S'ng · AJ Ammit
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    ABSTRACT: Airway smooth muscle cells (ASMCs) secrete eotaxin and RANTES (regulated on activation, normal T-cell expressed and secreted) in response to tumour necrosis factor (TNF)-α, which is inhibited by the nuclear factor (NF)-κB inhibitor dimethylfumarate (DMF). NF-κB/IκB (inhibitor of NF-κB) glutathionylation and changes in chromatin remodelling can inhibit NF-κB activity. In this study, we determined whether NF-κB/IκB glutathionylation and reduced histone H3 phosphorylation might underlie the inhibitory effect of DMF on NF-κB activity, and eotaxin and RANTES secretion. Primary human ASMCs were treated with DMF, diamide and/or glutathione (GSH) ethylester (OEt) prior to TNF-α stimulation and were subsequently analysed by ELISA, electrophoretic mobility shift assay, immunofluorescence, co-immunoprecipitation or immunoblotting. DMF reduced intracellular GSH and induced IκBα glutathionylation (IκBα-SSG), which inhibited IκBα degradation, NF-κB p65 nuclear entry and NF-κB/DNA binding. In addition, DMF inhibited the phosphorylation of histone H3, which was possibly mediated by the inhibitory effect of DMF on mitogen- and stress-activated protein kinase (MSK)-1. However, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase MAPK and MAPK phosphatase-1, upstream of MSK-1, were not inhibited by DMF. Importantly, DMF-mediated effects on NF-κB, histone H3, eotaxin and RANTES were reversed by addition of GSH-OEt. Our data suggest that DMF inhibits NF-κB-dependent eotaxin and RANTES secretion by reduction of GSH with subsequent induction of IκBα-SSG and inhibition of histone H3 phosphorylation. Our findings offer new potential drug targets to reduce airway inflammation in asthma.
    No preview · Article · Jun 2011 · European Respiratory Journal
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    N Miglino · M Roth · M Tamm · P Borger
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    ABSTRACT: Reduced translation of CEBPA mRNA has been associated with increased proliferation of bronchial smooth muscle (BSM) cells of asthma patients. Here, we assessed the effect of house dust mite (HDM) extracts on the cell proliferation ([(3)H]-thymidine incorporation), inflammation (interleukin (IL)-6 release) and upstream translation regulatory proteins of CCAAT/enhancer-binding protein (C/EBP)α in human BSM cells of healthy controls and asthmatic patients. HDM extract significantly increased IL-6 protein and proliferation of BSM cells of asthma patients only. HDM extract reduced the C/EBPα expression in BSM cells of asthma patients, which coincided with significantly increased levels of calreticulin (CRT) protein, an inhibitor of CEBPA mRNA translation. HDM extract elicited both protease-dependent and -independent responses, which were mediated via protease-activated receptor (PAR)2 and CRT, respectively. In conclusion, HDM extract reduced CEBPA mRNA translation, specifically in asthmatic BSM cells, and 1) upregulated CRT, 2) activated PAR2, and increased 3) IL-6 expression and 4) the proliferation of asthmatic BSM cells. Hence, HDM exposure contributes to inflammation and remodelling by a nonimmune cell-mediated mechanism via a direct interaction with BSM cells. These findings may potentially explain several pathological features of this disease, in particular BSM cell hyperplasia.
