S R Bornstein

Technische Universität Dresden, Dresden, Saxony, Germany

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Publications (374)1388.91 Total impact

  • Experimental and Clinical Endocrinology & Diabetes; 03/2015
  • Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1547686 · 1.76 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1547699 · 1.76 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1549081 · 1.76 Impact Factor
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    ABSTRACT: The antiepileptic drug valproic acid (VPA) has been shown to influence the neural differentiation and neurite outgrowth of neural stem cells. Sympathoadrenal progenitor cells share properties with neural stem cells and are considered a potential cell source in the treatment of neurodegenerative diseases. The present study therefore aims at modulating the neural differentiation potential of these cells by treatment with the histone deacetylase inhibitor VPA. We studied the epigenetic effects of VPA in two culture conditions: suspension conditions aimed to expand adrenomedullary sympathoadrenal progenitors within free-floating chromospheres and adherent cell cultures optimized to derive neurons. Treatment of chromospheres with VPA may launch neuronal differentiation mechanisms and improve their neurogenic potential upon transplantation. However, also transplantation of differentiated functional neurons could be beneficial. Treating chromospheres for 7 days with clinically relevant concentrations of VPA (2 mm) revealed a decrease of neural progenitor markers Nestin, Notch2 and Sox10. Furthermore, VPA initiated catecholaminergic neuronal differentiation indicated by upregulation of the neuronal marker β-III-tubulin, the dopaminergic transcription factor Pitx3 and the catecholaminergic enzymes TH and GTPCH. In adherent neural differentiation conditions, VPA treatment improved the differentiation of sympathoadrenal progenitor cells into catecholaminergic neurons with significantly elevated levels of nor- and epinephrine. In conclusion, similar to neural stem cells, VPA launches differentiation mechanisms in sympathoadrenal progenitor cells that result in increased generation of functional neurons. Thus, data from this study will be relevant to the potential use of chromaffin progenitors in transplantation therapies of neurodegenerative diseases.Molecular Psychiatry advance online publication, 24 February 2015; doi:10.1038/mp.2015.3.
    Molecular Psychiatry 02/2015; DOI:10.1038/mp.2015.3 · 15.15 Impact Factor
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    ABSTRACT: Background: Adrenocortical cancer (ACC) is a rare malignant endocrine tumor. Previously we found that erlotinib (inhibitor of EGFR) had an additive cytotoxic effect to standard therapy with mitotane in H295R cell line, especially after EGF stimulation. Primary cultures of ACC have been proven to be challenging to establish and maintain for further experiments, especially for assessing their steroid profile. Design: The aim of this study was to test the effect in the use of Erlotinib on primary ACC cultures. We successfully cultured 3 ACCs. In 2 ACC cases radical surgery was a treatment of choice, whereas in the last case - surgery was after neo-adjuvant chemotherapy. Because last tumour was very heterogeneous, we cultured 2 samples from macroscopically different areas. Cell proliferation rate and the effect of the drugs were assessed by AlamarBlue assay. We used LCMS/MS to assess tumour steroids production from primary cultures derived from metastatic ACC cases. Results: Treatment with mitotane resulted in the decrease of cell proliferation (9%±2%) in all cases at 10uM and total death at 50μM. In one of radically operated ACCs, erlotinib (10μM) decreased proliferation by 24%, whereas in another it was not effective. Surprisingly, erlotinib has opposite effect on cell proliferation in two samples from metastatic ACC, however its combination with low dose of mitotane (10μM) was sufficient to induce total death. Furthermore the basal steroid production was different in those samples and it changed in a different manner after treatment with mitotane and/or erlotinib (with or without EGF stimulation). Conclusion: Erlotinib can have an anti-proliferative effect in primary ACC cultures and can reduce mitotane effective concentration. For cases pre-treated with neo-adjuvant therapy, erlotinib may cause opposite responses in different parts of the same tumour; hence its clinical use needs further careful consideration. Different responses in steroidogenesis from different parts of the same ACC tumour has not been previously described underlines ACC heterogeneity.
