bluuebunny/crossref_metadata_2025 huggingface dataset:
Unruptured Intracranial Vertebral Artery Dissection
Authors: Yoshimoto Yuhei , Wakai Susumu
Published: June 2011

Background and Purpose
Intracranial vertebral artery dissection is an increasingly recognized cause of stroke. However, little is known about its natural history and clinical manifestations, and appropriate management protocol has not yet been established. This study was performed to clarify its clinical course and determine the best management protocol.

Methods
This study is a retrospective clinical and radiographic review of 11 patients with 13 lesions who presented between 1990 and 1996. Patients with a history of trauma and those who presented with subarachnoid hemorrhage were excluded. The 11 patients comprised seven men and four women, who ranged in age from 34 to 71 years, with a mean age of 47 years. Ten patients presented with ischemic symptoms.

Results
Although recurrent ischemic attacks were observed in two patients, most (90%) subsequently made a good recovery and returned to their previous lifestyle. Five arteries showed the typical “string sign” or “pearl and string sign” on initial angiography. They changed in the follow-up examinations, which demonstrated either resolution of the stenosis or progression to complete occlusion. In contrast, the angiographic signs of complete occlusion (three arteries) or aneurysmal dilatation without luminal stenosis (four arteries) remained unchanged during the observation period of 5 months to 2.5 years. MRI was a sensitive tool for diagnosing intracranial vertebral artery dissection; intramural thrombus and intimal flap were the two major findings. MR angiography was also useful for demonstrating abnormalities of the arterial signal column such as pseudolumen or aneurysmal dilatation.

Conclusions
The natural history of unruptured intracranial vertebral artery dissection seems relatively benign, with a high probability (62%) of spontaneous angiographic cure. Some persistent aneurysmal dilatation may be amenable to intravascular coil embolization.
Protection With Lubeluzole Against Delayed Ischemic Brain Damage in Rats
Authors: Haseldonckx Marc , Van Reempts Jos , Van de Ven Mies , Wouters Luc , Borgers Marcel
Published: June 2011

Background and Purpose
Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vulnerable brain areas. Lubeluzole is not an
N
-methyl-
d
-aspartate antagonist but prevents postischemic increase in extracellular glutamate concentrations. The present study examined whether lubeluzole, administered after global incomplete ischemia in rats, is capable of preserving the structural integrity of CA1 hippocampus.

Methods
Ischemia was induced by bilateral carotid artery occlusion and severe hypotension for a duration of 9 minutes. Delayed neuronal cell death was histologically evaluated 7 days later. This was done by scoring acidophilic cell change and coagulative necrosis and by counting the number of surviving neurons in the CA1 subfield. Experiments were performed according to a paired design (13 animals per treatment group).

Results
Posttreatment with lubeluzole (0.31 mg/kg IV bolus at 5 minutes and 0.31 mg/kg IV infusion during 1 hour) resulted in significant neuroprotection. Whereas in the untreated rats there were 42 (median) viable neurons per millimeter CA1 layer in the left and 69 in the right hemisphere, in the drug-treated rats 99 viable neurons per millimeter were found in the left (
P
=.002) and 113 in the right hemisphere (
P
=.013). Histological scores, reflecting altered staining properties of the hippocampal cells, correlated strongly with the quantitative data, reflecting the structural integrity of CA1 pyramidal neurons.

Conclusions
Lubeluzole, when administered after an ischemic insult in rats, protects vulnerable brain regions against delayed structural injury. The results support the potential clinical use of this new drug in stroke treatment.
Neuroprotection With NBQX in Rat Focal Cerebral Ischemia
Authors: Lo Eng H. , Pierce Allen R. , Mandeville Joseph B. , Rosen Bruce R.
Published: June 2011

Background and Purpose
We have previously shown that treatment with glutamate receptor antagonists after focal ischemia can partially reverse acute lesions measured with diffusion-weighted MRI. The goal of this study was to examine the quantitative nature of these effects of neuroprotection.

Methods
Rats were subjected to permanent occlusion of the middle cerebral artery under halothane anesthesia and treated with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (30 mg/kg IP; two doses given immediately after ischemia and 1 hour after ischemia) or given injections of saline. Diffusion-weighted MRI scans were performed to map the changes in water diffusivity during the first 3 hours after ischemia. Apparent diffusion coefficients (ADCs) within the ischemic hemisphere were calculated, and ischemic changes were expressed as absolute reductions and as a percentage of contralateral mean values. Relative perfusion deficits in the ischemic hemisphere were assessed with dynamic MRI of transient changes in transverse relaxation rates (ΔR2*).

Results
Analysis with ADC probability distribution functions showed that focal ischemia was present with gradients in ADC reductions emanating from the center to the periphery of the lesion. Ischemic evolution in control rats was manifested as a progressive shift of the probability distribution functions over time. NBQX treatment resulted in a reverse shift of these probability functions. By 3 hours after occlusion, probability distribution functions were significantly improved in treated rats (
P
<.05). Because of the temporal evolution of the probability distribution functions, ADC thresholds that correlated with histological outcomes of infarction changed over time. NBQX did not alter the cerebral perfusion index, measured as ΔR2* peak values.

