bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Uric Acid Is a Strong Predictor of Stroke in Patients With Non–Insulin-Dependent Diabetes Mellitus
Authors: Lehto Seppo , Niskanen Leo , Rönnemaa Tapani , Laakso Markku
Published: June 2011

Background and Purpose
—Patients with non–insulin-dependent diabetes mellitus (NIDDM) are at increased risk for stroke. Hyperuricemia is a common finding in NIDDM, but its significance as an independent risk factor for cardiovascular disease has remained uncertain. Therefore, we investigated serum urate as a predictor of stroke in NIDDM patients free of clinical nephropathy (ie, with a serum creatinine level of ≤120 μmol/L).

Methods
—In this population-based study, cardiovascular risk factors were determined in 1017 patients (551 men and 466 women) with NIDDM, aged 45 to 64 years at baseline. The patients were followed up for 7 years with respect to stroke events.

Results
—During the follow-up period, 31 NIDDM patients (12 men [2.2%] and 19 women [4.1%]) died from stroke and 114 NIDDM patients (55 men [10.0%] and 59 women [12.7%]) had a fatal or nonfatal stroke. The incidence of stroke increased significantly by quartiles of serum uric acid levels (
P
<.001). High uric acid level (above the median value of >295 μmol/L) was significantly associated with the risk of fatal and nonfatal stroke by Cox regression analysis (hazard ratio, 1.93 [1.30 to 2.86];
P
=.001). This association remained statistically significant even after adjustment for all cardiovascular risk factors (hazard ratio, 1.91 [1.24 to 2.94[;
P
=.003).

Conclusions
—Our results indicate that hyperuricemia is a strong predictor of stroke events in middle-aged patients with NIDDM independently of other cardiovascular risk factors.
Effect of Acetazolamide Reactivity and Long-term Outcome in Patients With Major Cerebral Artery Occlusive Diseases
Authors: Yokota Chiaki , Hasegawa Yasuhiro , Minematsu Kazuo , Yamaguchi Takenori
Published: June 2011

Background and Purpose
—It remains unclear whether hemodynamic insufficiency plays a major role in ischemic events. We performed a prospective follow-up study in ischemic stroke patients with occlusive large-artery diseases to determine whether stroke recurrence is related to reduced vasodilatory capacity, judged with single-photon emission CT and acetazolamide (ACZ) challenge.

Methods
—During the period from 1987 to 1995, we examined cerebral vasodilatory capacity with single-photon emission CT and an ACZ challenge in 105 consecutive stroke patients with severe stenosis (>75% in diameter) or occlusion of the internal carotid artery or the trunk of the middle cerebral artery who had no or minimal infarcts on CT. According to criteria reported earlier, the patients were divided into two groups: normal (negative ACZ, n=50) or reduced ACZ reactivity (positive ACZ, n=55). They were prospectively followed at regular intervals for a median period of 2.7 years.

Results
—The Kaplan-Meier analysis revealed no difference in cumulative recurrence-free survival rate between the two groups. The multivariate analysis with Cox proportional hazards model demonstrated that a high systolic blood pressure at entry into the study significantly increased stroke recurrence (coefficient=.0466; hazard ratio=1.0477; 95% confidence interval=1.0017 to 1.0957;
P
=.04), whereas antihypertensive medication significantly reduced stroke recurrence (coefficient=−1.527; hazard ratio=0.217; 95% confidence interval=0.0612 to 0.771;
P
=.02), but no other variables including ACZ reactivity affected stroke recurrence rate.

Conclusions
—The present results demonstrate that reduced vasodilatory capacity does not play a major role in stroke recurrence. Antihypertensive therapy appears to reduce stroke recurrence even in patients with hemodynamically significant arterial diseases.
Dynamics of Cerebral Tissue Injury and Perfusion After Temporary Hypoxia-Ischemia in the Rat
Authors: Dijkhuizen Rick M. , Knollema Siert , van der Worp H. Bart , Ter Horst Gert J. , De Wildt Dick J. , van der Sprenkel Jan Willem Berkelbach , Tulleken Kees A. F. , Nicolay Klaas
Published: June 2011

Background and Purpose
—Selective regional sensitivity and delayed damage in cerebral ischemia provide opportunities for directed and late therapy for stroke. Our aim was to characterize the spatial and temporal profile of ischemia-induced changes in cerebral perfusion and tissue status, with the use of noninvasive MRI techniques, to gain more insight in region-specific vulnerability and delayed damage.

Methods
—Rats underwent 20 minutes of unilateral cerebral hypoxia-ischemia (HI). We performed combined repetitive quantitative diffusion-weighted, T2-weighted, and dynamic susceptibility contrast-enhanced MRI from before HI to 5 hours after HI. Data were correlated with parallel blood oxygenation level–dependent MRI and laser-Doppler flowmetry. Finally, MRI and histology were done 24 and 72 hours after HI.

Results
—Severe hypoperfusion during HI caused acute reductions of the apparent diffusion coefficient (ADC) of tissue water in the ipsilateral hemisphere. Reperfusion resulted in dynamic perfusion alterations that varied spatially. The ADC recovered completely within 1 hour in the hippocampus (from 0.68±0.07 to 0.83±0.09×10
−3
mm
2
/s), cortex (from 0.56±0.06 to 0.77±0.07×10
−3
mm
2
/s), and caudate putamen (from 0.58±0.06 to 0.75±0.06×10
−3
mm
2
/s) but only partially or not at all in the thalamus (from 0.65±0.07 to 0.68±0.12×10
−3
mm
2
/s) and substantia nigra (from 0.80±0.08 to 0.76±0.10×10
−3
mm
2
/s). Secondary ADC reductions, accompanied by significant T2 elevations and histological damage, were observed after 24 hours. Initial and secondary ADC decreases were observed invariably in the hippocampus, cortex, and caudate putamen and in approximately 70% of the animals in the thalamus and substantia nigra.

