TY - JOUR A1 - Canesi, Margherita A1 - Giordano, Rosaria A1 - Lazzari, Lorenza A1 - Isalberti, Maurizio A1 - Isaias, Ioannis Ugo A1 - Benti, Riccardo A1 - Rampini, Paolo A1 - Marotta, Giorgio A1 - Colombo, Aurora A1 - Cereda, Emanuele A1 - Dipaola, Mariangela A1 - Montemurro, Tiziana A1 - Vigano, Mariele A1 - Budelli, Silvia A1 - Montelatici, Elisa A1 - Lavazza, Cristiana A1 - Cortelezzi, Agostino A1 - Pezzoli, Gianni T1 - Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy JF - Journal of Translational Medicine N2 - Background: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders. Methods: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration. Results: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up. Conclusions: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach. KW - Progressive supranuclear palsy KW - Mesenchymal stem/stromal cells KW - Cell therapy KW - Regenerative medicine Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165725 VL - 14 IS - 127 ER - TY - JOUR A1 - Binder, Tobias A1 - Lange, Florian A1 - Pozzi, Nicolò A1 - Musacchio, Thomas A1 - Daniels, Christine A1 - Odorfer, Thorsten A1 - Fricke, Patrick A1 - Matthies, Cordula A1 - Volkmann, Jens A1 - Capetian, Philipp T1 - Feasibility of local field potential-guided programming for deep brain stimulation in Parkinson’s disease: a comparison with clinical and neuro-imaging guided approaches in a randomized, controlled pilot trial JF - Brain Stimulation N2 - Highlights • Beta-Guided programming is an innovative approach that may streamline the programming process for PD patients with STN DBS. • While preliminary findings from our study suggest that Beta Titration may potentially mitigate STN overstimulation and enhance symptom control, • Our results demonstrate that beta-guided programming significantly reduces programming time, suggesting it could be efficiently integrated into routine clinical practice using a commercially available patient programmer. Background Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson's disease (PD). Clinical outcomes after DBS can be limited by poor programming, which remains a clinically driven, lengthy and iterative process. Electrophysiological recordings in PD patients undergoing STN-DBS have shown an association between STN spectral power in the beta frequency band (beta power) and the severity of clinical symptoms. New commercially-available DBS devices now enable the recording of STN beta oscillations in chronically-implanted PD patients, thereby allowing investigation into the use of beta power as a biomarker for DBS programming. Objective To determine the potential advantages of beta-guided DBS programming over clinically and image-guided programming in terms of clinical efficacy and programming time. Methods We conducted a randomized, blinded, three-arm, crossover clinical trial in eight Parkinson's patients with STN-DBS who were evaluated three months after DBS surgery. We compared clinical efficacy and time required for each DBS programming paradigm, as well as DBS parameters and total energy delivered between the three strategies (beta-, clinically- and image-guided). Results All three programming methods showed similar clinical efficacy, but the time needed for programming was significantly shorter for beta- and image-guided programming compared to clinically-guided programming (p < 0.001). Conclusion Beta-guided programming may be a useful and more efficient approach to DBS programming in Parkinson's patients with STN-DBS. It takes significantly less time to program than traditional clinically-based programming, while providing similar symptom control. In addition, it is readily available within the clinical DBS programmer, making it a valuable tool for improving current clinical practice. KW - beta power KW - deep brain stimulation KW - local field potentials KW - Parkinson's disease KW - DBS programming KW - DBS biomarkers Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350280 VL - 16 IS - 5 ER - TY - JOUR A1 - Kraft, Peter A1 - Fleischer, Anna A1 - Wiedmann, Silke A1 - Rücker, Viktoria A1 - Mackenrodt, Daniel A1 - Morbach, Caroline A1 - Malzahn, Uwe A1 - Kleinschnitz, Christoph A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study JF - BMC Neurology N2 - Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital Würzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95% confidence intervals (95% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95% CI 0.71–0.89) to 0.93 (95% CI 0.87–0.96), and κ from 0.39 (−95% CI 0.14–0.92) to 0.79 (95% CI 0.67–0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96–1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95% CI 0.40–0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies. KW - ischemic stroke KW - systolic dysfunction KW - point-of-care echocardiography KW - ejection fraction KW - stroke unit KW - feasibility KW - accuracy Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158081 VL - 17 IS - 159 ER - TY - JOUR A1 - Golombeck, Stefanie Kristin A1 - Wessig, Carsten A1 - Monoranu, Camelia-Maria A1 - Schütz, Ansgar A1 - Solymosi, Laszlo A1 - Melzer, Nico A1 - Kleinschnitz, Christoph T1 - Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report JF - Journal of Medical Case Reports N2 - Introduction: Reversible posterior leukoencephalopathy syndrome – a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures – is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode. Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death. Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions. KW - reversible posterior leukoencephalopathy syndrome KW - generalized cerebral edema KW - cerebral autoregulation KW - blood pressure Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135517 VL - 7 IS - 14 ER - TY - JOUR A1 - Golombeck, Stefanie Kristin A1 - Wessig, Carsten A1 - Monoranu, Camelia-Maria A1 - Schütz, Ansgar A1 - Solymosi, Laszlo A1 - Melzer, Niko A1 - Kleinschnitz, Christoph T1 - Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report JF - Journal of Medical Case Reports N2 - Introduction: Reversible posterior leukoencephalopathy syndrome – a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures – is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode. Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death. Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions. KW - reversible posterior leukoencephalopathy syndrome KW - generalized cerebral edema KW - cerebral autoregulation KW - blood pressure Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129456 VL - 7 IS - 14 ER - TY - THES A1 - Nowak, Eva T1 - Expression und Funktion von Integrin α-4 in humanen zerebralen Endothelzellen - Analysen unter Zuhilfenahme des therapeutisch eingesetzten Antikörpers Natalizumab T1 - Expression and function of integrin α-4 in human brain endothelial cells - analysis using theantibody Natalizumab N2 - Natalizumab ist ein humanisierter monoklonaler Antikörper gegen das Oberflächenadhäsionsmolekül Integrin α-4, der zur Therapie von schweren Verlaufsformen der Multiplen Sklerose (MS) zugelassen ist. Integrin α-4/β-1 wird durch Leukozyten exprimiert und steuert deren Extravasation über die Bindung an VCAM-1 (vascular cell adhesion molecule-1) auf Endothelzellen. Natalizumab wirkt über eine Blockade der Leukozytenadhäsion. In einigen Publikationen konnte darüber hinaus gezeigt werden, dass Integrin α-4 auch auf zerebralen Endothelzellen von Mäusen und Ratten exprimiert wird. In der vorliegenden Arbeit wurde die Expression und Funktion von Integrin α-4 in kultivierten primären humanen zerebralen Endothelzellen untersucht. Die im Rahmen dieser Arbeit an verschiedenen Einzelspenderpräparationen durchgeführten FACS-Analysen zeigten, dass Integrin α-4 in unterschiedlicher Ausprägung auf primären zerebralen Endothelzellisolationen nachzuweisen war. Mit Hilfe immunzytochemischer Färbungen konnte ein spezifisches Verteilungsmuster des Integrin α-4 in Form eines feinen, granulären Musters im Bereich des Zellleibes dokumentiert werden. In Adhäsionsversuchen zeigten Integrin α-4-exprimierende Endothelzellen nach Zugabe von Natalizumab in niedriger Konzentration eine verminderte Fähigkeit zur Haftung an Fibronectin, einem Bindungspartner in der extrazellulären Matrix. In hohen Konzentrationen dominierte im eingesetzten experimentellen System ein unspezifischer Blockadeeffekt, der auch mit Kontrollantikörpern zu beobachten war. In MS-Läsionen findet sich auch die lösliche Form des VCAM-1 (sVCAM-1), die möglicherweise mit endothelialem Integrin α-4 interagiert. Daher wurde mit Hilfe von Western-Blot-Untersuchungen die intrazelluläre Signaltransduktion unter Stimulation mit sVCAM-1 untersucht. Es zeigte sich wie in anderen Endothelarten vorbeschrieben eine Aktivierung des p38-MAP-Kinase-Signalweges. Zusammenfassend wurde demonstriert, dass primäre humane zerebrale Endothelzellen Integrin α-4 exprimieren und dass dieses wahrscheinlich nicht nur für die mechanische Verankerung in der Extrazellulärmatrix eine Bedeutung besitzt, sondern auch als Induktor intrazellulärer Signaltransduktion fungiert, welche die Schrankeneigenschaften zerebraler Endothelzellen beeinflussen könnte. N2 - Expression and function of integrin α-4 in human brain endothelial cells - analysis using theantibody Natalizumab KW - Integrin KW - Endothelzelle KW - VCAM KW - Integrin alpha-4 KW - zerebrale Endothelzelle KW - Natalizumab KW - cerebral endothelial cell KW - vascular cell adhesion molecule-1 Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-99300 ER - TY - JOUR A1 - Bittner, Stefan A1 - Bobak, Nicole A1 - Feuchtenberger, Martin A1 - Herrmann, Alexander M A1 - Göbel, Kerstin A1 - Kinne, Raimund W A1 - Hansen, Anker J A1 - Budde, Thomas A1 - Kleinschnitz, Christoph A1 - Frey, Oliver A1 - Tony, Hans-Peter A1 - Wiendl, Heinz A1 - Meuth, Sven G T1 - Expression of K\(_2\)\(_P\)5.1 potassium channels on CD4\(^+\)T lymphocytes correlates with disease activity in rheumatoid arthritis patients JF - Arthritis Research & Therapy N2 - Introduction CD4+ T cells express K2P5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K2P5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K2P5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients. Methods Expression levels of K2P5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K2P5.1. Results