bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased IL-1β, IL-8, and IL-17 mRNA Expression in Blood Mononuclear Cells Observed in a Prospective Ischemic Stroke Study
Authors: Kostulas Nikolaos , Pelidou Sigliti Henrietta , Kivisäkk Pia , Kostulas Vasilios , Link Hans
Published: June 2011

Background and Purpose
—Ischemic brain injury secondary to arterial occlusion is characterized by acute local inflammation, which involves accumulation of polymorphonuclear neutrophils (PMN). Factors that influence the recruitment of PMN could represent new therapeutic targets in acute stroke. In this prospective study we evaluated numbers of peripheral blood mononuclear cells (PBMC) expressing mRNA for interleukin (IL)-1β, IL-8, and IL-17 and macrophage inflammatory protein-1α (MIP-1α) after ischemic stroke.

Methods
—Peripheral blood was obtained on days 1 to 3, 4 to 10, and 20 to 31 after onset of symptoms. In situ hybridization with radiolabeled synthetic oligonucleotide probes was adopted to measure cytokine mRNA expression in PBMC. Plasma and cerebrospinal fluid levels of IL-8 were measured by an enzyme-linked immunosorbent assay.

Results
—Most patients with ischemic stroke had clearly elevated numbers of IL-1β, IL-8, and IL-17 mRNA expressing PBMC 1 to 3 days after onset of symptoms compared with healthy individuals (
P
<0.0001 for all comparisons). At follow-up after 20 to 31 days, numbers of IL-8 mRNA expressing PBMC were lower than during the acute stage (
P
<0.001), but only IL-1β and IL-17 mRNA expression had returned to the level of the healthy individuals. Numbers of MIP-1α mRNA expressing PBMC did not differ between patients with ischemic stroke and healthy individuals at any time point. A correlation was observed between numbers of IL-1β, IL-8, and IL-17 mRNA expressing PBMC and the degree of neurological impairment as measured by the Scandinavian Stroke Scale 1 to 3 days after onset of symptoms (
r
=0.5;
P
<0.01 for all correlations).

Conclusions
—A longitudinal study of patients with ischemic stroke revealed systemic increases of levels of IL-1β, IL-8, and IL-17 that correlated with Scandinavian Stroke Scale scores. IL-8 levels were further increased in cerebrospinal fluid.
Chronic Estrogen Treatment Increases Levels of Endothelial Nitric Oxide Synthase Protein in Rat Cerebral Microvessels
Authors: McNeill Anne Marie , Kim Nancy , Duckles Sue P. , Krause Diana N.
Published: June 2011

Background and Purpose
—A number of studies indicate that the female gonadal hormone, estrogen, confers protection against cerebrovascular disorders such as stroke. One postulated mechanism for these effects of estrogen is an action on the enzyme endothelial nitric oxide synthase (eNOS), which produces the vasodilatory molecule NO. We have investigated the hypothesis that estrogen increases expression of eNOS in cerebral microvessels of male and female rats.

Methods
—We measured levels of eNOS protein by Western blot in cerebral microvessels isolated from 7 groups of animals: females, ovariectomized females, ovariectomized females treated with estrogen, males, castrated males, castrated males treated with estrogen, and castrated males treated with testosterone.

Results
—Ovariectomized female rats treated with estrogen had 17.4-fold greater levels of eNOS protein in cerebral microvessels than ovariectomized females, and intact females had 16.6-fold greater levels than ovariectomized females (
P
<0.01). In intact females, cerebral microvessel eNOS protein levels were 9.2-fold higher than those of intact males (
P
<0.05). Levels of eNOS protein in castrated males, castrated males treated with testosterone, and males were not different from each other. Estrogen treatment of castrated animals resulted in an 18.8-fold increase in cerebral microvessel eNOS protein (
P
<0.05).

Conclusions
—Chronic estrogen treatment increases levels of eNOS protein in cerebral microvessels of male and female rats. This increase in eNOS protein correlates with our previous functional findings indicating that estrogen exposure increases NO modulation of cerebrovascular reactivity in both male and female animals. Upregulation of eNOS expression may contribute to the neuroprotective effect of estrogen.
Expanding the Window for Thrombolytic Therapy in Acute Stroke
Authors: Albers Gregory W.
Published: June 2011

Background
—Effective therapy was not available for treatment of acute stroke until 1995, when tissue plasminogen activator (tPA) was shown to improve neurological and functional outcome in stroke patients who were treated within 3 hours of symptom onset.

Summary of Review
—Currently, many patients do not qualify for tPA therapy because they present for evaluation beyond 3 hours after stroke onset. Attempts to expand the treatment window to 6 hours, using CT to select patients, have failed. Use of early MR imaging may provide significant advantages over CT for identification of patients who are likely to benefit from thrombolytic therapy because (1) the early perfusion-weighted imaging (PWI) lesion estimates the region of acute dysfunctional brain tissue, whereas the acute diffusion-weighted imaging (DWI) lesion appears to correspond to the core of the early infarction; (2) the mismatch between the acute PWI lesion and the smaller DWI lesion represents potentially salvageable brain tissue (an estimate of the ischemic penumbra); and (3) in patients with a PWI/DWI mismatch, early reperfusion is often associated with substantial clinical improvement and reversal or reduction of DWI lesion growth.

Conclusions
—Clinical trials that use new MRI techniques to screen patients may be able to identify a subset of acute stroke patients who are ideal candidates for thrombolytic therapy even beyond 3 hours after stroke onset.
Risk Factors for Early Death in Acute Ischemic Stroke and Intracerebral Hemorrhage
Authors: Wong K. S.
Published: June 2011

Background and Purpose
—In Asia, there has been no international study to investigate the risk factors for early death in patients with ischemic stroke and intracerebral hemorrhage.

