Timothy R Billiar

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (834)3756.08 Total impact

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    ABSTRACT: Excessive inflammation resulting from activation of the innate immune system significantly contributes to ischemia/reperfusion injury (IRI). Inflammatory reactions in both IRI and infections share the same signaling pathways evoked by danger/pathogen associated molecular pattern molecules. The cytosolic retinoid-inducible gene I(RIG-I)-like RNA receptor (RLR) RNA sensing pathway mediates type I IFN production during viral infection and the sensing of viral RNA is regulated by adenosine deaminase acting on RNA 1 (ADAR1). Using a model of liver IRI, we provide evidence that ADAR1 also regulates cytosolic RNA-sensing pathways in the setting of ischemic stress. Suppression of ADAR1 significantly enhanced inflammation and liver damage following IRI, which was accompanied by significant increases in type I IFN through cytosolic RNA-sensing pathways. In addition, knocking ADAR1 down in hepatocytes exaggerates inflammatory signaling to dsRNA or endotoxin and results in over production of type I IFN, which could be abolished by the interruption of RIG-I. Therefore, we identified a novel ADAR1-dependent protective contribution through which hepatocytes guard against aberrant cytosolic RLR-RNA-sensing pathway mediated inflammatory reaction in response to acute liver IR. ADAR1 protects against over activation of viral RNA-sensing pathways in non-infectious tissue stress.
    Preview · Article · Feb 2016 · Scientific Reports
  • Shuqing Jin · Zhixia Chen · Xibing Ding · Xiang Zhao · Xi Jiang · Yao Tong · Timothy R Billiar · Quan Li
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    ABSTRACT: Mechanical ventilation can improve hypoxemia, but can also cause the so-called ventilator-induced lung injury (VILI). Polyinosinic-polycytidylic acid (poly(I:C)), an analogue of natural double strand RNA virus, can induce lung inflammation. The purpose of this study was to determine whether moderate tidal volume mechanical ventilation (MTV) augments Poly(I:C)-induced lung injury, and if so, the mechanism responsible for it. Poly(I:C) (2μg/g) were instilled intratracheally in C57BL/6J wide type (WT) mice. They were then randomized to MTV (10ml/kg tidal volume) or spontaneous breath. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected 4h later for various measurements. Our results showed that MTV did not cause significant injury in normal lungs, but augmented Poly(I:C)-induced lung injury. The expression level of WNT-induced secreted protein 1 (WISP1) was consistent with lung injury, and the amplification of lung injury by MTV can be alleviated by anti-WISP1 antibody treatment. MTV further increased Poly(I:C)-induced integrin β3 expression in the lung. And co-immunoprecipitation (Co-IP) results suggested there was an interaction between WISP1 and β3. WISP1 significantly increased Poly(I:C)-induced TNF-α production in macrophages isolated from WT mice but not in macrophages isolated from β3 knock-out mice. Co-treatment with WISP1 and Poly(I:C) markedly increased the phosphorylation of extracellular signal-related kinase (ERK) in macrophages. Pretreating macrophages with an ERK inhibitor, U0126, dose-dependently antagonized WISP's synergistic effect on Poly(I:C)-induced TNF-α release. In conclusion, MTV exaggerates Poly(I:C)-induced lung injury in a WISP1 and integrin β3 dependent manner, involving, at least part, the activation of the ERK pathway. The WISP1-integrin β3 pathway could be an important target for novel therapy.
    No preview · Article · Jan 2016 · Molecular Medicine

