bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological Effects of the Spin Trap Agents
N
-t-Butyl-Phenylnitrone (PBN) and 2,2,6,6-Tetramethylpiperidine-
N
-Oxyl (TEMPO) in a Rabbit Thromboembolic Stroke Model
Authors: Lapchak Paul A. , Chapman Deborah F. , Zivin Justin A.
Published: June 2011

Background and Purpose
—It has been proposed that spin trap agents such as
N
-t-butyl-phenylnitrone (PBN) may be useful as neuroprotective agents in the treatment of ischemia and stroke. However, to date, there is little information concerning the effectiveness of spin trap agents when administered in combination with the only Food and Drug Administration–approved pharmacological agent for the treatment of stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of PBN when administered before tPA on hemorrhage and infarct rate and volume. We also compared the effects of PBN with those of 2,2,6,6-tetramethylpiperidine-
N
-oxyl (TEMPO), another spin trap agent that has a different chemical structure and trapping profile, on the incidence of infarcts and hemorrhage.

Methods
—One hundred sixty-five male New Zealand White rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five minutes after embolization, PBN or TEMPO (100 mg/kg) was infused intravenously. Control rabbits received saline, the vehicle required to solubilize the spin traps. In tPA studies, rabbits were given intravenous tPA starting 60 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis.

Results
—In the control group, the hemorrhage rate after a thromboembolic stroke was 24%. The amount of hemorrhage was significantly increased to 77% if the thrombolytic tPA was administered. The rabbits treated with PBN in the absence of tPA had a 91% incidence of hemorrhage compared with 33% for the TEMPO-treated group. In the combination drug–treated groups, the PBN/tPA group had a 44% incidence of hemorrhage, and the TEMPO/tPA group had a 42% incidence of hemorrhage. tPA, PBN/tPA, and TEMPO/tPA were similarly effective at lysing clots (49%, 44%, and 33%, respectively) compared with the 5% rate of lysis in the control group. There was no significant effect of drug combinations on the rate or volume of infarcts.

Conclusions
—This study suggests that certain spin trap agents may have deleterious effects when administered after an embolic stroke. However, spin trap agents such as PBN or TEMPO, when administered in combination with tPA, may improve the safety of tPA by reducing the incidence of tPA-induced hemorrhage. Overall, the therapeutic benefit of spin trap agents for the treatment of ischemic stroke requires additional scrutiny before they can be considered “safe” therapeutics.
Reduced Cerebrovascular CO
2
Reactivity in CADASIL
Authors: Pfefferkorn Thomas , von Stuckrad-Barre Sebastian , Herzog Jürgen , Gasser Thomas , Hamann Gerhard F. , Dichgans Martin
Published: June 2011

Background and Purpose
—Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in
Notch3
. Cerebral microvessels show an accumulation of granular osmiophilic material in the vicinity of degenerating vascular smooth muscle cells. To study cerebrovascular function in CADASIL, we performed measurements on cerebral hemodynamics by using transcranial Doppler sonography.

Methods
—Middle cerebral artery (MCA) mean blood flow velocity (MFV), cerebrovascular CO
2
reactivity, and the resistance index were measured by bilateral transcranial Doppler sonography in 29 CADASIL individuals (mean age, 49.0±2.4 years) and an equal number of age- and sex-matched control subjects.

Results
—Compared with control subjects, CO
2
reactivity was reduced in CADASIL (33.4±2.7% versus 45.3±3.0%;
P
<0.01). This difference remained significant when only nondisabled CADASIL individuals (Rankin=0, n=21) were included in the analysis (
P
<0.05). CO
2
reactivity was significantly lower in disabled than in nondisabled CADASIL individuals (24.5±2.7% versus 36.8±3.4%;
P
<0.05). MCA MFV was reduced in CADASIL (45.6±2.2 cm/s versus 54.2±2.4 cm/s;
P
<0.05) and correlated negatively with age both in affected individuals (
r
=−0.314;
P
<0.05) and control subjects (
r
=−0.339;
P
<0.05). Resistance index was not significantly altered (59.0±1.0% versus 57.7±1.2%;
P
=0.42).

Conclusions
—In CADASIL, there is a reduction of both CO
2
reactivity and basal MCA MFV. The reduced CO
2
reactivity suggests functional impairment of cerebral vasoreactivity probably related to vascular smooth muscle cell dysfunction. The reduction of CO
2
reactivity in nondisabled CADASIL individuals suggests an early role of impaired cerebral vasoreactivity in the evolution of the disease.
Inhibition of Poly(ADP-Ribose) Polymerase Attenuates Cerebral Vasospasm After Subarachnoid Hemorrhage in Rabbits
Authors: Satoh Motoyoshi , Date Isao , Nakajima Masaaki , Takahashi Kenji , Iseda Keiichi , Tamiya Takashi , Ohmoto Takashi , Ninomiya Yoshifumi , Asari Shoji
Published: June 2011

Background and Purpose
—Poly(ADP-ribose) polymerase (PARP) is important in modulating inflammation, which has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). We investigated the role of PARP in vasospasm using 3-aminobenzamide (3-AB), a PARP inhibitor, in a rabbit model.

Methods
—Twenty-four New Zealand White rabbits were divided into 4 groups: (1) no treatment (control group, n=6); (2) blood injection without pretreatment (SAH-only group, n=6); (3) blood injection with pretreatment by vehicle (SAH+vehicle group, n=6); and (4) blood injection with pretreatment by 3-AB (SAH+3-AB group, n=6). We used the single-hemorrhage model of SAH, injecting autologous arterial blood into the cisterna magna. Angiography was performed before (baseline) and after (day 2) SAH, and the diameter of the basilar artery (BA) was measured. Animals were euthanatized after the second angiogram. After perfusion and fixation, the brains were cut into sections for hematoxylin and eosin and immunohistochemical staining for poly(ADP-ribosyl)ation.

