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  • 1
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    A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 3 ( 2023-03-01), p. 977-990
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 3 ( 2023-03-01), p. 977-990
    Abstract: Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P & lt; 5 × 10−8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10−16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187–0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci ( & gt;90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10−4, OR = 2.5, 95%CI = 1.499–4.157) and DRB1*04:01 allele (P = 8.3 × 10−5, OR = 2.4, 95%CI = 1.548–3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac119
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
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  • 2
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    Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 2 ( 2023-02-13), p. 600-611
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 2 ( 2023-02-13), p. 600-611
    Abstract: Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/ or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac090
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 3
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    Impact of Thrombolysis on Stroke Outcome at 12 Months in a Population : The Bern Stroke Project
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Stroke Vol. 43, No. 4 ( 2012-04), p. 1039-1045
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. 4 ( 2012-04), p. 1039-1045
    Abstract: Thrombolysis improves outcome of patients with acute ischemic stroke, but it is unknown whether thrombolysis has a measurable effect on long-term outcome in a defined population. Methods— We prospectively assessed demographic data, management, and outcome of acute ischemic stroke patients admitted within 48 hours to 18 primary care hospitals of the canton of Bern (969 299 inhabitants) during 12 months. Blinded follow-up was obtained at 3 and 12 months. Predictors of mortality and favorable outcome (modified Rankin Scale score ≤2) at 3 and 12 months using logistic regression were analyzed. Results— From December 2007 to December 2008, 807 patients (mean age, 72 years) were included. Median National Institutes of Health Stroke Scale score on admission was 5; 107 patients (13%) received intravenous, intra-arterial, or mechanical thrombolysis. Estimated cumulative mortality at 3 months was 20.6% and at 12 months 27.4%. Age 75 years or older, higher National Institutes of Health Stroke Scale scores, and higher Charlson comorbidity index were independent predictors of mortality at 3 and 12 months. Estimated favorable outcome at 3 months was 48.2% and at 12 months was 44.6%. Thrombolysis was the only modifiable independent predictor of favorable outcome at 3 (relative risk, 1.49; 95% CI, 1.18–1.89) and 12 months (relative risk, 1.59; 95% CI, 1.24–2.04), whereas age younger than 75 years, male gender, National Institutes of Health Stroke Scale score 〈 4, and lower Charlson comorbidity index were nonmodifiable predictors. Conclusions— Thirteen percent of acute ischemic stroke patients admitted within 48 hours to Bernese hospitals underwent thrombolysis, which exerted a measurable effect on 3-month outcome in this population. This effect was sustained at 12 months. Age, stroke severity, Charlson comorbidity index, and male gender were independent nonmodifiable predictors of outcome.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.111.630384
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
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  • 4
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    Preexisting Cerebral Microbleeds on Susceptibility-Weighted Magnetic Resonance Imaging and Post-Thrombolysis Bleeding Risk in 392 Patients
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. 6 ( 2014-06), p. 1684-1688
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. 6 ( 2014-06), p. 1684-1688
    Abstract: The question whether cerebral microbleeds (CMBs) visible on MRI in acute stroke increase the risk for intracerebral hemorrhages (ICHs) or worse outcome after thrombolysis is unresolved. The aim of this study was to analyze the impact of CMB detected with pretreatment susceptibility-weighted MRI on ICH occurrence and outcome. Methods— From 2010 to 2013 we treated 724 patients with intravenous thrombolysis, endovascular therapy, or intravenous thrombolysis followed by endovascular therapy. A total of 392 of the 724 patients were examined with susceptibility-weighted MRI before treatment. CMBs were rated retrospectively. Multivariable regression analysis was used to determine the impact of CMB on ICH and outcome. Results— Of 392 patients, 174 were treated with intravenous thrombolysis, 150 with endovascular therapy, and 68 with intravenous thrombolysis followed by endovascular therapy. CMBs were detected in 79 (20.2%) patients. Symptomatic ICH occurred in 21 (5.4%) and asymptomatic in 75 (19.1%) patients, thereof 61 (15.6%) bleedings within and 35 (8.9%) outside the infarct. Neither the existence of CMB, their burden, predominant location nor their presumed pathogenesis influenced the risk for symptomatic or asymptomatic ICH. A higher CMB burden marginally increased the risk for ICH outside the infarct ( P =0.048; odds ratio, 1.004; 95% confidence interval, 1.000–1.008). Conclusions— CMB detected on pretreatment susceptibility-weighted MRI did not increase the risk for ICH or worsen outcome, even when CMB burden, predominant location, or presumed pathogenesis was considered. There was only a small increased risk for ICH outside the infarct with increasing CMB burden that does not advise against thrombolysis in such patients.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.114.004796
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 5
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    Younger Stroke Patients With Large Pretreatment Diffusion-Weighted Imaging Lesions May Benefit From Endovascular Treatment
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Stroke Vol. 46, No. 9 ( 2015-09), p. 2510-2516
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. 9 ( 2015-09), p. 2510-2516
