bluuebunny/crossref_metadata_2025 huggingface dataset:
Alterations of the Blood-Brain Barrier and Glial Cells in White-Matter Lesions in Cerebrovascular and Alzheimer's Disease Patients
Authors: Tomimoto Hidekazu , Akiguchi Ichiro , Suenaga Toshihiko , Nishimura Masaki , Wakita Hideaki , Nakamura Shinichi , Kimura Jun
Published: June 2011

Background and Purpose
The underlying cause of white-matter lesions, which are frequent findings in cerebrovascular disease (CVD) and Alzheimer's disease (AD), remains uncertain. We performed immunohistochemical analysis of serum protein extravasation to investigate the function of the blood-brain barrier in white-matter lesions.

Methods
White-matter lesions were estimated by use of Klüver-Barrera staining in patients diagnosed clinicopathologically as having ischemic CVD (n=14) and AD (n=12) and from nonneurological control subjects (n=6). Axonal damages were investigated by use of immunohistochemistry for amyloid protein precursor. Alteration of the blood-brain barrier was examined with fibrinogen and immunoglobulins used as markers. The numbers of HLA-DR–positive microglia and glial fibrillary acidic protein–positive astroglia were examined comparatively.

Results
White-matter lesions were graded as normal (grade 0) in 14 of the 32 cases (44%), slight (grade I) in 10 cases (31%), moderate (grade II) in 6 cases (19%), and severe (grade III) in 2 cases (6%). Amyloid precursor protein was accumulated most frequently in grade II white-matter lesions. Immunohistochemistry for serum proteins labeled astroglial cell bodies and their processes, which seemed to have sequestered extravasated proteins. The groups with detectable white-matter lesions had significantly higher grading scores for fibrinogen and immunoglobulins than the control group (
P
<.05). Although the higher scores for serum protein extravasation were statistically significant in ischemic CVD cases (
P
<.05), there was no significant increase in AD cases. Activated microglia and astroglia were more numerous in the groups with white-matter lesions in both ischemic CVD and AD cases, although this increase in the number of astroglia was not evident in regions with clasmatodendrosis.

Conclusions
Dysfunction of the blood-brain barrier is more prominent in white-matter lesions seen in ischemic CVD than in AD and may have a role in the pathogenesis of cerebrovascular white-matter lesions.
Can Motor Recovery in Stroke Patients Be Predicted by Early Transcranial Magnetic Stimulation?
Authors: Rapisarda G. , Bastings E. , de Noordhout A. Maertens , Pennisi G. , Delwaide P.J.
Published: June 2011

Background and Purpose
We used transcranial magnetic stimulation of the motor cortex to evaluate the functional state of corticospinal pathways innervating the first dorsal interosseous muscle of the hand in 26 patients suffering from a first-ever ischemic stroke in the middle cerebral artery territory.

Methods
All patients had complete hand palsy and were tested within the first 24 hours from stroke onset. Patients were also tested clinically with the MRC, Rankin, and National Institutes of Health (NIH) stroke scales at day 1 and with MRC and NIH scales and the Barthel Index at day 14. Electrophysiological testing was repeated at day 14. Patients were divided into three subgroups according to the amplitude of the maximal response (motor evoked potential [MEP]) evoked at day 1.

Results
After 2 weeks, all 6 patients with initial MEPs >5% maximum motor response (M
max
) showed some first dorsal interosseous muscle motor function recovery, whereas 19 of 20 patients with initially absent or small (<5% M
max
) MEPs were left with complete hand palsy. There were strong positive correlations between MEP amplitude at day 1 and MRC and Barthel Index scores at day 14. However, measurement of central motor conduction time proved to be of little prognostic value.

Conclusions
We conclude that early-performed transcranial magnetic stimulation is a valuable prognostic tool for motor recovery from stroke and that relatively preserved MEP amplitude shortly after stroke is a better prognostic factor than normal central motor conduction time.
Percutaneous Transluminal Angioplasty of the Symptomatic Atherosclerotic Carotid Arteries
Authors: Gil-Peralta Alberto , Mayol Antonio , Marcos Jose R. Gonzalez , Gonzalez Alejandro , Ruano Jose , Boza Fernando , Duran Fernando
Published: June 2011

Background and Purpose
Carotid endarterectomy reduces stroke risk in patients with >70% symptomatic stenosis. We present our results of percutaneous transluminal angioplasty (PTA) as an alternative treatment.

Methods
Ninety-eight patients with symptomatic >70% stenosis of the internal carotid artery were considered for PTA. Details of the procedure, complications, and 4-year follow-up were registered.

Results
Eighty-five PTAs were performed in a 4-year period. Transient cardiovascular effects were frequent: hypotension (54.1%), bradycardia (67.1%), asystole (25.9%), and syncope (16.5%). Transient ischemic attack occurred in 3 of 82 patients (3.7%), and disabling stroke occurred in 4 (4.9%); mortality was 0%. After a mean follow-up period of 18.7 months, 4 patients died, 1 due to fatal stroke. The overall probability of surviving any stroke or death was 86.7%. Restenosis (>70%) was seen in 6 cases (7.4%).

Conclusions
PTA may be a reasonable treatment for symptomatic atherosclerotic stenosis, at least in patients at high risk for carotid endarterectomy.
Tacrolimus (FK506) Ameliorates Skilled Motor Deficits Produced by Middle Cerebral Artery Occlusion in Rats
Authors: Sharkey John , Crawford Jane H. , Butcher Steven P. , Marston Hugh M.
Published: June 2011

Background and Purpose
Tacrolimus (FK506) is a potent immunosuppressant that is presently in clinical use for prevention of allograft rejection. Recently, animal studies reporting significant reductions in the volume of tissue damage associated with cardiac, hepatic, and cerebral ischemia suggest that tacrolimus may also be of use in the clinical management of stroke. In the present study, we examine whether the neuroprotective effects of tacrolimus, as assessed by histological outcome, are accompanied by an amelioration of the skilled motor deficits induced in the rat by middle cerebral artery occlusion (MCAO).