Results
—In the control group, there were no differences in the BA lumen caliber between baseline and day 2 (96.8±10.4%). Cerebral vasospasm in the SAH+3-AB group (88.2±6.2%) was remarkably attenuated in comparison with that in the SAH-only group (64.9±8.0%) and the SAH+vehicle group (65.6±10.8%). The BA in the SAH+3-AB group showed less corrugation of the tunica elastica interna than that in the SAH-only and SAH+vehicle groups. Staining for poly(ADP-ribosyl)ation was markedly inhibited in smooth muscle and adventitial cells of the BA in the SAH+3-AB group compared with other groups.

Conclusions
—Inhibiting ADP-ribosylation attenuates cerebral vasospasm after SAH in rabbits, and PARP activation may play an important role in the development of cerebral vasospasm.
Prolonged Mild Hypothermia Therapy Protects the Brain Against Permanent Focal Ischemia
Authors: Yanamoto H. , Nagata I. , Niitsu Y. , Zhang Z. , Xue J.-H. , Sakai N. , Kikuchi H.
Published: June 2011

Background and Purpose
—The efficacy of hypothermic intervention for permanent focal ischemia has yet to be clarified. This study investigated the effect of a prolonged moderate or mild hypothermia on permanent focal ischemia in rats.

Methods
—Two permanent focal ischemia models in male Sprague-Dawley rats were used. Moderate (30°C, in experiment 1) or mild (33°C, in experiment 2) hypothermia was achieved at the time of the induction of focal ischemia and was maintained for 2 hours under general anesthesia. Thereafter, the hypothermic condition was maintained by means of a cold room for a total of 24 hours. The infarct volume and neurological function were analyzed for a maximum of 21 days and compared with that of the normothermia group. Regional cerebral blood flow was monitored for 6 hours in the ischemic core and penumbra region.

Results
—In experiment 1, the total infarct volume in the normothermic group was 368±59 mm
3
; in contrast, it was significantly smaller in the hypothermia group: 169±33 mm
3
at 48 hours (mean±SEM,
P
<0.05). In experiment 2, the infarct volume was 211±19 mm
3
in the normothermia group and 88±15 mm
3
in the hypothermia group at 21 days (
P
<0.05). There were significant differences in neurological function from days 2 through 21 between the two groups. Mean regional cerebral blood flow in the penumbra region increased to a level >50% of baseline.

Conclusions
—Prolonged mild hypothermia suppressed the development of cerebral infarct and neurological deficit chronically after the induction of permanent focal ischemia.
Ethanol-Induced Contractions in Cerebral Arteries
Authors: Yang Zhi-wei , Wang Jun , Zheng Tao , Altura Bella T. , Altura Burton M.
Published: June 2011

Background and Purpose
—The relationship between alcohol consumption and stroke appears complex; moderate ingestion is associated with reduced stroke risk, while heavy intake is associated with increased stroke risk. Ethanol has been shown both experimentally and epidemiologically to induce hemorrhagic and ischemic strokes, which are associated with cerebral vasoconstriction. Ethanol is known to induce contraction in isolated cerebral arteries and intact microvessels from diverse mammalian animals. The relationships between ethanol-induced contractions in cerebral arteries, intracellular free Ca
2+
([Ca
2+
]
i
), tyrosine kinases (including the src family), and mitogen-activated protein kinases (MAPK) were investigated in the present study.

Methods
—Cerebral arterial muscle tension and [Ca
2+
]
i
were quantified by an isometric contraction technique and direct visualization of Ca
2+
in single cells.

Results
—Ethanol induces concentration-dependent contractions in intact canine basilar arteries, which are attenuated significantly by pretreatment of the arteries with low concentrations of an antagonist of protein tyrosine kinases (genistein); an src homology 2 (SH2) domain inhibitor peptide; a highly specific antagonist of p38 MAPK (SB-203580); a potent, selective antagonist of MEK1/MEK2 (U0126); and a selective antagonist of mitogen-activated protein kinase kinase (MAPKK) (PD-98059). IC
50
levels obtained for these 5 antagonists are consistent with reported
K
i
values for these tyrosine kinase, MAPK, and MAPKK antagonists. Ethanol induces transient and sustained increases in [Ca
2+
]
i
in primary single smooth muscle cells from canine basilar arteries, which are markedly attenuated in the presence of genistein, an SH2 domain inhibitor peptide, SB-203580, U0126, and PD-98059. Several specific antagonists of known endogenously formed vasoconstrictors do not inhibit or attenuate either the ethanol-induced contractions or the elevation of [Ca
2+
]
i
.

Conclusions
—The present study suggests that activation of protein tyrosine kinases (including the src family) and MAPK appear to play important roles in the ethanol-induced contractions and the elevation of [Ca
2+
]
i
in smooth muscle cells from canine basilar arteries. The results could be used to suggest that selective antagonists of protein tyrosine kinases and MAPK may be useful both prophylactically and therapeutically in alcohol-induced strokes.
Cerebrovascular Risk Factors and Stroke Subtypes
Authors: Hajat Cother , Dundas Ruth , Stewart Judy A. , Lawrence Enas , Rudd Anthony G. , Howard Robin , Wolfe Charles D. A.
Published: June 2011

Background and Purpose
—The excess risk of stroke seen in the black population has not been explained by differences in age, sex, and social class, although differences in the frequency of cerebrovascular risk factors may be partly responsible. Data on risk factor profiles for the UK black stroke population are sparse. Previous studies have contrasted the association of cerebrovascular risk factors between hemorrhagic and ischemic stroke and between etiologic subtypes of infarct. The relationship of cerebrovascular risk factors to clinical classifications of stroke, however, has been little examined. The aim of this study was to establish the frequency of cerebrovascular risk factors in patients with first-ever strokes in the South London, UK, population and to examine the relationship of these risk factors to both ethnicity and Bamford stroke subtype.