Conclusions
—Region-specific responses and delayed ischemic damage after transient HI were demonstrated by MRI. Acute reperfusion-induced normalization of ADCs appeared to poorly predict ultimate tissue recovery since secondary, irreversible damage developed eventually.
Consensus on Microembolus Detection by TCD
Authors: Bernd Ringelstein E. , Droste Dirk W. , Babikian Viken L. , Evans David H. , Grosset Donald G. , Kaps Manfred , Markus Hugh S. , Russell David , Siebler Mario
Published: June 2011

Abstract
—Transcranial Doppler ultrasound is capable of detecting microembolic material, both gaseous and solid, within the intracranial cerebral arteries. To avoid discrediting this promising and exciting new technique, experts in this field met in January 1997 in Frankfurt, Germany, to discuss the limitations and problems of embolus detection and to determine guidelines for its proper use in clinical practice, as well as in scientific investigations. In particular, the authors suggest that studies report the following parameters: (1) ultrasound device, (2) transducer type and size, (3) insonated artery, (4) insonation depth, (5) algorithms for signal intensity measurement, (6) scale settings, (7) detection threshold, (8) axial extension of sample volume, (9) fast Fourier transform (FFT) size (number of points used), (10) FFT length (time), (11) FFT overlap, (12) transmitted ultrasound frequency, (13) high-pass filter settings, and (14) recording time. There was agreement that no current system of automatic embolus detection has the required sensitivity and specificity for clinical use.
Hypervolemic Hemodilution in Acute Ischemic Stroke
Authors: Aichner Franz T. , Fazekas Franz , Brainin Michael , Pölz Werner , Mamoli Bruno , Zeiler Karl
Published: June 2011

Background and Purpose
—Experimental studies suggest a beneficial effect of hemodilution on acute ischemic stroke. This was not proven by previous multicenter trials in the clinical setting. Various reasons have been suggested for the failure of these studies, which we attempted to consider in the Multicenter Austrian Hemodilution Stroke Trial (MAHST).

Methods
—MAHST is a randomized, double-blind, placebo-controlled study of hypervolemic hemodilution (HHD) within 6 hours of a clinically first ischemic stroke localized in the middle cerebral artery territory. The treatment consisted of 10% hydroxyethyl starch 200/0.5 (HES) and was tested against pure rehydration with Ringer’s lactate over a period of 5 days. Our primary outcome measure was clinical improvement within 7 days as measured by the Graded Neurologic Scale (GNS). We performed an adaptive interim analysis to reevaluate the study goal after entering half of the projected number of patients (n=200). At least 600 patients per group would have been required for significant results, and therefore we decided to terminate the trial.

Results
—Ninety-eight patients received HHD and 102 patients placebo. The baseline characteristics were comparable between both groups. In the HHD group the absolute reduction of the hematocrit was 2.5% on day 2 with a maximum of 3.7% on day 5, which compares with a reduction in the placebo group of 1% and 1.9%, respectively. Intention-to-treat analysis showed no significant difference of the change of the GNS scores between HHD-treated (median, −8.5; 95% confidence interval, −14.2 to −4.0) and placebo-treated patients (median, −6.0; 95% confidence interval, −11.0 to 0.0) on day 7, and GNS scores remained similar in both treatment groups throughout the trial. At 3 months, slightly more HHD patients showed complete independence on the Barthel Index (28 versus 24), and fewer HHD than placebo patients had died (13 versus 17), but these differences were not statistically significant. HHD treatment was not associated with any specific adverse event.

Conclusions
—Mild HHD is safe but failed to demonstrate a significant beneficial effect over the pure rehydration regimen in patients with acute ischemic stroke.
Outcome of Subacute Stroke Rehabilitation
Authors: Rønning Ole Morten , Guldvog Bjørn
Published: June 2011

Background and Purpose
—Organized acute stroke treatment reduces mortality, functional deficits, and the need of institutionalization after stroke. It is largely unknown whether the effects of treatment are due to early or subacute efforts. The aim of this randomized, controlled study was to test the hypothesis that rehabilitation of stroke patients in the subacute phase in a hospital rehabilitation unit is beneficial in reducing death and dependency and increasing health-related quality of life.

Methods
—251 patients initially treated in the hospital were randomized to subacute rehabilitation in a hospital rehabilitation unit (n=127) or to the health services in the municipality (n=124) and were followed up for 7 months.

Results
—The combined outcome of patients being dead or dependent (Barthel Index score of <75) was 23% in the hospital group and 38% in the municipality group (
P
=.01). Seven-month survival rates were 90.6% and 83.9% (
P
=.11), respectively. Dependency in activities of daily living was 12.6% in the hospital group and 25.0% in the municipality group (
P
=.07). Patients with a BI score of <50 before rehabilitation had significantly better outcome in the hospital rehabilitation unit, with fewer patients becoming dependent (
P
=.005) and patients having higher Scandinavian Stroke Scale (
P
=.026) and BI scores (
P
=.005). No significant differences in health-related quality of life were found. Many patients treated in the municipalities (30%) did not receive any organized rehabilitation in this study.

Conclusions
—Subacute rehabilitation of stroke patients in a hospital-based rehabilitation unit improves outcome. Patients with moderate or severe stroke appear to benefit most.
Survival and Functional Status 20 or More Years After First Stroke
Authors: Gresham Glen E. , Kelly-Hayes Margaret , Wolf Philip A. , Beiser Alexa S. , Kase Carlos S. , D’Agostino Ralph B.
Published: June 2011

Background and Purpose
—We examined the 20-or-more-year survival and functional levels of 148 stroke survivors and 148 age- and sex-matched control subjects from the Framingham Study Cohort, whom we originally studied in 1972–1974 to ascertain the survival and disability status of stroke survivors compared with that of controls.

