Alexander Zarbock

University of Münster, Muenster, North Rhine-Westphalia, Germany

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Publications (119)851.16 Total impact

  • J Rossaint · A Zarbock
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    ABSTRACT: Acute kidney injury (AKI) is a common complication in hospitalized patients and great efforts by leading experts have been made in order to establish common definitions of AKI. The clinical use of these consensus definitions has led to a substantially improved understanding of AKI. In addition, the consensus definitions allow comparing the incidence of AKI and outcomes between different patient populations. As a result it became evident, that AKI in the western population represents a clinical syndrome with an incidence close to myocardial infarction. The aim of this review is to revisit the current concepts and definitions of AKI, to highlight the diagnosis, and to emphasize the epidemiological characteristics of AKI. Here, we will focus on the available literature reporting the epidemiology of AKI in critically ill patients. Sepsis, major surgery, and nephrotoxic drugs are the main causes of AKI in these patients and the occurrence of AKI is associated with an increased probability for sustained chronic kidney injury. We also discuss the concept of renal angina as a possible future concept for improved clinical risk stratification to discover AKI. In the context of this new concept, we emphasize the use of novel biomarkers in the diagnosis of AKI which may hold the potential to improve the early diagnosis and prevention of AKI in the clinical setting.
    Minerva urologica e nefrologica = The Italian journal of urology and nephrology 09/2015; · 0.97 Impact Factor
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    ABSTRACT: Neutrophil recruitment to the site of inflammation plays a pivotal role in host defense. However, overwhelming activation and accumulation of neutrophils in the tissue may cause tissue damage and autoimmunity due to the release of cytokines, oxidants, and proteases. Neutrophil adhesion in acute inflammation is initiated by activation of αLβ2 (LFA-1), which can be induced by rolling on E-selectin (slowly) or by exposure to the chemokine CXCL1 (rapidly). Despite the clinical importance, cell-intrinsic molecular mechanisms of negative regulation of integrin adhesiveness and neutrophil recruitment are poorly understood. Mice deficient in the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase 1 (Shp1) show increased leukocyte adhesion, but the interpretation of these data is limited by the severe global phenotype of these mice. In this study, we used mice with global and myeloid-restricted deletion of Shp1 to study neutrophil arrest, adhesion, crawling, and transendothelial migration in vitro and in vivo. Shp1 deficiency results in increased neutrophil adhesion in vivo; however, neutrophil crawling, transmigration, and chemotaxis were reduced in these mice. Mechanistically, Shp1 binds and controls PIPKIγ activity and, thereby, modulates phosphatidylinositol (4,5)-bisphosphate levels and adhesion. Thus, Shp1 is involved in the deactivation of integrins and regulation of neutrophil recruitment into inflamed tissue. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 06/2015; 195(3). DOI:10.4049/jimmunol.1500606 · 4.92 Impact Factor
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    ABSTRACT: No interventions have yet been identified to reduce the risk of acute kidney injury in the setting of cardiac surgery. To determine whether remote ischemic preconditioning reduces the rate and severity of acute kidney injury in patients undergoing cardiac surgery. In this multicenter trial, we enrolled 240 patients at high risk for acute kidney injury, as identified by a Cleveland Clinic Foundation score of 6 or higher, between August 2013 and June 2014 at 4 hospitals in Germany. We randomized them to receive remote ischemic preconditioning or sham remote ischemic preconditioning (control). All patients completed follow-up 30 days after surgery and were analyzed according to the intention-to-treat principle. Patients received either remote ischemic preconditioning (3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham remote ischemic preconditioning (control), both via blood pressure cuff inflation. The primary end point was the rate of acute kidney injury defined by Kidney Disease: Improving Global Outcomes criteria within the first 72 hours after cardiac surgery. Secondary end points included use of renal replacement therapy, duration of intensive care unit stay, occurrence of myocardial infarction and stroke, in-hospital and 30-day mortality, and change in acute kidney injury biomarkers. Acute kidney injury was significantly reduced with remote ischemic preconditioning (45 of 120 patients [37.5%]) compared with control (63 of 120 patients [52.5%]; absolute risk reduction, 15%; 95% CI, 2.56%-27.44%; P = .02). Fewer patients receiving remote ischemic preconditioning received renal replacement therapy (7 [5.8%] vs 19 [15.8%]; absolute risk reduction, 10%; 95% CI, 2.25%-17.75%; P = .01), and remote ischemic preconditioning reduced intensive care unit stay (3 days [interquartile range, 2-5]) vs 4 days (interquartile range, 2-7) (P = .04). There was no significant effect of remote ischemic preconditioning on myocardial infarction, stroke, or mortality. Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery (remote ischemic preconditioning, 0.36 vs control, 0.97 ng/mL2/1000; difference, 0.61; 95% CI, 0.27-0.86; P < .001). No adverse events were reported with remote ischemic preconditioning. Among high-risk patients undergoing cardiac surgery, remote ischemic preconditioning compared with no ischemic preconditioning significantly reduced the rate of acute kidney injury and use of renal replacement therapy. The observed reduction in the rate of acute kidney injury and the need for renal replacement warrants further investigation. German Clinical Trials Register Identifier: DRKS00005333.