Methods
Animals were trained to perform a skilled paw-reaching task before MCAO by perivascular microinjections of endothelin-1. Tacrolimus (1 mg/kg, n=6) or vehicle (n=6) was administered by intravenous infusion 1 minute after MCAO. After a 5-day postoperative recovery period, the rats were retested for skilled paw-reaching ability for an additional 9 days.

Results
In vehicle-treated rats, MCAO resulted in a profound bilateral impairment in skilled paw use. Rats treated with tacrolimus, although still impaired, performed significantly better than those treated with vehicle alone (
P
<.01). Histological analysis, 14 days after occlusion, confirmed the neuroprotective efficacy of tacrolimus with a 66% reduction in the volume of hemispheric brain damage produced by MCAO (
P
<.01).

Conclusions
The present studies show that tacrolimus not only protects neural tissue from focal cerebral ischemia but also significantly ameliorates the deficits in skilled motor ability produced by this lesion. These data provide further support for the view that tacrolimus may be of use in the treatment of stroke.
Simplified Model of Krypton LaserInduced Thrombotic Distal Middle Cerebral Artery Occlusion in Spontaneously Hypertensive Rats
Authors: Yao Hiroshi , Ibayashi Setsuro , Sugimori Hiroshi , Fujii Kenichiro , Fujishima Masatoshi
Published: June 2011

Background and Purpose
The effects of thrombotic occlusion of the middle cerebral artery on compromised ischemic tissue may be different from and more severe than those of cerebral ischemia induced by mechanical occlusion of the artery. Photothrombosis, which is based on photochemical damage to the endothelium and subsequent platelet aggregation, is an efficient method to induce thrombosis in vivo. This study aimed to improve and simplify this unique method for an ischemia model of middle cerebral artery occlusion in rats.

Methods
Male spontaneously hypertensive rats (5 to 6 months old, 300 to 450 g) were anesthetized with halothane, endotracheally intubated, and mechanically ventilated. A krypton laser operating at 568 nm was used to irradiate the exposed distal middle cerebral artery with an intact dura above the rhinal fissure. The photosensitizing dye rose bengal (20 mg/kg body wt) was administered intravenously over 90 seconds starting simultaneously with 4 minutes of laser irradiation at a power of 20 mW to cause thrombotic occlusion of this artery.

Results
The irradiated middle cerebral artery was completely occluded by intraluminal thrombi within 3 minutes after simultaneous laser irradiation and rose bengal infusion. Thrombosed materials were not stained by phosphotungstic acid–hematoxylin stain (ie, aggregated platelets lacked apparent fibrin). The mean volume of 3-day-old infarction, indicated by the lack of staining with 2,3,5-triphenyltetrazolium chloride, was 84.8±17.4 mm
3
(mean±SD, n=6).

Conclusions
We demonstrated a reproducible and minimally traumatic model of brain infarction induced by the thrombotic distal middle cerebral artery occlusion in rats.
Twenty-Five-Year Prediction of Stroke Deaths in the Seven Countries Study
Authors: Menotti Alessandro , Jacobs David R. , Blackburn Henry , Kromhout Daan , Nissinen Aulikki , Nedeljkovic Srecko , Buzina Ratko , Mohacek Ivan , Seccareccia Fulvia , Giampaoli Simona , Dontas Anastasios , Aravanis Christ , Toshima Hironori
Published: June 2011

Background and Purpose
This report explores the prediction of long-term stroke mortality in cohorts of the Seven Countries Study.

Methods
Sixteen cohorts of men aged 40 to 59 years at entry were examined at years 0, 5, and 10, with mortality follow-up through 25 years.

Results
Stroke death rates in 25 years were high in rural Serbia, Croatia, and Japan; intermediate in Italy, Greece, and urban Serbia; and low in Finland, the Netherlands, and the United States. Age and blood pressure were powerful predictors of 25-year stroke mortality in almost all cohorts and countries. Proportional hazards regression coefficients were .0232 increase in stroke death hazard per millimeter of mercury (
t
=14.60) for systolic blood pressure and .0409 (
t
=13.41) for diastolic blood pressure. Moderate blood pressure increases from low usual levels were associated with lower stroke mortality rates in years 10 to 25. Increases of blood pressure starting from high usual levels were associated with increased rates of stroke mortality. Systolic blood pressure was associated with stroke mortality at given levels of diastolic pressure, but diastolic blood pressure was not predictive of stroke mortality at given levels of systolic blood pressure.

Conclusions
Associations of systolic and diastolic blood pressure with stroke mortality were similar in cultures with different stroke mortality rates. Increases in blood pressure were associated with subsequent excess stroke mortality only in those who started from high usual levels; this study finds lower stroke risk in those men whose blood pressure increased moderately from low usual levels. Diastolic blood pressure is not independently associated with stroke risk in these populations.
Reliability of Longitudinal Ultrasonographic Measurements of Carotid Intimal-Medial Thicknesses
Authors: Espeland Mark A. , Craven Timothy E. , Riley Ward A. , Corson John , Romont Alicia , Furberg Curt D.
Published: June 2011

Background and Purpose
Serial ultrasonic B-mode measurements of intimal-medial thickness (IMT) of the carotid artery are commonly used as surrogates for describing atherosclerosis progression. This report describes the longitudinal reliability of IMT measurement during a multicenter clinical trial, quantifies the error attributable to differences among readers, and discusses how studies can be efficiently designed.

