bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrocephalus: A Previously Unrecognized Predictor of Poor Outcome From Supratentorial Intracerebral Hemorrhage
Authors: Diringer Michael N. , Edwards Dorothy F. , Zazulia Allyson R.
Published: June 2011

Background and Purpose
—Although several factors have been identified that predict outcome after intracerebral hemorrhage (ICH), no previous study has investigated the impact of hydrocephalus. The purpose of this study was to determine whether the presence of hydrocephalus after ICH would predict mortality and functional outcome.

Methods
—Patients with spontaneous supratentorial ICH were identified in our prospectively collected database to determine the following: age, sex, race, past medical history; Glasgow Coma Scale (GCS) score and blood pressure on admission; use of mechanical ventilation, mannitol, and ventriculostomy; and medical complications. CT scans performed within 24 hours of hemorrhage were retrospectively analyzed to determine lesion size and location, pineal shift, cisternal effacement, intraventricular hemorrhage (IVH), and hydrocephalus. Outcome was determined with use of hospital disposition (dead, nursing home, rehabilitation, home) and functional outcome (Functional Independence Measure [FIM]) at 3 months. Patients with and without hydrocephalus were compared and univariate and multivariate analyses performed to determine whether hydrocephalus was an independent predictor of mortality. Data are presented as mean±SD.

Results
—Of the 81 patients studied, 40 had hydrocephalus. Those with hydrocephalus were younger (57±15 versus 67±15 years), had lower GCS scores (8.2±4.2 versus 11±2.9), were more likely to have ganglionic or thalamic hemorrhages, and were intubated more frequently (70% versus 27%). Hospital mortality was higher in patients with hydrocephalus (51% versus 2%), and fewer patients went home (21% versus 35%). Those who died had higher hydrocephalus scores (9.67±7.1 versus 5.75±4.5). Outcome was no different if a ventriculostomy was placed. The final logistic regression model included hydrocephalus score, gender, GCS, and pineal shift, and it correctly predicted 85% of patients as dead or alive. Multivariate analyses indicated that hydrocephalus is an independent predictor of mortality.

Conclusions
—We conclude that hydrocephalus is an independent predictor of mortality after ICH.
Increased Bone Resorption During the First Year After Stroke
Authors: Sato Yoshihiro , Kuno Haruko , Kaji Masahide , Ohshima Yuki , Asoh Takeshi , Oizumi Kotaro
Published: June 2011

Background and Purpose
—Significant bone mineral density (BMD) reduction occurs in stroke patients on the hemiplegic side compared with the intact side. To elucidate the pathogenesis of hip fractures in this population, we measured serum markers of bone metabolism and BMD in the stroke patients within 1 year (early group) and between 1 and 2 years after onset of hemiplegia (long-term group).

Methods
—Sera were collected from 51 patients from the early group and 93 patients from the long-term group. All patients had hemiplegia. Sera were assayed for pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP; a bone resorption marker) and bone Gla protein (a bone formation marker). The
z
score of BMD was determined in both second metacarpals.

Results
—Serum ICTP concentrations (ng/mL) were higher in the early group (15.4±4.1) than in the long-term group (6.7±4.4). Bone Gla protein was normal or low in both groups. Multiple regression analysis identified Barthel Index, degree of hemiplegia, and illness duration as independent determinants of ICTP in the early group, whereas Barthel Index, degree of hemiplegia, and serum calcium were determinants of ICTP in the long-term group. There were statistically significant correlations between the
z
score of the hemiplegic side and age, Barthel Index, degree of hemiplegia, illness duration, 25-hydroxyvitamin D (25-OHD), and ICTP in the early group and between the
z
score and degree of hemiplegia and 25-OHD level in the long-term group.

Conclusions
—The pathogenesis of reduced BMD differed between the early and long-term stroke groups. These results suggest that in the early group, increased bone resorption caused by immobilization was responsible for osteopenia on the hemiplegic side, whereas the degree of hemiplegia and 25-OHD level were the determinants of osteopenia in the long-term group.
Activation of Protease-Activated Receptor-2 (PAR-2) Elicits Nitric Oxide–Dependent Dilatation of the Basilar Artery In Vivo
Authors: Sobey Christopher G. , Cocks Thomas M.
Published: June 2011

Background and Purpose
—Protease-activated receptors (PARs) are a family of G-protein–coupled receptors activated by a tethered ligand amino acid sequence within the amino terminal that is revealed by site-specific proteolysis. In the vascular endothelium, activation of PAR-2 by treatment with trypsin or by using the amino acid ligand sequence (SLIGRL) produces endothelium-dependent relaxation of isolated noncerebral vascular segments. In this study, we first tested whether PAR-2 activation produces cerebral vasodilatation in vivo and then examined whether PAR-2–mediated vasodilatation is dependent on the production of nitric oxide.

Methods
—Concentration-dependent vasodilator effects of the PAR-2 agonist peptide SLIGRL and trypsin were examined on the basilar artery using a cranial window in anesthetized rats. In addition, the vasodilator effects of SLIGRL, acetylcholine (ACh), and sodium nitroprusside (SNP) were examined in the absence and presence of
N
G
-nitro-
l
-arginine (L-NNA), an inhibitor of nitric oxide synthase, and 1
H
-[1,2,4]oxadiazolo[4,3-
a
]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase.

