bluuebunny/crossref_metadata_2025 huggingface dataset:
CT Angiography for the Detection and Characterization of Carotid Artery Bifurcation Disease
Authors: Anderson Glenn B. , Ashforth Rob , Steinke David E. , Ferdinandy Reka , Findlay J. Max
Published: June 2011

Background and Purpose
—Computed tomographic angiography (CTA) is a relatively new and minimally invasive method of imaging intracranial and extracranial blood vessels. The main purpose of this study was to compare CTA to the current gold standard of arterial imaging, digital subtraction angiography (DSA), for the detection and quantification of carotid artery bifurcation stenosis. We also compared Doppler ultrasound (US) with these 2 techniques.

Methods
—In a prospective study, 40 patients (80 carotid arteries) underwent CTA, US, and DSA. Patients chosen for inclusion were symptomatic with TIAs or stroke and had initial US screening that indicated >50% carotid stenosis on the side appropriate for the symptoms. Source axial, maximum intensity projection (MIP), and shaded-surface display (SSD) images were produced for each CTA study. The US, CTA, and DSA images were reviewed, with the degree of stenosis quantified and presence of ulcers determined; each type of imaging was reviewed by a separate investigator blinded to the results of the other 2 modalities. The results of CTA and US imaging were compared with the DSA images for degrees of carotid stenosis.

Results
—CTA source axial images correlated with DSA more closely than MIP or SSD images for all degrees of stenosis. The correlation between US and DSA (0.808) was poorer than that between CTA and DSA (0.892 to 0.922). CTA performed well in the detection of mild (0% to 29%) carotid stenosis, as well as carotid occlusion, with values for sensitivity, specificity, and accuracy near 100%. In determining that a stenosis was >50% by DSA measurement, CTA was again useful, with a sensitivity, specificity, and accuracy of 89%, 91%, and 90%, respectively. While CTA was quite specific and accurate in identifying degrees of stenoses in either the 50% to 69% or the 70% to 99% ranges, in this task it was much less sensitive: 65% for 50%–69% stenosis and 73% for 70%–99% stenosis. These results did not change significantly when only the data from the most clinically relevant symptomatic arteries were analyzed. CTA was found to correlate quite well with DSA in the detection of ulcers associated with the carotid stenosis.

Conclusions
—CTA was found to be an excellent examination for the detection of carotid occlusion and categorization of stenosis in either the 0%–29% or >50% ranges. However, CTA was unable to reliably distinguish between moderate (50%–69%) and severe (70%–99%) stenosis, which is an important limitation in the investigation and treatment of carotid stenosis.
Impact of White Matter Changes on Clinical Manifestation of Alzheimer’s Disease
Authors: Hirono Nobutsugu , Kitagaki Hajime , Kazui Hiroaki , Hashimoto Mamoru , Mori Etsuro
Published: June 2011

Background and Purpose
—There have been conflicting results involving the clinical significance of white matter changes in patients with Alzheimer’s disease (AD). We studied the association between the volume of white matter hyperintensities (WMHs) on T2-weighted images and cognitive, neurological, and neuropsychiatric symptoms.

Methods
—The subjects were 76 AD patients who had WMHs but no obvious cerebrovascular diseases. We quantified the volume of WMHs by using fast-fluid–attenuated inversion recovery images and whole brain atrophy by using 3D spoiled gradient-echo images. Effects of WMHs and brain atrophy on dementia severity, cognitive function, neuropsychiatric disturbances, and neurological findings were examined.

Results
—Whole brain atrophy was significantly associated with dementia severity and cognitive disturbances, as well as with grasp reflex and some kinds of neuropsychiatric disturbances. After we controlled for the effects of brain atrophy, duration of symptoms, and demographic factors, we found that WMH volume was not associated with global cognitive disturbances or dementia severity but was significantly associated with urinary incontinence, grasp reflex, and aberrant motor behaviors. Brain atrophy and WMH volume were not significantly correlated either before or after controlling for age, sex, education, and duration of symptoms. WMH volume was associated with hypertension, but brain atrophy was not positively correlated with any vascular risk factors.

Conclusions
—Our results support the hypothesis that WMHs in AD patients are superimposed phenomena of vascular origin. WMHs contribute to specific neurological and neuropsychiatric manifestations but not to global cognitive impairment, which is more closely associated with brain atrophy.
Prognostic Influence of Increased C-Reactive Protein and Fibrinogen Levels in Ischemic Stroke
Authors: Di Napoli Mario , Papa Francesca , Bocola Vittorio
Published: June 2011

Background and Purpose
—The prognostic influences of fibrinogen and C-reactive protein (CRP) levels and their relations in ischemic stroke have not been well described. The aim of this study was to investigate and compare the 1-year prognostic influences of fibrinogen and CRP levels on outcome in ischemic stroke.

Methods
—Fibrinogen and CRP were determined within 24 hours after stroke and related to 1-year outcome in 128 patients with first-ever ischemic stroke. The Kaplan-Meier technique was applied in survival analysis. Multiple logistic regression analysis was used to evaluate the associations between risk factors and outcome.

Results
—The probabilities of death or new vascular event were 21.1%, 27.9%, and 51.7% (
P
=0.0172, χ
2
for trend), respectively, in patients stratified by tertiles of fibrinogen (<3.78, 3.78 to 6.17, and >6.17 g/L). The probabilities of a primary end point were 12.1%, 29.7%, and 54.8% (
P
=0.0004), respectively, after stratification of patient data by tertiles of CRP level (<5, 5 to 33, and >33 mg/L). In multiple logistic regression analysis, higher CRP levels (odds ratio, 2.39; 95% CI, 1.28 to 4.49;
P
=0.0066) and stroke severity on the Canadian Neurological Stroke Scale (odds ratio, 2.37; 95% CI, 1.01 to 5.58;
P
=0.0472) were independently associated with death or new vascular event.