    Full-text · Article · Nov 2010 · European Respiratory Journal
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    ABSTRACT: The antipsoriatic dimethylfumarate (DMF) has been anecdotically reported to reduce asthma symptoms and to improve quality of life of asthma patients. DMF decreases the expression of proinflammatory mediators by inhibiting the transcription factor NF-kappaB and might therefore be of interest for the therapy of inflammatory lung diseases. In this study, we determined the effect of DMF on platelet-derived growth factor (PDGF)-BB- and TNFalpha-induced asthma-relevant cytokines and NF-kappaB activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1-100 microM) and/or dexamethasone (0.0001-0.1 microM), NF-kappaB p65 siRNA (100 nM), the NF-kappaB inhibitor helenalin (1 microM) before stimulation with PDGF-BB or TNFalpha (10 ng/ml). Cytokine release was measured by ELISA. NF-kappaB, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNFalpha-induced eotaxin, RANTES, and IL-6 as well as PDGF-BB-induced IL-6 expression was inhibited by DMF and by dexamethasone from asthmatic and nonasthmatic ASMC, but the combination of both drugs showed no glucocorticoid sparing effect in either of the two groups. NF-kappaB p65 siRNA and/or the NF-kappaB inhibitor helenalin reduced PDGF-BB- and TNFalpha-induced cytokine expression, suggesting the involvement of NF-kappaB signaling. DMF inhibited TNFalpha-induced NF-kappaB p65 phosphorylation, NF-kappaB nuclear entry, and NF-kappaB-DNA complex formation, whereas PDGF-BB appeared not to activate NF-kappaB within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-kappaB p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-kappaB but a wider range of NF-kappaB-linked signaling proteins, which may explain its potential beneficial effect in asthma.
    Preview · Article · Jun 2009 · AJP Lung Cellular and Molecular Physiology
  • J L Black · M Roth
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    ABSTRACT: The traditional view of the pathophysiology of asthma is that its characteristic features are secondary to a major allergic or immunological dysfunction. However, this does not explain intrinsic asthma, which can occur in the absence of atopy. An alternative view is that an abnormality in the airway smooth muscle cell, which is capable of producing inflammatory, immunological and growth factors as well as molecules, which facilitate interaction with inflammatory cells, is the primary or instigating event. Evidence is rapidly accumulating that the smooth muscle is abnormal, in that it proliferates faster, produces more chemokines and cytokines as well as a different profile of extracellular matrix proteins than its non-asthmatic counterpart. These abnormalities may arise from altered calcium homoeostasis leading to increased mitochondrial biogenesis and/or decreases in the levels of key transcription factors such as CCAAT enhancer binding protein-alpha. Conditions under which smooth muscle is ablated, such as bronchial thermoplasty, may help us to understand more about the contribution of an airway smooth muscle dysfunction to asthma aetiology.
    No preview · Article · May 2009 · Clinical & Experimental Allergy
  • H Alkhouri · M Roth · B Oliver · CL Armour · JM Hughes

    No preview · Conference Paper · Apr 2009
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    ABSTRACT: Glycosaminoglycans (GAG) are essential extracellular matrix molecules which regulate tissue flexibility, a parameter that is reduced in airways of patients with asthma and chronic obstructive pulmonary disease (COPD). We investigated the expression of GAG and their metabolising enzymes in primary human airway smooth muscle cells (ASMC) obtained from healthy donors (controls) and patients with asthma or COPD. Total GAG synthesis was assessed by [(3)H]-glucosamine incorporation. GAG were isolated, purified, fractionated by electrophoresis and characterised using specific GAG-degrading enzymes. Secretion of hyaluronic acid (HA) by ASMC from patients with asthma or COPD was significantly decreased compared with controls. RT-PCR analysis and western blotting revealed that this decrease was associated with a significant reduction in the expression of HA synthase-1 and -2 and a significant increase of hyaluronidase-1. Furthermore, the expression of the HA receptor CD44 was significantly decreased, whereas the receptor for HA-mediated motility was not expressed in asthma or COPD. Our results indicate that there is a decreased expression of HA in asthma and COPD associated with a synergistic regulation of HA metabolising enzymes that may regulate the pathological airway remodelling in these lung diseases.
