Relationship between Alcohol Intake and Stroke Severity in Japanese Patients: a Sex- and Subtype-Stratified Analysis.

OBJECTIVES: This study aims to clarify the association between alcohol intake and stroke severity at admission and discharge according to sex and stroke subtype in Japanese patients with acute stroke. MATERIALS AND METHODS: We analyzed the data of 199,599 patients registered in the Japan Stroke Data Bank from 1999 to 2018, including sex, age, stroke subtypes (cardioembolic ischemic, noncardioembolic ischemic, hypertensive hemorrhagic, nonhypertensive hemorrhagic, and subarachnoid hemorrhagic), dates of onset and admission, National Institutes of Health Stroke Scale score at admission, modified Rankin Scale score at discharge, and alcohol intake. Multivariable logistic regression analysis adjusted for stroke-related factors was performed to estimate the odds ratios of alcohol intake for stroke severity. RESULTS: In cardioembolic ischemic stroke, a significant protective effect of moderate intake on severity at admission was observed in both sexes. In noncardioembolic ischemic stroke, a significant protective effect on stroke severity at admission was found for each sex. At discharge, the results also showed a significant protective effect for each sex with moderate intake. For both subtypes of ischemic stroke, a J-shaped relationship between alcohol intake and stroke severity at admission and discharge was observed in women and men. In hypertensive hemorrhagic stroke, a significant protective effect was found in men at both admission and discharge. In women, heavy drinking had a significant harmful effect on stroke severity at admission. CONCLUSIONS: Habitual alcohol intake is associated with stroke severity at admission and discharge regardless of sex.

Visualisation of the non-linear correlation between age and poor outcome in patients with aneurysmal subarachnoid haemorrhage.

OBJECTIVE: To visualise the non-linear correlation between age and poor outcome at discharge in patients with aneurysmal subarachnoid haemorrhage (SAH) while adjusting for covariates, and to address the heterogeneity of this correlation depending on disease severity by a registry-based design. METHODS: We extracted data from the Japanese Stroke Databank registry for patients with SAH treated via surgical clipping or endovascular coiling within 3 days of SAH onset between 2000 and 2017. Poor outcome was defined as a modified Rankin Scale Score ≥3 at discharge. Variable importance was calculated using machine learning (random forest) model. Correlations between age and poor outcome while adjusting for covariates were determined using generalised additive models in which spline-transformed age was fit to each neurological grade of World Federation of Neurological Societies (WFNS) and treatment. RESULTS: In total, 4149 patients were included in the analysis. WFNS grade and age had the largest and second largest variable importance in predicting the outcome. The non-linear correlation between age and poor outcome was visualised after adjusting for other covariates. For grades I-III, the risk slope for unit age was relatively smaller at younger ages and larger at older ages; for grade IV, the slope was steep even in younger ages; while for grade V, it was relatively smooth, but with high risk even at younger ages. CONCLUSIONS: The clear visualisation of the non-linear correlation between age and poor outcome in this study can aid clinical decision making and help inform patients with aneurysmal SAH and their families better.

Effect of Edaravone on Neurological Symptoms in Real-World Patients With Acute Ischemic Stroke.

