bluuebunny/crossref_metadata_2025 huggingface dataset:
Serial Measurement of Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 in Serum of Patients With Acute Ischemic Stroke
Authors: Slevin M. , Krupinski J. , Slowik A. , Kumar P. , Szczudlik A. , Gaffney J.
Published: June 2011

Background and Purpose
—Both vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) are expressed in higher than normal concentrations in the penumbra of patients after ischemic stroke. Because both cytokines are central to the processes of angiogenesis, tissue inflammation, and fibrosis, we performed serial measurements of these cytokines in patients with cerebral infarction and determined their relationship to stroke etiology and volume.

Methods
—We serially (at days 0, 1, 3, 7, and 14) measured the serum levels of VEGF and active TGF-β1 in 29 patients with acute ischemic stroke. Age-matched healthy subjects (n=26) were used as controls.

Results
—Expression of VEGF was significantly increased in the majority of patients after acute stroke at each of the time points compared with normal controls. Highest expression occurred at day 7 (588±121 pg/mL;
P
=0.005), and it remained significantly elevated at 14 days after stroke. Expression of VEGF correlated with infarct volume, clinical disability (Scandinavian Stroke Scale), and peripheral leukocytosis and was significantly higher in patients with atherothrombotic large-vessel disease and ischemic heart disease (
P
<0.05 in all cases). In contrast, expression of active TGF-β1 was not significantly different from control patients at any of the measured time points. When the mean concentration of TGF-β1 from each patient (pooled time points) was compared with the control mean, a significant increase was found in only 2 patients, whereas levels decreased in 12 patients (
P
<0.05). There was no correlation between circulating active TGF-β1 and VEGF expression, leukocytosis, stroke subtype, or patient disability as assessed by Scandinavian Stroke Scale score.

Conclusions
—VEGF but not TGF-β1 showed a dramatic increase in serum of stroke patients. Correlation between stroke severity and VEGF concentration suggests it could be involved in the subsequent repair processes resulting in partial recovery after stroke. Correlation between VEGF expression and peripheral leukocytosis suggests that these changes may also reflect the immunologic status of the patient. VEGF may play an important role in the pathophysiology of acute ischemic stroke and could be of value in future treatment strategies.
Comparison of Risk Factors for Stroke Incidence and Stroke Mortality in 20 Years of Follow-Up in Men and Women in the Renfrew/Paisley Study in Scotland
Authors: Hart Carole L. , Hole David J. , Smith George Davey
Published: June 2011

Background and Purpose
—The aim of this study was to relate risk factors in middle-aged men and women to stroke incidence (defined by having a hospital discharge with a main diagnosis of stroke) and compare this with the associations between risk factors and stroke mortality.

Methods
—In the early to mid-1970s, when they were 45 to 64 years of age, 7052 men and 8354 women from the Renfrew/Paisley prospective cohort study in Scotland were screened. Risk factors measured included blood pressure, blood cholesterol and glucose, respiratory function, cardiothoracic ratio, smoking habit, height, body mass index, preexisting coronary heart disease, and diabetes. These were related to stroke incidence over 20 years of follow-up.

Results
—Diastolic and systolic blood pressure, smoking, cardiothoracic ratio, preexisting coronary heart disease, and diabetes were positively related to stroke incidence for men and women, whereas adjusted FEV
1
(forced expiratory volume in 1 second) and height were negatively related. Cholesterol was not related to stroke. Glucose for nondiabetic subjects had a U-shaped relationship with stroke. Body mass index was not clearly related to stroke, although participants with the highest body mass index had the highest stroke rate. Former smokers had similar stroke rates to never-smokers. Tests between the associations of risk factors and stroke incidence revealed these were not statistically different from the associations with stroke mortality.

Conclusions
—The risk factors had a similar effect on stroke incidence as on stroke mortality. Epidemiological studies with information on stroke mortality are likely to give results applicable to stroke incidence.
Dehydroepiandrosterone Sulfate Is Neuroprotective in a Reversible Spinal Cord Ischemia Model
Authors: Lapchak Paul A. , Chapman Deborah F. , Nunez Sonia Y. , Zivin Justin A.
Published: June 2011

Background and Purpose
—Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) may function as neurotrophic or neuroprotective factors to protect central nervous system (CNS) neurons against a variety of insults, including excitotoxicity. The present study evaluated the pharmacological effects of DHEAS in a reversible spinal cord ischemia model.

Methods
—DHEAS was administered (50 mg/kg IV) 5 or 30 minutes after the start of occlusion to groups of rabbits exposed to ischemia induced by temporary (15 to 60 minutes) occlusion of the infrarenal aorta. The group P
50
represents the duration of ischemia (in minutes) associated with 50% probability of resultant permanent paraplegia.

Results
—The P
50
of the vehicle-treated control group, when behavioral analysis was assessed 18 hours after aortal occlusion, was 28.8±2.0 minutes. Neuroprotection was demonstrated if a drug significantly prolonged the P
50
compared with the vehicle-treated control group. Treatment with DHEAS at 5 minutes significantly (
P
<0.05) prolonged the P
50
of the group to 36.8±3.9 minutes. In addition, the DHEAS effect appeared durable, because a significant difference between the control and DHEAS-treated groups was still measurable at the 4-day time point. At 4 days, the P
50
of the control group was 26.1±2.2 minutes, whereas the P
50
for the DHEAS-treated group was 38.6±5.9 minutes. DHEAS was not neuroprotective if administered 30 minutes after occlusion. In addition, the GABA
A
antagonist bicuculline abolished the neuroprotective effect of DHEAS.

