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We report the case of a 67-year-old woman with non-convulsive status epilepticus (NCSE) due to hyponatremia. She had a history of psychogenic polydipsia but not epilepsy. She was admitted to our hospital with dysbulia. On admission, she was confused and disoriented (Glasgow Coma Scale: 6, E1V1M4). Magnetic resonance imaging of the brain showed no abnormalities. Laboratory test showed hyponatremia (Na

Diffraction limit of resolution has been one of the biggest limitations in the optical microscopy. Super-resolution fluorescence microscopy has enabled us to break this limit. However, for the observations of real biological specimens, especially for the imaging of tissues or whole body, the target structures of interest are often embedded deep inside the specimen. Here, we would present our results to extend the target of the super-resolution microscopy deeper into the cells. Confocal microscope optics work effectively to minimize the effect by the aberrations by the cellular components, but at the expense of the signal intensities. Spherical aberrations by the refractive index mismatch between the cellular environment and the immersion liquid can be much larger, but can be reduced by adjusting the correction collar at the objective lens.

APP associates with kinesin-1 via JIP1. In JIP1-decicient neurons, the fast velocity and high frequency of anterograde transport of APP cargo are impaired to reduced velocity and lower frequency, respectively. Interaction of JIP1 with KLC via two novel elements in JIP1 plays an important role in efficient APP axonal transport., Alzheimer's β-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity (∼2.7 μm/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity (∼1.83 μm/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function, located in the central region of JIP1b, that interact with the coiled-coil domain of kinesin light chain 1 (KLC1), in addition to the conventional interaction of the JIP1b 11–amino acid C-terminal (C11) region with the tetratricopeptide repeat of KLC1. High frequency of APP anterograde transport is dependent on one of the novel elements in JIP1b. Fast velocity of APP cargo transport requires the C11 domain, which is regulated by the second novel region of JIP1b. Furthermore, efficient APP axonal transport is not influenced by phosphorylation of APP at Thr-668, a site known to be phosphorylated by JNK. Our quantitative analysis indicates that enhanced fast-velocity and efficient high-frequency APP anterograde transport observed in neurons are mediated by novel roles of JIP1b.

Intravenous nicardipine is commonly used to reduce elevated blood pressure in acute intracerebral hemorrhage (ICH). We determined factors associated with nicardipine dosing and the association of dose with clinical outcomes in hyperacute ICH.Hyperacute (3 hours from onset) ICH patients with initial systolic blood pressure (SBP) greater than 180 mm Hg were included. All patients initially received 5 mg/hour of intravenous nicardipine. The dose was adjusted to maintain SBP between 120 and 160 mm Hg. Associations of maximum hourly and total doses with early neurologic deterioration (END), hematoma expansion (33%), and modified Rankin Scale score 4-6 at 3 months were assessed.Two hundred six patients (81 women, 65.8 ± 11.8 years) were studied. Initial SBP was 201.9 ± 15.9 mm Hg. Maximum and total nicardipine doses were 9.1 ± 4.2 mg/hour and 123.7 ± 100.2 mg/day, respectively. Multivariate analyses revealed that men (standardized regression coefficient [β] = .20, P = .0030 for maximum dose; β = .25, P = .0002 for total dose), age (β = -.28, P = .0002; β = -.25, P = .0005), and initial SBP (β = .19, P = .0018; β = .18, P = .0021) were independently associated with both maximum and total doses. Body weight (β = .20, P = .0084) was independently associated with total dose. After multivariate adjustment, maximum dose (per 1 mg/hour; odds ratio [OR], 1.25; 95% confidence interval [CI], 1.09-1.45) was independently, and total dose (per 10 mg/day; OR, 1.06; 95% CI, .998-1.132) tended to be independently, associated with END. Nicardipine dose was not associated with hematoma expansion or 3-month outcome.Nicardipine dose is roughly predictable with sex, age, body weight, and initial SBP in acute ICH. The maximum dose was associated with neurologic deterioration.

Objective Although adiponectin is a major adipocytokine that affects the pathogenesis of various cardiovascular diseases, its clinical significance in stroke remains controversial. We investigated the clinical significance of plasma adiponectin for the diagnosis, neurological severity and functional outcomes of patients with ischemic stroke. Methods We prospectively enrolled 171 patients with ischemic stroke and 171 age- and sex-matched healthy controls. Blood samples and clinical information were obtained at day 0, 3, 7, 14 and 90 after stroke onset. Results Average adiponectin values at day 0 did not significantly differ between the controls and the patients, but were significantly lower and higher in patients with atherothrombotic brain (ATBI) (p = 0.047) and cardioembolic (CE) (p = 0.008) infarction, respectively, than in the controls. Multivariate logistic regression analyses showed that the adiponectin value at day 0 could predict ATBI (odds ratio, 0.75; 95% confidence interval, 0.58 to 0.91, p = 0.009, per 1-μg/mL increase). Adiponectin values at day 0 were positively associated with neurological severity as evaluated by the National Institute of Health Stroke Scale upon admission (r = 0.420, p = 0.003) and were higher in the groups with poor outcomes (modified Rankin Scale (mRS) ≥ 3 on day 90) than in those with good ones (mRS ≤ 2) in all stroke subtypes, with statistical significance in ATBI (p = 0.015). Conclusions Plasma adiponectin values may help to classify stroke subtypes and predict neurological severity and functional outcome in ischemic stroke patients.

The presence or absence of the penumbra area is important when performing reperfusion therapy in patients with acute ischemic stroke. As a predictor of this penumbra area, magnetic resonance angiography (MRA)-diffusion-weighted imaging (DWI) mismatch is attracting attention. The usefulness of MRA-DWI mismatch (MDM) using the DWI-Alberta Stroke Program Early Computed Tomography Score (ASPECTS) in endovascular treatment (EVT) of patients with cerebral large vessel occlusion was evaluated.Of 1442 patients registered in the Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism-Japan Registry between July 1, 2010 and June 30, 2011 who presented to the hospital within 24 hours of the onset of acute cerebral infarction because of cerebral large vessel occlusion, 188 patients who had internal carotid artery or middle cerebral artery occlusion and achieved recanalization with EVT were included. Of these, 71 patients underwent intracranial EVT because intravenous recombinant tissue plasminogen activator therapy was ineffective. The associations between the presence or absence of MDM (MDM-positive [MDM-P], DWI-ASPECTS≥6; MDM-negative [MDM-N], DWI-ASPECTS6) and 90-day prognosis (modified Rankin Scale [mRS]) and symptomatic intracranial hemorrhage (sICH) were examined.Of the 188 patients analyzed, the time from symptom onset to admission was within 3 hours in 143 patients, 3-8 hours in 36 patients, and 8 hours or more in 9 patients. The time from the onset was within 3 hours in 118 patients in the MDM-P and 25 patients in the MDM-N cases. Favorable outcomes (mRS score≤2 at 90 days) were seen in 63 patients (53.4%) in the MDM-P group and 7 patients (28.0%) in the MDM-N group, showing a significantly more favorable clinical outcome in the MDM-P group (P=.027). The incidence of sICH was significantly lower in the MDM-P group (MDM-P group 3.4%, MDM-P group 20.0%; P=.009). The time from the onset was 3-8 hours in 29 patients in the MDM-P group and in 7 patients in the MDM-N group. Favorable outcomes were seen in 12 patients (41.4%) in the MDM-P group and 2 patients (28.6%) in the MDM-N group, with no significant difference between the 2 groups. No patients had sICH. The patients admitted 8 hours or more after the onset were all MDM-P. Five patients (55.6%) had a favorable outcome.This study demonstrated the safety and efficacy of EVT in MDM-P patients within 3 hours of symptom onset. Although the ratio of patients who had a favorable outcome was high in the MDM-P patients admitted 3-8 hours after the onset, the difference was not significant.