Methods
—The study included 1254 first-ever stroke patients registered in the South London Community Stroke Register between 1995 and 1998; 995 patients (79.3%) were white, 203 (16.2%) were black, 52 (4.1%) were of other ethnic origin, and 4 (0.3%) were of unknown ethnic origin.

Results
—In multivariate analysis, increasing age (
P
<0.001) and previous cerebrovascular disease (
P
=0.007) were independently associated with infarct rather than hemorrhage. Atrial fibrillation was associated with all nonlacunar (
P
=0.02), total anterior circulation (
P
=0.007), and partial anterior circulation infarcts (
P
=0.02) compared with the lacunar group. All other risk factors were similar between infarct subtypes. Risk factors for hemorrhage subtypes were similar in multivariate analysis; increasing age was the only factor associated with primary intracerebral hemorrhage over subarachnoid hemorrhage (
P
<0.001). The black stroke population suffered significantly less atrial fibrillation (
P
=0.001) and engaged in less alcohol excess (
P
<0.001) and were less likely to have ever smoked (
P
<0.001). Hypertension (
P
<0.001) and diabetes mellitus (
P
<0.001) were more prevalent in the black population.

Conclusions
—Physiological cerebrovascular risk factors for the UK black population are similar to those of the US black population, but behavioral risk factors differ. Risk factors differ between ethnic groups in the United Kingdom, and future measures for secondary prevention should take this into consideration. Bamford clinical subtypes bear little association with cerebrovascular risk factors. Other classification systems, such as those that classify stroke by etiology, may be more useful in explaining the excess risk of stroke and the scope for its prevention.
Plasma Homocysteine Concentrations in the Acute and Convalescent Periods of Atherothrombotic Stroke
Authors: Meiklejohn D. J. , Vickers M. A. , Dijkhuisen R. , Greaves M.
Published: June 2011

Background and Purpose
—Homocysteine is a proposed causal risk factor for atherosclerosis, but this remains controversial. We measured fasting plasma homocysteine concentrations immediately after atherothrombotic stroke and in the convalescent period to investigate this controversy.

Methods
—One hundred six patients (59 men and 47 women, mean age 57.2 [25 to 70] and 56.5 [26 to 69] years, respectively) were recruited within 24 hours of admission, and 82 patients were resampled at least 3 months later. Fasting total plasma homocysteine (tHcy) concentrations were measured by high-performance liquid chromatography.

Results
—Median tHcy in the acute phase of stroke was not significantly higher than in matched control subjects (men 9.2 [range 4.4 to 22.8] versus 8.7 [4.9 to 20] μmol/L,
P
=0.09, Mann-Whitney
U
test; women 8.1 [4.8 to 32.3] versus 7.6 [3.3 to 14.4] μmol/L,
P
=0.58). Median plasma concentrations increased significantly in the convalescent period (from 8.5 [4.8 to 19.2] to 10.1 [4.3 to 31.5] μmol/L,
P
<0.001, Wilcoxon signed rank test) and were then significantly higher than in control subjects in both men and women (
P
=0.03 and 0.05, respectively, Mann-Whitney
U
test). This did not appear to be explained by alteration in the known covariates red-cell folate, serum B
12
, or creatinine concentrations.

Conclusions
—Homocysteine concentrations are not elevated after recent atherothrombotic stroke but rise in the convalescent period. These data do not support the hypothesis that raised plasma homocysteine concentrations predate atherothrombotic stroke. Instead, they offer an explanation for the discrepancies between prospective and retrospective studies and suggest that elevated tHcy levels may be caused by the disease process itself.
Thrombolysis in Brain Ischemia (TIBI) Transcranial Doppler Flow Grades Predict Clinical Severity, Early Recovery, and Mortality in Patients Treated With Intravenous Tissue Plasminogen Activator
Authors: Demchuk Andrew M. , Burgin W. Scott , Christou Ioannis , Felberg Robert A. , Barber Philip A. , Hill Michael D. , Alexandrov Andrei V.
Published: June 2011

Background and Purpose
—TIMI angiographic classification measures coronary residual flow and recanalization. We developed a Thrombolysis in Brain Ischemia (TIBI) classification by using transcranial Doppler (TCD) to noninvasively monitor intracranial vessel residual flow signals. We examined whether the emergent TCD TIBI classification correlated with stroke severity and outcome in patients treated with intravenously administered tPA (IV-tPA).

Methods
—TCD examination occurred acutely and on day 2. TIBI flows were determined at distal MCA and basilar artery depths, depending on occlusion site. TIBI waveforms were graded as follows: 0, absent; 1, minimal; 2, blunted; 3, dampened; 4, stenotic; and 5, normal. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours after administration of tPA.

Results
—One hundred nine IV tPA patients were studied. Mean±SD age was 68±16 years; median NIHSS score before administration of tPA (pre-tPA) was 17.5. The tPA bolus was administered 143±58 minutes and the TCD examination 141±57 minutes after symptom onset. Pre-tPA NIHSS scores were higher in patients with TIBI grade 0 than TIBI grade 4 or 5 flow. TIBI flow improvement to grade 4 or 5 occurred in 35% of patients (19/54) with an initial grade of 0 or 1 and in 52% (12/23) with initial grade 2 or 3. The 24-hour NIHSS scores were higher in follow-up in patients with TIBI grade 0 or 1 than those with TIBI grade 4 or 5 flow. TIBI flow recovery correlated with NIHSS score improvement. Lack of flow recovery predicted worsening or no improvement. In-hospital mortality was 71% (5/7) for patients with posterior circulation occlusions; it was 22% (11/51) for patients with pre-tPA TIBI 0 or 1 compared with 5% (1/19) for those with pre-tPA TIBI 2 or 3 anterior circulation occlusions.