Background and Purpose- In Japan, nearly half of ischemic stroke patients receive edaravone for acute treatment. The purpose of this study was to assess the effect of edaravone on neurological symptoms in patients with ischemic stroke stratified by stroke subtype. Methods- Study subjects were 61 048 patients aged 18 years or older who were hospitalized ≤14 days after onset of an acute ischemic stroke and were registered in the Japan Stroke Data Bank, a hospital-based multicenter stroke registration database, between June 2001 and July 2013. Patients were stratified according to ischemic stroke subtype (large-artery atherosclerosis, cardioembolism, small-vessel occlusion, and cryptogenic/undetermined) and then divided into 2 groups (edaravone-treated and no edaravone). Neurological symptoms were evaluated using the National Institutes of Health Stroke Scale (NIHSS). The primary outcome was changed in neurological symptoms during the hospital stay (ΔNIHSS=NIHSS score at discharge-NIHSS score at admission). Data were analyzed using multivariate linear regression with inverse probability of treatment weighting after adjusting for the following confounding factors: age, gender, and systolic and diastolic blood pressure at the start of treatment, NIHSS score at admission, time from stroke onset to hospital admission, infarct size, comorbidities, concomitant medication, clinical department, history of smoking, alcohol consumption, and history of stroke. Results- After adjusting for potential confounders, the improvement in NIHSS score from admission to discharge was greater in the edaravone-treated group than in the no edaravone group for all ischemic stroke subtypes (mean [95% CI] difference in ΔNIHSS: -0.46 [-0.75 to -0.16] for large-artery atherosclerosis, -0.64 [-1.09 to -0.2] for cardioembolism, and -0.25 [-0.4 to -0.09] for small-vessel occlusion). Conclusions- For any ischemic stroke subtype, edaravone use (compared with no use) was associated with a greater improvement in neurological symptoms, although the difference was small (<1 point NIHSS) and of limited clinical significance.

Relationships between Alcohol Intake and Ischemic Stroke Severity in Sex Stratified Analysis for Japanese Acute Stroke Patients.

BACKGROUND: The aim of this study is to evaluate in the relationships between alcohol intake and ischemic stroke severity in Japanese stroke patients. METHODS: Of a total of 101,165 registered cases of stroke in Japan, patient data of total strokes (n = 60,836), cardiogenic strokes (n = 11,894), and noncardiogenic strokes (n = 29,129) were extracted. The National Institutes of Health Stroke Scale (NIHSS) score at admission and the modified Rankin Scale (mRS) score at discharge were used. Significant alcohol consumption in regard to stroke severity at admission and discharge was identified by multivariate adjusted logistic regression analysis. RESULTS: Among all subject and males, nondrinkers had significantly poorer NIHSS scores of cardiogenic strokes as did those consuming greater than or equal to 60 g/day, whereas there was a significant difference in past heavy drinkers with noncardiogenic strokes. Among females, nondrinkers had a significance of cardiogenic stroke and non-cardiogenic strokes. Among all subjects and males, 20-39 g/day and 40-59 g/day were significantly associated with protective effects on mRS severity of cardiogenic strokes, whereas 40-59 g/day also had significant protective effects for noncardiogenic strokes. Among females, greater than or equal to 60 g/day had a significant protective effect for cardiogenic strokes. CONCLUSIONS: For males, alcohol intake of less than 60 g/day played a protective role in functional prognosis at discharge and showed a J-shape relationship. For females, although there was a limitation that the number of female drinkers was small, negative effects were shown at admission with less consumption than males.

Analysis of outcome at discharge after aneurysmal subarachnoid hemorrhage in Japan according to the Japanese stroke databank.

The outcomes at discharge for ruptured cerebral aneurysms after subarachnoid hemorrhage (SAH) were investigated using data from the Japanese stroke databank. Among 101,165 patients with acute stroke registered between 2000 and 2013, 4693 patients had SAH caused by ruptured saccular aneurysm. Of these, 3593 patients (1140 men and 2453 women; mean age 61.3 ± 13.7 years) were treated by surgical clipping (SC) and/or endovascular coiling (EC). The outcomes of modified Rankin scale (mRS) at discharge were compared between the SC and EC groups. There were 2666 cases in the SC group, 881 cases in the EC group, and 46 cases in the SC and EC group. The rates of poor outcome of mRS > 2 were 33.0 and 45.5% in the SC and EC groups (p < 0.05), respectively. Cases were selected using two types of criteria compatible with both treatments. Under the first compatible criteria, the rates of poor outcome of mRS > 2 were 18.9 and 24.8% in the SC and EC groups (p < 0.05), respectively. Under the second compatible criteria, the rates of poor outcome of mRS > 2 were 16.0 and 14.8% in the SC and EC groups (p = 0.22), respectively. No significant differences were found in clinical characteristics or outcomes between the two groups. Multivariate analysis of aneurysmal SAH revealed no significant risk for poor outcome associated with the treatment method. The present study was not a randomized controlled study, but no significant differences in mRS at discharge were found between SC and EC in the Japanese stroke databank.

