bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular pH, Ca
2+
Influx, and Response of Vascular Smooth Muscle Cells to 5-Hydroxytryptamine
Authors: Nazarov Vitaly , Aquino-DeJesus Janette , Apkon Michael
Published: June 2011

Background and Purpose
—Cerebral vascular smooth muscle cells (VSMCs) contract on extracellular pH (pH
o
) increases and relax on pH
o
decreases. These changes in tone are believed to result from changes in [Ca
2+
]
i
, although the responsible mechanisms are not fully understood. VSMCs also contract in response to 5-hydroxytryptamine (5-HT), which increases [Ca
2+
]
i
via both Ca
2+
release and influx. We hypothesized that examining effects of pH
o
decreases on 5-HT–induced [Ca
2+
]
i
changes would allow us to identify mechanisms whereby pH
o
influences tone. Accordingly, we compared [Ca
2+
]
i
increases in cerebral VSMCs, evoked by 5-HT, with increases evoked by increased pH
o
and examined 5-HT–dependent [Ca
2+
]
i
increases at normal and decreased pH
o
.

Methods
—We monitored [Ca
2+
]
i,
, using the Ca
2+
-sensitive dye fura 2, in cultured rat cerebral VSMCs obtained by enzymatic digestion of middle cerebral arteries and their branches (passages 1 to 3) grown on glass coverslips and superfused with physiological saline.

Results
—Increasing pH
o
from 7.3 to 7.8 increased [Ca
2+
]
i
, and these increases were prevented in Ca
2+
-free solutions. Decreasing pH
o
from 7.3 to 6.9 did not alter [Ca
2+
]
i
unless [Ca
2+
]
i
was first raised by treatment with 5-HT (10 μmol/L). 5-HT resulted in biphasic [Ca
2+
]
i
increases characterized by transient peaks blocked by the Ca
2+
-ATPase inhibitor thapsigargin (10 nmol/L) and prolonged plateaus blocked by the Ca
2+
channel blocker Ni
2+
(1 mmol/L). Acidification did not alter the transient peaks but significantly reduced 5-HT–induced Ca
2+
influx.

Conclusions
—We conclude that increasing pH
o
induces Ca
2+
influx in rat cerebral VSMCs and decreasing pH
o
inhibits 5-HT–stimulated Ca
2+
entry but not intracellular Ca
2+
release.
Surgery in Intracerebral Hemorrhage
Authors: Fernandes H. M. , Gregson B. , Siddique S. , Mendelow A. D.
Published: June 2011

Background and Purpose
—Primary intracerebral hemorrhage (ICH) accounts for 10% to 20% of stroke but carries the highest rates of mortality and morbidity of all stroke subtypes. Current treatment, however, is varied and haphazard. The most recent Cochrane systematic review refers to 4 prospective, randomized controlled trials. We present a further meta-analysis to include 3 new trials. In addition, we review the trials of Chen et al and McKissock et al and discuss aspects of their quality that, we believe, prevent their inclusion in modern day meta-analysis.

Methods
—Literature databases and articles were searched from 1966 to October 1999. Using the end points of death and dependency, the results of the 7 identified randomized trials were expressed as odds ratios. All available data were then analyzed with meta-analysis techniques. Analysis of relevant subsets of trials was also carried out.

Results
—Meta-analysis of all 7 trials shows a trend toward a higher chance of death and dependency after surgery (OR 1.20; 95% CI 0.83 to 1.74). Meta-analysis was also carried out after exclusion of the Chen and McKissock trials for reasons discussed in the text. This meta-analysis suggests a benefit from surgery, with a reduction in the chances of death and dependency after surgical treatment by a factor of 0.63 (OR 0.63; 95% CI 0.35 to 1.14).

Conclusions
—When meta-analysis is restricted to modern-day, post-CT, well-constructed, balanced trials, a trend for surgery to reduce the chances of death and dependency is found. Perhaps, then, in the modern era of CT, good neuroanesthesia, intensive care, and the operating microscope, surgery has a role in the treatment of supratentorial intracerebral hemorrhage. The results of a large, multicenter, randomized controlled trial are urgently needed, and the ongoing International Surgical Trial of Intracerebral Hemorrhage should fulfill this objective.
Lubeluzole in Acute Ischemic Stroke Treatment
Authors: Diener H. C. , Cortens M. , Ford G. , Grotta J. , Hacke W. , Kaste M. , Koudstaal P. J. , Wessel T.
Published: June 2011

Background and Purpose
—This trial was a double-blind, placebo-controlled, phase III trial with an 8-hour inclusion window to assess the efficacy and safety of an intravenous loading dose of 7.5 mg followed by a daily intravenous dose of 10 mg lubeluzole for 5 days in acute ischemic stroke patients.

Methods
—A total of 1786 patients were randomized: 901 to lubeluzole and 885 to placebo. Overall, 212 patients (23.5%) from the lubeluzole group and 213 (24.1%) from the placebo group discontinued the trial prematurely. In the lubeluzole group 201 patients (22.3%) discontinued because of adverse events compared with 193 patients (21.8%) in the placebo group.