Conclusions
—Emergent TCD TIBI classification correlates with initial stroke severity, clinical recovery, and mortality in IV-tPA–treated stroke patients. A flow-grade improvement correlated with clinical improvement.
Characteristics, Outcome, and Care of Stroke Associated With Atrial Fibrillation in Europe
Authors: Lamassa Maria , Di Carlo Antonio , Pracucci Giovanni , Basile Anna Maria , Trefoloni Gloria , Vanni Paola , Spolveri Stefano , Baruffi Maria Cristina , Landini Giancarlo , Ghetti Augusto , Wolfe Charles D. A. , Inzitari Domenico
Published: June 2011

Background and Purpose
—The role of atrial fibrillation (AF) as a determinant of stroke outcome is not well established. Studies focusing on this topic relied on relatively small samples of patients, scarcely representative of the older age groups. We aimed at evaluating clinical characteristics, care, and outcome of stroke associated with AF in a large European sample.

Methods
—In a European Concerted Action involving 7 countries, 4462 patients hospitalized for first-in-a-lifetime stroke were evaluated for demographics, risk factors, clinical presentation, resource use, and 3-month survival, disability (Barthel Index), and handicap (Rankin scale).

Results
—AF was present in 803 patients (18.0%). AF patients, compared with those without AF, were older, were more frequently female, and more often had experienced a previous myocardial infarction; they were less often diabetics, alcohol consumers, and smokers (all
P
<0.001). At 3 months, 32.8% of the AF patients were dead compared with 19.9% of the non-AF patients (
P
<0.001). With control for baseline variables, AF increased by almost 50% the probability of remaining disabled (multivariate odds ratio 1.43, 95% CI 1.13 to 1.80) or handicapped (multivariate odds ratio 1.51, 95% CI 1.13 to 2.02). Before stroke, only 8.4% of AF patients were on anticoagulants. The chance of being anticoagulated was reduced by 4% per year of increasing age. AF patients underwent CT scan and other diagnostic procedures less frequently and received less physiotherapy or occupational therapy.

Conclusions
—Stroke associated with AF has a poor prognosis in terms of death and function. Prevention and care of stroke with AF is a major challenge for European health systems.
Angiotensinogen Gene Promoter Haplotype and Microangiopathy-Related Cerebral Damage
Authors: Schmidt Helena , Fazekas Franz , Kostner Gert M. , van Duijn Cornelia M. , Schmidt Reinhold
Published: June 2011

Background and Purpose
—Microangiopathy-related cerebral damage (MARCD) is a common finding in the elderly. It may lead to cognitive impairment and gait disturbances. Arterial hypertension and age are the most important risk factors. We assessed the association between MARCD and sequence alterations in the promoter region of the angiotensinogen (AGT) gene.

Methods
—We studied 410 randomly selected community-dwelling individuals aged 50 to 75 years. MARCD was defined as early confluent or confluent white matter hyperintensities or lacunes on a 1.5-T MRI. The AGT promoter was analyzed by temporal temperature gradient gel electrophoresis and automated sequencing.

Results
—We detected 4 polymorphic sites, at positions −6, −20, −153, and −218. They created 5 haplotypes, which we coded as A (−6:g, −20:a, −153:g, −218g), B (−6:a, −20:c, −153:g, −218:g), C (−6:a, −20:c, −153:a, −218:g), D (−6:a, −20:a, −153:g, −218:g), and E (−6:a, −20:a, −153:g, −218:a). MARCD was seen in 7 subjects (63.6%) carrying 2 copies of the B haplotype (B/B), in 12 subjects (38.7%) carrying 1 copy of the B haplotype in the absence of the A haplotype (B+/A−), but in only 70 subjects (19.0%) in the remaining cohort (
P
<0.001). The odds ratios for the B/B and the B+/A− genotypes were 8.0 (95% CI, 2.1 to 31.1;
P
=0.003) and 1.8 (95% CI, 0.8 to 4.2;
P
=0.14) after adjustment for possible confounders.

Conclusions
—The B haplotype of the AGT promoter in the absence of the wild-type A haplotype might represent a genetic susceptibility factor for MARCD.
Reproducibility of Measurements of Cerebral Infarct Volume on CT Scans
Authors: van der Worp H. B. , Claus S. P. , Bär P. R. , Ramos L. M. P. , Algra A. , van Gijn J. , Kappelle L. J.
Published: June 2011

Background and Purpose
—Infarct volume is increasingly used as an outcome measure in clinical trials of therapies for acute ischemic stroke. We tested which of 5 different methods to measure infarct size or volume on CT scans has the highest reproducibility.

Methods
—Infarct volume and total intracranial volume were measured with Leica Q500 MCP image analysis software, or with a caliper, on 38 CT scans of patients who participated in the Tirilazad Efficacy Stroke Study II (TESS II). The scans were performed 8 days (±2 days) after the onset of symptoms. The 5 methods tested were based on (1) semiautomated pixel thresholding, (2) manual tracing of the perimeter, (3) a stereological counting grid, (4) measurement of the 3 largest diameters, and (5) the single largest diameter. The measurements were performed independently by 2 observers; the first observer performed all measurements twice.

Results
—The single largest diameter did not correlate well with infarct volume. Of the other methods, manual tracing of the perimeter of the infarct had the lowest intraobserver and interobserver variability: coefficients of variation were 8.6% and 14.1%, respectively. For total intracranial volume, manual tracing also provided the highest reproducibility: intraobserver and interobserver coefficients of variation were 3.3% and 4.9%, respectively.