Results
—Baseline diameter of the basilar artery averaged 239±4 μm. Under control conditions, SLIGRL (10
–6
to 10
–4
mol/L) and trypsin (0.01 to 10 U/mL) produced concentration-dependent vasodilator responses. In time-control experiments, SLIGRL (3×10
–6
and 10
–5
mol/L), ACh (10
–6
and 10
–5
mol/L), and SNP (10
–8
and 10
–7
mol/L) elicited reproducible dilatation of the basilar artery. In another group of rats, L-NNA (10
–4
mol/L) markedly inhibited dilator responses to both SLIGRL (13±3% versus 1±1% and 39±7% versus 11±2%; both
P
<0.05) and ACh (8±1% versus 0±0% and 13±2% versus 3±1%; both
P
<0.05). By contrast, responses to SNP were significantly augmented after treatment with L-NNA (
P
<0.05 versus control), indicating that inhibitory effects of L-NNA were specific for responses mediated by endogenous nitric oxide. Furthermore, in another group ODQ (10
−5
mol/L) inhibited responses to SLIGRL to a degree similar to that seen with L-NNA, consistent with a mechanism of PAR-2–mediated vasodilatation that involves activation of guanylate cyclase by nitric oxide.

Conclusions
—To the best of our knowledge, this study is the first to examine whether PAR-2–mediated vasodilatation is functional in cerebral arteries and is also the first to directly assess the effects of PAR-2 activation on vascular tone in vivo. The results suggest that activation of PAR-2 is an effective and powerful vasodilator mechanism in cerebral arteries in vivo. Cerebral vasodilator responses to PAR-2 activation are mediated by nitric oxide and are likely to be endothelium dependent.
A Model of Transient Unilateral Focal Ischemia With Reperfusion in the P7 Neonatal Rat
Authors: Renolleau S. , Aggoun-Zouaoui D. , Ben-Ari Y. , Charriaut-Marlangue C.
Published: June 2011

Background and Purpose
—The mechanisms leading to delayed cell death after hypoxic-ischemic injury in the developing brain remain to be elucidated. The aim of this study was to develop a model of transient focal ischemia in the neonatal rat in an attempt to create a reperfusion phase since in the filament model of reversible middle cerebral artery occlusion, size limitations precluded performing this procedure before 14 to 18 days. We then analyze whether apoptosis or necrosis occurs in this model.

Methods
—Seven-day-old Wistar rat pups (n=96) underwent permanent left middle cerebral artery occlusion in association with 1-hour occlusion of the left common carotid artery. Evolution of the brain infarction was studied from 24 hours to 3 months on cresyl violet–stained coronal sections. Infarct volume was determined with the use of the mitochondrial stain 2,3,5-triphenyltetrazolium chloride. Neuronal death was demonstrated by the silver staining method of Gallyas et al (1980). Chromatin condensation was shown by DNA fragmentation assessed with the use of terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end-labeling (TUNEL) assay in cryostat sections and electron microscopic analysis.

Results
—Almost all of the animals who survived had reproducible cortical infarcts. The mean infarct volume was 31±7 mm

3

(mean±SD). The ipsilateral hemisphere showed a well-delineated lesion in the frontoparietal cortex at 3-month recovery. Argyrophilic (dying) neurons were observed a few hours after reperfusion and increased with time. Cells exhibiting DNA fragmentation were shown as early as 6 hours, increased up to and peaked at 24 to 96 hours, then progressively decreased and persisted for several days, suggesting an ongoing process. Electron microscopy analysis demonstrated high condensation and clumping of chromatin beneath nuclear membrane in shrunken neurons.

Conclusions
—Our study demonstrates the feasibility of performing ischemia-reperfusion in 7-day-old rats that develop progressive neuronal death with features characteristic of apoptosis. The reperfusion phase mimics events that occur during neonatal human hypoxic-ischemic encephalopathy at birth, since perinatal intensive care most often permits recirculation.
Effects of Hypertonic Saline Hydroxyethyl Starch Solution and Mannitol in Patients With Increased Intracranial Pressure After Stroke
Authors: Schwarz Stefan , Schwab Stefan , Bertram Markus , Aschoff Alfred , Hacke Werner
Published: June 2011

Background and Purpose
—The purpose of this study was to prospectively evaluate a protocol with hypertonic saline hydroxyethyl starch (HS-HES) and mannitol in stroke patients with increased intracranial pressure (ICP).

Methods
—We studied 30 episodes of ICP crisis in 9 patients. ICP crisis was defined as (1) a rise of ICP of more than 25 mm Hg (n=22), or (2) pupillary abnormality (n=3), or (3) a combination of both (n=5). Baseline treatment was performed according to a standardized protocol. For initial treatment, the patients were randomly assigned to either infusion of 100 mL HS-HES or 40 g mannitol over 15 minutes. For repeated treatments the 2 substances were alternated. ICP, blood pressure, and cerebral perfusion pressure (CPP) were monitored over 4 hours. Blood gases, hematocrit, blood osmolarity, and sodium were measured before and 15 and 60 minutes after the start of infusion. Treatment was regarded as effective if ICP decreased >10% below baseline value or if the pupillary reaction had normalized.

Results
—Treatment was effective in all 16 HS-HES–treated and in 10 of 14 mannitol-treated episodes. ICP decreased from baseline values in both groups,
P
<0.01. The maximum ICP decrease was 11.4 mm Hg (after 25 minutes) in the HS-HES–treated group and 6.4 mm Hg (after 45 minutes) in the mannitol-treated group. There was no constant effect on CPP in the HS-HES–treated group, whereas CPP rose significantly in the mannitol-treated group. Blood osmolarity rose by 6.2 mmol/L in the mannitol-treated group and by 10.5 mmol/L in the HS-HES–treated group; sodium fell by 3.2 mmol/L in the mannitol and rose by 4.1 mmol/L in the HS-HES–treated group.

