At the 4th Presidential Lecture of the Japan Stroke Society (JSS), I talked about the status and achievements of the JSS in 2007, as well as the progress towards realizing the 20 manifesto points that I proposed about 4 years ago, when I was inaugurated as president of the JSS.
1. The number of active members was 5,116, and the number of authorized stroke specialists certified by the JSS was 2,708. The number of stroke specialists amounts to 1.1% of the total number of Japanese medical doctors. This means that one stroke specialist has to take care of 47,177 Japanese people who may develop stroke. However, the situation may be even more difficult than this, because the distribution of stroke specialists throughout the country is not uniform. We need more stroke specialists in Japan.
2. Among the 20 manifesto points that I proposed 4 years ago, about 70 to 75% have been successfully completed so far.
3. In 2007, our major achievements were as follows:
1) The official journal, "Journal of Stroke and Cerebrovascular Diseases", was accepted into the National Library of Medicine, an outcome that JSS members have sought for many years.
2) A retirement age for the directors and councillors of the JSS was established.
3) Arrangements were made for closer communication with related medical societies, such as the Japanese Society of Hypertension, and so on.
4) Progress was made in promoting communication with local communities about stroke, as well as improving the education of the general public about stroke.
5) Closer relationships were established with Western countries, and particularly with Asian countries, concerning stroke-related matters.
4. Plans for the immediate future of the JSS include:
1) Reaching agreement with the Japanese Ministry of Health, Labor and Welfare for stroke specialists to be allowed to advertise.
2) Further emphasizing the importance of team medical management, particularly stroke education for co-medical workers, at the annual meeting of the JSS.
3) To make a part of the JSS homepages available in English, and so on.
The JSS should progress into the 21^st century with a broad vision for its future, looking beyond a conventional science-focused role.

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Molecular imaging is a useful method for diagnosis of cerebral ischemic diseases as well as evaluation and monitoring of the effects of various treatments. Cu (II)-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) is a promising tracer for hypoxic imaging, which is considered to represent mitochondrial deficiency in cerebral infarction. Imaging of microglial activation using ligands for peripheral benzodiazepine receptors would be useful for evaluation of self-restoration function toward degeneration or impairment caused by cerebral infarction or other brain damages. Molecular imaging technique with PET would be able to utilize for monitoring and follow-up of various treatments such as gene therapy and transplantation.

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Advent of extrinsic molecular probes, such as superparamagnetic iron oxides, has enabled molecular imaging of experimental animals using magnetic resonance imaging (MRI). In addition, several MRI techniques, such as diffusion-weighted imaging, arterial spin labeling, MR spectroscopy, and susceptibility-weighted imaging, can visualize subtle alterations in hydrogen-containing molecules in the central nervous system, and can be applied to cerebrovascular disease assessment. However, further technical advancement, standardization, and cross-validation are necessary to establish clinical significance of these techniques in stroke management.

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Brain perfusion and iomazenil SPECT have been applied for the following three clinical condition in stroke. First, brain perfusion SPECT have established the cerebral blood flow thresholds for the development of infarction or hemorrhage and the results have suggested that pretreatment SPECT can provide useful parameters to increase the efficacy of thrombolysis by reducing hemorrhagic complications. Iomazenil SPECT detects a selective loss of cortical neurons in patients with transient hypoperfused tissue, which is morphologically intact on MRI. Second, reduced cerebrovascular reactivity to acetazolamide determined by quantitative brain perfusion SPECT is significantly associated with an increased risk of stroke recurrence in patients with symptomatic intracranial main trunk occlusion. Combination of brain perfusion SPECT and iomazenil SPECT may accurately detects misery perfusion. Lastly, preoperative measurement of acetazolamide-induced changes in cerebral blood flow using SPECT can identify patients at risk for hyperperfusion after carotid endarterectomy. Iomazenil SPECT detects wide loss of cortical neurons due to cerebral hyperperfusion following carotid endarterectomy.