Conclusions
The results indicate that ADC probability distribution functions can be used to quantitatively evaluate the effects of neuroprotective treatment on the gradients of injury in focal cerebral ischemia. The probability functions also allow for intrasubject comparisons and may therefore be useful for exploring therapeutic windows.
Infection-Associated Cervical Artery Dissection
Authors: Grau Armin J. , Brandt Tobias , Forsting Michael , Winter Ralph , Hacke Werner
Published: June 2011

Background
The pathogenesis of cervical artery dissection remains unknown. Infection-mediated damage of the arterial wall may be one contributing mechanism. We present three male patients with respiratory infection prior to cervical artery dissection.

Case Descriptions
Case 1: During an upper respiratory tract infection, a 49-year-old patient developed bilateral carotid and vertebral artery dissection with complete vessel restitution. Case 2: Within 3 years, a 40-year-old patient experienced two episodes of bilateral internal carotid artery dissection, both preceded by febrile upper respiratory tract infection. Case 3: A 52-year-old patient developed right-sided and, 2 years later, left-sided internal carotid artery dissection, each following upper respiratory tract infection.

Conclusions
Infection may be a trigger factor in the pathogenesis of cervical artery dissection.
Status of Risk Factors for Dementia Associated With Stroke
Authors: Gorelick Philip B.
Published: June 2011

Background
Cognitive impairment associated with vascular disease may be the only preventable form of dementia of late life. Identification of risk factors for dementia associated with stroke may be a prelude to improved intervention.

Summary of Review
I reviewed putative risk factors for dementia associated with stroke. These included demographic, atherogenic, stroke-related, and genetic factors. Key studies from the English literature were reviewed and graded according to quality of evidence ratings (classes I, II, and III). Although many of the cardiovascular disease risk factors are logical antecedents of dementia associated with stroke, age was the only factor that could be considered a well-documented risk factor.

Conclusions
We should continue to support efforts directed at primary stroke prevention and the brain-at-risk and predementia stages. Additional rigorous epidemiological study is needed to clarify risk factors for dementia associated with stroke.
Stroke Trends in the WHO MONICA Project
Authors: Thorvaldsen Per , Kuulasmaa Kari , Rajakangas Anna-Maija , Rastenyte Daiva , Sarti Cinzia , Wilhelmsen Lars
Published: June 2011

Background and Purpose
Stroke registers were established as part of the international collaborative World Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease (WHO MONICA) Project in 17 centers in 10 countries. The aim of the present analyses was to estimate and compare temporal stroke trends across the MONICA populations.

Methods
All stroke events in defined populations were ascertained and validated according to a common protocol and uniform criteria. Almost 25 000 stroke events in more than 15 million person-years were analyzed. Age-standardized rates for fatal stroke and for all stroke events were calculated for whole calendar years for each of the populations. Temporal stroke trends were estimated using annual rates for 5 to 6 years.

Results
Annual stroke attack rates decreased among men in 13 populations and among women in 15 of the 17 MONICA populations. Stroke mortality rates declined among men in 11 populations and among women in 14 of the populations studied. The estimated trends reached the level of statistical significance at the 5% level in only a small number of populations. The trends in official cerebrovascular death rates were in agreement with those estimated on the basis of MONICA data in the majority of the populations studied.

Conclusions
Decreasing stroke mortality and attack rates in a large proportion of populations studied can be interpreted as an indication of declining stroke rates in most of the populations studied. The numbers of populations with statistically significant trends were small, and it is therefore not possible to determine with certainty in which of the populations were the changes real.
Variables Associated With Hospital Arrival Time After Stroke
Authors: Azzimondi Giuseppe , Bassein Leona , Fiorani Laila , Nonino Francesco , Montaguti Ubaldo , Celin Daniela , Re Giuseppe , D’Alessandro Roberto
Published: June 2011

Background and Purpose
A limiting criterion for the eligibility of patients in clinical trials investigating acute stroke therapies is that time between onset of symptoms and arrival in the hospital should fall within the “therapeutic window.” The aims of this study were to estimate hospital arrival time in an unselected sample of stroke patients, to assess the association with some clinical and demographic variables, and to evaluate the effects of the delay on the clinical efficiency of an effective treatment.

Methods
We evaluated the delay in hospital arrival time in 189 patients (84 men, 105 women; mean age, 76.5 years) prospectively collected in the S Orsola-Malpighi Community Teaching Hospital in Bologna, Italy. Cutoffs of 2 and 5 hours were chosen to allow for hypothetical treatment within 3 and 6 hours, respectively. Exact multiple logistic regression was used to predict the delay as a function of dichotomized age, sex, symptoms on awakening, day of the week, hour of the day, area of residence, level of consciousness, and level of motor power defect. We then projected the effectiveness of tissue plasminogen activator (TPA) on disability as estimated with the aid of the odds ratio from the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial onto our unselected sample to evaluate clinical efficiency of treatment as a function of arrival time and of hypothetical effects of educational efforts to reduce it.

Results
The mean interval between onset of symptoms and hospital arrival was 680 minutes; 59 patients (31%) arrived within 2 hours and 100 (53%) within 5 hours. Onset of symptoms when awake, drowsiness or coma, and paralysis of at least one limb were the only independent predictors of hospital arrival within 2 and 5 hours in both the total sample and the subgroup of patients who were awake at stroke onset. The effectiveness of 17%, extrapolated with the aid of the odds ratio of 1.6 of having a favorable outcome (Barthel Index ≥95 at 3 months) in treated versus untreated patients in the NINDS rt-PA Stroke Trial, corresponded to a projected clinical efficiency of 5%. This could be doubled by hypothesizing a 100% effect of educational efforts in reducing the delay in hospital arrival time.

