bluuebunny/crossref_metadata_2025 huggingface dataset:
Reperfusion in a Gerbil Model of Forebrain Ischemia Using Serial Magnetic Resonance FAIR Perfusion Imaging
Authors: Pell Gaby S. , Lythgoe Mark F. , Thomas David L. , Calamante Fernando , King Martin D. , Gadian David G. , Ordidge Roger J.
Published: June 2011

Background and Purpose
—Existing methods for the quantitative measurement of the changing cerebral blood flow (CBF) during reperfusion suffer from poor spatial or temporal resolution. The aim of this study was to implement a recently developed MRI technique for quantitative perfusion imaging in a gerbil model of reperfusion. Flow-sensitive alternating inversion recovery (FAIR) is a noninvasive procedure that uses blood water as an endogenous tracer.

Methods
—Bilateral forebrain ischemia of 4 minutes’ duration was induced in gerbils (n=8). A modified version of FAIR with improved time efficiency was used to provide CBF maps with a time resolution of 2.8 minutes after recirculation had been initiated. Quantitative diffusion imaging was also performed at intervals during the reperfusion period.

Results
—On initiating recirculation after the transient period of ischemia, the FAIR measurements demonstrated either a symmetrical, bilateral pattern of flow impairment (n=4) or an immediate side-to-side difference that became apparent with respect to the cerebral hemispheres in the imaged slice (n=4). The flow in each hemisphere displayed a pattern of recovery close to the preocclusion level or, alternatively, returned to a lower level before displaying a delayed hypoperfusion and a subsequent slow recovery. The diffusion measurements during this latter response suggested the development of cell swelling during the reperfusion phase in the striatum.

Conclusions
—The CBF during the reperfusion period was monitored with a high time resolution, noninvasive method. This study demonstrates the utility of MRI techniques in following blood flow changes and their pathophysiological consequences.
Hemorrhagic Transformation in Acute Ischemic Stroke
Authors: Jaillard Assia , Cornu Catherine , Durieux Anne , Moulin Thierry , Boutitie Florent , Lees Kennedy R. , Hommel Marc
Published: June 2011

Background and Purpose
—Hemorrhagic transformation (HT) is the most critical complication of thrombolytics in clinical trials in acute stroke. The aim of this study was to determine the rates and the predictors of HT in the Multicenter Acute Stroke Trial–Europe (MAST-E) study.

Methods
—We performed a post hoc analysis of MAST-E data designed to assess the safety and efficacy of streptokinase administered intravenously within 6 hours of stroke onset. HT included all intracerebral hemorrhages and symptomatic hemorrhages (SHT) associated with clinical worsening. The predictors of HT and SHT were determined using multivariate modeling.

Results
—Among the 310 patients included, 159 patients had HT and 37 SHT (97 and 33 in the streptokinase group and 62 and 4 in the placebo group, respectively). Patients with SHT had significantly more atrial fibrillation, diabetes mellitus, no heparin use, streptokinase treatment, and early CT signs. In the multivariate analysis, HT was predicted by early CT signs and streptokinase treatment. SHT was predicted by diabetes mellitus, early CT signs, streptokinase treatment, and the interaction between streptokinase treatment and decreased level of consciousness. Among the streptokinase-treated patients, the same predictors remained.

Conclusions
—The relative risks of HT after streptokinase were in the same range in MAST-E as in other streptokinase and tPA trials. Early CT signs were strong predictors of both HT and SHT, stressing that these patients are at high risk of bleeding. In our study, the predictors of HT and SHT were similar to those of tPA trials in acute stroke.
Physical Activity and Ischemic Stroke Risk
Authors: Evenson Kelly R. , Rosamond Wayne D. , Cai Jianwen , Toole James F. , Hutchinson Richard G. , Shahar Eyal , Folsom Aaron R.
Published: June 2011

Background and Purpose
—The relationship between physical activity and stroke is inconclusive according to the 1996 US Surgeon General’s Report on Physical Activity and Health. Therefore, this study examined the relationship between physical activity and ischemic stroke risk among 14 575 Atherosclerosis Risk in Communities Study participants aged 45 to 64 years free of self-reported stroke and coronary heart disease at baseline.

Methods
—Eligible potential stroke hospitalizations were identified from ongoing hospital surveillance and from hospitalizations reported by the cohort study participants. All strokes were validated by hospitalization records. Physical activity was measured as sport, leisure (nonsport), and work with the use of the Baecke questionnaire. Multivariable Poisson and Cox proportional hazards models were used to determine the association of differing levels of physical activity with ischemic stroke incidence.

Results
—During an average of 7.2 years of follow-up, 189 incident ischemic strokes occurred. Ischemic stroke incidence rates were highest in the lowest quartile of sport, leisure, and work scores. The hazard rate ratios with 95% CIs for ischemic stroke for the highest quartile compared with the lowest quartile of activity adjusted for age, sex, race-center, education, and smoking, were sport 0.83 (0.52, 1.32), leisure 0.89 (0.57, 1.37), and work 0.69 (0.47, 1.00). Further adjustment for factors that likely were intermediate variables (hypertension, diabetes, fibrinogen, and body mass index) between physical activity and stroke attenuated the associations.