Conclusions
—The present study suggests that neurosteroids may have substantial therapeutic benefit for the treatment of ischemic stroke.
Role of Endothelial Nitric Oxide Generation and Peroxynitrite Formation in Reperfusion Injury After Focal Cerebral Ischemia
Authors: Gürsoy-Özdemir Yasemin , Bolay Hayrunnisa , Saribaş Okay , Dalkara Turgay
Published: June 2011

Background and Purpose
—Reperfusion injury is one of the factors that unfavorably affects stroke outcome and shortens the window of opportunity for thrombolysis. Surges of nitric oxide (NO) and superoxide generation on reperfusion have been demonstrated. Concomitant generation of these radicals can lead to formation of the strong oxidant peroxynitrite during reperfusion.

Methods
—We have examined the role of NO generation and peroxynitrite formation on reperfusion injury in a mouse model of middle cerebral artery occlusion (2 hours) and reperfusion (22 hours). The infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride staining; blood-brain barrier permeability was evaluated by Evans blue extravasation. Nitrotyrosine formation and matrix metalloproteinase-9 expression were detected by immunohistochemistry.

Results
—Infarct volume was significantly decreased (47%) in animals treated with the nonselective nitric oxide synthase (NOS) inhibitor N
ω
-nitro-
l
-arginine (L-NA) at reperfusion. The specific inhibitor of neuronal NOS, 7-nitroindazole (7-NI), given at reperfusion, showed no protection, although preischemic treatment with 7-NI decreased infarct volume by 40%. Interestingly, prereperfusion administration of both NOS inhibitors decreased tyrosine nitration (a marker of peroxynitrite toxicity) in the ischemic area. L-NA treatment also significantly reduced vascular damage, as indicated by decreased Evans blue extravasation and matrix metalloproteinase-9 expression.

Conclusions
—These data support the hypothesis that in addition to the detrimental action of NO formed by neuronal NOS during ischemia, NO generation at reperfusion plays a significant role in reperfusion injury, possibly through peroxynitrite formation. Contrary to L-NA, failure of 7-NI to protect against reperfusion injury suggests that the source of NO is the cerebrovascular compartment.
An Uncommon Cause of Recurrent Strokes
Authors: Naegeli Barbara , Bannwart Fridolin , Bertel Osmund
Published: June 2011

Background
—Cardiac involvement in Whipple’s disease is not an uncommon phenomenon in autopsies, but its clinical occurrence is often overshadowed by gastrointestinal symptoms. We report a very atypical manifestation of this disorder.

Summary of Report
— An extraordinary presentation of an extremely long-lasting, culture-negative endocarditis caused by
Tropheryma whippelii
is described, the clinical consequence of which has become apparent in recurrent strokes.

Conclusions
—Cardiac involvement of Whipple’s disease should always be considered in culture and serologically negative endocarditis. The polymerase chain reaction technique may be a useful tool to confirm a presumed diagnosis of
T whippelii
endocarditis and consequently to apply an effective treatment regimen.
Long-Term Clinical and Angiographic Outcomes in Symptomatic Patients With 70% to 99% Carotid Artery Stenosis
Authors: Paciaroni Maurizio , Eliasziw Michael , Sharpe Brenda L. , Kappelle L. Jaap , Chaturvedi Seemant , Meldrum Heather , Barnett Henry J.M.
Published: June 2011

Background and Purpose
—In 1991, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) reported the benefit of carotid endarterectomy for 659 patients with 70% to 99% stenosis. Follow-up continued until 1997.

Methods
—The present study examined the risks and causes of ipsilateral stroke in the randomized groups and in those who had delayed endarterectomy or continued on medical therapy and also examined the evolution of carotid disease on follow-up imaging.

Results
—By on-treatment (efficacy) analysis, the risk of any ipsilateral stroke at 3 years was 28.3% for medically randomized and 8.9% for surgically randomized patients (19.4% absolute risk reduction,
P
<0.001). For combined disabling or fatal ipsilateral stroke, the risks were 14.0% and 3.4%, respectively (10.6% absolute risk reduction). In medical patients, >80% of the first strokes at 3 years were of large-artery origin. After February 1991, 116 suitable medical patients underwent endarterectomy within 6 months, and 115 continued on medical therapy. The 3-year risk of any ipsilateral stroke in the groups of 116 and 115 patients was 7.9% and 15.0%, respectively (7.1% absolute risk reduction). During follow-up, 81 patients had angiograms comparable to the baseline images. Progression by ≥10% occurred in 7 patients; regression, in 8; no change, in 39; and occlusion, in 27. By use of both angiography and ultrasound, 63 (25.5%) of the 247 medically treated patients progressed to occlusion, of whom 31.7% had an ipsilateral stroke before or on the day of occlusion.

Conclusions
—Endarterectomy for patients with 70% to 99% stenosis and recent symptoms was efficacious in the long term. Compared with patients who continued on medical therapy, medical patients with delayed endarterectomy experienced a moderate benefit. Medically treated patients experienced a high risk of occlusion.
Apolipoprotein E Polymorphism
Authors: Schiefermeier M. , Kollegger H. , Madl C. , Schwarz C. , Holzer M. , Kofler J. , Sterz F.
Published: June 2011

Background and Purpose
—The apolipoprotein E 3/3 (apoE 3/3) genotype is associated with a reduced risk of developing Alzheimer’s disease and with a favorable neurological outcome after traumatic head injury. In vitro studies suggest that the most common genotype, apoE 3/3, may be involved in neuroprotective and neuroregenerative mechanisms. The aim of this study was to determine whether the apoE 3/3 genotype has an impact on survival and neurological outcome after cardiopulmonary resuscitation.