Methods
—This long-term evaluation was done with use of data from the 1993–1995 Framingham Study Cohort Examination 23 on the 10 stroke survivors and 20 control subjects still living to identify and compare the host characteristics and functional status of each group. The survival curves for both stroke survivors and controls were derived from the ongoing Framingham Study database.

Results
—Twenty-plus-year stroke survivors experienced a greater mortality than age- and sex-matched controls (92.5% and 81%, respectively). The slopes of the two survival curves were essentially the same. Functional status (eg, walking and independence in activities of daily living) of stroke survivors, however, compared very favorably with that of the control subjects. Stroke survivors were more likely to be female and to have a number of comorbidities, including elevated blood pressures, greater use of medications, less use of alcohol, and less depressive symptomology.

Conclusions
—In the Framingham cohort, 20-plus-year stroke survivors showed greater mortality than age- and sex-matched control subjects; functionally, however, the groups were very similar and in general quite independent.
Quality of Life in Patients and Partners After Aneurysmal Subarachnoid Hemorrhage
Authors: Hop Jeannette W. , Rinkel Gabriel J. E. , Algra Ale , van Gijn Jan
Published: June 2011

Background and Purpose
—Outcome after subarachnoid hemorrhage (SAH) is often graded as “poor,” “fair,” or “good.” Such categories are usually based on physicians’ assessments of physical abilities of patients rather than on how patients themselves perceive their physical, psychological, and social well-being. We assessed functional outcome and quality of life (QoL) in patients with SAH and their partners.

Methods
—In a consecutive series of 64 patients and 51 partners studied 4 months after the SAH, we assessed functional outcome by means of the Rankin Scale, and QoL by means of the SF-36, the Sickness Impact Profile (SIP), and a visual analogue scale. Additionally, we asked two “simple questions” about dependency and recovery. All questionnaires were completed in an interview setting. The scores on the QoL instruments from patients and partners were stratified according to the Rankin grades of the patients and were compared with data from a Dutch reference population.

Results
—Only patients who had no symptoms at all (Rankin grade 0) had no reduction in QoL compared with the reference population; some of these patients even indicated an improvement in QoL from before the SAH according to the visual analogue scale. Patients who had symptoms but were independent (Rankin grades 1 to 3) and therefore usually designated as having “good outcome” often had reductions in QoL, on both the physical and psychosocial subscores of the SIP and SF-36. The QoL of partners was considerably reduced in several psychosocial domains.

Conclusions
—SAH has a considerable impact on the QoL of patients and their partners. Only patients without residual symptoms (Rankin grade 0) have a good outcome in terms of physical performance and QoL.
Low Glucose Enhances Na
+
/Glucose Transport in Bovine Brain Artery Endothelial Cells
Authors: Nishizaki Tomoyuki , Matsuoka Toshiyuki
Published: June 2011

Background and Purpose
—Brain arteries are structurally characterized by the tight junctions of the endothelium and by no vasa vasorum that feed arteries themselves. This raises the question of how brain arteries are provided with glucose. A possible explanation is that glucose uptake into arteries may be mediated by both GLUT1, a facilitative glucose transporter, and a Na
+
/glucose cotransporter (SGLT)-like glucose transporter. The functional role for the SGLT-like glucose transporter, however, is unknown. In the present study we investigated SGLT-like glucose transporter–operated glucose uptake into brain arterial endothelial cells by recording glucose-evoked Na
+
currents and monitoring uptake of [
3
H]-2-deoxy-
d
-glucose ([
3
H]-2-DOG).

Methods
—Endothelial cells were cultured from bovine cerebral cortical arteries. Whole-cell patches were made to cells, and glucose-evoked currents were recorded. Cells were incubated with [
3
H]-2-DOG, and the uptake was determined by a liquid scintillation counter.

Results
—Glucose and α-methyl-
d
-glucoside (αMeDG), a specific compound for the SGLTs, evoked Na
+
currents in a whole-cell voltage-clamp configuration, and the currents were enhanced in cells with over 30 minutes’ preincubation in glucose-free media. Glucose-induced currents were inhibited by αMeDG, by the selective SGLT inhibitor phlorizin, by dinitrophenol (DNP), an inhibitor of energy metabolism, or by deletion of Na
+
from extracellular solution, which indicates that glucose uptake into endothelial cells was mediated by a Na
+
- and energy-dependent glucose transporter. Notably, the currents were desensitized, reduced in a glucose concentration–dependent manner, and markedly inhibited by either a second application of glucose or the addition of glucose to the patch electrode filling solution; they were potentiated, however, by treatment with cytochalasin B, a GLUT1 to GLUT5 inhibitor. Consistent with the results of patch-clamp recordings, uptake of [
3
H]-2-DOG into endothelial cells was enhanced by glucose-free insult, and the enhancement was mediated by an SGLT-like glucose transporter.

Conclusions
— The results presented demonstrate that an SGLT-like glucose transporter takes part in glucose uptake into brain artery endothelial cells and that the uptake is regulated by intracellular glucose concentrations; glucose-free insult and the ensuing low cytosolic glucose enhance activity of the SGLT-like glucose transporter. The SGLT-like glucose transporter in the brain arterial endothelium thus may be important in the maintenance of an adequate glucose concentration in the arterial wall under conditions of stress, such as hypoglycemia.
Different Apparent Diffusion Coefficient
Authors: Kuroiwa Toshihiko , Nagaoka Tsukasa , Ueki Masato , Yamada Ichiro , Miyasaka Naoyuki , Akimoto Hideaki
Published: June 2011

Background and Purpose
—Early and accurate diagnosis of brain edema in stroke patients is essential for the selection of appropriate treatment. We examined the correlations between the changes in the apparent diffusion coefficient (ADC), regional water content, and tissue ultrastructure during early focal cerebral ischemia.

