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Background and Purpose: The influence of a weather front passage is rarely evaluated on stroke events. We hypothesized that a weather front passage on the stroke onset day or during the previous days may play an important role in the incidence of stroke.Methods: A multicenter retrospective study was conducted to evaluate the frequency of stroke events and their interaction with weather front passages. Consecutive acute stroke patients (n = 3935, 73.5 ± 12.4 years, 1610 females) who were admitted to 7 stroke hospitals in 3 cities from January 2012 to December 2013 were enrolled in this study. Multivariate Poisson regression models involving time lag variables were used to compare the daily rates of stroke events with the day of a weather front passage and the previous 6 days, adjusting for considerable influences of ambient temperature and atmospheric pressure.Results: There were a total of 33 cold fronts and 13 warm fronts that passed over the 3 cities during the study period. The frequency of ischemic stroke significantly increased when a warm front passed on the previous day (risk ratio 1.34, 95% confidence interval 1.07-1.69, P= .016).Conclusions: This study indicated that a weather front passage on the previous days may be associated with the occurrence of stroke. [ABSTRACT FROM AUTHOR]

Background: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in GLA, which encodes the enzyme α-galactosidase A (α-Gal A). Although the prevalence of Fabry disease in patients with stroke has been reported to range from 0% to 4%, few cohort studies have examined Japanese stroke patients. We aimed to clarify the prevalence of Fabry disease and the frequency of GLA mutations among patients with young-onset stroke in Japan.Methods: From April 2015 to December 2016, we enrolled patients with young-onset (≤60 years old) ischemic stroke or intracerebral hemorrhage. We measured α-Gal A activity and the concentration of globotriaosylsphingosine in plasma. Genetic evaluations were performed in patients with low α-Gal A activity or high concentrations of globotriaosylsphingosine.Results: Overall, 516 patients (median age of onset, 52 years old; 120 women) were consecutively enrolled in this study. Five patients (4 men and 1 woman) had low α-Gal A activity, and no patients were detected with the screen for plasma globotriaosylsphingosine levels. The genetic analysis did not identify a causative mutation responsible for classic Fabry disease in any of the patients, but 2 patients (.4%) carried the p.E66Q in GLA.Conclusions: No patient with Fabry disease was detected in our young-onset stroke cohort. [ABSTRACT FROM AUTHOR]

Background: A transient visual symptom (TVS) is a clinical manifestation of transient ischemic attack (TIA). The aim of this study was to investigate differences in clinical characteristics among subtypes of TVS using multicenter TIA registry data.Materials and Methods: Patients with TIA visiting within 7 days of onset were prospectively enrolled from 57 hospitals between June 2011 and December 2013. Clinical characteristics were compared between patients with 3 major subtypes of TVS (transient monocular blindness [TMB], homonymous lateral hemianopia [HLH], and diplopia).Results: Of 1365 patients, 106 (7.8%) had TVS, including 40 TMB (38%), 34 HLH (32%), 17 diplopia (16%), and 15 others/unknown (14%). Ninety-one patients with 1 of the 3 major subtypes of TVS were included. Symptoms persisted on arrival in 12 (13%) patients. Isolated TVS was significantly more common in TMB than in HLH and diplopia (88%, 62%, and 0%, respectively; P < .001). Duration of symptoms was shorter in patients with TMB than those with HLH (P = .004). The ABCD2 score was significantly lower in patients with TMB compared with those with HLH and diplopia (median 2 [interquartile range 2-3] versus 3 [2-4] and 4 [2-5], respectively; P = .005). Symptomatic extracranial internal carotid artery stenosis or occlusion was seen in 14 (16%) patients, and was more frequent in TMB than in HLH and diplopia (28%, 9%, and 0%, respectively; P = .015).Conclusions: TVS was an uncommon symptom in our TIA multicenter cohort. Some differences in clinical characteristics were found among subtypes of TVS. [ABSTRACT FROM AUTHOR]

Background: Underweight patients have recently been reported as a group with a high risk of poststroke death. Anemia also increases mortality rates in stroke patients. However, the causal associations between body weight and anemia resulting in stroke-related death remain unclear. We examined the association of weight status and hemoglobin levels with 3-month mortality after ischemic stroke.Methods: The study enrolled all consecutive patients with acute ischemic stroke and no history of stroke admitted to our hospital between January 2010 and December 2013. The patients were categorized into 4 body mass index (BMI) categories (underweight, normal-weight, overweight, and obese). Anemia was evaluated according to the World Health Organization criteria (men, <13 g/dL; women, <12 g/dL).Results: A total of 1733 acute ischemic stroke patients (149 underweight, BMI < 18.5 kg/m2; 1076 normal-weight, BMI = 18.5-24.9 kg/m2; 436 overweight, BMI = 25-29.9 kg/m2; and 72 obese, BMI > 30 kg/m2) were included. Death within 3 months occurred in 65 patients (underweight, 10.1%; normal-weight, 3.4%; overweight, 2.3%; and obese, 5.6%). Compared to nonanemic patients, those with anemia (n = 329, 19.0%) had lower BMI (21.8 kg/m2 versus 23.7 kg/m2, P <.001) and higher mortality rates (9.1% versus 2.5%, P <.001). Underweight status was associated with 3-month mortality after adjusting for age, sex, comorbidities, and initial stroke severity. However, in the models that included laboratory findings, it was anemia status (odds ratio, 2.81; 95% confidence interval, 1.46-5.43), not underweight status, that was independently associated with 3-month mortality.Conclusion: Anemia on admission was associated with stroke mortality independent of underweight status. [ABSTRACT FROM AUTHOR]

