bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological Inhibition of the Na
+
/Ca
2+
Exchanger Enhances Depolarizations Induced by Oxygen/Glucose Deprivation but Not Responses to Excitatory Amino Acids in Rat Striatal Neurons
Authors: Calabresi Paolo , Marfia Girolama A. , Amoroso Salvatore , Pisani Antonio , Bernardi Giorgio
Published: June 2011

Background and Purpose
—Neuronal Na
+
/Ca
2+
exchanger plays a relevant role in maintaining intracellular Ca
2+
and Na
+
levels under physiological and pathological conditions. However, the role of this exchanger in excitotoxicity and ischemia-induced neuronal injury is still controversial and has never been studied in the same neuronal subtypes.

Methods
—We investigated the effects of bepridil and 3′,4′-dichlorobenzamil (DCB), 2 blockers of the Na
+
/Ca
2+
exchanger, in rat striatal spiny neurons by utilizing intracellular recordings in brain slice preparations to compare the action of these drugs on the membrane potential changes induced either by oxygen and glucose deprivation (OGD) or by excitatory amino acids (EAAs).

Results
—Bepridil (3 to 100 μmol/L) and DCB (3 to 100 μmol/L) caused a dose-dependent enhancement of the OGD-induced depolarization measured in striatal neurons. The EC
50
values for these effects were 31 μmol/L and 29 μmol/L, respectively. At these concentrations neither bepridil nor DCB altered the resting membrane properties of the recorded cells (membrane potential, input resistance, and current-voltage relationship). The effects of bepridil and DCB on the OGD-induced membrane depolarization persisted in the presence of
d
-2-amino-5-phosphonovalerate (50 μmol/L) plus 6-cyano-7-nitroquinoxaline-2,3-dione (20 μmol/L), which suggests that they were not mediated by an enhanced release of EAAs. Neither tetrodotoxin (1 μmol/L) nor nifedipine (10 μmol/L) affect the actions of these 2 blockers of the Na
+
/Ca
2+
exchanger, which indicates that voltage-dependent Na
+
channels and
l
-type Ca
2+
channels were not involved in the enhancement of the OGD-induced depolarization. Conversely, the OGD-induced membrane depolarization was not altered by 5-(
N
,
N
-hexamethylene) amiloride (1 to 3 μmol/L), an inhibitor of the Na
+
/H
+
exchanger, which suggests that this antiporter did not play a prominent role in the OGD-induced membrane depolarization recorded from striatal neurons. Bepridil (3 to 100 μmol/L) and DCB (3 to 100 μmol/L) did not modify the amplitude of the excitatory postsynaptic potentials evoked by cortical stimulation. Moreover, these blockers did not affect membrane depolarizations caused by brief applications of glutamate (0.3 to 1 mmol/L), AMPA (0.3 to 1 μmol/L), and NMDA (10 to 30 μmol/L).

Conclusions
—These results provide pharmacological evidence that the activation of the Na
+
/Ca
2+
exchanger exerts a protective role during the early phase of OGD in striatal neurons, although it does not shape the amplitude and the duration of the electrophysiological responses of these cells to EAA.
Second Harmonic Imaging In Acute Middle Cerebral Artery Infarction
Authors: Postert Thomas , Federlein Jens , Weber Sepp , Przuntek Horst , Büttner Thomas
Published: June 2011

Background
—Second harmonic imaging (SHI) is a new ultrasound technique that is able to detect microbubbles in the tissue vascular space. The aim of this pilot study was to prove that this technique may detect focal abnormalities of cerebral echo-contrast enhancement in acute hemispheric stroke.

Case Descriptions
—Two male patients (aged 72 and 64 years) were included who presented with acute onset of severe hemiparesis and no established demarcation of the ischemic area in CT scans. After bolus application of galactose-based microbubbles, axial SHI examinations in a diencephalic plane of sections were performed using the transtemporal approach. Ultrasound investigations were recorded and evaluated offline. In both individuals demarcated focal abnormalities of cerebral contrast enhancement were detectable: in patient 1 the region of the lentiform nucleus and the adjacent parts of the temporoparietal lobe was affected, and in patient 2 a large region including the lentiform nucleus and cortical white matter was involved for at least 24 hours. Follow-up CT scans demonstrated a striatocapsular infarct in patient 1 and complete MCA infarction in patient 2, correlating with the presumed ischemic area in acute ultrasound examinations. The patient with complete MCA infarction showed missing contrast enhancement in the entire hemisphere of the affected side in follow-up SHI examinations. He died of malignant space-occupying brain edema. In the patient with the striatocapsular infarction, reappearance of echo-contrast enhancement in the ischemic area was assessable after 1 week.

Conclusions
—SHI may identify focal abnormalities of cerebral echo-contrast enhancement in acute hemispheric stroke. Furthermore, this technique helps to determine size, localization, and prognosis of the ischemic region and could be useful for bedside assessment of echo-contrast agent distribution related to brain tissue perfusion.
Proteinuria Is an Independent Risk Factor for Ischemic Stroke in Non–Insulin-Dependent Diabetes Mellitus
Authors: Guerrero-Romero Fernando , Rodríguez-Morán Martha
Published: June 2011

Background and Purpose
—Proteinuria is an independent risk factor for cardiovascular disease in patients with NIDDM. The aim of this study was to assess the relationship between proteinuria and ischemic stroke in subjects with NIDDM, and to determine whether proteinuria is an independent risk factor for stroke.