Conclusions
—Our findings suggest that physical activity was weakly associated with a reduced risk of ischemic stroke among middle-aged adults. The association may be due to links between physical activity and other risk factors or due to chance.
Middle Cerebral Artery Stroke That Includes the Premotor Cortex Reduces Mobility Outcome
Authors: Miyai Ichiro , Suzuki Tsunehiko , Kang Jin , Kubota Kisou , Volpe Bruce T.
Published: June 2011

Background and Purpose
—The premotor cortex (PMC) (Brodmann 6) contributes uniquely to proximal upper and lower limb power and plays a role in the organization of motor behaviors. We assessed the degree to which PMC damage affected functional outcome.

Methods
—We prospectively compared the functional outcome of patients with a first stroke in the middle cerebral artery distribution that either left the PMC intact (PMC−; n=19) or damaged the PMC (PMC+; n=12). The Functional Independence Measure for disability and the motor score of the Stroke Impairment Assessment Set for impairment assessed outcome.

Results
—Demographic and clinical features and lesion volume were comparable for the PMC+ and PMC− groups. However, the PMC− group demonstrated significant gain in mobility and in proximal leg movement. This focal improvement contributed to the trend in the PMC− group toward greater independent ambulation.

Conclusions
—Decreased motor recovery of proximal lower limbs in humans with PMC damage supports the idea that it is the origin of corticoreticulospinal pathways that subserve proximal lower extremity function. Furthermore, persistent proximal weakness after PMC damage may amplify other motor impairments, which include defects in planning, initiating, and sequencing. Neurorehabilitation outcomes may contribute to a more detailed functional anatomy after stroke and partial recovery.
Electrical Stimulation of Wrist Extensors in Poststroke Hemiplegia
Authors: Powell Joanna , Pandyan A. David , Granat Malcolm , Cameron Margaret , Stott David J.
Published: June 2011

Background and Purpose
—It has been suggested that cyclic neuromuscular electrical stimulation (ES) may enhance motor recovery after stroke. We have investigated the effects of ES of the wrist extensors on impairment of wrist function and on upper-limb disability in patients being rehabilitated after acute stroke.

Methods
—We recruited 60 hemiparetic patients (mean age, 68 years) 2 to 4 weeks after stroke into a randomized, controlled, parallel-group study comparing standard rehabilitation treatment with standard treatment plus ES of wrist extensors (3 times 30 minutes daily for 8 weeks). Isometric strength of wrist extensors was measured using a device built for that purpose. Upper-limb disability was assessed with use of the Action Research Arm Test (ARAT). Observations were continued for 32 weeks (24 weeks after the finish of ES or the control intervention phase).

Results
—The change in isometric strength of wrist extensors (at an angle of 0° extension) was significantly greater in the ES group than the control group at both 8 and 32 weeks (
P
=0.004,
P
=0.014 by Mann Whitney
U
test). At week 8 the grasp and grip subscores of the ARAT increased significantly in the ES group compared with that in the control group (
P
=0.013 and
P
=0.02, respectively); a similar trend was seen for the total ARAT score (
P
=0.11). In the subgroup of 33 patients with some residual wrist extensor strength at study entry (moment at 0° extension >0), the ARAT total score had increased at week 8 by a mean of 21.1 (SD, 12.7) in the ES group compared with 10.3 (SD, 9.0) in the control group (
P
=0.024, Mann Whitney
U
test); however, at 32 weeks the differences between these 2 subgroups were no longer statistically significant.

Conclusions
—ES of the wrist extensors enhances the recovery of isometric wrist extensor strength in hemiparetic stroke patients. Upper-limb disability was reduced after 8 weeks of ES therapy, with benefits most apparent in those with some residual motor function at the wrist. However, it is not clear how long the improvements in upper-limb disability are maintained after ES is discontinued.
Effects of Citicoline Combined With Thrombolytic Therapy in a Rat Embolic Stroke Model
Authors: Andersen Martin , Overgaard Karsten , Meden Per , Boysen Gudrun
Published: June 2011

Background and Purpose
—We sought to evaluate the effects of the combination of cytidine-5′-diphosphocholine (citicoline) and thrombolysis on infarct size, clinical outcome, and mortality in a rat embolic stroke model.

Methods
—Eighty-three Sprague-Dawley rats were embolized in the carotid territory with a single fibrin embolus and randomly assigned to the following treatment groups: (1) control (saline), (2) citicoline 250 mg/kg, (3) citicoline 500 mg/kg, (4) recombinant tissue plasminogen activator (rtPA) 5 mg/kg, (5) rtPA 5 mg/kg plus citicoline 250 mg/kg, and (6) rtPA 5 mg/kg plus citicoline 500 mg/kg. rtPA was administered as a continuous intravenous infusion over 45 minutes starting 45 minutes after embolization; citicoline was given intraperitoneally 30 minutes and 24, 48, and 72 hours after embolization. At 96 hours, the brains were fixed and stained by hematoxylin-eosin, and infarct volumes were measured. Neurological scores were determined daily.

Results
—The median infarct size, measured as percentage of the affected hemisphere, in the control group was 37% (interquartile range, 26% to 69%) compared with 22% (5% to 52%;
P
=NS) in group 2, 11% (5% to 34%;
P
=NS) in group 3, 24% (12% to 31%;
P
=NS) in group 4, 11% (3% to 22%;
P
=0.02) in the combined group 5, and 19% (9% to 51%;
P
=NS) in group 6. The infarct size was significantly reduced in the combined citicoline+rtPA–treated groups to a median of 13% (5% to 30%;
P
<0.01). Citicoline 500 mg/kg and citicoline combined with rtPA also promoted functional recovery.