Objective: The preventive effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on progression of carotid intima-media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study aims to determine the effect of pravastatin on carotid IMT in Japanese patients with hyperlipidemia who developed noncardioembolic ischemic stroke.Design: This is a substudy of the J-STARS, a multicenter, randomized, open-label, blinded-end point, parallel-group trial to examine whether pravastatin reduces stroke recurrence in patients with noncardioembolic stroke. The patients are randomized to receive pravastatin (10 mg daily) or not to receive any statins. Carotid ultrasonography is performed by well-trained certified examiners in each participating institute, and the recorded data are measured centrally. The primary outcome is change in the IMT of the distal wall in a consecutive 2-cm section on the central side of the common carotid artery bifurcation over 5 years of observation.Conclusion: The trial may help determine if the usual dose of pravastatin for daily clinical practice in Japan can affect carotid IMT in Japanese patients with noncardioembolic stroke. [ABSTRACT FROM AUTHOR]

Background Results from the J-ROCKET AF study revealed that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcomes in patients with non-valvular atrial fibrillation. This subgroup analysis evaluated whether non-major clinically relevant bleeding (NMCRB) could be a predictive factor for major bleeding (MB). Other predictive factors for MB were also obtained in both rivaroxaban and warfarin treatment groups. Methods The temporal incidence of MB was compared between the rivaroxaban and warfarin treatment groups. Assessment was made whether MB events were often preceded by NMCRB. Univariate and multivariate analyses were carried out to identify any independent predictive factors for MB in both treatment groups. Results The incidences of MB and NMCRB were 18.04% (138/639 patients) in the rivaroxaban arm, and 16.42% in the warfarin arm (124/639 patients). NMCRB preceded MB in only four patients in each treatment group (rivaroxaban: 4/117 and warfarin: 4/98). Multivariate analysis identified predictive factors for bleeding events: anemia with warfarin treatment and concomitant use of antiplatelet agents with rivaroxaban treatment. Conclusions Results from this subgroup analysis, particularly the fact that there was no repeated or sequential pattern between NMCRB and MB occurrences in both treatment groups, suggests that NMCRB might not be a predictive factor for MB. On the contrary, anemia and concomitant use of antiplatelet therapy were likely predictive factors for bleeding with warfarin and rivaroxaban treatment, respectively. [ABSTRACT FROM AUTHOR]

Background: Symptoms of transient ischemic attack (TIA) persist on arrival and subsequently resolve in some patients admitted to hospitals early after onset. Differences in clinical characteristics between patients with acute TIA whose symptoms do and do not persist on arrival remain unclear.Methods: We retrospectively extracted data of consecutive TIA patients with an onset-to-door time (ODT) of 24 hours or less and without a history of stroke from a multicenter TIA database. Clinical characteristics were compared between patients with and without persisting symptoms on arrival.Results: Two hundred sixty-six patients (158 men, 68.0 ± 12.9 years) were included. Of the total number of patients, 105 (39.5%) had persisting symptoms with a mean National Institutes of Health Stroke Scale score of 2.4 (median, 1.0). Patients with persisting symptoms were more likely to have sensory disorder, ambulance-transported admission, long-duration TIA (≥60 minutes), and shorter ODT than those without. Multivariate analysis showed that sensory disorder (odds ratio [OR] 2.52, 95% confidence interval [CI] 1.35-4.77), ambulance-transported admission (OR 1.80, 95% CI 1.00-3.28), and long-duration TIA (OR 3.96, 95% CI 2.12-7.71) were positively associated and that an ODT of more than 12 hours (OR .18, 95% CI .04-.63) was inversely associated with the presence ofpersisting symptoms. Patients with persisting symptoms were more likely to be examined by a stroke physician at first (69% versus 57%, P = .049) and then hospitalized in a stroke unit (59% versus 43%, P = .010).Conclusion: Clinical manifestations and management after admission might differ between patients with acute TIA whose symptoms do and do not persist on arrival. [ABSTRACT FROM AUTHOR]

Background: Few studies have examined the prevalence of peripheral arterial disease (PAD) with the use of computed tomography angiography (CTA) in patients with acute ischemic stroke (AIS), although several reports have examined its prevalence using an ankle brachial index (ABI). We aimed to determine the prevalence of PAD indicated by CTA in patients with AIS and to clarify the prevalence of PAD in each clinical ischemic stroke subtype.Methods: We included 199 consecutive patients with AIS admitted to our hospital and divided them into PAD and non-PAD groups according to the CTA findings.Results: Of the 199 patients, 40 (20.1%) had PAD; 27 (67.5%) of the PAD patients were asymptomatic. The prevalence of abnormal ABI (≤.9) was 12.2%. Patients with PAD were older (78.3 ± 10.2 versus 71.5 ± 10.9, P <.001) and had a significantly lower ABI value (.89 ± .24 versus 1.15 ± .09, P <.001) and higher prevalence of diabetes mellitus (50.0% versus 31.4%, P = .028), atrial fibrillation (40.0% versus 16.4%, P = .001), coronary artery disease (32.5% versus 8.2%, P <.001), and intracranial arterial stenosis (47.5% versus 28.9%, P = .025) than patients without PAD. The prevalence of cerebral microbleeds was not different between patients with PAD and those without PAD (25.6% versus 25.4%, P = .985). The prevalence of PAD among ischemic stroke subtypes was highest in patients with cardioembolic infarction (40.5%).Conclusions: Almost one fourth of the AIS patients examined had PAD on CTA. Cardioembolic infarction patients showed the highest prevalence of PAD among the clinical ischemic subtypes, suggesting the coexistence of atheromatous diseases and atrial fibrillation. [ABSTRACT FROM AUTHOR]