Effect of actual age on outcome at discharge in patients by surgical clipping and endovascular coiling for ruptured cerebral aneurysm in Japan.

The Japanese population features the highest rate of elderly individuals worldwide. However, the difference of actual age indication for surgical clipping (SC) and endovascular coiling (EC) has never reported. We clarified the effect of actual age on poor outcome at discharge in patients by each treatment for ruptured cerebral aneurysm according to the Japanese Stroke Data Bank. A total of 3593 patients with ruptured saccular cerebral aneurysm were treated by SC and/or EC between 2000 and 2013. The effect of actual age on poor outcome (modified Rankin scale [mRS] score > 2) at discharge was evaluated by the cutoff age using receiver operating characteristic analysis for each treatment. There were 2666 cases in the SC group and 881 cases in the EC group. The cutoff age for poor outcome was 3 to 9 years older for EC than for SC. The gap of cutoff age between two treatments was 3 years shorter in mild subarachnoid hemorrhage than severe cases. The gap of cutoff age between two treatments was 7 years in elderly patients over 65 years old. The cutoff age was 78 years old for both SC and EC in elderly female patients. In conclusion, the cutoff age for poor mRS score > 2 was 3 to 9 years older for EC than for SC. Actual age was one of the indications for elderly patients to achieve the optimum outcome; however, the treatment indication should be carefully considered based on the condition in each country.

Greater Severity of Neurological Defects in Women Admitted With Atrial Fibrillation-Related Stroke.

BACKGROUND: The magnitude of the CHA2DS2-VASc score is associated with not only stroke incidence but also long-term outcomes. The association between sex and initial stroke severity in AF-related cardioembolic stroke patients has not been clarified. The present study aimed to elucidate the risk factors for initial stroke severity among patients with cardioembolic stroke enrolled in a multicenter registry. METHODS AND RESULTS: We selected 12,701 patients (age, 77±10 years; 5,653 women) with AF-related cardioembolic stroke from the Japan Standard Stroke Registry Study between January 2000 and July 2013. Indicators of National Institutes of Health Stroke Scale (NIHSS) scores at admission were identified using a multiple linear regression. Increased NIHSS scores positively correlated with CHA2DS2-VASc score (ρ=0.197; P<0.001). The initial neurological deficits were more severe in women than in men (NIHSS scores, median [interquartile range] 14 [5-22] vs. 8 [3-18]; P<0.001). Multiple regression analysis revealed that higher age (standardized partial regression coefficient [ß] 0.162; P<0.001), female sex (ß 0.120; P<0.001), diabetes mellitus (ß 0.020; P=0.019), dyslipidemia (ß -0.076; P<0.001), congestive heart failure (ß 0.039; P<0.001), vascular disease (ß 0.030; P=0.001), prior stroke/TIA (ß 0.085; P<0.001) and prior anticoagulant use (ß -0.020; P=0.028) were associated with the NIHSS score at admission. CONCLUSIONS: Female sex was independently associated with the initial neurological severity among AF-related cardioembolic stroke patients.

Temporal Trends in Stroke Severity and Prior Antithrombotic Use Among Acute Ischemic Stroke Patients in Japan.

BACKGROUND: Few existing stroke registries allow for evaluation of stroke severity, stroke subtype and antithrombotic usage prior to stroke onset over a given time period. The present study aimed to elucidate temporal trends in initial presenting stroke severity, stroke subtype and prior antithrombotic use over a 12-year period in a Japanese multicenter stroke registry. METHODS AND RESULTS: We included 71,017 acute ischemic stroke patients (72±12 years old; 27,445 women) from the Japan Standard Stroke Registry Study (JSSRS) who were admitted to 94 hospitals between 2001 and 2012. The mean age of stroke onset increased gradually over time (P<0.001). Cardioembolic stroke patients (n=19,247) exhibited more severe NIHSS scores when compared with those with non-cardioembolic stroke (n=50,427). The proportion of cardioembolic stroke patients tended to increase over time, rising from 25.9% in 2001-2002 to 30.2% in 2011-2012 (P<0.001). Among the cardioembolic stroke patients, the frequency of prior anticoagulant use significantly increased from 15.6% in 2001-2002 to 24.8% in 2011-2012 (P<0.001). The frequency of prior antiplatelet use increased from 2001-2002 to 2007-2008 but decreased after 2007-2008. Among both cardioembolic and non-cardioembolic stroke patients, initial stroke severity at admission decreased over time, particularly after 2008. CONCLUSIONS: In this Japanese study, the mean age of ischemic stroke onset increased, while the initial neurological severity at presentation decreased, over a 12-year period. (Circ J 2016; 80: 2033-2036).