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Out-of-office blood pressure (BP) monitoring, i.e., ambulatory and home blood BP monitoring, has better predict power of stroke than dose conventional BP. A large part of such evidence has been derived from a population-based prospective study in Japan (the Ohasama study). The Ohasama study has also revealed unique predictive power of theses monitoring. The predictive value of home BP increased progressively with the number of measurements. Even the initial-first home BP values (1 measurement) showed a significantly greater relation with stroke risk than conventional BP values (mean of 2 measurements). Home BP increased the predictive power of categorizations of guidelines compared to conventional BP. A disturbed nocturnal decline in BP determined by ambulatory BP is associated with cerebral infarction, whereas a large morning surge is associated with cerebral hemorrhage. Morning home hypertension, which is characterized specifically high home BP only in the morning might be a good predictor of stroke, particularly among individuals using anti-hypertensive medication. Since the Japan Home versus Office BP Measurement Evaluation (J-HOME) study demonstrated a poorly controlled condition of morning home BP in treated hypertensive patients, more aggressive treatment targeting morning home BP would be necessary to better prevent future stroke.

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Antiplatelet agents are used in patients with ischemic stroke not only in the acute stage, but also in the chronic stage, Aspirin at 160-300 mg/day is recommended within 24-48 h after onset, but is not a substitute for tissue plasminogen activator. Ozagrel sodium, a thromboxane A₂ synthase inhibitor, is used in Japan within 5 days after onset of cerebral thrombosis, which also increases cerebral blood flow in the penumbral area. No other antiplatelet agents have been verified to be effective in the acute phase of cerebral ischemia. In the chronic phase of non-cardioembolic stroke, aspirin, clopidogrel or aspirin with extended-release dipyridamole represent the initial options used around the world. However, cilostazol, a phosphodiesterase inhibitor, has been approved for secondary prevention of ischemic stroke in Japan. Cilostazol is known to not prolong bleeding time. Combination therapies such as aspirin plus clopidpgrel, aspirin plus dipyridamole or aspirin plus cilostazol are used for high-risk patients, where risk is determined by factors such as diabetes mellitus, dyslipidemia, and major vessel occlusion or stenosis as diagnosed on magnetic resonance angiography or carotid echosonography. However, care is required regarding hemorrhagic complications. New antiplatelet agents such as P₂Y₁₂ ADP receptor antagonists (prasugrel, cangrelor, AZD 6140), thromboxane receptor antagonists (S18886-terutroban) and thrombin receptor antagonists (SCH530348) are under investigation.

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Hypertension is still one of the major risk factors for stroke. There are guidelines on best medical treatment against acute and chronic stages of stroke. In acute phase, aggressive antihypertensive treatment was shown to cause impairment of cerebral circulation, and even in chronic stage, J-curve phenomenon used to be one of the topics in recurrent stroke. Thereafter, modest approach to control blood pressure has been recommended, especially in case of atherothrombotic brain infarction. On the other hand, rather earlier smooth landing from acute stroke hospital to the convalescent and chronic rehabilitation hospital is generally accepted these days. The current status and future on hypertension therapy in acute as well as chronic stages will be discussed in this issue. Moreover, treatment against arrhythmia such as non-valvular atrial fibrillation and thrombotic as well as metabolic disorders is also important in this field; then, so-called pleiotherapy (an novel abbreviated terminology of pleiotropic therapy) is quite indispensable nowadays.

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In a cohort of patients with cerebral infarction, we investigated the factors related to individual patients and the institutions in which they were treated, in relation to management outcome. All of the study patients were registered at 27 institutions in Japan between 2004 and 2007. The correlations between management outcome and patient- and institution-related factors were investigated using multivariate analysis.
Among the patient-related factors, age, NIH stroke score on admission, and hypercholesterolemia significantly affected the management outcome. Among the institution-related factors, the number of clinicians in the neurological and neurosurgical departments significantly affected the management outcome. When the number of clinicians was higher, management outcome was better.
In order to improve the management outcome of patients with cerebral infarction, it is necessary to increase the number of clinicians, and to concentrate them in major stroke care units.

