OTSUKI Toshiho

Researcher Information

URL

https://kaken.nii.ac.jp/d/r/20418792.ja.html

J-Global ID

• 201501028200900089

Research Interests

• 地域医療連携   Neurological Emergency   Stroke and TIA   

Research Areas

• Life sciences / Neurology / Neurocritical Care and Stroke

Academic & Professional Experience

• 2019/10 - Today  Kindai HospitalStroke CentreChief
• 2016/10 - Today  Kindai UniversityFaculty of Medicine副センター長
• 2018/10 - 2020/09  Kindai UniversityFaculty of Medicine病院長補佐（脳卒中センター）
• 2012/07 - 2019/09  Kindai University HospitalStroke CentreProfessor
• 2005/07 - 2012/06  Hiroshima University HospitalDepartment of Neurogy and Clinical NeuroscienceAssistant Professor
• 2001/10 - 2005/06  National Cardiovascular Center HospitalDepartment of Internal Medicine, Stroke BranchMedical Doctor
• 1997/07 - 2001/09  The Hospital of Osaka University, School of MedicineDepartment of Cardiology, Neurology and StrokeMedical doctor
• 1997/01 - 1997/06  Osaka University, Graduate School of Medicine病態情報内科学研究生
• 1994/08 - 1996/12  National Institute of Neurological Disorders and Stroke, NIHStroke BranchVisiting Fellow
• 1990/09 - 1994/06  Osaka University, School of MedicineFirst Department of Internal MedicineResearch Fellow
• 1989/07 - 1990/08  Yao Municipal HospitalDepartment of Internal MedicineMedical Doctor
• 1986/07 - 1989/06  Hoshigaoka Kosei-Nenkin HospitalDepartment of Internal MedicineMedical Doctor

Education

• 1980/04 - 1986/03  Kobe Univesity  Medical School

Association Memberships

• European Stroke Organization   American Heart Association   Japanese Society of Cerebral Blood Flow and Metabolism   Japanese Society of Hypertension   THE JAPAN GERIATRICS SOCIETY   THE JAPANESE CIRCULATION SOCIETY   JAPANESE SOCIETY OF NEUROLOGY   THE JAPANESE SOCIETY OF INTERNAL MEDICINE   THE JAPAN STROKE SOCIETY   

Published Papers

• Japan Stroke Society Guideline 2021 for the Treatment of Stroke.

  Susumu Miyamoto; Kuniaki Ogasawara; Satoshi Kuroda; Ryo Itabashi; Kazunori Toyoda; Yoshiaki Itoh; Yasuyuki Iguchi; Yoshiaki Shiokawa; Yasushi Takagi; Toshiho Ohtsuki; Hiroyuki Kinouchi; Yasushi Okada; Jun C Takahashi; Hiroyuki Nakase; Wataru Kakuda

  International journal of stroke : official journal of the International Stroke Society 17 (9) 1039 - 1049 2022/04 [Refereed][Invited]
   

  The revised Japan Stroke Society Guidelines for the Treatment of Stroke were published in Japanese in July 2021. In this article, the extracted recommendation statements are published. The revision keeps pace with the great progress in stroke control based on the recently enacted Basic Act on Stroke and Cardiovascular Disease in Japan. The guideline covers the following areas: primary prevention, general acute management of stroke, ischemic stroke and transient ischemic attack, intracerebral hemorrhage, subarachnoid hemorrhage, asymptomatic cerebrovascular disease, other cerebrovascular disease, and rehabilitation.
• Thrombolysis for Acute Ischemic Stroke on Flail Elderly.

  Kei Hamanaka; Toshiho Ohtsuki

  Med.J.Kindai.Univ. Kindai Medical Association 46 (1/2) 45 - 58 2021/06 [Refereed][Invited]
   

  Ischemic stroke, the most common cause of disability to need nursing care among aged adults, keeps the vital and neurological emergent disorders for which physicians can reverse disabling deficits by making occluded cerebral vessels recanalized to supply cerebral blood flow for the ischemic brain tissue. Intravenous tissue plasminogen activator (alteplase) is the available reperfusion therapy for acute ischemic stroke, and its clinical effectiveness is critically time-dependent; either within therapeutic actual time window (<4.5 hours) after symptom onset or MRI-guided tissue time window in case of unknown time of onset with a lot of eligibility criteria for use. Clinical frailty is reported to independent risk factor for stroke and post-stroke mortality, remains common after stroke and has implication of vicious circle. Improvement of ischemic stroke following intravenous thrombolysis can be attenuated as well as hemorrhagic complication should increase with frailty, as a newly emerging independent risk factor of stroke. Covid-19 catastrophe may so jeopardize the staying-home aged vulnerable to ischemic stroke and thrombolysis treatment, that we always keep in mind the principle of “time is brain for the frail aged”.
• Baseline carotid intima-media thickness and stroke recurrence during secondary prevention with pravastatin

  Shinichi Wada; Masatoshi Koga; Kazuo Minematsu; Kazunori Toyoda; Rieko Suzuki; Tatsuo Kagimura; Yoji Nagai; Shiro Aoki; Tomohisa Nezu; Naohisa Hosomi; Hideki Origasa; Toshiho Ohtsuki; Hirofumi Maruyama; Masahiro Yasaka; Kazuo Kitagawa; Shinichiro Uchiyama; Masayasu Matsumoto

  Stroke 50 (6) 1586 - 1589 2019/06 [Refereed]
   

  Background and Purpose: As a pre-specified post hoc analysis of the Japan Statin Treatment Against Recurrent Stroke Echo Study, the 5-year stroke recurrence rate according to the baseline mean carotid intima-media thickness (IMT) with and without pravastatin treatment was investigated.
  Methods: Patients were randomly assigned to receive pravastatin 10 mg/day (pravastatin group) or control group (non-statin treatment) (1:1) for 5 years. Baseline mean IMT of the common carotid artery was measured by ultrasonography. Cox proportional hazards models were used to investigate whether the stroke [any ischemic stroke, atherothrombotic brain infarction (ATBI) or lacunar infarction] recurrence rate was different according to tertiles of baseline mean IMT.
  Results: A total of 793 patients, including 388 in the pravastatin group and 405 in the control group, were investigated. In the control group, Cox proportional hazards models showed that participants in the highest-tertile IMT group (≥0.931 mm) had a higher rate of ATBI than those in the lowest-tertile IMT group (<0.812 mm) [hazard ratio: 9.08, 95% confidence interval: 1.15-71.43]. Patients in the pravastatin group had a lower risk of ATBI than those in the control group only in the highest-tertile IMT group by the log-rank test (P-value=0.045).
  Conclusions: Long-term pravastatin administration may prevent the occurrence of ATBI in non-cardioembolic infarction patients with the highest-tertile IMT.
  Clinical Trial Registration: URL:http://www.clinicaltrials.gov. Unique identifier: NCT00361530.
• Cumulative Effects of LDL Cholesterol and CRP Levels on Recurrent Stroke and TIA

  Kazuo Kitagawa; Naohisa Hosomi; Yoji Nagai; Tatsuo Kagimura; Toshiho Ohtsuki; Hirofumi Maruyama; Hideki Origasa; Kazuo Minematsu; Shinichiro Uchiyama; Masakazu Nakamura; Masayasu Matsumoto; for the J-STARS collaborators

  J Atheroscler Thromb. 26 (5) 432 - 444 2019/05 [Refereed]
   

  Aims: To investigate the relative contribution of on-treatment low-density lipoprotein (LDL) cholesterol and
  C-reactive protein (CRP) to the risk of recurrent stroke and transient ischemic attack (TIA) in patients with history
  of ischemic stroke.
  Methods: A total of 1095 patients with non-cardioembolic ischemic stroke were randomized into two groups:
  control and patients receiving 10 mg of pravastatin per day. After excluding 18 patients who did not have baseline
  CRP data, the effects of LDL cholesterol and CRP on recurrent stroke and TIA were prospectively assessed
  in 1077 patients.
  Results: During the follow-up of 4.9±1.4 years, there were 131 recurrent stroke or TIA cases. Patients with ontreatment
  LDL cholesterol ＜120 mg/dL showed 29% reduction in recurrent stroke and TIA than those with
  LDL cholesterol ≥ 120 mg/dL (event rate 2.20 vs. 3.11 per 100 person-years, hazard ratio [HR] 0.71, 95% confidence
  interval (CI) 0.50–0.99, p= 0.048). Patients with CRP ＜1 mg/L had 32% reduction compared with that
  of patients with CRP ≥ 1 mg/L (event rate 2.26 vs. 3.40 per 100 person-years; HR 0.68, 95% CI 0.48–0.96, p=
  0.031). Although LDL cholesterol and CRP levels were not correlated in individual patients, those who achieved
  both LDL cholesterol ＜120 mg/dL and CRP ＜1 mg/L showed 51% reduction compared with that of patients
  with LDL cholesterol ≥ 120 mg/dL and CRP ≥ 1 mg/L (event rate 2.02 vs. 4.19 per 100 person-years; HR 0.49,
  95% CI 0.31–0.79).
  Conclusions: The control of both LDL cholesterol and CRP levels appears to be effective for preventing recurrent
  stroke and TIA in patients with non-cardiogenic ischemic stroke.
• Factors associated with intima-media complex thickness of the common carotid artery in Japanese noncardioembolic stroke patients with hyperlipidemia: The J-STARS echo study

  Shinichi Wada; Masatoshi Koga; Kazunori Toyoda; Kazuo Minematsu; Masahiro Yasaka; Yoji Nagai; Shiro Aoki; Tomohisa Nezu; Naohisa Hosomi; Tatsuo Kagimura; Hideki Origasa; Kenji Kamiyama; Rieko Suzuki; Toshiho Ohtsuki; Hirofumi Maruyama; Kazuo Kitagawa; Shinichiro Uchiyama; Masayasu Matsumoto; The Japan Statin Treatment Against Recurrent Stroke (J-Stars) Echo Study Collaborators

  Journal of Atherosclerosis and Thrombosis Japan Atherosclerosis Society 25 (4) 359 - 373 1880-3873 2018 [Refereed]
   

  Aims: There may be ethnic differences in carotid atherosclerosis and its contributing factors between Asian and other populations. The purpose of this study was to examine intima-media complex thickness (IMT) of the carotid artery and associated clinical factors in Japanese stroke patients with hyperlipidemia from a cohort of the Japan Statin Treatment Against Recurrent Stroke Echo Study. Methods: Patients with hyperlipidemia, not on statins, who developed noncardioembolic ischemic stroke were included in this study. Mean IMT and maximum IMT of the distal wall of the common carotid artery were centrally measured using carotid ultrasonography. Significant factors related to mean IMT and maximum IMT were examined using multivariable analysis. Results: In 793 studied patients, mean IMT was 0.89±0.15 mm and maximum IMT was 1.19±0.32 mm. Age (per 10 years, parameter estimate=0.044, p< 0.001), smoking (0.022, p=0.004), category of blood pressure (0.022, p=0.006), HDL cholesterol (per 10 mg/dl, −0.009, p=0.008), and diabetes mellitus (0.033, p=0.010) were independently associated with mean IMT. Age (per 10 years, 0.076, p=0.001), smoking (0.053, p=0.001), HDL cholesterol (−0.016, p=0.036), and diabetes mellitus (0.084, p=0.002) were independently associated with maximum IMT. Conclusion: Baseline mean and maximum values of carotid IMT in Japanese noncardioembolic stroke patients with hyperlipidemia were 0.89±0.15 mm and 1.19±0.32 mm, respectively, which were similar to those previously reported from Western countries. Age, smoking, hypertension, HDL cholesterol, and diabetes mellitus were associated with mean IMT, and those, except for hypertension, were associated with maximum IMT.
• Long-term effect of pravastatin on carotid intima-media complex thickness the J-STARS Echo Study (Japan Statin Treatment Against Recurrent Stroke)

  Masatoshi Koga; Kazunori Toyoda; Kazuo Minematsu; Masahiro Yasaka; Yoji Nagai; Shiro Aoki; Tomohisa Nezu; Naohisa Hosomi; Tatsuo Kagimura; Hideki Origasa; Kenji Kamiyama; Rieko Suzuki; Toshiho Ohtsuki; Hirofumi Maruyama; Kazuo Kitagawa; Shinichiro Uchiyama; Masayasu Matsumoto

  Stroke Lippincott Williams and Wilkins 49 (1) 107 - 113 1524-4628 2018 [Refereed]
   

  Background and Purpose-The effect of statins on progression of carotid intima-media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. This study aimed to determine the effect of low-dose pravastatin on carotid IMT in Japanese patients with noncardioembolic ischemic stroke. Methods-This is a substudy of the J-STARS trial (Japan Statin Treatment Against Recurrent Stroke), a multicenter, randomized, open-label, parallel-group trial to examine whether pravastatin reduces stroke recurrence. Patients were randomized to receive pravastatin (10 mg daily, usual dose in Japan pravastatin group) or not to receive any statins (control group). The primary outcome was IMT change of the common carotid artery for a 5-year observation period. IMT change was compared using mixed-effects models for repeated measures. Results-Of 864 patients registered in this substudy, 71 without baseline ultrasonography were excluded, and 388 were randomly assigned to the pravastatin group and 405 to the control group. Baseline characteristics were not significantly different, except National Institutes of Health Stroke Scale scores (median, 0 [interquartile range, 0-2] versus 1 [interquartile range, 0-2] P=0.019) between the 2 groups. Baseline IMT (mean±SD) was 0.887±0.155 mm in the pravastatin group and 0.887±0.152 mm in the control group (P=0.99). The annual change in the IMT at 5-year visit was significantly reduced in the pravastatin group as compared with that in the control group (0.021±0.116 versus 0.040±0.118 mm P=0.010). Conclusions-The usual Japanese dose of pravastatin significantly reduced the progression of carotid IMT at 5 years in patients with noncardioembolic stroke.
• Ischemic Stroke Mortality Is More Strongly Associated with Anemia on Admission Than with Underweight Status

  Satoshi Kubo; Naohisa Hosomi; Naoyuki Hara; Shuichiro Neshige; Takahiro Himeno; Shinichi Takeshima; Kazuhiro Takamatsu; Yutaka Shimoe; Taisei Ota; Hirofumi Maruyama; Toshiho Ohtsuki; Masaru Kuriyama; Masayasu Matsumoto

  JOURNAL OF STROKE & CEREBROVASCULAR DISEASES ELSEVIER SCIENCE BV 26 (6) 1369 - 1374 1052-3057 2017/06 [Refereed]
   

  Background: Underweight patients have recently been reported as a group with a high risk of poststroke death. Anemia also increases mortality rates in stroke patients. However, the causal associations between body weight and anemia resulting in stroke-related death remain unclear. We examined the association of weight status and hemoglobin levels with 3-month mortality after ischemic stroke. Methods: The study enrolled all consecutive patients with acute ischemic stroke and no history of stroke admitted to our hospital between January 2010 and December 2013. The patients were categorized into 4 body mass index (BMI) categories (underweight, normal-weight, overweight, and obese). Anemia was evaluated according to the World Health Organization criteria (men, <13 g/dL; women, <12 g/dL). Results: A total of 1733 acute ischemic stroke patients (149 underweight, BMI < 18.5 kg/m(2); 1076 normal-weight, BMI = 18.5-24.9 kg/m(2); 436 overweight, BMI = 25-29.9 kg/m(2); and 72 obese, BMI > 30 kg/m(2)) were included. Death within 3 months occurred in 65 patients (underweight, 10.1%; normal-weight, 3.4%; overweight, 2.3%; and obese, 5.6%). Compared to nonanemic patients, those with anemia (n = 329, 19.0%) had lower BMI (21.8 kg/m(2) versus 23.7 kg/m(2), P < .001) and higher mortality rates (9.1% versus 2.5%, P < .001). Underweight status was associated with 3-month mortality after adjusting for age, sex, comorbidities, and initial stroke severity. However, in the models that included laboratory findings, it was anemia status (odds ratio, 2.81; 95% confidence interval, 1.46-5.43), not underweight status, that was independently associated with 3-month mortality. Conclusion: Anemia on admission was associated with stroke mortality independent of underweight status.
• Fighting against acute vertebro-basilar ischemic and hemorrhagic stroke

  Toshiho Ohtsuki

  Equilibrium Research Japan Society for Equilibrium Research 76 (2) 98 - 111 0385-5716 2017/04 [Refereed]
   

  For patients presenting to the ER or clinics with sudden onset of vertigo and dizziness, immediate medical attention for suspected stroke is critical, as immediate treatment can minimize the long-term functional outcome after stroke and prevent death. Patients with cerebellar or brainstem stroke because of compromised vertebral and/or basilar arterial supply often present not only with vertigo/dizziness and nystagmus, but also with dysarthria/dysphagia, ataxia, disturbed consciousness, restriction of eye movements and hemiparesis. There are two broad types of stroke: hemorrhagic and ischemic. An ischemic stroke occurs as a result of obstruction of the blood vessel supplying blood to the brain. Atrial fibrillation can cause cardiogenic embolism, and the risk factors such as hypertension, diabetes, dyslipidemia and smoking induce arterial occlusion to lead to atherothrombotic or lacunar infarction. Hemorrhagic stroke occurs when a weakened blood vessel ruptures and blood leaks into the cerebellum and brainstem. The most common cause of such blood vessel rupture is uncontrolled hypertension or anti-thrombotic treatment. CT and MRI with diffusion-weighted imaging and MR angiography play critical and essential roles in the definitive diagnosis of ischemic or hemorrhagic stroke. The gold standard treatment for ischemic stroke is administration of a tissue plasminogen activator (t-PA) by intravenous injection via through vein in the arm. The t-PA works by dissolving the clot and improving the blood flow to the part of the brain that is deprived of blood flow. If administered within 4.5 hours of the onset, t-PA may improve the chances of complete recovery from a stroke. Another treatment option is an endovascular procedure called mechanical thrombectomy using the stent or suction after detection of the ischemic penumbra by MRI. To attenuate the brain damage caused by the intraparenchymal hematoma and its expansion, intensive blood-pressure lowering, optional hemostasis against anti-thrombotic agents or surgical removal of the hematoma could be performed immediately after serial CT. The concept that "Time is Brain" in the treatment strategy of acute stroke strongly depends upon quick triage for stroke using the A2B2C2D2 score, and an attempt at immediate diagnosis based on an accurate medical history for ABC-DEMON, neurological examination, immediate CT followed by MRI, and face-to-face cooperation and collaboration between specialists in otorhinolaryngology and cerebrovascular neurology.
• Relationship Between Infarct Volume and Prothrombin Time-International Normalized Ratio in Ischemic Stroke Patients With Nonvalvular Atrial Fibrillation

  Mari Matsumoto; Manabu Sakaguchi; Shuhei Okazaki; Kazuo Hashikawa; Tsutomu Takahashi; Masayasu Matsumoto; Toshiho Ohtsuki; Takeshi Shimazu; Toshiki Yoshimine; Hideki Mochizuki; Kazuo Kitagawa

  CIRCULATION JOURNAL JAPANESE CIRCULATION SOC 81 (3) 391 - 396 1346-9843 2017/03 [Refereed]
   

  Background: In Japan, warfarin treatment at prothrombin time-international normalized ratio (PT-INR) of 1.60-2.60 is recommended for elderly patients with nonvalvular atrial fibrillation (NVAF). But it remains unknown whether PT-INR 1.60-1.99 has a similar effect on stroke severity as a value > 2.0. The purpose of this study was to clarify the association between infarct volume and PT-INR levels. Methods and Results: The 180 patients (mean age, 76 years [SD, 10 years], 53% male) selected from 429 consecutive ischemic stroke patients admitted within 48 h of onset between 2004 and 2014 with NVAF were included. We classified them into 4 groups according to their PT-INR values on admission: no warfarin (NW), 129 patients; PT-INR < 1.60 (poor control: PC), 29 patients; PT-INR 1.60-1.99 (low-intensity control: LC), 14 patients; and PT-INR >= 2.00 (high-intensity control: HC), 8 patients. Median (interquartile range: IQR) of infarct volume was 55 mL (IQR 14-175) in the NW, 42 mL (IQR 27-170) in the PC, 36 mL (IQR 6-130) in the LC, and 11 mL (IQR 0-39) in the HC groups. The infarct volume of the HC group was significantly smaller than in the other 3 groups, but no difference existed between the LC and PC groups or the LC and NW groups. Conclusions: Warfarin control at PT-INR of 1.60-1.99 is not effective for reducing the severity of ischemic stroke in NVAF patients.
• Ability of the ankle brachial index and brachial-ankle pulse wave velocity to predict the 3-month outcome in patients with non-cardioembolic stroke

  Hayato Matsushima; Naohisa Hosomi; Naoyuki Hara; Takeshi Yoshimoto; Shuichiro Neshige; Ryuhei Kono; Takahiro Himeno; Shinichi Takeshima; Kazuhiro Takamatsu; Yutaka Shimoe; Taisei Ota; Hirofumi Maruyama; Toshiho Ohtsuki; Masaru Kuriyama; Masayasu Matsumoto

  Journal of Atherosclerosis and Thrombosis Japan Atherosclerosis Society 24 (11) 1167 - 1173 1880-3873 2017 [Refereed]
   

  Aim: Both the ankle brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are surrogates for atherosclerosis. In this study, we aimed to evaluate the ability of ABI and baPWV to predict stroke outcome in patients with first-ever non-cardioembolic stroke. Methods: This study included consecutive patients with first-ever non-cardioembolic stroke admitted within 1 week after onset to Ota Memorial Hospital between January 2011 and December 2013. Baseline characteristics and National Institutes of Health stroke scale scores at admission were noted. ABI and baPWV were evaluated within 5 days of admission. The patients were categorized according to ABI (cut-off 0.9) and baPWV (cut-off 1870 cm/s) determined using the receiver operation curve for poor outcome. Clinical outcomes were defined based on the modified Rankin scale (mRS) scores 3 months after stroke onset as good (0 and 1) or poor (2–6). Results: A total of 861 patients were available for evaluation. ABI＜0.9 and baPWV＞1870 cm/s were associated with poor outcome in the univariate analysis (p＜0.001 and p＜0.001, respectively). After adjusting for factors that showed differences between groups, ABI＜0.9 was associated with poor outcome. Among patients with ABI ≥ 0.9, higher baPWV showed a slight association with poor outcome after adjustment [odds ratio 1.46 (95% CI 0.95–2.27)]. Conclusion: Our study suggests that the stroke outcome can be predicted using ABI and to an extent using baPWV when ABI ≥ 0.9 in patients with non-cardioembolic stroke.
• Reduction in high-sensitivity C-reactive protein levels in patients with ischemic stroke by statin Treatment: Hs-CRP Sub-Study in J-STARS

  Kazuo Kitagawa; J-STARS Investigators; Naohisa Hosomi; Yoji Nagai; Tatsuo Kagimura; Toshiho Ohtsuki; Hideki Origasa; Kazuo Minematsu; Shinichiro Uchiyama; Masakazu Nakamura; Masayasu Matsumoto

  Journal of Atherosclerosis and Thrombosis Japan Atherosclerosis Society 24 (10) 1039 - 1047 1880-3873 2017 [Refereed]
   

  Aims: The pleiotropic effects of statins on recurrent stroke remain unclear. We investigated the effects of pravastatin on high-sensitivity C-reactive proteins (Hs-CRP) in ischemic stroke, and explored the impact of Hs-CRP on recurrent stroke and vascular events. Methods: This randomized open-label trial was ancillary to the J-STARS trial. One thousand and ninety-five patients with non-cardiogenic ischemic stroke were assigned to the pravastatin (n=545) or control groups (n=550). The primary and secondary endpoints were serum Hs-CRP reduction and stroke recurrence, including both ischemic and hemorrhagic ones, respectively. Onset of vascular events and each stroke subtype in relation to Hs-CRP levels were also determined. Results: In the pravastatin treatment group, Hs-CRP levels (median 711 μg/L, IQR 344–1500) significantly decreased 2 months later (median 592 μg/L, IQR 301–390), and they remained significantly lower until the end of the study. However, in the control group, baseline Hs-CRP levels were similar to those 2 months later. The reduction of Hs-CRP levels from the baseline to 2 months in the pravastatin group was statistically significant compared with the control (p=0.007). One SD increase in log-transformed Hs-CRP increased the risk of stroke recurrence (HR 1.17, 95% CI 0.97 −1.40) and vascular events (HR 1.30, 95% CI 1.12 −1.51). With an Hs-CRP cut-off of 1000 < g/L, higher Hs-CRP significantly increased the risk of recurrent stroke (HR 1.50, 95% CI 1.03−2.17) and vascular events (HR 1.68, 95% CI 1.23−2.29). Conclusion: In non-cardiogenic ischemic stroke, pravastatin treatment may reduce vascular inflammation as assessed by Hs-CRP, and higher Hs-CRP levels appeared to increase the risk of recurrent stroke and vascular events.
• Multicenter Study of Intravenous Recombinant Tissue Plasminogen Activator Infusion around Hiroshima, Japan: The Hiroshima Acute Stroke Retrospective and Prospective Registry Study

  Shiro Aoki; Naohisa Hosomi; Yoshimasa Sueda; Tomoyuki Kono; Kazuhiro Takamatsu; Hideo Ohyama; Tsuyoshi Torii; Takeshi Kitamura; Eiichi Nomura; Koichi Noda; Toshiho Ohtsuki; Masayasu Matsumoto

  JOURNAL OF STROKE & CEREBROVASCULAR DISEASES ELSEVIER SCIENCE BV 24 (12) 2747 - 2753 1052-3057 2015/12 [Refereed]
   

  Objective: Approximately 10 years have passed since intravenous (IV) recombinant tissue plasminogen activator therapy was approved in Japan. The aim of this retrospective study was to identify the effectiveness and safety of IV alteplase therapy with the Japanese original dose around Hiroshima via consideration of the patients' backgrounds, examination findings, and outcomes. Methods: All consecutive patients with ischemic stroke who received IV alteplase therapy between October 2005 and October 2010 were registered. Results: Four hundred twenty-nine patients with ischemic stroke (172 female [40.1%], mean age 73.7 +/- 11.8 years) were registered. The proportion of patients over 75 years old was 51.5% (221 patients). The median National Institutes of Health Stroke Scale (NIHSS) scores at admission were 13 (interquartile range, 9-19), and the NIHSS scores 24 hours after alteplase infusion were 8 (interquartile range, 3-15). The proportion of intracerebral hemorrhage within the initial 36 hours was 20.2% (86 patients). After the multivariate regression analysis, a history of hypertension (odds ratio = 4.14; 95% confidence interval, 1.32-14.79; P=.01) and no recanalization (odds ratio = 10.10; 95% confidence interval, 3.03-39.33; P<.0001) were independently associated with a modified Rankin Scale (mRS) score of 2 or higher at 3 months. Patients over 75 years old were not significantly associated with an intracerebral hemorrhage within the initial 36 hours and an mRS score of 2 or higher at 3 months. Conclusions: The results of our study demonstrated that IV alteplase therapy with the Japanese original dose was effective and exhibited a safety profile similar to other studies. Moreover, we should not hesitate to IV alteplase therapy simply because of advanced age. (C) 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.
• The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study

  Naohisa Hosomi; Yoji Nagai; Tatsuo Kohriyama; Toshiho Ohtsuki; Shiro Aoki; Tomohisa Nezu; Hirofumi Maruyama; Norio Sunami; Chiaki Yokota; Kazuo Kitagawa; Yasuo Terayama; Makoto Takagi; Setsuro Ibayashi; Masakazu Nakamura; Hideki Origasa; Masanori Fukushima; Etsuro Mori; Kazuo Minematsu; Shinichiro Uchiyama; Yukito Shinohara; Takenori Yamaguchi; Masayasu Matsumoto

  EBIOMEDICINE ELSEVIER SCIENCE BV 2 (9) 1071 - 1078 2352-3964 2015/09 [Refereed]
   

