記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: JTR-161 is a novel allogeneic human cell product consisting of dental pulp stem cells isolated from the extracted teeth of healthy adults. It is currently under development as a cell-based therapy for ischaemic stroke. The aim of this study is to evaluate the safety and efficacy of JTR-161 in patients with acute ischaemic stroke when given as a single intravenous administration within 48 hours of symptom onset. METHODS AND ANALYSIS: This is a first-in-human, randomised, double-blind, placebo-controlled, multicentre, phase 1/2 clinical trial to be conducted in Japan (from January 2019 to July 2021). Patients with a clinical diagnosis of anterior circulation ischaemic stroke with a National Institutes of Health Stroke Scale (NIHSS）score of 5-20 at baseline were enrolled. Patients previously treated with recombinant tissue-type plasminogen activator and/or endovascular thrombectomy were allowed to be enrolled. The study consists of three cohorts: cohorts 1 and 2 (each eight patients) and cohort 3 (60 patients). Subjects were randomly assigned to receive either JTR-161 or placebo in a 3:1 ratio in cohorts 1 and 2, and in a 1:1 ratio in cohort 3. The number of cells administered was increased sequentially from 1×108 (cohort 1) to 3 x 108 (cohort 2). In cohort 3, the higher tolerated dose among the two cohorts was administered. The primary endpoint is the proportion of patients who achieve an excellent outcome as defined by all of the following criteria at day 91 in cohort 3: modified Rankin Scale ≤1, NIHSS ≤1 and Barthel Index ≥95. ETHICS AND DISSEMINATION: The protocol and informed consent form were approved by the institutional review board at each participating study site. A manuscript with the results of the primary study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04608838; JapicCTI-194570 and Clinical Trials. gov.

DOI： 10.1136/bmjopen-2021-054269

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The pathophysiology of unilateral cortical fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (MOG)-associated encephalitis with seizures (FLAMES) is unclear. A 26-year-old man was referred because of a seizure. FLAIR showed an increased signal intensity and swelling of the right frontal cortex. His symptoms and imaging abnormalities were improved after intravenous methylprednisolone therapy. MOG antibody was detected both in serum and cerebrospinal fluid (CSF). Therefore, the patient was diagnosed with FLAMES. Myelin basic protein (MBP) was elevated in CSF. The high MBP value in the CSF in the present case suggested that demyelination as well as inflammation can occur in some FLAMES patients.

DOI： 10.2169/internalmedicine.9439-22

PubMed

researchmap

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Regenerative medicine aims to restore human functions by regenerating organs and tissues using stem cells or living tissues for the treatment of organ and tissue defects or dysfunction. Clinical trials investigating the treatment of cerebral infarction using mesenchymal stem cells, a type of somatic stem cell therapy, are underway. The development and production of regenerative medicines using somatic stem cells is expected to contribute to the treatment of cerebral infarction, a central nervous system disease for which there is no effective treatment. Numerous experimental studies have shown that cellular therapy, including the use of human dental pulp stem cells, is an attractive strategy for patients with ischemic brain injury. This review describes the basic research, therapeutic mechanism, clinical trials, and future prospects for dental pulp stem cell therapy, which is being investigated in Japan in first-in-human clinical trials for the treatment of patients with acute cerebral ischemia.

DOI： 10.3390/biomedicines10040737

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Intracerebral hemorrhage (ICH) is a devastating hemorrhagic event and is associated with high mortality or severe neurological sequelae. Age-associated differences in hematoma location for nonlobar ICH are not well known. The aims of the present study were to elucidate the relationship between age and hematoma location and to assess the differences in small-vessel disease (SVD) burden as a potential surrogate marker for longstanding hypertension among various hematoma locations. METHODS: From September 2014 through July 2019, consecutive patients with acute, spontaneous ICH were retrospectively enrolled from a prospective registry. Magnetic resonance imaging was performed during admission, and the total SVD burden score (including microbleeds, lacunes, enlarged perivascular spaces, and white matter hyperintensities) was calculated. The relationships of hematoma location with aging and SVD burden were assessed by using multivariate logistic regression analyses. RESULTS: A total of 444 patients (156 women [35%]; median age 69 [interquartile range 59-79] years; National Institutes of Health Stroke Scale score 9 [17][3-17]) were enrolled in the present study. Multivariate logistic regression analyses showed that advanced age was independently associated with thalamic (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.19-1.84, p < 0.001 for 10-year increment) and lobar hemorrhage (OR: 1.58, 95% CI: 1.19-2.09, p = 0.002) and was independently and negatively related to putaminal hemorrhage (OR: 0.55, 95% CI: 0.44-0.68, p < 0.001). The total SVD burden score was independently and positively associated with thalamic hemorrhage (OR: 1.27, 95% CI: 1.01-1.59, p = 0.045) and negatively with lobar hemorrhage (OR: 0.74, 95% CI: 0.55-0.99, p = 0.042), even after adjusting by age, but not with putaminal hemorrhage (OR: 0.91, 95% CI: 0.73-1.14, p = 0.395). CONCLUSION: Putaminal, thalamic, and lobar hemorrhages are prone to occur in specific ages and SVD states: putaminal in young patients, thalamic in old and high SVD burden patients, and lobar hemorrhages in old and low SVD burden patients. Susceptibility to bleeding with aging or severe SVD accumulation seems to differ considerably among brain locations.

DOI： 10.1159/000515411

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

PURPOSE: This study aimed to evaluate the risk factors, etiology, and outcomes of ischemic stroke (IS) in Japanese young adults. METHODS: This was a prospective multicenter study. We enrolled patients aged 16 to 55 years with IS within seven days of the onset of symptoms. We assessed the demographic data, risk factors, stroke etiology, and outcome at discharge. The clinical characteristics were compared between sexes and among age groups. RESULTS: We prospectively enrolled 519 patients (median age, 48 years: 139 females). The mean National Institute of Health Stroke Scale score was 3.6 ± 0.2. The most common risk factors were hypertension (HT) (55%), dyslipidemia (DL) (47%), and current smoking (42%). Body mass index, incidence of current smoking, and heavy alcohol consumption were higher in males. The prevalence of current smoking, HT, DL, and diabetes mellitus increased with aging. The most common etiologic subgroup of IS was small vessel disease (145/510, 28%). Intracranial arterial dissection (IAD) was the most common among the other determined causes (56/115, 49%). The outcome at discharge was relatively good (mRS 0-1, 71.7%); however, poor outcome (mRS ≥ 4) was observed at an incidence of 9.5%. CONCLUSIONS: Most young adults with IS had modifiable risk factors, of which prevalence increased with age. This emphasizes lifestyle improvement to prevent IS in the young population. Furthermore, we indicated that the incidence rate of IAD was high among the other determined causes.

DOI： 10.1016/j.jns.2020.117068

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stroke is the most prevalent cardiovascular disease worldwide, and is still one of the leading causes of death and disability. Stem cell-based therapy is actively being investigated as a new potential treatment for certain neurological disorders, including stroke. Various types of cells, including bone marrow mononuclear cells, bone marrow mesenchymal stem cells, dental pulp stem cells, neural stem cells, inducible pluripotent stem cells, and genetically modified stem cells have been found to improve neurological outcomes in animal models of stroke, and there are some ongoing clinical trials assessing their efficacy in humans. In this review, we aim to summarize the recent advances in cell-based therapies to treat stroke.

DOI： 10.3390/ijms21186718

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

researchmap

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J02615&link_issn=&doc_id=20210210460046&doc_link_id=%2Fcq3neuro%2F2020%2F003703%2F050%2F0385-0385%26dl%3D2&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcq3neuro%2F2020%2F003703%2F050%2F0385-0385%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Cognitive assessment is not performed routinely in the acute stroke setting. We investigated factors associated with cognitive impairment and the differences between the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores in patients with acute stroke. METHODS: In this prospective study, 881 consecutive patients (median age, 73 years) with acute stroke were enrolled. Clinical characteristics, such as education, vascular risk factors, premorbid cognitive status using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), and stroke severity, were assessed. Cognitive performance was measured using MMSE and MoCA within 5 days of stroke onset. RESULTS: Both MMSE and MoCA were feasible in 621 (70.5%) patients. Factors independently associated with nonfeasibility were age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.02-1.08), IQCODE score (OR: 1.02; 95%CI: 1.00-1.04), and National Institutes of Health Stroke Scale (NIHSS) score (OR, 1.16; 95%CI, 1.12-1.20). Impaired MoCA (with a cut-off <26/30) performance was observed in 544 of 621 (87.6%) patients. Factors independently associated with cognitive impairment were age (OR: 1.06; 95%CI: 1.03-1.10) and NIHSS score (OR: 1.34; 95%CI: 1.14-1.57). Eighty percent of patients with normal MMSE scores had an impaired MoCA score (MMSE-MoCA mismatch). The differences were highest in the visuospatial (94.8% versus 65.3%; P < .0001), recall (76.6% versus 35.6%; P < .0001), abstraction (82.5% versus 49.8%; P < .0001), and language (72.3% versus 65.9%; P < .0001) domains between the normal MMSE and MoCA group and MMSE-MoCA mismatch group. CONCLUSIONS: The MoCA can be particularly useful in patients with cognitive deficits undetectable on the MMSE in the acute stroke phase.

DOI： 10.1016/j.jstrokecerebrovasdis.2020.104688

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The feasibility of performing MRI first for patients with suspected hyperacute stroke in real-world practice has not been fully examined. Moreover, most past studies of reducing door-to-reperfusion time (DRT) in endovascular treatment (EVT) were conducted using CT. The aim of this study was to evaluate the feasibility of an MRI-first policy and to examine the effects of a quality improvement (QI) process for reducing DRT using MRI. METHODS: From January 2013 to December 2018, consecutive patients with acute stroke who came to hospital directly and were treated with emergent EVT were prospectively enrolled into the present study. In principle, MRI was performed first for patients with suspected acute stroke. A step-by-step QI process for decreasing DRT was adopted during this period. Time metrics for EVT were compared between specific time periods. RESULTS: A total of 180 patients (71 women; median age 76 years (range 69-64); National Institutes of Health Stroke Scale score 17 (range 10-23)) were included in the present study. More patients in the late phase were managed with the MRI-first policy (p<0.001). DRT (199 min in Phase 1, 135 min in Phase 2, 129 min in Phase 3, and 121 min in Phase 4, p<0.001) was significantly reduced across the phases. The percentage of patients with DRT <120 min increased significantly across time periods (p<0.001). Symptomatic intracerebral hemorrhage did not increase across phases (p=0.575). CONCLUSION: An MRI-first policy was feasible, and DRT decreased considerably with a step-by-step QI process. This process may be applicable to other hospitals.

DOI： 10.1136/neurintsurg-2019-015625

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Anticoagulant therapy often requires temporary interruption. Nevertheless, the frequency and clinical characteristics of stroke patients who develop stroke during anticoagulant interruption are not fully known. METHODS: From March 2011 through May 2017, consecutive acute ischemic stroke patients with AF who were admitted to our stroke unit were retrospectively recruited. Patients who developed ischemic stroke during anticoagulant interruption were defined as those who developed ischemic stroke within 30 days from anticoagulant interruption. The frequency and clinical characteristics of patients during anticoagulant interruption were analyzed. RESULTS: A total of 561 patients with AF and acute ischemic stroke (237 women; median age 78 [IQR 71-85] years) were admitted during the study period. Of these, 21 (3.7%, 12 patients discontinued vitamin K antagonist [VKA] and 9 discontinued direct oral anticoagulants [DOACs]) patients were admitted during the period of anticoagulant interruption. Severity and functional outcomes in stroke patients during anticoagulant interruption were not different from those without anticoagulant treatment. The number of days between anticoagulant interruption and stroke onset was shorter in patients who discontinued DOACs (3 [3-5] days) than in those who discontinuedVKAs (10 [7-20] days, p = .004). The major reason for interruption was planning of invasive procedures (52%). Guideline deviations were suspected in 82% of such cases. CONCLUSION: Patients developing stroke during anticoagulant interruption accounted for 3.7% of stroke patients with AF. Strokes occurred relatively early after interruption, especially in patients who discontinued DOACs. Guideline deviations was frequent.