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Background and Purpose: A post-marketing surveillance reported fatalities following recombinant tissue plasminogen activator (rt-PA) administration among acute cerebral infarction (CI) patients with acute aortic dissection (AAD). The aim of our investigation was to seek methods for diagnosing AAD in CI patients by basic and less-invasive methods in the emergency room (ER). Methods: The study subjects consisted of 107 CI(group A) and 50 AAD patients; 13 AAD (group B) had no chest, back or abdominal pain (26%). The patients' blood pressure (BP), past history, cardiothoracic ratio (CTR) and superior mediastinum-thoracic ratio (SMTR) were extracted from medical records and supine chest radiographs obtained in the ER. Results: Seven (54%) and four (31%) patients in Group B presented with consciousness disturbance and motor deficit, respectively. There were no significant differences in the age, sex, past history or CTR between the two groups. In groups A and B, the systolic BP (mmHg) was 155 and 106, and SMTR (%) was 29 and 38, respectively, and the differences were statistically significant. Conclusions: The propriety of administration of rt-PA should be decided after careful scrutiny by chest contrast computed tomography in CI patients with hypotension or superior mediastinal enlargement in the ER.

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Animal models of cerebral ischemia have been widely used to elucidate the pathophysiology of ischemic brain injury and to test potential therapeutic approaches. In contrast to the previously considered impact of brief global cerebral ischemia, in which selective neuronal vulnerability is the hallmark of pathology, ischemic stroke is characterized by the progressive additional involvement of glial cells and blood vessels as the duration of focal ischemia is increased. Characterized by long lasting or even permanent intervals of ischemia, the main issue in focal ischemia is the concept of cerebral blood flow threshold. The so-called "ischemic penumbra" is of particular interest as a zone of non-functioning but still metabolically viable tissue that may recover if adequate blood flow can be restored.
As the forcal cerebral ischemia model, the middle cerebral artery occlusion model in rats and mice, such as surgical occlusion, intraluminal occlusion and photochemical thrombosis are most widely used. In this paper, the advantages and disadvantages of these models are discussed. And the evaluation systems of cerebral infarction are also discussed.

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Molecular mechanisms underlying ischemic neuronal death have been extensively investigated these twenty years. While several drugs such as glutamate receptor antagonists and free radical scavengers attracted much attention as potential neuroprotive agents, randomized clinical trials have failed to show any beneficial effect of those drugs for acute ischemic stroke patients. However, recent advance in molecular biology of NMDA receptor may explain why NMDA receptor antagonists were toxic rather than beneficial in ischemic stroke patients. NMDA receptors consisted of two subtypes, synaptic and extrasynaptic receptors. It is likely that activation of synaptic receptors results in survival while that of extrasynatpic ones causes cell death in cultured neuron. Antagonists specific to extrasynaptic receptor could be promising for neuroprotection. Hibernation and hypothermia both show robust protection against decreased levels of cerebral blood flow in experimental animals. Ischemic tolerance is well known phenomenon in that sublethal ischemic stress induces resistance of neurons against subsequent severe ischemic insult. Recent studies using cDNA microarray revealed that gene expression of cell metabolism and ion channel was down-regulated in tolerant brain. Metabolic downregulation would underlie the protective action of hibernation, hypothermia and ischemic tolerance. Therapeutic application of metabolic downregulation could be further investigated in next few years.

