@article{KraftSchwarzMeijersetal.2010, author = {Kraft, Peter and Schwarz, Tobias and Meijers, Joost C. M. and Stoll, Guido and Kleinschnitz, Christoph}, title = {Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68519}, year = {2010}, abstract = {Background: Thrombus formation is a key step in the pathophysiology of acute ischemic stroke and results from the activation of the coagulation cascade. Thrombin plays a central role in this coagulation system and contributes to thrombus stability via activation of thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. Although substantial in vitro data on the influence of TAFI on the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia are still lacking. In the present study we analyzed stroke development and post stroke functional outcome in TAFI-/- mice. Methodology/Principal Findings: TAFI-/- mice and wild-type controls were subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 hours, functional outcome scores were assessed and infarct volumes weremeasured from 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin and eosin (H\&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Infarct volumes and functional outcomes did not significantly differ between TAFI-/- mice and controls (p.0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. TAFI deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO. Conclusion: Our study shows that TAFI does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challenge.}, subject = {Thrombus}, language = {en} } @article{KleinschnitzGrundWingleretal.2010, author = {Kleinschnitz, Christoph and Grund, Henrike and Wingler, Kirstin and Armitage, Melanie E. and Jones, Emma and Mittal, Manish and Barit, David and Schwarz, Tobias and Geis, Christian and Kraft, Peter and Barthel, Konstanze and Schuhmann, Michael K. and Herrmann, Alexander M. and Meuth, Sven G. and Stoll, Guido and Meurer, Sabine and Schrewe, Anja and Becker, Lore and Gailus-Durner, Valerie and Fuchs, Helmut and Klopstock, Thomas and de Angelis, Martin Hrabe and Jandeleit-Dahm, Karin and Shah, Ajay M. and Weissmann, Norbert and Schmidt, Harald H. H. W.}, title = {Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68416}, year = {2010}, abstract = {Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90\% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.}, subject = {Schlaganfall}, language = {en} } @article{NeubauerMorbachSchwarzetal.2011, author = {Neubauer, Henning and Morbach, Henner and Schwarz, Tobias and Wirth, Clemens and Girschick, Hermann and Beer, Meinrad}, title = {Popliteal Cysts in Paediatric Patients: Clinical Characteristics and Imaging Features on Ultrasound and MRI}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68662}, year = {2011}, abstract = {Popliteal cysts, or Baker cysts, are considered rare in children and may exhibit particular features, as compared with adults. We studied data from80 paediatric patients with 55 Baker cysts, examined over a period of 7 years, and correlated clinical presentation with findings on ultrasonography and MRI. Prevalence of popliteal cysts was 57\% in arthritic knees, 58\% with hypermobility syndrome, and 28\% without risk factors. Only one patient had a trauma history and showed an ipsilateral cyst. Mean cyst volume was 3.4 mL; cysts were larger in boys. Patients with arthritis had echogenic cysts in 53\%. Cyst communication with the joint space was seen in 64\% on ultrasonography and 86\% on MRI. In conclusion, Baker cysts are a common finding in a clinically preselected paediatric population. Children with Baker cysts should be assessed for underlying arthritis and inherited joint hypermobility, while sporadic Baker cysts appear to be common, as well.}, subject = {Medizin}, language = {en} } @article{SchwarzRemerNahrendorfetal.2013, author = {Schwarz, Tobias and Remer, Katharina A. and Nahrendorf, Wiebke and Masic, Anita and Siewe, Lisa and M{\"u}ller, Werner and Roers, Axel and Moll, Heidrun}, title = {T Cell-Derived IL-10 Determines Leishmaniasis Disease Outcome and Is Suppressed by a Dendritic Cell Based Vaccine}, series = {PLoS Pathogens}, volume = {9}, journal = {PLoS Pathogens}, number = {6}, doi = {10.1371/journal.ppat.1003476}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130385}, pages = {e1003476}, year = {2013}, abstract = {Abstract In the murine model of Leishmania major infection, resistance or susceptibility to the parasite has been associated with the development of a Th1 or Th2 type of immune response. Recently, however, the immunosuppressive effects of IL-10 have been ascribed a crucial role in the development of the different clinical correlates of Leishmania infection in humans. Since T cells and professional APC are important cellular sources of IL-10, we compared leishmaniasis disease progression in T cell-specific, macrophage/neutrophil-specific