@article{BellutPappBieberetal.2022, author = {Bellut, Maximilian and Papp, Lena and Bieber, Michael and Kraft, Peter and Stoll, Guido and Schuhmann, Michael K.}, title = {NLPR3 inflammasome inhibition alleviates hypoxic endothelial cell death in-vitro and protects blood-brain barrier integrity in murine stroke}, series = {Cell Death \& Disease}, volume = {13}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-021-04379-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265693}, year = {2022}, abstract = {In ischemic stroke (IS) impairment of the blood-brain barrier (BBB) has an important role in the secondary deterioration of neurological function. BBB disruption is associated with ischemia-induced inflammation, brain edema formation, and hemorrhagic infarct transformation, but the underlying mechanisms are incompletely understood. Dysfunction of endothelial cells (EC) may play a central role in this process. Although neuronal NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome upregulation is an established trigger of inflammation in IS, the contribution of its expression in EC is unclear. We here used brain EC, exposed them to oxygen and glucose deprivation (OGD) in vitro, and analyzed their survival depending on inflammasome inhibition with the NLRP3-specific drug MCC950. During OGD, EC death could significantly be reduced when targeting NLRP3, concomitant with diminished endothelial NLRP3 expression. Furthermore, MCC950 led to reduced levels of Caspase 1 (p20) and activated Gasdermin D as markers for pyroptosis. Moreover, inflammasome inhibition reduced the secretion of pro-inflammatory chemokines, cytokines, and matrix metalloproteinase-9 (MMP9) in EC. In a translational approach, IS was induced in C57Bl/6 mice by 60 mins transient middle cerebral artery occlusion and 23 hours of reperfusion. Stroke volume, functional outcome, the BBB integrity, and-in good agreement with the in vitro results-MMP9 secretion as well as EC survival improved significantly in MCC950-treated mice. In conclusion, our results establish the NLRP3 inflammasome as a critical pathogenic effector of stroke-induced BBB disruption by activating inflammatory signaling cascades and pyroptosis in brain EC.}, language = {en} } @article{VogtKollikowskiWeidneretal.2022, author = {Vogt, Marius L. and Kollikowski, Alexander M. and Weidner, Franziska and Strinitz, Marc and Feick, J{\"o}rn and Essig, Fabian and Neugebauer, Herrmann and Haeusler, Karl Georg and Pham, Mirko and Maerz, Alexander}, title = {Safety and Effectiveness of the New Generation APERIO® Hybrid Stent-retriever Device in Large Vessel Occlusion Stroke}, series = {Clinical Neuroradiology}, volume = {32}, journal = {Clinical Neuroradiology}, number = {1}, doi = {10.1007/s00062-021-01122-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-264817}, pages = {141-151}, year = {2022}, abstract = {Background It is unknown whether technological advancement of stent-retriever devices influences typical observational indicators of safety or effectiveness. Methods Observational retrospective study of APERIO® (AP) vs. new generation APERIO® Hybrid (APH) (Acandis®, Pforzheim, Germany) stent-retriever device (01/2019-09/2020) for mechanical thrombectomy (MT) in large vessel occlusion (LVO) stroke. Primary effectiveness endpoint was successful recanalization eTICI (expanded Thrombolysis In Cerebral Ischemia) ≥ 2b67, primary safety endpoint was occurrence of hemorrhagic complications after MT. Secondary outcome measures were time from groin puncture to first pass and successful reperfusion, and the total number of passes needed to achieve the final recanalization result. Results A total of 298 patients with LVO stroke who were treated by MT matched the inclusion criteria: 148 patients (49.7\%) treated with AP vs. 150 patients (50.3\%) treated with new generation APH. Successful recanalization was not statistically different between both groups: 75.7\% for AP vs. 79.3\% for APH; p = 0.450. Postinterventional hemorrhagic complications and particularly subarachnoid hemorrhage as the entity possibly associated with stent-retriever device type was significantly less frequent in the group treated with the APH: 29.7\% for AP and 16.0\% for APH; p = 0.005; however, rates of symptomatic hemorrhage with clinical deterioration and in domo mortality were not statistically different. Neither the median number of stent-retriever passages needed to achieve final recanalization, time from groin puncture to first pass, time from groin puncture to final recanalization nor the number of cases in which successful recanalization could only be achieved by using a different stent-retriever as bail-out device differed between both groups. Conclusion In the specific example of the APERIO® stent-retriever device, we observed that further technological developments of the new generation device were not associated with disadvantages with respect to typical observational indicators of safety or effectiveness.}, language = {en} } @article{HerzbergScherlingStahletal.2021, author = {Herzberg, Moritz and Scherling, Korbinian and Stahl, Robert and Tiedt, Steffen and Wollenweber, Frank A. and K{\"u}pper, Clemens and Feil, Katharina and Forbrig, Robert and Patzig, Maximilian and Kellert, Lars and Kunz, Wolfgang G. and Reidler, Paul and Zimmermann, Hanna and Liebig, Thomas and Dieterich, Marianne and Dorn, Franziska}, title = {Late Thrombectomy in Clinical Practice: Retrospective Application of DAWN/DEFUSE3 Criteria within the German Stroke Registry}, series = {Clinical Neuroradiology}, volume = {31}, journal = {Clinical Neuroradiology}, number = {3}, doi = {10.1007/s00062-021-01033-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-264765}, pages = {799-810}, year = {2021}, abstract = {Background and Purpose To provide real-world data on outcome and procedural factors of late thrombectomy patients. Methods We retrospectively analyzed patients from the multicenter German Stroke Registry. The primary endpoint was clinical outcome on the modified Rankin scale (mRS) at 3 months. Trial-eligible patients and the subgroups were compared to the ineligible group. Secondary analyses included multivariate logistic regression to identify predictors of good outcome (mRS ≤ 2). Results Of 1917 patients who underwent thrombectomy, 208 (11\%) were treated within a time window ≥ 6-24 h and met the baseline trial criteria. Of these, 27 patients (13\%) were eligible for DAWN and 39 (19\%) for DEFUSE3 and 156 patients were not eligible for DAWN or DEFUSE3 (75\%), mainly because there was no perfusion imaging (62\%; n = 129). Good outcome was not significantly higher in trial-ineligible (27\%) than in trial-eligible (20\%) patients (p = 0.343). Patients with large trial-ineligible CT perfusion imaging (CTP) lesions had significantly more hemorrhagic complications (33\%) as well as unfavorable outcomes. Conclusion In clinical practice, the high number of patients with a good clinical outcome after endovascular therapy ≥ 6-24 h as in DAWN/DEFUSE3 could not be achieved. Similar outcomes are seen in patients selected for EVT ≥ 6 h based on factors other than CTP. Patients triaged without CTP showed trends for shorter arrival to reperfusion times and higher rates of independence.