TY - JOUR A1 - Sommer, Claudia A1 - Richter, Helmut A1 - Rogausch, Jan P. A1 - Frettloh, Jule A1 - Lungenhausen, Margitta A1 - Maier, Christoph T1 - A modified score to identify and discriminate neuropathic pain: a study on the German version of the neuropathic pain symptom inventory (NPSI) N2 - Background: Neuropathic pain must be correctly diagnosed for optimal treatment. The questionnaire named Neuropathic Pain Symptom Inventory (NPSI) was developed in its original French version to evaluate the different symptoms of neuropathic pain. We hypothesized that the NPSI might also be used to differentiate neuropathic from non-neuropathic pain. Methods: We translated the NPSI into German using a standard forward-backward translation and administered it in a case-control design to patients with neuropathic (n = 68) and non-neuropathic pain (headache and osteoarthritis, n = 169) to validate it and to analyze its discriminant properties, its sensitivity to change, and to detect neuropathic pain subgroups with distinct profiles. Results: Using a sum score (the NPSI-G score), we found sensitivity to change (r between 0.37 and 0.5 for pain items of the graded chronic pain scale) and could distinguish between neuropathic and other pain on a group basis, but not for individual patients. Post hoc development of a discriminant score with optimized diagnostic properties to distinguish neuropathic pain from non-neuropathic pain resulted in an instrument with high sensitivity (91%) and acceptable specificity (70%). We detected six different pain profiles in the patient group with neuropathic pain; three profiles were found to be distinct. Conclusions: The NPSI-G potentially combines the properties of a diagnostic tool and an instrument to identify subtypes of neuropathic pain. KW - Neuralgie KW - NPSI Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68716 ER - TY - JOUR A1 - Kreissl, Michael C. A1 - Stout, David B. A1 - Wong, Koon-Pong A1 - Wu, Hsiao-Ming A1 - Caglayan, Evren A1 - Ladno, Waldemar A1 - Zhang, Xiaoli A1 - Prior, John A1 - Reiners, Christoph A1 - Huang, Sung-Cheng A1 - Schelbert, Heinrich R. T1 - Influence of Dietary Interventions and Insulin on Myocardial, Skeletal Muscle and Brain [18F]-Fluorodeoxyglucose Kinetics in Mice N2 - Background: We evaluated the effect of insulin stimulation and dietary changes on myocardial, skeletal muscle and brain [18F]-fluorodeoxyglucose (FDG) kinetics and uptake in vivo in intact mice. Methods: Mice were anesthetized with isoflurane and imaged under different conditions: non-fasted (n = 7; "controls"), non-fasted with insulin (2 IU/kg body weight) injected subcutaneously immediately prior to FDG (n = 6), fasted (n = 5), and fasted with insulin injection (n = 5). A 60-min small-animal PET with serial blood sampling and kinetic modeling was performed. Results: We found comparable FDG standardized uptake values (SUVs) in myocardium in the non-fasted controls and non-fasted-insulin injected group (SUV 45-60 min, 9.58 ± 1.62 vs. 9.98 ± 2.44; p = 0.74), a lower myocardial SUV was noted in the fasted group (3.48 ± 1.73; p < 0.001). In contrast, the FDG uptake rate constant (Ki) for myocardium increased significantly by 47% in non-fasted mice by insulin (13.4 ± 3.9 ml/min/100 g vs. 19.8 ± 3.3 ml/min/100 g; p = 0.030); in fasted mice, a lower myocardial Ki as compared to controls was observed (3.3 ± 1.9 ml/min/100 g; p < 0.001). Skeletal muscle SUVs and Ki values were increased by insulin independent of dietary state, whereas in the brain, those parameters were not influenced by fasting or administration of insulin. Fasting led to a reduction in glucose metabolic rate in the myocardium (19.41 ± 5.39 vs. 3.26 ± 1.97 mg/min/100 g; p < 0.001), the skeletal muscle (1.06 ± 0.34 vs. 0.34 ± 0.08 mg/min/100 g; p = 0.001) but not the brain (3.21 ± 0.53 vs. 2.85 ± 0.25 mg/min/100 g; p = 0.19). Conclusions: Changes in organ SUVs, uptake rate constants and metabolic rates induced by fasting and insulin administration as observed in intact mice by small-animal PET imaging are consistent with those observed in isolated heart/muscle preparations and, more importantly, in vivo studies in larger animals and in humans. When assessing the effect of insulin on the myocardial glucose metabolism of non-fasted mice, it is not sufficient to just calculate the SUV - dynamic imaging with kinetic modeling is necessary. KW - Insulin KW - Gehirn KW - Skelettmuskel KW - Maus Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68775 ER - TY - JOUR A1 - Puschmann, Anne-Katrin A1 - Sommer, Claudia T1 - Hypervigilance or avoidance of trigger related cues in migraineurs? - A case-control study using the emotional stroop task N2 - Background: “Negative affect” is one of the major migraine triggers. The aim of the study was to assess attentional biases for negative affective stimuli that might be related to migraine triggers in migraine patients with either few or frequent migraine and healthy controls. Methods: Thirty-three subjects with frequent migraine (FM) or with less frequent episodic migraine, and 20 healthy controls conducted two emotional Stroop tasks in the interictal period. In task 1, general affective words and in task 2, pictures of affective faces (angry, neutral, happy) were used. For each task we calculated two emotional Stroop indices. Groups were compared using one-way ANOVAs. Results: The expected attentional bias in migraine patients was not found. However, in task 2 the controls showed a significant attentional bias to negative faces, whereas the FM group showed indices near zero. Thus, the FM group responded faster to negative than to positive stimuli. The difference between the groups was statistically significant. Conclusions: The findings in the FM group may reflect a learned avoidance mechanism away from affective migraine triggers. KW - Migräne Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69103 ER - TY - THES A1 - Subramanian, Narayan T1 - Role of NaV1.9 in activity dependent axon growth in embryonic cultured motoneurons T1 - Die Rolle der NaV1.9 in Aktivität abhängig Axonwachstum in embryonalen kultivierten Motoneuronen N2 - Spontaneous neural activity has been shown to regulate crucial events in neurite growth including axonal branching and path finding. In animal models of spinal muscular atrophy (SMA) cultured embryonic mouse motoneurons show distinct defect in axon elongation and neural activity. This defect is governed by abnormal clustering of Ca2+ channels in the axonal regions and the protruding growth cone area. The mechanisms that regulate the opening of calcium channels in developing motoneurons are not yet clear. The question was addressed by blocking neural activity in embryonic cultured motoneurons by pharmacological inhibition of voltage-gated sodium channels (VGSC) by saxitoxin (STX) and tetrodotoxin (TTX). Low dosages of STX resulted in significant reduction of axon growth and neural activity in cultured motoneurons. This pharmacological treatment did not affect survival of motoneurons in comparison to control motoneurons that was grown in the presence of survival neurotrophic factors BDNF and CNTF. It was also found that STX was 10 times more potent than TTX a common inhibitor of VGSC with a reduced activity on the TTX-insensitive sodium channels NaV1.5, NaV1.8 and NaV1.9. Reverse Transcriptase-PCR experiments revealed the presence of NaV1.9 as the likely candidate that begins to express from embryonic stage sixteen in the mouse spinal cord. Immunolabelling experiments showed that the channel is expressed in the axonal compartments and axonal growth cones in cultured motoneurons. Suppression of NaV1.9 in cultured motoneurons by lentivirus mediated short hairpin-RNA (shRNA) resulted in shorter axon length in comparison with uninfected and scrambled constructs. Further, embryonic motoneurons cultured from NaV1.9 knockout mice also showed a significant reduction in neural activity and axon growth. The findings of this work highlight the role of NaV1.9 as an important contender in regulating activity dependent axon growth in embryonic cultured motoneurons. NaV1.9 could therefore be considered as a prospective molecule that could play an important role in regulating axon growth in motoneuron disease models like spinal muscular atrophy (SMA). N2 - Spontane neuronale Aktivität reguliert essentielle Ereignisse im Neuritenwachstum, wie beispielsweise die axonale Verzweigung und die Erkennung des Wachstumspfades. Motoneurone, die aus Tiermodellen der Spinalen Muskelatrophie (SMA) gewonnen werden, zeigen einen auffälligen Defekt im Streckenwachstum von Axonen und in der neuronalen Aktivität. Dieser Defekt wird von anormaler Clusterbildung von Ca2+ Kanälen in axonalen Regionen und in Wachstumskegeln begleitet. Die Mechanismen, die das Öffnen von Kalziumkanälen in embryonalen Motoneuronen in der Entwicklung regulieren, und die für das aktivitätsabhängige Axonwachstum benötigt werden, sind nicht bekannt. Diese Frage wurde in dieser Studie bearbeitet, indem neuronale Aktivität in embryonalen Motoneuronen durch pharmakologische Inhibition von spannungsabhängigen Natriumkanälen durch Saxitoxin (STX) und Tetrodotoxin blockiert wurde. Geringe Dosen von Saxitoxin bewirkten eine deutliche Reduktion des Axonwachstums und der neuronalen Aktivität in kultivierten Motoneuronen. Diese pharmakologische Behandlung beeinflusste nicht das Überleben von Motoneuronen im Vergleich zu Kontroll-Motoneuronen, die in der Anwesenheit der neurotrophen Faktoren BDNF und CNTF kultiviert wurden. Saxitoxin war etwa 5-10-mal potenter als TTX, ein üblicher Blocker spannungsabhängiger Natriumkanäle mit einer verminderte Aktivität auf die TTX-insensitiven Natriumkanäle NaV1.5, NaV1.8, und NaV1.9. Reverse-Transkriptase-PCR Experimente bestätigten die Anwesenheit von NaV1.9 am Tag E16 (embryonaler Tag 16) im Rückenmark der Maus. NaV1.9 ist ein einzigartiger Typus von einem Natriumkanal welcher in der Lage ist neuronale Erregbarkeit in der Nähe des Ruhemembranpotentials zu steuern. Deshalb war NaV1.9 ein guter Kandidat für einen Kanal, der spontane Erregung in Motoneuronen vermittelt. Immunofärbungen zeigten, dass NaV1.9 in axonalen Kompartimenten und axonalen Wachstumskegeln von kultivierten Motoneuronen exprimiert ist. Die Unterdrückung von NaV1.9 in kultivierten Motoneuronen durch lentiviralexprimierte short hairpin-RNA (shRNA) resultierte in kürzerer Axonlänge, im Vergleich zu nicht-infizierten Motoneuronen oder Motoneuronen, die eine sinnlose Kontroll-shRNA Sequenz exprimierten. Embryonale, kultivierte Motoneurone von NaV1.9 knockout Mäusen zeigten eine signifikante Verringerung der neuronalen Aktivität und verkürzte Axone. Diese Ergebnisse weisen auf eine Bedeutung von NaV1.9 im aktivitätsabhängigen Axonwachstum hin KW - Axon KW - Embryonalentwicklung KW - Motoneuron