Background: It is important to determine the usage of anticoagulants by defining the actual risk of cardioembolic stroke in patients with old myocardial infarction. In the present study, we aimed to more precisely evaluate the risks of each segment associated with cardioembolic stroke using a 16-segment model. The usage of the plasma brain natriuretic peptide (BNP) associated with cardioembolic stroke was also evaluated in comparison with a left ventricle ejection fraction less than 40%.Methods: There were a total of 190 ischemic stroke patients who had premorbid myocardial infarction. The study included a total of 143 ischemic stroke patients with old myocardial infarction who were available for evaluation and excluded patients with atrial fibrillation or acute myocardial infarction. Their left ventricle wall motion abnormality and the level of plasma BNP at their admission were analyzed.Results: Hypertension and a plasma BNP level of 206.9 pg/mL or higher, determined from the receiver operating characteristic curve, were independently associated with cardioembolic stroke (χ(2) = 35.6, R(2) = .30, P < .001). Adjusting for these factors, statistically independent high risk was observed at the basal-inferior, basal-inferolateral, mid-anterior, mid-anteroseptal, apical-anterior, and apical-septal left ventricles.Conclusion: High plasma BNP levels and left ventricular wall motion abnormalities in the segments perfused with left anterior descending coronary artery or right coronary artery show a high risk for cardioembolic stroke in patients with old myocardial infarction. Considering these factors, it could be possible to more precisely define the risk of cardioembolic stroke and to perform appropriate antithrombotic treatments in old myocardial infarction patients. [ABSTRACT FROM AUTHOR]

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

Background: Few studies have reported on the association between inflammatory markers and atherosclerosis by smoking status. We investigated the effect of plasma levels of fibrinogen and high-sensitive C-reactive protein (hsCRP) on subclinical atherosclerosis stratified by smoking in a general urban population.Methods: From participants of the Suita study without a history of cardiovascular diseases, a total of 2502 subjects (805 men, median age 64 years) who underwent carotid ultrasonography were enrolled. Subjects were divided into current smokers (n = 566) and never-smokers. Ex-smokers were not included in the study. Each group was subdivided according to the median levels of markers (plasma fibrinogen [2.99 g/L] and hsCRP [.51 mg/L]) and the smoking amounts. We compare the adjusted maximum and mean intima-media thickness (IMT).Results: In men and women, maximum IMT and mean IMT of the high fibrinogen and high hsCRP (Fib(H)CRP(H)) with smoking were thicker than those of the low fibrinogen and low hsCRP (Fib(L)CRP(L)) without smoking, the Fib(L)CRP(L) with smoking, and the Fib(H)CRP(H) without smoking after adjusting for covariates. The Fib(L)CRP(L) with smoking had thicker IMTs than the Fib(L)CRP(L) without smoking. There was a dose-dependent smoking effect on IMT in men. These trends were similar in age 60, 65, and 70.Conclusions: Plasma fibrinogen and hsCRP levels were related to multivariate-adjusted IMT, and smoking was associated with IMT in men. The combination of plasma fibrinogen and hsCRP levels could be a potential marker on subclinical carotid atherosclerosis in urban people. [ABSTRACT FROM AUTHOR]

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

Background The timing of warfarin administration for acute ischemic stroke (AIS) patients with atrial fibrillation (Af) has not been established. We hypothesized that achieving targeted prothrombin time and international normalized ratio (PT-INR) at 2 weeks could prevent AIS patients with Af from developing a new lesion on diffusion-weighted magnetic resonance imaging (DW-MRI). Methods Of consecutively enrolled AIS patients with Af between 2008 and 2011, we selected the patients who were given warfarin within 2 weeks of admission and had DW-MRI and blood test for PT-INR both on admission and at 2 weeks. Warfarin was started as early as possible and heparin was administered until the targeted PT-INR (2.0-3.0 for patients aged <70 years or 1.6-2.6 for those aged ≥70 years) was achieved. Results One hundred and twenty-three patients were selected, consisting of 88 patients without a new lesion and 35 patients with a new lesion. Patients with a new lesion had a significantly higher median score on National Institutes of Health Stroke Scale (11.0 vs. 5.5, P = .0053), a lower rate of achieving targeted PT-INR at 2 weeks (25.7% vs. 48.9%, P = .0190), and a lower median dosage of warfarin at 2 weeks (2.0 mg vs. 2.5 mg, P = .0209) than patients without a new lesion. Multivariate logistic regression analysis showed that failure to achieve targeted PT-INR ( P = .0298) was significantly associated with the occurrence of a new lesion. Conclusions Our findings suggest that achieving targeted PT-INR at 2 weeks by using warfarin prevents new lesions in AIS patients with Af. [ABSTRACT FROM AUTHOR]

