Center for Stroke Research Berlin

Berlin, Germany

Center for Stroke Research Berlin

Berlin, Germany
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Obrig H.,University of Leipzig | Obrig H.,Max Planck Institute for Human Cognitive and Brain Sciences | Steinbrink J.,Center for Stroke Research Berlin
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2011

The acute onset of a neurological deficit is the key clinical feature of stroke. In most cases, however, pathophysiological changes in the cerebral vasculature precede the event, often by many years. Persisting neurological deficits may also require long-term rehabilitation. Hence, stroke may be considered a chronic disease, and diagnostic and therapeutic efforts must include identification of specific risk factors, and the monitoring of and interventions in the acute and subacute stages, and should aim at a pathophysiologically based approach to optimize the rehabilitative effort. Non-invasive optical techniques have been experimentally used in all three stages of the disease and may complement the established diagnostic and monitoring tools. Here, we provide an overview of studies using the methodology in the context of stroke, and we sketch perspectives of how they may be integrated into the assessment of the highly dynamic pathophysiological processes during the acute and subacute stages of the disease and also during rehabilitation and (secondary) prevention of stroke. This journal is © 2011 The Royal Society.

Kufner A.,Charité - Medical University of Berlin | Nolte C.H.,Charité - Medical University of Berlin | Nolte C.H.,Center for Stroke Research Berlin | Galinovic I.,Center for Stroke Research Berlin | And 7 more authors.
Stroke | Year: 2013

BACKGROUND AND PURPOSE - : The so-called smoking-thrombolysis paradox of an improved outcome after thrombolysis was first described in smokers with myocardial infarction. We investigated whether reperfusion rates and clinical outcome differ between smokers and nonsmokers with ischemic stroke after intravenous tissue plasminogen activator. METHODS - : Consecutive acute ischemic stroke patients, who had magnetic resonance imaging before and 1 day after thrombolysis, were included for analysis. All of the patients received intravenous tissue plasminogen activator within 4.5 hours. Reperfusion was defined as a 75% reduction in perfusion deficit (mean transit time >6 s) after thrombolysis compared with baseline. Magnetic resonance angiography was used to evaluate arterial stenosis and occlusion. Functional outcome was assessed 3 months after stroke using the modified Rankin Score. RESULTS - : Of 148 patients, 21.6% were smokers (n=32). Smokers were younger (median, 61 years [SD, 9.4 years] versus 75 years [SD, 11.6 years]; P<0.001), less often women (28% versus 51%; P=0.03), had lower baseline glucose levels (median, 6.2 mmol/L [interquartile range, 5.7-6.8 mmol/L] versus 6.7 mmol/L [interquartile range, 6.1-8.2 mmol/L]; P<0.01) and higher baseline perfusion deficits (median, 53 mL [interquartile range, 13-141 mL] versus 17 mL [interquartile range, 2-66 mL]; P=0.04). In a backward stepwise regression analysis including age, sex, hypertension, glucose, perfusion deficit, and smoking, smoking had an odds ratio of 4 (95% confidence interval, 1-16; P=0.03) for reperfusion and 6 (95% confidence interval, 1-30; P=0.05) for recanalization (regression analysis for recanalization also included localization of arterial occlusion). Smokers had a better outcome (modified Rankin Score=0-2) than nonsmokers (77% versus 55%; P=0.05). CONCLUSIONS - : Smoking is independently associated with recanalization and reperfusion, indicating that thrombolytic therapy acts more effectively in smokers; because of small numbers, these results should be considered preliminary. © 2013 American Heart Association, Inc.