    No preview · Article · Apr 2009 · European Respiratory Journal
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    ABSTRACT: Airway remodelling is a key feature of asthma and chronic obstructive pulmonary disease (COPD). The remodelling process involves the deposition of extracellular matrix (ECM) proteins within the airways. Current therapies for asthma and COPD consist of inhaled corticosteroids and long-acting beta(2)-agonists (LABA). However, their effect on airway remodelling is not well understood so far. In this study we investigated the effect of fluticasone and salmeterol, either alone or in combination, on fibronectin and tenascin-C protein, isoform, and mRNA levels in primary human lung fibroblasts. In our model, fibroblasts cultured in serum-free medium represented a non-inflammatory condition and stimulation with 5% fetal calf serum and/or TGF-beta(1) mimicked a pro-fibrotic environment with activation of tissue repair. Using these two different conditions, the effects of fluticasone and salmeterol on fibronectin and tenascin-C protein and mRNA levels were analysed by immunoblotting and semi-quantitative RT-PCR. In both conditions, fluticasone increased fibronectin transcript and protein levels, whereas it decreased those of tenascin-C. Salmeterol neither affected fibronectin and tenascin-C synthesis significantly nor did it influence the effect of fluticasone when applied in combination. Furthermore, we found that treatment with fluticasone had an opposite effect on extra domain A and B containing fibronectin isoforms generated by alternative splicing compared with total fibronectin transcript levels, whereas tenascin-C isoforms were not differently modulated by fluticasone. Our results indicate that standard therapies for inflammatory lung disorders influence ECM protein composition and relative expression levels. In contrast to corticosteroids, LABA did not significantly alter the expression of tenascin-C and fibronectin in cultures of primary human lung fibroblasts.
    No preview · Article · Apr 2009 · Clinical & Experimental Allergy
  • P Seidel · I Merfort · JM Hughes · BG Oliver · M Tamm · M Roth

    No preview · Conference Paper · Apr 2009
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    ABSTRACT: Rhinovirus infection is responsible for considerable morbidity and mortality as the major cause of exacerbations of asthma, and is also known to induce exacerbations of cystic fibrosis and chronic obstructive pulmonary disease. Exacerbations of these diseases are also frequently associated with bacterial and atypical bacterial infection. Alveolar macrophages are the major immune cells in the airways and are important in defence against bacterial infections. The authors investigated whether rhinovirus modifies cytokine release, the pattern recognition receptor expression and phagocytosis by human alveolar macrophages in response to bacterial products. Viable rhinovirus was detected in macrophages up to 3 days after exposure and viral RNA expression persisted for 10 days. Infectious but not UV inactivated rhinovirus increased tumour necrosis factor alpha (TNFalpha) and interleukin (IL)8 release by macrophages. In contrast, infectious rhinovirus impaired lipopolysaccharide and lipoteichoic acid induced TNFalpha and IL8 secretion by macrophages. Rhinovirus induced impairment of macrophage antibacterial immune responses did not involve IL10, prostaglandin E(2) or downregulation of Toll-like receptor 2. Furthermore, the macrophage phagocytic response to labelled bacterial particles, but not to latex beads, was impaired. The authors have identified impairment of cytokine responses to bacterial lipopolysaccharide and lipoteichoic acid by alveolar macrophages in response to infectious rhinovirus. Virus induced impairment of antibacterial host defence has important implications in the pathogenesis of exacerbations of respiratory diseases.
    No preview · Article · Jul 2008 · Thorax
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    ABSTRACT: In the healthy lung, airway epithelial cells (AEC) regulate fibroblast proliferation through release of soluble factors, such as prostaglandins and proteins. Fibroproliferative diseases and airway remodelling may result from an inadequate generation of suppressive factors by AEC or the inability of fibroblasts to respond to them appropriately. The aim of this study was to study the effect of primary human AEC on the proliferation of fibroblasts obtained from healthy and fibrotic lungs in an interactive cell culture model. Conditioned medium (CM) from 14 out of 16 AEC lines significantly inhibited proliferation of normal human lung fibroblasts by 51.2+/-6.0%. The proliferation of fibroblasts derived from patients with lung fibrosis was equally inhibited by CM of AEC. The inhibitory effect of AEC-CM was completely reversed when fibroblasts were pre-incubated with 2.5 microm indomethacin. Furthermore, primary human AEC, but not fibroblasts, secrete TGF-beta, and the inhibitory effect of the AEC-CM was blocked by neutralizing anti-TGF-beta antibodies. These results demonstrate that AEC actively inhibit the proliferation of both normal and fibrotic fibroblasts via TGF-beta, which induces the prostaglandin E(2) synthesis in fibroblasts. The data indicate that proliferative lung diseases may be treated using the epithelial cell as the target of medication.