Conclusions
—Increased levels of CRP are associated with a worse outcome in patients with ischemic stroke. The increased risk associated with elevated CRP levels is independent of the prognostic influence of fibrinogen.
Venous Thromboembolism After Acute Stroke
Authors: Kelly J. , Rudd A. , Lewis R. , Hunt B. J.
Published: June 2011

Background
—Treatment for venous thromboembolism (VTE) is highly effective in preventing morbidity and mortality, yet pulmonary embolism (PE) accounts for up to 25% of early deaths after stroke. This is because the current diagnostic paradigm is reactive rather than proactive: the clinician responds to VTE when it becomes symptomatic, in the expectation that initiation of treatment will prevent progression to more serious manifestations. This approach is flawed, because sudden death from PE is frequently unheralded and nonfatal symptomatic pulmonary emboli are often unrecognized or misdiagnosed.

Summary of Comment
—Morbidity and mortality from PE could be reduced either by more effective thromboprophylaxis or earlier diagnosis and treatment of established VTE. The fact that early use of short-term, low-dose, unfractionated heparin (UFH) is not associated with sustained, clinically meaningful benefit suggests that a fundamental change in the diagnostic approach to VTE is needed, one which requires a greater appreciation that clinically apparent events are merely the tip of the thromboembolism iceberg.

Conclusions
—Research into a strategy of screening for subclinical VTE in these patients is needed, with a view to identifying a subgroup at risk of progression to symptomatic and life-threatening events, in whom outcome might be improved by anticoagulation.
Effect of Endogenous Estrogen on Blood Flow Through Carotid Arteries
Authors: Krejza Jaroslaw , Mariak Zenon , Huba Magdalena , Wolczynski Slawomir , Lewko Janusz
Published: June 2011

Background and Purpose
—Recent evidence suggests that physiological changes in the concentration of endogenous estrogens may influence stroke outcome. The purpose of this study was to determine a menstrual cycle–related profile of blood flow through the carotid arteries and its correlation with estrogen concentration.

Methods
—The flow velocity and cross-sectional area of the common carotid artery, internal carotid artery (ICA), and external carotid artery (ECA) were measured with duplex Doppler sonography throughout the menstrual cycle in 14 healthy women. Concentration of plasma 17β-estradiol, progesterone, hematocrit, hemoglobin, and blood pressure were also determined.

Results
—In the follicular phase, the concentration of estrogen increased to reach a peak on day 14, whereas concentration of progesterone remained low. The mean and end-diastolic velocities in the ICA increased on average by 15% of their base values, along with increasing concentrations of estrogen (
r
=0.59 and 0.65, respectively). The profile of flow velocity changes in this artery corresponded to the profile of estrogen concentration. In contrast to the ICA, flow velocities in the ECA decreased from their base value, reaching their minimum in the luteal phase. The mean flow velocity in the common carotid artery increased on day 14 by just 2% of its base value. The lumen of the carotid arteries was stable throughout the cycle. Hematocrit, hemoglobin, and systolic blood pressure also remained unchanged.

Conclusions
—Increased concentration of endogenous estrogen correlates with substantial augmentation of flow in the internal carotid artery. This promotion of flow is caused mainly by decreased cerebrovascular resistance with consequent “stealing” of blood from the ECA.
Spermidine: A Predictor for Neurological Outcome and Infarct Size in Focal Cerebral Ischemia?
Authors: Els Th. , Bruckmann J. , Röhn G. , Daffertshofer M. , Mönting J. Schulte , Ernestus R.-I. , Hennerici M.
Published: June 2011

Background and Purpose
—Polyamines are mainly restricted to the intracellular space. During focal cerebral ischemia, polyamines are released from the intracellular compartment. Experimental studies have implicated a marked elevation in brain tissue and blood. The aim of our study was to investigate whether the elevation of polyamines in the blood of patients with focal cerebral ischemia correlates with the clinical outcome and the infarct volume.

Methods
—Polyamines were measured in 16 patients with focal cerebral ischemia and in 8 healthy control subjects. Blood samples for polyamine measurement were taken at admission and at fixed time points for the next 28 days. Polyamines were analyzed in red blood cells by a high-pressure liquid chromatography system. Clinical findings were recorded with the NIH Stroke Scale score. Volume of infarction was analyzed from cranial CT at admission and on days 4 to 6 after ischemia.

Results
—A significant increase of the spermidine level in the peripheral blood could be observed in all patients with focal cerebral ischemia as compared with control subjects (
P
<0.01), starting with the admission. Spermidine values correlated positively with the clinical outcome at several time points in the first 48 hours (
r
=0.90 to 0.40;
P
<0.01) and with the infarct volume in cranial CT on days 4 to 6 (
r
=0.91;
P
<0.01).

Conclusions
—As hypothesized from experimental data, polyamine levels in blood increase in patients after focal cerebral ischemia. The results indicate that the peripheral spermidine level is closely associated with the clinical outcome as well as with the infarction volume. Therefore, polyamines may be used as a novel predictor for the prognosis of patients with focal cerebral ischemia.
Delay in Presentation and Evaluation for Acute Stroke
Authors: Lacy Clifton R. , Suh Dong-Churl , Bueno Maureen , Kostis John B.
Published: June 2011

Background and Purpose
—Early treatment is a critical determinant of successful intervention in acute stroke. The study was designed to find current patterns of stroke care by determining delays in time from onset of signs or symptoms to arrival at the emergency department and to initial evaluation by physicians and by identifying factors associated with these delays.