K2P5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K2P5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K2P5.1 expression to disease activity parameters during a longitudinal follow-up for six months. Conclusions Disease activity in RA patients correlates strongly with K2P5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K2P5.1 as a potential biomarker for disease activity and differential diagnosis. KW - neurology Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139334 VL - 13 IS - R21 ER - TY - JOUR A1 - Feldheim, Jonas A1 - Kessler, Almuth F A1 - Schmitt, Dominik A1 - Wilczek, Lara A1 - Linsenmann, Thomas A1 - Dahlmann, Mathias A1 - Monoranu, Camelia M A1 - Ernestus, Ralf-Ingo A1 - Hagemann, Carsten A1 - Löhr, Mario T1 - Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients JF - OncoTargets and Therapy N2 - Background: ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM. Patients and methods: ATF5 mRNA was extracted from frozen samples of patients’ GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry. Results: ATF5 mRNA was overexpressed in LGA (sevenfold, P<0.001) and GBM (tenfold, P<0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients’ age (r=0.339, P=0.028) and inversely with Ki67-staining (r=-0.421, P=0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan–Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (t<12 months, median survival 18 vs 13 months, P=0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, P=0.024). This advantage vanished after 24 months (P=0.084). Conclusion: ATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors. KW - glioblastoma multiforme KW - recurrence KW - growth pattern KW - protein and mRNA expression Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177541 VL - 11 ER - TY - THES A1 - Fischer, Cindy Erika Elisabeth T1 - Expression des fetalen Acetylcholinrezeptors im Muskel bei experimenteller Nervenläsion der Ratte und bei Neuropathien des Menschen N2 - No abstract available KW - Acetylcholinrezeptor KW - Nicotinischer Acetylcholinrezeptor KW - Denervierung KW - Nervenregeneration KW - Muskel KW - Muskelhypertonie KW - Motorische Endplatte KW - Alkoholische Polyneuropathie KW - Diabetische Polyneuropathie KW - Polyneuropathie KW - Atrophie KW - neurogen KW - fetal KW - SMA Y1 - 2009 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-36619 ER - TY - JOUR A1 - Schnabel, Renate B. A1 - Camen, Stephan A1 - Knebel, Fabian A1 - Hagendorff, Andreas A1 - Bavendiek, Udo A1 - Böhm, Michael A1 - Doehner, Wolfram A1 - Endres, Matthias A1 - Gröschel, Klaus A1 - Goette, Andreas A1 - Huttner, Hagen B. A1 - Jensen, Christoph A1 - Kirchhof, Paulus A1 - Korosoglou, Grigorius A1 - Laufs, Ulrich A1 - Liman, Jan A1 - Morbach, Caroline A1 - Navabi, Darius Günther A1 - Neumann-Haefelin, Tobias A1 - Pfeilschifter, Waltraut A1 - Poli, Sven A1 - Rizos, Timolaos A1 - Rolf, Andreas A1 - Röther, Joachim A1 - Schäbitz, Wolf Rüdiger A1 - Steiner, Thorsten A1 - Thomalla, Götz A1 - Wachter, Rolf A1 - Haeusler, Karl Georg T1 - Expert opinion paper on cardiac imaging after ischemic stroke JF - Clinical Research in Cardiology N2 - This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience. KW - cardiac imaging KW - echocardiography KW - ischemic stroke KW - transient ischemic attack KW - expert opinion KW - magnetic resonance imaging KW - computed tomography Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266662 SN - 1861-0692 VL - 110 IS - 7 ER - TY - THES A1 - Rott, Evelyn T1 - Experimentelle autoimmune Enzephalomyelitis in beta2 Mikroglobulin knock-out Mäusen : axonaler Schaden entsteht unabhängig von MHC-I Expression T1 - EAE in beta-2 microglobulin-deficient mice: axonal damage is not dependent on MHC-I restricted immune responses N2 - CD4 T-Zellen wurden lange als die vor allem pathogen wirkenden Immunzellen bei chronisch entzündlichen ZNS-Erkrankungen angesehen. Wir untersuchten die Wirkung von CD8 T-Zellen in der EAE (exp. autoimmunen Enzephalomyelitis = Tiermodell der Multiplen Sklerose) anhand von beta2-Mikroglobulin knock-out Mäusen (fehlende CD8 T-Zellen). Ergebnis: im Vergleich zu den Wildtyptieren zeigten die Knock-outs eine signifikant stärker ausgeprägte Erkrankung bei der mit verschiedenen Antigenen (MOG, MBP) induzierten EAE mit erhöhter Mortalität. Histologisch fnad sich eine vermehrte Infiltration von Makrophagen und Mikroglia. Die Demyelinisierung war bei den Knock-outs stärker ausgeprägt, ebenso auch der axonale Schaden. Das Fehlen von funktionellen CD8 T-Zellen führte demnach zu einer Verstärkung der autoimmunen Gewebsschädigung im ZNS. N2 - There is accumulating evidence that CD8-positive (CD8+) T-cells and MHC-I expression may also play a role in neurodegeneration associated with multiple sclerosis (MS). We investigated the role of MHC-I and CD8+ T-cells by studying experimental autoimmune encephalomyelitis (EAE) in beta-2 microglobulin knockout mice induced by myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 or whole rat myelin basic protein (rMBP). For both encephalitogens and even after reconstitution of the immune system with MHC-I-positive bone marrow and transfer of mature