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Swidsinski A.,Center for Stroke Research | Schroedl W.,Institute of Bacteriology and Mycology | Watson A.,University of East Anglia | Valentova M.,University of Gottingen | And 5 more authors.
Journal of the American College of Cardiology | Year: 2014

BACKGROUND Blood flow in the intestinal arteries is reduced in patients with stable heart failure (HF) and relates to gastrointestinal (GI) symptoms and cardiac cachexia. OBJECTIVES The aims of this study were to measure arterial intestinal blood flow and assess its role in juxtamucosal bacterial growth, GI symptoms, and cachexia in patients with HF. METHODS A total of 65 patients and 25 controls were investigated. Twelve patients were cachectic. Intestinal blood flow and bowel wall thickness were measured using ultrasound. GI symptoms were documented. Bacteria in stool and juxtamucosal bacteria on biopsies taken during sigmoidoscopy were studied in a subgroup by fluorescence in situ hybridization. Serum lipopolysaccharide antibodies were measured. RESULTS Patients showed 30% to 43% reduced mean systolic blood flow in the superior and inferior mesenteric arteries and celiac trunk (CT) compared with controls (p < 0.007 for all). Cachectic patients had the lowest blood flow (p < 0.002). Lower blood flow in the superior mesenteric artery and CT was correlated with HF severity (p < 0.04 for all). Patients had more feelings of repletion, flatulence, intestinal murmurs, and burping (p < 0.04). Burping and nausea or vomiting were most severe in patients with cachexia (p < 0.05). Patients with lower CT blood flow had more abdominal discomfort and immunoglobulin A-antilipopolysaccharide (r = 0.76, p < 0.02). Antilipopolysaccharide response was correlated with increased growth of juxtamucosal but not stool bacteria. Patients with intestinal murmurs had greater bowel wall thickness of the sigmoid and descending colon, suggestive of edema contributing to GI symptoms (p < 0.05). In multivariate regression analysis, lower blood flow in the superior mesenteric artery, CT (p < 0.04), and inferior mesenteric artery (p = 0.056) was correlated with the presence of cardiac cachexia. CONCLUSIONS Intestinal blood flow is reduced in patients with HF. This may contribute to juxtamucosal bacterial growth and GI symptoms in patients with advanced HF complicated by cachexia. (J Am Coll Cardiol 2014;64:1092-102) © 2014 by the American College of Cardiology Foundation.


Puetz V.,Dresden University Stroke Center | Bodechtel U.,Dresden University Stroke Center | Gerber J.C.,Dresden University Stroke Center | Dzialowski I.,Dresden University Stroke Center | And 13 more authors.
Neurology | Year: 2013

Objective: To determine the reliability and therapeutic impact of standardized cerebral CT evaluation and quantification of early ischemic changes (EIC) with the Alberta Stroke Program Early CT Score (ASPECTS) by stroke neurologists in the Stroke Eastern Saxony Network (SOS-NET), which provides telemedical consultations for patients with acute ischemic stroke. Methods: Two neuroradiologists re-evaluated all CT scans of consecutive SOS-NET patients in 2009 blinded to clinical information providing reference standard. We defined discrepant CT findings as all false-positive or false-negative EIC and brain pathology findings and ASPECTS deviations >1 point. We subsequently discussed the clinical impact of discrepant CT findings unblinded to clinical information. Weighted kappa (kw) statistic was used to determine the interobserver agreement for ASPECTS. Results: Of 582 patients, complete imaging data were available for 536 patients (351 cerebralischemic events, 105 primary intracranial hemorrhages, and 80 stroke mimics). The neuroradiologists detected discrepant CT findings in 43 patients (8.0%) that were rated as clinically relevant in 9 patients (1.7%). Stroke neurologists recommended IV thrombolysis in 8 patients despite extensive EIC (ASPECTS ≤5). One of these patients had symptomatic intracranial hemorrhage. In 1 nonthrombolyzed patient, the stroke neurologist missed subdural hematoma. The interobserver agreement on ASPECTS between stroke neurologists and expert readers was substantial (kw = 0.62; 95% confidence interval 0.54-0.71). Conclusions: Clinically relevant misinterpretation of the CT scans was rare in our acute telestroke service. ASPECTS is a reliable tool to assess the extent of EICby stroke neurologists in telemedicine in real time. Copyright © 2013 American Academy of Neurology.