Methods
—Data were prospectively collected by nurses and physicians from patients, patients’ family members, and medical records from 10 hospitals of the Robert Wood Johnson Health System in New Jersey.

Results
—A total of 553 patients who presented with signs or symptoms of acute stroke were studied. Thirty-two percent of patients arrived at the emergency department within 1.5 hours of stroke onset. Forty-six percent of patients arrived within 3 hours and 61% within 6 hours. Delays in arrival time were significantly associated with sex, race, transportation mode, and history of cardiovascular disease. Patients arriving by ambulance were more likely to present earlier (odds ratio [OR] 3.7 for arrival within 3 hours; OR 4.5 for arrival within 6 hours). Patients arriving by ambulance (OR 2.3 within 15 minutes; OR 1.7 within 30 minutes) and those requiring admission to intensive care units (OR 4.5 within 15 minutes and OR 5.2 within 30 minutes) were examined sooner by physicians.

Conclusions
—Despite national efforts to promote prompt stroke evaluation and treatment, significant delays still exist. The lack of improvement throughout the past decade underscores the need for implementation of effective public health programs designed to minimize the time to evaluation and treatment of stroke.
Aneurysmal Forms of Cervical Artery Dissection
Authors: Touzé Emmanuel , Randoux Bruno , Méary Eric , Arquizan Caroline , Meder Jean-François , Mas Jean-Louis
Published: June 2011

Background and Purpose
—The natural history of aneurysmal forms of cervical artery dissection (CAD) is ill defined. The aims of this study were to assess (1) clinical and anatomic outcome of aneurysmal forms of extracranial internal carotid artery (ICA) and vertebral artery (VA) dissections and (2) factors associated with aneurysmal forms of CAD.

Methods
—Seventy-one consecutive patients with CAD were reviewed. Aneurysmal forms of CAD were identified from all available angiograms by 2 neuroradiologists. The frequency of arterial risk factors, of multiple vessel dissections, and of artery redundancies was compared in patients with and without aneurysm. Patients with aneurysm were invited by mail to undergo a final clinical and radiological evaluation.

Results
—Of the 71 patients, 35 (49.3%) had a total of 42 aneurysms. Thirty aneurysms were located on a symptomatic artery (ICA, 23; VA, 7) and 12 on an asymptomatic artery (ICA, 10; VA, 2). Patients with aneurysm had multiple dissections of cervical vessels (18/35 versus 7/36;
P
=0.005) and arterial redundancies (20/35 versus 11/36;
P
=0.02) more frequently than patients without aneurysm. They were also more often migrainous (odds ratio=2.7 [95% CI, 0.8 to 8.5]) and tobacco users (odds ratio=2.2 [95% CI, 0.7 to 6.3]). Clinical and anatomic follow-up information was available for 35 (100%) and 33 patients (94%), respectively. During a mean follow-up of >3 years, no patient had signs of cerebral ischemia, local compression, or rupture. At follow-up, 46% of the aneurysms involving symptomatic ICA were unchanged, 36% had disappeared, and 18% had decreased in size. Resolution was more common for VA than for ICA aneurysms (83% versus 36%). None of the aneurysms located on an asymptomatic ICA had disappeared.

Conclusions
—Although aneurysms due to CAD frequently persist, patients carry a very low risk of clinical complications. This favorable clinical outcome should be kept in mind before potential harmful treatment is contemplated.
Calcium Antagonists for Ischemic Stroke
Authors: Horn J. , Limburg M.
Published: June 2011

Background and Purpose
—Stroke is a common disease, and many trials with calcium antagonists as possible neuroprotective agents have been conducted. The aim of this review is to determine whether calcium antagonists reduce the risk of death or dependency after acute ischemic stroke.

Methods
—Acute stroke trials were identified with help of the Cochrane Collaboration Stroke Group and personal contacts. All randomized trials (published and unpublished) investigating a calcium antagonist (acting on voltage-sensitive calcium channels) were included. Poor outcome, defined as death or dependency in activities of daily living, was used as main outcome. Analyses were, if possible, “intention-to-treat”; pooled relative risks with 95% CIs were calculated.

Results
—Forty-seven trials were identified, of which 29 were included (7665 patients). No effect of calcium antagonists on poor outcome at the end of follow-up (relative risk, 1.04; 95% CI, 0.98 to 1.09) or on death at end of follow-up (relative risk, 1.07; 95% CI, 0.98 to 1.17) was found. Sensitivity analyses on route of administration and time interval between stroke and start of treatment showed no effect on outcome. In subgroups of unpublished and methodologically sound trials, a statistically significant negative effect for calcium antagonists was found. This contrasts with results of published trials and trials of moderate or poor methodological quality.

Conclusions
—The presented evidence rules out a clinically important effect of calcium antagonists after ischemic stroke. The large amount of data leads to narrow CIs with no significant heterogeneity, and the overall results are therefore likely to be statistically robust.
Correlations Between Clinical Findings and Magnetization Transfer Imaging Metrics of Tissue Damage in Individuals With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Authors: Iannucci G. , Dichgans M. , Rovaris M. , Brüning R. , Gasser T. , Giacomotti L. , Yousry T.A. , Filippi M.
Published: June 2011

Background and Purpose
—We obtained magnetization transfer imaging (MTI) scans from individuals with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1) to investigate the presence, extent, and nature of pathology in white and gray matter outside proton density (PD)-visible lesions; (2) to quantify the degree of tissue damage occurring in lesions seen on PD-weighted scans; and (3) to correlate MTI-derived measures of disease burden with age, physical disability, and cognitive performance.