KW - Natriumkanal KW - Motoneuronen KW - NaV1.9 KW - motoneuron KW - Nav1.9 KW - axon growth Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-57536 ER - TY - THES A1 - Graulich, Michael T1 - Spinale Effekte von TNF-α am Modell des tumorinduzierten Knochenschmerzes der Maus T1 - Spinal effects of TNF-α in a mouse model of bone cancer pain N2 - Am Modell des tumorinduzierten Schmerzes der Maus wurden sowohl das Schmerzverhalten der Tiere als auch spezifische morphologische Veränderungen im Hinterhorn des Rückenmarks (Aktivierung von Astrozyten) und im tumorbefallenen Knochen analysiert. Durch Analyse von Mäusen mit Defizienz für TNF-Rezeptor 1, TNF-Rezeptor 2 oder für beide Rezeptoren konnte die Rolle von TNF-α seiner Rezeptoren bei der Entstehung von tumorinduziertem Schmerz untersucht werden. Im Unterschied zu neuropathischen Schmerzmodellen konnte gezeigt werden, dass beide TNF-Rezeptoren ausgeschaltet werden müssen, um eine signifikante Schmerzreduktion zu erzielen. Die systemische Behandlung mit dem TNF-neutralisierenden Fusionsprotein Etanercept konnte die im genetischen Modell gezeigte Reduktion der mechanischen Allodynie teilweise, aber nicht vollständig reproduzieren. Eine Hemmung der Mikrogliaaktivierung mittels Minocyclin erbrachte im Tumor-schmerzmodell keinen Effekt auf das Schmerzverhalten der Tiere. Die histologische Analyse der tumoraffizierten Knochen zeigte eine signifikante Zunahme der Osteoklastenaktivität in tumortragenden Tieren. Die Behandlung mit Minocyclin war ohne erkennbaren Effekt auf die Differenzierung und die Aktivität der Osteoklasten. Es ergaben sich jedoch Hinweise, dass TNF-α einen hemmenden Einfluss auf die Osteoklastenaktivität im Knochentumormodell hat, da sowohl in den TNFR-KO-Tieren als auch unter Gabe von Etanercept eine Steigerung der Osteoklastenaktivität nachgewiesen werden konnte. Die Ergebnisse dieser Arbeit zeigen, dass TNF-α eine wichtige Rolle, sowohl in der Entstehung, als auch in der Aufrechterhaltung von tumorinduziertem Schmerz spielt. Hier liegt der Ansatzpunkt für weitere Studien mit dem Ziel, eine spezifische Pharmakotherapie zu entwickeln mit wirksamer TNF-α Blockade auch bei Patienten mit Tumorschmerzen. Nach den Erkenntnissen dieser Arbeit mit Etanercept sollte ein spezielles Augenmerk auf die ZNS-Gängigkeit dieser Substanzen gelegt werden und die Gefahr der Möglichkeit eines vermehrten Tumorwachstum bedacht werden. N2 - Bone-cancer-related pain is one of the most disabling factors in patients suffering from primary bone cancer or bone metastases. Recent studies point toward an important role of proinflammatory cytokines, example tumor necrosis factor-alpha (TNF), for tumor growth and bone-cancer-associated pain. Mechanisms by which TNF, through its receptor subtypes, TNF receptor 1 (TNFR1) and -2 (TNFR2), elicits altered sensation and pain behavior, are still incompletely understood. To look for a potential role of TNF in bone cancer pain, cancer-related pain was analyzed in fibrosarcoma-bearing C57Bl/6J wild type mice after systemic antagonism of TNF. To further clarify the role of TNF receptor (TNFR) in bone-cancer pain, naive and fibrosarcoma-bearing C57Bl/ 6J wild type and transgenic mice with a deficiency of TNFR1 (TNFR1ko), TNFR2 (TNFR2ko), and TNFR1+2 (TNFR1+2ko) were compared regarding cancer-related pain and hyperalgesia, tumor growth, osteoclast activation, and spinal astrogliosis. Systemic antagonism of TNF significantly alleviated tactile hypersensitivity and spontaneous bone-cancer-related pain behavior. Most interestingly, combined deletion of the TNFR1 and TNFR2, but not of either gene alone, almost completely inhibited the development of tactile hypersensitivity, whereas spontaneous pain behavior was transiently increased. Accordingly, spinal astrogliosis was markedly reduced, whereas tumor growth was significantly increased in TNFR1+2ko mice. In contrast, deletion of the TNFR1 or TNFR2 gene alone did not change tumor growth or spinal astrogliosis. Our findings suggest that the combined absence of TNFR1 and TNFR2 is necessary for the attenuation of cancer-related tactile hypersensitivity and concomitant spinal astrogliosis, whereas tumor growth seems to be inhibited by combined TNFR activation. These findings support the hypothesis of cytokine-dependent pain development in cancer pain. Differential targeting of TNFR activation could be an interesting strategy in bone-cancer-related pain conditions. KW - Neuralgie KW - Schmerz KW - Schmerzforschung KW - Tumor-Nekrose-Faktor KW - Tumor-Nekrose-Faktor -Inhibitor KW - Experimentaltumor KW - Knochentumor KW - pain KW - tumor KW - bone KW - neuropathy KW - tnf KW - glia KW - minocycline KW - etanercept Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-54439 ER - TY - RPRT A1 - Magnus, Tim A1 - Linker, Ralf A. A1 - Meuth, Sven G. A1 - Kleinschnitz, Christoph A1 - Korn, Thomas T1 - Report on the 2nd scientific meeting of the "Verein zur Foerderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Oct. 29'th - Oct. 31'st, 2010 N2 - Summary of the scientific contributions to the NEUROWIND meeting 2010: Contributions in the fields of neuroimmunology and neurodegeneration KW - Wissenschaftlicher Nachwuchs KW - Neurologie Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68789 ER - TY - THES A1 - Schubert, Andrea Julia T1 - Vergleich der Ergebnisse von Karotis-Stenting und -TEA an der Universitätsklinik Würzburg T1 - Comparing the results of carotid stenting and carotid endarterectomy at the university of Würzburg N2 - Der Vergleich der Verfahren Karotisstenting und Karotis-TEA an der Universitätsklinik Würzburg zeigt, dass bei richtiger Indikationsstellung sowie ausreichender Erfahrung der Neuroradiologen, CAS eine ernstzunehmende Alternative zu CEA darstellt. Besonderes Augenmerk lag dabei auf periprozeduale Komplikationen sowie Langzeitergebnisse bezüglich Tod,Insult und Restenose. N2 - Comparing carotid artery stenting and endarterectomy at the university of Würzburg, we showed that CAS is a serious alternative to CEA if the right indication is given and when interventionalists have enough experience. Our endpoints were periprocedual complications and long-term outcomes regarding stroke, death and recurrent stenosis. KW - Carotis KW - Arteria carotis interna KW - Carotisstenose KW - Carotischirurgie KW - Endarteriektomie KW - Würzburg / Universität Würzburg KW - Vergleich KW - Stent KW - CEA KW - CAS KW - versus KW - vs KW - CEA KW - CAS KW - versus KW - vs Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67130 ER - TY - THES A1 - Fackelmann, Stefanie T1 - Langzeitkorrelation evozierter Potentialparameter mit dem klinischen Verlauf bei Patienten mit Multipler Sklerose T1 - Early abnormalities of evoked potentials and future disability in patients with multiple sclerosis N2 - Evozierte Potenziale werden bereits als Hilfsmittel zur Diagnosestellung der Multiplen Sklerose herangezogen. Das Spektrum der Verläufe der Erkrankung ist sehr unterschiedlich. Ziel der Studie war es, zu prüfen, ob visuell (VEP), somatosensibel (SEP) und Magnet- (MEP) evozierte Potentiale durch das Aufdecken klinisch noch stummer Läsionen eine prognostische Bedeutung haben. Es wurden 94 Patienten bei Erstvorstellung sowie zum 5-Jahres- und 10-Jahresverlaufszeitpunkt untersucht. Es wurde ein Zusammenhang von MEP- und SEP-Scores mit dem späteren Behinderungsgrad, gemessen in Form der EDSS nach fünf und zehn jahren gefunden, sofern die elektrophysiologischen Untersuchungen in den ersten beiden Jahren nach Erstmanifestation klinischer Symptome durchgeführt worden waren (Gruppe 1, 44 Patienten). Für Gruppe 2 (50 Patienten), deren Erstuntersuchung später im Verlauf stattgefunden hatte (im Mittel 9,6a) konnte keine prognostische Bedeutung gesehen werden. Die Durchführung multimodaler evozierter Potenziale ist kann somit eine Hilfestellung zur frühzeitigen Therapieentscheidung geben. N2 - Evoked potentials (EP) have a role in making the diagnosis of multiple sclerosis (MS) but their implication for predicting the future disease course in MS is under debate. EP data of 94 MS patients examined at first presentation, and after five and ten years were retrospectively analysed. Patients were divided into two groups in relation to the prior duration of disease at the time point of first examination: group 1 patients (n-44) were first examined within two years after disease onset, and group 2 patients (n-50) at later time points. As primary measures sum scores were calculated for abnormalities of single and combined EP (visual (VEP), somatosensory (SEP), magnetic motor evoked potentials (MEP)). In patients examined early after disease onset (group 1), a significant predictive value for abnormal EP was found with MEP and SEP sum scores at first presentation correlating significantly with Expanded Disability Status Scale (EDSS) values after five years, while the VEP sum score was not. The cumulative number of abnormal MEP, SEP and VEP results also indicated higher degrees of disability (EDSS≥ 3.5) after five years. Combined pathological SEP and MEP findings at first presentation best predicted clinical disability (EDSS≥ 3.5) after five years (odds ratio 11.0). EP data and EDSS at first presentation were not significantly linked suggesting that EP abnormalities at least in part represented clinically silent lesions not mirrored by EDSS. For patients in later disease phases (group 2), no significant associations between EP data at first presentation and EDSS at five and ten years were detected. Together with clinical findings and MR imaging, combined EP data may help to identify patients at high risk of long-term clinical deterioration and guide decisions as to immunomodulatory treatment. KW - Multiple Sklerose KW - Evozierte Potenziale KW - multiple sclerosis KW - evoked potentials Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64840 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 - Puschmann, Anne-Katrin A1 - Sommer, Claudia T1 - Hypervigilance or avoidance of trigger related cues in migraineurs? - A case-control study using the emotional stroop task JF - BMC Neurology N2 - Background "Negative affect" is one of the major migraine triggers. The aim of the study was to assess attentional biases for negative affective stimuli that might be related to migraine triggers in migraine patients with either few or frequent migraine and healthy controls. Methods Thirty-three subjects with frequent migraine (FM) or with less frequent episodic migraine, and 20 healthy controls conducted two emotional Stroop tasks in the interictal period. In task 1, general affective words and in task 2, pictures of affective faces (angry, neutral, happy) were used. For each task we calculated two emotional Stroop indices. Groups were compared using one-way ANOVAs. Results The expected attentional