    JAMA The Journal of the American Medical Association 05/2015; 313(21). DOI:10.1001/jama.2015.4189 · 35.29 Impact Factor
  • J M Herter · F Kraft · H Van Aken · M Meersch · A Zarbock · J Rossaint
    Thrombosis and Haemostasis 05/2015; 114(2). DOI:10.1160/TH14-12-1060 · 4.98 Impact Factor
  • Florian Kraft · Christoph Schmidt · Hugo Van Aken · Alexander Zarbock
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    ABSTRACT: Patients undergoing cardiac surgery with extracorporeal circulation (EC) frequently develop a systemic inflammatory response syndrome. Surgical trauma, ischaemia-reperfusion injury, endotoxaemia and blood contact to nonendothelial circuit compounds promote the activation of coagulation pathways, complement factors and a cellular immune response. This review discusses the multiple pathways leading to endothelial cell activation, neutrophil recruitment and production of reactive oxygen species and nitric oxide. All these factors may induce cellular damage and subsequent organ injury. Multiple organ dysfunction after cardiac surgery with EC is associated with an increased morbidity and mortality. In addition to the pathogenesis of organ dysfunction after EC, this review deals with different therapeutic interventions aiming to alleviate the inflammatory response and consequently multiple organ dysfunction after cardiac surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Baillière&#x27 s Best Practice and Research in Clinical Anaesthesiology 03/2015; 29(2). DOI:10.1016/j.bpa.2015.03.001
  • J. M. Herter · J. Rossaint · A. Zarbock
    Journal of Thrombosis and Haemostasis 03/2015; 13(3):490-490. DOI:10.1111/jth.12848 · 5.72 Impact Factor
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    Jan Rossaint · Alexander Zarbock
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    ABSTRACT: Platelets have a longstanding recognition as an essential cellular component of the coagulation system. However, substantial research over the last decade has added another important aspect to platelet function in that they are also an integral part of the innate immune system. Complex organisms are facing a constant threat of infections by invading pathogens, and they have developed a sophisticated and elegant measure to combat this threat, namely the immune system. Leukocyte recruitment to sites of infections is an essential step at the forefront of the immune response. Platelets have been shown to be involved in several steps of this process and they are an integrated connecting element among hemostasis, host defense, and additional immunological functions (e.g. neutrophil extracellular traps formation). However, the immune system also requires a tight regulation, as an overshooting immune response carries the risk of harming the host itself. This review aims at highlighting the unique features and molecular mechanisms that allow for the interactions of platelets and leukocytes and the regulation of this process. Furthermore, this article identifies the functional relevance of these events for the immune response. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email:
    Cardiovascular Research 02/2015; 107(3). DOI:10.1093/cvr/cvv048 · 5.94 Impact Factor
  • Alexander Zarbock · Hugo Van Aken · Christoph Schmidt
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    ABSTRACT: Although advancements in perioperative care have been made over the last decades, the perioperative outcome could not be improved adequately. Therefore, new therapeutic strategies are required to decrease morbidity and all-cause mortality in surgical patients. Remote ischemic preconditioning (RIPC), defined as brief and transient episodes of ischemia at a remote site before a subsequent injury of the target organ, is an adaptive response to protect for organ injury elicited by different stimuli. This review evaluates the current clinical evidence for RIPC as a potential tissue-protective strategy and discusses the underlying mechanism. Several studies demonstrated the tissue-protective effect of RIPC in various organs, including the heart, brain, and kidney. However, the existence of controversial results may be explained by the fact that different study protocols were used and different patient populations were recruited. RIPC may offer a novel inexpensive and noninvasive therapeutic strategy to alleviate organ injury in the perioperative period. However, adequately powered, large, multicenter clinical studies are necessary to accurately determine whether ischemic conditioning can improve the clinical outcomes of patients at risk for ischemia-reperfusion injury.