  Background: Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. Methods: This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpointwas the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. Finding: Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 +/- 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95% CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. Interpretation: Althoughwhether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
• Effects of Meteorological Conditions on the Risk of Ischemic Stroke Events in Patients Treated with Alteplase-HEWS-tPA

  Yoshimasa Sueda; Naohisa Hosomi; Miwako Tsunematsu; Kazuhiro Takamatsu; Eiichi Nomura; Tsuyoshi Torii; Toshiho Ohtsuki; Shiro Aoki; Tomoya Mukai; Tomohisa Nezu; Masayuki Kakehashi; Masayasu Matsumoto

  JOURNAL OF STROKE & CEREBROVASCULAR DISEASES ELSEVIER SCIENCE BV 24 (7) 1500 - 1505 1052-3057 2015/07 [Refereed]
   

  Background: Predicting a day that presents a high risk for the occurrence of ischemic stroke events may enable health professionals to prepare for emergency stroke therapy more properly. We evaluated the association between meteorological conditions and the frequency of ischemic stroke events in Japanese patients. Methods: Ischemic stroke patients (n = 299) who were treated with alteplase at 9 stroke hospitals in 3 restricted areas were examined. The daily rates of ischemic stroke events were compared with the daily mean thermo-hydrological index (THI), the atmospheric pressure, and the daily changes of these variables for the 6 days preceding an ischemic stroke event using Poisson regression analysis. Results: We trisected onset days based on the THI (low-temperature, intermediate-temperature, and high-temperature), atmospheric pressure (low-pressure, intermediate-pressure, and high-pressure), changes in THI for preceding 6 days from the previous day (cooler, unchanged-temperature, and warmer), and changes in atmospheric pressure (decreased-pressure, unchanged-pressure, and increased-pressure). The frequency of ischemic stroke was significantly higher on low-temperature or high-pressure days (risk ratio, 1.398, P = .022; risk ratio, 1.374, P = .039), on warmer-temperature days, and when atmospheric pressure varied from the day before (P < .05). There were significantly lower risks for ischemic stroke events on cooler-temperature days, and higher risks were associated with a variation in atmospheric pressure 3 days before the onset from 4 days before (P < .05). Conclusions: There were higher risks for ischemic stroke events associated with low ambient temperature, high atmospheric pressure, increased temperature, and varied atmospheric pressure. Also, atmospheric pressure variation 3 days before may be associated.
• Surgical Accessibility of the Distal Internal Carotid Artery on Carotid Endarterectomy Evaluated Using Magnetic Resonance Angiography

  Hisashi Kubota; Yasuhiro Sanada; Takayuki Tasaki; Masaharu Miyauchi; Rokuya Tanikawa; Toshiho Ohtsuki; Amami Kato

  NEUROSURGERY LIPPINCOTT WILLIAMS & WILKINS 76 (5) 633 - 637 0148-396X 2015/05 [Refereed]
   

  BACKGROUND:Magnetic resonance angiography (MRA) is helpful for preoperatively evaluating the degree of carotid stenosis, although it is not always useful for assessing surgical accessibility to the distal internal carotid artery (ICA) due to the lack of osteological information.OBJECTIVE:To demonstrate a method for evaluating the accessible distal portion of the ICA for carotid endarterectomy (CEA) using MRA.METHODS:As an indicator of the upper limit of the operating field, a line drawn from the C1 transverse process to the hyoid bone (C1-H line) was defined. The cross-point between the C1-H line and distal ICA was delineated on 3-dimensional (3-D) MRA and 3-D tomography angiography (CTA). The distance between the carotid bifurcation and C1-H line was measured in 11 patients. The exposed distal ICA was compared with the extent of intraoperative ICA exposure.RESULTS:The mean vertical distance (27.5 mm) from the carotid bifurcation to the C1-H line measured using 3-D MRA was almost the same as the distance (28 mm) evaluated on 3-D CTA. The discrepancy in distance between the 2 modalities was 1.9 1.7 mm. Furthermore, the point of the ICA across the C1-H line created on 3-D MRA was in accordance with the intraoperative measurement (28.7 mm) of the exposed ICA.CONCLUSION:The C1-H line measured on 3-D MRA is a simple and useful indicator of the distal point of the accessible ICA during CEA, especially in patients with renal dysfunction and allergies to contrast medium.
• CD34+/CD144+ circulating endothelial cells as an indicator of carotid atherosclerosis

  Takamichi Sugimoto; Naohisa Hosomi; Tomohisa Nezu; Tetsuya Takahashi; Shiro Aoki; Ikuko Takeda; Tomoya Mukai; Kazuhide Ochi; Takeshi Kitamura; Toshiho Ohtsuki; Masayasu Matsumoto

  Journal of Stroke and Cerebrovascular Diseases W.B. Saunders 24 (3) 583 - 590 1532-8511 2015/03 [Refereed]
   

  Background The relationships between the number of circulating endothelial cells (CECs) or endothelial progenitor cells (EPCs) and indicators of carotid atherosclerosis, such as the intima-media thickness (IMT) and plaque score are not well characterized in patients with chronic ischemic stroke. The objective of this study was to investigate these relationships in patients with chronic ischemic stroke and in patients with risk factors for stroke. Methods A total of 58 patients (69.6 ± 10.0 years, 21 females) with chronic ischemic stroke or with risk factors for stroke were included in this study. IMT was measured using an IntimaScope, and the numbers of CECs and EPCs were measured using flow cytometry. CECs and EPCs were defined as CD34+/CD144+ and CD34+/CD133+ cells, respectively. Results The number of CECs in patients with large artery atherosclerosis was higher than that in patients with cardioembolism or small vessel occlusion (P < .05). In contrast, there were no significant differences in the number of EPCs between groups. A positive correlation was also observed between the plaque score and the number of CECs (r2 =.139, P < .05, n = 36). Moreover, the number of CECs in patients with moderate and severe atherosclerosis (.32 ±.11/μL, n = 22) was higher than that in patients with no plaque and mild atherosclerosis (.25 ±.07/μL, n = 34, P < .05). Conclusions The number of CECs was high in patients with large artery atherosclerosis who experienced chronic ischemic stroke. And this number may reflect severity of carotid atherosclerosis.
• C1 transverse process-hyoid bone line for preoperative evaluation of the accessible internal carotid artery on carotid endarterectomy: technical note

  Hisashi Kubota; Yasuhiro Sanada; Hiromasa Yoshioka; Takayuki Tasaki; Jun Shiroma; Masaharu Miyauchi; Rokuya Tanikawa; Mitsuru Matsuki; Toshiho Ohtsuki; Amami Kato

  ACTA NEUROCHIRURGICA SPRINGER WIEN 157 (1) 43 - 48 0001-6268 2015/01 [Refereed]
   

  The preoperative imaging diagnosis of the distal portion of the internal carotid artery (ICA) is extremely important for carotid endarterectomy (CEA). Herein the authors defined a line from the C1 transverse process to the hyoid bone (C1-H line) and evaluated whether the line can be used to predict an accessible ICA in CEA. A cross point between the C1-H line and distal ICA was analyzed using three-dimensional computerized tomographic angiography (3D-CTA) in 20 patients. The C1-H line was compared to the line drawn from the mastoid process to the mandible (M-M line). Intraoperative exposure of the distal ICA was evaluated using both lines. Furthermore, the distance of each line from the C2 vertebra was measured to identify the distance difference of each line in relation to the cervical posture. A distal ICA exposed at a cross point of the C1-H line corresponded well with the intraoperative findings. The cross point between the C1-H line and distal ICA was positioned at an average of 7.0 +/- 0.7 mm cranially in comparison to the M-M line. The C1-H line showed smaller distance differences at different cervical positions than the M-M line. The C1-H line moved an average of 2.8 +/- 2.5 mm from a cervical neutral position to an extensional one in the perpendicular direction. The C1-H line measured by 3D-CTA is a simple and useful indicator of the distal ICA exposure in the preoperative diagnosis for CEA.
• Isolated Unilateral Hypoglossal Nerve Paralysis Caused by Internal Carotid Artery Dissection

  Hiroki Fujii; Toshiho Ohtsuki; Ikuko Takeda; Naohisa Hosomi; Masayasu Matsumoto

  JOURNAL OF STROKE & CEREBROVASCULAR DISEASES ELSEVIER SCIENCE BV 23 (8) E405 - E406 1052-3057 2014/09 [Refereed]
   

  We here report the case of isolated hypoglossal nerve paralysis. Magnetic resonance imaging demonstrated characteristic findings of internal carotid artery dissection that should be considered as one of the differential diagnosis of ipsilateral pure hypoglossal nerve paralysis.
• The Association between Hyperintense Vessel Sign and Final Ischemic Lesion Differ in Its Location

  Tomoyuki Kono; Hiromitsu Naka; Eiichi Nomura; Naohisa Hosomi; Shiro Aoki; Eiji Imamura; Yoshimasa Sueda; Tomohisa Nezu; Tomoya Mukai; Tomohiko Ohshita; Toshiho Ohtsuki; Shinichi Wakabayashi; Masayasu Matsumoto

  JOURNAL OF STROKE & CEREBROVASCULAR DISEASES ELSEVIER SCIENCE BV 23 (6) 1337 - 1343 1052-3057 2014/07 [Refereed]
   

  Background: The hyperintense vessel sign (HVS) on fluid-attenuated inversion recovery images can frequently be detected in patients with acute cerebral infarction attributable to large artery stenosis or occlusion. The prognostic values and clinical characteristics of HVS remain to be elucidated. The aim of this study was to evaluate the association of HVS with ischemic lesions and severity of neurologic deficit. Methods: A total of 96 consecutive acute ischemic stroke patients (54 women, median age 76.5 [range 39-97] years), who had symptomatic severe stenosis or occlusion in the proximal middle cerebral artery that was detected with magnetic resonance angiography within 24 hours of onset, were enrolled. The extent of HVS was graded by a systematic quantitative scoring system (the HVS distribution score) based on Alberta Stroke Program Early Computed Tomographic Score. Results: An HVS was detected in 89 patients (93%) at admission, and the patients who displayed wider HVS distribution scores exhibited more severe neurologic deficits at admission (P < .05). The follow-up magnetic resonance imaging, which was obtained in 79 patients (82%), was performed an average of 13 days. The association between HVS distribution score and final ischemic lesions was strongly observed (n 5 67, P < .05) but not in the patients with intravenous thrombolysis (n = 12, P = .06). Conclusions: Although the distribution of HVS reflected final ischemic lesion, this association might not apply to the patients with the thrombolysis treatment. The interpretation of HVS distribution score with acute ischemic stroke patients should be discussed dependent on thrombolysis.
• Safety Evaluation of Substituting Clopidogrel for Ticlopidine in Japanese Patients with Ischemic Stroke-Hiroshima Ticlopidine, Clopidogrel Safe Exchange Trial

  Tatsuo Kohriyama; Chie Mihara; Takakazu Yokoyama; Tsuyoshi Torii; Atsuo Yamada; Kazuhiro Takamatsu; Taisei Ota; Kouichi Noda; Satoshi Kataoka; Hijiri Ito; Eiichi Nomura; Toshiho Ohtsuki; Shiro Aoki; Tomohisa Nezu; Ikuko Takeda; Tomoya Mukai; Naohisa Hosomi; Masayasu Matsumoto

  JOURNAL OF STROKE & CEREBROVASCULAR DISEASES ELSEVIER SCIENCE BV 23 (6) 1485 - 1490 1052-3057 2014/07 [Refereed]
   

  Background: Clopidogrel is sometimes substituted for ticlopidine when cerebrovascular or cardiovascular patients develop hematologic abnormalities after ticlopidine treatment. However, the adverse event rate after the substitution to clopidogrel remains undetermined. Therefore, in this study, we aimed to define the risk of adverse events after substituting clopidogrel for ticlopidine without a washout period. Methods: We prospectively enrolled patients older than 20 years who had a history of noncardioembolic strokes, including transient ischemic attacks, were treated with ticlopidine for at least 6 months. This study was conducted from August 26, 2008, when the first patient was enrolled, to January 16, 2012, the date of the last patient examination, at 8 active stroke centers in Hiroshima, Japan. We excluded patients who had severe disabilities, evidence of cardioembolic stroke, or history of a bleeding event. Each patient received clopidogrel (either 50 mg or 75 mg) once a day in place of ticlopidine without a washout period. Follow-up exams were scheduled within 12 months after the medication substitution. The primary end point of this study was adverse events of interest, including clinically significant reduced blood cell counts, hepatic dysfunction, bleeding, and other serious side effects. Results: In this study, 110 patients were enrolled and analyzed in an intent-to-treat manner (modified intent to treat). Within the scheduled follow-up periods, 9 primary end point events were observed in separate patients. The primary end point events were observed at a rate of 8.4% per year (Kaplan-Meier method). At the time of enrolment, 16 patients met the exclusion criteria, of which 8 recovered from their abnormal hematologic results to the institutional normal limit after the substitution of ticlopidine for clopidogrel (57.4% per year). Conclusions: The adverse event rates after the substitution of ticlopidine for clopidogrel is similar to the adverse event rates of patients who were initially treated with clopidogrel. The substitution of clopidogrel for ticlopidine should be considered for patients who develop hematologic abnormalities from ticlopidine treatment. (C) 2014 by National Stroke Association
• Rationale, design, and baseline features of a randomized controlled trial to assess the effects of statin for the secondary prevention of stroke: the Japan Statin Treatment Against Recurrent Stroke (J-STARS).

  Yoji Nagai; Tatsuo Kohriyama; Hideki Origasa; Kazuo Minematsu; Chiaki Yokota; Shinichiro Uchiyama; Setsuro Ibayashi; Yasuo Terayama; Makoto Takagi; Kazuo Kitagawa; Eiichi Nomura; Naohisa Hosomi; Toshiho Ohtsuki; Takemori Yamawaki; Yoshihiro Matsubara; Masakazu Nakamura; Yoshimitsu Yamasaki; Etsuro Mori; Masanori Fukushima; Shotai Kobayashi; Yukito Shinohara; Takenori Yamaguchi; Masayasu Matsumoto

  International journal of stroke : official journal of the International Stroke Society 9 (2) 232 - 9 2014/02 [Refereed]
   

  BACKGROUND: Although statin therapy is beneficial for preventing first strokes, the benefit for recurrent stroke and its sub-types remains unknown in Asian populations. The aim of this study is to examine the role of pravastatin in the secondary prevention of stroke in Japanese patients. METHODS: This is a multicenter, randomized, open-label, parallel group study of patients with noncardioembolic ischemic stroke (atherothrombotic infarction, lacunar infarction, and infarction of undetermined etiology). All patients were diagnosed with hyperlipidemia and with a total cholesterol level between 180 and 240 mg/dl at enrollment. Patients in the treatment group receive 10 mg/day of pravastatin, and those in the control group receive no statin treatment. The primary end-point is the recurrence of stroke, including transient ischemic attack. The secondary end-points include the onset of respective stroke sub-types and functional outcomes related to stroke. The patients were enrolled for five-years and will be followed up for five-years. RESULTS: A total of 1578 eligible patients (age: 66·2 years, men: 68·8%), including 64·2% with lacunar infarction, 25·4% with atherothrombotic infarction, and 10·4% with infarction of undetermined etiology were included in this study. Lipid levels were generally well controlled (total cholesterol: 210·0 mg/dl, low density lipoprotein cholesterol: 129·5 mg/dl) at baseline. In addition, the disability of patients was relatively mild, and cognitive function was preserved in the majority of patients. CONCLUSION: This article reports the rationale, design, and baseline features of a randomized controlled trial to assess the effects of statin for the secondary prevention of stroke. Follow-ups of patients are in progress and will end in 2014.
• 広島県における心原性脳塞栓症に対するt-PA治療の現状 HARP Registry Study

  青木 志郎; 細見 直永; 末田 芳雅; 河野 智之; 大槻 俊輔; 丸山 博文; 松本 昌泰

  脳循環代謝 (一社)日本脳循環代謝学会 25 (1) 162 - 162 0915-9401 2013/11
• Alpha2-macroglobulin as a promising biomarker for cerebral small vessel disease in acute ischemic stroke patients.

  Tomohisa Nezu; Naohisa Hosomi; Shiro Aoki; Kazushi Deguchi; Hisashi Masugata; Noriko Ichihara; Hideo Ohyama; Toshiho Ohtsuki; Masakazu Kohno; Masayasu Matsumoto

  Journal of neurology SPRINGER HEIDELBERG 260 (10) 2642 - 9 0340-5354 2013/10 [Refereed]
   

  Alpha2-macroglobulin is a protease inhibitor that enhances procoagulant properties via the neutralization of plasmin, plasminogen activators and metalloproteinases. Additionally, alpha2-macroglobulin is thought to be involved in inflammatory reactions as a carrier protein for interleukin-6 (IL-6). The objective of this study was to evaluate the usefulness of alpha2-macroglobulin as a biomarker for cerebrovascular diseases. Patients with acute ischemic stroke (n = 159; 93 male and 66 female, 71.6 ± 10.3 years) and patients with no previous history of stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. White matter lesions were assessed via the fluid-attenuated inversion recovery image of magnetic resonance images using the Fazekas classification. The serum alpha2-macroglobulin levels were measured by nephelometry. The serum alpha2-macroglobulin levels at admission in patients with acute ischemic stroke were higher than those in the control patients (230.2 ± 73.7 vs. 205.0 ± 55.8 mg/dl, p = 0.009). The serum alpha2-macroglobulin levels were positively correlated with age and the severity of the white matter lesions (R (2) = 0.048, p < 0.001 and R (2) = 0.058, p < 0.001, respectively), although there was no significant association between serum alpha2-macroglobulin levels and IL-6 levels. In addition, multivariate analysis showed that increased serum alpha2-macroglobulin levels were independently associated with the severity of white matter lesions [standardized partial regression coefficient (β) 0.102, p = 0.026]. Increased serum alpha2-macroglobulin levels might be involved in the pathophysiology of acute ischemic stroke. Furthermore, serum alpha2-macroglobulin levels, which were associated with high-grade white matter lesions, may reflect the chronic pathophysiological condition of cerebral small vessel disease.
• ULTRASONOGRAPHIC REFERENCE SIZES OF THE MEDIAN AND ULNAR NERVES AND THE CERVICAL NERVE ROOTS IN HEALTHY JAPANESE ADULTS

  Takamichi Sugimoto; Kazuhide Ochi; Naohisa Hosomi; Tomoya Mukai; Hiroki Ueno; Tetsuya Takahashi; Toshiho Ohtsuki; Tatsuo Kohriyama; Masayasu Matsumoto

  ULTRASOUND IN MEDICINE AND BIOLOGY ELSEVIER SCIENCE INC 39 (9) 1560 - 1570 0301-5629 2013/09 [Refereed]
   

  The objective of this study was to identify, for practical use, ultrasonographic reference values for nerve sizes at multiple sites, including entrapment and non-entrapment sites along the median and ulnar nerves and among the cervical nerve roots. We verified reliable sites and site-based differences between the reference values. In addition, we found associations between the reference nerve sizes and several physical characteristics (gender, dominant hand, age, height, weight, body mass index [BMI] and wrist circumference). Nerves were measured bilaterally at 26 sites or levels in 60 healthy Japanese adults (29 males; age, 35.4 +/- 9.7 y; BMI, 22.3 +/- 3.6 kg/m(2); wrist circumference, 16.0 +/- 1.3 cm on the right side and 15.9 +/- 1.2 cm on the left side). The mean reference nerve sizes were 5.6-9.1 mm(2) along the median nerve, 4.1-6.7 mm(2) along the ulnar nerve and 2.14-3.39 mm among the cervical nerve roots. Multifactorial regression analyses revealed that the physical characteristics most strongly associated with nerve size were age, BMI and wrist circumference at the entrapment sites (F = 7.6, p < 0.01, at the pisiform bone level of the carpal tunnel; F = 15.1, p < 0.001, at the level of Guyon's canal), as well as wrist circumference and gender at the non-entrapment sites (F = 70.6, p < 0.001, along the median nerve; F = 24.7, p < 0.001, along the ulnar nerve). Our results suggest that the factors with the greatest influence on nerve size differed between entrapment and non-entrapment sites. Site-based differences in nerve size were determined using one-way analyses of variance (p < 0.001). Intra- and inter-observer reliability was highest for the median nerve, at both the distal wrist crease and mid-humerus; at the arterial split along the ulnar nerve; and at the fifth cervical nerve root level. No systematic error was indicated by Bland-Altman analysis; the coefficients of variation were 5.5%-9.2% for intra-observer reliability and 7.1%-8.7% for inter-observer reliability. (E-mail: sugitkmc@hiroshima-u.ac.jp) (c) 2013 World Federation for Ultrasound in Medicine & Biology.
• Brain areas associated with sentence processing: A functional MRI study and a lesion study

  Rieko Okada; Takeshi Okuda; Naoki Nakano; Kazuhiko Nishimatsu; Hiroyuki Fukushima; Minori Onoda; Toshiho Otsuki; Kazunari Ishii; Takamichi Murakami; Amami Kato

  JOURNAL OF NEUROLINGUISTICS PERGAMON-ELSEVIER SCIENCE LTD 26 (4) 470 - 478 0911-6044 2013/07 [Refereed]
   

  The aim of this study was to identify the location associated with primitive sentence processing. Processing related to generation and comprehension of sentences ("sentence processing") is postulated to be largely divided into syntactic processing (processing related to the formation of sentences and to verb reflection and particles) and verb information (argument structure and thematic role). Numerous lesion studies and functional brain imaging studies on unimpaired individuals have suggested that the left inferior frontal gyrus (IFG) is involved in syntactic processing. In addition, some studies have reported that the area from the left parietal lobe to the posterior superior temporal gyrus is involved in processing information such as argument structure and thematic role. However, studies on sentence processing using functional brain imaging have used complex sentences as tasks, raising the possibility that the results show the demands on not only language processing, but also on working memory. To clarify the brain areas involved in basic sentence processing in human language, there is a need to examine tasks involved in sentence processing that assume more primitive processing with minimal demands on working memory. The present study used sentence-completion tasks in the Japanese language that include basic sentence processing. The results showed activation in the left IFG and left parietal lobe, suggesting that these areas are involved in sentence processing. We then investigated the proportion of patients showing impaired sentence processing from among patients with aphasia and a lesion in the left IFG or from the parietal lobe to the posterior superior temporal gyrus. Four of 5 patients (80%) with lesions mostly in the left IFG showed impaired sentence processing, suggesting that this site plays a critical role in sentence processing. Of the 4 patients with lesions mostly in the area from the left parietal lobe to the posterior superior temporal gyrus, 1 patient (25%) showed impaired sentence processing. Unlike the other 3 subjects, this subject exhibited impaired recalling of verbs. This area is mainly involved in lexical-semantics and the present results suggest that verb information within that field became impaired, in turn causing impaired sentence processing. (C) 2013 Elsevier Ltd. All rights reserved.
• Cancer-associated ischemic stroke is associated with elevated d-dimer and fibrin degradation product levels in acute ischemic stroke with advanced cancer

  Tomoyuki Kono; Toshiho Ohtsuki; Naohisa Hosomi; Ikuko Takeda; Shiro Aoki; Yoshimasa Sueda; Kayoko Ishihara; Takeshi Nakamura; Takemori Yamawaki; Masayasu Matsumoto

  GERIATRICS & GERONTOLOGY INTERNATIONAL WILEY-BLACKWELL 12 (3) 468 - 474 1444-1586 2012/07 [Refereed]
   

  Aim: Although several studies have reported various causes of ischemic stroke in patients with cancer, only a few have evaluated the clinical relevance of ischemic stroke pathogenesis to cancer. The aim of the present study was to elucidate the clinical characteristics of cancer-associated ischemic stroke. Methods: We evaluated 154 ischemic stroke patients without cancer and 57 ischemic stroke patients with cancer who had either received continuous treatment for cancer within 5 years before to the onset of ischemic stroke, or who had been diagnosed with cancer within 1 year after the onset of ischemic stroke. Cancer patients were grouped into cancer-associated ischemic stroke, the conventional ischemic stroke, or other. Results: A total of 15 patients (26%) were classified into the cancer-associated ischemic stroke in cancer patients. In univariate analysis of the cancer-associated ischemic stroke and the others, there were significant differences in the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d-dimer, fibrin degradation product and hemoglobin. With multivariate regression analysis of those factors, the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d-dimer and fibrin degradation product remained as statistically independent factors, which were associated with cancer-associated ischemic stroke (n = 111, ?2 = 67.21, P < 0.0001). Conclusion: In acute ischemic stroke, the cancer-associated ischemic stroke is associated with elevated d-dimer and fibrin degradation products, even after controlling hypertension, hyperlipidemia and advanced cancer (clinical stage IV). Geriatr Gerontol Int 2012; 12: 468474.
• Relationship between 3-O-methyldopa and the clinical effects of entacapone in advanced Parkinson's disease

  Aiko Ishihara; Takafumi Miyachi; Takeshi Nakamura; Toshiho Ohtsuki; Yasuhiro Kimura; Kenji Kihira; Takemori Yamawaki; Masayasu Matsumoto

  Hiroshima Journal of Medical Sciences 60 (3) 57 - 62 0018-2052 2011/09 [Refereed]
   

  The aim of this study is to clarify the relationship between serum 3-O-methyldopa (3-OMD) and the clinical effects of entacapone. The 3-OMD and maximum serum concentration (Cmax) of levodopa were measured in 21 Parkinson's Disease patients who took 100 mg levodopa / dopa decarboxylase inhibitor. After the administration of entacapone, the 3-OMD concentration and percentage of "on" time during waking hours (% of "on" time) were studied for 8 weeks. The 3-OMD concentration was reduced by 34%, and the increase in % of "on" time was 28% at the 8th week compared with baseline. We defined the COMT-index as [baseline 3-OMD concentration] / [levodopa Cmax when 100 mg levodopa was administered alone]. The COMT-index was significantly correlated with the increase in % of "on" time at the 8th week. In conclusion, the measurement of baseline 3-OMD and levodopa pharmacokinetics is useful for predicting the clinical effects of entacapone.
• Blood pressure variability and prognosis in acute ischemic stroke with vascular compression on the rostral ventrolateral medulla (RVLM)

  Shiro Aoki; Toshiho Ohtsuki; Naohisa Hosomi; Yoshimasa Sueda; Tomoyuki Kono; Takemori Yamawaki; Masayasu Matsumoto

  Hypertension Research NATURE PUBLISHING GROUP 34 (5) 617 - 622 0916-9636 2011/05 [Refereed]
   

  One of the known causes of hypertension is vascular compression on the rostral ventrolateral medulla (RVLM). However, it remains unknown whether RVLM vascular compression causes the significant variability in blood pressure observed during acute ischemic stroke. The purpose of this study was to evaluate differences in blood pressure variability and prognosis in acute ischemic stroke patients based on the presence or absence of RVLM vascular compression. We evaluated 56 patients with acute ischemic stroke. Blood pressure was measured every 6 h for 72 h after admission and evaluated with successive variation (SV). The presence of RVLM vascular compression was evaluated using time-of-flight 3D magnetic resonance imaging. Neurological severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) at admission and 14 days after admission, and clinical improvement was determined by taking the difference in the NIHSS scores between admission and at 14 days. Patient clinical outcome was evaluated with the modified Rankin scale on discharge. Vascular compression of the RVLM was identified in 15 patients (26.8%). The proportion of patients showing clinical improvement was significantly higher in the non-compression group (odds ratio, 0.21 (95% CI0.06-0.78) P0.01). The SV value for systolic blood pressure was significantly higher in the compression group (P0.0001). We found that patients with RVLM vascular compression had a greater variability in blood pressure during the acute ischemic stroke phase, which may be related to poorer prognosis. © 2011 The Japanese Society of Hypertension All rights reserved.
• Clinical characteristics of ischemic stroke in elderly patients with cancer