}, language = {en} } @article{VollmuthMuljukovAbuMugheisibetal.2021, author = {Vollmuth, Christoph and Muljukov, Olga and Abu-Mugheisib, Mazen and Angermeier, Anselm and Barlinn, Jessica and Busetto, Loraine and Grau, Armin J. and G{\"u}nther, Albrecht and Gumbinger, Christoph and Hubert, Nikolai and H{\"u}ttemann, Katrin and Klingner, Carsten and Naumann, Markus and Palm, Frederick and Remi, Jan and R{\"u}cker, Viktoria and Schessl, Joachim and Schlachetzki, Felix and Schuppner, Ramona and Schwab, Stefan and Schwartz, Andreas and Trommer, Adrian and Urbanek, Christian and Volbers, Bastian and Weber, Joachim and Wojciechowski, Claudia and Worthmann, Hans and Zickler, Philipp and Heuschmann, Peter U. and Haeusler, Karl Georg and Hubert, Gordian Jan}, title = {Impact of the coronavirus disease 2019 pandemic on stroke teleconsultations in Germany in the first half of 2020}, series = {European Journal of Neurology}, volume = {28}, journal = {European Journal of Neurology}, number = {10}, doi = {10.1111/ene.14787}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259396}, pages = {3267-3278}, year = {2021}, abstract = {Background and purpose The effects of the coronavirus disease 2019 (COVID-19) pandemic on telemedical care have not been described on a national level. Thus, we investigated the medical stroke treatment situation before, during, and after the first lockdown in Germany. Methods In this nationwide, multicenter study, data from 14 telemedical networks including 31 network centers and 155 spoke hospitals covering large parts of Germany were analyzed regarding patients' characteristics, stroke type/severity, and acute stroke treatment. A survey focusing on potential shortcomings of in-hospital and (telemedical) stroke care during the pandemic was conducted. Results Between January 2018 and June 2020, 67,033 telemedical consultations and 38,895 telemedical stroke consultations were conducted. A significant decline of telemedical (p < 0.001) and telemedical stroke consultations (p < 0.001) during the lockdown in March/April 2020 and a reciprocal increase after relaxation of COVID-19 measures in May/June 2020 were observed. Compared to 2018-2019, neither stroke patients' age (p = 0.38), gender (p = 0.44), nor severity of ischemic stroke (p = 0.32) differed in March/April 2020. Whereas the proportion of ischemic stroke patients for whom endovascular treatment (14.3\% vs. 14.6\%; p = 0.85) was recommended remained stable, there was a nonsignificant trend toward a lower proportion of recommendation of intravenous thrombolysis during the lockdown (19.0\% vs. 22.1\%; p = 0.052). Despite the majority of participating network centers treating patients with COVID-19, there were no relevant shortcomings reported regarding in-hospital stroke treatment or telemedical stroke care. Conclusions Telemedical stroke care in Germany was able to provide full service despite the COVID-19 pandemic, but telemedical consultations declined abruptly during the lockdown period and normalized after relaxation of COVID-19 measures in Germany.}, language = {en} } @article{WinterKernGalletal.2021, author = {Winter, Carla and Kern, Florian and Gall, Dominik and Latoschik, Marc Erich and Pauli, Paul and K{\"a}thner, Ivo}, title = {Immersive virtual reality during gait rehabilitation increases walking speed and motivation: a usability evaluation with healthy participants and individuals with multiple sclerosis and stroke}, series = {Journal of Neuroengineering and Rehabilitation}, volume = {18}, journal = {Journal of Neuroengineering and Rehabilitation}, number = {1}, issn = {1743-0003}, doi = {10.1186/s12984-021-00848-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258698}, year = {2021}, abstract = {Background: The rehabilitation of gait disorders in patients with multiple sclerosis (MS) and stroke is often based on conventional treadmill training. Virtual reality (VR)-based treadmill training can increase motivation and improve therapy outcomes. The present study evaluated an immersive virtual reality application (using a head-mounted display, HMD) for gait rehabilitation with patients to (1) demonstrate its feasibility and acceptance and to (2) compare its short-term effects to a semi-immersive presentation (using a monitor) and a conventional treadmill training without VR to assess the usability of both systems and estimate the effects on walking speed and motivation. Methods: In a within-subjects study design, 36 healthy participants and 14 persons with MS or stroke participated in each of the three experimental conditions (VR via HMD, VR via monitor, treadmill training without VR). Results: For both groups, the walking speed in the HMD condition was higher than in treadmill training without VR and in the monitor condition. Healthy participants reported a higher motivation after the HMD condition as compared with the other conditions. Importantly, no side effects in the sense of simulator sickness occurred and usability ratings were high. No increases in heart rate were observed following the VR conditions. Presence ratings were higher for the HMD condition compared with the monitor condition for both user groups. Most of the healthy study participants (89\%) and patients (71\%) preferred the HMD-based training among the three conditions and most patients could imagine using it more frequently. Conclusions For the first time, the present study evaluated the usability of an immersive VR system for gait rehabilitation in a direct comparison with a semi-immersive system and a conventional training without VR with healthy participants and patients. The study demonstrated the feasibility of combining a treadmill training with immersive VR. Due to its high usability and low side effects, it might be particularly suited for patients to improve training motivation and training outcome e. g. the walking speed compared with treadmill training using no or only semi-immersive VR. Immersive VR systems still require specific technical setup procedures. This should be taken into account for specific clinical use-cases during a cost-benefit assessment.