Conclusions
Patients with milder symptoms, for whom treatment might be more effective, were less likely to arrive in time for therapy. The proposed model of the relationship between the delay in hospital presentation after a stroke and the clinical efficiency of a given treatment might be useful for planning future clinical trials on early stroke treatment and predicting the impact of an educational program aimed at shortening arrival time.
Specific Changes in Human Brain After Hypoglycemic Injury
Authors: Fujioka Masayuki , Okuchi Kazuo , Hiramatsu Ken-Ichiro , Sakaki Toshisuke , Sakaguchi Syouji , Ishii Yoshinobu
Published: June 2011

Background and Purpose
Very few reports are available on serial changes in the human brain after severe hypoglycemic injury. The aim of this study was to investigate sequential neuroradiological changes in brains of patients after hypoglycemic coma compared with those after cardiac arrest previously studied with the same methods.

Methods
We repeatedly studied CT scans and MR images obtained at 1.5 T in four vegetative patients after profound hypoglycemia associated with diabetes mellitus.

Results
In all patients, consecutive CT scans showed symmetrical, persistent low-density lesions with transient enhancement in the caudate and lenticular nuclei and transient enhancement in the cerebral cortex 7 to 14 days after onset. Serial MR images consistently revealed symmetrical lesions of persistent hyperintensity and hypointensity on T1- and T2-weighted images, respectively, in the caudate and lenticular nuclei, cerebral cortex, substantia nigra, and/or hippocampus from 8 days to 12 months after onset.

Conclusions
Repeated MR images revealed specific lesions in the bilateral basal ganglia, cerebral cortex, substantia nigra, and hippocampus, which suggests the particular vulnerability of these areas to hypoglycemia in the human brain. We speculate that the localized lesions represent tissue degeneration, including some combination of selective neuronal death, proliferation of astrocytic glial cells, paramagnetic substance deposition, and/or lipid accumulation. The absence of localized hemorrhages on MR images in hypoglycemic encephalopathy is in marked contrast to the presence of regional minor hemorrhages in postischemic-anoxic encephalopathy.
Pathogenesis of Leukoaraiosis
Authors: Pantoni Leonardo , Garcia Julio H.
Published: June 2011

Background
Changes in the cerebral hemispheric white matter, detectable with increasing frequency by modern neuroimaging methods, are associated with aging and conceivably may contribute to the development of specific cognitive deficits. The pathogenesis of these cerebral white matter abnormalities (sometimes described as leukoaraiosis) is unknown. This review evaluates the available evidence in support of the hypothesis that the etiology of leukoaraiosis is related to a specific type of cerebral ischemia and highlights mechanisms by which ischemic injury to the brain may induce selected structural alterations limited to the cerebral white matter.

Summary of Review
The review is based on the critical analysis of over 100 publications (most appearing in the last decade) dealing with the anatomy and physiology of the arterial circulation to the cerebral white matter and with the pathogenesis of leukoaraiosis.

Conclusions
A significant number of clues support the hypothesis that some types of leukoaraiosis may be the result of ischemic injury to the brain. Structural changes affecting the small intraparenchymal cerebral arteries and arterioles that are associated with aging and with stroke risk factors, altered cerebral blood flow autoregulation, and the conditions created by the unique arterial blood supply of the hemispheric white matter each seem to contribute to the development of leukoaraiosis. To the best of our ability to interpret current information, the type of ischemic injury that is most likely responsible for these white matter changes involves transient repeated events characterized by moderate drops in regional cerebral blood flow that induce an incomplete form of infarction. This hypothesis could be tested in appropriate experimental models.
Duration of Glutamate Release After Acute Ischemic Stroke
Authors: Dávalos Antoni , Castillo José , Serena Joaquín , Noya Manuel
Published: June 2011

Background and Purpose
High levels of glutamate in plasma and cerebrospinal fluid (CSF) have been demonstrated in patients with acute ischemic stroke. The duration of this excitatory amino acid release has not been studied, and therefore the window of opportunity of treatment with glutamate antagonists is unknown. The aim of this investigation was to study the duration of the glutamate increase in patients with stable and progressing ischemic stroke.

Methods
Glutamate in CSF was measured by high-performance liquid chromatography in 184 patients with an acute cerebral infarction of less than 24 hours’ duration and in 43 control subjects.

Results
Among the 120 patients with stable ischemic stroke, median glutamate levels were significantly lower—and within the reference range of control subjects—in those patients studied 6 to 24 hours from onset of symptoms than in patients studied in the first 6 hours (3 [range, 2 to 10] versus 5 μmol/L [range, 2 to 17];
P
<.0001). In 64 patients with progressing ischemic stroke, glutamate concentrations measured at any time interval during the first 24 hours from onset were significantly higher than in the stable stroke and control groups.

Conclusions
The presence of glutamate increase in the CSF cannot be documented for greater than 6 hours in stable ischemic stroke. The sustained elevation of glutamate observed in progressing stroke suggests that the window to prevent neurological deterioration may be wider.
Fall Prediction Index for Patients in Stroke Rehabilitation
Authors: Nyberg Lars , Gustafson Yngve
Published: June 2011

Background and Purpose
The identification of stroke patients who are prone to falls is essential to the development of prevention strategies. This study aimed at developing an easily administered fall risk index for patients in stroke rehabilitation.