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Investigation of cerebral circulation and metabolism in stroke patients with PET has given clinicians useful information in interpreting the results of SPECT examinations in clinical practice. In patients with atherothrombotic internal carotid artery (ICA) or middle cerebral artery (MCA) occlusive disease, the chronic reduction in cerebral perfusion pressure (chronic hemodynamic compromise) increases the risk for cerebral ischemic damage. We have shown that severe hemodynamic compromise, demonstrated as increased oxygen extraction fraction (misery perfusion) with PET, is a risk factor for subsequent ischemic stroke. We have also shown that selective neuronal damage demonstrated as a decrease in central benzodiazepine receptor in the normal-appearing cerebral cortex is associated with increased oxygen extraction fraction (misery perfusion). Detection and appropriate treatment of the patients with misery perfusion is important for preventing ischemic damage in patients with atherothrombotic ICA or MCA occlusive disease. Using PET, we have correlated CBF response to acetazolamide with hemodynamic and metabolic parameters in patients with atherothrombotic ICA or MCA occlusive disease, which suggested that evaluation of cerebral vasodilatory capacity using SPECT with acetazolamide could detect patients with hemodynamic compromise including patients with misery perfusion. A Japanese EC/IC bypass trial for patients with severe hemodynamic compromise, demonstrated as decreased CBF and decreased CBF response to acetazolamide with SPECT, showed a benefit of bypass surgery for preventing ischemic stroke. Thus, detection of the patients with severe hemodynamic compromise is crucial for improving the prognosis of patients with atherothrombotic ICA or MCA occlusive disease. Understanding the pathophysiology of hemodynamic cerebral ischemia is essential for the management of patients with atherothrombotic ICA or MCA occlusive disease. Pathophysiology of hemodynamic cerebral ischemia studied with PET has had impact on clinical significance of SPECT examinations for improving prognosis of patients.

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In this article, the author reviews the historical aspects of the development of neuroprotective drugs including a oxygen radical scavenger, NXY-059 and discusses the missing steps in translating bone marrow stromal cell (BMSC) transplantation for cerebral stroke from laboratory to clinic. Furthermore, the authors describes what we should scientifically clarify to apply BMSC transplantation therapy into the patients with cerebral stroke.

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Blockade of renin angiotensin system (RAS) is effective to prevent onset of stroke. However, the detailed mechanism is still an enigma. Here we discuss about the role of RAS in brain damage after stroke and cognitive decline associated with metabolic syndrome. Increase in angiotensin II in the brain enhanced ischemic damage after middle cerebral artery occlusion. On the other hand, temporal blockade of RAS even after cessation of angiotensin II type-1 receptor blocker (ARB) treatment prevented brain damage with increase capillary density in the brain. Angiotensin II type-2 (AT₂) receptor signaling contributes to protect brain via enhancement of neural differentiation. Moreover, AT₂ receptor signaling in the other tissue also contributes to brain protection. For example, bone marrow stromal cells (MSCs) have been expected to improve the brain damage by transplantation after stroke; however, MSCs prepared from AT₂ receptor deficient mice could not improve survival rate in mice after ischemia-reperfusion injury. Finally, cognitive impairment observed in type 2 diabetic model mice and mice fed with metabolic syndrome prone diet was prevented by treatment with nonhypotensive dose of ARBs. These results suggest that regulation of RAS by ARB could be a therapeutical benefit to prevent brain damage in patients with hypertension.

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We performed a genomewide linkage study of intracranial aneurysm (IA) in 104 Japanese affected sib pairs and positive evidence of linkage on chromosomes 5q22-31, 7q11, and 14q22 were found. The best evidence of linkage was detected at D7S2472, in the vicinity of the elastin gene (ELN). We extensively analyzed a 4.6Mb linkage region around D7S2472 by genotyping 166 single nucleotide polymorphisms (SNPs). SNP and haplotype-based association studies revealed a susceptibility locus for IA on a single LD block covering the 3' untranslated region (3'UTR) of ELN and the entire region of LIMK1. An association study showed that the ELN 3'UTR G (+659) C SNP has the strongest association to IA and constitutes a tag-SNP for an at-risk haplotype, which contains two functional SNPs, ELN 3'UTR (+502) A insertion and LIMK1 promoter C (-187) T SNP. Functional analyses demonstrated that both SNPs decrease transcript levels, either through accelerated ELN mRNA degradation or through decreased LIMK1 promoter activity. Elastin and LIMK1 protein are involved in the actin depolymerization signaling pathway, therefore, it is suggested that a combined effect of the SNPs in the at-risk haplotype may weaken the vascular wall and promote the development of IA.