Macrez R.,University of Caen Lower Normandy | Ali C.,University of Caen Lower Normandy | Toutirais O.,University of Caen Lower Normandy | Le Mauff B.,University of Caen Lower Normandy | And 5 more authors.
The Lancet Neurology | Year: 2011

Stroke is the second most common cause of death worldwide and a major cause of acquired disability in adults. Despite tremendous progress in understanding the pathophysiology of stroke, translation of this knowledge into effective therapies has largely failed, with the exception of thrombolysis, which only benefits a small proportion of patients. Systemic and local immune responses have important roles in causing stroke and are implicated in the primary and secondary progression of ischaemic lesions, as well as in repair, recovery, and overall outcome after a stroke. However, potential therapeutic targets in the immune system and inflammatory responses have not been well characterised. Development of novel and effective therapeutic strategies for stroke will require further investigation of these pathways in terms of their temporal profile (before, during, and after stroke) and risk-to-benefit therapeutic ratio of modulating them. © 2011 Elsevier Ltd.

Prinz V.,Charité - Medical University of Berlin | Prinz V.,Center for Stroke Research Berlin | Endres M.,Charité - Medical University of Berlin | Endres M.,Center for Stroke Research Berlin
Current Opinion in Neurology | Year: 2011

Purpose of review: Large clinical trials have clearly demonstrated that statins reduce the risk of first and recurrent stroke. This review aims to highlight the current findings and recent developments in this field. Recent findings: In addition to risk reduction, statins may also improve stroke outcome, even when administered after the event. Due to the multitargeted vasoprotective effects of statins, statins may be beneficial in various conditions and disorders in which acute and chronic endothelial dysfunction play a key role. Vice-versa, abrupt interruption of statin therapy following acute cerebrovascular or cardiovascular events may impede vascular function and increase morbidity and mortality. Furthermore, statins could serve as an adjuvant for enhancing the efficacy of thrombolytic therapy and other promising neuroprotective compounds, as it stabilizes endothelial function and additionally exerts profibrinolytic, immunomodulatory, and antioxidant effects. However, so far, there are only limited clinical data on the effect of statin therapy on stroke outcome. Summary: Statins are emerging as a new and promising avenue for the prevention and potentially treatment of ischemic stroke. New clinical trials are necessary to clarify the impact of acute statin treatment on stroke outcome. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Doehner W.,Center for Stroke Research Berlin | Doehner W.,Charité - Medical University of Berlin | Erdmann E.,University of Cologne | Cairns R.,Clinical Trials Center | And 5 more authors.
International Journal of Cardiology | Year: 2012

Context: Although weight reduction is a recommended goal in type 2 diabetes mellitus (T2DM), weight loss is linked to impaired survival in patients with some chronic cardiovascular diseases. Objective: To assess the association of weight and weight change with mortality and non-fatal cardiovascular outcomes (hospitalisation, myocardial infarction and stroke) in T2DM patients with cardiovascular co-morbidity and the effect of pioglitazone-induced weight change on mortality. Setting and participants: We assessed in a post hoc analysis body weight and weight change in relation to outcome in 5202 patients from the PROactive trial population who had T2DM and evidence of pre-existing cardiovascular disease. Patients were randomized to treatment with pioglitazone or placebo in addition to their concomitant glucose-lowering and cardiovascular medication. Mean follow up was 34.5 months. Main outcome measure: The impact of body weight and body weight change on all-cause mortality, cardiovascular mortality, on non-fatal cardiovascular events and on hospitalisation. Results: The lowest mortality was seen in patients with BMI 30-35 kg/m2 at baseline. In comparison to this (reference group), patients in the placebo group with BMI < 22 kg/m2 (Hazard Ratio (95% confidence intervals) 2.96 [1.27 to 6.86]; P = 0.012) and BMI 22 to 25 kg/m2 (HR 1.88 [1.11 to 3.21]; P = 0.019) had a higher all-cause mortality. Weight loss was associated with increased total mortality (HR per 1% body weight: 1.13 [1.11 to 1.16]; P < 0.0001), with increased cardiovascular mortality, all-cause hospitalisation and the composite of death, myocardial infarction and stroke. Weight loss of ≥ 7.5% body weight (seen in 18.3% of patients) was the strongest cut-point to predict impaired survival (multivariable adjusted HR 4.42 [3.30 to 5.94]. Weight gain was not associated with increased mortality. Weight gain in patients treated with pioglitazone (mean + 4.0 ± 6.1 kg) predicted a better prognosis (HR per 1% weight gain: 0.96 [0.92 to 1.00] P = 0.037) compared to patients without weight gain. Conclusion: Among patients with T2DM and cardiovascular co-morbidity, overweight and obese patients had a lower mortality compared to patients with normal weight. Weight loss but not weight gain was associated with increased mortality and morbidity. There may be an obesity paradox in patients with type 2 diabetes and cardiovascular risk. The original PROactive trial is registered as an International Standard Randomized Controlled Trial (Number ISRCTN NCT00174993). © 2011 Elsevier Ireland Ltd.

