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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2015, Vol. 17(suppl5), pp.v41-v41
    Description: BACKGROUND: Hypoxia is a key driver for infiltrative growth in experimental gliomas. It has remained elusive whether tumor hypoxia in glioblastoma patients contributes to distant or diffuse recurrences. We therefore investigated the influence of perioperative cerebral ischemia on patterns of progression in glioblastoma patients. METHODS: We retrospectively screened MRI scans of 245 patients with newly diagnosed glioblastoma undergoing resection for perioperative ischemia near the resection cavity. 46 showed relevant ischemia nearby the resection cavity. A control cohort without perioperative ischemia was generated by a 1:1 matching using an algorithm based on gender, age and adjuvant treatment. Both cohorts were analyzed for patterns of progression by a blinded neuroradiologist. RESULTS: The percentage of diffuse or distant recurrences at first relapse was significantly higher in the cohort with perioperative ischemia (61.1%) compared to the control cohort (19.4%). The results of the control cohort matched well with historical data. The change in patterns of progression was not associated with a difference in survival. CONCLUSIONS: This study reveals an unrecognized association of perioperative cerebral ischemia with distant or diffuse recurrence in glioblastoma. It is the first clinical study supporting the concept that hypoxia is a key driver of infiltrative tumor growth in glioblastoma patients.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 January 2014, Vol.111(1), pp.409-14
    Description: A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
    Keywords: Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents, Alkylating -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Cell Cycle Proteins -- Metabolism ; Glioblastoma -- Drug Therapy ; Glioma -- Drug Therapy ; Intracellular Signaling Peptides and Proteins -- Metabolism ; O(6)-Methylguanine-DNA Methyltransferase -- Pharmacology ; Tor Serine-Threonine Kinases -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    In: Stroke, 2017, Vol.48(5), pp.1397-1399
    Description: BACKGROUND AND PURPOSE—: Little is known about the frequency and the clinical characteristics of neurogenic dysphagia in pontine strokes. In this study, we sought to identify predictors for dysphagia in a cohort of patients with isolated pontine infarctions. METHODS—: We included all patients admitted to our department between 2008 and 2014 having an acute (〈48 hours after symptom onset) ischemic stroke in the pons, as documented by means of diffusion-weighted magnetic resonance imaging. Precise infarct localization was stratified according to established vascular territories. The presence of dysphagia was the primary end point of the study and was assessed by a Speech-Language Pathologist according to defined criteria. RESULTS—: The study recruited 59 patients, 14 with and 45 without dysphagia. Median (interquartile range) stroke severity (in terms of National Institutes of Health Stroke Scale values) was higher in the dysphagic group as compared with patients without dysphagia (8.5 [6–12] versus 2 [1–5]; P〈0.001). Infarct localization in the upper part of the pons (78.6% versus 33.3%; P=0.004) and in the anterolateral vascular territory (78.6% versus 31.1%; P=0.002) occurred more often in the dysphagic group. In a multivariate model, age, infarct volume, and National Institutes of Health Stroke Scale value were independent predictors of dysphagia. CONCLUSIONS—: Dysphagia occurs frequently in patients with isolated pontine infarctions. Clinical and imaging predictors of dysphagia may help to provide optimal screening, to prevent complications and to improve long-term prognosis.
    Keywords: Aspiration ; Dysphagia ; Infarction ; Pons ; Stroke ; Brain Stem Infarctions -- Complications ; Deglutition Disorders -- Etiology ; Pons -- Diagnostic Imaging;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 4
    Language: English
    In: Clinical chemistry, January 2017, Vol.63(1), pp.377-385
    Description: Recent studies have suggested that glial fibrillary acidic protein (GFAP) serum concentrations distinguish between intracerebral hemorrhage (ICH) and ischemic stroke (IS) shortly after symptom onset. In this prospective multicenter trial we validated GFAP in an independent patient cohort and assessed the quantitative relationship between GFAP release, bleeding size, and localization. We included patients with a persistent neurological deficit (NIH Stroke Scale ≥4) suggestive of stroke within 6 h of symptom onset. Blood samples were drawn at hospital admission. GFAP serum concentrations were measured using an electrochemiluminometric immunoassay. Primary endpoint was the final diagnosis established at hospital discharge (ICH, IS, or stroke mimic). 202 patients were included (45 with ICH, 146 with IS, 11 stroke mimics). GFAP concentrations were significantly higher in ICH than in IS patients [median (interquartile range) 0.16 μg/L (0.04-3.27) vs 0.01 μg/L (0.01-0.01), P 〈0.001]. A GFAP cutoff of 0.03 μg/L provided a sensitivity of 77.8% and a specificity of 94.2% in distinguishing ICH from IS and stroke mimics [ROC analysis area under the curve 0.872 (95% CI, 0.802-0.942), P 〈0.001]. GFAP serum concentrations were positively correlated with ICH volume. Lobar ICH volumes were larger and thus associated with higher GFAP concentrations as compared to deep ICH. Serum GFAP was confirmed to be a biomarker indicating ICH in patients presenting with acute stroke symptoms. Very small ICH may be missed owing to less tissue destruction.
