bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycine Site Antagonist Attenuates Infarct Size in Experimental Focal Ischemia
Authors: Takano Kentaro , Tatlisumak Turgut , Formato James E. , Carano Richard A. D. , Bergmann Andreas G. , Pullan Linda M. , Bare Thomas M. , Sotak Christopher H. , Fisher Marc
Published: June 2011

Background and Purpose
The glycine site on the
N
-methyl-
d
-aspartate (NMDA) receptor complex offers a therapeutic target for acute focal ischemia, potentially devoid of most side effects associated with competitive and noncompetitive NMDA antagonists.

Methods
A novel glycine receptor antagonist, ZD9379, was studied in 70 Sprague-Dawley rats using the suture occlusion model of permanent middle cerebral artery occlusion (MCAO). In the first experiment, 20 rats received an initial bolus of vehicle or 10 mg/kg ZD9379 (n=10 in each group) 30 minutes after MCAO, followed by a continuous infusion of the same dose per hour for 4 hours. Diffusion-weighted MRI with echo-planar acquisition was used to generate maps of the apparent diffusion coefficient (ADC) of water. In a second experiment, 50 rats were assigned to five groups: vehicle and 10, 5, 2.5, and 1 mg/kg ZD9379 (n=10 in each group) with the same dosing protocol but no imaging. In both experiments, infarct volume was determined by 2,3,5-triphenyltetrazolium chloride staining.

Results
In the first experiment, before therapy was begun, there was no significant difference in ADC-derived ischemic lesion volume between the two groups. Over time, the 10-mg/kg ZD9379–treated rats had a significant delayed regional recovery of reduced ADC values in the peripheral parietal cortex (
P
=.0156). Postmortem corrected infarct volume at 24 hours after MCAO was significantly smaller in the group treated with 10 mg/kg ZD9379 than in the vehicle group (119.2±52.2 versus 211.2±50.0 mm
3
[mean±SD];
P
=.0008; a reduction of 43.6%). In the second experiment, postmortem corrected infarct volumes in rats receiving 10, 5, and 2.5 mg/kg ZD9379 were significantly smaller than in those receiving vehicle, a reduction of 42.6%, 51.4%, and 42.9%, respectively (
P
=.0001).

Conclusions
This study demonstrates that 2.5- to 10-mg/kg doses of ZD9379 initiated 30 minutes after MCAO significantly reduced infarct size. Diffusion mapping disclosed a delayed treatment effect of this glycine antagonist in focal ischemia, confirmed by the postmortem study.
Role of Potassium Channels in Relaxations of Canine Middle Cerebral Arteries Induced by Nitric Oxide Donors
Authors: Onoue Hisashi , Katusic Zvonimir S.
Published: June 2011

Background and Purpose
The mechanisms underlying smooth muscle relaxations of cerebral arteries in response to nitric oxide (NO) and cyclic GMP (cGMP) are still not completely understood. The present study was designed to determine the role of potassium channels in the relaxations to NO donors 3-morpholinosydnonimine (SIN-1) and sodium nitroprusside (SNP), as well as 8-bromo-3′,5′-cGMP (a synthetic analogue of cGMP) and zaprinast (a selective cGMP phosphodiesterase inhibitor).

Methods
Rings of canine middle cerebral arteries without endothelium were suspended in Krebs-Ringer bicarbonate solution for isometric tension recording. The levels of cGMP were measured by radioimmunoassay. Relaxations to NO donors 8-bromo-cGMP and zaprinast were studied in the presence and in the absence of K
+
channel blockers charybdotoxin (large-conductance Ca
2+
-activated K
+
channels), glyburide (ATP-sensitive K
+
channels), 4-aminopyridine (delayed rectifier K
+
channels), and BaCl
2
(multiple types of K
+
channels).

Results
Concentration-dependent relaxations caused by NO donors (SIN-1 and SNP) were significantly reduced in arteries treated with BaCl
2
(3×10
−4
mol/L) or charybdotoxin (3×10
−8
mol/L). Relaxations to 8-bromo-cGMP were not affected by the same concentrations of BaCl
2
and charybdotoxin; however, they were reduced by higher concentrations of BaCl
2
(3×10
−3
mol/L) and charybdotoxin (10
−7
mol/L). Zaprinast-induced relaxations were significantly reduced by BaCl
2
(3×10
−4
mol/L) or charybdotoxin (3×10
−8
mol/L). Glyburide (10
−5
mol/L) and 4-aminopyridine (10
−3
mol/L) did not alter the relaxations to SIN-1 or SNP. The production of cGMP stimulated by SIN-1 in the vascular smooth muscle was not affected by BaCl
2
(3×10
−3
mol/L) or charybdotoxin (10
−7
mol/L).

Conclusions
These results indicate that in canine middle cerebral arteries, a significant portion of relaxations to NO liberated from nitrovasodilators is mediated by large-conductance Ca
2+
-activated K
+
channels. Other K
+
channels, sensitive to BaCl
2
, may also be involved in the mechanism of relaxations induced by NO.
CP-0597, a Selective Bradykinin B
2
Receptor Antagonist, Inhibits Brain Injury in a Rat Model of Reversible Middle Cerebral Artery Occlusion
Authors: Relton Jane K. , Beckey Virginia E. , Hanson Wendy L. , Whalley E. T.
Published: June 2011

Background and Purpose
Recent studies demonstrated a significant neuroprotective action of the selective peptide-based bradykinin B
2
receptor antagonist CP-0597 after permanent middle cerebral artery (MCA) occlusion (MCAO) in the rat. We therefore evaluated the efficacy of this compound after reversible MCAO in the rat.