Methods
Serial B-mode measurements of carotid IMT from the 3-year Asymptomatic Carotid Artery Progression Study (ACAPS; formerly Asymptomatic Carotid Artery Plaque Study) were used to estimate the contributions to longitudinal measurement error of systematic reader effects, nonvisualization, and nonsystematic error and to describe the distribution of “true” progression rates that underlie the observed data. Variance components were estimated from random-effects models fitted to outcome measures formed by averaging IMTs from different sets of carotid artery walls. These were used to contrast the relative efficiency of study designs.

Results
Of the total variance of measured IMT, 11% was attributable to systematic differences among readers. Nonvisualization contributed less than 7%. Thus, the predominant source of error was unaccounted for (ie, random error or “noise,” which in our analyses included any drift, nonlinearity, and sonographer differences). For studies with measurement protocols similar to ACAPS, follow-up times of 2 years or more are desirable for describing the mean progression rates of cohorts, and of 6 years or more for categorizing progression within individuals. In 3-year studies, sample sizes as low as 237 provide 90% statistical power for detecting risk factors that have correlations with IMT progression of .50 or greater.

Conclusions
The ACAPS measurement protocol provided highly reliable serial IMT data. Moderate-sized multicenter studies using B-mode outcomes are feasible.
Lobar Intracerebral Hemorrhage Model in Pigs
Authors: Wagner Kenneth R. , Xi Guohua , Hua Ya , Kleinholz Marla , de Courten-Myers Gabrielle M. , Myers Ronald E. , Broderick Joseph P. , Brott Thomas G.
Published: June 2011

Background and Purpose
The mechanisms underlying brain injury from intracerebral hemorrhage (ICH) are complex and poorly understood. To comprehensively examine pathophysiological and pathochemical alterations after ICH and to examine the effects of hematoma removal on these processes, we developed a physiologically controlled, reproducible, large-animal model of ICH in pigs (weight, 6 to 8 kg).

Methods
We produced lobar hematomas by pressure-controlled infusions of 1.7 mL of autologous blood into the right frontal hemispheric white matter over 15 minutes. We froze brains in situ at 1, 3, 5, and 8 hours after hematoma induction and cut coronal sections for hematoma assessment, morphological brain examination, and immunohistochemical and water content determinations.

Results
At 1 hour after blood infusion, “translucent” white matter areas were present directly adjacent to the hematoma. These markedly edematous regions had a greater than 10% increase in water content (>85%) compared with the contralateral white matter (73%), and this increased water content persisted through 8 hours. In addition, these areas were strongly immunoreactive for serum proteins. Intravascular Evans blue dye failed to penetrate into the brain tissue at all time points, demonstrating that this serum protein accumulation and edema development were not due to increased blood-brain barrier permeability.

Conclusions
Experimental lobar ICH in pigs models a prominent pathological feature of human ICH, ie, early perihematomal edema. Our findings suggest that serum proteins, originating from the hematoma, accumulate in adjacent white matter and result in rapid and prolonged edema after ICH. This interstitial edema likely corresponds to the low densities on CT scans and the hyperintensities on T
2
-weighted MR images that surround intracerebral hematomas acutely after human ICH.
Gender Influences the Magnitude of the Inflammatory Response Within Embolic Cerebral Infarcts in Young Rats
Authors: Li Kewa , Futrell Nancy , Samuel Tovar J. , Wang LiJuan C. , Wang DO David Z. , Schultz Lonni R.
Published: June 2011

Background and Purpose
The inflammatory response within cerebral infarcts may have an influence on tissue damage. Since old animals with an impaired immune response have decreased inflammation after experimental cerebral infarction, we postulated that female animals with an increased immune response will have an increased inflammatory response after cerebral infarction.

Methods
Embolic cerebral infarcts were produced by photochemical irradiation of the right carotid artery in 12 female Fischer rats. The inflammatory response within 4-day-old infarcts was quantitated by histology with the use of computer-assisted image analysis and compared with that in 12 male rats from a previous series.

Results
Severe infarcts had the most pronounced inflammatory response. Female rats had an increased inflammatory response in infarcts of all severity, which was statistically significant in severe cerebral infarcts even after adjustment for infarct size. Severe infarcts in males were significantly larger than those in females.

Conclusions
Gender influences the outcome of embolic cerebral infarcts after photochemical damage to the carotid artery, both in terms of the magnitude of the inflammatory response and infarct size. There are numerous gender-related differences in neurochemicals, cytokine production, and drug metabolism that may influence tissue damage after stroke and responsiveness to therapeutic intervention. The preponderance of male animals in stroke research may produce results not applicable to female stroke patients. The use of female animals will be required to provide adequate models for the study of stroke in women.
Cholinergic Changes in the Hippocampus of Stroke-Prone Spontaneously Hypertensive Rats
Authors: Togashi Hiroko , Kimura Shinichi , Matsumoto Machiko , Yoshioka Mitsuhiro , Minami Masaru , Saito Hideya
Published: June 2011

Background and Purpose
We investigated age-related changes in the central cholinergic systems in stroke-prone spontaneously hypertensive rats (SHRSP) to examine whether the regional and progressive cholinergic changes occur and are correlated with behavioral changes in the passive avoidance task.