Cramer L.,Applied Cachexia Research | Hildebrandt B.,Charite Medical School | Kung T.,Applied Cachexia Research | Wichmann K.,Applied Cachexia Research | And 13 more authors.
Journal of the American College of Cardiology | Year: 2014

Background Patients with colorectal cancer (CRC) often present with dyspnea and fatigue. These are also frequent symptoms in patients with chronic heart failure (CHF).Objectives We hypothesized that similar patterns of cardiovascular perturbations are present in CRC and CHF.Methods We prospectively studied 50 patients with CRC, 51 patients with CHF, and 51 control subjects. The CRC group was divided into 2 subgroups: patients who underwent chemotherapy (n = 26) and chemotherapy-naive patients (n = 24). We assessed exercise capacity (spiroergometry), cardiac function (echocardiography), heart rate variability (Holter electrocardiography), body composition (dual-energy x-ray absorptiometry), and blood parameters.Results Compared with the control arm, the left ventricular ejection fraction (CRC group 59.4%; control group 62.5%) and exercise performance as assessed by peak oxygen consumption (peak VO2) (CRC group 21.8 ml/kg/min; control group 28.0 ml/kg/min) were significantly reduced in CRC patients (both p < 0.02). Markers of heart rate variability were markedly impaired in CRC patients compared with control subjects (all p < 0.008). Compared with the control group, the CRC group also showed reduced lean mass in the legs and higher levels of the endothelium-derived C-terminal-pro-endothelin-1 (both p < 0.02). Major determinants of cardiovascular function were impaired in chemotherapy-treated patients and in the chemotherapy-naive patients, particularly with regard to exercise capacity, left ventricular ejection fraction, lean mass, and heart rate variability (all p < 0.05 vs. control subjects).Conclusions Some aspects of cardiovascular function are impaired in patients with CRC. More importantly, our findings were evident independently of whether patients were undergoing chemotherapy. © 2014 American College of Cardiology Foundation.


Ringelstein E.B.,University of Munster | Thijs V.,Catholic University of Leuven | Thijs V.,Vesalius Research Center | Norrving B.,Lund University | And 21 more authors.
Stroke | Year: 2013

Background and Purpose-Granulocyte colony-stimulating factor (G-CSF; AX200; Filgrastim) is a stroke drug candidate with excellent preclinical evidence for efficacy. A previous phase IIa dose-escalation study suggested potential efficacy in humans. The present large phase IIb trial was powered to detect clinical efficacy in acute ischemic stroke patients. Methods-G-CSF (135 μg/kg body weight intravenous over 72 hours) was tested against placebo in 328 patients in a multinational, multicenter, randomized, and placebo-controlled trial (NCT00927836; www.clinicaltrial.gov). Main inclusion criteria were ≤9-hour time window after stroke onset, infarct localization in the middle cerebral artery territory, baseline National Institutes of Health Stroke Scale score range of 6 to 22, and baseline diffusion-weighted imaging lesion size ≥15 mL. Primary and secondary end points were the modified Rankin scale score and the National Institutes of Health Stroke Scale score at day 90, respectively. Data were analyzed using a prespecified model that adjusted for age, National Institutes of Health Stroke Scale score at baseline, and initial infarct volume (diffusion-weighted imaging). Results-G-CSF treatment failed to meet the primary and secondary end points of the trial. For additional end points such as mortality, Barthel index, or infarct size at day 30, G-CSF did not show efficacy either. There was, however, a trend for reduced infarct growth in the G-CSF group. G-CSF showed the expected peripheral pharmacokinetic and pharmacodynamic profiles, with a strong increase in leukocytes and monocytes. In parallel, the cytokine profile showed a significant decrease of interleukin-1. Conclusions-G-CSF, a novel and promising drug candidate with a comprehensive preclinical and clinical package, did not provide any significant benefit with respect to either clinical outcome or imaging biomarkers. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836. © 2013 American Heart Association, Inc.