Methods
Male Wistar rats underwent reversible MCAO by insertion of a nylon monofilament to the origin of the MCA. After 1 hour the filament was retracted and the ischemic tissue reperfused. Immediately after MCAO, primed miniosmotic pumps containing either vehicle or CP-0597 (300 ng/kg per minute) were implanted into the subcutaneous space (n=14 per group). Twenty-four hours after surgery, animals were killed and brains fixed, and 4-μm sections were taken from five sequential tissue blocks labeled A through E and stained with hematoxylin and eosin. Clinical evaluation of rats was performed by neurological scoring and change in body weight.

Results
Treatment with CP-0597 significantly reduced percent increase in hemisphere size of the ischemic hemisphere in all brain sections (C section: vehicle, 40.6±4.3% versus CP-0597, 20.8±5.3%;
P
<.001), total infarct volume (vehicle, 206.5±7.7 mm
3
versus CP-0597, 94.0±19.2 mm
3
;
P
<.001), cortical infarct volume (vehicle, 145.5±4.5 mm
3
versus CP-0597, 64.0±15.1 mm
3
;
P
<.001), subcortical infarct volume (vehicle, 55.8±4.1 mm
3
versus CP-0597, 27.5±4.5 mm
3
;
P
<.001), and the number of necrotic neurons (vehicle, 42.9±3.8 versus CP-0597, 23.6±4.7 per field;
P
<.01). Neurological score (vehicle, 2.78±0.36 versus CP-0597, 6.29±0.87;
P
<.01) and change in body weight (vehicle, −28.7±2.0 g versus CP-0597, −18.2±2.8 g;
P
<.01) were also significantly improved.

Conclusions
The present data demonstrate the significant overall efficacy profile of CP-0597 in a rat model of reversible MCAO and provide strong rationale for the use of such a bradykinin B
2
receptor antagonist in the treatment of stroke.
Cushing’s ‘Variant’ Response (Acute Hypotension) After Subarachnoid Hemorrhage
Authors: Marshman Laurence A.G.
Published: June 2011

Background and Purpose
Hypertension is considered common and appropriate with subarachnoid hemorrhage (SAH), maintaining cerebral perfusion. Hypotension, in contrast, is considered rare and detrimental. This study was designed to assess the frequency of each in both acute and subacute phases of primary SAH.

Methods
SAH was created by arterial rupture in spontaneously breathing rats under urethane anesthesia without craniotomy (n=32). Arterial pressure and intracranial pressure (ICP) were monitored invasively.

Results
After extensive extravasation, the mean ICP rose acutely from 8±1 to 53±4 mm Hg over 2.4±0.3 minutes. Acute pressor changes occurred transiently in 71%. The most common acute response was hypotension (63%). Hypertension, in contrast, was rare (6%); the remainder was invariant (29%). Hypertension was associated with significantly lower maximum ICP values (39±4 versus 69±4 mm Hg,
P
<.001) with a negative correlation between hypotension and ΔICP (
r
=−.7,
P
<.01). Distinct and independent of acute responses, hypotension also occurred subacutely as a cardiovascular collapse (38%).

Conclusions
In contrast to popular belief, the most common acute response with SAH is hypotension; hypertension is rare. This, in fact, is in full agreement with Cushing: hypertension was seen only with gradual ΔICPs. In contrast, a “variant” to the classic response (hypotension) occurred with sudden ΔICPs. In the present study, hypotension stanched SAH at lower maximum ICP values, and thus with less cerebral compression. Despite this, cardiovascular collapse developed in a large proportion irrespective of acute change. Such collapse without prior hypertension (94%) implies a nonadrenergic etiology.
Platelet Activation and Lipid Peroxidation in Patients With Acute Ischemic Stroke
Authors: van Kooten Fop , Ciabattoni Giovanni , Patrono Carlo , Dippel Diederik W. J. , Koudstaal Peter J.
Published: June 2011

Background and Purpose
Both platelet activation and lipid peroxidation are potential sources of vasoactive eicosanoids that can be produced via the cyclooxygenase pathway, ie, thromboxane (TX) A
2
, or by free radical–catalyzed peroxidation of arachidonic acid, ie, isoprostanes. We investigated the biosynthesis of TXA
2
and F
2
-isoprostanes, as reflected by the urinary excretion of 11-dehydro-TXB
2
and 8-epi-prostaglandin (PG) F
2
α
, respectively, in 62 consecutive patients (30 men, 32 women; mean age, 67±14 years) with acute ischemic stroke.

Methods
At least two consecutive 6-hour urine samples were obtained during the first 72 hours after onset of symptoms. Urinary eicosanoids were measured by previously described radioimmunoassays.

Results
Repeated periods of enhanced thromboxane biosynthesis were found in 52% of patients. Urinary 11-dehydro-TXB
2
averaged 221±207 (mean±SD; n=197; range, 13 to 967) pmol/mmol creatinine in 30 patients treated with cyclooxygenase inhibitors (mostly aspirin) at the time of study versus 392±392 (n=186; range, 26 to 2533) in 32 untreated patients (
P
<.001). The corresponding values for 8-epi-PGF
2
α
excretion were 74±42 (range, 14 to 206) and 83±65 (range, 24 to 570) pmol/mmol creatinine (
P
>.05). The correlation between the two metabolites was moderate in both untreated patients (
r
=.41,
P
<.001) and patients with cyclooxygenase inhibitors (
r
=.31,
P
<.001). In a multiple regression analysis, increased thromboxane production was independently associated with severity of stroke on admission, atrial fibrillation, and treatment with cyclooxygenase-inhibiting drugs.