Conclusions
—These results demonstrate that the combination of low-dose citicoline and rtPA significantly reduced infarct size in this focal ischemia model.
The Neuroprotective Effect of the Novel AMPA Receptor Antagonist PD152247 (PNQX) in Temporary Focal Ischemia in the Rat
Authors: Schielke Gerald P. , Kupina Nancy C. , Boxer Peter A. , Bigge Christopher F. , Welty Devin F.
Published: June 2011

Background and Purpose
—Evidence suggests that glutamate contributes to ischemic brain damage through activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor. We tested the novel, selective AMPA receptor antagonist
PD152247
(PNQX) in a model of temporary focal ischemia to determine the dose-response relationship and to investigate the contribution of drug-induced hypothermia to the neuroprotective action of AMPA receptor antagonists.

Methods
—Temporary focal cerebral ischemia was induced in Sprague-Dawley rats by occluding the middle cerebral artery and both carotid arteries for 3 hours. Body temperature was monitored by telemetry. PNQX was administered intraperitoneally or by intravenous infusion with various doses for 6 hours. Lesion volume was determined after 3 days by stereological methods.

Results
—PNQX reduced the lesion volume by 51% after intraperitoneal administration. The intravenous dose-response study demonstrated that the lowest effective dose of PNQX was 1.0 mg/kg per hour, which corresponded to a steady state plasma level of 685 ng/mL. Neuroprotection was demonstrated at PNQX plasma concentrations that did not lower body temperature over the entire course of the experiment.

Conclusions
—AMPA receptor activation plays an important role in the development of ischemic brain damage. Thus, novel AMPA receptor antagonists may be useful for the treatment of stroke in humans.
Stroke Patients’ Informal Caregivers
Authors: Bugge Carol , Alexander Helen , Hagen Suzanne
Published: June 2011

Background and Purpose
—Research has revealed that caring for a stroke patient can result in caregiver strain and a myriad of other difficulties for caregivers. This study aims to identify the level of strain experienced by caregivers in the early months after stroke and to assess the relationship between caregiver strain and caregiver characteristics, patient characteristics, and service inputs.

Methods
—Stroke patients were identified through a random stratified sample of general practices. Patients were asked to identify their principal informal caregiver. Strain was measured with the Caregiver Strain Index, and all data were collected from caregivers at 1, 3, and 6 months after the patient’s stroke. Multiple regression analysis was used to examine the factors associated with caregiver strain.

Results
—Six months after stroke, 37% of caregivers were experiencing considerable strain. The amount of time a caregiver spent helping a stroke patient, the amount of time the caregiver spent with the patient, and the caregiver’s health were all significantly associated with the level of strain experienced. Although none of the services or patient factors tested in this study were consistently associated with strain, an indicator of stroke severity was significant at each time point.

Conclusions
—Caregivers are experiencing strain, which has implications for research and service provision. Service providers need to identify caregivers at risk of greater strain and to help caregivers work through situations that services cannot alter. Research is needed to identify services that are effective in strain alleviation. Future research should also aim to identify the interface between patient characteristics and strain, burden, and depression and particularly to assess the caregiver’s perception of these relationships.
Agreement and Variability in the Interpretation of Early CT Changes in Stroke Patients Qualifying for Intravenous rtPA Therapy
Authors: Grotta James C. , Chiu David , Lu Mei , Patel Suresh , Levine Steven R. , Tilley Barbara C. , Brott Thomas G. , Haley E. Clarke , Lyden Patrick D. , Kothari Rashmi , Frankel Michael , Lewandowski Christopher A. , Libman Richard , Kwiatkowski Thomas , Broderick Joseph P. , Marler John R. , Corrigan John , Huff Stephen , Mitsias Panayiotis , Talati Sanjay , Tanne David
Published: June 2011

Background and Purpose
—Ischemic changes identified on CT scans performed in the first few hours after stroke onset, which are thought to possibly represent early cytotoxic edema and development of irreversible injury, may have important implications for subsequent treatment. However, insecurity and conflicting data exist over the ability of clinicians to correctly recognize and interpret these changes. We performed a detailed review of selected baseline CT scans from the NINDS rt-PA Stroke Trial to test agreement among experienced stroke specialists and other physicians on the presence of early CT ischemic changes.

Methods
—Seventy baseline CT scans from the NINDS Stroke Trial were read and classified for the presence or absence of various early findings of ischemia by 16 individuals, including NINDS trial investigators, other neurologists, other emergency medicine physicians, and radiology or stroke fellows. CT scans included normal scans and scans from patients who later developed symptomatic intracranial hemorrhage, as well as scans on which the NINDS rt-PA Stroke Trial neuroradiologist identified clear-cut early CT changes. For each CT finding, κ-statistics were used to assess the proportion of agreement beyond chance.

Results
—κ-Values (95% confidence interval [CI]) ranged from 0.20 (−0.20, 0.61) (fair agreement) to 0.41 (0.37, 0.45) (moderate agreement) among the 16 viewers, and the κ-value was only 0.39 (0.29, 0.49) (fair) in answer to the question “do early CT changes involve more than one third of the MCA [middle cerebral artery] territory?” There was substantial variability within each specialty group and between groups. κ-Values were only fair to moderate even among physicians experienced in selecting and treating acute stroke patients with rtPA. Observed agreement ranged from 68% to 85%. Physicians agreed on the finding of early CT changes involving >33% of the MCA territory 77% of the time, although the κ-value of 0.39 suggested only moderate agreement beyond chance.