Methods
—Dual-echo, T1-weighted, and MTI scans of the brain were obtained from 33 individuals with CADASIL and 12 control subjects. Magnetization transfer ratio (MTR) values from PD-visible lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM) were measured. Histograms of MTR from the whole brain and normal-appearing brain tissue were also produced.

Results
—All MTR values from NAWM and NAGM regions studied were significantly lower for individuals with CADASIL than for control subjects, with the exception of those obtained from the NAWM of the infratentorial structures and the NAGM of the occipital cortex. The average MTR from PD lesions in individuals with CADASIL was significantly lower than that from all the NAWM regions. Average MTR and peak location from whole-brain and normal-appearing brain tissue histograms were significantly lower for individuals with CADASIL than for control subjects. MTR values from NAWM were strongly correlated with the extent of macroscopic lesions and their average MTR. Apart from NAGM, average MTR from all other tissues studied significantly decreased with increasing age, physical disability, and cognitive impairment.

Conclusions
—PD lesions of individuals with CADASIL have variable degrees of tissue damage. Brain tissue outside PD abnormalities is also damaged. This study suggests that the extent and the severity of the brain tissue damage are critical factors in determining clinical status in CADASIL.
Regional Access to Acute Ischemic Stroke Intervention
Authors: Riopelle R.J. , Howse D.C. , Bolton C. , Elson S. , Groll D.L. , Holtom D. , Brunet D.G. , Jackson A.C. , Melanson M. , Weaver D.F.
Published: June 2011

Background and Purpose
—Benefit-risk ratios from recombinant tissue plasminogen activator (rtPA) therapy for acute ischemic stroke demonstrate lack of efficacy if intravenous administration is commenced beyond 3 hours of symptom onset. We undertook to enhance therapeutic effectiveness by ensuring equitable access to rtPA for patients affected by acute ischemic stroke within a 20 000 km
2
population referral base served by a tertiary facility.

Methods
—Representatives of all provider groups involved in emergency medical services developed a Regional Acute Stroke Protocol (RASP), a coordinated regional system response by dispatch personnel, paramedics, physicians, community service providers, emergency and inpatient staff in community hospitals, and the tertiary facility acute stroke team.

Results
—As of July 26, 1999, all ambulance services in Southeastern Ontario began bypassing the closest hospital to deliver patients meeting the criteria for the RASP to the Kingston General Hospital. At 12 months, approximately 403 ischemic strokes have occurred in the region, the RASP has been activated 191 times, and 42 patients have received rtPA.

Conclusions
—We conclude that (1) acute stroke patients in Southeastern Ontario have improved access to interventions for stroke care; (2) geography of the region is not a barrier to access to interventions for patients with acute stroke; and (3) acute ischemic stroke patients treated with rtPA account for 5% of all acute strokes and 10% of all ischemic strokes in this region.
Clinical Deterioration Following Improvement in the NINDS rt-PA Stroke Trial
Authors: Grotta James C. , Welch K. M. A. , Fagan Susan C. , Lu Mei , Frankel Michael R. , Brott Thomas , Levine Steven R. , Lyden Patrick D.
Published: June 2011

Background and Purpose
—Little is known in regard to cerebral arterial reocclusion after successful thrombolysis. In the absence of arteriographic information, the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial investigators prospectively identified clinical deterioration following improvement (DFI) as a possible surrogate marker of cerebral arterial reocclusion after rt-PA–induced recanalization. Also, we identified any significant clinical deterioration (CD) even if not preceded by improvement. This observational analysis was designed to determine the incidence of DFI and CD in each treatment group, to identify baseline or posttreatment variables predictive of DFI or CD, and to determine any relationship between DFI, CD, and clinical outcome.

Methods
—DFI was defined as any 2-point deterioration on the NIH Stroke Scale after an initial 2-point improvement after treatment. CD was defined as any 4-point worsening after treatment compared with baseline. All data were collected prospectively by investigators blinded to treatment allocation. A noncontrast brain CT was mandated when a 2-point deterioration occurred. All cases were validated by a central review committee.

Results
—DFI was identified in 81 of the 624 patients (13%); 44 were treated with rt-PA and 37 were treated with placebo (
P
=0.48). DFI occurred more often in patients with a higher baseline NIH Stroke Scale score. CD within the first 24 hours occurred in 98 patients (16% of all patients); 43 were given rt-PA and 55 were given placebo (
P
=0.19). Baseline variables associated with CD included a less frequent use of prestroke aspirin and a higher incidence of early CT changes of edema or mass effect or dense middle cerebral artery sign. Patients with CD had higher rates of increased serum glucose and fibrin degradation products, and they also had higher rates of symptomatic intracranial hemorrhage and death. Patients who experienced either DFI or CD were less likely to have a 3-month favorable outcome.

Conclusions
—We found no association between DFI, CD, and rt-PA treatment, and no clinical evidence to suggest reocclusion. Deterioration was strongly associated with stroke severity and poor outcome and was less frequent in patients whose stroke occurred while they were on aspirin.
Acute-Phase Proteins Before Cerebral Ischemia in Stroke-Prone Rats
Authors: Sironi Luigi , Tremoli Elena , Miller Ingrid , Guerrini Uliano , Calvio Anna Maria , Eberini Ivano , Gemeiner Manfred , Asdente Maria , Paoletti Rodolfo , Gianazza Elisabetta
Published: June 2011

Background and Purpose
—A high degree of proteinuria has been reported in stroke-prone spontaneously hypertensive rats (SHRSP). We studied the effect of salt loading on the detailed protein pattern of serum and urine in 3 rat strains: Wistar-Kyoto, spontaneously hypertensive rats, and SHRSP, an inbred animal model for a complex form of cerebrovascular disorder resembling the human disease.