Conclusions
—Infusion of 40 g mannitol and 100 mL HS-HES decreases increased ICP after stroke. The maximum effect occurs after the end of infusion and is visible over 4 hours. HS-HES seems to lower ICP more effectively but does not increase CPP as much as does mannitol.
Consumption of Fruit and Wine and the Decline in Cerebrovascular Disease Mortality in Spain (1975–1993)
Authors: Artalejo Fernando Rodríguez , Guallar-Castillón Pilar , Banegas José Ramón Banegas , Manzano Belén de Andrés , Calero Juan del Rey
Published: June 2011

Background and Purpose
—This study examines the changes in provincial distribution of cerebrovascular disease (CVD) mortality and its socioeconomic and lifestyle risk factors to identify those factors that have most greatly contributed to the decline in CVD mortality in Spain during the period 1975–1993.

Methods
—We performed a study using data aggregated at a provincial level. Mortality data were taken from official vital statistics, while data on risk factors were obtained from surveys of representative large Spanish population samples. Correlation and multiple linear regression analyses were performed on percent changes in age-standardized CVD mortality from 1975–1979 to 1989–1993 and its potential determinants during the period 1964–1980.

Results
—CVD mortality was higher in the southern and eastern (Mediterranean coast) provinces in 1975–1979 and again in 1989–1993. Between these periods there was a 55% decline in CVD mortality, which affected all provinces but was greater in those with a lower CVD mortality (
r
=−0.31,
P
=0.03). The 1964–1980 period witnessed an increase in the intake of most foodstuffs and all types of fats. However, there was a decrease in the consumption of vegetables and legumes and in the proportion of illiteracy among the population older than 45 years. The greatest increase in fruit and fish consumption and the greatest decrease in illiteracy were registered by Spain’s northernmost provinces, the same provinces that recorded the greatest decline in CVD mortality. Changes in fruit, wine, and fish intake accounted for 22% of the variation in the decline in CVD mortality. The increase in fruit consumption and decrease in wine consumption showed a statistically significant relationship (
P
≤0.04) with the decline in CVD mortality.

Conclusions
—The increase in fruit and decrease in wine consumption from 1964–1980 may have contributed to the decline in CVD mortality in Spain during 1975–1993.
Incidence and Risk Factors for Stroke in an Occupational Cohort
Authors: Berger K. , Schulte H. , Stögbauer F. , Assmann G.
Published: June 2011

Background and Purpose
—The purpose of this study was to assess the incidence of stroke and the magnitude of classic stroke risk factors in an occupational cohort of white-collar and blue-collar workers.

Methods
—We studied a prospective cohort of 12 866 male employees, aged 30 to 65 years, in 52 companies in northwestern Germany, with an average follow-up of 7.2 years. Participants were free of self-reported stroke, transient ischemic attack, and myocardial infarction at baseline. Physical examination, blood tests, and a face-to-face interview to assess presence of various risk factors were performed at the workplace. Follow-up was done by standardized mailed questionnaire. Main outcome measure was first stroke occurrence.

Results
—Overall stroke incidence was 42.4 per 100 000 person-years, increasing from 10.1 per 100 000 person-years in the age category 30 to 39 years to 33.6, 80.6, and 159.2 per 100 000 person-years in the age categories 40 to 49, 50 to 59, and 60 years and older, respectively. After adjustment for potential confounders, the relative risks of total stroke associated with systolic blood pressure ≤120, 121 to 140, and ≥141 mm Hg were 1.00 (reference), 2.99 (95% confidence interval, 0.85 to 10.49), and 5.56 (1.56 to 19.88). The risks associated with smoking status of never/past, ≤20 cigarettes per day, and >20 cigarettes per day) were 1.00 (reference), 1.65 (0.62 to 4.42), and 3.56 (1.78 to 7.15), respectively. A history of hypertension at baseline (yes versus no) was independently associated with a relative risk of 2.37 (1.20 to 4.71) for total stroke and a history of diabetes mellitus (yes versus no) with a risk of 2.21 (1.00 to 4.87). A comparison of risk factor levels with a general population study revealed only small differences.

Conclusions
—This occupational cohort had a 2-fold lower stroke incidence than that observed in cohorts of the general population. In the absence of a strong healthy-worker effect, moderate differences in behavioral risk factors and a higher treatment rate for hypertension contribute to the explanation of this favorable stroke incidence.
Expression of Nerve Growth Factor and trkA After Transient Focal Cerebral Ischemia in Rats
Authors: Lee Tsong-Hai , Kato Hiroyuki , Chen Sien-Tsong , Kogure Kyuya , Itoyama Yasuto
Published: June 2011

Background and Purpose
—In vitro studies have shown that nerve growth factor (NGF) is protective to cortical neurons against various insults. However, the role of NGF in relation to its high-affinity trkA receptor in the cortical neurons has not been well discussed. In this experiment, we studied the possible involvement of the NGF/receptor system in the ischemic injury of cortical neurons after focal cerebral ischemia in rats.

Methods
—Male Wistar rats received right middle cerebral artery occlusion of 90 minutes’ duration. The rats were decapitated at different reperfusion time points: hour 4 and days 1, 3, 7, and 14 of recirculation. Brain sections at the level of striatum were immunostained against NGF, trkA, glial fibrillary acidic protein (GFAP), and stress protein HSP70. Double immunostaining against NGF and GFAP was also performed. Optical density of NGF immunoreactivity in the ischemic and nonischemic cortexes was compared between sham-control and ischemic animals.