We aimed to evaluate the influence of prestroke cognitive impairment (PSCI) on outcomes in stroke patients treated with IV recombinant tissue plasminogen activator (rtPA).OPHELIE-COG was a prospective observational multicenter study conducted in French and Japanese patients treated with IV rtPA for cerebral ischemia. The preexisting cognitive status was evaluated by the short version of the Informant Questionnaire on Cognitive Decline in the Elderly. PSCI was defined as a mean score3. The primary endpoint was a favorable outcome (modified Rankin Scale [mRS] score 0-1) after 3 months. Secondary endpoints were symptomatic intracerebral hemorrhage (sICH), mRS scores 0-2, and mortality at 3 months. We performed a pooled analysis with Biostroke and Strokdem.Of 205 patients, 62 (30.2%) met criteria for PSCI. They were 11 years older (p0.001). Although they had more sICH and were less frequently independent after 3 months, they did not differ for any endpoint after adjustment for age, baseline NIH Stroke Scale score, and onset-to-needle time: sICH (odds ratio [OR] 2.78; 95% confidence interval [CI] 0.65-11.86), mRS 0-1 (OR 0.82; 95% CI 0.41-1.65), mRS 0-2 (OR 0.62; 95% CI 0.28-1.37), death (OR 0.40; 95% CI 0.08-2.03). The pooled analysis found no association of PSCI with any endpoint.Ischemic stroke patients with PSCI should receive rtPA if they are eligible. This conclusion cannot be extended to severe cognitive impairment or severe strokes.This study provides Class IV evidence that in patients with PSCI presenting with acute ischemic stroke, IV rtPA improves outcomes.

Background There have only been a few reports regarding the outcomes and risk factors after CEA. To clarify the factors associated with outcome in patients with carotid stenosis who underwent carotid endarterectomy (CEA), we investigated cardiovascular events and mortality in the Kyushu Medical Center in Japan. Methods We consecutively registered patients with significant carotid stenosis who had CEA performed over 10 years and compared the incidences of stroke, myocardial infarction, and death. On admission, we evaluated medical records for stroke risk factors, including hypertension, diabetes mellitus, hypercholesterolemia, atrial fibrillation, and current smoking habits. When performing CEA, blood pressure, heart rate, blood gases, and Doppler flow parameters in the carotid artery, and an electroencephalogram, were continuously monitored during the procedure. A shunt tube was inserted into both ends of the carotid artery, and a microscope was used. Although it was recommended that patients be evaluated by magnetic resonance imaging and ultrasound after the operation, we attempted to obtain information from the patient or a family member through a questionnaire or telephone survey if a patient did not come for assessment. We determined the factors associated with stroke, myocardial infarction, and death using Kaplan–Meier analyses. Results Of 312 CEA patients, 302 (96.8%) with confirmed outcomes were analyzed. We found that a factor associated with stroke was a history of ischemic stroke ( P = .028). A history of myocardial infarction ( P = .009) and the presence of peripheral arterial disease (PAD) ( P = .001) were factors related to the future occurrence of myocardial infarction. Perioperative complications occurred in 6 patients (1.99%) including 1 death because of sepsis and 1 major ipsilateral stroke. Of the 302 patients who underwent CEA, 43 patients died in the follow-up period, and the 5-year survival rate was 83.9%. The number of patients who died because of myocardial infarction and cancer was 9 for each, and they were the leading causes of their death. Only 1 patient died because of stroke (2.3%). Patients with PAD had a significantly high mortality ( P Conclusions In patients who underwent CEA, a risk factor of future stroke was a history of stroke. A history of myocardial infarction or PAD was strongly associated with future occurrence of myocardial infarction or high mortality.

Background: We conducted a survey by questionnaire to identify the essential components of stroke centers in Japan and compared our results with the European Expert Survey. Methods: In 2007, a questionnaire was mailed to the directors of 740 facilities certified by the Japan Stroke Society to ask their opinion on the essential components of comprehensive stroke centers (CSC), primary stroke centers (PSC) and any hospital ward (AHW) admitting acute stroke patients. The directors were asked to provide 1 of the following 6 possible answers regarding 112 components: ‘irrelevant'; ‘useful but not necessary'; ‘desirable'; ‘important but not absolutely necessary'; ‘absolutely necessary', or ‘question unclear or ambiguous'. The components considered ‘absolutely necessary' by more than 75% of the respondents were compared between our survey and the European Expert Survey. In addition, we compared the rates of neurosurgeons and neurologists who answered ‘absolutely necessary' with regard to each component. Results: Responses were obtained from 428 directors (57.8% response rate). Among these respondents, 298 (69.6%) were neurosurgeons. There was no component considered ‘absolutely necessary' for AHW by more than 75% of the respondents, and this was similar to the results of the European Expert Survey. The following components were considered ‘absolutely necessary' for PSC in our survey: brain CT scanning 24 h a day, 7 days a week (24/7); automated monitoring of the ECG, pulse oximetry, blood pressure and breathing, and respiratory support. In both our survey and the European Expert Survey, the essential components for CSC were as follows: physiotherapist; brain CT scanning 24/7; monitoring of the ECG, pulse oximetry and blood pressure; carotid surgery; angioplasty and stenting, and intravenous recombinant tissue plasminogen activator protocols. The components multidisciplinary stroke team, stroke-trained nurse, ultrasonography, collaboration with an outside rehabilitation center, stroke pathway and clinical research were deemed essential only in the European Expert Survey. However, MRI 24/7, MR angiography 24/7, conventional angiography 24/7, respiratory support as well as most neuroendovascular and neurosurgical treatments were considered necessary for CSC by more than 75% of the respondents in our survey. Analyzing the responses from only neurologists reduced the differences between our survey and the European Expert Survey. Conclusions: The present study indicated the essential components expected for stroke centers in Japan. Our survey demonstrated that more emphasis was likely to be placed on installations than on a dedicated stroke team and the use of stroke care maps. In addition, the results of this study may reflect some characteristics of the stroke care environment in Japan, such as the predominance of neurosurgeons and widespread use of MRI.

BACKGROUND The features of acute aortogenic embolic stroke on magnetic resonance diffusion-weighted imaging (DWI) have not been fully elucidated, so we compared patients with acute aortogenic embolic stroke and those with acute cardioembolic stroke. METHODS AND RESULTS This study included 40 consecutive patients with acute aortogenic embolic stroke, and 40 age- and sex-matched patients with acute cardioembolic stroke. The diagnosis of aortogenic embolic stroke was made when patients met 5 criteria: (1)acute neurologic event lasting >24h; (2) positive signals on DWI; (3) atherosclerotic lesions ≥3.5-mm thick at the aortic arch on transesophageal echocardiography; (4) neuroradiologic features suggesting embolic stroke, such as lesions involving the brain cortex or the re-opening phenomenon of previously occluded vessels on Magnetic Resonance Angiography (MRA); and (5) absence of other embolic sources, including heart disease and carotid stenosis. The number, site, and maximal diameter of the infarct lesions on DWI were compared between the aortogenic and cardiogenic groups. The aortogenic patients more frequently had ≥3 lesions (25.0% vs. 2.5%, P

