Hans H Hirsch

University of Zurich, Zürich, Zurich, Switzerland

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Publications (267)1444.48 Total impact

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    ABSTRACT: BK polyomavirus (BKPyV) infection represents a major problem in transplantation, particularly for renal recipients developing polyomavirus-associated nephropathy (PyVAN). The possibility that BKPyV may also be oncogenic is not routinely considered. Twenty high-grade renourinary tumors expressing polyomavirus large T antigen in the entirety of the neoplasm in 19 cases, including the metastases in six, have been reported in transplant recipients with a history of PyVAN or evidence of BKPyV infection. Morphological and phenotypical features consistent with inactivation of the tumor suppressors pRB and p53 were found in the bladder tumors, suggesting a carcinogenesis mechanism involving the BKPyV large tumor oncoprotein/antigen. The pathogenesis of these tumors is unclear, but given the generally long interval between transplantation and tumor development, the risk for neoplasms after BKPyV infections may well be multifactorial. Other elements potentially implicated include exposure to additional exogenous carcinogens, further viral mutations, and cell genomic instability secondary to viral integration, as occurs with the Merkel cell PyV–associated carcinoma. The still scarce but increasingly reported association between longstanding PyVAN and renourinary neoplasms requires a concerted effort from the transplant community to better understand, diagnose, and treat the putative association between the BKPyV and these neoplasms.
    Full-text · Article · Jan 2016 · American Journal of Transplantation
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    ABSTRACT: An accurate quantification of low viremic HCV RNA plasma samples has gained importance since the approval of direct acting antivirals and since only one single measurement predicts the necessity of a prolonged or shortened therapy. As reported previously, HCV quantification assays such as Abbott RealTime HCV and Roche COBAS AmpliPrep/COBAS TaqMan HCV version 2 (CTM v2) may vary in sensitivity and precision particularly in low-level viremia. Importantly, substantial variations were previously demonstrated between some of these assays compared to the Roche High Pure System/COBAS TaqMan assay (HPS) reference assay, which was used to establish the clinical decision points in clinical studies. In this study, the reproducibility of assay performances across several laboratories was assessed by analysing quantification results generated by six independent laboratories (3× RealTime, 3× CTM v2) in comparison with one HPS reference laboratory. The 4th WHO Standard was diluted to 100, 25 and 10 IU/ml, and aliquots were tested in triplicates in 5 independent runs by each assay in the different laboratories to assess assay precision and detection rates. In a second approach, 2 clinical samples (GT 1a & GT 1b) were diluted to 100 and 25 IU/ml and tested as described above. While the result range for WHO 100 IU/ml replicates across all laboratories was similar in this analysis, the CVs of each laboratory ranged from 19.3 to 25.6 % for RealTime laboratories and were lower than CVs of CTM v2 laboratories with a range of 26.1-47.3 %, respectively, and also in comparison with the CV of the HPS reference laboratory (34.9 %). At WHO standard dilution of 25 IU/ml, 24 replicates were quantified by RealTime compared to 8 replicates with CTM v2. Results of clinical samples again revealed a higher variation of CTM v2 results as compared to RealTime values. (CVs at 100 IU/ml: RealTime: 13.1-21.0 % and CTM v2: 15.0-32.3 %; CVs at 25 IU/ml: RealTime 17.6-34.9 % and CTM v2 28.2-54.9 %). These findings confirm the superior precision of RealTime versus CTM v2 at low-level viremia even across different laboratories including the new clinical decision point at 25 IU/ml. A highly precise monitoring of HCV viral load during therapy will remain crucial for patient management with regard to futility rules, therapy efficacy and SVR.
    No preview · Article · Dec 2015 · Medical Microbiology and Immunology
  • M. Cioni · C. Leboeuf · P. Comoli · F. Ginevri · H. H. Hirsch