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Background and purpose: Genetic factors associated with ischemic stroke are still not well understood. To identify a gene susceptible to ischemic stroke, we performed a genome-wide association study of ischemic stroke using 52,608 single nucleotide polymorphism (SNP) markers.
Methods and results: We performed two-step screening analysis using 1,112 cases with ischemic stroke and age- and sex-matched control subjects of the same number. After a linkage disequilibrium analysis in a candidate locus, we found an SNP in the 5'-flanking region of angiotensin receptor like-1 (AGTRL1) gene (rs9943582, -154 G/A) to have a significant association with ischemic stroke(odds ratio, 1.30; 95% confidence interval (CI), 1.14-1.47; p=0.000066). We also found the binding of Sp1 transcription factor to the region including the susceptible G allele, but not the non-susceptible A allele. Real-time PCR analysis and luciferase assay demonstrated that exogenously introduced Sp1 induced transcription of AGTRL1. Furthermore, a 14 year follow-up cohort study in a Japanese community in Hisayama Town revealed that the GG genotype of this particular SNP had a significantly higher risk of ischemic stroke (hazard ratio, 2.00; 95%CI, 1.22-3.29; p=0.006).
Conclusion: Our results indicate that the SNP in the AGTRL1 gene is significantly associated with the susceptibility to ischemic stroke.

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Hereditary small vessel diseases of the brain with autosomal dominant inheritance can be divided into two types, CADASIL caused by the NOTCH3 mutation (NOTCH-C) and the NOTCH3 non-related CADASIL-like syndrome (Non-NOTCH-C). Portuguese-French family and Swedish family were reported as a new hereditary small vessel diseases of the brain not related NOTCH3. Clinicoradiological features in Non-NOTCH-C were compared with those in NOTCH-C. Subjects included 21 Japanese patients with multiple lacunar infarctions in 18 families with autosomal dominant inheritance. After screening 1-24 exon (s) of NOTCH3 using denaturing high-performance liquid chromatography, mutations were confirmed by direct sequencing. Of the 21 Japanese patients, 12 were determined to have NOTCH-C and 9 to have Non-NOTCH-C. Although Non-NOTCH-C patients had significantly less granular osmiophilic material in skin biopsies and less white matter lesions at the temporal pole identified by MRI, the clinical course and symptoms in Non-NOTCH-C patients resembled those in NOTCH-C patients. We report the identification of CADASIL-like syndrome not related to the NOTCH3 mutation in Japan as well as Sweden and France.

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Two years has passed since thrombolytic therapy was approved for acute ischemic stroke with intravenous alteplase in Japan. Clinical results from 7 acute stroke centers in Fukuoka city demonstrated that the numbers of patients who admitted to those hospitals within 3 hours were not significantly increased. However, the numbers and the frequency of the patients treated with recombinant tissue plasminogen activator alteplase (rt-PA) were significantly increased during 2 years. We should enlighten the citizens what to do when they encounter or experience stroke, and should make close relationship and networks in each local emergency systems.
In Kyushu Medical Center, 33 patients (4% of acute brain infarction) were treated with rt-PA, of whom 18 patients were cardioembolic stroke. The patients with severe cardioembolism (NIHSS>15) and those with hypertension at onset tended to be worse outcome. Patients with aortic dissection should be diagnosed carefully, since they showed unexpected worse outcome after the rt-PA therapy. Clinical outcome of the patients with rt-PA in a post-marketing research did not reach the satisfactory level compared with that of J-ACT phase III study. Attendant doctors in some hospitals have not submitted the medical record documents sufficiently. Vascular neurologist should obey the indication for rt-PA therapy, and have the ability to assess early CT findings. Hyper-acute stroke patients should be treated in a standard stroke center with enough stroke specialist and staffs although many issues have not yet been solved.