DOI： 10.1016/j.jns.2019.03.018

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Atrial fibrillation (AF) is the leading cause of cardioembolic stroke (CES), and patients with stroke and AF are frequently assumed to have CES. However, strokes presumably due to atherosclerotic pathophysiologies in large or small vessels can also occur in patients with AF. The aims of the present study were to clarify the prevalence of and factors related to a non-cardioembolic etiology in acute stroke patients with AF. METHODS: From March 2011 through May 2017, consecutive acute ischemic stroke patients with AF were retrospectively recruited. The concomitant presence of non-cardioembolic features (small vessel occlusion [SVO] or large artery atherosclerosis [LAA]) on imaging was evaluated. The frequency of and factors associated with co-existing SVO/LAA features were assessed. RESULTS: A total of 560 consecutive patients with AF and acute stroke (237 women; median age 78 [IQR 71-85] years; NIHSS score 9 [3-20]) were enrolled. Of these, 42 (7.5%) had co-existing SVO/LAA features. Multivariable logistic regression analysis showed that the brain natriuretic peptide level (BNP, OR 0.78, p = .030 per 100 pg/mL increase) was independently and negatively associated with co-existing SVO/LAA features and receiver operating characteristic curve analysis revealed the practical cut-off BNP value was 130 pg/mL (sensitivity 54% and specificity 68%). CONCLUSION: SVO/LAA features were found in 7.5% of acute stroke patients with AF. A relatively low BNP level on admission was independently associated with co-existing SVO/LAA features. Thorough examination for a more appropriate etiology may be particularly necessary in acute stroke patients with AF and a relatively low BNP level.

DOI： 10.1016/j.jns.2019.03.031

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: We investigated the precise clinical and radiologic characteristics of intracerebral hemorrhage associated with direct oral anticoagulant use. METHODS: Patients with acute spontaneous intracerebral hemorrhage admitted to our department from September 2014 to November 2017 were retrospectively analyzed. Clinical and neuroradiological characteristics of patients with direct oral anticoagulant-related intracerebral hemorrhage, and effects of prior treatment on the severity at admission and on outcome at discharge were assessed. RESULTS: Of the 301 enrolled patients (103 women; median age 68 years), 261 received no oral anticoagulants (86.8%), 20 received warfarin (6.6%), and 20 received direct oral anticoagulants (DOACs) (6.6%). Median initial National Institutes of Health Stroke Scale scores differed significantly among the groups (P = .0283). Systolic blood pressure (P = .0031) and estimated glomerular filtration rate (P = .0019) were significantly lower in the oral anticoagulant-related intracerebral hemorrhage group than in other groups. Total small vessel disease scores were significantly higher in the oral anticoagulant-related intracerebral hemorrhage group than in the warfarin group (P = .0413). Multivariate analysis revealed that prior oral anticoagulant treatment (odds ratio: 0.21, 95% confidence interval: 0.05-0.96, P = .0445) was independently negatively associated with moderate-to-severe neurological severity (stroke scale score ≥10) after adjusting for intracerebral hemorrhage location and various risk factors. There were significant differences in hematoma volume in the basal ganglia (P = .0366). CONCLUSIONS: DOAC-related intracerebral hemorrhage may occur particularly in patients with a high risk of bleeding; however, they had a milder initial neurological severity than those with warfarin-related intracerebral hemorrhage, possibly due to relatively smaller hematoma volume, especially in the basal ganglia.

DOI： 10.1016/j.jstrokecerebrovasdis.2018.12.013

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Because the efficacy and safety of anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) are not fully known, present study aimed to elucidate the current status and the safety of anticoagulant therapy, mainly direct oral anticoagulants (DOACs), for acute ICH and anticoagulant-indicated patients. Methods and Results: From September 2014 through March 2017, consecutive patients with acute (<7 days from onset), spontaneous ICH were retrospectively enrolled from a prospective registry. Whether to start anticoagulation was at the attending physicians' discretion, and thromboembolic or hemorrhagic events during hospitalization were analyzed. A total of 236 patients (80 women [34%]; median age 69 [interquartile range 61-79] years; National Institutes of Health stroke scale score 7 [3-16]) were enrolled. Of them, 47 patients (20%) had an indication for anticoagulant therapy (33 had atrial fibrillation, 14 developed deep vein thrombosis), and 41 of 47 patients (87%) were actually treated with anticoagulant therapy (DOACs were used in 34 patients) after a median of 7 days from ICH onset. There was neither hematoma expansion nor excessive hemorrhagic complications during hospitalization after starting anticoagulant therapy. CONCLUSIONS: Anticoagulant therapy was conducted for approximately 90% of anticoagulation-indicated patients after a median of 7 days from ICH onset. The predominant anticoagulant medications were DOACs. Anticoagulant therapy started from the acute phase of ICH should be safe.

DOI： 10.1253/circj.CJ-18-0938

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Matrix metalloproteinases (MMPs) damage the neurovascular unit, promote the blood-brain barrier (BBB) disruption following ischemic stroke, and play essential roles in hemorrhagic transformation (HT), which is one of the most severe side effects of thrombolytic therapy. However, no biomarkers have presently been identified that can be used to track changes in the distribution of MMPs in the brain. Here, we developed a new 19F-molecular ligand, TGF-019, for visualizing the distribution of MMPs in vivo using 19F-magnetic resonance spectroscopic imaging (19F-MRSI). We demonstrated TGF-019 has sufficient sensitivity for the specific MMPs suspected in evoking HT during ischemic stroke, i.e., MMP2, MMP9, and MMP3. We then utilized it to assess those MMPs at 22 to 24 hours after experimental focal cerebral ischemia on MMP2-null mice, as well as wild-type mice with and without the systemic administration of the recombinant tissue plasminogen activator (rt-PA). The 19F-MRSI of TGN-019-administered mice showed high signal intensity within ischemic lesions that correlated with total MMP2 and MMP9 activity, which was confirmed by zymographic analysis of ischemic tissues. Based on the results of this study, 19F-MRSI following TGN-019 administration can be used to assess potential therapeutic strategies for ischemic stroke.

DOI： 10.1155/2019/8908943

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Numerous experimental studies have shown that cellular therapy, including human dental pulp stem cells (DPSCs), is an attractive strategy for ischemic brain injury. Herein, we examined the effects of intravenous DPSC administration after transient middle cerebral artery occlusion in rats. METHODS: Male Sprague-Dawley rats received a transient 90 min middle cerebral artery occlusion. DPSCs (1 × 106 cells) or vehicle were administered via the femoral vein at 0 h or 3 h after ischemia-reperfusion. PKH26, a red fluorescent cell linker, was used to track the transplanted cells in the brain. Infarct volume, neurological deficits, and immunological analyses were performed at 24 h and 72 h after reperfusion. RESULTS: PKH26-positive cells were observed more frequently in the ipsilateral than the contralateral hemisphere. DPSCs transplanted at 0 h after reperfusion significantly reduced infarct volume and reversed motor deficits at 24 h and 72 h recovery. DPSCs transplanted at 3 h after reperfusion also significantly reduced infarct volume and improved motor function compared with vehicle groups at 24 h and 72 h recovery. Further, DPSC transplantation significantly inhibited microglial activation and pro-inflammatory cytokine expression compared with controls at 72 h after reperfusion. Moreover, DPSCs attenuated neuronal degeneration in the cortical ischemic boundary area. CONCLUSIONS: Systemic delivery of human DPSCs after reperfusion reduced ischemic damage and improved functional recovery in a rodent ischemia model, with a clinically relevant therapeutic window. The neuroprotective action of DPSCs may relate to the modulation of neuroinflammation during the acute phase of stroke.

DOI： 10.1016/j.biopha.2018.09.084

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND PURPOSE: The association between thyroid hormone levels and long-term clinical outcome in patients with acute stroke has not yet been thoroughly studied. The purpose of the present study was to test the hypothesis that thyroid hormone levels are associated with 3-month functional outcome and mortality after acute stroke. METHODS: We retrospectively analyzed 702 consecutive patients with acute stroke (251 women; median age, 73 years) who were admitted to our department. General blood tests, including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), were performed on admission. Neurological severity was evaluated using National Institutes of Health Stroke Scale (NIHSS) scores on admission and modified Rankin Scale (mRS) scores at 3 months after stroke onset. Poor outcome was defined as an mRS score of 3-5 or death. The impact of thyroid function on 3-month outcome was evaluated using multiple logistic regression analysis. RESULTS: Poor functional outcome was observed in 295 patients (42.0%). Age (P < .0001), female sex (P < .0001), admission NIHSS score (P < .0001), smoking (P = .0026), arterial fibrillation (P = .0002), preadmission mRS (P < .0001), estimated glomerular filtration rate (P = .0307), and ischemic heart disease (P = .0285) were significantly associated with poor functional outcome, but no relationship between FT4, TSH, and poor functional outcome was found. A multivariate logistic regression analysis showed that low FT3 values (<2.00 pg/mL) were independently associated with poor functional outcome (odds ratio [OR], 3.16; 95% confidence interval [CI], 1.60-6.24) and mortality (OR, 2.55; 95% CI, 1.33-4.91) at 3 months after stroke onset. CONCLUSIONS: Our data suggest that a low FT3 value upon admission is associated with a poor 3-month functional outcome and mortality in patients with acute stroke.

DOI： 10.1016/j.jstrokecerebrovasdis.2018.06.009

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study investigated changes in anticoagulant use, treatment, and functional outcomes in acute ischemic stroke (AIS) patients with non-valvular atrial fibrillation (NVAF) over a 6-year period. Methods and Results: Patients with AIS and NVAF admitted to our department from April 2011 to March 2017 were analyzed retrospectively. Patients were divided into 3 groups based on the time of the initial visit (Periods 1-3, corresponding to April 2011-March 2013, April 2013-March 2015, and April 2015-March 2017, respectively). Associations between prescribed medication prior to event and stroke severity, reperfusion therapy, and outcomes were assessed. There was no significant change in the rate of insufficient warfarin and inappropriately lowered doses of direct oral anticoagulant (DOAC) treatment over time. The number of patients receiving prior DOAC treatment increased, but neurological severity on admission was milder than in the other 2 groups. The rate of reperfusion therapy increased from 19.9% (Period 1) to 42.7% (Period 3) for moderate-to-severe stroke patients. Multivariate logistic regression analysis revealed that reperfusion therapy was independently positively associated with good functional outcomes, but negatively associated with mortality (odds ratios [95% confidence intervals] 7.14 [3.34-15.29] and 0.13 [0.008-0.69], respectively). CONCLUSIONS: Inappropriate anticoagulant use for stroke patients with NVAF did not decrease over time. An increase in reperfusion therapy was a strong factor in improved functional outcomes and mortality.

DOI： 10.1253/circj.CJ-18-0561

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatocyte growth factor (HGF) has neuroprotective effects against ischemia-induced injuries. Dental pulp stem cell (DPSC) transplantation attenuates tissue injury in the brain of rats with post-transient middle cerebral artery occlusion. We sought to determine whether DPSCs that overexpress HGF can enhance their therapeutic effects on brain damage post-ischemia/reperfusion injury. Treatment with DPSCs overexpressing HGF reduced infarct volumes compared to unmodified DPSC treatment at 3 and 7 days post-transient middle cerebral artery occlusion. The use of unmodified DPSCs and DPSCs overexpressing HGF was associated with improved motor function compared to that with administration of vehicle at 7 days post-transient middle cerebral artery occlusion. DPSCs overexpressing HGF significantly inhibited microglial activation and pro-inflammatory cytokine production along with suppression of neuronal degeneration. Post-reperfusion, DPSCs overexpressing HGF attenuated the decreases in tight junction proteins, maintained blood-brain barrier integrity, and increased microvessel density in peri-infarct areas. The administration of DPSCs overexpressing HGF during the acute phase of stroke increased their neuroprotective effects by modulating inflammation and blood-brain barrier permeability, thereby promoting improvements in post-ischemia/reperfusion brain injury.

DOI： 10.1016/j.omtm.2018.07.009

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background The aims of the present study were to investigate the relationships between prior direct oral anticoagulant ( DOAC ) therapy and infarct volume and the site of arterial occlusion in patients with acute ischemic stroke and non-valvular atrial fibrillation. Methods and Results From March 2011 through November 2016, consecutive patients with acute ischemic stroke in the middle cerebral artery territory and non-valvular atrial fibrillation were recruited. The infarct volume was assessed semi-automatically using initial diffusion-weighted imaging, and the arterial occlusion site was evaluated on magnetic resonance angiography. The effect of prior DOAC treatment on the site of arterial occlusion was assessed by multivariate ordinal logistic regression analysis. A total of 330 patients (149 women; median age 79 [quartiles 71-86] years; median National Institutes of Health Stroke Scale score 11 [4-21]) were enrolled. Of these, 239 were on no anticoagulant, 40 were undertreated with a vitamin K antagonist ( VKA ), 22 were sufficiently treated with VKA ( PT - INR ≥1.6), and 29 were on a DOAC before the acute ischemic stroke. The infarct volume on admission differed among the groups (median 14.5 [2.0-59.8] cm3 in patients with no anticoagulation, 24.8 [2.1-63.0] in undertreated VKA , 1.3 [0.3-13.5] in sufficient VKA , and 2.3 [0.5-21.0] in DOAC , P=0.001). Multivariate analysis showed that prior DOAC treatment was independently and negatively associated with more proximal artery occlusion (odds ratio [OR] 0.34, P=0.015), compared with no anticoagulant. Conclusions DOAC treatment before the event was associated with smaller infarct volume and decreased risk of greater proximal artery occlusion in acute ischemic stroke patients with non-valvular atrial fibrillation, compared with no anticoagulation.

DOI： 10.1161/JAHA.118.009507

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist, clinically used for seizure control, has been reported to exert neuroprotective effects in experimental models of neurodegenerative diseases. However, few studies have investigated the therapeutic effects of PER in brain injury including stroke. Our aim was to investigate the neuroprotective potential of PER using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90-min MCAO followed by intraperitoneal PER administration at a dose of 1.5 mg/kg. Infarct volumes, neurological deficits, and immunological analyses were performed at 7 days after MCAO. PER significantly reduced infarct volumes (p < 0.05) and improved motor function (p < 0.05) compared with vehicle. Immunological analysis showed that PER significantly inhibited microglial activation, pro-inflammatory cytokine expression, and oxidative stress compared with vehicle. Moreover, PER suppressed neurodegeneration in the cortical ischemic boundary zone, via downregulation of Bcl-2-associated x and upregulation of Bcl-extra-large with Akt activation. In addition, post-stroke secondary neuronal damage and cognitive impairments, using the Y-maze test, were assessed 30 days after MCAO. PER significantly improved spatial working memory, which was accompanied by hippocampal CA1 neuronal loss and cortical thinning, compared with vehicle. These results indicate that PER attenuates infarct volumes and motor function deficits possibly through its anti-inflammatory, antioxidant, and anti-apoptotic activities, mediated via activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathways in the acute ischemic phase, and further ameliorates post-stroke cognitive impairments via the suppression of secondary neuronal damage in the chronic ischemic phase.

DOI： 10.1016/j.neuroscience.2018.06.043

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Circulation Society  

BACKGROUND: Insufficient anticoagulant intensity on admission is common in stroke patients with atrial fibrillation (AF) on vitamin K antagonist (VKA) therapy. Nevertheless, the effects of VKA under-treatment on stroke severity or arterial occlusion are not well known. The aim of the present study was to investigate the relationship between insufficient VKA therapy and stroke severity, or the site of arterial occlusion in patients with acute ischemic stroke (AIS) and AF.Methods and Results:From March 2011 through July 2016, 446 consecutive patients with AF and AIS were recruited. Of the 446 patients, 364 (167 women; median age, 79 years; IQR, 71-86 years) with anterior-circulation stroke were assessed to investigate the effects of insufficient VKA. Of these, 281 were on no anticoagulant, 53 were undertreated with a VKA, and 30 were sufficiently treated with VKA on admission (PT-INR ≥2.0 for patients <70 years and PT-INR ≥1.6 for ≥70 years old). On multivariate analysis, insufficient VKA was independently associated with severe stroke (i.e., initial NIHSS score ≥10; OR, 2.70, P=0.022) and higher prevalence of proximal artery occlusion (OR, 1.91; P=0.039) compared with no anticoagulant therapy. CONCLUSIONS: Insufficient VKA therapy on admission was associated with higher severity of stroke and higher prevalence of proximal artery occlusion in patients with AF and acute anterior-circulation stroke compared with no anticoagulant medication.

DOI： 10.1253/circj.CJ-17-1110

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Dr. Dietrich Steinkopff Verlag GmbH and Co. KG  

Stroke-associated infection (SAI) is a common and serious complication of stroke. This study aimed to assess the effects of SAI on patient mortality and functional outcome at 3 months after stroke onset. We retrospectively analyzed 809 consecutive patients with acute stroke (517 men and 292 women; median age, 72 years) who were admitted to our department between September 2014 and June 2016. SAI was defined as an infection diagnosed during the hospitalization period. Poor outcome was defined as a modified Rankin Scale (mRS) score of 3-5 or death (mRS score of 6). The effect of SAI on functional outcome was evaluated using a multivariate logistic regression analysis. SAI occurred in 169 patients (20.9%); of these, 106 (62.7%) had pneumonia, 23 (13.6%) had a urinary-tract infection, and 40 (23.7%) had other types of infection. Patients with SAI were older, more likely to be female, had lower body mass indices, had higher stroke severity, and were more likely to have atrial fibrillation and a history of ischemic heart disease than patients without SAI. Poor functional outcome and mortality were more common in patients with SAI than in patients without SAI (poor functional outcome 41.8 vs. 4.8%, mortality 24.3 vs. 3.9%, respectively). After adjusting for age, sex, stroke severity, and various comorbidities, SAI was independently associated with poor functional outcome [odds ratio (OR) 6.88; 95% confidence interval (CI) 3.72-12.73] and mortality (OR 4.45, 95% CI 2.27-8.72) at 3 months after stroke onset. Our results suggest that SAI during the hospitalization period is independently associated with 3-month poor functional outcome and mortality.

DOI： 10.1007/s00415-017-8714-6

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W.B. Saunders  

BACKGROUND: Poststroke infection (PSI) is common and is usually associated with a severe prognosis. We investigated the association between PSI and thyroid hormones, which are critical to immune regulation, in patients with acute stroke. METHODS: We retrospectively enrolled 520 consecutive patients with acute ischemic stroke (326 men; age, 71.9 ± 13.2 years) admitted to our department between September 2014 and June 2016. The impact of serum thyroid hormone levels measured at admission (thyroid-stimulating hormone [TSH], free triiodothyronine [FT3], and free thyroxine [FT4]) on the PSI was evaluated using multivariate logistic regression analysis. RESULTS: We diagnosed 107 patients (20.6%; pneumonia, 65; urinary tract infection, 19; others, 23) with PSIs. While age (P <.001), body mass index (P = .0012), preadmission modified Rankin scale score (P = .0001), National Institutes of Health Stroke Scale score on admission (P <.001), admission FT3 level (P <.001), atrial fibrillation (P <.001), and ischemic heart disease (P = .0451) were significantly associated with PSI, we found no relationship among TSH levels, FT4 levels, and PSI occurrence. After multivariate adjustment, patients with PSIs were more frequently in the Q1 quartile (≤2.25 pg/mL) than in the Q2 (2.26-2.55 pg/mL; P = .0251), Q3 (2.56-2.89 pg/mL; P = .0007), or Q4 (≥2.90 pg/mL; P = .0010) quartiles of FT3 levels. Moreover, low FT3 levels (<2.29 pg/mL) were independently associated with PSI occurrence (P = .0013). CONCLUSIONS: Low FT3 levels at admission are independently associated with PSI occurrence.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.09.012

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER HEIDELBERG  

Cortical superficial siderosis (cSS) is a pathologic and radiologic diagnosis of hemosiderin deposition in subpial brain layers. However, cSS has not been fully studied in patients with acute stroke. Here, we investigated the prevalence of cSS in patients with acute stroke and analyzed the relationship between cSS and different clinical and neuroimaging characteristics. From September 2014 through June 2016, consecutive patients with acute stroke who were admitted to our department were retrospectively investigated. We analyzed the prevalence of cSS and the associations between cSS and risk factors, the topographic distribution of cerebral microbleeds (CMBs), and the severity of white matter lesions (WMLs). In total, 739 patients (589 patients with ischemic stroke/transient ischemic stroke [IS/TIA] and 150 with intracerebral hemorrhage [ICH]; mean age, 71.4 years) were enrolled. We identified cSS in six (1.0%) patients with IS/TIA and seven (4.7%) patients with ICH. The presence of cSS was associated with ICH (P < 0.0001), WMLs (P = 0.0105), and lobar and non-lobar CMBs (both P < 0.0001); no associations between cSS and age, sex, cardiovascular risk factors, IS subtype classification, or antiplatelet and anticoagulant therapy were found. In a multivariable logistic regression analysis, high numbers of lobar CMBs (≥ 2; odds ratio, 11.03; 95% confidence interval, 2.03-205.40; P = 0.0029) were independently associated with cSS. Furthermore, cSS was often located near lobar CMBs. Our results suggest that cSS is prevalent in ICH and is independently associated with lobar CMBs; however, no associations between cSS and other risk factors or comorbidities were observed.

DOI： 10.1007/s00415-017-8646-1

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Given the abundance of stroke patients and deaths from stroke worldwide, many studies concerning the aftermath of stroke are being carried out. To reveal the precise effect of ischemic infarction, we conducted a comprehensive gene expression analysis. Alongside a middle cerebral artery occlusion (MCAO) Sprague-Dawley rat model, we used a group undergoing sham surgery for comparison, which was the same as MCAO surgery but without blood vessel occlusion. Subsequently, infarction of the brains of MCAO-treated rats occurred, but did not occur in the sham-treated rats. Using whole blood, we carried out DNA microarray analysis, revealing the gene expression alterations caused by stroke. Downregulation of immune pathways and cluster of differentiation (CD) molecules indicated immunodepression. By conducting miRNA microarray analysis, we extracted seven miRNAs as significantly regulated: miR-107-5p, miR-383-5p, miR-24-1-5p, mir-191b, miR-196b-5p, and miR-3552 were upregulated, and mir-194-1 was downregulated. Among these seven miRNAs, three had one target mRNA each that was extracted as differentially expressed, and the expression levels of all pairs were inversely correlated. This indicates the occurrence of miRNA-mRNA regulatory systems in blood: between miR-107-5p and H2A histone family member Z (H2afz), miR-196b-5p and protein tyrosine phosphatase receptor type C (Ptprc), and miR-3552 and serine/arginine-rich splicing factor 2 (Srsf2). Moreover, six miRNAs had matching human miRNAs with similar sequences, which are potential human stroke biomarkers.

DOI： 10.3390/ijms18112335

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background and purposeAnticoagulant treatment with a vitamin K antagonist (VKA) has been reported to reduce stroke severity when patients with atrial fibrillation (AF) suffer acute ischaemic stroke (AIS). Direct oral anticoagulant (DOAC) therapy also has the potential to reduce the initial severity of AIS. However, the effect of DOAC therapy on the severity of AIS is not well known. The aim of the present study was to investigate the effect of DOACs on initial stroke severity in patients with AIS and non-valvular AF.
MethodsFrom March 2011 to July 2016, consecutive patients with AIS having non-valvular AF were recruited. The effects of prior DOAC treatment on severity were assessed by multivariate logistic regression analyses.
ResultsA total of 484 patients [208 women; median age 79 (interquartile range, 71-85) years; National Institutes of Health Stroke Scale (NIHSS) score 9 (interquartile range, 3-20)] were enrolled. Of these, 352 (73%) were on no anticoagulant medication, 54 (11%) were undertreated with a VKA, 35 (7%) were sufficiently treated (admission prothrombin time-international normalized ratio: 2.0 for patients &lt;70 years old and 1.6 for 70 years old) with a VKA and 43 (9%) were on a DOAC. The initial NIHSS score (median 10 in patients with no anticoagulation, 13 in undertreated VKA, 7 in sufficient VKA and 6 in DOAC, P = 0.018) was different among the groups. Multivariate analysis showed that DOAC was independently and negatively associated with severe (initial NIHSS score 10) stroke (odds ratio, 0.39; P = 0.041), compared with no anticoagulant therapy.
ConclusionsDirect oral anticoagulant treatment prior to the event should reduce initial stroke severity in patients with AIS and non-valvular AF.

DOI： 10.1111/ene.13405

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

Interleukin (IL)-10 is a contributing factor to neuroprotection of mesenchymal stem cell (MSC) transplantation after ischemic stroke. Our aim was to increase therapeutic effects by combining MSCs and ex vivo IL-10 gene transfer with an adeno-associated virus (AAV) vector using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90 min MCAO followed by intravenous administration of MSCs alone or IL-10 gene-transferred MSCs (MSC/IL-10) at 0 or 3 hr after ischemia reperfusion. Infarct lesions, neurological deficits, and immunological analyses were performed within 7 days after MCAO. 0-hr transplantation of MSCs alone and MSC/IL-10 significantly reduced infarct volumes and improved motor function. Conversely, 3-hr transplantation of MSC/IL-10, but not MSCs alone, significantly reduced infarct volumes (p < 0.01) and improved motor function (p < 0.01) compared with vehicle groups at 72 hr and 7 days after MCAO. Immunological analysis showed that MSC/IL-10 transplantation significantly inhibits microglial activation and pro-inflammatory cytokine expression compared with MSCs alone. Moreover, overexpressing IL-10 suppressed neuronal degeneration and improved survival of engrafted MSCs in the ischemic hemisphere. These results suggest that overexpressing IL-10 enhances the neuroprotective effects of MSC transplantation by anti-inflammatory modulation and thereby supports neuronal survival during the acute ischemic phase.

DOI： 10.1016/j.omtm.2017.06.005

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

BACKGROUND: The presence of white matter lesions (WML) is an indicator of small vessel disease; however, the underlying pathological mechanisms are still unclear. We aimed to investigate the association of estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) with WML severity in first-ever stroke patients. METHODS: We retrospectively enrolled 284 consecutive patients (177 male; median age 72years) admitted to our stroke center between May 2010 and January 2012. eGFR and UACR measurements were performed on admission. WML severity was assessed using the Fazekas classification. Severe WML was defined as a Fazekas grade of 2 or higher. The impact of eGFR and UACR on severe WML was evaluated using multiple logistic regression analysis. RESULTS: Age (P<0.0001), sex (P=0.0094), eGFR (P=0.0173), UACR (P=0.0001), hypertension (P=0.0436), and brain natriuretic peptide (P=0.0354) were significantly associated with severe WML. On multivariable logistic regression analysis, high UACR (≥39.6mg/g creatinine, P=0.039), but not low eGFR (≤74ml/min/1.73m2, P=0.3672), was independently associated with severe WML. Comparisons between the UACR levels showed that severe WML was more frequent in the UACR ≥300mg/g creatinine group than in the UACR <30.0mg/g creatinine group after multivariate adjustment (OR, 2.25; 95% CI, 1.04-5.00; P=0.039). However, there was no significant association between eGFR and severe WML. CONCLUSIONS: Our data suggest that high UACR, but not eGFR, is independently associated with severe WML.

DOI： 10.1016/j.jns.2017.01.011

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

AIMS: Rats subjected to transient focal ischemia and cultured neuronal cells subjected to oxygen-glucose deprivation (OGD) were treated with clarithromycin (CAM) to evaluate the effects of CAM in protecting against neuronal damage. MAIN METHODS: Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 90min and then reperfused. Each animal was given an oral dose clarithromycin (CAM, 100mg/kg) or vehicle alone just after the ischemia was commenced. The infarct volume, edema index and neurological performance were assessed after 24 and 72h of reperfusion. The cerebral blood flow (CBF) was measured with an MRI system at 90min after MCAO. After 24 and 72h, oxidative stress (4-HNE, 8-OHdG) and inflammation (Iba-1, TNF-α) were assessed by immunohistochemical analyses and degenerative cells were assessed in the cortex by Fluoro-Jade C (FJC) labeling. The cultured neuronal cells were also used to examine the effects of CAM exposure on the viability of the cells after OGD. KEY FINDINGS: CBF was unchanged between the two groups. Significant reductions of the infarct volume and edema index, an improved neurological deficit score, a significant suppression of 4-HNE and 8-OHdG expression, marked reductions of Iba-1 and TNF-α expression, and a significant reduction of FJC-positive cells were also observed in the CAM-treated animals at both time points. Treatment with 10μM and 100μM CAM in vitro significantly reduced cell death after OGD. SIGNIFICANCE: CAM appears to provide antioxidant and anti-inflammatory effects and protect against neuronal damage after cerebral ischemia and OGD.

DOI： 10.1016/j.lfs.2016.11.004

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

BACKGROUND: Thrombus visualization in patients with acute ischemic stroke has been detected and reported using various imaging modalities. T1-weighted imaging (T1-WI) can depict thrombi as hyperintense signals within vessels. Moreover, in addition to thrombi, T1-WI hyperintensities in arteries may suggest arterial dissection. However, the frequency of and factors related to the T1-hyperintense vessel sign (T1-HVS) are not fully known. The aim of this study was to clarify the prevalence of and related factors for the T1-HVS in patients with acute ischemic stroke. METHODS: From September 2014 through December 2015, consecutive acute ischemic stroke patients who were admitted to our stroke unit within 7 days from symptom onset were retrospectively recruited from the prospective registry. A T1-HVS was defined as the presence of a hyperintense signal, with intensity higher than surrounding brain, within the vessel lumen. Moreover, T1-HVSs were separated into filled T1-HVSs (hyperintensity fills whole vessel lumen) and non-filled T1-HVSs. The frequency of the T1-HVS and the timing of emersion and the relationship between the presence of the T1-HVS and arterial occlusion were assessed. RESULTS: A total of 399 patients (139 women; median age 73 years; National Institutes of Health Stroke Scale score 3) were enrolled in the present study. Of these, 327 (82%) patients had T1-WI on admission. Two hundred and sixty-seven (67%) subjects had at least one follow-up T1-WI (median 6 days after admission), and 134 (34%) cases had ≥2 follow-up T1-WI examinations. The T1-HVS was observed in 18 patients during admission; therefore, the frequency of the T1-HVS in acute ischemic stroke patients was 4.5% (95% CI 2.5-6.5%). All but one (94%) of the T1-HVSs were first observed on follow-up imaging, and the median number of days from onset to T1-HVS appearance was 9. For patients having initial major artery occlusion and follow-up MRI (n = 95), sensitivity and specificity of the T1-HVS for persistent arterial occlusion on follow-up MR angiography were 22 and 100%, respectively. T1-HVS persisted for a few months and then normalized. Although there were no significant differences between filled and non-filled T1-HVS, more patients with non-filled T1-HVS had arterial dissection (43%) than those with filled T1-HVS (9%, p = 0.245). CONCLUSION: The T1-HVS was observed in 4.5% of acute ischemic stroke patients. T1-HVSs appeared in the subacute phase in arteries with persistent occlusion and remained for a few months.

DOI： 10.1159/000479593

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.jns.2016.07.050

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

A 59-year-old woman was admitted to our hospital because of repeated episodes of bilateral hand weakness. She had a 10-year history of combined estrogen-progestin therapy for menopausal symptoms. Magnetic resonance imaging on admission showed multiple hyperintense lesions in bilateral cerebral and cerebellar cortices on diffusion-weighted imaging. Transesophageal echocardiography showed thrombus formation on the aortic valve and moderate aortic insufficiency. Laboratory test demonstrated elevated CA125 (334.8 U/mL) and D-dimer (7.0 µg/mL) levels. Trousseau's syndrome (cancer-related hypercoagulation) was considered, but various examinations showed only uterine adenomyosis and no evidence of cancer. Multiple cerebral infarctions were considered to be caused by Trousseau's syndrome-like condition associated with uterine adenomyosis. CA125 and coagulation markers should be measured in adenomyosis patients treated with hormone replacement therapy, because a mucinous tumor and coagulation markers may be good markers for the risk of thromboembolism in such patients.

DOI： 10.1016/j.jstrokecerebrovasdis.2016.07.024

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

BACKGROUND AND PURPOSE: The aim of this study was to investigate the association of admission serum thyroid hormone concentration with clinical characteristics and functional outcomes in patients after acute ischemic stroke. METHODS: We retrospectively enrolled 398 consecutive patients admitted to our stroke center between July 2010 and April 2012. Serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were evaluated upon admission. Neurological severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) upon admission and the modified Rankin Scale (mRS) upon discharge. Poor outcome was defined as a mRS score of 3-5 or death (mRS score 6). Separate analyses were conducted according to outcome and quartile serum FT3 concentration. RESULTS: In total, 164 patients (41.2%) demonstrated a poor outcome. Age, male gender, blood glucose level, arterial fibrillation, dyslipidemia, smoking, NIHSS score, cardioembolic stroke type, and periventricular hyperintensities, but not FT4 or TSH, were significantly associated with poor functional outcome. Furthermore, poor functional outcome was independently associated with low FT3 (<2.29pg/mL). In comparisons between FT3 quartiles (Q1 [≤2.11pg/mL], Q2 [2.12-2.45pg/mL], Q3 [2.46-2.77pg/mL], Q4 [≥2.78pg/mL]), patients with poor outcomes were more frequent in Q1 than in Q4 after multivariate adjustment. Death was more frequent in Q1 than in Q4 after adjustment for risk factors and comorbidities, but this difference was non-significant after additional adjustment for age and NIHSS score. CONCLUSIONS: Our data suggest that a lower FT3 value upon admission may predict a poor functional outcome in patients with acute ischemic stroke. Further large-scale prospective studies are required to clarify the role of thyroid hormone in the acute phase of ischemic stroke.

DOI： 10.1016/j.jns.2016.06.063

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.jns.2016.05.044

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Spontaneous cervical artery dissection (sCAD) is a major cause of ischemic stroke in young adults. Frequently, sCAD involves multiple neck arteries, accounting for 13%-28% of the total sCAD cases. However, little is known about factors related to multiple sCAD. In this case, a 52-year-old man was admitted due to headache without aura. There was a personal history of migraine with aura and a family history of similar symptoms. The patient's younger brother had a left vertebral artery (VA) dissecting aneurysm and underwent endovascular occlusion of his parent artery at the age of 48. Magnetic resonance imaging of our admitted patient showed hyperintensities in the right internal carotid artery (ICA) without acute infarction, and magnetic resonance angiography revealed a narrowing of the right ICA. Angiography was then performed, which showed a trace of dissection of the left ICA and both VAs as well as the right ICA. The patient did not fulfill any major criteria of collagen vascular disease such as Ehlers-Danlos syndrome type IV or Loeys-Dietz syndrome. The data in our patient are quite similar to those reported in patients with single-nucleotide polymorphism (SNP) of PHACTR1. Obtaining the patient's informed consent, we analyzed a common SNP variation in the rs9349379[G] allele (PHACTR1), which has been reported to be associated with a lower risk of sCAD.