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

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

Background: The risk factors that have been identified for bleeding events with rivaroxaban are predominantly the same as those predicting thromboembolic ones in patients with atrial fibrillation (AF). Our aim was to determine the net clinical benefit (NCB) from the results of the J-ROCKET AF trial, in which rivaroxaban was compared with warfarin in Japanese patients with AF. Methods: Two strategies were adopted to quantify the NCB. First, the NCB was calculated as the number of ischemic strokes avoided with anticoagulation minus the number of excess intracranial hemorrhage (ICH) with a weight of 1.5. Second, the composite end point of major bleeding events and secondary efficacy end points (stroke, noncentral nervous system systemic embolism, myocardial infarction and death) to ascertain the NCB were established. Subgroup analysis by CHADS2 score or creatinine clearance was also performed. Results: The adjusted NCB, which was given a weight of 1.5 for ICH, was nominally significant in favor of rivaroxaban therapy (difference in incidence rate −2.13; 95% confidence interval [CI]: −.26 to −3.99). Furthermore, the event rate of the composite end point tended to be lower in patients treated with rivaroxaban than in those treated with warfarin (rivaroxaban: 4.97% per year, warfarin: 6.11% per year; difference in incidence rate: −1.14; 95% CI: −3.40 to 1.12). The event rate of the composite end point tended to be consistently low in patients treated with rivaroxaban in the subanalysis by CHADS2 score and renal function. Conclusion: Analysis of the NCB supports that rivaroxaban therapy provides clinical benefit for Japanese patients with AF. [Copyright &y& Elsevier]

BACKGROUND: Results from a trial of rivaroxaban versus warfarin in 1280 Japanese patients with atrial fibrillation (J-ROCKET AF) revealed that rivaroxaban was noninferior to warfarin with respect to the principal safety outcome. In this subanalysis, we investigated the safety and efficacy of rivaroxaban and warfarin in relation to patients' CHADS2 scores. RESULTS: The mean CHADS2 score was 3.25, and the most frequent scores were 3 and 4. No statistically significant interactions were observed between principal safety outcome event rates and CHADS2 scores with respect to treatment groups (P value for interaction = .700). Irrespective of stratification into moderate- and high-risk groups based on CHADS2 scores of 2 and 3 or more, respectively, no differences in principal safety outcome event rates were observed between rivaroxaban- and warfarin-treated patients (moderate-risk group: hazard ratio [HR], 1.06; 95% confidence interval [CI], .58-1.95; high-risk group: HR, 1.11; 95% CI, .86-1.45; P value for interaction = .488). The primary efficacy end point rate in the rivaroxaban-treated group was numerically lower than in the warfarin-treated group, regardless of risk group stratification (moderate-risk group: HR, .46; 95% CI, .09-2.37; high-risk group: HR, .49; 95% CI, .22-1.11; P value for interaction = .935). CONCLUSION: This subanalysis indicated that the safety and efficacy of rivaroxaban compared with warfarin were similar, regardless of CHADS2 score. [ABSTRACT FROM AUTHOR]

Background: Results from a trial of rivaroxaban versus warfarin in 1280 Japanese patients with atrial fibrillation (J-ROCKET AF) revealed that rivaroxaban was noninferior to warfarin with respect to the principal safety outcome. In this subanalysis, we investigated the safety and efficacy of rivaroxaban and warfarin in relation to patients' CHADS2 scores. Results: The mean CHADS2 score was 3.25, and the most frequent scores were 3 and 4. No statistically significant interactions were observed between principal safety outcome event rates and CHADS2 scores with respect to treatment groups (P value for interaction = .700). Irrespective of stratification into moderate- and high-risk groups based on CHADS2 scores of 2 and 3 or more, respectively, no differences in principal safety outcome event rates were observed between rivaroxaban- and warfarin-treated patients (moderate-risk group: hazard ratio [HR], 1.06; 95% confidence interval [CI], .58-1.95; high-risk group: HR, 1.11; 95% CI, .86-1.45; P value for interaction = .488). The primary efficacy end point rate in the rivaroxaban-treated group was numerically lower than in the warfarin-treated group, regardless of risk group stratification (moderate-risk group: HR, .46; 95% CI, .09-2.37; high-risk group: HR, .49; 95% CI, .22-1.11; P value for interaction = .935). Conclusion: This subanalysis indicated that the safety and efficacy of rivaroxaban compared with warfarin were similar, regardless of CHADS2 score. [Copyright &y& Elsevier]

Background: The overall analysis of the rivaroxaban versus warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban was not inferior to warfarin with respect to the primary safety outcome. In addition, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin. Methods: In this subanalysis of the J-ROCKET AF trial, we investigated the consistency of safety and efficacy profile of rivaroxaban versus warfarin among the subgroups of patients with previous stroke, transient ischemic attack, or non–central nervous system systemic embolism (secondary prevention group) and those without (primary prevention group). Results: Patients in the secondary prevention group were 63.6% of the overall population of J-ROCKET AF. In the secondary prevention group, the rate of the principal safety outcome (% per year) was 17.02 in rivaroxaban-treated patients and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was 1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR 0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal safety and the primary efficacy endpoints of rivaroxaban compared to warfarin between the primary and secondary prevention groups (P = .090 and .776 for both interactions, respectively). Conclusions: The safety and efficacy profile of rivaroxaban compared with warfarin was consistent among patients in the primary prevention group and those in the secondary prevention group. [Copyright &y& Elsevier]