    Modern Pathology 02/2015; 28(2 (Suppl 2)):133. DOI:10.1038/modpathol.2015.14 · 6.36 Impact Factor
  • S Saha, S R Bornstein, J Graessler, S Kopprasch
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    ABSTRACT: Low-density lipoprotein (LDL) is considered to be a risk factor for atherosclerosis. In the presence of hyperglycemia, LDL undergoes glycoxidative modification and this glycoxidized (glycox) LDL promotes atherosclerosis in type 2 diabetic (T2D) individuals. Moreover, because of its cholesterol content, LDL contributes to aldosterone biosynthesis, which is modulated by angiotensin II (AngII) and has been implicated in cardiovascular complications of T2D. However, the molecular mechanism of the crosstalk between glycoxLDL, AngII, and aldosterone has not been explained clearly. Therefore, this study has been aimed to investigate the impact of in vitro modified glycoxLDL on aldosterone release in an AngII-sensitized adrenocortical carcinoma cell line (NCI H295R). Native LDL (natLDL), isolated from healthy volunteers by sequential density gradient ultracentrifugation, was subjected to d-glucose (200 mmol/l), for glycoxidative modification, at 37°C for 6 days. The AngII-sensitized H295R cells were treated with natLDL and glycoxLDL for 24 h and the supernatant was used for aldosterone measurement. The treated cells were utilized for protein isolation and mRNA quantification. Compared to natLDL, glycoxLDL produced a significantly greater effect on aldosterone release from AngII-sensitized cells. The treatment with specific pharmacological inhibitors suggests that modified LDL recruits ERK1/2 and janus kinase-2 for transcriptional regulation of aldosterone synthase. Moreover, glycoxLDL modulates aldosterone release via cAMP-dependent protein kinase A (PKA) pathway. However, glycoxLDL induces ERK phosphorylation independent of PKA activation and this novel mechanism could be targeted for therapeutic trials. In conclusion, this in vitro study emphasizes a possible causal relationship between LDL glycoxidative modification, AngII-sensitization, and adrenocortical steroid hormone release. © Georg Thieme Verlag KG Stuttgart · New York.
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    ABSTRACT: Solid organ and cell transplantation, including pancreatic islets constitute the treatment of choice for chronic terminal diseases. However, the clinical use of allogeneic transplantation is limited by the growing shortage of human organs. This has prompted us to initiate a unique multi-center and multi-team effort to promote translational research in xenotransplantation to bring xenotransplantation to the clinical setting. Supported by the German Research Foundation, an interdisciplinary group of surgeons, internal medicine doctors, diabetologists, material sciences experts, immunologists, cell biologists, virologists, veterinarians, and geneticists have established a collaborative research center (CRC) focusing on the biology of xenogeneic cell, tissue, and organ transplantation. A major strength of this consortium is the inclusion of members of the regulatory bodies, including the Paul-Ehrlich Institute (PEI), infection specialists from the Robert Koch Institute and PEI, veterinarians from the German Primate Center, and representatives of influential ethical and religious institutions. A major goal of this consortium is to promote islet xenotransplantation, based on the extensive expertise and experience of the existing clinical islet transplantation program. Besides comprehensive approaches to understand and prevent inflammation-mediated islet xenotransplant dysfunction [immediate blood-mediated inflammatory reaction (IBMIR)], we also take advantage of the availability of and experience with islet macroencapsulation, with the goal to improve graft survival and function. This consortium harbors a unique group of scientists with complementary expertise under a cohesive program aiming at developing new therapeutic approaches for islet replacement and solid organ xenotransplantation. © Georg Thieme Verlag KG Stuttgart · New York.