Conclusions
—Manual tracing of the perimeter is the most reproducible method for measuring the volumes of the infarct and the total intracranial space in multicenter trials of therapies for acute ischemic stroke.
Very Early Nimodipine Use in Stroke (VENUS)
Authors: Horn J. , de Haan R. J. , Vermeulen M. , Limburg M.
Published: June 2011

Backgound and Purpose
—The Very Early Nimodipine Use in Stroke (VENUS) trial was designed to test the hypothesis that early treatment with nimodipine has a positive effect on survival and functional outcome after stroke. This was suggested in a previous meta-analysis on the use of nimodipine in stroke. However, in a recent Cochrane review we were unable to reproduce these positive results. This led to the early termination of VENUS after an interim analysis.

Methods
—In this randomized, double-blind, placebo-controlled trial, treatment was started by general practitioners or neurologists within 6 hours after stroke onset (oral nimodipine 30 mg QID or identical placebo, for 10 days). Main analyses included comparisons of the primary end point (poor outcome, defined as death or dependency after 3 months) and secondary end points (neurological status and blood pressure 24 hours after inclusion, mortality after 10 days, and adverse events) between treatment groups. Subgroup analyses (on final diagnosis and based on the per-protocol data set) were performed.

Results
—At trial termination, after inclusion of 454 patients (225 nimodipine, 229 placebo), no effect of nimodipine was found. After 3 months of follow-up, 32% (n=71) of patients in the nimodipine group had a poor outcome compared with 27% (n=62) in the placebo group (relative risk, 1.2; 95% CI, 0.9 to 1.6). A treatment effect was not found for secondary outcomes and in the subgroup analyses.

Conclusions
—The results of VENUS do not support the hypothesis of a beneficial effect of early nimodipine in stroke patients.
Role of the Distal Balloon Protection Technique in the Prevention of Cerebral Embolic Events During Carotid Stent Placement
Authors: Martin Jean-Baptiste , Pache Jean-Claude , Treggiari-Venzi Miriam , Murphy Kieran J. , Gailloud Philippe , Puget Evelyne , Pizzolato Gianpaolo , Sugiu Kenji , Guimaraens Leopoldo , Théron Jacques , Rüfenacht Daniel A.
Published: June 2011

Background and Purpose
—We sought to quantitatively and qualitatively evaluate the release of atheromatous plaque debris induced by carotid stenting procedures.

Methods
—Eight patients with severe carotid atheromatous stenoses were treated by stent implantation under distal balloon protection. Blood samplings were obtained after stent deployment in the blood pooled below the inflated protection balloon. The samples were centrifuged and evaluated for plaque debris with the use of light microscopy. The debris release was quantitatively estimated by dividing the total volume of debris obtained by the mean debris size. Five patients without endovascular procedure were used as a control group.

Results
—The 2 main debris types found were nonrefringent cholesterol crystals (4 to 389 μm; 115 to 8697 in number) and lipoid masses (7 to 600 μm; 341 to 34 000 in number). There was a statistically significant difference compared with the samples obtained in the control group (
P
=0.017).

Conclusions
—Blood samples collected during stent implantation procedures contain a large quantity of atheromatous plaque debris. This emphasizes the role of distal protection techniques in avoiding migration of this plaque material into the cerebral circulation.
Increased Cytochrome
c–Mediated DNA Fragmentation and Cell Death in Manganese–Superoxide Dismutase–Deficient Mice After Exposure to Subarachnoid Hemolysate
Authors: Matz Paul G. , Fujimura Miki , Lewen Anders , Morita-Fujimura Yuiko , Chan Pak H.
Published: June 2011

Background and Purpose
—We sought to investigate the mechanisms for oxidative injury caused by subarachnoid hemolysate, a pro-oxidant.

Methods
—Injection of 50 μL of subarachnoid hemolysate or saline was performed in CD1 mice (n=75), mutant mice deficient in Mn–superoxide dismutase (
Sod2
+/−; n=23), and their wild-type littermates (n=23). Subcellular location of cytochrome
c
was studied by immunocytochemistry, immunofluorescence, and immunoblotting of cellular fractions. DNA fragmentation was assessed though DNA laddering and terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end-labeling (TUNEL). Cell death was examined through basic histology.

Results
—Cytochrome
c
immunoreactivity was present in the cytosol of neurons at 2 hours after hemolysate injection and increased by 4 hours compared with saline-injected animals (
P
<0.02). Cytosolic cytochrome
c
was more abundant in
Sod2
+/− mutants. DNA fragmentation was evident at 24 hours, but not 4 hours, after hemolysate injection as determined by DNA laddering and TUNEL staining (
P
<0.02). DNA fragmentation colocalized to cells with cytosolic cytochrome
c
and iron. In
Sod2
+/− mutants, the extent of fragmentation was increased as determined by TUNEL staining (52% increase;
P
<0.02) and DNA laddering (optical density=0.819 versus 0.391;
P
<0.01). Cell death was evident on basic histology as early as 4 hours after hemolysate injection. No cell death was evident in controls. In
Sod2
+/− mutants, cell death was increased by 51% compared with wild-type littermates (
P
<0.05).

Conclusions
—These results demonstrate that subarachnoid blood products are associated with the presence of cytochrome
c
in the cytosol and subsequent cell death in neurons. It appears that Mn–superoxide dismutase plays a role in preventing cell death after exposure to subarachnoid blood products.
Functional Recovery After Rehabilitation for Cerebellar Stroke
Authors: Kelly P. J. , Stein J. , Shafqat S. , Eskey C. , Doherty D. , Chang Y. , Kurina A. , Furie K. L.
Published: June 2011

Background and Purpose
—Relatively few data exist concerning functional recovery after ischemic and hemorrhagic cerebellar stroke. We studied patients admitted to a rehabilitation hospital after cerebellar stroke to quantify recovery after rehabilitation therapy and to identify variables that predicted functional outcome.