Results
—The primary population for the efficacy analysis comprised the core stroke patients (exclusion of older patients aged >75 years with severe stroke) in the 0- to 6-hour inclusion time window. The primary efficacy parameter was a 3-category functional status (Barthel Index 70 to 100/0 to 70/vegetative, dead) at week 12. In the lubeluzole group 207 patients (47.8%) were classified as mildly dependent/independent at week 12, 131 (30.3%) were moderately/severely dependent, and 95 (21.9%) were vegetative/dead. In the placebo group these numbers were 221 (54.4%), 112 (27.6%), and 73 (18.0%), respectively. Logistic regression analysis showed no statistically significant difference between the treatment groups (
P
=0.162). Additionally, for none of the secondary efficacy parameters (mortality at week 12, modified Rankin score, total Barthel score) was a statistically significant difference between the lubeluzole and placebo groups obtained. There were no statistically significant differences between the 2 treatments for all treated patients, patients included within the 6- to 8-hour window, and patients with severe strokes aged >75 years. Overall, of all treated patients, 401 (22.5%) died: 203 (22.5%) in the lubeluzole group and 198 (22.4%) with placebo. Of all subjects treated, 853 (95%) on lubeluzole and 826 (93%) on placebo reported an adverse event during their treatment period or within the next 2 days after discontinuation of treatment. The most frequently observed adverse events were fever (25.9% lubeluzole; 23.4% placebo), constipation (20.2%; 19.7%), and headache (17.6%; 21.2%). Imbalances were found for atrial fibrillation (1.8% lubeluzole; 1.1% placebo) and QT prolongation (0.9%; 0.2%).

Conclusions
—This study failed to show an efficacy of lubeluzole in the treatment of acute stroke. On the other hand, lubeluzole treatment by the current dosage schedule was not associated with a significant safety problem.
Effect of Acute Stroke Unit Care Integrated With Care Continuum Versus Conventional Treatment: A Randomized 1-Year Study of Elderly Patients
Authors: Fagerberg Björn , Claesson Lisbeth , Gosman-Hedström Gunilla , Blomstrand Christian
Published: June 2011

Background and Purpose
—The aim of the study was to compare the effect of conventional treatment with the effect of acute stroke unit care integrated with geriatric stroke unit care continuum.

Methods
—A 1-year study was undertaken with 2:1 randomization to stroke unit care or conventional care, with assessment by an independent team. The study was composed of 249 elderly patients (aged ≥70 years) hospitalized for acute stroke, without previous cerebral lesion and without recognized need of care. Main outcome measures were patients at home after 1 year, ability in daily living activities, health-related quality of life score according to questionnaire, death or institutional care, and death or dependence.

Results
—One hundred two patients (61%) in the stroke unit and 49 patients (59%) in the general ward group were alive and at home after 1 year (95% CI −10% to 16%). There were no significant differences in daily life activities or quality of life. In patients with concomitant cardiac disease, there was a reduction in death or institutional care after 3 months in the stroke unit group compared with the group receiving conventional care (28% versus 49%, respectively; 95% CI −40% to −3%). This effect did not remain after 1 year. Patients seeking care after 24 hours often had mild stroke and lived alone.

Conclusions
—There was no effect on the number of patients living at home after 1 year, but after 3 months of stroke unit care, a beneficial effect was found on mortality and the need for institutional care among those with concomitant heart disease. This study involved patients who were considerably older than those investigated in previous randomized studies of acute stroke unit care; thus, these findings will contribute to the specialized register of controlled trials in stroke.
Analysis of Endoglin Expression in Normal Brain Tissue and in Cerebral Arteriovenous Malformations
Authors: Matsubara Shunji , Bourdeau Annie , terBrugge Karel G. , Wallace Christopher , Letarte Michelle
Published: June 2011

Background and Purpose
—A high incidence of arteriovenous malformations (AVMs) is associated with hereditary hemorrhagic telangiectasia type 1. Endoglin, the gene mutated in this disorder, is expressed at reduced levels on blood vessels of these patients. Since endoglin is a component of the transforming growth factor-β receptor complex critical for vascular development and homeostasis, we determined its expression in sporadic cerebral AVMs and in normal brain vessels.

Methods
—Twenty cerebral AVMs and 10 normal brain samples were analyzed for endoglin, platelet endothelial cell adhesion molecule 1 (PECAM-1), α-smooth muscle cell actin, vimentin, and desmin by immunohistochemistry.

Results
—In normal brain, endoglin was found not only on the endothelium of all vessels but also on the adventitial layer of arteries and arterioles. In cerebral AVMs, the numerous vessels present expressed endoglin on both endothelium and adventitia. Arterialized veins, identified by lack of elastin and uneven thickness of smooth muscle cells, revealed endoglin-positive mesenchymal cells in the adventitia and perivascular connective tissue. These cells were fibroblasts since they expressed vimentin but not actin and/or desmin.

Conclusions
—This is the first report of endoglin expression on adventitia of normal brain arteries and on arterialized veins in cerebral AVMs. Increasing numbers of endoglin-positive endothelial and adventitial cells were seen in sporadic cerebral AVMs, but endoglin density was normal. Thus, it is not involved in the generation of these lesions. However, the presence of endoglin on fibroblasts in the perivascular stroma suggests an active role for this protein in vascular remodeling in response to increased blood flow and shear stress.
Frequency and Location of Microbleeds in Patients With Primary Intracerebral Hemorrhage
Authors: Roob Gudrun , Lechner Anita , Schmidt Reinhold , Flooh Erich , Hartung Hans-Peter , Fazekas Franz
Published: June 2011

Background and Purpose
—MRI is known to detect clinically silent microbleeds (MBs) in patients with primary intracerebral hemorrhage (pICH), but the frequency and diagnostic and clinical significance of this finding are still debated. Therefore, we investigated a consecutive series of pICH patients and analyzed the patterns of MB distribution in the context of clinical variables and location of the symptomatic hematoma.

Methods
—The study population consisted of 109 patients with pICH. There were 59 women and 50 men aged 22 to 91 years (mean 64.6 years). MRI was obtained on a 1.5-T system with use of a gradient-echo T2*-weighted sequence. A cohort of 280 community-dwelling asymptomatic elderly individuals who underwent the same imaging protocol served for comparison.