Methods
—Eighty patients with cardiac arrest were investigated prospectively for their apoE genotype. Epidemiological data were assessed according to recommended guidelines. Patients were divided into 2 groups, ie, with the apoE 3/3 genotype present or absent, and tested for differences in survival and neurological outcome. Further statistical analysis with respect to survival and neurological outcome was performed by using a stepwise logistic regression analysis.

Results
—Patients with the apoE 3/3 genotype had a significantly higher survival rate (64% versus 33%,
P
=0.007) and more often a favorable neurological outcome (55% versus 27%,
P
=0.013) compared with patients with other apoE genotypes. The apoE 3/3 genotype was shown to be a substantial predictive factor for a favorable neurological outcome (odds ratio 3.2) and was, apart from other essential factors, predictive for survival (odds ratio 4.4) after cardiopulmonary resuscitation.

Conclusions
—These data give evidence that patients with the apoE 3/3 genotype have a better chance of recovery after cardiopulmonary resuscitation than do patients with apoE genotypes other than 3/3.
Parental History of Stroke Predicts Subclinical But Not Clinical Stroke
Authors: Morrison Alanna C. , Fornage Myriam , Liao Duanping , Boerwinkle Eric
Published: June 2011

Background and Purpose
—An individual with a positive family history of a disease may be at increased risk for the disease. We sought to examine whether parental history of stroke is associated with subclinical or clinical stroke in the Atherosclerosis Risk in Communities (ARIC) Study, and whether any observed association is independent of established stroke risk factors.

Methods
—Parental history of stroke was determined by home interview at the baseline examination. Cerebral MRI was performed on individuals from 2 ARIC field centers. Subclinical cerebral infarct cases (n=202) were defined by the presence of cerebral infarcts >3 mm. The comparison group for the subclinical cases included all individuals participating in the MRI examination who were not identified as a subclinical case (n=1533). Incidence of clinical ischemic stroke was determined by following the ARIC cohort for potential cerebrovascular events. Two hundred sixty-one validated ischemic strokes were identified; 13 775 individuals from the ARIC cohort did not experience an ischemic event.

Results
—Parental history of stroke was significantly associated with subclinical stroke after adjusting for age, gender, and race (OR 1.67, 95% CI1.23 to 2.26) and after further adjustment for multiple stroke risk factors (OR1.64, 95% CI1.20 to 2.24). Parental history of stroke was not a significant predictor of clinical stroke in either adjustment model.

Conclusions
—The observed increased risk of subclinical stroke among individuals with a parental history of stroke is consistent with the expression of genetic susceptibility, a shared environment, or both in the etiology of stroke. This effect did not appear to be mediated by established stroke risk factors. Parental history of stroke does not confer an increased risk of clinical stroke in this sample of middle-aged Americans.
Cerebral Infarction in Adult AIDS Patients
Authors: Connor M.D. , Lammie G.A. , Bell J.E. , Warlow C.P. , Simmonds P. , Brettle R.D.
Published: June 2011

Background and Purpose
—Autopsy series of patients with AIDS have found a 4% to 29% prevalence of cerebral infarction. Little is known of the prevalence of cerebral infarction when not associated with non-HIV central nervous system (CNS) infection, lymphoma, or cardioembolic sources. Clinical correlation has seldom been available. We describe the pathological and clinical features of patients from the Edinburgh HIV Cohort Study found to have had cerebral infarcts without evidence of non-HIV CNS infection, CNS lymphoma, or cardioembolic sources at autopsy.

Methods
—From 183 autopsy cases, 26 without evidence of opportunistic cerebral infection or lymphoma were selected. These 26 cases went through a second selection process in which the presence of cerebral infarction, in the absence of the conditions mentioned, was verified. Histology and clinical records for the remaining patients were reviewed.

Results
—Ten (5.5%) cases fulfilled the inclusion criteria and demonstrated similar hypoxic-ischemic lesions. Small-vessel thickening was seen in all cases, and perivascular space dilatation, rarefaction, and pigment deposition, with vessel wall mineralization and perivascular inflammatory cell infiltrates, were seen in some cases. Vasculitis was not found. One patient had had a transient ischemic attack, and no patient had had a stroke.

Conclusions
—Cerebral infarcts in HIV-infected patients are not common in the absence of cerebral non-HIV infection, lymphoma, or embolic sources. We found an HIV-associated vasculopathy with similar features in all risk groups. In AIDS patients presenting with stroke or transient ischemic attack, potentially treatable causes, such as cerebral coinfection or tumor, should be sought.
Quantitative Analysis of the Loss of Distinction Between Gray and White Matter in Comatose Patients After Cardiac Arrest
Authors: Torbey M. T. , Selim M. , Knorr J. , Bigelow C. , Recht L.
Published: June 2011

Background and Purpose
—Anecdotal reports suggest that a loss of distinction between gray (GM) and white matter (WM) as adjudged by CT scan predicts poor outcome in comatose patients after cardiac arrest. To address this, we quantitatively assessed GM and WM intensities at various brain levels in comatose patients after cardiac arrest.

Methods
—Patients for whom consultation was requested within 24 hours of a cardiac arrest were identified with the use of a computerized database that tracks neurological consultations at our institution. Twenty-five comatose patients were identified for whom complete medical records and CT scans were available for review. Twenty-five consecutive patients for whom a CT scan was interpreted as normal served as controls. Hounsfield units (HUs) were measured in small defined areas obtained from axial images at the levels of the basal ganglia, centrum semiovale, and high convexity area.