Methods
—This study was a retrospective review of consecutive cases admitted in a 4-year period with new cerebellar infarct or hemorrhage. Clinical features of stroke were recorded and comorbidities scored with the Charlson Index. Follow-up information was obtained by telephone interview. The Functional Independence Measure (FIM) was scored at admission (AFIM), discharge (DFIM), and follow-up (FFIM). Outcome measures were DFIM and FFIM. Univariate and multivariate analyses were performed.

Results
—Fifty-eight cases were identified (mean age 69.2 years; 49 infarcts, 9 hemorrhages). Mean AFIM was 65.5, and mean DFIM was 89.8. Mean AFIM was significantly higher in the infarct than in the hemorrhage subgroup (70 versus 43,
P
=0.006). Mean DFIM was also higher in the infarct subgroup but did not reach statistical significance (93 versus 74,
P
=0.1). Follow-up information was obtained for 45 cases (78%) (mean interval 19.5 months). Median FFIM was 123.5. Outcome was significantly positively correlated with AFIM and initial presenting syndrome of vertigo/vomiting/ataxia/headache. Outcome correlated negatively with preexisting comorbidity score, altered level of consciousness at initial presentation, and superior cerebellar artery infarction. On multivariate analysis, AFIM and comorbidity score were independent predictors of outcome.

Conclusions
—Substantial improvement of mean FIM score frequently occurs after rehabilitation after cerebellar infarction. Functional outcome is best predicted by preexisting comorbidities and functional status at the time of discharge from acute hospitalization.
Treatment of Unruptured Cerebral Aneurysms in California
Authors: Johnston S. Claiborne , Zhao Shoujun , Dudley R. Adams , Berman Mitchell F. , Gress Daryl R.
Published: June 2011

Background and Purpose
—The impact of endovascular therapy on treatment outcomes of unruptured cerebral aneurysms has not been studied in a defined geographic area.

Methods
—All primary diagnoses of unruptured aneurysms were retrieved from a statewide database of hospital discharges in California from January 1990 through December 1998. Admissions for initial treatment and all follow-up care were combined to reflect the entire course of therapy. An adverse outcome was defined as an in-hospital death or discharge to nursing home or rehabilitation hospital at any point during the treatment course. Multivariable analyses were performed with generalized estimating equations with adjustment for age, sex, ethnicity, source of admission, year of treatment, hospital volume, and clustering of observations at institutions.

Results
—A total of 2069 patients were treated for unruptured aneurysms. Adverse outcomes were more frequent in the 1699 patients treated with surgery (25%) than in those treated with endovascular therapy (10%;
P
<0.001). The difference persisted after multivariable adjustment (surgery versus endovascular therapy: odds ratio for adverse outcomes, 3.1; 95% CI, 2.5 to 4.0;
P
<0.001). Adverse outcomes declined from 1991 to 1998 in patients treated with endovascular therapy (
P
<0.005) but not for surgery. In-hospital deaths occurred in 3.5% of surgical cases and 0.5% of endovascular cases (
P
=0.003), and the difference remained significant after adjustment (odds ratio, 6.3; 95% CI, 3.5 to 11.4;
P
<0.001). Total length of stay and hospital charges were greater in surgical cases (both
P
<0.001). Results were similar in a confirmatory analysis focusing on treatment differences between institutions. Institutional treatment volume was also associated with outcome but did not account for the differences between surgery and endovascular therapy.

Conclusions
—In California, endovascular therapy of unruptured aneurysms is associated with less risk of adverse outcomes and in-hospital death, lower hospital charges, and shorter hospital stays compared with surgery. Differences between therapies became more distinct through the years. Uncontrolled differences in prognosis of patients receiving endovascular therapy and surgery cannot be ruled out in this study of discharge abstracts.
Is There a Temporal Pattern in the Occurrence of Subarachnoid Hemorrhage in the Southern Hemisphere?
Authors: Feigin Valery L. , Anderson Craig S. , Anderson Neil E. , Broad Joanna B. , Pledger Megan J. , Bonita Ruth
Published: June 2011

Background and Purpose
—Publications on the temporal pattern of the occurrence of subarachnoid hemorrhage (SAH) have produced conflicting results. Variations between studies may relate to the relatively small numbers of SAH cases analyzed, including those in meta-analyses.

Methods
—We identified all cases of SAH from 3 well-designed population-based studies in Australia (Adelaide, Hobart, and Perth) and New Zealand (Auckland) during 3 periods between 1981 and 1997. The diagnosis of SAH was confirmed with CT, cerebral angiography, cerebrospinal fluid analysis, or autopsy in all cases. Information on the time of occurrence of each event was obtained. Risk ratios (RRs) and 95% CIs were calculated using Poisson regression, with age, sex, smoking status, and history of hypertension entered in the model as covariates.

Results
—A total of 783 cases of SAH were registered. Age- and sex-adjusted RRs of SAH occurrence were highest in the period between 6
am
and 12
midnight
(RR 3.2, 95% CI 2.4–4.3) and in winter and spring (RR 1.3, 95% CI 1.1–1.5; RR 1.3, 95% CI 1.1–1.5; respectively). No particular pattern of SAH occurrence was observed according to the day of the week. Restriction of the analyses to proved aneurysmal SAH did not substantially change the point estimates.

Conclusions
—Circadian and circaseptan (weekly) fluctuations of SAH occurrence in the southern hemisphere are similar to those in the northern hemisphere, but the occurrence of SAH in Australasia exhibits clear seasonal (winter and spring) peaks.
Tolerability and Pharmacokinetics of the Nitrone NXY-059 in Patients With Acute Stroke
Authors: Lees K. R. , Sharma A. K. , Barer D. , Ford G. A. , Kostulas V. , Cheng Y.-F. , Odergren T.
Published: June 2011

Background and Purpose
—Increased free radical formation contributes to the damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based free radical trapping agent in development for acute stroke. NXY-059 has neuroprotective efficacy when given 5 hours after onset of transient focal ischemia in the rat.