    Current Opinion in Anaesthesiology 01/2015; 28(2). DOI:10.1097/ACO.0000000000000161 · 1.98 Impact Factor
  • 01/2015; 3(Suppl 1):A411. DOI:10.1186/2197-425X-3-S1-A411
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    ABSTRACT: Rationale: Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic lesion formation is largely undefined. Objective: Because of the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand annexin A1 in atherogenesis. Methods and results: Deletion of FPR2 or its ligand annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically, we identify annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in the presence of selective antagonists to CCR5, CCR2, or CXCR2, whereas Ac2-26 was without effect when all 3 chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation. Conclusions: Instructing the annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment when compared with blocking individual chemokine receptors.
    Circulation Research 12/2014; 116(5). DOI:10.1161/CIRCRESAHA.116.305825 · 11.02 Impact Factor
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    ABSTRACT: Neutrophil recruitment to the site of inflammation plays a pivotal role in host defense. Src family kinases (SFKs) activation is required for integrin and chemokine signaling as well as immune cell function. The receptor-like protein tyrosine phosphatase CD45 positively regulates chemoattractant signaling acting on SFK activity. To further investigate the role of CD45 in neutrophil recruitment and function, we analyzed transgenic mice carrying a single point mutation (CD45E613R), which constitutively activates CD45. By using intravital microscopy experiments, we demonstrated that different steps of the leukocyte recruitment cascade were affected in CD45E613R mutant mice. The rolling velocity of CD45E613R mutant neutrophils was decreased compared with wild-type neutrophils that subsequently resulted in an increased number of adherent cells. The analysis of β2 integrins LFA-1 and macrophage-1 Ag (Mac-1) showed that in CD45E613R mutant neutrophils LFA-1 adhesiveness was impaired, and avidity was enhanced, whereas Mac-1 adhesiveness was increased. Because of the increased Mac-1 adhesiveness, neutrophil crawling was impaired in CD45E613R mutant compared with wild-type neutrophils. In an Escherichia coli lung infection model, CD45E613R mice displayed a decreased neutrophil recruitment into the alveolar compartment, which resulted in an increased number of CFUs in the lung. Our data demonstrate that the CD45E613R mutation modulates integrin activation and leukocyte recruitment during inflammation. Copyright © 2014 by The American Association of Immunologists, Inc.
    The Journal of Immunology 12/2014; 194(2). DOI:10.4049/jimmunol.1401646 · 4.92 Impact Factor
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    ABSTRACT: Immune and inflammatory responses require leukocytes to migrate within and through the vasculature, a process that is facilitated by their capacity to switch to a polarized morphology with an asymmetric distribution of receptors. We report that neutrophil polarization within activated venules served to organize a protruding domain that engaged activated platelets present in the bloodstream. The selectin ligand PSGL-1 transduced signals emanating from these interactions, resulting in the redistribution of receptors that drive neutrophil migration. Consequently, neutrophils unable to polarize or to transduce signals through PSGL-1 displayed aberrant crawling, and blockade of this domain protected mice against thromboinflammatory injury. These results reveal that recruited neutrophils scan for activated platelets, and they suggest that the neutrophils' bipolarity allows the integration of signals present at both the endothelium and the circulation before inflammation proceeds. Copyright © 2014, American Association for the Advancement of Science.
    Science 12/2014; 346(6214):1234-8. DOI:10.1126/science.1256478 · 33.61 Impact Factor
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    ABSTRACT: Background: The lack of early biomarkers for acute kidney injury (AKI) seriously inhibits the initiation of preventive and therapeutic measures for this syndrome in a timely manner. We tested the hypothesis that insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, function as early biomarkers for AKI after congenital heart surgery with cardiopulmonary bypass (CPB). Methods: We prospectively studied 51 children undergoing cardiac surgery with CPB. Serial urine samples were analyzed for TIMP-2].[IGFBP7]. The primary outcome measure was AKI defined by the pRIFLE criteria within 72 hours after surgery. Results: 12 children (24%) developed AKI within 1.67 (SE 0.3) days after surgery. Children who developed AKI after cardiac surgery had a significant higher urinary [TIMP-2].[IGFBP7] as early as 4 h after the procedure, compared to children who did not develop AKI (mean of 1.93 ((ng/ml)(2)/1000) (SE 0.4) vs 0.47 ((ng/ml)(2)/1000) (SE 0.1), respectively; p<0.05). Urinary [TIMP-2].[IGFBP7] 4 hours following surgery demonstrated an area under the receiver-operating characteristic curve of 0.85. Sensitivity was 0.83, and specificity was 0.77 for a cutoff value of 0.70 ((ng/ml)(2)/1000). Conclusions: Urinary [TIMP-2].[IGFBP7] represent sensitive, specific, and highly predictive early biomarkers for AKI after surgery for congenital heart disease.