Ebner N.,Applied Cachexia Research | Steinbeck L.,Applied Cachexia Research | Doehner W.,Applied Cachexia Research | Doehner W.,Center for Stroke Research Berlin | And 2 more authors.
Journal of Cachexia, Sarcopenia and Muscle | Year: 2014

This article highlights preclinical and clinical studies in the field of wasting disorders that were presented at the 7th Cachexia Conference held in Kobe, Japan, in December 2013. This year, the main topics were the development of new methods and new biomarkers in the field of cachexia and wasting disorders with particular focus on inflammatory pathways, growth differentiation factor-15, myostatin, the ubiquitin proteasome-dependent pathway, valosin and the regulation of ubiquitin-specific protease 19 that is involved in the differentiation of myogenin and myosin heavy chain. This article presents highlights from the development of drugs that have shown potential in the treatment of wasting disorders, particularly the ghrelin receptor agonist anamorelin, the myostatin antagonist REGN1033, the selective androgen receptor modulators enobosarm and TEI-E0001, and the anabolic catabolic transforming agent espindolol. In addition, novel data on the prevalence and detection methods of muscle wasting/sarcopenia are presented, including the D3-creatine dilution method and several new biomarkers. © 2014 Springer-Verlag Berlin Heidelberg.

von Haehling S.,Applied Cachexia Research | von Haehling S.,Center for Cardiovascular Research | Steinbeck L.,Applied Cachexia Research | Doehner W.,Applied Cachexia Research | And 6 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2013

Patients with heart failure are frequently limited in their exercise capacity. Although this clinical phenomenon is mostly attributed to the failing myocardium, the effects of skeletal muscle wasting should not be underestimated. Muscle wasting may present in the form of loss of muscle mass and function, termed sarcopenia in healthy aging, or in the form of cachexia. Only cachexia is associated with loss of body weight. The mechanisms involved embrace an anabolic-/catabolic imbalance with increased degradation of myofibrils and myocyte apoptosis. Clinical effects include reduced muscle mass, strength and consequently reduced exercise capacity. This article describes the terminology, molecular pathways, prevalence, clinical implications and possible treatment approaches to muscle wasting in patients with heart failure. This article is part of a Directed Issue entitled: Muscle wasting. © 2013 Elsevier Ltd. All rights reserved.

Haeusler K.G.,Charité - Medical University of Berlin | Haeusler K.G.,Center for Stroke Research Berlin | Kirchhof P.,University of Munster | Kirchhof P.,University of Birmingham | And 2 more authors.
Stroke | Year: 2012

Left atrial catheter ablation (LACA) has become an established therapy to abolish drug-refractory symptomatic paroxysmal and persistent atrial fibrillation. Restoring sinus rhythm by LACA may help to prevent atrial fibrillation-related strokes, but presently there is no evidence from randomized clinical trials to support this notion. This review summarizes the current knowledge and uncertainties regarding LACA and procedure-related ischemic stroke. In fact, most patients who undergo LACA have a rather low annual stroke risk even when left untreated, whereas LACA imposes a risk of procedure-related stroke of ≈0.5% to 1%. In addition, LACA may cause cerebral microemboli, resulting in ischemic lesions. These cerebral lesions, detectable by high-resolution MRI, could contribute to neuropsychological deficits and cognitive dysfunction. Furthermore, recurrent atrial fibrillaton episodes can be detected up to years after LACA and might cause ischemic strokes, especially in those patients in whom therapeutic anticoagulation was discontinued. Further prospective multicenter trials are needed to identify procedure-dependent risk factors for stroke and to optimize postprocedural anticoagulation management. © 2011 American Heart Association. All rights reserved.