bias in migraine patients was not found. However, in task 2 the controls showed a significant attentional bias to negative faces, whereas the FM group showed indices near zero. Thus, the FM group responded faster to negative than to positive stimuli. The difference between the groups was statistically significant. Conclusions The findings in the FM group may reflect a learned avoidance mechanism away from affective migraine triggers. KW - migraineur KW - cue Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137750 VL - 11 IS - 141 ER - TY - JOUR A1 - Weise, Gesa A1 - Basse-Lüsebrink, Thomas C. A1 - Kleinschnitz, Christoph A1 - Kampf, Thomas A1 - Jakob, Peter M. A1 - Stoll, Guido T1 - In Vivo Imaging of Stepwise Vessel Occlusion in Cerebral Photothrombosis of Mice by \(^{19}\)F MRI JF - PLoS One N2 - Background \(^{19}\)F magnetic resonance imaging (MRI) was recently introduced as a promising technique for in vivo cell tracking. In the present study we compared \(^{19}\)F MRI with iron-enhanced MRI in mice with photothrombosis (PT) at 7 Tesla. PT represents a model of focal cerebral ischemia exhibiting acute vessel occlusion and delayed neuroinflammation. Methods/Principal Findings Perfluorocarbons (PFC) or superparamagnetic iron oxide particles (SPIO) were injected intravenously at different time points after photothrombotic infarction. While administration of PFC directly after PT induction led to a strong \(^{19}\)F signal throughout the entire lesion, two hours delayed application resulted in a rim-like \(^{19}\)F signal at the outer edge of the lesion. These findings closely resembled the distribution of signal loss on T2-weighted MRI seen after SPIO injection reflecting intravascular accumulation of iron particles trapped in vessel thrombi as confirmed histologically. By sequential administration of two chemically shifted PFC compounds 0 and 2 hours after illumination the different spatial distribution of the \(^{19}\)F markers (infarct core/rim) could be visualized in the same animal. When PFC were applied at day 6 the fluorine marker was only detected after long acquisition times ex vivo. SPIO-enhanced MRI showed slight signal loss in vivo which was much more prominent ex vivo indicative for neuroinflammation at this late lesion stage. Conclusion Our study shows that vessel occlusion can be followed in vivo by \(^{19}\)F and SPIO-enhanced high-field MRI while in vivo imaging of neuroinflammation remains challenging. The timing of contrast agent application was the major determinant of the underlying processes depicted by both imaging techniques. Importantly, sequential application of different PFC compounds allowed depiction of ongoing vessel occlusion from the core to the margin of the ischemic lesions in a single MRI measurement. KW - in vivo imaging KW - magnetic resonance imaging KW - macrophages KW - emulsions KW - infarction KW - fluorine KW - prefrontal cortex KW - developmental signaling Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137792 VL - 6 IS - 12 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Topuzoğlu, Tengü A1 - Schießer, Peter A1 - Hahnenkamp, Saskia A1 - Sommer, Claudia T1 - IL-4 Deficiency Is Associated with Mechanical Hypersensitivity in Mice JF - PLoS One N2 - Interleukin-4 (IL-4) is an anti-inflammatory and analgesic cytokine that induces opioid receptor transcription. We investigated IL-4 knockout (ko) mice to characterize their pain behavior before and after chronic constriction injury (CCI) of the sciatic nerve as a model for neuropathic pain. We investigated opioid responsivity and measured cytokine and opioid receptor gene expression in the peripheral and central nervous system (PNS, CNS) of IL-4 ko mice in comparison with wildtype (wt) mice. Naïve IL-4 ko mice displayed tactile allodynia (wt: 0.45 g; ko: 0.18 g; p<0.001), while responses to heat and cold stimuli and to muscle pressure were not different. No compensatory changes in the gene expression of tumor necrosis factor-alpha (TNF), IL-1β, IL-10, and IL-13 were found in the PNS and CNS of naïve IL-4 ko mice. However, IL-1β gene expression was stronger in the sciatic nerve of IL-4 ko mice (p<0.001) 28 days after CCI and only IL-4 ko mice had elevated IL-10 gene expression (p = 0.014). Remarkably, CCI induced TNF (p<0.01), IL-1β (p<0.05), IL-10 (p<0.05), and IL-13 (p<0.001) gene expression exclusively in the ipsilateral spinal cord of IL-4 ko mice. The compensatory overexpression of the anti-inflammatory and analgesic cytokines IL-10 and IL-13 in the spinal cord of IL-4 ko mice may explain the lack of genotype differences for pain behavior after CCI. Additionally, CCI induced gene expression of μ, κ, and δ opioid receptors in the contralateral cortex and thalamus of IL-4 ko mice, paralleled by fast onset of morphine analgesia, but not in wt mice. We conclude that a lack of IL-4 leads to mechanical sensitivity; the compensatory hyperexpression of analgesic cytokines and opioid receptors after CCI, in turn, protects IL-4 ko mice from enhanced pain behavior after nerve lesion. KW - mouse models KW - animal behavior KW - sciatic nerves KW - spinal cord KW - opioids KW - cytokines KW - gene expression KW - mice Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137924 VL - 6 IS - 12 ER - TY - JOUR A1 - Burlina, Alessandro P. A1 - Sims, Katherine B. A1 - Politei, Juan M. A1 - Bennett, Gary J. A1 - Baron, Ralf A1 - Sommer, Claudia A1 - Moller, Anette Torvin A1 - Hilz, Max J. T1 - Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel JF - BMC Neurology N2 - Background: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. Methods: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. Results: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e. g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. Conclusions: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate. KW - Enzyme replacement therapy KW - Quality of life KW - Small-fiber neuropathy KW - Rochester diabetic neuropathy KW - Randomized controlled trial KW - Agalsidase beta therapy KW - Outcome survey KW - Pharmacological management KW - Clinical manifestations KW - Alpha galactosidase KW - Diagnosis KW - Fabry KW - Disease KW - Neuropathy KW - Pain KW - Treatment Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135309 VL - 11 IS - 61 ER - TY - JOUR A1 - Weise, Gesa A1 - Stoll, Guido T1 - Magnetic resonance imaging of blood brain/nerve barrier dysfunction and leukocyte infiltration: closely related or discordant? JF - Frontiers in Neurology N2 - Unlike other organs the nervous system is secluded from the rest of the organism by the blood brain barrier (BBB) or blood nerve barrier (BNB) preventing passive influx of fluids from the circulation. Similarly, leukocyte entry to the nervous system is tightly controlled. Breakdown of these barriers and cellular inflammation are hallmarks of inflammatory as well as ischemic neurological diseases and thus represent potential therapeutic targets. The spatiotemporal relationship between BBB/BNB disruption and leukocyte infiltration has been a matter of debate. We here review contrast-enhanced magnetic resonance imaging (MRI) as a non-invasive tool to depict barrier dysfunction and its relation to macrophage infiltration in the central and peripheral nervous system under pathological conditions. Novel experimental contrast agents like Gadofluorine M (Gf) allow more sensitive assessment of BBB dysfunction than conventional Gadolinium (Gd)-DTPA enhanced MRI. In addition, Gf facilitates visualization of functional and transient alterations of the BBB remote from lesions. Cellular contrast agents such as superparamagnetic iron oxide particles (SPIO) and perfluorocarbons enable assessment of leukocyte (mainly macrophage) infiltration by MR technology. Combined use of these MR contrast agents disclosed that leukocytes can enter the nervous system independent from a disturbance of the BBB, and vice versa, a dysfunctional BBB/BNB by itself is not sufficient to attract inflammatory cells from the circulation. We will illustrate these basic imaging findings in animal models of multiple sclerosis, cerebral ischemia, and traumatic nerve injury and review corresponding findings in patients. KW - contrast-enhanced MRI KW - neuroinflammation KW - gadolinium-DTPA KW - gadofluorine KW - iron oxide nanoparticles KW - blood brain barrier Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123359 VL - 3 IS - 178 ER - TY - JOUR A1 - Hansen, Niels A1 - Seiler, Carola A1 - Rumpf, Julian A1 - Kraft, Peter A1 - Dlaske, Henry A1 - Abele-Horn, Marianne A1 - Muellges, Wolfgang T1 - Human Tuberculous Meningitis Caused by \(Mycobacterium\) \(caprae\) JF - Case Reports in Neurology N2 - INTRODUCTION: Tuberculous meningitis (TM) causes substantial morbidity and mortality in humans. Human TM has been known to be induced by bacteria from the Mycobacterium tuberculosis complex (MTBC), such as M. tuberculosis and M. bovis. CASE PRESENTATION: We describe a case of meningitis treated with fosfomycin, which showed partial effectiveness in an 80-year-old patient. After a lethal myocardial infarction, M. caprae (MC) was identified in cerebrospinal fluid culture. This isolated acid-fast organism was first identified as MTBC by MTBC-specific PCR (16S rDNA-PCR). Furthermore, species-specific identification of the isolate was done by gyrB PCR-restriction fragment length polymorphism analysis of a part of gyrB DNA. Colony morphology of the isolated MC strain showed dysgonic growth on Lowenstein-Jensen medium. The strain was susceptible to pyrazinamide (PZA). CONCLUSION: This isolated strain was convincingly identified as MC according to the phenotypic and genotypic characteristics and PZA sensitivity. This is the first report of MC causing TM. KW - Mycobacterium caprae KW - Mycobacterium caprae KW - fosfomycin KW - Tuberkulose KW - Mycobacterium tuberculosis complex KW - tuberculous meningitis KW - cerebrospinal fluid culture Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123425 VL - 4 IS - 1 ER - TY - JOUR A1 - Boltze, Johannes A1 - Kleinschnitz, Christoph A1 - Reymann, Klaus G. A1 - Reiser, Georg A1 - Wagner, Daniel-Christoph A1 - Kranz, Alexander A1 - Michalski, Dominik T1 - Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain – current trends in basic, translational and clinical research JF - Experimental & Translational Stroke Medicine N2 - The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood–brain barrier, recent findings regarding the pathomechanism of Alzheimer’s disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting. KW - translational research KW - small vessel disease KW - Alzheimer’s disease KW - cerebral ischemia KW - neurorepair KW - neuroprotection KW - vascular dementia KW - mitochondria KW - astrogliosis KW - in vivo imaging Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126679 