Universitatsmedizin Greifswald

Greifswald, Germany

Universitatsmedizin Greifswald

Greifswald, Germany
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Schafer S.T.,Salk Institute for Biological Studies | Schafer S.T.,University of Greifswald | Schafer S.T.,Universitatsmedizin Greifswald | Han J.,Salk Institute for Biological Studies | And 4 more authors.
Journal of Neuroscience | Year: 2015

In the mammalian hippocampus, canonical Wnt signals provided by the microenvironment regulate the differentiation of adult neural stem cells (NSCs) toward the neuronal lineage. Wnts are part of a complex and diverse set of signaling pathways and the role of Wnt/ Planar cell polarity (PCP) signaling in adult neurogenesis remains unknown. Using in vitro assays on differentiating adult NSCs, we identified a transition of Wnt signaling responsiveness from Wnt/β-catenin to Wnt/PCP signaling. In mice, retroviral knockdown strategies against ATP6AP2, a recently discovered core protein involved in both signaling pathways, revealed that its dual role is critical for granule cell fate and morphogenesis. We were able to confirm its dual role in neurogenic Wnt signaling in vitro for both canonical Wnt signaling in proliferating adult NSCs and non-canonical Wnt signaling in differentiating neuroblasts. Although LRP6 appeared to be critical for granule cell fate determination, in vivo knockdown of PCP core proteins FZD3 and CELSR1-3 revealed severe maturational defects without changing the identity of newborn granule cells. Furthermore, we found that CELSR1-3 control distinctive aspects of PCP-mediated granule cell morphogenesis with CELSR1 regulating the direction of dendrite initiation sites and CELSR2/3 controlling radial migration and dendritic patterning. The data presented here characterize distinctive roles for Wnt/β-catenin signaling in granule cell fate determination and for Wnt/PCP signaling in controlling the morphological maturation of differentiating neuroblasts. © 2015 the authors.

Freund M.,Universitatsmedizin Greifswald | Walther T.,University College Cork | Walther T.,University of Leipzig | Von Bohlen und Halbach O.,Universitatsmedizin Greifswald
European Neuropsychopharmacology | Year: 2014

Aside from the well-known biologically active angiotensin II, other biologically active angiotensins have been discovered, including angiotensin IV and angiotensin-(1-7). Some years ago, we and others discovered that the Mas proto-oncogene encodes a G protein-coupled receptor being essential for angiotensin-(1-7) signaling. Mas is not only expressed in the periphery but also within the brain, e.g. in the dentate gyrus (DG) and the piriform cortex (PC). Since the DG is capable of adult neurogenesis, we examined the impact of a deletion of Mas upon adult neurogenesis. Deletion of Mas did not alter cell proliferation in the adult DG (as monitored with phosphohistone H3) and did not alter cell death (as monitored with activated Caspase 3). However, Mas deficiency resulted in an increase in the number of doublecortin (DCX) positive cells, indicating that lack of Mas increases the number of this cell population. Concerning the PC, it is discussed whether adult neurogenesis occurs under physiological conditions in this area. We could demonstrate that Mas deficiency has an impact on cell division and on the population of DCX-positive cells within the PC. Since Mas is not expressed before birth within the brain, our data may suggest that adult hippocampal neurogenesis and neurogenesis occurring during prenatal development share several common mechanisms, but are, at least in part, differentially regulated. Moreover, since deficiency for Mas increases the numbers of DCX-positive young neurons, blockage of Mas might be beneficial in stimulating neurogenesis in adults. © 2013 Elsevier B.V. and ECNP.