Jiang Q.,Max Delbrück Center for Molecular Medicine | Lagos-Quintana M.,Max Delbrück Center for Molecular Medicine | Liu D.,Max Delbrück Center for Molecular Medicine | Shi Y.,Max Delbrück Center for Molecular Medicine | And 5 more authors.
Hypertension | Year: 2013

Microvascular rarefaction increases vascular resistance and pressure in systemic arteries and is a hallmark of fixed essential hypertension. Preventing rarefaction by activation of angiogenic processes could lower blood pressure. Endothelial tip cells in angiogenic sprouts direct branching of microvascular networks; the process is regulated by microRNAs, particularly the miR-30 family. We investigated the contribution of miR-30 family members in arteriolar branching morphogenesis via delta-like 4 (Dll4)-Notch signaling in a zebrafish model. The miR-30 family consists of 5 members (miR-30a-e). Loss-of-function experiments showed that only miR-30a reduced growth of intersegmental arterioles involving impaired tip cell function. Overexpression of miR-30a stimulated tip cell behavior resulting in augmented branching of intersegmental arterioles. In vitro and in vivo reporter assays showed that miR-30a directly targets the Notch ligand Dll4, a key inhibitor of tip cell formation. Coadministration of a Dll4 targeting morpholino in miR-30a morphants rescued the branching defects. Conversely, conditional overexpression of Notch intracellular domain restored arteriolar branching in miR-30a gain-of-function embryos. In human endothelial cells, loss of miR-30a increased DLL4 protein levels, activated Notch signaling as indicated in Notch reporter assays, and augmented Notch downstream effector, HEY2 and EFNB2 (ephrin-B2), expression. In spheroid assays, miR-30a loss- and gain-of-function affected tip cell behavior, consistent with miR-30a targeting Dll4. Our data suggest that miR-30a stimulates arteriolar branching by downregulating endothelial Dll4 expression, thereby controlling endothelial tip cell behavior. These findings could have relevance to the rarefaction process and, therefore, to hypertension. © 2013 American Heart Association, Inc.

Ebinger M.,Center for Stroke Research Berlin | Ebinger M.,Charité - Medical University of Berlin | Kufner A.,Charité - Medical University of Berlin | Galinovic I.,Charité - Medical University of Berlin | And 7 more authors.
Stroke | Year: 2012

Background and Purpose-: We investigated if hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences in arteries and parenchyma are associated with poor outcome 3 months after thrombolysis. Methods-: Consecutive acute stroke patients with known time of symptom onset who had an MRI before and 1 day after thrombolysis were included in this study. Blinded to follow-up imaging and outcome, 2 raters independently judged the presence or absence of arterial and parenchymal FLAIR hyperintensities. Functional outcome (modified Rankin Scale) was assessed after 3 months. Results-: Out of 90 patients, 22 had parenchymal FLAIR hyperintensities and 42 had hyperintense vessels. The combination of FLAIR hyperintensities in arteries and parenchyma occurred in 15 patients. Stepwise forward regression analysis revealed an adjusted odds ratio of 14.5 for a worse outcome (modified Rankin Scale score >2) in patients with FLAIR hyperintensities in arteries and parenchyma (95% confidence interval, 1.3-158.5; P=0.03). Conclusions-: FLAIR hyperintensities in arteries and parenchyma are an easy-to-use MRI feature in acute ischemic stroke associated with poor outcome 3 months after thrombolysis. © 2011 American Heart Association, Inc.

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