}, language = {en} } @article{FrankeBieberStolletal.2021, author = {Franke, Maximilian and Bieber, Michael and Stoll, Guido and Schuhmann, Michael Klaus}, title = {Validity and Efficacy of Methods to Define Blood Brain Barrier Integrity in Experimental Ischemic Strokes: A Comparison of Albumin Western Blot, IgG Western Blot and Albumin Immunofluorescence}, series = {Methods and Protocols}, volume = {4}, journal = {Methods and Protocols}, number = {1}, issn = {2409-9279}, doi = {10.3390/mps4010023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234214}, year = {2021}, abstract = {The clinical and preclinical research of ischemic strokes (IS) is becoming increasingly comprehensive, especially with the emerging evidence of complex thrombotic and inflammatory interactions. Within these, the blood brain barrier (BBB) plays an important role in regulating the cellular interactions at the vascular interface and is therefore the object of many IS-related questions. Consequently, valid, economic and responsible methods to define BBB integrity are necessary. Therefore, we compared the three ex-vivo setups albumin Western blot (WB), IgG WB and albumin intensity measurement (AIM) with regard to validity as well as temporal and economic efficacy. While the informative value of the three methods correlated significantly, the efficacy of the IgG WB dominated.}, language = {en} } @article{KolominskyRabasWiedmannWeingaertneretal.2015, author = {Kolominsky-Rabas, Peter L. and Wiedmann, Silke and Weing{\"a}rtner, Michael and Liman, Thomas G. and Endres, Matthias and Schwab, Stefan and Buchfelder, Michael and Heuschmann, Peter U.}, title = {Time Trends in Incidence of Pathological and Etiological Stroke Subtypes during 16 Years: The Erlangen Stroke Project}, series = {Neuroepidemiology}, volume = {44}, journal = {Neuroepidemiology}, number = {1}, issn = {0251-5350}, doi = {10.1159/000371353}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196503}, pages = {24-29}, year = {2015}, abstract = {Background: Population-based data, which continuously monitors time trends in stroke epidemiology are limited. We investigated the incidence of pathological and etiological stroke subtypes over a 16 year time period. Methods: Data were collected within the Erlangen Stroke Project (ESPro), a prospective, population-based stroke register in Germany covering a total study population of 105,164 inhabitants (2010). Etiology of ischemic stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results: Between January 1995 and December 2010, 3,243 patients with first-ever stroke were documented. The median age was 75 and 55\% were females. The total stroke incidence decreased over the 16 year study period in men (Incidence Rate Ratio 1995-1996 vs. 2009-2010 (IRR) 0.78; 95\% CI 0.58-0.90) but not in women. Among stroke subtypes, a decrease in ischemic stroke incidence (IRR 0.73; 95\% CI 0.57-0.93) and of large artery atherosclerotic stroke (IRR 0.27; 95\% CI 0.12-0.59) was found in men and an increase of stroke due to small artery occlusion in women (IRR 2.33; 95\% CI 1.39-3.90). Conclusions: Variations in time trends of pathological and etiological stroke subtypes were found between men and women that might be linked to gender differences in the development of major vascular risk factors in the study population.}, language = {en} } @article{Koepsell2020, author = {Koepsell, Hermann}, title = {Glucose transporters in brain in health and disease}, series = {Pfl{\"u}gers Archiv - European Journal of Physiology}, volume = {472}, journal = {Pfl{\"u}gers Archiv - European Journal of Physiology}, issn = {0031-6768}, doi = {10.1007/s00424-020-02441-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232746}, pages = {1299-1343}, year = {2020}, abstract = {Energy demand of neurons in brain that is covered by glucose supply from the blood is ensured by glucose transporters incapillaries and brain cells. In brain, the facilitative diffusion glucose transporters GLUT1-6 and GLUT8, and the Na+-D-glucosecotransporters SGLT1 are expressed. The glucose transporters mediate uptake of D-glucose across the blood-brain barrier anddelivery of D-glucose to astrocytes and neurons. They are critically involved in regulatory adaptations to varying energy demandsin response to differing neuronal activities and glucose supply. In this review, a comprehensive overview about verified andproposed roles of cerebral glucose transporters during health and diseases is presented. Our current knowledge is mainly based onexperiments performed in rodents. First, the functional properties of human glucose transporters expressed in brain and theircerebral locations are described. Thereafter, proposed physiological functions of GLUT1, GLUT2, GLUT3, GLUT4, andSGLT1 for energy supply to neurons, glucose sensing, central regulation of glucohomeostasis, and feeding behavior are compiled, and their roles in learning and memory formation are discussed. In addition, diseases are described in which functionalchanges of cerebral glucose transporters are relevant. These are GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer's disease (AD), stroke, and traumatic brain injury (TBI). GLUT1-SD is caused by defect mutations in GLUT1. Diabetes and AD are associated with changed expression of glucose transporters in brain, and transporter-related energy defi-ciency of neurons may contribute to pathogenesis of AD. Stroke and TBI are associated with changes of glucose transporter expression that influence clinical outcome}, language = {en} } @article{GabbertDillingMeybohmetal.2020, author = {Gabbert, Lydia and Dilling, Christina and Meybohm, Patrick and Burek, Malgorzata}, title = {Deletion of Protocadherin Gamma C3 Induces Phenotypic and Functional Changes in Brain Microvascular Endothelial Cells In Vitro}, series = {Frontiers in Pharmacology}, volume = {11}, journal = {Frontiers in Pharmacology}, issn = {1663-9812}, doi = {10.3389/fphar.2020.590144}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219828}, year = {2020}, abstract = {Inflammation of the central nervous system (CNS) is associated with diseases such