Results
—In the sham-control rats, NGF immunoreactivity was present in the cortical and striatal neurons. However, beginning at hour 4 after recirculation, there was a significant decrease of NGF in the ischemic cortex and striatum. Beginning at day 1, NGF was absent completely in the infarcted striatum and cortex. However, in the peri-infarct penumbra area, despite a decrease in NGF at hour 4 and day 1, NGF recovered beginning at day 3 and returned almost to the sham-control level at day 14. In the nonischemic cortex, NGF increased beginning at hour 4, peaked at day 7, and returned almost to the sham-control level at day 14. The trkA and HSP70 immunoreactivities were not present in the sham-control cortex. However, trkA was induced at hour 4 in the ischemic cortex and at days 1 and 3 in the peri-infarct penumbra cortex. The HSP70 was induced at days 1 and 3 in the peri-infarct penumbra area. Double immunostaining showed that the number of GFAP-positive cells increased gradually, and NGF immunoreactivity in the GFAP-positive cells became gradually intense after ischemia.

Conclusions
—Our study demonstrated a temporal profile of NGF and trkA in the ischemic cortex and NGF expression by reactive astrocytes. Our data suggest that the NGF/receptor system may play a role in the astrocyte/neuron interaction under certain pathological conditions, such as focal cerebral ischemia.
Ethical Challenges in Stroke Research
Authors: Slyter Howard
Published: June 2011

Background
—Ethical issues are a critical consideration in the design and conduct of clinical research.

Summary of Review
—A number of completed trials of proposed stroke treatments raise classical ethical issues in challenging ways. The combination of acutely ill and vulnerable patients, the use of potentially toxic drugs, and very short time frames for decision making and drug administration demand an especially careful evaluation of risk and benefit, the process of consent, and the permissible treatment of control patients.

Conclusions
—The study of acute stroke treatments may require more complex safeguards than other neuroclinical trials.
Mechanisms of Cerebrovascular Events as Assessed by Procoagulant Activity, Cerebral Microemboli, and Platelet Microparticles in Patients With Prosthetic Heart Valves
Authors: Geiser Thomas , Sturzenegger Matthias , Genewein Urs , Haeberli André , Beer Jürg H.
Published: June 2011

Background and Purpose
—Cerebrovascular events (CVE) in patients with prosthetic heart valves (PHV) have remained a severe and frequent complication despite oral anticoagulation with or without aspirin. We studied the possible pathophysiological involvement of platelet-derived microparticles (PMP) as a contributing factor for the increased incidence of CVE in patients with PHV.

Methods
—We compared in a retrospective, case-control study the clinical outcome after the implantation of the PHV with several different independent morphological and functional methods, including simultaneous transcranial Doppler monitoring of both middle cerebral arteries, PMP detection by flow cytometry with use of platelet-specific antibodies, coagulation markers, and determination of the procoagulant activity by Russell’s viper venom time, a phospholipid-dependent coagulation assay.

Results
—Eight of 26 patients with PHV had 9 CVE during 136 person-years of observation. Transcranial Doppler monitoring revealed an increased frequency of microembolic signals recorded over a 30-minute period in patients with CVE (75±25; median, 55; range, 27 to 248) compared with those without CVE (23±12; median, 7; range, 0 to 153;
P
<0.05) or with control subjects (0;
P
<0.001). Flow cytometry analysis showed increased levels of PMP in patients with compared to those without CVE (4.1±0.6% versus 2.4±0.4% of all fluorescence-positive events gated;
P
<0.05). Increased procoagulant activity was documented by the shortened Russell’s viper venom time expressed as an increased level of platelet equivalents per microliter of plasma in patients compared with control subjects (+24.7±14.9%;
P
<0.01). Subgroup analysis revealed that patients with CVE had a higher excess of platelet equivalents per microliter of plasma than patients without CVE in relation to the controls (+68.7±36.7%;
P
<0.05). Mildly elevated thrombin–antithrombin III complexes (2.9±0.7; median, 2.3; normal, <2.0 μg/L) suggested incompletely suppressed thrombin formation, and fibrin generation (fibrinopeptide A) was in the upper normal range (2.1±0.2; median, 1.8; normal, <2.0 ng/mL), despite adequate anticoagulation (INR=3.6±0.1).

Conclusions
—Our data show increased microembolic signals, platelet microparticles, and procoagulant activity in symptomatic patients with PHV and provide a potential pathophysiological explanation of CVE.
Perilesional Blood Flow and Edema Formation in Acute Intracerebral Hemorrhage
Authors: Mayer Stephan A. , Lignelli Angela , Fink Matthew E. , Kessler Deborah B. , Thomas Carole E. , Swarup Rupendra , Van Heertum Ronald L.
Published: June 2011

Background and Purpose
—Secondary brain injury and edema formation contribute significantly to morbidity and mortality after intracerebral hemorrhage (ICH). The pathogenesis of this process is poorly understood. We sought to characterize alterations in perilesional blood flow that occur during the acute phase of ICH and to determine whether progressive enlargement of edema surrounding ICH is related to increased or decreased perfusion.

Methods
—We performed paired consecutive CT and
99m
Tc-hexamethylpropylenamine oxime single-photon emission computed tomography (SPECT) scans during the acute (mean, 18 hours) and subacute (mean, 72 hours) phase of ICH in 23 patients. Hematoma and edema volumes were traced and calculated from CT images. SPECT-derived hypothetical flow deficit volumes (FDV) around each hematoma were calculated by measuring a “zero-flow” volume within a large perilesional region of interest (based on percent tracer count loss compared with the contralateral side) and subtracting the corresponding ICH volume. Patients with significant midline shift (>5 mm) or global blood flow reduction were excluded from the analysis.