Methods
—We performed a case-control study of 59 diabetic patients with first-ever ischemic stroke due to thrombotic arterial occlusion, who were considered cases, and 180 diabetic patients without stroke, matched by gender, age, and diabetes duration, as a control group. WHO criteria for verified definite or possible stroke were used to ascertain the diagnosis of stroke. For the purpose of this study proteinuria was defined as a 24-hour urinary protein excretion rate of ≥20 and <200 μg/min. Risk factors included were smoking, blood pressure, body mass index, serum total cholesterol, hyperglycemia, and proteinuria.

Results
—Subjects with stroke had higher proteinuria proportion and systolic and diastolic blood pressures. Both frequency of antihypertensive treatment and antihypertensive drugs used were similar among subjects with and without stroke. In multivariate logistic regression analysis, the ORs and 95% CIs for the variables identified as risk factors for stroke were as follows: systolic pressure (OR 3.10; 95% CI 3.01 to 4.21;
P
=0.03); diastolic pressure (OR 3.30; 95% CI 1.04 to 4.48;
P
<0.0001); fasting glucose ≥11.1 mmol (OR 1.82; 905% CI 1.4 to 3.8;
P
=0.04), HbA1c ≥9.5% (OR 1.7; 95% CI 1.3 to 5.1;
P
<0.01), and proteinuria (OR 3.23; 95% CI 1.06 to 4.36;
P
<0.0001).

Conclusions
—Our case-control study gives evidence that proteinuria is an independent risk factor for ischemic stroke in patients with NIDDM.
Clinical Application of Asymptomatic Embolic Signal Detection in Acute Stroke
Authors: Kaposzta Zoltan , Young Elaine , Bath Philip M. W. , Markus Hugh S.
Published: June 2011

Background and Purpose
—The detection of asymptomatic embolization with the use of Doppler ultrasound has a number of potential applications in patients with acute stroke. It may provide information on the stroke pathogenesis in individual cases, identify patients with continued embolization, and allow localization of the active embolic source.

Methods
—We recruited 119 patients with acute anterior circulation infarction within 72 hours of stroke onset. Transcranial Doppler recordings were possible in 100 (84.0%). Bilateral 1-hour middle cerebral artery (MCA) recordings were made and saved on digital audiotape for blinded offline analysis. When embolic signals were detected during screening of the first recording, simultaneous recording was performed from the ipsilateral MCA and common carotid artery for an additional 30 minutes. In all patients with embolic signals at screening and in matched negative controls, recordings were repeated on days 4, 7, and 14.

Results
—Embolic signals were detected in the symptomatic MCA in 16 patients (16%). They were more common in patients with carotid stenosis (
P
<0.0001), occurring in 50% of this group. They were rare in patients with cardioembolic stroke (4.5%) and were not detected in patients with lacunar stroke. In the 16 patients with embolic signals, the proportion with embolic signals fell over time (
P
=0.0025), but they were still present in a third at 2 weeks. In 10 patients, localization of the embolic source was possible by simultaneous recording from the MCA and the ipsilateral common carotid artery.

Conclusions
—Continued asymptomatic embolization is common after stroke in patients with carotid artery disease and is still present in a significant proportion at 2 weeks. The technique may identify patients at risk of further stroke for more aggressive antiplatelet therapy; this needs to be tested in large prospective studies. The technique may also allow localization of the active embolic source.
Contrast-Enhanced Transcranial Color-Coded Sonography in Acute Hemispheric Brain Infarction
Authors: Postert Thomas , Braun B. , Meves S. , Köster O. , Przuntek H. , Weber S. , Büttner T.
Published: June 2011

Purpose
—The aim of the present study was to investigate the diagnostic potential of contrast-enhanced transcranial color-coded real-time sonography (CE-TCCS) in otherwise ultrasound-refractory acute stroke patients with an ischemia in the territory of the middle cerebral artery (MCA). Furthermore, correlations of CE-TCCS findings with clinical, angiographic, and CT results were investigated.

Methods
—In 90 acute stroke patients with inadequate insonation conditions in unenhanced transcranial color-coded real-time sonography (TCCS) examinations, CE-TCCS, clinical, angiographic, and CT examinations were performed within 12 hours, 36 hours (CE-TCCS only), and 1 week after onset of clinical symptoms. A CT angiography (CTA) as reference method was available in 39 individuals. After application of a galactose-based echo-enhancing agent, the portion of conclusive ultrasound examinations of the MCA, as manifested by an MCA occlusion, decreased or increased flow velocity (FV), and symmetrical MCA FV, was evaluated. CE-TCCS findings on admission and during follow-up were correlated with infarction size as demonstrated on follow-up CT, and clinical findings were assessed by use of the European Stroke Scale.

Results
—Adequate diagnosis was achieved in 74 of 90 patients (82%) by the use of echo contrast agents. MCA occlusion or reduction of MCA FV was found in 20 and 27 patients, respectively. MCA occlusion was confirmed by CTA in 17 cases. In one individual, false-positive diagnosis of MCA occlusion was made according to ultrasound criteria. In 5 patients with MCA occlusion, vessel recanalization was observed during follow-up; 15 of 27 patients with decreased flow velocities showed normalization after the third examination that was associated with a significantly better clinical outcome (
P
<0.0001). Furthermore, MCA occlusion or decreased FV in the first 12 hours were associated with significantly larger infarctions in the MCA territory compared with normal CE-TCCS findings (
P
<0.0001).

Conclusions
—CE-TCCS enables adequate diagnosis in approximately 80% of acute hemispheric stroke patients with insufficient unenhanced TCCS examinations. It is a reliable diagnostic tool regarding MCA mainstem and branch occlusions. Because this method conveys useful information concerning cerebral tissue and clinical prognosis, it may be useful to identify those patients who benefit most from local or intra-arterial thrombolytic therapy.
Evaluation of the American Heart Association Stroke Outcome Classification
Authors: Lai Sue-Min , Duncan Pamela W.
Published: June 2011

Background and Purpose
—The purpose of this study was to evaluate the concurrent validity of the American Heart Association Stroke Outcome Classification (AHA.SOC) and compare performance of its function classification with that of the Modified Rankin Scale.