CD8+ T-cells (iMHC-I+ CD8+ beta2m-/- mice), the disease course in beta2m-/- mice was significantly more severe with a 10-fold increased mortality in the beta2m-/- mice as compared to wild-type C57BL/6 mice. EAE in beta2m-/- mice caused more severe demyelination after immunization with MOG than with rMBP and axonal damage was more marked with rMBP as well as MOG even in iMHC-I+ CD8+ beta2m-/- mice. Immunocytochemical analysis of spinal cord tissue revealed a significant increase in macrophage and microglia infiltration in beta2m-/- and iMHC-I+ CD8+ beta2m-/- mice. The different pattern of T-cell infiltration was underscored by a 2.5-fold increase in CD4-positive (CD4+) T-cells in beta2m-/- mice after induction of MOG 35-55 EAE. We conclude that lack of functional MHC-I molecules and CD8+ T-cells aggravates autoimmune tissue destruction in the CNS. Enhanced axonal damage speaks for pathways of tissue damage independent of CD8+ T-cells and neuronal MHC-I expression. KW - EAE KW - beta2 Mikroglobulin knock-out Mäuse KW - axonaler Schaden KW - axonal damage KW - beta2 microglobulin knock-out mice Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-19500 ER - TY - JOUR A1 - Jírů-Hillmann, Steffi A1 - Gabriel, Katharina M. A. A1 - Schuler, Michael A1 - Wiedmann, Silke A1 - Mühler, Johannes A1 - Dötter, Klaus A1 - Soda, Hassan A1 - Rascher, Alexandra A1 - Benesch, Sonka A1 - Kraft, Peter A1 - Pfau, Mathias A1 - Stenzel, Joachim A1 - von Nippold, Karin A1 - Benghebrid, Mohamed A1 - Schulte, Kerstin A1 - Meinck, Ralf A1 - Volkmann, Jens A1 - Haeusler, Karl Georg A1 - Heuschmann, Peter U. T1 - Experiences of family caregivers 3-months after stroke: results of the prospective trans-regional network for stroke intervention with telemedicine registry (TRANSIT-Stroke) JF - BMC Geriatrics N2 - Background Long-term support of stroke patients living at home is often delivered by family caregivers (FC). We identified characteristics of stroke patients being associated with receiving care by a FC 3-months (3 M) after stroke, assessed positive and negative experiences and individual burden of FC caring for stroke patients and determined factors associated with caregiving experiences and burden of FC 3 M after stroke. Methods Data were collected within TRANSIT-Stroke, a regional telemedical stroke-network comprising 12 hospitals in Germany. Patients with stroke/TIA providing informed consent were followed up 3 M after the index event. The postal patient-questionnaire was accompanied by an anonymous questionnaire for FC comprising information on positive and negative experiences of FC as well as on burden of caregiving operationalized by the Caregiver Reaction Assessment and a self-rated burden-scale, respectively. Multivariable logistic and linear regression analyses were performed. Results Between 01/2016 and 06/2019, 3532 patients provided baseline and 3 M-follow-up- data and 1044 FC responded to questionnaires regarding positive and negative caregiving experiences and caregiving burden. 74.4% of FC were older than 55 years, 70.1% were women and 67.5% were spouses. Older age, diabetes and lower Barthel-Index in patients were significantly associated with a higher probability of receiving care by a FC at 3 M. Positive experiences of FC comprised the importance (81.5%) and the privilege (70.0%) of caring for their relative; negative experiences of FC included financial difficulties associated with caregiving (20.4%). Median overall self-rated burden was 30 (IQR: 0–50; range 0–100). Older age of stroke patients was associated with a lower caregiver burden, whereas younger age of FC led to higher burden. More than half of the stroke patients in whom a FC questionnaire was completed did self-report that they are not being cared by a FC. This stroke patient group tended to be younger, more often male with less severe stroke and less comorbidities who lived more often with a partner. Conclusions The majority of caregivers wanted to care for their relatives but experienced burden at the same time. Elderly patients, patients with a lower Barthel Index at discharge and diabetes are at higher risk of needing care by a family caregiver. Trial registration The study was registered at “German Clinical Trial Register”: DRKS00011696. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011696 KW - family caregiver KW - informal care KW - stroke KW - stroke care KW - telemedicine network Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313330 VL - 22 ER - TY - JOUR A1 - Badr, Mohammad A1 - McFleder, Rhonda L. A1 - Wu, Jingjing A1 - Knorr, Susanne A1 - Koprich, James B. A1 - Hünig, Thomas A1 - Brotchie, Jonathan M. A1 - Volkmann, Jens A1 - Lutz, Manfred B. A1 - Ip, Chi Wang T1 - Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson’s disease mice JF - Journal of Neuroinflammation N2 - Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson’s disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson’s disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson’s disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson’s disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson’s disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson’s disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson’s disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson’s disease patients. KW - Parkinson’s disease KW - neuroinflammation KW - T cells KW - regulatory T cells KW - neuroprotection Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300580 VL - 19 ER - TY - JOUR A1 - Zeller, Daniel A1 - Dang, Su-Yin A1 - Weise, David A1 - Rieckmann, Peter A1 - Toyka, Klaus V. A1 - Classen, Joseph T1 - Excitability decreasing central motor plasticity is retained in multiple sclerosis patients N2 - Background: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. Methods: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. Results: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 ± 22% of baseline amplitude, p < 0.001) and in MS patients (69 ± 18%, p < 0.001). In contrast, postcTBS force production performance was only impaired in controls (2.2 ± 2.8, p = 0.011), but not in MS patients (2.0 ± 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. Conclusions: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS. KW - Medizin KW - Multiple sclerosis KW - LTD KW - Motor plasticity KW - TMS KW - Motor cortex Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76333 ER - TY - THES A1 - Hähnel, Luzia Maria T1 - Evaluation von Beta-2-Mikroglobulin, Laktat und Angiotensin-Converting Enzyme im Liquor als Biomarker der Multiplen Sklerose T1 - Evaluation of beta-2-microglobulin, lactate and angiotensin-converting enzyme in CSF as biomarkers in multiple sclerosis N2 - This study investigates the suitability of beta-2-microglobulin (β2-microglobulin), lactate and angiotensin-converting enzyme (ACE) as biomarkers, given the good availability of these parameters in routine diagnostics but lack of data in this regard. For this purpose, 6,310 CSF samples obtained at the Neurological Clinic of the University Hospital of Würzburg were analyzed. Closer analysis was carried out of 276 cases with non-inflammatory neurological diseases (NIND; control group) and 438 MS cases not taking an immunotherapy treatment (study group). In the MS cases, the form of progression of the disease and the disease activity (clinical relapses, progression index) were recorded. A clear correlation could be seen between age and CSF levels of β2-microglobulin, lactate and ACE in both the MS and control groups, whereby a correction was required for the subsequent comparison studies; this could also at least partly explain the contradictory data obtained in other studies to date. The MS cases showed elevated β2-microglobulin and lactate levels and decreased ACE levels in CSF compared to the controls. In both groups, there was a positive correlation between β2-microglobulin and ACE levels. In the separate analysis of the forms of progression of MS, cases with clinically-isolated syndrome (CIS) and relapsing-remitting MS (RRMS) revealed elevated β2-microglobulin levels, whilst cases with secondary-progressive or primary-progressive MS (SPMS or PPMS) did not. Lactate levels were only increased in cases of CIS. Cases with a relapsing course showed reduced ACE levels. The disease activity could not reliably be mapped by the parameters. Lactate levels tended to be elevated during a relapse, but this result was no longer significant after correction. Lactate levels also showed a positive correlation with the progression index. Our findings in this study provide evidence that the examined analysis parameters cannot be used in isolation to assess progression, disease activity and duration of disease. However, the significant differences between relapsing and chronic-progressive courses support the hypothesis of different underlying mechanisms of pathogenesis, and could serve as a starting basis for further studies. N2 - In der vorliegenden Arbeit wurde die Eignung der im Rahmen der Routinediagnostik verfügbaren, aber unzu¬reichend charakterisierten Analyten Beta-2-Mikroglobulin (β2-Mikroglobulin), Laktat und Angiotensin-Converting Enzyme (ACE) als Biomarker untersucht. Dazu wurden 6.310 an der Neurologischen Klinik des Universitätsklinikums Würzburg gewonnene Liquorproben analysiert. Näher analysiert wurden 276 Fälle mit nicht entzünd¬lichen neurologischen Erkrankungen (NIND; Kontrollgruppe) und 438 nicht immuntherapeutisch behandelte MS-Fälle (Untersuchugsgruppe). Bei den MS-Fällen wurde die Verlaufs¬form und Krankheitsaktivität (klinische Schübe, Progressionsindex) dokumentiert. Es zeigte sich eine deutliche Altersabhängigkeit der Liquorspiegel von β2-Mikroglobulin, Laktat und ACE in der MS- und Kontrollgruppe, was für die sich anschließenden weiteren Vergleichsuntersuchungen eine Korrektur erforderte und zumindest teilweise die wider¬sprüchliche Datenlage bisheriger Studien erklären könnte. MS-Fälle zeigten im Liquor im Vergleich zu Kontrollen erhöhte β2-Mikroglobulin- und Laktat- sowie er¬niedrigte ACE-Spiegel. In beiden Gruppen korrelierten die β2-Mikroglobulin- und ACE-Spiegel positiv miteinander. Bei der getrennten Analyse der MS-Verlaufsformen zeigten Fälle mit klinisch isoliertem Syndrom (CIS) und schubförmig remittierender MS (RRMS) erhöhte