Results
—ICH volume (18 mL) did not change, mean edema volume increased by 36% (from 19 to 25 mL,
P
<0.0001), and mean FDV decreased by 55% (from 14 to 6 mL,
P
=0.0004) between the acute and subacute phases. Edema volume on the second CT scan correlated positively with FDV on the first SPECT scan (Spearman’s ρ=0.48,
P
=0.02), and with the volume of reperfused perilesional tissue (FDV
acute
−FDV
subacute
) (Spearman’s ρ=0.41,
P
=0.05). Perilesional edema on CT always corresponded topographically with perfusion deficits on SPECT. In 4 patients, delayed focal hyperemia was identified in more peripheral cortical regions, but these areas appeared normal on CT.

Conclusions
—Perilesional blood flow normalizes from initially depressed levels as edema forms during the first 72 hours after ICH, and the eventual extent of edema correlates with the volume of reperfused tissue. These results suggest that the potential for perilesional ischemia is highest in the earliest hours after ICH onset and implicate reperfusion injury in the pathogenesis of perihematoma edema formation.
Microemboli in Cerebral Circulation and Alteration of Cognitive Abilities in Patients With Mechanical Prosthetic Heart Valves
Authors: Deklunder Ghislaine , Roussel Martine , Lecroart Jean-Louis , Prat Alain , Gautier Corinne
Published: June 2011

Background and Purpose
—It has been shown previously that cerebral microemboli may occur frequently in patients with a normal mechanical heart valve (MHV) without prior history of stroke. Some arguments strongly suggest that these microemboli have a gaseous origin. In other circumstances such as extracorporeal circulation or decompression in divers, it has been demonstrated that cerebral microbubbles could lead to some deterioration in cognitive functions. Therefore, we have studied attention and memory, which are among the most impaired cognitive functions as demonstrated in previous studies, in patients with an MHV.

Methods
—Three groups of 12 volunteers each were composed of patients with an MHV and embolic signals in the cerebral circulation (group 1), patients with biological prostheses (group 2), and healthy subjects (group 3). Groups were carefully matched for age and verbal intellectual abilities. For each group, a transcranial Doppler examination was performed and a set of cognitive tests assessing sustained and selective attention and episodic and working memory was administered.

Results
—The mean embolic rate was 29 per hour in patients with an MHV. No embolus was detected in the other 2 groups. Episodic memory was significantly modified in both groups 1 and 2 compared with the control group for tasks that required high-processing resources. Working memory performance was significantly decreased in MHV patients. No between-groups differences were observed for the other parameters.

Conclusions
—Alteration of episodic memory can be attributed to a long-term effect of the surgical procedure. Deterioration of working memory can be related to the presence of cerebral microemboli in MHV patients.
Association Between Mitral Annulus Calcification and Carotid Atherosclerotic Disease
Authors: Adler Yehuda , Koren Arnon , Fink Noam , Tanne David , Fusman Renato , Assali Abid , Yahav Jakov , Zelikovski Avigdor , Sagie Alex
Published: June 2011

Background and Purpose
—It has been established that mitral annulus calcification (MAC) is an independent predictor of stroke, though a causative relationship was not proved, and that carotid artery atherosclerotic disease is also associated with stroke. The aim of this study was to determine whether there is an association between the presence of MAC and carotid artery atherosclerotic disease.

Methods
—Of the 805 patients in whom the diagnosis of MAC was made by transthoracic echocardiography between 1995 and 1997, 133 patients (60 men and 73 women; mean age, 74.3±8 years; range, 47 to 89 years) underwent carotid artery duplex ultrasound for various indications; the study group comprised these patients. They were compared with 129 age- and sex-matched patients without MAC (57 men and 72 women; mean age, 73.6±7 years; range, 61 to 96 years) who underwent carotid artery duplex ultrasound during the same period for the same indications. MAC was defined as a dense, localized, highly reflective area at the base of the posterior mitral leaflet. MAC was considered severe when the thickness of the localized, highly reflective area was ≥5 mm on 2-dimensional echocardiography in the 4-chamber view. Carotid artery stenosis was graded as follows: 0%, 20%, 40%, 60%, 80%, and 100%.

Results
—Compared with the control group, the MAC group showed a significantly higher prevalence of carotid stenosis of ≥40% (45% versus 29%,
P
=0.006), which was associated with ≥2-vessel disease (23% versus 10%,
P
=0.006) and bilateral carotid artery atherosclerotic disease (21% versus 10%,
P
=0.011). Severe MAC was found in 48 patients. More significant differences were found for the severe MAC subgroup (for carotid stenosis of ≥40%) in rates of carotid artery atherosclerotic disease (58% versus 29%,
P
=0.001), and ≥2-vessel disease (31% versus 10%,
P
=0.001), in addition to bilateral carotid artery stenosis (27% versus 10%,
P
=0.004) and even bilateral proximal internal carotid artery stenosis (21% versus 8%,
P
=0.015). Furthermore, significant carotid artery atherosclerotic disease (stenosis of ≥60%) was significantly more common in the severe MAC subgroup than in the controls (42% versus 26%,
P
<0.05) and was associated with higher rates of ≥2-vessel disease (19% versus 7%,
P
=0.02) and bilateral carotid artery stenosis (17% versus 7%,
P
=0.05). On multivariate analysis, MAC and age but not traditional risk factors were the only independent predictors of carotid atherosclerotic disease (
P
=0.007 and
P
=0.04, respectively).