Methods
—The individuals in this study included the last 105 consecutive subjects who were part of a cohort of 459 stroke patients in the Kansas City Stroke Study. The patients were evaluated with a variety of standardized assessments at enrollment (within 14 days of stroke onset) and followed at 1, 3, and 6 months after stroke. Specifically, we examined validity of AHA.SOC by comparing its 3 domains (ie, Domain, Severe, and Function) with stroke severity. We correlated AHA.SOC-Function with scores of the Barthel Index, Lawton Instrumental Activities of Daily Living (IADL) Scale, and Medical Outcome Study 36-Item Short-Form Health Survey (SF-36) measures of physical function and mental health. Finally, we compared the discriminant ability of AHA.SOC-Function and the Modified Rankin Scale in assessing disability and handicap. These data were analyzed with the use of Spearman rank correlations and Kruskal-Wallis tests.

Results
—All 3 domains of the AHA.SOC were significantly associated with stroke severity and scores of Barthel Index, Lawton IADL, and SF-36 physical function (all
P
<0.001). Both AHA.SOC-Function and the Modified Rankin Scale discriminated well the disabilities and handicap measured by Barthel Index, Lawton IADL, and SF-36 physical function (all
P
<0.001).

Conclusions
—The AHA.SOC was able to capture impairments, disabilities, and handicap after stroke. The AHA.SOC-Function performed equally as well as the Modified Rankin Scale in assessing disabilities related to basic activities of daily living but differentiated slightly better than the Modified Rankin Scale in assessing disabilities/handicap related to instrumental activities of daily living. Neither the AHA.SOC-Function nor the Modified Rankin Scale captured differences in mental health after stroke.
Adenovirus-Mediated Kallikrein Gene Delivery Reduces Aortic Thickening and Stroke-Induced Death Rate in Dahl Salt-Sensitive Rats
Authors: Zhang Jenny J. , Chao Lee , Chao Julie
Published: June 2011

Background and Purpose
—Kallikrein gene delivery has been shown to attenuate hypertension, cardiac hypertrophy, and renal injury in hypertensive animal models. The aim of this study was to investigate the potential protective effects of kallikrein gene delivery in salt-induced stroke and cerebrovascular disorders.

Methods
—Adenovirus harboring the human tissue kallikrein gene (AdCMV-cHK) was delivered intravenously into Dahl salt-sensitive (DS) rats after 4 weeks of high salt loading, and blood pressure was monitored weekly for 9 weeks.

Results
—A single injection of AdCMV-cHK caused a significant reduction of systolic blood pressure compared with that in control rats, with or without an injection of adenovirus carrying the LacZ (control) gene (AdCMV-LacZ). A maximal blood pressure reduction of 21 mm Hg was observed 2 weeks after gene delivery. The stroke mortality rate of DS rats (AdCMV-LacZ group versus the AdCMV-cHK group) was significantly decreased: 38% versus 9% at 3 weeks and 54% versus 27% at 5 weeks after gene delivery. Kallikrein gene delivery significantly attenuated salt-induced aortic hypertrophy, as evidenced by reduced thickness of the aortic wall. Recombinant human tissue kallikrein was detected in rat serum and urine after gene transfer. Kinin-releasing activities in the brain as well as urinary kinin and cGMP levels were significantly increased in rats receiving the kallikrein gene.

Conclusions
—This is the first study to demonstrate the protective effect of kallikrein gene delivery in reducing salt-induced stroke mortality and vascular dysfunction.
Brain Natriuretic Peptide and Cerebral Vasospasm in Subarachnoid Hemorrhage
Authors: Sviri Gil E. , Feinsod Moshe , Soustiel Jean F.
Published: June 2011

Background and Purpose
—Hyponatremia has been shown in association with cerebral vasospasm (CVS) following aneurysmal subarachnoid hemorrhage (SAH). In the past few years there has been increasing evidence that brain natriuretic peptide (BNP) is responsible for natriuresis after SAH. The purpose of the present study was to investigate the relationship between BNP plasma concentrations and CVS after aneurysmal SAH.

Methods
—BNP plasma concentrations were assessed at 4 different time periods (1 to 3 days, 4 to 6 days, 7 to 9 days, and 10 to 12 days) in 19 patients with spontaneous SAH. BNP plasma levels were investigated with respect to neurological condition, SAH severity on CT, and flow velocities measured by means of transcranial Doppler .

Results
—Thirteen patients had Doppler evidence of CVS; 7 of these had nonsymptomatic CVS. In 6 patients, CVS was severe and symptomatic, with delayed ischemic lesion on CT in 5 of these. CVS was severe and symptomatic in 6 patients, and delayed ischemic lesions were revealed on CT in 5 of these. BNP levels were found to be significantly elevated in SAH patients compared with control subjects (
P
=0.024). However, in patients without CVS or with nonsymptomatic CVS, BNP concentrations decreased throughout the 4 time periods, whereas a 6-fold increase was observed in patients with severe symptomatic CVS between the first and the third periods (
P
=0.0096). A similar trend in BNP plasma levels was found in patients with severe SAH compared with those with nonvisible or moderate SAH (
P
=0.015).