    No preview · Article · Dec 2015
  • Martina Sester · Céline Leboeuf · Tina Schmidt · Hans H. Hirsch
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    ABSTRACT: Transplant patients are at increased risk of viral complications due to the impaired control of viral replication, resulting from HLA-mismatching between graft and host and the immunosuppression needed to avert alloimmune reactions. In the past decade, quantitative viral load measurements have become widely available to identify patients at risk and to inform treatment decisions with respect to immunosuppressive drugs and antivirals. Since viral loads are viewed as the result of viral replication and virus-specific immune control, virus-specific T-cell monitoring has been explored to optimize management of adenovirus, BK polyomavirus, and cytomegalovirus in transplant patients. Although most studies are descriptive using different technologies, the overall results show that the quantity and quality of virus-specific T-cells inversely correlate with viral replication, whereby strong cellular immune responses are associated with containment of viral replication. The key obstacles to the introduction of assays for virus-specific T-cells into clinical practice is the definition of reliable cut-offs for clinical decision making, the poor negative predictive value of some assays, and the absence of interventional trials justifying changes of antiviral treatment or immunosuppression. More clinical research is needed using optimized assays and targets, before standardization and commutability can be envisaged as achieved for viral load testing. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · American Journal of Transplantation
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    ABSTRACT: BK polyomavirus (BKPyV) commonly reactivates after kidney transplantation, and can cause polyomavirus-associated nephropathy (PyVAN), whereas after allogeneic stem cell transplantation the most frequent manifestation of BKPyV is polyomavirus-associated hemorrhagic cystitis (PyVHC). Despite high-level BKPyV replication in both, the pathogenesis and manifestation of both BKPyV entities appears to differ substantially. We describe an unusual case of simultaneous PyVAN and PyVHC presenting with acute symptoms in a BKPyV-IgG positive recipient eight months after kidney transplantation from a haploidentical living donor, who was BKPyV-IgG negative. Symptoms of cystitis and viremia subsided rapidly after reduction of immunosuppression.
    No preview · Article · Dec 2015 · Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology
  • H. H. Hirsch · K. Yakhontova · M. Lu · J. Manzetti