  Tomoyuki Kono; Toshiho Ohtsuki; Naohisa Hosomi; Ikuko Takeda; Shiro Aoki; Kayoko Ishihara; Yoshimasa Sueda; Takeshi Nakamura; Takemori Yamawaki; Masayasu Matsumoto

  Japanese Journal of Geriatrics 48 (1) 57 - 62 0300-9173 2011 [Refereed]
   

  Aim: We classified acute ischemic stroke patients with cancer according to their causal relations, and attempted to evaluate the clinical characteristics of ischemic stroke associated with cancer. Methods: This is a retrospective study of all acute ischemic stroke patients admitted to our hospital between January 2006 and March 2009. Among acute ischemic stroke patients, we identified 30 patients with a history of cancer, or who developed cancer within 1 year from their ischemic stroke onset. There were 2 patients excluded from our evaluation because they had undergone extirpation of their cancer more than 5 years before stroke onset, and no recurrence of cancer within 5 years of stroke onset was noted. Finally, 28 patients were enrolled and evaluated in this study. Ischemic stroke was classified based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. In addition, we classified the patients according to their causal relations of ischemic stroke with cancer. Results: The median patient age was 74 years (range, 56 to 91 years) 68% of patients were men. Of these, 8 (29%) were classified into an ischemic stroke related to cancer group. There was a higher prevalence of ischemic stroke related to cancer in patients under 75 years old with clinical stage IV cancer (p=0.02). D-dimer tended to be higher in those patients with ischemic stroke related to cancer in this study (p=0.13). Conclusion: Ischemic stroke related to cancer was found more frequently in patients under 75 years old with advanced cancer. Additionally, D-dimer tended to be higher in those patients with ischemic stroke related to cancer.
• Two Cases of Cerebral Embolism Caused by Apical Thrombi in Midventricular Obstructive Cardiomyopathy

  Ikuko Takeda; Mayu Sekine; Hayato Matsushima; Naohisa Hosomi; Takeshi Nakamura; Toshiho Ohtsuki; Takemori Yamawaki; Masayasu Matsumoto

  INTERNAL MEDICINE JAPAN SOC INTERNAL MEDICINE 50 (9) 1059 - 1060 0918-2918 2011 [Refereed]
   

  Midventricular obstructive hypertrophic cardiomyopathy (MOHC) is a rare form of cardiomyopathy that was demonstrated to have caused embolic stroke in two patients. In both cases, the embolic sources of stroke were thrombi in an apical aneurysm caused by turbulent stasis of blood flow and subsequent injury of myocardial endocardium. Even without atrial fibrillation, apical aneurysm can induce emboligenic stroke in MOHC.
• Prevention of intracranial hemorrhage. III Intracranical cerebral hemorrhage. In Japanese Guidelines for the Management of Stroke 2009

  T. Ohtsuki, M. Matsumoto.

  J Stroke Cerebrovasc Dis 20 s75 - s77 2011 [Refereed][Invited]
   

  高血圧性脳内出血は機能的および生命的転帰不良であり、発症予防が重要である．高血圧に対して安定的な降圧療法が推奨される。禁煙、節酒という生活習慣も推奨される。また、血栓症予防の抗血栓療法は出血性合併症を鑑みて、適切な強度の治療を選択することが推奨される。
• The pathophysiology of prospective memory failure after diffuse axonal injury - Lesion-symptom analysis using diffusion tensor imaging

  Keita Kondo; Masaharu Maruishi; Hiroki Ueno; Kozue Sawada; Yukari Hashimoto; Tomohiko Ohshita; Tetsuya Takahashi; Toshiho Ohtsuki; Masayasu Matsumoto

  BMC NEUROSCIENCE BIOMED CENTRAL LTD 11 147  1471-2202 2010/11 [Refereed]
   

  Background: Prospective memory (PM) is one of the most important cognitive domains in everyday life. The neuronal basis of PM has been examined by a large number of neuroimaging and neuropsychological studies, and it has been suggested that several cerebral domains contribute to PM. For these activation studies, a constellation of experimental PM trials was developed and adopted to healthy subjects. In the present study, we used a widely used clinical PM assessment battery to determine the lesions attributable to PM failure, with the hypothesis that lesion-symptom analysis using diffusion tensor imaging (DTI) in subjects with diffuse axonal injury (DAI) can reveal the neuronal basis of PM in everyday life. Results: Fourteen DAI patients (age: range of 18-36, median 24) participated in this study. PM failure was scored in the range of 0-6 using three sub-tests of the Rivermead Behavioural Memory Test. The PM scores of DAI patients were in the range of 2-6 (median 4.5, inter-quartile range 2.25). The severity of axonal injury following DAI was examined using fractional anisotropy (FA), one of the DTI parameters, at voxel level in each subject. We then obtained clusters correlated with PM failure by conducting voxel-based regression analysis between FA values and PM scores. Three clusters exhibited significant positive correlation with PM score, the left parahippocampal gyrus, left inferior parietal lobe, and left anterior cingulate. Conclusions: This is the first lesion-symptom study to reveal the neuronal basis of PM using DTI on subjects with DAI. Our findings suggest that the neuronal basis of PM is in the left parahippocampal gyrus, left inferior parietal lobe, and/or left anterior cingulate. These findings are similar to those of previous activation studies with loading experimental PM tasks.
• 発熱、クモ膜下出血が先行した感染性心内膜炎の1例 アトピー性皮膚炎を誘因として

  山口 恵美; 杉本 太路; 倉重 毅志; 竹田 育子; 河野 智之; 青木 志郎; 末田 芳雅; 石原 佳代子; 中村 毅; 大槻 俊輔; 山脇 健盛; 松本 昌泰

  広島医学 広島医学会 63 (9) 674 - 679 0367-5904 2010/09 

  18歳女。生後8ヵ月にアトピー性皮膚炎と診断され、12歳時よりステロイド治療を自己中断していた。今回、発熱、意味不明な言動が出現し、その後尿失禁を認めたため当院搬送された。入院時、全身の皮膚に苔癬化を認め、神経学的にはJCS II-20であった。頭部CTで右前頭葉・中心前溝からシルビウス裂にかけて脳溝に沿って高吸収域を認め、クモ膜下出血と診断した。脳血管造影で動脈瘤は発見されず、経胸壁心エコーで疣贅は認めなかった。血液・髄液培養ではメチシリン感受性黄色ブドウ球菌が検出された。第5病日の頭部MRI拡散強調像で大脳・小脳に多発する高信号域を認め、再度の心エコーで僧帽弁に1.4cm大の疣贅を認め、感染性心内膜炎と診断した。ペニシリン投与で解熱が得られたが、経過中に右後頭葉の血腫形成や多発腎梗塞を認めた。第51病日には心尖部を最強点とする収縮期雑音を聴取し、心エコーで重症僧帽弁逆流を認めた。逆流率は徐々に悪化し、心不全症状も出現したため、第83病日に僧帽弁形成術を施行した。術後心不全症状は消失し、僧帽弁逆流は軽減した。
• Positional relationship between recurrent intracerebral hemorrhage/lacunar infarction and previously detected microbleeds

  Yoshimasa Sueda; H. Naka; T. Ohtsuki; T. Kono; S. Aoki; T. Ohshita; E. Nomura; S. Wakabayashi; T. Kohriyama; M. Matsumoto

  American Journal of Neuroradiology 31 (8) 1498 - 1503 0195-6108 2010/09 [Refereed]
   

  BACKGROUND AND PURPOSE: Although MBs, ICH, and LI are secondary to cerebral microangiopathy, it remains unclear whether the location of subsequent ICH/LI corresponds to the previous location of MBs. We performed this study to clarify the positional relationship between recurrent ICH/LI and previously detected MBs. MATERIALS AND METHODS: We evaluated patients with recurrent ICH/LI who had MBs, as shown on prior T2*-weighted MR imaging. We assessed retrospectively whether the location of recurrent ICH/LI corresponded to that of the prior MB. Patients with ICH were divided into the deep ICH group and the lobar ICH group, and the positional relationship between hematoma and previously detected MBs was evaluated. RESULTS: A total of 55 patients, including 34 with recurrent ICH and 21 with recurrent LI were evaluated. Although the location of the LI corresponded to prior MBs in only 1 patient (4.8%), the location of ICH corresponded to prior locations of MBs in 21 patients (61.8%) (OR, 32.3 95% CI, 3.86-270.3 P < .001). Among the patients with ICH, the correspondence ratio was higher in the deep ICH group (19 of 24 patients, 79.2%) than in the lobar ICH group (2 of 10 patients, 20%) (OR, 15.2 95% CI, 2.42-95.3 P < .002). CONCLUSIONS: The close positional association between recurrent ICH and prior MBs suggests that MBs represent hemorrhage-prone microangiopathy. In addition, different correspondence ratios between the deep ICH group and the lobar ICH group may be attributable to their different pathogenesis.
• 痙攣発作にて発症し、皮質から皮質下白質にかけて腫瘍状の病変を認めたHLAB54陽性の一例

  音成 秀一郎; 竹田 育子; 大下 智彦; 中村 毅; 大槻 俊輔; 山脇 健盛; 松本 昌泰

  臨床神経学 (一社)日本神経学会 50 (7) 517 - 517 0009-918X 2010/07
• Trigeminal neuropathy from perineural spread of an amyloidoma detected by blink reflex and thin-slice magnetic resonance imaging

  Yuu Yamazaki; Kazuhide Ochi; Yuki Nakata; Eisuke Dohi; Kuniki Eguchi; Satoshi Yamaguchi; Toshinori Matsushige; Takeshi Ueda; Vishwa J. Amatya; Yukio Takeshima; Takeshi Nakamura; Toshiho Ohtsuki; Tatsuo Kohriyama; Masayasu Matsumoto

  Muscle and Nerve 6 41 (6) 875 - 878 0148-639X 2010/06 [Refereed]
   

  The purpose of this study was to describe a trigeminal neuropathy caused by the perineural spread of an amyloidoma. A 62-year-old woman had an amyloidoma of the Gasserian ganglion that was hypointense on T2-weighted images; the lesion was enhanced by gadolinium on thin-slice magnetic resonance imaging. There was no evidence of systemic amyloidosis or underlying inflammatory or neoplastic disorders. Her blink reflex and thin-slice magnetic resonance imaging demonstrated that the right trigeminal nerve was involved. A rare trigeminal neuropathy resulted from the perineural spread of a primary amyloidoma that was difficult to detect by conventional magnetic resonance imaging. © 2010 Wiley Periodicals, Inc.
• Cerebral sinus thrombosis and heparin-induced thrombocytopenia in a patient with paroxysmal nocturnal hemoglobinuria

  Kayoko Ishihara-Kawase; Toshiho Ohtsuki; Sayaka Sugihara; Hitomi Tanaka; Takeshi Nakamura; Akiro Kimura; Masayasu Matsumoto

  Internal Medicine 49 (10) 941 - 943 0918-2918 2010/05 [Refereed]
   

  Paroxysmal nocturnal hemoglobinuria is a rare acquired disorder of clonal hematopoietic stem cells and it is characterized as a hypercoagulable disorder. We report a 36-year-old woman with the rare triad of paroxysmal nocturnal hemoglobinuria, cerebral sinus thrombosis triggered by infection, and rapid-onset heparininduced thrombocytopenia after resensitization of heparin. This case raises caution for heparin-induced thrombocytopenia in paroxysmal nocturnal hemoglobinuria. © 2010 The Japanese Society of Internal Medicine.
• Diagonal Ear-Lobe Crease is Correlated With Atherosclerotic Changes in Carotid Arteries

  Isha Shrestha; Toshiho Ohtsuki; Tetsuya Takahashi; Eiichi Nomura; Tatsuo Kohriyama; Masayasu Matsumoto

  CIRCULATION JOURNAL JAPANESE CIRCULATION SOC 73 (10) 1945 - 1949 1346-9843 2009/10 [Refereed]
   

  Background: The diagonal ear-lobe crease (ELC) is reported to be a marker of cardiovascular disease. Very few reports have assessed the relationship of ELC with atherosclerosis. This relationship is investigated here using a Japanese population. Methods and Results: A prospective cross-sectional Study included 212 consecutive patients. Bilateral ear lobes were checked for the ELC and this was followed by carotid ultrasonography to measure the far wall common carotid artery intima-media thickness (CCA-IMT), plaque score (PS) and plaque number (PN). Patients with ELC had significantly higher carotid IMT than controls (0.90 +/- 0.24 vs 0.77 +/- 0.15, respectively, P<0.001). ELC presence correlated significantly with carotid IMT, PS, and PN (r=0.306, P<0.0001; r=0.198, P<0.008 and r=0.221, P<0.0001, respectively), and also with age, male sex and hypertension. ELC presence and absence in mild or no PS and moderate or severe PS subgroups was significant, with a chi-squared value of 7.59 (P<0.006). In multivariate regression analysis, ELC presence correlated with CCA-IMT independently. The odds ratio for the presence of ELC in patients with CCA-IMT of <0.8 mm vs patients with CCA-IMT of >= 0.8 mm (the median value) was 0.41 (95% confidence interval, 0.22-0.76). Conclusions: The present study showed an association between ELC and increased CCA-IMT, PS, and PN. (Circ J 2009; 73: 1945-1949)
• Association between central systolic blood pressure, white matter lesions in cerebral MRI and carotid atherosclerosis

  Isha Shrestha; Tetsuya Takahashi; Eiichi Nomura; Toshiho Ohtsuki; Tomohiko Ohshita; Hiroki Ueno; Tatsuo Kohriyama; Masayasu Matsumoto

  HYPERTENSION RESEARCH NATURE PUBLISHING GROUP 32 (10) 869 - 874 0916-9636 2009/10 [Refereed]
   

  White matter hyperintensities (WMHs) observed on cerebral magnetic resonance images (MRIs) are associated with age and hypertension, suggesting a vascular mechanism of pathogenesis. Central systolic blood pressure (cSBP) correlates more closely with measures of cardiovascular disease risk than brachial pressure. We sought to determine whether cSBP correlates with WMHs and if cSBP is predictive of cerebrovascular disease. Radial applanation tonometric measurements for cSBP and augmentation index (AI) were carried out in unselected individuals undergoing carotid ultrasound. WMHs were assessed retrospectively using fluid-attenuated inversion recovery (FLAIR)-MRIs as periventricular (PVH) and deep white matter hyperintensities (DWMH), and they were rated using the Fazekas scale. A total of 179 patients, 94 (53%) men and 85 (47%) women, with a mean age of 66 +/- 13 years were included in the study. On MRI, 17, 74, 67 and 21 patients had PVH grades 0, 1, 2 and 3, respectively. Forty-eight, 69, 49 and 13 had DWMH grades 0, 1, 2 and 3, respectively. In our study population, PVH correlated with age, brachial SBP, cSBP and AI (r=0.49, 0.28, 0.23; P<0.002 and r=0.13; P<0.05, respectively). DWMH also correlated with age, brachial SBP and cSBP (r=0.41, 0.30, 0.22; P<0.003, respectively), but not with AI. cSBP values were associated with PVH/DWMH grades 2 and 3, but brachial SBP correlated only with grade 3. Mean carotid intima-media thickness (common carotid arteries (CCA)-IMT) was 0.68 +/- 0.13mm. CCA-IMT and plaque score (PS) correlated with PVH/DWMH. Multivariate regression analysis showed cSBP, age and PS to be independently associated with PVH and DWMH. Correlation of cSBP with PVH and DWMH was independent of PS. Central SBP correlated with PVH and DWMH in FLAIR-MRIs and can better predict WMHs than brachial SBP in earlier stages. Hypertension Research (2009) 32, 869-874; doi: 10.1038/hr.2009.121; published online 31 July 2009
• Adult onset Alexander disease with a novel variant (S398F) in the glial fibrillary acidic protein gene

  Yoshimasa Sueda; Tetsuya Takahashi; Kazuhide Ochi; Toshiho Ohtsuki; Michito Namekawa; Tatsuo Kohriyama; Yoshihisa Takiyama; Masayasu Matsumoto

  Clinical Neurology Societas Neurologica Japonica 49 (6) 358 - 363 0009-918X 2009 [Refereed]
   

  We report a 58-year-old woman with adult onset Alexander disease. At the age of 54 she noticed numbness in bilateral legs and at 57 she developed left sided spastic gait. Her walking difficulty was gradually worsened and followed by the development of weakness in left arm, dysarthria and dysphagia. Her mother and elder brother also had similar clinical presentations which suggested an autosomal dominant neurological disorder. With MRI findings showing localized atrophy of medulla oblongata and upper cervical cord with hyperintensities on T2-weighted image, diagnosis of adult onset Alexander disease was made. We performed genetic analysis and found novel variant (S398F) in the glial fibrillary acidic protein gene. In case of slowly progressive myelopathy with bulbar palsy of unknown origin, especially those with atrophy limited to medulla oblongata and upper cervical cord, adult onset Alexander disease should be taken into consideration.
• Association between cerebral microbleeds on T2*-weighted MR images and recurrent hemorrhagic stroke in patients treated with warfarin following ischemic stroke

  Hiroki Ueno; H. Naka; T. Ohshita; K. Kondo; E. Nomura; T. Ohtsuki; T. Kohriyama; S. Wakabayashi; M. Matsumoto

  American Journal of Neuroradiology 29 (8) 1483 - 1486 0195-6108 2008/09 [Refereed]
   

  BACKGROUND AND PURPOSE: Although accumulating evidence suggests the presence of microbleeds as a risk factor for intracerebral hemorrhage (ICH), little is known about its significance in anticoagulated patients. The aim of this study was to determine whether the presence of microbleeds is associated with recurrent hemorrhagic stroke in patients who had received warfarin following atrial fibrillation-associated cardioembolic infarction. MATERIALS AND METHODS: A total of 87 consecutive patients with acute recurrent stroke, including 15 patients with ICH and 72 patients with cerebral infarction, were enrolled in this study. International normalized ratios (INRs), vascular risk factors, and imaging characteristics, including microbleeds on T2*-weighted MR images and white matter hyperintensity (WMH) on T2-weighted MR images, were compared in the 2 groups. RESULTS: Microbleeds were noted more frequently in patients with ICH than in patients with cerebral infarction (86.7% versus 38.9%, P = .0007). The number of microbleeds was larger in patients with ICH than in patients with cerebral infarction (mean, 8.4 versus 2.1 P = .0001). INR was higher in patients with ICH than in patients with cerebral infarction (mean, 2.2 versus 1.4 P < .0001). The frequency of hypertension was higher in patients with ICH than in patients with cerebral infarction (86.7% versus 45.8%, P = .0039). Multivariate analysis revealed that the presence of cerebral microbleeds (odds ratio, 7.383 95% confidence interval, 1.052-51.830) was associated with ICH independent of increased INR and hypertension. CONCLUSION: The presence of cerebral microbleeds may be an independent risk factor for warfarin-related ICH, but more study is needed because of strong confounding associations with elevated INR and hypertension.
• 経口腔頸部血管超音波検査(Transoral Carotid Ultrasonography)の有用性

  河野 智之; 大槻 俊輔; 青木 志郎; 末田 芳雅; 野村 栄一; 郡山 達男; 松本 昌泰

  広島医学 広島医学会 61 (7) 563 - 566 0367-5904 2008/07 

  経口腔頸部血管超音波検査を行った患者21名(男17名、女4名、31〜82歳)を対象に、頸部血管超音波検査とMR血管造影(MRA)とのギャップを補う検査法として経口腔頸部血管超音波検査を紹介し、また頸部血管超音波検査と比較検討した。経口腔頸部血管超音波検査は頸部血管超音波検査で観察困難な内頸動脈分岐部高位症例や頭蓋外内頸動脈遠位部狭窄症例に対し、安定した評価が可能であった。内頸動脈解離などの病態の経時的変化が重要な症例に対し経口腔頸動脈超音波検査はベッドサイドで簡便に行うことができ有用であった。経口腔頸部血管超音波検査は口腔からのアプローチであるが非侵襲的に評価でき、頸部血管超音波検査とMRAのギャップを補う検査法として有用であった。
• 【アテローム血栓症の予防と管理】Diagnosis アテローム血栓症のリスク評価

  青木 志郎; 大槻 俊輔; 松本 昌泰

  Vascular Lab (株)メディカ出版 4 (6) 610 - 613 1349-4023 2007/12
• Siah-1 facilitates lubiquitination and degradation of factor inhibiting HIF-1 alpha (FIH) (Retracted article. See vol. 388, pg. 618, 2009)

  Hiromasa Fukuba; Hiroshi Yamashita; Yoshito Nagano; Hong Guo Jin; Masanori Hiji; Toshiho Ohtsuki; Tetsuya Takahashi; Tatsuo Kohriyama; Masayasu Matsumoto

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 353 (2) 324 - 329 0006-291X 2007/02 [Refereed]
   

  Hypoxia-inducible factor-1 alpha (HIF-1 alpha) has a central role in neuroprotective responses to hypoxia in the brain. Hydroxylation of HIF-1 alpha by prolyl-hydroxylase PHD and aspargynyl-hydroxylase FIH (factor inhibiting HIF-1 alpha) causes proteasomal degradation and transcriptional inhibition of HIF-1 alpha. Siah ubiquitin ligases regulate the abundance of PHD via targeting for proteasomal degradation. The present study identified Siah-1 as a binding partner for another hydroxylase FIH. Siah-1 and FIH coimmunoprecipitated each other in mammalian cells. Siah-1 was found both to interact with the JmjC domain of FIH through its substrate-binding domain and to specifically ubiquitinate FIH via its RING finger domain. Siah-1 facilitated FIH degradation via the ubiquitin-proteasome pathway under hypoxic conditions. Such findings suggest that Siah ubiquitin ligases might play a role as up-stream regulators of both hydroxylases for HIF-1 alpha, i.e., PHD and FIH, by targeting them for proteasomal degradation, leading to increased HIF-1 alpha abundance, and transcriptional activity in hypoxia. (c) 2006 Elsevier Inc. All rights reserved.
• Hypoxia-induced upregulation of endothelial small G protein RhoA and Rho-kinase/ROCK2 inhibits eNOS expression

  Hong Guo Jin; Hiroshi Yamashita; Yoshito Nagano; Hiromasa Fukuba; Masanori Hiji; Toshiho Ohtsuki; Tetsuya Takahashi; Tatsuo Kohriyama; Kozo Kaibuchi; Masayasu Matsumoto

  NEUROSCIENCE LETTERS ELSEVIER IRELAND LTD 408 (1) 62 - 67 0304-3940 2006/11 [Refereed]
   

  The small G protein RhoA and its downstream effector Rho-kinase/ROCK2 play an important role in regulation of various vasculature cellular functions. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is an important mediator of vascular homeostasis and cerebral blood flow. Using the human endothelial cell line HUVEC, the present study investigated the role of RhoA and Rho-kinase in endothelial eNOS protein expression under hypoxic conditions as an in vitro model of ischemia. RhoA protein levels in HUVEC were low under normoxic conditions, but were significantly increased after 5 h of hypoxia. Endothelial Rho-kinase expression was not detected until after 3 It of hypoxia; such expression remained significantly increased after 5 h. On the other hand, endothelial eNOS expression was similar after 3 h of hypoxia, but was significantly decreased after 5 h. The hypoxia-induced decrease in eNOS expression was significantly enhanced by expression of the constitutively active form of RhoA and significantly inhibited by suppression of RhoA expression by small interfering RNA. The hypoxia-induced decrease in eNOS expression was significantly inhibited when endogenous Rho-kinase activation was inhibited by Rho-binding domain expression. Furthermore, the hypoxia-induced decrease in eNOS expression was significantly enhanced by expression of the constitutively active form of Rho-kinase. Since expression and activation of RhoA and Rho-kinase inhibit eNOS expression in endothelial cells, attempts to down-regulate RhoA and Rho-kinase by multiple drugs, such as statins or Rho-kinase inhibitors, might provide endothelial and cardiovascular benefits through upregulation of eNOS. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
• Embolic cerebral infarction caused by intraluminal thrombus in the carotid siphon successfully treated with combination of anticoagulant and antiplatelet drugs

  H Yamagami; K Kitagawa; T Ohtsuki; M Matsumoto; M Hori

  CIRCULATION JOURNAL JAPANESE CIRCULATION SOCIETY 69 (9) 1147 - 1149 1346-9843 2005/09 [Refereed]
   

  A 54-year-old-man experienced serial ischemic embolic strokes and retinal artery embolism in the left carotid territory. In the acute phase, intraluminal thrombus in the left carotid siphon and frequent microembolic signals (MES) in the left middle cerebral artery were detected with magnetic resonance angiography (MRA) and transcranial Doppler (TCD). The patient was initially treated with only heparin for 3 days; however, more than 30 MES per 30 min were still detected. After adding ticlopidine as an antiplatelet therapy, MES were suppressed completely. After starting combination therapy of heparin (later warfarin) and ticlopidine, repeated MRA confirmed resolution of carotid thrombus and ischemic stroke did not recur. For management of intraluminal thrombus in the carotid artery, MES with TCD was useful in evaluating the risk of distal embolism. Combination treatment with anticoagulants and ticlopidine can both resolve the thrombus and prevent distal embolism.
• Critical analysis of hemodynamic insufficiency by head-up tilt in patients with carotid occlusive disease

  Manabu Sakaguchi; Kazuo Kitagawa; Naohiko Oku; Masao Imaizumi; Hiroshi Yamagami; Toshiho Ohtsuki; Kohji Matsushita; Hidetaka Hougaku; Masayasu Matsumoto; Jun Hatazawa; Masatsugu Hori

  Circulation Journal 69 (8) 971 - 975 1346-9843 2005 [Refereed]
   

  Background: The objective of this study was to evaluate the diagnostic value of the head-up-tilt (HUT) test for detecting cerebral hemodynamic insufficiency in patients with major cerebral artery occlusion disease because such patients may benefit from extracranial - intracranial bypass surgery. Methods and Results: In 13 cases of transient ischemic attacks in patients with carotid or middle cerebral artery occlusive disease, the HUT test was used to determine whether or not the symptoms appear during induced hypotension before investigating cerebral hemodynamics with positron emission tomography. Three of the 13 patients showed focal symptoms such as hemiparesis and limb shaking during the HUT test. In all 3 patients, the oxygen extraction fraction (OEF) increased beyond 53.3% (ie, misery perfusion), whereas only 2 of the other 10 patients without focal symptoms showed an increase in OEF during HUT. Conclusions: The HUT test was highly useful for screening patients with cerebral hemodynamic insufficiency in carotid occlusive disease.
• Circulating adhesion molecules are correlated with ultrasonic assessment of carotid plaques

  Hiroyuki Hashimoto; Kazuo Kitagawa; Keisuke Kuwabara; Hidetaka Hougaku; Toshiho Ohtsuki; Masayasu Matsumoto; Masatsugu Hori

  Clinical Science 104 (5) 521 - 527 0143-5221 2003/05 [Refereed]
   

  The relationship between levels of circulating intercellular cell-adhesion molecule-1 (cICAM-1) or P-selectin (cP-selectin) and the severity of carotid atherosclerosis was examined in 301 outpatients undergoing duplex ultrasonographic examination. Carotid plaque was defined as an intima-media thickness greater than 1.0 mm, and a plaque score (PS) was calculated from the plaque thickness in both carotid arteries. Multivariate analysis demonstrated significant positive associations between cICAM-1 and the number of plaques [β = 0.11 confidence interval (CI), 0.007-0.213], maximum intima-media thickness (β = 0.11 CI, 0.01-0.219), and PS (β = 0.10 CI, 0.001-0.205). In contrast, no significant association was found for cP-selectin, cP-selectin did not increase until atherosclerosis was advanced (PS > 10), showing a marked increase in patients with ≥ 50% stenosis. The circulating levels of both proteins are related to real measurements of plaque formation in the carotid arteries independently of classical risk factors. Marked elevation of cP-selectin occurs in advanced carotid atherosclerosis after gradual elevation of cICAM-1.
• Hypertension associated with reduced plasma thrombomodulin levels and a hypercoagulable state in rats

  Kazuyoshi Sawada; Mitsuru Naiki; Hisashi Yago; Kohji Matsushita; Toshiho Ohtsuki; Kazuo Kitagawa; Masayasu Matsumoto; Masatsugu Hori

  Clinical and Experimental Hypertension 25 (2) 73 - 84 1064-1963 2003/02 [Refereed]
   

  The plasma thrombomodulin (TM) level, an indicator of systemic endothelial cell damage, was measured in spontaneously hypertensive rats (SHR), deoxycorticosteron acetate (DOCA)-induced hypertensive rats and normotensive Wistar-Kyoto (WKY) rats to clarify its changes in hypertension. Plasma TM levels, measured by enzyme-linked immuno-sorbent assay, decreased with aging (5-20-weeks-old) in both SHR and WKY, and they were lower in SHR than age-matched WKY in all ages examined. Deoxycorticosteron acetate-induced hypertensive WKY also showed decreased TM levels compared with normotensive WKY. Accelerated coagulation and fibrinolysis shown by the increases in thrombin-antithrombin complex (TAT) and D-dimer levels were observed in both groups of hypertensive rats. These results suggest that hypertension may decrease plasma TM levels and induce a hypercoagulable state in rats.
• Equivalence of plaque score and intima-media thickness of carotid ultrasonography for predicting severe coronary artery lesion

  M Sakaguchi; K Kitagawa; Y Nagai; H Yamagami; K Kondo; K Matsushita; N Oku; H Hougaku; T Ohtsuki; T Masuyama; M Matsumoto; M Hori

  ULTRASOUND IN MEDICINE AND BIOLOGY ELSEVIER SCIENCE INC 29 (3) 367 - 371 0301-5629 2003 [Refereed]
   

  Carotid atherosclerosis appears to be predictive of myocardial infarction. Because several sonographical indices are available for carotid ultrasound (US), we compared "blindly" the potential utilities of those indices for predicting coronary lesions in 270 patients. Carotid atherosclerosis was evaluated by the following four indices: plaque score (PlaS), intima-media thickness (IMT) of common carotid artery (CCA-IMT), IMT of bulb to internal carotid artery (Bulb-ICA-IMT), and combined IMT measurement from all segments. The existence of coronary lesions was diagnosed by > 50% stenosis in diameter in coronary arteries. All indices were associated with coronary lesions independent of risk factors. By receiver-operating characteristic (ROC) curve analyses, ROC areas defined by Bulb-ICA-IMT (0.76 to 0.86), combined IMT (0.76 to 0.86) and PS (0.76 to 0.87) were greater than that defined by CCA-IMT (0.64 to 0.76). In conclusion, PlaS, Bulb-ICA-IMT and combined IMT are equally effective and could be better than CCA-IMT for predicting coronary lesions in a population with cardiovascular risk. (C) 2003 World Federation for Ultrasound in Medicine Biology.
• Prominent matched hypoperfusion in an intact cerebellum after a solitary middle cerebellar peduncle infarct

  Masashi Takasawa; Kazuo Kitagawa; Toshiho Ohtsuki; Naohiko Oku; Kazuo Hashikawa; Saburo Sakoda; Masatsugu Hori; Masayasu Matsumoto

  American Journal of Neuroradiology 23 (8) 1356 - 1358 0195-6108 2002/09 [Refereed]
   

  We examined the cerebellar metabolism of a 61-year-old man with a small infarct in the left middle cerebellar peduncle and an intact cerebellum. Positron emission tomographic images obtained 28 days after onset showed prominent hypoperfusion and hypometabolism (almost 50% below the normal level) in the left cerebellar hemisphere. This case report shows that neural deafferentation may cause prominent hypometabolism without morphologic changes in the cerebellum. An arrest in synaptic activity may be the most important factor for the adaptive decrease in oxygen metabolism seen in ischemic brain.
• Detection of misery perfusion with split-dose 123I-iodoamphetamine single-photon emission computed tomography in patients with carotid occlusive diseases

  Masao Imaizumi; Kazuo Kitagawa; Kazuo Hashikawa; Naohiko Oku; Tadamasa Teratani; Masashi Takasawa; Takuya Yoshikawa; Piao Rishu; Toshiho Ohtsuki; Masatsugu Hori; Masayasu Matsumoto; Tsunehiko Nishimura

  Stroke 33 (9) 2217 - 2223 0039-2499 2002/09 [Refereed]
   

  Background and Purpose - Patients with carotid occlusive disease and stage 2 cerebral hemodynamic failure, characterized by an increased oxygen extraction fraction (OEF) as measured by positron emission tomography (PET) and otherwise known as misery perfusion, have a high risk of cerebral ischemia and subsequent stroke. In clinical practice, the detection of patients with misery perfusion through the use of widely available, noninvasive, and cost-effective modalities such as single-photon emission computed tomography (SPECT) is extremely important. Methods - We evaluated the relationships between the regional hemodynamic status of cerebral circulation, measured with split-dose [123I] N-isopropyl-p-iodoamphetamine SPECT (123I-IMP SPECT) and an acetazolamide challenge, and hemodynamic parameters, including OEF measured with PET, in 27 patients with both unilateral and bilateral carotid occlusive diseases. Results - A significant negative correlation was found between the SPECT-measured cerebrovascular reserve after acetazolamide administration and both the PET-measured OEF and cerebral blood volume. Neither the cerebrovascular reserve nor the cerebral blood flow index, when expressed as a SPECT-measured cerebrum-to-cerebellum ratio, was useful for detecting lesions with an elevated OEF. However, a combination of the cerebrovascular reserve and cerebral blood flow index showed high sensitivity, specificity, and positive predictive value for the detection of misery perfusion. Conclusions - Our study suggests that split-dose 123I-IMP SPECT with an acetazolamide challenge could be useful for screening patients with misery perfusion in carotid occlusive diseases.
• Protective effect of apolipoprotein E against ischemic neuronal injury is mediated through antioxidant action

  K Kitagawa; M Matsumoto; K Kuwabara; KI Takasawa; S Tanaka; T Sasaki; K Matsushita; T Ohtsuki; T Yanagihara; M Hori

  JOURNAL OF NEUROSCIENCE RESEARCH WILEY-LISS 68 (2) 226 - 232 0360-4012 2002/04 [Refereed]
   

  Recent studies have demonstrated that apolipoprotein E (APOE) deficiency worsened neuronal injuries after transient focal and global cerebral ischemia. However, the molecular mechanism underlying the protective effect of APOE remains uncertain, even though several mechanisms, including excitotoxicty, free radicals, and apoptosis, have been cited as causes of selective neuronal vulnerability in cerebral ischemia. In the present study, we first compared the vulnerability of cultured neurons prepared from APOE-knockout mice upon exposure to glutamate, hydrogen peroxide, and staurosporine. No significant difference in cell viability was observed after exposure to glutamate or staurosporine between APOE-deficient and wild-type mice. However, exposure to hydrogen peroxide significantly increased the level of cell death in APOE-deficient mice compared with that in wild-type mice. After transient forebrain ischemia for 12 min, APOE-deficient mice showed more neuronal death than wild-type mice. Pretreatment of APOE-deficient mice with vitamin E for 2 months markedly reduced neuronal death caused by ischemia. The results suggest that APOE exerted its neuroprotective effect against ischemia through its antioxidant action but not through mitigation of glutamate toxicity or blocking of apoptosls. (C) 2002 Wiley-Liss, Inc.
• Involvement of ICAM-1 in the progression of atherosclerosis in APOE-knockout mice

  K Kitagawa; M Matsumoto; T Sasaki; H Hashimoto; K Kuwabara; T Ohtsuki; M Hori

  ATHEROSCLEROSIS ELSEVIER SCI IRELAND LTD 160 (2) 305 - 310 0021-9150 2002/02 [Refereed]
   

  Recent clinical evidence has indicated that the level of soluble ICAM-1 (sICAM-1) is correlated with the severity of atherosclerosis and can predict future cardiovascular events. Here, using apolipoprotein E (APOE)-deficient mice, we investigated the level of sICAM-1 in parallel with endothelial ICAM-1 expression and aortic atherosclerosis. We also examined the effect of ICAM-1 deficiency during the progression of atherosclerosis using double knockout mice. The level of sICAM-1 increased significantly in parallel with the progression of atherosclerosis in APOE-deficient mice. while the sICAM-1 level remained constant in wild-type mice from 3 to 10 months of age. ICAM-1 staining was detected in virtually all endothelial cells, however, ICAM-1 was expressed strongly in the endothelium overlying atheromatous palque in APOE-deficient mice. Deficiency of ICAM-1 in APOE-deficient nice significantly reduced lesions after 5 and 10 months. The present study supported the notion that the level of sICAM-1 is closely related with the severity of atherosclerosis and cardiovascular events, and also suggested that inhibition of ICAM-1 can delay the progression of atherosclerosis, (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
• Synergistic induction of HSP40 and HSC70 in the mouse hippocampal neurons after cerebral ischemia and ischemic tolerance in gerbil hippocampus

  S Tanaka; K Kitagawa; T Ohtsuki; Y Yagita; K Takasawa; M Hori; M Matsumoto

  JOURNAL OF NEUROSCIENCE RESEARCH WILEY-LISS 67 (1) 37 - 47 0360-4012 2002/01 [Refereed]
   

  An ischemia-induced gene was screened using a differential display technique in mouse transient forebrain ischemia. One of the ischemia-responsive clones was found to encode mouse hsp40. HSP40 has a critical regulatory function in the HSC70 ATPase activity. Expression of hsp40 mRNA was low in the nonischemic mouse hippocampus, but it was significantly upregulated 4 hr after ischemia by Northern blot analysis. In situ hybridization analysis revealed hsp40 mRNA induction in the neuron. HSP40 protein expression was also enhanced in the pyramidal and dentate granular neurons from 2 to 4 days after ischemia. The temporal expression and distribution profile of HSC70 protein was similar to that of HSP40, and both proteins were colocalized in ischemic hippocampal neurons. In the gerbil transient forebrain ischemia model, both HSP40 and HSC70 proteins were expressed strongly in ischemia-resistant CA3 neurons and dentate granule cells 1 day after 5 min ischemia, but were not expressed in vulnerable CA1 neurons. However, both proteins were in parallel expressed in the tolerance-acquired CA1 neurons. Based on the current observation that both HSP40 and HSC70 proteins were synergistically expressed in the ischemia-resistant and tolerance-acquired neurons, cochaperone HSP40 may play a significant role against postischemic neuronal response and lead to cell survival through interaction with simultaneously induced HSC70. (C) 2002 Wiley-Liss, Inc.
• Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo

  T. Mabuchi; K. Kitagawa; K. Kuwabara; K. Takasawa; T. Ohtsuki; Z. Xia; D. Storm; T. Yanagihara; M. Hori; M. Matsumoto

  Journal of Neuroscience 21 (23) 9204 - 9213 0270-6474 2001/12 [Refereed]
   

  Although accumulating evidence indicates that cAMP response element-binding protein (CREB) phosphorylation mediates not only synaptic plasticity but also survival of certain neurons, it remains uncertain whether CREB phosphorylation induced after metabolic insult leads to CRE-mediated gene transcription and is involved in cell survival or not. In the present study, we clarified that (1) CREB phosphorylation and ischemic tolerance induced after preconditioning ischemia in the hippocampal neurons was abolished by MK801 administration in gerbil global ischemia model, (2) CREB phosphorylation induced after exposure to glutamate in cultured neurons was inhibited by removal of extracellular calcium, by MK801 and by an inhibitor of calcium-calmodulin-dependent protein kinase (CaMK) II and IV, (3) inhibitor of CaMK II-IV or CRE-decoy oligonucleotide suppressed upregulation of BCL-2 expression and accelerated neuronal damage after exposure to glutamate, and (4) CREB phosphorylation induced in the hippocampal neurons after ischemia and in cultured neurons after exposure to glutamate was followed by CRE-mediated gene transcription in transgenic mice with a CRE-LacZ reporter. Our results suggest that CREB phosphorylation in neurons after ischemia and exposure to glutamate is induced by NMDA receptor-gated calcium influx and subsequent activation of CaMK II-IV and that CREB phosphorylation after metabolic stress might show a neuroprotective response through CRE-mediated gene induction.
• Delayed, but marked, expression of apolipoprotein E is involved in tissue clearance after cerebral infarction

  K Kitagawa; M Matsumoto; K Kuwabara; T Ohtsuki; M Hori

  JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LIPPINCOTT WILLIAMS & WILKINS 21 (10) 1199 - 1207 0271-678X 2001/10 [Refereed]
   

  Clearance of infarct tissue would be an important process for tissue repair after a stroke. Delayed clearance may hamper reconstitution of the blood-brain barrier and glial boundary formation. Recent growing evidence has indicated that apolipoprotein E (APOE), a major apoprotein, plays an important role in lipid transport and homeostasis in the brain. The tissue in the infarction contains abundant lipids must be removed for tissue clearance. In the current study, the authors investigated APOE expression after focal ischemia and the functional role of APOE in tissue clearance using APOE-knockout mice. Expression of APOE was delayed, but marked, in immunohistochemistry and immunoblotting 7 days after permanent focal ischemia. Macrophages were found to express APOE in the infarct center. Infarct size was similar after focal ischemia between wild-type and APOE-knockout mice, although there was no APOE protein expression in knockout mice. However, clearance of infarct tissue 2 weeks after ischemia was significantly delayed in APOE-knockout mice compared with wild-type mice. The current study supports current thinking that APOE is a key molecule for tissue remodeling in the brain. Clearance of damaged tissue may be one of the important functions of APOE in the brain.
• Significance of earlier carotid atherosclerosis for stroke subtypes

  Y Nagai; K Kitagawa; M Sakaguchi; Y Shimizu; H Hashimoto; H Yamagami; M Narita; T Ohtsuki; M Hori; M Matsumoto

  STROKE LIPPINCOTT WILLIAMS & WILKINS 32 (8) 1780 - 1785 0039-2499 2001/08 [Refereed]
   

  Background and Purpose-In addition to advanced stenosis, earlier stages of carotid atherosclerosis are associated with the risk for stroke. However. the significance has not been established for specific stroke subtypes. This study examines the association of earlier carotid atherosclerosis with stroke subtypes. Methods-The subjects comprised 1059 patients (mean +/- SID age, 62 +/- 11 years) with < 60% carotid stenosis. With the use of ultrasound, carotid atherosclerosis was evaluated by the plaque score. as defined by the sum of all plaque heights in bilateral carotid arteries. On the basis of neurological signs and symptoms, medical history, and brain MRI, we diagnosed stroke and its subtypes as follows: no stroke (n=738), atherothrombotic infarction (AI) (n=56), lacunar infarction (LI) (n=117), cardioembolic infarction (n=65), cerebral hemorrhage (n=26), and other or unclassified stroke (n=57). Results-The plaque score was higher in Al (10.5 +/-5.9) and LI (6.0 +/-5.1) groups than in the no-stroke group (4.3 +/-4.9) (both P <0.05), although it was similar between other stroke groups and the no-stroke group. Each I SID greater plaque score was associated with 2.5-fold (95% Cl, 2.0 to 3.2) higher risk for Al and 1.4-fold (95% CI, 1.2 to 1.7) higher risk for LI compared with the no-stroke group. When we adjusted for cardiovascular risk factors, plaque score remained significantly associated with Al but not with LI. By receiver operating characteristic curve analyses, the receiver operating characteristic area for Al (0.81 to 0.86) was greater than that for LI (0.62 to 0.67) when we used plaque score either alone or in combination with cardiovascular risk factors. Conclusions-Although evaluation of carotid atherosclerosis may aid in the risk assessment for Al and LI, the benefit appears to be greater for Al.
• Induction of the HSP110/105 family in the rat hippocampus in cerebral ischemia and ischemic tolerance

  Y Yagita; K Kitagawa; T Ohtsuki; S Tanaka; M Hori; M Matsumoto

  JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LIPPINCOTT WILLIAMS & WILKINS 21 (7) 811 - 819 0271-678X 2001/07 [Refereed]
   

  Recently, the authors isolated a novel gene of the HSP110 family, ischemia responsive protein 94 kDa (irp94), and demonstrated the expression of this gene after transient forebrain ischemia. In the current study, the authors investigated the expression profiles of all HSP110 family members including hsp110/105 and osp94/apg-1, after transient forebrain ischemia using rat four-vessel occlusion model. Among three members of the HSP110 family, induction of hsp 110/105 was the most prominent after ischemia. hsp110/105 mRNA expression was clearly enhanced from 4 to 24 hours after a 6-minute or longer ischemic period. First, hsp110/105 mRNA expression was induced in the dentate gyrus, and later in the pyramidal layer. HSP110/105 protein expression also was enhanced by a 6-minute or longer period of ischemia. Profiles of HSP110/105 expression after ischemia were similar to those of inducible HSP70. After transient forebrain ischemia for 10 minutes, HSP110/105 protein was induced in the dentate gyrus and the CA3 pyramidal layer, but not in the CA1 pyramidal neurons. However, 6 minutes of ischemia induced the HSP110/105 protein, as well as the HSP70 protein, in the CAI region. CA1 pyramidal neurons expressing HSP110/105 acquired tolerance against subsequent severe ischemia. In conclusion, HSP110/105 showed the most prominent induction after ischemia among the three HSP110 gene family members. Colocalization of HSP110/105 and HSP70 in the CA1 neurons that acquired tolerance suggested that induced HSP110/105 might contribute to ischemic tolerance together with HSP70.
• Neurogenesis by progenitor cells in the ischemic adult rat hippocampus

  Yoshiki Yagita; Kazuo Kitagawa; Toshiho Ohtsuki; Ken-Ichiro Takasawa; Takaki Miyata; Hideyuki Okano; Masatsugu Hori; Masayasu Matsumoto

  Stroke Lippincott Williams and Wilkins 32 (8) 1890 - 1896 0039-2499 2001 [Refereed]
   

  Background and Purpose - Recently, there has been great interest in adult neurogenesis. We investigated whether transient forebrain ischemia could influence the proliferation of neuronal progenitor in the subgranular zone (SGZ) of the rat hippocampus and whether aging could influence the neurogenesis after ischemia. Methods - Male Wistar rats were subjected to 4-vessel occlusion model. We used a bromodeoxyuridine (BrdU) labeling method to identify the postproliferation cells and double-immunostaining with confocal microscopy to determine the cell phenotype. Results - The number of BrdU-positive cells in the SGZ increased ≈ 5.7-fold 8 days after ischemia, compared with the control. BrdU-positive cells formed clusters, which suggested that these cells had divided from an original progenitor cell, and expressed Musashi I (Msi I), a marker of neural stem/progenitor cells. Although astrocytes also expressed Msi 1 in the adult brain, Msi1-positive cells that formed clusters in the SGZ did not express glial fibrillary acidic protein, an astrocyte marker. About 70% of all BrdU-positive cells in the SGZ represented the neuronal phenotype 4 weeks after the BrdU injection. Although proliferation of progenitor cells was stimulated in both young and older animals, aging accelerated the reduction in newborn cells after ischemia. Conclusions - Our results indicate that ischemic stress stimulated the proliferation of neuronal progenitor cells in the SGZ of both young and old rats but resulted in increased neurogenesis only in young animals. Our findings will be important in developing therapeutic intervention to enhance endogenous neurogenesis after brain injury.
• Transient crossed cerebellar diaschisis following thalamic hemorrhage

  Masashi Takasawa; Kazuo Hashikawa; Toshiho Ohtsuki; Masao Imaizumi; Naohiko Oku; Kazuo Kitagawa; Masatsugu Hori; Masayasu Matsumoto

  Journal of Neuroimaging SAGE Publications Inc. 11 (4) 438 - 440 1051-2284 2001 [Refereed]
   

  This report concerns a 65-year-old right-handed woman with cerebral hemorrhage who presented with mild right-sided hemiparesis. Computed tomography (CT) revealed hematoma in the left thalamus and compression of the posterior limb of the internal capsule by a brain edema surrounding the lesion. 99mTc-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) images obtained 4 days after onset showed hypoperfusion in the left thalamus containing a hematoma as well as contralateral cerebellar hypoperfusion to the supratentorial lesion, which is well recognized as crossed cerebellar diaschisis (CCD) after stroke. CT 14 days after the onset revealed reduction of the brain edema of the posterior limb of the internal capsule accompanied by gradual neurological improvement. SPECT obtained 14 and 28 days later showed that CCD had disappeared. In this case report, the authors discuss the disappearance of CCD due to transient edematous compression of the internal capsule following thalamic hemorrhage on serial 99mTc-HMPAO SPECT scans. CCD was possibly caused by the lesion confined to the posterior limb of the internal capsule, which anatomically constitutes the cerebropontocerebellar pathway.
• Regional difference of neuronal vulnerability in the murine hippocampus after transient forebrain ischemia

  G Yang; K Kitagawa; T Ohtsuki; K Kuwabara; T Mabuchi; Y Yagita; K Takazawa; S Tanaka; T Yanagihara; M Hori; M Matsumoto

  BRAIN RESEARCH ELSEVIER SCIENCE BV 870 (1-2) 195 - 198 0006-8993 2000/07 [Refereed]
   

  We have investigated the regional difference of neuronal vulnerability within the hippocampus in the C57BL/6 strain mice after forebrain ischemia. Both common carotid arteries of fifty mice were occluded for 12 min and the mouse brain was examined with cresyl violet staining. The CA4 sector was found to be the most vulnerable within the hippocampus. The CA2 and the medial CA1 sector was the 2nd and 3rd most vulnerable regions. However, The lateral part of the CA1 sector, CA3 sector and the dentate gyrus were resistant to ischemic insult. (C) 2000 Elsevier Science B.V. All rights reserved.
• Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats

  T Mabuchi; K Kitagawa; T Ohtsuki; K Kuwabara; Y Yagita; T Yanagihara; M Hori; M Matsumoto

  STROKE LIPPINCOTT WILLIAMS & WILKINS 31 (7) 1735 - 1742 0039-2499 2000/07 [Refereed]
   

  Background and Purpose-The purpose of this study was (1) to examine the contribution of microglia and macrophages with their interleukin-lp production and (2) to assess the vulnerability and response of oligodendrocytes in cerebral infarction. Methods-Male Wistar rats were subjected to permanent occlusion of the left middle cerebral artery. Expansion of ischemic infarction and response of oligodendrocytes were investigated together with accumulation of inflammatory cells, production of interleukin-1 beta, and disruption of the blood-brain barrier. Apoptotic cell death was inferred from fragmented DNA and the expression of proapoptotic Bar protein. Results-During expansion of infarction, amoeboid microglia and extravasation of serum albumin were observed not only in the infarcted area but also in the adjacent surviving area, whereas macrophages accumulated along the boundary and granulocytes migrated into the center of the infarction. Both amoeboid microglia and macrophages produced interleukin-1 beta, an inflammatory cytokine, during an early ischemic period. Furthermore, macrophages within the infarcted tissue expressed Bar protein and subsequently showed fragmented nuclear DNA. Oligodendrocytes were detected in the infarcted area even after 24 hours following middle cerebral artery occlusion, but they subsequently developed fragmented DNA. A week after onset of ischemia, oligodendrocytes were found to be accumulated in the intact area bordered with the infarct together with reactive astrocytes. Conclusions-Our results suggest the importance of amoeboid microglia, macrophages, and their interleukin-1 beta production in gradual expansion of cerebral infarction. Resident oligodendrocytes may be resistant to ischemic insults, and oligodendrocytes accumulated at the border of the infarction may participate in tissue repair after cerebral infarction.
• Extended neuronal protection induced after sublethal ischemia adjacent to the area with delayed neuronal death

  K Kitagawa; M Matsumoto; T Ohtsuki; K Kuwabara; T Mabuchi; Y Yagita; M Hori; T Yanagihara

  NEUROSCIENCE PERGAMON-ELSEVIER SCIENCE LTD 96 (1) 141 - 146 0306-4522 2000 [Refereed]
   

  In the present study, we investigated whether neurons adjacent to an ischemic lesion acquire tolerance against subsequent ischemia or not. We initially used unilateral hemispheric ischemia for 3 min in gerbils to produce an ischemic lesion confined to the unilateral CA1 sector, and the presence of tolerance was examined in the adjacent CA3 sector through transient global ischemia by occlusion of both common carotid arteries. Attenuation of neuronal damage was clearly observed in neurons in the CA3 sector adjacent to the ischemic lesion in the CA1 sector. The phenomenon lasted for up to two weeks after the initial hemispheric ischemia, but was no longer present two months later. Reactive astrocytes as identified by the presence of glial fibrillary acidic protein were visible in the CA3 hippocampus four days and two weeks after hemispheric ischemia, but they were scarce two months later. Expression of heat shock protein 72 in the CA3 neurons was observed four days after hemispheric ischemia, but the reaction returned to the control level two weeks later. In conclusion, the present study showed that tolerance in the neurons adjacent to an ischemic lesion could be sustained at least for two weeks, and raised the possibility that reactive astrocytes might contribute to the extended tolerance in neurons. (C) 2000 IBRO. Published by Elsevier Science Ltd.
• Deficiency of intercellular adhesion molecule 1 fails to mitigate selective neuronal death after transient global ischemia

  K Kitagawa; M Matsumoto; T Ohtsuki; K Kuwabara; T Mabuchi; Y Yagita; M Hori; T Yanagihara

  BRAIN RESEARCH ELSEVIER SCIENCE BV 847 (2) 166 - 174 0006-8993 1999/11 [Refereed]
   

  Recent studies have shown a crucial role of intercellular adhesion molecule 1 (ICAM-1) in expansion of infarction after focal cerebral ischemia. The purpose of the present study was to assess whether ICAM-1 is involved in selective neuronal vulnerability and reactive gliosis after transient forebrain ischemia. ICAM-1 knockout mice and wild-type mice were subjected to transient forebrain ischemia for 5, 10 or 15 min, and the hippocampus and caudoputamen were examined 7 days later with conventional histological and immunohistochemical methods. Bilateral common carotid artery occlusion with less than 10% of baseline cortical microperfusion for 10 or 15 min resulted in ischemic neuronal damage in the hippocampus and caudoputamen. The frequency and the severity of neuronal damage were similar in wild-type and knockout mice. Proliferation of reactive astrocytes in the hippocampus was also similar in both types of mice. Therefore, it is highly unlikely that ICAM-1 plays a key role in delayed neuronal death after transient global ischemia or in astroglial responses after ischemic neuronal injury. (C) 1999 Elsevier Science B.V. All rights reserved.
• Dna cleavage and proteolysis of microtubule-associated protein 2 after cerebral ischemia of different severity

  Y. Yagita; M. Matsumoto; K. Kitagawa; T. Mabuchi; T. Ohtsuki; M. Hori; T. Yanagihara

  Neuroscience 92 (4) 1417 - 1424 0306-4522 1999/06 [Refereed]
   

  We report temporal profiles of cytoplasmic proteolysis and genomic DNA cleavage after cerebral ischemia of different severity in gerbils. Global forebrain ischemia by bilateral common carotid artery occlusion for 5 min with reperfusion, severe unilateral hemispheric ischemia by unilateral common carotid artery occlusion for 30 min with reperfusion, and complete ischemia by decapitation were used. The hippocampus was examined for proteolysis by using immunohistochemistry for microtubule-associated protein 2, DNA cleavage by using in situ nick-end labelling, and nuclear morphology by Hematoxylin staining. During evolution of delayed neuronal death after transient forebrain ischemia, loss of the immunoreaction for microtubule-associated protein 2 occurred almost in parallel with DNA cleavage in the CA1 region. In contrast, disappearance of the immunoreaction for microtubule-associated protein 2 was much faster than genomic DNA cleavage after unilateral hemispheric ischemia and reperfusion. The microtubule-associated protein 2 immunoreactivity was completely lost before development of changes in nuclear morphology or DNA cleavage after complete ischemia. The present study demonstrated the differences between necrosis and delayed neuronal death, but the nuclear morphology in the latter was not exactly the same as seen in apoptosis. Some elements of both necrotic and apoptotic machineries may work following transient ischemia, and the degree of ischemic insult may determine the character of cell death process.
• Species differences in fodrin proteolysis in the ischemic brain

  K Kitagawa; M Matsumoto; TC Saido; T Ohtsuki; K Kuwabara; Y Yagita; T Mabuchi; T Yanagihara; M Hori

  JOURNAL OF NEUROSCIENCE RESEARCH WILEY-LISS 55 (5) 643 - 649 0360-4012 1999/03 [Refereed]
   

  There has been growing evidence that the breakdown of cytoskeletal proteins is an important biochemical change leading to ischemic neuronal death, In the present study, we investigated species differences in the susceptibility of fodrin to calpain activation induced by cerebral ischemia in gerbils, rats, and mice. In vivo fodrin proteolysis and degradation of microtubule-associated protein 2 after complete ischemia occurred more rapidly in the hippocampus and cerebral cortex of the gerbil brain than in the corresponding area of the rat and mouse brain. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 injected intraperitoneally before ischemia did not diminish fodrin degradation in the gerbil hippocampus. In vivo fodrin proteolysis was inhibited at 33 degrees C and enhanced at 41 degrees C compared with proteolysis at 37 degrees C during ischemia, However, in vitro fodrin proteolysis after addition of Ca2+ into the crude membrane fraction did not show any differences among three species. Although it is highly unlikely that the difference in the sensitivity of NMDA receptor or the sensitivity of calpain activation to calcium was the crucial determinant of susceptibility of fodrin degradation in the gerbil brain, the present study clearly demonstrated that fodrin in the gerbil brain was more susceptible to calpain activation induced by ischemia than that in the rat and mouse brains. Enhanced proteolysis may be one of the reasons neurons in the gerbil brain are highly vulnerable to ischemia, (C) 1999 Wiley-Liss, Inc.
• Molecular cloning of a novel member of the HSP110 family of genes, ischemia-responsive protein 94 kDa (irp94), expressed in rat brain after transient forebrain ischemia

  Yoshiki Yagita; Kazuo Kitagawa; Akihiko Taguchi; Toshiho Ohtsuki; Keisuke Kuwabara; Takuma Mabuchi; Masayasu Matsumoto; Takehiko Yanagihara; Masatsugu Hori

  Journal of Neurochemistry 72 (4) 1544 - 1551 0022-3042 1999 [Refereed]
   

  To identify genes induced by transient forebrain ischemia, we used the mRNA differential display technique in the four-vessel occlusion model in rats. Some genes were identified as candidates that encode ischemia- responsive protein, and one of them was cloned as ischemia-responsive protein 94 kDa (irp94) from the rat hippocampal cDNA library. Sequence analysis suggested that rat irp94 was a transcriptional variant or a homologue of mouse apg-2 and human heat shock protein (hsp) 70RY and a member of the HSP110 family, because IRP94 was > 90% identical to APG-2 and HSP70RY and ~60% identical to the other members of the HSP110 family. Although irp94 mRNA was constitutively expressed in the normal hippocampus, it was clearly enhanced 4-24 h after ischemia for 10 (1.9-fold increase) and 15 min (3.4- fold increase). These changes mainly occurred in neuronal cells, as judged by the localization of irp94 mRNA using in situ hybridization histochemistry. On the other hand, hyperthermic stress did not enhance irp94 mRNA expression, suggesting that irp94 expression was enhanced under ischemic stress and not related to the heat shock signaling mechanism. Our study suggested that irp94, a novel member of the HSP110 family, might play an important role in the environment altering neuronal functions, especially after transient forebrain ischemia.
• Deficiency of intercellular adhesion molecule 1 attenuates microcirculatory disturbance and infarction size in focal cerebral ischemia

  K Kitagawa; M Matsumoto; T Mabuchi; Y Yagita; T Ohtsuki; M Hori; T Yanagihara

  JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LIPPINCOTT WILLIAMS & WILKINS 18 (12) 1336 - 1345 0271-678X 1998/12 [Refereed]
   

  Recent evidence has shown crucial roles for cell-adhesion molecules in inflammation-induced rolling, adhesion, and accumulation of neutrophils in tissue. Intercellular adhesion molecule-1 (ICAM-1) is one of these adhesion molecules. Previous studies have shown marked reduction in the size of infarction after focal cerebral ischemia by depletion of granulocytes and administration of the antibody against TCAM-1. In the present study we investigated the role of ICAM-1 in the size of ischemic lesions, accumulation of granulocytes, and microcirculatory compromise in focal cerebral ischemia by using ICAM-1-knockout mice. Ischemic lesions were significantly mitigated in knockout mice after permanent and transient focal ischemia, even though the number of granulocytes in the infarcted tissue was almost the same between knockout and wildtype mice. Depletion of granulocytes further decreased the size of ischemic lesions after transient focal ischemia in ICAM-1-knockout mice. Microcirculation was reduced after focal ischemia. but it was better preserved in the cerebral cortex of knockout mice than that of wild-type mice, The present study demonstrated that ICAM-1 played a role in microcirculatory failure and subsequent development and expansion of infarction after focal cerebral ischemia. However, it is highly unlikely that ICAM-1 played a key role in accumulation of granulocytes after focal cerebral ischemia.
• Stimulation of tyrosine phosphorylation of a brain protein by hibernation

  T Ohtsuki; H Jaffe; M Brenner; N Azzam; R Azzam; KU Frerichs; JM Hallenbeck

  JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM NATURE PUBLISHING GROUP 18 (9) 1040 - 1045 0271-678X 1998/09 [Refereed]
   

  Mammalian hibernation is a state of natural tolerance to severely decreased brain blood flow. As protein tyrosine phosphorylation is believed to be involved in the development of resistance to potentially cell-damaging insults, we used immunoblotting for the phosphotyrosine moiety to analyze extracts from various tissues of hibernating and nonhibernating ground squirrels. A single, hibernation-specific phosphoprotein was detected in the brain, but not in any other tissue tested. This protein: designated pp98 to reflect its apparent molecular weight, is distributed throughout the brain, and is associated with the cellular membrane fraction. The presence of the protein is tightly linked to the hibernation state; it is not present in contemporaneously assayed animals that are exposed to the same cold temperature as the hibernators, is present for the duration of a hibernation bout (tested from 1 to 14 days), and disappears within 1 hour of arousal from hibernation. The close association of pp98 with the hibernation state, its presence in cellular membranes, and the known properties of membrane phosphotyrosine proteins suggest that it may transduce a signal for adaptation to the limited availability of oxygen and glucose and low cellular temperature that characterizes hibernation in the ground squirrel.
• Amelioration of hippocampal neuronal damage after global ischemia by neuronal overexpression of BCL-2 in transgenic mice

  Kazuo Kitagawa; Masayasu Matsumoto; Yoshihide Tsujimoto; Toshiho Ohtsuki; Keisuke Kuwabara; Kohji Matsushita; Gongming Yang; Hiroki Tanabe; Jean-Claude Martinou; Masatsugu Hori; Takehiko Yanagihara

  Stroke Lippincott Williams and Wilkins 29 (12) 2616 - 2621 0039-2499 1998 [Refereed]
   

  Background and Purpose - Reports suggesting the involvement of apoptosis in ischemic neuronal damage have been accumulating, and protection against apoptotic death by BCL-2 has been shown in many types of cells. Overexpression of BCL-2 has been shown to reduce infarct size after focal ischemia. The purpose of the present study was to assess whether BCL-2 exerted its effect on selective neuronal vulnerability after transient global ischemia. Methods - Transgenic mice overexpressing BCL-2 in neurons and their littermates were subjected to transient forebrain ischemia for 12 minutes, and the hippocampus was examined 7 days later with conventional histology, immunohistochemistry, and in situ terminal deoxynucleotidyl transferase- mediated dUTP-biofin nick end-labeling of fragmented DNA. Results - Although both types of mice showed a similar degree of ischemic insult, transgenic mice showed a lesser degree of neuronal death together with DNA fragmentation in the hippocampus than their littermates. Conclusions - Overexpression of BCL-2 in neurons mitigates selective neuronal vulnerability in the hippocampus of transgenic mice after transient global ischemia.
• Ischemic damage and subsequent proliferation of oligodendrocytes in focal cerebral ischemia

  K Mandai; M Matsumoto; K Kitagawa; K Matsushita; T Ohtsuki; T Mabuchi; DR Colman; T Kamada; T Yanagihara

  NEUROSCIENCE PERGAMON-ELSEVIER SCIENCE LTD 77 (3) 849 - 861 0306-4522 1997/04 [Refereed]
   

  In order to achieve a better understanding of the pathophysiology of ischemic white matter lesions, oligodendrocytic degeneration and subsequent proliferation were examined in the mouse model of middle cerebral artery occlusion. In situ hybridization histochemistry for proteolipid protein messenger RNA was employed as a sensitive and specific marker of oligodendrocytes, and immunohistochemistry for myelin basic protein was used as a compact myelin marker. Immunohistochemistry for microtubule-associated protein 2 and albumin was employed to monitor neuronal degeneration and the breakdown of the blood-brain barrier, respectively. In the ischemic core of the caudoputamen, the immunoreactivity for microtubule-associated protein 2 disappeared and massive albumin extravasation occurred several hours after vessel occlusion, while proteolipid protein messenger RNA signals remained relatively strong at this time. The messenger RNA signals began to attenuate 12 h after ischemia and were hardly detectable 24 h after ischemica in the whole ischemic lesion. In situ end-labeling of fragmented DNA showed some cells with proteolipid protein messenger RNAs to have DNA fragmentation at this period. In contrast to proteolipid protein messenger RNA signals, the immunoreactivity for myelin basic protein was detected as long as five days after ischemia. An apparent increase in the cells prossessing strong proteolipid protein messenger RNA signals was found five days after ischemia, mainly in the corpus callosum and the cortex bordering the infarcted areas. A double simultaneous procedure with in situ hybridization for proteolipid protein messenger RNA and immunohistochemistry for glial fibrillary acid protein or lectin histochemistry for macrophages/microglia showed proliferating oligodendrocytes to be co-localized with reactive astrocytes and macrophages/microglia. These findings show that oligodendrocytic damage occurred following ischemic neuronal damage and the breakdown of the blood-brain barrier, but preceded the breakdown of myelin proteins in the ischemic lesion, that an apoptosis-like process was involved in ischemic oligodendrocytic death, and that surviving oligodendrocytes responded and proliferated in the outer border of the infarcted area. (C) 1997 IBRO.
• Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats

  K Tasaki; CA Ruetzler; T Ohtsuki; D Martin; H Nawashiro; JM Hallenbeck

  BRAIN RESEARCH ELSEVIER SCIENCE BV 748 (1-2) 267 - 270 0006-8993 1997/02 [Refereed]
   

  Ischemic tolerance was induced in spontaneously hypertensive rats (SHR) by injection of a single dose of Lipopolysaccharide (LPS) (0.9 mg/kg, i.v.) 1-7 days prior to permanent middle cerebral artery occlusion (MCAO). Infarct volume, evaluated 24 h after MCAO, was significantly reduced by LPS administration 2, 3 or 4 days prior to MCAO (22.8, 25.9 and 20.5%, respectively). The beneficial effect of LPS pre-treatment was completely nullified by concurrent administration of TNFbp. On this basis, the tolerance to ischemia induced by LPS is likely to be mediated by TNF-alpha.
• Effect of systemic zinc administration on delayed neuronal death in the gerbil hippocampus

  K Matsushita; K Kitagawa; T Matsuyama; T Ohtsuki; A Taguchi; K Mandai; T Mabuchi; Y Yagita; T Yanagihara; M Matsumoto

  BRAIN RESEARCH ELSEVIER SCIENCE BV 743 (1-2) 362 - 365 0006-8993 1996/12 [Refereed]
   

  The divalent cation zinc has been reported to possess several physiological properties such as blocking apoptetic cell death through an inhibitory effect on Ca2+-Mg2+ endonuclease activity, or modulating the neurotoxicity via glutamate receptor subtypes. In the present study, we investigated the effect of peripherally injected zinc on delayed neuronal death seen in the hippocampus after transient global ischemia, in order to elucidate a possible beneficial role on zinc in ischemic neuronal cell death. Forty-five adult Mongolian gerbils of both sexes underwent transient bilateral clipping of the common carotid arteries for 3 min. In the pretreated animals, ZnCl2 (20 mg/kg) was injected subcutaneously once, 1 h before ischemia (superacute group n = 6) or twice at 24 and 48 h before ischemia (subacute group; n = 14). Histological survey was carried out 3 days later by in situ DNA fragmentation method and 4 days later by hematoxylin-eosin staining by semiquantatively counting dead neurons in the CA1 sector. Subacute zinc pre-administration significantly reduced the nuclear damage and subsequent neuronal death; however, superacutely pre-administered zinc did not protect hippocampal neurons against ischemia but it did not aggravate the effect of ischemia, either. The present study suggested that transfer of exogenous zinc into the intracellular space is required for neuroprotection, presumably via the anti-endonuclease activity.
• Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons

  T Ohtsuki; CA Ruetzler; K Tasaki; JM Hallenbeck

  JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LIPPINCOTT-RAVEN PUBL 16 (6) 1137 - 1142 0271-678X 1996/11 [Refereed]
   

  A series of experiments was performed to determine the role of interleukin (IL)-1 in the induction of tolerance to global ischemia in Mongolian gerbils. In Group I, a 2-min ''preconditioning'' ischemia protected CA1 hippocampal neurons in gerbils subjected to 3.5 min ischemia 3 days later. CA1 neuronal density was: sham, 171 +/- 3/mm; 3.5 min ischemia, 30 +/- 30/mm; 2 and 3.5 min ischemia 162 +/- 6/mm. Experiments in Group II addressed the role of IL-1 in the induction of tolerance by sublethal ischemia. Arterial IL-1 alpha and IL-1 beta became elevated between 1 and 3 days after a 2-min ischemic exposure. IL-1 alpha was: sham, 6.4 +/- 0.6 ng/ml; and 2-day, 10.2 +/- 1.2 ng/ml. IL-1 beta was: sham, 6.4 +/- 0.5 ng/ml; and 2-day, 17.3 +/- 2 ng/ml. Recombinant human IL-1 receptor antagonist (IL-1ra) i.p. blocked ischemic tolerance induction by 2-min preconditioning ischemia: 2-min ischemia + vehicle, 162 +/- 6/mm; and 2-min ischemia + IL-1ra, 67 +/- 17/mm. Experiments in Group III assessed the capacity of IL-1 to induce tolerance to brain ischemia. IL-1 alpha i.p. (0, 10, 20 mu g/kg) for 3 days prior to 3.5-min forebrain ischemia provided significant CA1 neuroprotection in a dose-dependent manner: 2 +/- 2, 68 +/- 83, and 129 +/- 42/mm, respectively. IL-1 beta (15 mu g/kg) in combination with either IL-1ra (100 mg/kg) or IL-1ra vehicle i.p. on the same schedule demonstrated a significant CA1 neuroprotection that could be nullified by IL-1ra: IL-1 beta + IL-1ra vehicle, 153 +/- 16/mm; and IL-1 beta +/- IL-1ra, 67 +/- 36/mm. Recognition that tolerance arises from stimulation of a known receptor (IL-1RI) permits molecular analysis of the intracellular signaling that is critical for production of that state.
• Delayed neuronal death in ischemic hippocampus involves stimulation of protein tyrosine phosphorylation.

  T Ohtsuki; M Matsumoto; K Kitagawa; T Mabuchi; K Mandai; K Matsushita; K Kuwabara; M Tagaya; S Ogawa; H Ueda; T Kamada; T Yanagihara

  The American journal of physiology 271 (4 Pt 1) C1085-97  0002-9513 1996/10 

  Glutamate triggers neuronal degeneration after ischemia-reperfusion in the brain. However, the details of intracellular signal transduction that propagates cell death remain unknown. The present work investigated whether protein tyrosine phosphorylation mediates neuronal death in the ischemic brain. Transient forebrain ischemia for 5-10 min in Mongolian gerbils or intoxication with the glutamate analogue kainic acid (12 mg/kg) in Sprague-Dawley rats caused neuronal death selectively in the hippocampus 2-4 days or 1 day later, respectively. Under these conditions, 160-, 115-, 105-, 92-, and 85-kDa proteins showed a significant increase in tyrosyl residue phosphorylation selectively in the hippocampus 3-12 h after ischemia or 4-8 h after kainic acid-induced seizures. Tyrosine kinases, including pp60c-src, were activated without a change of tyrosine phosphatases. Administration of radicicol, a selective inhibitor of tyrosine kinases, attenuated stimulation of tyrosine phosphorylation and hippocampal degeneration after ischemia or kainic acid injection. The results suggest that protein tyrosine phosphorylation might propagate delayed neuronal death in the mature hippocampus through glutamate overload after ischemia-reperfusion.
• Effect of immunosuppressant FK506 on ischemia-induced degeneration of hippocampal neurons in gerbils

  Y Yagita; K Kitagawa; K Matsushita; A Taguchi; T Mabuchi; T Ohtsuki; T Yanagihara; M Matsumoto

  LIFE SCIENCES PERGAMON-ELSEVIER SCIENCE LTD 59 (19) 1643 - 1650 0024-3205 1996/10 [Refereed]
   

  To evaluate the effect of FK506 on delayed neuronal death in gerbils after forebrain ischemia, 84 adult Mongolian gerbils were used in this study. Transient forebrain ischemia was induced by clipping common carotid arteries bilaterally for 5 minutes. One hour after reperfusion, we intraperitoneally injected FK506 (1.0 mg/kg), cyclosporin A (CsA) (10.0 mg/kg) or the vehicle solution into each gerbil. In one group, each agent was additionally administered daily 3 more times at 24, 48 and 72 hours after ischemia. The gerbils were killed 4 days or 10 days after transient ischemia, and damage to their hippocampal pyramidal cells was histologically assessed. Additionally, the body temperature was measured following administration of each drug to investigate drug-induced hypothermia. Post-ischemic repeated treatment with FK506 significantly (p<0.01) reduced degeneration of hippocampal neurons. However, partial treatment did not modify neuronal degeneration CsA did not show a neuroprotective effect in this study. Drug-induced mild hypothermia (35-37 degrees C) was observed following administration of FK506 or CsA. There was no significant difference in the time course of the body temperature between the FK506 and CsA group. We demonstrated that the repeated FK506 treatment, but not the CsA treatment, reduced ischemia-induced degeneration of hippocampal neurons in gerbils. Although FK506-induced hypothermia might have modified neuronal degeneration, a comparison with CsA indicated that the neuroprotective effect of FK506 was not solely due to hypothermia per se.
• Delayed neuronal death in ischemic hippocampus involves stimulation of protein tyrosine phosphorylation

  T Ohtsuki; M Matsumoto; K Kitagawa; T Mabuchi; K Mandai; K Matsushita; K Kuwabara; M Tagaya; S Ogawa; H Ueda; T Kamada; T Yanagihara

  AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY AMER PHYSIOLOGICAL SOC 271 (4) C1085 - C1097 0363-6143 1996/10 [Refereed]
   

  Glutamate triggers neuronal degeneration after ischemia-reperfusion in the brain. However, the details of intracellular signal transduction that propagates cell death remain unknown. The present work investigated whether protein tyrosine phosphorylation mediates neuronal death in the ischemic brain. Transient forebrain ischemia for 5-10 min in Mongolian gerbils or intoxication with the glutamate analogue kainic acid (12 mg/kg) in Sprague-Dawley rats caused neuronal death selectively in the hippocampus 2-4 days or 1 day later, respectively. Under these conditions, 160-, 115-, 105-, 92-, and 85-kDa proteins showed a significant increase in tyrosyl residue phosphorylation selectively in the hippocampus 3-12 h after ischemia or 4-8 h after kainic acid-induced seizures. Tyrosine kinases, including pp60(c-src), were activated without a change of tyrosine phosphatases. Administration of radicicol, a selective inhibitor of tyrosine kinases, attenuated stimulation of tyrosine phosphorylation and hippocampal degeneration after ischemia or kainic acid injection. The results suggest that protein tyrosine phosphorylation might propagate delayed neuronal death in the mature hippocampus through glutamate overload after ischemia-reperfusion.
• Induction of cyclooxygenase-2 mRNA in gerbil hippocampal neurons after transient forebrain ischemia

  T Ohtsuki; K Kitagawa; K Yamagata; K Mandai; T Mabuchi; K Matsushita; T Yanagihara; M Matsumoto

  BRAIN RESEARCH ELSEVIER SCIENCE BV 736 (1-2) 353 - 356 0006-8993 1996/10 [Refereed]
   

  We examined the effect of brain ischemia on neuronal expression of cyclooxygenase-2 gene in the hippocampus. Transient forebrain ischemia was produced by occluding bilateral carotid arteries for 5 min in Mongolian gerbil. Northern blotting and in situ hybridization demonstrated that expression of cyclooxygenase-2 mRNA was transiently induced in the hippocampal neurons. Although future studies will be needed to clarify if induced cyclooxygenase-2 following ischemia is involved in neuronal damage or neuronal protection, selective cyclooxygenase-2 inhibitors may be a new therapeutical approach for the treatment of stroke.
• Bifemelane hydrochloride enhances 'ischemic tolerance' phenomenon in gerbil hippocampal CA1 neurons

  T Ohtsuki; M Matsumoto; A Taguchi; GM Yang; T Mabuchi; K Matsushita; K Kuwabara; K Kitagawa; T Yanagihara

  LIFE SCIENCES PERGAMON-ELSEVIER SCIENCE LTD 59 (12) 979 - 985 0024-3205 1996/08 [Refereed]
   

  Neurons are so vulnerable to ischemic insults that transient forebrain ischemia for 5 min killed most CA1 neurons in the gerbil hippocampus (surviving neurons: 4%). In contrast, 2 days after a nonlethal challenge of 2-min ischemia, 51% of CA1 neurons became resistant to subsequent, otherwise lethal ischemia for 5 min. Bifemelane hydrochloride (20 mg/kg, i.p.), which helps ischemic brain recover from oxidative stress and inhibition of protein synthesis, significantly enhanced the 'ischemic tolerance' phenomenon if injected 1 day after 2-min ischemia: 94% of neurons survived after 5-min ischemia. This finding carries implications for possible preventive treatment following warning signs of transient ischemic attack.
• Exposure of astrocytes to hypoxia/reoxygenation enhances expression of glucose-regulated protein 78 facilitating astrocyte release of the neuroprotective cytokine interleukin 6

  Osamu Hori; Masayasu Matsumoto; Keisuke Kuwabara; Yusuke Maeda; Hirokazu Ueda; Toshiho Ohtsuki; Taroh Kinoshita; Satoshi Ogawa; David M. Stern; Takenobu Kamada

  Journal of Neurochemistry 66 (3) 973 - 979 0022-3042 1996/03 [Refereed]
   

  Astrocytes exposed to hypoxia (H) or hypoxia/reoxygenation (H/R) maintain cell viability and display changes in protein biosynthesis. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of metabolically labeled astrocytes exposed to H showed induction of an ≃78-kDa polypeptide that demonstrated sequence identity with glucose-regulated protein (GRP) 78. Cell lysates from H/R astrocytes displayed induction of neuroprotectire interleukin (IL) 6, which was present in a high-molecular-weight complex also containing GRP78, suggesting that GRP78 might be functioning as a chaperone during cellular stress consequent on H/R. Introduction of antisense oligonucleotide to GRP78 into astrocytes prevented expression of the protein and suppressed H/R-induced astrocyte release of IL-6 by ≃50%. These data indicate that modulation of astrocyte properties during oxygen deprivation results, in part, from intracellular glucose depletion and subsequent expression of GRP78, which sustains generation of neuroproteotive IL-6 under the stress of H/R.
• MITOCHONDRIAL LIPID-PEROXIDATION AND SUPEROXIDE-DISMUTASE IN RAT HYPERTENSIVE TARGET ORGANS

  T OHTSUKI; M MATSUMOTO; K SUZUKI; N TANIGUCHI; T KAMADA

  AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY AMER PHYSIOLOGICAL SOC 268 (4) H1418 - H1421 0363-6135 1995/04 [Refereed]
   

  Mitochondrial respiratory chains leak a large amount of superoxide anion radicals, which chain react with membrane phospholipid to develop lipid peroxidation. Manganese superoxide dismutase (MnSOD) is then inducible and catalyzes superoxide detoxification within mitochondria. We examined mitochondrial thiobarbituric acid-reactive substance, an end product of lipid peroxidation, and MnSOD concentration in hypertensive target organs of spontaneously hypertensive and deoxycorticosterone acetate salts-induced hypertensive rats. Normotensive rats showed significant increases in thiobarbituric acid-reactive substance and MnSOD in the brain as they matured. Mature spontaneously hypertensive and induced hypertensive rats showed a marked elevation of lipid peroxidation but no increase in superoxide dismutase in the brain. The heart and kidney presented no significant difference of lipid peroxidation and superoxide dismutase among strains, ages, and treatments. Abnormal mitochondrial metabolism of oxygen radicals was observed selectively in the brain during hypertension and may contribute to mitochondrial injury and lead to neuronal degeneration or susceptibility to brain ischemia in mature hypertensive rats.
• REPERFUSION INDUCES 5-LIPOXYGENASE TRANSLOCATION AND LEUKOTRIENE C-4 PRODUCTION IN ISCHEMIC BRAIN

  T OHTSUKI; M MATSUMOTO; Y HAYASHI; K YAMAMOTO; K KITAGAWA; S OGAWA; S YAMAMOTO; T KAMADA

  AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY AMER PHYSIOLOGICAL SOC 268 (3) H1249 - H1257 0363-6135 1995/03 [Refereed]
   

  5-Lipoxygenase (5-LO) converts arachidonic acid, released from membrane phospholipids upon external stimulation, to leukotriene C-4 (LTC(4)), which induces various kinds of cellular and molecular responses. We examined the effects of 5 min of ischemia on brain 5-LO and LTC(4) during reperfusion using the gerbil model of transient forebrain ischemia that develops neuronal necrosis selectively in the hippocampus. Neurons exhibited dense 5-LO immunoreactivity; 5-LO was partially redistributed from cytosolic to particulate fractions 3 min during reperfusion. LTC(4) was generated in neurons and was increased in all forebrain regions during reperfusion. Postischemic increases in LTC(4) were inhomogeneous; a greater increase was observed in the hippocampus (13.37 +/- 0.24 pmol/g tissue) than in the other regions (cerebral cortex: 3.29 +/- 1.09 pmol/g). Superoxide dismutase and dimethylthiourea, oxygen radical scavengers, attenuated the production of LTC(4) and damage to the neurons in the hippocampus during reperfusion. Our findings indicated that reperfusion, which was associated with translocation of cytosolic 5-LO to membranes and generation of oxygen radicals, induced the production of LTC(4) and suggested that excess LTC(4) production may mediate irreversible reperfusion injuries in the hippocampal neurons.
• Hypoxia/reoxygenation-mediated induction of astrocyte interleukin 6: A paracrine mechanism potentially enhancing neuron survival

  Yusuke Maeda; Masayasu Matsumoto; Osamu Hori; Keisuke Kuwabara; Satoshi Ogawa; Shi Du Yan; Toshiho Ohtsuki; Taroh Kinoshita; Takenobu Kamada

  Journal of Experimental Medicine 180 (6) 2297 - 2308 1540-9538 1994/12 [Refereed]
   