Methods
—We conducted a prospective study of consecutive patients with acute stroke who were admitted to 36 participating hospitals in China, India, Indonesia, Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. With the use of a simple identical data sheet, we recorded the demographics and cardiovascular risk factors of each patient. Early death was defined as death on discharge from the acute hospital.

Results
—We enrolled 2403 patients with ischemic stroke and 783 patients with intracerebral hemorrhage. Among patients with ischemic stroke, previous use of antiplatelet drugs (adjusted odds ratio [OR] 0.53; 95% confidence interval [CI] 0.30 to 0.95) and relatively young age group 56 to 75 years (OR 0.65; 95% CI 0.42 to 1.00) were protective factors; atrial fibrillation (OR 2.23; 95% CI 1.40 to 3.57), ischemic heart disease (OR 2.03; 95% CI 1.37 to 3.05), diabetes (OR 1.52; 95% CI 1.04 to 2.22), and ex-smoker status (OR 2.18; 95% CI 1.18 to 4.05) were risk factors for early death. Among patients with intracerebral hemorrhage, hypertension (OR 0.56; 95% CI 0.38 to 0.82) and young age group 56 to 75 years old (OR 0.55; 95% CI 0.34 to 0.87) were associated with lower death rate, whereas diabetes (OR 1.74; 95% CI 1.01 to 2.98) was a risk factor for early death.

Conclusions
—In Asian patients with stroke, previous use of antiplatelet drugs nearly halved the risk of early death in patients with ischemic stroke, whereas atrial fibrillation, ischemic heart disease, diabetes, and ex-smoker status were risk factors for early death. Among patients with intracerebral hemorrhage, diabetes was associated with early death, whereas young age group and hypertension were associated with lower death rates, though no clear explanation for the hypertension association could be discerned from the data available.
Cortical Language Activation in Stroke Patients Recovering From Aphasia With Functional MRI
Authors: Cao Yue , Vikingstad Eric M. , George K. Paige , Johnson Alex F. , Welch K. M. A.
Published: June 2011

Background and Purpose
—Two mechanisms for recovery from aphasia, repair of damaged language networks and activation of compensatory areas, have been proposed. In this study, we investigated whether both mechanisms or one instead of the other take place in the brain of recovered aphasic patients .

Methods
—Using blood oxygenation level–dependent functional MRI (fMRI), we studied cortical language networks during lexical-semantic processing tasks in 7 right-handed aphasic patients at least 5 months after the onset of left-hemisphere stroke and had regained substantial language functions since then.

Results
—We found that in the recovered aphasic patient group, functional language activity significantly increased in the right hemisphere and nonsignificantly decreased in the left hemisphere compared with that in the normal group. Bilateral language networks resulted from partial restitution of damaged functions in the left hemisphere and activation of compensated (or recruited) areas in the right hemisphere. Failure to restore any language function in the left hemisphere led to predominantly right hemispheric networks in some individuals. However, better language recovery, at least for lexical-semantic processing, was observed in individuals who had bilateral rather than right hemisphere–predominant networks.

Conclusions
—The results indicate that the restoration of left-hemisphere language networks is associated with better recovery and inversely related to activity in the compensated or recruited areas of the right hemisphere.
Significant Reductions in Length of Stay After Carotid Endarterectomy Can Be Safely Accomplished Without Modifying Either Anesthetic Technique or Postoperative ICU Monitoring
Authors: Angevine Peter D. , Choudhri Tanvir F. , Huang Judy , Quest Donald O. , Solomon Robert A. , Mohr J. P. , Heyer E. J. , Connolly E. Sander
Published: June 2011

Background and Purpose
—We sought to determine whether postoperative length of stay (LOS) and resource utilization could be safely reduced without changing our uniform protocol of performing carotid endarterectomy (CEA) under general anesthesia with postoperative intensive care unit monitoring.

Methods
—We retrospectively reviewed the hospital records of 421 consecutive CEA operations performed during a 3-year period of transition in discharge policy to determine LOS, complications, and resource utilization. We divided operated patients into 3 cohorts: cohort I patients were operated on before a stay reduction policy was instituted (1995, n=171); cohort II patients were operated on after the institution of a single-day-stay policy for selected patients (January to August 1996, n=95); and cohort III patients were operated on after the institution of a universal single-day-stay policy (September 1996 to December 1997, n=155).

Results—
While significant in-hospital complications leading to increased LOS remained essentially unchanged over time (cohort I: 4.0%; II: 6.3%; III: 3.9%;
P
=NS), the mean postoperative LOS decreased from 2.6±0.3 days in cohort I to 1.6±0.1 days in cohort III (
P
<0.0001). The median postoperative LOS also decreased from 2 days to 1 day from cohort I to III, with 70% of patients discharged after 1 day in cohort III compared with only 32% for cohort I (
P
<0.0001). In addition, the total number of laboratory studies ordered decreased from 8.0±0.8 per patient in cohort I to 6.4±0.5 in cohort III (
P
<0.01).

Conclusions
—A uniform policy of discharge home from the intensive care unit on postoperative day 1 following CEA under general anesthesia can reduce LOS and decrease resource utilization without compromising care.
Mild Hypothermia Improves Recovery of Cortical Extracellular Potassium Ion Activity and Excitability After Middle Cerebral Artery Occlusion in the Rat
Authors: Sick Thomas J. , Xu Guangping , Pérez-Pinzón Miguel A.
Published: June 2011

Background and Purpose
—Mild brain hypothermia significantly alleviates damage after focal ischemia, although the mechanism of this protection remains poorly defined. In the present study, we tested the hypothesis that mild hypothermia would protect cortex from early deterioration of ion homeostasis and loss of excitability associated with reperfusion after focal ischemia.