Conclusions
—There is considerable lack of agreement, even among experienced clinicians, in recognizing and quantifying early CT changes. Improved methods of recognizing and quantifying early ischemic brain damage are needed.
Reliability and Validity of Estimating the NIH Stroke Scale Score from Medical Records
Authors: Kasner Scott E. , Chalela Julio A. , Luciano Jean M. , Cucchiara Brett L. , Raps Eric C. , McGarvey Michael L. , Conroy Molly B. , Localio A. Russell
Published: June 2011

Background and Purpose
—The aim of our study was to determine whether the National Institutes of Health Stroke Scale (NIHSS) can be estimated retrospectively from medical records. The NIHSS is a quantitative measure of stroke-related neurological deficit with established reliability and validity for use in prospective clinical research. Recently, retrospective observational studies have estimated NIHSS scores from medical records for quantitative outcome analysis. The reliability and validity of estimation based on chart review has not been determined.

Methods
—Thirty-nine patients were selected because their NIHSS scores were formally measured at admission and discharge. Handwritten notes from medical records were abstracted and NIHSS scores were estimated by 6 raters who were blinded to the actual scores. Estimated scores were compared among raters and with the actual measured scores.

Results
—Interrater reliability was excellent, with an intraclass correlation coefficient of 0.82. Scores were well calibrated among the 6 raters. Estimated NIHSS scores closely approximated the actual scores, with a probability of 0.86 of correctly ranking a set of patients according to 5-point interval categories (as determined by the area under the receiver-operator characteristic curve). Patients with excellent outcomes (NIHSS score of ≤5) could be identified with sensitivity of 0.72 and specificity of 0.89. There were no significant differences between these parameters at admission and discharge.

Conclusions
—For the purposes of retrospective studies of acute stroke outcome, the NIHSS can be abstracted from medical records with a high degree of reliability and validity.
Combined Diffusion and Perfusion MRI With Correlation to Single-Photon Emission CT in Acute Ischemic Stroke
Authors: Karonen Jari O. , Vanninen Ritva L. , Liu Yawu , Østergaard Leif , Kuikka Jyrki T. , Nuutinen Juho , Vanninen Esko J. , Partanen P. L. Kaarina , Vainio Pauli A. , Korhonen Katja , Perkiö Jussi , Roivainen Reina , Sivenius Juhani , Aronen Hannu J.
Published: June 2011

Background and Purpose
—More effective imaging methods are needed to overcome the limitations of CT in the investigation of treatments for acute ischemic stroke. Diffusion-weighted MRI (DWI) is sensitive in detecting infarcted brain tissue, whereas perfusion-weighted MRI (PWI) can detect brain perfusion in the same imaging session. Combining these methods may help in identifying the ischemic penumbra, which is an important concept in the hemodynamics of acute stroke. The purpose of this study was to determine whether combined DWI and PWI in acute (<24 hours) ischemic stroke can predict infarct growth and final size.

Methods
—Forty-six patients with acute ischemic stroke underwent DWI and PWI on days 1, 2, and 8. No patient received thrombolysis. Twenty-three patients underwent single-photon emission CT in the acute phase. Lesion volumes were measured from DWI, SPECT, and maps of relative cerebral blood flow calculated from PWI.

Results
—The mean volume of infarcted tissue detected by DWI increased from 46.1 to 75.6 cm
3
between days 1 and 2 (
P
<0.001; n=46) and to 78.5 cm
3
after 1 week (
P
<0.001; n=42). The perfusion-diffusion mismatch correlated with infarct growth (
r
=0.699,
P
<0.001). The volume of hypoperfusion on the initial PWI correlated with final infarct size (
r
=0.827,
P
<0.001). The hypoperfusion volumes detected by PWI and SPECT correlated significantly (
r
=0.824,
P
<0.001).

Conclusions
—Combined DWI and PWI can predict infarct enlargement in acute stroke. PWI can detect hypoperfused brain tissue in good agreement with SPECT in acute stroke.
Yield of Transcranial Doppler in Acute Cerebral Ischemia
Authors: Alexandrov Andrei V. , Demchuk Andrew M. , Wein Theodore H. , Grotta James C.
Published: June 2011

Background and Purpose
—The objective of this study was to evaluate the yield of emergent transcranial Doppler (TCD) for the evaluation of acute cerebral ischemia.

Methods
—We performed urgent bedside non–contrast-enhanced TCD in patients with acute cerebral ischemia before or immediately after baseline CT scanning. A fast-track scanning protocol (≤15 minutes) and detailed diagnostic criteria were developed for portable single-channel TCD testing. TCD results were compared with angiography.

Results
—Of 130 consecutive patients studied, 36 were eligible for thrombolytic therapy; 46 with ischemic strokes and 48 with transient ischemic attacks were not eligible for thrombolysis. TCD identified occlusions in 69% of thrombolysis-eligible patients, compared with 24% and 0% of patients with strokes and transient ischemic attacks, respectively, not eligible for thrombolysis (
P
<0.01). Stenosis was present in 17%, 33%, and 35%, and normal vessels were found in 14%, 43%, and 65% in the respective patient subgroups. TCD also identified abnormal pulsatility of flow (12 patients), abnormal flow velocities (12), microembolic signals (5), or early recanalization (5) (34 of 130; 26%). In 65% of all patients, TCD was compared with angiography (digital subtraction angiography, MR angiography, or CT angiography). Despite a 15% rate of absent temporal windows, TCD had 88% accuracy for abnormal (occlusion and stenosis) versus normal vessels: sensitivity 87.5%, specificity 88.6%, positive predictive value 87.5%, and negative predictive value 88.6%.