    No preview · Article · Nov 2015
  • Piotr Kardas · Céline Leboeuf · Hans H Hirsch
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    ABSTRACT: Background: Polyomavirus JC (JCPyV) and BK (BKPyV) can cause significant diseases in immunocompromised patients including nephropathy, hemorrhagic cystitis, and leukoencephalopathy. Recently, JCPyV and BKPyV IgG have been explored as risk predictors in multiple sclerosis and transplant patients, but sensitivity, specificity and quantification issues limit current performance. Objective: To improve JCPyV and BKPyV-specific antibody testing. Study design: Healthy blood donor sera (N=400) were tested at dilutions 1:100, 1:200, and 1:400 for JCPyV- and BKPyV-specific IgG using VP1 virus-like particle (VLP)-based ELISAs normalized to a laboratory reference serum. Normalized optical density 492nm greater or equal 0.1 in all 3 dilutions was regarded as reactive. Sera with discordant reactivity in at least one dilution were retested after VLP preadsorption. Results: At dilutions 1:100, 1:200, and 1:400, IgG reactivity was 74%, 60% and 53% for JCPyV, and 93%, 86% and 74% for BKPyV, respectively. At these dilutions, JCPyV-VLP preadsorption identified 56, 4 and 0 false-positives and 0, 4 and 27 false-negatives, respectively. Dilution-dependent sensitivity was 100%, 98%, and 89%, and specificity 65, 98%, and 100%, respectively. For sera diluted 100-, 200-, and 400-fold, BKPyV-VLP preadsorption identified 28, 1 and 0 false-positives, and 0, 0 and 46 false-negatives, and sensitivity was 100%, 100%, 86%, and specificity 50%, 98%, 100%, respectively. Conclusion: For seroepidemiology studies, normalized JCPyV and BKPyV IgG ELISA at 1:200 serum dilution provides optimal sensitivity and specificity with the lowest false-positive and false-negative rate. For individual risk assessment, dilutions of 100, 200, and 400 combined with preadsorption for low-reactive sera may be most appropriate.
    No preview · Article · Sep 2015 · Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology
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    ABSTRACT: Multidrug-resistant (MDR) cytomegalovirus (CMV) emerged after transient responses to ganciclovir, foscarnet, and cidofovir in a CMV-seropositive recipient who underwent allogeneic hematopoietic stem cell transplantation from a CMV-seronegative donor. Experimental treatments using leflunomide and artesunate failed. Re-transplantation from a CMV-seropositive donor supported by adoptive transfer of pp65-specific T cells and maribavir was followed by lasting suppression. This case illustrates that successful MDR CMV therapy may require individualized multidisciplinary approaches.This article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2015 · Transplant Infectious Disease
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    Christiane Beckmann · Hans H. Hirsch
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    ABSTRACT: Rapid diagnosis of influenza is important for controlling outbreaks and starting antiviral therapy. Direct antigen detection (DAD) is rapid, but lacks sensitivity, whereas nucleic acid amplification testing (NAT) is more sensitive, but also more time-consuming. To evaluate the performance of a rapid isothermal NAT and two DADs. During February-May 2014, we tested 211 consecutive patients with influenza-like illness using a commercial isothermal NAT (Alere™ Influenza A&B) as well as the DAD Sofia(®) Influenza A+B and BinaxNOW(®) Influenza A&B for detection of influenza-A and -B virus. RespiFinder-22(®) a commercial multiplex NAT served as reference test. Serial 10-fold dilutions of influenza-A and -B cell culture supernatants were examined. Another 225 patient samples were tested during December 2014-February 2015. Compared to RespiFinder-22(®), the isothermal NAT Alere™ Influenza A&B, and the DAD Sofia(®) Influenza A+B and BinaxNOW(®) Influenza A&B had sensitivities of 77.8%, 59.3% and 29.6%, and specificities of 99.5%, 98.9% and 100%, respectively, for the first 211 patient samples. Alere™ Influenza A&B showed 85.7% sensitivity and 100% specificity in the second cohort. Isothermal NAT was 10-100-fold more sensitive compared to DAD for influenza virus culture supernatants with a lower limit of detection of 5000-50,000 copies/mL. The average turn-around time (TAT) of isothermal NAT and DADs was 15min, but increased to 110min for Alere™ Influenza A&B, 30min for BinaxNOW(®) Influenza A&B, and 45min for Sofia(®) Influenza A+B, when analyzing batches of 6 samples. Simple sample processing and a TAT of 15min render isothermal NAT Alere™ Influenza A&B suitable for sequential near-patient testing, but the TAT advantage is lost when testing of larger series. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jun 2015 · Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology
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    ABSTRACT: Condomless sex is a key driver of sexually transmitted diseases. In this study, we assess the long-term changes (2000–2013) of the occurrence of condomless sex among human immunodeficiency virus (HIV)-infected individuals enrolled in the Swiss HIV Cohort study. The frequencies with which HIV-infected individuals reported condomless sex were either stable or only weakly increasing for 2000–2008. For 2008–2013, these rates increased significantly for stable relationships among heterosexuals and men who have sex with men (MSM) and for occasional relationships among MSM. Our results highlight the increasing public health challenge posed by condomless sex and show that condomless sex has been increasing even in the most recent years.
    Full-text · Article · Jun 2015 · Open Forum Infectious Diseases
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    ABSTRACT: Natural killer cell function is regulated by inhibitory and activating killer cell immunoglobulin-like receptors (KIR). Previous studies have documented associations of KIR genotype with the risk of cytomegalovirus (CMV) replication after solid organ transplantation. In this study of 649 solid organ transplant recipients, followed prospectively for infectious disease events within the Swiss Transplant Cohort Study, we were interested to see if KIR genotype associated with virus infections other than CMV. We found that KIR B haplotypes (which have previously been linked to protection from CMV replication) were associated with protection from varicella zoster virus infection (hazard ratio, 0.43; 95% confidence interval, 0.21-0.91; P = 0.03). No significant associations were detected regarding the risk of herpes simplex, Epstein-Barr virus or BK polyomavirus infections. In conclusion, these data provide evidence that the relative protection of KIR haplotype B from viral replication after solid organ transplantation may extend beyond CMV to other herpes viruses, such as varicella zoster virus and possibly Epstein-Barr virus.
    No preview · Article · Jun 2015 · Transplantation
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    ABSTRACT: Prospective cohort studies significantly contribute to answering specific research questions in a defined population. Since 2008, the Swiss Transplant Cohort Study (STCS) systematically enrolled >95 % of all transplant recipients in Switzerland, collecting predefined data at determined time points. Designed as an open cohort, the STCS has included >3900 patients to date, with a median follow-up of 2.96 years (IQR 1.44-4.73). This review highlights some relevant findings in the field of transplant-associated infections gained by the STCS so far. Three key general aspects have crystallized: (i) Well-run cohort studies are a powerful tool to conduct genetic studies, which are crucially dependent on a meticulously described phenotype. (ii) Long-term real-life observations are adding a distinct layer of information that cannot be obtained during randomized studies. (iii) The systemic collection of data, close interdisciplinary collaboration, and continuous analysis of some key outcome data such as infectious diseases endpoints can improve patient care.
    No preview · Article · Jun 2015 · Current Infectious Disease Reports
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    ABSTRACT: Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infection among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patient's risk stratification. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    No preview · Article · May 2015 · Clinical Infectious Diseases