VL - 4 IS - 14 ER - TY - JOUR A1 - Kraft, Peter A1 - De Meyer, Simon F. A1 - Kleinschnitz, Christoph T1 - Next-Generation Antithrombotics in Ischemic Stroke: Preclinical Perspective on ‘Bleeding-Free Antithrombosis’ JF - Journal of Cerebral Blood Flow and Metabolism N2 - The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIbα) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIbα and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed. KW - von Willebrand factor KW - platelets KW - glycoprotein Ib KW - FXII KW - coagulation KW - Stim Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126538 VL - 32 IS - 10 ER - TY - JOUR A1 - Langhauser, Friederike L. A1 - Heiler, Patrick M. A1 - Grudzenski, Saskia A1 - Lemke, Andreas A1 - Alonso, Angelika A1 - Schad, Lothar R. A1 - Hennerici, Michael G. A1 - Meairs, Stephen A1 - Fata, Marc T1 - Thromboembolic stroke in C57BL/6 mice monitored by 9.4 T MRI using a 1H cryo probe JF - Experimental and Translational Stroke Medicine N2 - Background A new thromboembolic animal model showed beneficial effects of t-PA with an infarct volume reduction of 36.8% in swiss mice. Because knock-out animal experiments for stroke frequently used C57BL76 mice we evaluated t-PA effects in this mouse strain and measured infarct volume and vascular recanalisation in-vivo by using high-field 9.4 T MRI and a 1H surface cryo coil. Methods Clot formation was triggered by microinjection of murine thrombin into the right middle cerebral artery (MCA). Animals (n = 28) were treated with 10 mg/kg, 5 mg/kg or no tissue plasminogen activator (t-PA) 40 min after MCA occlusion. For MR-imaging a Bruker 9.4 T animal system with a 1H surface cryo probe was used and a T2-weighted RARE sequence, a diffusion weighted multishot EPI sequence and a 3D flow-compensated gradient echo TOF angiography were performed. Results The infarct volume in animals treated with t-PA was significantly reduced (0.67 ± 1.38 mm3 for 10 mg/kg and 10.9 ± 8.79 mm3 for 5 mg/kg vs. 19.76 ± 2.72 mm3 ; p < 0.001) compared to untreated mice. An additional group was reperfused with t-PA inside the MRI. Already ten minutes after beginning of t-PA treatment, reperfusion flow was re-established in the right MCA. However, signal intensity was lower than in the contralateral MCA. This reduction in cerebral blood flow was attenuated during the first 60 minutes after reperfusion. 24 h after MCA occlusion and reperfusion, no difference in signal intensity of the contralateral and ipsilateral MCAs was observed. Conclusions We confirm a t-Pa effect using this stroke model in the C57BL76 mouse strain and demonstrate a chronological sequence MRI imaging after t-PA using a 1H surface cryo coil in a 9.4 T MRI. This setting will allow testing of new thrombolytic strategies for stroke treatment in-vivo in C57BL76 knock-out mice. KW - animal models KW - MRI KW - experimental KW - embolic stroke KW - T-PA Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124218 VL - 4 IS - 18 ER - TY - JOUR A1 - Horn, Michael A1 - Baumann, Reto A1 - Pereira, Jorge A. A1 - Sidiropoulos, Páris N. M. A1 - Somandin, Christian A1 - Welzl, Hans A1 - Stendel, Claudia A1 - Lühmann, Tessa A1 - Wessig, Carsten A1 - Toyka, Klaus V. A1 - Relvas, João B. A1 - Senderek, Jan A1 - Suter, Ueli T1 - Myelin is dependent on the Charcot–Marie–Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells JF - Brain N2 - Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot–Marie–Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4–Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4–Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies. KW - Frabin/Fgd4 KW - myelination KW - hereditary motor and sensory neuropathy KW - Charcot–Marie–Tooth disease KW - Rho-GTPase Cdc42 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125390 VL - 135 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Stetter, Christian A1 - Meuth, Sven G. A1 - Göbel, Kerstin A1 - Bader, Michael A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - Blocking of Bradykinin Receptor B1 Protects from Focal Closed Head Injury in Mice by Reducing Axonal Damage and Astroglia Activation JF - Journal of Cerebral Blood Flow and Metabolism N2 - The two bradykinin receptors B1R and B2R are central components of the kallikrein–kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration. KW - R-715 KW - kinin receptors KW - closed head injury KW - β-APP KW - astrocytes KW - TNF-α Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125903 VL - 32 IS - 9 ER - TY - JOUR A1 - Minnerup, Jens A1 - Sutherland, Brad A. A1 - Buchan, Alastair M. A1 - Kleinschnitz, Christoph T1 - Neuroprotection for Stroke: Current Status and Future Perspectives JF - International Journal of Molecular Science N2 - Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade. KW - free radical scavenger KW - ischemic cascade KW - acute ischemic stroke KW - trial KW - focal cerebral-ischemia KW - interleukin-1 receptor antagonist KW - colony-stimulating factor KW - tissue-plasminogen activator KW - traumatic brain injury KW - placebo-controlled KW - alias pilot trial KW - damage cool aid KW - neuroprotection KW - ischemic stroke KW - translation KW - STAIR Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134730 VL - 13 IS - 9 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Marzegan, Alberto A1 - Pezzoli, Gianni A1 - Marotta, Giorgio A1 - Canesi, Margherita A1 - Biella, Gabriele E. M. A1 - Volkmann, Jens A1 - Cavallari, Paolo T1 - A role for locus coeruleus in Parkinson tremor JF - Frontiers in Human Neuroscience N2 - We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease(PD), in 12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated by single photon computed tomography imaging (SPECT) with [\(^{123}\)I] N-\(\omega\)-fluoropropyl-2 \(\beta\)-carbomethoxy-3 \(\beta\)-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27), unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson tremor. KW - locus coeruleus KW - disease KW - basal ganglia KW - resting tremor KW - functional neuroanatomy KW - dopamine KW - norepinephrine KW - progression KW - binding KW - rat KW - noradrenalin KW - parkinson disease KW - tremor Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133955 VL - 5 IS - 179 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Volkmann, Jens A1 - Marzegan, Alberto A1 - Marotta, Giorgio A1 - Cavallari, Paolo A1 - Pezzoli, Gianni T1 - The Influence of Dopaminergic Striatal Innervation on Upper Limb Locomotor Synergies JF - PLoS One N2 - To determine the role of striatal dopaminergic innervation on upper limb synergies during walking, we measured arm kinematics in 13 subjects with Parkinson disease. Patients were recruited according to several inclusion criteria to represent the best possible in vivo model of dopaminergic denervation. Of relevance, we included only subjects with normal spatio-temporal parameters of the stride and gait speed to avoid an impairment of upper limbs locomotor synergies as a consequence of gait impairment per se. Dopaminergic innervation of the striatum was measured by FP-CIT and SPECT. All patients showed a reduction of gait-associated arms movement. No linear correlation was found between arm ROM reduction and contralateral dopaminergic putaminal innervation loss. Still, a partition analysis revealed a 80% chance of reduced arm ROM when putaminal dopamine content loss was >47%. A significant correlation was described between the asymmetry indices of the swinging of the two arms and dopaminergic striatal innervation. When arm ROM was reduced, we found a positive correlation between upper-lower limb phase shift modulation ( at different gait velocities) and striatal dopaminergic innervation. These findings are preliminary evidence that dopaminergic striatal tone plays a modulatory role in upper-limb locomotor synergies and upper-lower limb coupling while walking at different velocities. KW - pet KW - Parkinsons disease KW - basal ganglia KW - spinal-cord KW - walking KW - gait KW - arm KW - coordination KW - movements Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133976 VL - 7 IS - 12 ER - TY - JOUR A1 - Brandt, Alexander U. A1 - Zimmermann, Hanna A1 - Kaufhold, Falko A1 - Promesberger, Julia A1 - Schippling, Sven A1 - Finis, David A1 - Aktas, Orhan A1 - Geis, Christian A1 - Ringelstein, Marius A1 - Ringelstein, E. Bernd A1 - Hartung, Hans-Peter A1 - Paul, Friedemann A1 - Kleffner, Ilka A1 - Dörr, Jan T1 - Patterns of Retinal Damage Facilitate Differential Diagnosis between Susac Syndrome and MS JF - PLoS One N2 - Susac syndrome, a rare but probably underdiagnosed combination of encephalopathy, hearing loss, and visual deficits due to branch retinal artery occlusion of unknown aetiology has to be considered as differential diagnosis in various conditions. Particularly, differentiation from multiple sclerosis is often challenging since both clinical presentation and diagnostic findings may overlap. Optical coherence tomography is a powerful and easy to perform diagnostic tool to analyse the morphological integrity of retinal structures and is increasingly established to depict characteristic patterns of retinal pathology in multiple sclerosis. Against this background we hypothesised that differential patterns of retinal pathology facilitate a reliable differentiation between Susac syndrome and multiple sclerosis. In this multicenter cross-sectional observational study optical coherence tomography was performed in nine patients with a definite diagnosis of Susac syndrome. Data were compared with age-, sex-, and disease duration-matched relapsing remitting multiple sclerosis patients with and without a history of optic neuritis, and with healthy controls. Using generalised estimating equation models, Susac patients showed a significant reduction in either or both retinal nerve fibre layer thickness and total macular volume in comparison to both healthy controls and relapsing remitting multiple sclerosis patients. However, in contrast to the multiple sclerosis patients this reduction was not distributed over the entire scanning area but showed a distinct sectorial loss especially in the macular measurements. We therefore conclude that patients with Susac syndrome show distinct abnormalities in optical coherence tomography in comparison to multiple sclerosis patients. These findings recommend optical coherence tomography as a promising tool for differentiating Susac syndrome from MS. KW - optical coherence tomography KW - vasculopathy KW - artery occlusion KW - hearing loss KW - microangiopathy KW - brain KW - endotheliopathy KW - antibodies KW - multiple-sclerosis KW - retinocochleocerebral Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134013 VL - 7 IS - 6 ER - TY - JOUR A1 - Jarius, Sven A1 - Ruprecht, Klemens A1 - Wildemann, Brigitte A1 - Kuempfel, Tania A1 - Ringelstein, Marius A1 - Geis, Christian A1 - Kleiter, Ingo A1 - Kleinschnitz, Christoph A1 - Berthele, Achim A1 - Brettschneider, Johannes A1 - Hellwig, Kerstin A1 - Hemmer, Bernhard A1 - Linker, Ralf A. A1 - Lauda, Florian A1 - Hayrettin, Christoph A. A1 - Tumani, Hayrettin A1 - Melms, Arthur A1 - Trebst, Corinna A1 - Stangel, Martin A1 - Marziniak, Martin A1 - Hoffmann, Frank A1 - Schippling, Sven A1 - Faiss, Jürgen H. A1 - Neuhaus, Oliver A1 - Ettrich, Barbara A1 - Zentner, Christian A1 - Guthke, Kersten A1 - Hofstadt-van Oy, Ulrich A1 - Reuss, Reinhard A1 - Pellkofer, Hannah A1 - Ziemann, Ulf A1 - Kern, Peter A1 - Wandinger, Klaus P. A1 - Bergh, Florian Then A1 - Boettcher, Tobias A1 - Langel, Stefan A1 - Liebetrau, Martin A1 - Rommer, Paulus S. A1 - Niehaus, Sabine A1 - Münch, Christoph A1 - Winkelmann, Alexander A1 - Zettl, Uwe K A1 - Metz, Imke A1 - Veauthier, Christian A1 - Sieb, Jörn P. A1 - Wilke, Christian A1 - Hartung, Hans P. A1 - Aktas, Orhan A1 - Paul, Friedemann T1 - Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients JF - Journal of Neuroinflammation N2 - Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of <= 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades <= 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions >= 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. KW - cerebrospinal-fluid KW - intractable hiccup KW - extensiv transverse myelitis KW - multiple sclerosis KW - anti-aquaporin-4 antibody KW - NMO-IGG KW - aquaporin-4 autoantibodies KW - immune-response KW - myasthenia gravis KW - immunoglobulin-G Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133636 VL - 9 IS - 14 ER - TY - JOUR A1 - Brecht, Isabel A1 - Weissbrich, Benedikt A1 - Braun, Julia A1 - Toyka, Klaus Viktor A1 - Weishaupt, Andreas A1 - Buttmann, Mathias T1 - Intrathecal, Polyspecific Antiviral Immune Response in Oligoclonal Band Negative Multiple Sclerosis JF - PLoS One N2 - Background: Oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) in more than 95% of patients with multiple sclerosis (MS) in the Western hemisphere. Here we evaluated the intrathecal, polyspecific antiviral immune response as a potential diagnostic CSF marker for OCB-negative MS patients. Methodology/Principal Findings: We tested 46 OCB-negative German patients with paraclinically well defined, definite MS. Sixteen OCB-negative patients with a clear diagnosis of other autoimmune CNS disorders and 37 neurological patients without evidence for autoimmune CNS inflammation served as control groups. Antibodies against measles, rubella, varicella zoster and herpes simplex virus in paired serum and CSF samples were determined by ELISA, and virus-specific immunoglobulin G antibody indices were calculated. An intrathecal antibody synthesis against at least one neurotropic virus was detected in 8 of 26 (31%) patients with relapsing-remitting MS, 8 of 12 (67%) with secondary progressive MS and 5 of 8 (63%) with primary progressive MS, in 3 of 16 (19%) CNS autoimmune and 3 of 37 (8%) non-autoimmune control patients. Antibody synthesis against two or more viruses was found in 11 of 46 (24%) MS patients but in neither of the two control groups. On average, MS patients with a positive antiviral immune response were older and had a longer disease duration than those without. Conclusion: Determination of the intrathecal, polyspecific antiviral immune response may allow to establish a CSF-supported diagnosis of MS in OCB-negative patients when two or more of the four virus antibody indices are elevated. KW - MS KW - cerebrospinal fluid KW - differential diagnosis KW - nervous-system KW - criteria KW - serum Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134426 VL - 7 IS - 7 ER - TY - JOUR A1 - Ip, Chi Wang A1 - Kroner, Antje A1 - Groh, Janos A1 - Huber, Marianne A1 - Klein, Dennis A1 - Spahn, Irene A1 - Diem, Ricarda A1 - Williams, Sarah K. A1 - Nave, Klaus-Armin A1 - Edgar, Julia M. A1 - Martini, Rudolf T1 - Neuroinflammation by Cytotoxic T-Lymphocytes Impairs Retrograde Axonal Transport in an Oligodendrocyte Mutant Mouse JF - PLoS One N2 - Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage. KW - myelin KW - experimental autoimmune encephalomyelitis KW - degeneration KW - axonopathic changes KW - neural apoptosis KW - nervous system KW - motor function KW - proteolipid protein gene KW - retinal ganglion cells KW - granzyme B KW - multiple sclerosis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134982 VL - 7 IS - 8 ER - TY - JOUR A1 - Dupuis, Luc A1 - Dengler, Reinhard A1 - Heneka, Michael T. A1 - Meyer, Thomas A1 - Zierz, Stephan A1 - Kassubek, Jan A1 - Fischer, Wilhelm A1 - Steiner, Franziska A1 - Lindauer, Eva A1 - Otto, Markus A1 - Dreyhaupt, Jens A1 - Grehl, Torsten A1 - Hermann, Andreas A1 - Winkler, Andrea S. A1 - Bogdahn, Ulrich A1 - Benecke, Reiner A1 - Schrank, Bertold A1 - Wessig, Carsten A1 - Grosskreutz, Julian A1 - Ludolph, Albert C. T1 - A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis JF - PLoS One N2 - Background: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). Methods/Principal Findings: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. Conclusion/Significance: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. KW - ALS KW - transgenic mouse model KW - central nervous system KW - nonalcoholic steatohepatitis KW - PPAR-gamme KW - hexanucleotide repeat KW - disease progression KW - delays progression KW - SOD1 mutations KW - monocycline Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130255 VL - 7 IS - 6 ER - TY - JOUR A1 - Raslan, Furat A1 - Albert-Weißenberger, Christiane A1 - Westermaier, Thomas A1 - Saker, Saker A1 - Kleinschmitz, Christoph A1 - Lee, Jin-Yul T1 - A modified double injection model of cisterna magna for the study of delayed cerebral vasospasm following subarachnoid hemorrhage in rats N2 - Delayed cerebral vasospasm following subarachnoid hemorrhage (SAH) is a serious medical complication, characterized by constriction of cerebral arteries leading to varying degrees of cerebral ischemia. Numerous clinical and experimental studies have been performed in the last decades; however, the pathophysiologic mechanism of cerebral vasospasm after SAH still remains unclear. Among a variety of experimental SAH models, the double hemorrhage rat model involving direct injection of autologous arterial blood into the cisterna magna has been used most frequently for the study of delayed cerebral vasospasm following SAH in last years. Despite the simplicity of the technique, the second blood injection into the cisterna magna may result in brainstem injury leading to high mortality. Therefore, a modified double hemorrhage model of cisterna magna has been developed in rat recently. We describe here step by step the surgical technique to induce double SAH and compare the degree of vasospasm with other cisterna magna rat models using histological assessment of the diameter and cross-sectional area of the basilar artery KW - Medizin KW - Cerebral vasospasm KW - Cisterna magna KW - Double hemorrhage model KW - Rat KW - Subarachnoid Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76038 ER - TY - JOUR A1 - Kunze, Ekkehard A1 - Pham, Mirko A1 - Raslan, Furat A1 - Stetter, Christian A1 - Lee, Jin-Yul A1 - Solymosi, Laszlo A1 - Ernestus, Ralf-Ingo A1 - Hamilton Vince, Giles A1 - Westermaier, Thomas T1 - Value of Perfusion CT, Transcranial Doppler Sonography and Neurological Examination to detect delayed Vasospasm after aneurysmal Subarachnoid Hemorrhage [Research Article] N2 - Background If detected in time, delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) may be treated by balloon angioplasty or chemical vasospasmolysis in order to enhance cerebral blood flow (CBF) and protect the brain from ischemic damage. This study was conceived to compare the diagnostic accuracy of detailed neurological examination, Transcranial Doppler Sonography (TCD), and Perfusion-CT (PCT) to detect angiographic vasospasm. Methods The sensitivity, specificity, positive and negative predictive values of delayed ischemic neurological deterioration (DIND), pathological findings on PCT- maps, and accelerations of the mean flow velocity (MVF) were calculated. Results The accuracy of DIND to predict angiographic vasospasm was 0.88. An acceleration of MFV in TCD (>140 cm/s) had an accuracy of 0.64, positive PCT-findings of 0.69 with a higher sensitivity, and negative predictive value than TCD. Interpretation Neurological assessment at close intervals is the most sensitive and specific parameter for cerebral vasospasm. PCT has a higher accuracy, sensitivity and negative predictive value than TCD. If detailed neurological evaluation is possible, it should be the leading parameter in the management and treatment decisions. If patients are not amenable to detailed neurological examination, PCT at regular intervals is a helpful tool to diagnose secondary vasospasm after aneurysmal SAH. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76241 ER - TY - JOUR A1 - Westermaier, Thomas A1 - Stetter, Christian A1 - Raslan, Furat A1 - Vinc, Giles Hamilton A1 - Ernestus, Ralf-Ingo T1 - Brain edema formation correlates with perfusion deficit during the first six hours after experimental subarachnoid hemorrhage in rats N2 - Background: Severe brain edema is observed in a number of patients suffering from subarachnoid hemorrhage (SAH). Little is known about its pathogenesis and time-course in the first hours after SAH. This study was performed to investigate the development of brain edema and its correlation with brain perfusion after experimental SAH. Methods: Male Sprague–Dawley rats, randomly assigned to one of six groups (n = 8), were subjected to SAH using the endovascular filament model or underwent a sham operation. Animals were sacrificed 15, 30, 60, 180 or 360 minutes after SAH. Intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP) and bilateral local cerebral blood flow (LCBF) were continuously measured. Brain water content (BWC) was determined by the wet/dry-weight method. Results: After SAH, CPP and LCBF rapidly decreased. The decline of LCBF markedly exceeded the decline of CPP and persisted until the end of the observation period. BWC continuously increased. A significant correlation was observed between the BWC and the extent of the perfusion deficit in animals sacrificed after 180 and 360 minutes. Conclusions: The significant correlation with the perfusion deficit after SAH suggests that the development of brain edema is related to the extent of ischemia and acute vasoconstriction in the first hours after SAH. KW - Medizin KW - Subarachnoid hemorrhage KW - Cerebral blood flow KW - Brain ischemia KW - Brain edema KW - Animal models Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75765 ER - TY - RPRT A1 - Linker, Ralf, A. A1 - Meuth, Sven G. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Kleinschnitz, Christoph T1 - Report on the 4'th scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 2'nd - Nov. 4'th, 2012 [meeting report] N2 - From November 2nd - 4th 2012, the 4th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Again more than 60 participants, predominantly at the doctoral student or postdoc level, gathered to share their latest findings in the fields of neurovascular research, neurodegeneration and neuroinflammation. Like in the previous years, the symposium provided an excellent platform for scientific exchange and the presentation of innovative projects in the stimulating surroundings of the Brandenburg outback. This year’s keynote lecture on the pathophysiological relevance of neuronal networks was given by Christian Gerloff, Head of the Department of Neurology at the University Clinic of Hamburg-Eppendorf. Another highlight of the meeting was the awarding of the NEUROWIND e.V. prize for young scientists working in the field of experimental neurology. The award is donated by the Merck Serono GmbH, Darmstadt, Germany and is endowed with 20.000 Euro. This year the jury decided unanimously to adjudge the award to Michael Gliem from the Department of Neurology at the University Clinic of Düsseldorf (group of Sebastian Jander), Germany, for his outstanding work on different macrophage subsets in the pathogenesis of ischemic stroke published in the Annals of Neurology in 2012. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76407 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 - Schmid, Benedikt T1 - Relation between cerebral arterio-venous transit time and neuropsychological performance in patients with vascular dementia T1 - Beziehung zwischen zerebraler arterio-venöser Transitzeit und neuropsychologischer Testleistung bei Patienten mit vaskulärer Demenz N2 - Dementia, or any form of degenerative cognitive decline, is one of the major problems in present, and even more will be in future medicine. With Alzheimer's disease (AD) being the most prevalent, Vascular Dementia is the second most entity of dementing processes in the elderly. As diagnostic criteria are still imprecise and in many cases do not embrace early stages of the disease, recent studies have proposed more detailed classifications of the newly created condition Vascular Cognitive Impairment (VCI). Of all conditions subsumed under this term, subcortical small-vessel alterations are the most common cause for cognitive decline. The diagnosis of dementia / cognitive impairment is presently often made in late stages of the disease, when therapeutical options are poor. Thus, early detection of changes of the subcortical small vessels is desirable, when there is still time to identify and aggressively treat risk factors and underlying conditions like diabetes, hyper- or hypotension, and hyperlipidemia. This study aimed to evaluate whether cTT correlates to cognitive dysfunction, i.e. if cTT is fit as an early diagnostic tool for VCI. The study cohort included 38 patients from the Neurological Clinic of the Würzburg University hospital admitted due to diagnoses other than dementia or stroke. As a result of this study it turned out that cTT is certainly capable of fulfilling the task to easily and effectively detect and evaluate possible microvascular lesions of the brain with respect to the actual clinical relevance for the patient. When compared to the other proposed diagnostic tools, neuropsychological testing and MRI, the advantages of cTT are obvious: its measurement is a low-cost and quick procedure which would spare both patients and examiners a long neuropsychological exam or complement it. cTT is safe to assess as the only possible risks derive from the use of the contrast agent, which are rare and easily manageable. It has also proven to be more accurate in showing the extent of cognitive impairment than MRI. Finally, it is widely available. The only prerequisite is an ultrasound machine capable of transcranial color-coded duplex sonography. No cost-intensive procedures like MRI are needed. So, with neuropsychological testing remaining the gold standard, cTT here proved to be a reliable alternative which is more time- and cost-effective than MRI. N2 - Demenzen und alle anderen Formen kongnitiver Leistungseinschränkungen gehören heute zu den bedeutendsten medizinischen Herausforderungen und werden in der Zukunft noch weiter an Bedeutung gewinnen. Die häufigste der Demenzerkrankungen bei älteren Patienten ist die Alzheimer-Krankheit, gefolgt von den vaskulären Demenzen. Da die Diagnosekriterien in vielen Fällen noch unpräzise sind und vor allem frühe Stadien der Erkrankung nicht erfassen, wurden in der neueren Literatur detailliertere Untergruppen der neu eingeführten Entität „vaskuläre kognitive Funktionsstörung“ (vascular cognitive impairment, VCI) etabliert. Subkortikale Veränderungen an den kleinsten Gefäßen stellen unter allen Pathologien, die unter diesem Begriff subsumiert sind, die häufigste Ursache für kognitive Leistungseinschränkungen dar. Die Diagnose Demenz bzw. VCI wird oft erst in späten Stadien der Krankheit gestellt, wenn die therapeutischen Mittel bereits stark begrenzt sind. Deshalb wäre eine Möglichkeit zur frühen Entdeckung subkortikaler Gefäßveränderungen wünschenswert in einem Stadium der Krankheit, in dem es noch möglich ist, Risikofaktoren wie Diabetes mellitus, arterielle Hyper- und Hypotonie und Fettstoffwechselstörungen auszumachen und konseqeuent zu behandeln. Das Ziel dieser Studie war es zu untersuchen, ob cTT mit dem Ausmaß kognitiver Dysfunktion korreliert, ob also cTT als frühes diagnostisches Verfahren für vaskuläre demenzielle Prozesse geeignet ist. Die Studienpopulation umfasste 38 Patienten aus der Klinik und Poliklinik für Neurologie der Universität Würzburg. Ein Ergebnis dieser Studie ist, dass die cTT sicherlich in der Lage ist, einfach und zuverlässig mögliche mikrovaskuläre Schädigungen des Gehirns auch im Hinblick auf ihre tatsächliche klinische Relevanz zu entdecken. Im Vergleich mit anderen Diagnoseverfahren (Testpsychologie und MRT) sind die Vorteile der cTT offensichtlich: die Messung ist ein kostengünstiges und schnelles Verfahren, das sowohl Patienten als auch Untersuchern eine langwierige neuropsychologische Untersuchung erspart. Die Messung der cTT ist ein sicheres Verfahren, da die wenigen aus der Anwendung des Kontrastmittels sich ergebenden Risiken selten und gegebenenfalls leicht behandelbar sind. Zudem erwies sich die cTT als präziser bei der Aufgabe, das Ausmaß kognitiver Dysfunktion zu messen, als es die MRT vermochte. Zuletzt ist die cTT auch flächendeckend verfügbar. Die einzige Voraussetzung ist ein Duplex-fähiges Ultraschallgerät. Kostenintesive Untersuchungen wie die MRT können vermieden werden. Wenn auch die Testpsychologie der Goldstandard bleiben wird, erwies sich die cTT als zuverlässige Alternative die im Vergleich zur MRT sowohl Zeit als auch Kosten spart. KW - Demenz KW - Psychologische Diagnostik KW - Neuropsychologie KW - Ultraschall KW - Ultraschalldiagnostik KW - dementia KW - neuropsychology KW - ultrasound Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71234 ER - TY - THES A1 - Topuzoglu, Tengü Gülsüm T1 - Charakterisierung von IL-4 Knockout-Mäusen und ihrer Zytokin- und Opioidrezeptor-Expression im peripheren und zentralen Nervensystem T1 - Characterization of IL-4 knockout-mice and their cytokine- and opioidreceptor gene expression in the peripheral and central nervous system N2 - In der vorliegenden Arbeit wurde der Einfluss eines Mangels des antiinflammatorischen Zytokins Interleukin(IL)-4 am Tiermodell einer experimentellen Mononeuropathie (engl. chronic constriction injury, CCI) untersucht. Zentrale Fragestellung der Studie war, ob IL-4 knockout(ko)-Mäuse im Vergleich zu Wildtyp(wt)-Mäusen mit einem gesteigerten Schmerzverhalten sowie einer veränderten Zytokinantwort und Opioidrezeptor-Expression nach Anwendung eines neuropathischen Schmerzmodells (CCI) reagieren. In mehreren Tierstudien war zuvor eine antiinflammatorische und analgetische Wirkung von IL-4 belegt worden (Vale et al. 2003; Hao et al. 2006) und in klinischen Studien war ein verminderter IL-4-Spiegel bei Patienten mit verschiedenen neuropathischen Schmerzsyndromen mit einer gesteigerten Schmerzempfindung verbunden (Üçeyler et al. 2006; Üçeyler et al. 2007b). Da IL-4 die Transkription von Opioidrezeptoren induziert (Kraus et al. 2001; Börner et al. 2004), wurde zudem das Ansprechen von IL-4 ko-Mäusen auf Morphin und die Genexpression zentraler Opioidrezeptoren untersucht. Vor sowie bis vier Wochen nach Durchführung einer CCI wurden IL-4 ko- sowie wt- Mäuse hinsichtlich ihrer Empfindlichkeit auf mechanische und thermische Stimuli analysiert. Zum Zeitpunkt des Schmerzmaximums nach CCI (Tag 7 bis 9) wurde zudem das Ansprechen beider Genotypen auf Morphin untersucht. Die Genexpression pro- (IL-1 beta, TNF) und antiinflammatorischer Zytokine (IL-10, IL- 13) im peripheren (N. ischiadicus) und zentralen Nervensystem (lumbales und zervikales Rückenmark, Pons, Thalamus, Hypothalamus, Striatum, Kortex) sowie die Genexpression zentraler Opioidrezeptoren (mü-OR, delta-OR, kappa-OR) wurde bei beiden Genotypen vor sowie vier Wochen nach CCI mittels Real-Time-PCR bestimmt. Unbehandelte IL-4 ko-Mäuse zeigten im Vergleich zu wt-Mäusen bereits vor Durchführung einer CCI eine mechanische Überempfindlichkeit (Hyperalgesie), was möglicherweise durch die bei IL-4-Mangel fehlenden zentralen inhibitorischen Mechanismen bedingt ist. Nach CCI entwickelten sowohl IL-4 ko- als auch wt-Mäuse eine gleich ausgeprägte mechanische und thermische Hyperalgesie. Die Tatsache, dass die mechanische Überempfindlichkeit bei IL-4 ko-Mäusen nach Nervenläsion nicht überproportional steigt, kann Ausdruck der nachgewiesenen kompensatorisch stärker ausgeprägten Genexpression proinflammatorischer, aber insbesondere auch antiinflammatorischer Zytokine in diesem Genotyp sein. Nur bei IL-4 ko-Mäusen war vier Wochen nach CCI die Genexpression der anti- inflammatorischen Zytokine im N. ischiadicus (IL-10) und ipsilateralen Rückenmark (IL-10, IL-13), jedoch auch die der proinflammatorischen Zytokine im ipsilateralen Rückenmark (TNF, IL-1 beta) erhöht. Nach CCI sprachen IL-4 ko-Mäuse schneller auf Morphingabe an als wt-Mäuse, was durch den bei diesem Genotyp stärker ausgeprägten Anstieg der Genexpression der Opioidrezeptortypen delta-OR und kappa-OR im kontralateralen Thalamus bedingt sein kann. N2 - In this study the pain behavior of IL-4 knockout (ko) mice was characterized before and after chronic constriction injury (CCI) of the sciatic nerve as an established model for neuropathic pain. The opioid responsivity of IL-4 ko-mice was tested and four weeks after CCI the cytokine and opioid receptor gene expression