Conclusions
—A proximal occlusion on TCD was found in 69% of thrombolysis-eligible patients. In 26% of all patients, TCD provided further relevant information that, in addition to angiography, helped to refine the severity of a stenosis and determine stroke pathogenesis. Emergent TCD is both sensitive and specific in determining arterial occlusion and stenosis in acute cerebral ischemia.
Marfan Syndrome Is Not Associated With Intracranial Aneurysms
Authors: Conway James E. , Hutchins Grover M. , Tamargo Rafael J.
Published: June 2011

Background and Purpose
—It has been proposed that patients with Marfan syndrome have an increased prevalence of intracranial aneurysms. This proposition is based on 10 clinical reports, 1 pathology case, and an autopsy series of 7 patients. By contrast, 5 clinical series of Marfan patients have failed to document any such relationship. We present our institution’s autopsy and clinical experience with Marfan syndrome and analyze in our patient population the purported association between this condition and intracranial aneurysms.

Methods
—The results of an autopsy series at the Johns Hopkins Hospital of 25 confirmed Marfan syndrome patients from 1939 to the present were reviewed retrospectively. The prevalence of intracranial aneurysms in this Marfan syndrome autopsy series was compared with that in the autopsy population at this institution and with that in the general autopsy population as reported in the literature. In addition, the prevalence of Marfan syndrome in a recent neurosurgical series of 710 consecutive aneurysm cases (1990–1998) was determined.

Results
—Of the 25 autopsy cases, only 1 had evidence on autopsy of an unruptured, 2-mm aneurysmal dilatation at the anterior communicating artery complex. Three autopsy patients suffered intracranial hemorrhages but had negative angiography and postmortem examinations for intracranial aneurysms. The remaining 21 patients had negative autopsies for intracranial hemorrhages or intracranial aneurysms. The neurosurgical series of 710 patients treated for intracranial aneurysms did not include any patient with Marfan syndrome.

Conclusions
—The prevalence of 1 patient of 25 with an intracranial aneurysm is not statistically different from the 1.3% prevalence of intracranial aneurysms in the autopsy population at this institution (
P
=0.24) or from the 2.0% prevalence of intracranial aneurysms in the general autopsy population (
P
=0.31). We therefore conclude that there exists no evidence that Marfan syndrome is associated with an increased prevalence of intracranial aneurysms.
Fibrinogen and Vascular Smooth Muscle Cell Grafts Promote Healing of Experimental Aneurysms Treated by Embolization
Authors: Raymond Jean , Desfaits Anne Cécile , Roy Daniel
Published: June 2011

Background and Purpose
—Residual necks and recurrences frequently occur after endovascular treatment of cerebral aneurysms. Addition of fibrinogen and vascular smooth muscle cells (VSMCs) to the embolic material may promote healing of embolized aneurysms by increasing neointima formation at the neck.

Methods
—Bilateral carotid aneurysms were constructed with venous pouches in 31 dogs. Aneurysms were packed intraoperatively with bare Gelfoam sponges, sponges treated with fibrinogen, or fibrinogen sponges seeded with the animal’s own VSMCs or peripheral blood mononuclear cells. Animals were killed after angiography at 3 weeks, and morphometric studies were performed to measure the thickness of the neointima at the neck of treated lesions. Angiographic results and mean thickness of neointimas were compared using ANOVA. In 8 animals, 1 aneurysm was embolized with sponge seeded with VSMCs transduced by adenoviral infection to express a fluorescent protein (green fluorescent protein), and gene expression was monitored for 4, 7, 14, and 21 days by fluorescent microscopy.

Results
—Aneurysms treated with sponges seeded with VSMCs had significantly thicker neointimas and were more completely obliterated at 3 weeks than control aneurysms treated with fibrinogen sponges. Peripheral blood mononuclear cells could not reproduce these findings. Sponges treated with fibrinogen alone promoted formation of a thicker neointima than bare sponges. Transduced cells transplanted into in vivo aneurysms still expressed green fluorescent protein at 3 weeks.

Conclusions
—VMSC grafts can improve healing of experimental aneurysms treated by embolization. Transplantation of cells transduced to express a foreign gene opens the way for in situ gene therapy for cerebral aneurysms.
Transforming Growth Factor-β Mediates Astrocyte-Specific Regulation of Brain Endothelial Anticoagulant Factors
Authors: Tran Nam D. , Correale Jorge , Schreiber Steven S. , Fisher Mark
Published: June 2011

Background and Purpose
—Astrocytes are potent regulators of brain capillary endothelial cell function. Recently, astrocytes were shown to regulate brain capillary endothelial expression of the fibrinolytic enzyme tissue plasminogen activator (tPA) and the anticoagulant thrombomodulin (TM). To study the mechanism of this process, we examined the hypothesis that astrocyte regulation of endothelial tPA and TM is mediated by transforming growth factor-β (TGF-β).

Methods
—Brain capillary endothelial cells were grown in blood-brain barrier models. We examined astrocyte-endothelial cocultures, endothelial monocultures, and astrocyte-conditioned media (ACM) for the expression of TGF-β. We also incubated endothelial cells with ACM to determine the role of TGF-β. Following 24 hours of incubation, we assayed for tPA and TM mRNA, as well as tPA and TM activity.

