Masafumi Tagaya

Hyperthermia-Induced Neuronal Protection against Ischemic Injury in Gerbils

We investigated the effect of hyperthermic pretreatment before induction of ischemia using a gerbil model of 5-min forebrain ischemia. A single hyperthermic treatment 18 h before ischemia exhibited a partial protective effect, and repetitive hyperthermic pretreatments at 18-h intervals before ischemia showed clear protection against neuronal death in the CA1 area of the hippocampus, whereas single hyperthermic treatment 3, 6, 24, or 50 h before ischemia exhibited little protective effect. This transient and cumulative neuroprotective effect of hyperthermic pretreatment strongly suggested the involvement of stress reactions after hyperthermia in the protective mechanism against ischemic neuronal death.

A validation study on the reproducibility of transcranial doppler velocimetry

The transcranial Doppler method for the measurement of intracranial arterial blood flow velocity is a useful noninvasive technique with a number of applications. The present study validated the reproducibility of this method for repeated measurements of flow velocity in the middle cerebral and basilar arteries. Fifteen healthy volunteers were studied. Measurements were made twice by one examiner and once by another in a single day and again by the first examiner on another day. The reproducibility was evaluated by calculating the correlation coefficient (r) and the coefficient of variation (CV) of the difference between the values obtained from each pair of measurements. Although depending on the examiner, the time interval between the examinations and the vessels studied some differences were noted in the reproducibility, both the r (0.69-0.95) and CV (6.7%-19.5%) values in the whole study were good enough to warrant the applicability of this method for the repeated measurements of the intracranial arterial blood flow velocity in future studies.

Carotid Intima-Media Thickness and Risk of Cardiovascular Events in High-Risk Patients

Background and Purpose: There is epidemiological evidence that increased carotid intima-media thickness (IMT) is a predictor of cardiovascular disease (CVD) events. However, the significance of carotid IMT in high-risk patients in whom risk factors are managed clinically has not been adequately investigated. The purpose of this study was to determine the usefulness of carotid IMT measurement in such patients. Methods: The study comprised 900 outpatients with cardiovascular risk factors or established atherosclerosis. Carotid IMT was calculated as the mean bilateral IMT of the common carotid artery, bifurcation, and internal carotid artery. Baseline vascular risk factors, medications, and history of CVD were recorded at the time of enrollment. The incidence of CVD events was determined prospectively. Results: During a mean follow-up period of 2.6 years, there were 64 CVD events. The relative risk (RR) of a CVD event increased with increased IMT. Association between CVD events and carotid IMT was significant after adjustment for risk factors and history of CVD, showing an increased risk per IMT tertile from the middle tertile (RR, 2.5; 95% confidence interval [CI]: 1.0–6.3) to the highest (RR, 3.6; 95% CI: 1.4–9.0). When patients with a history of CVD were excluded (n = 574), the predictive value of IMT was significant even after adjustment for risk factors (hazard ratio per 1 SD IMT increase was 1.57 [95% CI: 1.11–2.20]). Conclusions: Carotid IMT is an independent predictor of vascular events in high-risk patients in whom risk factors are managed clinically.

Fas antigen mRNA induction in postischemic murine brain.

Fas antigen mRNA induction in the brain was examined using a transient global cerebral ischemia model in BALB/C mice. Northern blot analysis revealed little Fas antigen mRNA expression in the brains of sham-operated mice. A marked induction of Fas mRNA expression was detected in the brains of mice 6 h after 30 min of cerebral ischemia. These results suggest a possible apoptotic mechanism for cell death, mediated by the Fas antigen, in postischemic brain.

Localization of Fas antigen mRNA induced in postischemic murine forebrain by in situ hybridization

The expression of mRNA for the Fas antigen, a membrane-associated protein mediating apoptosis, was localized by in situ hybridization histochemistry in murine brains following 30 min of global cerebral ischemia. Six hours following the ischemia, many labeled cells were detected anew throughout the brain. The hybridization was seen in the small neural cells and in the cells along the walls of the ventricles and vessels, and became undetectable 24 h following the ischemia. These results suggest that the Fas antigen is expressed in the neuron, glia and periventricular cells of the post-ischemic brain.

Cerebral microbleeds predict impending intracranial hemorrhage in infective endocarditis.

Background: Cerebral microbleeds (CMBs) detected by T2*-weighted MRI are a potential indicator of hypertension, microvascular disease and hemorrhagic stroke. An association between infective endocarditis (IE) and CMBs has been reported recently, but the clinical significance remains unclear. We hypothesized that CMBs in patients with IE are associated with vascular vulnerabilities such as mycotic aneurysm or pyogenic vasculitis. Methods: We retrospectively reviewed 26 consecutive patients with definite IE who underwent T2*-weighted MRI and were admitted to 2 medical centers in Osaka, Japan, between January 2006 and June 2010. We examined the incidence of symptomatic intracranial hemorrhage (ICH) occurring after initial MRI examination and investigated the association between ICH, CMBs and other clinical characteristics. Results: CMBs were identified in 14 patients (54%), and 72% of CMBs were found in the lobar region. Symptomatic ICH was observed in 8 patients (31%) during the 3-month follow-up period after initial MRI examination. In multiple logistic regression analyses, the presence of preceding ICH [odds ratio (OR) 40.0, 95% confidence interval (CI) 2.5–2,870] and the presence of CMBs (OR 34.0, 95% CI 1.3–17,300) were independent predictors of the development of ICH. Using cutoff values for CMBs of ≧2 and ≧3, the adjusted ORs for ICH increased (OR 42.1, 95% CI 1.9–24,300, and OR 70.1, 95% CI 2.5–105,000, respectively). Conclusions: In addition to prior ICH, the presence of CMBs was a strong predictor of impending ICH in patients with IE. CMBs might represent vascular vulnerability related to IE.

Serial Changes in Cerebral Blood Flow and Flow—Metabolism Uncoupling in Primates with Acute Thromboembolic Stroke

The authors recently developed a primate thromboembolic stroke model. To characterize the primate model, the authors determined serial changes in cerebral blood flow (CBF) and the relation between CBF and cerebral metabolic rate of glucose (CMRglc) using high-resolution positron emission tomography. Thromboembolic stroke was produced in male cynomolgus monkeys (n = 4). Acute obstruction of the left middle cerebral artery was achieved by injecting an autologous blood clot into the left internal carotid artery. Cerebral blood flow was measured with [15O]H2O before and 1, 2, 4, 6, and 24 hours after embolization. CMRglc was measured with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) 24 hours after embolization. Lesion size and location 24 hours after embolization was determined by the 2,3,5-triphenyltetrazolium chloride (TTC) staining method. The results are summarized as follows: (1) 1 hour after embolization, CBF in the temporal cortex and the basal ganglia decreased to < 40% of the contralateral values. In these regions, regarded as an ischemic core, CBF decreased further with time and CMRglc at 24 hours also decreased. Infarcted lesions as indicated by being unstained with TTC were consistently observed in these regions. (2) In the parietal cortex and several regions surrounding the ischemic core, CBF was >40% of the contralateral values 1 hour after embolization and recovered gradually with time (ischemic penumbra). In these regions, CMRglc at 24 hours increased compared with that in the contralateral regions, indicating an uncoupling of CBF and CMRglc. No obvious TTC-unstained lesions were detected in these regions. The authors demonstrated a gradual recovery of reduced CBF, an elevated CMRglc and a CBF-CMRglc uncoupling in the penumbra regions of the primate model. Positron emission tomography investigations using this model will provide better understanding of the pathophysiology of thromboembolic stroke in humans.

Recombinant human superoxide dismutase can attenuate ischemic neuronal damage in gerbils

The effects of recombinant human superoxide dismutase (r-hSOD) on ischemic neuronal injury were examined. Cerebral ischemia was produced in Mongolian gerbils by occluding bilateral common carotid arteries for 5 min. Preischemic treatment with r-hSOD clearly reduced hippocampal neuronal damages while postischemic treatment did not. This result suggests that oxygen free radicals play an important role in selective vulnerability to ischemia and r-hSOD has a potential clinical usefulness against cerebral ischemia.

Computer-Assisted Analysis of Heterogeneity on B-Mode Imaging Predicts Instability of Asymptomatic Carotid Plaque

Background: Computerized assessment of plaque echogenicity by B-mode ultrasonography has demonstrated that the gray-scale median (GSM) pixel intensity of the entire plaque predicts future ischemic stroke in patients with symptomatic carotid stenosis, but not those with asymptomatic stenosis. This study investigated whether plaque heterogeneity (i.e., the distribution of pixel intensities) could predict the instability of asymptomatic plaque. Methods: By comparison with carotid endarterectomy specimens and the GSM values of known tissues on B-mode images, the GSM values for blood, lipid, muscle/fibrous tissue, and calcification were determined. Then we estimated the percent area of each tissue component for 297 asymptomatic plaques causing 40–99% carotid artery stenosis in 250 patients, and monitored the incidence of atherothrombotic cerebral infarction due to carotid stenosis during follow-up. Results: Eight infarcts occurred during a follow-up period of 22 ± 15 months. Plaques in the top tertile for the percent area of lipid-like echogenicity (p < 0.05) and in the lowest tertile for calcification (p = 0.06) showed an association with future infarction according to Kaplan-Meier analysis. This association remained significant after adjustment for the severity of carotid stenosis (hazard ratio 4.4 for lipid-like and 0.24 for calcification-like component, both p < 0.05) according to Cox proportional hazards analysis. Conclusions: The distribution of pixel intensities in carotid plaque on B-mode ultrasonography can be employed to predict instability of asymptomatic plaque and possibly to select patients for interventional procedures. A large-scale investigation will be needed to confirm that estimating the percentage of plaque components relative to the total plaque area can predict ischemic stroke.

The synapsin I brain distribution in ischemia

We examined the distribution of synapsin I in the gerbil brain and investigated ischemic damage of presynaptic terminals immunohistochemically by using this protein as a marker protein of synaptic vesicles. The reaction for synapsin I in normal gerbil brain is exclusively localized in the neuropil, and other brain structures such as neuronal soma, dendrites, axon bundles, glia and endothelial cells exhibited little immunoreactivity. In a reproducible gerbil model of unilateral cerebral ischemia, ischemic loss of synapsin I immunoreactivity in the affected hemisphere was confined to the area exhibiting overt infarction, where the breakdown of this protein was also confirmed by the immunoblot analysis, and noted much later than that of microtubule-associated protein 2 immunoreactivity, which was demonstrated in neuronal soma and dendrites. In the non-affected hemisphere, selective damage of presynaptic terminals due to Wallerian degeneration and subsequently occurring resynaptogenesis at the molecular layer of the dentate gyrus were clearly demonstrated as a loss and recovery of immunoreaction for synapsin I, respectively. In a gerbil model of bilateral cerebral ischemia, immunoreaction for synapsin I was persistently preserved after seven days to two months recirculation following a brief period of global forebrain ischemia in the CA1 region of the hippocampus, where delayed neuronal death was consistently observed.(ABSTRACT TRUNCATED AT 250 WORDS)