Results
—At each level tested, lower GM intensity and higher WM intensity were noted in comatose patients compared with normal controls. The GM/WM ratio was significantly lower among comatose patients compared with controls (
P
<0.0001, rank sum test). There was essentially no overlap in GM/WM ratios between control and study patients. The difference was greatest at the basal ganglia level. We also observed a marginally significant difference in the GM/WM ratio at the basal ganglia level between those patients who died and those who survived cardiac arrest (
P
=0.035, 1-tailed
t
test). Using receiver operating characteristic curve analysis, we determined that a difference in GM/WM ratio of <1.18 at the basal ganglia level was 100% predictive of death. At the basal ganglia level, none of 12 patients below this threshold survived, whereas the survival rate was 46% among patients in whom the ratio was >1.18. The empirical risk of death was 21.67 for comatose patients with a value below threshold.

Conclusions
—The ratio in HUs of GM to WM provides a reproducible measure of the distinction between gray and white matter. A lower GM/WM ratio is observed in comatose patients immediately after cardiac arrest. The basal ganglia level seems to be the most sensitive location on CT for measuring this relationship. Although a GM/WM ratio <1.18 at this level predicted death in this retrospective study, the difference in this study is not robust enough to recommend that management decisions be dictated by CT results. The results, however, do warrant consideration of a prospective study to determine the reliability of CT scanning in predicting outcome for comatose patients after cardiac arrest.
Mechanisms of Cerebral Arterial Relaxations to Hydrogen Peroxide
Authors: Iida Yasuhiko , Katusic Zvonimir S.
Published: June 2011

Background and Purpose
—The role of hydrogen peroxide in the regulation of cerebral arterial tone is not completely understood. Previous studies have demonstrated that hydrogen peroxide causes vasodilation of small cerebral arteries. The present study was designed to determine the mechanisms responsible for relaxations of large cerebral arteries to hydrogen peroxide.

Methods
—Rings of canine middle cerebral arteries without endothelium were suspended for isometric force recording in modified Krebs-Ringer bicarbonate solution bubbled with 94% O
2
/6% CO
2
(37°C, pH 7.4). Radioimmunoassay technique was used to determine the levels of cAMP and cGMP.

Results
—During contraction to UTP (3×10
−
6
or 10
−
5
mol/L), hydrogen peroxide (10
−
6
to 10
−
4
mol/L) caused concentration-dependent relaxations. Catalase (1200 U/mL) abolished the relaxations to hydrogen peroxide. Inhibition of cyclooxygenase by indomethacin (10
−
5
mol/L) significantly reduced relaxations to hydrogen peroxide. In arteries contracted by KCl (20 mmol/L), the relaxations to hydrogen peroxide were significantly reduced. In the presence of a nonselective potassium channel inhibitor, BaCl
2
(10
−
4
mol/L), a delayed rectifier potassium channel inhibitor, 4-aminopyridine (10
−
3
mol/L), or a calcium-activated potassium channel inhibitor, charybdotoxin (3×10
−
8
mol/L), the relaxations to hydrogen peroxide were also significantly reduced. An ATP-sensitive potassium channel inhibitor, glyburide (5×10
−
6
mol/L), did not affect the relaxations to hydrogen peroxide. Hydrogen peroxide produced concentration-dependent increase in levels of cAMP. Indomethacin (10
−
5
mol/L) inhibited the stimulatory effect of hydrogen peroxide on cAMP production. In contrast, hydrogen peroxide did not affect the levels of cGMP.

Conclusions
—These results suggest that hydrogen peroxide may cause relaxations of large cerebral arteries in part by activation of arachidonic acid metabolism via cyclooxygenase pathway with subsequent increase in cAMP levels and activation of potassium channels.
Autoregulation of Cerebral Blood Flow in Patients Resuscitated From Cardiac Arrest
Authors: Sundgreen Claus , Larsen Fin Stolze , Herzog Tina Maria , Knudsen Gitte Moos , Boesgaard Soren , Aldershvile Jan
Published: June 2011

Background and Purpose
—Under normal circumstances, autoregulation maintains cerebral blood flow (CBF) constant within a wide range of mean arterial pressure (MAP). It remains unknown whether patients resuscitated from cardiac arrest have preserved CBF autoregulation. In this study, CBF autoregulation was investigated within the first 24 hours after resuscitation from cardiac arrest.

Methods
—Eighteen patients and 6 healthy volunteers had relative changes in CBF determined by transcranial Doppler mean flow velocity (V
mean
) in the middle cerebral artery during a stepwise rise in MAP by use of norepinephrine infusion. V
mean
was plotted against MAP, and a lower limit of autoregulation was identified by double regression analysis based on the least-squares method.

Results
—In patients, V
mean
increased from a median of 33 (range 19 to 73) to 37 (22 to 100) cm/s (
P
<0.001) during a norepinephrine-induced rise in MAP from 78 (46 to 118) to 106 (60 to 149) mm Hg. Eight of 18 patients had impaired CBF autoregulation, and in 5 of the 10 patients with preserved CBF autoregulation, the lower limit of autoregulation could be identified. The lower limit of CBF autoregulation was 76 mm Hg (41 to 105 mm Hg) in the volunteers and 114 mm Hg (80 to 120 mm Hg) in the 5 patients with preserved autoregulation (
P
<0.01).