and complete IL-10-deficient C57BL/6 as well as T cell-specific and complete IL-10-deficient BALB/c mice. As early as two weeks after infection of these mice with L. major, T cell-specific and complete IL-10-deficient animals showed significantly increased lesion development accompanied by a markedly elevated secretion of IFN-γ or IFN-γ and IL-4 in the lymph nodes draining the lesions of the C57BL/6 or BALB/c mutants, respectively. In contrast, macrophage/neutrophil-specific IL-10-deficient C57BL/6 mice did not show any altered phenotype. During the further course of disease, the T cell-specific as well as the complete IL-10-deficient BALB/c mice were able to control the infection. Furthermore, a dendritic cell-based vaccination against leishmaniasis efficiently suppresses the early secretion of IL-10, thus contributing to the control of parasite spread. Taken together, IL-10 secretion by T cells has an influence on immune activation early after infection and is sufficient to render BALB/c mice susceptible to an uncontrolled Leishmania major infection. Author Summary The clinical symptoms caused by infections with Leishmania parasites range from self-healing cutaneous to uncontrolled visceral disease and depend not only on the parasite species but also on the type of the host's immune response. It is estimated that 350 million people worldwide are at risk, with a global incidence of 1-1.5 million cases of cutaneous and 500,000 cases of visceral leishmaniasis. Murine leishmaniasis is the best-characterized model to elucidate the mechanisms underlying resistance or susceptibility to Leishmania major parasites in vivo. Using T cell-specific and macrophage-specific mutant mice, we demonstrate that abrogating the secretion of the immunosuppressive cytokine IL-10 by T cells is sufficient to render otherwise susceptible mice resistant to an infection with the pathogen. The healing phenotype is accompanied by an elevated specific inflammatory immune response very early after infection. We further show that dendritic cell-based vaccination against leishmaniasis suppresses the early secretion of IL-10 following challenge infection. Thus, our study unravels a molecular mechanism critical for host immune defense, aiding in the development of an effective vaccine against leishmaniasis.}, language = {en} } @article{EberhardtHaasGirschicketal.2015, author = {Eberhardt, Christiane S. and Haas, Johannes-Peter and Girschick, Hermann and Schwarz, Tobias and Morbach, Henner and R{\"o}sen-Wolff, Angela and Foell, Dirk and Dannecker, Guenther and Schepp, Carsten and Ganser, Gerd and Honke, Nora and Eggermann, Thomas and M{\"u}ller-Berghaus, Jan and Wagner, Norbert and Ohl, Kim and Tenbrock, Klaus}, title = {No association of IL-12p40 pro1.1 polymorphism with juvenile idiopathic arthritis}, series = {Pediatric Rheumatology}, volume = {13}, journal = {Pediatric Rheumatology}, number = {61}, doi = {10.1186/s12969-015-0059-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-136281}, year = {2015}, abstract = {Background: IL-12p40 plays an important role in the activation of the T-cell lines like Th17 and Th1-cells. Theses cells are crucial in the pathogenesis of juvenile idiopathic arthritis. A polymorphism in its promoter region and the genotype IL12p40 pro1.1 leads to a higher production of IL-12p40. We studied whether there is a difference in the distribution of the genotype in patients with JIA and the healthy population. Methods: In 883 patients and 321 healthy controls the IL-12p40 promoter genotype was identified by ARMS-PCR. Results: There is no association of IL-12p40 pro polymorphism neither in patients with JIA compared to controls nor in subtypes of JIA compared to oligoarthritis. We found a non-significant tendency of a higher prevalence of the genotype pro1.1 in systemic arthritis (32.4 \%) and in rheumatoid factor negative polyarthritis (30.5 \%) and a lower pro1.1 genotype in persistent oligoarthritis (20.7 \%) and in enthesitis-related arthritis (17 \%). Likelihood of the occurrence of genotype IL12-p40 pro1.1 in patients with systemic arthritis (OR 1.722, CI 95 \% 1.344-2.615, p 0.0129) and RF-negative polyarthritis (OR 1.576, CI 95 \% 1.046-2.376, p 0.0367) compared to persistent oligoarthritis was significantly higher. This was also true for comparison of their homozygous genotypes IL-12p40 pro 1.1 and 2.2 in systemic arthritis (OR 1.779, CI 95 \% 1.045-3.029, p 0.0338). However, in Bonferroni correction for multiple hypothesis this was not significant. Conclusion: A tendency of a higher prevalence of the genotype IL-12p40 pro1.1 in systemic arthritis and in rheumatoid factor negative polyarthritis was observed but not significant. Further investigations should be done to clarify the role IL-12p40 in the different subtypes of JIA.}, language = {en} }