Results
—MBs were seen in 59 (54%) patients and ranged in number from 1 to 90 lesions (mean 14, median 6). In the majority of patients, MBs were located simultaneously in various parts of the brain, with a preference for cortical-subcortical regions (39%) and the basal ganglia/thalami (38%). There was some tendency toward a regional association between MB location and the site of the symptomatic hematoma, but we could not discern specific patterns of MB distribution. Logistic regression analysis identified MBs, periventricular hyperintensity grades, and lacunes but not risk factors as independent variables contributing to a correct classification of pICH and control individuals.

Conclusions
—MBs can be detected in more than half of the patients with pICH and appear to be quite general markers of various types of bleeding-prone microangiopathy.
Heritability of Intracerebral Hemorrhagic Lesions and Cerebral Aneurysms in the Rat
Authors: Coutard Michèle , Huang Wei , Osborne-Pellegrin Mary
Published: June 2011

Background and Purpose
—Under certain conditions, the Brown Norway (BN) rat is susceptible to intracerebral hemorrhagic vascular (ICV) lesions within the cerebral cortex, whereas the Long-Evans (LE) rat is prone to develop aneurysms in the circle of Willis. The incidence of these 2 pathological phenotypes was studied in progeny of different BNXLE crosses to determine their heritability in these new rat models. In addition, a possible link between ICV lesion occurrence and either the susceptibility to spontaneous rupture of the arterial internal elastic lamina (IEL) or basal plasma angiotensin-converting enzyme (ACE) activity was also studied in back-cross (BC) F1XBN rats, the only second-generation group with a high incidence of ICV lesions.

Methods
—To induce cerebrovascular lesions, rats were submitted to experimental hypertension associated with ligation of 1 carotid artery. After death, the brain was examined for cerebral lesions. Numbers of arterial IEL ruptures were determined microscopically with the use of
en face
preparations. Plasma ACE activity was determined before the induction of hypertension.

Results
—In general, groups that developed ICV lesions presented a low incidence of aneurysms. ICV lesion incidence was similar in F1 hybrids and BC(F1XBN) and greatly decreased in F2 and BC(F1XLE) rats compared with BN rats. No cerebral aneurysms developed in F1 rats. Aneurysmal incidence was 24% (20% ruptured) in LE, 42% (59% ruptured) in F2, and 50% (75% ruptured) in BC(F1XLE) rats. In BC(F1XBN) rats, neither the incidence of IEL rupture nor the plasma ACE activity was higher in the rats with ICV lesions. However, the mean blood pressure level was higher in these rats, and peak blood pressure was higher in rats with the most severe grades of ICV lesions.

Conclusions
—These data suggest a polygenic and dominant mode of inheritance of ICV pathology. The formation of aneurysms in the circle of Willis tended to be favored, and their rupture was clearly increased by the presence of BN rat alleles within the LE rat genome. These data may provide the basis for future studies to determine, in new rat models, which genes are involved in these pathologies.
Stroke Outcome in Double-Mutant Antioxidant Transgenic Mice
Authors: Sampei Kenji , Mandir Allen S. , Asano Yoshio , Wong Phillip C. , Traystman Richard J. , Dawson Valina L. , Dawson Ted M. , Hurn Patricia D.
Published: June 2011

Background and Purpose
—Both NO and superoxide cytotoxicity are important in experimental stroke; however, it is unclear whether these molecules act within parallel pathological pathways or as coreagents in a common reaction. We examined these alternatives by comparing outcomes after middle cerebral artery occlusion in male and female neuronal NO synthase (nNOS)-deficient (nNOS−/−) or human CuZn superoxide dismutase–overexpressing (hSOD1+/−) mice and a novel strain with both mutations.

Methods
—Permanent middle cerebral artery occlusion was performed by use of the intraluminal filament technique (18 hours). Neurological status was scored, and tissue infarction volume was determined by 2,3,5-triphenyltetrazolium staining and image analysis.

Results
—Hemispheric infarction volume was reduced in each transgenic strain relative to the genetically matched, wild-type, control cohorts (WT mice): nNOS−/− (80±6 mm
3
) and double-mutant (49±6 mm
3
) mice versus WT mice (114±7 mm
3
) and hSOD1+/− mice (52±7 mm
3
) versus WT mice (95±5 mm
3
). Human CuZn superoxide dismutase had a larger effect on mean infarction volume (30% of contralateral hemisphere) than did nNOS deficiency (46%). Although infarction volume was less in double-mutant mice compared with nNOS−/− mice, injury was not improved relative to hSOD1+/− mice. There was no difference in histological damage by sex within each strain; however, female nNOS−/− mice were not protected from ischemic injury, unlike male mutants.

Conclusions
—Superoxide generation contributes to severe ischemic brain injury in vivo to a greater extent than does neuronally derived NO. In vivo, significant superoxide scavenging by CuZn superoxide dismutase occurs within cellular compartments or through biochemical pathways that are not restricted to, and may be distinct from, neuronal NO/superoxide reaction and peroxynitrite synthesis.
Chlamydia pneumoniae Does Not Influence Atherosclerotic Plaque Behavior in Patients With Established Carotid Artery Stenosis
Authors: Gibbs R. G. J. , Sian M. , Mitchell A. W. M. , Greenhalgh R. M. , Davies A. H. , Carey N.
Published: June 2011

Background and Purpose
—Research for infectious agents in the etiology of atherosclerosis has identified
Chlamydia pneumoniae
as a possible candidate. While there is evidence of an association between presence of this microorganism and atherosclerosis, it is unclear whether infection has a genuinely etiologic role in this disease, whether its presence influences clinical outcomes, and, if so, at which stages of disease this occurs. We have approached this issue in patients with advanced carotid artery atherosclerosis using molecular biological detection methods and clinically relevant indicators of pathology in carotid artery atheroma to determine whether the presence of
C pneumoniae
correlates with plaque instability.