  • Fabian H Weissbach · Hans H Hirsch
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    ABSTRACT: Despite availability of protective vaccines, tick-borne encephalitis virus (TBEV) infections have been increasingly reported to the European centres of disease control over the past two decades. Since diagnosis of TBEV exposure relies on serologic testing, we compared two commercial assays, ImmunozymFSME-IgG (ELISA-1) and FSMEVienna-IgG Euroimmun (ELISA-2). Both assays use whole TBEV antigens, but differ in viral strains (Neudoerfl for ELISA-1; K23 for ELISA-2), and cut-off definitions. Testing 398 healthy blood donors, ELISA-1 showed higher reactivity than ELISA-2 (p<0.001) suggesting different assay properties. This was supported by Bland-Altman analysis for OD450nm (mean bias +0.32; 95% limits of agreement: -0.31 to +0.95) and persisted after transformation in Vienna units. Concordant results were observed for 276 (69%) sera (44 positive, 232 negative). Discordant results were observed for 122 (31%) sera: 15 fully discordant, all being ELISA-1 positive/ELISA-2 negative; 107 partially discordant sera (101 sera being ELISA-1 indeterminate/ELISA-2 negative; 6 having positive or indeterminate reactivity in both ELISAs). Neutralization at 1:10 dilution tested positive in 33 of 44 concordant positive sera; in 1 of 15 fully discordant sera; and 1 of 33 partially discordant sera. Indirect immunofluorescence revealed high antibody titres of ≥100 for yellow fever virus in 18 cases, and dengue virus in one case suggesting that cross-reactivity contributed to ELISA-1 results. We conclude that 1. cross-reactivity among flaviviruses remains a limitation of TBEV serology; 2. ELISA-2 revealed reasonable sensitivity and specificity for anti-TBEV IgG population screening of human sera; 3. neutralization testing is most specific, and should be reserved for selective questions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    No preview · Article · Apr 2015 · Clinical and vaccine Immunology: CVI
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    ABSTRACT: Demonstration of survival and outcome of progressive multifocal leukoencephalopathy (PML) in a 56-year-old patient with common variable immunodeficiency, consisting of severe hypogammaglobulinemia and CD4+ T lymphocytopenia, during continuous treatment with mirtazapine (30 mg/day) and mefloquine (250 mg/week) over 23 months. Regular clinical examinations including Rankin scale and Barthel index, nine-hole peg and box and block tests, Berg balance, 10-m walking tests, and Montreal Cognitive Assessment (MoCA) were done. Laboratory diagnostics included complete blood count and JC virus (JCV) concentration in cerebrospinal fluid (CSF). The noncoding control region (NCCR) of JCV, important for neurotropism and neurovirulence, was sequenced. Repetitive MRI investigated the course of brain lesions. JCV was detected in increasing concentrations (peak 2568 copies/ml CSF), and its NCCR was genetically rearranged. Under treatment, the rearrangement changed toward the archetype sequence, and later JCV DNA became undetectable. Total brain lesion volume decreased (8.54 to 3.97 cm(3)) and atrophy increased. Barthel (60 to 100 to 80 points) and Rankin (4 to 2 to 3) scores, gait stability, and box and block (7, 35, 25 pieces) and nine-hole peg (300, 50, 300 s) test performances first improved but subsequently worsened. Cognition and walking speed remained stable. Despite initial rapid deterioration, the patient survived under continuous treatment with mirtazapine and mefloquine even though he belongs to a PML subgroup that is usually fatal within a few months. This course was paralleled by JCV clones with presumably lower replication capability before JCV became undetectable. Neurological deficits were due to PML lesions and progressive brain atrophy.
    No preview · Article · Apr 2015 · Journal of NeuroVirology
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    ABSTRACT: Background. The hepatitis C virus (HCV) epidemic is evolving rapidly in patients infected with human immunodeficiency virus (HIV). We aimed to describe changes in treatment uptake and outcomes of incident HCV infections before and after 2006, the time-point at which major changes in HCV epidemic became apparent. Methods. We included all adults with an incident HCV infection before June 2012 in the Swiss HIV Cohort Study, a prospective nationwide representative cohort of individuals infected with HIV. We assessed the following outcomes by time period: the proportion of patients starting an HCV therapy, the proportion of treated patients achieving a sustained virological response (SVR), and the proportion of patients with persistent HCV infection during follow-up. Results. Of 193 patients with an HCV seroconversion, 106 were diagnosed before and 87 after January 2006. The proportion of men who have sex with men increased from 24% before to 85% after 2006 (P < .001). Hepatitis C virus treatment uptake increased from 33% before 2006 to 77% after 2006 (P < .001). Treatment was started during early infection in 22% of patients before and 91% after 2006 (P < .001). An SVR was achieved in 78% and 29% (P = .01) of patients treated during early and chronic HCV infection. The probability of having a detectable viral load 5 years after diagnosis was 0.67 (95% confidence interval [CI], 0.58-0.77) in the group diagnosed before 2006 and 0.24 (95% CI, 0.16-0.35) in the other group (P < .001). Conclusions. In recent years, increased uptake and earlier initiation of HCV therapy among patients with incident infections significantly reduced the proportion of patients with replicating HCV.
    Full-text · Article · Mar 2015 · Open Forum Infectious Diseases
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    ABSTRACT: BK polyomavirus (BKPyV)-associated hemorrhagic cystitis (PyVHC) complicates 5 - 15% of allogeneic hematopoietic stem cell transplantations. Targeted antivirals are still unavailable. Brincidofovir (BCV, previously CMX001) has shown inhibitory activity against diverse viruses, including BKPyV in a primary renal tubule cell culture model of polyomavirus-associated nephropathy. We investigated the effects of BCV in BKPyV-infected and uninfected primary human urothelial cells (HUCs), the target cells of BKPyV in PyVHC. The BCV concentrations causing 50 and 90% reductions (EC50 and EC90) in the number of intracellular BKPyV genome equivalents per cell (icBKPyV) were 0.27 μM (95%CI 0.24-0.29) and 0.59 μM (95%CI 0.53-0.65) respectively. At 0.63 μM, BCV reduced viral late gene expression by 90% and halted progeny release. Preinfection treatment for only 24 hours reduced icBKPyV similarly to treatment from 2-72 hours postinfection, while combined pre- and postinfection treatment suppressed icBKPyV completely. After investigating BCV's effects on HUC-viability, mean selectivity indices at 50 and 90% inhibition (SI50 and SI90) were calculated for cellular DNA replication at 2.7 and 2.9 respectively, mitochondctivity at 8.9 and 10.4, total ATP at 8.6 and 8.2 and membrane integrity at 25.9 and 16.7. The antiviral and cytostatic effects, but less so the cytotoxic effects, were inversely related to cell density. The cytotoxic effects at concentrations ≥10 μM were rapid and likely related to BCV's lipid moiety. After carefully defining the antiviral, cytostatic, and cytotoxic properties of BCV in HUCs, we conclude that a preemptive or prophylactic approach in PyVHC is likely to give the best results. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    No preview · Article · Mar 2015 · Antimicrobial Agents and Chemotherapy
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    ABSTRACT: The plasmid pBKV (34-2) (ATCC 45025) contains the entire BK polyomavirus Dunlop genome. Sequencing revealed 12 point mutations compared to the GenBank sequence, but only 4 point mutations compared to the published sequence. The origin of these differences is unknown, but may impact virological as well as diagnostic research and development.
    Full-text · Article · Mar 2015 · Genome Announcements
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    ABSTRACT: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice.
    Full-text · Article · Mar 2015 · PLoS Medicine
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    Rainer Gosert · Hans H. Hirsch