Methods
—Cortical extracellular potassium ion activity ([K
+
]
o
) and the response of [K
+
]
o
to direct cortical stimulation was measured both in the ischemic core and in the ischemic penumbra of normothermic and mildly hypothermic (31.5°C to 32°C) rats after distal middle cerebral artery occlusion (MCAO) and reperfusion.

Results
—The response of [K
+
]
o
during MCAO was similar in normothermic and hypothermic animals. However, within 1 hour of reperfusion, [K
+
]
o
in the ischemic core region of normothermic animals showed incomplete recovery and was refractory to direct cortical stimulation. [K
+
]
o
in hypothermic animals returned to preischemic levels on reperfusion and continued to respond to direct cortical stimulation. Mild hypothermia prevented extensive infarction 24 hours after transient MCAO.

Conclusions
—The data suggest that transient focal ischemia is accompanied by early disturbances of potassium ion homeostasis during reperfusion, which are accompanied by loss of excitability and which may contribute ultimately to cortical infarction.
Early Decrease of XRCC1, a DNA Base Excision Repair Protein, May Contribute to DNA Fragmentation After Transient Focal Cerebral Ischemia in Mice
Authors: Fujimura Miki , Morita-Fujimura Yuiko , Sugawara Taku , Chan Pak H.
Published: June 2011

Background and Purpose
—DNA damage and the DNA repair mechanism are known to be involved in ischemia/reperfusion injury in the brain. The x-ray repair cross-complementing group 1 (XRCC1) protein plays a central role in the DNA base excision repair pathway by interacting with DNA ligase III and DNA polymerase β. The present study examined the protein expression of XRCC1 and DNA fragmentation before and after transient focal cerebral ischemia (FCI).

Methods
—Adult male CD-1 mice were subjected to 60 minutes of FCI by intraluminal blockade of the middle cerebral artery. XRCC1 protein expression was analyzed by immunohistochemistry and Western blot analysis. DNA damage was evaluated by gel electrophoresis and terminal deoxynucleotidyl transferase–mediated uridine 5′-triphosphate-biotin nick end-labeling (TUNEL). The spatial relationship between XRCC1 expression and DNA damage was examined by double staining with XRCC1 and TUNEL after FCI.

Results
—Immunohistochemistry showed the nuclear expression of XRCC1 in all regions of the control brains and that it was predominant in the hippocampus. The XRCC1 level was markedly reduced in the caudate putamen at 10 minutes, further decreased in the entire middle cerebral artery territory at 1 hour, and remained reduced until 4 and 24 hours after FCI. Western blot analysis of the normal control brain showed a characteristic band of 70 kDa, which decreased after FCI. A significant amount of DNA fragmentation was detected by DNA gel electrophoresis 24 hours but not 4 hours after FCI. Double staining showed that the neurons that lost XRCC1 immunoreactivity became TUNEL positive.

Conclusions
—These results suggest that the early decrease of XRCC1 and the failure of the DNA repair mechanism may contribute, at least in part, to DNA fragmentation after FCI.
Autoantibodies Against Oxidatively Modified LDL Do Not Constitute a Risk Factor for Stroke
Authors: Ahmed Ejaz , Trifunovic Jasmina , Stegmayr Birgitta , Hallmans Göran , Lefvert Ann Kari
Published: June 2011

Background and Purpose
—Autoantibodies against oxidatively modified LDL have been shown to be associated with atherosclerosis. Their possible pathogenic role is not yet fully understood, and earlier published data are inconsistent. In this prospective study, we have investigated the association of these antibodies with future stroke.

Methods
—A prospective case-control study in which 44 725 men and women from the World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project and the Västerbotten Intervention Program (VIP) were enrolled and followed from January 1, 1985, to August 31, 1996. One hundred nineteen cases of stroke (male 75, female 44) were noted and compared with 233 age- and sex-matched controls from the same population. Antibodies against oxidatively modified LDL (copper-oxidized LDL and malonaldehyde [MDA]-LDL) were analyzed by ELISA.

Results
—There was no difference in the levels or in the prevalence of IgG, IgA, and IgM autoantibodies against copper-oxidized LDL or MDA-LDL between patients and controls. Risk ratios for these antibodies, when adjusted for diabetes mellitus, hypertension, and smoking habits, did not confer a risk of stroke. Serum triglycerides (1.7 versus 1.4 mmol/L,
P
=0.01), fasting blood sugar, and systolic and diastolic blood pressures were significantly higher in the patient group than in the control group, as was the prevalence of hypertension (51.8% versus 27.4%,
P
<0.0001) and diabetes mellitus (9.6% versus 0.8%,
P
<0.001).

Conclusions
—Autoantibodies against oxidatively modified LDL do not constitute a risk factor for stroke in an adult population.
Markers of Thrombin and Platelet Activity in Patients With Atrial Fibrillation
Authors: Feinberg William M. , Pearce Lesly A. , Hart Robert G. , Cushman Mary , Cornell Elaine S. , Lip Gregory Y.H. , Bovill Edwin G.
Published: June 2011

Background and Purpose
—Markers of thrombin generation and platelet activation are often elevated in patients with nonvalvular atrial fibrillation, but it is unclear whether such markers usefully predict stroke. Therefore, we undertook the present study to assess the relationship between prothrombin fragment F1.2 (F1.2), β-thromboglobulin (BTG), fibrinogen, and the factor V Leiden mutation with stroke in atrial fibrillation.