  • No preview · Article · Jan 2016 · Journal of Trauma and Acute Care Surgery
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    ABSTRACT: Significance: High mobility group protein 1 (HMGB1) is an evolutionarily conserved and multi-functional protein. The biological function of HMGB1 depends on its cellular locations, binding partners, and redox states. Extracellular HMGB1 is a mediator of inflammation during infection or tissue injury. Immune cells actively release HMGB1 in response to infection, which in turn orchestrates both innate and adaptive immune responses. Recent advances: Hyperacetylation of HMGB1 within its nuclear localization sequences mobilizes HMGB1 from the nucleus to the cytoplasm and subsequently promotes HMGB1 release. The redox states of the cysteines in position 23, 45 and 106 determine the biological activity of the extracellular HMGB1. Critical issues: The full picture and the detailed molecular mechanisms of how cells regulate the post-translational modifications and the redox status of HMGB1 during immune responses or under stress are still unclear. Future directions: It is important to identify the signaling pathways that regulate the post-translational modifications and the redox status of HMGB1 and to find their roles in host immune responses and pathogenesis of diseases. Future works toward these directions will not only unravel the molecular mechanisms by which cells regulate the release and the biological function of HMGB1, but may also provide novel therapeutic targets to treat inflammatory diseases.
    No preview · Article · Dec 2015 · Antioxidants & Redox Signaling
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    ABSTRACT: Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.
    Full-text · Article · Dec 2015 · The Journal of clinical investigation
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    ABSTRACT: Background: Toll-like receptor 4 (TLR4) is a critical receptor involved in the sensing of Gram negative bacterial infection. However, the roles of TLR4 in sepsis are cell type specific. Dendritic cells (DC) are known to play a central role in microbial detection, alerting the immune system to the presence of infection and coordinating adaptive immune response. The goal of this study was to investigate the impact of DC-specific TLR4 signaling on host defense against intra-abdominal polymicrobial sepsis. Methods: C57BL/6, global Tlr4 knockout, cell specific knockout control, and CD11c-specific Tlr4(-/-) mice underwent cecal ligation and puncture (CLP). Results: Specific deletion of TLR4 on DC in mice improved survival and enhanced bacterial clearance. Deletion of TLR4 on DC was associated with lower circulating IL10, higher polymorphonuclear leukocytes (PMN) accumulation in the peritoneal cavity, and higher expression of chemokine (C-X-C motif) receptor 2 (CXCR2) on PMN after CLP. In vitro studies of DC and neutrophil cocultures confirmed that TLR4-dependent secretion of IL-10 from DC regulated neutrophil CXCR2 expression. Conclusions: Our data shed light on a previously unrecognized role for TLR4-signaling on DC in driving IL-10 secretion during sepsis, and through this pathway regulates PMN recruitment via suppression of CXCR2 expression.
    No preview · Article · Nov 2015 · The Journal of Infectious Diseases
  • Hui Zhou · Meihong Deng · Melanie Scott · Matthew Neal · Jianguo Li · Timothy Billiar