Tong D.,Comprehensive Care | Tong D.,Center for Stroke Research | Reeves M.J.,Michigan State University | Hernandez A.F.,Duke Clinical Research Institute | And 5 more authors.
Stroke | Year: 2012

Background and Purpose-Time from symptom onset to hospital arrival is the most important factor in determining eligibility for intravenous tissue-type plasminogen activator. We used data from a large contemporary nationwide study to determine temporal trends in the proportions of patients arriving within time windows for potential acute ischemic stroke therapies. Methods-Trends in symptom onset to hospital arrival time ("onset-to-door time") for patients with acute ischemic stroke in the Get With The Guidelines-Stroke (GWTG-Stroke) program were analyzed between 2003 and 2009. Factors associated with early onset-to-door time (≤2 hours) were also examined. Results-Between April 2003 and March 2009, 1287 hospitals submitted data on 413 147 patients with acute ischemic stroke of whom 194 352 (47.0%) had a specific onset time documented. Among all 413 147 patients, onset-to-door time was documented as ≤2 hours in 20.6%, ≤3 hours in 25.1%, ≤3.5 hours in 26.8%, and ≤8 hours in 35.8%. Early arrival within 2 hours was significantly associated with emergency medical services transport (P<0.0001). There was no substantial change in onset-to-door time over the 6-year study period. Expansion of the tissue-type plasminogen activator treatment window from 3 to 4.5 hours (allowing 60 minutes for provision of tissue-type plasminogen activator) increases the pool of potentially eligible patients by 6.3% (30.1% relative increase). Conclusions-More than one fourth of patients with ischemic stroke arrive within the time window for tissue-type plasminogen activator therapy; however, this percentage has remained unchanged over recent years. Further efforts are needed to increase the portion of patients with acute ischemic stroke presenting within the time window for acute interventions. © 2012 American Heart Association, Inc.


Schabitz W.R.,University of Munster | Laage R.,Sygnis Bioscience | Vogt G.,Sygnis Bioscience | Koch W.,HaaPACS GmbH | And 11 more authors.
Stroke | Year: 2010

Background and Purpose: Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data. Methods: Four intravenous dose regimens (total cumulative doses of 30-180 μg/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch. Results: Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions >14-17 cm. Conclusions: We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points. © 2010 American Heart Association, Inc.


Royl G.,Charité - Medical University of Berlin | Royl G.,Center for Stroke Research | Ploner C.J.,Charité - Medical University of Berlin | Leithner C.,Charité - Medical University of Berlin | Leithner C.,NeuroCure Research Center
European Neurology | Year: 2011

Background: Dizziness is among the most frequent neurological chief complaints in emergency room (ER) patients. Although the majority of underlying disorders are benign, serious causes that require immediate in-hospital treatment may occur that are difficult to identify clinically. Methods: Retrospective study of 475 consecutive ER neurological consultations with dizziness as the chief complaint. Results: Of all ER dizziness patients, 73% were initially assigned to benign and 27% to serious diagnoses. The two most frequent disorders were benign paroxysmal positional vertigo (22%) and stroke (20%). On follow-up (available in 124 patients), 43% of all ER diagnoses were corrected: 6% of benign ER diagnoses were corrected to serious diagnoses, 23% of serious ER diagnoses were revised to benign. The most frequent corrections concerned patients with an ER diagnosis of stroke or vestibular neuronitis. Conclusions: In the patient sample studied here, serious causes of dizziness were more prevalent than can be expected from population-based surveys or data from specialized outpatient departments. However, inappropriate assignment of dizziness patients to benign diagnoses still occurred in a relevant proportion of patients. ER clinical pathways, planning of imaging resources and followup of patients in- and outside the hospital must take these points into consideration. Copyright © 2011 S. Karger AG, Basel.