    Full-text · Article · Jun 2008 · Clinical & Experimental Allergy

  • No preview · Article · Jun 2008 · Annals of the rheumatic diseases
  • M Roth · J L Black
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    ABSTRACT: The essential features of persistent severe asthma include structural changes in the airway wall (remodelling). It is not known whether these are the sequelae of chronic inflammation or indeed its initiators. Several transcription factors have been implicated in the inflammatory process in asthma, including the glucocorticoid receptor (GR), NFkappaB, Activator Protein-1 (AP-1), Nuclear Factor of Activated T-cells (NF-AT), cyclic AMP Response Element Binding Protein and more recently, the CCAAT/Enhancer Binding Protein (C/EBP), Peroxisome Proliferator-activated Receptor (PPAR) and the bZIP transcription factor, Nrf2. Could a pathological de-regulation of one of these transcription factors explain the broad spectrum of asthma pathology and can their modulation lead to better symptom control? Although some of the transcription factors seem to be valid targets (NFkappaB, Nrf2 or STAT6) or tools (PPARgamma, -alpha and C/EBP-alpha) for new therapeutic approaches, since many transcription factors play a central role in tissue and organ homeostasis, a longterm general suppression or overexpression, would cause severe side effects in other organs. Cell type specific application of decoy or antisense oligonucleotides for NFkappaB, Nrf2 or STAT6, or specific agonists for PPARgamma and -alpha may help to control the inflammatory response in lung epithelial cells and infiltrated immune cells, but additional, unwanted, effects on other resident cells of the lung cannot be excluded and a beneficial effect over known anti-asthma drugs has first to be proven. In order to progress with such novel therapeutic strategies, the only option seems to be to link transcription factor inhibitors/activators to a cell type specific delivery system.
    No preview · Article · Jun 2006 · Current Drug Targets
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    ABSTRACT: Hypoxia, a common manifestation in various lung pathologies, is linked to extensive remodeling of the extracellular matrix in the affected tissue, and involves, among others, disrupted homeostasis of collagenous proteins. In this study we demonstrated that hypoxia upregulated the expression of matrix metalloproteinase (MMP)-1 in human pulmonary vascular smooth muscle cells (VSMC) and human lung fibroblasts (LF) and MMP-13 in LF only. The hypoxia induced upregulation of MMP was inhibited by platelet-derived growth factor-BB (PDGF-BB). The expression of tissue inhibitor of matrix metalloproteinase (TIMP)-1 and TIMP-2 was not affected by hypoxia, but TIMP-1 was significantly elevated by PDGF in both cell types. Hypoxia in combination with PDGF stimulated the production of soluble collagen type I by LF. Our data suggest that the combination of hypoxia and PDGF has a synergistic net-effect leading to accumulation of collagenous protein that may be associated to lung pathology.
    No preview · Article · Jan 2006 · Review of Clinical Pharmacology and Pharmacokinetics, International Edition
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    M Tamm · M Roth
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    ABSTRACT: For many years asthma has been regarded as an inflammatory disease of the airway mucosa leading to bronchial hyperreactivity. Recent studies showed marked abnormalities in airway smooth muscle behaviour in patients with asthma. The pathogenesis of asthma seems to consist of airway inflammation combined with airway smooth muscle remodelling. The latter pathology is linked to a lack of the ant-proliferative transcription factor C/EBP-alpha in this specific cell type.