    No preview · Article · Nov 2015 · Critical care medicine
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    ABSTRACT: Significance: Traumatic injury elicits a complex, dynamic, multi-dimensional inflammatory response that is intertwined with complications such as multiple organ dysfunction and nosocomial infection. The complex interplay between inflammation and physiology in critical illness remains a challenge for translational research, including the extrapolation to human disease from animal models. Recent Advances: Over the past decade, we and others have attempted to decipher the bio-complexity of inflammation in these settings of acute illness, using computational models to improve clinical translation. In silico modeling has been suggested as a computationally-based framework for integrating data derived from basic biology experiments as well as preclinical and clinical studies. Critical Issues: Extensive studies in cells, mice, and human blunt trauma patients have led us to suggest: 1) that while an adequate level of inflammation is required for healing post-trauma, inflammation can be harmful when it becomes self-sustaining via a Damage-Associated Molecular Pattern (DAMP) / Toll-Like Receptor (TLR)-driven, feed-forward circuit; 2) that chemokines play a central regulatory role in driving either self-resolving or self-maintaining inflammation that drives the early activation of both classical innate and more recently-recognized lymphoid pathways; and 3) the presence of multiple thresholds and feedback loops which could significantly affect the propagation of inflammation across multiple body compartments. Future Directions: These insights from data-driven models into the primary drivers and interconnected networks of inflammation have been used to generate mechanistic computational models. Together, these models may be used to gain basic insights as well as serving to help define novel biomarkers and therapeutic targets.
    Full-text · Article · Nov 2015 · Antioxidants & Redox Signaling
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    ABSTRACT: Thrombosis and inflammation are intricately linked in several major clinical disorders, including disseminated intravascular coagulation and acute ischemic events. The damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1) is upregulated by activated platelets in multiple inflammatory diseases; however, the contribution of platelet-derived HMGB1 in thrombosis remains unexplored. Here, we generated transgenic mice with platelet-specific ablation of HMGB1 and determined that platelet-derived HMGB1 is a critical mediator of thrombosis. Mice lacking HMGB1 in platelets exhibited increased bleeding times as well as reduced thrombus formation, platelet aggregation, inflammation, and organ damage during experimental trauma/hemorrhagic shock. Platelets were the major source of HMGB1 within thrombi. In trauma patients, HMGB1 expression on the surface of circulating platelets was markedly upregulated. Moreover, evaluation of isolated platelets revealed that HMGB1 is critical for regulating platelet activation, granule secretion, adhesion, and spreading. These effects were mediated via TLR4- and MyD88-dependent recruitment of platelet guanylyl cyclase (GC) toward the plasma membrane, followed by MyD88/GC complex formation and activation of the cGMP-dependent protein kinase I (cGKI). Thus, we establish platelet-derived HMGB1 as an important mediator of thrombosis and identify a HMGB1-driven link between MyD88 and GC/cGKI in platelets. Additionally, these findings suggest a potential therapeutic target for patients sustaining trauma and other inflammatory disorders associated with abnormal coagulation.
    Full-text · Article · Nov 2015 · Journal of Clinical Investigation
  • Brian S. Zuckerbraun · Changchun Cai · Timothy R. Billiar