Conclusions
We conclude that during the first few days after an acute ischemic stroke (1) platelet activation occurs repeatedly in a cyclooxygenase-dependent fashion; (2) platelet activation is not associated with concurrent changes in isoprostane biosynthesis; (3) platelet activation is independently associated with stroke severity and atrial fibrillation; and (4) isoprostane biosynthesis is largely independent of platelet cyclooxygenase activity.
Predictive Factors of Early Seizures After Acute Cerebrovascular Disease
Authors: Arboix Adrià , García-Eroles Luis , Massons Juan B. , Oliveres Montserrat , Comes Emili
Published: June 2011

Background and Purpose
Seizures within the first 48 hours of a first stroke or transient ischemic attack (TIA) are an independent prognostic factor for in-hospital mortality. The aim of this study was to determine predictive factors of early seizures in first-ever stroke patients.

Methods
Data of 1220 first-ever stroke patients admitted consecutively to an acute stroke unit of a 450-bed teaching hospital between January 1986 and December 1993 were collected from a stroke registry. Demographic, anamnestic, clinical, neurological, and neuroimaging variables in the seizure and nonseizure group were compared using the
t
test and the χ
2
test. The independent predictive value of each variable on the development of early seizures was assessed with a logistic regression analysis.

Results
Early epileptic seizures were diagnosed in 29 patients (2.4%). Seizures were significantly more frequent in patients with hemorrhagic stroke (4.3%) than in those with ischemic stroke (2%). Patients with seizures were significantly younger and significantly more likely to have acute confusional state, cortical involvement, large stroke, and involvement of the parietal, frontal, occipital, and temporal lobes than patients without seizures. The in-hospital mortality rate was 37.9% in the seizure group and 14.4% in the nonseizure group (
P
<.0005). After multivariate analysis, only cortical involvement (odds ratio of 6.01) and acute agitated confusional state (odds ratio of 4.44) were independent clinical factors for developing epileptic seizures.

Conclusions
Cortical involvement in the neuroimaging studies and agitated acute confusional state at the onset of stroke were independent predictive factors of early seizures in first-ever stroke patients. The efficacy of anticonvulsant drugs in the prophylactic control of seizures should be assessed in prospective, randomized, double-blind clinical trials conducted in the subgroup of patients with the highest risk of developing epileptic seizures.
Venous Microembolic Signals Detected in Patients With Cerebral Sinus Thrombosis
Authors: Valdueza José Manuel , Harms Lutz , Doepp Florian , Koscielny Jürgen , Einhäupl Karl Max
Published: June 2011

Background and Purpose
We sought to assess the usefulness of the Doppler technique in the monitoring of microembolic signals in the main venous outflow pathways in superior sagittal sinus thrombosis.

Methods
Transcranial Doppler ultrasound was performed with a range-gated 2-MHz transducer in 6 patients with superior sagittal sinus thrombosis, in 5 subjects with platelet hyperaggregability, and in 20 healthy volunteers. Emboli monitoring was performed mainly in one distal internal jugular vein for 10 to 15 minutes.

Results
Three of the six patients (50%) with superior sagittal sinus thrombosis had microemboli. None of the patients with platelet hyperaggregation or healthy volunteers revealed microemboli.

Conclusions
Microemboli can be found in superior sagittal sinus thrombosis by Doppler ultrasound. Their prognostic significance remains to be determined.
Microalbuminuria and Carotid Artery Intima-Media Thickness in Nondiabetic and NIDDM Subjects
Authors: Mykkänen Leena , Zaccaro Daniel J. , O’Leary Daniel H. , Howard George , Robbins David C. , Haffner Steven M.
Published: June 2011

Background and Purpose
Microalbuminuria is associated with cardiovascular mortality in subjects with non–insulin-dependent diabetes mellitus (NIDDM). However, little is known about this association in nondiabetic subjects. Specifically, it is not known whether microalbuminuria is related to an early stage of atherosclerosis manifested as increased intima-media thickness (IMT) of carotid arteries. We investigated the relationship between microalbuminuria and carotid artery IMT in 991 nondiabetic and 450 NIDDM subjects aged 40 to 69 years.

Methods
Microalbuminuria was defined as albumin-to-creatinine ratio ≥2 mg/mmol in a morning spot urine sample. B-mode ultrasound was used to assess the IMT of the common and internal carotid arteries.

Results
Altogether 13.9% of nondiabetic and 27.6% of NIDDM subjects had microalbuminuria, and 31.1% of nondiabetic and 50.8% of NIDDM subjects had hypertension. Subjects with microalbuminuria had greater common carotid artery (CCA) IMT than those without microalbuminuria (nondiabetic: 0.84±0.02 versus 0.80±0.01 mm,
P
=.010; NIDDM: 0.89±0.02 versus 0.86±0.01 mm,
P
=.152; combined: 0.86±0.01 versus 0.82±0.01,
P
=.005). The association of microalbuminuria and CCA IMT was independent of age, sex, ethnicity, smoking, and lipoprotein levels. Although further adjustment for hypertension in the multivariate linear regression analysis attenuated the difference in CCA IMT between subjects with and without microalbuminuria, this difference continued to be significant (combined: 0.86±0.01 versus 0.83±0.01,
P
=.015). In contrast to CCA IMT, microalbuminuria was not related to ICA IMT.