Background: The incidence of intracranial bleeding during dabigatran treatment is lower than that during warfarin treatment. The characteristics of intracranial hemorrhage during dabigatran therapy, however, remain unclear. Methods and Results: The clinical data and treatment summaries of 9 intracranial bleeds that developed during dabigatran treatment in 8 patients with non-valvular atrial fibrillation were retrospectively reviewed. Five patients had small–moderate subdural hematomas, 2 had intracerebral hemorrhage and 1 had traumatic subarachnoid and parenchymal hemorrhage associated with cerebral contusion. Activated partial thromboplastin time upon admission ranged from 31.6 to 72.4s. After admission, systolic blood pressure in the 2 patients with intracerebral hemorrhage was maintained below 140mmHg, and the subdural hematomas in 4 patients were surgically treated. None of the hematomas became enlarged and outcome was good in most cases. Conclusions: Hematomas that arise due to acute intracranial bleeding during dabigatran treatment seem to remain small to moderate, hard to expand, and manageable. (Circ J 2014; 78: 1335–1341)

To evaluate if esomeprazole prevents recurrent peptic ulcer in adult patients with a history of peptic ulcer receiving low-dose acetylsalicylic acid (ASA, aspirin) for cardiovascular protection in East Asia.In this prospective, randomised, double-blind, placebo-controlled trial conducted in Japan, Korea and Taiwan, eligible patients receiving low-dose ASA for cardiovascular protection (81-324 mg/day) were randomised to esomeprazole 20 mg/day or placebo for ≤72 weeks. All patients received concomitant mucosal protection (gefarnate 100 mg/day). The primary endpoint was time to ulcer recurrence (Kaplan-Meier analysis). Efficacy findings are presented up to week 48, as per a planned interim analysis within the study protocol.A total of 364 patients (79.9% men; mean age, 67.1 years) comprised the full analysis set (esomeprazole, n=182; placebo, n=182). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p0.001). The estimated ulcer-free rate at week 12 was 99.3% (esomeprazole) and 89.0% (placebo). The high estimated ulcer-free rate for esomeprazole was maintained through to week 48 (98.3% vs. 81.2% of placebo-treated patients). No factors, other than female gender, reduced time to ulcer recurrence in addition to the effect of esomeprazole (p0.001). Treatment with esomeprazole was generally well tolerated.Daily esomeprazole 20 mg is efficacious and well tolerated in reducing the recurrence of peptic ulcer in East-Asian patients with a history of ulcers who are taking low-dose ASA for cardiovascular protection.NCT01069939.

Background and purpose The characteristics of reverse magnetic resonance angiography and diffusion-weighted imaging (MRA-DWI) mismatch (RMM), defined as a large DWI lesion in the absence of major artery occlusion (MAO), remain unknown, especially in patients treated with intravenous recombinant tissue plasminogen activator (rt-PA). Methods Patients with stroke in the middle cerebral artery territory were included. Early ischaemic changes (EIC) were assessed with the Alberta Stroke Program Early CT Score on DWI (DWI-ASPECTS). All patients were divided into four groups based on the presence of MAO and a DWI-ASPECTS cut-off value of

Background The therapeutic efficacy of low-dose intravenous alteplase (0.6 mg/kg) for basilar artery occlusion (BAO) remains unknown. Methods BAO patients enrolled from the Japanese multicenter registry involving 600 stroke patients treated with the low-dose intravenous alteplase were studied. Results Twenty-five patients had BAO (8 women ranging from 32-92 years of age; mean baseline National Institutes of Health Stroke Scale [NIHSS] score 16). The stroke subtype was cardioembolic in 15 patients and atherothrombotic in 4 patients. BAO was recanalized during hospitalization in 18 (78%) of 23 patients undergoing follow-up angiography. Within the initial 24 hours, 14 patients (56%) had a ≥8-point decrease in the NIHSS score, being more common than 267 patients with middle cerebral artery occlusion (MCO) from the same registry (odds ratio [OR] 2.50; 95% confidence interval [CI] 1.06-5.97) after adjustment by sex, age, and baseline NIHSS score. In addition, 4 patients (16%) had a ≥4-point increase in the score, being marginally more common than MCO patients (OR 3.13; 95% CI 0.81-10.25). Symptomatic intracranial hemorrhage within the initial 36 hours (8% v 5%), independence at 3 months (modified Rankin Scale score ≤2, 48% v 52%), and mortality at 3 months (4% v 6%) were similar when comparing BAO and MCO patients. When compared with previous studies of BAO, vital and functional outcomes at 3 months were relatively better in our study. Conclusions The use of low-dose alteplase resulted in similar outcomes when comparing acute BAO and MCO patients.

The heteroduplex mobility assay (HMA) is widely used to characterize strain variants of human viruses. To determine whether it can detect small sequence differences in homologous templates, we constructed a series of deletion constructs (1–10 bp deletions) in the multiple cloning site (MCS) of pBluescript II. After PCR amplification of the MCS using a mixture of wild-type and one of the deletion constructs, the resulting PCR amplicons were electrophoresed using 15% polyacrylamide gels. Two types of heteroduplexes exhibited retarded electrophoretic migration compared with individual homoduplexes. Therefore, we applied this HMA to detect transcription activator-like effector nucleases (TALEN)-induced insertion and/or deletion (indel) mutations at an endogenous locus. We found that TALEN in vivo activity was easily estimated by the degree of multiple HMA profiles derived from TALEN-injected F0 embryos. Furthermore, TALEN-injected F0 founder fish produced several unique HMA profiles in F1 embryos. Sequence analysis confirmed that the different HMA profiles contained distinct indel mutations. Thus, HMA is a rapid and sensitive analytical method for the detection of the TALEN-mediated genome modifications.

Background We aimed to devise a scale comprising a simple multiplication of initial National Institutes of Health Stroke Scale (NIHSS) score and onset-to-treatment time (OTT) as a scale for predicting outcomes after recombinant tissue plasminogen activator (rt-PA) therapy. Methods Data from rt-PA patients in 10 stroke centers in Japan were investigated. NIHSS-time score was calculated as initial NIHSS score × OTT. Results Subjects comprised 526 patients. Median NIHSS score was 12 (7–18), and median OTT was 2.42 h (2.00–2.75 h). Median NIHSS-time score was 27.7 (16.9–41.7). Good (modified Rankin Scale [mRS] 0–1) and poor (mRS 4–6) outcome rates at 3 months for patients with NIHSS-time scores ≤ 10 were 71.1% and 7.8%, compared to 54.7% and 16.5% for scores > 10 and ≤ 20, 38.9% and 31.9% for scores > 20 and ≤ 30, 25.0% and 44.6% for scores > 30 and ≤ 40, and 17.4% and 61.8% for scores > 40, respectively. Cut-off NIHSS-time scores to predict good and poor outcomes with 50% probability were defined as 20 and 40, respectively. Multivariate logistic regression analysis revealed NIHSS-time score as an independent predictor of good (odds ratio [OR], 0.587; 95% confidence interval [CI], 0.422–0.818, p = 0.002) and poor (OR, 1.756; 95%CI, 1.227–2.514, p = 0.002) outcomes after adjusting for age, sex, NIHSS score, OTT, Alberta Stroke Program Early CT Score, internal carotid artery occlusion, and glucose level. Conclusions NIHSS-time score predicts clinical outcomes in rt-PA patients.