Methods
—The left middle cerebral arteries of cats were occluded with an intramagnet occlusion/recirculation device. T2-weighted, diffusion-weighted, and perfusion imaging were performed repeatedly during the initial 3 hours after occlusion. The ADCs obtained from ADC maps were compared with the corresponding tissue water content values determined by gravimetry and electron microscopic water localization.

Results
—ADC reduction was detected in areas of low perfusion 15 minutes after occlusion and thereafter. The water content increase correlated linearly with the ADC decreases in both the gray and white matter. However, both the water content corresponding to an ADC value and the rate of ADC change of the gray and white matter differed significantly (
P
<.05) as follows:
y
=−10105
x
+8533 (
r
=.86) and
y
=−6174
x
+4611 (
r
=.67), respectively, where
x
is the water content (grams water per gram tissue) and
y
is the ADC (×10
−6
mm
2
/s). Hydropic astrocytic swelling was seen in both structures, and in the white matter, oligodendroglial and myelinated axonal swelling and periaxonal space enlargement were observed.

Conclusions
—When early ischemic edema in experimental focal cerebral ischemia is evaluated with ADC mapping, the different slopes and intercepts of the water content and ADC correlation lines for the gray and white matter, which probably reflect different ultrastructural localization of water, should be taken into account.
Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats
Authors: Romanic Anne M. , White Raymond F. , Arleth Anthony J. , Ohlstein Eliot H. , Barone Frank C.
Published: June 2011

Background and Purpose
—Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix and are implicated in numerous pathological conditions including atherosclerosis, inflammation, and tumor growth and metastasis. In the brain, the endothelial cell wall, strengthened by tight junctions, defines the blood-brain barrier (BBB). The extracellular matrix molecules constitute the basement membrane underlying the vasculature and play a critical role in maintaining the integrity of the BBB. After focal stroke, there is a breakdown of the BBB with an associated increase in vascular permeability, inflammatory cell influx, and neuronal cell death. The present study was designed to investigate the effects of MMP expression after stroke.

Methods
—Focal stroke was produced by permanent middle cerebral artery occlusion (MCAO) in the rat, and MMP protein expression was measured by Western blot and zymogram analysis over a time course ranging from 6 hours to 30 days (n=32). Immunohistochemistry at 1 and 5 days (n=8 and 6, respectively) was also utilized to characterize the expression of several MMPs and related proteins after stroke, including their cellular source. To test the hypothesis that early increased MMP-9 expression is involved in ischemic brain injury, a neutralizing monoclonal antibody directed against MMP-9 was administered intravenously (n=7 per group) 1 hour before MCAO, and infarct size was measured 24 hours later.

Results
—MMP expression increased progressively over time after stroke. After 12 hours, significant (
P
<0.05) MMP-9 activity was observed that reached maximum levels by 24 hours (
P
<0.001), then persisted for 5 days at this level and returned to basal (zero) levels by 15 days. On the basis of morphological criteria, MMP-9 appeared to stain with endothelial cells and neutrophils identified both within and at the periphery of the infarct within 24 hours of focal ischemia. After 5 days, MMP-9 appeared to stain with macrophages present within the infarcted brain. MMP-2 activity was significantly (
P
<0.001) increased by 24 hours and was maximum after 5 days following MCAO. MMP-2 appeared to stain with macrophages present within the infarcted region. Unlike MMP-9 and MMP-2, tissue inhibitor of metalloproteinase-1 was identified at comparable levels in both control and ischemic tissue after MCAO. MMP-1 and MMP-3 could not be detected in the brain after focal stroke. When an MMP-9–neutralizing monoclonal antibody was administered systemically, animals exhibited significantly reduced infarct size (ie, a 30% reduction compared with non–immune antibody controls;
P
<0.05).

Conclusions
—These results demonstrate that early increased MMP-9 expression in endothelial cells and infiltrating neutrophils is a significant response to cerebral focal ischemia and that selective inhibition of MMP-9 activity can significantly reduce brain injury after stroke.
Core and Penumbral Nitric Oxide Synthase Activity During Cerebral Ischemia and Reperfusion
Authors: Ashwal Stephen , Tone Beatriz , Tian Hui Rou , Cole Daniel J. , Pearce William J.
Published: June 2011

Background and Purpose
—The present studies examined the hypothesis that the distribution of cerebral injury after a focal ischemic insult is associated with the regional distribution of nitric oxide synthase (NOS) activity.

Methods
—Based on previous studies that certain anatomically well-defined areas are prone to become either core or penumbra after middle cerebral artery occlusion (MCAO), we measured NOS activity in these areas from the right and left hemispheres in a spontaneously hypertensive rat filament model. Four groups were studied: (1) controls (immediate decapitation); (2) 1.5 hours of MCAO with no reperfusion (R0); (3) 1.5 hours of MCAO with 0.5 hour of reperfusion (R0.5); and (4) 1.5 hours of MCAO with 24 hours of reperfusion (R24). Three groups of corresponding isoflurane sham controls were also included: 1.5 (S1.5) or 2 (S2.0) hours of anesthesia and 1.5 hours of anesthesia+24 hours of observation (S24).