Background: Although brain microbleed has been reported to be a risk factor for antiplatelet-associated intracerebral hemorrhage, data on the use of specific antiplatelet agents are lacking. In this study, we examined the associations between specific antiplatelets and brain microbleeds in order to help select antiplatelet agents in patients with microbleeds. Methods: We evaluated 1914 consecutive acute stroke patients, including 412 patients with intracerebral hemorrhage and 1502 patients with ischemic stroke. The associations between the presence of microbleeds and antiplatelet use were evaluated, including specific antiplatelet agents (aspirin, clopidogrel, cilostazol, and ticlopidine). Results: Antiplatelet use was associated with the presence of microbleeds in patients with intracerebral hemorrhage (odds ratio [OR] 2.418; 95% confidence interval [CI] 1.236-4.730; P = .0099), but not in patients with ischemic stroke. The use of a single antiplatelet medication was not associated with the presence of microbleeds. In patients with intracerebral hemorrhage, aspirin (OR 2.160; 95% CI 1.050-4.443; P = .0364) but not clopidogrel, cilostazol, or ticlopidine was associated with microbleeds. In these patients, dividing brain microbleeds into deep microbleeds and lobar microbleeds revealed an association only between antiplatelet use and the presence of deep microbleeds (OR 2.397; 95% CI 1.258-4.567; P = .0079). None of the antiplatelet agents were associated with the presence of deep microbleeds, although aspirin had a trend of association (OR 1.986; 95% CI 1.000-3.946; P = .0501). Conclusions: Attention to microbleed-positive patients is necessary for the safe use of aspirin in order to avoid antiplatelet-associated hemorrhages, but prospective studies are needed to verify our results. [Copyright &y& Elsevier]

Background: Patients with recent ischemic stroke may have higher risk of atherothrombosis than stable patients with established vascular events. Our aims were to investigate 1-year atherothrombotic vascular event rates and to assess the risk factors for recurrent ischemic stroke in this population. Methods: This prospective cohort study was conducted between January 2007 and July 2009 at 313 hospitals in Japan. Outpatients who were at least 45 years of age and who had received oral antiplatelet therapy were enrolled within 2 weeks to 6 months from the last onset of noncardioembolic ischemic stroke. At 12 ± 3 months after enrollment, data on presence/absence of atherothrombotic vascular events were collected. The primary endpoint was the occurrence of fatal or nonfatal ischemic stroke. Results: A total of 3452 patients were enrolled, and 3411 patients who had baseline data were included in the analysis. The 1-year event rate was 3.81% (95% confidence interval 3.15-4.48%) for fatal or nonfatal ischemic stroke and 0.84% (95% confidence interval 0.52-1.15%) for all-cause mortality. The annual rate of recurrent ischemic stroke was significantly higher in patients who had ischemic stroke at least twice than in patients who had first-ever ischemic stroke (5.02% vs 3.59%; P = .0313). In the multivariable Cox regression analysis, recurrent ischemic stroke was significantly associated with age (P = .0033), the presence of diabetes (P = .0129), and waist circumference ≥80 cm (P = .0056). Conclusions: Patients with recent ischemic stroke have a higher risk of stroke recurrence than stable patients enrolled in the REduction of Atherothrombosis for Continued Health (REACH) registry even though they received antiplatelet therapy. The rigorous management of risk factors is needed. [Copyright &y& Elsevier]

Stroke is a major health problem worldwide, and is often fatal or associated with poor long-term outcomes. Atrial fibrillation (AF) is responsible for up to 20% of all strokes; and the risk of stroke in patients with AF increases with age. Although warfarin is well established for the prevention of stroke in patients with AF, it has some limitations, particularly a narrow therapeutic window, variable/unpredictable pharmacokinetic/pharmacodynamic properties, the restriction of vitamin K intake, and the need for regular coagulation monitoring. Therefore, warfarin is underused for stroke prevention in patients with AF. Several anticoagulants that inhibit thrombin or factor Xa have been developed. Dabigatran is a direct thrombin (factor IIa) inhibitor that overcomes many of the limitations associated with warfarin. The recent Randomized Evaluation of Long Term Anticoagulant Therapy study showed the noninferiority of 110 mg and 150 mg dabigatran twice daily, and the superiority of 150 mg dabigatran twice daily versus adjusted-dose warfarin in the prevention of stroke or systemic embolism in patients with nonvalvular AF. In addition, the rate of intracranial hemorrhage was much lower with both doses of dabigatran than with warfarin. Dabigatran was recently approved in Japan for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular AF. Therefore, in this review, we discuss the properties of dabigatran and its clinical efficacy, safety, and positioning in the prevention of stroke. We also discuss precautions for the use of dabigatran and future perspectives with a view to reducing the risk of stroke with new oral anticoagulants, including factor Xa inhibitors in AF patients. [Copyright &y& Elsevier]