    Full-text · Article · Feb 2015

Publication Stats

9k Citations
1,444.48 Total Impact Points

Institutions

  • 2011-2015
    • University of Zurich
      • Institute of Virology
      Zürich, Zurich, Switzerland
  • 2001-2015
    • Universitätsspital Basel
      • Klinik für Infektiologie & Spitalhygiene
      Bâle, Basel-City, Switzerland
  • 1991-2015
    • Universität Basel
      • • Department of Biomedicine
      • • Institut für Medizinische Mikrobiologie
      • • Institute of Geology and Paleontology
      Bâle, Basel-City, Switzerland
  • 2012
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
    • Universität des Saarlandes
      • Institut für Virologie
      Saarbrücken, Saarland, Germany
  • 2008-2011
    • University Hospital of North Norway
      • Department of Microbiology and Infection Control
      Tromsø, Troms, Norway
  • 2006
    • Kantonsspital St. Gallen
      San Gallo, Saint Gallen, Switzerland
    • Cornell University
      Итак, New York, United States
  • 2003
    • University of Geneva
      • Division of Infectious Diseases
      Carouge, GE, Switzerland
  • 2002
    • Universitäre Psychiatrische Kliniken Basel
      Bâle, Basel-City, Switzerland
  • 1991-1992
    • Universität Stuttgart
      • Institute of Biochemistry
      Stuttgart, Baden-Württemberg, Germany
  • 1988
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany