Joost P H Drenth

Radboud University Medical Centre (Radboudumc), Nymegen, Gelderland, Netherlands

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Publications (346)2205.03 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established AIH risk alleles. To study the immune modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch autoimmune hepatitis (AIH) type 1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five per cent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01 positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01 negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase (ALT) levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5), however HLA-DRB1*03:01 was independently associated with higher IgG levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01 positive patients were received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.
    Genes and Immunity 01/2015; · 3.79 Impact Factor
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    ABSTRACT: Background Cyst infection is a severe complication of hepatic cystic disease. However, an evidence-based treatment strategy is not available.AimTo assess the available treatment strategies and provide a treatment advice for de novo hepatic cyst infection.Methods We systematically searched PubMed (1948–2014), EMBASE (1974–2014), and the Cochrane Library (until 2014) for studies involving humans (≥18 years) treated for a hepatic cyst infection. We extracted data on patient characteristics, treatment and follow-up.ResultsWe identified 41 articles; all were case series or case reports, implicating a high risk of bias. We included 54 hepatic cyst infection cases (male 39%; mean age 63 ± 12 years; diabetes 6%; dialysis 19%; transplant recipients 30%). Initial therapy consisted of antimicrobial (56%), percutaneous (31%) or surgical treatment (13%). We identified 42 antimicrobial regimens consisting of 23 different combinations. Most used antibiotic classes were quinolones (34%) and cephalosporins (34%). Antimicrobials failed in 70% of cases, eventually requiring percutaneous or surgical treatment in, respectively, 37% and 27%. Recurrent hepatic cyst infection was frequent (20%). Median time to recurrence was 8 weeks (IQR 3–24 weeks). In 46%, recurrence occurred in renal transplant recipients. Cyst infection related deaths occurred in 9%, of whom 40% were on dialysis.Conclusions The literature shows that treatment of hepatic cyst infection is highly heterogeneous. We recommend first line treatment with oral ciprofloxacin. In case of failure, percutaneous cyst drainage needs to be considered.
    Alimentary Pharmacology & Therapeutics 12/2014; · 4.55 Impact Factor
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    ABSTRACT: Mass-related symptoms caused by hepatic cysts are effectively treated by aspiration sclerotherapy (AS). This minimal-invasive intervention is regarded as a safe procedure. Hence, occurrence of complications is low. Transient fever is commonly reported as a side effect. However, documentation on a post-procedural hepatic cyst infection as a complication of AS is limited. We present five cases in which a tentative diagnosis of post-procedural hepatic cyst infection was made. Patients typically presented with abdominal pain and fever, had to be admitted to our hospital, and were treated with long term antibiotics. Ultimately, the cyst infection successfully resolved with ciprofloxacin in all cases.
    Journal of gastrointestinal and liver diseases: JGLD 12/2014; 23(4):441-4. · 1.85 Impact Factor
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    ABSTRACT: Chronic pancreatitis is a complex disease with many unanswered questions regarding the natural history and therapy. Prospective longitudinal studies with long-term follow-up are warranted. The Dutch Chronic Pancreatitis Registry (CARE) is a nationwide registry aimed at prospective evaluation and follow-up of patients with chronic pancreatitis. All patients with (suspected) chronic or recurrent pancreatitis are eligible for CARE. Patients are followed-up by yearly questionnaires and review of medical records. Study outcomes are pain, disease complications, quality of life, and pancreatic function. The target sample size was set at 500 for the first year and 1000 patients within 3 years. A total of 1218 patients were included from February 2010 until June 2013 by 76 participating surgeons and gastroenterologist from 33 hospitals. Participation rate was 90% of eligible patients. Eight academic centers included 761 (62%) patients, while 25 community hospitals included 457 (38%). Patient centered outcomes were assessed by yearly questionnaires, which had a response rate of 85 and 82% for year 1 and 2, respectively. The median age of patients was 58 years, 814 (67%) were male, and 38% had symptoms for less than 5 years. The CARE registry has successfully recruited over 1200 patients with chronic and recurrent pancreatitis in about 3 years. The defined inclusion criteria ensure patients are included at an early disease stage. Participation and compliance rates are high. CARE offers a unique opportunity with sufficient power to investigate many clinical questions regarding natural course, complications, and efficacy and timing of treatment strategies. Copyright © 2014 IAP and EPC. Published by Elsevier B.V. All rights reserved.