Results
—Astrocyte-endothelial cocultures and ACM exhibited significantly higher levels of active TGF-β than brain endothelial monocultures and endothelial cells grown in nonconditioned media, respectively. Brain endothelial cells incubated with ACM exhibited reduced tPA and TM mRNA and activity. Treatment with exogenous TGF-β produced dose-dependent reductions in tPA and TM. The effects of ACM on both tPA and TM were blocked by TGF-β neutralizing antibody.

Conclusions
—These data indicate that TGF-β mediates astrocyte regulation of brain capillary endothelial expression of tPA and TM.
Stroke Mortality in Blacks
Authors: Gillum Richard F.
Published: June 2011

Background
—Despite long-term declines in US stroke mortality rates, declines have slowed in the past decade and targets for blacks for the years 2000 and 2010 seem attainable only by extraordinary measures, if at all. This review focuses attention on key aspects of this problem. Data from the US National Center for Health Statistics and reports of population-based studies of stroke mortality published since 1987 retrieved by computerized literature searches were reviewed.

Summary of Review
—The third leading cause of death in black women and the sixth in black men in the United States in 1996, stroke accounted for 10 509 deaths in women and 7972 in men among blacks: 7.92% and 5.33%, respectively, of the total deaths. Age-adjusted death rates per 100 000 were black women, 39.2; white women, 22.9; black men, 50.9; and white men, 26.3. Available data indicate that compared with US whites, US blacks have greater mortality rates for every stroke subtype, with the likely exception of cerebral infarction due to extracranial carotid artery occlusion. These differences will persist into the 21st century. The number of stroke deaths in blacks increased by >8% between 1992 and 1996.

Conclusions
—Increased research on stroke in blacks is needed to develop more effective strategies for primary and secondary prevention of stroke to reduce the high burden of premature mortality and morbidity. Renewed efforts to prevent and control stroke risk factors (in particular elevated blood pressure, diabetes, and smoking) are needed among US blacks.
Nonfasting Serum Glucose and Insulin Concentrations and the Risk of Stroke
Authors: Wannamethee S. Goya , Perry Ivan J. , Shaper A. Gerald
Published: June 2011

Background and Purpose
—Type 2 diabetes is an established risk factor for stroke, but the relations between asymptomatic hyperglycemia, hyperinsulinemia, and stroke incidence remain uncertain. We have examined the relationship between established diabetes, nonfasting serum glucose and serum insulin concentrations, and subsequent risk of stroke.

Methods
—We performed a prospective study of 7735 men aged 40 to 59 years drawn from general practices in 24 British towns. Men with missing serum glucose values (n=50) and men on insulin injection (n=36) were excluded, leaving 7649 men available for analysis. Baseline nonfasting serum was analyzed for insulin with a specific enzyme-linked immunosorbent assay method in 18 of the 24 towns (n=5663 men).

Results
—During the mean follow-up period of 16.8 years, there were 347 stroke cases (fatal and nonfatal) in the 7649 men. Men who developed diabetes during follow-up (n=320) and men with established type 2 diabetes at screening (n=98) both showed significantly increased risk of stroke, even after adjustment for cardiovascular risk factors, including blood pressure (adjusted relative risk [RR], 2.27; 95% CI, 1.23 to 4.20; RR, 2.07; 95% CI, 1.44 to 2.98, respectively). In men with no diagnosed diabetes at screening (n=7551), risk of stroke was increased significantly only in the top 2.5% of the nonfasting glucose distribution (≥8.2 mmol/L), and this persisted even after adjustment for cardiovascular risk factors, including hypertension (RR, 1.86; 95% CI, 1.11 to 3.13). Exclusion of the 320 men who developed diabetes during follow-up attenuated this risk so that it was no longer significant (RR, 1.56; 95% CI, 0.83 to 2.91). In the 5567 men with insulin measurements and no diagnosis of diabetes at screening, a J-shaped relationship was seen between nonfasting insulin and risk of stroke. Risk was significantly raised in the first quintile and in the fourth quintile and above compared with the second quintile, with all findings of marginal significance. Part of the increased risk at higher levels of insulin was due to men who developed diabetes in the follow-up period.

Conclusions
—This study confirms the importance of established type 2 diabetes as an independent risk factor for stroke. The increased risk of stroke seen in hyperglycemic subjects and those with elevated serum insulin levels at screening reflected to some extent the high proportion of men who subsequently developed diabetes.
Four-Dimensional Ultrasonographic Characterization of Plaque Surface Motion in Patients With Symptomatic and Asymptomatic Carotid Artery Stenosis
Authors: Meairs Stephen , Hennerici Michael
Published: June 2011

Background and Purpose
—In vitro studies of atherosclerotic plaque fracture mechanics suggest that analysis of local variations in surface deformability may provide information on relative vulnerability to plaque fissuring or rupture. We investigated plaque surface deformations in patients with symptomatic and asymptomatic carotid artery disease using 4-dimensional ultrasonography and techniques for measuring optical flow.

Methods
—Four-dimensional ultrasound examinations of carotid artery plaques were performed in 23 asymptomatic and 22 symptomatic patients with 50% to 90% stenosis of the internal carotid artery. Plaque surface motion during 1 cardiac cycle was computed with a hierarchical model-based motion estimator. Results were compared with plaque echogenicity and surface structure.