Methods
—
C pneumoniae
was detected with the use of a sensitive nested polymerase chain reaction. Preoperative embolization and preoperative infarcts were recorded with the use of transcranial Doppler insonation of the middle cerebral artery and cerebral CT, respectively.

Results
—
C pneumoniae
DNA was detected in 25.5% of a cohort of 98 symptomatic patients. There was no significant difference in plaque stability as measured by embolization rates between the chlamydial-positive and -negative specimens. There was also no correlation between the number of ipsilateral hemispheric infarcts in the territory of the middle cerebral artery and chlamydial status.

Conclusions
—This study confirms that
C pneumoniae
is a common finding in atherosclerotic plaques of the carotid artery but suggests that the presence of the infectious organism has little detectable impact on plaque instability when measured by clinically significant markers. This raises important questions for the rationale of antibiotic therapy in atherosclerosis.
High Proinsulin Levels Precede First-Ever Stroke in a Nondiabetic Population
Authors: Lindahl Bernt , Dinesen Bo , Eliasson Mats , Røder Michael , Hallmans Göran , Stegmayr Birgitta
Published: June 2011

Background and Purpose
—Diabetic subjects have a 3- to 6-fold increased risk for stroke compared with nondiabetic subjects, and hyperinsulinemia shows strong and consistent associations with a cluster of cardiovascular risk factors. Methods separating proinsulin from (true) insulin have demonstrated proinsulin to be more strongly associated with cardiovascular disease than insulin. The present study evaluates the associations between first-ever stroke, proinsulin, and insulin.

Methods
—In this incident case-referent study of a nondiabetic population, 94 cases of first-ever stroke (59 men and 35 women) were individually age- and sex-matched to 178 referents. Blood sampling was collected before the stroke event. Proinsulin and insulin were measured with highly sensitive 2-site sandwich enzyme-linked immunosorbent assays.

Results
—In the study population, high proinsulin concentration more than tripled the risk for first-ever stroke after adjustments for total cholesterol, systolic blood pressure, smoking, body mass index, and insulin, with an odds ratio of 3.4 (95% CI, 1.4 to 8.4). In women the risk was even more pronounced, with an odds ratio of 13.7 (95% CI, 1.3 to 146). Synergy was found between proinsulin and systolic blood pressure. In women, synergy was also found between proinsulin and diastolic blood pressure as well as between insulin and both blood pressures.

Conclusions
—High levels of proinsulin may predict later occurrence of first-ever stroke in a nondiabetic population.
The Quest for Early Predictors of Stroke Evolution
Authors: Baracchini Claudio , Manara Renzo , Ermani Mario , Meneghetti Giorgio
Published: June 2011

Background and Purpose
—The present study aimed at evaluating the prognostic value of transcranial Doppler ultrasonography (TCD) in the acute phase of ischemic stroke, when major therapeutic decisions must be made.

Methods
—Seventy-three patients with a first-ever ischemic hemispheric stroke underwent neurological assessment according to the Unified Neurological Stroke Scale, clinical subgrouping according to the criteria of Bamford, CT scan, cervical duplex sonography, and TCD, all within 12 hours from stroke onset. TCD was repeated on days 2 and 7. Patients were followed for 90 days, during which we calculated the fatality rate and then assessed clinical outcome.

Results
—Emergency TCD revealed middle cerebral artery (MCA) no-flow in 24 cases and MCA asymmetry in 30 subjects. Serial TCD showed early (<24 hours) MCA recanalization in 6 patients. After 90 days, no patient with MCA occlusion at admission was autonomous, while 17 of 19 patients (89.5%) with a normal baseline TCD were independent. The fatality rate at 3 months was 21% but was 46% in patients with MCA occlusion and 61% in patients without signs of early MCA recanalization. Total anterior circulation infarct and abnormal TCD were significantly correlated (
P
<0.001) with higher mortality rate and worse outcome (Barthel Index score ≤60), whereas early CT ischemic signs and severe carotid disease were not. Furthermore, TCD identified within the total anterior circulation infarct subgroup 2 prognostic clusters according to MCA patency at admission (
P
<0.001). Logistic regression selected normal baseline TCD as an independent predictor of good long-term outcome and MCA no-flow as an independent predictor of disability or death.

Conclusions
—TCD findings play an important role in the early prognosis of anterior circulation stroke, providing possible guidance for therapeutic interventions.
Stroke and Pregnancy
Authors: Jaigobin Cheryl , Silver Frank L.
Published: June 2011

Background and Purpose
—We sought to characterize the subtypes of stroke associated with pregnancy and the puerperium, with emphasis on timing, etiology, risk factors, and outcome.

Methods
—We conducted a retrospective analysis of patients admitted to the Toronto Hospital between January 1, 1980, and June 30, 1997, with a diagnosis of stroke during pregnancy or within 6 weeks postpartum. Strokes were classified as ischemic (arterial or venous) or hemorrhagic (subarachnoid or intracerebral). All patients were investigated with at least a CT scan of the head, and most had MRI and/or cerebral angiography.