Arman M.,University of Birmingham | Krauel K.,Universitatsmedizin Greifswald | Tilley D.O.,Molecular Therapeutics | Weber C.,University of Greifswald | And 4 more authors.
Blood | Year: 2014

Bacterial adhesion to platelets is mediated via a range of strain-specific bacterial surface proteins that bind to a variety of platelet receptors. It is unclear how these interactions lead to platelet activation. We demonstrate a critical role for the immune receptor FcγRIIA, αIIbβ3, and Src and Syk tyrosine kinases in platelet activation by Staphylococcus aureus, Streptococcus sanguinis, Streptococcus gordonii, Streptococcus oralis, and Streptococcus pneumoniae. FcγRIIA activation is dependent on immunoglobulin G (IgG) and αIIbβ3 engagement. Moreover, feedback agonists adenosine 59-diphosphate and thromboxane A2 aremandatory for platelet aggregation. Additionally, platelet factor 4 (PF4) binds to bacteria and reduces the lag time for aggregation, and gray platelet syndromea-granule-deficient platelets do not aggregate to 4 of 5 bacterial strains. We propose that FcγRIIA-mediated activation is a common response mechanism used against a wide range of bacteria, and that release of secondary mediators and PF4 serve as a positive feedback mechanism for activation through an IgG-dependent pathway. © 2014 by The American Society of Hematology.

Arman M.,University of Birmingham | Krauel K.,Universitatsmedizin Greifswald
Journal of Thrombosis and Haemostasis | Year: 2015

Beyond their prominent role in hemostasis and thrombosis, platelets are increasingly recognized as having immunologic functions. Supporting this, human platelets express FcγRIIA (CD32a), a low-affinity Fc receptor (FcR) for the constant region of IgG that recognizes immune complexes (ICs) and IgG-opsonized cells with high avidity. In leukocytes, FcγRIIA engagement initiates strong effector functions that are key for immune and inflammatory responses, including cytokine release, antibody-dependent cell-mediated killing of pathogens, and internalization of ICs. However, the physiologic relevance of platelet-expressed FcγRIIA has received little attention in previous reviews on FcRs. This article summarizes and discusses the available information on human platelet FcγRIIA. The importance of this receptor in heparin-induced thrombocytopenia, a prothrombotic adverse drug effect, is well documented. However, studies demonstrating platelet activation by IgG-opsonized bacteria point to the physiologic relevance of platelet FcγRIIA in immunity. In this context, platelet activation and secretion may facilitate both a direct antimicrobial function of platelets and crosstalk with other immune cells. Additionally, a role for platelet FcγRIIA in IgG-independent hemostasis and physiologic thrombosis, by means of amplifying integrin αIIbβ3 outside-in signaling, has also been proposed. Nonetheless, the thrombotic complications found in some infective and autoimmune diseases may result from unbalanced FcγRIIA-mediated platelet aggregation. Moreover, FcγRIIA is not expressed in mice, and thrombocytopenia and/or thrombotic events found after drug administration can only be recapitulated by the use of human FcγRIIA-transgenic mice. Altogether, the available data support a functional role for platelet FcγRIIA in health and disease, and emphasize the need for further investigation of this receptor. © 2015 International Society on Thrombosis and Haemostasis.

Endlich N.,Universitatsmedizin Greifswald | Simon O.,Universitatsmedizin Greifswald | Gopferich A.,University of Regensburg | Wegner H.,Universitatsmedizin Greifswald | And 4 more authors.
Journal of the American Society of Nephrology | Year: 2014

Podocytes are an essential component of the glomerular filtration barrier and cover the outer aspect of glomerular capillaries. Theyform a complex actin-based cytoskeleton in vivo and show prominent motility in vitro,but whether podocytes are stationary or mobile in vivo is debated. To address thi squestion, the pronephros of translucent zebrafish larvae (casper) expressing enhanced green fluorescent protein (eGFP) specifically in podocytes (wt1a:eGFP larvae) was observed by in travital two-photon microscopy over extended periods of time.Podocyte cell bodies and the interdigitating branching pattern of major processes could be resolved with are solution of approximately 1 μm in thexy-plane. Time-lapse imaging of zebrafish larvae at 5-7 days after fertilization demonstrated that podocytes neither migrated nor changed the branching pattern of their major processes over a time period of up to 23hours. In summary, we show by extended intravital two-photon microscopy that podocytes are stationary cells in the intact glomerulus of a translucent zebrafish with fluorescently-labeled podocytes. Copyright © 2014 by the American Society of Nephrology.