Methods
A consecutive series of 135 patients in geriatric stroke rehabilitation was studied. Patient characteristics viewed as potential fall predictor variables were assessed at admission. Univariate and multiple Cox regression analyses of these variables were used in the development of a fall prediction index.

Results
The final index included the following items: male sex, poor performance of activities of daily living, urinary incontinence, impaired postural stability, bilateral motor impairment, presence of bilateral cortical or white matter lesions, visuospatial hemineglect, and use of diuretics, antidepressants, or sedatives. The index score correlated significantly with the fall risk (odds ratio, 1.46; 95% confidence interval, 1.26 to 1.69). The score was also used to classify individuals into low-, intermediate-, and high-risk groups, among which the fall rates differed significantly (log rank statistics, 29.86;
P
<.001).

Conclusions
An easily administered fall risk index is suggested, which might serve as a basis for prevention strategies among patients in stroke rehabilitation.
We Need Stronger Predictors of Major Vascular Events in Patients With a Recent Transient Ischemic Attack or Nondisabling Stroke
Authors: Dippel Diederik W.J. , Koudstaal Peter J.
Published: June 2011

Background
It has been proposed that most prognostic factors in patients with transient ischemic attack or nondisabling stroke are weak and consequently that patients at high risk of recurrent major vascular events cannot be reliably identified.

Methods
In the Dutch TIA trial, a multicenter, double-blind study of low-dose versus medium-dose aspirin, 3127 patients were included within 3 months after onset of a transient ischemic attack, amaurosis fugax, or nondisabling stroke. In a previous analysis, we developed a prediction model by means of Cox proportional hazards regression for the composite outcomes of fatal or nonfatal stroke and for myocardial infarction, stroke, or vascular death, based on clinical and demographic information as well as on the results of ancillary investigations. We assessed the discriminatory power and the calibration of the prediction models.

Results
The median numbers of prognostic factors for stroke, myocardial infarction, or vascular death outcome and for stroke alone were 3 and 4, respectively. The proportion of patients with a predicted probability exceeding 30% was less than 5% for both models; here the calibration of the models was poor. Only four of the patients with stroke, myocardial infarction, or vascular death were assigned a probability of greater than 50% for that outcome, and only one of the patients with stroke was given such a high probability. The models’ discriminatory ability was a little disappointing (areas under the curve of 0.73 and 0.75, respectively).

Conclusion
This analysis indicates that we need stronger predictors of recurrence risk in patients with a transient ischemic attack or nondisabling stroke.
Circadian Fluctuations in Onset of Subarachnoid Hemorrhage
Authors: Vermeer Sarah E. , Rinkel Gabriel J. E. , Algra Ale
Published: June 2011

Background and Purpose
Several studies have found a morning peak in onset of stroke. A similar peak has been suggested for subarachnoid hemorrhage (SAH), which seems in contradiction with the physical activities associated with aneurysmal rupture. Most studies included only a few patients with SAH. We analyzed time of onset of aneurysmal SAH in our patients and in data pooled from previous studies. We also studied time of onset in patients with perimesencephalic hemorrhage, which is believed to have a nonaneurysmal venous origin.

Methods
Of all 468 patients registered from 1989 through 1995, 385 fulfilled the criteria for aneurysmal SAH and 37 the criteria for perimesencephalic hemorrhage. Time of onset was categorized in 2-hour and 6-hour intervals. We did a Medline search to find previous studies on time of onset of SAH and pooled the data in 2-hour, 3-hour, and 6-hour intervals. Analysis of all intervals was performed by calculating rate ratios with 95% confidence intervals by means of Poisson methods.

Results
The risk of aneurysmal rupture was lower at night (from 12
pm
to 6
am
) in our series and in the pooled-data series. Risk remained high throughout the day and evening, with a nadir around noon. For perimesencephalic hemorrhage, we found the same fluctuation in onset but without a nadir around noon.

Conclusions
The risk of aneurysmal SAH is low during the night and at noon and high during working hours. This circadian fluctuation parallels that of blood pressure and suggests that an increase in blood pressure is a risk factor for aneurysmal rupture.
Prevention of Carotid Artery Thrombosis by Oral Platelet GPIIb/IIIa Antagonist in Dogs
Authors: Mousa Shaker A. , Mu Dun-Xue , Lucchesi Benedict R.
Published: June 2011

Background and Purpose
Current antithrombotic therapy in acute ischemic stroke and myocardial infarction in which a combination of antiplatelet agents (aspirin) and anticoagulants (heparin) was used led to partial reduction of acute thrombotic complications. Recent advances in antiplatelet research led to the discovery of the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), the final common pathway for platelet aggregation. The present study was undertaken to determine the oral antithrombotic efficacy of a potent and specific platelet GPIIb/IIIa antagonist, DMP728, in an electrically induced carotid artery thrombosis model in dogs. Based on the powerful antiplatelet efficacy of this mechanism in inhibiting all agonist-induced platelet aggregation as well as in inhibiting platelet procoagulant activity (thrombin generation and hence fibrin formation), an orally active antagonist for this integrin receptor might have potential benefits in stroke.