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The key points of acute stroke therapy are summarized as follows: 1) 24 hours' operation of CT and MRI, 2) prompt intravenous rt-PA therapy, 3) specific therapies according to stroke subtype, 4) immediate secondary prevention, 5) acute rehabilitation, 6) infection control and nutrition support, 7) surgical therapy, 8) endovascular therapy.
Within 3 hours of stroke onset, administration of rt-PA to appropriate patient is the top priority. Evaluation of early ischemic changes on CT or DWI, and blood test's result (platelet counts, glucose, PT-INR, and APTT) are required.
Beyond 3 hours, identification of ischemic penumbra and site of vessel occlusion need to be evaluated. Endovascular therapy is considered as effective up to 6 hours. New generation plasminogen activator may further expand the therapeutic time window. The concept of diffusion-perfusion mismatch will help the selection of proper candidate.
After 3 hours, accurate diagnosis of stroke subtype is essential. Special drugs approved in Japan are all restricted to selected subtype. Brain imaging, ultrasound examination, blood tests, cerebral blood flow evaluation and cerebral angiography are used to determine the subtype. To monitor stroke severity and efficacy of therapy, neurological examination is important. NIHSS is most commonly used in clinical practice.

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We evaluated the recanalization rate and clinical outcome of intravenous tissue plasminogen activator (t-PA) and intra-arterial urokinase (PTA) in acute ischemic stroke with large vessel occlusion. The recanalization of the occlusion site and the ischemic change were evaluated with pre-and post-treated MRI and MRA. Total recanalization rates after the IV t-PA and the PTA therapy were 35.6 and 21.9%, respectively. These rates were 50.0 and 16.7% in the distal middle cerebral artery (MCA), 52.6 and 25.0% in the proximal MCA, 6.3 and 5.3% in the internal carotid artery (ICA), 25.0 and 26.3% in the basilar artery (BA), respectively. The rates of the symptomatic intracerebral hemorrhage after IV t-PA and PTA were 0 and 5.2%, respectively. The proportion of modified Rankin Scale (mRS) of 0 to 1 at 3 months after treatments were 17.4% in IV t-PA and 12.5% in PTA. Our results indicated better recanalization rate and outcome of MCA with t-PA than that of PTA. However, the recanalization rate of ICA and BA were very poor in both tPA and PTA as yet. It is necessary to investigate newly strategies and/or modality for ICA and BA occlusion.

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Evidence based medicine (EBM) was proposed by Guyatt in the early 1990s. Sackett and colleagues have established basic concept of EBM. They defined that EBM was the conscientious, explicit, and judicious use of current best evidence in making clinical decisions for each patient. Recently, although many clinicians recognized epidemiology as an importance tool for EBM, there were some misunderstandings in the decision-making process to use evidence level. Some clinicians believe EBM must need randomized-controlled trials (RCT). However, RCT is not always best available evidence. RCT is not suitable to examine harmful exposures, such as smoking, due to ethical problems. Furthermore, to clarify very week association, such as dietary habit and stroke, RCT requires too huge sample size to perform practically. When we are looking for second best evidence, the consistency is a main target. For example, cohort studies anywhere on the globe showed the positive relationship between smoking and cerebral infarction. Although EBM is substantially made to resolve a one-on-one clinical relationship (one therapy and one outcome), clinical questions usually consist of more complex matters with many-to-many, many-to-one, one-to-many associations. We should combine the best available external evidence with our clinical expertise, and neither alone may work enough.