in the peripheral and central nervous system of IL-4 ko mice was measured compared to wildtype (wt) mice. Before CCI IL-4 ko mice showed tactile allodynia, while responses to heat did not differ in comparison to wt-mice. No compensatory changes in the gene expression of the measured cytokines (tumor necrosis factor-alpha (TNF), IL-1b, IL-10, and IL-13) were found in the PNS and CNS of na ̈ıve IL-4 ko mice. Four weeks after CCI IL-1b gene expression was stronger in the sciatic nerve of IL-4 ko mice (p,0.001) and only IL-4 ko mice had elevated IL-10 gene expression in the sciatic nerve. Only in IL-4 ko-mice there was an upregulated gene expression four weeks after CCI of TNF (p,0.01), IL-1b (p,0.05), IL-10 (p,0.05), and IL-13 (p,0.001) in the ipsilateral spinal cord. The compensatory overexpression of the anti-inflammatory cytokines IL-10 and IL-13 in the spinal cord of IL-4 ko mice may explain the lack of genotype differences for pain behavior after CCI. CCI upregulated gene expression of k, and d opioid receptors in the contralateral thalamus of IL-4 ko mice, in accordance with an observed fast onset of morphine analgesia compared to wt mice. KW - Neuralgie KW - Interleukin-4 KW - Zytokin KW - Opioidrezeptor KW - Genexpression KW - Neuropathischer Schmerz KW - Interleukin-4 KW - cytokine KW - opioidreceptor KW - mRNA expression KW - mice Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-72372 ER - TY - JOUR A1 - Albert-Weißenberger, Christiane A1 - Várrallyay, Csanád A1 - Raslan, Furat A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena T1 - An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice N2 - Traumatic brain injury (TBI) is a result of an outside force causing immediate mechanical disruption of brain tissue and delayed pathogenic events. In order to examine injury processes associated with TBI, a number of rodent models to induce brain trauma have been described. However, none of these models covers the entire spectrum of events that might occur in TBI. Here we provide a thorough methodological description of a straightforward closed head weight drop mouse model to assess brain injuries close to the clinical conditions of human TBI. KW - Medizin KW - closed head injury KW - traumatic brain injury KW - neurobehavioural deficits KW - astrocyte KW - microglia KW - neurons Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75368 ER - TY - JOUR A1 - Kleinschnitz, Christph A1 - Meuth, Sven G. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Linker, Ralf A. T1 - Report on the 3'rd scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 4'th - Nov. 6'th, 2011 N2 - From November 4th- 6th 2011, the 3rd NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Like in the previous years, the meeting provided an excellent platform for scientific exchange and the presentation of innovative projects for young colleagues in the fields of neurovascular research, neuroinflammation and neurodegeneration. As kick-off to the scientific sessions, Reinhard Hohlfeld, Head of the Institute for Clinical Neuroimmunology in Munich, gave an illustrious overview on the many fascinations of neuroimmunologic research. A particular highlight on the second day of the meeting was the award of the 1’st NEUROWIND e.V. prize for young academics in the field of experimental neurology. This award is posted for young colleagues under the age of 35 with a significant achievement in the field of neurovascular research, neuroinflammation or neurodegeneration and comprises an amount of 20.000 Euro, founded by Merck Serono GmbH, Darmstadt. Germany. The first prize was awarded to Ivana Nikic from Martin Kerschensteiner’s group in Munich for her brilliant work on a reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis, published in Nature Medicine in 2011. This first prize award ceremony was a great incentive for the next call for proposals now upcoming in 2012. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75388 ER - TY - THES A1 - Patzkó, Ágnes T1 - CSF-1 receptor as a target for the treatment of Charcot-Marie-Tooth disease 1 T1 - CSF-1 Rezeptor als Target für die Behandlung der Charcot-Marie-Tooth Krankheit Typ 1 N2 - Previous studies by our group revealed that chronic low grade inflammation implicating phagocytosing macrophages is a highly relevant mechanism in the pathogenesis of Charcot-Marie-Tooth disease. The lack of CSF-1, the primary regulator of macrophage function and survival, led to a robust and persistent amelioration of the phenotype in two authentic mouse models of CMT. Moreover, a close contact between CSF-1 producing fibroblasts and endoneurial macrophages carrying CSF-1R has been confirmed in nerve biopsies of CMT patients, further supporting the clinical significance of this pathway. In the current study we treated 3 distinct mouse models of CMT1: the PMP22tg mice as a model for CMT1A, the P0+/- mice as a model for CMT1B and the Cx32def mice as a model for CMT1X, with a CSF-1R specific kinase (c-FMS) inhibitor (800-1200 mg PLX5622/ kg chow) according to different treatment regimes mimicking an ideal early onset treatment, a late onset treatment and the withdrawal of the drug. Using the above mentioned doses of PLX5622, we documented a dramatic decrease in macrophage numbers in the PNS of all 3 myelin mutants, except for the quadriceps nerve of Cx32def mice. Fibroblast numbers remained unchanged in treated animals. Surprisingly, in spite of the decrease in the number of detrimental macrophages we could not detect an unequivocal phenotypic improvement. CMAP amplitudes were reduced in both wild type and myelin mutant mice treated with CSF-1R inhibitor in comparison to untreated littermates. Corresponding to the electrophysiological findings, the axon number and the percentage of large diameter axons were reduced in the quadriceps nerve of treated P0+/- and Cx32def mice. By contrast we observed a higher number of fully myelinated axons, in parallel with a decrease in the percentage of demyelinated (and hypermyelinated in PMP22tg mice) fibers in the ventral roots of P0+/- mice treated with CSF-1R inhibitor from 3 months up to 6 months of age and PMP22tg animals treated from 9 months up to 15 months of age. Our results indicate that CSF-1R inhibitor has the potential to improve the demyelinating phenotype of at least two models of CMT1. Nevertheless, further studies are necessary (for example with lower doses of the inhibitor) to minimize or even eliminate the putative neurotoxic effect we observed with high dose treatment conditions. N2 - Vorhergehende Studien unserer Gruppe haben gezeigt, dass eine niedriggradige Entzündung, die von phagozytierenden Makrophagen ausgeht, von ausserordentlicher Bedeutung für die Pathogenese der Charcot-Marie-Tooth Krankheit ist. In Abwesenheit von CSF-1, des primären Regulators für Funktion und Überleben von Makrophagen, trat eine stabile und dauerhafte Verbesserung des Phänotyps in den zwei etablierten CMT Mausmodellen auf. Darüber hinaus konnte ein enger Kontakt zwischen CSF-1-produzierenden Fibroblasten und Makrophagen, die den zugehörigen Rezeptor CSF-1Rexprimieren, in Nervbiopsien von CMT Patienten bestätigt werden, was die klinische Relevanz dieses Mechanismus weiter verdeutlicht. In der aktuellen Studie wurden drei verschiedene CMT1 Mausmodelle, PMP22tg Mäuse als Modell für CMT1A, P0+/- Mäuse als Modell für CMT1B und Cx32-defiziente Mäuse als Modell für CMT1X, mit einem Inhibitor der CSF-1R spezifischen Kinase (c-FMS) (800-1200 mg PLX5622/kg Futter) behandelt. Der Inhibitor wurde gemäß den verschiedenen Behandlungsmethoden eingesetzt, um den Verlauf eineridealerweise frühzeitigen und einer spät-beginnenden Behandlung und des Entzug des Medikaments zu imitieren. Nach der Behandlung mit PLX5622 konnten wir im PNS aller drei Myelin-Mutanten, mit Ausnahme des N. quadriceps von Cx32-defizienten Mäusen, einen drastischen Rückgang der Makrophagenanzahl feststellen. Die Anzahl der Fibroblasten blieb in den behandelten Tieren unverändert. Überraschenderweise konnten wir, trotz des Rückgangs der Anzahl an schädlichen Makrophagen, keine einheitliche Verbesserung des Phänotyps dokumentieren. CMAP Amplituden waren nach CSF-1R Inhibitor Behandlung sowohl in Wild-Typ Mäusenals auch in den Myelin-Mutanten geringer als in unbehandelten Kontrolltieren. Passend zu den elektrophysiologischen Ergebnissen war die Anzahl an Axonen und die Prozentzahl an großkalibrigen Axonen im N. quadriceps von behandelten P0+/- und Cx32-defizienten Mäusen reduziert.Im Gegensatz dazu war eine erhöhte Menge an normalmyelinisierten Axonen, mit einer gleichzeitigen Reduktiondemyelinisierter Fasern (und hypermyelinisierten in PMP22tg Mäusen) in den ventralen Spinalwurzeln von P0+/- Mäusen zu beobachten, die mit dem CSF-1R Inhibitor im Alter von 3 bis 6 Monaten behandelt worden waren sowie bei PMP22tg Mäusen, die im Alter von 9 bis 15 Monaten den Inhibitor erhalten hatten. Unsere Ergebnisse deuten an, dass der CSF-1R Inhibitor das Potential besitzt, zumindest in zwei Modellen von CMT1 den demyelinisierenden Phänotyp zu verbessern. Dennoch müssen weitere Studien durchgeführt werden (z.B. die Verwendung einer niedrigeren Dosis des Inhibitors), um den möglichen neurotoxischen Effekt, der bei oben genannten Behandlungsbedingungen zu beobachten war, zu minimieren oder ganz zu beheben. KW - Makrophage KW - Charcot-Marie-Tooth KW - Charcot-Marie-Tooth disease KW - Myelin KW - CSF-1 Rezeptor KW - Neuropathie KW - macrophage KW - CSF-1 receptor KW - neuropathy KW - myelin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-85325 ER - TY - JOUR A1 - Kress, Michaela A1 - Hüttenhofer, Alexander A1 - Landry, Marc A1 - Kuner, Rohini A1 - Favereaux, Alexandre A1 - Greenberg, David A1 - Bednarik, Josef A1 - Heppenstall, Paul A1 - Kronenberg, Florian A1 - Malcangio, Marzia A1 - Rittner, Heike A1 - Üçeyler, Nurcan A1 - Trajanoski, Zlatko A1 - Mouritzen, Peter A1 - Birklein, Frank A1 - Sommer, Claudia A1 - Soreq, Hermona T1 - microRNAs in nociceptive circuits as predictors of future clinical applications JF - Frontiers in Molecular Neuroscience N2 - Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs – and microRNAs (miRNAs) in particular – regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals. KW - chronic pain KW - biomarker KW - polymorphism KW - miRNA-based diagnostics KW - miRNA expression patterns KW - miRNA polymorphisms KW - antagomir KW - miRNA-based analgesic Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154597 VL - 6 IS - 33 ER - TY - JOUR A1 - Ablin, Jacob A1 - Fitzcharles, Mary-Ann A1 - Buskila, Dan A1 - Shir, Yoram A1 - Sommer, Claudia A1 - Häuser, Winfried T1 - Treatment of Fibromyalgia Syndrome: Recommendations of Recent Evidence-Based Interdisciplinary Guidelines with Special Emphasis on Complementary and Alternative Therapies JF - Evidence-Bayed