    Hormone and Metabolic Research 12/2014; 47(01). DOI:10.1055/s-0034-1395518 · 2.04 Impact Factor
  • Hormone and Metabolic Research 12/2014; 47(01). DOI:10.1055/s-0034-1394453 · 2.04 Impact Factor
  • M Hanefeld, S R Bornstein, A Barthel
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    ABSTRACT: The role of incretins in glucose homeostasis is well known. Yet, in recent years, the sustained weight loss and rapid glycemic control following bariatric surgery has challenged our understanding of the intestinal-pancreatic interaction. This in turn led to the introduction of metabolic surgery, an innovative medical discipline in which a surgical manipulation of the gastrointestinal tract (e. g., through a Roux-en-Y gastric bypass, RYGB, or Bilio-Pancreatic-Diversion, BPD) yields a sustained remission of diabetes mellitus. The pathophysiological background of this metabolic effect is, amongst other things, based on the anti-incretin theory. This theory postulates that in addition to the well-known incretin effect, nutrient passage through the GI-tract could also activate negative feedback mechanisms (anti-incretins) to balance the effects of incretins and other postprandial glucose-lowering mechanisms (i. e., suppression of ghrelin, glucagon, and hepatic glucose production via activation of nutrient sensing). This in turn prevents postprandial hyperinsulinemic hypoglycemia. The bypass of the duodenum, the entire jejunum and the first portion of the ileum by BPD induce normalization of peripheral insulin sensitivity, while the bypass of a shorter intestinal tract by RYGB mainly improves the hepatic insulin sensitivity. In addition, RYGB greatly increases insulin secretion. Therefore, metabolic surgery highlights the important role of the small intestine in glucose homeostasis, while until few years ago, it was only the pancreas and the liver that were thought to represent the regulatory organs for glucose disposal.
    Hormone and Metabolic Research 11/2014; 47(01). DOI:10.1055/s-0034-1394374 · 2.04 Impact Factor
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    ABSTRACT: Inflammation in the central nervous system (CNS) and disruption of its immune privilege are major contributors to the pathogenesis of multiple sclerosis (MS) and of its rodent counterpart, experimental autoimmune encephalomyelitis (EAE). We have previously identified developmental endothelial locus-1 (Del-1) as an endogenous anti-inflammatory factor, which inhibits integrin-dependent leukocyte adhesion. Here we show that Del-1 contributes to the immune privilege status of the CNS. Intriguingly, Del-1 expression decreased in chronic-active MS lesions and in the inflamed CNS in the course of EAE. Del-1-deficiency was associated with increased EAE severity, accompanied by increased demyelination and axonal loss. As compared with control mice, Del-1(-/-) mice displayed enhanced disruption of the blood-brain barrier and increased infiltration of neutrophil granulocytes in the spinal cord in the course of EAE, accompanied by elevated levels of inflammatory cytokines, including interleukin-17 (IL-17). The augmented levels of IL-17 in Del-1-deficiency derived predominantly from infiltrated CD8(+) T cells. Increased EAE severity and neutrophil infiltration because of Del-1-deficiency was reversed in mice lacking both Del-1 and IL-17 receptor, indicating a crucial role for the IL-17/neutrophil inflammatory axis in EAE pathogenesis in Del-1(-/-) mice. Strikingly, systemic administration of Del-1-Fc ameliorated clinical relapse in relapsing-remitting EAE. Therefore, Del-1 is an endogenous homeostatic factor in the CNS protecting from neuroinflammation and demyelination. Our findings provide mechanistic underpinnings for the previous implication of Del-1 as a candidate MS susceptibility gene and suggest that Del-1-centered therapeutic approaches may be beneficial in neuroinflammatory and demyelinating disorders.Molecular Psychiatry advance online publication, 11 November 2014; doi:10.1038/mp.2014.146.