β2-Mikroglobulin-Spiegel, Fälle mit sekundär bzw. primär pro¬gredienter MS (SPMS bzw. PPMS) dagegen nicht. Die Laktat-Spiegel waren lediglich bei CIS-Fällen erhöht. Fälle mit schubförmigen Verläufen zeigten reduzierte ACE-Spiegel. Die Krankheitsaktivität wurde durch die Parameter nicht zuverlässig abgebildet. Die Laktat-Spiegel waren tendenziell bei einem Schub erhöht, das Ergebnis war nach Korrektur aber nicht mehr signifikant. Die Laktat-Spiegel korrelierten zudem positiv mit dem Progressionsindex. Die vorliegenden Befunde belegen, dass die untersuchten Analyten alleine nicht in der Lage sind, die Verlaufsform, Krankheitsaktivität und -dauer zu beurteilen. Die deutlichen Unterschiede zwischen schubförmigen und chronisch progredienten Verläufen unterstützen jedoch die Hypothese unterschiedlicher zugrundeliegender Pathomechanismen und könnten als Ausgangspunkt für weitere Untersuchungen dienen. KW - Multiple Sklerose KW - Biomarker KW - Liquor cerebrospinalis KW - Mikroglobulin KW - ACE KW - Laktat Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258503 ER - TY - JOUR A1 - Haarmann, Axel A1 - Deiss, Annika A1 - Prochaska, Juergen A1 - Foerch, Christian A1 - Weksler, Babette A1 - Romero, Ignacio A1 - Couraud, Pierre-Olivier A1 - Stoll, Guido A1 - Rieckmann, Peter A1 - Buttmann, Mathias T1 - Evaluation of Soluble Junctional Adhesion Molecule-A as a Biomarker of Human Brain Endothelial Barrier Breakdown N2 - Background: An inducible release of soluble junctional adhesion molecule-A (sJAM-A) under pro-inflammatory conditions was described in cultured non-CNS endothelial cells (EC) and increased sJAM-A serum levels were found to indicate inflammation in non-CNS vascular beds. Here we studied the regulation of JAM-A expression in cultured brain EC and evaluated sJAM-A as a serum biomarker of blood-brain barrier (BBB) function. Methodology/Principal Findings: As previously reported in non-CNS EC types, pro-inflammatory stimulation of primary or immortalized (hCMEC/D3) human brain microvascular EC (HBMEC) induced a redistribution of cell-bound JAM-A on the cell surface away from tight junctions, along with a dissociation from the cytoskeleton. This was paralleled by reduced immunocytochemical staining of occludin and zonula occludens-1 as well as by increased paracellular permeability for dextran 3000. Both a self-developed ELISA test and Western blot analysis detected a constitutive sJAM-A release by HBMEC into culture supernatants, which importantly was unaffected by pro-inflammatory or hypoxia/reoxygenation challenge. Accordingly, serum levels of sJAM-A were unaltered in 14 patients with clinically active multiple sclerosis compared to 45 stable patients and remained unchanged in 13 patients with acute ischemic non-small vessel stroke over time. Conclusion: Soluble JAM-A was not suited as a biomarker of BBB breakdown in our hands. The unexpected non-inducibility of sJAM-A release at the human BBB might contribute to a particular resistance of brain EC to inflammatory stimuli, protecting the CNS compartment. KW - Biomarker KW - Gehirn Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68468 ER - TY - THES A1 - Bischofs, Stefan T1 - Evaluation der antihyperalgetischen und neuroregenerativen Wirkung von Topiramat nach tierexperimenteller peripherer Nervenläsion T1 - Evaluation of topiramate as an antihyperalgesic and/or neuroregenerative agent after peripheral nerve injury N2 - Evaluation der antihyperalgetischen wie neuroregenerativen Potenz von Topiramat nach peripherer Nervenläsion. Untersuchung im Tiermodell nach CCI / Crush-Nervenläsion. Verhaltenstestungen, morphometrisch histologische Analysen, Immunhistochemische Färbungen, elektrophysiologische Studien sowie RT-PCR. Topiramat zeigte hierbei - modulierende Wirkung auf die Entwicklung einer mechanischen Hyperalgesie wie Kälteallodynie nach CCI, auf Hitzehyperalgesie wie Kälteallodynia nach Crush - keine neuroprotektive oder pro-regenerative Wirkung in den von uns verwendeten Läsionsmodellen - eine ausgeprägte Modulation des zellulären Zytokinmilieus distal der Nervenläsion im Sinne einer Hochregulation proinflammatorischer Zytokine. N2 - Evaluation of Topiramate as an antihyperalgesic and/or neuroregenerative agent after peripheral nerve injury. Behavioral testing, morphometric analysis, immunohistochemistry, electrophysiological study and RT-PCR. Topiramate showed - a modulation of the development of mechanical hyperalgesia and cold allodynia post CCI, further on heat hyperalgesia and cold allodynia after crush lesion of the peripheral nerve. - no neuroprotective or pro-regenerative effect in the lesion models applied - a marked alteration of the cellular cytokine-mileu, elevation of pro-inflammatory cytokines. KW - Topiramat KW - CCI KW - Crush KW - Neuroregeneration KW - neuropathischer Schmerz KW - Topiramate KW - CCI KW - crush KW - neuroregeneration KW - neuropathic pain Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-18352 ER - TY - THES A1 - Magg, Barbara T1 - Etablierung und Validierung des Würzburger Fabry Schmerzfragebogens für erwachsene Patienten T1 - A comprehensive Fabry-related pain questionnaire for adult patients N2 - Der