Antithrombotic Drugs Play a Significant Role in Intracerebral Hemorrhage in the Elderly Patients.

BACKGROUND: Japan has the fastest aging society in the world. Compared with younger patients, older ones have a different stroke risk profile and different stroke features. The aim of this study was to examine the risk factor profiles, stroke severities, and functional outcomes of hypertensive intracerebral hemorrhage (ICH) in different age groups. METHODS: A total of 14,599 patients with hypertensive ICH were included in a multicenter, hospital-based registration study using a computerized database involving 95 Japanese institutes from 2000 to 2012. RESULTS: The frequencies of atrial fibrillation, previous stroke, and coronary artery disease peaked in patients in their 80s and decreased thereafter. The frequency of the use of antithrombotic agents increased with age and reached its peak (26.7%) in patients in their 80s and sustained 18.6% in patients aged 90 years or older. More severe symptoms on admission and worse functional outcomes were observed with an increase in age, which might be related with the increased rate of antithrombotic therapy. CONCLUSIONS: The rate of use of antithrombotic agents increases with age. The role of these agents in ICH becomes larger in aged people, which may be one of the causes of poorer outcome in aged patients with ICH. Given that the population is rapidly aging, the use of antithrombotic agents should be considered an emerging risk factor.

Influence of Antiplatelet Drugs on the Outcome of Subarachnoid Hemorrhage Differs with Age.

BACKGROUND: The aim of this study was to examine the risk factor profiles and functional outcomes of subarachnoid hemorrhage (SAH) in different age groups, focusing on the effect of antiplatelet drugs when used before stroke. METHODS: A total of 5344 patients with SAH were included in a multicenter, hospital-based registration study involving 95 Japanese institutes from 2000 to 2012. Patients' profiles and use of antithrombotic agents were retrospectively reviewed. A modified Rankin Scale score of 4 or more at discharge was defined as poor outcome. RESULTS: The frequency of antithrombotic agent use increased with age; it reached its peak (10.9%) among patients in their 80s and remained constant at 7.5% for those 90 years or older. Poorer outcomes were evident as age increased. The frequency of hypertension increased with age, whereas current smoking and heavy drinking reached its peak among patients in their 40s and 50s, respectively. The use of antiplatelet agents significantly improved outcome in patients younger than 60 years (P = .04). In contrast, in the older group (≥60 years), the use of antiplatelet agents tended to worsen the outcome; patients aged 70-79 years who had used these agents had a significantly worse outcome compared with those who had not (P = .03). CONCLUSIONS: In the present study, the influence of antiplatelet agents was different among age groups. The potential beneficial effects of antiplatelet agents must be weighed against their potential adverse effects in the context of SAH, considering the differences in age-related outcomes.

Cardioembolic stroke is the most serious problem in the aging society: Japan standard stroke registry study.

BACKGROUND: Japan has the fastest aging society in the world. Older patients have a different stroke risk profile and different stroke features compared with younger patients. The aim of the present study was to examine the stroke subtypes, risk factor profiles, stroke severities, and functional outcomes in the different age groups. METHODS: A total of 78,096 patients with acute ischemic stroke, including transient ischemic attacks, were included in a multicenter, hospital-based registration study based on a computerized database involving 95 Japanese institutes between 2000 and 2012. RESULTS: The frequency of atrial fibrillation increased even after the age of 90 years; consequently, the proportion of patients experiencing cardioembolic stroke also increased in the same age group. Furthermore, more severe symptoms on arrival and worse functional outcomes were observed with increasing age. The frequency of hypertension increased with age, peaking in patients in their 70s, and decreasing slightly thereafter. The frequency of diabetes mellitus and hyperlipidemia peaked in patients in their 50s or 60s and gradually decreased thereafter. CONCLUSION: The findings of the present study suggest that in the currently aging society, cardioembolic stroke is the most important stroke subtype. The roles of hypertension, diabetes mellitus, and hyperlipidemia are greatest in stroke patients in their 50s to 60s. In older patients, the role of atrial fibrillation is more significant.