Results
—Control core NOS activity for combined right and left hemispheres was 129% greater than penumbral NOS activity (
P
<0.05). Combined core NOS activity was also greater (
P
<0.05) in the three sham groups: 208%, 122%, and 161%, respectively. In the three MCAO groups, ischemic and nonischemic core NOS remained higher than penumbral regions (
P
<0.05). However, NOS activity was lower in the ischemic than in the nonischemic core in all three groups: R0 (29% lower), R0.5 (48%), and R24 (86%) (
P
<0.05). Addition of cofactors (10 μmol/L tetrahydrobiopterin, 3 μmol/L flavin adenine dinucleotide, and 3 μmol/L flavin mononucleotide) increased NOS activity in all groups and lessened the decrease in ischemic core and penumbral NOS.

Conclusions
—Greater NOS activity in core regions could explain in part the increased vulnerability of that region to ischemia and could theoretically contribute to the progression of the infarct over time. The data also suggest that NOS activity during ischemia and reperfusion could be influenced by the availability of cofactors.
Glutamate, Glutamine, and GABA as Substrates for the Neuronal and Glial Compartments After Focal Cerebral Ischemia in Rats
Authors: Pascual José M. , Carceller Fernando , Roda José M. , Cerdán Sebastián
Published: June 2011

Background and Purpose
—Even though the utilization of substrates alternative to glucose may play an important role in the survival of brain cells under ischemic conditions, evidence on changes in substrate selection by the adult brain in vivo during ischemic episodes remains very limited. This study investigates the utilization of glutamate, glutamine, and GABA as fuel by the neuronal and glial tricarboxylic acid cycles of both cerebral hemispheres after partially reversible focal cerebral ischemia (FCI).

Methods
—Right hemisphere infarct was induced in adult Long-Evans rats by permanent occlusion of the right middle cerebral artery and transitory occlusion of both common carotid arteries. (1,2-
13
C
2
) acetate was infused for 60 minutes in the right carotid artery immediately after carotid recirculation had been re-established (1-hour group) or 23 hours later (24-hour group). Extracts from both cerebral hemispheres were prepared and analyzed separately by
13
C nuclear magnetic resonance and computer-assisted metabolic modeling.

Results
—FCI decreased the oxidative metabolism of glucose in the brain in a time-dependent manner. Reduced glucose oxidation was compensated for by increased oxidations of (
13
C) glutamate and (
13
C) GABA in the astrocytes of the ipsilateral hemispheres of both groups. Increased oxidative metabolism of (
13
C) glutamine in the neurons was favored by increased activity of the neuronal pyruvate recycling system in the 24–hour group.

Conclusions
—Data were obtained consistent with time-dependent changes in the utilization of glutamate and GABA or glutamine as metabolic substrates for the glial or neuronal compartments of rat brain after FCI.
Role of CT Angiography in Patient Selection for Thrombolytic Therapy in Acute Hemispheric Stroke
Authors: Wildermuth Susanne , Knauth Michael , Brandt Tobias , Winter Ralph , Sartor Klaus , Hacke Werner
Published: June 2011

Background and Purpose
—It has been shown that thrombolytic therapy can improve clinical outcome in a subgroup of patients with acute cerebral ischemia. This subgroup was characterized by certain clinical and imaging findings (eg, moderate to severe neurological deficit for less than 3 to 6 hours, occlusion of the middle cerebral artery, lack of extended infarct signs on CT, and efficient leptomeningeal collaterals). Although not part of published prospective randomized rtPA trials, information about the status of the brain vessels would be helpful in the selection of patients who may benefit the most. Our purpose was to determine the feasibility of CT angiography (CTA) in patients with acute hemispheric ischemia and to evaluate its relevance for thrombolytic therapy.

Methods
—CTA was performed in 40 consecutive patients (11 women and 29 men; age range, 19 to 80 years) with moderate or severe symptoms (National Institutes of Health Stroke Scale score of ≥8) of acute hemispheric ischemia. CTA findings were compared with Doppler ultrasonography (US; n=22) and intra-arterial digital subtraction angiography (DSA; n=7). Twenty patients received thrombolytic therapy, the remaining patients received intravenous heparin.

Results
—Images and 3-dimensional reconstructions of diagnostic quality could be obtained in all patients. Thirty-four patients had a vessel occlusion. The extent of leptomeningeal collaterals correlated significantly with the outcome after thrombolytic therapy (
r
s
=0.46,
P
<0.05). The evaluation of diagnostic accuracy showed a high agreement with US (22 of 22) and DSA (6 of 7).

Conclusions
—CTA can provide important information for the initiation of therapy in patients with acute hemispheric ischemia. Identification of patients with autolyzed thrombi, occlusion of the internal carotid artery bifurcation, and poor leptomeningeal collaterals is feasible with the use of CTA. These patients may have little potential for benefit from thrombolytic therapy.
Regional Ischemia and Ischemic Injury in Patients With Acute Middle Cerebral Artery Stroke as Defined by Early Diffusion-Weighted and Perfusion-Weighted MRI
Authors: Rordorf Guy , Koroshetz Walter J. , Copen William A. , Cramer Steven C. , Schaefer Pamela W. , Budzik Ronald F. , Schwamm Lee H. , Buonanno Ferdinando , Sorensen A. Gregory , Gonzalez Gilberto
Published: June 2011

Background and Purpose
—We sought to map early regional ischemia and infarction in patients with middle cerebral artery (MCA) stroke and compare them with final infarct size using advanced MRI techniques. MRI can now delineate very early infarction by diffusion-weighted imaging (DWI) and abnormal tissue perfusion by perfusion-weighted imaging (PWI).

