Georg Schett

Universitätsklinikum Erlangen, Erlangen, Bavaria, Germany

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Publications (523)3026.92 Total impact

  • Annals of the rheumatic diseases. 10/2014;
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    ABSTRACT: BACKGROUND: The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion. AIM: To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors. METHODS: One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded. RESULTS: Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016). CONCLUSIONS: A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.
    Alimentary Pharmacology & Therapeutics 10/2014; · 4.55 Impact Factor
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    ABSTRACT: Angiogenesis is an important pathophysiological process of chronic inflammation, especially in inflammatory arthritis. Quantitative measurement of changes in vascularization may improve the diagnosis and monitoring of arthritis. The aim of this work is the development of a 3D imaging and analysis framework for quantification of vascularization in experimental arthritis.
    BMC Musculoskeletal Disorders 09/2014; 15(1):298. · 1.88 Impact Factor
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    ABSTRACT: Objective: As single cytokine inhibition of e.g. TNFα or IL-6 produces clinically meaningful responses in only about half of RA patients, this study is designed to investigate whether combined inhibition of TNFα and IL-17 has additive/synergistic effects in suppression of mesenchymal cell activation in vitro and inflammation and tissue destruction in arthritis in vivo.Methods: Cultures of human fibroblast-like synoviocytes (FLS) were stimulated with TNFα, IL-17 or a combination of both. Single/combined neutralizing antibodies against TNFα and IL-17 were used to interrogate in vitro cytokine responses and in vivo development of arthritis, bone and cartilage destruction in TNFα-transgenic mice. Bi-specific anti-TNFα/IL-17 antibodies were designed and tested for their potential to block cytokine responses in human FLS.Results: TNFα and IL-17 had additive/synergistic effects in promoting IL-6, -8 and G-CSF as well as MMP production in FLS. Bi-specific anti-TNFα/IL-17 antibodies showed superior efficacy to block cytokine and chemokine responses in vitro. Furthermore, dual versus single inhibition of both cytokines using neutralizing antibodies was more effective in inhibiting the development of inflammation, bone and cartilage destruction in arthritic mice.Conclusion: Combined blockade of TNFα and IL-17 is more effective in inhibiting cytokine, chemokine and matrix enzyme responses from human mesenchymal cells and in blocking tissue destruction associated with arthritis and also showed positive impact on rebalance of bone homeostasis. Bi-specific anti-TNFα/IL-17 antibodies may have superior efficacy in the treatment of arthritis and may overcome the limited therapeutic responses of single cytokine neutralization. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 09/2014;
  • Georg Schett, Aline Bozec
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    ABSTRACT: Osteoporosis results from an imbalance between bone resorption and bone formation. While bone resorption inhibitors are widely used to treat osteoporosis, stimulating bone formation is more challenging. Recently, McClung et al. (2014) found that neutralization of sclerostin, a potent inhibitor of bone formation, effectively increased bone mass in postmenopausal women.
    09/2014; 20(3):394–395.
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    ABSTRACT: Sirt1 is a member of the sirtuin family of proteins. Sirt1 is a class III histone deacetylase with important regulatory roles in transcription, cellular differentiation, proliferation and metabolism. As aberrant epigenetic modifications have been linked to the pathogenesis of systemic sclerosis (SSc), we aimed to investigate the role of Sirt1 in fibroblast activation.
    Annals of the rheumatic diseases. 09/2014;
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    ABSTRACT: To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.
    Annals of the rheumatic diseases. 08/2014;
  • Zeitschrift fur Rheumatologie. 08/2014;
  • Bernhard Manger, Georg Schett
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    ABSTRACT: For patients that present with musculoskeletal symptoms, diagnostic procedures carried out by physicians and rheumatologists are primarily aimed at confirming or excluding the occurrence of primary rheumatic diseases. Another important trigger for musculoskeletal disease, however, is the presence of a tumour. Careful clinical investigation and knowledge of the gestalt of musculoskeletal syndromes related to respective tumour entities is of utmost importance for the diagnosis of paraneoplastic rheumatic diseases such as hypertrophic osteoarthropathy, paraneoplastic polyarthritis, RS3PE syndrome, palmar fasciitis and polyarthritis, cancer-associated myositis and tumour-induced osteomalacia. This places great responsibility on rheumatologists in diagnosing malignancies and referring the patient for effective treatment. The selective influence of tumours on musculoskeletal tissue is surprising and indicates that tumours alter tissues such as the periosteum, synovial membrane, subcutaneous connective tissue, fascia, muscles and bones by specific molecular processes. Some of the underlying mechanisms have been unravelled, providing valuable information on the physiologic and pathophysiologic roles of mediators such as vascular endothelial growth factor and fibroblast growth factor 23.
    Nature Reviews Rheumatology 08/2014; · 9.75 Impact Factor
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    ABSTRACT: To determine whether there is an additive effect of anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) on the number and size of bone erosions in patients with rheumatoid arthritis (RA) METHODS: 242 patients with RA received high-resolution peripheral quantitative CT (HR-pQCT) scans of the metacarpophalangeal joints. Demographic and disease-specific parameters including ACPA and RF levels were recorded from all patients. Erosion numbers and their size were assessed in 238 patients at 714 individual joints (MCP 2, 3 and 4) and 5712 sites (each 4 quadrants in metacarpal heads and phalangeal bases). The volume of erosions was calculated by a semiellipsoid formula.