Methods
—This was a randomized, double-blind, placebo-controlled, parallel group, multicenter study that evaluated the safety and tolerability of 2 NXY-059 dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059 was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded up to 30 days.

Results
—One hundred fifty patients were recruited, of whom 147 received study treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49 higher-dose NXY-059). Mean (±SD) age was 68 (±10) years, and baseline National Institutes of Health Stroke Scale score was 7.9 (±6.2). Serious adverse events occurred in 16%, 23%, and 16% of patients, respectively, with deaths in 0%, 10%, and 4%, largely following the proportions with primary intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, and fever were common but not related to treatment. The mean unbound steady state NXY-059 plasma concentrations were 25 and 45 μmol/L, respectively. Population pharmacokinetic analysis estimated clearance to be 4.6 L/h.

Conclusions
—NXY-059 was well tolerated in patients with an acute stroke. The testing of higher doses in future trials may be justified.
Comparison of TNK With Wild-Type Tissue Plasminogen Activator in a Rabbit Embolic Stroke Model
Authors: Chapman Deborah F. , Lyden Patrick , Lapchak Paul A. , Nunez Sonia , Thibodeaux Harold , Zivin Justin
Published: June 2011

Background and Purpose
—Tissue plasminogen activator (tPA) is an effective treatment for stroke, but its utility is limited by fear of cerebral hemorrhage. Tenecteplase (TNK), a genetically modified form of wild-type tPA, exhibits a longer biological half-life and greater fibrin specificity, features that could lead to fewer cerebral hemorrhages than wild-type tPA in stroke patients.

Methods
—We injected radiolabeled blood clots into the cerebral circulation of New Zealand White rabbits. One hour later, we administered tPA (n=57), 0.6 mg/kg TNK (n=43), 1.5 mg/kg TNK (n=27), or vehicle control (n=37). A blinded observer examined the brains for macroscopic hemorrhage using a semiquantitative score. We estimated thrombolysis by assessing the amount of radiolabel remaining in the cerebral vessels postmortem.

Results
—Both wild-type tPA and TNK caused thrombolysis in most subjects. Hemorrhage was detected in 26% (6/23) of the control group, 66% (27/41) of the wild-type tPA group, 55% (16/29) in the 0.6-mg/kg TNK group, and 53% (9/17) in the 1.5-mg/kg TNK group (
P
<0.05, χ
2
test). The tPA group was statistically significantly different from the control group, but the TNK and tPA groups did not differ from each other. Neither TNK nor tPA affected the size of the hemorrhages.

Conclusions
—TNK shows comparable rates of recanalization compared with wild-type tPA in a model of embolic stroke. While tPA increases hemorrhage rate, the hemorrhage associated with TNK treatment is not statistically different compared with controls or the tPA group. These findings suggest that TNK shows promise as an alternative thrombolytic treatment for stroke, but we could not demonstrate improved safety compared with wild-type tPA.
Methamphetamine Potentiates Ischemia/Reperfusion Insults After Transient Middle Cerebral Artery Ligation
Authors: Wang Yun , Hayashi Teruo , Chang Chen-Fu , Chiang Yung-Hsiao , Tsao Li-I , Su Tsung-Ping , Borlongan Cesario , Lin Shinn-Zong
Published: June 2011

Background and Purpose
—Previous studies have indicated that both methamphetamine (MA) and ischemia/reperfusion injuries involve reactive oxygen species formation and activation of apoptotic mechanism. That MA could have a synergistic or additive effect with stroke-induced brain damage is possible. The purpose of the present study was to investigate whether administration of MA in vivo would potentiate ischemic brain injury.

Methods
—Adult CD-1 mice were pretreated with MA or saline. Each animal later was anesthetized with chloral hydrate and placed in a stereotaxic frame. A subset of animals received intracerebral administration of glial cell line–derived neurotrophic factor (GDNF). The right middle cerebral artery and bilateral carotids were transiently occluded for 45 minutes. Regional cerebral blood flow was measured by laser Doppler. Animals were sacrificed for triphenyltetrazolium chloride staining and p53 mRNA Northern blot assay after 24 hours of reperfusion. Cortical and striatal GDNF levels were assayed by ELISA.

Results
—We found that pretreatment with MA increased ischemia-induced cerebral infarction. Ischemia or MA alone enhanced p53 mRNA expression. Moreover, MA potentiated expression of p53 mRNA in the ischemic mouse brain. MA pretreatment decreased GDNF levels in ischemic striatum. Intracerebral administration of GDNF before ischemia reduced MA-facilitated infarction.

Conclusions
—Our data indicate that MA exacerbates ischemic insults in brain, perhaps through the inhibition of GDNF-mediated pathways and suggest that MA may antagonize endogenous neuroprotective pathways as part of its mechanism of action.
Anticonvulsant Lamotrigine Administered on Reperfusion Fails To Improve Experimental Stroke Outcomes
Authors: Traystman Richard J. , Klaus Judith A. , DeVries A. Courtney , Shaivitz Amanda B. , Hurn Patricia D.
Published: June 2011

Background and Purpose
—Recent results suggest that selective inhibitors of presynaptic neuronal ion channels can diminish glutamate release during cerebral ischemia and modulate excitotoxic cell death. The aim of the present study was to evaluate lamotrigine (LTG), an antiepileptic that inhibits presynaptic sodium and voltage-sensitive calcium channels, as a potential stroke resuscitation agent in the rat. Three dosages of LTG were examined for effect on infarction volume and sensorimotor behavioral recovery after middle cerebral artery (MCA) occlusion.