Methods
Anesthetized dogs were instrumented for monitoring of arterial blood pressure, heart rate, and carotid artery flow velocity. Animals were treated with saline or DMP728 (0.1 to 1.0 mg/kg PO). Thrombus formation (platelet-rich aggregate with fibrous coating and a few erythrocytes) by anodal electrolytic stimulation (300 μA) to the intimal surface of the right carotid artery was initiated 120 minutes after oral DMP728 administration and continued for 180 minutes. Whole blood cell counts, ex vivo platelet aggregation, and template bleeding time were determined at different time points throughout the study.

Results
DMP728 administered at 0.1 to 1.0 mg/kg PO exhibited dose-dependent antithrombotic efficacy in this model. DMP728 was shown to be significantly effective in inhibiting ex vivo platelet aggregation and in inhibiting thrombosis at 0.3 to 1.0 mg/kg PO. The antiplatelet, antithrombotic effects of DMP728 were demonstrated without any significant changes in the different hemodynamic or coagulation parameters. These data demonstrated the oral antithrombotic efficacy of DMP728 in dogs.

Conclusions
Platelet GPIIb/IIIa blockade with an orally active antagonist was shown to be safe and effective in the prevention of carotid artery occlusive thrombosis.
Characteristics of Transcranial Doppler Signal Enhancement Using a Phospholipid-Containing Echocontrast Agent
Authors: Kaps Manfred , Schaffer Peter , Beller Klaus-Dieter , Eng  , Seidel Günter , Bliesath Harald , Diletti Edgar , Eng
Published: June 2011

Background and Purpose
Ultrasound attenuation caused by the skull is a major limitation of transcranial Doppler. Echocontrast agents (EAs) may solve this problem. The aim of the present study was to investigate the characteristics of a new echocontrast agent (BY963) containing air bubbles stabilized by phospholipids.

Methods
Nine healthy volunteers received three different doses (2.5, 5.0, and 10 mL) of BY963 at an injection rate of 0.25 mL/s. The Doppler signal amplitude obtained from the middle cerebral artery was recorded with a 2-MHz pulsed-wave Doppler system. After complete decay of the signal enhancement, upward stroking of the veins of the upper arm was performed to evaluate the stability of the EA in the venous system.

Results
A dose-dependent increase of at least 30 dB in the Doppler signal amplitude lasted 19 to 47, 35 to 64, and 48 to 126 heart cycles (68% range) after 2.5, 5.0, and 10 mL EA, respectively. In 6 cases, there was a biphasic increase in EA enhancement. Upward stroking of the forearm, in general 12 to 18 minutes after administration, caused a Doppler signal enhancement of at least 30 dB in 6 cases.

Conclusions
Each injection of BY963 caused a diagnostically relevant Doppler signal enhancement. A considerable amount of EA remained stable in the venous system for at least 12 minutes. The biphasic dose-response fits to models of dilution-indicator theory and indicates free recirculation, as well as a nonlinear washout curve.
Cerebrovascular Changes in Chronic Hypertension
Authors: Nag Sukriti , Kilty Daniel W.
Published: June 2011

Background and Purpose
Our recent study demonstrated that in chronic hypertension, hypertrophy of intracerebral arterioles was associated with an increase in the vascular extracellular matrix proteins: fibronectin, laminin, and collagen IV. An additional cerebral finding in chronic hypertension was hypertensive encephalopathy, in which breakdown of the blood-brain barrier (BBB) to serum proteins occurred in multifocal areas of the cortex and basal ganglia. This study was undertaken to determine which of these alterations were attenuated by antihypertensive therapy.

Methods
Two weeks after the surgery to produce chronic renal hypertension, half the hypertensive rats were treated orally with enalapril (30 mg/kg), an angiotensin-converting enzyme inhibitor, for 5 weeks. Rats were perfusion-fixed, and their brains were removed and processed for morphological studies. The effect of treatment on vascular hypertrophy was assessed by quantitative morphometry and on the vascular extracellular matrix proteins and BBB permeability alterations by immunohistochemistry.

Results
There was increased immunoreactivity for laminin, fibronectin, and collagen IV in pial and intracerebral arterioles of untreated hypertensive rats. Immunoreactivity was greatest in arterioles in areas with breakdown of the BBB to serum proteins. Enalapril treatment for 5 weeks resulted in a significant reduction of the mean systolic blood pressure, which was accompanied by attenuation of vascular hypertrophy and attenuation of changes in the vascular extracellular matrix proteins. In addition, there was reduction in the magnitude of BBB breakdown after treatment.

Conclusions
Enalapril treatment had a protective effect and attenuated vascular hypertrophy and the increase in vascular extracellular matrix proteins observed in chronic hypertension. In addition, there was reduction in the magnitude of BBB breakdown.
Genetic Susceptibility to Experimental Cerebral Aneurysm Formation in the Rat
Authors: Coutard Michèle , Osborne-Pellegrin Mary
Published: June 2011

Background and Purpose
The susceptibility to experimental cerebral aneurysm formation in arteries of the circle of Willis was studied in four strains of rats presenting different susceptibilities to the spontaneous rupture of the internal elastic lamina in extracerebral arteries: Brown-Norway (BN)>Wistar>Long-Evans (LE)>LOU.

Methods
Rats (150 g body weight) of the four strains were subjected to hypertension and a change in local cerebral blood flow by ligation of one common carotid artery for about 7 months. Six-month-old BN and LE rats were subjected to carotid ligation only for 11 to 13.5 months and treated or not (from 3 to 7 months of age) with an inhibitor of connective tissue fiber maturation, β-aminopropionitrile (BAPN).