    Preview · Article · Nov 2005 · Swiss medical weekly: official journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology
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    ABSTRACT: Hypoxia not only controls organogenesis, embryogenesis, and wound repair, but also triggers tumor progression and metastasis. Matrix metalloproteinases (MMP), especially gelatinases (MMP-2, MMP-9) regulate the composition and stability of the extracellular matrix (ECM), which affects cell proliferation, migration, and differentiation. This study investigated the effect of hypoxia alone and in combination with ECM compounds and nutrition on MMP-2 and MMP-9 expression, activity, and synthesis in human lung fibroblasts and pulmonary vascular smooth muscle cells (VSMC). We also determined the expression of the tissue inhibitors of MMP (TIMP-1, -2). Cells were grown on plastic, collagen-I, collagen-IV, or gelatin and in either starving medium (0.1% serum) or growth medium (5% serum), and were subjected to normoxia or hypoxia (1% O(2)). Collagenases expression was determined by zymography. TIMP-1, -2 expression was assessed by Western blotting and RT-PCR. Depending on serum concentration human lung cells expressed pro-MMP-2 on all substrates. Hypoxia increased pro-MMP-2 expression, on collagen type I or type IV further via Erk1/2 and p38 MAP kinase signaling. MMP-9 was only expressed when cells were grown on collagen type IV and increased with serum concentration, and by hypoxia. TIMP-1 expression was only expressed when cells were grown on collagen type I and was significantly increased by hypoxia, while TIMP-2 expression was unchanged. We demonstrated that the hypoxia, ECM composition, and nutrition, rather than one of these conditions alone, modulate the expression and activity of collagenases and their inhibitors in primary human lung fibroblasts.
    Full-text · Article · Jul 2005 · Journal of Cellular Physiology
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    M Roth · P Borger · M Tamm

    Full-text · Article · Nov 2004 · New England Journal of Medicine
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    ABSTRACT: Asthma is characterized by airway remodelling, involving changes in deposition of extracellular matrix molecules. First-line therapy of persistent asthma involves the combination of inhaled corticosteroids and β 2 adrenergic agonists. The aim of this study was to investigate the effect of corticosteroids, β2 agonists and their combination in the secretion and deposition of glycosaminoglycans (GAGs) by human lung cells. Human bronchial epithelial and smooth muscle cells and lung fibroblasts were incubated for 48 h in the presence of budesonide, ciclesonide, formoterol or salmeterol. GAGs were determined in the cell culture medium and in the cell-associated matrix by 3H-glucosamine incorporation. We found that budesonide and ciclesonide resulted in a dose-dependent decrease in both cell-associated and secreted GAGs to approximately 50% of control levels. This effect was inhibited by the corticosteroid antagonist mifepristone, indicating the involvement of corticosteroid receptors. Formoterol and salmeterol had no effect. However, the combination of β2 agonists with corticosteroids further enhanced the inhibitory effect of corticosteroids. This effect was mediated via adrenergic receptors since it was abolished by propranolol. These results demonstrate that the anti-inflammatory action of corticosteroids when used alone or in combination with β2 adrenergic agonists in the treatment of asthma may also be associated with a beneficiary decrease in the deposition of matrix molecules in the lung.
    No preview · Article · Jan 2004 · Review of Clinical Pharmacology and Pharmacokinetics, International Edition

  • No preview · Article · Jan 2002 · The Journal of Heart and Lung Transplantation

Publication Stats

2k Citations
367.43 Total Impact Points


  • 1995-2011
    • Universitätsspital Basel
      • Klinik für Infektiologie & Spitalhygiene
      Bâle, Basel-City, Switzerland
  • 2002-2009
    • University of Sydney
      • Respiratory Research Group
      Sydney, New South Wales, Australia
  • 2005-2008
    • Woolcock Institute of Medical Research
      Sydney, New South Wales, Australia
  • 2001-2005
    • Royal Prince Alfred Hospital
      Camperdown, New South Wales, Australia
  • 1999
    • Netherlands Cancer Institute
      Amsterdamo, North Holland, Netherlands
  • 1991-1998
    • Universität Basel
      Bâle, Basel-City, Switzerland
  • 1991-1997
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1993-1996
    • University of Vienna
      • Department of Internal Medicine III
      Vienna, Vienna, Austria