Abstract: According to recent epidemiological data in Japan, stroke affects roughly 5.3 males and 3.9 females per 1000 person-years and is the third leading cause of mortality. At present, management strategies for secondary prevention of stroke include aggressive treatment of cardiovascular risk factors (i.e., hypertension, smoking cessation, etc.). Antiplatelet drugs in Japan, namely aspirin and cilostazol, are utilized regularly for the prevention of secondary stroke. While aspirin is beneficial for a wide range of cardiovascular endpoints, including total and ischemic strokes, it is also associated with significantly increased risks for hemorrhagic infarction. Cilostazol, by contrast, has been shown to significantly reduce the risk of recurrent strokes without affecting the occurrence of intracranial hemorrhage. In the Cilostazol Stroke Prevention Study, a randomized double-blind, placebo-controlled trial involving more than 1000 Japanese patients, cilostazol was found to reduce the risk of secondary stroke by 41.7% compared with placebo, a statistically significant reduction (P =0.015). The greatest risk reduction (43.4% in cilostazol versus placebo, P =0.0373) was found in patients who initially had a lacunar infarction, suggesting that cilostazol has a specific effect against small-vessel disease. In addition, cilostazol achieved significant risk reductions on a number of combined endpoints (e.g., cerebral infarction, intracranial hemorrhage, myocardial infarction, or vascular death), and was associated with benefits in intent-to-treat analyses. These findings indicate that cilostazol may have a role as a vascular neuroprotectant, but the clinical implications are limited by the fact that patients were randomized to placebo instead of aspirin, which is the standard of care. [Copyright &y& Elsevier]

Cerebral ischemia induces 5-lipoxygenase translocation and leukotriene production in the brain. We tried to clarify the pathological significance of 5-lipoxygenase on cerebral ischemia using 5-lipoxygenase knockout mice. No significant difference was observed in the infarct size following permanent and transient ischemia for 60 min between both types of mice. The present study did not support the idea that leukotriene production is involved in infarct expansion in focal cerebral ischemia. [Copyright &y& Elsevier]

Cardiovascular diseases are the leading cause of death and disability in industrialized countries. Because the etiologies are related to alteration of arterial wall properties, the noninvasive evaluation could help the presymptomatic diagnosis and potentially the prevention of future events. Ultrasound (US) is currently the only modality to image the arterial wall in real-time with sufficient resolution to allow for observation of its morphological, hemodynamic and elastic properties. Increased wall thickness and atheromatous plaques of carotid arteries are associated with cardiovascular risk factors and diseases. Also, carotid Doppler waveforms and wall elasticity may have associations with arterial health. Although evaluation of these arterial properties are currently limited to the research laboratories, most of such properties can be evaluated in the standard setting of carotid ultrasonography. This article reviews “potential” utilities of carotid US evaluation for cardiovascular risk assessment in apparently healthy individuals. (E-mail: nagaiy@medone.med.osaka-u.ac.jp) [Copyright &y& Elsevier]

Recent clinical evidence has indicated that the level of soluble ICAM-1 (sICAM-1) is correlated with the severity of atherosclerosis and can predict future cardiovascular events. Here, using apolipoprotein E (APOE)-deficient mice, we investigated the level of sICAM-1 in parallel with endothelial ICAM-1 expression and aortic atherosclerosis. We also examined the effect of ICAM-1 deficiency during the progression of atherosclerosis using double knockout mice. The level of sICAM-1 increased significantly in parallel with the progression of atherosclerosis in APOE-deficient mice, while the sICAM-1 level remained constant in wild-type mice from 3 to 10 months of age. ICAM-1 staining was detected in virtually all endothelial cells, however, ICAM-1 was expressed strongly in the endothelium overlying atheromatous palque in APOE-deficient mice. Deficiency of ICAM-1 in APOE-deficient mice significantly reduced lesions after 5 and 10 months. The present study supported the notion that the level of sICAM-1 is closely related with the severity of atherosclerosis and cardiovascular events, and also suggested that inhibition of ICAM-1 can delay the progression of atherosclerosis. [Copyright &y& Elsevier]

Case Report: A 66-year-old man with acute ischemic stroke in the setting of lung adenocarcinoma developed acute-onset deep vein thrombosis (DVT) of the lower limbs after changing to warfarin from a heparin combination. The diagnosis of warfarin-resistant DVT was established based on the laboratory data and clinical evaluation. Heparin administration resulted in good control of thrombin regulation. Cancer patients are at high risk of venous thromboembolism, and the combination of these 2 conditions is known as Trousseau's syndrome.Conclusion: Our report suggests that heparin administration may provide good control of thromboembolic events, although there is no established medical treatment to extend the survival of patients with Trousseau's syndrome. [ABSTRACT FROM AUTHOR]

Case Report: A 58-year-old man presenting with no vascular risk factors visited our hospital with right hemiparesis and total aphasia. Diffusion-weighted magnetic resonance imaging of the brain showed multiple hyperintensities in watershed distributions in the left hemisphere. Magnetic resonance angiography (MRA) revealed stenosis of the middle cerebral artery, despite normal MRA findings 2 months prior. One year after the first stroke, the patient experienced a recurrent ischemic stroke involving the left anterior choroidal artery, pulmonary embolism, and deep venous thrombosis. After the recurrent stroke event, hemoglobin levels increased gradually. Two years after the first stroke, a JAK2V-617F mutation was detected.Conclusion: Our report suggests that progressive intracranial arterial sclerosis and venous thrombosis of undetermined etiologies could be several initial symptoms of polycythemia vera. [ABSTRACT FROM AUTHOR]

We here report the case of isolated hypoglossal nerve paralysis. Magnetic resonance imaging demonstrated characteristic findings of internal carotid artery dissection that should be considered as one of the differential diagnosis of ipsilateral pure hypoglossal nerve paralysis. [ABSTRACT FROM AUTHOR]