Methods
—Seventeen patients seen within 12 hours of onset of MCA stroke had MR angiography, standard MRI, and PWI and DWI MRI. PWI maps were generated by analysis of the passage of intravenous contrast bolus through the brain. Cerebral blood volume (CBV) was determined after quantitative analysis of PWI data. Volumes of the initial DWI and PWI lesion were calculated and compared with a final infarct volume from a follow-up imaging study (CT scan or MRI).

Results
—Group 1 (10 patients) had MCA stem (M1) occlusion by MR angiography. DWI lesion volumes were smaller than the volumes of CBV abnormality. In 7 patients the final stroke volume was larger or the same, and in 3 it was smaller than the initial CBV lesion. Group 2 (7 patients) had an open M1 on MR angiography with distal MCA stroke. In 6 group 2 patients, the initial DWI lesion matched the initial CBV abnormality and the final infarct.

Conclusions
—Most patients with M1 occlusion showed progression of infarction into the region of abnormal perfusion. In contrast, patients with open M1 had strokes consistent with distal branch occlusion and had maximal extent of injury on DWI at initial presentation. Application of these MRI techniques should improve definition of different acute stroke syndromes and facilitate clinical decision making.
Age and Sex Differences in Cerebral Hemodynamics
Authors: Matteis Maria , Troisi Elio , Monaldo Bruno C. , Caltagirone Carlo , Silvestrini Mauro
Published: June 2011

Background and Purpose
—Hemodynamic factors seem to play an important role in the pathogenesis of cerebral ischemic events. The aim of this study was to evaluate whether changes in cerebrovascular reactivity occur in women after menopause.

Methods
—Using transcranial Doppler ultrasonography, we studied the changes of flow velocity after hypercapnia in the middle cerebral arteries of 45 healthy premenopausal women (mean age, 32.3 years; range, 20 to 47 years) and 40 postmenopausal women (mean age, 54.4 years; range, 48 to 64 years). The same measurements were recorded in two groups of healthy male subjects age matched with premenopausal (45 subjects) and postmenopausal women (40 subjects). Moreover, a subgroup of postmenopausal women aged 48 to 53 years (15 subjects) were compared with a group of 15 premenopausal women of the same age. We obtained hypercapnia with breath holding and evaluated cerebrovascular reactivity with the breath-holding index (BHI).

Results
—BHI was significantly lower in postmenopausal women (0.89±0.3) than in premenopausal women (1.59±0.3;
P
<0.0001) and in young (1.34±0.5;
P
<0.001) and old men (1.20±0.4;
P
<0.04). In the latter group, BHI was significantly lower than in premenopausal women (
P
<.0001). BHI values were also significantly lower in postmenopausal than in premenopausal women of the same age (0.81±0.1 versus 1.34±0.1;
P
<0.0001).

Conclusions
—These findings suggest that the large reduction of cerebrovascular reactivity in postmenopausal women cannot be considered a simple factor related to aging but is probably influenced by hormonal changes. The alteration in cerebrovascular regulation could be involved in the increase of cerebrovascular disease in postmenopausal women.
Cost-Effectiveness of Preference-Based Antithrombotic Therapy for Patients With Nonvalvular Atrial Fibrillation
Authors: Gage Brian F. , Cardinalli Andria B. , Owens Douglas K.
Published: June 2011

Background and Purpose
—Recent atrial fibrillation guidelines recommend the incorporation of patient preferences into the selection of antithrombotic therapy. However, no trial has examined how incorporating such preferences would affect quality-adjusted survival or medical expenditure. We compared 10-year projections of quality-adjusted survival and medical expenditure associated with two atrial fibrillation treatment strategies: warfarin-for-all therapy versus preference-based therapy. The preference-based strategy prescribed whichever antithrombotic therapy, warfarin or aspirin, had the greater projected quality-adjusted survival.

Methods
—We used decision analysis stratified by the number of stroke risk factors (history of stroke, transient ischemic attack, hypertension, diabetes, or heart disease). The base case focused on compliant 65-year-old patients who had nonvalvular atrial fibrillation and no contraindications to antithrombotic therapy.

Results
—In patients whose only risk factor for stroke was atrial fibrillation, preference-based therapy improved projected quality-adjusted survival by 0.05 quality-adjusted life year (QALY) and saved $670. For patients who had atrial fibrillation and one additional risk factor for stroke, preference-based therapy improved quality-adjusted survival by 0.02 QALY and saved $90. In patients who had atrial fibrillation and multiple additional risk factors for stroke, preference-based therapy increased medical expenditures and did not improve quality-adjusted survival substantially. The benefits of preference-flexible therapy arose from the minority of patients who would have had a longer quality-adjusted survival if they had been prescribed aspirin rather than warfarin.

Conclusions
—As do risks of stroke and of hemorrhage, patients’ preferences help to determine which antithrombotic therapy is optimal. Preference-based treatment should improve quality-adjusted survival and reduce medical expenditure in patients who have nonvalvular atrial fibrillation and not more than one additional risk factor for stroke.
Early Spontaneous Improvement and Deterioration of Ischemic Stroke Patients
Authors: Toni D. , Fiorelli M. , Zanette E. M. , Sacchetti M. L. , Salerno A. , Argentino C. , Solaro M. , Fieschi C.
Published: June 2011

Background and Purpose
—The purpose of our study was to investigate whether emergency transcranial Doppler (TCD) findings and their modifications over the first 48 hours are related to early neurological changes in acute ischemic stroke patients.

Methods
—Ninety-three patients underwent CT scan within 5 hours of a first-ever ischemic hemispheric stroke, and TCD serial examinations at 6, 24, and 48 hours after stroke onset. We classified TCD findings as follows: normal; middle cerebral artery (MCA) asymmetry (asymmetry index between affected and contralateral MCAs below –21%); and MCA no-flow (absence of flow signal from the affected MCA in the presence of ipsilateral anterior and posterior cerebral artery signals through the same acoustic window). We considered early deterioration and early improvement to be a decrease or an increase of 1 or more points, respectively, in the Canadian Neurological Scale score over the same period.