Methods
—Rats were given a permissive diet and received 1% NaCl in drinking water. The protein pattern in body fluids was assessed over time by 2-dimensional electrophoretic analysis. Brain alterations were monitored by MRI and histology.

Results
—Several proteins were excreted in urine after weeks of treatment and in advance of stroke: transferrin, hemopexin, albumin, α
2
-HS-glycoprotein, kallikrein-binding protein, α
1
-antitrypsin, Gc-globulin, and transthyretin. Markers of an inflammatory response, including very high levels of thiostatin, were detected in the serum of SHRSP at least 4 weeks before a stroke occurred.

Conclusions
—In SHRSP subjected to salt loading, an atypical inflammatory condition and widespread alterations of vascular permeability developed before the appearance of anomalous features in the brain detected by MRI. Urinary concentrations of each of the excreted serum proteins correlated positively with time before stroke occurred.
Mechanisms That Produce Nitric Oxide–Mediated Relaxation of Cerebral Arteries During Atherosclerosis
Authors: Didion Sean P. , Heistad Donald D. , Faraci Frank M.
Published: June 2011

Background and Purpose
—The first goal of the present study was to examine the hypothesis that relaxation of cerebral arteries to nitric oxide in primates is dependent on activation of soluble guanylate cyclase (sGC). The second goal was to determine whether the role of sGC in mediating responses to nitric oxide is altered in atherosclerosis.

Methods
—Basilar arteries from normal and atherosclerotic monkeys were studied in vitro. After precontraction with prostaglandin F
2α
(0.1 to 1 μmol/L), concentration-response curves to authentic nitric oxide (1 nmol/L to 1 μmol/L), sodium nitroprusside (10 nmol/L to 10 μmol/L; a nitric oxide donor), and papaverine (10 nmol/L to 10 μmol/L; a non–nitric oxide, non–sGC-dependent stimulus) were generated in the presence and absence of 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 and 10 μmol/L; an inhibitor of sGC). The effect of ODQ on basal tone of basilar arteries from normal and atherosclerotic monkeys was also examined.

Results
—Nitric oxide, sodium nitroprusside, and papaverine produced relaxation that was similar (
P
>0.05) in normal and atherosclerotic monkeys. ODQ produced marked inhibition (
P
<0.05) of vasorelaxation in response to nitric oxide and nitroprusside but not papaverine. For example, relaxation of the basilar artery in response to nitric oxide (0.1 μmol/L) was inhibited by approximately 85% and 73% by ODQ (1 μmol/L) in normal and atherosclerotic monkeys, respectively. ODQ produced contraction of the basilar arteries, and the increase in tension to ODQ was greater in normal (2.7±0.3 g; mean±SE) than in atherosclerotic monkeys (1.4±0.4 g;
P
<0.05). In contrast, contraction to prostaglandin F
2α
was similar in the basilar artery from normal and atherosclerotic monkeys.

Conclusions
—These findings suggest that (1) relaxation of cerebral arteries in primates in response to nitric oxide is normally dependent, in large part, on activation of sGC and (2) the influence of sGC (via reduced production and/or activity of basal nitric oxide) on cerebral vascular tone is reduced in atherosclerosis.
Therapeutic Benefit of Intravenous Administration of Bone Marrow Stromal Cells After Cerebral Ischemia in Rats
Authors: Chen Jieli , Li Yi , Wang Lei , Zhang Zhenggang , Lu Dunyue , Lu Mei , Chopp Michael
Published: June 2011

Background and Purpose
—We tested the hypothesis that intravenous infusion of bone marrow derived–marrow stromal cells (MSCs) enter the brain and reduce neurological functional deficits after stroke in rats.

Methods
—Rats (n=32) were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Test groups consisted of MCAO alone (group 1, n=6); intravenous infusion of 1×10
6
MSCs at 24 hours after MCAO (group 2, n=6); or infusion of 3×10
6
MSCs (group 3, n=7). Rats in groups 1 to 3 were euthanized at 14 days after MCAO. Group 4 consisted of MCAO alone (n=6) and group 5, intravenous infusion of 3×10
6
MSCs at 7 days after MCAO (n=7). Rats in groups 4 and 5 were euthanized at 35 days after MCAO. For cellular identification, MSCs were prelabeled with bromodeoxyuridine. Behavioral tests (rotarod, adhesive-removal, and modified Neurological Severity Score [NSS]) were performed before and at 1, 7, 14, 21, 28, and 35 days after MCAO. Immunohistochemistry was used to identify MSCs or cells derived from MSCs in brain and other organs.

Results
—Significant recovery of somatosensory behavior and Neurological Severity Score (
P
<0.05) were found in animals infused with 3×10
6
MSCs at 1 day or 7 days compared with control animals. MSCs survive and are localized to the ipsilateral ischemic hemisphere, and a few cells express protein marker phenotypic neural cells.

Conclusions
—MSCs delivered to ischemic brain tissue through an intravenous route provide therapeutic benefit after stroke. MSCs may provide a powerful autoplastic therapy for stroke.
Calbindin D28K Overexpression Protects Striatal Neurons From Transient Focal Cerebral Ischemia
Authors: Yenari Midori A. , Minami Masabumi , Sun Guo Hua , Meier Timothy J. , Kunis David M. , McLaughlin John R. , Ho Dora Y. , Sapolsky Robert M. , Steinberg Gary K.
Published: June 2011

Background and Purpose
—Increased intracellular calcium accumulation is known to potentiate ischemic injury. Whether endogenous calcium-binding proteins can attenuate this injury has not been clearly established, and existing data are conflicting. Calbindin D28K (CaBP) is one such intracellular calcium buffer. We investigated whether CaBP overexpression is neuroprotective against transient focal cerebral ischemia.