Methods
Tissue levels of choline (Ch) and acetylcholine (ACh) were determined in the cerebral regions, including the hippocampus, of SHRSP (at two ages: 15 to 20 and 30 to 40 weeks) that had been tested in a passive avoidance task and were compared with those of age-matched controls, Wistar-Kyoto rats (WKY). With the use of in vivo microdialysis, high K
+
-stimulated release of hippocampal ACh, a functional parameter of the cholinergic system, was also determined in 15- to 20-week-old SHRSP.

Results
We found that 15- to 20-week-old SHRSP demonstrated a markedly lower level of hippocampal Ch than age-matched WKY. The decrease in the Ch level in 15- to 20-week-old SHRSP was observed in all regions examined; however, in the hippocampus a significant difference from WKY was subsequently observed at the age of 30 to 40 weeks. The hippocampal ACh release was markedly decreased by repetitive stimulation with high K
+
in 15- to 20-week-old SHRSP. Behavioral impairment in the passive avoidance task was observed in the two age groups of SHRSP, with significant and positive correlations between the hippocampal ACh levels and the response latency.

Conclusions
A decrease in hippocampal Ch level was observed in both 15- to 20-week-old and 30- to 40-week-old SHRSP, accompanied by performance failure in the passive avoidance task. The abnormal release of hippocampal ACh in response to the repetitive K
+
stimulation was also noted in 15- to 20-week-old SHRSP. Thus, cholinergic dysfunction in the hippocampal system may be responsible for behavioral abnormality in the passive avoidance task in SHRSP.
Determination of Duplex Doppler Ultrasound Criteria Appropriate to the North American Symptomatic Carotid Endarterectomy Trial
Authors: Carpenter Jeffrey P. , Lexa Frank J. , Davis Julia T.
Published: June 2011

Background and Purpose
The North American Symptomatic Carotid Endarterectomy Trial (NASCET) demonstrated the benefit of carotid endarterectomy for symptomatic patients with ≥70% carotid stenosis. Screening for detection of significant carotid occlusive disease has relied on duplex Doppler imaging. However, traditional duplex categories (50% to 79%, 80% to 99%) are not directly applicable to NASCET. We sought to evaluate duplex criteria for determination of ≥70% carotid stenosis.

Methods
Duplex scans and arteriograms of 110 patients (210 carotids), performed within 1 month of each other, were reviewed by blinded readers. Arteriographic stenosis was determined by the NASCET method. Duplex measurements of peak systolic and end-diastolic velocity (PSV, EDV) were recorded, and ratios of velocities in the internal and common carotid arteries (ICA, CCA) were calculated. Receiver-operator characteristic (ROC) curves of sensitivity, specificity, positive and negative predictive values (PPV, NPV), and accuracy were determined.

Results
Interobserver agreement for measurement of arteriographic stenosis was “almost perfect” (κ=0.86). The criteria chosen for detection of ≥70% stenosis were PSV
ICA
>210 cm/s (sensitivity, 94%; specificity, 77%; PPV, 68%; NPV, 96%; accuracy, 83%), EDV
ICA
>70 cm/s (sensitivity, 92%; specificity, 60%; PPV, 73%; NPV, 86%; accuracy 77%), PSV
ICA
/PSV
CCA
>3.0 (sensitivity, 91%; specificity, 78%; PPV, 70%; NPV, 94%; accuracy, 83%), and EDV
ICA
/EDV
CCA
>3.3 (sensitivity, 100%; specificity, 65%; PPV, 65%; NPV, 100%; accuracy, 79%).

Conclusions
We conclude that ≥70% carotid stenosis can be reliably determined by duplex Doppler ultrasound. Individual vascular laboratories must validate their own results.
Brain Capillary Tissue Plasminogen Activator in a Diabetes Stroke Model
Authors: Kittaka Mamoru , Wang Liang , Sun Ning , Schreiber Steven S. , Seeds Nicholas W. , Fisher Mark , Zlokovic Berislav V.
Published: June 2011

Background and Purpose
Tissue plasminogen activator (TPA) is normally expressed in rat brain capillaries. This study examines the expression of TPA in brain capillaries of diabetic rats in relation to focal ischemic brain injury.

Methods
Diabetes type 1 was induced by streptozotocin for 7 days. Acute hyperglycemia was induced by 50% dextrose. Expression of TPA in brain capillaries was determined by Western blot and reverse transcription-polymerase chain reaction analyses. Focal stroke was produced by 1 hour of reversible middle cerebral artery occlusion. Physiological variables and cerebral blood flow were monitored during occlusion and within 1 hour of reperfusion. Neurological and neuropathologic examinations were performed after 24 hours of reperfusion.

Results
All rats developed comparable hyperglycemia (≈15 mmol/L). A complete depletion of TPA protein and 6.5-fold decrease in TPA mRNA were found in brain capillaries of diabetic rats, in contrast to normal TPA capillary levels in hyperglycemic rats. The blood flow in the periphery of the ischemic core was significantly reduced during reperfusion by 52% to 62% (
P
<.001) in diabetic rats and by 23% to 25% (
P
<.05) in hyperglycemic rats. The neurological score was worsened by 3.2-fold (
P
<.0003) by diabetes and by 24% by hyperglycemia only. Significant 41% (
P
<.007) and 29% (
P
<.05) increases in infarct volume and 163% (
P
<.007) and 60% increases in edema volume were found in diabetic rats relative to control and hyperglycemic rats, respectively.

Conclusions
Diabetes type 1, but not acute hyperglycemia, produces downregulation of TPA in rat brain capillaries. This TPA reduction is associated with impaired restoration of blood flow after an ischemic insult, poor neurological outcome, and enhanced ischemic brain injury.
Ketamine Antagonizes Nitric Oxide Release From Cerebral Cortex After Middle Cerebral Artery Ligation in Rats
Authors: Lin Shinn-Zong , Chiou Ai-Lin , Wang Yun
Published: June 2011

Background and Purpose
Ischemia or hypoxia activates
N
-methyl-
d
-aspartate (NMDA) receptors and results in nitric oxide (NO) production. The purpose of this study was to investigate whether an NMDA channel blocker can inhibit NO production during ischemia.