Conclusions
—There is a significant association between the presence of MAC and carotid artery atherosclerotic disease. MAC may be an important marker for atherosclerotic disease of the carotid arteries. This association may explain the high prevalence of stroke in patients with MAC.
Hypocapnia and Cerebral Hypoperfusion in Orthostatic Intolerance
Authors: Novak Vera , Spies Judith M. , Novak Peter , McPhee Benjamin R. , Rummans Teresa A. , Low Phillip A.
Published: June 2011

Background and Purpose
—Orthostatic and other stresses trigger tachycardia associated with symptoms of tremulousness, shortness of breath, dizziness, blurred vision, and, often, syncope. It has been suggested that paradoxical cerebral vasoconstriction during head-up tilt might be present in patients with orthostatic intolerance. We chose to study middle cerebral artery (MCA) blood flow velocity (BFV) and cerebral vasoregulation during tilt in patients with orthostatic intolerance (OI).

Methods
—Beat-to-beat BFV from the MCA, heart rate, CO
2
, blood pressure (BP), and respiration were measured in 30 patients with OI (25 women and 5 men; age range, 21 to 44 years; mean age, 31.3±1.2 years) and 17 control subjects (13 women and 4 men; age range, 20 to 41 years; mean age, 30±1.6 years); ages were not statistically different. These indices were monitored during supine rest and head-up tilt (HUT). We compared spontaneous breathing and hyperventilation and evaluated the effect of CO
2
rebreathing in these 2 positions.

Results
—The OI group had higher supine heart rates (
P
<0.001) and cardiac outputs (
P
<0.01) than the control group. In response to HUT, OI patients underwent a greater heart rate increment (
P
<0.001) and greater reductions in pulse pressure (
P
<0.01) and CO
2
(
P
<0.001), but total systemic resistance failed to show an increment. Among the cerebrovascular indices, all BFVs (systolic, diastolic, and mean) decreased significantly more, and cerebrovascular resistance (CVR) was increased in OI patients (
P
<0.01) compared with control subjects. In both groups, hyperventilation induced mild tachycardia (
P
<0.001), a significant reduction of BFV, and a significant increase of CVR associated with a fall in CO
2
. Hyperventilation during HUT reproduced hypocapnia, BFV reduction, and tachycardia and worsened symptoms of OI; these symptoms and indices were improved within 2 minutes of CO
2
rebreathing. The relationships between CO
2
and BFV and heart rate were well described by linear regressions, and the slope was not different between control subjects and patients with OI.

Conclusions
—Cerebral vasoconstriction occurs in OI during orthostasis, which is primarily due to hyperventilation, causing significant hypocapnia. Hypocapnia and symptoms of orthostatic hypertension are reversible by CO
2
rebreathing.
Transient Response Harmonic Imaging
Authors: Postert Thomas , Muhs Andrea , Meves Saskia , Federlein Jens , Przuntek Horst , Büttner Thomas
Published: June 2011

Background and Purpose
—Gray-scale harmonic imaging is the first method to visualize blood perfusion and capillary blood flow with ultrasound after intravenous contrast agent application. The purpose of the present study was to evaluate the potential of transient response second harmonic imaging (TRsHI) to assess normal echo contrast characteristics in different brain areas by transcranial ultrasound.

Methods
—In 18 patients without cerebrovascular diseases, TRsHI examinations were performed bilaterally with the use of the transtemporal approach after application of 6.5 mL of a galactose-based microbubble suspension (400 mg/mL). The transmission rate was once every 4 cardiac cycles. Regional cerebral contrast was visually assessed and then quantified off-line with the use of time-intensity curves. In 4 different regions of interest (ROI) (posterior part of the thalamus [ROIa], anterior part of the thalamus [ROIb], lentiform nucleus [ROIc], and white matter [ROId]), the following parameters were evaluated: peak intensity, area under the curve (AUC), and time to peak intensity. AUC ratios for ROIc/a, d/a, c/b, and d/b were calculated.

Results
—In all patients parenchymal contrast enhancement was visually detectable. One hundred thirty-one characteristic time-intensity curves (baseline phase, peak contrast intensity, slow washout phase) were demonstrable in 144 ROIs. In ROIc and ROId, characteristic contrast curves could be observed most frequently (68/72 examinations), whereas time-intensity curves in ROIa and ROIb could not be evaluated because of inadequate contrast enhancement in 9 of 72 examinations. Time to peak intensity varied between 20 and 52 cardiac cycles; in 1 patient it was 88 cardiac cycles. In all individuals AUCs and in 16 of 18 subjects peak intensity in ROIc and ROId showed a 2- to 10-fold increase compared with ROIa and ROIb. In no examination did AUC ratios show a >2-fold side difference irrespective of the ROI.

Conclusions
—The present study demonstrates for the first time that TRsHI produces accurate contrast in different brain areas and represents an ultrasonic tool related to brain perfusion. Absolute values of quantitative parameters show high variations caused by different temporal bone thicknesses and a complex relationship between echo contrast concentrations and measurements of optic intensities. Ratios between different ROIs help to compare contrast enhancement in different brain areas. Furthermore, because of the fact that attenuation of contrast enhancement in TRsHI depends strictly on the insonation depth, harmonic imaging studies of brain perfusion cannot be compared directly with other imaging techniques such as positron emission tomography.
Endothelin B Receptor Antagonists Attenuate Subarachnoid Hemorrhage–Induced Cerebral Vasospasm
Authors: Zuccarello Mario , Boccaletti Riccardo , Romano Alberto , Rapoport Robert M.
Published: June 2011

Background and Purpose
—While it has been widely reported that the vasospasm following subarachnoid hemorrhage (SAH) is prevented/reversed by endothelin (ET) receptor antagonists selective for the ET
A
receptor and by nonselective ET receptor antagonists, ie, antagonists of both the ET
A
and ET
B
receptors, there are no reports on the possible attenuation of the spasm by selective ET
B
receptor antagonists. The purpose of this study was to investigate whether (1) ET
B
receptor antagonists prevent and reverse SAH-induced spasm and (2) attenuation of the spasm results from blockade of smooth muscle ET
B
(ET
B2
) receptor–mediated constriction and/or endothelial ET
B
(ET
B1
) receptor– mediated ET-1–induced ET-1 release.