Methods
—Specimens were obtained from 1531 participants in the Stroke Prevention in Atrial Fibrillation III study. The results were correlated with patient features, antithrombotic therapy, and subsequent thromboembolism (ischemic stroke and systemic embolism) by multivariate analysis.

Results
—Increased F1.2 levels were associated with age (
P
<0.001), female sex (
P
<0.001), systolic blood pressure (
P
=0.006), and heart failure (
P
=0.001). F1.2 were not affected by aspirin use and were not associated with thromboembolism after adjustment for age (
P
=0.18). BTG levels were higher with advanced age (
P
=0.006), coronary artery disease (
P
=0.05), carotid disease (
P
=0.005), and heart failure (
P
<0.001), lower in regular alcohol users (
P
=0.05), and not significantly associated with thromboembolism. Fibrinogen levels were not significantly related to thromboembolism but were associated with elevated BTG levels (
P
<0.001). The factor V Leiden mutation was not associated with thromboembolism (relative risk 0.5, 95% CI 0.1 to 3.8).

Conclusions
—Elevated F1.2 levels were associated with clinical risk factors for stroke in atrial fibrillation, whereas increased BTG levels were linked to manifestations of atherosclerosis. In this large cohort of patients with atrial fibrillation who were receiving aspirin, F1.2, BTG, fibrinogen, and factor V Leiden were not independent, clinically useful predictors of stroke.
Measurement of Hemostatic Indexes in Conjunction With Transcranial Doppler Sonography in Patients With Ventricular Assist Devices
Authors: Wilhelm Carl R. , Ristich Julianne , Knepper Laurie E. , Holubkov Richard , Wisniewski Stephen R. , Kormos Robert L. , Wagner William R.
Published: June 2011

Background and Purpose
—Clinical thromboembolism (TE) remains an impediment to the chronic application of ventricular assist devices (VADs). Microembolic signals (MES) have been detected by transcranial Doppler ultrasound (TCD) in patients with VADs, although their origin and relation to TE remain undefined. We have investigated the hypothesis that hemostatic alterations are related to MES and that MES are associated with TE in a group of 27 VAD patients.

Methods
—Indexes of coagulation, fibrinolysis, and cellular activation and aggregation were measured before and during the VAD implantation period in conjunction with TCD. Groups were defined on the basis of presence of MES, degree of MES showering, and incidence of TE.

Results
—MES were observed in 67 (58%) of 115 of individual postoperative TCD measurements and in 21 (78%) of 27 patients. Of patients with TE, 10 (83%) of 12 had detectable MES compared with 11 (73%) of 15 patients without TE (
P
=0.66). MES were significantly associated with elevated thrombin generation during the implantation period, as reflected by plasma prothrombin fragment F1.2. Elevations in indexes of coagulation, platelet activation, and fibrinolysis relative to normal control subjects were found for patients with VADs with and without detected MES.

Conclusions
—Although no significant relation between MES and TE in VAD patients was found, the data support the hypothesis that MES are related to increased hemostatic activity in this patient group despite aggressive anticoagulant therapy.
Outcome After Endovascular Treatment of Hunt and Hess Grade IV or V Aneurysms
Authors: Kremer Christine , Groden Christoph , Hansen Hans Christian , Grzyska Ulrich , Zeumer Hermann
Published: June 2011

Background and Purpose
—The most common cause of poor treatment outcome in patients suffering aneurysmal subarachnoid hemorrhage is cerebral vasospasm, especially in cases of poor Hunt and Hess grades (IV and V). A further prognostic factor in surgically treated patients is aneurysm localization. The aim of the present retrospective study is to compare the endovascular treatment outcome in such poor-grade patients according to aneurysm localization in either the anterior (AC) or posterior (PC) circulation.

Methods
—Forty poor-grade patients admitted between 1993 and July 1998 were treated by endovascular approach within 23 days after aneurysm rupture. Eighteen had aneurysms in the AC, 22 in the PC. Mean treatment delay was 4 days after rupture and median, 2 days. One patient showed multiple aneurysms. In 36 cases, aneurysms were occluded by Guglielmi detachable coils; in 4 cases, by parent vessel balloon occlusion.

Results
—The incidence of delayed ischemic neurological dysfunction or cerebral infarct due to vasospasm did not differ significantly between the AC and PC groups. Two procedure-related complications with clinical effect were observed in each group. At 6 months’ follow-up, the result was good in 5 patients and poor in 13 in the AC group and good in 11 patients and poor in 11 in the PC group.

Conclusions
—Given comparable incidence of vasospasm in poor-grade patients, a tendency toward better treatment outcome was found in patients with aneurysms in the posterior circulation (χ
2
=2.04;
P
=0.15) than in the anterior circulation. Endovascular therapy for poor-grade patients is recommended, as are further studies to determine treatment differences.
Clinical Severity in CADASIL Related to Ultrastructural Damage in White Matter
Authors: Chabriat H. , Pappata S. , Poupon C. , Clark C. A. , Vahedi K. , Poupon F. , Mangin J. F. , Pachot-Clouard M. , Jobert A. , Le Bihan D. , Bousser M.-G.
Published: June 2011

Background and Purpose
—CADASIL is a newly recognized cause of subcortical ischemic strokes that progressively leads to dementia associated with pseudobulbar palsy and severe motor disability. This deleterious progression and the severity of clinical presentation are widely variable among affected subjects. The exact role played by MRI white-matter abnormalities, a hallmark of the disease, in the severity of the clinical phenotype remains poorly understood.

Methods
—To address this issue, we used diffusion tensor imaging (DTI), a new MRI technique highly sensitive to white-matter microstructural changes, in 16 symptomatic patients and 10 age-matched controls. Mean diffusivity and anisotropy of diffusion were measured within hyperintensities identified on T2-weighted images (T2WI) and outside these lesions on 4 slices at the level of centrum semiovale.