Conclusions
—In conclusion, our results show that BNP plasma levels are elevated shortly after SAH, although they increase markedly during the first week in patients with symptomatic CVS. The present findings suggest that secretion of BNP secretion after spontaneous SAH may exacerbate blood flow reduction due to arterial vasospasm.
Harmonic Imaging of the Human Brain
Authors: Seidel Günter , Algermissen Christian , Christoph Arnd , Claassen Lars , Vidal-Langwasser Marion , Katzer Tobias
Published: June 2011

Background and Purpose
—Through harmonic gray-scale imaging, it is possible to analyze brain tissue perfusion with different ultrasound methods.

Methods
—In 12 healthy volunteers, 2 doses (0.5 and 1.5 mL) of Optison, a perfluoropropane-containing contrast agent, were injected intravenously and produced a strong increase of brightness in the brain parenchyma. We used harmonic imaging for quantification of ultrasound intensity in the thalamus, ipsilateral temporoparietal white matter (TPWM), and ipsilateral lateral fissure at both sides. Time-intensity curves were calculated, and peak increase (PI) of intensity and the area under the time-intensity curve (AUC) from baseline were compared.

Results
—We found a significant dose dependence of the AUC in all regions at both sides. PI only showed a significant dose dependence in the TPWM but not in the ipsilateral thalamus and lateral fissure. No side differences for AUC and PI were detected in all regions and doses used. We found a significantly higher value of the PI insonating the thalamus from the ipsilateral side compared with the contralateral side. The same result was obtained for the AUC in the left thalamus for both doses and in the right thalamus for the high dose. Using 0.5 mL for insonation of the right thalamus AUC again showed a higher value for the insonation from the ipsilateral compared with the contralateral side but failed to show statistical significance (
P
=0.08, n=12).

Conclusions
—Harmonic gray-scale imaging with Optison showed a strong enhancement effect in the brain parenchyma. A quantitative analysis of perfusion seems difficult because of the depth dependence of the effect. The most robust parameter is the AUC.
Ovariectomy Exacerbates and Estrogen Replacement Attenuates Photothrombotic Focal Ischemic Brain Injury in Rats
Authors: Fukuda Kenji , Yao Hiroshi , Ibayashi Setsuro , Nakahara Tatsuo , Uchimura Hideyuki , Fujishima Masatoshi
Published: June 2011

Background and Purpose
—We previously reported the infarct volumes in female spontaneously hypertensive rats (SHR) to be significantly smaller than those in male SHR. The purpose of the present study was to determine whether estrogen is responsible for the sex difference in ischemic vulnerability in SHR.

Methods
—In experiment 1, 1 week (short-term) or 4 weeks (long-term) after the ovariectomy (OVX), female SHR (5 months old) were randomly subjected to photothrombotic occlusion of the middle cerebral artery, and the infarct volumes were determined. In experiment 2, the rats were randomly assigned to 3 groups (ie, the sham-ovariectomized, ovariectomized, and estrogen replacement groups). In the replacement group, estradiol valerate (200 μg/kg) was subcutaneously injected once a week after the OVX. Four weeks after the OVX or sham-OVX, all rats were subjected to middle cerebral artery occlusion. Changes in regional cerebral blood flow were determined by laser-Doppler flowmetry.

Results
—In experiment 1, the infarct volume produced 1 week after the OVX was not different from that of the sham-ovariectomized group. In contrast, the infarct volume produced 4 weeks after the OVX was significantly larger than that of the sham-ovariectomized group (82.4±11.6 versus 54.5±16.0 mm
3
,
P
=0.0058). In experiment 2, estradiol replacement after the OVX was observed to attenuate the infarct volume compared with the ovariectomized group (55.6±18.8 versus 78.5±21.0 mm
3
,
P
=0.0321). The degrees of regional cerebral blood flow reduction did not differ among the sham-ovariectomized, ovariectomized, and estrogen replacement groups.

Conclusions
—Chronic estrogen depletion was thus found to increase the infarct size, which was attenuated by estradiol replacement. These findings indicate that estrogen contributes to the sex difference in ischemic vulnerability and that endogenous estrogen also has a neuroprotective effect against ischemic brain damage.
Spinal Cord Ischemia
Authors: Lang-Lazdunski Loic , Matsushita Kohji , Hirt Lorenz , Waeber Christian , Vonsattel Jean-Paul G. , Moskowitz Michael A.
Published: June 2011

Background and Purpose
—Spinal cord ischemia with resulting paraplegia is a devastating complication of thoracoabdominal aortic surgery. Experimental models of spinal cord ischemia have been developed in primate, dog, pig, rabbit, and rat with variable reproducibility, but none has been developed in mouse. Because genetically engineered mice have become important to examine the impact of specific genes in ischemic pathophysiology, we sought to develop a reproducible mouse model of spinal cord ischemia.

Methods
—C57BL/6NCrlBR mice were subjected to cross-clamping of the aortic arch, left subclavian artery, and internal mammary artery for 9 minutes (group A; n=8) or 11 minutes (group B; n=29) followed by reperfusion for 24 or 48 hours. Mean distal arterial blood pressure (left femoral artery) and lumbar (L1) spinal cord blood flow (laser-Doppler flowmetry) were measured for the duration of the procedure. The arterial blood supply of the spinal cord was visualized by intravascular perfusion of carbon black ink. We evaluated motor function in the hind limbs at 0, 1, 3, 6, and 24 hours after reperfusion using a rating scale of 0 (normal function) to 6 (total absence of movement). Spinal cord histopathology was evaluated after 24 and 48 hours of reperfusion by Luxol fast blue–hematoxylin and eosin.