Polarization of node cells along the anterior-posterior axis of mouse embryos is responsible for left-right symmetry breaking. How node cells become polarized has remained unknown, however. Wnt5a and Wnt5b are expressed posteriorly relative to the node, whereas genes for Sfrp inhibitors of Wnt signaling are expressed anteriorly. Here we show that polarization of node cells is impaired in Wnt5a(−/−)Wnt5b(−/−) and Sfrp mutant embryos, and also in the presence of a uniform distribution of Wnt5a or Sfrp1, suggesting that Wnt5 and Sfrp proteins act as instructive signals in this process. The absence of planar cell polarity (PCP) core proteins Prickle1 and Prickle2 in individual cells or local forced expression of Wnt5a perturbed polarization of neighboring wild-type cells. Our results suggest that opposing gradients of Wnt5a and Wnt5b and of their Sfrp inhibitors, together with intercellular signaling via PCP proteins, polarize node cells along the anterior-posterior axis for breaking of left-right symmetry.

The eukaryotic genome is organized within cells as chromatin. For proper information output, higher-order chromatin structures can be regulated dynamically. How such structures form and behave in various cellular processes remains unclear. Here, by combining super-resolution imaging (photoactivated localization microscopy [PALM]) and single-nucleosome tracking, we developed a nuclear imaging system to visualize the higher-order structures along with their dynamics in live mammalian cells. We demonstrated that nucleosomes form compact domains with a peak diameter of ∼160 nm and move coherently in live cells. The heterochromatin-rich regions showed more domains and less movement. With cell differentiation, the domains became more apparent, with reduced dynamics. Furthermore, various perturbation experiments indicated that they are organized by a combination of factors, including cohesin and nucleosome-nucleosome interactions. Notably, we observed the domains during mitosis, suggesting that they act as building blocks of chromosomes and may serve as information units throughout the cell cycle.

Background: Little has been investigated about associations between timing of blood pressure lowering and clinical outcome of intracerebral hemorrhage (ICH). Methods: The Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI)-ICH Study is a multicenter, prospective, observational study investigating the safety and feasibility of early (within 3 hours from symptom onset) systolic blood pressure (SBP) reduction to less than 160 mmHg with intravenous nicardipine for acute hypertension in patients with spontaneous ICH. We retrospectively examined the relationship between time from onset, CT imaging, and initiation of antihypertensive treatment to target SBP achievement and hematoma growth in ICH patients. Hematoma growth was defined as an absolute growth of ≥ 6 ml from baseline to second imaging at 24 (±6) hours after the initiation of antihypertensive treatment. Results: Among 211 patients (81 women (38.4%), mean age 66 years), mean baseline hematoma volume was 13 ml and hematoma growth was seen in 36 (17.1%) patients. Time from image to target SBP and time from treatment to target SBP were significantly shorter in patients without hematoma growth than those with ( P = 0.043 and P = 0.032, respectively), whereas there was not significant difference in time from onset to target SBP between the two groups ( P = 0.177). Lower quartiles of time from image to target SBP and time from treatment to target SBP had lower incidences of hematoma growth (P trend = 0.023 and 0.037, respectively, Cochran-Armitage test), whereas there was not significant trend in time from onset to target SBP ( P = 0.074). The lowest quartile of time from image to target SBP was negatively associated with hematoma growth on multivariate logistic regression (odds ratio 0.182, 95% confidential interval 0.038-0.867, P = 0.032). Conclusions: Early achievement to target SBP

Introduction: The relationship between treatment with antithrombotic agents and the presence of cerebral microbleeds[CMBs] remains unclear. We investigated the relationship between the type of past treatment with antithrombotic agents and the presence of CMBs in acute ischemic stroke patients. Methods: A total of 493 acute ischemic stroke patients (mean age 71; 60% male) who had undergone 1.5T gradient-echo T2*-weighted MR imaging after acute ischemic stroke onset were enrolled. The patients were classified into 6 groups according to the type of past treatment with antithrombotic agents: 337 patients with no antithrombotic agent, 58 patients treated with aspirin only, 33 patients with a single antiplatelet agent other than aspirin, 34 patients with aspirin and other antithrombotic agents, 5 patients with antiplatelet agent other than aspirin and other antithrombotic agents and 26 patients with anticoagulant only. The associations between the type of antithrombotic agents and the presence of CMBs were studied using a logistic regression analysis. Results: A total of 173(35%) of 493 had CMBs. Of theses, 35(7%) had strictly lobar CMBs and 138(28%) had deep or infratentorial CMBs. The presence of CMBs were significantly associated with age (P Conclusions: It seems that past treatment with aspirin is associated with the presence of CMBs in acute ischemic stroke patients.

Introduction: Cerebral small vessel diseases (SVDs) i.e. white matter lesion and cerebral microbleeds (CMBs) are related to the patients with stroke more deeply than those without. In general population, in addition to age, hypertension, diabetes chronic kidney diseases (CKD) is well known to be related to SVDs, but it remains unclear in patients with stroke. We investigated the relationship between CKD and the presence of SVDs in patients with acute ischemic stroke. Methods: We enrolled 493 patients with acute ischemic stroke patients or transient ischemic attack patients (mean age 71; 60% male) who had undergone 1.5T MR imaging within a week of the index events from April 2013 to march 2015. We evaluated kidney function by estimated glomerular filtration rate (eGFR) with the modification of diet in Renal Disease. CKD was defined as an eGFR less than 60mil/min/1.73m 2 . CMBs were defined as focal areas of very low signal intensity smaller than 10mm. White matter lesion as Periventricular hyper intensity (PVH)>grade 2 and Deep and Subcortical White Matter Hyper intensity (DSWMH)> grade 2 were defied as advanced PVH and advanced DSWMH, respectively. We investigated relationship between CKD and CMBs, advanced PVH and advanced DSWMH using a logistic regression analysis. Results: We noted CMBs in 173 patients (35%), PVH in 81 (16%), and DSWMH in 151 (31%). An univariate analysis revealed that the age, CKD, history of stroke, and antiplatelet agents were associated with presence of CMBs, advanced PVH and severe DSWMH . The multivariate analysis revealed that CMBs, advanced PVH and advanced DSWMH were associated with age (CMBs: odds ratio(OR) ; 1.32 ; 95% confidence interval(CI), 1.10-1.60, p=0.004, advanced PVH : OR ; 3.00 ; 95% CI, 2.17-4.26, p Conclusions: It seems that age and history of stroke are related to CMBs, advanced PVH and advanced DSWMH, and that CKD is associates with CMBs but not with either advanced PVH or advanced DSWMH.

Background and purpose: Less severe and smaller infarct are features in acute stroke patients treated with warfarin within a therapeutic range of PT-INR than in those without. But it remains unclear the severity and size of infarct in acute stroke patients treated with direct oral anticoagulants [DOAC]. We investigated the features of acute stroke in patients treated with DOAC, warfarin or without. Methods: We enrolled consecutive 190 non-valvular atrial fibrillation patients (mean age 78; 63% male) who developed acute ischemic stroke and classified them into 4 groups, 109 patients with no anticoagulant therapy [Control group], 25 patients with DOAC therapy [DOAC group], 19 patients treated with warfarin within a therapeutic range of PT-INR [>= 1.6 in patients aged 70 years old or older, >= 2.0 in those aged younger than 70 years old, Warfarin well controlled group], and 37 patients treated with warfarin with subtherapeutic PT-INR values [Warfarin not controlled group]. Infarcts sizes were defined as the maximum diameter of infarct, using the brain MRI diffusion-weighted image. Stroke severity on admission were assessed by the National Institutes of Health Stroke Scale[NIHSS].We compared them among the groups. Results: There were no significant differences in preadmission CHADS2 score among the 4 groups. The median infarct size were 31mm (interquartile (IQR) 13-59) in the control group, 10mm (IQR 7.4-38) in the DOAC group, 12mm (IQR 8.0-45) in the warfarin well controlled group, and 24mm (IQR 13-67) in the warfarin not controlled group. The size of infarct was significantly smaller in the DOAC group than the control group (P=0.01). The NIHSS on admission was 4 ([IQR] 2-15) in the control group, 2 (1-6) in the DOAC group, 4 (1-17) in the warfarin well controlled group and 5 (3-17) in e warfarin not controlled group. Stroke severity on admission was also more favorable in the DOAC group when compared with the control group (P=0.03) Conclusions: Smaller and less severe infarct may be feature of acute ischemic stroke during DOAC therapy when compared to that without any anticoagulant therapy.