Results
—We found a 60% increase of water mean diffusivity and a parallel loss of diffusion anisotropy in hyperintensities identified on T2WI. The same pattern of diffusion changes, but of lesser intensity, was found in the normal-appearing white matter on T2WI. Mean diffusivity in regions with increased signal on T2WI was higher in patients with severe clinical disability compared with those with no or mild deficit (1.33±0.11 versus 1.13±0.11 10
−3
mm
2
/s,
P
<0.01). Furthermore, diffusion measured within T2 hyperintensities correlated with both the Mini-Mental State Examination and Rankin scale scores. In patients with a severe clinical status, the increase of water diffusion in these regions exceeded 70% in comparison with values obtained in the normal white matter in control subjects.

Conclusions
—These results indicate that DTI is able to detect important ultrastructural changes in regions with increased signal on T2WI and within the normal-appearing white matter in CADASIL. The diffusion changes might be related to both neuronal loss and demyelination. The degree of the underlying ultrastructural alterations is related to the severity of the clinical status with a possible threshold level of white-matter damage above which severe neurological impairment may occur in this disease. DTI appears to be a promising technique for monitoring disease progression in CADASIL.
Primary Somatosensory Cortex Activation Is Not Altered in Patients With Ventroposterior Thalamic Lesions
Authors: Remy Philippe , Zilbovicius Mônica , Cesaro Pierre , Amarenco Pierre , Degos Jean-Denis , Samson Yves
Published: June 2011

Background and Purpose
—We know remarkably little about the mechanisms underlying cortical activation. Such mechanisms might be better understood by studying the effect of well-localized lesions on the cortical activations in simple paradigms.

Methods
—We used H
2
15
O and positron emission tomography to measure regional cerebral blood flow (rCBF) at rest and during hand vibration in 7 patients with unilateral thalamic lesion involving the ventroposterior (VP) somatosensory thalamic relay nuclei. We compared the results with those obtained in 6 patients with thalamic lesions sparing the VP nuclei and 6 healthy controls.

Results
—The patients with VP lesions had a selective hypoperfusion at rest in the ipsilesional primary sensorimotor cortex (SM1). This hypoperfusion was significantly correlated with the degree of contralateral somatosensory deficit. This abnormality may reflect the deafferentation of SM1 from its somatosensory thalamic input. Despite this deafferentation, the ipsilesional SM1 was normally activated by the vibration of the hypesthetic hand.

Conclusions
—The fact that a lesion of the somatosensory thalamic relay nuclei alters the rCBF at rest in SM1 but not its activation by hand vibration indicates that the mechanism of cortical activation is complex, even in the case of simple sensory stimulation. In addition, a dissociation may occur between obvious neurological deficits and apparently normal activation patterns, which suggests that activation studies should be interpreted cautiously in patients with focal brain lesions.
Association Between Large Aortic Arch Atheromas and High-Intensity Transient Signals in Elderly Stroke Patients
Authors: Rundek Tanja , Di Tullio Marco R. , Sciacca Robert R. , Titova Inna V. , Mohr Jay P. , Homma Shunichi , Sacco Ralph L.
Published: June 2011

Background and Purpose
—Aortic arch atheromas (AAs) have been shown to be a risk factor for ischemic stroke (IS) in the elderly because of their potential for cerebral embolization. However, the association between AAs and the presence of cerebral microemboli has not been clearly established. The aim of this study was to determine whether large AAs are associated with an increased frequency of high-intensity transient signals (HITS) in elderly patients with IS.

Methods
—We performed bitemporal simultaneous HITS monitoring of both middle cerebral arteries in 62 consecutive elderly patients with acute IS (mean age 72.5±8.8 years, 65% men). In 16 patients, one or both temporal windows were inadequate; therefore, the analysis of HITS was performed in the remaining 46 patients. All patients underwent omniplane transesophageal echocardiography (TEE), and they had no significant extracranial or intracranial artery disease and no cardiac prosthetic valves. Large AA was defined as ≥4 mm in thickness. Complex AA was defined as ulcerated or mobile, regardless of plaque thickness. HITS monitoring was performed within 24 hours of TEE and analyzed by an experienced neurologist-sonographer blinded to TEE findings. A 9-dB threshold was chosen to discriminate HITS from background Doppler signal. The HITS counts in the left and in the right middle cerebral arteries were added and reported as a total number of HITS in 30 minutes.

Results
—HITS were detected in 14 (78%) of 18 patients with large AAs versus 8 (29%) of 28 patients with no or small AAs (odds ratio [OR] 8.8, 95% CI 2.2 to 34.8;
P
=0.001). The association was also present in 27 patients with no other cardiac embolic sources, such as atrial fibrillation, patent foramen ovale, spontaneous echo contrast, and thrombus (7 of 10 patients with large AAs versus 3 of 17 patients with small or no AA; OR 10.9, 95% CI 1.7 to 68.5;
P
=0.013). Complex AAs were associated with a higher frequency of HITS than were noncomplex AAs (6 of 6 patients with complex AAs versus 15 of 39 patients with noncomplex AAs; OR 2.6, 95% CI 1.7 to 3.9;
P
=0.005).

Conclusions
—HITS are significantly associated with large AAs in elderly stroke patients. This observation may support the causal role of large AAs in IS.
Reference Values for Vertebral Artery Flow Volume by Duplex Sonography in Young and Elderly Adults
Authors: Seidel E. , Eicke B. M. , Tettenborn B. , Krummenauer F.
Published: June 2011

Background and Purpose
—Vertebrobasilar ischemia has been attributed to a reduction of net vertebral artery flow volume, the product of mean flow velocity and the cross-sectional area of the vessel. It can be determined by duplex sonography. There are no reference values for vertebral artery flow volume in an age group representative of patients with cerebrovascular disease.