Background: Transient monocular blindness (TMB) is associated with a transient ischemic attack (TIA). The purpose of this study was to investigate the features of TMB in the Japanese population using data from a multicenter retrospective study of TIA. Methods: The subjects were consecutive TIA patients admitted to 13 stroke centers within 7 days after symptom onset. We compared clinical characteristics of patients with TMB and those without TMB who had other symptoms of cerebral TIA. Results: A total of 464 patients were registered between January 2008 and December 2009, and 444 patients (283 men, mean age: 68.5 years) were included in the analysis. Thirteen patients (2.9%) presented with TMB. Patients with TMB were less likely to arrive at the specialized stroke center quickly than those without TMB (P = .013). Stenotic lesions in the extracranial internal carotid artery were more common in patients with TMB (33.3% versus 9.1%, P = .022). Conclusions: TMB was not common in our TIA inpatients. This study suggests that patients with TMB should immediately undergo a diagnostic workup, including brain and vessel imaging, and cardiac evaluation, as is performed in patients with other cerebral TIA symptoms. A larger, prospective cohort is needed to confirm the risks and outcomes of patients with TMB in the Japanese population. [Copyright &y& Elsevier]

Background: This study investigated factors associated with the presence of acute ischemic lesions after transient ischemic attack (TIA), using diffusion-weighted imaging (DWI) data from a multicenter retrospective, observational study. Methods: Of the 464 patients admitted to 13 stroke centers in Japan within 7 days after TIA onset, 458 patients underwent a DWI examination in this registry. Patients were divided into those with acute ischemic lesions and those without. We analyzed associations between DWI lesions and baseline characteristics, including age, sex, comorbidities, large artery atherosclerosis (LAA), type and duration of symptoms, the presence of multiple occurrences of TIA within 90 days before hospital visits (multiple TIAs) and the time from symptom onset to DWI examination (time-to-DWI). Results: Among the 458 patients (291 men, 68.4 ± 13.2 years old), 374 (81.7%) underwent a DWI examination within the initial 24 hours after the symptom onset. DWI lesions were found in 96 patients (21.0%), and divided into a single lesion (56 patients, 12.2%) or multiple lesions (40 patients, 8.7%). The presence of DWI lesions had an association with male sex (odds ratio [OR] 1.84; 95% confidence interval [CI] 1.07-3.29), time-to-DWI longer than 24 hours (OR 2.96; CI 1.57-5.52), and intracranial LAA (OR 1.99; CI 1.02-3.79). The presence of a single DWI lesion had an association with atrial fibrillation (OR 2.70; CI 1.41-5.03), and multiple DWI lesions did with time-to-DWI longer than 24 hours (OR 6.20; CI 2.60-15.20), multiple TIAs (OR 3.04; CI 1.35-6.76), intracranial LAA (OR 3.63; CI 1.44-8.89), and extracranial LAA (OR 3.53; CI 1.08-10.78). Conclusions: Acute ischemic lesions on DWI were associated with time-to-DWI and LAA in patients with classically defined TIA. Additionally, we identified some differences in relating factors between patients with single and multiple DWI lesions. These results indicate that time-to-DWI and DWI lesion pattern may be important for the diagnosis and management of TIA. [Copyright &y& Elsevier]

Background: The effect of prasugrel in terms of the prevention of recurrence of ischaemic stroke is unknown. We investigated the non-inferiority of prasugrel to clopidogrel for prevention of ischaemic stroke, myocardial infarction, and death from other vascular causes in Japanese patients with non-cardioembolic stroke.Methods: In this phase 3 randomised, double-blind, non-inferiority trial, patients aged 20-74 years who had had a non-cardioembolic stroke in the previous 1-26 weeks were recruited from 224 hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive prasugrel (3·75 mg/day) or clopidogrel (75 mg/day) orally for 96-104 weeks. Randomisation was stratified according to stroke subtype. The randomisation schedule was generated by an independent statistician who created a computer-generated random number sequence. Patients, investigators, and the funder were masked to treatment allocation. The primary endpoint was combined incidence of ischaemic stroke (fatal and non-fatal), myocardial infarction (fatal and non-fatal), and death from other vascular causes in the intention-to-treat population. The safety endpoint was incidence of bleeding events, comprising life-threatening bleeding, major bleeding, and clinically relevant bleeding. The safety analysis was done in the population excluding trial patients with serious Good Clinical Practice violations, and those who had not taken the trial drug. The predefined non-inferiority margin was an upper 95% CI limit for the risk ratio (RR) of 1·35. The trial was registered with the Japan Pharmaceutical Information Center (JapicCTI-111582).Findings: Patients were recruited between Sept 1, 2011, and June 12, 2015. 3747 patients (797 [21%] women) were enrolled, with a mean age of 62·1 (SD 8·5) years. 3753 patients were randomly assigned to treatment and, of these patients, 1885 in the prasugrel group and 1862 in the clopidogrel group were confirmed to have taken the trial drug at least once, and six patients withdrew from the trial before administration of the trial drug. Thus, a total of 3747 patients were included in the full analysis set. 73 (4%) of 1885 patients in the prasugrel group and 69 (4%) of 1862 patients in the clopidogrel group reached the primary endpoint (RR 1·05, 95% CI 0·76-1·44). The incidence of bleeding events was not significantly different between treatment groups; life-threatening bleeding was observed in 18 (1%) patients in the prasugrel group and 23 (1%) patients in the clopidogrel group (RR 0·77, 0·41-1·42).Interpretation: The non-inferiority of prasugrel to clopidogrel for the prevention of ischaemic stroke, myocardial infarction, and death from other vascular causes was not confirmed in Japanese patients with non-cardioembolic stroke. No safety concerns were identified.Funding: Daiichi Sankyo. [ABSTRACT FROM AUTHOR]