Results
—The vascular anatomy of the mouse and human spinal cord appeared similar in that blood was supplied by 1 anterior and 2 posterior spinal arteries and heterosegmental radicular arteries. During combined occlusion of aortic arch and left subclavian artery, mean distal arterial blood pressure dropped to 10±5 mm Hg, and spinal cord blood flow at the L1 level decreased to 27±7% of baseline. All animals recovered from anesthesia with acute paraplegia. Animals in the 9-minute group (group A) showed steady recovery of hind limb function over the ensuing 24 hours, whereas the majority (80%) in the 11-minute group (group B) remained paralyzed with maximum deficit throughout the postoperative period. Mortality was 0% and 21% in groups A and B, respectively. Maximal ischemic damage was observed at the lower thoracic and higher lumbar spinal levels in both groups. In group A (9 minutes), tissue damage was mild, affecting predominantly dorsal horns and intermediate gray matter, whereas ventral horns were minimally involved. All mice in group B (11 minutes) showed extensive gray matter lesions particularly involving dorsal horns and intermediate areas; in ventral horns, >50% of motor neurons died. White matter lesions were present in the most severely damaged cords only.

Conclusions
—Spinal cord ischemia caused by aortic arch plus left subclavian artery cross-clamping provides a mouse model useful for the study of spinal cord injury and of potential relevance to the complications following thoracoabdominal aortic surgery in humans.
Tissue Plasminogen Activator, Plasminogen Activator Inhibitor-1, and Tissue Plasminogen Activator/Plasminogen Activator Inhibitor-1 Complex as Risk Factors for the Development of a First Stroke
Authors: Johansson Lars , Jansson Jan-Håkan , Boman Kurt , Nilsson Torbjörn K. , Stegmayr Birgitta , Hallmans Göran
Published: June 2011

Background and Purpose
—Abnormalities in the fibrinolytic system have been associated with an increased risk for stroke in a few studies. This study was designed to test whether plasma levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and tPA/PAI-1 complex could predict a first-ever stroke.

Methods
—The study was an incident case-control study nested within the Västerbotten Intervention Program and the Northern Sweden Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) cohorts. In this study 108 first-ever stroke cases were defined according to the MONICA classification, and 216 controls from the same cohort were randomly selected and matched for age, sex, sampling time, and geographic region.

Results
—Stroke occurred on average 30 months after the blood sampling date. The mean plasma concentration of tPA/PAI-1 complex was higher for the stroke cases than for the controls (3.9 versus 3.0 μg/L). In univariate regression analysis, significantly higher odds ratios were found for the tPA/PAI-1 complex as continuous variable. When divided into quartiles, the odds ratio was 2.74 for the highest quartile compared with the lowest. In the multivariate model, the tPA/PAI-1 complex remained an independent predictor for stroke. Additionally, tPA mass concentration quartiles 3 and 4 showed a significant association with all stroke as outcome. No association was found, however, for PAI-1. In subgroup analysis of cerebral hemorrhage (n=18), the mean tPA/PAI-1 complex level was higher for the cases than for the controls (4.8 versus 3.0 μg/L), and in multivariate analysis including all controls (n=216), only tPA/PAI-1 complex remained significant.

Conclusions
—This prospective study shows that tPA/PAI-1 complex, a novel fibrinolytic marker, is independently associated with the development of a first-ever stroke, especially hemorrhagic stroke. This finding supports the hypothesis that disturbances in fibrinolysis precede a cerebrovascular event.
Increased Matrix Metalloproteinase-9 Activity in Unstable Carotid Plaques
Authors: Loftus Ian M. , Naylor A. Ross , Goodall Stephen , Crowther Matthew , Jones Louise , Bell Peter R. F. , Thompson Matthew M.
Published: June 2011

Background and Purpose
—Acute disruption of atherosclerotic plaques precedes the onset of clinical syndromes, and studies have implicated a role for matrix metalloproteinases (MMPs) in this process. The aim of this study was to establish the character, level, and expression of MMPs in carotid plaques and to correlate this with clinical status, cerebral embolization, and histology.

Methods
—Plaques were obtained from 75 consecutive patients undergoing carotid endarterectomy and divided into 4 groups according to symptomatology (group 1, asymptomatic; group 2, symptomatic >6 months before surgery; group 3, symptomatic within 1 to 6 months; group 4, symptomatic within 1 month). All patients underwent preoperative and intraoperative transcranial Doppler monitoring. Plaques were subjected to histological examination and quantification of MMPs by zymography and ELISA.

Results
—The level of MMP-9 was significantly higher in group 4 (median 125.7 ng/mL for group 4, median <32 ng/mL for all other groups;
P
=0.003), with no difference in the levels of MMPs 1, 2, or 3. Furthermore, the MMP-9 concentration was significantly higher in plaques undergoing spontaneous embolization (
P
=0.019) and those with histological evidence of plaque instability (
P
<0.03). In situ hybridization demonstrated increased MMP-9 expression in highly symptomatic plaques in areas of intense inflammatory infiltrate.

Conclusions
—The concentration, production, and expression of MMP-9 is significantly higher in unstable carotid plaques. If this proves to be a causal relationship, MMP-9 may be a strong candidate for pharmacotherapy aimed at stabilizing plaques and preventing stroke.
Results in 95 Hemorrhagic Stroke Patients Included in CLASS, a Controlled Trial of Clomethiazole Versus Placebo in Acute Stroke Patients
Authors: Wahlgren N. G. , Díez-Tejedor E. , Teitelbaum J. , Arboix A. , Leys D. , Ashwood T. , Grossman E.
Published: June 2011

Background and Purpose
—Clomethiazole is a neuroprotective drug that enhances γ-aminobutyrate type A (GABA
A
) receptor activity. Its efficacy and safety were tested in the CLomethiazole Acute Stroke Study (CLASS). The protocol allowed a CT scan to be done after randomization but within 7 days of stroke onset to minimize delays before start of treatment. Ninety-five of the 1360 patients randomized were diagnosed as having intracranial hemorrhage rather than ischemic stroke. Safety results for clomethiazole compared with placebo in this group are reported.