Results
—Of the 45 patients examined, plaque surface motion estimates were obtained for 18 asymptomatic and 13 symptomatic patients. There were no significant differences in echogenicity or surface structure of asymptomatic and symptomatic plaques (
P
>0.05). Results of motion estimation showed that asymptomatic plaques had surface motion vectors of equal orientation and magnitude to those of the internal carotid artery, whereas symptomatic plaques demonstrated evidence of inherent plaque movement. There was no significant difference in maximal plaque velocity between symptomatic and asymptomatic plaques (
P
<0.14). Maximal discrepant surface velocity (MDSV) in symptomatic plaques was 3.85±1.26 mm/s (mean±SD), which was significantly higher (
P
<0.001) than MDSV of asymptomatic plaques with 0.58±0.42 mm/s (mean±SD).

Conclusions
—MDSV of carotid artery plaques is significantly different in asymptomatic and symptomatic disease. Further studies are warranted to determine whether plaque surface motion patterns can identify vulnerable plaques in patients with carotid artery stenosis.
Contrast Transcranial Doppler Ultrasound in the Detection of Right-to-Left Shunts
Authors: Droste Dirk W. , Kriete Jens-Uwe , Stypmann Jörg , Castrucci Marco , Wichter Thomas , Tietje Ralf , Weltermann Birgitta , Young Peter , Ringelstein E. Bernd
Published: June 2011

Background and Purpose
—Cardiac right-to-left shunts can be identified by transesophageal echocardiography (TEE) and by transcranial Doppler ultrasound (TCD) with the use of different contrast agents and different provocation procedures. Currently, data on an appropriate time window for the appearance of contrast bubbles in the TCD recording after the injection of the contrast medium and the comparison of different provocation maneuvers to increase right-to-left shunting are insufficient.

Methods
—Forty-six patients were investigated by both TEE and bilateral TCD of the middle cerebral artery. The following protocol with 6 injection modes was applied in a randomized way: (1) injection of 10 mL of agitated saline without Valsalva maneuver, (2) injection of 10 mL of agitated saline with Valsalva maneuver, (3) injection of 10 mL of a commercial galactose-based contrast agent (Echovist) without Valsalva maneuver, (4) injection of 10 mL of Echovist with Valsalva maneuver, (5) injection of 10 mL of Echovist with standardized Valsalva maneuver, and (6) injection of 10 mL of Echovist with coughing.

Results
—In 20 patients, a right-to-left shunt was demonstrated by TEE and contrast TCD (shunt-positive). Sixteen patients were negative in both investigations, no patient was positive on TEE and negative on TCD, and 10 patients were only positive on at least 1 TCD investigation but negative during TEE. The amount of microbubbles detected in the various tests decreased in the following order: Echovist and Valsalva maneuver, Echovist with coughing, Echovist and standardized Valsalva maneuver, saline with Valsalva maneuver, Echovist, and saline. With a time window of 20 to 25 seconds for the bubbles to appear in the TCD recording and with a sequence of first Echovist and Valsalva maneuver and then Echovist with coughing, all shunts were reliably identified with a specificity of 65% compared with TEE as the traditional gold standard. The time of first microbubble appearance was not helpful to distinguish between shunts detected on TEE and other shunts.

Conclusions
—TCD performed twice with 2 provocation maneuvers using Echovist is a sensitive method to identify cardiac right-to-left shunts also identified by TEE.
The Role of Diaschisis in Stroke Recovery
Authors: Seitz Rüdiger J. , Azari Nina P. , Knorr Uwe , Binkofski Ferdinand , Herzog Hans , Freund Hans-Joachim
Published: June 2011

Background and Purpose
—Recovery from hemiparesis after stroke has been shown to involve reorganization in motor and premotor cortical areas. However, whether poststroke recovery also depends on changes in remote brain structures, ie, diaschisis, is as yet unresolved. To address this question, we studied regional cerebral blood flow in 7 patients (mean±SD age, 54±8 years) after their first hemiparetic stroke.

Methods
—We analyzed imaging data voxel by voxel using a principal component analysis by which coherent changes in functional networks could be disclosed. Performance was assessed by a motor score and by the finger movement rate during the regional cerebral blood flow measurements.

Results
—The patients had recovered (
P
<0.001) from severe hemiparesis after on average 6 months and were able to perform sequential finger movements with the recovered hand. Regional cerebral blood flow at rest differentiated patients and controls (
P
<0.05) by a network that was affected by the stroke lesion. During blindfolded performance of sequential finger movements, patients were differentiated from controls (
P
<0.05) by a recovery-related network and a movement-control network. These networks were spatially incongruent, involving motor, sensory, and visual cortex of both cerebral hemispheres, the basal ganglia, thalamus, and cerebellum. The lesion-affected and recovery-related networks overlapped in the contralesional thalamus and extrastriate occipital cortex.

Conclusions
—Motor recovery after hemiparetic brain infarction is subserved by brain structures in locations remote from the stroke lesion. The topographic overlap of the lesion-affected and recovery-related networks suggests that diaschisis may play a critical role in stroke recovery.
Attenuated Stroke Severity After Prodromal TIA
Authors: Weih M. , Kallenberg K. , Bergk A. , Dirnagl U. , Harms L. , Wernecke K. D. , Einhäupl K. M.
Published: June 2011

Background and Purpose
—Ischemic tolerance has been extensively studied in experimental models of heart and brain ischemia. While there is some clinical evidence of ischemic tolerance in the heart, it is not known whether the same is true for the human brain.

Methods
—We conducted a retrospective case-control study in 148 stroke patients with and without antecedent TIA.

Results
—Despite no significant differences in baseline characteristics, independence (Rankin scale score of 0 to 1) and favorable outcome (Glasgow Coma Scale score of 5) were significantly associated with prior TIA in univariate analysis. After correction for other cardiovascular risk factors, TIA before stroke also was an independent predictor of mild stroke (Canadian Neurological Scale score of ≥6.5) in multivariate models (absolute difference 21.6%;
P
=0.01).