Conclusions
—We conclude that in a majority of patients in the acute phase after cardiac arrest, cerebral autoregulation is either absent or right-shifted. These results indicate that MAP should be kept at a higher level than commonly accepted to secure cerebral perfusion. We recommend, however, that further randomized clinical trials are performed to determine whether sympathomimetic drugs improve neurological outcome.
Systemic Complement Depletion Diminishes Perihematomal Brain Edema in Rats
Authors: Xi Guohua , Hua Ya , Keep Richard F. , Younger John G. , Hoff Julian T.
Published: June 2011

Background and Purpose
—The complement cascade is activated after experimental intracerebral hemorrhage (ICH). It remains unclear, however, whether depleting the complement system will improve injury resulting from ICH. This study investigated the effects of systemic complement depletion on brain edema formation after ICH.

Methods
—Fifty-six pentobarbital-anesthetized Sprague-Dawley rats were used. Treatment animals were complement-depleted with cobra venom factor (CVF) (intraperitoneally). Control rats received an equal volume of saline injection (intraperitoneally). In both treatment and control rats, autologous blood (100 μL) was infused stereotaxically into the right basal ganglia. Rats were killed 2, 24, or 72 hours later for brain water, ion, and tumor necrosis factor-α (TNF-α) measurements, for Western blot analysis, and for immunohistochemical studies. Brain edema was quantitated by wet/dry weight. TNF-α levels were measured by enzyme-linked immunosorbent assay. Western blot analysis was applied for C9 semiquantification. Immunohistochemistry was used to detect complement C3d, C5a, C9, and myeloperoxidase.

Results
—Perihematomal brain edema was reduced by systemic complement depletion at 24 hours (78.8±0.6% versus 81.5±0.8% in control,
P
<0.01) and 72 hours (81.5±1.5% versus 83.6±0.9% in control,
P
<0.05), while cerebellar water content was unaffected (78.2±0.3% versus 78.0±0.1%). Complement depletion reduced TNF-α production 2 hours after ICH. Immunocytochemistry showed that complement depletion significantly reduced perihematomal C9 deposition, C3d production, and the number of C5a- and myeloperoxidase-positive cells.

Conclusions
—Complement depletion by CVF attenuates brain edema in ICH, indicating that complement activation plays an important role in ICH-induced brain edema. Preventing complement activation may be effective in the treatment of ICH.
Identification of Differentially Expressed Genes in Rat Hippocampus After Transient Global Cerebral Ischemia Using Subtractive cDNA Cloning Based on Polymerase Chain Reaction
Authors: Yokota Naoki , Uchijima Masato , Nishizawa Shigeru , Namba Hiroki , Koide Yukio
Published: June 2011

Background and Purpose—The purpose of this study is to identify new molecules that play important roles in the phenomena that occur in the hippocampus after transient global cerebral ischemia, as clues to better understanding of the mechanisms.

Methods
—A subtractive cDNA library was established by suppression subtractive hybridization of rat hippocampal tissues after transient global cerebral ischemia. With differential screening of the library, upregulated fragments were identified. The mRNA expression levels of selected genes were measured with semiquantitative reverse transcriptase polymerase chain reaction (PCR).

Results
—Among more than 100 isolated fragments, approximately half were determined to be identical to known sequences. The rest showed high homology to known sequences, and only 2 did not exhibit homology to any known sequences. The expression of 5 genes identified in this study increased in 24 hours after ischemia to a level twice as high as that in sham-operated controls. These included furin, prosaposin, synaptotagmin IV, heat shock protein 105, and the neutral and basic amino acid transporter (NBAT). The increases in the mRNA expression levels of the genes except NBAT, as revealed by semiquantitative reverse transcription PCR, were statistically significant at both 6 and 24 hours after ischemia.

Conclusions
—Genes isolated are thought to be associated with production of proteins necessary for degeneration, neuroprotection, and reconstruction of neurons. How the expression of these genes relates to functional changes after ischemia remains to be determined. PCR-based subtractive cDNA cloning is demonstrated to be a useful tool for analyzing in vivo gene expression in animal ischemia models.
Perfusion Mapping Using Computed Tomography Allows Accurate Prediction of Cerebral Infarction in Experimental Brain Ischemia
Authors: Nabavi Darius G. , Cenic Aleksa , Henderson Sarah , Gelb Adrian W. , Lee Ting-Yim
Published: June 2011

Background and Purpose
—We have developed a dynamic CT method to measure absolute cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). In this study we evaluated the ability of CT-derived functional maps to detect infarction in a rabbit model of focal cerebral ischemia.

Methods
—Sequential dynamic CT studies were performed at 2 different slices in 5 control rabbits and another 8 after induction of focal cerebral ischemia. The size of critically ischemic tissue was correlated to size of infarction measured by postmortem 2,3,5-triphenyltetrazolium chloride staining. In the control rabbits, short-term variability of the parameters was assessed by ANOVA analysis.

Results
—In 7 of 8 animals of the ischemia group, cerebral infarction was visible on 2,3,5-triphenyltetrazolium chloride staining, constituting 16.7±10.6% of the ipsilateral hemisphere. Good agreement of CBF functional maps with tissue specimens was found with respect to size and location of infarction. Best prediction of infarction was found for thresholds of CBF <10 mL/100 g per minute (mean size, 17.5±13.4%;
r
=0.95) and MTT >6 seconds (mean size, 15.6±13.5%;
r
=0.85), with regression slopes close to unity. CBV maps were less predictive of occurrence of infarction, especially in cases of small infarction. The short-term variability of CBF, CBV, and MTT in the control group was 10.9%, 15.2%, and 19.9%, respectively.