    Pancreatology 11/2014; · 2.50 Impact Factor
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    ABSTRACT: Human studies have firmly implicated voltage-gated sodium channels in human pain disorders, and targeted and massively parallel genomic sequencing is beginning to be used in clinical practice to determine which sodium channel variants are involved. Missense substitutions of SCN9A, the gene encoding sodium channel NaV1.7, SCN10A, the gene encoding sodium channel NaV1.8, and SCN11A, the gene encoding sodium channel NaV1.9, produce gain-of-function changes that contribute to pain in many human painful disorders. Genomic sequencing might help to establish a diagnosis, and in the future might support individualisation of therapeutic approaches. However, in many cases, and especially in sodium channelopathies, the results from genomic sequencing can only be appropriately interpreted in the context of an extensive functional assessment, or family segregation analysis of phenotype and genotype.
    The Lancet Neurology 11/2014; 13(11):1152–1160. · 21.82 Impact Factor
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    ABSTRACT: Background & AimSeveral trials have demonstrated that somatostatin analogues decrease liver volume in mixed populations of patients with autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease. Chronic renal dysfunction in ADPKD may affect treatment efficacy of lanreotide and possibly enhances risk for adverse events. The aim of this open-label clinical trial (RESOLVE trial) was to assess efficacy of 6 months lanreotide treatment 120 mg subcutaneously every 4 weeks in ADPKD patients with symptomatic polycystic liver disease.Methods Primary outcome was change in liver volume after 6 months, secondary outcomes were changes in kidney volume, eGFR, symptom relief and health-related quality of life (Euro-Qol5D). We excluded patients with an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2. We used the Wilcoxon signed-rank test or paired two-sided t-test to analyze within-group differences.ResultsWe included 43 ADPKD patients with polycystic liver disease (84% female, median age 50 years, mean eGFR 63 ml/min/1.73m2). Median liver volume decreased from 4,859 ml to 4,595 ml (-3.1%;p<0.001), and median kidney volume decreased from 1,023 ml to 1,012 ml (-1.7%;p=0.006). eGFR declined 3.5% after the first injection, remained stable up to study end, to decline again after lanreotide withdrawal. Lanreotide significantly relieved postprandial fullness, shortness of breath and abdominal distension. Three participants had a suspected episode of hepatic or renal cyst infection during the study.Conclusion Lanreotide reduced polycystic liver and kidney volumes and decreases symptoms in ADPKD patients. Moreover, eGFR decreased acutely after starting lanreotide, stabilized thereafter and declined again after withdrawal.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 11/2014; · 4.41 Impact Factor
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    ABSTRACT: Background and objectives Hereditary haemochromatosis (HH) is the most prevalent genetic liver disease, with an incidence of 1/200 to 1/400 in the Caucasian population. HH patients are treated by family physicians as well as different specialists. When left untreated or insufficiently treated, the complications can become life threatening. To support and evaluate qualitative care for HH, we evaluated and compared the available structured guidelines on screening, diagnosis and management of HH patients. Methods Seven appraisers systematically reviewed the retrieved guidelines. The Appraisal of Guidelines Research and Evaluation II (AGREE II) was used to score and discuss the quality and reach consensus. The content of recommendations and the evidence behind them, were evaluated. Results Three guidelines, developed by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL) and a DUTCH guideline were found. Fifty-seven percent of the recommendations were not shared between the guidelines, pointing to inconsistency of their content. Only two references supporting the recommendations were shared between all three guidelines. The AASLD guideline contains no information about management and follow-up. Moreover, the methodological quality of the AASLD guideline was rated insufficient, except for ‘clarity and presentation’ (77%). Applicability of the guidelines was scored very low in all three (AASLD: 31%, EASL: 23%, DUTCH: 35%). The DUTCH guideline was judged best. Conclusions Very poor consistency between available guidelines for HH hampers qualitative care and its evaluation. An updated high-quality and evidence-based guideline that covers follow-up and management of patients with HH is needed.