Conclusions
Microalbuminuria was associated with increased CCA IMT. This relationship was only partly mediated by hypertension. Thus, microalbuminuria is related to atherosclerosis at an early stage of the disease process.
Neurovascular Compression at the Ventrolateral Medulla in Autosomal Dominant Hypertension and Brachydactyly
Authors: Naraghi Ramin , Schuster Herbert , Toka Hakan R. , Bähring Sylvia , Toka Okan , Öztekin Özgür , Bilginturan Nihat , Knoblauch Hans , Wienker Thomas F. , Busjahn Andreas , Haller Hermann , Fahlbusch Rudolf , Luft Friedrich C.
Published: June 2011

Background and Purpose
Autosomal dominant hypertension with brachydactyly features severe hypertension that causes stroke usually before the age of 50 years. We recently characterized the hypertension as featuring normal renin, aldosterone, and catecholamine responses and mapped the gene responsible to chromosome 12p. Since angiography in an affected subject had earlier shown tortuous vessels, we performed magnetic resonance tomography (MRT) angiography to look for possible neurovascular anomalies (NVA), which have been previously associated with hypertension. NVA can be caused by a looping posterior inferior cerebellar or vertebral artery. Experimental and clinical evidence suggests that NVA may cause hypertension by a compression of the ventrolateral medulla.

Methods
We performed MRT in 15 hypertensive affected (aged 14 to 57 years) and 12 normotensive nonaffected (aged 12 to 59 years) family members. We then tested for linkage between the hypertension-brachydactyly phenotypes and the presence of NVA.

Results
All 15 affected persons had MRT evidence for NVA. All had left-sided posterior inferior cerebellar artery or vertebral artery loops, while 6 had bilateral NVA. None of the nonaffected family members had NVA. The phenotypes were linked with an LOD score of 9.2 given a penetrance of 99%.

Conclusions
Autosomal dominant hypertension and brachydactyly regularly feature NVA, which is frequently bilateral. The early age at which NVA was identified suggests that the condition is primary. We suggest that NVA may be involved in the pathogenesis of this form of hypertension and perhaps essential hypertension as well. Further studies are necessary to address the question of causation.
TP-9201, A Glycoprotein IIb/IIIa Platelet Receptor Antagonist, Prevents Rethrombosis After Successful Arterial Thrombolysis in the Dog
Authors: Rebello Sam S. , Driscoll Edward M. , Lucchesi Benedict R.
Published: June 2011

Background and Purpose
We examined the ability of TP-9201, a platelet glycoprotein IIb/IIIa receptor antagonist, to prevent carotid artery rethrombosis in the anesthetized dog.

Methods
Occlusive thrombosis was induced by electrolytic injury of the left carotid artery. Thirty minutes later, 0.05 U/kg of anisoylated plasminogen streptokinase activator complex (APSAC) was infused locally to achieve clot lysis. Carotid artery recanalization was followed immediately by the infusion of either saline (10 mL/h, 240 minutes; n=9), low-dose TP-9201 (120 μg/kg plus 3 μg · kg
–1
· min
–1
, 240 minutes; n=7), or high-dose TP-9201 (185 μg/kg plus 5 μg · kg
–1
· min
–1
, 240 minutes; n=7). Ex vivo platelet aggregation responses to ADP or arachidonic acid were determined.

Results
TP-9201 produced complete inhibition of platelet aggregation in citrated platelet-rich plasma but a partial and dose-dependent inhibition in heparinized platelet-rich plasma. A twofold and eightfold increase in the template bleeding time was associated with the infusion of low-dose and high-dose TP-9201, respectively. There were frequent cyclic flow reductions in both the saline and low-dose TP-9201–treated groups after thrombolysis. However, the high-dose TP-9201–treated group exhibited a sustained flow with minimal evidence of cyclic flow reductions. At the conclusion of the protocol, patent vessels were found more frequently in the high-dose TP-9201 (5/7;
P
=.0048) than in the low-dose TP-9201 treatment group (2/7;
P
=.17) when compared with the saline group (0/9). Infusion of high-dose TP-9201 was associated with a significant reduction in the thrombus mass as compared with the control vessels.

Conclusions
Administration of TP-9201 in conjunction with successful thrombolysis inhibited ex vivo platelet aggregation and prevented rethrombosis of the canine carotid artery. This study demonstrates that TP-9201, an inhibitor of the platelet GPIIb/IIIa receptor, can inhibit platelet–vessel wall interaction and thus prevent rethrombosis.
L-Type Ca
2+
Channel Blockers Attenuate Electrical Changes and Ca
2+
Rise Induced by Oxygen/Glucose Deprivation in Cortical Neurons
Authors: Pisani Antonio , Calabresi Paolo , Tozzi Alessandro , D’Angelo Vincenza , Bernardi Giorgio
Published: June 2011

Background and Purpose
—Experimental evidence supports a major role of increased intracellular calcium [Ca
2+
]
i
levels in the induction of neuronal damage during cerebral ischemia. However, the source of Ca
2+
rise has not been fully elucidated. To clarify further the role and the origin of Ca
2+
in cerebral ischemia, we have studied the effects of various pharmacological agents in an in vitro model of oxygen (O
2
)/glucose deprivation.

Methods
—Pyramidal cortical neurons were intracellularly recorded from a slice preparation. Electrophysiological recordings and microfluorometric measurements of [Ca
2+
]
i
were performed simultaneously in slices perfused with a glucose-free physiological medium equilibrated with a 95% N
2
/5% CO
2
gas mixture.

Results
—Eight to twelve minutes of O
2
/glucose deprivation induced an initial membrane hyperpolarization, followed by a delayed, large but reversible membrane depolarization. The depolarization phase was accompanied by a transient increase in [Ca
2+
]
i
levels. When O
2
/glucose deprivation exceeded 13 to 15 minutes, both membrane depolarization and [Ca
2+
]
i
rise became irreversible. The dihydropyridines nifedipine and nimodipine significantly reduced either the membrane depolarization or the [Ca
2+
]
i
elevation. In contrast, tetrodotoxin had no effect on either of these parameters. Likewise, antagonists of ionotropic and group I and II metabotropic glutamate receptors failed to reduce the depolarization of the cell membrane and the [Ca
2+
]
i
accumulation. Finally, dantrolene, blocker of intracellular Ca
2+
release, did not reduce both electrical and [Ca
2+
]
i
changes caused by O
2
/glucose depletion.