Results
—Of approximately 50 700 admissions for delivery, 34 patients with a diagnosis of stroke were identified (21 infarctions and 13 hemorrhages). Of patients with infarction, 13 were arterial and 8 were venous. Nine of 13 arterial events occurred in the third trimester or puerperium. Seven of 8 venous occlusions occurred postpartum. An etiologic diagnosis was made in 7 of 13 patients with arterial territory infarction, including cardiac emboli, coagulopathies, and carotid artery dissection. Of patients with hemorrhage, 7 were subarachnoid and 6 were intracerebral. The etiology was identified in 10 patients: 3 were due to ruptured aneurysms, 5 were associated with arteriovenous malformations, and 2 were associated with disseminated intravascular coagulation. All patients with infarction survived, but 3 patients with hemorrhage died.

Conclusions
—The majority of strokes associated with pregnancy were arterial occlusions. Most presented during the third trimester and puerperium.
A Modified Transorbital Baboon Model of Reperfused Stroke
Authors: Huang Judy , Mocco J. , Choudhri Tanvir F. , Poisik Alexander , Popilskis Sulli J. , Emerson Ronald , DelaPaz Robert L. , Khandji Alexander G. , Pinsky David J. , Connolly E. Sander
Published: June 2011

Background and Purpose
—Although pathophysiological studies of focal cerebral ischemia in nonhuman primates can provide important information not obtainable in rodent models, primate experimentation is limited by considerations of cost, availability, effort, and ethics. A reproducible and quantitative model that minimizes the number of animals necessary to detect differences between treatment groups is therefore crucial.

Methods
—Eight male baboons (weight, 22±2 kg) underwent left transorbital craniectomy followed by 1 hour of temporary ipsilateral internal carotid artery occlusion at the level of the anterior choroidal artery together with bilateral temporary occlusion of both anterior cerebral arteries (A1) proximal to the anterior communicating artery. A tightly controlled nitrous oxide–narcotic anesthetic allowed for intraoperative motor evoked potential confirmation of middle cerebral artery (MCA) territory ischemia. Animals survived to 72 hours or 10 days if successfully self-caring. Outcomes were assessed with a 100-point neurological grading system, and infarct volume was quantified by planimetric analysis of both MRI and triphenyltetrazolium chloride–stained sections.

Results
—Infarction volumes (on T2-weighted images) were 32±7% (mean±SEM) of the ipsilateral hemisphere, and neurological scores averaged 29±9. All animals demonstrated evidence of hemispheric infarction, with damage evident in both cortical and subcortical regions in the MCA vascular territory. Histologically determined infarction volumes differed by <3% and correlated with absolute neurological scores (
r
=0.9,
P
=0.003).

Conclusions
—Transorbital temporary occlusion of the entire anterior cerebral circulation with strict control of physiological parameters can reliably produce reperfused MCA territory infarction. The magnitude of the resultant infarct with little interanimal variability diminishes the potential number of animals required to distinguish between 2 treatment regimens. The anatomic distribution of the infarct and associated functional deficits offer comparability to human hemispheric strokes.
Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke in Patients Aged 80 Years and Older
Authors: Tanne David , Gorman Mark J. , Bates Vernice E. , Kasner Scott E. , Scott Phillip , Verro Piero , Binder Jeffrey R. , Dayno Jeffrey M. , Schultz Lonni R. , Levine Steven R.
Published: June 2011

Background and Purpose
—Intravenous tissue plasminogen activator (tPA) administered within 3 hours of symptom onset is the first available effective therapy for acute ischemic stroke (AIS). Few data exist, however, on its use in very elderly patients. We examined the characteristics, complications, and short-term outcome of AIS patients aged ≥80 years treated with tPA.

Methods
—Patients aged ≥80 years (n=30) were compared with counterparts aged <80 years (n=159) included in the tPA Stroke Survey, a US retrospective survey of 189 consecutive AIS patients treated with intravenous tPA at 13 hospitals.

Results
—Risk of intracerebral hemorrhage (fatal, symptomatic, and total) was 3%, 3%, and 7% in the elderly age group and 2%, 6%, and 9%, respectively, in their younger counterparts (
P
=NS for all comparisons). Likelihood of favorable outcome, defined as modified Rankin score 0 to 1, National Institutes of Health Stroke Scale score ≤5, or marked improvement by hospital discharge, was comparable between groups (37%, 54%, and 43% versus 30%, 54%, and 43%, respectively;
P
=NS for all comparisons). Elderly patients were more likely to be treated by stroke specialists (87% versus 60%;
P
=0.005) and less likely to have an identified protocol deviation (13% versus 33%;
P
=0.03). Elderly patients were discharged more often to nursing care facilities (17% versus 5%;
P
=0.003). In logistic regression models there were no differences in odds ratio for favorable or poor outcome, other than tendency for higher in-hospital mortality in elderly patients (odds ratio, 2.8; 95% CI, 0.81 to 9.62;
P
=0.10).

Conclusions
—Among AIS patients treated with intravenous tPA, age-related differences in characteristics and disposition were identified. No evidence for withholding tPA treatment for AIS in appropriately selected patients aged ≥80 years was identified.
A Predictive Risk Model for Outcomes of Ischemic Stroke
Authors: Johnston K. C. , Connors A. F. , Wagner D. P. , Knaus W. A. , Wang X.-Q. , Haley E. Clarke
Published: June 2011

Background and Purpose
—The great variability of outcome seen in stroke patients has led to an interest in identifying predictors of outcome. The combination of clinical and imaging variables as predictors of stroke outcome in a multivariable risk adjustment model may be more powerful than either alone. The purpose of this study was to determine the multivariable relationship between infarct volume, 6 clinical variables, and 3-month outcomes in ischemic stroke patients.