Results
—At 6-hour TCD examination, MCA asymmetry and MCA no-flow were present in 6 (22%) and 2 (7%), respectively, of 27 improving patients; in 20 (43%) and 10 (22%) of 46 stable patients, and in 9 (45%) and 8 (40%) of 20 deteriorating patients. TCD findings were normal in the remaining patients (
P
=0.001). At serial TCD, we detected early (within 24 hours) recanalization (from no-flow to asymmetry or normal and from asymmetry to normal) in 2 (25%) improving patients, in 7 (23%) stable patients, and in 5 (29%) deteriorating patients and late (between 24 and 48 hours) recanalization in 4 (50%) improving patients, in 6 (20%) stable patients, and in none of the deteriorating patients (
P
=0.03, χ

2

for trend, improving versus nonimproving irrespective of the timing of recanalization). One deteriorating patient (5%) developed a no-flow from an initial MCA asymmetry. Logistic regression selected normal TCD (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.06 to 0.46) as an independent predictor of early improvement and abnormal TCD (asymmetry plus no-flow) (OR, 5.02; 95% CI, 1.31 to 19.3) as an independent predictor of early deterioration.

Conclusions
—TCD examination within 6 hours after stroke can help to predict both early deterioration and early improvement. Serial TCD shows that propagation of arterial occlusion is rarely related to early deterioration, whereas the fact that it can detect early recanalization (within 24 hours) in deteriorating patients and both early and late recanalization (after 24 hours) in improving patients suggests the existence of individual time frames for tissue recovery.
Multivariate Analysis of Predictors of Hematoma Enlargement in Spontaneous Intracerebral Hemorrhage
Authors: Fujii Yukihiko , Takeuchi Shigekazu , Sasaki Osamu , Minakawa Takashi , Tanaka Ryuichi
Published: June 2011

Background and Purpose
—We conducted this study to determine, through use of multivariate analyses, the independent predictors of hematoma enlargement occurring after hospital admission in patients with spontaneous intracerebral hemorrhage (ICH).

Methods
—We reviewed 627 patients with ICH admitted within 24 hours of onset. The first CT was performed at admission and the second within 24 hours of admission, and a blood sample was taken for laboratory examinations. Univariate and multivariate analyses were performed to assess the relationships between hematoma enlargement and time from onset, consciousness level, CT findings, amount of alcohol consumption, systolic blood pressure at and after admission, clinical outcome, and hematologic parameters.

Results
—Eighty-eight patients (14.0%) showed enlarged hematomas after admission. Multivariate analyses revealed that the following five factors were independently associated with hematoma enlargement: the time from onset (odds ratio [OR], 0.26 for a 1-SD change; 4.9 hours;
P
<0.001); the amount of alcohol consumption (OR, 1.50 for 1 SD; 46.3 g/d;
P
=0.002); the sharp of hematoma (OR, 1.40 for 1 SD; 0.45 round;
P
=0.006); the presence of consciousness disturbance (OR, 1.38 for 1 SD; 0.50 coma;
P
=0.026); and the level of fibrinogen (OR, 0.74 for 1 SD; 87.1 mg/dL;
P
=0.042). Hematoma enlargement was an independent factor increasing the mortality rate in the ICH patients (OR, 1.57;
P
<0.001).

Conclusions
—A particularly high likelihood of hematoma enlargement was observed in patients who (in order of importance) were admitted shortly after onset, who were heavy drinkers; who had an irregularly shaped hematoma, whose consciousness was disturbed, and who had a low level of fibrinogen.
Plasminogen Activators Potentiate Thrombin-Induced Brain Injury
Authors: Figueroa Bryan E. , Keep Richard F. , Betz A. Lorris , Hoff Julian T.
Published: June 2011

Background and Purpose
—Evidence suggests that cerebral edema following intracerebral hemorrhage (ICH) results from a mass effect in combination with neurotoxic injury from clot-derived substrates such as thrombin. Thrombolytics can compete for thrombin inhibitors endogenous to the brain. This study examines the effect of intracerebral infusion of thrombolytics, tissue plasminogen activator (tPA), and urokinase (uPA), individually and in combination with thrombin.

Methods
—Various 100 μL solutions were stereotactically infused into the right basal ganglia of adult male rats. Animals were euthanized 24 hours later, and brain sections were taken for measurement of water, sodium, and potassium content.

Results
—Regardless of dose, when infused independently tPA (2 μg) and uPA (2000 and 5000 Plough units) failed to produce any significant tissue edema compared with vehicle control tissues. However, when either thrombolytic was infused concomitantly with thrombin (1 or 5 U), brain water, sodium, and potassium content all demonstrated a potentiation of thrombin-induced brain injury (
P
<0.05). In addition, animal deaths were significantly greater than expected in animals receiving a combination of tPA (2 μg) and thrombin (5 U) compared with either drug alone (
P
<0.001).

Conclusions
—This study indicates that brain edema caused by thrombin can be greatly amplified by the presence of plasminogen activators, perhaps because the latter compete for naturally occurring thrombin inhibitors. In the context of ICH, our results suggest that the use of tPA or uPA to lyse clotted blood in brain parenchyma may promote edema formation in surrounding tissue.
The Selective Inhibitor of Neuronal Nitric Oxide Synthase, 7-Nitroindazole, Reduces the Delayed Neuronal Damage Due to Forebrain Ischemia in Rats
Authors: Nanri Kazunori , Montécot Céline , Springhetti Véronique , Seylaz Jacques , Pinard Elisabeth
Published: June 2011

Background and Purpose
—The present study was designed to investigate whether neuronally derived nitric oxide (NO) plays a toxic role in the cascade of cellular events triggered by global cerebral ischemia in rats.