Subsequent vascular events after ischemic stroke: the Japan Statin Treatment Against Recurrent Stroke-Longitudinal.

BACKGROUND: We undertook a multicenter cohort observational study to investigate the frequency and type of subsequent vascular events after an ischemic stroke and to compare the rates of vascular events between patients with and without hyperlipidemia. METHODS: This nationwide study was conducted in 19 hospitals participating in the Japan Standard Stroke Registry Study. We enrolled ischemic stroke patients, including those with a transient ischemic attack, who had not experienced any vascular events before enrollment after their ischemic stroke events. Each subject was observed prospectively from September 1, 2003, to October 1, 2005, or until a primary end point or death. Primary end points included subsequent fatal or nonfatal vascular events: stroke, angina pectoris, acute myocardial infarction, aortic aneurysm, or arteriosclerosis obliterans. RESULTS: A total of 449 patients (mean age, 67.6 years; 64.8% men) were enrolled in this study. Of the 41 vascular events observed during follow-up, 40 were stroke. The median observation period was 568 days. We found that patients with hyperlipidemia had a significantly higher rate of vascular events compared with those without hyperlipidemia according to the Kaplan-Meier method and the log-rank test (P = .013). Hyperlipidemia significantly increased the risk of vascular events (hazard ratio, 2.169 [1.125-4.312]; P = .021) according to the Cox proportional hazard model after adjusting for confounding factors (age, sex, days from ischemic stroke until enrollment, smoking habits, and daily drinking habits). CONCLUSIONS: This study demonstrated that stroke was the most common subsequent vascular event after ischemic stroke; the study also indicated that hyperlipidemia could be a risk factor for subsequent vascular events after ischemic stroke.

Detection of common single nucleotide polymorphisms synthesizing quantitative trait association of rarer causal variants.

Genome-wide association (GWA) studies have identified hundreds of common (minor allele frequency ≥5%) single nucleotide polymorphisms (SNPs) associated with phenotype traits or diseases, yet causal variants accounting for the association signals have rarely been determined. A question then raised is whether a GWA signal represents an "indirect association" as a proxy of a strongly correlated causal variant with similar frequency, or a "synthetic association" of one or more rarer causal variants in linkage disequilibrium (D' ≈ 1, but r(2) not large); answering the question generally requires extensive resequencing and association analysis. Instead, we propose to test statistically whether a quantitative trait (QT) association of an SNP represents a synthetic association or not by inspecting the QT distribution at each genotype, not requiring the causal variant(s) to be known. We devised two test statistics and assessed the power by mathematical analysis and simulation. Testing the heterogeneity of variance was powerful when low-frequency causal alleles are linked mostly to one SNP allele, while testing the skewness outperformed when the causal alleles are linked evenly to either of the SNP alleles. By testing a statistic combining these two in 5000 individuals, we could detect synthetic association of a GWA signal when causal alleles sum up to 3% in frequency. Such signal only partially explains the heritability contributed by the whole locus. The proposed test is useful for designing fine mapping after studying association of common SNPs exhaustively; we can prioritize which GWA signal and which individuals to be resequenced, and identify the causal variants efficiently.

Favorable prognosis in posterior circulation ischemic stroke: Insights from a nationwide stroke databank.