DOI： 10.1016/j.jstrokecerebrovasdis.2016.04.027

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.jns.2016.04.014

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

OBJECTIVE: This study aims to determine if erythromycin provides neuroprotective effects against ischemic injury following permanent focal cerebral ischemia. METHODS: Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). Each animal received a single subcutaneous injection of erythromycin lactobionate (EM, 50 mg/kg) or vehicle immediately after ischemia. The infarct volume, edema index and neurological performance were evaluated at 24 and 72 h after MCAO. The cerebral blood flow (CBF) was measured with an MRI system at 30 min after MCAO. TUNEL staining and immunohistochemical analyses for oxidative stress (4-HNE, 8-OHdG) and inflammation (Iba-1, TNF-α) in the cortex were conducted at 24 and 72 h after MCAO. RESULTS: The CBF did not differ between the EM-treated and vehicle-treated groups. The EM treatment significantly reduced the infarct volume (p < 0.01) at 24 and 72 h after MCAO and significantly reduced the edema index (p < 0.01) at 24 h. The EM treatment significantly improved the neurological deficit scores (p < 0.05) at 24 and 72 h. EM also significantly suppressed the accumulation of 4-HNE (p < 0.01) and 8-OHdG (p < 0.01) and markedly reduced Iba-1 (p < 0.01) and TNF-α expression (p < 0.05) at both time points. The EM treatment significantly reduced TUNEL-positive cells (p < 0.01) at both time points. CONCLUSION: These findings suggest that EM can protect against the neuronal damage caused by cerebral ischemia by alleviating inflammation and reducing oxidant stress.

DOI： 10.1080/01616412.2016.1138662

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MANEY PUBLISHING  

OBJECTIVE: This study aims to determine if macrolide antibiotics have neuroprotective effects against transient cerebral ischemia. METHODS: Sprague-Dawley rats were subjected to cerebral ischemia for 90 minutes followed by 24 or 72 hours of reperfusion. An oral suspension of roxithromycin (RXM), clarithromycin (CAM), erythromycin (EM), azithromycin (AZM), or kitasamycin (INN) was given at 10 or 100 mg/kg for 7 days before ischemia. The infarct volume, edema volume, and neurological performance were evaluated after 24 and 72 hours of reperfusion. The cerebral blood flow (CBF) was measured with a magnetic resonance imaging (MRI) system after 90 minutes of ischemia. Another experiment was conducted to investigate how the ischemic injury was affected by the interval from the antibiotic pretreatment to the ischemia in rats pretreated with CAM. RESULTS: Roxithromycin, CAM, AZM, and INN significantly reduced the infarct volume in the high-dose group after 24 and 72 hours of reperfusion. All of the agents significantly decreased the edema in the high-dose groups at 24 and 72 hours, while only CAM and AZM significantly reduced the edema volume in the low-dose groups at 24 hours. All of the macrolide antibiotics at the high dose significantly improved neurological deficit scores at 24 and 72 hours. There were no differences in the CBF between the vehicle and respective antibiotic groups. In the experiment examining the interval, the 24-hour interval group exhibited the strongest neuroprotective effect. DISCUSSION: These results demonstrate that the macrolide antibiotics RXM, CAM, EM, AZM, and INN may confer neuroprotective effects against ischemic damage following cerebral ischemia without affecting the CBF.

DOI： 10.1179/1743132815Y.0000000005

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Valproic acid (VPA) is widely used for the clinical treatment of epilepsy. Previous studies have demonstrated that VPA ameliorates brain injury following experimental stroke. However, the effect of VPA in stroke models featuring comorbid conditions has not been fully explored. In this study, we investigate the effects of VPA on permanent ischemic stroke with hyperglycemia. Hyperglycemia was induced by streptozotocin (STZ) injection 3 days before. Test animals received a single injection of VPA immediately after induction of ischemia. Control animals received occlusion and physiological saline injection, or STZ, occlusion, and saline. Magnetic resonance imaging of cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) was performed 60 min after ischemia. Infarct volume, neurological deficits, rotarod test performance, and immunohistological markers were assessed 3 days after ischemia. Hyperglycemia significantly expanded the area of decreased of CBF and ADC, and increased the number of myeloperoxidase-positive cells, ionized calcium binding adapter molecule 1-positive cells, inducible nitric oxide synthase-positive cells, von Willebrand factor-positive cells, and Fluoro-Jade C-positive cells in the ischemic boundary zone, which was accompanied by increased infarct volume and deteriorated neurological deficit and rotarod test compared with normoglycemia (P < 0.05). VPA significantly alleviated the aggravation of functional outcome accompanied by suppressing these inflammation, endothelial injury, and neuronal degeneration compared with saline-treated group (P < 0.05). A single injection of VPA following permanent ischemia in STZ-induced hyperglycemic rats ameliorates neurological deficits and reduces neuronal degeneration by inhibiting inflammation and endovascular injury. VPA may be promising as a candidate therapy for human stroke.

DOI： 10.1016/j.brainres.2015.02.013

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

This study aims to determine if erythromycin has neuroprotective effects against transient ischemia and oxygen-glucose deprivation (OGD) in cultured neuronal cells. Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 90 min, followed by reperfusion. The animals received a subcutaneous single injection of erythromycin lactobionate (EM, 50mg/kg) or vehicle immediately after ischemia. Infarct volume, edema index, and neurological performance were evaluated at 24 and 72 h after reperfusion. Immunohistochemical analyses for oxidative stress (4-HNE, 8-OHdG) and inflammation (Iba-1, TNF-α) were conducted in the cortex at 24h. Primary cortical neuronal cell cultures were prepared from the cerebral cortices of the animals and then subjected to OGD for 3h. Ten or 100 μM EM was added before OGD to determine the effect of EM on cell viability after OGD. EM significantly reduced infarct volume (p<0.01) and edema volume (p<0.05) and improved neurological deficit scores (p<0.05) at 24 and 72 h. EM significantly suppressed the accumulation of 4-HNE (p<0.01) and 8-OHdG (p<0.01) and markedly reduced Iba-1 (p<0.01) and TNF-α expression (p<0.01). Treatment with 100 μM EM in vitro significantly reduced cell death after OGD. EM reduces neuronal damage following cerebral ischemia and OGD and may have antioxidant and anti-inflammatory effects.

DOI： 10.1016/j.brainres.2014.09.016

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

AIMS: Transplantation of bone marrow mononuclear cells (BMMCs) exerts neuroprotection against cerebral ischemia. We examined the therapeutic timepoint of allogeneic BMMC transplantation in a rat model of focal cerebral ischemia, and determined the effects of repeated transplantation outside the therapeutic window. MAIN METHODS: Male Sprague-Dawley rats were subjected to 90 minute focal cerebral ischemia, followed by intravenous administration of 1 × 10(7) allogeneic BMMCs or vehicle at 0, 3 or 6 h after reperfusion or 2 × 10(7) BMMCs 6 h after reperfusion. Other rats administered 1 × 10(7) BMMCs at 6 h after reperfusion received additional BMMC transplantation or vehicle 9 h after reperfusion. Infarct volumes, neurological deficit scores and immunohistochemistry were evaluated 24 or 72 h after reperfusion. KEY FINDINGS: Infarct volumes at 24 h were significantly decreased in transplantation rats at 0 and 3 h, but not at 6 h, after reperfusion, compared to vehicle-treatment. Even high dose BMMC transplantation at 6h after reperfusion was ineffective. Repeated BMMC transplantation at 6 and 9h after reperfusion reduced infarct volumes and significantly improved neurological deficit scores at 24 and 72 h. Immunohistochemistry showed repeated BMMC transplantation reduced ionized calcium-binding adapter molecule 1, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine expression at 24 and 72 h after reperfusion. SIGNIFICANCE: Intravenous allogeneic BMMCs were neuroprotective following transient focal cerebral ischemia, and the therapeutic time window of BMMC transplantation was >3 h and <6 h after reperfusion in this model. Repeated transplantation at 6 and 9 h after reperfusion suppressed inflammation and oxidative stress in ischemic brains, resulting in improved neuroprotection.

DOI： 10.1016/j.lfs.2013.12.016

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Aims: Pre-treatment with statins is known to ameliorate ischemic brain damage after experimental stroke, and is independent of cholesterol levels. We undertook pre- vs post-ischemic treatment with atorvastatin after focal cerebral ischemia in rats.
Main methods: Male Sprague-Dawley rats underwent transient 90-min middle cerebral artery occlusion (MCAO). Atorvastatin (20 mg/kg/day) or vehicle was administered orally. Rats were divided into vehicle-treated, atorvastatin pre-treatment, atorvastatin post-treatment, and atorvastatin continuous-treatment groups. In the pre-treatment, rats were given atorvastatin or vehicle for 7 days before MCAO. In the post-treatment, rats received atorvastatin or vehicle for 7 days after MCAO. Measurement of infarct volume, as well as neurological and immunohistochemical assessments, were done 24 h and 7 days after reperfusion.
Key findings: Each atorvastatin-treated group demonstrated significant reductions in infarct and edema volumes compared with the vehicle-treated group 24 h after reperfusion. Seven days after reperfusion, infarct volumes in the post-treatment group and continuous-treatment group (but not the pre-treatment group) were significantly smaller than in the vehicle-treated group. Only the continuous-treatment group had significantly improved neurological scores 7 days after reperfusion compared with the vehicle group. Post-treatment and continuous-treatment groups had significantly decreased lipid peroxidation, oxidative DNA damage, microglial activation, expression of tumor necrosis factor-alpha, and neuronal damage in the cortical ischemic boundary area after 7 days of reperfusion.
Significance: These results suggest that continuous oral administration (avoiding withdrawal) with statins after stroke may reduce the extent of post-ischemic brain damage and improve neurological outcome by inhibiting oxidative stress and inflammatory responses. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2013.11.018

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：The Japanese Society of Cerebral Blood Flow and Metabolism  

Aims: Previous studies suggest that both statins and calcium-channel blockers inhibit cardiovascular and cerebrovascular diseases by their pleiotropic effects, such as antioxidation and anti-inflammatory actions. By using stroke-prone spontaneously hypertensive rats (SHRSPs), the isolated effect of each pharmaceutical has been reported, but the effect of a combination of both pharmaceuticals has not been reported. In this study, we evaluated combination therapy of atorvastatin and amlodipine for its efficacy in preventing stroke in the SHRSP model. Main Methods: We initiated treatment of SHRSPs at 8 weeks of age with atorvastatin (2 mg/kg), amlodipine (1 mg/kg), a combination of atorvastatin (2 mg/kg) and amlodipine (1 mg/kg), or vehicle. Measurement of physiological parameters and immunohistochemical assessments for oxidative stress and inflammation were done at each group. Key findings: At 13 weeks of age, the combination therapy group showed greater inhibition of an antioxidation and anti-inflammatory marker than the vehicle group, although there were no differences in blood pressure. Significance: Our study suggests that the combination therapy of atorvastatin and amlodipine may protect against hypertension-induced stroke by the additive effect of the antioxidation and the anti-inflammatory action of the both agents.