Methods
Temporary cerebral ischemia was induced by middle cerebral artery ligation while common carotid arteries were clamped bilaterally for 40 minutes in urethane-anesthetized rats. Extracellular NO concentration in the cortex was recorded through Nafion- and porphyrine-coated carbon fiber electrodes. Ketamine, an NMDA channel blocker, was administered (50 mg/kg) intraperitoneally 15 minutes before the cerebral artery ligation.

Results
During middle cerebral artery ligation, cortical NO was increased to its peak (18.76±3.36 nmol/L) in 7 minutes and then declined. The overflow of NO can be antagonized by pretreatment with ketamine, dizocilpine maleate (MK801), or
N
G
-nitro-
l
-arginine methyl ester (L-NAME). Local application of nitroprusside also induced NO production. However, this effect was not antagonized by ketamine.

Conclusions
These findings demonstrated that NO release induced by short-term cerebral ischemia can be attenuated by pretreatment with NMDA antagonists.
Carotid Artery Thrombus Associated With Severe Iron-Deficiency Anemia and Thrombocytosis
Authors: Akins Paul T. , Glenn Susan , Nemeth Patti M. , Derdeyn Colin P.
Published: June 2011

Background
Thrombus within the carotid artery usually occurs in vessels with severe atherosclerotic disease and may embolize to cause transient ischemic attacks and cerebral infarctions. The risk factors for carotid artery thrombus formation in the absence of atherosclerosis are not well characterized. A case series is presented that suggests an association of carotid artery thrombus with severe iron-deficiency anemia and thrombocytosis.

Case Descriptions
We describe three women with severe iron-deficiency anemia and thrombocytosis secondary to menorrhagia who developed carotid artery thrombi. Thrombi were detected radiographically. The patients were treated with anticoagulation and antiplatelet therapy. In two patients, follow-up neuroimaging 10 to 14 days later demonstrated resolution of the thrombus and no identifiable vascular disease.

Conclusions
Severe iron-deficiency anemia with thrombocytosis may be a risk factor for carotid artery thrombus formation. Medical management with anticoagulation and antiplatelet therapy is a reasonable approach for these patients while the thrombus resolves.
US National Survey of Physician Practices for the Secondary and Tertiary Prevention of Ischemic Stroke
Authors: Goldstein Larry B. , Bonito Arthur J. , Matchar David B. , Duncan Pamela W. , Samsa Gregory P.
Published: June 2011

Background and Purpose
Data from several randomized clinical trials concerning the efficacy of carotid endarterectomy (CE) in patients with symptomatic and asymptomatic stenoses of the extracranial carotid artery are now available. Yet, there are few data concerning the patterns of use of CE by physicians for their patients at risk for stroke. These data are critical for the rational allocation of resources and targeting of educational efforts.

Methods
Between August 1993 and February 1994, we surveyed the stroke prevention practices of a stratified random sample of 2000 US physicians. The survey queried the perceived availability and use of diagnostic studies and surgery for specific types of patients who might be considered candidates for CE.

Results
Of eligible physicians, 67% (n=1006) completed the survey. Seventy percent reported that they always or often obtain carotid ultrasonography for evaluation of patients with asymptomatic bruits; 89% do so in patients with recent transient ischemic attack or minor stroke (
P
<.001). For asymptomatic patients, 13% always or often obtain a cerebral angiogram if carotid ultrasonography indicates 50% to 70% stenosis versus 33% if carotid ultrasonography indicates >70% stenosis (
P
<.001). For asymptomatic patients with >70% stenosis, a cerebral angiogram was reported as seldom or never used by 42% of physicians who viewed the test as readily available versus 67% if cerebral angiography was perceived as not readily available (
P
=.005). Multinomial multiple logistic regression analysis showed that symptom status, the degree of stenosis, perceived availability of CE, and physician specialty independently contributed to the explained variance in the reported use of CE (
P
<.001). The odds of performing CE were approximately four times greater in patients with recent symptoms compared with asymptomatic patients (
P
<.001) and four times greater in patients with >70% stenosis compared with patients with 50% to 70% stenosis (
P
<.001). Physicians who perceived CE as not being readily available were one third as likely to report using the procedure compared with physicians who reported having ready access (
P
=.004). CE was reported as being always or often used by more than 80% of neurologists and surgeons but by only about half of internists and noninternist primary care physicians for patients with newly symptomatic high-grade stenosis (
P
<.001). Almost one in four noninternist primary care physicians responded that they would seldom or never use CE for these patients.

Conclusions
These data show that (1) symptom status and degree of carotid artery stenosis strongly influence the reported frequency with which CE is used by practicing physicians; (2) the perceived availability of cerebral angiography and CE significantly affects their reported frequency of use; and (3) physician specialty significantly influences the reported frequency of use of CE.
Relationships Between ATP Depletion, Membrane Potential, and the Release of Neurotransmitters in Rat Nerve Terminals
Authors: Santos Maria S. , Moreno António J. , Carvalho Arsélio P.
Published: June 2011

Background and Purpose
It is known that the extracellular accumulation of glutamate during anoxia/ischemia is responsible for initiating neuronal injury. However, little information is available on the release of monoamines and whether the mechanism of its release resembles that of glutamate, which may itself influence the release of monoamines by activating presynaptic receptors. This study was designed to characterize the release of both amino acids and monoamines under chemical conditions that mimic anoxia, hypoglycemia, and ischemia.