    PLoS ONE 10/2014; 9(10):e110865. DOI:10.1371/journal.pone.0110865 · 3.23 Impact Factor
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    ABSTRACT: Background: During systemic inflammation, leucocytes are activated and extravasate into damaged tissue. Activation and recruitment are influenced by different mechanisms, including the interaction of leucocytes with platelets and neutrophil extracellular traps (NET) formation. Here, we investigated the molecular mechanism by which hydroxyethyl starch (HES 130/0.4) dampens systemic inflammation in vivo. Methods: Systemic inflammation was induced in C57Bl/6 wild-type mice by caecal ligation and puncture and cytokine concentrations in the blood, neutrophil recruitment, platelet-neutrophil aggregates, and NET formation were investigated in vivo. Intravascular adherent and transmigrated neutrophils were analysed by intravital microscopy (IVM) of the cremaster muscle and the kidneys. Flow chamber assays were used to investigate the different steps of the leucocyte recruitment cascade. Results: By using flow cytometry, we demonstrated that HES 130/0.4 reduces neutrophil recruitment into the lung, liver, and kidneys during systemic inflammation (n=8 mice per group). IVM revealed a reduced number of adherent and transmigrated neutrophils in the cremaster and kidney after HES 130/0.4 administration (n=8 mice per group). Flow chamber experiments showed that HES 130/0.4 significantly reduced chemokine-induced neutrophil arrest (n=4 mice per group). Furthermore, HES 130/0.4 significantly reduced the formation of platelet-neutrophil aggregates, and NET formation during systemic inflammation (n=8 mice per group). Conclusions: Our findings suggest that HES 130/0.4 significantly reduces neutrophil-platelet aggregates, NET formation, chemokine-induced arrest, and transmigration of neutrophils under inflammatory conditions.
    BJA British Journal of Anaesthesia 10/2014; 114(3). DOI:10.1093/bja/aeu340 · 4.85 Impact Factor
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    Alexander Zarbock · Hernando Gomez · John A Kellum
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    ABSTRACT: Purpose of review: Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis is the most common cause of AKI. Considerable evidence now suggests that the pathogenic mechanisms of sepsis-induced AKI are different from those seen in other causes of AKI. This review focuses on the recent advances in this area and discusses possible therapeutic interventions that might derive from these new insights into the pathogenesis of sepsis-induced AKI. Recent findings: The traditional paradigm that sepsis-induced AKI arises from ischemia has been challenged by recent evidence that total renal blood flow in is not universally impaired during sepsis, and AKI can develop in the presence of normal or even increased renal blood flow. Animal and human studies suggest that adaptive responses of tubular epithelial cells to injurious signals are responsible for renal dysfunction. Simultaneously occurring renal inflammation and microcirculatory dysfunction further amplify these mechanisms. Summary: An understanding of the pathologic mechanisms of sepsis-induced AKI emphasizes the important role of maladaptive responses to the septic insult. Preventive and therapeutic measures should be based on counteracting these maladaptive responses of tubular epithelial cells, inflammation, and microvascular dysfunction.