Results
Aneurysmal structures (AS) occurred mainly in the anterior cerebral/anterior communicating arterial complex and proximal part of the posterior artery. In hypertensive rats, the AS incidence was LE, 56%; Wistar, 33%; BN, 17%; and LOU, 11%. When normotensive and subjected to carotid ligation only, LE rats showed an even greater susceptibility to AS formation (86%) than BN (7%). BAPN treatment did not influence AS formation: LE (60%) versus BN (8%).

Conclusions
These results suggest that genetic factors are involved in cerebral aneurysm formation in the rat. The susceptibility of the internal elastic lamina of extracerebral arteries to spontaneous rupture does not appear to be a determinant genetic trait in the propensity to develop aneurysms in arteries of the circle of Willis. The comparison of these different rat strains may be very useful for studying factors contributing to cerebral aneurysm pathogenesis.
Synergistic Effects of Citicoline and MK-801 in Temporary Experimental Focal Ischemia in Rats
Authors: Önal M. Zülküf , Li Fuhai , Tatlisumak Turgut , Locke Kenneth W. , Sandage Bobby W. , Fisher Marc
Published: June 2011

Background and Purpose
Citicoline, a naturally occurring precursor of phosphatidylcholine, is neuroprotective and is currently being assessed in clinical trials. To evaluate potential synergistic neuroprotective effects of prolonged citicoline treatment and early
N
-methyl-
d
-aspartate (NMDA) antagonist therapy, suboptimal treatment regimens of citicoline and MK-801 were tested alone and in combination in a rat model of temporary focal ischemia.

Methods
Four groups of Sprague-Dawley rats (n=12 per group) underwent 90 minutes of temporary middle cerebral artery occlusion (MCAO) with the suture model. Animals were randomly and blindly assigned to one of four treatment groups: (1) saline, vehicle; (2) MK-801, 0.5 mg/kg IV bolus at 60 minutes after MCAO followed by saline 1 mL/kg IP daily for 7 days; (3) saline IV at 60 minutes after MCAO followed by citicoline 250 mg/kg IP daily for 7 days; or (4) both MK-801 and citicoline (daily for 7 days) active treatment. Triphenyltetrazolium chloride staining was used to assess postmortem infarct volume. Neurological scores were determined daily.

Results
Premature mortality between days 2 and 4 was 33.3% in group 1, 41.7% in groups 2 and 3, and 25.0% in group 4. Mean corrected infarct volume was significantly reduced in group 4 compared with the others (175.2±89.3 mm
3
in group 1, 179.1±78.5 mm
3
in group 2, 163.9±73.7 mm
3
in group 3, and 84.7±56.8 mm
3
in group 4 [
P
<.02, ANOVA and
P
<.05, Scheffé’s test for group 1 versus group 4]). Mean infarct volume in animals dying prematurely was significantly (
P
<.05, Student’s
t
test) larger in group 1 than those surviving for 7 days (247.2±89.5 versus 139.2±68.2 mm
3
), but there was no significant difference in infarct volume in groups 2, 3, and 4 between animals dying prematurely and those surviving for 7 days.

Conclusions
These results demonstrate synergistic neuroprotective effects of citicoline and an NMDA antagonist in temporary experimental focal ischemia.
Relationship Between Prothrombin Activation Fragment F1.2 and International Normalized Ratio in Patients With Atrial Fibrillation
Authors: Feinberg William M. , Cornell Elaine S. , Nightingale Sarah D. , Pearce Lesly A. , Tracy Russell P. , Hart Robert G. , Bovill Edwin G.
Published: June 2011

Background and Purpose
The prothrombin time (expressed as the international normalized ratio [INR]) is the standard method of monitoring warfarin therapy in patients with atrial fibrillation. Prothrombin activation fragment F1.2 provides an index of in vivo thrombin generation and might provide a better index of the effective intensity of anticoagulation. We examined the relationship between F1.2 and INR in patients with atrial fibrillation.

Methods
We measured INR and F1.2 levels in 846 patients with atrial fibrillation participating in the Stroke Prevention in Atrial Fibrillation III study. Two hundred nineteen (26%) were taking aspirin alone, 326 (39%) were taking adjusted-dose warfarin, and 301 (36%) were taking a low fixed dose of warfarin (1 to 3 mg) plus aspirin (combination therapy). F1.2 levels were measured with an enzyme-linked immunosorbent assay.

Results
Patients receiving adjusted-dose warfarin or combination therapy had significantly higher INR and significantly lower F1.2 values than those on aspirin alone (
P
≤.0001 for each of the four comparisons). F1.2 values (nanomolar) were inversely correlated with INR (F1.2=−0.1+2.3[1/INR];
R
2
=.37;
P
<.0001; simple linear regression). However, significant variability remained. Among patients receiving warfarin, older patients had higher F1.2 values than younger patients after adjustment for INR intensity (
P
<.001) in the model. There was no difference in the relationship between F1.2 and INR between men and women.