  To elucidate mechanisms underlying neuroprotective properties of astrocytes in brain ischemia, production of neurotrophic mediators was studied in astrocytes exposed to hypoxia/reoxygenation (H/R). Rat astrocytes subjected to H/R released increased amounts of interleukin (IL) 6 in a time-dependent manner, whereas levels of tumor necrosis factor and IL-1 remained undetectable. IL-6 transcripts were induced in hypoxia and the early phase of reoxygenation, whereas synthesis and release of IL-6 antigen/activity occurred during reoxygenation. Elevated levels of 1I.-6 mRNA were due, at least in part, to increased transcription, as shown by nuclear runoff analysis. The mechanism stimulating synthesis and release of IL-6 antigen by astrocytes was probably production of reactive oxygen intermediates (ROIs), which occurred within 15-20 minutes after placing hypoxia cultures back into normoxia, as the inhibitor diphenyl iodonium inhibited the burst of ROIs and subsequent IL-6 generation (blockade of nitric oxide formation had no effect on ROI generation or IL-6 production). Enhanced IL-6 generation was also observed in human astrocytoma cultures exposed to H/R. Survival of differentiated PC12 cells exposed to H/R was potentiated by conditioned medium from H/R astrocytes, an effect blocked by neutralizing anti-IL-6 antibody. In a gerbil model of brain ischemia, IL-6 activity was lower in the hippocampus, an area sensitive to ischemia, compared with IL-6 activity in the cortex, an area more resistant to ischemia. IL-6 antigen, demonstrated immunohistochemicaUy, was increased in astrocytes from ischemic regions of gerbil brain. These data suggest that H/R enhances transcription of IL-6, resulting in increased translation and release of IL-6 antigen after the burst of ROI generated early during reoxygenation. Release of IL-6 from astrocytes could exert a paracrine neurotrophic effect in brain ischemia. © 1994, Rockefeller University Press., All rights reserved.
• Metabolic and Biosynthetic Alterations in Cultured Astrocytes Exposed to Hypoxia/Reoxygenation

  Osamu Hori; Masayasu Matsumoto; Yusuke Maeda; Hirokazu Ueda; Toshiho Ohtsuki; David M. Stern; Taroh Kinoshita; Satoshi Ogawa; Takenobu Kamada

  Journal of Neurochemistry 62 (4) 1489 - 1495 1471-4159 1994 [Refereed]
   

  To investigate the astrocyte response to hypoxia/reoxygenation, as a model relevant to the pathogenesis of ischemic injury, cultured rat astrocytes were exposed to hypoxia. On restoration of astrocytes to normoxia, there was a dramatic increase in protein synthesis within 3 h, and sodium dodecyl sulfate‐polyacrylamide gel electrophoresis of metabolically labeled astrocyte lysates showed multiple induced bands on fluorograms. Levels of cellular ATP declined during the first 3 h of reoxygenation and the concentration of AMP increased to ± 3.6 nmol/mg of protein within 1 h of reoxygenation. Reoxygenated astrocytes generated oxygen free radicals early after replacement into ambient air, and addition of diphenyliodonium, an NADPH oxidase inhibitor, diminished the generation of free radicals as well as the induction of several bands on fluorogram. Although addition of cycloheximide on reoxygenation resulted in inhibition of both astrocyte protein synthesis and accumulation of cellular AMP, it caused cell death within 6 h, suggesting the importance of protein synthesis in adaptation of hypoxic astrocytes to reoxygenation. Potential physiologic significance of biosynthetic products of astrocytes in hypoxia/reoxygenation was suggested by the recovery of glutamate uptake. These results indicate that the astrocyte response to hypoxia/reoxygenation includes generation of oxygen free radicals and de novo synthesis of products that influence cell viability and function in ischemia. Copyright © 1994, Wiley Blackwell. All rights reserved
• A new gerbil model of hindbrain ischemia by extracranial occlusion of the bilateral vertebral arteries

  Ryuji Hata; Masayasu Matsumoto; Kazuo Kitagawa; Tomohiro Matsuyama; Toshiho Ohtsuki; Masafumi Tagaya; Nobuo Handa; Michio Niinobe; Katsuhiko Mikoshiba; Tsunehiko Nishimura; Takehiko Yanagihara; Takenobu Kamada

  Journal of the Neurological Sciences 121 (1) 79 - 89 0022-510X 1994 [Refereed]
   

  A new gerbil model of hindbrain ischemia was induced by extracranial occlusion of the bilateral vertebral arteries just before their entry into the transverse foramen of the cervical vertebra. Carbon black studies, performed at 5 min after occlusion, revealed that the pons-medulla oblongata, and the cerebellum were quite ischemic in all animals. Cardiovascular changes in mean arterial blood pressure (MABP) and heart rate were recorded until 30 min after occlusion, and revealed that the typical cerebral ischemic response (i.e., abrupt increase in MABP, bradycardia, and apnea) was elicited in all animals (n = 10). Thirty minutes after occlusion, animals (n = 4) were decapitated and immersion-fixed. Brain sections were stained with hematoxylin-eosin (HE) and also immunostained for microtubule-associated protein 2 in order to evaluate ischemic neuronal damage from 30 min of ischemia. By HE staining, ischemic lesions were detected bilaterally in the oculomotor, the trigeminal motor, the lateral vestibular, and the cerebellar interpositus nucleus. In addition, immunostaining revealed ischemic lesions in several other hindbrain areas. In conclusion, we could successfully establish a new gerbil model of hindbrain ischemia. Carbon black perfusion and hemodynamic studies revealed that severe and reproducible hindbrain ischemia was produced. By histopathological examination, we could also clearly demonstrate symmetrical ischemic lesions in several hindbrain areas. © 1994.
• AN ISCHEMIC OPENING OF THE BLOOD-BRAIN-BARRIER MAY DETERIORATE BRAIN-STEM AUDITORY-EVOKED POTENTIALS FOLLOWING TRANSIENT HINDBRAIN ISCHEMIA IN GERBILS

  R HATA; M MATSUMOTO; K YAMAMOTO; T OHTSUKI; S OGAWA; N HANDA; T KUBO; T MATSUNAGA; T NISHIMURA; T KAMADA

  BRAIN EDEMA IX SPRINGER-VERLAG 60 197 - 199 0065-1419 1994 [Refereed]
  
• AN ISCHEMIC OPENING OF THE BLOOD-BRAIN-BARRIER MAY DETERIORATE BRAIN-STEM AUDITORY-EVOKED POTENTIALS FOLLOWING TRANSIENT HINDBRAIN ISCHEMIA IN GERBILS

  R HATA; M MATSUMOTO; K YAMAMOTO; T OHTSUKI; S OGAWA; N HANDA; T KUBO; T MATSUNAGA; T NISHIMURA; T KAMADA

  ACTA NEUROCHIRURGICA SPRINGER WIEN 197 - 199 0001-6268 1994 [Refereed]
   

  To clarify the effect of vasogenic brain edema on the brainstem, the relationships between waveform changes in brainstem auditory evoked potentials (BAEP) and blood-brain barrier (BBB) disturbance following transient hindbrain ischemia were investigated. Hindbrain ischemia was induced in gerbils by bilateral occlusion of the vertebral arteries. The animals were divided into three groups subjected to 0, 5, and 30 min of bilateral vertebral occlusion (BVO-0', -5', and -30' groups; n = 4 in each group). Two hours after recirculation, Evans blue (EB) solution was injected into the saphenous vein. The brains were removed after 30 min of circulation, and all areas stained macroscopically by EB were noted and recorded. During hindbrain ischemia, BAEP disappeared within 3 min. In the BVO-5' group, BAEP reappeared and returned to normal within 10 min after reperfusion, whereas in the BVO-30' group, BAEP never returned -to normal and finally disappeared within 30 min after reperfusion. In the BVO-5' group, no EB staining was visible. On the other hand, in the BVO-30' group, EB staining was seen in the medial part of the tegmentum in the midbrain in two animals, and around the vestibular nucleus in the lateral parts of the pons in three. These results demonstrate the close relationship between the reversibility of ischemia-induced changes in BAEP and BBB disturbance in the brainstem.
• Internucleosomal DNA cleavage involved in ischemia-induced neuronal death

  Masaya Okamoto; Masayasu Matsumoto; Toshiho Ohtsuki; Akihiko Taguchi; Katsuhiko Mikoshiba; Takehiko Yanagihara; Takenobu Kamada

  Biochemical and Biophysical Research Communications 196 (3) 1356 - 1362 1090-2104 1993/11 [Refereed]
   

  Pyramidal neurons of the hippocampal CA1 are known to be particularly vulnerable to transient ischemia resulting in "delayed neuronal death". Recent studies using aurintricarboxylic acid suggested that ischemia- or excitotoxin-induced neuronal death should share intracellular mechanisms in commom with apoptosis. It is, however, unclear about involvement of endonucleases. Here using a transient (5 min) forebrain ischemia model in gerbils, we found that internucleosomal DNA fragmentation developed between 48 and 54 hr recirculations, accompanied with simultaneous or slightly preceding destruction of microtubule-associated protein 2. These results suggest that endonucleases, maybe activated by elevated intracellular Ca2+, play an important role in delayed neuronal death as well as in apoptosis. © 1993 Academic Press, Inc.
• EFFECT OF TRANSIENT FOREBRAIN ISCHEMIA ON SUPEROXIDE DISMUTASES IN GERBIL HIPPOCAMPUS

  T OHTSUKI; M MATSUMOTO; K SUZUKI; N TANIGUCHI; T KAMADA

  BRAIN RESEARCH ELSEVIER SCIENCE BV 620 (2) 305 - 309 0006-8993 1993/08 [Refereed]
   

  Substantial generation of oxygen-derived free radicals has been implicated in pathophysiology of ischemic brain damage. Immunoreactive mitochondrial manganese and cytosolic copper-zinc superoxide dismutases, initial and essential enzymes to scavenge superoxide radical anions, increased in the gerbil hippocampal neurons after transient forebrain ischemia. Neuronal cells responded to oxidative stress in ischemia and induced the protective mechanism to increase superoxide dismutases.
• INDUCED RESISTANCE AND SUSCEPTIBILITY TO CEREBRAL-ISCHEMIA IN GERBIL HIPPOCAMPAL-NEURONS BY PROLONGED BUT MILD HYPOPERFUSION

  T OHTSUKI; M MATSUMOTO; K KITAGAWA; A TAGUCHI; Y MAEDA; R HATA; S OGAWA; H UEDA; N HANDA; T KAMADA

  BRAIN RESEARCH ELSEVIER SCIENCE BV 614 (1-2) 279 - 284 0006-8993 1993/06 [Refereed]
   

  Brief periods of non-lethal cerebral ischemia can induce resistance against subsequent lethal ischemia. In this study, asymptomatic gerbils after unilateral carotid artery ligation were subjected to 5 min of forebrain ischemia. The prolonged but mild hypoperfusion, by carotid occlusion, induced susceptibility at 1 day and tolerance at 30 days to lethal ischemia in the hippocampal neurons. The neuroprotective effect correlated well with induction of heat shock protein 72 in the hippocampal neurons. These results suggested that neuronal cells possess a cellular response to sublethal hypoperfusion and can survive forthcoming ischemic stress.
• Differential vulnerability in the hindbrain neurons and local cerebral blood flow during bilateral vertebral occlusion in gerbils

  R. Hata; M. Matsumoto; T. Hatakeyama; T. Ohtsuki; N. Handa; M. Niinobe; K. Mikoshiba; S. Sakaki; T. Nishimura; T. Yanagihara; T. Kamada

  Neuroscience 56 (2) 423 - 439 0306-4522 1993 [Refereed]
   

  Differential vulnerability in the hindbrain neurons was examined immunohistochemically during hindbrain ischemia in the gerbil. Hindbrain ischemia was produced by extracranial occlusion of the bilateral vertebral arteries just before their entry into the transverse foramen of the cervical vertebra. Local cerebral blood flow was measured by quantitative autoradiographic technique after 5 min of ischemia and was reduced to less than 5 ml/100 g per min in the cerebellum, the pons, and the medulla, indicating that severe and reproducible hindbrain ischemia was induced immediately after occlusion. For immunohistochemical investigation, four gerbils each were used for each ischemie period of 5, 10, 15, and 30 min. Immunohistochemical lesions, detected by the reaction for microtubule-associated protein 2, were visible in the lateral vestibular nucleus and the cerebellar interpositus nucleus even after 5 min of ischemia. These results suggested that these areas were more vulnerable than others, although blood flow was markedly reduced in various regions of the hindbrain. In contrast, areas related to respiratory or cardiovascular control were rather resistant to ischemia. The present study suggests that selective vulnerability during hindbrain ischemia depends mainly on different metabolic characteristics inherent to various neurons in the hindbrain. © 1993.
• INFLUENCE OF OXIDATIVE STRESS ON INDUCED TOLERANCE TO ISCHEMIA IN GERBIL HIPPOCAMPAL-NEURONS

  T OHTSUKI; M MATSUMOTO; K KUWABARA; K KITAGAWA; K SUZUKI; N TANIGUCHI; T KAMADA

  BRAIN RESEARCH ELSEVIER SCIENCE BV 599 (2) 246 - 252 0006-8993 1992/12 [Refereed]
   

  We investigated whether reversible oxidative stress induced by the administration of the superoxide dismutase inhibitor, diethyldithiocarbamate, could induce tolerance to subsequent cerebral ischemia in gerbil hippocampal neurons. Mature male gerbils received intraperitoneal injections of diethyldithiocarbamate (1.0 g/kg), which led to reduced superoxide dismutase activity and increases in thiobarbituric acid-reactive substance in the brain. Cerebral ischemia was produced by occluding the bilateral common carotid arteries for 5 min, either 2 or 4 days after diethyldithiocarbamate injection. One week after ischemia, samples from each brain were stained with hematoxylin-eosin to evaluate ischemic neuronal damage in the hippocampal CA1 sector. Diethyldithiocarbamate treatment 4 days before ischemia had significant protective effects against cerebral ischemia, while diethyldithiocarbamate 2-day pretreatment and vehicle treatment failed to show neuroprotection. Biochemical examinations showed a clear induction of heat shock protein 72 and a significant increase in manganese-containing superoxide dismutase in the hippocampus in animals treated with diethyldithiocarbamate 4 days prior to ischemia. These results suggested that the oxidative stress caused by diethyldithiocarbamate could induce tolerance to ischemia in the gerbil brain, and that the increase in the biosynthesis of manganese-containing superoxide dismutase and heat shock protein 72 could provide a biochemical explanation of the tolerance induced under these conditions.
• THE CHARACTERISTICS OF BLOOD-BRAIN-BARRIER IN 3 DIFFERENT CONDITIONS - INFARCTION, SELECTIVE NEURONAL DEATH AND SELECTIVE LOSS OF PRESYNAPTIC TERMINALS - FOLLOWING CEREBRAL-ISCHEMIA

  K KITAGAWA; M MATSUMOTO; T OHTSUKI; M TAGAYA; T OKABE; R HATA; H UEDA; N HANDA; K SOBUE; T KAMADA

  ACTA NEUROPATHOLOGICA SPRINGER VERLAG 84 (4) 378 - 386 0001-6322 1992/09 [Refereed]
   

  We investigated the extravasation of serum albumin using immunohistochemistry in three different conditions, i.e., infarction, selective neuronal death and selective loss of presynaptic terminals following cerebral ischemia in gerbils. In selective neuronal death, which is typically found in the CA1 neurons of the hippocampus after 5-min bilateral cerebral ischemia, selective damage of postsynaptic components with intact presynaptic sites was demonstrated by immunohistochemical examination for microtubule-associated protein 2 and synapsin I, and albumin extravasation did not become apparent before postsynaptic structures were destroyed. In cerebral infarction, which was consistently observed in the thalamus after 15-min forebrain ischemia, massive albumin extravasation was visible early after ischemia due probably to the ischemic endothelial necrosis. In selective loss of presynaptic terminals, which was detected at the molecular layer of the dentate gyrus in the contralateral. nonischemic hippocampus after unilateral cerebral ischemia, immunoreaction for albumin was not visualized. Since endothelium and glial cells were intact in morphological aspects in selective damage of both pre- and postsynaptic sites, it was thought that extravasation was facilitated by the stimulation of endothelial cells and glial cells with unknown factors that were induced by the destruction of post- but not presynaptic elements.
• The synapsin I brain distribution in ischemia

  K. Kitagawa; M. Matsumoto; K. Sobue; M. Tagaya; T. Okabe; M. Niinobe; T. Ohtsuki; N. Handa; K. Kimura; K. Mikoshiba; T. Kamada

  Neuroscience 46 (2) 287 - 299 0306-4522 1992 [Refereed]
   

  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. Although it is not clear whether loss of immunoreaction for synapsin I is truly consistent with the destruction of presynaptic terminals, the present results suggest that (1) presynaptic terminals are relatively resistant to ischemic stress and are affected much later than neuronal soma and dendrites, and (2) the immunohistochemical method for synapsin I is quite useful for investigation of deafferentation due to Wallerian degeneration and reactive synaptogenesis following neuronal injuries caused by various stresses including ischemia. © 1991.
• RECOMBINANT HUMAN SUPEROXIDE-DISMUTASE CAN ATTENUATE ISCHEMIC NEURONAL DAMAGE IN GERBILS

  M TAGAYA; M MATSUMOTO; K KITAGAWA; M NIINOBE; T OHTSUKI; R HATA; S OGAWA; N HANDA; K MIKOSHIBA; T KAMADA

  LIFE SCIENCES PERGAMON-ELSEVIER SCIENCE LTD 51 (4) 253 - 259 0024-3205 1992 [Refereed]
   

  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.
• INDUCTION OF MN-SOD AND CU, ZN-SOD AFTER TRANSIENT FOREBRAIN ISCHEMIA AND ISCHEMIC TOLERANCE

  T OHTSUKI; M MATSUMOTO; K SUZUKI; K KIMURA; N TANIGUCHI; T KAMADA

  OXYGEN RADICALS ELSEVIER SCIENCE PUBL B V 998 425 - 428 0531-5131 1992 [Refereed]
  
• INDUCED TOLERANCE TO FOLLOWING ISCHEMIC NEURONAL DAMAGES BY PRECEDING OXYGEN RADICAL STRESS

  T OHTSUKI; M MATSUMOTO; K KUWABARA; K SUZUKI; K KIMURA; N TANIGUCHI; T KAMADA

  OXYGEN RADICALS ELSEVIER SCIENCE PUBL B V 998 421 - 424 0531-5131 1992 [Refereed]
  
• DELAYED BLOOD-BRAIN-BARRIER OPENING WAS INDUCED NOT BY PRESYNAPTIC BUT BY POSTSYNAPTIC ISCHEMIC NEURONAL DAMAGES

  M MATSUMOTO; K KITAGAWA; M TAGAYA; T OHTSUKI; R HATA; N HANDA; K KIMURA; T KAMADA

  ROLE OF NEUROTRANSMITTERS IN BRAIN INJURY PLENUM PRESS DIV PLENUM PUBLISHING CORP 299 - 304 1992 [Refereed]
  
• ISCHEMIC TOLERANCE PHENOMENON DETECTED IN VARIOUS BRAIN-REGIONS

  K KITAGAWA; M MATSUMOTO; K KUWABARA; M TAGAYA; T OHTSUKI; R HATA; H UEDA; N HANDA; K KIMURA; T KAMADA

  BRAIN RESEARCH ELSEVIER SCIENCE BV 561 (2) 203 - 211 0006-8993 1991/10 [Refereed]
   

  We investigated the effects of mild and non-lethal ischemic insult on neuronal death following subsequent lethal ischemic stress in various brain regions, using a gerbil model of bilateral cerebral ischemia. Single 10-min ischemia consistently caused neuronal damage in the hippocampal CA1, CA2, CA3 and CA4, layer III/IV of the cerebral cortex, dorsolateral part of the caudoputamen and ventrolateral part of the thalamus. On the other hand, in double ischemia groups, 2-min ischemic insult 2 days before 10-min ischemia exhibited significant protection in the CA1 and CA3 of the hippocampus, the cerebral cortex, the caudoputamen and the thalamus. Five-min ischemic insult 2 days before 10-min ischemia also showed protective effect in the same areas as those of 2-min ischemia except for the CA1 region of the hippocampus, while 1-min ischemic insult exhibited no protective effect in any brain regions. In the immunoblot analysis, both 2- and 5-min ischemia caused increased synthesis of heat shock protein 72 (HSP 72) in the hippocampus, but 1-min ischemia did not. The present study demonstrated that the 'ischemic tolerance' phenomenon was widely found in the brain and also suggested that ischemic treatment severe enough to cause HSP 72 synthesis might be needed for induction of 'ischemic tolerance'.
• TEMPORAL PROFILE OF SERUM-ALBUMIN EXTRAVASATION FOLLOWING CEREBRAL-ISCHEMIA IN A NEWLY ESTABLISHED REPRODUCIBLE GERBIL MODEL FOR VASOGENIC BRAIN EDEMA - A COMBINED IMMUNOHISTOCHEMICAL AND DYE TRACER ANALYSIS

  K KITAGAWA; M MATSUMOTO; M TAGAYA; H UEDA; N OKU; K KUWABARA; T OHTSUKI; N HANDA; K KIMURA; T KAMADA

  ACTA NEUROPATHOLOGICA SPRINGER VERLAG 82 (3) 164 - 171 0001-6322 1991 [Refereed]
   

  We investigated the temporal profile of the extravasation of serum albumin in a reproducible gerbil model of unilateral cerebral ischemia, using immunohistochemical and dye-tracer techniques to evaluate albumin accumulation and the occurrence of active extravasation, respectively. After 30 min of cerebral ischemia and subsequent reperfusion, immunostaining for albumin became visible in the lateral part of the thalamus during the first 3 h, and then expanded to other brain regions up to 24 h. At both 24 h and 3 days after reperfusion, massive extravasation of albumin was noted in the whole ischemic hemisphere, and this had decreased again by 7 days after reperfusion. The extent and the degree of albumin immunopositivity were almost the same in all animals examined at each period after reperfusion. The extravasation of Evans blue, which was allowed to circulate for 30 min before death, was limited to the lateral part of the thalamus during the first 6 h of reperfusion. In the circumscribed area of massive albumin extravasation, many neurons were immunopositive for albumin; most of these neurons appeared to be intact and also showed immunostaining for microtubule-associated protein 2. The current investigation clearly demonstrated that (1) albumin extravasation was produced with reliable reproducibility in this model, (2) the lateral part of the thalamus was the region most vulnerable to ischemic blood-brain barrier damage, and (3) many apparently intact neurons in the ischemic region were positive for albumin.

Books etc

• 今日の臨床サポート（第7版）

  大槻俊輔 (Contributor脳出血)エルゼビアジャパン 2023/04
• 脳卒中治療controversy

  大槻俊輔 (Contributor高血圧性脳内出血超急性期におけるトラネキサム酸の止血効果に臨床的有用性はあるか？)中外医学社 2023/03 9784498328969
• 最新主要文献とガイドラインでみる脳神経内科学レビュー2022-23

  大槻俊輔 (Contributor高血圧性脳内出血)総合医学社 2022/03 433 23-29 

  脳出血は救命目的、次に機能回復を目指すため、エビデンスレベルが高くない治療もあることを理解して脳出血治療ガイドライン2021を紐解き、本稿では指針で採用された論文以降に刊行された質が保たれたものを厳選して解説する。最近の動向を日々の実地臨床の参考にしていただき、科学的根拠に基づいた無理なく、安心安全かつ総合的な有効性が期待できる治療として患者に還元していただけば幸いです。
• Nippon Kinsho vol. 80 suppl1

  toshiho Ohtsuki (ContributorDizziness and Vertigo)日本臨床社 2022/01 710 362-368 

  めまいとは、安静時または動作中に、自分と周囲の空間との位置関係や相互関係が乱れて不快感を伴う症状とされる。内耳は三半規管、前庭、蝸牛の３構造からなり、体位変換を三半規管が感知、前庭が受容し脳へ刺激を送り、外眼筋を調整する動眼神経・外転神経・滑車神経へ投影される。末梢由来の内耳前庭器官、中枢由来の内耳神経（前庭神経と蝸牛神経）および前庭神経核から構築される前庭神経系の経路が障害されることにより、外眼筋に異常運動を起こしめまいが生じる。中枢・前庭系の障害を原因として命に関わることがある中枢性めまいと、末梢・前庭系の障害を原因とする末梢性めまいがあるので迅速な鑑別が必要である。めまい疾患では前庭自律反射による悪心嘔吐などの不快な症状が合併するので短時間に要領よく予め手順を決めて対応すると患者への負担が少ない。
• Clinical Support 6th Ed.

  大槻俊輔、松本昌泰 (ContributorCerebral hemorrhage)エルゼビア ジャパン 2021/10 

  脳卒中治療ガイドライン2021に基づき、治療について改訂を行なった。脳出血急性期における高血圧に対して、できるだけ早期に収縮期血圧を140mmHg未満へ降圧し、７日間維持することは妥当である。ただし、降圧の下限を110mmHg以上に維持することを考慮する。またこの過剰な降圧による急性腎疾患を回避するために収縮期血圧を90mmHg以上の降圧は回避するべき、下限の追加となりました。
• Japanese guidelines for the Management of Stroke 2021

  日本脳卒中学会脳卒中ガイドライン委員会 (ContributorPrimary prevention of intracranial hemorrhage)協和企画 2021/07 9784877942229 xvii, 299p 120 

  高血圧症に対して降圧療法が勧められる。大量飲酒者への節酒および喫煙者への禁煙の指導は妥当である。血栓塞栓症予防においての脳出血発症リスクを考慮した抗血栓薬選択は妥当である。
• Stroke: Innovation physicians must know

  T. Ohtsuki (ContributorStrategic treatment for antithrombotic medication-related brain hemorrhage)診断と治療社 2021/05 725 655-658 

  抗血栓療法中の脳出血の治療原則は、高頻度で起きうる血腫拡大を中断させ、症状進行を防ぐことである。高血圧への降圧療法、抗血栓薬の中止、抗凝固薬に応じて中和療法を迅速に選択する。
• Practice of Internal Medicine

  Yoshio Yazaki (Contributorcerebrovascular and spinal vascular disease and stroke)医学書院 2020/04 9784260038065 1960 1275-1278
• Japanese Guidelines for the Management of Stroke 2015

  Toshiho Ohtsuki (ContributorCerebral Hemorrhage)協和企画 2019/11 9784877942106 345 144-189 

  脳出血急性期の血圧の管理、抗血栓療法に伴う脳出血、妊娠分娩に伴う脳出血の治療指針を改定した。
• Medication for stroke update

  Toshiho Ohtsuki (Contributorantiplatelet drug)メディカ出版 2019/05 3 526-529 

  脳梗塞治療薬として抗血小板薬、オザグレルナトリウム、アスピリン、シロスタゾール、クロピドグレル硫酸塩について概説した。
• Clinical Support 5th Ed.

  Toshiho Ohtsuki, Masayasu Matsumoto (ContributorIntracranial hemorrhage)Elsevier Japan 2019/05 

  高血圧性脳内出血はひとたび発症すると重篤であり死亡率16％、また機能良好群は15％を割るノックアウト型脳卒中と言える。超急性期の治療目的は、血腫拡大による症状進行を止め、生命および機能転帰を改善させることである。高度の高血圧に対しては迅速に目標血圧を140mmHg未満とすること、止血剤の併用と抗凝固薬に対する中和療法が適応となっている。この降圧と止血を来院３０分以内に行うことを目標に院内連携による迅速治療が患者救命と機能転帰良好に直結するTime is Brain疾患である。再発予防における降圧目標がさらに厳格に130/80mmHg未満とする高血圧治療ガイドライン２０１９、欧州脳卒中治療ガイドライン、米国脳卒中治療ガイドラインの最新版を反映させた教科書とした。
• Case study of Tactical diagnosis and treatment for acute stroke

  Toshiho Ohtsuki (Joint workIntracerebral hemorrhage in antithrombotic medication)Nanzando 2019/03 9784525249311 8 201-208 

  抗血栓療法中の脳内出血は血小板止血や凝固システムが抑制されており、発症短期間で急速に血腫が拡大し、重篤な臨床症状をきたす。迅速に診断、降圧、止血剤として病態生理に応じた選択をする必要がある。エビデンスによる治療の実際を解説する論文である。
• Medical Treatment Today, 6th ed.