Conclusions
—Functional CT measurements of absolute CBF and MTT early after onset of ischemia allow prediction of the size and location of cerebral infarction with good accuracy.
Inhibition of α4 Integrin Protects Against Transient Focal Cerebral Ischemia in Normotensive and Hypertensive Rats
Authors: Relton Jane K. , Sloan Kevin E. , Frew Erica M. , Whalley Eric T. , Adams Steven P. , Lobb Roy R.
Published: June 2011

Background and Purpose
—The present study was performed to determine the role of α4 (CD49d), a member of the integrin family of adhesion molecules, in ischemic brain pathology.

Methods
—Male spontaneously hypertensive rats (SHR) or Sprague-Dawley rats underwent 60-minute middle cerebral artery occlusion (MCAO) followed by 23-hour reperfusion. Animals were injected intravenously with 2.5 mg/kg anti-rat α4 antibody (TA-2) or isotype control antibody (anti-human LFA-3 IgG
1
, 1E6) 24 hours before MCAO. Infarct volume was quantified by staining of fresh tissue with tetrazolium chloride and myeloperoxidase activity measured in SHR tissue homogenates 24 hours after MCAO. In SHR, mean arterial blood pressure was recorded before and after MCAO in animals treated with TA-2 and 1E6. Fluorescence-activated cell sorting analysis was performed on peripheral blood leukocytes before and after MCAO.

Results
—TA-2 treatment significantly reduced total infarct volume by 57.7% in normotensive rats (1E6, 84.2±11.5 mm
3
, n=17; TA-2, 35.7±5.9 mm
3
, n=16) and 35.5% in hypertensive rats (1E6, 146.6±15.5 mm
3
, n=15; TA-2, 94.4±25.8 mm
3
, n=11). In both strains, TA-2 treatment significantly reduced body weight loss and attenuated the hyperthermic response to MCAO. In SHR, treatment with TA-2 significantly reduced brain myeloperoxidase activity. Resting mean arterial blood pressure was unaffected by treatment. Leukocyte counts were elevated in TA-2–treated rats. Fluorescence-activated cell sorting analysis demonstrated the ability of TA-2 to bind to CD3+, CD4+, CD8+, and CD11b+ cells in both naive animals and after MCAO.

Conclusions
—These data demonstrate that inhibition of α4 integrin can protect the brain against ischemic brain injury and implicate endogenous α4 integrin in the pathogenesis of acute brain injury. The mechanism by which α4 integrin inhibition offers cerebroprotection is independent of blood pressure modulation and is likely due to inhibition of leukocyte function.
Antibody to the α4 Integrin Decreases Infarct Size in Transient Focal Cerebral Ischemia in Rats
Authors: Becker Kyra , Kindrick Darin , Relton Jane , Harlan John , Winn Robert
Published: June 2011

Background and Purpose
—Inflammation, a process that involves neutrophils, lymphocytes, and monocytes, contributes to cerebral ischemic injury. Blockade of neutrophil adhesion to endothelium improves outcome after experimental stroke. In this study we sought to assess the contribution of lymphocytes and monocytes to ischemic brain injury.

Methods
—Male Lewis rats underwent 3 hours of middle cerebral artery occlusion followed by 45 hours of reperfusion. Two hours after the onset of ischemia, one group of animals received an intraperitoneal injection of antibodies to the α
4
integrin (n=16); another group was injected with an isotype control antibody (n=11). Neurological examination, body temperature, and body weight were assessed at different time points after stroke. Animals were killed 48 hours after the onset of ischemia for determination of infarct volume and leukocyte counts.

Results
—There were no significant differences in body temperature or weight at any time. Neurological scores (deficits) were significantly less in animals treated with anti-α
4
antibodies at 24 (2.0±1.2 versus 3.0±0.4;
P
=0.006) and 48 (2.0±1.2 versus 3.0±0.8;
P
=0.011) hours after ischemia. Peripheral blood leukocyte counts were significantly higher in anti-α
4
–treated animals (6.8±2.2×10
9
versus 2.9±1.9×10
9
;
P
=0.001) and revealed a lymphocyte/monocyte predominance (86.0±16.2% versus 71.0±15.6%;
P
=0.008). Infarct volume was significantly less in animals treated with antibodies to α
4
(120.1±51.21 versus 173.7±42.29 mm
3
;
P
=0.012).

Conclusions
—These data support a role for lymphocytes and monocytes in cerebral ischemic injury and show that blockade of α
4
, even when instituted after the onset of ischemia, can improve neurological outcome and decrease infarct volume.
Hyperdense Sylvian Fissure MCA “Dot” Sign
Authors: Barber Philip A. , Demchuk Andrew M. , Hudon Mark E. , Pexman J.H. Warwick , Hill Michael D. , Buchan Alastair M.
Published: June 2011

Background and Purpose
—The hyperdense appearance of the main middle cerebral artery (HMCA) is now a familiar early warning of large cerebral infarction, brain edema, and poor prognosis. This article describes the hyperdensity associated with embolic occlusion of branches of the middle cerebral artery in the sylvian fissure (MCA “dot” sign). We define it and determine its incidence, diagnostic value, and reliability.

Methods
—CT scans performed on patients with acute ischemic stroke within 3 hours of symptom onset were analyzed for signs of thromboembolic stroke and evidence of early CT ischemia. Two neuroradiologists and 2 stroke neurologists initially blinded to all clinical information and then with knowledge of the affected hemisphere evaluated scans for the presence of the MCA dot sign, the HMCA sign, and early MCA territory ischemic changes.