    Abstract: Lesion volume on diffusion-weighted magnetic resonance imaging (DWI) before acute stroke therapy is a predictor of outcome. Therefore, patients with large volumes are often excluded from therapy. The aim of this study was to analyze the impact of endovascular treatment in patients with large DWI lesion volumes ( 〉 70 mL). Methods— Three hundred seventy-two patients with middle cerebral or internal carotid artery occlusions examined with magnetic resonance imaging before treatment since 2004 were included. Baseline data and 3 months outcome were recorded prospectively. DWI lesion volumes were measured semiautomatically. Results— One hundred five patients had lesions 〉 70 mL. Overall, the volume of DWI lesions was an independent predictor of unfavorable outcome, survival, and symptomatic intracerebral hemorrhage ( P 〈 0.001 each). In patients with DWI lesions 〉 70 mL, 11 of 31 (35.5%) reached favorable outcome (modified Rankin scale score, 0–2) after thrombolysis in cerebral infarction 2b-3 reperfusion in contrast to 3 of 35 (8.6%) after thrombolysis in cerebral infarction 0-2a reperfusion ( P =0.014). Reperfusion success, patient age, and DWI lesion volume were independent predictors of outcome in patients with DWI lesions 〉 70 mL. Thirteen of 66 (19.7%) patients with lesions 〉 70 mL had symptomatic intracerebral hemorrhage with a trend for reduced risk with avoidance of thrombolytic agents. Conclusions— There was a growing risk for poor outcome and symptomatic intracerebral hemorrhage with increasing pretreatment DWI lesion volumes. Nevertheless, favorable outcome was achieved in every third patient with DWI lesions 〉 70 mL after successful endovascular reperfusion, whereas after poor or failed reperfusion, outcome was favorable in only every 12th patient. Therefore, endovascular treatment might be considered in patients with large DWI lesions, especially in younger patients.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.115.010250
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 6
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    Abstract 84: An Index to Identify Cryptogenic Stroke Patients whose Stroke is likely Attributable to Patent Foramen Ovale
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Stroke Vol. 43, No. suppl_1 ( 2012-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. suppl_1 ( 2012-02)
    Abstract: Background: A patent foramen ovale (PFO) discovered in the setting of a cryptogenic stroke (CS) may be incidental or pathogenic. Based on Bayes theorem, the proportion of CS that is PFO-attributable among patients found to have a PFO has been shown to be related to PFO prevalence in CS versus control patients. However, the prevalence of PFO in CS patients is itself dependent on the presence or absence of other risk factors. We exploited this relationship to create an index to stratify CS patients with PFO by their likelihood that the CS is PFO-attributable. Methods This project is part of the Risk of Paradoxical Embolism (RoPE) Study, an international, multicenter collaboration that has combined data for patients with CS and cryptogenic TIA who have known PFO status from 12 component studies (n=3665). For this study, we included those subjects within the 7 databases enrolling subjects both with and without PFO (n=3023). We used generalized linear mixed models to identify variables associated with the presence of a PFO, accounting for clustering within study. Based on this model, we created a simple index. Bayes theorem was used to estimate the PFO-attributable fraction in each stratum assuming a PFO prevalence in the general population of ∼25%. Results: Variables negatively associated with the presence of a PFO included: age (odds ratio [OR] = 0.97 per 1 year increase, p 〈 0.0001); diabetes (OR= 0.65, p 〈 0.001); hypertension (OR =0.68, p 〈 0.0001); smoking (OR = 0.70, p 〈 0.60); prior stroke or TIA (OR = 0.78, p=0.04). Cortical stroke on neuroimaging (OR = 1.46, p 〈 0.001) was also associated with PFO. Based on this, a simple index was created in which the absence of each stroke risk factor was assigned a point, with age dichotomized at 50 years. PFO prevalence in each stratum is shown in the table for patients 〈 age 60, i.e. the subset of patients likely to be considered for PFO closure trials. Conclusion: Even among CS patients in the younger age range considered eligible for closure trials, there is considerable heterogeneity in the distribution of risk factors for stroke and other characteristics that identify subgroups of CS patients with variation in PFO prevalence. This reflects substantial and clinically important variation in the probability that a discovered PFO is likely to be pathogenic rather than incidental. This score may be useful in selecting patients for closure trials, or for stratification within trials, particularly if combined with a recurrence risk model.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.43.suppl_1.A84
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
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  • 7
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    Abstract 198: PFO and Recurrent Stroke: Predictors Differ In Patients With “Probable Pathogenic” Versus Other PFOs
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Stroke Vol. 44, No. suppl_1 ( 2013-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. suppl_1 ( 2013-02)
    Abstract: Background The “RoPE Score” is a predictive model created to stratify patients by the likelihood that a patent foramen ovale (PFO) is incidental or pathogenic using clinical variables. We hypothesized that the predictors of recurrent stroke differ between patients with pathogenic and incidental PFOs. Methods Patients in the Risk of Paradoxical Embolism (RoPE) database with cryptogenic stroke (CS) and PFO were classified as having a probable pathogenic PFO (RoPE Score of 〉 6, estimated PFO attributable fraction 72-99%, n=646) and others (RoPE Score of 〈 6 points estimated PFO attributable fraction 0-72%, n=678). We tested 15 clinical, 5 radiological, and 3 echo variables for associations with stroke recurrence using Cox survival models with component database as a stratification factor. An interaction with RoPE score was checked for the variables that were significant. Results Follow-up was available for 91%, 80%, and 58% at 1, 2, and 3 years. Overall, a higher recurrence risk was associated with an index TIA, not being on a statin at baseline, and having a prior radiological stroke. For the low RoPE score group, older age, male sex, high cholesterol and antiplatelet (vs warfarin) treatment predicted recurrence. For those with high RoPE scores, predictors were prior (clinical) stroke/TIA and 2 echo features: septal hypermobility and a small shunt ( 〈 10 bubbles). Conclusions Predictors of recurrence differ when PFO relatedness is classified by the RoPE Score. The hypothesis that patients with CS and PFO form a heterogenous group with different stroke mechanisms is supported. Conventional stroke risk factors were strong predictors among patients with lower RoPE scores. Echocardiographic features - including a counterintuitive association between smaller shunts and increased recurrence risk - were uniquely predictive in the high RoPE score group (likely pathogenic PFO).