Background and Purpose: TIAregistry.org is an international prospective registry in patients with TIA or minor stroke (mRS 0 or 1) within 7 days after the onset. Main analysis of one-year follow-up data have been reported (N Engl J Med 2016;374:1533-42). We performed Japanese vs non-Japanese sub-analysis on the baseline and one-year follow-up data. Methods: Patients were classified into two groups according to their countries of origin (Japanese and non-Japanese). All comparisons between the two groups were adjusted on age, sex and mRS. Variables included demographic characteristics, intracranial and extracranial arterial stenosis, acute infarcts, TOAST classification, ABCD 2 score, and time to first contact. We compared the 1-year event rates of cardiovascular death, non-fatal stroke, and non-fatal acute coronary syndrome between the two groups using Cox proportional hazard models. Results: A total of 4,583 patients were included in the analysis. From them, 345 (7.5%) were Japanese. Proportion of patients with mRS 1 was higher in Japanese (58.5% vs 27.9%, p 50% was more common in Japanese (19.6% vs 12.9%, p = 0.01). Distribution of ABCD 2 score was also different between Japanese and non-Japanese (20.1% vs 33.5% in scores 0-3, 28.6% vs 18.3% in scores 6 and 7, p = 0.02 in total). Time to first contact Conclusions: Higher risk conditions in baseline characteristics as well as delay of time to contact, and a higher one-year stroke rate were identified in Japanese patients enrolled in this registry.

Background: We aimed to design a prehospital scale to predict candidates for endovascular thrombectomy (CET) in patients with acute ischemic stroke (AIS). Materials and methods: In the Fukuoka Stroke Registry, we identified 3,470 patients with AIS who were transferred by emergency medical service within 24 hours of stroke onset and underwent intracranial vessel evaluation on admission from September 2007 to December 2015. CET were defined as patients with causative occlusion of internal carotid artery, middle cerebral artery, or basilar artery, and National Institute of Health Stroke Scale (NIHSS) score ≥ 6. The Fukuoka Acute Stroke ThrombEctomy pRediction (FASTER) scale was developed with NIHSS items based on the predictive importance derived from random forest analysis to predict CET. The discriminative performance was compared with other published scales for large vessel occlusion. Results: The FASTER scale was designed comprising of 4 NIHSS items : one point each was given for extinction and inattention (NIHSS subscore ≥ 1), best gaze (≥ 1), best language (≥ 1), and motor arm (≥ 2). Receiver operator curves demonstrated that the area under the curve of the FASTER scale was significantly larger than that of the Cincinnati Prehospital Stroke Severity Scale (0.907 vs 0.881, p Conclusion: The FASTER scale is a simple and promising tool that can identify CET in the prehospital setting.

Summary Artificially designed nucleases such as zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) can induce a targeted DNA double-strand break at the specific target genomic locus, leading to the frameshift-mediated gene disruption. However, the assays for their activity on the endogenous genomic loci remain limited. Herein, we describe a versatile modified lacZ assay to detect frameshifts in the nuclease target site. Short fragments of the genome DNA at the target or putative off-target loci were amplified from the genomic DNA of TALEN-treated or control embryos, and were inserted into the lacZα sequence for the conventional blue–white selection. The frequency of the frameshifts in the fragment can be estimated from the numbers of blue and white colonies. Insertions and/or deletions were easily determined by sequencing the plasmid DNAs recovered from the positive colonies. Our technique should offer broad application to the artificial nucleases for genome editing in various types of model organisms.

To assess the efficacy and safety of telaprevir (TVR) when used in combination with natural human interferon-β (IFN-β) and ribavirin (RBV) for genotype 1 patients with depression compared to IFN-β/RBV therapy in Japan. We also examined the efficacy of the TVR/IFN-β/RBV therapy in treatment failure genotype 2 patients with depression.For the genotype 1 patients, 30 patients received TVR (750 mg every 8 h) for 12 weeks combined with IFN-β and RBV for 24 weeks (Group A), and 30 received IFN-β and RBV for 48 weeks (Group B). For the genotype 2 patients, 14 patients were dosed only with the TVR-based regimen.The sustained virologic response (SVR) rates for Group A and Group B were 63.3% and 20.0%, respectively (P = 0.001, likelihood ratio test). The SVR rate for genotype 2 patients previously treated with pegylated IFN and/or RBV was 71.4%. No patient dropped out due to exacerbation of depression. The trend of platelet counts after the drugs were given was similar in the TVR/IFN-β/RBV therapy group and the IFN-β/RBV therapy group. Common resistance-associated variants of TVR were identified in 4 of the 13 patients who did not achieve SVR.This study showed that an addition of TVR to IFN-β/RBV therapy raised SVR in previously treated and untreated genotype 1 patients and previously treated genotype 2 patients with chronic hepatitis C and depression.

Antidotes appropriate for non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) are not yet in widespread clinical use. Efficacy of prothrombin complex concentrate (PCC) in NOAC-associated bleeding remains unclarified.Ten NOAC users (4 women, median 74years old) who developed major bleeding and received PCC were prospectively enrolled. Eight single-center NOAC users (0 women, median 74years old) with intracerebral hemorrhage, who over the same period did not receive PCC, were studied for comparison.Of the 10 PCC-treated patients, 8 developed intracerebral hemorrhage, 1 developed subdural hematoma, and another developed gastrointestinal bleeding. The median size of intracerebral hemorrhage was 8mL, relatively lower than the reported size for patients without NOACs. Patients received a median of 1000IU or 16IU/kg of PCC. Before and 1h after PCC administration, the median PT-INR changed from 1.41 to 1.09 (p0.05) and median aPTT changed from 35.4 to 38.0s (p=0.39). Five patients developed intracranial hematoma expansion and 4 required surgical hematoma evacuation. No symptomatic thrombotic events occurred in either group, no participants died, and 2 participants from each group were independent.Ten NOAC users developed major bleeding and were given relatively low doses of PCC. The effect of PCC on early cessation of bleeding was unclear, while the therapy did not trigger thromboembolic complications.

Japanese Guidelines for the Management of Stroke 2015 was published. Here, we describe several points revised from the 2009 edition about "Cerebral infarction and transient ischemic attack (TIA)". The revision points are as follows; 1. Extension of possible time window of intravenous recombinant tissue-plasminogen activator treatment (from within 3 hours to within 4.5 hours); 2. Antiplatelet therapy in acute stage (dual antiplatelet therapy (DAPT) for non-cardioembolic ischemic stroke or TIA); 3. Endovascular recanalization therapy in acute stage; 4. Antiplatelet therapy in chronic stage (Cilostazol is recommended similar to aspirin or clopidogrel); 5. Non-vitamin K antagonist oral anticoagulants (NOACs) for non-valvular atrial fibrillation (NVAF) stroke or TIA patients; 6. Management of TIA. We explain the revised points of the guideline in the text.