    No preview · Article · Nov 2015 · Hepatology
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    ABSTRACT: Background: Regionalized trauma care improves outcomes; however access to care is not uniform across the US. The objective was to evaluate whether geographic distribution of trauma centers correlates with injury mortality across state trauma systems. Methods: Level I/II trauma centers in the contiguous US were mapped. State-level age-adjusted injury fatality rates/100,000people were obtained and evaluated for spatial autocorrelation. Nearest neighbor ratios (NNR) were generated for each state. A NNR<1 indicates clustering, while NNR>1 indicates dispersion. NNR were tested for difference from random geographic distribution. Fatality rates and NNR were examined for correlation. Fatality rates were compared between states with trauma center clustering versus dispersion. Trauma center distribution and population density were evaluated. Spatial-lag regression determined the association between fatality rate and NNR, controlling for state-level demographics, population density, injury severity, trauma system resources, and socioeconomic factors. Results: Fatality rates were spatially autocorrelated (Moran's I=0.35, p<0.01). Nine states had a clustered pattern (median NNR 0.55, IQR 0.48-0.60), 22 had a dispersed pattern (median NNR 2.00, IQR 1.68-3.99), and 10 had a random pattern (median NNR 0.90, IQR 0.85-1.00) of trauma center distribution. Fatality rate and NNR were correlated (ρ=0.34, p=0.03). Clustered states had a lower median injury fatality rate compared to dispersed states (56.9 [IQR 46.5-58.9] versus 64.9 [IQR 52.5-77.1], p=0.04). Dispersed compared to clustered states had more counties without a trauma center that had higher population density than counties with a trauma center (5.7% versus 1.2%, p<0.01). Spatial-lag regression demonstrated fatality rates increased 0.02/100,000persons for each unit increase in NNR (p<0.01). Conclusions: Geographic distribution of trauma centers correlates with injury mortality, with more clustered state trauma centers associated with lower fatality rates. This may be a result of access relative to population density. These results may have implications for trauma system planning and requires further study to investigate underlying mechanisms. Level of evidence: IV, ecological study.
    No preview · Article · Oct 2015
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    ABSTRACT: Objective: Endoluminal vascular interventions such as angioplasty initiate a sterile inflammatory response resulting from local tissue damage. This response drives the development of intimal hyperplasia (IH) that, in turn, can lead to arterial occlusion. We hypothesized that the ubiquitous nuclear protein and damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1), is one of the endogenous mediators that activates processes leading to IH after endoluminal injury to the arterial wall. The aim of this study is to investigate whether approaches that reduce the levels of HMGB1 or inhibit its activity suppresses IH after arterial injury. Approach and results: Here, we show that HMGB1 regulates IH in a mouse carotid wire injury model. Induced genetic deletion or neutralization of HMGB1 prevents IH, monocyte recruitment, and smooth muscle cell growth factor production after endoluminal carotid artery injury. A specific inhibitor of HMGB1 myeloid differentiation factor 2-toll-like receptor 4 (TLR4) interaction, P5779, also significantly inhibits IH. HMGB1 deletion is mimicked in this model by global deletion of TLR4 and partially replicated by myeloid-specific deletion of TLR4 but not TLR2 or receptor for advanced glycation endproducts deletion. The specific HMGB1 isoform known to activate TLR4 signaling (disulfide HMGB1) stimulates smooth muscle cell to migrate and produce monocyte chemotactic protein 1/CCL2) via TLR4. Macrophages produce smooth muscle cell mitogens in response to disulfide HMGB1 also in a TLR4/myeloid differentiation primary response gene (88)/Trif-dependent manner. Conclusions: These findings place HMGB1 and its receptor, TLR4 as critical regulators of the events that drive the inflammation leading to IH after endoluminal arterial injury and identify this pathway as a possible therapeutic target to limit IH to attenuate damage-associated molecular pattern molecule-mediated vascular inflammatory responses.
    No preview · Article · Oct 2015 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: Objective: The aim of this study was to develop and internally validate a triage score that can identify trauma patients at the scene who would potentially benefit from helicopter emergency medical services (HEMS). Summary background data: Although survival benefits have been shown at the population level, identification of patients most likely to benefit from HEMS transport is imperative to justify the risks and cost of this intervention. Methods: Retrospective cohort study of subjects undergoing scene HEMS or ground emergency medical services (GEMS) in the National Trauma Databank (2007-2012). Data were split into training and validation sets. Subjects were grouped by triage criteria in the training set and regression used to determine which criteria had a survival benefit associated with HEMS. Points were assigned to these criteria to develop the Air Medical Prehospital Triage (AMPT) score. The score was applied in the validation set to determine whether subjects triaged to HEMS had a survival benefit when actually transported by helicopter. Results: There were 2,086,137 subjects included. Criteria identified for inclusion in the AMPT score included GCS <14, respiratory rate <10 or >29, flail chest, hemo/pneumothorax, paralysis, and multisystem trauma. The optimal cutoff for triage to HEMS was ≥2 points. In subjects triaged to HEMS, actual transport by HEMS was associated with an increased odds of survival (AOR 1.28; 95% confidence interval [CI] 1.21-1.36, P < 0.01). In subjects triaged to GEMS, actual transport mode was not associated with survival (AOR 1.04; 95% CI 0.97-1.11, P = 0.20). Conclusions: The AMPT score identifies patients with improved survival following HEMS transport and should be considered in air medical triage protocols.
    No preview · Article · Oct 2015 · Annals of surgery
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    ABSTRACT: Objective: Evaluate the effect of US geographic region on outcomes of helicopter transport (HT) for trauma. Background: HT is an integral component of trauma systems. Evidence suggests that HT is associated with improved outcomes; however, no studies examine the impact of geographic variation on outcomes for HT. Methods: Retrospective cohort study of patients undergoing scene HT or ground transport in the National Trauma Databank (2009-2012). Subjects were divided by US census region. HT and ground transport subjects were propensity-score matched based on prehospital physiology and injury severity. Conditional logistic regression was used to evaluate the effect of HT on survival and discharge to home in each region. Region-level characteristics were assessed as potential explanatory factors. Results: A total of 193,629 pairs were matched. HT was associated with increased odds of survival and discharge to home; however, the magnitude of these effects varied significantly across regions (P < 0.01). The South had the greatest survival benefit (odds ratio: 1.44; 95% confidence interval: 1.39-1.49, P < 0.01) and the Northeast had the greatest discharge to home benefit (odds ratio: 1.29; 95% confidence interval: 1.18-1.41, P < 0.01). A subset of region-level characteristics influenced the effect of HT on each outcome, including helicopter utilization, injury severity, trauma center and helicopter distribution, trauma center access, traffic congestion, and urbanicity (P < 0.05). Conclusions: Geographic region impacts the benefits of HT in trauma. Variations in resource allocation partially account for outcome differences. Policy makers should consider regional factors to better assess and allocate resources within trauma systems to optimize the role of HT.
    No preview · Article · Oct 2015 · Annals of Surgery
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    ABSTRACT: Adenosine deaminase acting on RNA 1 (ADAR1) is an essential protein for embryonic liver development. ADAR1 loss is embryonically lethal because of severe liver damage. Although ADAR1 is required in adult livers to prevent liver cell death, as demonstrated by liver-specific conditional knockout (LKO) mice, the mechanism remains elusive. We systematically analyzed ADAR1 LKO mice for liver damage. Differentiation genes and inflammatory pathways were examined in hepatic tissues from LKO and littermate controls. Inducible ADAR1 LKO mice were used to validate regulatory effects of ADAR1 on inflammatory cytokines. We found that ADAR1 LKO mice showed dramatic growth retardation and high mortality because of severe structural and functional damage to the liver, which showed overwhelming inflammation, cell death, fibrosis, fatty change, and compensatory regeneration. Simultaneously, ADAR1 LKO showed altered expression of key differentiation genes and significantly higher levels of hepatic inflammatory cytokines, especially type I interferons, which was also verified by inducible ADAR1 knockdown in primary hepatocyte cultures. We conclude that ADAR1 is an essential molecule for maintaining adult liver homeostasis and, in turn, morphological and functional integrity. It inhibits the production of type I interferons and other inflammatory cytokines. Our findings may provide novel insight in the pathogenesis of liver diseases caused by excessive inflammatory responses, including autoimmune hepatitis.
    No preview · Article · Oct 2015 · American Journal Of Pathology