Conclusions
—This work supports a role of L-type Ca
2+
channels both in the electrical and ionic changes occurring during the early phases of O
2
/glucose deprivation.
Depressed Platelet Status in an Elderly Patient With Hemorrhagic Stroke After Thrombolysis for Acute Myocardial Infarction
Authors: Serebruany Victor L. , Gurbel Paul A. , Shustov Andrew R. , Dalesandro Margaret R. , Gumbs Cindy I. , Grabletz Laura B. , Bahr Raymond D. , Ohman E. Magnus , Topol Eric J.
Published: June 2011

Background
—Impaired platelet function has been reported in acute myocardial infarction (AMI) and stroke. However, prospective data on the changes of platelet status in patients before the occurrence of hemorrhagic stroke after thrombolytic therapy are unavailable.

Case Description
—An 86-year-old male patient was among the 23 AMI patients enrolled in the platelet study for the GUSTO-III trial. He received 325 mg of aspirin daily for at least 6 years, suffered an AMI, and was successfully reperfused with alteplase, but after 44 hours developed a large hemorrhagic stroke resulting in paraplegia. Platelet aggregation and receptor expression were measured by flow cytometry and ELISA before thrombolysis and at 3, 6, 12, and 24 hours thereafter. The percentage of platelet aggregation was lower in the stroke patient at every time point when induced by 5 μmol/L of ADP, by 10 μmol/L of ADP, and by thrombin than in the rest of the AMI group. Ristocetin and collagen-induced aggregability were within the group range. Decreased platelet glycoprotein Ib, IIb, IIIa, and IIb/IIIa and vitronectin receptor expression were observed in the stroke patient. No other differences in p24 (CD9), very late antigen-2, P-selectin, and platelet/endothelial cell adhesion molecule-1 expression were determined.

Conclusions
—Profound depression of platelet status preceded the occurrence of hemorrhagic stroke in an elderly long-term aspirin user treated with thrombolytic therapy. Initial “exhausted” platelets may be responsible for the increased risk for hemorrhagic stroke after coronary thrombolysis.
Etiopathogenesis of Transient Ischemic Attacks and Minor Ischemic Strokes
Authors: Sempere Angel P. , Duarte Jacinto , Cabezas Carmen , Clavería Luis Erik
Published: June 2011

Background and Purpose
—We sought to analyze the etiology and underlying vascular risk factors of transient ischemic attacks (TIAs) and minor ischemic strokes (MISs).

Methods
—We prospectively studied the vascular risk factors and etiologic categories in 235 patients with TIAs and MISs from a community-based register in a rural area of Spain. Five etiologic categories were considered: (1) cardioembolism, (2) large-artery atherosclerosis, (3) small-artery disease, (4) other etiologies, and (5) undetermined etiology. Systematic investigations included neuroimaging (CT/MRI) and vascular studies (duplex scan/MR angiography and angiography in selected cases).

Results
—The two most frequent etiologic categories were small-artery disease (31%) and cardioembolism (26%). Large-artery atherosclerosis was detected in 11% of the patients. Significant carotid stenosis (≥50%) was present in 13% of patients with carotid territory events. No cause could be found or it was uncertain in almost one third of the patients. The distribution of etiologic categories was similar in TIAs and MISs. The most prevalent vascular risk factors were as follows: arterial hypertension (50%), smoking (26%), atrial fibrillation (20%), hypercholesterolemia (17%), diabetes (15%), ischemic heart disease (12%), and peripheral vascular disease (3%). Carotid bruits were detected in 3% of the patients.

Conclusions
—An etiologic classification of TIAs and MISs is feasible. The two most frequent pathogenetic mechanisms in our study were small-artery disease and cardioembolism. The prevalence of large-artery atherosclerosis was low.
Changes in Subarachnoid Hemorrhage Mortality, Incidence, and Case Fatality in New Zealand Between 1981–1983 and 1991–1993
Authors: Truelsen Thomas , Bonita Ruth , Duncan John , Anderson Neil E. , Mee Edward
Published: June 2011

Background and Purpose
—As with total stroke, mortality rates from subarachnoid hemorrhage (SAH) have declined in New Zealand since the mid-1970s. Data from the Auckland Region Stroke studies allow an understanding of reasons for the change, as SAH incidence and 28-day case fatality rates were measured as part of population-based stroke registers.

Methods
—National death registrations were used to describe the trends in mortality rates from SAH (
International Classification of Diseases
[ICD] code 430) among men and women in New Zealand. Changes in incidence and case fatality rates were determined from 2 large-scale population-based stroke registries carried out in 1981–1983 and 10 years later in Auckland. Similar methodology and case ascertainment techniques were used in both studies.

Results
—The mortality rates from SAH declined in both men and women after the mid-1970s. The mortality rate remained higher among women than men. The incidence of SAH was lower in 1991–1993 (11.3 per 100 000) compared with 1981–1983 (14.6 per 100 000). In the younger age groups, the decrease was mostly due to a lower incidence among men, whereas in the older age groups women older than 65 years had a lower incidence. There was no consistent change in case fatality rates between the 2 periods in either men or women.

Conclusions
—Mortality rates from SAH have decreased in both men and women. This decrease may be explained by a decrease in the incidence of SAH, because case fatality rates showed no change.
Angiographic and Histological Evaluation of Porcine Retinal Vascular Damage and Protection With Perfluorocarbons After Massive Air Embolism
Authors: Herren Janelle I. , Kunzelman Karyn S. , Vocelka Craig , Cochran R.P. , Spiess Bruce D.
Published: June 2011

Background and Purpose
—We have previously shown that perfluorocarbon emulsions (PFEs) reduce the severity of cerebral injury (indicated by infarct, reduced blood flow, and depressed EEG) induced by air embolism during cardiopulmonary bypass (CPB). This study used retinal fluorescein angiography to define the mechanisms of cerebral injury and to determine the efficacy of PFEs in cerebral protection. These angiographic findings were correlated to previously reported histologic findings.