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Purpose
We aimed to assess the natural history of unruptured intracranial aneurysms and considered the risk factors of their rupture.
Objectives and Methods
We assessed 192 unruptured aneurysms in 162 patients that were managed conservatively. Concerning the cases that presented subarachnoid hemorrhage during observation, we assessed the risk factors of rupture, including location, size, shape, and enlargement of aneurysms.
Results
Among 192 aneurysms, 36% were located at internal carotid artery, 32% at middle cerebral artery, 11% at vertebro-basilar artery, and 11% at anterior communicating artery. During observation, 9 aneurysms ruptured. Three aneurysms were located at basilar artery, 3 at middle cerebral artery, 1 at anterior communicating artery, 1 at distal anterior cerebral artery, and 1 at posterior cerebral artery. Among 9 cases, 5 had multiple aneurysms and 3 had previous history of subarachnoid hemorrhage. Four aneurysms were larger than 10 mm, but 4 were smaller than 5 mm. Enlargement of aneurysms were found in 4 cases. All cases had more than two risk factors of rupture.
Conclusions
We thought that even for patients of high age with unruptured aneurysms, if he has more than two risk factors of rupture, we have to consider surgical treatment positively.

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Hypertension is the most powerful risk factor for stroke. Blood pressures (BP) measured out of clinic, such as self-measured BP at home and ambulatory BP are the better predictor of stroke than clinic BP. As well as higher 24-hr BP level, disruption of diurnal BP variation is also associated with increased risk for stroke. Recent prospective studies clearly demonstrated that the riser pattern with higher nocturnal BP than daytime BP and nocturnal hypertension per se are closely associated with cardiovascular death and cardiovascular events such as stroke and cardiac disease. The following pathological conditions are closely associated with this riser and non-dipper patter: increased circulating blood volume such as chronic kidney disease and congestive heart failure, autonomic nervous dysfunction such as diabetes particularly with neuropathy, and poor sleep quality such as sleep apnea syndrome. We have developed nocturnal hypoxia-triggered BP monitoring, and have detected marked midnight BP surges at the time of sleep apnea episodes. As the cardiovascular risk is increased in a sleep period in patients with obstructive sleep apnea, this surge may trigger the sleep-onset stroke. Considering that morning BP surge is the risk of stroke in a general population, the time of BP surge may be the time of increased cardiovascular risk. The perfect 24-hr BP control with diminishing exaggerated BP surge may achieve more effective prevention in stroke in hypertensive patients.

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Hypertension is also one of the major risk factors for recurrent stroke. There are many clinical studies and evidence on blood pressure control and first-ever stroke, whilst few studies have been reported so far on the secondary prevention of stroke. In chronic stage of stroke, rather strong control of blood pressure sometimes causes an increase in recurrence rate of another stroke; the fact is so-called J-curve phenomenon between blood pressure and stroke recurrence. That is why modest approach to control blood pressure has been recommended, especially in case of hemodynamic atherothrombotic brain infarction.
Recent clinical studies which have been purely aimed to witness secondary prevention of stroke; namely, PROGRESS, MOSES, and PRoFESS are briefly presented. According to these new clinical studies against stroke reccurence, the ideal blood pressure level is thought to be lower than 130/80 mmHg. Still, however, we must pay attention in those cases of aged or unsettled arterial lesions. Moreover, other metabolic risk factors should be also take into consideration to prevent cardiovascular events in the future.

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1. Introduction Cost of antihypertensive therapy has increased constantly. It accounts 7.8% in total cost of medical treatments in japan. Cost of antihypertension drugs also accounts 12.5% in all kinds of medical drugs. Especially, angiotensin receptor blocker (ARB) is discussed to be set cheaper. We verified the performance of antihypertensive therapy with our cohort study.
2. Methods We performed (1) cohort study to compare blood pressure levels and total disease's mortality in general population, (2) calculated hazard rates of antihypertensive therapy in general population, and (3) odds ratio of hypertension and antihypertensive therapy between general population and patients with stroke.
3. Results The total mortality were in lowest level until SBP/DBP of 160/100 mmHg. The hazard rate in persons who had cure of hypertension and blood pressure more than 180/110 mmHg at the baseline was increased five times than that in persons who did not have the cure. Hypertension did not show risk of stroke for older people over 60 years. Hypertensive therapy was risk of stroke for younger and elder people.
4. Conclusion Severe antihypertensive therapy will cause increase of total mortality and incidence of stroke. The target of the therapy should be restricted to people who have hypertension over 160/100 mmHg without atrial fibrillation. We should not decrease acutely blood pressure beyond 20 mmHg by drugs.