Methods
—Bipromoter, replication-incompetent herpes simplex virus vectors that encoded the genes for
cabp
and, as a reporter gene,
lacZ
were used. Sprague-Dawley rats received bilateral striatal injections of viral vector 12 to 15 hours before ischemia onset. With the use of an intraluminal occluding suture, animals were subjected to 1 hour of middle cerebral artery occlusion followed by 47 hours of reperfusion. Brains were harvested and stained with X-gal (to visualize β-galactosidase, the gene product of
lacZ
). The number of remaining virally transfected, X-gal–stained neurons in both the ischemic and contralateral striata were counted and expressed as the percentage of surviving neurons in the ischemic striatum relative to the contralateral nonischemic striatum.

Results
—Striatal neuron survivorship among
cabp
-injected animals was 53.5±4.1% (n=10) versus 26.8±5.4% among those receiving
lacZ
(n=9) (mean±SEM;
P
<0.001).

Conclusions
—We conclude that viral vector–mediated overexpression of CaBP leads to neuroprotection in this model of central nervous system injury. This is the first demonstration that CaBP overexpression protects neurons in a focal stroke model.
G-Protein β3 Subunit and α-Adducin Polymorphisms and Risk of Subclinical and Clinical Stroke
Authors: Morrison Alanna C. , Doris Peter A. , Folsom Aaron R. , Nieto F. Javier , Boerwinkle Eric
Published: June 2011

Background and Purpose
—Essential hypertension is a significant risk factor for stroke. Genes contributing to interindividual variation in blood pressure levels and essential hypertension status may play a role in the etiology of stroke either through their effects on blood pressure levels or through separate pathways. For this reason, we sought to examine the association between the α-adducin (
ADD1
) G/W460 and G-protein β3 subunit (
GNβ3
) 825C/T polymorphisms and subclinical and clinical stroke in the Atherosclerosis Risk in Communities (ARIC) Study.

Methods
—Subclinical stroke was determined by cerebral MRI. Subclinical cerebral infarct cases (n=202) were compared with a stratified random sample (MRI-CRS) identified from individuals participating in the MRI examination (n=211). Incidence of clinical ischemic stroke was determined by following the ARIC cohort for an average of 7.2 years for potential cerebrovascular events; 231 validated clinical ischemic strokes were identified. A stratified random sample of the ARIC cohort (CRS) (n=984) was used as the comparison group for the clinical cases.

Results
—The frequency of the
ADD1
W460 allele was determined for the subclinical cases (0.12), MRI-CRS (0.16), clinical cases (0.14), and CRS (0.17). The frequency of the
GNβ3
825T allele was determined in whites and blacks, respectively, for the subclinical cases (0.26, 0.73), MRI-CRS (0.31, 0.75), clinical cases (0.36, 0.72), and CRS (0.30, 0.72). The
ADD1
W460 and GNβ3 825T alleles were not significantly associated with subclinical stroke. The
ADD1
W460 allele was also not a significant predictor of clinical stroke. The
GNβ3
825T allele was significantly associated with clinical stroke in whites after adjustment for age and sex (hazard rate ratio, 1.45; 95% CI, 1.05 to 2.00) and after further adjustment for multiple stroke risk factors (hazard rate ratio, 1.68; 95% CI, 1.18 to 2.41). The
GNβ3
825T allele was not significantly associated with clinical stroke in blacks for either adjustment model.

Conclusions
—The
GNβ3
gene 825C/T polymorphism is significantly associated with incident clinical ischemic stroke in a white middle-aged American population, but not in blacks. This association does not appear to be mediated by established stroke risk factors, specifically blood pressure levels or hypertension status.
Estrogens Decrease Reperfusion-Associated Cortical Ischemic Damage
Authors: Shi Jiong , Bui Jonathan D. , Yang Shao-Hua , He Zhen , Lucas Timothy H. , Buckley David L. , Blackband Stephen J. , King Michael A. , Day Arthur L. , Simpkins James W.
Published: June 2011

Background and Purpose
—Early identification of irreversible cerebral ischemia is critical in defining strategies that influence neuronal survival after stroke. We used MRI to investigate the effects of 17β-estradiol (E2) on the temporal evolution of focal ischemia.

Methods
—Female rats were ovariectomized and divided into 1 of 2 groups: ovariectomy alone (OVX; n=4) or ovariectomy with estrogen replacement (OVX+E2; n=3). Both groups were then subjected to 1-hour middle cerebral artery occlusion (MCAO), with the use of a standardized endovascular monofilament model, followed by reperfusion. Sequential diffusion-weighted (DWI) and T2-weighted (T2WI) MRI were obtained during and after the MCAO. In separate groups of animals (n=5 for OVX and OVX+E2), cerebral blood flow (CBF) was measured by laser-Doppler methods before, during, and after occlusion.

Results
—DWI detected similar lesion characteristics during MCAO in both groups. In the OVX group, lesion size did not change during reperfusion, but the signal intensity ratio increased early and stabilized during the latter stages. In contrast, DWI lesion size decreased during reperfusion in OVX+E2 rats by 50% to 60% (
P
<0.05), a size reduction almost exclusively limited to cortical regions. During MCAO, the signal intensity ratio in OVX+E2 rats was reduced compared with OVX rats. Reperfusion further attenuated the signal intensity ratio in cortical but not subcortical regions (
P
<0.05 versus OVX). T2WI revealed no lesions in either group during MCAO, but it detected lesion sizes similar to that of DWI during reperfusion. Furthermore, similar patterns and magnitudes of estrogen treatment–related decrease in lesion size were noted after reperfusion. T2WI demonstrated less intense signal intensity ratio changes in both groups compared with DWI. There were no differences in CBF between groups either during occlusion, early reperfusion, or 1 day after reperfusion.