DOI： 10.16977/cbfm.25.2_23

researchmap

その他リンク： http://search.jamas.or.jp/link/ui/2015176453

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Long-chain n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), have been shown to reduce ischemic neuronal injury. We investigated the effects of ethyl-EPA (EPA-E) on ischemic brain damage using a rat transient focal cerebral ischemia model. Male Sprague-Dawley rats (n=105) were subjected to 90 min of focal cerebral ischemia. EPA-E (100 mg/kg/day) or vehicle was administered once a day for 3, 5 or 7 days prior to ischemia. Different withdrawal intervals of 3, 5, and 7 days prior to ischemia following 7-day pretreatment with EPA-E or vehicle were also examined. In addition, post-ischemic administration of EPA-E was investigated. Pretreatment with EPA-E for 7 and 5 days, but not 3 days, showed significant infarct volume reduction and neurological improvements when compared with vehicle pretreatment. In addition, withdrawal of EPA-E administration for 3 days, but not 5 and 7 days, also demonstrated significant infarct volume reduction and neurological improvements when compared with vehicle treatment. Post-ischemic treatment of EPA-E did not show any neuroprotection. Immunohistochemistry revealed that 7-day pretreatment with EPA-E significantly reduced cortical expression of 8-hydroxydeoxyguanosine (maker for oxidative DNA damage), 4-hydroxy-2-nonenal (maker for lipid peroxidation), phosphorylated adducin (marker for Rho-kinase activation) and von Willebrand factor (endothelial marker) when compared with vehicle pretreatment. In addition, phosphorylated adducin expression co-localized with von Willebrand factor immunoreactivity. The present study established the neuroprotective effect of EPA-E on ischemic brain damage following transient focal cerebral ischemia in rats, which may be involved in the suppression of oxidative stress and endothelial Rho-kinase activation. © 2013 Elsevier B.V.

DOI： 10.1016/j.brainres.2013.04.046

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MARY ANN LIEBERT, INC  

Brain edema after ischemic brain injury is a key determinant of morbidity and mortality. Aquaporin-4 (AQP4) plays an important role in water transport in the central nervous system and is highly expressed in brain astrocytes. However, the AQP4 regulatory mechanisms are poorly understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs), which are involved in changes in osmolality, might mediate AQP4 expression in models of rat cortical astrocytes after ischemia. Increased levels of AQP4 in primary cultured astrocytes subjected to oxygen-glucose deprivation (OGD) and 2 h of reoxygenation were observed, after which they immediately decreased at 0 h of reoxygenation. Astrocytes exposed to OGD injury had significantly increased phosphorylation of three kinds of MAPKs. Treatment with SB203580, a selective p38 MAPK inhibitor, or SP600125, a selective c-Jun N-terminal kinase inhibitor, significantly attenuated the return of AQP4 to its normal level, and SB203580, but not SP600125, significantly decreased cell death. In an in vivo study, AQP4 expression was upregulated 1-3 days after reperfusion, which was consistent with the time course of p38 phosphorylation and activation, and decreased by the p38 inhibition after transient middle cerebral artery occlusion (MCAO). These results suggest that p38 MAPK may regulate AQP4 expression in cortical astrocytes after ischemic injury.

DOI： 10.1089/neu.2012.2430

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MANEY PUBLISHING  

Objective: The immunosuppressant FK506 (tacrolimus) is neuroprotective in experimental models of cerebral ischemia. However, the precise mechanisms underlying this neuroprotection remain unknown. In the present study, we hypothesized that FK506 treatment could protect rat brain from oxidative injuries through antioxidative and anti-inflammatory pathways after ischemia-reperfusion injury.
Methods: Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 120 minutes, followed by reperfusion. Animals received a single injection of FK506 (0.3 mg/kg) or vehicle intravenously at 30 minutes after ischemic induction. Infarct volume and neurological performance were evaluated at 24 hours after reperfusion. Immunohistochemical analysis for 4-hydroxy-2-nonenal (4-HNE), 8-hydroxydeoxyguanosine (8-OHdG), ionized calcium-binding adapter molecule 1 (Iba-1), and tumor necrosis factor-alpha (TNF-alpha) were conducted at 24 hours after reperfusion.
Results: FK506 significantly reduced infarct volume (61.7%; P=0.01) and improved neurological deficit scores (P&lt;0.05) 24 hours after reperfusion compared to vehicle. In FK506-treated rats, accumulation of 4-HNE (P&lt;0.01) and 8-OHdG (P&lt;0.01) was significantly suppressed in the cerebral cortex 24 hours after reperfusion. In addition, FK506 markedly reduced microglial activation (P&lt;0.01) and TNF-alpha expression (P&lt;0.01).
Discussion: These results demonstrate that FK506 may have antioxidant as well as anti-inflammatory effects and reduces ischemic damage following cerebral infarction.

DOI： 10.1179/1743132811Y.0000000019

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：The Medical Association of Nippon Medical School  

DOI： 10.1272/jnms.78.60

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background and Purpose-p53-upregulated modulator of apoptosis (PUMA), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and-independent forms of apoptosis. PUMA localizes to mitochondria and interacts with antiapoptotic Bcl-2 and Bcl-X(L) or proapoptotic Bax in response to death stimuli. Although studies have shown that PUMA is associated with pathomechanisms of cerebral ischemia, clearly defined roles for PUMA in ischemic neuronal death remain unclear. The purpose of this study was to determine potential roles for PUMA in cerebral ischemia.
Methods-Five minutes of transient global cerebral ischemia (tGCI) were induced by bilateral common carotid artery occlusion combined with hypotension.
Results-PUMA was upregulated in vulnerable hippocampal CA1 neurons after tGCI as shown by immunohistochemistry. In Western blot and coimmunoprecipitation analyses, PUMA localized to mitochondria and was bound to Bcl-XL and Bax in the hippocampal CA1 subregion after tGCI. PUMA upregulation was inhibited by pifithrin-alpha, a specific inhibitor of p53, suggesting that PUMA is partly controlled by the p53 transcriptional pathway after tGCI. Furthermore, reduction in oxidative stress by overexpression of copper/zinc superoxide dismutase, which is known to be protective of vulnerable ischemic hippocampal neurons, inhibited PUMA upregulation and subsequent hippocampal CA1 neuronal death after tGCI.
Conclusions-These results imply a potential role for PUMA in delayed CA1 neuronal death after tGCI and that it could be a molecular target for therapy. (Stroke. 2009;40:618-625.)

DOI： 10.1161/STROKEAHA.108.524447

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Humana Press  

The transient global ischemia model is used to analyze selective neuronal death in vulnerable regions including the CA1 subregion of the hippocampus and in certain cortical neurons. In this mouse global ischemia model, bilateral common carotid arteries are reversibly occluded, and the individual anatomical backgrounds are normalized by evaluating the patency of the posterior communicating artery. Using this evaluation, this model might be used for mouse strains with various genetic backgrounds. © 2009 Humana Press.

DOI： 10.1007/978-1-60327-185-1_10

Scopus

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

A brief period of global brain ischemia, such as that induced by cardiac arrest or cardiopulmonary bypass surgery, causes cell death in vulnerable hippocampal CA1 pyramidal neurons days after reperfusion. Although numerous factors have been suggested to account for this phenomenon, the mechanisms underlying it are poorly understood. We describe a cell death signal called the PIDDosome, a protein complex of p53-induced protein with a death domain (PIDD), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and procaspase-2. We induced 5 min of transient global cerebral ischemia (tGCI) using bilateral common carotid artery occlusion with hypotension. Western blot analysis showed that expression of twice-cleaved fragment of PIDD (PIDD-CC) increased in the cytosolic fraction of the hippocampal CA1 subregion and preceded procaspase-2 activation after tGCI. Caspase-2 cleaved Bid in brain homogenates. Co-immunoprecipitation and immunofluorescent studies demonstrated that PIDD-CC, RAIDD, and procaspase-2 were co-localized and bound directly, which indicates the formation of the PIDD death domain complex. Furthermore, we tested inhibition of PIDD expression by using small interfering RNA (siRNA) treatment that was initiated 48 h before tGCI. Administration of siRNA against PIDD decreased not only expression of PIDD-CC, but also activation of procaspase-2 and Bid, resulting in a decrease in histological neuronal damage and DNA fragmentation in the hippocampal CA1 subregion after tGCI. These results imply that PIDD plays an important role in procaspase-2 activation and delayed CA1 neuronal death after tGCI. We propose that PIDD is a hypothetical molecular target for therapy against neuronal death after tGCI.

DOI： 10.1073/pnas.0806222105

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Cytosolic phospholipase A(2) (cPLA(2)) is a key enzyme that mediates arachidonic acid metabolism, which causes cerebral ischemia-induced oxidative injury, blood-brain barrier (BBB) dysfunction, and edema. Recent reports have shown that p38 mitogen-activated protein kinase (MAPK) is related to phosphorylation and activation of cPLA(2) and release of arachidonic acid. However, involvement of the p38 MAPK pathway in cPLA(2) activation and of reactive oxygen species in expression of p38 MAPK/cPLA(2) after ischemia-reperfusion injury in the brain remains unclear. To address these issues, we used a model of transient focal cerebral ischemia (tFCI) in rats. Western blot analysis showed a significant increase in expression of phospho-p38 MAPK and phospho-cPLA(2) in rat brain cortex after tFCI. Activity assays showed that both p38 MAPK and cPLA2 activation markedly increased 1 day after reperfusion. Intraventricular administration of SB203580 significantly suppressed activation and phosphorylation of cPLA(2) and attenuated BBB extravasation and subsequent edema. Moreover, overexpression of copper/zinc-superoxide dismutase remarkably diminished activation and phosphorylation of both p38 MAPK and cPLA(2) after reperfusion. These findings suggest that the p38 MAPK/cPLA(2) pathway may promote BBB disruption with secondary vasogenic edema and that superoxide anions can stimulate this pathway after ischemia-reperfusion injury.

DOI： 10.1038/jcbfm.2008.60

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Recent studies have revealed that oxidative stress has detrimental effects in several models of neurodegenerative diseases, including subarachnoid hemorrhage (SAH). However, how oxidative stress affects acute brain injury after SAH remains unknown. We have previously reported that overexpression of copper/zinc superoxide dismutase (SOD1) reduces oxidative stress and subsequent neuronal injury after cerebral ischemia. In this study, we investigated the relationship between oxidative stress and acute brain injury after SAH using SOD1 transgenic ( Tg) rats. SAH was produced by endovascular perforation in wild- type (Wt) and SOD1 Tg rats. Apoptotic cell death at 24 h, detected by a cell death assay, was significantly decreased in the cerebral cortex of the SOD1 Tg rats compared with the Wt rats. The mortality rate at 24 h was also significantly decreased in the SOD1 Tg rats. A hydroethidine study demonstrated that superoxide anion production after SAH was reduced in the cerebral cortex of the SOD1 Tg rats. Moreover, phosphorylation of Akt and glycogen synthase kinase-3 beta (GSK3 beta), which are survival signals in apoptotic cell death, was more enhanced in the cerebral cortex of the SOD1 Tg rats after SAH using Western blot analysis and immunohistochemistry. We conclude that reduction in oxidative stress by SOD1 overexpression may attenuate acute brain injury after SAH via activation of Akt/GSK3 beta survival signaling.

DOI： 10.1038/sj.jcbfm.9600399

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background and Purpose - Hyperglycemia is linked to a worse outcome after ischemic stroke. Among the manifestations of brain damage caused by ischemia are blood-brain barrier (BBB) disruption and edema formation. Oxidative stress and matrix metalloproteinase-9 (MMP-9) activation are implicated in BBB dysfunction after ischemia/reperfusion injury. Our present study was designed to clarify the relation among hyperglycemia, oxidative stress, and MMP-9 activation associated with BBB dysfunction after transient focal cerebral ischemia (tFCI).
Methods - We used a model of 60 minutes of middle cerebral artery occlusion on the following animals: normoglycemic wild-type rats, wild-type rats with hyperglycemia induced by streptozotocin, and human copper/zinc superoxide dismutase (SOD1) transgenic rats with streptozotocin-induced hyperglycemia. We evaluated edema volume, Evans blue leakage, and oxidative stress, such as the carbonyl groups and oxidized hydroethidine (HEt), SOD activity, and gelatinolytic activity, including MMP-9.
Results - Hyperglycemia significantly increased edema volume and Evans blue leakage. Moreover, it enhanced the levels of the carbonyl groups, the oxidized HEt signals, and MMP-9 activity after tFCI without alteration in SOD activity. Gelatinolytic activity and oxidized HEt signals had a clear spatial relation in the hyperglycemic rats. SOD1 overexpression reduced the hyperglycemia-enhanced Evans blue leakage and MMP-9 activation after tFCI.
Conclusions - Hyperglycemia increases oxidative stress and MMP-9 activity, exacerbating BBB dysfunction after ischemia/reperfusion injury. Superoxide overproduction may be a causal link among hyperglycemia, MMP-9 activation, and BBB dysfunction.

DOI： 10.1161/01.STR.0000258041.75739.cb

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Bad, a proapoptotic Bcl- 2 family protein, plays a critical role in determining cell death/ survival. The phosphatidylinositol 3- kinase ( PI3- K)/ Akt pathway and the c- Jun N- terminal kinase ( JNK) pathway are thought to be involved in regulation of Bad. Therefore, the present study was performed to clarify the role of Bad as a common target of the PI3- K/ Akt and JNK pathways after transient focal cerebral ischemia ( tFCI) in rats. We found that Akt activity increased at 3 h and then decreased, whereas JNK activity increased 7 to 24 h in the peripheral area after tFCI. Administration of LY294002, a PI3- K- specific inhibitor, exacerbated DNA fragmentation, whereas administration of SP600125, a JNK- specific inhibitor, attenuated it. Inhibited by LY294002, phospho- Bad ( Ser136) expression increased in the peripheral area 3 h after tFCI, with suppression of Akt activity. Furthermore, phospho- Bad ( Ser136) and phospho- Akt ( Ser473) were colocalized. Decreases in phospho- Bad ( Ser136) and Bad/ 14- 3- 3 dimerization and increases in Bcl- XL/ Bad or Bcl- 2/ Bad dimerization observed 7 to 24 h after tFCI, were prevented by SP600125 administration, with inhibition of JNK activity. The present study indicates that signal predominance varies from PI3- K/ Akt- mediated survival signaling to JNK- mediated death signaling with the development of neuronal damage in the peripheral area after tFCI. This study also suggests that PI3- K/ Akt has a role in Bad inactivation, whereas the JNK pathway is involved in Bad activation. We conclude that Bad may be an integrated checkpoint of PI3- K/ Akt- mediated survival signaling and JNK- mediated death signaling and that it contributes to cell fate in the peripheral area after cerebral ischemia.

DOI： 10.1038/sj.jcbfm.9600367

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Recent studies have revealed that the phosphatidylinositol 3-kinase (PI3-K) pathway is involved in apoptotic cell death after experimental cerebral ischemia. The serine-threonine kinase, Akt, functions in the PI3-K pathway and prevents apoptosis by phosphorylation at Ser473 after a variety of cell death stimuli. After phosphorylation, activated Akt inactivates other apoptogenic factors, including glycogen synthase kinase-3 beta (GSK3 beta), thereby inhibiting cell death. However, the role of Akt/GSK3 beta signaling in the delayed death of hippocampal neurons in the CA1 subregion after transient global cerebral ischemia (tGCI) has not been clarified. Transient global cerebral ischemia for 5mins was induced by bilateral common carotid artery occlusion combined with hypotension. Western blot analysis showed a significant increase in phospho-Akt (Ser473) and phospho-GSK3 beta (Ser9) in the hippocampal CA1 subregion after tGCl. Immunohistochemistry showed that expression of phospho-Akt (Ser473) and phospho-GSK3 beta (Ser9) was markedly increased in the vulnerable CA1 subregion, but not in the ischemic-tolerant CA3 subregion. Double staining with phospho-GSK3 beta (Ser9) and terminal deoxynucleotidyl transferase-mediated uridine 5-triphosphate-biotin nick end labeling showed different cellular distributions in the CA1 subregion 3 days after tGCI. Phosphorylation of AM and GSK3 beta was prevented by LY294002, a PI3-K inhibitor, which facilitated subsequent DNA fragmentation 3 days after tGCl. Moreover, transgenic rats that overexpress copper/zinc-superoxide dismutase, which is known to be neuroprotective against delayed hippocampal CA1 injury after tGCl, had enhanced and persistent phosphorylation of both Akt and GSK3 beta after tGCl. These findings suggest that activation of the Akt/GSK3 beta signaling pathway may mediate survival of vulnerable hippocampal CA1 neurons after tGCl.

DOI： 10.1038/sj.jcbfm.9600303

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background and Purpose-Apoptotic cell death is associated with acute brain injury after subarachnoid hemorrhage (SAH). The Akt/glycogen synthase kinase-3 beta (GSK3 beta) pathway plays an important role in the cell death/survival pathway after a variety of cell death stimuli. However, its role in acute brain injury after SAH remains unknown.
Methods-We used an endovascular perforation model of SAH in rats. Phospho-Akt and phospho-GSK3 beta expression was examined by Western blot analysis and immunohistochemistry. Terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) and a cell death assay were used for detection of apoptosis. We administered LY294002 to examine the role of the Akt/GSK3 beta pathway in the phosphoinositide 3-kinase pathway after SAH.
Results-Phosphorylation of Akt and GSK3 beta was accelerated after SAH. In the cerebral cortex, where acute brain injury was the most severe, phosphorylation of these proteins was observed in the early phase after SAH. Cortical neurons with continuous Akt phosphorylation did not colocalize with TUNEL-positive cells at 24 hours. LY294002 reduced Akt and GSK3 beta phosphorylation and increased brain injury after SAH.
Conclusions-The present study suggests that the Akt/GSK3 beta pathway might be involved in neuronal survival in acute brain injury after SAH.

DOI： 10.1161/01.STR.0000229888.55078.72

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NEUROSCIENCE  

Although p53 is a key modulator of cellular stress responses, the mechanism of p53-mediated apoptosis is ambiguous. p53 can mediate apoptosis in response to death stimuli by transcriptional activation of proapoptotic genes and transcriptional-independent mechanisms. Recent studies have shown that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming a inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release. However, how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischemia remains unclear. We examined the interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons in rats using a transient global cerebral ischemia (tGCI) model. Western blot analysis and immunofluorescent staining revealed mitochondrial p53 translocation after tGCI in the hippocampal CA1 neurons. Coimmunoprecipitation revealed that translocated p53 bound to Bcl-X-L in the mitochondrial fraction. To examine the effect of a specific p53 inhibitor on the mitochondrial p53 pathway and apoptotic cell death after tGCI, we intravenously administered pifithrin-alpha (PFT). Mitochondrial p53 translocation and interaction between p53 and Bcl-X-L were prevented by treatment with PFT. Moreover, cytochrome c release from mitochondria and subsequent apoptotic CA1 neuronal death were decreased with PFT treatment. These results suggest that the mitochondrial p53 pathway is one of the novel mechanisms mediating delayed death of vulnerable hippocampal CA1 neurons after tGCI.

DOI： 10.1523/JNEUROSCI.0897-06.2006

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

To investigate the effect of an antioxidant edaravone on the apoptotic process, we examined Bax and Bcl-2 immunohistochemical expression and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) reactivity. Rat focal ischemia models were prepared by 2 h transient middle cerebral artery occlusion. Edaravone or physiological saline was intravenously administered after reperfusion. After 24 It of reperfusion, infarction volume assessments, Bax and Bcl-2 immunohistochemistry and TUNEL staining were performed as well as neurological evaluation. Cortical cerebral blood flow was not statistically different between the treatment-groups. Edaravone-treated animals showed significantly improved neurological outcome. Total and cortical infarct volumes in the edaravone group significantly decreased. In addition, edaravone-treatment provided a significant reduction in the number of TUNEL-positive apoptotic cells, a decrease in Bax immunoreactivity and an increase in Bcl-2 expression within the peri-infarct area. Edaravone shows an excellent neuroprotective effect against ischemia/reperfusion brain injury through a Bax/Bcl-2 dependent antiapoptotic mechanism. (c) 2005 Elsevier B.V All rights reserved.

DOI： 10.1016/j.ejphar.2005.04.036

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：HUMANA PRESS INC  

It has been demonstrated by numerous studies that apoptotic cell death pathways are implicated in ischemic cerebral injury in ischemia models in vivo. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the numerous reports suggest the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in ischemic lesions. In these models, reoxygenation during reperfusion provides oxygen as a substrate for numerous enzymatic oxidation reactions and for mitochondrial oxidative phosphorylation to produce adenosine triphosphate. Oxygen radicals, the products of these biochemical and physiological reactions, are known to damage cellular lipids, proteins, and nucleic acids and to initiate cell signaling pathways after cerebral ischemia. Genetic manipulation of intrinsic antioxidants and factors in the signaling pathways has provided substantial understanding of the mechanisms involved in cell death/survival signaling pathways and the role of oxygen radicals in ischemic cerebral injury. Future studies of these pathways could provide novel therapeutic strategies in clinical stroke.

DOI： 10.1385/MN:31:1-3:105

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Levodopa (LD) is one of the most effective drugs for clinical symptoms in patients with Parkinson disease (PD). Most PD patients are advanced in age and may have trouble with LD absorption because aging influences drug absorption processes. Previous reports have indicated that ascorbic acid (AsA) can reduce LD dosage without losing its effectiveness. The current study sought to determine whether AsA affects LD absorption in elderly PD patients. Sixty-seven elderly PD patients took a tablet orally containing 100 mg LD and 10 mg carbidopa following an overnight fast. Plasma LD concentrations were determined at 6 points up to 3 hours, using high-performance liquid chromatography with electrochemical detection. The area under the curve (AUC), peak drug concentration (Cmax), and time to peak drug concentration (Tmax) were calculated. The pharmacokinetic evaluation was repeatedly performed 1 week later in the same way except for adding 200 mg AsA to the tablet. The changes in AUC, Cmax, and Ttnax between the tests were evaluated. Significant changes in these parameters were not observed when analyzed using data from all patients. However, significant increases in AUC and Cmax, and a significant reduction in Tmax by adding AsA were observed in 25 patients with baseline AUC less than or equal to2500 ng(.)hour/mL. In conclusion, AsA can improve LD absorption in elderly PD patients with poor LD bioavailability. LD therapy in combination with AsA may be one of the strategies for PD treatment.

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

FK506 (tacrolimus), an immunosuppressant, reportedly reduces ischemic brain injury following transient middle cerebral artery occlusion (MCAO) in rats. The authors previously reported that the therapeutic window of FK506 in this model is more than 1 h, but less than 2 h. The aim of the present study is to determine whether mild hypothermia (35 degreesC) enhances the neuroprotective effects of FK506 and expands its therapeutic window. Sprague-Dawley rats were subjected to 2 h MCAO followed by 24 h reperfusion. Animals were randomly divided into four groups: (1) vehicle-treated normothermic group; (II) FK506-treated normothermic group; (III) vehicle-treated hypothermic group; (IV) FK506-treated hypothermic group. Animals received a single injection of FK506 (0.3 mg/kg) or vehicle intravenously at 2 h after ischemic induction. During ischemia, temporal muscle and rectal temperatures were maintained at 37 degreesC in the normothermic animals and at 35 degreesC in the hypothermic animals. Infarct volumes and neurological performance were evaluated at 24 h after reperfusion. The combination of FK 506 and mild hypothermia significantly reduced infarct volume (cortex, -61%; striatum, -31%) and edema volume (cortex, -57%; striatum, -41%), while mild hypothermia or FK506 alone failed to improve ischemic brain damage. Furthermore, this combination also provided for the best functional outcome. These results demonstrate that the combination of FK506 and mild hypothermia significantly reduces ischemic brain damage following transient MCAO in rats, and expands the therapeutic window for FK506. This therapy may be a new approach for treatment of acute stroke. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2004.02.031

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：ELSEVIER SCIENCE BV  

3-Methyl-1-phenyl-pyrazolin-5-one (edaravone), a novel free radical scavenger, has been reported to reduce ischemic damage in rats subjected to transient focal ischemia. The aim of this study is, therefore, to investigate the effect of a combined therapy with edaravone and mild hypothermia at 35 degreesC. Sprague-Dawley rats were subjected to middle cerebral artery (MCA) occluding using by an intraluminal suture technique for 2 h. The rats were reperfused for 24 h and decapitated for infarct and edema analysis. Animals were randomly divided into four groups: (I) vehicle+normothermia (control); (II) vehicle+mild hypothermia; (III) edaravone+normothermia; (IV) edaravone+mild hypothermia. Mild hypothermia alone had no reduction of the brain damage. The edaravone alone significantly reduced edema volume. The combined treatment with edaravone and mild hypothermia reduced both infarct and edema volume. In addition, this treatment provided for the best functional outcome. These results demonstrate that a free radical scavenger, edaravone, attenuates brain edema and that the combined therapy with edaravone and mild hypothermia significantly reduces not only edema but also infarct on transient focal cerebral ischemia in rats. The neuroprotective effects seen in this study may be due to the combined interaction of antiedema activity between edaravone and mild hypothermia, suppressing free radical production. (C) 2003 Published by Elsevier Science B.V.