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.44.suppl_1.A198
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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  • 8
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    Response to Letter by Bhatt
    Ovid Technologies (Wolters Kluwer Health) ; 2009
    In:  Stroke Vol. 40, No. 10 ( 2009-10)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 40, No. 10 ( 2009-10)
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.109.548776
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
    detail.hit.zdb_id: 1467823-8
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  • 9
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    Plaque Characteristics of Asymptomatic Carotid Stenosis and Risk of Stroke
    S. Karger AG ; 2012
    In:  Cerebrovascular Diseases Vol. 34, No. 5-6 ( 2012), p. 343-350
    Details
    In: Cerebrovascular Diseases, S. Karger AG, Vol. 34, No. 5-6 ( 2012), p. 343-350
    Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 The optimal treatment of asymptomatic carotid stenosis (ACS) is controversial. To optimize the risk-benefit ratio of carotid artery revascularization, it is crucial to identify ACS patients who are at increased stroke risk. Recent data suggest that plaque vulnerability depends on its composition. Therefore, we assessed plaque composition in ACS to determine predictors for ipsilateral cerebrovascular events. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 62 patients with 65 ACS ≥50% underwent 3-T MRI of the carotid bifurcation (TOF, special dark-blood weighted noncontrast and contrast-enhanced T 〈 sub 〉 1 〈 /sub 〉 and T 〈 sub 〉 2 〈 /sub 〉 images) and of the brain. The different plaque components (lipid core, intraplaque hemorrhage, calcification and the status of the fibrous cap) were assessed. Furthermore, the plaque volume and the volume of clinically silent cortical and subcortical infarcts in the territory of the stenosed carotid artery as seen on FLAIR images were determined by using a semi-automated software. Carotid stenosis was considered asymptomatic if there had not been any clinically apparent ischemic events in the corresponding vascular territory within the previous 6 months. During follow-up, information on the occurrence of cerebrovascular events, medical treatment and sonographic changes of the stenosis was collected. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 At baseline, 24 ACS (37%) were classified as high grade. A lipid-rich necrotic core was the dominant plaque component in 16 ACS (25%). The plaque volume was higher in ACS with a lipid-rich necrotic core as dominant plaque component (p = 0.002) and in patients with prior stroke/TIA (p = 0.010). After a median follow-up of 18.9 months (interquartile range 3.5–30.1) there were 2 ipsilateral strokes and 3 ipsilateral TIAs. The average annual event rate was 7.7%. A lipid-rich necrotic core (HR 7.21; 95% CI 1.12–46.28; p = 0.037), sonographic progression of the stenosis (HR 7.00; 95% CI 1.13–41.34; p = 0.036), history of stroke (HR 11.03; 95% CI 1.23–99.36; p = 0.032), and the volume of clinically asymptomatic ischemic brain lesions (HR 1.14/cm 〈 sup 〉 3 〈 /sup 〉 ; 95% CI 1.03–1.25; p = 0.008) predicted cerebrovascular events. Patients on statin therapy at follow-up were at lower risk of events (HR 0.17; 95% CI 0.03–1.00; p = 0.05). 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 In addition to medical history and sonographic findings, a lipid-rich necrotic core within the plaque turned out as a predictor of cerebrovascular events. Therefore, MR imaging of carotid plaques deserves further attention and might be helpful to improve risk stratification of asymptomatic carotid disease. The identified predictors could be combined in a risk model and tested in larger prospective studies.
    Type of Medium: Online Resource
    ISSN: 1015-9770 , 1421-9786
    URL: Article
    DOI: 10.1159/000343227
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2012
    detail.hit.zdb_id: 1482069-9
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  • 10
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    Outcome of patients with occlusions of the internal carotid artery or the main stem of the middle cerebral artery with NIHSS score of less than 5: comparison between thrombolysed and non-thrombolysed patients
    BMJ ; 2015
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 86, No. 7 ( 2015-07), p. 755-760
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 86, No. 7 ( 2015-07), p. 755-760
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2014-308401
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2015
    detail.hit.zdb_id: 1480429-3
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