as multiple sclerosis, stroke and neurodegenerative diseases. Compromised integrity of the blood-brain barrier (BBB) and increased migration of immune cells into the CNS are the main characteristics of brain inflammation. Clustered protocadherins (Pcdhs) belong to a large family of cadherin-related molecules. Pcdhs are highly expressed in the CNS in neurons, astrocytes, pericytes and epithelial cells of the choroid plexus and, as we have recently demonstrated, in brain microvascular endothelial cells (BMECs). Knockout of a member of the Pcdh subfamily, PcdhgC3, resulted in significant changes in the barrier integrity of BMECs. Here we characterized the endothelial PcdhgC3 knockout (KO) cells using paracellular permeability measurements, proliferation assay, wound healing assay, inhibition of signaling pathways, oxygen/glucose deprivation (OGD) and a pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) treatment. PcdhgC3 KO showed an increased paracellular permeability, a faster proliferation rate, an altered expression of efflux pumps, transporters, cellular receptors, signaling and inflammatory molecules. Serum starvation led to significantly higher phosphorylation of extracellular signal-regulated kinases (Erk) in KO cells, while no changes in phosphorylated Akt kinase levels were found. PcdhgC3 KO cells migrated faster in the wound healing assay and this migration was significantly inhibited by respective inhibitors of the MAPK-, β-catenin/Wnt-, mTOR- signaling pathways (SL327, XAV939, or Torin 2). PcdhgC3 KO cells responded stronger to OGD and TNFα by significantly higher induction of interleukin 6 mRNA than wild type cells. These results suggest that PcdhgC3 is involved in the regulation of major signaling pathways and the inflammatory response of BMECs.}, language = {en} } @article{ElhfnawyAbdEl‐RaoufVolkmannetal.2020, author = {Elhfnawy, Ahmed Mohamed and Abd El-Raouf, Mervat and Volkmann, Jens and Fluri, Felix and Elsalamawy, Doaa}, title = {Relation of infarction location and volume to vertigo in vertebrobasilar stroke}, series = {Brain and Behavior}, volume = {10}, journal = {Brain and Behavior}, number = {3}, doi = {10.1002/brb3.1564}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218047}, year = {2020}, abstract = {Objective Vertigo is a common presentation of vertebrobasilar stroke. Anecdotal reports have shown that vertigo occurs more often in multiple than in single brainstem or cerebellar infarctions. We examined the relation between the location and volume of infarction and vertigo in patients with vertebrobasilar stroke. Methods Consecutive patients with vertebrobasilar stroke were prospectively recruited. The infarction location and volume were assessed in the diffusion-weighted magnetic resonance imaging. Results Fifty-nine patients were included, 32 (54.2\%) with vertigo and 27 (45.8\%) without vertigo. The infarction volume did not correlate with National Institute of Health Stroke Scale (NIHSS) score on admission (Spearman ρ = .077, p = .56) but correlated with modified Rankin Scale (ρ = .37, p = .004) on discharge. In the vertigo group, the proportion of men was lower (53.1\% vs. 77.8\%, p = .049), fewer patients had focal neurological deficits (65.6\% vs. 96.3\%, p = .004), patients tended to present later (median [IQR] was 7.5 [4-46] vs. 4 [2-12] hours, p = .052), numerically fewer patients received intravenous thrombolysis (15.6\% vs. 37\%, p = .06), and the total infarction volume was larger (5.6 vs. 0.42 cm3, p = .008) than in nonvertigo group. In multivariate logistic regression, infarction location either in the cerebellum or in the dorsal brainstem (odds ratio [OR] 16.97, 95\% CI 3.1-92.95, p = .001) and a total infarction volume of >0.48 cm3 (OR 4.4, 95\% CI 1.05-18.58, p = .043) were related to vertigo. In another multivariate logistic regression, after adjusting for age, sex, intravenous thrombolysis, serum level of white blood cells, and atrial fibrillation, vertigo independently predicted a total infarction volume of >0.48 cm3 (OR 5.75, 95\% CI 1.43-23.08, p = .01). Conclusion Infarction location in the cerebellum and/or dorsal brainstem is an independent predictor of vertigo. Furthermore, larger infarction volume in these structures is associated with vertigo. A considerable proportion of patients with vascular vertigo present without focal neurological deficits posing a diagnostic challenge. National Institute of Health Stroke Scale is not sensitive for vertebrobasilar stroke.}, language = {en} } @article{ElhfnawyVolkmannSchliesseretal.2019, author = {Elhfnawy, Ahmed Mohamed and Volkmann, Jens and Schliesser, Mira and Fluri, Felix}, title = {Are cerebral white matter lesions related to the presence of bilateral internal carotid artery stenosis or to the length of stenosis among patients with ischemic cerebrovascular events?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {919}, doi = {10.3389/fneur.2019.00919}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201241}, year = {2019}, abstract = {Background and purpose: Previous studies delivered contradicting results regarding the relation between the presence of an internal carotid artery stenosis (ICAS) and the occurence of white matter lesions (WMLs). We hypothesize that special characteristics related to the ICAS might be related to the WMLs. We examined the relation between the presence of bilateral ICAS, the degree and length of stenosis and ipsi-, contralateral as well as mean white matter lesion load (MWMLL). Methods: In a retrospective cohort, patients with ischemic stroke or transient ischemic attack (TIA) as well as ipsi- and/or contralateral ICAS were identified. The length and degree of ICAS, as well as plaque morphology (hypoechoic, mixed or echogenic), were assessed on ultrasound scans and, if available, the length was also measured on magnetic resonance angiography (MRA) scans, and/or digital subtraction angiography (DSA). The WMLs were assessed in 4 areas separately, (periventricular and deep WMLs on each hemispherer), using the Fazekas scale. The MWMLL was calculated as the mean of these four values. Results: 136 patients with 177 ICAS were identified. A significant correlation between age and MWMLL was observed (Spearman correlation coefficient, ρ = 0.41, p < 0.001). Before adjusting for other risk factors, a significantly positive relation was found between the presence of bilateral ICAS and MWMLL (p = 0.039). The length but not the degree of ICAS showed a very slight trend toward association with ipsilateral WMLs and with MWMLL. In an age-adjusted multivariate logistic regression with MWMLL ≥2 as the outcome measure, atrial fibrillation (OR 3.54, 95\% CI 1.12-11.18, p = 0.03), female sex (OR 3.11, 95\% CI 1.19-8.11, p = 0.02) and diabetes mellitus (OR 2.76, 95\% CI 1.16-6.53, p = 0.02) were significantly related to WMLs, whereas the presence of bilateral stenosis showed a trend toward significance (OR 2.25, 95\% CI 0.93-5.45, p = 0.074). No relation was found between plaque morphology and MWMLL, periventricular, or deep WMLs. Conclusion: We have shown a slight correlation between the length of stenosis and the presence of WMLs which might be due to microembolisation originating from the carotid plaque. However, the presence of bilateral ICAS seems also to be related to WMLs which may point to common underlying vascular risk factors contributing to the occurrence of WML.