Background and Purpose— The discrimination between paroxysmal and sustained (persistent or permanent) atrial fibrillation (AF) has not been considered in the approach to secondary stroke prevention. We aimed to assess the differences in clinical outcomes between mostly anticoagulated patients with sustained and paroxysmal AF who had previous ischemic stroke or transient ischemic attack. Methods— Using data from 1192 nonvalvular AF patients with acute ischemic stroke or transient ischemic attack who were registered in the SAMURAI-NVAF study (Stroke Management With Urgent Risk-Factor Assessment and Improvement-Nonvalvular AF; a prospective, multicenter, observational study), we divided patients into those with paroxysmal AF and those with sustained AF. We compared clinical outcomes between the 2 groups. Results— The median follow-up period was 1.8 (interquartile range, 0.93–2.0) years. Of the 1192 patients, 758 (336 women; 77.9±9.9 years old) and 434 (191 women; 77.3±10.0 years old) were assigned to the sustained AF group and paroxysmal AF groups, respectively. After adjusting for sex, age, previous anticoagulation, and initial National Institutes of Health Stroke Scale score, sustained AF was negatively associated with 3-month independence (multivariable-adjusted odds ratio, 0.61; 95% confidence interval, 0.43–0.87; P =0.006). The annual rate of stroke or systemic embolism was 8.3 and 4.6 per 100 person-years, respectively (multivariable-adjusted hazard ratio, 1.95; 95% confidence interval, 1.26–3.14) and that of major bleeding events was 3.4 and 3.1, respectively (hazard ratio, 1.13; 95% confidence interval, 0.63–2.08). Conclusions— Among patients with previous ischemic stroke or transient ischemic attack, those with sustained AF had a higher risk of stroke or systemic embolism compared with those with paroxysmal AF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01581502.

Cryoelectron microscopy reveals conformational changes at the contacts between tubulins between GMPCPP and GDP-taxol microtubules., Microtubules are dynamic polymers that stochastically switch between growing and shrinking phases. Microtubule dynamics are regulated by guanosine triphosphate (GTP) hydrolysis by β-tubulin, but the mechanism of this regulation remains elusive because high-resolution microtubule structures have only been revealed for the guanosine diphosphate (GDP) state. In this paper, we solved the cryoelectron microscopy (cryo-EM) structure of microtubule stabilized with a GTP analogue, guanylyl 5′-α,β-methylenediphosphonate (GMPCPP), at 8.8-Å resolution by developing a novel cryo-EM image reconstruction algorithm. In contrast to the crystal structures of GTP-bound tubulin relatives such as γ-tubulin and bacterial tubulins, significant changes were detected between GMPCPP and GDP-taxol microtubules at the contacts between tubulins both along the protofilament and between neighboring protofilaments, contributing to the stability of the microtubule. These findings are consistent with the structural plasticity or lattice model and suggest the structural basis not only for the regulatory mechanism of microtubule dynamics but also for the recognition of the nucleotide state of the microtubule by several microtubule-binding proteins, such as EB1 or kinesin.

Background The Essen stroke risk score is widely applied to predict the risk of recurrent ischemic stroke. We developed a modified Essen stroke risk score and validated it using a large prospective Effective Vascular Event REduction after STroke (EVEREST) registry including 3588 patients with ischemic stroke in Japan. Patients with cardioembolic stroke were excluded, and follow-up was one-year. Methods The modified Essen stroke risk score was calculated from scores for waist circumference, stroke subtype by etiology, and gender in addition to age, hypertension, diabetes mellitus, previous myocardial infarction, other cardiovascular diseases except myocardial infarction and atrial fibrillation, peripheral artery disease, smoking, and previous stroke or transient ischemic attack. A multiple logistic regression model identified the predictors (each assigned one or two points) and provided c-statistics for the modified Essen stroke risk score. We considered two outcomes, recurrent ischemic stroke and cardiovascular events (defined as the combined outcomes of fatal or nonfatal stroke, myocardial infarction, nonfatal unstable angina, and cardiac death). Results Recurrent ischemic stroke occurred in 121 patients (3·7%) and cardiovascular events occurred in 133 (4·0%) within a year. The c-statistic (used for discrimination) was 0·632 for recurrent stroke and 0·640 for cardiovascular events. Patients scoring 6 or greater were classified as high risk, otherwise were classified as low risk. Kaplan–Meier analysis revealed that the modified risk score was more predictive than the Essen stroke risk score in both men and women. Conclusions The modified Essen stroke risk score increased the ability of the Essen stroke risk score to predict recurrent cardiovascular events. Patients with a high modified Essen stroke risk score should be candidates for intensified secondary prevention strategies.

Background: Currently, there are only a few risk scores to predict long-term recurrence of ischemic stroke and no risk score has been developed for the Asian population. The aim of the present study was to develop a new risk score to predict 1-year recurrence in Japanese patients with ischemic stroke and compare it with the other ones. Methods: Data used in this analysis were extracted from the Fukuoka stroke registry (FSR) database, including 3,067 Japanese patients who experienced ischemic stroke. FSR is a multicenter, hospital-based, prospective registry of Japanese patients with acute stroke. Associations between potential clinical variables that could be involved in the increase of risk and recurrence of ischemic stroke within 1 year after initial stroke onset were evaluated using univariate and multivariate analyses. To calculate risk scores, weighted points proportionally based on standardized coefficient values were assigned to variables that were identified to be significant risks for recurrence by multivariate analysis. The Hosmer-Lemeshow goodness-of-fit test was used to test agreement between a predicted outcome using a model and an actual observed outcome. Kaplan-Meier analysis was used to estimate average cumulative recurrence rates within three risk groups. Intergroup comparisons in recurrence rate among the risk groups were performed using a log-rank test. Results: Univariate and multivariate analyses identified nine significant predictors for 1-year recurrence, to which we assigned the following points: age (65–74 years, 1 point; ≥75 years, 2 points), hypertension (1 point), diabetes mellitus (1 point), smoker (1 point), atrial fibrillation (1 point), cardiac diseases (1 point), chronic kidney disease (1 point), nonlacunar stroke (1 point), and previous ischemic stroke (2 points). The Hosmer-Lemeshow goodness-of-fit test demonstrated good agreement between the observed and predicted recurrence rate (χ2 = 2.30, p = 0.97). The ROC curve for the risk score models showed acceptable discriminant power with a C-statistic of 0.636 (95% confidence interval: 0.573–0.698). Trends toward increased risk of recurrence with higher scores were observed. The 1-year recurrence rates were 2.93, 5.83 and 7.96% in low- (≤3 points), intermediate (4–5 points), and high-risk groups (≥6 points), respectively. Kaplan-Meier curves with log-rank test showed a significant difference in recurrence among the three risk groups (p < 0.0001). Conclusions: A new risk score was developed and successfully validated. Our results suggest that this simple risk score enables clinicians to assess 1-year recurrence risk in Japanese patients with ischemic stroke.