    Gastroentérologie Clinique et Biologique 10/2014; · 1.98 Impact Factor
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    ABSTRACT: A new era for the treatment of chronic hepatitis C is about to transpire. With the introduction of the first-generation protease inhibitors the efficacy of hepatitis C treatment improved significantly. Since then, the therapeutic agenda has moved further forward with the recent approval of sofosbuvir and the expected approval of agents such as simeprevir and daclatasvir. This paper, developed parallel to the approval of sofosbuvir, is to serve as a guidance for the therapeutic management of chronic hepatitis C.
    The Netherlands Journal of Medicine 10/2014; 72(8):388-400. · 2.21 Impact Factor
  • Gut 09/2014; · 13.32 Impact Factor
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    ABSTRACT: Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort.
    Gut 09/2014; · 13.32 Impact Factor
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    ABSTRACT: Sodium channel Nav1.7, encoded by SCN9A, is expressed in DRG neurons and regulates their excitability. Genetic and functional studies have established a critical contribution of Nav1.7 to human pain disorders. We have now characterized a novel Nav1.7 mutation (R1279P) from a female human subject with distal limb pain, in which depolarized fast inactivation overrides impaired activation to produce hyperexcitability and spontaneous firing in DRG neurons. Whole-cell voltage-clamp recordings in human embryonic kidney (HEK) 293 cells demonstrated that R1279P significantly depolarizes steady-state fast-, slow-, and closed-state inactivation. It accelerates deactivation, decelerates inactivation, and facilitates repriming. The mutation increases ramp currents in response to slow depolarizations. Our voltage-clamp analysis showed that R1279P depolarizes channel activation, a change that was supported by our multistate structural modeling. Because this mutation confers both gain-of-function and loss-of-function attributes on the Nav1.7 channel, we tested the impact of R1279P expression on DRG neuron excitability. Current-clamp studies reveal that R1279P depolarizes resting membrane potential, decreases current threshold, and increases firing frequency of evoked action potentials within small DRG neurons. The populations of spontaneously firing and repetitively firing neurons were increased by expressing R1279P. These observations indicate that the dominant proexcitatory gating changes associated with this mutation, including depolarized steady-state fast-, slow-, and closed-state inactivation, faster repriming, and larger ramp currents, override the depolarizing shift of activation, to produce hyperexcitability and spontaneous firing of nociceptive neurons that underlie pain.
    Journal of Neuroscience 09/2014; 34(37):12328-40. · 6.75 Impact Factor
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    ABSTRACT: Chronic pain, defined as pain existing for >4-6 weeks, affects >60% of patients with autosomal-dominant polycystic disease (ADPKD). It can have various causes, indirectly or directly related to the increase in kidney and liver volume in these patients. Chronic pain in ADPKD patients is often severe, impacting physical activity and social relationships, and frequently difficult to manage. This review provides an overview of pathophysiological mechanisms that can lead to pain and discusses the sensory innervation of the kidneys and the upper abdominal organs, including the liver. In addition, the results of a systematic literature search of ADPKD-specific treatment options are presented. Based on pathophysiological knowledge and evidence derived from the literature an argumentative stepwise approach for effective management of chronic pain in ADPKD is proposed.
    09/2014; 29(suppl 4):iv142-iv153.
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    ABSTRACT: Abstract Background and aims. Epidemiological data on autoimmune hepatitis (AIH) are scarce. Here, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). Methods. Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. Results. The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3-19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5-2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1-44 years). Familial occurrence was reported in three cases. Conclusion. This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.
    Scandinavian Journal of Gastroenterology 08/2014; · 2.33 Impact Factor
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    ABSTRACT: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. We performed a genome-wide association study of 649 adults in the Netherlands with AIH type-1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type-1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the MHC region. We associated AIH with a variant in the MHC region, at rs2187668 (P=1.5x10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3x10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P=2.8x10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P=7.7x10(-8)) and CARD10 (rs6000782, 22q13.1; P=3.0x10(-6)). Furthermore, strong inflation of association signal was found with single-nucleotide polymorphisms (SNPs) associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with SNPs associated with other genetic traits. In a genome-wide association study, we associated AIH type-1with variants in the MHC region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.