    Annals of the rheumatic diseases. 08/2014;
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    ABSTRACT: Objective: Nuclear receptors regulate cell growth, differentiation and homeostasis. Selective nuclear receptors promote fibroblast activation, which leads to tissue fibrosis, the hallmark of systemic sclerosis (SSc). Our aim was to investigate the effects of constitutive androstane receptor (CAR/NR1I3), an orphan nuclear receptor, on fibroblast activation and experimental dermal fibrosis.Methods: Expression of CAR was quantified by quantitative PCR, western blot, immunohistochemistry, and immunofluorescence. CAR expression was modulated by small molecules, siRNA, forced overexpression and site-directed mutagenesis. The effects of CAR activation were analyzed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, and in mice overexpressing a constitutively active TGF-β receptor-I (TβRICA).Results: Upregulation of CAR was detected in the skin and in dermal fibroblasts of SSc patients. Stimulation of healthy fibroblasts with TGF-β induced the expression of CAR mRNA and protein in a Smad dependent manner. Pharmacologic activation or overexpression of CAR in healthy fibroblasts significantly increased the stimulatory effects of TGF-β on collagen synthesis and myofibroblast differentiation, and amplified the stimulatory effects of TGF-β on COL1A2 transcriptional activity. Treatment with CAR agonist increased the activation of canonical TGF-β signaling in murine models of SSc and exacerbated bleomycin-induced and TβRICA induced fibrosis with increased dermal thickening, myofibroblasts counts and collagen accumulation.Conclusion: CAR is upregulated in SSc and regulates TGF-β signaling. Activation of CAR increases the profibrotic effects of TGF-β in cultured fibroblasts and in different preclinical models of SSc. Thus, inactivation of CAR might be a novel approach to target aberrant TGF-β signaling in SSc and in other fibrotic diseases. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 08/2014;
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    ABSTRACT: Objective: To investigate the factors associated with cartilage proteoglycan content in patients with rheumatoid arthritis (RA)Methods: 32 RA patients received high-field 3 Tesla Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) for determining cartilage proteoglycan content. Measurements were performed in three individual cartilage regions (medial, central, lateral) of the metacarpophalangeal joints 2 and 3. dGEMRIC values were then related to disease duration, disease activity, anti-citrullinated protein antibody (ACPA) status, rheumatoid factor status and C-reactive protein level.Results: dGEMRIC values were not significantly different between the MCP2 and MCP3 joint. Inter-class correlations were high (>0.92) for all three (medial, central and lateral) cartilage compartments. dGEMRIC values were significantly lower in RA patients with longer disease duration (≥3years) and those with ACPA positivity than those with a short disease duration (<3 years)(p=0.034) or negative ACPA (p=0.0002), respectively. In contrast, no association between cartilage proteoglycan content and disease activity, C-reactive protein level and rheumatoid factor status was found.Conclusion: Decreased cartilage proteoglycan content in RA patients is associated with disease duration and ACPA positivity but not with the actual disease activity, CRP level or rheumatoid factor status. These data suggest that the cumulative burden of inflammation as well as ACPA are the determinants for cartilage damage in RA. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 08/2014;
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    ABSTRACT: Introduction A major subset of patients with rheumatoid arthritis (RA) is characterised by the presence of circulating autoantibodies directed to citrullinated proteins/peptides (ACPA). These autoantibodies, which are commonly detected using an ELISA assay based on synthetic cyclic citrullinated peptides (CCP), predict clinical onset and a destructive disease course. In the present study, we have utilised plasma and synovial fluids from patients with RA, for the affinity purification and characterisation of anti-CCP2 reactive antibodies, with an aim to generate molecular tools that can be utilized in vitro and in vivo for future investigations into the pathobiology of the ACPA response. Specifically, this study aims to demonstrate that the surrogate marker CCP2 can capture ACPA that bind to autoantigens expressed in vivo, in the major inflammatory lesions of RA, i.e. in the rheumatoid joint. Methods Plasma (n = 16) and synovial fluid (n = 26) samples were collected from RA patients with anti-CCP2 IgG levels above 300 AU/ml. Total IgG was isolated on Protein G columns, and subsequently applied to CCP2 affinity columns. Purified anti-CCP2 IgG was analysed for reactivity and specificity using the CCPlus® ELISA assay, in-house peptide-ELISAs, western blot and immunohisto-/immunocytochemistry. Results Approximately 2 % of the total IgG pool in both plasma and synovial fluid was CCP2-reactive. Purified anti-CCP2 reactive antibodies from different patients showed differences in binding to CCP2 and differences in binding to citrullinated peptides from α-enolase, −vimentin, −fibrinogen, and -collagen type II, illustrating different ACPA fine-specificity profiles. Furthermore, the purified ACPA bound not only in vitro citrullinated proteins but more importantly, in vivo-generated epitopes on synovial fluid cells and synovial tissues from RA patients. Conclusions We have isolated ACPA from plasma and synovial fluid, and demonstrated that the CCP2 peptides, frequently used in diagnostic ELISA assays, de facto act as surrogate antigens for at least four different, well-characterised, largely non cross-reactive, ACPA fine-specificities. Moreover, we have determined the concentration and proportion of CCP2-reactive IgG molecules in rheumatoid plasma and synovial fluid, and we have shown that the purified ACPA can be used to detect both in vitro- and in vivo-generated citrullinated epitopes by various techniques. We anticipate that these antibodies will provide us with new opportunities to investigate the potential pathogenic effects of human ACPAs.