  • No preview · Article · Oct 2015
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    ABSTRACT: Background: Although survival benefits have been shown at the population level, it remains unclear what drives the outcome benefits for helicopter emergency medical services (HEMS) in trauma. Although speed is often cited as the vital factor of HEMS, we hypothesized a survival benefit would exist in the absence of a time savings over ground emergency medical services (GEMS). The objective was to examine the association of survival with HEMS compared with GEMS transport across similar prehospital transport times. Methods: We used a retrospective cohort of scene HEMS and GEMS transports in the National Trauma Databank (2007-2012). Propensity score matching was used to match HEMS and GEMS subjects on the likelihood of HEMS transport. Subjects were stratified by prehospital transport times in 5-minute increments. Conditional logistic regression determined the association of HEMS with survival across prehospital transport times strata controlling for confounders. Transport distance was estimated from prehospital transport times and average HEMS/GEMS transport speeds. Results: There were 155,691 HEMS/GEMS pairs matched. HEMS had a survival benefit over GEMS for prehospital transport times between 6 and 30 minutes. This benefit ranged from a 46% increase in odds of survival between 26 and 30 minutes (adjusted odds ratio [AOR], 1.46; 95% CI, 1.11-1.93; P < .01) to an 80% increase in odds of survival between 16 and 20 minutes (AOR, 1.80; 95% CI, 1.51-2.14; P < .01). This prehospital transport times window corresponds to estimated transport distance between 14.3 and 71.3 miles for HEMS and 3.3 and 16.6 miles for GEMS. Conclusion: When stratified by prehospital transport times, HEMS had a survival benefit concentrated in a window between 6 and 30 minutes. Because there was no time-savings advantage for HEMS, these findings may reflect care delivered by HEMS providers.
    No preview · Article · Oct 2015 · Surgery