    Molecular Psychiatry 11/2014; DOI:10.1038/mp.2014.146 · 15.15 Impact Factor
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    ABSTRACT: Background:Adipocyte fatty acid-binding protein (FABP4) is a member of a highly conserved family of cytosolic proteins that bind with high affinity to hydrophobic ligands such as saturated and unsaturated long-chain fatty acids and eicosanoids. Recent evidence has supported a novel role for FABP4 in linking obesity with metabolic and cardiovascular disorders. In this context we identified FABP4 as a main bioactive factor released from human adipose tissue that directly suppresses heart contraction in vitro. Since FABP4 is known to be a transport protein, it cannot be excluded that lipid ligands are involved in the cardiodepressant effect as well, acting in an additional and/or synergistic way.Objectives:We investigated a possible involvement of lipid ligands in the negative inotropic effect of adipocyte-factors in vitro.Results:We verified that blocking the CYP epoxygenase pathway in adipocytes attenuates the inhibitory effect of adipocyte-conditioned medium (AM) on isolated adult rat cardiomyocytes, thus suggesting the participation of epoxyeicosatrienoic acids (EETs) in the cardiodepressant activity. Analysis of AM for EETs revealed the presence of 5,6-, 8,9-, 11,12- and 14,15-EET, whereas 5,6-EET represented about 45% of total EET-concentration in AM. Incubation of isolated cardiomyocytes with EETs in similar concentrations as found in AM showed that 5,6-EET directly suppresses cardiomyocyte contractility. Furthermore, after addition of 5,6-EET to FABP4, the negative inotropic effect of FABP4 was strongly potentiated in a concentration-dependent manner.Conclusions:These data suggest that adipocytes release 5,6-EET and FABP4 into the extracellular medium and that the interaction of these factors modulates cardiac function. Therefore, elevated levels of FABP4 and 5,6-EET in obese patients may contribute to the development of heart dysfunction in these subjects.International Journal of Obesity accepted article preview online, 05 November 2014. doi:10.1038/ijo.2014.193.
    International journal of obesity (2005) 11/2014; 121(3). DOI:10.1038/ijo.2014.193 · 5.39 Impact Factor
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    ABSTRACT: Revascularisation of transplanted islets is an essential prerequisite for graft survival and function. However, current islet isolation procedures deprive the islets of endothelial tubulets. This may have a detrimental effect on the revascularisation process of islets following transplantation. We hypothesise that modification of the isolation procedure that preserves islet endothelial vessels may improve the islet revascularisation process following transplantation. Here, we present a modified islet isolation method by which a substantial amount of endothelial cells still attached to the islets could be preserved. The islets with preserved endothelial cells isolated by this method were revascularised within 3 days, not observed in islets isolated by standard methods. Further, we observed that grafts of islets isolated by standard methods had more patches of dead tissue than islet grafts obtained by the modified method, indicating that attached endothelial cells may play an important role in the islet revascularisation process and potentially help to improve the transplantation outcome.
    Hormone and Metabolic Research 11/2014; 47(01). DOI:10.1055/s-0034-1390489 · 2.04 Impact Factor
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    ABSTRACT: We comment here on the suitability of available mouse models for type 1 diabetes research including research on therapeutic pancreatic islet transplantation. The major emphasis will be laid on models that require minimal invasive procedures.Most biological processes are too complex for a complete recapitulation in a test tube. The study of innate or even adaptive immune responses involves a number of different cell types and organs making in vitro studies unreliable but also providing extreme challenges for the use of surrogate model organisms. Studying these processes directly in humans is impossible due to ethical and technical constraints. To resolve this problem small animal models such as mice or rats are frequently used to study mechanisms of complex diseases. This has brought much insight into hematopoiesis and immune cell function including type 1 diabetes (T1D); however, 65 million years of evolution introduced striking differences between mice and humans 1. In fact, none of the many suggested therapies arising from studies using mice 2 3 that have promised prevention or even reversion of T1D made it into the clinic yet 4 5 6. The reason for this are major species-specific differences between rodents and humans regarding the immune system and beta cells.