    Keywords: Brain Ischemia -- Blood ; Cerebral Hemorrhage -- Blood ; Glial Fibrillary Acidic Protein -- Blood ; Stroke -- Blood
    ISSN: 00099147
    E-ISSN: 1530-8561
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  • 5
    Language: English
    In: International Journal of Stroke, July 2014, Vol.9(5), pp.569-575
    Description: Background Direct oral anticoagulants (DOAC) are alternatives to the use of vitamin K antagonists (VKA) as oral anticoagulant therapies to prevent stroke in patients with atrial fibrillation. Aims We assembled a representative secondary prevention cohort from four tertiary care stroke centers to identify factors that independently influence therapeutic decision making 1) not to anticoagulate with either VKA or DOAC and 2) to use DOAC if the patient appears suitable for oral anticoagulant therapy. Methods We identified all patients discharged with the diagnoses ‘ischemic stroke’ (ICD-10 code 163) or ‘transient ischemic attack’ (G45) in combination with ‘atrial fibrillation’ (148) during 1 year. We performed binary logistic regression analyses to identify factors independently influencing the aforementioned decisions. Results Our cohort comprised 758 patients. At discharge from the stroke service, 374 patients (49·3%) received oral anticoagulant therapy. Older age, severe stroke, poor recovery in the acute phase, and higher serum creatinine were independent factors to withhold oral anticoagulant therapy, whereas prior oral anticoagulant therapy favored the decision to anticoagulate. Among patients who were anticoagulated, prescription was balanced for VKA (50·3%) and DOAC (49·7%). Renal function and prior oral anticoagulant therapies were the most important factors in this decision. Conclusions Shortly after their marketing, DOAC are used as frequently as VKA for secondary stroke prevention in patients with atrial fibrillation. The decision between VKA and DOAC is mainly determined by the patient's renal function and the absence or presence of prior oral anticoagulant therapy.
    Keywords: Adherence ; Atrial Fibrillation ; Safety ; Stroke ; Thrombin ; Xa ; Medicine
    ISSN: 1747-4930
    E-ISSN: 1747-4949
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  • 6
    Language: English
    In: Clinical and experimental rheumatology, 2013, Vol.31(3 Suppl 77), pp.93-5
    Description: Familial Mediterranean fever (FMF) is an autoinflammatory autosomal recessive disease caused by mutations of the Mediterranean fever (MEFV) gene on chromosome 16p. Clinically, it is characterized by recurrent episodes of fever and painful polyserositis. An association of FMF with systemic vasculitis, namely Henoch-Schönlein purpura, polyarteritis nodosa and Behçet's disease has been described. Neurological manifestations of FMF occur rarely and include demyelinating (MS-like) lesions, posterior reversible encephalopathy syndrome, and pseudotumour cerebri. Hitherto hardly known, we herein present a young patient with a genetically proven FMF who suffered a brain stem infarction during a typical FMF attack. After a careful diagnostic workup including cerebrospinal fluid analysis, intra-arterial angiography and leptomeningeal biopsy, a FMF-associated central nervous system vasculitis was identified as the cause of stroke. The pathophysiological background and potential therapeutic strategies are discussed.