Engel O.,Center for Stroke Research | Dirnagl U.,Center for Stroke Research | Meisel A.,Center for Stroke Research
Journal of Experimental Stroke and Translational Medicine | Year: 2010

Many publications show that infections have a tremendous impact on both general medical and neurological outcome. Summarizing the findings from several experimental studies we conclude that controlling infections in animal models of stroke is indispensable similar to checking body temperature in order to avoid misinterpretations of study results. In our manuscript we followed the structure used in the original article to provide a consistent outline. In brief, we reviewed the necessity of monitoring post-stroke infections, followed by a section on how to exclude the impact of infections in stroke models. Copyright © 2010 SFES.


De Silva D.A.,Royal Melbourne Hospital | De Silva D.A.,Singapore General Hospital Campus | Brekenfeld C.,National Stroke Research Institute | Ebinger M.,Royal Melbourne Hospital | And 11 more authors.
Stroke | Year: 2010

Background and Purpose-In ischemic stroke, the site of arterial obstruction has been shown to influence recanalization and clinical outcomes. However, this has not been studied in randomized controlled trials, nor has the impact of arterial obstruction site on reperfusion and infarct growth been assessed. We studied the influence of site and degree of arterial obstruction patients enrolled in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). Methods-EPITHET was a prospective, randomized, placebo-controlled trial of intravenous tissue plasminogen activator (tPA) in the 3-to 6-hour time window. Arterial obstruction site and degree were rated on magnetic resonance angiography blinded to treatment allocation and outcomes. Results-In 101 EPITHET patients, 87 had adequate quality magnetic resonance angiography, of whom 54 had baseline arterial obstruction. Infarct growth attenuation was greater in those with tPA treatment compared to placebo among patients with middle cérébral artery (MCA) obstruction (P=0.037). The treatment benefit of tPA over placebo in attenuating infarct growth was greater for MCA than internal carotid artery (ICA) obstruction (P=0.060). With tPA treatment, good clinical outcome was more likely with MCA than with ICA obstruction (P=0.005). Most patients with ICA obstruction did not achieve good clinical outcome, whether treated with tPA (100%) or placebo (77%). The study was underpowered to prove any treatment benefit of tPA among patients with any or severe degree of arterial obstruction. Conclusions-Arterial obstruction site strongly predicts outcomes. ICA obstruction carries a uniformly poor prognosis, whereas good outcomes with MCA obstruction are associated with tPA therapy. Copyright © 2010 American Heart Association. All rights reserved.


Little D.M.,645 West Jackson Suite 400 | Little D.M.,Center for Stroke Research | Little D.M.,Center for Cognitive Medicine | Kraus M.F.,645 West Jackson Suite 400 | And 13 more authors.
Neurology | Year: 2010

Objective: To quantify the effects of traumatic brain injury on integrity of thalamocortical projection fibers and to evaluate whether damage to these fibers accounts for impairments in executive function in chronic traumatic brain injury. Methods: High-resolution (voxel size: 0.78 mm × 0.78 mm × 3 mm) diffusion tensor MRI of the thalamus was conducted on 24 patients with a history of single, closed-head traumatic brain injury (TBI) (12 each of mild TBI and moderate to severe TBI) and 12 age-and education-matched controls. Detailed neuropsychological testing with an emphasis on executive function was also conducted. Fractional anisotropy was extracted from 12 regions of interest in cortical and corpus callosum structures and 7 subcortical regions of interest (anterior, ventral anterior, ventral lateral, dorsomedial, ventral posterior lateral, ventral posterior medial, and pulvinar thalamic nuclei). Results: Relative to controls, patients with a history of brain injury showed reductions in fractional anisotropy in both the anterior and posterior corona radiata, forceps major, the body of the corpus callosum, and fibers identified from seed voxels in the anterior and ventral anterior thalamic nuclei. Fractional anisotropy from cortico-cortico and corpus callosum regions of interest did not account for significant variance in neuropsychological function. However, fractional anisotropy from the thalamic seed voxels did account for variance in executive function, attention, and memory. Conclusions: The data provide preliminary evidence that traumatic brain injury and resulting diffuse axonal injury Results in damage to the thalamic projection fibers and is of clinical relevance to cognition. © 2010 by AAN Enterprises, Inc.

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