    Current Opinion in Critical Care 10/2014; 20(6). DOI:10.1097/MCC.0000000000000153 · 2.62 Impact Factor
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    ABSTRACT: Acute inflammation is the pathophysiological basis of important clinical conditions associated with organ failure. The initial inflammatory response is controlled by the chemokine system, yet recent data have indicated that the neuronal guidance cues are significantly involved in the orchestration of this process. Previous work has shown the pro-inflammatory capacity of the guidance cue semaphorin 7a (Sema 7a), but the role of one of its target receptors, the plexin C1 (PLXNC1) receptor is to date unknown. We report here that PLXNC1 is expressed outside the nervous system and induced during acute inflammation. PLXNC1−/− mice with C57BL/6 background demonstrated decreased inflammatory responses during zymosan A (ZyA)-induced peritonitis. Subsequent in vivo studies revealed altered rolling, adhesion and transmigration properties of PLXNC1−/− leukocytes. Blockade of PLXNC1 was associated with attenuated chemotactic transendothelial migration properties in vitro. Studies in chimeric mice revealed that hematopoietic PLXNC1−/− animals demonstrated an attenuated inflammatory response. To probe the therapeutic potential of PLXNC1 we treated C57BL/6 WT mice with an anti-PLXNC1 antibody and a PLXNC1 binding peptide. Both of these interventions significantly dampened ZyA-induced peritonitis. These results implicate an important role of PLXNC1 during an acute inflammatory response and indicate PLXNC1 as a potential target for the control of conditions associated with acute inflammation.This article is protected by copyright. All rights reserved
    European Journal of Immunology 09/2014; 44(9). DOI:10.1002/eji.201343968 · 4.03 Impact Factor
  • Jan M. Herter · Jan Rossaint · Alexander Zarbock
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    ABSTRACT: The paradigm of platelets as mere mediators of hemostasis has long since been replaced by a dual role, hemostasis and inflammation. Now recognized as key players in innate and adaptive immune responses, platelets have the capacity to interact with virtually all known immune cells. These platelet-immune cell interactions are a hallmark of immunity as they can potently enhance immune cell functions and in some cases even constitute a prerequisite for host defense mechanisms like NETosis. In addition, recent studies have revealed a new role for platelets in immunity: They are ubiquitous sentinels and rapid first line immune responders as platelet-pathogen interactions within the vasculature appear to precede all other host defense mechanisms. Here, we discuss recent advances in our understanding of platelets as inflammatory cells and provide an exemplary review of their role to acute inflammation in acute lung injury.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 09/2014; 12(11). DOI:10.1111/jth.12730 · 5.72 Impact Factor
  • Journal of the American College of Cardiology 08/2014; 64(7):737–738. DOI:10.1016/j.jacc.2014.05.034 · 16.50 Impact Factor
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    ABSTRACT: The focus of this study is the characterization of human T cell blood-brain barrier migration and corresponding molecular trafficking signatures. We examined peripheral blood and cerebrospinal fluid immune cells from patients under long-term anti-very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients&apos; cerebrospinal fluid T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of PSGL-1 expression on peripheral T cells. Although vascular cell adhesion molecule-1 (VLA-4 receptor) was expressed at all CNS barriers, P-selectin (PSGL-1-receptor) was mainly detected at the choroid plexus. Accordingly, in vitro experiments under physiological flow conditions using primary human endothelial cells and LTNT patients&apos; T cells showed increased PSGL-1-mediated rolling and residual adhesion, even under VLA-4 blockade. Adhesion of MCAM(+)/TH17 cells was not affected by VLA-4 blocking alone, but was abrogated when both VLA-4 and MCAM were inhibited. Consistent with these data, MCAM(+) cells were detected in white matter lesions, and in gray matter of multiple sclerosis patients. Our data indicate that lymphocyte trafficking into the CNS under VLA-4 blockade can occur by using the alternative adhesion molecules, PSGL-1 and MCAM, the latter representing an exclusive pathway for TH17 cells to migrate over the blood-brain barrier.
    Journal of Neuroimmunology 08/2014; 211(9-9):1833-1846. DOI:10.1084/jem.20140540 · 2.47 Impact Factor

Publication Stats

3k Citations
851.16 Total Impact Points


  • 2007–2015
    • University of Münster
      • • Department of Anesthesiology, Intensive Care and Pain Therapy
      • • Department of Anaesthesiology and Intensive Care
      Muenster, North Rhine-Westphalia, Germany
  • 2005–2015
    • Universitätsklinikum Münster
      • • Klinik und Poliklinik für Neurologie
      • • Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
      Muenster, North Rhine-Westphalia, Germany
  • 2014
    • University of Pittsburgh
      • Department of Critical Care Medicine
      Pittsburgh, Pennsylvania, United States
  • 2013
    • Spanish National Centre for Cardiovascular Research
      • Department of Epidemiology, Atherothrombosis and Imaging (EAI)
      Madrid, Madrid, Spain
  • 2011–2013
    • Max Planck Institute for Molecular Biomedicine
      Muenster, North Rhine-Westphalia, Germany
    • Universität Bremen
      • Center for Biomolecular Interactions CBIB
      Bremen, Bremen, Germany
  • 2008–2012
    • La Jolla Institute for Allergy & Immunology
      La Jolla, California, United States
  • 2006–2007
    • University of Virginia
      • • Department of Biomedical Engineering
      • • Robert M. Berne Cardiovascular Research Center
      Charlottesville, Virginia, United States