}, language = {en} } @article{LendersWeidemannKurschatetal.2016, author = {Lenders, Malte and Weidemann, Frank and Kurschat, Christine and Canaan-K{\"u}hl, Sima and Duning, Thomas and Stypmann, J{\"o}rg and Schmitz, Boris and Reiermann, Stefanie and Kr{\"a}mer, Johannes and Blaschke, Daniela and Wanner, Christoph and Brand, Stefan-Martin and Brand, Eva}, title = {Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant}, series = {Orphanet Journal of Rare Diseases}, volume = {11}, journal = {Orphanet Journal of Rare Diseases}, number = {54}, doi = {10.1186/s13023-016-0441-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166559}, year = {2016}, abstract = {Background Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. Methods To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations. Results p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 \% of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed. Conclusions We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option.}, language = {en} } @article{MalschLimanWiedmannetal.2018, author = {Malsch, Carolin and Liman, Thomas and Wiedmann, Silke and Siegerink, Bob and Georgakis, Marios K. and Tiedt, Steffen and Endres, Matthias and Heuschmann, Peter U.}, title = {Outcome after stroke attributable to baseline factors—the PROSpective Cohort with Incident Stroke (PROSCIS)}, series = {PLoS ONE}, volume = {13}, journal = {PLoS ONE}, number = {9}, doi = {10.1371/journal.pone.0204285}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177342}, pages = {e0204285}, year = {2018}, abstract = {Background The impact of risk factors on poor outcome after ischemic stroke is well known, but estimating the amount of poor outcome attributable to single factors is challenging in presence of multimorbidity. We aim to compare population attributable risk estimates obtained from different statistical approaches regarding their consistency. We use a real-life data set from the PROSCIS study to identify predictors for mortality and functional impairment one year after first-ever ischemic stroke and quantify their contribution to poor outcome using population attributable risks. Methods The PROSpective Cohort with Incident Stroke (PROSCIS) is a prospective observational hospital-based cohort study of patients after first-ever stroke conducted independently in Berlin (PROSCIS-B) and Munich (PROSCIS-M). The association of baseline factors with poor outcome one year after stroke in PROSCIS-B was analysed using multiple logistic regression analysis and population attributable risks were calculated, which were estimated using sequential population attributable risk based on a multiple generalized additive regression model, doubly robust estimation, as well as using average sequential population attributable risk. Findings were reproduced in an independent validation sample from PROSCIS-M. Results Out of 507 patients with available outcome information after 12 months in PROSCIS-B, 20.5\% suffered from poor outcome. Factors associated with poor outcome were age, pre-stroke physical disability, stroke severity (NIHSS), education, and diabetes mellitus. The order of risk factors ranked by magnitudes of population attributable risk was almost similar for all methods, but population attributable risk estimates varied markedly between the methods. In PROSCIS-M, incidence of poor outcome and distribution of baseline parameters were comparable. The multiple logistic regression model could be reproduced for all predictors, except pre-stroke physical disability. Similar to PROSCIS-B, the order of risk factors ranked by magnitudes of population attributable risk was almost similar for all methods, but magnitudes of population attributable risk differed markedly between the methods. Conclusions Ranking of risk factors by population impact is not affected by the different statistical approaches. Thus, for a rational decision on which risk factor to target in disease interventions, population attributable risk is a supportive tool. However, population attributable risk estimates are difficult to interpret and are not comparable when they origin from studies applying different methodology. The predictors for poor outcome identified in PROSCIS-B have a relevant impact on mortality and functional impairment one year after first-ever ischemic stroke.}, language = {en} } @article{PfitznerMayNuechter2018, author = {Pfitzner, Christian and May, Stefan and N{\"u}chter, Andreas}, title = {Body weight estimation for dose-finding and health monitoring of lying, standing and walking patients based on RGB-D data}, series = {Sensors}, volume = {18}, journal = {Sensors}, number = {5}, doi = {10.3390/s18051311}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176642}, pages = {1311}, year = {2018}, abstract = {This paper describes the estimation of the body weight of a person in front of an RGB-D camera. A survey of different methods for body weight estimation based on depth sensors is given. First, an estimation of people standing in front of a camera is presented. Second, an approach based on a stream of depth images is used to obtain the body weight of a person walking towards a sensor. The algorithm first extracts features from a point cloud and forwards them to an artificial neural network (ANN) to obtain an estimation of body weight. Besides the algorithm for the estimation, this paper further presents an open-access dataset based on measurements from a trauma room in a hospital as well as data from visitors of a public event. In total, the dataset contains 439 measurements. The article illustrates the efficiency of the approach with experiments with persons lying down in a hospital, standing persons, and walking persons. Applicable scenarios for the presented algorithm are body weight-related dosing of emergency patients.