Methods
—We examined 50 nonvascular neurological patients (age 55.8±14.0 years). Flow velocities and vessel diameters were recorded in the intertransverse (V2) segments bilaterally, and the flow volume was calculated according to the following equations: (1) Q1=time-averaged mean velocity×area and (2) Q2=(time-averaged maximum velocity/2)×area.

Results
—Flow velocities and vessel diameters tended to be lower on the right side, resulting in a lower flow volume. Flow volumes (according to Equation 1

) were 77.2±29.8 mL/min on the right side, 105.3±46.4 mL/min on the left side, and 182.0±56.0 mL/min net. Side-to-side differences were not significant. Flow volumes calculated with the 2 equations did not differ significantly. An age dependence could not be shown, but vessel diameters and net vertebral artery flow volumes were significantly lower in women than in men. The normal range for net vertebral artery flow volume defined by the 5th to 95th percentiles is between 102.4 and 301.0 mL/min. This wide range is due to the high interindividual variability of the parameters.

Conclusions
—On the basis of the reference values presented here, the association of decreased vertebral artery flow volume and vertebrobasilar ischemia should be reevaluated. Additional areas for investigation include the quantification of collateral flow in the vertebral arteries in carotid artery occlusive disease and their contribution to overall cerebral blood flow volume.
Combination of Intraischemic and Postischemic Hypothermia Provides Potent and Persistent Neuroprotection Against Temporary Focal Ischemia in Rats
Authors: Yanamoto H. , Nagata I. , Nakahara I. , Tohnai N. , Zhang Z. , Kikuchi H.
Published: June 2011

Background and Purpose
—It is not known whether a combination of intraischemic and postischemic mild hypothermia provides extra neuroprotection and if so, whether the neuroprotection is persistent.

Methods
—Sixty-eight Sprague-Dawley rats were used. In group 1, ischemia and reperfusion were performed under normothermic (N) conditions (control, N-N). In group 2, ischemia was induced and maintained under hypothermic conditions (33°C for 2 hours) and reperfusion was performed under normothermic conditions, H-N. In group 3, both ischemia and reperfusion were performed under hypothermic conditions for an additional 21 hours after the surgery, H-22H. In group 4, ischemia was induced and maintained under hypothermic conditions and reperfusion was performed under hypothermic conditions only for the initial 3 hours (H-3H). In group 5, ischemia was induced and maintained under normothermic conditions and reperfusion was performed under hypothermic conditions (33°C) (N-22H). All rats were perfused 48 hours after the induction of ischemia. In addition, the normothermic or hypothermic therapy used for groups 1, 3, and 4 was performed again, and these rats were killed 30 days after the induction of ischemia. Furthermore, neurological deficits were monitored in groups N-N and H-22H for 4 weeks.

Results
—In the H-3H and H-22H groups, the total infarct volume was significantly reduced by 41% or 66%, respectively, assessed 48 hours after ischemia. The significant reduction in group H-22H was again confirmed 30 days after ischemia, ie, 50% reduction was observed. In contrast, the reduction in group H-3H (31%) was not significant. The neurological deficits were significantly more severe in the N-N group than in the H-22H group during week 4.

Conclusions
—The neuroprotective effects against temporary focal ischemia evaluated by infarct volume and neurological functions by the combination therapy with intraischemic and prolonged postischemic mild hypothermia were persistent in rats. Appropriate design of mild hypothermia therapy extending into the late reperfusion period is important to maximize the neuroprotective effects of hypothermia.
Early Clinical and Radiological Predictors of Fatal Brain Swelling in Ischemic Stroke
Authors: Krieger Derk W. , Demchuk Andrew M. , Kasner Scott E. , Jauss Marek , Hantson Ludwig
Published: June 2011

Background and Purpose
—Early identification of acute stroke patients at risk of fatal brain swelling is necessary to facilitate implementation of aggressive therapies. Initial clinical, laboratory, and CT characteristics that may be used as selection criteria were analyzed to determine predictors of herniation and neurological death.

Methods
—Data from the placebo arm of the Lubeluzole-International-9 trial were reviewed to identify patients with fatal brain edema. Early clinical, laboratory, and radiographic parameters were evaluated in a case-control design. Initial CT scans were analyzed for early ischemic abnormalities by 2 blinded investigators.

Results
—Twenty-three patients died from brain swelling, with minimum baseline National Institutes of Health Stroke Scale (NIHSS) scores of 20 (n=12; mean, 23.2±1.8) with left and 15 (n=11; mean, 17.6±2.2) with right hemispheric infarctions (
P
=0.0001). A sample of 112 subjects with comparably severe strokes, but who did not die from brain swelling, was selected from the remaining population according to the same NIHSS scores. Among clinical and laboratory characteristics, nausea/vomiting within 24 hours after onset (odds ratio [OR], 5.1; 95% CI, 1.7 to 15.3;
P
=0.003) and 12-hour systolic blood pressure ≥180 mm Hg (OR, 4.2; 95% CI, 1.4 to 12.9;
P
=0.01) were independently associated with fatal brain swelling. Among radiographic factors, only hypodensity of >50% of the middle cerebral artery territory on initial CT scan was an independent predictor (OR, 6.1; 95% CI, 2.3 to 16.6;
P
=0.0004).