  • No preview · Article · Oct 2015 · Journal of the American College of Surgeons
  • Mostafa H. Ramadan · Rosemary A. Hoffman · Timothy R. Billiar

    No preview · Article · Oct 2015 · Journal of the American College of Surgeons
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    ABSTRACT: Introduction: We sought to examine the association between the clinical outcomes and the early, dynamic, systemic acute inflammatory response in the setting of major bone/soft tissue injury. Methods: From a cohort of 472 blunt trauma survivors, two stringently matched cohorts were derived: 32 patients who had a severe extremity injury (AIS ≥ 3) following blunt trauma (18 males and 14 females; age: 52.5 ± 3.1; ISS: 21.5 ± 1.5) and 30 trauma patients with mild/moderate extremity injury (AIS < 3; 15 males and 15 females; age: 53 ± 2.4; ISS: 22.4 ± 1.4). Serial blood samples (3 samples within the first 24 h and then from days 1 to 7 post- injury) were assayed for multiple inflammation mediators. Two-Way ANOVA was used to compare groups, and Dynamic Bayesian Network (DyBN) analysis to infer network connectivity. Results: ICU length of stay [LOS], total LOS, days on mechanical ventilation, Marshall MODScore, as well admission lactate and CPK were significantly altered in AIS ≥ 3 group. Plasma levels of IL-6, IL-8, MIG, IP-10, and MCP-1 were significantly elevated in the AIS ≥ 3 group, while plasma levels of IL-7, Eotaxin, and MIP- 1α were significantly elevated in the AIS < 3 group over the 7 days post-injury. DyBN inference suggested a different core chemokine-based network upstream of mediators including IL-6 and IL-10. Conclusion: Our results suggest that severe extremity/soft tissue injury can drive a differential inflammation program including multiple chemokines that affect systemic IL-6 and IL-10, in a manner associated with worse clinical outcomes as compared to mild/moderate soft tissue injury.
    No preview · Article · Sep 2015 · Shock (Augusta, Ga.)

Publication Stats

40k Citations
3,756.08 Total Impact Points


  • 1988-2016
    • University of Pittsburgh
      • • Department of Surgery
      • • Department of Medicine
      Pittsburgh, Pennsylvania, United States
    • Washington University in St. Louis
      • Department of Surgery
      San Luis, Missouri, United States
  • 2015
    • University Center Rochester
      • Department of Surgery
      Рочестер, Minnesota, United States
  • 2014
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 1998-2014
    • Pittsburg State University
      Питсбург, Kansas, United States
  • 2011
    • Southern Medical University
      • Department of Pathophysiology
      Guangzhou, Guangdong Sheng, China
  • 2009
    • University of Groningen
      • Department of Surgery
      Groningen, Groningen, Netherlands
  • 2008
    • University of Helsinki
      • Transplantation Laboratory
      Helsinki, Uusimaa, Finland
  • 2006
    • Columbia University
      • Department of Surgery
      New York, New York, United States
  • 2005
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2002
    • Kangwon National University
      • Department of Molecular and Cellular Biochemistry
      Shunsen, Gangwon, South Korea
  • 2001
    • Baylor College of Medicine
      • Section of Infectious Diseases
      Houston, Texas, United States
  • 1995
    • Montefiore Medical Center
      New York City, New York, United States
  • 1994-1995
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 1993-1994
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1990
    • Cornell University
      Итак, New York, United States
  • 1988-1989
    • University of Minnesota Duluth
      • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States