INTRODUCTION: Clinical trials have historically underrepresented patients with posterior circulation ischemic stroke (PCIS). This study aimed to comprehensively assess the clinical characteristics and outcomes of PCIS patients compared to those with anterior circulation ischemic stroke (ACIS). METHODS: A retrospective analysis was conducted using data from the Japan Stroke Data Bank, encompassing 20 years across 130 stroke centers. The study focused on patients diagnosed with PCIS or ACIS. RESULTS: Among 37,069 patients reviewed, 7425 had PCIS, whereas 29,644 had ACIS. PCIS patients were younger and had a lower female representation than ACIS patients. Notably, PCIS patients had more favorable outcomes: 71% achieved a modified Rankin Scale of 0-2 or showed no deterioration at discharge (17 days at the median after admission), compared to 60% for ACIS patients (p < 0.001). Factors associated with an unfavorable outcome in the PCIS subgroup were older age, female sex (assigned at birth), history of hypertension, and higher National Institute of Health Stroke Scale (NIHSS) scores at admission. In both sexes, older age and higher NIHSS scores were negatively associated with favorable outcomes. CONCLUSIONS: PCIS patients demonstrated a more favorable prognosis than ACIS patients. Factors like older age, female sex, and higher NIHSS scores at admission were identified as independent predictors of unfavorable outcomes in PCIS patients. Older age and higher NIHSS scores at admission were common independent negative factors for a favorable outcome regardless of sex.

Improvement of Functional Outcomes in Patients with Stroke who Received Alteplase for Over 15 Years: Japan Stroke Data Bank.

AIM: The nationwide verification of intravenous thrombolysis (IVT) was rarely performed after the extension of the therapeutic time window of alteplase or after the expansion of mechanical thrombectomy (MT). We aimed to examine the long-term change in accurate real-world outcomes of IVT in patients with acute ischemic stroke (AIS) using the Japan Stroke Databank, a representative Japan-wide stroke database. METHODS: We extracted all patients with AIS who received IVT with alteplase between October 11, 2005, the approval date for alteplase use for AIS in Japan, and December 31, 2020. Patients were categorized into three groups using two critical dates in Japan as cutoffs: the official extension date of the therapeutic time window for IVT to within 4.5 h of symptom onset and the publication date of the revised guideline, where the evidence level of MT was heightened. We assessed the yearly trend of IVT implementation rates and the secular changes and three-group changes in clinical outcomes at discharge. RESULTS: Of 124,382 patients with AIS, 9,569 (7.7%) received IVT (females, 41%; median age, 75 years). The IVT implementation rate has generally increased over time and plateaued in recent years. The proportion of favorable outcomes (modified Rankin Scale score of 0-2) increased yearly over 15 years. The results of the changes in the outcomes of the three groups were similar to those of the annual changes. CONCLUSIONS: We revealed that IVT implementation rates in patients with AIS increased, and the functional outcome in these patients improved over 15 years. Therefore, the Japanese IVT dissemination strategy is considered appropriate and effective.

Clinical impact of body mass index on outcomes of ischemic and hemorrhagic strokes.

BACKGROUND AND AIM: To investigate the prognostic implication of body mass index (BMI) on clinical outcomes after acute ischemic and hemorrhagic stroke. METHODS: The subjects of the study included adult patients with available baseline body weight and height data who had suffered an acute stroke and were registered in the Japan Stroke Data Bank-a hospital-based, multicenter stroke registration database-between January 2006 and December 2020. The outcome measures included unfavorable outcomes defined as a modified Rankin Scale (mRS) score of 5-6 and favorable outcomes (mRS 0-2) at discharge, and in-hospital mortality. Mixed effects logistic regression analysis was conducted to determine the relationship between BMI categories (underweight, normal weight, overweight, class I obesity, class II obesity; <18.5, 18.5-23.0, 23.0-25.0, 25-30, ⩾30 kg/m2) and the outcomes, after adjustment for covariates. RESULTS: A total of 56,230 patients were assigned to one of the following groups: ischemic stroke (IS, n = 43,668), intracerebral hemorrhage (ICH, n = 9741), and subarachnoid hemorrhage (SAH, n = 2821). In the IS group, being underweight was associated with an increased likelihood of unfavorable outcomes (odds ratio, 1.47 (95% confidence interval (CI):1.31-1.65)) and in-hospital mortality (1.55 (1.31-1.83)) compared to outcomes in those with normal weight. Being overweight was associated with an increased likelihood of favorable outcomes (1.09 (1.01-1.18)). Similar associations were observed between underweight and these outcomes in specific IS subtypes (cardioembolic stroke, large artery stroke, and small-vessel occlusion). Patients with a BMI ⩾30.0 kg/m2 was associated with an increased likelihood of unfavorable outcomes (1.44 (1.01-2.17)) and in-hospital mortality (2.42 (1.26-4.65)) in large artery stroke. In patients with ICH, but not those with SAH, being underweight was associated with an increased likelihood of unfavorable outcomes (1.41 (1.01-1.99)). CONCLUSIONS: BMI substantially impacts functional outcomes following IS and ICH. Lower BMI consistently affected post-stroke disability and mortality, while higher BMI values similarly affected these outcomes after large artery stroke.