Conclusions
—This study strongly suggests that estrogens selectively protect cortical tissue from ischemic damage during MCAO and that this protection is exerted during both the occlusion and reperfusion phases of ischemia and does not involve an estrogen-related change in CBF.
Usefulness of Magnetic Resonance–Derived Quantitative Measurements of Cerebral Blood Flow and Volume in Prediction of Infarct Growth in Hyperacute Stroke
Authors: Grandin Cécile B. , Duprez Thierry P. , Smith Anne M. , Mataigne Fréderic , Peeters André , Oppenheim Catherine , Cosnard Guy
Published: June 2011

Background and Purpose
—The identification of the tissue at risk for infarction remains challenging in stroke patients. In this study, we evaluated the value of quantitative cerebral blood flow (CBF) and cerebral blood volume (CBV) measurements in the prediction of infarct growth in hyperacute stroke.

Methods
—Fluid-attenuated inversion recovery (FLAIR), diffusion-weighted (DW), and gradient-echo echo-planar perfusion-weighted (PW) sequences were obtained in 66 patients within 6 hours of stroke onset; ischemia was confirmed on follow-up FLAIR images. We delineated the following: (1) the initial infarct on DW images, (2) the area of hemodynamic disturbance on mean transit time (MTT) maps, and (3) the final infarct on follow-up FLAIR images. MTT, CBF, and CBV were calculated in the following areas: area of initial infarct (INF), area of infarct growth (IGR, final minus initial infarct), the hemodynamically disturbed area that remained viable (OLI, hemodynamic disturbance minus final infarct), and all contralateral mirror regions.

Results
—Compared with mirror regions, the MTT in abnormal areas was always prolonged. The respective mean±SD CBF and CBV values were as follows: for INF, 28±16 mL/min per 100 g and 6.9±2.7%; for IGR, 36±20 mL/min per 100 g and 8.9±3.1%; for OLI, 50±17 mL/min per 100 g and 11.2±3%; and for mirror regions, 64±23 mL/min per 100 g and 8.7±2.5%. The CBV and CBF values were significantly different between all abnormal areas (except for the CBF between INF and IGR). In the area of DW/PW mismatch, a combined CBF or CBV threshold of 35 or 8.2, respectively, predicted evolution to infarction with a sensitivity of 81% and a specificity of 76%.

Conclusions
—Quantitative measurements of CBF and CBV in hyperacute stroke may help to predict infarct growth and to select the subjects who will benefit from thrombolysis.
Neurological Deterioration in Acute Lacunar Infarctions
Authors: Serena Joaquín , Leira Rogelio , Castillo José , Pumar José Manuel , Castellanos Mar , Dávalos Antoni
Published: June 2011

Background and Purpose
—The mechanisms involved in the neurological deterioration of acute lacunar strokes are unknown. Although accumulating evidence suggests that glutamate release plays a role in the progression of territorial infarctions, it remains to be established whether excitotoxicity also participates in lacunar stroke progression. We investigated whether excitatory and inhibitory amino acid concentrations in blood predict subsequent progressive motor deficits in lacunar infarctions.

Methods
—We studied 113 consecutive patients with lacunar infarct, defined by clinical and computed tomography/magnetic resonance imaging criteria, within the first 24 hours after stroke onset. Neurological deterioration was defined as a decrease of ≥1 points in the motor items of the Canadian Stroke Scale in the first 48 hours after admission. Glutamate, glycine, and GABA were determined by high-performance liquid chromatography in plasma samples obtained on admission. Predictive values, sensitivity, specificity, and accuracy of specific glutamate and GABA concentrations and glutamate×glycine/GABA index for progression of lacunar stroke were calculated.

Results
—Twenty-seven patients (23.9%) had neurological worsening. Plasma concentrations of glutamate (253±70 versus 123±73 μmol/L, mean±SD) were higher and those of GABA (140±63 versus 411±97 nmol/L) were lower in the progressing group than in the nonprogressing group (both
P
<0.001). Glutamate concentrations >200 μmol/L and GABA levels <240 nmol/L had a positive predictive value for neurological deterioration of 67% and 84%, respectively. A excitotoxic index >106 had a positive predictive value of 85%.

Conclusions
—These findings suggest that an imbalance between the glutamate and GABA concentrations may play a role in the pathophysiology of progressing lacunar infarctions.
Association of Apolipoprotein E Polymorphism With Outcome After Aneurysmal Subarachnoid Hemorrhage
Authors: Niskakangas Tero , Öhman Juha , Niemelä Mika , Ilveskoski Erkki , Kunnas Tarja A. , Karhunen Pekka J.
Published: June 2011

Background and Purpose
—Variation in the outcome after aneurysmal subarachnoid hemorrhage (SAH) is not fully explained by known prognostic factors.
APOE
genotype is the most important genetic determinant of susceptibility to Alzheimer’s disease, and it is also shown to be associated with the outcome after traumatic brain injury. We studied the association of apolipoprotein E polymorphism with the outcome after aneurysmal SAH.

Methods
—A total of 160 consecutive patients were admitted after SAH to a neurosurgical unit. The clinical assessment after the SAH was performed with the Hunt and Hess grading scale. The severity of the bleeding as visualized on CT was assessed by Fisher’s grading system. Outcome was assessed with the Glasgow Outcome Scale.
APOE
genotypes were determined by polymerase chain reaction–restriction fragment length polymorphism.