Methods
—Included in the study were 256 eligible patients from the Randomized Trial of Tirilazad Mesylate in Acute Stroke (RANTTAS). Six clinical variables and 1-week infarct volume were the prespecified predictor variables. The National Institutes of Health Stroke Scale, Barthel Index, and Glasgow Outcome Scale were the outcomes. Multivariable logistic regression techniques were used to develop the model equations, and bootstrap techniques were used for internal validation. Predictive performance of the models was assessed for discrimination with receiver operator characteristic (ROC) curves and for calibration with calibration curves.

Results
—The predictive models had areas under the ROC curve of 0.79 to 0.88 and demonstrated nearly ideal calibration curves. The areas under the ROC curves were statistically greater (
P
<0.001) with both clinical and imaging information combined than with either alone for predicting excellent recovery and death or severe disability.

Conclusions
—Combined clinical and imaging variables are predictive of 3-month outcome in ischemic stroke patients. Demonstration of this relationship with acute clinical variables and 1-week infarct information supports future attempts to predict 3-month outcome with all acute variables.
The Stroke Prognosis Instrument II (SPI-II)
Authors: Kernan Walter N. , Viscoli Catherine M. , Brass Lawrence M. , Makuch Robert W. , Sarrel Philip M. , Roberts Robin S. , Gent Michael , Rothwell Peter , Sacco Ralph L. , Liu Ruei-Che , Boden-Albala Bernadette , Horwitz Ralph I.
Published: June 2011

Background and Purpose
—In 1991 we developed the Stroke Prognosis Instrument (SPI-I) to stratify patients with transient ischemic attack or ischemic stroke by prognosis for stroke or death in 2 years. In this article we validate and improve SPI-I (creating SPI-II).

Methods
—To validate SPI-I, we applied it to 4 test cohorts and calculated pooled outcome rates. To create SPI-II, we incorporated new predictive variables identified in 1 of the test cohorts and validated it in the other 3 cohorts.

Results
—For SPI-I, pooled rates (all 4 test cohorts) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 24%, respectively (
P
<0.01, log-rank test). SPI-II was created by adding congestive heart failure and prior stroke to SPI-I. Each patient’s risk group was determined by the total score for 7 factors: congestive heart failure (3 points); diabetes (3 points); prior stroke (3 points); age >70 years (2 points); stroke for the index event (not transient ischemic attack) (2 points); hypertension (1 point); and coronary artery disease (1 point). Risk groups I, II, and III comprised patients with 0 to 3, 4 to 7, and 8 to 15 points, respectively. For SPI-I, pooled rates (3 cohorts excluding the SPI-II development cohort) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 23%, respectively. For SPI-II, pooled rates were 10%, 19%, and 31%, respectively. In receiver operator characteristic analysis, the area under the curve was 0.59 (95% CI, 0.57 to 0.60) for SPI-I and 0.63 (95% CI, 0.62 to 0.65) for SPI-II, confirming the better performance of the latter.

Conclusions
—Compared with SPI-I, SPI-II achieves greater discrimination in outcome rates among risk groups. SPI-II is ready for use in research design and may have a role in patient counseling.
Antithrombotic and Antihypertensive Management 3 Months After Ischemic Stroke
Authors: Hillen Thomas , Dundas Ruth , Lawrence Enas , Stewart Judith A. , Rudd Anthony G. , Wolfe Charles D. A.
Published: June 2011

Background and Purpose
—We sought to examine the frequency, predictors, and effects of nontreatment with antithrombotic and antihypertensive therapies 3 months after ischemic stroke.

Methods
—The population-based South London Community Stroke Register prospectively collected data on first-in-a-lifetime strokes between 1995 and 1997. Among patients registered with ischemic stroke, treatment status with antithrombotic and antihypertensive therapies was examined 3 months after the event.

Results
—In a cohort of 457 patients with ischemic stroke, 393 (86.0%) were considered appropriate for antiplatelet medication, 32 (7.0%) for anticoagulant medication, and 254 (55.9%) for antihypertensive medication. The rates of nontreatment observed 3 months after the event were 24.4% for antiplatelet, 59.4% for anticoagulant, and 29.5% for antihypertensive medication. Independent risk factors for nontreatment with antithrombotic therapies (antiplatelets and anticoagulants) were the subtype of stroke (nonlacunar infarct: OR=1.60, 95% CI 1.07 to 2.54), stroke severity measured by the Glasgow Coma Scale (GCS) score (GCS ≤13: OR 2.08, 95% CI 1.18 to 3.66) and the Barthel Index (BI) score 5 days after the event (BI ≤10: OR 1.85, 95% CI 1.17 to 2.93). For antihypertensive therapies the stroke subtype (OR 2.46, 95% CI 1.33 to 4.54), GCS score (OR 2.97, 95% CI 1.35 to 6.53), BI score (OR 2.33, 95% CI 1.27 to 4.29), and ethnicity (Caucasian: OR 2.43, 95% CI 1.15 to 5.14) were independently associated with nontreatment. Cox regression modeling showed no significant association between the treatment status and recurrence-free 3-year survival rates after controlling for severity and subtype of stroke.

Conclusions
—Secondary prevention for a common disease such as stroke appears to be inadequate in the study area. Healthcare professionals need to consider antithrombotic and antihypertensive therapies for all stroke patients.
Growth Factors Stimulate Neointimal Cells In Vitro and Increase the Thickness of the Neointima Formed at the Neck of Porcine Aneurysms Treated by Embolization
Authors: Desfaits Anne-Cécile , Raymond Jean
Published: June 2011

Background and Purpose
—Growth factors (GFs) may favor the healing of aneurysms treated with endovascular techniques by stimulating neointima formation.