Conclusions
Increasing intensity of anticoagulation, as measured by the INR, is associated with decreasing thrombin generation as measured by the F1.2 level, but significant variability exists in this relationship. Older anticoagulated patients have higher F1.2 values than younger patients at equivalent INR values. The clinical significance of these differences is not clear. F1.2 measurement might provide information regarding anticoagulation intensity in addition to that reflected by the INR.
Measurement Properties of the NIH Stroke Scale During Acute Rehabilitation
Authors: Heinemann Allen W. , Harvey Richard L. , McGuire John R. , Ingberman Dinora , Lovell Linda , Semik Patrick , Roth Elliot J.
Published: June 2011

Background and Purpose
The scale of stroke impairment characteristics by Brott and associates, the National Institutes of Health (NIH) Stroke Scale, has been used widely in various studies of stroke outcome; however, the measurement properties of the items applied to patients during medical rehabilitation have not been evaluated thoroughly. This study evaluated the extent to which scale items cohere to define a unidimensional construct and have a useful range for application to patients during medical rehabilitation.

Methods
Rating scale (or Rasch) analysis of the 15 NIH Stroke Scale items was conducted using the BIGSTEPS computer program to evaluate (1) the range of impairment assessed by the items, (2) the items’ coherence with an underlying construct of impairment, and (3) range of impairment measured in rehabilitation patients. We sought to maximize the range of impairment measured by conducting analyses recursively; at each subsequent step, the worst fitting item was deleted or rescored. The sample comprised 1291 admission and discharge records from 693 rehabilitation inpatients with stroke.

Results
Thirteen items arrayed the sample across a sufficient range of impairment. The limb ataxia item fit poorly and was deleted; lower ratings for this item were associated with higher scores on the total scale. Pupillary response was also deleted because ratings reflected poor congruence with the total score. Best language was rescored because intermediate ratings were inconsistently related to the total score. Patients with hemorrhagic strokes had poorer fitting measures than did patients with ischemic strokes.

Conclusions
The items in a revised NIH Stroke Scale worked well together to define the severity of impairment resulting from stroke that is observed during medical rehabilitation. Directions regarding limb ataxia should be modified to indicate untestability due to hemiplegia.
Predictors of Hemorrhagic Transformation Occurring Spontaneously and on Anticoagulants in Patients With Acute Ischemic Stroke
Authors: Alexandrov Andrei V. , Black Sandra E. , Ehrlich Lisa E. , Caldwell Curtis B. , Norris John W.
Published: June 2011

Background and Purpose
Hemorrhagic transformation (HT) is a common evolution of large-volume ischemic lesions, particularly of cardioembolic origin. We used transcranial Doppler ultrasound (TCD), single-photon emission computed tomography (SPECT) with
99m
Tc–hexamethylpropyleneamine oxime (HMPAO), and the Toronto Embolic Scale (TES) to decide (1) whether TCD, HMPAO-SPECT, and TES can improve on clinical and CT tests to predict spontaneous HT and (2) whether SPECT can help to predict the outcome of symptomatic HT.

Methods
Prognostic criteria included Canadian Neurological Scale (CNS) scores ≤50 on admission, early ischemic changes on CT, M1 middle cerebral artery occlusion on TCD, the focal absence of brain perfusion on SPECT, and a high risk of cardiogenic embolism on TES.

Results
In part 1, 85 consecutive patients admitted within the first 6 hours were studied. No patient received thrombolysis. HT was found in 11 patients (13%) at 3 to 5 days. Admission CNS and CT were not predictive of HT: odds ratios (95% confidence intervals) were 0.49 (0.18 to 1.23) (
P
=.1) and 0.88 (0.23 to 3.45) (
P
=.8), respectively. TCD, SPECT, and TES were significant predictors of HT (
P
<.05), as follows: TCD, 8.67 (1.42 to 70.59); SPECT, 17.40 (2.69 to 170.89); and TES, 18.13 (2.6 to 406.86). In part 2, 490 consecutive patients were studied and 21 (4%) had symptomatic HT, of which 12 had focal hypoperfusion on SPECT at 4 days after stroke onset and 9 had focal hyperperfusion. Patients with hypoperfusion had larger CT lesions (115±97 versus 42±29 cm
3
;
P
=.04) and poorer outcome at 2 weeks (CNS, 38±45 versus 96±10;
P
=.001), including death (6/12 versus 0/9;
P
=.04), compared with those with hyperperfusion on SPECT.

Conclusions
High risk of cardioembolism, M1 middle cerebral artery occlusion, and absence of collateral flow evaluated by TES, TCD, and SPECT help to identify patients at risk for spontaneous HT. Although TES was the most powerful predictor of HT, SPECT is the best single adjunct to the triage of clinical and CT tests. Patients with brain hyperperfusion on HMPAO-SPECT after symptomatic HT have better chances for recovery.
Intracranial Microembolic Signals in 500 Patients With Potential Cardiac or Carotid Embolic Source and in Normal Controls
Authors: Georgiadis D. , Lindner A. , Manz M. , Sonntag M. , Zunker P. , Zerkowski H. R. , Borggrefe M.
Published: June 2011

Background and Purpose
We undertook this study to evaluate the prevalence and clinical correlations of Doppler microembolic signals (MES) in stroke-prone patients.

Methods
Patients with potential cardiac (n=300) or carotid (n=100) embolic source and control subjects (n=100) were monitored with transcranial Doppler sonography for MES. Transthoracic (n=192) and/or transesophageal (n=134) echocardiography and carotid studies (continuous-wave Doppler, n=181; color-coded duplex, n=47) were performed in all patients with potential native cardioembolic source. Carotid disease was evaluated by means of continuous-wave Doppler (n=87), color-coded duplex (n=70), or intra-arterial angiography (n=24) in patients with potential carotid embolic source.