}, language = {en} } @article{KazuhinoWernerToriumietal.2018, author = {Kazuhino, Koshino and Werner, Rudolf A. and Toriumi, Fuijo and Javadi, Mehrbod S. and Pomper, Martin G. and Solnes, Lilja B. and Verde, Franco and Higuchi, Takahiro and Rowe, Steven P.}, title = {Generative Adversarial Networks for the Creation of Realistic Artificial Brain Magnetic Resonance Images}, series = {Tomography}, volume = {4}, journal = {Tomography}, number = {4}, doi = {10.18383/j.tom.2018.00042}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172185}, pages = {159-163}, year = {2018}, abstract = {Even as medical data sets become more publicly accessible, most are restricted to specific medical conditions. Thus, data collection for machine learning approaches remains challenging, and synthetic data augmentation, such as generative adversarial networks (GAN), may overcome this hurdle. In the present quality control study, deep convolutional GAN (DCGAN)-based human brain magnetic resonance (MR) images were validated by blinded radiologists. In total, 96 T1-weighted brain images from 30 healthy individuals and 33 patients with cerebrovascular accident were included. A training data set was generated from the T1-weighted images and DCGAN was applied to generate additional artificial brain images. The likelihood that images were DCGAN-created versus acquired was evaluated by 5 radiologists (2 neuroradiologists [NRs], vs 3 non-neuroradiologists [NNRs]) in a binary fashion to identify real vs created images. Images were selected randomly from the data set (variation of created images, 40\%-60\%). None of the investigated images was rated as unknown. Of the created images, the NRs rated 45\% and 71\% as real magnetic resonance imaging images (NNRs, 24\%, 40\%, and 44\%). In contradistinction, 44\% and 70\% of the real images were rated as generated images by NRs (NNRs, 10\%, 17\%, and 27\%). The accuracy for the NRs was 0.55 and 0.30 (NNRs, 0.83, 0.72, and 0.64). DCGAN-created brain MR images are similar enough to acquired MR images so as to be indistinguishable in some cases. Such an artificial intelligence algorithm may contribute to synthetic data augmentation for "data-hungry" technologies, such as supervised machine learning approaches, in various clinical applications.}, subject = {Magnetresonanztomografie}, language = {en} } @article{LugerHohmannNiemannetal.2015, author = {Luger, Sebastian and Hohmann, Carina and Niemann, Daniela and Kraft, Peter and Gunreben, Ignaz and Neumann-Haefelin, Tobias and Kleinschnitz, Christoph and Steinmetz, Helmuth and Foerch, Christian and Pfeilschifter, Waltraud}, title = {Adherence to oral anticoagulant therapy in secondary stroke prevention - impact of the novel oral anticoagulants}, series = {Patient Preference and Adherence}, volume = {9}, journal = {Patient Preference and Adherence}, doi = {10.2147/PPA.S88994}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144477}, pages = {1695-1705}, year = {2015}, abstract = {Background: Oral anticoagulant therapy (OAT) potently prevents strokes in patients with atrial fibrillation. Vitamin K antagonists (VKA) have been the standard of care for long-term OAT for decades, but non-VKA oral anticoagulants (NOAC) have recently been approved for this indication, and raised many questions, among them their influence on medication adherence. We assessed adherence to VKA and NOAC in secondary stroke prevention. Methods: All patients treated from October 2011 to September 2012 for ischemic stroke or transient ischemic attack with a subsequent indication for OAT, at three academic hospitals were entered into a prospective registry, and baseline data and antithrombotic treatment at discharge were recorded. At the 1-year follow-up, we assessed the adherence to different OAT strategies and patients' adherence to their respective OAT. We noted OAT changes, reasons to change treatment, and factors that influence persistence to the prescribed OAT. Results: In patients discharged on OAT, we achieved a fatality corrected response rate of 73.3\% (n=209). A total of 92\% of these patients received OAT at the 1-year follow-up. We observed good adherence to both VKA and NOAC (VKA, 80.9\%; NOAC, 74.8\%; P=0.243) with a statistically nonsignificant tendency toward a weaker adherence to dabigatran. Disability at 1-year follow-up was an independent predictor of lower adherence to any OAT after multivariate analysis, whereas the choice of OAT did not have a relevant influence. Conclusion: One-year adherence to OAT after stroke is strong (>90\%) and patients who switch therapy most commonly switch toward another OAT. The 1-year adherence rates to VKA and NOAC in secondary stroke prevention do not differ significantly between both therapeutic strategies.}, language = {en} } @article{NeugebauerHeuschmannJuettler2012, author = {Neugebauer, Hermann and Heuschmann, Peter U. and J{\"u}ttler, Eric}, title = {DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY - Registry (DESTINY-R): design and protocols}, series = {BMC Neurology}, volume = {12}, journal = {BMC Neurology}, number = {115}, doi = {10.1186/1471-2377-12-115}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133892}, year = {2012}, abstract = {Background: Randomized controlled trials (RCT) on the treatment of severe space-occupying infarction of the middle cerebral artery (malignant MCA infarction) showed that early decompressive hemicraniectomy (DHC) is life saving and improves outcome without promoting most severe disablity in patients aged 18-60 years. It is, however, unknown whether the results obtained in the randomized trials are reproducible in a broader population in and apart from an academical setting and whether hemicraniectomy has been implemented in clinical practice as recommended by national and international guidelines. In addition, they were not powered to answer further relevant questions, e. g. concerning the selection of patients eligible for and the timing of hemicraniectomy. Other important issues such as the acceptance of disability following hemicraniectomy, the existence of specific prognostic factors, the value of conservative therapeutic measures, and the overall complication rate related to hemicraniectomy have not been sufficiently studied