Methods
—Bilateral carotid aneurysms were constructed with venous pouches in 50 pigs and embolized intraoperatively with collagen sponges with and without GFs (platelet-derived growth factor-BB [PDGF-BB] 0.15 or 1.5 μg or transforming growth factor-β
1
[TGF-β
1
] 60 or 600 ng) in each animal. DNA synthesis, cell proliferation, and collagen secretion assays were performed to assess the in vitro effects of GFs on neointimal cells harvested from the treated aneurysms.
125
I-PDGF-BB was used to study in vivo GF release from sponges. The thickness of the neointima at the surface of the sponges was measured 2 weeks after surgery. Since porcine aneurysms tend to heal after collagen sponge embolization, this experiment was repeated in dogs, which have shown a propensity for recurrence with the same technique, with 600 ng TGF-β
1
or platelet extracts.

Results
—PDGF-BB stimulated DNA synthesis and cell proliferation, while TGF-β
1
strongly increased collagen synthesis of neointimal cells in vitro. Clearance of
125
I-PDGF-BB from the sponges followed a biphasic curve, with 1.5% of exogenous PDGF-BB remaining at 1 week. The local delivery of PDGF-BB (0.15 or 1.5 μg) and TGF-β
1
(600 ng) significantly increased neointimal thickness at the neck of porcine aneurysms, while 60 ng of TGF-β
1
had no demonstrable effect. TGF-β
1
(600 ng) or platelet extracts had no influence on canine aneurysms.

Conclusions
—PDGF-BB and TGF-β
1
can stimulate neointimal cells in vitro and neointima formation in vivo, but TGF-β
1
and platelet extracts do not compensate for deficient thrombosis in canine aneurysms. Effects on the long-term results of embolization remain speculative.
Is the Acetazolamide Test Valid for Quantitative Assessment of Maximal Cerebral Autoregulatory Vasodilation?
Authors: Démolis Pierre , Florence Geneviève , Thomas Lionel , Tran Dinh Yves Roger , Giudicelli Jean-François , Seylaz Jacques
Published: June 2011

Background and Purpose
—The cerebral vasodilating effect of acetazolamide (ACZ) injection has been used as an index of the autoregulatory vasodilation (or cerebral perfusion reserve). The question of whether the ACZ test assesses the maximal autoregulatory vasodilating capacity is not definitely resolved. The effects of ACZ injection on this reserve at a dose producing maximal vasodilation have never been evaluated and may help to resolve this problem.

Methods
—The effect of ACZ injection on cerebral blood flow (CBF) autoregulation was tested in anesthetized rats. A pilot experiment evaluated the dose-effect relationship of injected ACZ, cumulative doses (n=4, group 1), and independent bolus doses (n=6, group 2). CBF was estimated by laser-Doppler flowmetry, and cerebrovascular resistance (CVR) was calculated from mean arterial blood pressure (MABP) and from CBF (expressed as a percentage of baseline CBF). A bolus of ACZ of 21 mg/kg produced the maximal cerebral vasodilation that could be obtained by ACZ administration. In the main experiment, MABP was lowered from 110 to 20 mm Hg by stepwise bleeding in 3 groups of 6 animals treated 10 minutes before bleeding by injection of saline (group 3), 7 mg/kg ACZ (group 4), or 21 mg/kg ACZ (group 5).

Results
—The CVR-MABP relationship was linear in all groups, indicating that CBF autoregulation was still effective after ACZ administration.

Conclusions
—These results indicate that maximal ACZ-induced cerebral vasodilation is not quantitatively equivalent to maximal autoregulatory vasodilating capacity in anesthetized rats.
Effects of Stress Reduction on Carotid Atherosclerosis in Hypertensive African Americans
Authors: Castillo-Richmond Amparo , Schneider Robert H. , Alexander Charles N. , Cook Robert , Myers Hector , Nidich Sanford , Haney Chinelo , Rainforth Maxwell , Salerno John
Published: June 2011

Background and Purpose
—African Americans suffer disproportionately higher cardiovascular disease mortality rates than do whites. Psychosocial stress influences the development and progression of atherosclerosis. Carotid intima-media thickness (IMT) is a valid surrogate measure for coronary atherosclerosis, is a predictor of coronary outcomes and stroke, and is associated with psychosocial stress factors. Stress reduction with the Transcendental Meditation (TM) program decreases coronary heart disease risk factors and cardiovascular mortality in African Americans. B-mode ultrasound is useful for the noninvasive evaluation of carotid atherosclerosis.

Methods
—This randomized controlled clinical trial evaluated the effects of the TM program on carotid IMT in hypertensive African American men and women, aged >20 years, over a 6- to 9-month period. From the initially enrolled 138 volunteers, 60 subjects completed pretest and posttest carotid IMT data. The assigned interventions were either the TM program or a health education group. By use of B-mode ultrasound, mean maximum IMT from 6 carotid segments was used to determine pretest and posttest IMT values. Regression analysis and ANCOVA were performed.

Results
—Age and pretest IMT were found to be predictors of posttest IMT values and were used as covariates. The TM group showed a significant decrease of −0.098 mm (95% CI −0.198 to 0.003 mm) compared with an increase of 0.054 mm (95% CI −0.05 to 0.158 mm) in the control group (
P
=0.038, 2-tailed).

Conclusions
—Stress reduction with the TM program is associated with reduced carotid atherosclerosis compared with health education in hypertensive African Americans. Further research with this stress-reduction technique is warranted to confirm these preliminary findings.
Sex Differences in the Relationship of Risk Factors to Subclinical Carotid Atherosclerosis Measured 15 Years Later
Authors: Stensland-Bugge Eva , Bønaa Kaare H. , Joakimsen Oddmund , Njølstad Inger
Published: June 2011

Background and Purpose
—Ultrasound measurement of carotid artery intima-media thickness (IMT) is regarded as a valid index of atherosclerosis. Determinants of IMT in cross-sectional studies have been established, but the long-term relationship between cardiovascular risk factors and subclinical atherosclerosis has not been investigated thoroughly.