    Arthritis research & therapy 07/2014; · 4.27 Impact Factor
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    ABSTRACT: Objectives: Both psoriatic arthritis (PSA) and hand osteoarthrits (HOA) lead to periarticular bone proliferation. Aim of this study was to investigate the different patterns of bony spur formation in PSA and HOA by high-resolution peripheral quantitative computed tomography (HR-pQCT).Methods: 70 patients, 25 with PSA, 25 with HOA and 20 healthy controls, with similar age and sex distribution and clinical involvement of the metacarpophalangeal (MCP) joints received a HR-pQCT examination of the MCP 2, 3 and 4 joint of the dominantly affected hand. Demographic and disease-specific data were recorded and number, size and distribution of bony spur were assessed and compared between PsA and HOA.Results: Overall number and size of bony spurs was similar between PsA and HOA. PsA and HOA, however, substantially differed in the localization of lesions within individual joints: Bony spurs in PsA dominated the radial sides of the joints (PsA vs. HOA: metacarpal head 2: p<0.001; phalangeal base 2: p<0.001), whereas the palmar and dorsal sites were the predilection sites in HOA. Detailed anatomical analysis showed that enthesial regions are almost exclusively affected in PsA, but are spared in HOA, whereas bony spurs in HOA typically emerge at the cartilage-bone interphase and the joint margins.Conclusions: Our findings suggest a similar burden of bony spurs in PsA and HOA. Nonetheless, the anatomical sites of bony proliferation in PsA and HOA are different between PsA and HOA. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 07/2014;
  • Georg Schett
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    ABSTRACT: The simultaneous presence of bone erosions and bony spurs (osteophytes, enthesophytes) in the joints of patients with psoriatic arthritis (PsA) suggests that the disease leads to enhanced bone resorption as well as increased bone formation, the latter of which has not been observed in patients with rheumatoid arthritis. At the 2013 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members heard an update on the current research into the cytokine signature in PsA and its effects on new bone formation.
    The Journal of rheumatology. 06/2014; 41(6):1218-9.
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    ABSTRACT: The overexpression of tumor necrosis factor (TNF)-alpha leads to systemic as well as local loss of bone and cartilage and is also an important regulator during fracture healing. In this study, we investigate how TNF-alpha inhibition using a targeted monoclonal antibody affects fracture healing in a TNF-alpha driven animal model of human rheumatoid arthritis (RA) and elucidate the question whether enduring the anti TNF-alpha therapy after trauma is beneficial or not.
    BMC Musculoskeletal Disorders 05/2014; 15(1):184. · 1.88 Impact Factor
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    ABSTRACT: Vitamin D (Vit D) deficiency may be linked to the development of obesity-associated complications such as insulin resistance and type 2 diabetes. We therefore evaluated the relationship of Vit D serum concentrations with metabolic parameters and type 2 diabetes in middle-aged Caucasian men and women. One thousand six hundred and thirty-one Caucasians (832 males, 58.8 ± 9.7 years; 799 females, 59.7 ± 10.7 years) were evaluated in a cross-sectional study. Vit D status was assessed by measuring the serum concentration of 25-hydroxyvitamin D3 [25(OH)D3]. Type 2 diabetes prevalence was ascertained by medical history, fasting plasma glucose concentrations, oral glucose tolerance testing and/or glycosylated hemoglobin. Men displayed higher crude or seasonally adjusted 25(OH)D3 serum concentrations than women (24.64 ± 10.98 vs. 22.88 ± 11.6 ng/ml; P < 0.001). Strong associations between body mass index (BMI) and 25(OH)D3 were observed in both genders (P < 0.001). Seasonally adjusted levels of 25(OH)D3 revealed stronger associations with type 2 diabetes in women than men (P < 0.001). However, adjustment for BMI and other confounding variables revealed an independent inverse association of 25(OH)D3 with diabetes only in women (P < 0.001), whereas the association was abrogated in men. Using a 15 ng/ml 25(OH)D3 cutoff for binary comparison, adjusted odds ratios for having newly diagnosed or known type 2 diabetes more than doubled (2.95 [95 % CI 1.37-4.89] and 3.26 [1.59-6.68], respectively), in women below the cutoff. We conclude that in women, but not in men, low 25(OH)D3 serum levels are independently associated with type 2 diabetes. These findings suggest sex-specific effects of Vit D in the pathogenesis of type 2 diabetes.
    Acta Diabetologica 05/2014; · 4.63 Impact Factor
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    ABSTRACT: Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.
    Science translational medicine 05/2014; 6(235):235ra60. · 10.76 Impact Factor
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    ABSTRACT: Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated
    Nature medicine 04/2014; advance online publication. · 27.14 Impact Factor
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    ABSTRACT: Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated NETs. These findings suggest that aggregated NETs promote the resolution of neutrophilic inflammation by degrading cytokines and chemokines and disrupting neutrophil recruitment and activation.
    Nature medicine 04/2014; · 27.14 Impact Factor