Complementary and Alternative Medicine N2 - Objective. Current evidence indicates that there is no single ideal treatment for fibromyalgia syndrome (FMS). First choice treatment options remain debatable, especially concerning the importance of complementary and alternative medicine (CAM) treatments. Methods. Three evidence-based interdisciplinary guidelines on FMS in Canada, Germany, and Israel were compared for their first choice and CAM-recommendations. Results. All three guidelines emphasized a patient-tailored approach according to the key symptoms. Aerobic exercise, cognitive behavioral therapy, and multicomponent therapy were first choice treatments. The guidelines differed in the grade of recommendation for drug treatment. Anticonvulsants (gabapentin, pregabalin) and serotonin noradrenaline reuptake inhibitors (duloxetine, milnacipran) were strongly recommended by the Canadian and the Israeli guidelines. These drugs received only a weak recommendation by the German guideline. In consideration of CAM-treatments, acupuncture, hypnosis/guided imagery, and Tai Chi were recommended by the German and Israeli guidelines. The Canadian guidelines did not recommend any CAM therapy. Discussion. Recent evidence-based interdisciplinary guidelines concur on the importance of treatment tailored to the individual patient and further emphasize the need of self-management strategies (exercise, and psychological techniques). KW - metaanalysis KW - management KW - care Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122235 SN - 1741-427X ER - TY - JOUR A1 - Walter, Maggie C. A1 - Reilich, Peter A1 - Thiele, Simone A1 - Schessl, Joachim A1 - Schreiber, Herbert A1 - Reiners, Karlheinz A1 - Kress, Wolfram A1 - Müller-Reible, Clemens A1 - Vorgerd, Matthias A1 - Urban, Peter A1 - Schrank, Bertold A1 - Deschauer, Marcus A1 - Schlotter-Weigel, Beate A1 - Kohnen, Ralf A1 - Lochmüller, Hans T1 - Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial JF - Orphanet Journal of Rare Diseases N2 - Background: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). Methods: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences. Results: During one year of natural course, muscle strength declined about 2% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects. Conclusion: Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with dysferlinopathy, who may be often misdiagnosed as polymyositis. KW - Deflazacort KW - muscle strength KW - gridle muscular-dystrophy KW - Duchenne dystrphy KW - Miyoshi myopathy KW - mutation KW - prednisone KW - gene KW - 2B KW - children KW - design KW - steroids KW - therapy KW - dysferlinopathy KW - Limb girdle muscular dystrophy (LGMD) Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125663 SN - 1750-1172 VL - 8 IS - 26 ER - TY - JOUR A1 - Karle, Kathrin N. A1 - Schüle, Rebecca A1 - Klebe, Stephan A1 - Otto, Susanne A1 - Frischholz, Christian A1 - Liepelt-Scarfone, Inga A1 - Schöls, Ludger T1 - Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP) JF - Orphanet Journal of Rare Diseases N2 - Background: Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. Methods: We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. Results: Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. Conclusions: Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials. KW - motor evoked potential (MEP) KW - amyotrophic-lateral-sclerosis KW - somatosensory-evoked-potentials KW - Silver-syndrome KW - gene mutations KW - SPG4 KW - mouse model KW - ALSIN gene KW - neuropathy KW - paraparesis KW - protein KW - electrophysiology KW - hereditary spastic paraplegia (HSP) Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124763 SN - 1750-1172 VL - 8 IS - 158 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 - Volkmann, Jens A1 - Albanese, Alberto A1 - Antonini, Angelo A1 - Chaudhuri, K. Ray A1 - Clarke, Karl E. A1 - de Bie, Rob M. A. A1 - Deuschl, Günther A1 - Eggert, Karla A1 - Houeto, Jean-Luc A1 - Kulisevsky, Jaime A1 - Nyholm, Dag A1 - Odin, Per A1 - Ostergaard, Karen A1 - Poewe, Werner A1 - Pollak, Pierre A1 - Rabey, Jose Martin A1 - Rascol, Olivier A1 - Ruzicka, Evzen A1 - Samuel, Michael A1 - Speelman, Hans A1 - Sydow, Olof A1 - Valldeoriola, Francesc A1 - van der Linden, Chris A1 - Oertel, Wolfgang T1 - Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review JF - Journal of Neurology N2 - Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine. KW - Parkinson’s disease KW - apomorphine KW - deep brain stimulation KW - duodenal levodopa infusion Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132373 VL - 260 ER - TY - JOUR A1 - Ehling, Petra A1 - Göb, Eva A1 - Bittner, Stefan A1 - Budde, Thomas A1 - Ludwig, Andreas A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice? JF - Experimental & Translational Stroke Medicine N2 - Background Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing \(I_h\), stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts. Methods In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays. Results After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups. Conclusions Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model. KW - ischemia Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131887 VL - 5 IS - 16 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 - JOUR A1 - Fluri, Felix A1 - Heinen, Florian A1 - Kleinschnitz, Christoph T1 - Intravenous Thrombolysis in a Stroke Patient Receiving Rivaroxaban JF - Cerebrovascular Disease Extra N2 - No abstract available. KW - anticoagulants KW - intravenous thrombolysis KW - acute ischemic stroke Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128816 VL - 2013 IS - 3 ER - TY - JOUR A1 - Linker, Ralf A. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Report on the 5‘th scientific meeting of the “Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie” (NEUROWIND e.V.) held in Motzen, Germany, Oct. 25th – Oct. 27th, 2013 JF - Experimental & Translational Stroke Medicine N2 - From october 25th - 27th 2013, the 5th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. This year more than 60 doctoral students and postdocs from over 25 different groups working in German university hospitals or research institutes attended the meeting to discuss their latest findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. All participants appreciated the stimulating environment in Motzen, Brandenburg, and people took the opportunity for scientific exchange, discussion about ongoing projects and already started further collaborations. Like in the previous years, the symposium was regarded as a very well organized platform to support research of young investigators in Germany. According to the major aim of NEUROWIND e.V. to support younger researchers in Germany the 3rd NEUROWIND YOUNG SCIENTIST AWARD for experimental neurology was awarded to Ruth Stassart working in the group of Klaus Armin Nave and Wolfgang Brück (MPI Göttingen and Department of Neuropathology, Göttingen Germany). The successful work was published in Nature Neuroscience entitled “A role for Swann cell-derived neuregulin-1 in remyelination”. This outstanding paper deals with the function of Schwann cell neuregulin as an endogenous factor for myelin repair. The award is endowed with 20.000 Euro sponsored by Merck Serono GmbH, Darmstadt, Germany (unrestricted educational grant). This year’s keynote lecture was given by Albert Ludolph, Head of the Department of Neurology at the University Clinic of Ulm. Dr. Ludolph highlighted the particular role of individual scientists for the development of research concepts in Alzheimer´s disease (AD) and frontotemporal dementia (FTD). KW - NEUROWIND Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129230 VL - 5 IS - 15 ER - TY - JOUR A1 - Ehling, Petra A1 - Göb, Eva A1 - Bittner, Stefan A1 - Budde, Thomas A1 - Ludwig, Andreas A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice? JF - Experimental & Translational Stroke Medicine N2 - Background Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing Ih, stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts. Methods In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays. Results After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups. Conclusions Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model. KW - neurology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129240 VL - 5 IS - 16 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Mencl, Stine A1 - Garz, Cornelia A1 - Niklass, Solveig A1 - Braun, Holger A1 - Göb, Eva A1 - Homola, György A1 - Heinze, Hans-Jochen A1 - Reymann, Klaus G. A1 - Schreiber, Stefanie T1 - Early microvascular dysfunction in cerebral small vessel disease is not detectable on 3.0 Tesla magnetic resonance imaging: a longitudinal study in spontaneously hypertensive stroke-prone rats JF - Experimental & Translational Stroke Medicine N2 - Background Human cerebral small vessel disease (CSVD) has distinct histopathologic and imaging findings in its advanced stages. In spontaneously hypertensive stroke-prone rats (SHRSP), a well-established animal model of CSVD, we recently demonstrated that cerebral microangiopathy is initiated by early microvascular dysfunction leading to the breakdown of the blood–brain barrier and an activated coagulatory state resulting in capillary and arteriolar erythrocyte accumulations (stases). In the present study, we investigated whether initial microvascular dysfunction and other stages of the pathologic CSVD cascade can be detected by serial magnetic resonance imaging (MRI). Findings Fourteen SHRSP and three control (Wistar) rats (aged 26–44 weeks) were investigated biweekly by 3.0 Tesla (3 T) MRI. After perfusion, brains were stained with hematoxylin–eosin and histology was correlated with MRI data. Three SHRSP developed terminal CSVD stages including cortical, hippocampal, and striatal infarcts and macrohemorrhages, which could be detected consistently by MRI. Corresponding histology showed small vessel thromboses and increased numbers of small perivascular bleeds in the infarcted areas. However, 3 T MRI failed to visualize intravascular erythrocyte accumulations, even in those brain regions with the highest densities of affected vessels and the largest vessels affected by stases, as well as failing to detect small perivascular bleeds. Conclusion Serial MRI at a field strength of 3 T failed to detect the initial microvascular dysfunction and subsequent small perivascular bleeds in SHRSP; only terminal stages of cerebral microangiopathy were reliably detected. Further investigations at higher magnetic field strengths (7 T) using blood- and flow-sensitive sequences are currently underway. KW - Cerebral small vessel disease KW - SHRSP KW - MRI Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97056 UR - http://www.etsmjournal.com/content/5/1/8 ER -