Human mesenchymal stem cell transplantation changes proinflammatory gene expression through a nuclear factor-κB-dependent pathway in a rat focal cerebral ischemic model.

Previous studies have demonstrated the immunomodulatory functions of mesenchymal stem cells (MSCs) in cerebral ischemic rats. However, the underlying mechanisms are unclear. The purpose of this study is to investigate the effects of MSC transplantation on transcriptional regulations of proinflammatory genes in cerebral ischemia. Transient ischemia was induced by middle cerebral artery occlusion (MCAO) in adult male Sprague-Dawley rats. After 24 hr, vehicle (PBS) or a human MSC line (B10) was transplanted intravenously. The neurological deficits, infarct volume, cellular accumulations, and gene expression changes were monitored by means of behavior tests, MRI, immunohistochemistry, Western blotting, laser capture microdissection, and real-time PCR. In the core area of the B10 transplantation group, the number of ED1-positive macrophage/microglia was decreased compared with the PBS group. In the core, nuclear factor-κB (NF-κB) was decreased, although CCAAT/enhancer-binding protein ß was not changed; both were expressed mainly in ED1-positive macrophage/microglia. Likewise, mRNAs of NF-κB-dependent genes including interleukin-1ß, MCP-1, and inducible nitric oxide synthase were decreased in ED1-positive and Iba-1-positive macrophage/microglia in the B10 transplantation group. Moreover, upstream receptors of the NF-κB pathway, including CD40 and Toll-like receptor 2 (TLR2), were decreased. Immunofluorescence results showed that, in the B10 transplantation group, the percentages of NF-κB-positive, CD40-positive, and TLR2-positive cells were decreased in ED1-positive macrophage/microglia. Furthermore, NF-κB-positive cells in the CD40- or TLR2-expressing cell population were decreased in the B10 transplantation group. This study demonstrates that B10 transplantation inhibits NF-κB activation, possibly through inhibition of CD40 and TLR2, which might be responsible for the inhibition of proinflammatory gene expression in macrophage/microglia in the infarct lesion.

Effects of sex difference on clinical features of acute ischemic stroke in Japan.

BACKGROUND: Sex differences in stroke characteristics and outcomes have been inconsistent. The goal of this study was to determine the influence of sex on underlying patient characteristics, stroke subtypes and conditions, and outcomes after ischemic stroke from a nationwide registration study. METHODS: A total of 33,953 patients with acute ischemic stroke, including 13,323 women, were registered in a multicenter, hospital-based registration study based on a computerized database from 162 Japanese institutes (the Japan Standard Stroke Registry Study) between January 2000 and November 2007. RESULTS: Women were significantly older than men at stroke onset (75.0 ± 11.7 v 69.3 ± 11.4 years; P < .0001). After age adjustment, women more frequently had cardioembolic events (odds ratio [OR] 1.090; 95% confidence interval [95% CI] 1.036-1.146; P = .0009) and other strokes (OR 1.177; 95% CI 1.079-1.284; P = .0003) and were more hypertensive (OR 1.056; 95% CI 1.006-1.108; P = .0267) and more dyslipidemic (OR 1.301; 95% CI 1.234-1.373; P < .0001) than men. After multivariate adjustment, onset-to-arrival time was longer (ß = 0.0554; P = .026), the initial National Institutes of Health Stroke Scale score was higher (ß = 0.1565; P < .001), and the duration of hospitalization was longer (ß = 0.035; P = .010) in women than in men. At hospital discharge, women less commonly had a modified Rankin Scale (mRS) score of 0 to 1 (OR 0.802; 95% CI 0.741-0.868; P < .0001) and more commonly had a mRS score of 4 to 6 (OR 1.410; 95% CI 1.293-1.537; P < .0001) than men. CONCLUSIONS: Women developed more severe strokes than men in Japan. After multivariate adjustment for initial severity and other characteristics, acute care hospital stays were longer and stroke outcomes at discharge were worse in women than in men.