    Keywords: Brain Stem Infarctions -- Etiology ; Familial Mediterranean Fever -- Complications ; Vasculitis, Central Nervous System -- Etiology
    ISSN: 0392-856X
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 7
    Language: English
    In: Cerebrovascular Diseases, October 2013, Vol.36(2), pp.115-119
    Description: Background: The novel direct oral anticoagulants (NOA), dabigatran (a thrombin inhibitor), rivaroxaban and apixaban (factor Xa inhibitors) have shown at least noninferiority compared to warfarin concerning the prevention of stroke and systemic embolism as well as the risk of hemorrhagic complications in large phase III trials in patients with atrial fibrillation (AF). These results have been obtained under regular monitoring of side effects and reinforcement of medication adherence in carefully controlled clinical trials. To what extent they translate into clinical practice is a matter of ongoing research. While postmarketing registers, most prominently the GLORIA-AF registry, are currently recruiting and will not report data for several years, we aimed at extracting risk factors for hemorrhagic complications under NOA from all available case reports and single case series published to date. Methods: To identify risk factors which increase the risk of hemorrhage under NOA, we performed a PubMed search for both dabigatran and rivaroxaban, as well as three search terms for hemorrhagic complications. The cases of hemorrhagic complications were analyzed for the presence of the following four factors: ‘prescriber errors', ‘unfavorable comedications', ‘renal impairment' and ‘prescription of NOA in the frail elderly'. Results and Discussion: We found a discrepancy in the frequency of case reports on hemorrhagic complications to the disadvantage of dabigatran which can hardly be attributed to the earlier marketing time of dabigatran alone. As risk factors, we identified prescriber errors, impaired renal function, comedication with antiplatelet drugs or p-glycoprotein inhibitors, old age and low body weight. Strikingly, the majority of the bleeding complications reported in this compilation of case reports showed at least one and in most cases several risk factors. Conclusions: We should, therefore, carefully select our patients for treatment with the NOA with an emphasis on age, body weight, renal function and comedications and follow them faithfully concerning their medication adherence and eventual side effects.
    Keywords: Original Paper ; Anticoagulant Therapy ; Cardioembolic Stroke ; Intracranial Hemorrhage ; Warfarin-Associated Intracerebral Hemorrhage ; Medicine
    ISSN: 1015-9770
    E-ISSN: 1421-9786
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  • 8
    Language: English
    In: Patient preference and adherence, 2015, Vol.9, pp.1695-705
    Description: 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. 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. 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. 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.
    Keywords: Adherence ; Non-Vka Oral Anticoagulants ; Prevention ; Stroke ; Vitamin K Antagonists
    ISSN: 1177-889X
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  • 9
    Language: English
    In: Therapeutic Advances in Neurological Disorders, 17 April 2018, Vol.11
    Description: Background: Sphingolipids are versatile signaling molecules derived from membrane lipids of eukaryotic cells. Ceramides regulate cellular processes such as proliferation, differentiation and apoptosis and are involved in cellular stress responses. Experimental evidence suggests a pivotal role of sphingolipids in the pathogenesis of cardiovascular diseases, including ischemic stroke. A neuroprotective effect has been shown for beta-adrenergic antagonists in rodent stroke models and supported by observational clinical data. However, the exact underlying pathophysiological mechanisms are still under investigation. We aimed to examine the influence of propranolol on the ceramide metabolism in the stroke-affected brain. Methods: Mice were subjected to 60 or 180 min transient middle cerebral artery occlusion (tMCAO) and infarct size, functional neurological deficits, glucose tolerance, and brain ceramide levels were assessed after 12, 24, and 72 h to evaluate whether the latter two processes occur in a similar time frame. Next, we assessed the effects of propranolol (10 mg/kg bw) at 0, 4 and 8 h after tMCAO and FTY720 (fingolimod; 1 mg/kg) on infarct size, functional outcome, immune cell counts and brain ceramide levels at 24 h after 60 min tMCAO. Results: We found a temporal coincidence between stroke-associated impaired glucose tolerance and brain ceramide accumulation. Whereas propranolol reduced ischemic lesion size, improved functional outcome and reduced brain ceramide accumulation without an effect on circulating immune cells, FTY720 showed the known neuroprotective effect and strong reduction of circulating immune cells without affecting brain ceramide accumulation. Conclusions: Propranolol ameliorates both stroke-associated impairment of glucose tolerance and brain ceramide accumulation which are temporally linked, strengthening the evidence for a role of the sympathetic nervous system in regulating post-stroke glucose metabolism and its metabolic consequences in the brain.
    Keywords: Stroke ; Glucose Metabolism ; Hyperglycemia ; Ceramides ; Sphingolipids ; Fty720 ; Beta Blockade ; Medicine
    ISSN: 17562856
    E-ISSN: 1756-2864
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  • 10
    Language: English
    In: Stroke, 02/2019, Vol.50(Suppl_1)
    ISSN: 0039-2499
    E-ISSN: 1524-4628
    Source: Wolters Kluwer - Ovid (via CrossRef)
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