  Toshiho Ohtsuki (Contributorsubarachnoid hemorrage)Nankodo 2019/03 3 432-434 

  First line is to decrease blood pressure if systolic blood pressure exceeds 140mmHg, and the second line is to make the patient free from headache and awareness. Delayed vasospasm can be prevented by ozagrel, fasdil, and nicardipine.
• Medical Treatment Today, the 6th edition.

  Toshiho Ohtsuki (ContributorCerebral Hemorrhage)Nankodo 2019/03 9784524251193 3 425-427 

  First line is to decrease blood pressure if systolic blood pressure exceeds 150mmHg, and the second line is to replace the coagulation deficiency if available. We must keep in mind to check up the indication of neurosurgical intervention.
• To stop early expansion of intracranial hemorrhage associated with antithromobotic therapy

  Toshiho Ohtsuki (Joint workExpert for stroke antithrombotic therapy)中外医学社 2019/01 9784498328228 16 133-148 

  ➢ 抗血栓療法中の脳出血の治療原則は、高頻度で起きうる血腫拡大を停止させ神経徴候進行を防ぐことである。高度の高血圧があれば降圧療法を行う。凝固止血系異常がある症例への止血治療を第２とする。抗凝固療法中であれば、使用薬剤に応じた中和療法を迅速に選択する。一方、抗血小板療法中の血小板輸血の有用性は乏しい。また、血腫の部位と血腫量、神経学的所見の変容および手術に対する全身予備能から、発症8時間以内の適正な手術のタイミングを逸さないことも念頭に入れる。 ➢ 脳出血前使用の血栓・塞栓症予防のための抗血栓薬の再開については、その基盤疾患の再発や死亡を低減するベネフィットと頭蓋内出血再発のリスクをてんびんにかける必要がある。抗血小板薬再開は不安定な冠動脈疾患、抗凝固薬は心房細動による脳塞栓症既往例や機械弁置換術症例、下肢深部静脈血栓からの肺動脈塞栓症予防として、脳出血後１−８週間をめどとして再開する裁量が医師に与えられる。 ➢ 脳梗塞後の抗血小板療法や抗凝固療法を中止しての観血的処置や手術は一定の脳や冠動脈の血栓症や死亡のリスク伴うことを手術担当診療科や麻酔科と議論することが必要であり、緊急手術の場合抗血栓薬の中和療法や内服薬のヘパリンブリッジングの適応について、また術後適正な時期に必ず抗血栓薬再開することについて提言する。また出血の対処が容易な処置や小手術の施行時には抗血栓薬の内服続行が勧められる。 ➢ 脳梗塞超急性期治療において、直接作用型経口抗凝固薬の最終服用後4時間以内であることが確認できた場合にはアルテプラーゼ静注血栓溶解療法は適応外であり、各抗凝固薬の効果を緊急是正して後に静注血栓溶解療法を行うことは推奨されない。例外的にダビガトラン服用中における特異的中和抗体薬であるイダルシズマブを用いてアルテプラーゼ投与やその後の血管内治療を考慮しても良い。
• Journal of generalist medicine

  Toshiho Ohtsuki (Joint workSecondary Prevention against Stroke in the Aged.)医学書院 2018/08 6 1078-1083 

  脳卒中は健康生命を一瞬で奪う。しかし、その再発は予防できる。高血圧、糖尿病、脂質異常症、喫煙、心房細動、肥満をフレイル認知症高齢者に網羅的に治療するのではなく、ポリファーマシーを避け、脳卒中の病型分類による重要項目に絞り管理することが推奨される。
• Primary Care for Acute Vertebro-Basilar Ischemic and Hemorrhagic Stroke

  Toshiho Ohtsuki (ContributorENTONI 221号 ここが知りたい耳鼻咽喉科に必要な他科の知識)全日本病院出版社 2018/07 9 15-23 

  急性めまいのうちから超急性期初期治療を施せば後遺症を残さず回復させることができる脳卒中を選び出すにはどのようにすればいいでしょうか？病歴と既往歴、そして患者さんを丁寧に神経学的診察という昔ながらの診断が基本であり、補助診断として画像を迅速に展開する必要がある。脳幹や小脳の梗塞や出血に対する科学的根拠の高いtPA血栓溶解療法や降圧・止血という同じ症状でも正反対の個別治療をそれぞれ一分一秒でも早く行う．“構え、撃て、そして狙え。”
• Thrombolytic treatment and subsequent secondary prevention against atherothrombotic brain infarction

  Yukiko Horikawa; Toshiho Ohtsuki (Joint work)Med J KIndai Univ 43 2018/06 11 55-65 

  症例は56歳男性.突然左手足の不全麻痺, 呂律困難が出現し妻運転の自家用車での来院となった.神経診察では瞳孔右2mm左2.5mmと左右差あり, Barre試験左回内くぼみ手肘落ち10秒で5cm下垂, Mingazzini試験左下肢動揺して5秒で5cm下垂, 指鼻試験左拙劣運動分解あり, 回内回外試験左拙劣, 膝かかと試験左拙劣, 触覚下肢低下, 構音障害軽度認めNIHSSスコア 7であった.急性発症で小脳性または感覚性協調運動障害を伴った錐体路症状, 解離性感覚障害, 右不全型ホルネル現象を示す脳卒中を疑い, 病変は橋中下部右側もしくは延髄右内側, 腹側から背側への病変を考え頭部CT検査施行したが延髄, 橋下部右内側に明らかな病変は認めなかった.血液検査結果を確認しrt-PAによる血栓溶解療法の適応と判断した.禁忌項目に該当ないことを確認し発症から63分後にrt-PA投与開始となった.rt-PA直後より活性酸素消去薬にての神経保護を期待し麻痺改善を目指した.投与中のNIHSSスコアは投与開始時で7, 15分時点2, 30分時点0, 以降0を維持し劇的改善を得た.再灌流を確認するためrt-PA投与終了直後にMRI検査を実施した.MRAで脳底動脈に50%の狭窄残存認めたが, 閉塞して部位が再灌流したのではないかと考えた.以上より脳底動脈を責任血管とするアテローム血栓性脳梗塞, 虚血病変は脳幹と診断した.rt-PA投与終了後24時間推移してから再発予防の治療, 急性期再発予防治療を開始し入院から1週間後に完全寛解, 独歩退院となり現在当院外来に定期受診されている.
• Clinical Support

  Toshiho Ohtsuki; Masayasu Matsumoto (ContributorBrain hemorrhage)エルゼビア ジャパン 2018/03
• Japanese guideline for the management of stroke 2015

  Toshiho Ohtsuki (ContributorPrevention of cerebral hemorrhage)Kyowa Publishing 2017/10 9784877941949 2 142-143 

  高血圧に対して降圧療法が推奨される。抗血栓療法において虚血性疾患リスク低下と相反する脳出血合併症増加を考慮した管理が推奨される。
• Make sure to lose no time fighting against hypertensive intracranial hemorrhage.

  Ai Tanaka; Toshiho Ohtsuki (Contributorモーニングセミナーから)Med J KIndai Univ 42 2017/03 11 65-75
• ASAKURA Internal Medicine the 11th Edition

  Toshiho Ohtsuki (ContributorCerebral Infarction)ASAKURA 2017/03 9784254322705 2385 2107-2119
• Fighting against Stroke Update2017

  Toshiho Ohtsuki (Contributor研修医のための教育講座)Med J KIndai Univ 41 2016/03 7 111-128
• Uncommon Causes of Juvenile and Child Stroke

  Toshiho Ohtsuki (ContributorMedcare or Stroke)医学書院 2016/02 6 234-239
• ASAKURA Internal Medicine the 10th Edition

  Toshiho Ohtsuki; Masayasu Matsumoto (ContributorCerebral Thrombosis)朝倉書店 2013/06 2404 2121-2130
• Cardiology

  Toshiho Ohtsuki; Masayasu Matsumoto (ContributorStroke)西村書店 2010/07 9784890133949 1522 1370-1412
• Internal Medicine

  Toshiho Ohtsuki; Masayasu Matsumoto (Contributorcerebral Thrombosis)朝倉書店 2007/09 2208 1765-1771

Conference Activities & Talks

• Frailty and Thrombolysis for Ischemic Stroke  [Invited]

  Toshiho OHTSUKI

  STROKE 2020  2020/08  Yokohama  Japan Stroke Society
   

  高齢化が進み、要介護高齢者が増えるなか、健康寿命の延伸が社会の課題となっている。高齢者の要介護原因の第一位は認知症、次に脳卒中、第三位に高齢による衰弱と続く。フレイルとは加齢に伴うさまざまな臓器機能変化や予備能低下による、外的ストレスに対する脆弱性が高まる状態であり、健剛と自立した生活が困難である要介護状態の中間である。脳卒中を発症し急性期治療により一見非常に回復したにも関わらず、玄関や室内バリアのため、認知機能低下や家族支援が得られず自宅復帰ができず一気に衰弱する症例は稀ではない。日常生活機能障害、易転倒・骨折、認知症へ進み、また生活習慣病や脳卒中・心血管疾患、術後合併症が施設入所や入院へとつながる「負のスパイラル」を形成し自立を失う転帰に至る。高齢フレイルには栄養療法・運動療法は共通して有効であり、感染症予防、社会参加の促進、口腔機能の維持、およびポリファーマシー対策も必要であり、循環器病や脳卒中予防のため危険因子の層別評価をして治療をするべきであるが現場ではできていない。フレイル高齢者脳卒中急性期に対して脳卒中治療ガイドラインに従い健剛者同様積極治療を行うべきかそれとも緩和的かつ侵襲度の低い治療を選択するか、患者との十分なインフォームドコンセントが救急の現場で得ることが容易でない現状では主治医の裁量権に委ねられていると言える。しかし、高齢者に特異的なフレイルを理解し、発症予防、脳卒中早期発見し適正な早期治療介入策を講じる努力は必要である。
• Secondary prevention of aged non-cardiogenic infarction  [Not invited]

  Toshiho Ohtsuki

  堺市医師会内科医会学術講演会  2019/05
• Immediate reversal of dabigatran with idarucizumab for the purpose of subsequent intravenous thrombolysis for acute ischemic stroke.  [Not invited]

  Toshiho Ohtsuki

  5th European Stroke Organization Conference 2019  2019/05  Milano, Italy  European Stroke Organization
   

  he latest officially-authorized Japanese clinical guides 2018 recommend that thrombolysis can be approved both if the time of the late dose of direct oral anticoagulants exceeds 4 hours and if commonly available anticoagulation markers are normal or subnormal. Even for dabigatran users, if patients does not meet the above criteria, direct mechanical thrombectomy can be considered without idarucizumab or rt-PA, however, an alternative option of rapid antagonizaiton with idarucizumab enough to reverse the anticoagulant activity of dabigatoran can be applied to the patients who regain eligibility for intravenous thrombolysis, while thrombectomy cannot be promptly performed.
• Clinical diagnosis and treatment for acute ischemic stroke with frailty  [Invited]

  Toshiho Ohtsuki

  岸和田市医師会第二回学術講演会  2019/05
• Frailty and sarcopenia in stroke  [Invited]

  Toshiho Ohtsuki

  Stroke 2019  2019/03  Yokohama  Japan Society of Stroke and Vascular Neurosurgery
   

  高齢化が進み、要介護高齢者が増えるなか、健康寿命の延伸が社会の課題となっている。高齢者の要介護原因の第一位は認知症、次に脳卒中、第三位に高齢による衰弱と続く。この高齢による衰弱とは老衰と言ってもよく、フレイル・サルコペニアといった病態が強く関与しているとされる。フレイルとは加齢に伴うさまざまな臓器機能変化や予備能低下による、外的ストレスに対する脆弱性が高まる状態であり、健常と自立した生活が困難である要介護状態の中間である。軽症の脳卒中を発症したにも関わらず、段差の多い日本の家屋への家庭復帰ができず一気に衰弱する症例は稀ではない。日常生活機能障害、易転倒・骨折、認知症へ進み、また生活習慣病や脳卒中・心血管疾患、術後合併症が施設入所や入院へとつながる「負のスパイラル」を形成し、自律性を失う転帰に至る。サルコペニアは加齢に伴う骨格筋量の低下に歩行速度・握力等の身体機能の低下が合併した病態・症候群であり、QOLの低下、転倒・骨折、フレイル、身体機能低下、歩行速度低下、認知症、入院および死亡のリスクとなる。脳卒中発症前のフレイル・サルコペニア症候群が脳卒中発症の誘因となったのではないか、また脳卒中後フレイル・サルコペニアが合併し、機能転帰不良となったことは実地臨床でしばしば遭遇する。これらには栄養療法・運動療法は共通して有効であり、感染症予防、社会参加の促進、口腔機能の維持、およびポリファーマシー対策も必要である。脳卒中急性期から回復期、維持期の診療において、高齢者に特異的なこれらの病態を理解し、早期発見し早期治療介入策を適切に講じることは、再び健常な状態に戻りえる可能性がさらに高まるとされる。
• Poor Functional Outcome after Hemorrhagic Stroke in Active Infective Endocarditis.  [Not invited]

  Toshiho Ohtsuki

  European Stroke Organization Karolinska Stroke Update Conference  2018/11  Stockholm, Sweden  European Stroke Organization
   

  Background and Objective: Infective endocarditis (IE) suddenly causes not only ischemic stroke by bacterial emboli but also hemorrhagic stroke by inflamed arteries or aneurysms prone to rupture. Stroke in IE often makes the following valve-repairing surgery canceled or put off to lead to mortality. We examined which factors were associated with neurological outcome after stroke. Methods: We conducted the observational study on 22 consecutive patients (14 men, aged 23-82, median 55) with acute stroke after definite or possible IE according to the Duke criteria from October 2005 to September 2018. We evaluated modified Rankin Scale (mRS) at 3 months after stroke and divided each patient into either favorable outcome with mRS scale of 0 to 1 or poor outcome of from disability to death with mRS scale of 2 to 6. The best medical treatment and open-heart surgery requisite for survival were applied to every patient according to the AHA guidelines for treatment of IE. Results: Logistic regression analysis revealed no significant association between the poor outcome and age, gender, involvement of mitral valve, larger vegetation than 1 cm, isolated staphylococcus aureus from blood, and presence of disturbed consciousness or hemiplegia. After stroke, recurrence of stroke, symptomatic embolism to other organs than the brain, and complicated meningitis/brain or intraocular abscess failed to affect the clinical outcome. While 2 hemorrhages and 11 infarcts were noted in 13 favorable-outcome patients, 9 patients of the poor outcome consisted of subarachnoid hemorrhage in 6, parenchymal hematoma on infarcts in 4 and multiple infarctions in 2. Out of the poor outcome patients, 3 waited for cardiac operation but died of recurrent bleeding and heart failure. Eight of 10 hemorrhagic stroke led to the poor prognosis, while 11 out of 12 ischemic stroke got the advantageous outcome. Hemorrhagic stroke provided patients with the poor outcome so often as compared with pure ischemic stroke (Hazard ratio, 48: 95% CI, 3.7-622; p=0.00073). Conclusions: Hemorrhagic stroke was associated with the poor outcome. Further studies are under way to identify how long hemorrhagic stroke defers surgeons’ deciding open-heart surgery and how often intracranial bleeding takes place during operation.
• Primary Care for Acute Ischemic Stroke by Orthopedic Surgeon  [Not invited]

  Toshiho Ohtsuki

  第40回日本関節運動学的アプローチ医学会学術集会  2018/09
• Hemorrhagic transformation from ischemic perforating arteries around microbleed following winning rt-PA thrombolysis in the basilar branch atheromatous disease.  [Not invited]

  Toshiho Ohtsuki

  5th European Stroke Organisation Conference  2018/05
• Uncommon Causes of Stroke  [Invited]

  Toshiho Ohtsuki

  Stroke 2018  2018/03  Fukuoka, Japan  Japan Society of Stroke
   

  循環器疾患の危険因子に乏しい脳卒中症例は特殊な原因や病態による発症の可能性を考える必要がある。脳卒中データバンク2015によると脳梗塞のうち約８％が三大病型「ラクナ、アテローム血栓性脳梗塞、心原性脳塞栓症」以外の「その他の脳梗塞ないし分類不能の脳梗塞」と分類されている。脳卒中治療ガイドライン2015によると「その他の脳血管障害」として動脈解離、大動脈解離、もやもや病、卵円孔開在や肺動静脈奇形による奇異性脳塞栓症、悪性腫瘍やその他のさまざまな病態による凝固亢進状態、大動脈炎症候群、いわゆる高血圧性脳症として脳血管攣縮症候群や可逆性後頭葉白質脳症が記載されている。また、脳静脈・脳静脈洞血栓症、遺伝性脳血管障害としてFabry病やCADASIL、血液凝固循環動態変容による周産期脳梗塞等もいわゆるその他の脳梗塞uncommon ischemic strokeと言える。これらの超急性期脳卒中対応における時間的制約の中での診断と治療を進める救急の現場においてuncommon strokeであると疑うためのヒントやまた治療における落とし穴に注意を払い、最大の機能的および生命的な最良の転帰を得る努力が必要となる。すなわち、虚血性脳卒中に対するrt-PAや血管内治療による血行再建には科学的根拠が十分でないことがあり、治療の有用性と有害性を天秤にかけて主治医の裁量と決断により行われる。また、長期的転帰を鑑みた脳卒中再発予防として選ぶ治療が科学的根拠に乏しい条件にあれば、現時点では原疾患の病態生理に適うと思われる治療を選択せざるを得ない。
• Prevention of Stroke  [Invited]

  Toshiho Ohtsuki

  平成２９年第三回泉州地域リハ連携会議  2018/02  Kishiwada, Japan 

  回復期機能回復に最も有効とされるリハビリテーションに、 服薬アドヒランス向上と摂食摂食に注意を払い、再発予防と自宅生活を目標に「地域連携パス」を用いた地域包括システムで勝つ。
• Brain Attack 2018  [Invited]

  Toshiho Ohtsuki

  大阪市立大学大学院医学研究科医学研究セミナー  2018/01  大阪  大阪市立大学大学院医学研究科神経内科学
  
• Pinpoint hemorrhage in the choroid plexus of the dorsal third ventricle in eosinophilic granulomatosis with polyangitis  [Not invited]

  Toshiho Ohtsuki

  European Stroke Organization Conferece 2017  2017/05  Prague, Czech Republic.  European Stroke Organization
   

  Eosinophilic granulomatosis with polyangitis prone to hemorrhage, that is a type of systemic necrotizing arteritis, was challenging disease process to manage not only hemorrhagic and ischemic stroke but also a prudent indication of neurosurgery.
• Long-term post stoke management upon family doctor  [Invited]

  Toshiho Ohtsuki

  第３４回日本神経治療学会総会  2016/11 

  脳卒中は高齢者に頻発し、備えなく突然発症し、少なからず片麻痺、言語障害、認知機能障害等の後遺症を残す。地域ぐるみで患者の家庭や社会復帰への援助が必要であり、多くの医療機関、他職種の医療スタッフが力を合わせて医療、介護、行政サービス等を提供している。脳卒中における病院・診療所の医師の連携において、各医療圏域で採用されている脳卒中地域連携パスを用いて、急性期・回復期・かかりつけ家庭医への情報の共通化を行い、脳卒中治療ガイドライン2015記載の科学的根拠に基づいた治療の継続が、脳卒中患者の再発予防、最善の機能回復状態の維持に非常に役立ち、包括的な脳卒中地域医療では基本骨格であると思われる。本稿では、急性期治療から回復期リハビリテーションを経て、無事にかかりつけ主治医に患者が復し、健やかな状態を維持できるようにする治療、特に生活習慣病に対する治療について述べる。非心原性脳梗塞症に対して抗血小板療法としてアスピリン、シロスタゾール、クロピドグレルのいずれかを投与する。２剤併用長期投与による有用性は現在証明されていないため、出血性合併症予防のため単剤とするのが推奨される。非弁膜症性心房細動に伴う心原性脳塞栓症に対して経口凝固薬を投与する。ワルファリンと比較して直接経口抗凝固薬が消化管や頭蓋内出血性合併症の回避に有利である。高血圧性脳内出血および抗血栓療法中の脳梗塞症例への再発予防として２４時間にわたるまた日々変動の少ない安定的な降圧療法が推奨される。目標血圧140/90mmHg未満とする。長時間作用型カルシウム拮抗薬、少量の降圧利尿薬、アンジオテンシン変換酵素阻害薬・アンジオテンシン受容体拮抗薬等のクラスが選択され、降圧度に応じた予防効果が得られるが、その降圧目標値には高齢脳卒中症例に関してはまだ議論が必要である。脳梗塞、特にアテローム血栓性脳梗塞症例に対して動脈硬化の危険因子の管理が必要で、禁煙、運動励行・食生活の是正、適正体重を指導し、糖脂質代謝への介入を行う。糖尿病に対する治療では低血糖発作を予防し、大血管合併症予防のためのHbA1c目標を認知機能障害・ADL低下等を勘案して7.0-8.0%の間に設定すると糖尿病治療ガイドライン2016に記載された。インスリン抵抗性改善薬ピオグリタゾンや低血糖予防を第一としたDPP-4阻害薬、GLP-1受容体作動薬等のクラスのどれを第一選択するのがいいかはまだ根拠は乏しい。脂質異常症すなわち高LDL血症対して、脂質異常症治療ガイド2013や脳卒中治療ガイドライン2015、また日本人脳梗塞既往高コレステロール血症例に対する再発予防研究J-STARS等によると、多面的効果をも期待して脂質低下薬スタチンの投与やEPAの併用を行う(Fire and Forget)が目標LDLコレステロール値まで脂質吸収抑制薬やPCSK９阻害薬等併用してまで下降させる(Target to Treat)のがいいかは要議論であると思われる。また、脳卒中から回復した症例の主たる死亡原因は、癌、心臓病、肺炎、脳卒中であり、脳卒中再発予防以上に重要な長期マネージメントが必要である。高齢者ならでは訴えの少ない悪性腫瘍への検索、発見時における手術への備えや抗血栓薬中止のタイミング、術後衰えた機能回復への再リハビリテーションへの手配も必要である。また、非典型症状を呈する慢性心不全や急性冠動脈症候群への迅速な対応、誤嚥等による肺炎と呼吸器リハビリの対応も必要とされる。脳血管性うつ・アパシー・認知症は脳卒中機能回復への阻害因子となるので、心のケアや生活支援に加え、薬物療法が追加される。また、嚥下障害に伴う栄養摂取量低下とやせ・筋肉量減少ザルコペニア、虚弱性(フレイル)、骨粗鬆症や骨折、ロコモティブ症候群への対応、認知症によるADL悪化、すなわちEnd of Lifeの状態に至った時における新たなる総合的なケアの策定と重視してきた再発予防薬の中断や断念の時期、患者や家族へのこころのケア、老老介護における負担軽減を地域社会全体で対応できるように家庭医は応需していくことになる。
• Primary Care for Acute Vertebro-Basilar Ischemic and Hemorrhagic Stroke  [Invited]

  Toshiho Ohtsuki

  第75回日本めまい平衡医学会総会・学術講演会  2016/10  Osaka  日本めまい平衡医学会
   

  循環器疾患やその発症危険因子を有する高齢者に突然発症のめまいの中には表３のようにAICA/PICA（脳幹・小脳梗塞）とCerebellar Hemorrhage（脳幹・小脳出血）という脳卒中が混在しており、早期治療を行わないと症状進行し、後遺症を残し日常生活活動を大きく阻害する。しかし、実地臨床では典型的とは限らず非常に難解かつ意表をつくような症例もしばしば混入しており、脳卒中専門医であっても手こずる。実施医家の先生がたにとって「これは末梢性めまい、平衡器疾患でない」と疑うことから始まる言える． この鑑別診断のプロセスには、CT と拡散強調画像DWIが有用であるが、標準的な神経学的診察（NIHSS）が基本となります。表３に示す、急性めまいの鑑別診断として従来のABC-DEMONに CT & DWI, Neurological examinationを追加したABC2-D2EMON2を再度強調したい。 しかし、多忙な日常臨床において、このような作業過程を行うべきと判断するトリアージとして、表４の病歴A2BC2D2を採択するといいでしょう。循環器内科におけるABCDスコアは、心房細動における脳梗塞・全身塞栓症のリスクを示す指標（Age高齢、Blood Pressure高血圧、Coronary Disease冠動脈疾患、Diabetes糖尿病）であるが、これにAf心房細動、Cancer癌、Dyslipidemia脂質異常症を追加したA2BC2D2スコアで少なくとも２以上の場合、脳卒中を除外する診察、病歴、診察を追加することが推奨される。神経学的に異常が乏しい場合、めまい嘔気嘔吐で診察できない場合は画像検査を追加する必要がある。CTは小脳や橋出血の診断に強いが、脳梗塞診断には弱く、やはりMRIが必要である。拡散強調画像が脳梗塞巣検出で最速最強のツールであり、責任血管を調べるMRAは重症度判断含めて、上述の治療戦略立案に有用である。そして現場での心構えとして、急性めまいに対する初期治療は、画像検査と神経診察、その後脳虚血も脳出血に個別の初期治療を“構え、撃て、そして狙え(”Ready, Fire and Aim)である。これは時間との戦い(“Time is Brain.”)である
• Therapeutic Strategy for hypertensive intracranial hemorrhage  [Invited]

  Toshiho Ohtsuki

  第57回日本神経学会学術大会  2016/05  Kobe, Japan  日本神経学会
   

  脳卒中データバンク2015によると、7万人中18％が脳内出血、その半数が発症２時間以内に搬入、男性58％、平均男性65歳、女性71歳であった。死亡16％、退院時mRS４以上の機能転帰不良が57％に至り、ラクナ、アテローム血栓性脳梗塞と比し転帰不良であり、心原性脳塞栓症同様ノックアウト型脳卒中と言える． 転帰不良因子は、高齢、初期脳損傷すなわち血腫量や神経機能障害が大きいこと、高血圧、抗血栓薬内服、搬入後の血腫拡大、脳浮腫、神経徴候悪化とされている。脳出血急性期の血圧は、全身状態と病前血圧値を考慮し、カルシウム拮抗薬あるいは硝酸薬の微量点滴静注により1時間以内に収縮期血圧180mmHg以上の場合160mmHg未満に、150mmHg以上の場合140mmHg未満に、その後発症24時間、収縮期血圧130mmHgを目標に降下させ、発症3-7日まで24時間にわたる安定的な降圧療法を経口降圧薬併用にて維持することが推奨される。抗血栓療法に伴う脳出血の推奨文はこのように改訂されるのではないかと思う．1. ワルファリン内服中の脳出血の場合は、血液製剤を用いて可能な限り速やかにPT-INRを1.3未満に中和することが勧められるが、血液製剤としては、プロトロンビン複合体、新鮮凍結血漿、ビタミンKの併用を考慮しても良い。2. 直接経口抗凝固薬ダビガトラン、Xa阻害薬リバロキサバン・アピキサバン内服中の脳出血の場合それぞれに対しイダルシツマブ、アンデキサネットαの使用(保険適応未収載)を考慮しても良い。と変更になろう．脳内出血の超急性期治療目標は、一筋縄でない「血腫拡大からの神経症候悪化、転帰不良の流れ」を止めることである。降圧と止血を「より早く開始、より速く目標まで、そして安定的に」行うことが推奨される。 ”Time is Brain.”を脳出血にも再認識したい。
• To enjoy vascular neurology and stroke care  [Invited]

  Toshiho Ohtsuki

  Stroke 2015  2015/03 

  脳卒中医療のプロフェッショナルになる平坦でなく、曲がりくねり遠いが、昔ながらの路がある。幅広い内科の修練と知識、および関連各科の経験を欠くことができない。確かな臨床医からのマンツーマン、手をとり昔ながらの教育、無駄なく効率のよい研修、充実したプログラムはなく、一定期間集中的に各分野を学び、総合力をつけるコース、学会・論文報告は臨床的問題点の整理、解決法を論理的に学ぶことができる、難関な専門医をめざす 大学院での研究、臨床の不確実性と論理性、新しい病態生理、診断と治療法の発見、さまざまな指導医との出会い、真のプロフェッショナルは引く手あまた、第一線の仕事を長く続けることができるということである。よくわからない、よくならない、しかしあきらめない脳卒中・神経救急診療であるが、脳卒中をいう病をとことん知りたい、治し癒したいという貪欲さ、我を忘れて邁進する愚鈍さ、これを継続することができることが脳卒中診療を担う楽しみといえる。
• Prevention of intracranial hemorrhage.  [Invited]

  Toshiho Ohtsuki

  Stroke 2015  2015/03
• Hypertensive intracranial hemorrhage  [Not invited]

  Toshiho Ohtsuki

  Stroke 2015  2015/03
• rt-PA  [Not invited]

  Toshiho Ohtsuki

  Stroke 2015  2015/03

MISC

• 糖尿病性ケトアシドーシスに伴う脳症の一例

  松本 真林; 大槻 俊輔; 加藤 天美  臨床神経学  58-  (4)  268  -268  2018/04
• 糖尿病性ケトアシドーシスに伴う脳症の一例

  松本 真林; 大槻 俊輔; 加藤 天美  臨床神経学  58-  (4)  268  -268  2018/04
• 発作性夜間血色素尿症に伴う静脈洞血栓症に対しeculizumabを用い良好な経過を得た一例

  松本 真林; 田崎 貴之; 辻 潔; 加藤 天美; 大槻 俊輔  臨床神経学  57-  (6)  346  -346  2017/06
• 頸動脈内膜剥離術における到達可能な内頸動脈遠位端のMRAによる術前評価

  久保田尚; 真田皓寧; 田崎貴之; 宮内正晴; 谷川緑野; 大槻俊輔; 加藤天美  近畿大学医学雑誌  41-  (3-4)  18A  -18A  2016/12
• 頸動脈内膜剥離術における到達可能な内頸動脈遠位端のMRAによる術前評価

  久保田 尚; 真田 寧皓; 田崎 貴之; 宮内 正晴; 谷川 緑野; 大槻 俊輔; 加藤 天美  近畿大学医学雑誌  41-  (3-4)  18A  -18A  2016/12
• Serum Anti-Periodontal Pathogen Antibody associated with Atrial Fibrillation and Carotid Plaque

  Naohisa Hosomi; Shiro Aoki; Tomohisa Nezu; Toshiho Ohtsuki; Takemori Yamawaki; Masayasu Matsumoto  STROKE  44-  (2)  2013/02
• Is A Low Ankle-brachial Index A Predictive Factor For Poor Recovery From Acute Ischemic Stroke?