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The NIPPON DATA is a large-scale cohort study based on a representative Japanese population for men and women aged 30 years and over who were randomly selected through out Japan. The NIPPON DATA80 and the NIPPON DATA90 comprise about 10,000 and 8,000 participants, respectively. The baseline surveys were conducted in 1980 and 1990, respectively. These tow cohorts have been followed up to the year 2004 and 2005, respectively and cause specific deaths were determined by linking with the government mortality statistics in Japan with proper permission. Here, the findings of the 19-year follow-up from NIPPON DATA80 are mainly described.
For the relationship between blood pressure and stroke mortality; the higher the blood pressure level, the higher the risk of stroke mortality. Compared with the category of the optimal blood pressure level (systolic blood pressure (SBP) /diastolic blood pressure (DBP), <120/<80 mmHg) defined by the Joint National Committee, USA (JNC6), stroke mortality risk for the category of high blood pressure (SBP≥180 mmHg and/or DBP 110 mmHg) was 5-fold higher. For men, the significant graded and positive relationship of SBP with the risk of cardiovascular disease (CVD) death was observed from the young to the old age group (30-64 years, 65-74 years, and 75 years and more).
Age-adjusted stroke mortality in Japan has declined by around 80% during the period of 1965-1990, and this has been observed with a concomitant great decline in population blood pressure level.
In conclusion, it is very important for people to keep their blood pressure levels in control all along their life by maintaining healthy lifestyles.

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To monitor the effectiveness of anti-platelet therapy should be important since anti-platelet drug "resistance" or non-compliance can be evaluated clearly by it. However, the anti-platelet therapy monitoring is not widely practiced, probably due to poorly-standardized platelet function test. Among the anti-platelet drug resistance, aspirin resistance is one of the most important topics in clinical thrombosis and hemostasis field. Also, clopidogrel resistance recently became a big issue. Monitoring of anti-platelet therapy is needed for further understanding of these anti-platelet drug resistances.

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Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse effect of heparin therapy and is strongly associated with venous and arterial thrombosis. HIT should be recognized as a clinicopathologic syndrome in which clinical events (thrombocytopenia and thromboembolism) are attributed to platelet-activating antibodies (HIT Abs) that recognize platelet factor 4/heparin complexes. eTypicalf HIT occurs 5 to 14 days after heparin administration. Some patients develop HIT several days after heparin discontinuation (delayed-onset) or soon after the re-administration of heparin (rapid-onset), because of residual circulating HIT Abs due to recent heparin treatment. Thromboembolic events occur in 25 to 50% of HIT patients and the thrombotic death rate can reach 5%, if the diagnosis is delayed and/or patients are treated inappropriately. Therefore, all heparin administration including heparin flushes should be discontinued and substituted with a thrombin inhibitor such as argatroban, which was recently approved by the Japanese regulatory agency for HIT treatment. To investigate the incidence of HIT in acute stroke patients treated with heparin, we have conducted retrospective and multicenter, prospective cohort studies. Our results suggest that the incidence of HIT in Japan may be similar or slightly lower than that in Western countries. HIT diagnosis should be included in the medical management of stroke patients to avoid further complications.

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The development of thrombo-embolic events may happen when we withdraw antithrombotic agents for surgery, and bleeding becomes a big issue when it continues. As for the extraction of a tooth and the cataract surgery, antithrombotic agents should be continued. However, it is usually discontinued at major surgery or operation under the endoscope. Alternative therapy with heparin is acceptable for patients with high risk factors of thrombo-embolic events when atithrombotic agents is discontinued. Because, we can not remove any risk of thrombo-embolic evetns by the alternative therapy, informed consent is required when antithrombotic agents is discontinued.

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