Methods
The contents of synaptosomes in adenine nucleotides (ATP, ADP, and AMP), amino acids (aspartate, glutamate, taurine, and γ-aminobutyric acid), and monoamines (dopamine, noradrenaline, and 5-hydroxytryptamine) were measured by high-performance liquid chromatography, after the synaptosomes were subjected to anoxia (KCN+oligomycin), hypoglycemia (2 mmol/L 2-deoxyglucose in glucose-free medium), and ischemia (anoxia plus hypoglycemia).

Results
The anoxia- and ischemia-induced release of noradrenaline, dopamine, 5-hydroxytryptamine, and glutamate correlated well with ATP depletion. The correlation observed between glutamate levels and the release of dopamine and 5-hydroxytryptamine in ischemic conditions suggests a functional linkage between the two transmitter systems. However, the antagonists of presynaptic glutamate receptors failed to alter the amount of monoamines released. The inhibition of Na
+
,K
+
-ATPase by ouabain had an effect similar to that produced by ischemia.

Conclusions
The decrease in Na
+
and K
+
gradients resulting from the energy depletion of the synaptosomes under ischemic conditions or resulting from the inhibition of Na
+
,K
+
-ATPase by ouabain promotes the reversal of the neurotransmitter transporters. The decrease in uptake of neurotransmitters may also contribute to the rise in the extracellular concentration of different transmitters observed during brain ischemia.
Effects of Fluoxetine and Maprotiline on Functional Recovery in Poststroke Hemiplegic Patients Undergoing Rehabilitation Therapy
Authors: Dam M. , Tonin P. , De Boni A. , Pizzolato G. , Casson S. , Ermani M. , Freo U. , Piron L. , Battistin L.
Published: June 2011

Background and Purpose
In animals, drugs that increase brain amine concentrations influence the rate and degree of recovery from cortical lesions. It is therefore conceivable that antidepressants may influence outcome after ischemic brain injury in humans. We evaluated the effects of the norepinephrine reuptake blocker maprotiline and the serotonin reuptake blocker fluoxetine on the motor/functional capacities of poststroke patients undergoing physical therapy.

Methods
Fifty-two severely disabled hemiplegic subjects were randomly assigned to three treatment groups; during 3 months of physical therapy, patients were treated with placebo, maprotiline (150 mg/d), or fluoxetine (20 mg/d). Before and at the end of the observation period, we assessed activities of daily living by the Barthel Index, degree of neurological deficit by a neurological scale for hemiplegic subjects, and depressive symptomatology by the Hamilton Depression Rating Scale.

Results
The diverse treatments ameliorated walking and activities of daily living capacities to different extents. The greatest improvements were observed in the fluoxetine-treated group and the lowest in the maprotiline-treated group. Furthermore, fluoxetine yielded a significantly larger number of patients with good recovery compared with maprotiline or placebo. These effects of the drugs were not related to their efficacy in treating depressive symptoms.

Conclusions
Fluoxetine may facilitate or, alternatively, maprotiline may hinder recovery in poststroke patients undergoing rehabilitation. The effects of fluoxetine as an adjunct to physical therapy warrant further investigation, since treatment with fluoxetine may result in a better functional outcome from stroke than physical therapy alone.
How Good Is Intercenter Agreement in the Identification of Embolic Signals in Carotid Artery Disease?
Authors: Markus Hugh , Bland J. Martin , Rose Georg , Sitzer Matthias , Siebler Mario
Published: June 2011

Background and Purpose
There has been concern regarding the reproducibility of the detection of embolic signals, particularly in patients with carotid artery stenosis in whom the signals are of low intensity. No published studies have examined intercenter agreement in reporting specific embolic signals or the factors responsible for any lack of agreement. We examined reproducibility between two centers in which widely differing proportions of embolic signals have previously been reported in patients with carotid artery stenosis.

Methods
Recordings from the middle cerebral artery of eight patients with ipsilateral carotid artery stenosis in whom embolic signals had been detected during a previous study were independently examined by three experienced observers in one center and by one experienced observer in another center. We calculated agreement within and between centers by estimating the probability that one observer would identify a specific embolic signal if other observers had identified it (a probability of 1 indicates complete agreement). The influence of different characteristics of the embolic signal on the probability of its detection as an embolic signal was determined.

Results
A high level of agreement in the identification of specific embolic signals was found. This was similar between all observers (.90), between the three observers in one center (.89), and between observers in the two different centers (.94). The probability of detection was independently related to the relative intensity of the embolic signal (
P
<.0001). It was less (although significantly) independently related to the posi-tion of the embolic signal in the cardiac cycle (
P
=.02), with signals in systole being more reliably detected. There was no independent relationship between the probability of detection and either the duration of the embolic signal or the velocity at the maximum intensity increase. The use of threshold intensity as a criterion for embolic signal detection increased inter-observer agreement but reduced the sensitivity in detecting signals.

Conclusions
The high level of interobserver agreement suggests that the technique is sufficiently reproducible for clinical use.
E-Selectin Appears in Nonischemic Tissue During Experimental Focal Cerebral Ischemia
Authors: Haring Hans-Peter , Berg Ellen L. , Tsurushita Naoya , Tagaya Masafumi , del Zoppo Gregory J.
Published: June 2011

Background and Purpose
E-selectin participates in leukocyte-endothelial adhesion and the inflammatory processes that follow focal cerebral ischemia and reperfusion. The temporal and topographical patterns of microvascular E-selectin presentation after experimental focal cerebral ischemia are relevant to microvascular reactivity to ischemia.