Results
—Of 100 consecutive patients who presented within 3 hours of symptom onset, 91 were considered at symptom onset to have anterior circulation stroke syndromes. Early CT ischemia was seen in 74% of these baseline CT scans. The HMCA sign was seen in 5% of CT scans, whereas the MCA dot sign was seen in 16%. All patients then received intravenous tissue plasminogen activator. All 5 patients with an HMCA sign, including 2 with an associated MCA dot sign, were either dead or dependent at 3 months. The 14 patients with an MCA dot sign alone were independent at 3 months in 64% of cases, compared with 50% without the sign (Fisher’s exact test
P
=0.79). Balanced κ statistics for both the HMCA and the MCA dot sign were in the moderate to good range when the stroke symptom side was given.

Conclusions
—The MCA dot sign is an early marker of thromboembolic occlusion of the distal MCA branches seen in the sylvian fissure and is associated with better outcome than the HMCA sign.
Use of Aspirin, Epistaxis, and Untreated Hypertension as Risk Factors for Primary Intracerebral Hemorrhage in Middle-Aged and Elderly People
Authors: Saloheimo Pertti , Juvela Seppo , Hillbom Matti
Published: June 2011

Background and Purpose
—The incidence of primary intracerebral hemorrhage (ICH) increases exponentially with age, but the risk factors are not well known. We investigated lifestyle factors, previous diseases, and medications as risk factors for ICH in middle-aged and elderly people.

Methods
—We compared 98 consecutive patients with primary ICH between 36 and 90 years of age with 206 community-based control subjects matched for age and sex. Odds ratios (ORs) and 95% confidence intervals (CIs) after adjustment for possible confounding variables were calculated by logistic regression.

Results
—The independent risk factors for ICH were untreated hypertension (OR, 6.95; 95% CI, 3.06 to 15.8), previous ischemic stroke (OR, 3.83; 95% CI, 1.70 to 8.63), epilepsy (OR, 13.8; 95% CI, 2.49 to 76.6), recent strenuous physical exertion (OR, 3.97; 95% CI, 1.95 to 8.10), and a history of epistaxis (OR, 2.92; 95% CI, 1.28 to 6.62). In men, treated hypertension (OR, 2.67; 95% CI, 1.03 to 6.93) was also a significant risk factor. Patients with a history of epistaxis who had used nonsteroidal anti-inflammatory drugs, especially aspirin in high doses, had an increased risk for ICH (adjusted OR of epistaxis, 2.75; 95% CI, 1.11 to 6.81; adjusted OR of aspirin use, 14.7; 95% CI, 2.03 to 106). In addition, there was a significant (
P
<0.01) positive interaction between the history of epistaxis and the use of aspirin on the risk for ICH.

Conclusions
—Epistaxis is a risk factor for ICH in middle-aged and elderly people, both independently and combined with the use of aspirin. Other independent risk factors are untreated hypertension, previous ischemic stroke, epilepsy, and recent strenuous physical exertion. Epistaxis may be a warning sign of an increased risk for ICH in subjects using aspirin.
Sonographic Monitoring of Midline Shift in Space-Occupying Stroke
Authors: Gerriets T. , Stolz E. , König S. , Babacan S. , Fiss I. , Jauss M. , Kaps M.
Published: June 2011

Background and Purpose
—Transcranial color-coded duplex sonography (TCCS) allows bedside imaging of intracranial hemodynamics and parenchymal structures. It provides reliable information regarding midline shift (MLS) in space-occupying hemispheric stroke. We studied the value of MLS measurement to predict fatal outcome at different time points after stroke onset.

Methods
—Forty-two patients with acute, severe hemispheric stroke were enrolled. Cranial computed tomography (CCT) and extracranial duplex sonography were performed on admission. TCCS was carried out 8±3, 16±3, 24±3, 32±3, and 40±3 hours after stroke onset. Lesion size was determined from follow-up CCT.

Results
—Twelve patients died as the result of cerebral herniation (group 1); 28 survived (group 2). Two patients received decompressive hemicraniectomy and were therefore excluded from further evaluation. MLS was significantly higher in group 1 as early as 16 hours after onset of stroke. Specificity and positive predictive values for death caused by cerebral herniation of MLS ≥2.5, 3.5, 4.0, and 5.0 mm after 16, 24, 32, and 40 hours were 1.0.

Conclusions
—TCCS helps to estimate outcome as early as 16 hours after stroke onset and thus facilitates identification of patients who are unlikely to survive without decompressive craniectomy. Because of its noninvasive character and bedside suitability, sonographic monitoring of MLS might be a useful tool in management of critically ill patients who cannot undergo repeated CCT scans.
Effect of Intra-Arterial Papaverine on Regional Cerebral Blood Flow in Hemodynamically Relevant Cerebral Vasospasm
Authors: Vajkoczy Peter , Horn Peter , Bauhuf Christian , Munch Elke , Hubner Ulrich , Ing Dipl , Thome Claudius , Poeckler-Schoeninger Christiane , Roth Harry , Schmiedek Peter
Published: June 2011

Background and Purpose
—It remains controversial whether the intra-arterial administration of papaverine (IAP) is effective in reversing vasospasm-associated cerebral hypoperfusion after aneurysmal subarachnoid hemorrhage. The aim of the present study was to continuously assess regional cerebral blood flow (rCBF) during and after IAP with the use of quantitative, bedside thermal diffusion flowmetry.

Methods
—Eight patients with cerebral vasospasm after subarachnoid hemorrhage (mean flow velocity >120 cm/s; angiographic vessel constriction >33%; hemispheric cerebral blood flow [CBF] <32 mL/100 g per minute) were prospectively entered into the study. Before IAP, thermal diffusion microprobes were implanted into the white matter of each affected vascular territory (n=10) for rCBF monitoring. During and after IAP (300 mg papaverine/50 mL saline over 1 hour), mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, thermal diffusion rCBF (TD-rCBF), and cerebrovascular resistance (CVR) were recorded continuously.