    Gastroenterology 08/2014; 147(2):443-452. · 12.82 Impact Factor
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    ABSTRACT: To date, inter-genotypic recombinant hepatitis C viruses (HCV) and their treatment outcomes have not been well characterized. This study characterized 12 novel HCV recombinant strains and their response to sofosbuvir in combination with ribavirin (SOF/RBV) treatment. Across the phase II/III studies of sofosbuvir, HCV samples were genotyped using both the Siemens VERSANT® HCV Genotype INNO-LiPA 2.0 assay and NS5B sequencing. Among these patient samples, genotype assignment discordance between the two methods was found in 0.5% of all cases (12/2363) of which all were identified as genotype 2 by INNO-LiPA (12/487=2.5%). HCV full genome sequences were obtained for these 12 samples by a sequence-independent amplification method coupled with next-generation sequencing. HCV full genome sequencing revealed that these viruses were recombinant HCV strains with the 5’ part corresponding to genotype 2 and the 3’ part corresponding to genotype 1. The recombination breakpoint between genotype 2 and genotype 1 was consistently located within 80 amino acids of the NS2/NS3 junction. Interestingly, one of the recombinant viruses had a 34 amino acid duplication at the location of the recombination breakpoint. Eleven of these 12 patients were treated with a regimen for genotype 2 HCV infection, but responded like they had genotype 1 infection; one patient had received placebo. Conclusion: Twelve new HCV inter-genotypic recombinant genotype 2/1 viruses have been characterized. The antiviral response to a 12-16 week course of SOF/RBV treatment in these patients was more similar to responses among genotype 1 patients than genotype 2 patients, consistent with their genotype 1 NS5B gene. (Hepatology 2014;)
    Hepatology 08/2014; · 11.19 Impact Factor
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    ABSTRACT: Up to 41 % of patients report pain after cholecystectomy and in most studies follow-up for these symptoms did not exceed 5 years. The episodic nature of abdominal pain associated with symptomatic cholelithiasis warrants long-term follow-up studies. We assessed which patient and surgical factors were associated with absence of pain and patient-reported success of surgery after ≥5 years of follow-up.
    Surgical endoscopy. 06/2014;
  • Marten A Lantinga, Joost P H Drenth, Tom J G Gevers
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    ABSTRACT: Cyst infection is a severe complication of renal and hepatic cystic disease that frequently leads to hospitalization. In most cases the diagnosis of cyst infection is made empirically as a cyst aspirate is frequently unavailable. This study aims to evaluate diagnostic criteria, microbiological findings and imaging modalities needed to diagnose cyst infection. In order to do so, we evaluated reports that characterize cyst infection cases published in the English language between 1948 and January 2014. We identified 70 articles documenting a total of 215 cyst infection cases (renal n = 119; hepatic n = 96). Six studies, including 74 cases of renal and 61 cases of hepatic cyst infection, used diagnostic criteria. The criteria that led to a definite cyst infection diagnosis were consistent, whereas criteria for a 'probable diagnosis' varied considerably. Cyst infection cases commonly have abdominal pain, fever and elevated serum inflammatory markers. Urine and blood cultures frequently remained negative, even in definite cases. The diagnostic properties of (18)fluorodeoxyglucose positron-emission computed tomography ((18)F-FDG PET/CT) are probably best to diagnose cyst infection. Cyst aspirate indicating infection is currently the gold standard in diagnosing cyst infection. If not available, a combination of clinical and biochemical parameters is necessary to make a well-considered diagnosis, preferably including (18)F-FDG PET/CT.