    Hormone and Metabolic Research 11/2014; 47(01). DOI:10.1055/s-0034-1390446 · 2.04 Impact Factor
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    ABSTRACT: Xenotransplantation (xeno-Tx) is considered as an alternative solution to overcome the shortage of human donor organs. However, the success of xeno-Tx is hindered by immune reactions against xenogeneic cells (e. g. of porcine origin). More specifically, activation of innate immune mechanisms such as complement and triggering of the coagulation cascade occur shortly after xeno-Tx, and adhesion of human leukocytes to porcine endothelium is another early critical step mediating the immune attack. To investigate the therapeutic potential of complement inhibition in the context of xenogeneic interactions, we have employed a whole-blood model in the present study. Incubation of human blood with porcine endothelial cells (PAECs) led to activation of complement and coagulation as well as to increased leukocyte adhesion. The observed responses can be attributed to the pig-to-human xenogeneicity, since the presence of human endothelium induced a minor cellular and plasmatic inflammatory response. Importantly, complement inhibition using a potent complement C3 inhibitor, compstatin analogue Cp40, abrogated the adhesion of leukocytes and, more specifically, the attachment of neutrophils to porcine endothelium. Moreover, Cp40 inhibited the activation of PAECs and leukocytes, since the levels of the adhesion molecules E-selectin, ICAM-1, ICAM-2, and VCAM-1 on PAECs and the surface expression of integrin CD11b on neutrophils were significantly decreased. Along the same line, inhibition of CD11b resulted in decreased leukocyte adhesion. Taken together, our findings provide a better understanding of the mechanisms regulating the acute innate immune complications in the context of xeno-Tx and could pave the way for complement-targeting therapeutic interventions.
    Hormone and Metabolic Research 10/2014; 47(01). DOI:10.1055/s-0034-1390452 · 2.04 Impact Factor
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    ABSTRACT: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
    Nature Genetics 10/2014; DOI:10.1038/ng.3097 · 29.65 Impact Factor
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    ABSTRACT: Obesity is a well-known risk factor of atherosclerosis and heart failure. In the human heart, a local endothelin system containing prepro-endothelin-1, endothelin-converting enzyme-1, and endothelin receptors A and B has been described. The endothelin system is activated in heart failure; however, the impact of obesity on the cardiac endothelin system is unknown. In this study, 18-week-old male C57BL/6 mice fed either a control diet or a high-fat diet for 10 weeks were analyzed. High-fat diet significantly increased the body weight of the animals and augmented low-density lipoprotein, high-density lipoprotein, and cholesterol plasma levels, compared to control. The animal groups showed no significant differences in left ventricular size or function (heart rate, ejection fraction, fractional shortening, left ventricular posterior wall thickness, cardiac output) after control or high-fat diet. We did not observe signs of cardiac hypertrophy or changes in markers of cardiac fibrosis in these heart samples. The cardiac expression of prepro-endothelin-1 mRNA, endothelin-converting enzyme-1 mRNA, and protein and endothelin receptors A and B mRNA was increased in 18-week-old obese C57BL/6 mice compared to animals with normal weight (p<0.05 vs. control). Furthermore, endothelin-1 plasma levels showed an increasing trend. In conclusion, an increased expression of genes of the endothelin system was observed in the hearts of 18-week-old mice after high-fat diet, possibly contributing to later cardiovascular complications of obesity.