Methods
—Twenty domestic pigs underwent CPB with a prime of standard crystalloid or PFE (5 mg/kg) and crystalloid. After 10 minutes on CPB, a single (5 mL/kg) or double (2×2.5 mL/kg) bolus of room air or saline (control) was delivered via the right carotid artery. Retinal fluorescein angiograms were captured at 4 time points: baseline, air insult, postbypass, and postreperfusion. Following euthanasia, both eyes were removed and the retinas isolated for histological analysis with horseradish peroxidase (HRP), as previously reported.

Results
—In control pigs, postreperfusion angiograms showed small nonperfused areas, and retinal whole mounts demonstrated vascular damage as previously reported. In 5 PFE-primed animals, postreperfusion angiograms showed hyperfluorescence, but angiograms and HRP mounts were otherwise not significantly different from baseline. Severely hyperfluorescent vessels observed angiographically also showed a correlation with HRP extravasation but were not consistently indicative of severe vascular damage.

Conclusions
—Retinal fluorescein angiography and retinal staining with HRP indicate that mechanisms of cerebral air embolism include nonperfusion, vascular leakage and spasm, red blood cell sludging, and hemorrhage. Priming with PFE prevented many of the sequelae associated with air embolism.
Total Homocyst(e)ine Concentration and the Likelihood of Nonfatal Stroke
Authors: Giles Wayne H. , Croft Janet B. , Greenlund Kurt J. , Ford Earl S. , Kittner Steven J.
Published: June 2011

Background and Purpose
—Elevated serum total homocyst(e)ine [H(e)] is an independent risk factor for stroke. Few studies, however, have examined this association in blacks.

Methods
—Data from the Third National Health and Nutrition Examination Survey (n=4534), a nationally representative sample of US adults, were used to examine the relationship between H(e) and a physician diagnosis of stroke (n=185) in both black and white adults. Multivariate-adjusted logistic regression analyses were used to examine this relationship.

Results
—Serum vitamin B
12
and folate concentrations were significantly lower among participants in the highest H(e) quartile (≥12.1 μmol/L) than among participants in the lowest quartile (≤7.4 μmol/L). Those in the highest quartile were older, had higher mean cholesterol and blood pressure levels, and were more likely to smoke and to have completed <12 years of education. After adjustment for age, the odds ratio (OR) for stroke was 2.9 (95% confidence interval [CI], 1.4 to 5.7; highest versus lowest quartile). Adjustment for gender, race/ethnicity, education, systolic blood pressure, cholesterol, diabetes mellitus, and smoking reduced the magnitude of the association (OR, 2.3; 95% CI, 1.2 to 4.6). The association between H(e) and stroke did not differ by race [
P
=0.265 for race-H(e) interaction term]. The multivariate adjusted OR for the highest quartile versus the lowest was 2.5 (1.1 to 5.5) among whites and 1.4 (0.4 to 4.7) among blacks.

Conclusions
—In this nationally representative sample of US adults, H(e) concentration was independently associated with an increased likelihood of nonfatal stroke. This association was present in both black and white adults.
Preoperative Thallium Scanning, Selective Coronary Revascularization, and Long-Term Survival After Carotid Endarterectomy
Authors: Landesberg Giora , Wolf Yehuda , Schechter David , Mosseri Morris , Weissman Charles , Anner Haim , Chisin Roland , Luria Myron H. , Kovalski Nahum , Bocher Moshe , Erel Jacob , Berlatzky Yacov
Published: June 2011

Background and Purpose
—Long-term survival in patients after carotid endarterectomy (CEA) is determined mainly by their concomitant cardiac disease. We tested to determine whether preoperative thallium scanning (PTS) and subsequent selective coronary revascularization (CR), by either percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG), improve long-term survival after CEA.

Methods
—Two hundred twenty-six of 255 consecutive patients (88%) undergoing CEA from 1990 to 1996 had PTS. Those with significant reversible defects on PTS were referred for coronary angiography and possible CR. Patients who had undergone PTS were divided into the following 4 groups: group 1, normal or mild defects on PTS; group 2, moderate-severe fixed and/or reversible defects in patients who did not undergo CR; group 3, patients who had CR secondary to their PTS results; and group 4, patients who had CR in the past that was not related to the PTS. Perioperative data were prospectively recorded, and data on long-term survival and cardiac and neurological complications were collected.

Results
—Seventy-seven patients (34%) had preoperative coronary angiography, and 42 (19%) had subsequent CR: preoperative PTCA or CABG in 24, combined CEA+CABG in 10, and post-CEA CABG in 8 patients. No deaths resulted from the coronary angiography, CR, or CEA. Six patients had perioperative nonfatal myocardial infarction and 8 had stroke. During the follow-up (40±23 months), 47 patients (18%) died, 31 (66%) from cardiac disease and 4 (8.5%) from stroke. Independent predictors of long-term overall mortality were diabetes mellitus, preoperative T-wave inversion on ECG, lower-extremity arterial disease, and history of neurological symptoms [exp(β)=3.5, 3.4, 2.5, and 2.4;
P
=0.0003, 0.0004, 0.01, and 0.04, respectively]. In addition, preoperative moderate-severe thallium defect without CR (group 2) independently predicted long-term cardiac mortality [exp(β)=2.8;
P
=0.04]. Patients with preoperative CR (group 3) had long-term survival rate similar to that of group 1 and significantly better than that of group 2 (
P
=0.02).