Methods
The upregulation and fate of E-selectin antigen during 2 hours of middle cerebral artery occlusion (n=4) and 3 hours of occlusion with reperfusion (1 hour, n=4; 4 hours, n=6; 24 hours, n=6) were evaluated in the nonhuman primate. E-selectin and E:P-selectin immunoreactivities were semiquantitated with the use of computerized light microscopy video imaging and laser confocal microscopy.

Results
Three patterns of microvascular E-selectin expression, defined by the antibody E-1E4, were confirmed by complete elimination of E-1E4 binding after incubation with soluble recombinant human E-selectin: (1) Low immunoperoxidase intensity was observed in ischemic microvessels at 2 hours of occlusion extending to 4 hours of reperfusion (E-selectin/laminin=0.32±0.10). (2) A significant fraction of ischemic microvessels displayed high-intensity E-selectin signal by 24 hours of reperfusion (0.61±0.17) compared with control and nonischemic tissues (2
P
<.003). (3) In the contralateral nonischemic basal ganglia and other nonischemic tissues, low but significant E-selectin levels appeared by 24 hours of reperfusion (2
P
=.0005). The latter were further confirmed by an E:P-selectin immunoprobe.

Conclusions
E-selectin antigen is distinctively and significantly upregulated in nonhuman primate brain after focal ischemia and reperfusion. The late appearance of E-selectin in nonischemic cerebral tissues suggests stimulation by transferable factors generated during brain injury.
Cerebroprotective Effects of Aminoguanidine in a Rodent Model of Stroke
Authors: Cockroft Kevin M. , Meistrell Malcolm , Zimmerman Gary A. , Risucci Donald , Bloom Ona , Cerami Anthony , Tracey Kevin J.
Published: June 2011

Background and Purpose
During a cerebral infarction, a complex cascade of cytotoxic events ultimately determines the volume of brain cell loss. The studies presented here demonstrate that aminoguanidine, an experimental therapeutic currently in clinical trials to prevent diabetic complications, is cerebroprotective in focal cerebral infarction.

Methods
Adult Lewis rats (n=6 to 12 per group) were anesthetized with ketamine and subjected to focal cerebral infarction by tandem permanent occlusion of the right middle cerebral artery and ipsilateral common carotid artery (CCA), followed by temporary occlusion of the contralateral CCA. Infarct volume (cortical) was assessed 24 hours after the onset of ischemia by planimetric analysis of coronal brain slices stained with tetrazolium.

Results
Aminoguanidine (320 mg/kg IP) administered 15 minutes after the onset of ischemia resulted in a significant reduction of infarct volume (7.6±2.6% of hemisphere in controls versus 1.3±0.2% of hemisphere in aminoguanidine-treated rats;
P
<.05). Administration of aminoguanidine conferred significant cerebroprotection even when administered 1 or 2 hours after the onset of ischemia (88% and 85% reduction from control, respectively;
P
<.05). Cerebroprotection by aminoguanidine was independent of systemic physiological variables known to influence stroke size (eg, temperature, mean arterial blood pressure, blood glucose, and arterial pH, P
co
2
, and P
o
2
).

Conclusions
These results indicate that the stroke-reducing properties of aminoguanidine are dose and time dependent, with substantial cerebroprotection persisting even with drug delivery up to 2 hours after the onset of ischemia. It is now plausible to pursue development of aminoguanidine as an experimental therapeutic in stroke, and possible mechanisms of these cerebroprotective effects are under consideration.
Misdiagnosis of Symptomatic Cerebral Aneurysm
Authors: Mayer Peter L. , Awad Issam A. , Todor Roxanne , Harbaugh Kimberly , Varnavas Gus , Lansen Thomas A. , Dickey Philip , Harbaugh Robert , Hopkins L. Nick
Published: June 2011

Background and Purpose
It is not known what fraction of patients with symptomatic cerebral aneurysms are misdiagnosed at initial medical presentation. It is also not clear whether misdiagnosed patients more frequently deteriorate before definitive aneurysm diagnosis and therapy or achieve a poorer outcome than correctly diagnosed patients.

Methods
We reviewed records of consecutive patients with symptomatic cerebral aneurysms managed by four tertiary-care neurosurgical services during a recent 19-month period. Clinical course and outcome were analyzed according to misdiagnosis or correct diagnosis at initial medical evaluation.

Results
Fifty-four of 217 patients (25%) were misdiagnosed at initial medical evaluation, including 46 of 121 patients (38%) initially in good clinical condition (clinical grade 1 or 2). Forty-six of 54 patients (85%) in the misdiagnosis group were initially grade 1 or 2 compared with 75 of 163 patients (46%) with correct initial diagnosis (
P
<.01). Twenty-six of 54 misdiagnosed patients (48%) deteriorated or rebled before definitive aneurysm treatment compared with 4 of 165 correctly diagnosed patients (2%) (
P
<.001). Among patients initially presenting as clinical grade 1 or 2, overall good or excellent outcome was achieved in 91% of those with correct initial diagnosis and 53% of patients with initial misdiagnosis (
P
<.001). Deterioration before correct diagnosis accounted for 16 of 67 patients (24%) with poor or worse final outcome in this series.