Publication Stats

11k Citations
3,026.92 Total Impact Points

Institutions

  • 2007–2014
    • Universitätsklinikum Erlangen
      • Institute of Human Genetics
      Erlangen, Bavaria, Germany
    • Justus-Liebig-Universität Gießen
      • Department of Internal Medicine
      Gieben, Hesse, Germany
  • 2006–2014
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • • Nikolaus-Fiebiger-Center of Molecular Medicine (NFZ)
      • • Department of Biology
      Erlangen, Bavaria, Germany
  • 2013
    • Inselspital, Universitätsspital Bern
      • Department of Rheumatology, Clinical Immunology and Allergology
      Bern, BE, Switzerland
    • University of Leeds
      • Leeds Institute of Rheumatic and Musculoskeletal Medicine
      Leeds, England, United Kingdom
  • 1998–2013
    • Medical University of Vienna
      • Department of Medicine II
      Wien, Vienna, Austria
  • 1996–2013
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria
  • 2012
    • Nordic Bioscience
      København, Capital Region, Denmark
    • Universitair Ziekenhuis Leuven
      Louvain, Flanders, Belgium
    • Ghent University
      • Rheumatology
      Gent, VLG, Belgium
    • Ludwig Boltzmann Institute for Osteology
      Wien, Vienna, Austria
  • 2008–2012
    • University of Zurich
      • Center for Integrative Human Physiology
      Zürich, ZH, Switzerland
    • Technische Universität Dresden
      Dresden, Saxony, Germany
  • 2006–2012
    • Medizinische Universität Innsbruck
      • • Department für Innere Medizin
      • • Univ.-Klinik für Neurologie
      Innsbruck, Tyrol, Austria
  • 2011
    • Università degli studi di Parma
      Parma, Emilia-Romagna, Italy
    • National Academy of Sciences of Ukraine
      • Institute of Cell Biology
      Kharkiv, Kharkivs'ka Oblast', Ukraine
  • 2007–2011
    • University of Glasgow
      • • College of Medical, Veterinary and Life Sciences
      • • Institute of Infection, Immunity and Inflammation
      Glasgow, SCT, United Kingdom
  • 2010
    • Detská fakultná nemocnica s poliklinikou v Bratislave
      Presburg, Bratislavský, Slovakia
    • Comenius University in Bratislava
      Presburg, Bratislavský, Slovakia
  • 2009
    • University of California, San Diego
      • Division of Rheumatology, Allergy and Immunology
      San Diego, CA, United States
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
  • 1998–2008
    • University of Vienna
      • • Department of Internal Medicine III
      • • Department of Pharmacology and Toxicology
      • • Universitätsklinik für Innere Medizin I
      Wien, Vienna, Austria
  • 2004–2006
    • Biomedical Sciences Research Center Alexander Fleming
      • Institute of Immunology
      Βάρη, Attica, Greece
  • 2000
    • Vienna General Hospital
      Wien, Vienna, Austria
  • 1995–2000
    • Austrian Academy of Sciences
      • Institut für Biomedizinische Alternsforschung
      Vienna, Vienna, Austria
  • 1998–1999
    • Ludwig Boltzmann Institute of Rheumatology and Balneology
      Wien, Vienna, Austria