Conclusions
—PTS predicts long-term survival, and selective CR based on the thallium results improves the survival rate of patients undergoing CEA.
Effect of the No-Flow Interval and Hypothermia on Cerebral Blood Flow and Metabolism During Cardiopulmonary Resuscitation in Dogs
Authors: Shaffner Donald H. , Eleff Scott M. , Koehler Raymond C. , Traystman Richard J.
Published: June 2011

Background and Purpose
—We sought (1) to determine the effect of brief periods of no flow on the subsequent forebrain blood flow during cardiopulmonary resuscitation (CPR) and (2) to test the hypothesis that hypothermia prevents the impact of the no-flow duration on cerebral blood flow (CBF) during CPR.

Methods
—No-flow intervals of 1.5, 3, and 6 minutes before CPR at brain temperatures of 28°C and 38°C were compared in 6 groups of anesthetized dogs. Microsphere-determined CBF and metabolism were measured before and during vest CPR adjusted to maintain cerebral perfusion pressure at 25 mm Hg.

Results
—Increasing the no-flow interval from 1.5 to 6 minutes at 38°C decreased the CBF (18.6±3.6 to 6.1±1.7 mL/100 g per minute) and the cerebral metabolic rate (2.1±0.3 to 0.7±0.2 mL/100 g per minute) during CPR. Cooling to 28°C before and during the arrest eliminated the detrimental effects of increasing the no-flow interval on CBF (16.8±1.0 to 14.8±1.9 mL/100 g per minute) and cerebral metabolic rate (1.1±0.1 to 1.3±0.1 mL/100 g per minute). Unlike the forebrain, 6 minutes of preceding cardiac arrest did not affect brain stem blood flow during CPR.

Conclusions
—Increasing the no-flow interval to 6 minutes in normothermic animals decreases the supratentorial blood flow and cerebral metabolic rate during CPR at a cerebral perfusion pressure of 25 mm Hg. Cooling to 28°C eliminates the detrimental impact of the 6-minute no-flow interval on the reflow produced during CPR. The brain-protective effects of hypothermia include improving reflow during CPR after cardiac arrest. The effect of hypothermia and the impact of short durations of no flow on reperfusion indicate that increasing viscosity and reflex vasoconstriction are unlikely causes of the “no-reflow” phenomenon.
Comparison of the Use of Medical Resources and Outcomes in the Treatment of Aneurysmal Subarachnoid Hemorrhage Between Canada and the United States
Authors: Glick Henry A. , Polsky Daniel , Willke Richard J. , Alves Wayne M. , Kassell Neal , Schulman Kevin
Published: June 2011

Objective
—Using data from a randomized trial of tirilazad mesylate, we assessed the differences between Canada and the United States in the use of medical resources and outcomes in the treatment of aneurysmal subarachnoid hemorrhage during the first 90 days after admission to the hospital.

Methods
—Of the 877 patients for whom economic data were available, 194 were enrolled in Canada and 683 were enrolled in the United States. The differences between the countries in patient characteristics, use of medical resources, and outcomes were analyzed by comparing means and the 95% confidence intervals (CIs) around the differences in means. These differences also were predicted with use of multivariable regression analysis.

Results
—The average hospital stay was 4.2 days longer (95% CI, 1.3 to 7.1 days) in Canada, but most of the extra stay was among patients admitted to the study in poor neurological condition. In general, however, hospital stays in Canada were substantially less intensive. Patients treated in Canada spent 3.7 fewer days (95% CI, 1.2 to 6.1 days) in nursing homes and rehabilitation centers than did patients in the United States. No statistically significant differences were seen for Glasgow Outcome Scale score, death, and occurrence of vasospasm.

Conclusions
—For patients admitted to the study in good neurological condition, the apparent difference in length of stay between Canada and the United States was caused by a shift in the sites of formal care rather than to the length of this care. For those admitted in poor neurological condition, both the length and sites of care differed between the two countries. No significant difference in outcomes appeared to justify these differences in the use of medical resources.
tPA-Associated Reperfusion After Acute Stroke Demonstrated by SPECT
Authors: Grotta James C. , Alexandrov Andrei V.
Published: June 2011

Purpose
—The aim of our study was twofold: to determine the frequency and magnitude of perfusion defect in stroke patients who qualify for rtPA therapy within 3 hours of stroke onset and to determine the ability of rtPA to improve perfusion by 24 hours.

Subjects and Methods
—Patients with suspected hemispheric stroke who fulfilled entry criteria into the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study and also had pretreatment injection of
99m
Tc-HMPAO, with single-photon emission computed tomography (SPECT) performed using a triple-head camera at baseline and 24 hours, were included.

Results
—All 12 patients who qualified for rtPA therapy had perfusion defects on baseline SPECT (SPECT graded scale [SGS] score range, 16 to 79). Mean±SD perfusion defect was comparable in rtPA (n=4)versus placebo (n=5) groups (SGS score, 36±18 versus 39±12; NS) despite earlier injection time in the rtPA group (98±24 versus 141±21 minutes;
P
=.02). Total SPECT scanning time was 20 to 25 minutes. At 24 hours, reperfusion was greater in rtPA patients compared with the placebo group (SGS score, 7±9 versus 29±17;
P
=.05), with relative improvement in the region-of-interest scores of 87±16% after rtPA compared with 28±30% with placebo (
P
=.01).