yet. Methods/Design: DESTINY-R is a prospective, multicenter, open, controlled registry including a 12 months follow-up. The only inclusion criteria is unilateral ischemic MCA stroke affecting more than 50\% of the MCA-territory. The primary study hypothesis is to confirm the results of the RCT (76\% mRS <= 4 after 12 months) in the subgroup of patients additionally fulfilling the inclusion cirteria of the RCT in daily routine. Assuming a calculated proportion of 0.76 for successes and a sample size of 300 for this subgroup, the width of the 95\% CI, calculated using Wilson's method, will be 0.096 with the lower bound 0.709 and the upper bound 0.805. Discussion: The results of this study will provide information about the effectiveness of DHC in malignant MCA infarction in a broad population and a real-life situation in addition to and beyond RCT. Further prospectively obtained data will give crucial information on open questions and will be helpful in the plannig of upcomming treatment studies.}, language = {en} } @article{HaeuslerHermKunzeetal.2012, author = {Haeusler, Karl Georg and Herm, Juliane and Kunze, Claudia and Kr{\"u}ll, Matthias and Brechtel, Lars and Lock, J{\"u}rgen and Hohenhaus, Marc and Heuschmann, Peter U. and Fiebach, Jochen B. and Haverkamp, Wilhelm and Endres, Matthias and Jungehulsing, Gerhard Jan}, title = {Rate of cardiac arrhythmias and silent brain lesions in experienced marathon runners: rationale, design and baseline data of the Berlin Beat of Running study}, series = {BMC Cardiovascular Disorders}, volume = {12}, journal = {BMC Cardiovascular Disorders}, number = {69}, doi = {10.1186/1471-2261-12-69}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133677}, year = {2012}, abstract = {Background: Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing. Methods/Design: In the prospective observational "Berlin Beat of Running" study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38\(^{th}\) BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year. Results: Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 \(\pm\) 6.0 years, 24.5\% were female, 8.2\% had hypertension and 2.7\% had hyperlipidaemia. Participants have attended a mean of 7.5 \(\pm\) 6.6 marathon races within the last 5 years and a mean of 16 \(\pm\) 36 marathon races in total. Their weekly running distance prior to the 38\(^{th}\) BMW BERLIN-MARATHON was 65 \(\pm\) 17 km. Finally, 108 (98.2\%) Berlin Beat-Study participants successfully completed the 38\(^{th}\) BMW BERLIN-MARATHON 2011. Discussion: Findings from the "Berlin Beats of Running" study will help to balance the benefits and risks of extensive endurance sport. ECG-recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage.}, language = {en} } @article{WeidemannNiemannStorketal.2013, author = {Weidemann, F. and Niemann, M. and Stork, S. and Breunig, F. and Beer, M. and Sommer, C. and Herrmann, S. and Ertl, G. and Wanner, C.}, title = {Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications}, series = {Journal of Internal Medicine}, volume = {247}, journal = {Journal of Internal Medicine}, number = {4}, doi = {10.1111/joim.12077}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132075}, pages = {331-4}, year = {2013}, abstract = {The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease. METHODS: A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. RESULTS: During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7\%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. CONCLUSION: Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.}, language = {en} } @article{BugaMargaritescuScholzetal.2014, author = {Buga, Ana Maria and Margaritescu, Claudiu and Scholz, Claus J{\"u}rgen and Radu, Eugen and Zelenak, Christine and Popa-Wagner, Aurel}, title = {Transcriptomics of Post-Stroke Angiogenesis in the Aged Brain}, series = {Frontiers in Aging Neuroscience}, volume = {6}, journal = {Frontiers in Aging Neuroscience}, number = {44}, doi = {10.3389/fnagi.2014.00044}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120700}, year = {2014}, abstract = {Despite the obvious clinical significance of post-stroke angiogenesis in aged subjects, a detailed transcriptomic analysis of post-stroke angiogenesis has not yet been undertaken in an aged experimental model. In this study, by combining stroke transcriptomics with immunohistochemistry in aged rats and post-stroke patients, we sought to identify an age-specific gene expression pattern that may characterize the angiogenic process after stroke. We found that both young and old infarcted rats initiated vigorous angiogenesis. However, the young rats had a higher vascular density by day 14 post-stroke. "New-for-stroke" genes that were linked to the increased vasculature density in young animals included Angpt2, Angptl2, Angptl4, Cib1, Ccr2, Col4a2, Cxcl1, Lef1, Hhex, Lamc1, Nid2, Pcam1, Plod2, Runx3, Scpep1, S100a4, Tgfbi, and Wnt4, which are required for sprouting angiogenesis, reconstruction of the basal lamina (BL), and the resolution phase. The vast majority of genes involved in sprouting angiogenesis (Angpt2, Angptl4, Cib1, Col8a1, Nrp1, Pcam1, Pttg1ip, Rac2, Runx1, Tnp4, Wnt4); reconstruction of a new BL (Col4a2, Lamc1, Plod2); or tube formation and maturation (Angpt1, Gpc3, Igfbp7, Sparc, Tie2, Tnfsf10), had however, a delayed upregulation in the aged rats. The angiogenic response in aged rats was further diminished by the persistent upregulation of "inflammatory" genes (Cxcl12, Mmp8, Mmp12, Mmp14, Mpeg1, Tnfrsf1a, Tnfrsf1b) and vigorous expression of genes required for the buildup of the fibrotic scar (Cthrc1, Il6ra, Il13ar1, Il18, Mmp2, Rassf4, Tgfb1, Tgfbr2, Timp1). Beyond this barrier, angiogenesis in the aged brains was similar to that in young brains. We also found that the aged human brain is capable of mounting a vigorous angiogenic response after stroke, which most likely reflects the remaining brain plasticity of the aged brain.