Methods
—SAH-induced spasm of the rabbit basilar artery was induced with the use of a double hemorrhage model. In vivo effects of agents on the spasm were determined by angiography after their intracisternal infusion (10 μL/h) by mini osmotic pump. In situ effects of agents on the spasm were determined by direct measurement of vessel diameter after their suffusion in a cranial window.

Results
—SAH constricted the basilar artery by 30%. Intracisternal infusion with 10 μmol/L BQ788, an ET
B1/B2
receptor antagonist, reduced the spasm to 10%. To investigate whether BQ788 prevented the spasm by blockade of ET
B1
receptor–mediated ET-1–induced ET-1 release, as opposed to ET
B2
receptor–mediated constriction, we tested whether ET
B1
receptor blockade also prevented the spasm. Indeed, intracisternal infusion with 10 μmol/L RES-701-1, a selective ET
B1
receptor antagonist, reduced the spasm to 10%. Similarly, in situ superfusion with 1 μmol/L BQ788 reversed the spasm by 40%, and 1 μmol/L RES-701-1 reversed the spasm by 50%. However, both BQ788 and RES-701-1 enhanced by 40% to 50% the 3 nmol/L ET-1–induced constriction elicited in spastic vessels previously relaxed with 0.1 mmol/L phosphoramidon, an ET-converting enzyme inhibitor.

Conclusions
—These results demonstrate that ET
B
receptor antagonists prevent and reverse SAH-induced cerebral vasospasm in an animal model. The likely mechanism underlying the attenuation of the spasm is blockade of ET
B1
receptor–mediated ET-1–induced ET-1 release of newly synthesized ET-1. These studies provide rationale for the therapeutic use of ET
B1
receptor antagonists to relieve the vasospasm following SAH, as well as other pathophysiological conditions involving possible ET-1–induced ET-1 release.
Monoclonal Antibodies Against ICAM-1 and CD18 Attenuate Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage in Rabbits
Authors: Bavbek Murad , Polin Richard , Kwan Aij-Lie , Arthur Adam S. , Kassell Neal F. , Lee Kevin S.
Published: June 2011

Background and Purpose
—Inflammatory responses have been implicated in the elaboration of several forms of central nervous system injury, including cerebral vasospasm after subarachnoid hemorrhage (SAH). A critical event participating in such responses is the recruitment of circulating leukocytes into the inflammatory site. Two of the key adhesion molecules responsible for the attachment of leukocytes to endothelial cells are intercellular adhesion molecule-1 (ICAM-1) and the common β chain of the integrin superfamily (CD18). This study examined the effects of monoclonal antibodies on ICAM-1 and the effects of CD18 on cerebral vasospasm after SAH.

Methods
—A rabbit model of SAH was utilized to test the influence of intracisternally administered antibodies to ICAM-1 and CD18 on cerebral vasospasm. Antibodies were administered alone or in combination, and the cross-sectional area of basilar arteries was assessed histologically on day 2 post-SAH.

Results
—Treatment with antibodies to ICAM-1 or CD18 inhibited vasospasm by 22% and 27%, respectively. When administered together, the attenuation of vasospasm increased to 56%. All of these effects achieved statistical significance.

Conclusions
—These findings provide the first evidence that the severity of cerebral vasospasm can be attenuated using monoclonal antibodies against ICAM-1 and CD18. The results reinforce the concept that cell-mediated inflammation plays an important role in cerebral vasospasm after SAH and suggest that therapeutic targeting of cellular adhesion molecules can be of benefit in treating cerebral vasospasm.
Neuronal Damage and Plasticity Identified by Microtubule-Associated Protein 2, Growth-Associated Protein 43, and Cyclin D1 Immunoreactivity After Focal Cerebral Ischemia in Rats
Authors: Li Yi , Jiang Ning , Powers Cecylia , Chopp Michael
Published: June 2011

Background and Purpose
—An objective of therapeutic intervention after cerebral ischemia is to promote improved functional outcome. Improved outcome may be associated with a reduction of the volume of cerebral infarction and the promotion of cerebral plasticity. In the developing brain, neuronal growth is concomitant with expression of particular proteins, including microtubule-associated protein 2 (MAP-2), growth-associated protein 43 (GAP-43), and cyclin D1. In the present study we measured the expression of select proteins associated with neurite damage and plasticity (MAP-2 and GAP-43) as well as cell cycle (cyclin D1) after induction of focal cerebral ischemia in the rat.

Methods
—Brains from rats (n=28) subjected to 2 hours of middle cerebral artery occlusion and 6 hours, 12 hours, and 2, 7, 14, 21, and 28 days (n=4 per time point) of reperfusion and control sham-operated (n=3) and normal (n=2) rats were processed by immunohistochemistry with antibodies raised against MAP-2, GAP-43, and cyclin D1. Double staining of these proteins for cellular colocalization was also performed.