M. Fabry ist eine X-chromosomal vererbte lysosomale Speicherkankheit, die zu einem Multiorganversagen führt. Ein frühes Symptom sind Schmerzen, die meist schon in der frühen Kindheit einsetzen. Das Besondere an diesen Schmerzen ist, dass sie sich sehr unterschiedlich u.a. bezüglich ihres Verlaufs, ihrer Dauer und ihrer Lokalisation präsentieren können. Diese Fabry-assoziierten Schmerzen sind meist brennend und akral betont, können aber auch andere Qualitäten aufweisen und sehr variable Körperpartien erfassen, was ihre diagnostische Einordnung erschwert. Bisher verfügbare validierte Schmerzfragebögen können das Spektrum der Fabry-assoziierten Schmerzen nicht erfassen. In dieser Arbeit wird der erste M. Fabry spezifische Schmerzfragebogen für Erwachsene in zwei Versionen präsentiert. Die erste Version ist eine Interview Version (iFPQ), bei der der Arzt in einem persönlichen Gespräch mit dem Patienten mit Hilfe des Fragbogens alle wesentlichen Aspekte der Fabry-assoziierten Schmerzen erfragen kann. Die zweite Version kann eigenständig vom Patienten ausgefüllt werden (saFPQ). Zur Etablierung der Fragebögen wurde in einer Pilotstudie zunächst mit 20 Patienten eine erste Version des iFPQ entwickelt. Nach Verbesserungen wurde die Interview Version mit Hilfe von 42 Studienteilnehmern validiert, die jeweils an einem Erst- und Zweitgespräch im Abstand von zwei Wochen teilnahmen. Hierbei wurde auch der NPSI als vergleichender Fragebogen ausgefüllt. Bei der ersten statistischen Analyse ergab sich eine gute Reliabilität mit ICC-Werten von 0,896 bis 0,999 aber eine unzureichende Validität zwischen iFPQ und NPSI mit K-Werten von 0,257 bis 0,566. Nach der ersten statistischen Analyse wurde der Fragebogen erneut überarbeitet und mit Hilfe von 20 Studienteilnehmern erneut validiert. Anschließend zeigte sich eine gute Validität mit K-Werten von 0,634 bis 1,0. Der saFPQ wurde im Anschluss an die finale iFPQ Version entwickelt. Bei 40 Patienten erfolgte ein Erstgespräch, bei dem die Patienten die valide Version des iFPQ ausfüllten. Im Abstand von zwei Wochen schickten die Patienten dann die selbständig ausgefüllte Version des saFPQ postalisch zurück. Die postalische Version erweitert die Flexibilität dieses Fragebogens. Sie ist für den klinischen Alltag sehr relevant. Die Resonanz der Patienten hinsichtlich beider Fragebögen war sehr positiv. Perspektivisch ist die Entwicklung einer englischen Version geplant. N2 - Pain may be the earliest symptom in Fabry disease and presents with a distinct phenotype including triggerable pain attacks, evoked pain, pain crises, and chronic pain. Current pain questionnaires do not reflect the special phenotype of Fabry disease–associated pain, which hampers its systematic evaluation as the basis of correct diagnosis and effective treatment. A questionnaire specifically designed to assess Fabry disease–associated pain is thus urgently needed. At the Würzburg Fabry Center for Interdisciplinary Therapy (FAZIT), Germany, we developed and validated the first face-to-face Fabry Pain Questionnaire (FPQ) for adult patients. The initial version of the FPQ was tested in a pilot study with 20 consecutive Fabry disease patients. The performance of the revised FPQ was assessed in a first (n = 56) and second (n = 20) validation phase in consecutive Fabry disease patients. For this, patients were interviewed at baseline and 2 weeks later. We determined the test-retest reliability and validity of the FPQ in comparison to data obtained with the Neuropathic Pain Symptom Inventory. The FPQ contains 15 questions on the 4 pain phenotypes of Fabry disease (pain attacks, pain crises, evoked pain, chronic pain) in childhood and adulthood, on pain development during life with and without enzyme replacement therapy, and on everyday life impairment due to pain. a self-administered Version of the face-to-face Version was validated accordingly to the face-to-face version. To do this, consecutive Fabry patients with current or past pain history (n=56) were first interviewed face-to-face. Two weeks later patients` self-reported questionnaire results were collected by mail (n=55). Statistical analysis showed that the majority of questions were answered in high agreement in both sessions with a mean AC1-statistic of 0.857 for 55 nominal-scaled items and a mean ICC of 0.587 for 9 scores. This first disease-specific questionnaire is a valuable tool for baseline and follow-up assessment of pain in Fabry disease patients and may guide treatment in this distinct pain phenotype. The self-administered version allows a more flexible usage. In the future an english version is anticipated. KW - M.Fabry KW - neuropathischer Schmerz KW - Schmerzfragebogen KW - M. Fabry KW - neuropathischer Schmerz KW - Schmerzfragebogen Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154928 ER - TY - JOUR A1 - Schanbacher, Constanze A1 - Bieber, Michael A1 - Reinders, Yvonne A1 - Cherpokova, Deya A1 - Teichert, Christina A1 - Nieswandt, Bernhard A1 - Sickmann, Albert A1 - Kleinschnitz, Christoph A1 - Langhauser, Friederike A1 - Lorenz, Kristina T1 - ERK1/2 activity is critical for the outcome of ischemic stroke JF - International