Conclusions
—Patients with baseline NIHSS score ≥20 with left or ≥15 with right hemispheric infarctions within 6 hours of symptom onset who also have nausea/vomiting or >50% middle cerebral artery territory hypodensity are at high risk for developing fatal brain swelling.
Infarct Volume as a Surrogate or Auxiliary Outcome Measure in Ischemic Stroke Clinical Trials
Authors: Saver Jeffrey L. , Johnston Karen C. , Homer Daniel , Wityk Robert , Koroshetz Walter , Truskowski Laura L. , Haley E. Clarke
Published: June 2011

Background and Purpose
—Reduction in infarct volume is the standard measure of therapeutic success in animal stroke models. Reduction in infarct volume has been advocated as a biological surrogate or auxiliary outcome measure for human stroke clinical trials to replace or supplement deficit, disability, and global clinical scales. However, few studies have investigated correlations between infarct volume and clinical end points in acute ischemic stroke patients.

Methods
—CT scans at days 6 to 11 were acquired prospectively in 191 fully eligible patients enrolled in the Randomized Trial of Tirilazad Mesylate in Patients With Acute Stroke (RANTTAS). Patients were enrolled within 6 hours of onset of stroke in any vessel distribution. Infarct volume was measured by operator-assisted computerized planimetry.

Results
—One hundred thirty-two patients had visible new supratentorial infarcts, with median infarct volume of 28.0 cm
3
(interquartile range, 9.0 to 93.0 cm
3
). Fifty-nine patients had no visible new infarct. Correlations with standard 3-month outcome scales and mortality were as follows: Barthel Index,
r
=0.43; Glasgow Outcome Scale,
r
=0.53; National Institutes of Health Stroke Scale,
r
=0.54; mortality,
r
=0.31. For visible infarcts alone, correlations were as follows: BI,
r
=0.46; GOS,
r
=0.59; NIHSS,
r
=0.56; mortality,
r
=0.32.

Conclusions
—Subacute CT infarct volume correlates moderately with 3-month clinical outcome as assessed by widely used neurological and functional assessment scales. The modesty of this linkage constrains the use of infarct volume as a surrogate end point in ischemic stroke clinical trials.
Concentration Changes of Malondialdehyde Across the Cerebral Vascular Bed and Shedding of L-Selectin During Carotid Endarterectomy
Authors: Weigand Markus A. , Laipple Andreas , Plaschke Konstanze , Eckstein Hans-Henning , Martin Eike , Bardenheuer Hubert J.
Published: June 2011

Background and Purpose
—Oxidative stress has been postulated to account for delayed neuronal death due to ischemia/reperfusion. We investigated cerebral formation of malondialdehyde as an index of lipid peroxidation in relation to different sources of reactive oxygen species in patients undergoing carotid endarterectomy.

Methods
—In 25 patients undergoing carotid endarterectomy, jugular venous–arterial concentration differences of brain metabolites, malondialdehyde, plasma total antioxidant status, and soluble P-selectin and L-selectin were measured. A carotid artery shunt (n=5) was placed only after complete loss of somatosensory evoked potentials, indicating a focal cerebral blood flow <15 mL/min per 100 g.

Results
—As an indication of cerebral lipid peroxidation, jugular venous–arterial malondialdehyde concentration differences were significantly enhanced before reperfusion, and an additional rise was observed 15 minutes after reperfusion. Plasma total antioxidant status significantly decreased during carotid artery occlusion only in patients with carotid artery shunt. This decrease was matched by cerebral formation of adenosine, hypoxanthine, and nitrite/nitrate. While jugular venous–arterial concentration differences of soluble P-selectin showed changes similar to those of malondialdehyde, the concentration difference for soluble L-selectin was enhanced exclusively at 15 minutes after reperfusion.

Conclusions
—Short-term incomplete cerebral ischemia/reperfusion significantly enhanced cerebral lipid peroxidation, as indicated by malondialdehyde formation. The generation of reactive oxygen species by xanthine oxidase or nitric oxide metabolism might be involved in the induction of lipid peroxidation. The additional rise in cerebral release of malondialdehyde was found to coincide with a significant activation of polymorphonuclear leukocytes across the cerebral circulation.
Synergistic Effects of a Combination of Low-Dose Basic Fibroblast Growth Factor and Citicoline After Temporary Experimental Focal Ischemia
Authors: Schäbitz Wolf R. , Li Fuhai , Irie Katsumi , Sandage Bobby W. , Locke Kenneth W. , Fisher Marc
Published: June 2011

Background and Purpose
—Basic fibroblast growth factor (bFGF) and citicoline (cytidine 5′-diphosphate choline, an endogenous compound that stabilizes membrane function) have demonstrated neuroprotective effects after focal cerebral ischemia. Both agents are candidates for future stroke therapy in humans. For evaluation of synergistic effects of bFGF and citicoline, a low-dose combination of both compounds was tested against each compound alone and placebo.

Methods
—Four groups of Sprague-Dawley rats (n=12 per group) underwent 90 minutes of focal cerebral ischemia with the use of the suture model of middle cerebral artery occlusion. Animals were randomly and blindly assigned to one of the following treatment groups: placebo, low-dose citicoline (250 mg/kg IP daily for 4 days), low-dose bFGF (10 μg/kg per hour IV for 3 hours), and the combination of both (250 mg/kg citicoline and 10 μg/kg per hour bFGF). Triphenyltetrazolium chloride staining was used after 4 days to determine postmortem infarction. Neurological scores were assessed on a daily basis.