Background: The effects of lipid levels on clinical outcomes after ischemic stroke are controversial. Whether admission lipid levels and prior statin use are associated with early intracerebral hemorrhage (ICH) and long-term functional outcome after recombinant tissue plasminogen activator (rt-PA) therapy for stroke patients was investigated. Methods: Ischemic stroke patients who received intravenous rt-PA from a multicenter registry were studied. Lipid levels on admission, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and triglyceride levels, as well as prior statin use, were assessed. The primary outcome was favorable outcome at 3 months corresponding to a modified Rankin Scale score ≤1. The secondary outcome was any or symptomatic ICH within the initial 36 h. Results: Of 489 enrolled patients (171 women, 70.8 ± 11.6 years old), 60 used statins prior to stroke, 93 developed ICH (19.0%), and 188 (38.4%) had a favorable 3-month outcome. Of the lipid levels, only the HDL-C level was an independent predictor of favorable outcome after multivariate adjustment for baseline characteristics (OR 1.95, 95% CI 1.10–3.47 per 1 mmol/l; p = 0.023) and after further adjustment for pretreatment radiological findings (OR 2.03, 95% CI 1.07–3.84; p = 0.029). For the 187 stroke patients without cardioembolism, the HDL-C level was more strongly associated with favorable outcome (OR 4.94, 95% CI 1.91–12.76 per 1 mmol/l; p = 0.001). There were no significant associations between ICH and any lipid levels. Prior statin use was not associated with outcomes. Conclusions: The admission HDL-C level was associated with favorable outcome 3 months after intravenous rt-PA therapy in stroke patients without cardioembolism.

Purpose A nationwide survey was conducted regarding anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) on warfarin with nonvalvular atrial fibrillation (NVAF). Methods A questionnaire on standard therapeutic strategy for warfarin-related ICH in patients with NVAF was mailed to 416 institutes. Results A total of 329 physicians (79%) responded with a completed questionnaire. On admission, all respondents stopped warfarin medication and 94% normalized the international normalized ratio (INR) mainly by Vitamin K (63%), followed by fresh frozen plasma (20%), and prothrombin complex concentrate (10%). Afterwards, 91% of the respondents restarted anticoagulation and 3% used antiplatelet for prevention of thromboembolism, but the remaining 6% disagreed with restarting antithrombotic therapy. As contraindications for resuming anticoagulation, recurrent ICH (59%) and poor functional condition (59%) were often chosen. Of those who restarted anticoagulation, the timing was within 4 days in 7%, 5 to 7 days in 21%, 8 to 14 days in 25%, 15 to 28 days in 28% and 29 days or later in 18%. The major key finding on follow-up CT to restart anticoagulation was the absorption tendency of hematomas (47%). When restarting anticoagulation, 76% of the respondents used warfarin alone and 20% used either unfractionated heparin plus warfarin or heparin alone. Conclusion A large majority of respondents responsible for ICH management stopped oral warfarin medication and normalized INR on admission, and restarted anticoagulation after acute ICH in patients with NVAF. However, the strategies to normalize INR and to restart anticoagulant therapy varied greatly and depended on each individual physician's decision.

Background: The initial 24 h after thrombolysis are critical for patients’ conditions, and continuous neurological assessment and blood pressure measurement are required during this time. The goal of this study was to identify the clinical factors associated with early neurological deterioration (END) within 24 h of stroke patients receiving intravenous recombinant tissue plasminogen activator (rt-PA) therapy and to clarify the effect of END on 3-month outcomes. Methods: A retrospective, multicenter, observational study was conducted in 10 stroke centers in Japan. A total of 566 consecutive stroke patients [211 women, 72 ± 12 years old, the median initial NIH Stroke Scale (NIHSS) score of 13] treated with intravenous rt-PA (0.6 mg/kg alteplase) was studied. END was defined as a 4-point or greater increase in the NIHSS score at 24 h from the NIHSS score just before thrombolysis. Results: END was present in 56 patients (9.9%, 18 women, 72 ± 10 years old) and was independently associated with higher blood glucose [odds ratio (OR) 1.17, 95% confidence intervals (CI) 1.07–1.28 per 1 mmol/l increase, p < 0.001], lower initial NIHSS score (OR 0.92, 95% CI 0.87–0.97 per 1-point increase, p = 0.002), and internal carotid artery (ICA) occlusion (OR 5.36, 95% CI 2.60–11.09, p < 0.001) on multivariate analysis. Symptomatic intracranial hemorrhage within the initial 36 h from thrombolysis was more common in patients with END than in the other patients (per NINDS/Cochrane protocol, OR 10.75, 95% CI 4.33–26.85, p < 0.001, and per SITS-MOST protocol, OR 12.90, 95% CI 2.76–67.41, p = 0.002). At 3 months, no patients with END had a modified Rankin Scale (mRS) score of 0–1. END was independently associated with death and dependency (mRS 3–6, OR 20.44, 95% CI 6.96–76.93, p < 0.001), as well as death (OR 19.43, 95% CI 7.75–51.44, p < 0.001), at 3 months. Conclusions: Hyperglycemia, lower baseline NIHSS score, and ICA occlusion were independently associated with END after rt-PA therapy. END was independently associated with poor 3-month stroke outcome after rt-PA therapy.

Although aspirin has been widely prescribed for the prevention of cardiovascular events, its risk of gastrointestinal complications is of great concern. Despite expectations for such, few data are available on the prevalence or incidence of gastrointestinal complications in aspirin users in Japan. The Management of Aspirin-induced GastroIntestinal Complications (MAGIC) is the first attempt at collaboration among cardiologists, neurologists, and gastroenterologists to obtain such findings. We aim to share all about the MAGIC study. The MAGIC is a prospective cohort study involving patients taking low-dose aspirin (81 mg to 325 mg per day) for longer than 1 month. Participants are recruited from multiple disease categories, including those with coronary artery disease, cerebrovascular disease, atrial fibrillation, and other cardiovascular conditions requiring antithrombotic therapy. Its duration of follow-up is 1 year. At baseline and 1 year follow-up, all participants will undergo endoscopic examination. The primary outcome is upper gastrointestinal complications, classified as erosions, ulcers, and bleeding. Secondary outcomes include LANZA score, non-fatal cardiovascular events, any bleeding, cancer, and death. 1,533 participants were entered in the MAGIC cohort. By underlying disease, about 45% of them had coronary artery diseases, followed by cerebrovascular diseases (35%), atrial fibrillation (10%) and other cardiovascular diseases (10%). The MAGIC study will yield important findings with regard to the prevalence and incidence of gastrointestinal complications and related risk factors for low-dose aspirin users. It may also report that use of anti-secretory agents such as proton pump inhibitors reduces the risk of such complications.

Background and Purpose— Alberta Stroke Programme Early CT Score (ASPECTS) is a quantitative topographical score to evaluate early ischemic change in the middle cerebral arterial territory on CT as well as on diffusion-weighted imaging (DWI). The aim of the present study was to elucidate the relationship between CT-ASPECTS and DWI-ASPECTS for patients with hyperacute stroke and their associations with outcomes after recombinant tissue-type plasminogen activator therapy based on a multicenter registry. Methods— ASPECTS was assessed on both CT and DWI before intravenous 0.6 mg/kg alteplase in 360 patients with stroke (119 women, 71±11 years old). The outcomes were symptomatic intracerebral hemorrhage within 36 hours and independence at 3 months defined by a modified Rankin Scale score of 0 to 2. Results— DWI-ASPECTS was positively correlated with CT-ASPECTS (ρ=0.511, P P P P P =0.275). The area for predicting independence at 3 months (192 patients) was 0.621 (0.564 to 0.674) by CT and 0.639 (0.580 to 0.694) by DWI ( P =0.535). Conclusions— For patients with hyperacute stroke, DWI-ASPECTS scored approximately 1 point lower than CT-ASPECTS. Both CT-ASPECTS and DWI-ASPECTS were useful predictors of symptomatic intracerebral hemorrhage and independence at 3 months after recombinant tissue-type plasminogen activator.