Conclusions
—A substantial perfusion defect exists in stroke patients with larger hemispheric infarcts who meet NINDS criteria for rtPA therapy, and rtPA is better able than placebo to rectify this defect. SPECT is feasible for clinical trials and should be evaluated as a substituted end point in stroke therapeutic trials.
Collateralization of an Occluded Internal Carotid Artery Via a Vas Vasorum
Authors: Kemény Vendel , Droste Dirk W. , Nabavi Darius G. , Schulte-Altedorneburg Gernot , Schuierer Gerhard , Ringelstein E. Bernd
Published: June 2011

Background
—Reopening of an occluded internal carotid artery (ICA) is often seen in dissections but only rarely occurs in atherothrombotic occlusion of the internal carotid artery.

Case Description
—A 60-year-old man suffered a minor stroke with dysphasia in March 1995. Color-coded duplex ultrasonography of his neck arteries revealed a left ICA occlusion. He was placed on a regimen of aspirin and followed up clinically and with ultrasonography. At follow-up 18 months later, the patient was asymptomatic. On duplex ultrasonography his left occluded ICA was found to be reopened, with a residual, proximal, high-grade stenosis. However, intra-arterial digital subtraction angiography demonstrated a persistent ICA occlusion and a vas vasorum originating from the carotid bulb and draining into the ICA distal to the occlusion.

Conclusions
—The rare collateralization of an occluded ICA by vasa vasorum seems to take several months. It can be a pitfall in the ultrasound diagnosis of carotid artery occlusive disease.
Platelet Glycoprotein Receptor IIIa Polymorphism P1A2 and Ischemic Stroke Risk
Authors: Wagner Kathryn R. , Giles Wayne H. , Johnson Constance J. , Ou Chin-Yih , Bray Paul F. , Goldschmidt-Clermont Pascal J. , Croft Janet B. , Brown Vicki K. , Stern Barney J. , Feeser Barbara R. , Buchholz David W. , Earley Christopher J. , Macko Richard F. , McCarter Robert J. , Sloan Michael A. , Stolley Paul D. , Wityk Robert J. , Wozniak Marcella A. , Price Thomas R. , Kittner Steven J.
Published: June 2011

Background and Purpose
—Platelet glycoprotein IIb/IIIa (GpIIb-IIIa), a membrane receptor for fibrinogen and von Willebrand factor, has been implicated in the pathogenesis of acute coronary syndromes but has not been previously investigated in relation to stroke in young adults.

Methods
—We used a population-based case-control design to examine the association of the GpIIIa polymorphism P1A2 with stroke in young women. Subjects were 65 cerebral infarction cases (18 patients with and 47 without an identified probable etiology) 15 to 44 years of age from the Baltimore-Washington region and 122 controls frequency matched by age from the same geographic area. A face-to-face interview for vascular disease risk factors and a blood sample for the P1A2 allele and serum cholesterol were obtained from each participant. Logistic regression was used to estimate the odds ratio for one or more P1A2 alleles after adjustment for other risk factors.

Results
—Among cases and controls, the prevalence rates of one or more P1A2 alleles were 21% and 22% among blacks and 36% and 28% among whites, respectively. This genotype was significantly associated with hypertension only in black control subjects but otherwise not with any of the established vascular risk factors. The adjusted odds ratio for cerebral infarction of one or more P1A2 alleles was 1.1 (confidence interval [CI], 0.6 to 2.3) overall, 0.5 (CI, 0.1 to 7.1) among blacks, and 1.4 (CI, 0.5 to 3.7) among whites. For the cases with an identified probable etiology, the corresponding odds ratios were 3.0 (CI, 0.9 to 10.4) overall, 0.7 (CI, 0.1 to 7.1) among blacks, and 12.8 (CI, 1.2 to 135.0) among whites.

Conclusions
—No association was found between the P1A2 polymorphism of GpIIIa and young women with stroke. However, subgroup analyses showed that the P1A2 polymorphism of GpIIIa appeared to be associated with stroke risk among white women, particularly those with a clinically identified probable etiology for their stroke. Further work with an emphasis on stroke subtypes and with multiracial populations is warranted.
Effect of Vasospasm on Heme Oxygenases in a Rat Model of Subarachnoid Hemorrhage
Authors: Kuroki Minoru , Kanamaru Kenji , Suzuki Hidenori , Waga Shiro , Semba Reiji
Published: June 2011

Background and Purpose
—Subarachnoid hemorrhage (SAH)-induced heme oxygenase-1 (HO-1) in glia throughout the rat brain without affecting heme oxygenase-2 (HO-2). However, the relationship between cerebral vasospasm and the expression of heme oxygenases after SAH is thus far unknown. The purpose of the present study was to clarify the effect of vasospasm on the expression of heme oxygenases in a rat model of SAH.

Methods
—Endothelin, hemolysate, hemolysate saturated with carbon monoxide (CO-hemolysate), and saline were injected into the cisterna magna of adult rats. Angiography was repeated before each injection and 15 and 60 minutes and 24 hours after each injection. Immunocytochemistry for HO-1, HO-2, and glial fibrillary acidic protein (GFAP) was performed 24 hours after the injection.

Results
—A significant vasospasm occurred in the basilar artery after the injection of endothelin, hemolysate, and CO-hemolysate. The degree of vasospasm was most prominent 15 minutes after each injection. There was no significant difference in the degree of vasospasm among injections. The HO-1 was induced exclusively in the glial cells throughout the brain after injection of hemolysate and CO-hemolysate; however, it was not induced by endothelin and saline. In the dentate gyrus of the hippocampus and the molecular layer of the cerebellum, the HO-1−positive cells were also stained for GFAP, suggesting astrocytic glial cells. On the other hand, HO-2 immunoreactivity was abundant in neurons and was not affected by endothelin, hemolysate, CO-hemolysate, or saline.

Conclusions
—It is suggested that heme per se, rather than ischemia induced by vasospasm, plays a pivotal role in the expression of HO-1 in this rat model.