摘要:

Background—Six multivariable models predicting 3-month outcome of acute ischemic stroke have been developed and internally validated previously. The purpose of this study was to externally validate the previous models in an independent data set.Summary of Report—We predicted outcomes for 299 patients with ischemic stroke who received placebo in the National Institute of Neurological Disorders and Stroke rt-PA trial. The model equations used 6 acute clinical variables and head CT infarct volume at 1 week as independent variables and 3-month National Institutes of Health Stroke Scale, Barthel Index, and Glasgow Outcome Scale as dependent variables. Previously developed model equations were used to forecast excellent and devastating outcome for subjects in the placebo tissue plasminogen activator data set. Area under the receiver operator characteristic curve was used to measure discrimination, and calibration charts were used to measure calibration. The validation data set patients were more severely ill (National Institutes of Health Stroke Scale and infarct volume) than the model development subjects. Area under the receiver operator characteristic curves demonstrated remarkably little degradation in the validation data set and ranged from 0.75 to 0.89. Calibration curves showed fair to good calibration.Conclusions—Our models have demonstrated excellent discrimination and acceptable calibration in an external data set. Development and validation of improved models using variables that are all available acutely are necessary.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disorder typified by early onset lacunar strokes, subcortical dementia, psychiatric disturbances, and migraine. Mutations in theNotch3gene are responsible. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Therefore, we determined the yield of screening forNotch3mutations in lacunar stroke with or without leukoaraiosis.Methods—Two hundred eighteen consecutive patients were studied. All had brain and carotid imaging. Polymerase chain reaction-single-stranded conformational polymorphism analysis was used to screen exons 3, 4, 5, and 6 of theNotch3gene for mutations and polymorphisms.Results—A single mutation in exon 4 (C697T) was identified in a young patient, giving an overall carrier frequency of 0.05% (95% CI, 0.0 to 2.0). For patients with onset of lacunar stroke at ≤65 years and leukoaraiosis, the yield was 2.0% (95% CI, 0.4 to 10.9).Conclusions—Notch3mutations are rare in patients with typical strokes due to cerebral small-vessel disease. In the absence of classic features suggestive of CADASIL, screening forNotch3mutations has a low yield.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—Different strategies for neuroprotection of neonatal stroke may be required because the developing brain responds differently to hypoxia-ischemia than the mature brain. This study was designed to determine the role of caspase-dependent injury in the pathophysiology of pure focal cerebral ischemia in the immature brain.Methods—Postnatal day 7 rats were subjected to permanent or transient middle cerebral artery (MCA) occlusion. Diffusion-weighted MRI was used during occlusion to noninvasively map the evolving ischemic core. The time course of caspase-3 activation in ischemic brain tissue was determined with the use of an Asp-Glu-Val-Asp-aminomethylcoumarin cleavage assay. The anatomy of caspase-3 activation in the ischemic core and penumbra was mapped immunohistochemically with an anti–activated caspase-3 antibody in coronal sections that matched the imaging planes on diffusion-weighted MRI.Results—A marked increase in caspase-3 activity occurred within 24 hours of reperfusion after transient MCA occlusion. In contrast, caspase-3 activity remained significantly lower within 24 hours of permanent MCA occlusion. Cells with activated caspase-3 were prominent in the penumbra beginning at 3 hours after reperfusion, while a more delayed but marked caspase-3 activation was observed in the ischemic core by 24 hours after reperfusion.Conclusions—In the neonate, caspase-3 activation is likely to contribute substantially to cell death not only in the penumbra but also in the core after ischemia with reperfusion. Furthermore, persistent perfusion deficits result in less caspase-3 activation and appear to favor caspase-independent injury.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—The pathophysiology of cerebral ischemia is well studied in small-animal models, which offer reproducibility and control of confounding variables—factors essential to hypothesis-testing. This presentation first highlights insights into the ischemic penumbra enabled by a multimodal experimental approach; second, discusses gene expression in ischemia; and third, confronts the challenges of neuroprotectant therapy.Summary of Review—The ischemic penumbra:Transient (2-hour) middle cerebral artery suture-occlusion in anesthetized rats gives rise to highly consistent neurological and histopathological sequelae. Autoradiographic local cerebral blood flow (LCBF) studies at 2 hours of occlusion define the penumbra as a region of intermediate CBF depression (20% to 40% of control) surrounding the densely ischemic core (5% to 20% of control) and constituting one half of the entire lesion. Local glucose metabolic rate in the acute penumbra is not reduced despite the critical CBF reduction, so that the penumbral metabolism/blood flow ratio is markedly elevated. In contrast, following 1 hour of recirculation, glucose metabolism throughout the previously ischemic hemisphere has become markedly depressed, and the metabolism/flow ratio has pseudonormalized. By correlating these data with histopathology using multimodal image analysis, the probability of infarction is shown to be highly determined by the degree of antecedent CBF reduction. These animal data agree strikingly with published results in patients with acute stroke studied by positron emission tomography. This remarkable correspondence belies the assertion that data from lower species may not be relevant to human stroke.Gene expression:Perfusion gradients also determine differential patterns of gene expression in ischemia. This can be demonstrated by correlating in situ hybridization autoradiographs for gene expression with autoradiographic LCBF data and histological infarct maps derived from replicate series. In other studies, DNA microarray technology is used to screen for thousands of expressed genes. In the 2-hour middle cerebral artery occlusion model with 3-hour recirculation, we have identified 28 known ischemia-hypoxia response genes that are upregulated and 6 that are downregulated, together with 35 upregulated and 41 downregulated genes newly connected with ischemia. These findings underscore the enormous complexity of ischemic biology and suggest possible novel mechanisms for future exploration.Neuroprotection:A desirable neuroprotectant would, in theory, antagonize multiple injury mechanisms. We have explored 2 such therapies of particular promise. Mild brain hypothermia (32°C target temperature, for 5 hours) is highly neuroprotective even when initiated at the onset of recirculation. Another highly protective agent is human albumin, administered in doses of 1.25 to 2.5 g/kg—a therapy that reduces infarct volume in this ischemia model by 60% to 65%, markedly diminishes brain swelling, and has a therapeutic window extending to 4 hours.Conclusion—The careful study of rodent ischemia models can yield valuable, clinically relevant insights into the pathophysiology of ischemic stroke.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—Intracerebral hemorrhage (ICH) causes higher morbidity and mortality than other forms of stroke and has no proven effective treatment. Hematoma volume is a powerful predictor of outcome after ICH.Summary of Review—Historically, ICH bleeding was considered to be a monophasic event that stopped quickly as a result of clotting and tamponade by surrounding brain tissue. More recently, prospective and retrospective CT-based studies have demonstrated that hematoma growth occurs in up to 38% of patients initially scanned within 3 hours of onset and in 16% scanned between 3 and 6 hours, even in the absence of coagulopathy. Progressive bleeding of this type has been associated with contrast extravasation on CT angiography and poor outcome after early (<4 hours) surgical clot evacuation. On the basis of these observations, it is plausible that ultra-early hemostatic therapy given in the emergency setting might reduce ICH volume in some patients and improve outcome. Among candidate agents for this indication, the most promising is recombinant activated factor VIIa, which promotes local hemostasis at sites of vascular injury in both coagulopathic and normal patients.Conclusions—Ultra-early hemostatic therapy, given within 3 to 4 hours of onset, may potentially arrest ongoing bleeding and minimize hematoma growth after ICH. Given the current lack of effective therapy for ICH, clinical trials testing this treatment approach are justified.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID