Platelet aggregation is triggered by the activation of GPIIb/IIIa and binding of fibrinogen, which are induced by the ADP released from damaged vessels and red blood cells. Clopidogrel sulfate (SR25990C, clopidogrel) is an oral antiplatelet agent containing a thienopyridine ring within its structure, and its antiplatelet effect is based on its inhibitory action towards ADP receptor. The present double-blind controlled clinical pharmacology study was performed on 124 Japanese patients with cerebral infarction, who were given 10, 37.5, or 75mg/day of clopidogrel for 2 weeks in order to evaluate the relationship between dose of clopidogrel and inhibition of platelet aggregation. In addition, ticlopidine (200 mg/day) was administered to a positive control group. The percent inhibition of platelet aggregation with ticlopidine was 34.9%, and that with 10, 37.5, and 75 mg/day of clopidogrel was 14.0, 26.6, and 39.8%, respectively. On the basis of these results, the recommended clinical dose of clopidogrel for Japanese patients with cerebral infarction was concluded to be 75mg/day.

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Magnetic resonance imaging (MRI) has emerged as a leading technology in the diagnosis and care of the acute stroke patient because of the range of structural and physiological measurements possible in a relatively non-invasive and rapid manner and because of the wide dissemination and availability of MRI scanners in clinics and hospitals.
The ideal neurodiagnostic imaging exam for stroke must rule out intracranial hemorrhage, detect the presence of ischemic pathology (intracranial and extracranial arterial disease, ischemic parenchymal injury and brain hemodynamics), and be achievable in a brief scanning session. An emergency MRI exam including diffusion weighted (DWI), perfusion (PWI), MR angiography (MRA), susceptibility weighted and T2-weighted or FLAIR imaging meets all these requirements. At many institutions where emergency therapies and early diagnosis are part of stroke care, MRI has already taken on a role to accomplish the diagnostic objectives in acute stroke. Conclusions about the state of ischemic pathophysiology in an individual patient, once based solely on clinical conjecture in the first few hours after onset, may now be based on objective data as well. MRI has found a role in the decision making for thrombolytic therapy and in clinical trials. Clinical studies support the sensitivity and specificity of the MRI in early stroke diagnosis, predicting clinical outcome, predicting the fate of the tissue at risk at the earliest time points, and in demonstrating reversal of ischemic injury following success-ful early reperfusion. A reduction in ischemic lesion volume from very early DWI to final infarct is highly predictive of clinical recovery.
Imaging in clinical drug development and testing has become common and will become ever more important in Phase I and II clinical trials to evaluate brain pharmacokinetics, tissue viability, establish proof of pharmacological principle, and in Phase III trials to provide surrogate measures of potential clinical effects.

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Oligodendrocytes (OLGs) are myelin forming cells in central nervous system and are thought to be vulnerable to hypoxia and ischemia. However, little is known about the detailed mechanism by which these insults induce oligodendrocyte death. Using the Cre-loxP system, we have established a transgenic mouse line that selectively expresses p35, a broad-spectrum caspase inhibitor, in OLGs. Under the hypoxic condition, cultured OLGs derived from wild-type mice exhibited significant up-regulation of caspase-11 and substantial activation of caspase-3, which led to cell loss.
Expression of p35 or elimination of caspase-11 suppressed the caspase-3 activation and conferred significant protection against hypoxic injury. The expression of p35 in OLGs resulted in significant protection against ischemia-induced OLGs injury. Furthermore, the induction of caspase-11 was observed in the ischemic brain of wild-type mice and OLGs exhibited resistance to brain ischemia in mice deficient in caspase-11, suggesting that caspase-11 is critically implicated in the mechanism (s) underlying ischemia-induced OLG death.

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It is important to detect pathologic lesions in cerebral arteries in acute ischemic storoke patients. Neurosonographic examinations are non-invasive, convenient, ralatively inexpensive and can be performed at bedside. Carotid duplex sonography has been widely used as a tool to evaluate occlusive lesions in extracranial brain arteries such as the internal carotid artery (ICA) and the vertebral artery (VA). The diagnostic accuracy of the neurosonographic examination is high even in acute stroke patients. Furthermore, according to the findings of the carotid sonography performed within 6 hours of stroke onset, we can predict the outcome of acute stroke patients. Thus, neurosonology should be a useful tool for strokologist to manage acute stroke patients.

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Recent publishing Japanese guideline for the ultrasonic assessment of carotid artery disease -Preliminary issue- describes that among several parameters, we selected a maximum intima-meidia thickness (max-IMT) of whole carotid artery as a most valuable measurement parameter of carotid atherosclerosis. Then, the purpose of the study is to clarify the role of plaque score, which is one of authorized parameters, and max-IMT in the evaluation of carotid atherosclerosis.
Carotid atherosclerosis was examined by the high-resolution ultrasonography and by assessed both essential parameters, max-IMT and plaque score. Two hundred and fourteen patients were recruited for the prospective study. Eighteen hundred and fifty one persons were examined the carotid arteries to study the distribution of lesions and the correlation with plaque score and max-IMT. A max-IMT was defined as a maximum intima-meidia thickness of whole carotid and the plaque score was measured to sum of thickness of plaques on both carotid arteries.
Patients with severe carotid atherosclerosis suffered ischemic cerebrovascular events more frequently than patients without. This was observed in the criteria of the stenosis, the surface character of ulceration, and also the plaque score category. The largest lesion such as measured for max-IMT was observed frequently in the carotid sinus (45%), the common carotid artery (33%) and the internal carotid artery (17%), respectively. Among three carotid segments, size of atheromatous plaque in the internal carotid artery (3.0) was thicker than that in the carotid sinus (2.2) and in the common carotid artery (1.1). There was a significant positive correlation between the max-IMT and plaque score. Patients with cardiovascular disease had more severe carotid atherosclotic lesions than those without.
As a result, carotid atherosclerosis is a potent maker of systemic cardiovascular disease and both two parameters of carotid lesions had a similar potential for predicting these disease.

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We introduced transoral carotid ultrasonography (TOCU) which enabled us to evaluate the distal extracranial internal carotid artery (ICA). Examinations were performed using a color Doppler flow imaging system equipped with a convex array stick-like transducers (9 - 5 MHz). We inserted the probe covered with thin gum transorally, touching the tip to the pharyngeal postero-lateral wall. Then we could obtain image and measure flow velocity of the distal portion of extracranial internal carotid artery.
TOCU was successfully performed in healthy five volunteers without any difficulty. The ICA was identified at a depth of 2.2 ± 0.6cm and visualized as a vertical linear vessel about 3.0cm in length and bent slightly backwards. The diameter and mean flow velocity of the distal extracranial ICA was 4.7 ± 0.2mm and 50 ± 7 cm/sec, respectively.
In acute stage of embolic ICA occlusion, TOCU frequently demonstrated echo lucent lumen at the distal extracranial ICA, while it seldom does in acute stage of atherothrombotic ICA occlusion or in chronic stage of ICA occlusion. Therefore, TOCU seems useful to distinguish mechanism of ICA occlusion in its acute stage.
In internal carotid artery dissection, TOCU showed true and pseudo lumens or narrow lumens in the affected side. TOCU seems a useful technique to make up for conventional carotid ultrasonography.

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In the randomized control studies (RCS) as NASCET, ECST, ACAS et al., the benefit of carotid endarterectomy (CEA) for the cases with high-grade carotid artery stenosis have been presented. However, some controversies still remain and evaluation of endovascular stenting vs CEA is noticed as a recent subject in this field. In this report, we presented dthe following subjects ; 1) clinico-pathological features of an atheromatous plaque of carotid artery suggesting the significance of surgical removal of the symptomatic lesions, 2) reviw of the literature and clinical analysis of the reported RCSs, 3) results of retrospective investigations of CEA and stenting in the neurosurgical institutes during 2000 and 2001.
In the retrospective study, 2, 818 CEAs and 1, 084 endovascular treatment was performed in 637 institutes during this two years. Number of cases in about 80% of institutes were less than 10, and moderate indications have been considered, especially in an asymptomatic case, in the most institutes. In Japanese, occlusive carotid artery disease is not so common and some characteristic clinical features have been noticed compared with Caucasians. Prospective and original studies designed for Japanese will be needed to discuss and select an adequate treatment indications.

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We report surgical risks and complications in patients undergoing carotid endarterectomy (CEA) for carotid occlusive diseases by analyzing the results of a nationwide questionnaire. In 1014 patients who underwent CEA in Japan for 2 years from 2000 to 2001, the rate of disabling stroke and death was 1.9%, and in 394 patients who underwent endovascular surgery including stent placement for carotid artery stenosis during the same period, the rate of disabling stroke and death was 4.5%.
From our experience of 336 patients who underwent CEA in our institute between 1975 and 2002, ischemic heart disease was a major cause of death during the CEA perioperative and follow-up periods. Combined angiography and careful management of coronary artery stenosis can be expected to decrease the mortality and morbidity in patients treated with CEA. Intraoperative multiple monitoring system using deviation ration topography of EEG, somatosensory evoked potentials, near-infrared spectrophotometry for measurement of cerebral regional SO₂ and transcranial Doppler ultrasonography (TCD) is useful to prevent ischemic complications. Postoperative hyperperfusion syndrome can be checked serially and non-invasively by using TCD. The management of acute stroke patients with thrombosed occlusion or sever stenosis of the internal carotid artery is still controversial. Acute stage CEA was taken into consideration to treat the patients only in 5 (9%) of the 54 Japanese institutes which answered the questionnaire.

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Carotid artery stenting (CAS) has been developed in recent years as an alternative to carotid endarterectomy (CEA). We report our clinical experience of CAS and evaluate the feasibility and efficacy of this treatment. Since 1997 Feb, 237 patients (199 male, aged 50-85, mean 67.5), 235 carotid artery stenosis (109 symptomatic, 126 asymptomatic), 5 aortitis, 1 FMD, and 6 dissecting were treated with 259 endovascular stenting procedures. Our method in now is as follows;under local anesthesia, transfemoral approach, using guiding catheter, pre-dilation with low profile 3mm PTA balloon with. 014" long wire, and self-expandable stent deployment. Since 1998 Dec, we have used our originally made distal balloon protective system in post PTA. Procedural success was 99.2%, and complications occurred in 2 (0.77%) major and 6 (2.3%) minor stroke without mortality. Restenosis occurred in 12/155 (7.7%) of F/U angiography, 6-50 months after treatment. No complication occurred in re-treatment. Our results indicate that carotid stenting may well offer a similar safety profile and efficacy to those of carotid endarterectomy. The future status of carotid artery stenting will be determined with randomized trials and improvement in devices, technique and safety.

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Endopvascular therapy for carotid stenosis was performed for 168 lesions (164 cases). Percutaneous transluminal angioplasty (PTA) was performed for 66 lesions and carotid stenting was for 102 lesions. Morbidity rate was 3% (minor neurological deficit) in 66 PTA lesions but restenosis appeared in 36%. In stent-treated group, mortality rate was 1% (non-stroke death) and morbidity rate was 4% (major 1%, transient 3%). However, 75% of all morbidity cases were encountered in 15 cases treated without the protection balloon for cerebral microembolism. 87 cases were treated with stenting under the use of distal protection balloon. Only one case showed transient neurological deficit. Two cases demonstrated restenosis necessary to retreat with PTA during follow-up period. These two cases showed satisfactory dilatation after PTA for the restenosed lesion. Long-term follow-up results of stenting for carotid artery are still unknown, but the initial results especially after introduction of distal protection system are pretty good compared with those of carotid endarterectomy in our institute. Also, the reported results of carotid stenting with protection devices are excellent. It is time to start randomized controlled trial between carotid stenting and carotid endarterectomy to establish the indication of each treatment.

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Evidence-based medicine (EBM) has been emphasized in Japan for these years. Several randomized controlled trials (RCTs) in North America and Europe provided evidence that carotid endarterectomy (CEA) is beneficial in patients with symptomatic severe carotid artery stenosis grater than 70% in diameter. The efficacy, however, has not yet been confirmed in Japan. Although carotid artery stenting is a less invasive intervention against carotid artery stenosis, a potential benefit of the stenting remains a matter of investigation. The CREST study, a large-scale RCT on-going in U.S.A. and Europe, will provide evidence concerning the effects of carotid stenting as compared to that of CEA in near future.
Carotid ultrasonography is a noninvasive and accurate way to evaluate carotid artery lesions. Transcranial Doppler ultrasonography and diffusion MRI are providing new insights how often are microembolic brain lesions produced during carotid artery stenting. The effects of several antithrombotic agents and HMG-CoA reductase inhibitor (statin) are now under investigations in ischemic stroke patients. These noninvasive measures and new medical management strategies will help us make carotid artery interventions safer and more effective.
Several clinical studies including J-MUSIC indicated that atherothrombotic brain infarction particularly due to extracranial carotid artery lesions has rapidly been increasing in frequency in Japan. However, the number of potential candidates for carotid intervention is estimated to be 1, 500 to 15, 000 annually in Japan, be-ing only 1/10 to 1/100 of that in U.S.A.
The current situation of carotid artery diseases and clinical evidence on the effectiveness and limitations of carotid interventions should be collected for Japanese patients with carotid lesions.

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The usefulness of evidence-based medicine (EBM) has been discussed in various fields of clinical medicine. One method of the application of EBM is to make EBM-based clinical guideline for practitioners' clinical judgment.
In this communication, I presented the process of collecting clinical evidence to making the guideline for management of patients with cerebral infarction. This was done by research committee (Principal investingator : Yasuo Fukuuchi) on "Evidence-based Guideline for Patients with Cerebral Infarction ", which was supported by Japanese Ministry of Health, Labor and Warfare.
We collected about seventeen thousands literatures in English or Japanese on management of cerebral infarction, which were graded according the evidence levels. About six hundreds of these literatures were selected as high level of evidence, and stored in database.
Evidence in the database was summarized in each therapeutic item such as general management, neurological treatments, neurosurgical interventions and rehabilitation. Summaries of these items is not described here, which will be published in Annual Report 2002 of Japanese Ministry of Health, Labor and Warfare.
At present time, we have an insufficient amount of clinical evidence for making useful guideline for management of patients with cerebral infarction at acute and chronic stages.

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Although guidelines for treatment of stroke have been published by the American Heart Association (USA) and the Royal College of Physicians (UK) since 1994, there has been no guideline for stroke treatment for Japanese patients based on scientific evidence. In 1998, the Joint Committee for Establishment of the Japanese Guideline for Stroke was set up by the Japan Stroke Society, the Japanese Society of Neurology, the Japanese Society of Neurosurgery, the Japanese Society of Neurotherapeutics and the Japan Society of Rehabilitation (Chairman : Y. Shinohara, Co-chairmen : Y. Fukuuchi, T. Yoshimoto and S. Ishigami). The committee subdivided its work into 4 categories (general stroke, ischemic stroke, intracerebral hemorrhage and subarachnoid hemorrhage), and together with three research groups of the Japanese Ministry of Health, Labor and Welfare, is preparing the new guideline for Japanese patients, by Japanese doctors and using mainly Japanese data. This guideline is expected to be published in 2003.
However, there have been few randomized controlled trials (RCT) in the field of stroke in Japan, so one of aims of the joint Committee is to make recommendations concerning future RCTs for stroke treatment in Japan.
It is important to note that this guideline will describe the standard management and treatment in Japan, but doctors should always take into account the particular characteristics of individual patients, as well as the availability of various techniques and facilities in any situation.
Furthermore, the established guideline should be monitored in the light of new information and new methodology, and should be revised periodically as necessary.

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Supported by the Ministry of Health, Labour and Welfare, a guideline for the management of aneurismal subarachnoid hemorrhage (SAH) was prepared based on the procedures of evidence based medicine (EBM). To utilize this guideline effectively and correctly, the following precautions are suggested.
(1) The described "level of strength of recommendation" for each procedure is not identical to the"level of strength of evidence". (2) The procedures recommended in the guideline may not be always applicable to the individual patient. Because of significant variations in the intracranial pathophysiology of SAH or systemic condition of the patient, the feasible management may be determined not by the "guideline" but by "the physician in charge". (3) Due to same reason, it may not be appropriate to refer to the guideline in a lawsuit for medical malpractice. (4) The content of the guideline may be behind the current standard unless it is properly updated. (5) Strong evidence is not easy to accumulate in the field of surgery. In the management of SAH, we still have only a very few number of scientific evidence. It is recommended of SAH, we still have only a very few number of scientific evidence. It is recommended for each surgeon to review his own clinical results critically to improve his daily practice.

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The use of critical pathway is becoming increasingly important in acute stroke therapy. Rehabilitation in the recovery stage could be done in the specialized rehabilitation hospitals within Kumamoto according to inter-hospital cooperation. Our acute stroke team can concentrate on the treatment of stroke in the acute stage (within 2-3 week from the onset). We have been developing this stroke management system based on an acute stroke unit with referral to a rehabilitation unit in other hospital (inter-hospital referral model) in con-trast to the conventional system with a combined acute and rehabilitation stroke unit in a single hospital (intra-hospital referral model). Our outcome of critical pathway for stroke is not only discharge to home but also transfer to a rehabilitation hospital.
After the introduction of 3 types of critical pathway dedicated for various severity of acute ischemic stroke in 1995, the average length of hospital stay of both stroke and non-stroke patients declined from 30.0 days (1993) to 23.3 days (1995), and 13.9 days (2000) in our department. Now we have 5 types of stroke criti-cal pathway.
Critical pathway increased quality of care, and contributed to integrated multidisciplinary collaborations among various specialist, nursing and other paramedical personnel. Critical pathways should be viewed as components of total quality management. They should not be allowed to restrict the patient's or physician's choice of interventions, they should not inhibit in any way innovation or the introduction of novel methodologies. Yet, critical pathways generate a pressure on every member of the acute stroke tam, a sense of negative entropy constantly urging a move toward a higher level of excellence and quality.
The reduction of length of hospital stay was achieved by the use of critical pathway and the inter-hospital cooperation.

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Recently standardization of the early stroke rehabilitation has been promoted after the presentation of guidelines for the management of acute CVDs of AHA in 1994. In our hospital, clinical pathway of stroke rehabilitation was applied in order to facilitate the teamwork among different staffs and shorten the length of hospital stay. By the clinical impairments, stroke patients were divided into three groups and their lengths of stay were arranged, and then the variance analysis was done for the length of stay as a final outcome. It was revealed that the secondary complications, such as infections after stroke, elongated the hospital stay more than the original diseases, and the evaluation of activities of daily living was more practical than that of clinical impairments, in the performance of clinical pathway of stroke rehabilitation.

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We do not have enough understanding of the clinical course, correct treatment and long-term outcome of moyamoya patients. To confirm an accurate incidence and clarify the pathophysiology of this disease, we investigated the clinical data registered in this research committee on moyamoya disease of ministry of health, labor and Welfare in Japan. We also investigated moyamoya patients in Kumamoto, Okayama and Miyagi prefecture for details of newly diagnosed patients for these three years and patients diagnosed before 1990.
The total number of registerd cases in our research committee reached 1, 313 cases. The disease types at onset were ischemic type (57.9%), intracranial hemorrhages (19.5%) and others. The incidence of moyamoya diseasein three prefectures was 0.43 per 100, 000. The long-term follow-up study revealed that the rate of rebleeding (33.3%) was significantly higher in bleeding type than that of ischemic type (3.5%) patients. However the preventive effect of bypass surgery against recurrent bleedings has not been statistically evaluated, in operated group in this study, cumulative survival rate was significantly higher and the incidence of the death due to re-bleeding was significantly lower than those of non-operated group.

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Recurrent bleedings have been known to aggravate the prognoses of the patients who experienced cerebral bleeding attacks related to moyamoya disease. Hemodynamic stress on the moyamoya vessels as collateral pathways has been attributed to the bleeding episodes. Bypass surgery has been performed for these patients to reduce the hemodynamic stress on the moyamoya vessels. However, it has not yet been statistically proven whether the bypass surgery can significantly decrease the recurrent bleeding attacks.
To establish the treatment guidelines for moyamoya disease with hemorrhagic onset, 20 Japanese centers have combined to evaluate the benefit of direct anastomotic bypass surgery such as superficial temporal artery to middle cerebral artery anastomosis in randomized patients who have experienced hemorrahgic episodes related to moyamoya disease and who have received either best medical treatment alone or best medical treatment plus bypass surgery. This prospective randomized controlled trial named as Japan Adult Moyamoya (JAM) Trial was initiated in January, 2001. Twenty-one patients have been already enrolled in this study.

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We performed a series of molecular analysis about pathogenesis and epidemiology of the moyamoya disease. First, to identify the gene responsible for familial moyamoya disease, we performed linkage analysis at 3 p24.2-p26 using three new families and four new markers near D3S3050 locus in addition to the previously published data (Am J Human Genet. 64: 533-537, 1999). Non-parametric LOD score had two high peaks around the marker of D3S3525 (maximum LOD score=4.190) and D3S3706 (maximum LOD score=4.428). These score fulfilled the criteria of significant linkage of complex diseases. Secondly, to clarify the link between the spread of familial moyamoya disease over Asia and the human migration route in ancient, average sequence divergence among patients with moyamoya disease were determined. Both linkage analysis using familial moyamoya patients and analysis on the evolutional gene flow in patients with moyamoya disease showed a clear evidence of hereditary nature of the familial moyamoya disease. Thirdly, analysis on the clinical anticipation observed in familial moyamoya families by detecting CAG repeart expansion with RED method revealed no clearevidence of the causative factor of clinical anticipation. However, this study again resultedin supporting the supecific hereditary nature of familial moyamoya patients.

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In order to make sure the stratification of cerebral hemodynamics of child moyamoya disease, we evaluated ¹²³I-IMP SPECT before and after surgical revascularization. The aim of this paper is toestablish the semiquantitative parameters that can be applied to estimate severity of hemodynamic cerebral ischemia instead of quantitative parameters. Quantitative studies using IMP-ARG method were performed on thirteen patients to measure resting regional rCBF, and vascular reserve (rVR): (Diamox-activated rCBF/resting rCBF-1) × 100%. Semiquantitative parameters were calculated from the ratio of ROI counts in the ACA and MCA territory to the dominant cerebellum counts (ROI/Ce ratio) at resting and Diamox-activated conditions. From the quantitative study, both mean resting rCBF less than 40m1 /100g/min and rVR less than 10% could indicate stage 2 hemodynamic cerebral ischemia. The prediction of stage 2 ischemia using semiquantitative parameters (resting ROI/Ce ratio less than 0.9 and Diamox-activated ROI/Ce ratio less than 0.85 inthe MCA territory) was not statistically different comparison to the diagnosis using quantitativeparameters (using Fisher exact test<0.0001, Sensitivity and specificity were 87.5% and90.9%, respectively). The ROI/Ce ratio can be utilized as simple parameters instead of quantitative parameters.

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The changes in incidence and mortality of stroke and its risk factors were studied in a general population of Hisayama town, where a prospective cohort study was initiated in 1961 (Hisayama study). The characteristics of this study exist 1) 99% of the study subjects had been followed, 2) the development of stroke was completely evaluated by study physicians, and 3) the cause of death was verified by autopsy with average 81% over 40 years. Age and sex-adjusted incidence and mortality of cerebral hemorrhage were markedly and significantly decreased from first cohort (1961-) to second cohort (1974-) and third cohort (1988-). Incidence and mortality of cerebral infarction were halved from the first to the second cohort, but changed little from the second to the third cohort. As for subtypes of cerebral infarction, incidence of lacunar infarction was decreasing, while incidence of atherothrombotic infarction and cardiogenic embolism tended to increase in the recent cohort. As for risk factors, the prevalence of hypertension (≥160/95mmHg) consistently decreased due to increasing of drug treatment and salt restriction. However, the prevalence of metabolic disorders such as glucose intolerance, hypercholesterolemia and obesity continued to increase in recent years, because of westernization of life styple and dietary habits. Changing of incidence and mortality of stroke is apparent in Hisayama population, mainly due to hypertension management, although only less than one-fourth of the hypertensives had been treated appropriately (<140/90mmHg) even in recent years. More strict controlling of hypertension is necessary for further reduction of stroke incidence.

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Purpose: To clarify the relationship between blood pressure and mortality from stroke, heart disease, cardiovascular diseases and all causes of death among representative population of Japanese and to estimate category specific excess mortality from stroke due to SBP.
Methods: In 1994, 14 year-follow-up cohort study was conducted among participants of national survey on cardiovascular diseases in 1980, randomly selected from Japanese population.
Restults: Total observed person years were 54714 for men and 71481 for women. During follow-up 1327 deaths was observed and underlying causes of deaths were identified for 99.5% of deaths using national vital statistics data. Both SBP and DBP were significantly related to mortality from strokes, cardiovascular diseases and all causes of death for both sexes (p<0.001). Heart disease mortality was significantly related to SBP and DBP among men (p<0.05) while not among women.
Increased mortality rate from stroke was observed with high blood pressure for all ages. Estimated excess mortality was 67% for men and 46% for women and chiefly observed among moderate hypertensives (27 % for men and 15% for women).
Conclusion: High blood pressure was a risk factor for mortality from all causes as well as those from cardiovascular diseases, stroke and heart disease among Japanese. Since major part of excess mortality was due to mild hypertension, population strategy to reduce blood pressure should be encouraged.

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Measurements of ambulatory blood pressure (ABP) and of home blood pressure (HBP) as an adjunct to casual/clinic BP (CBP) measurements are currently widely used for the diagnosis and treatment of hypertension. We have monitored a rural cohort of people from the population of Ohasama, Japan, with respect to their prognosis and have previously reported that ABP level and HBP level are superior to CBP level for the prediction of cardiovascular mortality.
Our results also confirmed that short-term blood pressure variability (as measured every 30 min) was independently associated with cardiovascular mortality. In addition, research has recently focused on isolated systolic hypertension and pulse pressure as independent risk factors for poor cardiovascular prognosis. The Ohasama study also clearly demonstrated that isolated systolic hypertension and increased pulse pressure, as assessed by HBP, were associated with an increase in the risk of cardiovascular mortality. Concerning diurnal blood pressure variation, the incidence of stroke increased with an increased length of observation in dippers using antihypertensive medication but not in non-dippers using antihypertensive medication. In contrast, the relative hazard for mortality increased in non-dippers and inverted dippers. These results suggest a cause-and-effect relationship for both dippers and non-dippers.
The Ohasama study showed that the level and variability of hypertension as assessed by ABP and HBP are independent predictiors of cardiovascular mortality.

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The molecular understanding of the genes of cerebrovascular disease and hypertension may contribute to better development of new diagnosis and treatment. Under classical strategy, scientists have tried first to find a physiological phenomenon specific for essential hypertension, then to identify the protein underlying the physiological abnormality, and finally to clarify the causative gene which encoded the protein. On the other hand, under the reverse genetic approach, the correlation between hypertension and genetic abnormality is identified first, and then the pathogenesis is clarified-in reverse order. Therefore, it is not extraordinary for unexpected results to be obtained in the correlation between a gene and a disease, suggesting that this approach has a possibility to be a breakthrough in the chaos of the research of hypertension and cerebrovascular disease.

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There has been a long debate, whether anti-hypertensive treatment is safe and effective for preventing recurrent stroke. Although anti-hypertensive treatment is known to be effective for preventing first-ever stroke, blood pressure lowering treatment is thought to cause recurrent ischemic stroke especially in some chronic stroke patients with severe obstructive lesions, where decreased cerebrovascular reserve capacity and disturved autoregulation were demonstrated. The perindopril protection against recurrent stroke study (PROGRESS) was designed to clarify the concern about the efficacy and safety of blood-pressure-lowering treatments for the chronic stroke patients.
PROGRESS is a randomized, double-blind, placebo-controlled, international, trial of 6, 105 stroke patients, including 815 Japanese stroke patients. Normotensive or hypertensive patients with a history of stroke or tyransient cerebral ischemia within the previous 5 years were enrolled and were randomly assigned to treatment with the ACE inhibitor perindopril 4 mg or placebo, plus the diuretic indapamide (for individuals in whom it was not considered to be definitely indicated or contraindicated) or placebo. Over 4 years of follow up, active treatment reduced blood pressure by 9/4 mm Hg (from 147/86 mm Hg to 138/82 mm Hg). Perindopril group had a 28% relative risk reduction (95% CI 17-38%, p<0001) in primary endpoint (total strokes). Active treatment also reduced the risk of total major vascular events, significantly (26% relative risk reduction). Interestingly, there were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups (all p<0.01).
Through PROGRESS trial, Japanese investigators including myself could learn the at-most importance of mega-trial for obtaining a clear-cut evidence on the targeted clinical concern. According to the PROGRESS results, the blood-pressure-lowering treatmemnt with perindopril and indapamide should be quite safe and ef-fective for preventing recurrent stroke, irrespective of their blood pressure. The clinical significance of PRO-GRESS was fully discussed in the symposium.

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To clarify the clinical significance of transcranial harmonic perfusion imaging (HPI), we investigated qualitative comparisons between second- and ultra-harmonic imaging (SHI, UHI), power Doppler harmonic imaging (PHI), and quantitative correlations with dynamic CT (DCT) and/or transcranial Doppler (TCD) during acetazolamide vasoreactivity tests in neurological patients. Methods : The contrast images after a bolus Levovist^® injection were compared on the basis of the transmitting and receiving frequencies (MHz) of SONOS 5500, SHI and PHI (1.8/3.6) utilizing an S4 transducer (n=28), and UHI (1.3/3.6), SHI (1.3/2.6), and PHI (1.3/2.6 and 1.6/3.2) utilizing an S3 transducer (n=10). HPI parameters from time-intensity curves in the temporal lobe, basal ganglia, and thalamus were correlated with those of DCT parameters (n=25), and with TCD and DCT parameters during vasoreactivity tests (n=12). Refill kinetics during continuous Levovist^® infusion was analyzed at rest and during vasoreactivity tests. Results : a) Visualization of contrast effects was more sensitive in SHI, with a particularly low receiving frequency of 2.6 MHz, than UHI or PHI. b) Correlation of parameters was reduced in inter-individual variations, however mean transit time indicated closer correlations. Vasoreactivity of HPI tended to correlate with that of DCT and/or TCD. Conclusions : HPI allows qualitative and relatively quantitative comparisons of brain tissue perfusion, is non-invasively repeatable at bedside, and has a clinical significance in the evaluation of treatment and follow-ups for ischemic stroke patients.

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The usefulness of Cerebral Blood Flow (CBF) measurement by single photon emission computed tomography (SPECT) has been verified in patients with hyperacute stage of cerebral infarction, especially when a thrombolytic therapy is considered. Measuring residual CBF before thrombolysis is very important because patients with more than 40% decrease in CBF compared with the contralateral normal brain is at high risk of crucial hemorrhage after recanalization. Positron emission tomography (PET) can provide metabolic information of the ischemic brain in addition to the severity of CBF deterioration, and would be a powerful diagnostic tool if the measurement becomes feasible in emergency. We investigated qualitative PET measurement that took only half an hour for the examination, and demonstrated that qualitative PET could detect areas with misery perfusion in the affected cerebral hemisphere. Comparing the qualitative PET imaging with the functional magnetic resonance imaging (MRI) obtained within 6 hours after ischemic attack, we delineated that areas with perfusion-diffusion mismatch on MRI contained the area with decrease of oxygen metabolism where progressed to the irreversible brain damage without initial decrease of water diffusion. Qualitative PET measurement has the possibility to explicate the background of signal change of functional MRI that per-formed in the hyperacute stage of cerebral infarction.

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Ischemic stroke remains a common cause of death and disability in the industrialized world. In the treatment of ischemic stroke, conventional CT is still the primary imaging modality. However, positive CT findings do not appear during the narrow time window. There is a strong demand to establish a prompt diagnostic technique, which provides the cerebral perfusion information for the successful therapy. CT perfusion (CTP) is a new introduced image-processing technique which can provide quantitative cerebral blood flow by calculating functional maps such as cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT). CT angiography (CTA) has been also shown to be valuable for the detection of cerebral arterial occlusion and stenosis. Using multi-detector row CT, we performed both CTP and CTA as one time examination in the assessment of cerebral ischemia. In this symposium, we introduce our imaging protocols, and demonstrate the usefulness of combination diagnosis of CTP and CTP. The CTP and CTA are an accurate, convenient, and safe method in patients with cerebral ischemia. The combination diagnosis of CTP and CTA not only allows early detection of cerebral ischemia but also yields valuable information for planning management of acute ischemic stroke.

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MR angiography (MRA) is a non-invasive technique which can provide an important information about cerebral vascular diseases such as cerebral aneurysms or occlusive lesions. As recent progress in MRA, image quality has become excellent and acquisition time has become much shorter by contribution of several technologies including MTS, TONE, and ZIP. A first-pass, contrast-enhanced 3D MR angiography with very short acquisition time is useful for AVM and AVF. This MR technique can demonstrate arteriovenous shunts as well as the feeding arteries and draining veins of the lesions. After introduction of a new multidetector helical CT scanner, it has become possible to produce high-speed CT angiography (CTA) of high quality with significantly shorter acquisition time for the intracranial and cervical vessels. The feasibility of 3D views of intracranial and cervical vessels computed from planar digital angiograms acquired with a rotational angiography system has been evaluated. In the cases with aneurysm, 3D angiography is superior to conventional DSA concerning visualization of the aneurysm architecture. 3D angiography has now become essential for embolization of the cerebral aneurysms with GDC.

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The mechanism of poststroke motor functional recovery remains to be elucidated. We used functional MRI (fMRI) and near-infrared spectroscopic topography (NIRS) to evaluate the compensatory motor activation of cortical regions during a hand movement task in patients who recovered from poststroke hemiparesis. 1) We evaluated 9 patients with various types of stroke with mild-moderate hemiparesis using fMRI within 1 month of stroke onset and after 2-3 months. At the first examination, the activation of the contralateral hemisphere (primary sensorimotor cortex and supplementary motor area) was markedly reduced during the paretic hand movement. At the second examination, the contralateral activation had recovered in 8 of 9 patients. It addition, activation of ipsilateral motor cortex was seen during the paretic hand movement in 4 of 9 patients. 2) We evaluated 6 patients with massive cerebral infarction in the territory of middle cerebral artery without severe residual hemiparesis using both fMRI and NIRS. Both techniques showed that the activation of ipsilateral primary motor cortex was activated during the paretic hand movement in addition to activation of extended motor areas of the contralateral hemisphere. These observations suggest that motor cortical reorganization, including the ipsilateral hemisphere, contributes to the recovery from poststroke hemiparesis.

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