    Hormone and Metabolic Research 09/2014; DOI:10.1055/s-0034-1387761 · 2.04 Impact Factor
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    ABSTRACT: For the majority of patients with type 1 diabetes intensive insulin therapy is effective and safe for maintaining glycemia and minimizing diabetes-associated complications. However, a rare number of patients show highly labile metabolic control and experience repeated and unpredictable hypoglycemic episodes. Such condition is often caused by defective counterregulatory mechanisms and autonomous neuropathy. Patients are at high risk for severe acute and chronic complications, and quality of life is considerably impaired. For this small subset of patients, restoration of endogenous insulin secretion can substantially improve metabolic control and quality of life. In our experience, this is irrespective of insulin independency. Here, we report on our 5 years' experience with implementing islet transplantation as a potential treatment option for type 1 diabetes. All patients were treated by long-term insulin pump therapy prior to enrolment. The main indication was severely unstable diabetes and repeated hypoglycemia. From 2008 to 2013, 10 patients have been transplanted with single islet infusion; mean follow-up time was 35 months. All patients show persistent graft function, stable glycemic control with a reduction in HbA1c in the absence of hypoglycemia. All patients are kept on minimal exogenous insulin. In conclusion, islet transplantation can be an excellent therapy for selected patients. Key prerequisite for success is a strict indication. The primary goal for islet transplantation should be stabile glycemia and prevention of hypoglycemia rather than insulin independence. In fact, maintaining minimal exogenous insulin may protect the islet graft from metabolic stress and even prolong islet graft function.
    Hormone and Metabolic Research 08/2014; 47(01). DOI:10.1055/s-0034-1385876 · 2.04 Impact Factor
  • European Journal of Cancer 07/2014; 50:S53. DOI:10.1016/S0959-8049(14)50199-2 · 4.82 Impact Factor

Publication Stats

6k Citations
1,388.91 Total Impact Points


  • 1998–2015
    • Technische Universität Dresden
      • • Center for Internal Medicine
      • • Medical Clinic III
      • • Medical Clinic III, Department General Medicine
      • • Medizinische Fakultät Carl Gustav Carus
      Dresden, Saxony, Germany
    • National Institutes of Health
      Maryland, United States
    • Université de Rouen
      Mont-Saint-Aignan, Haute-Normandie, France
  • 2014
    • King's College London
      Londinium, England, United Kingdom
    • ICL
      Londinium, England, United Kingdom
  • 1999–2014
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
    • University of Gothenburg
      Goeteborg, Västra Götaland, Sweden
  • 2012
    • Institut für klinische Pharmakologie
      Stuttgart, Baden-Württemberg, Germany
  • 2011–2012
    • Center for Regenerative Therapies, Dresden
      Dresden, Saxony, Germany
    • University of Texas Health Science Center at San Antonio
      • Division of Diabetes
      San Antonio, TX, United States
  • 2008–2012
    • Universitätsklinikum Dresden
      • Medizinische Klinik und Poliklinik III
      Dresden, Saxony, Germany
  • 1998–2009
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 2007
    • University Hospital Regensburg
      Ratisbon, Bavaria, Germany
    • Royal Adelaide Hospital
      Tarndarnya, South Australia, Australia
    • Universität Regensburg
      • Department of Clinical Chemistry and Laboratory Medicine
      Ratisbon, Bavaria, Germany
  • 2004–2007
    • Universitätsklinikum Düsseldorf
      • Klinik für Endokrinologie und Diabetologie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2006
    • German Diabetes Center
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2003–2006
    • Heinrich-Heine-Universität Düsseldorf
      • • Institute of Molecular Medicine
      • • Deutsches Diabetes-Zentrum DDZ
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2002
    • Graz University of Technology
      • Institut für Medizintechnik
      Graz, Styria, Austria
    • Evangelic Hospital Bielefeld
      Bielefeld, North Rhine-Westphalia, Germany
  • 2001
    • University of Florence
      Florens, Tuscany, Italy
  • 1995–2001
    • University of Leipzig
      • Institute of Immunology
      Leipzig, Saxony, Germany
  • 2000
    • Northern Inyo Hospital
      BIH, California, United States
  • 1999–2000
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Роквилл, Maryland, United States
  • 1991–1994
    • Universität Ulm
      • • Clinic of Internal Medicine I
      • • Clinic of Gynecology and Obstetrics
      Ulm, Baden-Wuerttemberg, Germany