Results
—IAP significantly increased TD-rCBF from 7.3±1.6 to 37.9±6.6 mL/100 g per minute (mean±SEM), indicating reversal of cerebral hypoperfusion. This TD-rCBF response was dependent on the degree of cerebral vasospasm and reduced perfusion within the vascular territory. Long-term analysis of TD-rCBF, however, demonstrated that this beneficial effect of IAP on cerebral hypoperfusion was only transient: within 3 hours after treatment, TD-rCBF and CVR returned to baseline values. Furthermore, a lack of correlation between transcranial Doppler sonography and thermal diffusion flowmetry suggested that transcranial Doppler sonography is not suited for CBF-based neuromonitoring after IAP.

Conclusions
—IAP is not effective in permanently reversing cerebral hypoperfusion in patients with cerebral vasospasm. The need to validate alternative therapeutic strategies that seek to improve cerebral perfusion in vasospasm warrants continued development of CBF-based neuromonitoring strategies.
Incidence of and Risk Factors for Medical Complications During Stroke Rehabilitation
Authors: Roth Elliot J. , Lovell Linda , Harvey Richard L. , Heinemann Allen W. , Semik Patrick , Diaz Sylvia
Published: June 2011

Background and Purpose
—The aims of this study were to examine the frequency, types, and clinical factors associated with medical complications that occur during inpatient rehabilitation and to identify risk factors for complications that require a transfer to an acute care facility.

Methods
—A cohort of 1029 patients consecutively admitted for inpatient stroke rehabilitation was studied. Demographic and stroke information, impairment, preexisting medical conditions, and admission laboratory abnormalities were recorded. Medical complications, defined as new or exacerbated medical problems, were documented for each patient. Complications that required transfer off rehabilitation were noted. Univariate and multiple logistic regression analyses were used to determine factors that were associated with risk of medical complications and risk of transfer off rehabilitation.

Results
—Seventy-five percent of patients experienced ≥1 medical complication during rehabilitation. Significant factors for the development of any medical complication included greater neurological deficit (odds ratio [OR], 4.10; confidence interval [CI], 1.88 to 8.91), hypoalbuminemia (OR, 1.71; 95% CI, 1.15 to 2.52), and history of hypertension (OR, 1.81; 95% CI, 1.27 to 2.59). Nineteen percent of patients had a medical complication that required transfer to an acute care facility. Significant factors for transfers were elevated admission white blood cell counts (OR, 1.92; 95% CI, 1.32 to 2.79), low admission hemoglobin levels (OR, 1.89; 95% CI, 1.32 to 2.68), greater neurological deficit (OR, 2.46; 95% CI, 1.37 to 4.39), and a history of cardiac arrhythmia (OR, 1.79; 95% CI, 1.18 to 2.67).

Conclusions
—Medical complications are common among patients undergoing stroke rehabilitation. A significant number of these medical complications may require a transfer to an acute facility.
Calcium Ion Transients in Peri-Infarct Depolarizations May Deteriorate Ion Homeostasis and Expand Infarction in Focal Cerebral Ischemia in Cats
Authors: Ohta Kouichi , Graf Rudolf , Rosner Gerd , Heiss Wolf-Dieter
Published: June 2011

Background and Purpose
—Harmful effects of peri-infarct depolarizations (PIDs) may depend on recurrent Ca
2+
influx. Thus far, few studies have documented the relevance of PIDs in gyrencephalic animals, and the progressive nature of this process has not been investigated over extended periods. We therefore studied in prolonged focal ischemia in cats spatial and temporal profiles of extracellular calcium ([Ca
2+
]
o
) shifts in relation to direct current (DC) potential, nitric oxide (NO) concentration and regional cerebral blood flow alterations, and final pathological outcome.

Methods
—In halothane-anesthetized cats receiving either vehicle (n=12) or MK-801 treatment (5 mg/kg IV; n=10), the left middle cerebral artery was permanently occluded. Laser-Doppler probes, ion-selective microelectrodes, and NO electrodes measured simultaneously regional cerebral blood flow, DC potential, electrocorticogram, [Ca
2+
]
o
, and NO concentrations in ectosylvian and suprasylvian gyri of the left cerebral cortex.

Results
—Persistent depolarization immediately after middle cerebral artery occlusion occurred in 10 ectosylvian and 4 suprasylvian gyri of vehicle-treated animals and in 9 ectosylvian and 3 suprasylvian gyri of MK-801–treated animals. PIDs associated with transient decreases of [Ca
2+
]
o
were detected in suprasylvian gyri of only 4 vehicle-treated animals, of which 3 developed recurrent PIDs. Electrocorticogram was suppressed during PIDs, and electrocorticogram recovery worsened in a stepwise manner with consecutive depolarizations. PID duration increased slightly with ongoing ischemia and evolved to persistent depolarization at a final stage. NO transients were not detected during PID, and regional cerebral blood flow transients were not pronounced. Infarction was larger with initial persistent depolarization than with PID and was smallest in MK-801–treated animals.

Conclusions
—PID is not a common finding in peri-infarct zones in cats, and it is suppressed by the
N
-methyl-
d
-aspartate antagonist MK-801. However, if repeated PIDs are generated, they result in a stepwise, progressive breakdown of neuronal function and ion homeostasis, probably contributing to the growth of infarction in focal cerebral ischemia. Recurrent Ca
2+
influx is a mechanism that presumably contributes to this process.