}, language = {en} } @article{KraftDrechslerGunrebenetal.2014, author = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Nieswandt, Bernhard and Stoll, Guido and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph}, title = {Von Willebrand Factor Regulation in Patients with Acute and Chronic Cerebrovascular Disease: A Pilot, Case-Control Study}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {6}, issn = {1932-6203}, doi = {10.1371/journal.pone.0099851}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119588}, pages = {e99851}, year = {2014}, abstract = {Background and Purpose In animal models, von Willebrand factor (VWF) is involved in thrombus formation and propagation of ischemic stroke. However, the pathophysiological relevance of this molecule in humans, and its potential use as a biomarker for the risk and severity of ischemic stroke remains unclear. This study had two aims: to identify predictors of altered VWF levels and to examine whether VWF levels differ between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods A case-control study was undertaken between 2010 and 2013 at our University clinic. In total, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HV) were included. Blood was taken at days 0, 1, and 3 in patients with AIS or TIA, and once in CCD patients and HV. VWF serum levels were measured and correlated with demographic and clinical parameters by multivariate linear regression and ANOVA. Results Patients with CCD (158±46\%) had significantly higher VWF levels than HV (113±36\%, P<0.001), but lower levels than AIS/TIA patients (200±95\%, P<0.001). Age, sex, and stroke severity influenced VWF levels (P<0.05). Conclusions VWF levels differed across disease subtypes and patient characteristics. Our study confirms increased VWF levels as a risk factor for cerebrovascular disease and, moreover, suggests that it may represent a potential biomarker for stroke severity, warranting further investigation.}, language = {en} } @article{NeuhausGaiserMahringeretal.2014, author = {Neuhaus, Winfried and Gaiser, Fabian and Mahringer, Anne and Franz, Jonas and Riethm{\"u}ller, Christoph and F{\"o}rster, Carola}, title = {The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier}, series = {Frontiers in Cellular Neuroscience}, volume = {8}, journal = {Frontiers in Cellular Neuroscience}, issn = {1662-5102}, doi = {10.3389/fncel.2014.00352}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118297}, pages = {352}, year = {2014}, abstract = {Stabilization of the blood-brain barrier during and after stroke can lead to less adverse outcome. For elucidation of underlying mechanisms and development of novel therapeutic strategies validated in vitro disease models of the blood-brain barrier could be very helpful. To mimic in vitro stroke conditions we have established a blood-brain barrier in vitro model based on mouse cell line cerebEND and applied oxygen/glucose deprivation (OGD). The role of astrocytes in this disease model was investigated by using cell line C6. Transwell studies pointed out that addition of astrocytes during OGD increased the barrier damage significantly in comparison to the endothelial monoculture shown by changes of transendothelial electrical resistance as well as fluorescein permeability data. Analysis on mRNA and protein levels by qPCR, western blotting and immunofluorescence microscopy of tight junction molecules claudin-3,-5,-12, occludin and ZO-1 revealed that their regulation and localisation is associated with the functional barrier breakdown. Furthermore, soluble factors of astrocytes, OGD and their combination were able to induce changes of functionality and expression of ABC-transporters Abcb1a (P-gp), Abcg2 (bcrp), and Abcc4 (mrp4). Moreover, the expression of proteases (matrixmetalloproteinases MMP-2, MMP-3, MMP-9, and t-PA) as well as of their endogenous inhibitors (TIMP-1, TIMP-3, PAI-1) was altered by astrocyte factors and OGD which resulted in significant changes of total MMP and t-PA activity. Morphological rearrangements induced by OGD and treatment with astrocyte factors were confirmed at a nanometer scale using atomic force microscopy. In conclusion, astrocytes play a major role in blood-brain barrier breakdown during OGD in vitro.}, language = {en} } @article{UeceylerHomolaGonzalezetal.2014, author = {{\"U}{\c{c}}eyler, Nurcan and Homola, Gy{\"o}rgy A. and Gonz{\´a}lez, Hans Guerrero and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Solymosi, L{\´a}szl{\´o} and Sommer, Claudia}, title = {Increased Arterial Diameters in the Posterior Cerebral Circulation in Men with Fabry Disease}, doi = {10.1371/journal.pone.0087054}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112614}, year = {2014}, abstract = {A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males - females; normal - impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13\%) and 5/57 (9\%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1\%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87\%, specificity: 86\%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.}, language = {en} } @article{NeuhausBurekDjuzenovaetal.2012, author = {Neuhaus, Winfried and Burek, Malgorzata and Djuzenova, Cholpon C and Thal, Serge C and Koepsell, Hermann and Roewer, Norbert and F{\"o}rster, Carola Y}, title = {Addition of NMDA-receptor antagonist MK801 during oxygen/glucose deprivation moderately attenuates the up-regulation of glucose uptake after subsequent reoxygenation in brain endothelial cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-67241}, year = {2012}, abstract = {During stroke the blood-brain barrier (BBB) is damaged which can result in vasogenic brain edema and inflammation. The reduced blood supply leads to decreased delivery of oxygen and glucose to affected areas of the brain. Oxygen and glucose deprivation (OGD) can cause upregulation of glucose uptake of brain endothelial cells. In this letter, we investigated the influence of MK801, a non-competitive inhibitor of the NMDA-receptor, on the regulation of the glucose uptake and of the main glucose transporters glut1 and sglt1 in murine BBB cell line cerebEND during OGD. mRNA expression of glut1 was upregulated 68.7- fold after 6 h OGD, which was significantly reduced by 10 μM MK801 to 28.9-fold. Sglt1 mRNA expression decreased during OGD which was further reduced by MK801. Glucose uptake was significantly increased up to 907\% after 6 h OGD and was still higher (210\%) after the 20 h reoxygenation phase compared to normoxia. Ten micromolar MK801 during OGD was able to reduce upregulated glucose uptake after OGD and reoxygenation significantly. Presence of several NMDAR subunits was proven on the mRNA level in cerebEND cells. Furthermore, it was shown that NMDAR subunit NR1 was upregulated during OGD and that this was inhibitable by MK801. In conclusion, the addition of MK801 during the OGD phase reduced significantly the glucose uptake after the subsequent reoxygenation phase in brain endothelial cells.}, subject = {Blut-Hirn-Schranke}, language = {en} }