DOI： 10.1016/S0531-5131(03)00044-X

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：SPRINGER-VERLAG WIEN  

The aim of this study is to determine whether a selective thrombin inhibitor, Argatroban, would prevent neuronal cell death and whether extra-mild hypothermia (35degreesC) would enhance the neuroprotective effect of a selective thrombin inhibitor following transient focal ischemia in rats.
Sprague-Dawley rats were subjected to MCAo using an intraluminal suture technique for 2 firs. The rats were reperfused for 24 h and decapitated for infarct and edema analysis. Argatroban-treated animals received a continuous injection of argatroban (3.0 mg/kg) for 24 firs after onset of ischemia, while vehicle-treated groups received same dose of vehicle. During ischemia, temporal muscle and rectal temperatures were monitored and maintained at 37 degreesC in the normothermic animals and at 35degreesC in the hypothermic animals.
Argatroban ameliorated the cortical ischemic damage significantly (p &lt; 0.05). Moreover, argatroban with mild hypothermia decreased the cortical infarct or edema volume significantly compared with those of groups I and III (p &lt; 0.05). Argatroban improved neurological symptoms significantly and also improved survival rate.
These results demonstrate that extra-mild hypothermia (35degreesC) enhances neuroprotective effects of a selective thrombin inhibitor, argatroban, suggesting that this combined therapy may be a new therapeutic strategy for the treatment of acute stroke.

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：SPRINGER-VERLAG WIEN  

Edaravone, a novel free radical scavenger, has been reported to reduce ischemic damage in rats subjected to transient focal ischemia. The aim of this study is, therefore, to investigate the effect of a combined therapy with edaravone and mild hypothermia of 35degreesC. Sprague-Dawley rats were subjected to MCA occluding an intraluminal suture technique for 2 hrs. The rats were reperfused for 24 h and decapitated for infarct and edema analysis. Animals were randomly devided into four groups: (1) vehicle + normothermia (control) (11) vehicle + mild hypothermia (111) Edaravone + normothermia (IV) Edaravone + mild hypothermia. Mild hypothermia alone had no reduction of the brain damage. The edaravone alone significantly reduced edema volume. The combined treatment with edaravone and mild hypothermia reduced both infaret and edema volume. In addition, this treatment provided for the best functional outcome. These results demonstrate that free radical scavenger, edaravone attenuates brain edema and that the combined therapy with edaravone and mild hypothermia significantly reduces not only edema but also infaret on transient focal cerebral ischemia in rats. The neuroprotective effects seen in this study may be due to the combined interaction of antiedema activity between edaravone and mild hypothermia, suppressing free radical production.

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FOREFRONT PUBL GROUP  

Tacrolimus (FK506), an immunosuppressant currently used in clinic, is known to have neuroprotective properties. However, effects in focal ischemia are shown only in a endothelin induced middle cerebral artery (MCA) occlusion model or with filament technique at a relatively high dose. We have previously shown that FK506 had significant protective effects at a low dose of 0.3 mg kg(-1) when administered immediately after ischemia. In this study, we explored the therapeutic time window of FK506 at this low dose, in a transient focal ischemia model using filament technique. Male Sprague-Dawley rats were subjected to 2 h MCA occlusion and subsequent reperfusion. They received FK506 or vehicle (0.3 mg kg-1) i. v. at 30, 60 or 120 min after induction of ischemia, and were decapitated 24 h after ischemia. FK506 injected at 30 and 60 min significantly reduced cortical infarction volume (FK506 vs. vehicle; 30min: 95 +/- 33 mm(3) vs. 170 +/- 62 mm(3), P &lt; 0.05; 60 min: 93 +/- 45 mm(3), vs. 168 +/- 35 mm(3), p &lt; 0.05, respectively). FK506 was ineffective when given at 120 min after ischemia. FK506 had no effect on edema formation, nor on the infarct volume in striatum. The therapeutic time window for this low dose of FK506 given i.v. is between 60 and 120 min in this model.

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background/Objective: As the incidence of Parkinson's disease (PD) is related to aging, we consider it important to determine how the initial symptoms change with age in order to diagnose early elderly cases of PD accurately. Methods: 84 patients (age at onset 70.7 +/- 9.0 years; mean +/- 1 SD) were studied to see whether the initial symptoms change according to age. Results: The prevalence of resting tremor was significantly lower in patients of advanced age (p = 0.041). In contrast, the incidence of postural and gait disorders increased significantly with aging (p = 0.032). The prevalences of rigidity and kinetic disorders, which are important clinical features of PD, were not influenced by aging. Conclusion: These findings suggest that the cause of PD is not related to the aging process itself, since the prevalences of all symptoms were not influenced by aging. Knowledge of the prevalence of the initial symptoms of PD may contribute to the accurate diagnosis in early and elderly cases. Copyright (C) 2000 S. Karger AG, Basel.

Web of Science

researchmap

記述言語：日本語   出版者・発行元：The Japan Stroke Society  

Hypothermia has a neuroprotective effect for ischemia. The aim of this study was, therefore, to determine whether mild hypothermia (35°C) would enhance neuroprotecive effects of immunosuppressant FK 506 for focal ischemia. The left MCAO were occluded for 2 h by intraluminal suture and reperfused for 24 h. Animals were randomly devided into the following four groups. (I) vehicle-treated, normothermic (37°C) group (II) vehicle-treated, mild hypothermic (35°C) group (III) FK 506-treated, normothermic (37°C) group (IV) FK 506-treated, mild hypothermic (35°C) group. FK 506-treated animals received a single injection of FK 506 (0.3 mg/kg) intravenously 120 min after the onset of ischemia, while vehicle-treated groups received same dose of vehicle. The cortical and striatal infarct volume in group IV was significantly reduced compared with that in group I (p<0.001), whereas there was no significant difference between group II or III and group I. Moreover, edema volume in group IV was significantly smaller than that in group I (p<0.05). These results demonstrate that a combined therapy with mild hypothermia (35°C) and FK 506, each has no neuroprotective effects alone, significantly reduces the ischemic brain damage and enhances neuroprotecive actions for focal ischemia in rats.

DOI： 10.3995/jstroke.22.423

researchmap

記述言語：日本語   出版者・発行元：(一社)日本脳卒中学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objective: To determine susceptibility to neuroleptic malignant syndrome (NMS) in patients with PD in relation to central monoamine metabolism. Methods: CSF levels of homovanillic acid (HVA), 3-methoxy-4-hydroxy phenyletilene glycol (MHPG), and 5-hydroxyindole acetic acid (5-HIAA) were assayed in 98 PD patients (mean age, 77.2 years), including 11 patients with a prior NMS-like episode, by high-performance liquid chromatography with electrochemical detection. Results: Patients with a previous NMS-like episode had worse parkinsonian disability as measured by Hoehn & Yahr scale (3.7 +/- 0.8 versus 3.0 +/- 1.1; p = 0.038) and lower CSF HVA levels (20.9 +/- 17.3 versus 44.7 +/- 22.2 ng/mL; p = 0.001) compared to those without, despite similar age, disease duration, and daily dosages of antiparkinsonian drugs between groups. Logistic regression analysis showed that the CSF KVA level (p = 0.008), but not 5-HIAA level (p = 0.621), was significantly and independently related to NMS, and that the MHPG level (p = 0.070) was tendentially associated with the disorder. Odds ratios (95% confidence intervals) corresponding to 10 ng/mL increment in CSF HVA, MHPG, and 5-HIAA levels were 0.30 (0.13 to 0.73), 4.03 (0.89 to 18.2) and 1.29 (0.47 to 3.58), respectively. Conclusions: Central dopaminergic and possible noradrenergic activity contributes to NMS development in an elderly population of PD patients. Measuring CSF levels of monoamine metabolites may provide a means for identifying NMS susceptibility in PD patients.

Web of Science

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

researchmap

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J02615&link_issn=&doc_id=20191126230029&doc_link_id=10.15082%2Fjsnt.36.6_S127&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.36.6_S127&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

researchmap

記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

イブジラストは脳梗塞後遺症に伴う慢性脳循環障害に使用されている.今回,我々は中大脳動脈永久閉塞モデルを用いて,イブジラスト投与による脳保護効果について検討を行った.雄性SDラットに,イブジラスト30mg/kg/日を虚血7日前から経口胃管投与後,永久閉塞を行った.虚血後30分と24時間にMRIを撮像した.虚血後24時間後にMRIを用いて脳血流低下領域を測定し,神経徴候,梗塞体積,浮腫index(%)を評価すると共に,免疫組織化学的検討を行った.イブジラスト投与群はコントロール群と比較して脳血流低下領域が縮小し,神経徴候は改善し,梗塞体積および脳浮腫も縮小した.また,イブジラスト投与により,虚血周辺部の酸化ストレスマーカーや炎症マーカー発現の抑制を認めた.今回の結果から,イブジラストは脳虚血後の血流障害の改善や酸化ストレス軽減,虚血後炎症の抑制を介して脳保護作用を発揮することが示唆された.(著者抄録)

DOI： 10.16977/cbfm.26.2_19

researchmap

記述言語：日本語   出版者・発行元：メディカルレビュー社  

researchmap

その他リンク： http://search.jamas.or.jp/link/ui/2015190141

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

researchmap

記述言語：日本語   出版者・発行元：日本神経治療学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：KARGER  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：KARGER  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：KARGER  

Web of Science

researchmap

記述言語：日本語   出版者・発行元：日本脳循環代謝学会  

researchmap

記述言語：日本語   出版者・発行元：日本医科大学医学会  

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：NATURE PUBLISHING GROUP  

Web of Science

researchmap

記述言語：日本語   出版者・発行元：永井書店  

CiNii Books

researchmap

その他リンク： http://search.jamas.or.jp/link/ui/2009116332

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：英語   出版者・発行元：日本脳循環代謝学会  

著者らは,ラット光感受性脳血栓モデルの虚血72時間後における脳保護薬エダラボン(ED)の神経保護作用を検討し,更にトロンボキサン合成酵素阻害薬オザグレルナトリウム(OZG)を併用することで,その脳保護効果が増強するかどうかを検討した.実験動物は,I:対照群,II:OZG群,III:ED群,IV:OZG/ED群の4群に分類した. 1)脳梗塞体積の検討では,ED群とOZG群は対照群に比し共に縮小傾向を認めたが,有意差は認めなかった.しかし,OZG/ED群では,対照群に比し脳梗塞の有意な縮小を認め,脳浮腫体積や神経症候も有意に改善した(p&lt;0.05). 2)EDはラット脳血栓モデルにおいて脳梗塞抑制効果を示し,またOZGを併用することによりEDの脳保護効果が増強する可能性が示され,この併用療法の臨床応用の有用性が示唆された

researchmap

記述言語：日本語   出版者・発行元：(一社)日本脳卒中学会  

researchmap

記述言語：日本語   出版者・発行元：日本評論社  

CiNii Books

researchmap

その他リンク： http://search.jamas.or.jp/link/ui/2001112917

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

researchmap