Journal of Molecular Sciences N2 - Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2\(^{wt}\)) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood–brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP\(^{wt}\)) and its phosphorylation-deficient mutant RKIP\(^{S153A}\), known inhibitors of the ERK1/2 signaling cascade. RKIP\(^{wt}\) and RKIP\(^{S153A}\) attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke. KW - ERK1/2 KW - tMCAO KW - ischemic stroke KW - RKIP Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283991 SN - 1422-0067 VL - 23 IS - 2 ER - TY - THES A1 - Mötzing, Sandra T1 - Entwicklung von Merkelzellen in der Haut von P0-defizienten Mäusen T1 - Development of Merkel cells in P0-deficient mice N2 - Hereditäre periphere Neuropathien sind chronische Erkrankungen des peripheren Nervensystems, einhergehend mit Muskelschwäche und sensorischer Dysfunktion. Die Merkelzelle als Mechanorezeptor der Haut wird von einer myelinisierten langsam adaptierenden Afferenz (Aß) innerviert. Deshalb wurde in der vorliegenden Arbeit als sekundärer Indikator für die distale Innervation in P0-defizienten Mäusen, ein Tiermodell der hereditären motorisch-sensorischen Déjérine-Sottas-Neuropathie, die Merkelzellzahl in der Haut dieser Tiere untersucht. Zusätzlich wurde untersucht, ob durch den Gendefekt das unmyelinisierte Nervenfasersystem der Haut und das Vorkommen von Neurotrophinen (NT-3, NGF) in den P0-defizienten Mäusen beeinflußt wird. Zur Anwendung kamen 6 Wochen, 4 Monate und 6 Monate alte Wildtyp- und P0-defiziente Mäuse. Unter Zuhilfenahme immunhistochemischer Färbemethoden, computergestützter und lichtmikroskopischer Auswerteverfahren konnte ein Verlust von Merkelzellen in behaarter als auch in unbehaarter Haut mit fortschreitenden Alter der Tiere gezeigt werden. Die Bestimmung des NT-3- und NGF-Gehaltes mittels enzymgekoppelten Assays ergab keine signifikante Reduktion des Vorkommens dieser Neurotrophine. Neben dem beträchtlichen Verlust an Merkelzellen konnte man keinen Effekt auf unmyelinisierte intraepidermale Nervenfasern nachweisen. Im Gegensatz dazu stellte eine parallel durchgeführte Studie an Nervus femoralis und Nervus ischiadicus in 6 Monate alten P0-defizienten Tieren eine 70 Prozent Reduktion myelinisierter Axone fest, so daß wir daraus eine Abhängigkeit der Merkelzelle von ihrer assoziierten myelinisierten SAI-Afferenz sowohl in behaarter als auch in unbehaarter Haut in den P0-defizienten Tieren schlußfolgerten. Der Verlust an Merkelzellen und die Beeinträchtigung von myelinisierten Nervenfasern in den P0-defizienten Tieren kann nicht als sekundäre Wirkung eines veränderten trophischen Gehaltes an NT-3 oder NGF angesehen werden, sondern ist vielmehr durch den axonalen Verlust erklärbar. Die intraepidermalen unmyelinisierten Nervenfasern bleiben durch den Gendefekt unbeeinflußt, so daß die Mutation im P0-Gen eine Spezifität für das myelinisierte Nervenfasersystem zeigt. Wichtige Ergebnisse dieser Arbeit wurden bereits veröffentlicht. N2 - Inherited peripheral neuropathies are chronical diseases of the peripheral nervous system, associated with muscular weakness and sensory dysfunction. Merkel cells, which are specialized epidermal cells are innervated by slowly adapting mechanosensitive afferent fibres with large myelinated (Aß) axons. In P0-deficient mice, an animal modell of the inherited Charcot-Marie-Tooth Neuropathy, we examined the population of Merkel cells as an indirect indicator of the distal innervation. Additionally, we observed the intraepidermal nerve fibre system and the amount of neurotrophin-3 and nerve growth factor, if they are affected by the mutation in the P0-Gen. We used 6 weeks, 4 months and 6 months old mice, homozygot mutation of the P0-Gen and age-matched Wildtyp-Control-mice. By using immunhistochemical staining methods, computer-guided and light microscopical techniques, we find a profound loss of Merkel cells in both hairy and glabrous skin, increased with age of the animals. Despite of these loss, we could not obtain a corresponding reduction of neurotrophin-3 or nerve growth factor nor an effect of the number of intraepidermal umyelinated nerve fibres. A parallel study on the Femoral and Ischiatic nerve in 6 months old P0-deficient mice shows a reduction of 70 percent of myelinated axons. This finding indicates that the contact with the assosiated myelinated nerve fibre is crucial for the development and maintenance of the Merkel cells in both hairy and against previous studies in glabrous skin. The loss of Merkel cells and the reduction of myelinated nerve fibres are unlikely the cause of a changed amount of neurotrophins. The intraepidermal unmyelinated nerve fibre system are not affected by the mutation, suggests that the mutation of the P0-Gen is specific to myelinated nerve fibres. Important results are published in the Journal of Neuroscience 1999. KW - Hereditäre Neuropathien KW - Myelinprotein KW - Merkelzelle KW - Neurotrophine KW - Nervenfaser KW - Inherited neuropathies KW - myelin protein zero KW - Merkel cells KW - neurotrophins KW - nerve fibres Y1 - 2002 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-578 ER -