Methods
—7-Nitroindazole (7-NI) was used as a selective inhibitor of neuronal NO synthase. Global ischemia was induced for 20 minutes in anesthetized rats following the four-vessel occlusion model. Electroencephalogram and brain and body temperatures were continuously monitored. All rats were thermoregulated for the entire duration of anesthesia. 7-NI (25 mg/kg) or its vehicle was given intraperitoneally just after the carotid clamping and again 1 hour later. Rats were randomly divided into four groups: (1) vehicle (n=7); (2) 7-NI (n=7); (3)
l
-arginine (300 mg/kg IP)+7-NI (n=7); and (4) 7-NI associated with warming to 37°C for 7 hours after disruption of anesthesia to compensate for the decrease in temperature induced by 7-NI (n=9). Seven days after ischemia, hippocampal CA1 damage was evaluated by classic histology. The lesion was scored with the use of a point scale, and the surviving neurons were counted.

Results
—Lesion scores were significantly lower and neuron counts higher in the two (warmed and unwarmed) groups of rats in which 7-NI was given alone than in vehicle- and
l
-arginine+7-NI–treated rats.

Conclusions
—The results indicate that 7-NI was neuroprotective in 20-minute global ischemia in rats and that the neuroprotective effect of 7-NI was mostly due to the blockade of NO synthesis, suggesting that NO released from neurons in ischemic conditions has a deleterious influence on hippocampal pyramidal neurons.
Diminished Serotonin-Mediated Prolactin Responses in Nondepressed Stroke Patients Compared With Healthy Normal Subjects
Authors: Ramasubbu Rajamannar , Flint Alastair , Brown Gregory , Awad George , Kennedy Sidney
Published: June 2011

Background and Purpose
—The purpose of this study was to use hormonal responsiveness to
d
-fenfluramine (
d
-FEN) challenge as a measure of central serotonin (5-HT) function in a comparative evaluation of serotonergic abnormalities between stroke patients and healthy elderly normal subjects to test the hypothesis that stroke may be associated with diminished serotonergic functioning.

Methods
—Eight nondepressed medically stable stroke patients and 12 healthy volunteers completed a single-blind, placebo-controlled, fixed-order, crossover design challenge test with 30 mg of oral
d
-FEN. Baseline prolactin (PRL) and cortisol (CORT) and hormonal responses to
d
-FEN and placebo were measured at hourly intervals over a 4-hour period. Cardiovascular responses (pulse and blood pressure) and behavioral responses were also recorded at the same time points.

Results
—The 2 groups were comparable in demographics, body weight, plasma drug concentration, and behavioral and CORT responses. A 3-way ANOVA for repeated measures showed group differences for baseline adjusted PRL responses (change of scores from baseline). Peak PRL responses (maximal PRL change from baseline scores after treatment with
d
-FEN) in nondepressed stroke patients were attenuated compared with healthy elderly subjects, suggesting diminished serotonergic responsiveness in stroke patients.

Conclusions
—The demonstrated serotonergic hypofunctioning poststroke may contribute to the high incidence of depressive disorders in stroke patients. Serotonergic agents may have a role in augmentation of stroke recovery.
Risk Factors for Stroke and Type of Stroke in Persons With Isolated Systolic Hypertension
Authors: Davis Barry R. , Vogt Thomas , Frost Philip H. , Burlando Alfredo , Cohen Jerome , Wilson Alan , Brass Lawrence M. , Frishman William , Price Thomas , Stamler Jeremiah
Published: June 2011

Background and Purpose
—We sought to determine risk factors for stroke and stroke type in persons with isolated systolic hypertension (ISH).

Methods
—We performed proportional hazards analyses of data from the Systolic Hypertension in the Elderly Program, a double-blind, randomized, placebo-controlled trial of 4736 persons aged ≥60 years with ISH (systolic blood pressure, 160 to 219 mm Hg; diastolic blood pressure, <90 mm Hg). One treatment group received chlorthalidone (12.5 to 25 mg/d) with step-up to atenolol (25.0 to 50.0 mg/d) or reserpine (0.05 to 0.10 mg/d), if needed. The other treatment group received matching placebo. The main outcome measures were stroke, stroke or transient ischemic attack [TIA], and stroke types: ischemic (including lacunar, atherosclerotic, and embolic) and hemorrhagic.

Results
—During an average follow-up of 4.5 years, 384 strokes or TIAs and 262 strokes (including 217 ischemic, 66 lacunar, 26 atherosclerotic, and 25 embolic strokes) were documented. In multivariate analyses, placebo treatment, older age, smoking, history of diabetes, higher systolic blood pressure, lower HDL cholesterol, and ECG abnormality were significantly associated (
P
<0.05) with increased incidence of stroke or TIA, stroke, or ischemic stroke. Greater lacunar stroke risk was significantly related to placebo treatment, older age, history of diabetes (relative risk [RR]=3.03; 95% confidence interval [CI], 1.70 to 5.40), and smoking (RR=3.04; 95% CI, 1.73 to 5.37). Greater atherosclerotic and embolic stroke risk were significantly related to presence of carotid bruit (RR=5.75; 95% CI, 2.50 to 13.24) and older age (RR=1.65 per 5 years; 95% CI, 1.25 to 2.18), respectively.

Conclusions
—In older persons with ISH, history of diabetes and smoking are important risk factors for lacunar stroke, whereas carotid bruit and age are important risk factors for atherosclerotic and embolic stroke, respectively.