Methods
—The study included patients with a clinical diagnosis of acute hemispheric cerebral infarction. Treatment was a 24-hour intravenous infusion of 75 mg/kg clomethiazole or placebo. Patients with intracranial hemorrhage discovered on a postrandomization CT were withdrawn from study treatment if treatment was ongoing, and all patients were followed up to 90 days.

Results
—Ninety-four patients received treatment, 47 in each group. The hemorrhage was classified as intracerebral in 89 patients (94%). Mortality at 90 days was 19.1% in the clomethiazole group and 23.4% in the placebo group. Sedation was the most common adverse event, occurring at a higher incidence in clomethiazole-treated patients (clomethiazole 53%, placebo 17%), followed by rhinitis and coughing. The incidence and pattern of serious adverse events was similar between the treatment groups. The percentage of patients reaching relative functional independence on the Barthel Index (score ≥60) at 90 days was 59.6% in the clomethiazole group and 53.2% in the placebo group.

Conclusions
—Clomethiazole appears safe to administer to hemorrhagic stroke patients compared with placebo. These results would obviate the need for a CT scan before therapy is initiated in acute stroke. The safety of clomethiazole in hemorrhagic stroke patients will be further evaluated in a prospective study that is under way in North America.
Proinflammatory Cytokines and Early Neurological Worsening in Ischemic Stroke
Authors: Vila Nicolás , Castillo José , Dávalos Antonio , Chamorro Ángel
Published: June 2011

Background and Purpose
—The mechanisms for clinical deterioration in patients with ischemic stroke are not completely understood. Several proinflammatory cytokines are released early after the onset of brain ischemia, but it is unknown whether inflammation predisposes to neurological deterioration. We assessed the implication of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in early neurological worsening in ischemic stroke.

Methods
—Two hundred thirty-one patients consecutively admitted with first-ever ischemic cerebral infarction within the first 24 hours from onset were included. Neurological worsening was defined when the Canadian Stroke Scale (CSS) score fell at least 1 point during the first 48 hours after admission. IL-6 and TNF-α were determined in plasma and cerebrospinal fluid (CSF; n=81) obtained on admission.

Results
—Eighty-three patients (35.9%) deteriorated within the first 48 hours. IL-6 in plasma (>21.5 pg/mL; OR 37.7, CI 11.9 to 118.8) or in CSF (>6.3 pg/mL; OR 13.1, CI 2.2 to 77.3) were independent factors for early clinical worsening, with multiple logistic regression. The association was statistically significant in all ischemic stroke subtypes as well as in subjects with cortical or subcortical infarctions. IL-6 in plasma was highly correlated with body temperature, glucose, fibrinogen, and infarct volume. CSF and plasma concentrations of TNF-α were also higher in patients who deteriorated, but the differences observed did not remain significant on multivariate analysis.

Conclusions
—In addition to participating in the acute-phase response that follows focal cerebral ischemia, IL-6 levels on admission are associated with early clinical deterioration. The association between IL-6 and early neurological worsening prevails without regard to the initial size, topography, or mechanism of the ischemic infarction.
Effect of Contralateral Occlusion on Long-Term Efficacy of Endarterectomy in the Asymptomatic Carotid Atherosclerosis Study (ACAS)
Authors: Baker William H. , Howard Virginia J. , Howard George , Toole James F. , Investigators for the ACAS
Published: June 2011

Background and Purpose
—The Asymptomatic Carotid Atherosclerosis Study (ACAS) established the effectiveness of prophylactic carotid endarterectomy, for patients in good health who had stenosis ≥60%, if conducted by surgeons with a surgical morbidity and mortality of <3%. This secondary analysis was performed to determine whether the presence of contralateral cervical carotid occlusion alters the efficacy of asymptomatic ipsilateral carotid endarterectomy.

Methods
—One hundred sixty-three participants who had a baseline contralateral occlusion documented by Doppler ultrasound (77 medical, 86 surgical) were compared with 1485 participants with a patent contralateral carotid artery (748 medical, 737 surgical) for the risk of a combined end point of perioperative (30-day) death or stroke or long-term (5-year) ipsilateral stroke.

Results
—For those without contralateral occlusion, surgery was associated with a 6.7% absolute reduction in the 5-year risk (95% CI, 2.1% to 11.4%), while for those with a contralateral occlusion, surgery was associated with a 2.0% absolute increase in risk (95% CI, −9.3% to 5.2%), which was a statistically significant difference in the effect of surgery (
P
=0.047). This difference is primarily attributable to low long-term risk for medically managed patients with contralateral occlusion.

Conclusions
—While this post hoc analysis should be interpreted with caution, the findings suggest that endarterectomy in asymptomatic subjects with contralateral occlusion provides no long-term benefit (and may be harmful) in preventing stroke and death. These findings were a result of the benign course of medically treated subjects.
Incident Hemorrhage Risk of Brain Arteriovenous Malformations Located in the Arterial Borderzones
Authors: Stapf C. , Mohr J. P. , Sciacca R. R. , Hartmann A. , Aagaard B. D. , Pile-Spellman J. , Mast H.
Published: June 2011

Background and Purpose
—We sought to assess the relative risk of hemorrhagic presentation of brain arteriovenous malformations (AVMs) located in the arterial borderzone territories.