    Nephrology Dialysis Transplantation 06/2014; · 3.49 Impact Factor
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    ABSTRACT: Abstract Objective. According to screening studies, celiac disease (CD) is prevalent in Western Europe. Actual prevalence tends to be much lower. The width of this actual gap is determined by the balance between disease symptoms and the "case-finding" capabilities of the healthcare system. Therefore, we conducted a nationwide study to determine the temporal trends in the incidence in the Netherlands including a focus on demographic aspects. Materials and methods. We performed a nationwide search in the Dutch Pathology Registry (PALGA) to identify all biopsy-proven cases of CD in five different years between 1995 and 2010. Furthermore, demographic profiles and socioeconomic status (SES) of patients were studied. Results. The overall incidence of CD increased from 2.72 (confidence interval [CI] 2.46-2.99) in 1995 to 6.65 (CI 6.27-7.06) per 100,000 inhabitants in 2010. No significant regional differences were noticed. In men, rates increased from 2.28 (CI 1.95-2.65) to 4.71 (CI 4.25-5.20) per 100,000 in 2010. In women, the increase was from 3.27 (CI 2.88-3.70) to 8.66 (CI 8.04-9.31) per 100,000 in 2010. A trend toward leveling of incidence was observed from 2008 to 2010. Patients diagnosed during childhood live in areas with a higher SES compared with patients diagnosed at adult age. Conclusion. The incidence of biopsy-proven CD in the Netherlands increased almost threefold between 1995 and 2010. In areas with a higher SES, relatively more children were diagnosed.
    Scandinavian Journal of Gastroenterology 05/2014; · 2.33 Impact Factor
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    ABSTRACT: Chronic hepatitis C is a global health problem. To prevent or reduce complications, the hepatitis C virus (HCV) infection needs to be eradicated. There have been several developments in treating these patients since the discovery of the virus. As of 1 January 2014, the drugs that are approved for treatment of chronic HCV infection are peginterferon-α, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir. In this review we provide an overview of the clinical pharmacokinetic characteristics of these agents by describing their absorption, distribution, metabolism and excretion. In the pharmacodynamic part we summarize what is known about the relationships between the pharmacokinetics of each drug and efficacy or toxicity. We briefly discuss the pharmacokinetics and pharmacodynamics of chronic hepatitis C treatment in special patient populations, such as patients with liver cirrhosis, renal insufficiency or HCV/HIV coinfection, and children. With this knowledge, physicians, pharmacists, nurse practitioners, etc. should be educated to safely and effectively treat HCV-infected patients.
    Clinical Pharmacokinetics 04/2014; · 5.49 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S525-S526. · 10.40 Impact Factor

Publication Stats

6k Citations
2,205.03 Total Impact Points


  • 1996–2014
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
    • MetroHealth Medical Center
      Cleveland, Ohio, United States
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
  • 2013
    • Jeroen Bosch Ziekenhuis
      Hertogenbosch, North Brabant, Netherlands
  • 2012–2013
    • VU University Medical Center
      • Department of Gastroenterology and Hepatology
      Amsterdam, North Holland, Netherlands
    • University of Leipzig
      • Klinik und Poliklinik für Gastroenterologie und Rheumatologie
      Leipzig, Saxony, Germany
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands
  • 2011
    • University of Oxford
      Oxford, England, United Kingdom
  • 2010–2011
    • Yale University
      • Department of Neurology
      New Haven, CT, United States
  • 1993–2011
    • Radboud University Nijmegen
      • • Department of Gastroenterology and Hepatology
      • • Department of General Internal Medicine
      Nijmegen, Provincie Gelderland, Netherlands
  • 2007–2009
    • Charité Universitätsmedizin Berlin
      • Medical Department, Division of Hepatology and Gastroenterology
      Berlin, Land Berlin, Germany
  • 2008
    • Université de Montréal
      • Center for Mathematical Research
      Montréal, Quebec, Canada
  • 2006
    • Can Tho University of Medicine and Pharmacy
      Kan Tho, Cần Thơ, Vietnam
  • 2005
    • University of Antwerp
      Antwerpen, Flanders, Belgium
  • 2004–2005
    • National Institutes of Health
      • Cell Biology and Metabolism Program
      Bethesda, MD, United States
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 1997
    • Sheba Medical Center
      • Department of Pathology
      Gan, Tel Aviv, Israel
  • 1993–1994
    • Erasmus Universiteit Rotterdam
      • Department of Hematology
      Rotterdam, South Holland, Netherlands