Methods
—We included in the study 3128 middle-aged men and women in Tromsø, Norway, who in 1980 attended the baseline examination with measurements of cardiovascular risk factors and who underwent carotid ultrasonography after 15 years of follow-up.

Results
—Age, blood pressure, total cholesterol, HDL cholesterol, and body mass index were independent long-term predictors of IMT in both men and women. Triglyceride levels were associated with an increase in IMT in women only, while physical activity and smoking were predictors of IMT in men only. However, smoking was associated with increased risk of having atherosclerotic plaque in both men and women. There were no differences in the strength of risk factor effects on IMT in the common carotid artery and the carotid bifurcation.

Conclusions
—The present study indicates that established cardiovascular risk factors are independent predictors of subclinical atherosclerosis measured after 15 years of follow-up. However, there may be significant sex differences in the relationship between triglycerides, smoking, and physical activity and the risk of atherosclerosis.
Neurobehavioral Outcome Prediction After Cardiac Surgery
Authors: Herrmann Manfred , Ebert Anne D. , Galazky Imke , Wunderlich Michael T. , Kunz Wolfram S. , Huth Christof
Published: June 2011

Background and Purpose
—The goal of the present study was to investigate the predictive value of neurobiochemical markers of brain damage (protein S-100B and neuron-specific enolase [NSE]) with respect to the short- and long-term neuropsychological outcomes after cardiac surgery with cardiopulmonary bypass (CPB).

Methods
—We investigated 74 patients who underwent elective CABG or valve replacement surgery and who showed no severe neurological deficits after surgery. Patients were investigated with a standardized neurological examination and a comprehensive neuropsychological and neuropsychiatric assessment 1 to 2 days before surgery, 3 and 8 days after surgery, and 6 months later. Serial venous blood samples were taken preoperatively and 1, 6, 20, and 30 hours after skin closure. Protein S-100B and NSE were analyzed with immunoluminometric assays.

Results
—Patients with severe postoperative neuropsychological disorders showed a significantly higher and longer release of neurobiochemical markers of brain damage. Patients who presented with a delirium according to DSM-III-R criteria 3 days after surgery had significantly higher postoperative S-100B serum concentrations. Multivariate analysis (based on postoperative NSE and S-100B concentrations and age of patients, type of operation, length of cross-clamp and perfusion time, and intraoperative and postoperative oxygenation) identified NSE and S-100B concentrations 6 to 30 hours after skin closure as the only variables that contributed significantly to a predictive model of the neuropsychological outcome. NSE, but not S-100B, release was significantly higher in patients undergoing valve replacement surgery.

Conclusions
—Postoperative serum concentrations and kinetics of S-100B and NSE have a high predictive value with respect to the early neuropsychological and neuropsychiatric outcome after cardiac surgery. The analysis of NSE and S-100B release might allow insight into the underlying pathophysiology of brain dysfunction, thus providing a valuable tool to monitor and evaluate measures to improve cardiac surgery with CPB.
Relating MRI Changes to Motor Deficit After Ischemic Stroke by Segmentation of Functional Motor Pathways
Authors: Pineiro R. , Pendlebury S. T. , Smith S. , Flitney D. , Blamire A. M. , Styles P. , Matthews P. M.
Published: June 2011

Background and Purpose
—Infarct size on T2-weighted MRI correlates only modestly with outcome, particularly for small strokes. This may be largely because of differences in the locations of infarcts and consequently in the functional pathways that are damaged. To test this hypothesis quantitatively, we developed a “mask” of the corticospinal pathway to determine whether the extent of stroke intersection with the pathway would be more closely related to clinical motor deficit and axonal injury in the descending motor pathways than total stroke lesion volume.

Methods
—Eighteen patients were studied ≥1 month after first ischemic stroke that caused a motor deficit by use of brain T2-weighted imaging, MR spectroscopic (MRS) measurements of the neuronal marker compound
N
-acetyl aspartate in the posterior limb of the internal capsule, and motor impairment and disability measures. A corticospinal mask based on neuroanatomic landmarks was generated from a subset of the MRI data. The maximum proportion of the cross-sectional area of this mask occupied by stroke was determined for each patient after all brain images were transformed into a common stereotaxic brain space.

Results
—There was a significant linear relationship between the maximum proportional cross-sectional area of the corticospinal mask occupied by stroke and motor deficit (
r
2
=0.82,
P
<0.001), whereas the relationship between the total stroke volume and motor deficit was better described by a cubic curve (
r
2
=0.76,
P
<0.001). Inspection of the data plots showed that the total stroke volume discriminated poorly between smaller strokes with regard to the extent of associated motor deficit, whereas the maximum proportion of the mask cross-sectional area occupied by stroke appeared to be a more discriminatory marker of motor deficit and also
N
-acetyl aspartate reduction.

Conclusions
—Segmentation of functional motor pathways on MRI allows estimation of the extent of damage specifically to that pathway by the stroke lesion. The extent of stroke intersection with the motor pathways was more linearly related to the magnitude of motor deficit than total lesion volume and appeared to be a better discriminator between small strokes with regard to motor deficit. This emphasizes the importance of the anatomic relationship of the infarct to local structures in determining functional impairment. Prospective studies are necessary to assess whether this approach would allow improved early estimation of prognosis after stroke.