Methods
—The 464 consecutive, prospectively enrolled patients from the New York AVM Databank were analyzed. AVM borderzone location was coded positive when the malformation was supplied by branches of at least 2 of the major circle of Willis arteries (anterior, middle, and/or posterior cerebral arteries). AVMs fed by branches of only 1 major pial or any other single artery served as a comparison group. Clinical presentation (diagnostic event) was categorized as (1) intracranial hemorrhage, proven by brain imaging, or (2) seizure, focal neurological deficit, headache, or other event with no signs of AVM hemorrhage on brain imaging.

Results
—In 48% (n=222) of the patients, AVMs were located in the arterial borderzone territories; in 52% (n=242) a non-borderzone location was found. Hemorrhage was the presenting symptom in 44% (n=205); 28% (n=132) presented with seizures, 11% (n=52) with headaches, 7% (n=34) with a neurological deficit, and 9% (n=41) with other or no AVM-related symptoms. The frequency of incident AVM hemorrhage was significantly lower in borderzone AVMs (27%, n=61) than in non-borderzone malformations (60%, n=144;
P
<0.001). This difference remained significant in a multivariate model controlling for age, sex, AVM size, deep venous drainage, and presence of aneurysms (odds ratio, 0.4; 95% CI, 0.25 to 0.66).

Conclusions
—Our findings suggest that borderzone location is an independent determinant for a lower risk of AVM hemorrhage at initial presentation.
Ultrasound Perfusion Imaging of the Human Brain
Authors: Wiesmann Martin , Seidel Günter
Published: June 2011

Background and Purpose
—Color-coded perfusion maps can be calculated from ultrasound harmonic gray-scale imaging data to analyze brain tissue perfusion.

Methods
—In 13 healthy volunteers, 2 doses (0.5 and 1.5 mL) of Optison, a perfluoropropane-containing ultrasound contrast agent, were injected intravenously, and they produced a strong increase in echo enhancement in the brain parenchyma. The contrast agent was injected twice for ultrasound examination of both hemispheres. A total of 24 hemispheres per dose was available for further analysis. We used harmonic imaging for quantification of echo enhancement. Color-coded perfusion maps were calculated from the ultrasound data. In 1 subject, magnetic resonance images were obtained parallel to the orientation of the ultrasound scans.

Results
—After administration of both doses of Optison, it was possible to evaluate brain tissue perfusion in all 24 hemispheres. Subtraction of precontrast images and color coding enhanced the visualization of hemispheric perfusion. The epiphyseal gland, anterior interhemispheric fissure, third ventricle, and lateral fissure can be used as reliable anatomic landmarks. Artifacts caused by abrupt changes in thickness of the temporal bone are observed as signal-void streaks oriented from the ultrasound probe toward the cerebral midline.

Conclusions
—Harmonic gray-scale imaging with Optison shows strong echo enhancement in the brain parenchyma. By calculating color-coded perfusion maps, it is possible to visualize human brain tissue perfusion at the patient’s bedside.
Prediction of Functional Outcome and In-Hospital Mortality After Admission With Oral Anticoagulant–Related Intracerebral Hemorrhage
Authors: Berwaerts Joris , Dijkhuizen Roelf S. , Robb Olive J. , Webster John
Published: June 2011

Background and Purpose
—Early survival of patients with intracerebral hemorrhage in general is known to be most strongly dependent on the Glasgow Coma Scale score on admission. The aim of this study was to examine the factors determining functional outcome and in-hospital mortality of patients admitted with an intracerebral hemorrhage related to oral anticoagulant (OAC) use.

Methods
—Correlation studies and multiple logistic regression analyses were performed on data from a retrospective series of 42 patients admitted with OAC-related intracerebral hemorrhages over a 6-year period to a tertiary care center in the north of Scotland.

Results
—The functional outcome after an OAC-related intracerebral hemorrhage was dependent on maximum diameter of hematoma on CT scan (
R
=−0.72,
P
<0.001) and international normalized ratio (INR) (
R
=−0.35,
P
=0.024). Hematoma diameter and INR were not themselves strongly correlated (
R
=0.31,
P
=0.099). In-hospital mortality can be predicted by the Glasgow Coma Scale score alone (
R
2
=0.36, overall predictive accuracy 68%) but more accurately by a logistic regression model including hematoma diameter and CT signs of cerebrovascular disease (
R
2
=0.70, predictive accuracy 83%).

Conclusions
—Neither functional outcome nor in-hospital mortality appears to be strongly dependent on INR measured on admission. CT scan, however, provides essential information and allows accurate predictions about the short-term outcome of OAC-related intracerebral hemorrhages.
Safety and Cost of Low-Molecular-Weight Heparin as Bridging Anticoagulant Therapy in Subacute Cerebral Ischemia
Authors: Kalafut Mary A. , Gandhi Rohina , Kidwell Chelsea S. , Saver Jeffrey L.
Published: June 2011

Background and Purpose
—Anticoagulation with intravenous unfractionated heparin (IVUH) while awaiting therapeutic oral anticoagulant levels is a common practice in patients with acute and subacute cerebral ischemia. A promising alternative strategy is to use bridging subcutaneous low-molecular-weight heparin (LMWH), which may have a favorable risk-benefit profile compared with IVUH and may permit earlier discharge with completion of transition to warfarin therapy as an outpatient.

Methods
—A LMWH, enoxaparin 1 mg/kg BID, was used as bridging anticoagulation therapy in 24 consecutive patients admitted to a university stroke center in whom the treatment plan included transition from acute to chronic anticoagulation. The LMWH group was contrasted with the preceding 24 patients transitioned to warfarin with IVUH at the same center.

Results
—Fewer patients in the LMWH bridging therapy group experienced neurological worsening than in the IVUH bridging therapy group (2/24 versus 8/24;
P
=0.033). Fewer total adverse events were noted in the LMWH group than in the IVUH cohort (3 versus 20;
P
=0.002). Fifteen of the 24 LMWH patients (62.5%) were discharged while still receiving LMWH and completed transition to warfarin as outpatients, receiving an average of 3.6 days of outpatient transitional therapy. In these 15 patients, use of LMWH was associated with a net savings of $2197 per patient.