  Shuichiro Neshige; Toshiho Ohtsuki; Naoyuki Hara; Shinichi Takeshima; Takahiro Himemo; Tomoko Fukushima; Kazuhiro Takamatsu; Taisei Ota; Masaru Kuriyama; Masayasu Matsumoto  STROKE  44-  (2)  2013/02
• Association Of Alpha2-macroglobulin As A Novel Biomarker With Acute Ischemic Stroke

  Tomohisa Nezu; Naohisa Hosomi; Shiro Aoki; Toshiho Ohtsuki; Takemori Yamawaki; Masayasu Matsumoto  STROKE  44-  (2)  2013/02
• Delayed Increase In Blood Glucose Fluctuation And Neurological Outcome After Acute Stroke

  Shuichiro Neshige; Toshiho Ohtsuki; Naoyuki Hara; Shinichi Takeshima; Takahiro Himemo; Tomoko Fukushima; Kazuhiro Takamatsu; Taisei Ota; Masaru Kuriyama; Masayasu Matsumoto  STROKE  44-  (2)  2013/02
• Association of Hemorrhagic Stroke with Recurrence Stroke caused by Infective Endocarditis

  Toshiho Ohtsuki; Eiichi Nomura; Amami Kato; Masayasu Matsumoto  STROKE  44-  (2)  2013/02
• Knowledge of Stroke and Transient Ischemic Attack among Medical Students

  Toshiho Ohtsuki; Takuya Uchiyama; Amami Kato; Masayasu Matsumoto  CEREBROVASCULAR DISEASES  36-  44  -44  2013
• Accidental points beyond optimal warfarin-therapeutic-range and hemorrhagic complication in post-stroke aged patients

  T. Ohtsuki; M. Matsumoto  CEREBROVASCULAR DISEASES  35-  758  -758  2013
• The Consideration of the Patients with TIA Mimics in Our Hospital

  Shiro Aoki; Naohisa Hosomi; Tomihisa Nezu; Satoshi Kubo; Kazuhide Ochi; Toshiho Ohtsuki; Hirofumi Maruyama; Masayasu Matsumoto  CEREBROVASCULAR DISEASES  36-  10  -11  2013
• High Levels of Serum Alpha2-Macroglobulin are Associated with White Matter Lesions but not with IL-6 in Acute Ischemic Stroke Patients

  Tomohisa Nezu; Naohisa Hosomi; Shiro Aoki; Toshiho Ohtsuki; Hirofumi Maruyama; Masayasu Matsumoto  CEREBROVASCULAR DISEASES  36-  39  -39  2013
• 言語課題における「難易度」と脳賦活領域:fMRIによる検討

  岡田理恵子; 中野直樹; 宮内正晴; 石井一成; 村上卓道; 大槻俊輔; 加藤天美  日本ヒト脳機能マッピング学会プログラム・抄録集  15th-  84  2013
• 広島県を中心とした急性期脳梗塞症例に対する多施設共同研究(HARP Registry Study)

  青木 志郎; 細見 直永; 大槻 俊輔; 河野 智之; 末田 芳雅; 山脇 健盛; 松本 昌泰; HARP Registry Study Group  臨床神経学  52-  (12)  1420  -1420  2012/12
• t-PA静注療法に対する多施設共同研究(HARP Registry Study) 年齢別の検討

  青木 志郎; 細見 直永; 大槻 俊輔; 河野 智之; 末田 芳雅; 山脇 健盛; 松本 昌泰; HARP Registry Study Group  日本老年医学会雑誌  49-  (6)  825  -825  2012/11
• 総頸動脈起始部が閉塞し盲端となった総頸動脈内に可動性の血栓が疑われた2症例

  中森 正博; 末田 芳雅; 河野 通裕; 竹田 育子; 向井 智哉; 河野 智之; 青木 志郎; 細見 直永; 大槻 俊輔; 松本 昌泰  Neurosonology  25-  (増刊)  52  -52  2012/06
• t-PA静注療法症例に対する多施設共同研究 HARP Registry Study

  青木 志郎; 細見 直永; 大槻 俊輔; 河野 智之; 末田 芳雅; 山脇 健盛; 松本 昌泰; HARP Registry Study Group  日本血栓止血学会誌  23-  (2)  188  -188  2012/04
• 悪性腫瘍を合併した急性期脳梗塞における血液凝固異常

  河野 智之; 大槻 俊輔; 細見 直永; 竹田 育子; 青木 志郎; 末田 芳雅; 石原 佳代子; 中村 毅; 山脇 健盛; 松本 昌泰  広島医学  65-  (2)  130  -130  2012/02
• Pure Ipsilateral Hypoglossal Nerve Paralysis Caused by Internal Carotid Artery Dissection

  Hiroki Fujii; Toshiho Ohtsuki; Ikuko Takeda; Shiro Aoki; Hiroki Ueno; Kazuhide Ochi; Takeshi Nakamura; Naohisa Hosomi; Takemori Yamawaki; Masayasu Matsumoto  CEREBROVASCULAR DISEASES  34-  78  -78  2012
• Present Status of J-STARS and Substudies

  Masayasu Matsumoto; Takemori Yamawaki; Toshiho Ohtsuki; Naohisa Hosomi; Masanori Fukushima; Yoji Nagai; Kazuo Minematsu; Chiaki Yokota; Hideki Origasa; Shinichiro Uchiyama; Setsuro Ibayashi  CEREBROVASCULAR DISEASES  34-  129  -129  2012
• Association of Serum Anti-Periodontal Pathogen Antibody with Ischemic Stroke

  Naohisa Hosomi; Shiro Aoki; Katsuhiko Matsuo; Kazushi Deguchi; Hisashi Masugata; Koji Murao; Noriko Ichihara; Hideo Ohyama; Hiroaki Dobashi; Tomohisa Nezu; Toshiho Ohtsuki; Osamu Yasuda; Hirofumi Soejima; Hisao Ogawa; Yuichi Izumi; Masakazu Kohno; Junko Tanaka; Masayasu Matsumoto  CEREBROVASCULAR DISEASES  34-  (5-6)  385  -392  2012  [Refereed]
  
• 脳卒中医療連携推進専門委員会 平成22年度調査研究報告書 (広島県地域保健対策協議会 調査研究報告特集号(平成22年度))

  松本 昌泰; 大槻 俊輔  広島医学  64-  (12)  575  -581  2011/12
• Treatable dementia(治療可能な認知症)を見逃さないために (脳疾患画像読影のコツとpitfall)

  大槻 俊輔; 宮地 隆史; 松本 昌泰  Monthly book medical rehabilitation  (132)  139  -142  2011/06
• The Relationship Between Blood Glucose Fluctuation And Neurological Outcome In Acute Ischemic Stroke Patients

  Hiroki Fujii; Toshiho Ohtsuki; Satoshi Kubo; Kota Sato; Kazuhiro Takamatsu; Akiko Ota; Taisei Ota; Masaru Kuriyama; Masayasu Matsumoto  STROKE  42-  (3)  E337  -E337  2011/03
• 脳梗塞急性期の血圧変動と予後についての検討 吻側延髄腹外側への血管圧迫の関与

  青木 志郎; 大槻 俊輔; 末田 芳雅; 石原 佳代子; 河野 智之; 細見 直永; 山脇 健盛; 松本 昌泰  臨床神経学  50-  (12)  1076  -1076  2010/12
• 急性期脳梗塞における血圧変動と転帰 延髄吻側腹外側核(RVLM)への血管圧迫の影響

  青木 志郎; 大槻 俊輔; 細見 直永; 末田 芳雅; 河野 智之; 大下 智彦; 山脇 健盛; 松本 昌泰  脳循環代謝  22-  (1)  108  -108  2010/11
• Bilateral hypogeusia in a patient with a unilateral paramedian thalamic infarction

  Makoto Nakajima; Toshiho Ohtsuki; Kazuo Minematsu  JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY  81-  (6)  700  -701  2010/06
• 喫煙が脳卒中を引き起こしているのか? (特集 喫煙と生活習慣病のかかわりを探る)

  末田 芳雅; 大槻 俊輔; 松本 昌泰  Life style medicine  4-  (2)  120  -127  2010/04
• 脳に起きる大血管障害 (特集 たとえで病態・ケアがわかる! そのまま指導に使える! 糖尿病大血管障害)

  大槻 俊輔; 松本 昌泰  糖尿病ケア  7-  (6)  518  -529  2010
• The influences of smoking for incidence and prognosis of stroke

  末田 芳雅; 大槻 俊輔; 松本 昌泰  Respiration and circulation  57-  (10)  1015  -1022  2009/10
• Siah-1 facilitates ubiquitination and degradation of factor inhibiting HIF-1 alpha (FIH) (Retraction of vol 353, pg 324, 2007)

  Hiromasa Fukuba; Hiroshi Yamashita; Yoshito Nagano; Hong Guo Jin; Masanori Hiji; Toshiho Ohtsuki; Tetsuya Takahashi; Tatsuo Kohriyama; Masayasu Matsumoto  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS  388-  (3)  618  -618  2009/10
• Clinical relevance of central systolic blood pressure and augmentation index : comparison with carotid echo parameters

  SHRESTHA Isha; TAKAHASHI Tetsuya; NOMURA Eiichi; OHTSUKI Toshiho; KOHRIYAMA Tatsuo; MATSUMOTO Masayasu  神経超音波医学 = Neurosonology : official journal of Japan Academy of Neurosonology  22-  (1)  11  -16  2009/07
• ARBの臓器保護作用(脳血管) (特集 ARBと内科疾患) -- (ARBの臓器保護作用--Beyond blood pressure)

  大槻 俊輔; 松本 昌泰  診断と治療  97-  (4)  722  -727  2009/04
• The Relationship Between Hyperglycemia Or Blood Sugar Variation And Neurological Outcome In Diabetic Patients After Acute Intracranial Hemorrhage

  Hayato Matsushima; Toshiho Ohtsuki; Ikuko Takeda; Motonori Takamiya; Tomoko Fukushima; Kazuhiro Takamatsu; Katsuya Goto; Masayasu Matsumoto  STROKE  40-  (4)  E231  -E231  2009/04
• Correlation between Recurrent Intracerebral Hemorrhage and the Location of Microbleeds on Prior T2*-weighted MR Images

  Yoshimasa Sueda; Hiromitsu Naka; Toshiho Ohtsuki; Tomoyuki Kono; Shiro Aoki; Kayoko Kawase; Tomohiko Ohshita; Eiichi Nomura; Shinichi Wakabayashi; Tatsuo Kohriyama; Masayasu Matsumoto  STROKE  40-  (4)  E198  -E198  2009/04
• 糖尿病がひきおこす大血管症--脳血管障害:脳梗塞を中心に (糖尿病のすべて) -- (糖尿病の合併症)

  山崎 雄; 大槻 俊輔; 松本 昌泰  からだの科学  (261)  61  -65  2009
• Strategic therapeutics against stroke 2009

  大槻 俊輔; 松本 昌泰  綜合臨床  58-  942  -948  2009
• Advantages of High b Value Diffusion-Weighted Imaging in the Diagnosis of Acute Stroke - A Case Report

  Aidos Doskaliyev; Fumiyuki Yamasaki; Taiichi Saito; Eiichi Nomura; Kazuhiko Sugiyama; Toshiho Ohtsuki; Masayasu Matsumoto; Kaoru Kurisu  CEREBROVASCULAR DISEASES  27-  (6)  616  -617  2009
• Etiology, diagnosis, treatment, secondary prevention of hemorrhagic stroke

  大槻 俊輔; 松本 昌泰  Japanese journal of clinical medicine  66-  338  -344  2008/11
• Japan stain treatment against recurrent stroke

  郡山 達男; 大槻 俊輔; 松本 昌泰  Japanese journal of clinical medicine  66-  509  -516  2008/10
• Acute stroke

  大槻 俊輔; 松本 昌泰  綜合臨床  57-  1349  -1353  2008
• Paradigm shift of secondary prevention against stroke

  大槻 俊輔; 松本 昌泰  医学のあゆみ  223-  (5)  443  -447  2007/11
• 循環器疾患の予防と対策 脳内出血とくも膜下出血 (特集 高齢者の循環器疾患を予防する--動脈硬化性疾患の克服に向けて)

  大槻 俊輔; 松本 昌泰  綜合臨床  56-  (2)  315  -322  2007/02
• Mechanical compression of the extracranial vertebral artery during neck rotation.

  M Sakaguchi; K Kitagawa; H Hougaku; H Hashimoto; Y Nagai; H Yamagami; T Ohtsuki; N Oku; K Hashikawa; K Matsushita; M Matsumoto; M Hori  Neurology  61-  (6)  845  -7  2003/09
• 脳卒中・脳循環代謝異常による症状と早期発見のポイント (特集 「これだけは知っておきたい」脳循環代謝とケア)

  大槻 俊輔; 松本 昌泰  ブレインナーシング  17-  (3)  242  -249  2001/03
• 虚血性神経細胞死の機序 (11月第1土曜特集 脳梗塞超急性期--Brain attack時代の診断と治療) -- (超急性期の病態)

  大槻 俊輔; 松本 昌泰  医学のあゆみ  191-  (6)  639  -645  1999/11
• Induction of tolerance to ischemia by preconditioned interleukin-1 alpha in gerbil hippocampal neurons

  T Ohtsuki; CA Reutzler; K Tasaki; JM Hallenbeck  STROKE  27-  (1)  138  -138  1996/01

Awards & Honors

• 1995/11 Fogarty International Center of NIH Fellow Award of Research Excellence
   「interleukin-1の受容体刺激を介した神経細胞における虚血耐性現象獲得」 

  受賞者: Toshiho Ohtsuki
• 1994/03 Japan Heart Foundation Award for Excellent Research and Studying Abroad
   「冬眠時における脳虚血に対する神経細胞の虚血耐性現象獲得機序の解明および脳虚血治療への応用」 

  受賞者: Toshiho Ohtsuki
• 1992/04 Japan Society of Stroke Kusano's Best Awards of Excellent Research
   nfluence of oxidative stress on induced tolerance to ischemia in gerbil hippocampal neurons. 

  受賞者: Toshiho Ohtsuki

Research Grants & Projects

• 7. 遠隔脳卒中診断システムの基盤構築のための検討 遠隔脳卒中診断システムの基盤構築のための検討

  日本学術振興会：科学研究費補助金基盤研究(B)

  Date (from‐to) : 2011 -2013 

  Author : 大槻 俊輔
• 6. 動脈硬化の多角的評価による脳卒中個別化治療開発に関する研究

  厚生労働省：厚生労働科学研究費補助金

  Date (from‐to) : 2010 -2012 

  Author : 大槻 俊輔
• 4. 保健指導を中心とした地域における脳卒中および心筋梗塞の再発予防システムとエビデンス構築に関する研究

  厚生労働省：厚生労働科学研究費補助金

  Date (from‐to) : 2009 -2011 

  Author : 大槻 俊輔
• 3. 一過性脳虚血発作の診断基準の再検討、ならびにわが国の医療環境に即した適切な診断治療システムの確立に関する研究

  厚生労働省：厚生労働科学研究費補助金

  Date (from‐to) : 2009 -2011 

  Author : 大槻 俊輔
• 1. 人工無重力下で大量培養した間葉系細胞による虚血生損傷脳治療法の最適化

  日本学術振興会：科学研究費補助金基盤研究(B)

  Date (from‐to) : 2008 -2010 

  Author : 大槻 俊輔
• Establishment of regenerative medical technique on ischemic brain injury through optimal manipulation ofintrinsic and/or ES derived neuronal stem cell

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2006 -2007 

  Author : MATSUMOTO Masayasu; OHTSUKI Toshiho; TAKAHASHI Tetsuya

   

  Elucidation of the inna-cellular signal transduction during cerebral ischemia is essential for regenerative therapeutics against ischemic stroke induced brain damage. Hypoxia-inducible factor 1 (HIF1) is a ke transcription factor under hypoxic conditions, and those functional analyses are helpful far understanding the pathophysiology of cerebral ischemia The activity of HIF-1a is regulated by two types of hydroxylases, prolyl-hydroxylase (PHD) and aspargynylhydroxylase factor inhibiting HIF-1a (FIH). Hydroxylation of HIF-1a by PHD and FIH causes proteasomal degradation and transcriptional inhibition of HIF-1a, respectively. The present study investigated the role of Siah-1 in the regulation of FIH abundance under normoxic conditions. Immunohistochemical analysis of the rat brains revealed that both Siah-1 and FIH were widely distributed in the central nervous system. FIH expression levels were increased in the presence of a proteasomal inhibitor MG132, suggesting that FIH is degraded by the ubiquitin用roteasome system. Immunoprecipitation assay and ubiquitination assay revealed that Siah-1 interacted with, and ubiquitinated FIH. Under normoxic conditions, Siah-1 facilitated degradation of FIH. On the other hand, when endogenous Siah-1 expression was suppressed using siRNA, FIH expression levels were increased, as compared to control. We are plainning to examine Siah as a candidate target for the development of regenerative medicine.
• 虚血耐性・冬眠・老化予防関連チロシンリン酸化蛋白質の同定

  科研：若手研究(スタートアップ)

  Date (from‐to) : 2006 -2007 

  Author : 大槻俊輔
• 2. 本邦における低用量アスピリンによる上部消化管合併症に対する調査研究

  財団法人循環器病研究振興財団：財団法人循環器病研究振興財団研究助成

  Author : 大槻 俊輔

Teaching Experience

Neurosurgery (Stroke)Neurosurgery (Stroke) Kindai University
Neurology (Stroke and Cerebrovascular Disease)Neurology (Stroke and Cerebrovascular Disease) Hiroshima University and Kindai University

Social Contribution

• Stroke Forum

  Date (from-to) : 2013/07-Today

  Role : Appearance

  Category : Investigation

  Sponser, Organizer, Publisher  : Osaka Prefecture
• Fighting against Stroke in the Winter

  Date (from-to) : 2017/11/28

  Role : Appearance

  Category : Lecture

  Sponser, Organizer, Publisher  : 藤井寺市医師会

  Event, Program, Title : 市民公開講座
• 市民公開講座 脳卒中を知ろう！ここまで進んだ最新治療

  Date (from-to) : 2017/11/18

  Role : Appearance

  Category : Lecture

  Sponser, Organizer, Publisher  : 日本脳卒中協会・大阪よみうり文化センター
• 市民公開講座 脳卒中

  Date (from-to) : 2017/08/20

  Role : Panelist

  Sponser, Organizer, Publisher  : 日本脳神経外科学会

  Event, Program, Title : 近畿地方会市民公開講座
• 脳卒中の医療連携 脳卒中患者さんを地域みんなで支える

  Date (from-to) : 2017/03/01

  Role : Panelist

  Category : Festival

  Sponser, Organizer, Publisher  : 富田林保健所

  Event, Program, Title : 南河内圏域脳卒中フォーラム
• 広島県医療連携体制検討特別委員会

  Date (from-to) : 2008/04-2012/06

  Role : Organizing member

  Category : Others

  Sponser, Organizer, Publisher  : 広島県
• Primary Care for Stroke at Home

  Date (from-to) : 2007/09

  Role : Informant

  Category : Pr

  Sponser, Organizer, Publisher  : Hiroshima Prefectural Medical Association

  Event, Program, Title : 救急小冊子

  Hiroshima Prefectural Medical Association 本会は毎年、救急医療の一環として、一般の人々を対象にいざという時のための知識を正しく理解していただくため、また、そのときどきのテーマに対する知識を深めていただくため、分かりやすい内容の小冊子を作成し、普及啓発に努めております。 今回は、脳卒中のいろいろな事前症状（麻痺、頭痛、めまいなど）や、疾病に対する応急手当などをテーマに取り上げ、「家庭で知っておきたい脳卒中の救急」と題して、広島大学病院の脳神経内科の大槻俊輔先生に執筆いただき、広島大学大学院脳神経内科学教授の松本昌泰先生に監修をお願いしました。執筆をいただきました先生方には心から感謝申し上げます。 本書では、「救急車を呼ぶときには」「脳卒中予報からの脳卒中の予防！これだけは知っておこう」やＱ＆Ａによって分かりやすく説明され、現場での応急処置、適切な判断の手助けになるような内容になっています。必ずやみなさま方のお役に立つと思いますので、広くご活用いただければ幸いです。

Media Coverage

• 脳梗塞再発予防に抗凝固薬 発症早期の投与効果

  Date : 2023/06/20

  Publisher, broadcasting station: 読売新聞社

  Program, newspaper magazine: 読売新聞

  コメント Paper
• 病を克服 野球をしたい

  Date : 2021/03/04

  Writer: Other than myself

  Publisher, broadcasting station: 産経新聞社

  Program, newspaper magazine: 産経新聞

  クモ膜下出血の小６ 仲間に支えられ Paper
• 認知症になるのを予防して“もの忘れ”程度に留める方法とは？

  Date : 2019/09/22

  Publisher, broadcasting station: 小学館

  Program, newspaper magazine: サライ

  健康 Paper 認知症と生活習慣の関係が解明されつつあり、極めて軽症、もの忘れ程度に留めることができる可能性もあることが分かってきたそうです。サライ渡辺陽さんから取材を受けた。
• その痛み、放っておいて大丈夫！？胸痛でなくも心筋梗塞の痛みかも

  Date : 2018/12/22

  Publisher, broadcasting station: 神戸新聞社

  Program, newspaper magazine: まいどなニュース かんさい

  Paper 心筋梗塞などの心臓病の場合、激しい胸痛を感じるというのは容易に想像できる。しかし、胸痛ではなく、他の部位に、別の病気を思わせる症状が出ることもある。何かいつもと違う、しかし救急車を呼ぶのはためらわれる。そんな時は、＃７１１９（救急安心センター）に電話して相談してみよう。メディカルライター渡辺陽さんからインタビュー。
• 梅干し、塩おにぎり、味噌汁で熱中症対策

  Date : 2018/08/13

  Publisher, broadcasting station: 小学館

  Program, newspaper magazine: サライ

  名医に聞く健康の秘訣 Paper
• 「老いても若々しさを保つ」3つの秘訣

  Date : 2018/01/24

  Publisher, broadcasting station: 小学館

  Program, newspaper magazine: サライ

  健康 Paper 「人間は生き物なので、必ず病気をします。健康に気をつけて生きるよりも、“より良く生きようとする”ほうが体にいいし、若さを保つ秘訣でもあります」渡辺陽さんからの取材内容です。

Academic Contribution

• 日本神経学会代議員

  Date (from-to) :2020/09/03

  Role: Others

  Type: Academic society etc

  Organizer, responsible person: 日本神経学会
• 日本老年医学学会代議員

  Date (from-to) :2019/06

  Role: Planning etc

  Type: Academic society etc
• 日本脳卒中学会脳卒中治療ガイドライン2019追補版／2021作成委員会脳出血班副班長

  Date (from-to) :2017/04/01

  Role: Academic research planning

  Type: Academic research

  Organizer, responsible person: 日本脳卒中学会
• 日本脳卒中学会脳卒中治療ガイドライン2009/2015/2017追補版実務担当

  Date (from-to) :2007/03-2017/03

  Role: Academic research planning

  Type: Academic society etc

  Organizer, responsible person: 日本脳卒中学会
• 日本脳卒中学会幹事・代議員

  Date (from-to) :2015/04

  Role: Planning etc

  Type: Academic society etc
• 日本脳循環代謝学会幹事

  Date (from-to) :2014/04

  Role: Planning etc

  Type: Academic society etc

Others

• 2019/10 - Today  脳卒中指導医 

  日本脳卒中学会認定指導医050401号
• 2018/12 - Today  日本内科学会認定総合内科専門医 

  新内科専門医制度における指導医資格としての総合内科専門医
• 2017/01 - Today  日本内科学会指導医 

  新内科専門医制度における内科学会指導医552585
• 2016/04 - Today  日本老年医学会指導医 

  110081号
• 2013/04 - Today  Japan ISLS Committee 

  脳卒中の初期診療を標準化し決定的治療へ効果的に接続する研修におけるファシリテーター2713010011
• 2012/09 - Today  臨床研修指導医
• 2009/04 - Today  日本高血圧学会専門医・指導医 

  44号・67号
• 2006/04 - Today  日本循環器学会循環器専門医 

  15503号
• 2004/10 - Today  日本老年医学会老年病専門医・指導医 

  4027号・110081号
• 2003/03 - Today  日本脳卒中学会脳卒中専門医 

  20030747号
• 2017/04 -2017/04  日本神経学会指導医 

  日本神経学会専門医制度における指導医3167号
• 2011/07 -2011/07  日本神経学会神経内科専門医 

  4695号

Other link

researchmap

https://researchmap.jp/strokecentre