Results
—Loss of immunoreactivity of both MAP-2 and GAP-43 was observed in most damaged neurons in the ischemic core. In contrast, MAP-2, GAP-43, and cyclin D1 were selectively increased in morphologically intact or altered neurons localized to the ischemic core at an early stage (eg, 6 hours) of reperfusion and in the boundary zone to the ischemic core (penumbra) during longer reperfusion times.

Conclusions
—The selective expressions of the neuronal structural proteins (MAP-2 in dendrites and GAP-43 in axons) and the cyclin D1 cell cycle protein in neurons observed in the boundary zone to the ischemic core are suggestive of compensatory and repair mechanisms in ischemia-damaged neurons after transient focal cerebral ischemia.
Experimental Brain Prosthesis for Stroke
Authors: Pinneo L. R. , Kaplan J. N. , Elpel E. A. , Reynolds P. C. , GLICK J. H.
Published: June 2011

Electrical control of motor behavior by programmed electrical stimulation of the brain has been described. Such programmed brain stimulation is referred to as a "brain prosthesis," meaning, in effect, "artificial brain."

Areas in the brain which related to the production of elementary movements were located. From these preliminary experiments it was evident that programmed stimulation of the brain at sites typically unaffected by stroke could produce a "purposive" sequence of motor behaviors.

Monkeys were made monoplegic by surgical (two-stage) resection of appropriate cortical and subcortical regions. After recovery electrodes were implanted in the brain. This technique is described.

The electrodes are linked to a multiple-electrode programmable brain stimulator. The stimulator and computer programming make it possible to specify which electro-stimulators are to be turned on, and strength and duration of current to produce a pattern of complex motor function.

Programs of stimulation, which cause the paralyzed limb to reach out, grasp an object (such as food), and bring the object rapidly and smoothly to the mouth, have been written. The ultimate question of applicability of this model in humans remains to be studied.
Relationship of Serial Measurements of Cerebral Hemodynamics to Prognosis in Patients with Hypertension and Cerebrovascular Disease
Authors: Yamaoka Saburo , Takagi Yasuyuki , Okada Toshihiro , Saito Yoshio
Published: June 2011

Baseline and follow-up measurements of cerebral hemodynamics were performed in hypertensive patients by the N
2
O method with a certain time interval. A tendency for some decrease in the CBF was noted, but the difference was not statistically significant.

Twelve hypertensive patients suffered from a stroke during the period of observation. The CBF values prior to the stroke varied so widely that there was no predictive value from these measurements.

The decrease in CBF in a mild case of cerebral infarction is slight and is followed by little fluctuation. The decrease in a case of moderate severity is marked but returns to normal in two to five months. Clinically severe cases of infarction and hemorrhage are also characterized by a marked decrease in CBF, but this decrease of infarcted cases may be irreversible.

A higher incidence of recurrent infarction is noted in those patients in whom recovery of CBF following a stroke is poorest. This is most apparent in those patients suffering a recurrence within one year.
Pathophysiological Responses to Acute Cerebral Ischemia in the Gerbil
Authors: Wexler Bernard C. , Wexler Nancy C. , Conatser Dilmon
Published: June 2011

The left carotid artery of healthy, male gerbils was surgically ligated to induce a state of cerebral ischemia. The animals were sacrificed two, four, six, 12, 24 and 48 hours postligation to determine whether the induced cerebral ischemia would be reflected by changes in blood chemistry. The gerbil, unlike the rat, has a well-defined circle of Willis and cerebral arterial branches which resemble the arrangement of cerebral arteries found in man.

The gerbils withstood the induced cerebral ischemia relatively well with few overt signs of cerebral damage, e.g., muscular paralysis, and a low mortality rate. However, intense lipid mobilization accompanied by depletion of peripheral adipose tissue sites and fatty infiltration of the liver developed very promptly. Marked cerebral edema and definitive foci of cerebral infarction occurred in both the frontal and medial lobes of the brain. The adrenal cortices of the gerbil were markedly depleted of lipid concomitant with severe thymus gland involution indicative of intense corticosteroid release.

The serum enzymes, creatine phosphokinase and glutamic oxaloacetic transaminase, both rose promptly, indicating cerebral and hepatic damage respectively. Lipids, i.e., triglycerides, free fatty acids and total cholesterol, all rose promptly and to significantly above-normal levels and remained super-normal throughout the 48-hour course of the experiment. Concomitant with the hyperlipidemia and other metabolic changes there were definite hyperglycemia and elevation of BUN levels in a brisk response to the induced, acute cerebral ischemia. The gerbil adrenal gland produces hydrocortisone predominantly. Blood levels of hydrocortisone rose quickly to super-normal levels in response to the stress of cerebral ischemia but fell to significantly below-normal levels 24 and 48 hours after carotid artery ligation. These findings demonstrate that acute cerebral ischemia constitutes a severe stress in the gerbil which is reflected, almost quantitatively, by temporal changes in such blood constituents as enzymes, lipids, glucose, and adrenal stress hormones.
Newer Techniques of Cerebral Blood Flow Measurement
Authors: Posner Jerome B.
Published: June 2011

A variety of methods for measuring cerebral blood flow have been developed in the past 25 years since Kety and Schmidt developed their method based on the Fick principle. None of the currently used methods approaches the clinical ideal, since none of the techniques are accurate, reproducible and noninvasive. Most accurate techniques involve catheterization of internal carotid artery and/or jugular vein with those attendant risks. There has been considerable enhancement of our understanding of the pathophysiology of cerebral circulation, particularly in the areas of brain injury and disordered systemic metabolism, but the clinical usefulness of the test at the present time is limited.