Conclusions
—In this pilot cohort with subacute cerebral ischemia, bridging LMWH appeared to be safer than bridging IVUH and was associated with reduced hospital stay and reduced total cost of care.
Resource Utilization and Costs of Stroke Unit Care Integrated in a Care Continuum: A 1-Year Controlled, Prospective, Randomized Study in Elderly Patients
Authors: Claesson Lisbeth , Gosman-Hedström Gunilla , Johannesson Magnus , Fagerberg Björn , Blomstrand Christian
Published: June 2011

Background and Purpose
—The aim of the present study was to examine resource utilization during a 12-month period after acute stroke in elderly patients randomized to care in an acute stroke unit integrated with a care continuum compared with conventional care in general medical wards. A secondary aim was to describe costs related to the severity of stroke.

Methods
—Two hundred forty-nine consecutive patients aged ≥70 years with acute stroke within 7 days before admission, living in their own homes in Göteborg, Sweden, without recognized need of care were randomized to 2 groups: 166 patients were assigned to nonintensive stroke unit care with a care continuum, and 83 patients were assigned to conventional care. There was no difference in mortality or the proportion of patients living at home after 1 year. Main outcomes were costs from inpatient care, outpatient care, and informal care.

Results
—Mean annual cost per patient was 170 000 Swedish crowns (SEK) (equivalent to $25 373) and 191 000 SEK ($28 507) in the stroke unit and the general medical ward groups, respectively (
P
=NS). Seventy percent of the total cost was for inpatient care, and 30% was for outpatient and informal care. For patients with mild, moderate, and severe stroke, the mean annual costs per patient were 107 000 SEK ($15 970), 263 000 SEK ($39 254), and 220 000 SEK ($32 836), respectively (
P
<0.001). There was no statistical difference in age or nonstroke diagnosis.

Conclusions
—The total costs the first year did not differ significantly between the treatment groups in this prospective study. The total annual cost per patient showed a very large variation, which was related to stroke severity at onset and not to age or nonstroke diagnoses. Costs other than those for hospital care constituted a substantial fraction of total costs and must be taken into account when organizing the management of stroke patients. The high variability in costs necessitates a larger study to assess long-term cost effectiveness.
Prehospital and Emergency Department Delays After Acute Stroke
Authors: Morris Dexter L. , Rosamond Wayne , Madden Kenneth , Schultz Carol , Hamilton Scott
Published: June 2011

Background and Purpose
—Patient delays in seeking treatment for stroke and delays within the Emergency Department (ED) are major factors in the lack of use of thrombolytic therapy for stroke. The Genentech Stroke Presentation Survey was a multicentered prospective registry of patients with acute stroke. The study was designed to characterize prehospital delays and delays within the ED.

Methods
—Patients with stroke symptoms presenting to 48 EDs participating in a clinical trial of acute stroke therapy were enrolled prospectively. A 1-page data form was completed from patient interviews and medical records.

Results
—A total of 1207 subjects were entered into the study. Ninety-four percent of the 721 subjects with complete data had a diagnosis of stroke or transient ischemic attack, 13% were black, 50% were female, and 67% were aged >65 years. The median time from symptom onset to ED arrival was 2.6 (interquartile range 1.2 to 6.3) hours. The median time from ED arrival until CT scan completion was 1.1 (0.7 to 1.8) hours, and the total delay time (symptom onset until CT scan completion) had a median of 4.0 (2.3 to 8.3) hours. Patients who arrived by emergency medical services had significantly shorter prehospital delay times and times to CT scan. Age, race, sex, and educational level did not appear to affect prehospital delay times.

Conclusions
—Despite its limitations, this large geographically diverse study strongly suggests that the use of emergency medical services is an important modifiable determinant of delay time for the treatment of acute stroke.
Clinical Meaning of the Stroke-Adapted Sickness Impact Profile–30 and the Sickness Impact Profile–136
Authors: van Straten A. , de Haan R.J. , Limburg M. , van den Bos G.A.M.
Published: June 2011

Background and Purpose
—Handicap or health-related quality of life (HRQL) measures are seldom used in stroke trials, although the importance of these measures has been stressed frequently. We studied the clinical meaning of the Stroke-Adapted Sickness Impact Profile–30 (SA-SIP30) and the original SIP136 for use in stroke research.

Methods
—We included 418 patients who had had a stroke 6 months earlier. We studied the associations between the SA-SIP30 and SIP136 scores versus other frequently used outcome measures from the International Classification of Impairments, Disabilities, and Handicaps (ICIDH) (Barthel Index, Rankin Scale) and the HRQL model (health perception items, Euroqol). To interpret the continuous SA-SIP30 and SIP136 scores, we used receiver operating characteristic curve analysis with the aforementioned measures as external criteria.

Results
—The psychosocial dimension scores of both SIP versions remained largely unexplained. The physical dimension and total scores of both SIP versions were mainly associated with the disability measures derived from the ICIDH model, as well as with the physical HRQL domains. Most patients with an SA-SIP30 total score >33 or an SIP136 total score >22 had poor health profiles. There were no major differences between the SA-SIP30 and the SIP136, although the SA-SIP30 scores were less skewed toward the healthier outcomes than the SIP136.

Conclusions
—Our study showed that (1) both SIP total scores primarily represent aspects of physical functioning and not HRQL; (2) both SIP versions provide more clinical information than the frequently used disability measures; and (3) the SA-SIP30 should be preferred over the SIP136.