Results
—The premature mortality rate was 41.7% in the placebo and citicoline groups, 33.3% in the bFGF group, and 25% (
P
=NS) in the combination group. The mean neurological score on day 4 was 3.1±1.6 (placebo), 3.1±1.6 (citicoline), 2.9±1.5 (bFGF), and 2.4±1.4 (combination) (
P
=NS). The mean volume of infarction was significantly reduced in the combination group (136.5±25.4 mm
3
) versus placebo (172.6±48.9 mm
3
;
P
=0.036, Fisher test), versus citicoline alone (186.0±35.7 mm
3
;
P
=0.005, Fisher test), and versus bFGF alone (176.0±49.2 mm
3
;
P
=0.023, Fisher test).

Conclusions
—These results demonstrate synergistic effects of a low-dose combination of the growth factor bFGF and citicoline after temporary experimental focal cerebral ischemia and furthermore support the effectiveness of a combination treatment regimen for the management of acute stroke.
Inhibition of Ischemia-Induced Glutamate Release in Rat Striatum by Dihydrokinate and an Anion Channel Blocker
Authors: Seki Yukio , Feustel Paul J. , Keller Richard W. , Tranmer Bruce I. , Kimelberg Harold K.
Published: June 2011

Background and Purpose
—Increased activation of excitatory amino acid (EAA) receptors is considered a major cause of neuronal damage. Possible sources and mechanisms of ischemia-induced EAA release were investigated pharmacologically with microdialysis probes placed bilaterally in rat striatum.

Methods
—Forebrain ischemia was induced by bilateral carotid artery occlusion and controlled hypotension in halothane-anesthetized rats. During 30 minutes of ischemia, microdialysate concentrations of glutamate and aspartate were measured in the presence of a nontransportable blocker of the astrocytic glutamate transporter GLT-1, dihydrokinate (DHK), or an anion channel blocker, 4,4′-dinitrostilben-2,2′-disulfonic acid (DNDS), administered separately or together through the dialysis probe.

Results
—In control striata during ischemia, glutamate and aspartate concentrations increased 44±13 (mean±SEM) times and 19±5 times baseline, respectively, and returned to baseline values on reperfusion. DHK (1 mmol/L in perfusate; n=8) significantly attenuated EAA increases compared with control (glutamate peak, 9.6±1.7 versus control, 15.4±2.6 pmol/μL). EAA levels were similarly decreased by 10 mmol/L DHK. DNDS (1 mmol/L; n=5) also suppressed EAA peak increases (glutamate peak, 5.8±1.1 versus control, 10.1±0.7 pmol/μL). At a higher concentration, DNDS (10 mmol/L; n=7) further reduced glutamate and aspartate release and also inhibited ischemia-induced taurine release. Together, 1 mmol/L DHK and 10 mmol/L DNDS (n=5) inhibited 83% of EAA release (glutamate peak, 2.7±0.7 versus control, 10.9±1.2 pmol/μL).

Conclusions
—These findings support the hypothesis that both cell swelling–induced release of EAAs and reversal of the astrocytic glutamate transporter are contributors to the ischemia-induced increases of extracellular EAAs in the striatum as measured by microdialysis.
Brain Stem MRI Signal Abnormalities in CADASIL
Authors: Chabriat H. , Mrissa R. , Levy C. , Vahedi K. , Taillia H. , Iba-Zizen M. T. , Joutel A. , Tournier-Lasserve E. , Bousser M.-G.
Published: June 2011

Background
—We recently showed that the severity of MRI signal abnormalities increases with age in CADASIL, an arteriopathy due to mutations of
notch 3
gene on chromosome 19. Previous results also suggest that the various hemispheric subcortical areas have a different vulnerability to ischemia in this disease. The distribution of the lesions at the brain stem level has not yet been reported.

Case Descriptions
—We reviewed the MRIs of 68 affected patients having signal abnormalities in the hemispheric white matter to assess the distribution and clinical consequences of brain stem signal abnormalities in CADASIL. We found hypersignals on T2-weighted images in the brain stem in 45% of the subjects. The pons was more frequently involved (100%) than the mesencephalon (69%) and the medulla (35%). Hyposignals on T1-weighted images, at the brain stem level, were observed only in two thirds of these subjects. The lack of signal abnormalities reaching the brain stem surface and the absence of cerebellar lesions were noteworthy.

Conclusions
—Brain stem signal abnormalities observed in CADASIL are found in regions irrigated only by perforating arteries. These results support parallel observations made for CADASIL-associated signal abnormalities in the cerebral hemispheres and emphasize the importance of the angioarchitecture of the cerebral vasculature to explain why a condition characterized by a systemic vessel wall pathology is manifested only as a brain disease.
Neurochemical Monitoring of Fatal Middle Cerebral Artery Infarction
Authors: Berger C. , Annecke A. , Aschoff A. , Spranger M. , Schwab S.
Published: June 2011

Background
—Microdialysis is a method for neurochemical monitoring that has been applied more frequently over the past few years in patients suffering from subarachnoid hemorrhage, acute brain injury, and stroke. It is used to study the course of extracellular molecules of low molecular weight, such as excitatory amino acids or metabolic end products.

Case Description
—We report the case of a 43-year-old patient suffering from left hemispheric stroke with a space-occupying postischemic edema leading to a considerable mass effect on the contralateral side. For treatment of severe edema, hypothermia was initiated. The microdialysis and intracranial pressure probe were placed into the noninfarcted hemisphere. A massive increase in levels of glutamate, glycerine, and the lactate-pyruvate ratio was measured 24 hours before intracranial pressure elevation was observed and brain death occurred.

Conclusions
—Monitoring excitatory amino acids, glycerine as a membrane component, and lactate-pyruvate ratio as an energy marker by microdialysis is a useful tool to increase our understanding of biochemical events in secondary brain damage. For future prevention of secondary ischemia in patients with massive stroke, close neurochemical monitoring might be valuable to improve therapy, particularly in the critically ill.