Von Der Heyden M.,Universitatsmedizin Greifswald | Meissner K.,Universitatsmedizin Greifswald
Best Practice and Research: Clinical Anaesthesiology | Year: 2015

Emergency medicine has been a stronghold of simulation-based training ever since high-fidelity simulators became available. The preclinical setting differs remarkably from any in-hospital environment in both available technology and resources, and thus stress levels of the health-care professionals involved in patient care - ideal factors for the simulation-based teaching approach. This review reports on the current status of the method for teaching preclinical scenarios from an educational and practical perspective. Particular attention is given to contents, formats, and evaluation of success. © 2015 Published by Elsevier Ltd.

Greinacher A.,Universitatsmedizin Greifswald
New England Journal of Medicine | Year: 2015

A 64-year-old woman who is hospitalized with endocarditis and whose condition is clinically stable while she is receiving intravenous antibiotic agents has had a decrease in platelet count from 161,000 per cubic millimeter on day 7 of hospitalization to 60,000 per cubic millimeter on day 9. She has been receiving low-molecular-weight heparin at a dose of 40 mg per day since admission. How should her case be further evaluated and treated? Copyright © 2015 Massachusetts Medical Society. All rights reserved.

Greinacher A.,Universitatsmedizin Greifswald
Blood | Year: 2014

In this issue of Blood, Warkentin et al provide insight into certain rare but often catastrophic cases of thrombotic complications, termed "spontaneous" (or "autoimmune") heparin-induced thrombocytopenia (HIT). © 2014 by The American Society of Hematology.

Krauel K.,Universitatsmedizin Greifswald | Hackbarth C.,Universitatsmedizin Greifswald | Furll B.,Universitatsmedizin Greifswald | Greinacher A.,Universitatsmedizin Greifswald
Blood | Year: 2012

Heparin is a widely used anticoagulant. Because of its negative charge, it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG Abs. Resulting immune complexes activate platelets, leading to the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). HIT requires treatment with alternative anticoagulants. Approved for HIT are 2 direct thrombin inhibitors (DTI; lepirudin, argatroban) and danaparoid. They are niche products with limitations. We assessed the effects of the DTI dabigatran, the direct factor Xa-inhibitor rivaroxaban, and of 2-O, 3-O desulfated heparin (ODSH; a partially desulfated heparin with minimal anticoagulant effects) on PF4/ heparin complexes and the interaction of anti-PF4/heparin Abs with platelets. Neither dabigatran nor rivaroxaban had any effect on the interaction of PF4 or anti- PF4/heparin Abs with platelets. In contrast, ODSH inhibited PF4 binding to gel-filtered platelets, displaced PF4 from a PF4-transfected cell line, displaced PF4/heparin complexes from platelet surfaces, and inhibited anti-PF4/heparin Ab binding to PF4/heparin complexes and subsequent platelet activation. Dabigatran and rivaroxaban seem to be options for alternative anticoagulation in patients with a history of HIT. ODSH prevents formation of immunogenic PF4/heparin complexes, and, when given together with heparin, may have the potential to reduce the risk for HIT during treatment with heparin. © 2012 by The American Society of Hematology.

Dementia is one of the most prevalent chronic progressive diseases in older age. The progression of dementia is associated with an increasing demand for patient care. Thus, the nursing profession fulfills important tasks in the supply of care in dementia. Care of dementia patients requires nurses with more specialized professional knowledge. Consequently, the development of new qualification concepts in dementia is needed. Therefore, the German Center for Neurodegenerative Diseases, Rostock/Greifswald, has developed a qualification according to the Dementia Care Management concept. A prospective cross-sectional study identified the tasks and qualifications of nurses as Dementia Care Managers. Overall, 27 tasks and 28 qualification items were identified for a nurse to qualify as a Dementia Care Manager. In the next step, the first version of the Dementia Care Management Curriculum was developed. © 2013 Springer-Verlag Berlin Heidelberg.

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