Seasonal variation of stroke incidence in Japan for 35631 stroke patients in the Japanese Standard Stroke Registry, 1998-2007.

BACKGROUND: Seasonal variation of stroke incidence has been reported in many countries. The present study was designed to elucidate seasonal and monthly variations in the incidence of subtypes of acute ischemic stroke and hypertensive hemorrhagic stroke using the Japanese Standard Stroke Registry Study (JSSRS) database, which is currently the world's largest hospital-based stroke database, accumulating records from 163 Japanese institutions. METHODS: Among 47,782 patients with acute stroke registered with JSSRS between 1998 and 2007, we selected 35,631 for analysis (patients with ischemic or hemorrhagic stroke of unknown etiology were excluded). A simple moving average was used to examine monthly variation of stroke incidence. We also examined seasonal variation of ischemic stroke subtypes. RESULTS AND CONCLUSIONS: Monthly variation in incidence of all ischemic stroke was significant (P < .001). Noncardioembolic ischemic stroke was more frequent in summer than in winter (P < .001). Lacunar stroke showed higher incidence in summer than in winter (P < .001), although the increase did not reach significance for atherothrombotic stroke (P = .057). In contrast, cardioembolic stroke (P < .001) and hemorrhagic stroke (P < .001) occurred more frequently in winter than in summer. Hemorrhagic stroke showed a regional difference of incidence between northern and southern Japan. There is a temporal variation of stroke incidence in Japan, with different patterns of variation depending on stroke subtype. These findings may help in developing strategies for preventing stroke.

Low Alberta stroke program early computed tomography score within 3 hours of onset predicts subsequent symptomatic intracranial hemorrhage in patients treated with 0.6 mg/kg Alteplase.

BACKGROUND: The significance of early ischemic changes (EICs) on computed tomography (CT) in selecting candidates for thrombolysis remains controversial. The Alberta Stroke Program Early CT Score (ASPECTS) provides a semiquantitative scale that scores EICs within the middle cerebral artery territory using a 10-point grading system. We examined whether ASPECTS can predict the response to intravenous thrombolysis within 3 hours of stroke onset and incidence of secondary hemorrhage. METHODS: Data from the Japan Alteplase Clinical Trial (J-ACT), in which 103 patients were included, were evaluated to assess the efficacy and safety of 0.6 mg/kg alteplase within 3 hours. All CT hardcopies were reevaluated retrospectively using the ASPECTS system. Multivariate logistic regression analysis was undertaken to determine whether an effect of ASPECTS existed on a defined favorable outcome as 0 or 1 on the modified Rankin Scale at 3 months, and symptomatic intracranial hemorrhage (sICH) within 36 hours. RESULTS: The median ASPECTS value was 10 (range 3 to 10), and 56.3% revealed no evidence of EICs. ASPECTS had no effect on the patients' outcome, although a higher age and National Institutes of Health Stroke Scale score were negatively associated with a favorable outcome. On the other hand, lower ASPECTS was significantly associated with sICH (odds ratio [OR] 2.224; 95% confidence interval [CI] 1.227-4.032; P = .0084) and systolic blood pressure (OR 1.090; 95% CI 1.007-1.180; P = .0323) and the pre-ictal use of antiplatelet medications (OR 15.551; 95% CI 1.144-211.374; P = .0393). CONCLUSIONS: In J-ACT, patients with low ASPECTS values have an increased risk of thrombolysis-related sICH.