Conclusions
Patients in good clinical condition with symptomatic cerebral aneurysms were commonly misdiagnosed. Misdiagnosed patients were more likely than correctly diagnosed patients to deteriorate clinically and had a worse overall outcome. Misdiagnosed cases accounted for a significant fraction of overall poor outcomes among consecutive cases of symptomatic aneurysms.
Long-lasting Neuroprotective Effect of Postischemic Hypothermia and Treatment With an Anti-inflammatory/Antipyretic Drug
Authors: Coimbra Cicero , Drake Mikael , Boris-Möller Fredrik , Wieloch Tadeusz
Published: June 2011

Background and Purpose
It has been recognized that postischemic pharmacological interventions may delay the evolution of neuronal damage rather than provide long-lasting neuroprotection. Also, fever complicates recovery after stroke in humans. Here we report the effects of late postischemic treatment with hypothermia and an antipyretic/anti-inflammatory drug, dipyrone, on cell damage at 1 week and 2 months of survival.

Methods
Rats were subjected to 10 minutes of forebrain ischemia. Hypothermia (33°C) was induced at 2 hours of recovery and maintained for 7 hours. Dipyrone (100 mg·kg
−1
IP) was given every 3 hours from 14 to 72 hours of recovery. Temperature was measured every 6 hours for 60 days. Neuronal damage was assessed at 7 days and 2 months of recovery.

Results
From 17 to 72 hours of recovery, a period of hyperthermia was observed, which dipyrone abolished but postischemic hypothermia treatment did not. Dipyrone treatment diminished neuronal damage by 43% at 7 days, and at 2 months of survival, a minor (16%) protection was seen. Postischemic hypothermia treatment alone delayed neuronal damage. In contrast, combined treatment of hypothermia followed by dipyrone markedly diminished neuronal damage by more than 50% at both 7 days and 2 months of recovery.

Conclusions
Neuronal degeneration may be ongoing for months after a transient ischemic insult, and prolonged protective measures need to be instituted for long-lasting neuroprotective effects. Hyperthermia during recovery worsens ischemic damage, and processes associated with inflammation may contribute to the development of neuronal damage. An early and extended period of postischemic hypothermia provides a powerful and long-lasting protection if followed by treatment with anti-inflammatory/antipyretic drugs.
Ventricular Dilatation in Experimental Intraventricular Hemorrhage in Pigs
Authors: Mayfrank L. , Kissler J. , Raoofi R. , Delsing P. , Weis J. , Küker W. , Gilsbach J.M.
Published: June 2011

Background and Purpose
Hemorrhagic ventricular dilatation (HVD) is a prominent feature of human intraventricular hemorrhage (IVH) and a strong indicator for poor outcome. We developed an IVH model to define the mechanisms responsible for HVD and to test the efficacy of intraventricular administration of tissue plasminogen activator (TPA) in the treatment of HVD.

Methods
Isolated IVH was produced in pigs by injecting 10 mL of blood simultaneously with thrombin into the right lateral ventricle. The treatment group received 1.5 mg of TPA after induction of IVH. Intraventricular blood volume and the volume of the lateral ventricles were assessed by CT after 90 minutes, 7 days, and 42 days. Intracranial pressure, the pressure-volume index, and the resistance to outflow of cerebrospinal fluid (R
out
) were measured 30 minutes and 7 days after IVH.

Results
After IVH, the volume of the lateral ventricles increased from 1.98±0.69 to 6.43±1.23 mL (
P
<.001). There was a linear relationship between ventricular and clot volume (
P
=.014). Initially, R
out
increased from 24.34±7.13 to 63.56±64.91 mm Hg/mL per minute (
P
<.001). After 7 days, restoration of normal cerebrospinal fluid circulation occurred, but the ventricles were still significantly enlarged (5.24±1.76 mL,
P
<.001) and filled with blood. Within 6 weeks, ventricular volume had returned to normal values, paralleled by complete clot resolution. Intraventricular administration of TPA significantly accelerated clot clearance and restoration of normal ventricle volume.

Conclusions
These results suggest that intraventricular bleeding may cause impairment of cerebrospinal fluid circulation but that the mass effect of clots distending the ventricle walls is the most important mechanism responsible for HVD. This model closely imitates several prominent features of human IVH and may therefore be a useful tool for preclinical assessment of the efficacy and safety of treatment with TPA.
Carotid Plaque Morphology and Clinical Events
Authors: Hatsukami Thomas S. , Ferguson Marina S. , Beach Kirk W. , Gordon David , Detmer Paul , Burns David , Alpers Charles , Strandness D. Eugene
Published: June 2011

Background and Purpose
Studies have suggested that B-mode ultrasonography can be used to determine carotid plaque composition and that specific plaque characteristics are associated with a worse clinical outcome. However, histological studies examining the relationship between carotid plaque morphology and clinical outcome have reported conflicting findings. Furthermore, few investigators have described plaque morphology in quantifiable terms. This study examines the association between the volume of carotid plaque constituents and preoperative ischemic neurological symptoms. Constituents examined were chosen based on their potential for identification by current diagnostic imaging modalities such as ultrasound or MRI.

Methods
Atherosclerotic plaques from 43 patients undergoing carotid endarterectomy were examined histologically, with sections obtained every 0.5 to 1 mm. The lesions were examined for the presence and quantity of fibrous intimal tissue, intraplaque hemorrhage, lipid core, necrotic plaque core, and calcification. The quantity of each constituent was compared in plaques removed from symptomatic patients with those excised from asymptomatic individuals. Differences were analyzed with a Kolmogorov-Smirnov statistic.

Results
There was no difference between plaques removed from asymptomatic and symptomatic patients with regard to the presence and volume of fibrous intimal tissue, intraplaque hemorrhage, the lipid core, the necrotic core, or calcification.

Conclusions
In patients with highly stenotic carotid lesions who are undergoing carotid endarterectomy, gross plaque composition is similar regardless of preoperative symptom status. Given this similarity, it is unlikely that differences in the volume of intraplaque hemorrhage, lipid core, necrotic core, or calcification in atherosclerotic carotid plaques explain their embolic history.