Conclusions
—Assuming that a TIA represents an adequate stimulus to elicit ischemic tolerance, our results suggest that ischemic tolerance might occur in the human brain.
Evaluation of Genetic Risk Factors for Silent Brain Infarction
Authors: Notsu Yoshitomo , Nabika Toru , Park Hyun-Young , Masuda Junichi , Kobayashi Shotai
Published: June 2011

Background and Purpose
—Silent brain infarction (SBI) is often found with white matter hyperintensity. A recent genetic study on elderly twins indicated that the susceptibility to white matter hyperintensity was largely determined by genetic factors, implying the existence of genetic susceptibility for SBI as well. We therefore studied 3 genetic polymorphisms in SBI, the deletion/insertion polymorphism of angiotensin-converting enzyme (ACE) gene, the apolipoprotein(a) [apo(a)] size polymorphism, and the T677C polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene, by a case-control study.

Methods
—By MRI, 147 subjects with SBI and 214 without cerebral infarctions (control group) were selected from participants of a health examination of the brain. Seventy-four patients with symptomatic subcortical infarction (SSI) from the same area were also included in the study. In addition to the control group, 2 more reference populations were recruited. Typing of the apo(a) size polymorphism was done by Western blotting with the use of an anti-apo(a) antibody. Genotypes of ACE and MTHFR were determined by polymerase chain reaction amplification of the genomic DNA and subsequent restriction enzyme digestion.

Results
—The ACE polymorphism was not associated with either SBI or SSI. In contrast, the small apo(a) was associated with both SSI and SBI. The MTHFR polymorphism was associated only with SSI. The association of MTHFR and apo(a) was greater in the younger subjects.

Conclusions
—Among the 3 genetic polymorphisms studied, only the apo(a) size polymorphism is a risk factor for SBI.
Expression of Cyclooxygenase-2 mRNA After Global Ischemia Is Regulated by AMPA Receptors and Glucocorticoids
Authors: Koistinaho Jari , Koponen Susanna , Chan Pak H.
Published: June 2011

Background and Purpose
—Cyclooxygenase-2 (COX-2) is implicated in ischemic neuronal death. In focal ischemia, its mRNA induction is mediated through
N
-methyl-
d
-aspartic acid (NMDA) receptors and phospholipase A
2
. Because mechanisms of neuronal death involving COX-2 in global ischemia are unclear, we studied the time course and regulation of COX-2 expression in rat brain global ischemia.

Methods
—Global ischemia was induced by a 4-vessel occlusion method. COX-2 mRNA levels were demonstrated with in situ hybridization and COX-2 protein with immunocytochemistry. Several animals were pretreated with MK-801, an NMDA receptor antagonist; 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist; and dexamethasone.

Results
—In the cortex, the CA3 hippocampal region and dentate gyrus expression of COX-2 mRNA peaked at 4 to 8 hours, while in the CA1 region COX-2 mRNA levels were high at 4 to 24 hours. COX-2 protein was induced in the corresponding regions at 12 to 24 hours, but in the CA1 neurons the protein was still seen at 3 days. COX-2 mRNA induction in the cortex was inhibited by NBQX and dexamethasone and in CA1 neurons was inhibited by NBQX. MK-801 did not suppress COX-2 induction.

Conclusions
—COX-2 is differentially induced in the cortex and hippocampal structures after global ischemia. The prolonged COX-2 expression in the vulnerable CA1 neurons is regulated by AMPA receptors, suggesting that COX-2 expression is likely to be associated with AMPA receptor–mediated neuronal death in global ischemia. Glucocorticoids may not be efficiently used to inhibit ischemia-induced COX-2 expression in the hippocampus.
Neuroprotective Properties of Statins in Cerebral Ischemia and Stroke
Authors: Vaughan Carl J. , Delanty Norman
Published: June 2011

Background
—The atheroma-retarding properties of β-hydroxy-β-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, or “statins,” in both the coronary and carotid arterial beds are well established. However, a growing body of recent data suggests that statins possess important adjunctive properties that may confer additional benefit beyond the retardation of atherosclerosis. In this article, we review the emerging evidence that statins have beneficial effects within the cerebral circulation and brain parenchyma during ischemic stroke and reperfusion.

Summary of Review
—Clinical studies show that statins reduce the incidence of ischemic stroke through probable effects on precerebral atherosclerotic plaque and through antithrombotic mechanisms. Additionally, statins have been shown to reduce infarct size in experimental animal models of stroke. Statins both upregulate endothelial nitric oxide synthase (eNOS) and inhibit inducible nitric oxide synthase (iNOS), effects that are potentially neuroprotective. The preservation of eNOS activity in cerebral vasculature, particularly in the ischemic penumbra, may be especially important in preserving blood flow and limiting neurological loss. Statins may also attenuate the inflammatory cytokine responses that accompany cerebral ischemia, and they possess antioxidant properties that likely ameliorate ischemic oxidative stress in the brain.

Conclusions
—In addition to reducing stroke, the statin class of drugs exhibits a number of important neuroprotective properties that likely attenuate the effects of ischemia on the brain vasculature and parenchyma. Further investigation of the role of statins in human neuroprotection by use of neuroimaging and cognitive studies is warranted to explore these preliminary observations. In addition to reducing ischemic stroke, early evidence indicates that statins may also be neuroprotective.