Results
—126 patients had aneurysmatic SAH, and detailed information on outcome and
APOE
genotype was available for 108 patients (86%). Sixteen (40%) of 40 patients with
APOE
ε4 had an unfavorable outcome compared with 13 (19%) of 68 without the
APOE
ε4 allele (OR 2.8, 95% CI 1.18 to 6.77). Association was more significant after adjustment for age, rebleeding, clinical status on admission, and CT scan findings (OR 7.1, 95% CI 1.9 to 26.3;
P
=0.0035).

Conclusions
—Our findings show a significant genetic association of
APOE
polymorphism with outcome after spontaneous aneurysmal SAH. Genetic factors thus seem to explain a part of individual differences in the recovery of SAH.
Enhanced Expression of Iba1, Ionized Calcium-Binding Adapter Molecule 1, After Transient Focal Cerebral Ischemia In Rat Brain
Authors: Ito Daisuke , Tanaka Kortaro , Suzuki Shigeaki , Dembo Tomohisa , Fukuuchi Yasuo
Published: June 2011

Background and Purpose
—Iba1 is a novel calcium-binding protein and is specifically expressed in microglia in the brain. It has been suggested that Iba1 plays an important role in regulation of the function of microglia. In the present study we examined time-dependent Iba1 expression after transient middle cerebral artery occlusion and characterized microglial activation in various brain regions.

Methods
—Rat middle cerebral artery occlusion was induced by the intraluminal filament technique. After 1.5 hours of transient ischemia, Iba1 expression was examined by immunohistochemical and immunoblot analyses. The microglial activation in association with ischemic severity was characterized by double immunostaining with other specific markers.

Results
—In the peri-ischemic area, heavily Iba1 immunoreactive cells rapidly appeared at 3.5 hours after reperfusion. Immunoreactivity was further increased and peaked at 7 days. In the ischemic core, round Iba1-positive cells, which may be blood-borne monocytes, appeared from 24 hours and reached a peak at 4 to 7 days. Double immunostaining revealed that activated microglia in the peri-ischemic area upregulated Iba1 expression but were negative for the macrophage marker ED1. ED1-positive cells were clearly restricted to the ischemic core.

Conclusions
—These findings suggest the following: (1) Iba1 expression may be associated with microglial activation in ischemic brain, and Iba1 immunostaining can be useful to evaluate the pathophysiological roles of activated microglia in ischemic injury. (2) Expression of ED1 antigen is strictly restricted to severe ischemic damage, whereas activated microglia in the peri-ischemic area showed Iba1 upregulation without ED1. Therefore, microglia may exhibit difference of antigenicity in the severity of ischemic brain injury.
Chickenpox and Stroke in Childhood
Authors: Askalan Rand , Laughlin Suzanne , Mayank Supriya , Chan Anthony , MacGregor Daune , Andrew Maureen , Curtis Rosalind , Meaney Brandon , deVeber Gabrielle
Published: June 2011

Background and Purpose
—The purpose of this study was to determine whether infection with varicella is causal for arterial ischemic stroke (AIS) in children.

Methods
—First, a prospective cohort study was conducted in young children (aged 6 months to 10 years) with AIS at 2 institutions (cohort study). The presence of varicella infection <12 months before AIS was determined and compared with the published frequency of varicella infection in the healthy pediatric population. The clinical and radiographic features of AIS were compared between the varicella and nonvaricella study cohorts. Second, a literature search of varicella-associated AIS was conducted, and the clinical and radiographic features were compared with the study nonvaricella cohort.

Results
—In the cohort study, 22 (31%) of 70 consecutive children with AIS had a varicella infection in the preceding year compared with 9% in the healthy population. Children in the varicella cohort were more likely to have basal ganglia infarcts (
P
<0.001), abnormal cerebral vascular imaging (
P
<0.05), and recurrent AIS or transient ischemic attacks (
P
<0.05) than those in the nonvaricella cohort. The pooled literature analysis of 51 cases of varicella-associated AIS showed similar findings to the varicella cohort.

Conclusion
—In young children with AIS, there is a 3-fold increase in preceding varicella infection compared with published population rates, and varicella-associated AIS accounts for nearly one third of childhood AIS. Varicella-associated AIS has characteristic features, including a 2-fold increase in recurrent AIS and transient ischemic attacks. Varicella is an important risk factor for childhood AIS.
Sleep-Related Breathing Disorders and Risk of Stroke
Authors: Mohsenin Vahid
Published: June 2011

Background
—Stroke and sleep-related breathing disorders are both common and are associated with significant morbidity and mortality. Several recent large epidemiological studies have shown a strong association between these 2 disorders independent of known risk factors for stroke. This article will outline the scientific basis for this relationship and suggest sleep-related breathing disorders as modifiable risk factors for stroke.

Summary of Review
—Several studies have shown a characteristic circadian rhythmicity in stroke. We have discussed the influence of normal sleep states as well as the effect of sleep-related breathing disorders on cerebral hemodynamics. The hemodynamic, metabolic, and hematologic changes during sleep-related breathing disorders in the form of decreased cerebral perfusion and increased coagulability are possible pathogenetic mechanisms for stroke. There are accumulating lines of evidence that sleep apnea disorder may indeed cause diurnal hypertension. However, the increased risk of stroke in patients with sleep-related breathing disorders appears to be independent of coexisting hypertension; the presence of hypertension would increase the risk even further. Furthermore, several studies have documented high prevalence of sleep apnea disorders in patients with transient ischemic attacks and stroke.

Conclusions
—Sleep-related breathing disorder appears to contribute as a risk factor for stroke through hemodynamic and hematologic changes. Because of the high prevalence of sleep apnea disorder in this population, patients with transient ischemic attacks and stroke should undergo evaluation for these disorders.