Highlights • Synphilin-1 inhibited ROS production and cytochrome c release induced by MPP+ in vitro. • Synphilin-1 inhibited early steps in the intrinsic apoptotic pathway. • Synphilin-1 played a neuroprotective role in Parkinson's disease model cells. Abstract Synphilin-1, a cytoplasmic protein, interacts with α-synuclein which is one of the main constituents of Lewy bodies and plays an important role in the pathology of Parkinson's disease (PD), in neurons. This interaction indicates that synphilin-1 may also play a central role in PD. However, the biological functions of synphilin-1 are not fully understood, and whether synphilin-1 is neurotoxic or neuroprotective remains controversial. This study examined the function of synphilin-1 in a PD model in vitro. We used an inhibitor of mitochondrial complex I, 1-methyl-4-phenylpyridinium (MPP+). We established human neuroblastoma SH-SY5Y cell lines that stably expressed human synphilin-1. We found that overexpression of synphilin-1 increased SH-SY5Y cell viability after MPP+ treatment. We further found that synphilin-1 significantly suppressed apoptotic changes in nuclei, including nuclear condensation and fragmentation, after MPP+ treatment. We showed that synphilin-1 significantly decreased MPP+-induced cleaved caspase-3 and cleaved poly-ADP-ribose polymerase levels by using western blotting. Production of reactive oxygen species (ROS) induced by MPP+ was significantly reduced in cells expressing synphilin-1 compared to those expressing empty vector. Synphilin-1 inhibited MPP+-induced cytochrome c release from mitochondria into the cytosol. These data suggested that synphilin-1 may function to protect against dopaminergic cell death by preserving mitochondrial function and inhibiting early steps in the intrinsic apoptotic pathway. Taken together, our results indicated that synphilin-1 may play neuroprotective roles in PD pathogenesis by inhibiting ROS production and apoptosis. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) related decreases in muscle strength may result from both central and peripheral factors. However, the effect of PD on the neuromuscular system, such as motor unit activation properties, remains unclear. The purpose of the present study was to compare the spatial distribution pattern of electromyographic activity during sustained contractions in healthy subjects and PD patients. Twenty-five female PD patients and 25 healthy age-matched female control subjects performed ramp submaximal contractions during an isometric knee extension from 20% to 80% of the maximal voluntary contraction (MVC). To evaluate alterations in the spatial electromyography (EMG) potential distribution, normalized root mean square (RMS), modified entropy, coefficient of variation, and correlation coefficients were calculated from multi-channel surface electromyography at 10% force increments. The comparison between PD and healthy subjects revealed that, during increased force exertions, PD patients exhibited less change in normalized RMS, modified entropy, coefficient of variation, and pattern of spatial EMG distribution. These data showed that the heterogeneity and the changes in the activation pattern are smaller in the PD patients than in healthy subjects. This finding may be associated with central adaptation and/or peripheral changes in PD patients. [ABSTRACT FROM AUTHOR]

Inclusion-body myositis (IBM) and Alzheimer’s disease (AD) are biochemically characterized by the presence of aggregated β-amyloid protein and tau protein. In addition, both diseases are pathologically characterized by vacuolar changes, including rimmed vacuoles (RVs) in IBM and granulovacuolar degeneration (GVD) in AD. Previously, we demonstrated that RVs and GVD bodies are associated with a set of common molecules, leading us to speculate that both RVs and GVD bodies originate from similar structures on the plasma membrane of muscle cells and neuronal cells, namely, the neuromuscular junction (NMJ) and the postsynaptic spine especially in terms of Wnt signaling pathway. In this study, we investigated the presence of components of NMJ in RVs and/or postsynaptic spine in GVD bodies respectively by immunohistochemistry and immunofluorescence. The antigens probed included the following: (1) dishevelled (Dvl) family proteins (Dvl1, Dvl2 and Dvl3), (2) NMJ-associated proteins (low density lipoprotein-related protein 4 [Lrp4], heat shock protein 70 [Hsp70], β-catenin, phospho-β-catenin, rapsyn, P21-activated kinase 1 [PAK1], adenomatous polyposis coli [APC] and ADP-ribosylation factor 6 [Arf6]), (3) a lipid raft-associated molecule (phosphatidylinositol 4, 5-bisphosphate [PIP2]), and (4) other proteins [prion, glycogen-synthase kinase 3β (GSK-3β)]. In all cases of sporadic IBM examined, RVs were immunopositive for Dvl3, Hsp70, β-catenin, PIP2, APC, prion and GSK-3β. In all cases of AD examined, GVD bodies were immunopositive for Dvl3, phospho-β-catenin, rapsyn, APC and PIP2. These findings show that RVs and GVD bodies share common molecules associated with the Wnt signaling pathway, indicating that these structures share a common structural and functional origin. [ABSTRACT FROM AUTHOR]