Results
Overall MES prevalence was 23% in patients with potential native cardioembolic source (infective endocarditis [n=7] 43%, left ventricular aneurysm [n=38] 34%, intracardiac thrombus [n=23] 26%, dilative cardiomyopathy [n=39] 26%, nonvalvular atrial fibrillation [n=24] 21%, valvular disease [n=80] 15%), 55% in patients with prosthetic cardiac valves (mechanical [n=77] 58%, porcine [n=7] 43%, homografts [n=5] 20%), 28% in patients with carotid disease (symptomatic [n=46] 52%, asymptomatic [n=54] 7%;
P
<.01), and 5% in control subjects. No relationship between MES counts and patients’ age, sex, or actual medication was noted. The sensitivity and specificity of MES detection in identifying patients with potential embolic sources were 31% and 95%, respectively.

Conclusions
Our study confirmed the reported clinical significance of MES in patients with carotid disease and the high specificity of this technique. The demonstrated low sensitivity of MES detection could be due to short monitoring duration or application of antihemostatic treatment. Prospective large-scale studies are needed to determine the definitive value of MES detection as a diagnostic method in patients with potential cardioembolic source.
Grading Carotid Stenosis With Ultrasound
Authors: Alexandrov Andrei V. , Vital Doralene , Brodie Dianne S. , Hamilton Paul , Grotta James C.
Published: June 2011

Background and Purpose
Carotid ultrasound had modest accuracy in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) of carotid endarterectomy in predicting severe carotid stenosis when a 250-cm/s peak systolic velocity (PSV) criterion was applied to different laboratories. We compared the performance of two independent laboratories using similar equipment (ATL-HDI Ultramark 9) but different interpretation criteria.

Methods
Consecutive patients who underwent both color-coded duplex ultrasound and intra-arterial digital subtraction angiography were studied. PSV was determined with angle correction at the site of the tightest arterial narrowing. Carotid stenosis was measured on angiograms using the North American (N) method. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values with 95% confidence intervals were calculated for each laboratory.

Results
In 87 patients, 174 bifurcations were imaged. A 250-cm/s criterion was the best single predictor of a >70% N stenosis at one laboratory (sensitivity 93% [95% confidence interval, 85 to 101], specificity 86% [76 to 96], PPV 75% [62 to 87], and NPV 96% [90 to 102]) but had modest parameters at the other laboratory (50% [34 to 64], 87%, [77 to 97], 60 [44 to 76], and 91 [82 to 100], respectively). However, the diagnostic criteria routinely used in the second laboratory included different velocity values, which when applied decreased specificity by 17% but increased sensitivity by 35% (85% [74 to 96], 70% [56 to 84], 90% [81 to 99], and 77% [64 to 90], respectively).

Conclusions
Despite the use of similar equipment, ultrasound grading of carotid stenosis is operator dependent and relies on different and individually validated criteria. Greater sensitivity of ultrasound screening is achieved by applying diagnostic criteria specific to each laboratory. Multicenter studies should use laboratory-specific criteria and a local validation process.
Do Chronic Middle Cerebral Artery Stenoses Represent an Embolic Focus?
Authors: Sliwka Ulrich , Klötzsch Christof , Popescu Octavian , Brandt Katrin , Schmidt Peter , Berlit Peter , Noth Johannes
Published: June 2011

Background and Purpose
It remains uncertain whether the annual stroke risk of 7% to 8% in middle cerebral artery (MCA) stenosis is of embolic or hemodynamic origin. Preliminary reports provide evidence of emboli exiting from acute MCA stenoses, detected by transcranial Doppler (TCD) sonography. With multirange monitoring before and after the stenosis, TCD monitoring may help for the first time to differentiate microemboli exiting from the MCA stenosis from those with a source proximal to the MCA stenosis. We searched for microembolic signals (MES) using multigated monitoring in patients with chronic MCA stenoses.

Methods
Fifty-eight patients with 78 chronic stenoses of the MCA were enrolled in the study. Additional sources of embolism were ruled out by extensive clinical workup. Twenty-four patients were treated with coumarin, whereas 28 patients received aspirin. The remaining 6 patients discontinued their medication after a few weeks. The sample volume of the multirange probe was placed on either side of the stenotic area of the MCA.

Results
Twenty-three (29.5%) of the stenoses were low grade, 18 (23%) were moderate, and 37 (47.5%) were severe. Thirty-seven (47%) of the stenoses were symptomatic and 41 (53%) were asymptomatic before study entry. During follow-up, 2 strokes and 7 transient ischemic attacks occurred. Computer tomography revealed two watershed-type infarcts. Sufficient insonation of the prestenotic and poststenotic segments of the MCA was possible in 70 stenoses (90%). No MES could be detected during a total of 1740 minutes’ monitoring time distal to the MCA stenoses, regardless of the patients’ medication. MES were also absent in the contralateral MCA.

Conclusions
MES are not detectable in patients with chronic MCA stenoses of different degrees. No MES were found in either symptomatic or asymptomatic stenoses, regardless of the patients’ medication. These results indicate that chronic MCA stenoses do not represent a significant embolic source. The absence of MES in the prestenotic Doppler sample volume, the watershed-type infarcts during follow-up, and the absence of small-vessel disease on computed tomography suggests that hemodynamic mechanisms are responsible for recurrent cerebral ischemia.