Methods
—Halothane-anesthetized male Wistar rats were subjected to 2 hours of MCA occlusion by the intraluminal occlusion technique. Physiological variables were controlled, and ipsilateral cortical perfusion was monitored by laser Doppler flowmetry throughout ischemia. At onset of reperfusion, rats received intravenous LTG 5, 10, or 20 mg/kg or PBS (n=9 to 11 per group) during 15 minutes. Behavioral assessment was completed at 3 and 7 days after stroke, and the brain was harvested for histology (triphenyltetrazolium chloride staining).

Results
—Values are mean±SE. Cortical infarction volumes were unchanged in LTG-treated animals: 14±6% of contralateral cortex at 5 mg/kg LTG, 17±7% at 10 mg/kg, and 30±6% at 20 mg/kg, versus saline-treated cohorts (12±3%;
P
=0.19; n=9). Caudate-putamen infarction injury was also unchanged (37±11% of contralateral caudate-putamen at 5 mg/kg LTG, 44±8% at 10 mg/kg, and 65±9% at 20 mg/kg versus saline (38±11%;
P
=0.18). Total infarction was not different among groups (
P
=0.15). Consistent with histology, behavioral outcomes were unimproved by treatment.

Conclusions
—Histological damage and behavioral recovery at 7 days after MCA occlusion was not altered by LTG treatment over the dosage range used in the present study.
Efficacy of Antioxidant Therapies in Transient Focal Ischemia in Mice
Authors: Clark Wayne M. , Rinker Lisa G. , Lessov Nikola S. , Lowery Stuart L. , Cipolla Marilyn J.
Published: June 2011

Background and Purpose
—Ginkgo biloba extract (EGb) and α-lipoic acid (LA) are commercially available “antioxidant supplements” with a variety of actions that may be beneficial during acute stroke. These actions include inhibiting platelet and leukocyte activation and adhesion, reducing free radical generation, and increasing cerebral blood flow. Both EGb and LA have been shown to be neuroprotective in cell culture and global central nervous system ischemia models. In this study we investigated the neuroprotective efficacy of EGb and LA in a clinically relevant, transient focal central nervous system ischemic model.

Methods
—In the EGb study, 60 adult C57blk mice were randomized to treatment with EGb given orally (via gavage) for 7 days: low dose, 50 EGb mg/kg daily; high dose, 100 mg/kg daily; matched placebo. On day 7, reversible middle cerebral artery occlusion was produced by advancing a silicone-coated 8-0 filament into the internal carotid artery for 45 minutes followed by reperfusion. At 24 hours, the animals were evaluated on a 28-point clinical scale, and infarct volume was determined with the use of triphenyltetrazolium chloride. In the LA study, 24 C57blk mice were treated with 100 mg/kg SC of LA or placebo 1.5 hours before transient MCAO, as in the EGb study.

Results
—In the EGb study, values for infarct volume at 24 hours were as follows (mean±SD): low dose (n=18), 13±5 mm
3
; high dose (n=22), 22±12 mm
3
; placebo (n=20), 20±10 mm
3
(
P
=0.03 overall;
P
=0.02, low dose versus placebo). Infarct percentage of hemisphere values were as follows: low dose, 14±5%; high dose, 21±11%; placebo, 20±9% (
P
=0.03 overall;
P
=0.02, low dose versus placebo). Ten percent of the high-dose group showed significant intracerebral hemorrhage (ICH) within the infarct, while no ICH was seen in the other groups. Neurological function scores were as follows: low dose, 11.8±1.5; high dose, 11.4±1.7; placebo, 11.3±1.8 (
P
=NS). In the LA study, infarct volume was as follows: 100 mg/kg LA (n=12), 16.8±8.3 mm
3
; placebo (n=12), 27.2±14.6 mm
3
(
P
<0.05). LA also produced a significant improvement in neurological function at 24 hours: LA, 9.5±1.2; placebo, 11.2±1.8 (
P
=0.02). There was no evidence of ICH in any of the animals.

Conclusions
—Both oral EGb and LA therapies produced significant reductions in stroke infarct volume. However, for EGb this beneficial effect appears to be dose related, with higher doses potentially increasing the risk of ICH.
Molecular Anatomy of an Intracranial Aneurysm
Authors: Peters David G. , Kassam Amin B. , Feingold Eleanor , Heidrich-O’Hare Elisa , Yonas Howard , Ferrell Robert E. , Brufsky Adam
Published: June 2011

Background and Purpose
—Approximately 6% of human beings harbor an unruptured intracranial aneurysm. Each year in the United States, >30 000 people suffer a ruptured intracranial aneurysm, resulting in subarachnoid hemorrhage. Despite the high incidence and catastrophic consequences of a ruptured intracranial aneurysm and the fact that there is considerable evidence that predisposition to intracranial aneurysm has a strong genetic component, very little is understood with regard to the pathology and pathogenesis of this disease.

Methods
—To begin characterizing the molecular pathology of intracranial aneurysm, we used a global gene expression analysis approach (SAGE-Lite) in combination with a novel data-mining approach to perform a high-resolution transcript analysis of a single intracranial aneurysm, obtained from a 3-year-old girl.

Results
—SAGE-Lite provides a detailed molecular snapshot of a single intracranial aneurysm. These data suggest that, at least in this specific case, aneurysmal dilation results in a highly dynamic cellular environment in which extensive wound healing and tissue/extracellular matrix remodeling are taking place. Specifically, we observed significant overexpression of genes encoding extracellular matrix components (eg, COL3A1, COL1A1, COL1A2, COL6A1, COL6A2, elastin) and genes involved in extracellular matrix turnover (TIMP-3, OSF-2), cell adhesion and antiadhesion (SPARC, hevin), cytokinesis (PNUTL2), and cell migration (tetraspanin-5).

Conclusions
—Although these are preliminary data, representing analysis of only one individual, we present a unique first insight into the molecular basis of aneurysmal disease and define numerous candidate markers for future biochemical, physiological, and genetic studies of intracranial aneurysm. Products of these genes will be the focus of future studies in wider sample sets.