The high affinity of KIF5 for microtubules rich in GTP-tubulin results in polarized motor protein accumulation at axonal tips in neurons and may underlie polarized vesicle transport., Polarized transport in neurons is fundamental for the formation of neuronal circuitry. A motor domain–containing truncated KIF5 (a kinesin-1) recognizes axonal microtubules, which are enriched in EB1 binding sites, and selectively accumulates at the tips of axons. However, it remains unknown what cue KIF5 recognizes to result in this selective accumulation. We found that axonal microtubules were preferentially stained by the anti–GTP-tubulin antibody hMB11. Super-resolution microscopy combined with EM immunocytochemistry revealed that hMB11 was localized at KIF5 attachment sites. In addition, EB1, which binds preferentially to guanylyl-methylene-diphosphate (GMPCPP) microtubules in vitro, recognized hMB11 binding sites on axonal microtubules. Further, expression of hMB11 antibody in neurons disrupted the selective accumulation of truncated KIF5 in the axon tips. In vitro studies revealed approximately threefold stronger binding of KIF5 motor head to GMPCPP microtubules than to GDP microtubules. Collectively, these data suggest that the abundance of GTP-tubulin in axonal microtubules may underlie selective KIF5 localization and polarized axonal vesicular transport.

Purpose The purpose of this study was to evaluate the influences of volatile organic compounds (VOCs) emissions on hazardousness and photochemical reactivity and to propose efficient VOCs abatement strategies. Methods The atmospheric concentrations of 101 components of VOCs were measured at six sites which comprehend four urban areas, a roadside area, and an industrial area in Hyogo Prefecture. VOCs influence on hazardousness and photochemical reactivity were evaluated using VOCs measured data and the index on the health effect evaluation and ozone formation potential. The substances that require emissions reduction were selected from the evaluation results. The state and characteristics of environmental pollution were considered from the concentration trends of the selected substances. Results In industrial area, n-hexadecane, styrene, vinyl chloride monomer, and 1,2-dichloroethane showed a high concentration. In roadside area, n-hexane, n-undecane, n-dodecane, tetrachloroethylene, formaldehyde, acetaldehyde, and 1-butanol showed a high concentration. The excess cancer incidences for formaldehyde exceeded 10−5 of the level of concern for carcinogenic effect at all sites. Toluene had a high percentage of ozone production. The interannual and seasonal trends of toluene concentrations were different at a regional level and the formaldehyde concentrations in summer were significantly higher than those in winter at the urban sites. Conclusions The results show the need to prepare the emission reduction plan for the major sources such as vehicle exhaust, solvent use, and industrial processes to diminish the concentration of toluene that contributes significantly to the formation of photochemical oxidant.

Purpose: We tested the hypothesis that patients with carotid pseudo-occlusion (PO) have a different prognosis from those with carotid artery stenosis (CS) without PO. Materials and Methods: 500 patients were examined for CS by cerebral angiography; those with severe CS ≧70% (CS group) or with PO (PO group) were enrolled in this study. The primary endpoint was defined as the combined endpoint of the occurrence of stroke, myocardial infarction, or death. Patients without any events were censored at 60 months. We followed patients for the occurrence and date of primary endpoints and compared clinical characteristics and outcomes between the PO group and the CS group. Results: We enrolled 337 patients (281 men, 56 women, mean age: 70.4 years, mean follow-up period: 32.0 months), of whom 303 (89.9%) were allocated to the CS group while 34 (10.1%) were allocated to the PO group. The rate of diabetes mellitus in the PO group (55.9%) tended to be higher than in the CS group (39.9%). According to Kaplan-Meier analysis, the PO group suffered from the primary outcome more frequently than the CS group. The occurrence of the primary outcome was also associated with older age, peripheral arterial disease and a history of myocardial infarction. Multivariate analysis indicated that patients in the PO group had a significantly poorer outcome compared with those in the CS group (p = 0.013). Conclusion: Patients in the PO group more frequently had neurological and cardiac events or died compared with those in the CS group.

脳卒中急性期病院におけるTIA入院例のリスクと転帰との関連を明らかにする目的で，発症48時間以内のTIA入院例連続160例を解析した．TIAの定義は24時間以内の神経症状消失かつ画像上脳梗塞巣が認められないものとし，発症後90日以内の脳梗塞発症率およびリスク因子と転帰の関連をABCD2スコアで検討した．脳梗塞発症を8例(5%)に認め(全例7日以内の発症，中央値2.5日)，50%はラクナ梗塞であった．脳梗塞発症群で入院時血圧が有意に高かった．ABCD2スコアの各項目(年齢≥60 歳，血圧≥140/90 mmHg，臨床症候，症状持続時間，糖尿病)単独では有意な関連は認めないが，脳梗塞発症群のABCD2スコア中央値は5.5(非発症群中央値4，p=0.065)と高い傾向にあった．また，ABCD2スコア以外の要素では，心房細動合併例と主幹動脈病変合併例ではそれぞれ有意差を認めなかったが，両者の合併例では脳梗塞発症を高率(25%)に認めた．TIAではABCD2スコア高値に加えて心房細動と主幹動脈合併例が急性期脳梗塞発症と関連すると考えられた．

Background: To examine the therapeutic effect of intravenous recombinant tissue plasminogen activator (rt-PA) therapy for stroke patients receiving maintenance hemodialysis (HD). Methods: Of 600 stroke patients receiving intravenous rt-PA using 0.6 mg/kg alteplase who were enrolled in a multicenter observational study in Japan, 4 patients (3 men, 64–77 years old) on maintenance HD were studied. Results: The primary kidney disease requiring HD was glomerulonephritis in 2 patients, diabetic nephropathy in 1, and undetermined in 1. The duration of HD ranged between 1.2 and 28 years. Three patients developed stroke on the day of HD, including 1 during HD and another just after HD. All patients had stroke in the carotid arterial territory. Pretreatment NIH Stroke Scale scores ranged between 4 and 20, and decreased by 2–5 points at 7 days. One patient needed intravenous antihypertensive therapy before rt-PA; he developed an ectopic cortical hematoma and intraventricular hemorrhage after rt-PA. The other 3 did not develop hemorrhagic complications. The modified Rankin Scale score at 3 months was 0 in 1 patient, 2 in 2 patients, and 4 in 1 patient. Conclusions: rt-PA therapy for stroke patients receiving maintenance HD might improve the stroke outcome. Ectopic hematoma was a unique complication in our case series.

Purpose This study was designed to determine whether, among Japanese patients receiving medical treatment for carotid stenosis, symptomatic carotid stenosis was more strongly associated with subsequent neurological events than asymptomatic carotid stenosis. Methods We consecutively registered Japanese patients with carotid stenosis of 50% or more as evaluated by digital subtraction angiography who were treated medically. We reviewed medical records regarding previous neurological events as well as other stroke risk factors and underlying diseases at admission. We monitored the occurrence and date of stroke and death after the first evaluation. We also attempted to obtain information from patients or their family members by means of a questionnaire or telephone survey. Results Among 67 patients with carotid stenosis of 50% or more who were treated medically, follow-up was completed in 62 subjects (56 men, 6 women; median age, 72 years; mean follow-up period, 37.3 months). The number of patients with subsequent stroke with symptomatic carotid stenosis was five, while that with asymptomatic stenosis was four. A significantly higher rate of subsequent stroke was observed in patients with symptomatic carotid stenosis compared with those with asymptomatic stenosis (p=0.012). Cox proportional hazards model indicated that symptomatic carotid stenosis was significantly correlated with future neurologic events (p=0.019). Conclusion In a Japanese population with carotid stenosis treated medically, symptomatic carotid stenosis is associated with future stroke more frequently than asymptomatic carotid stenosis.

Background:Development of retrograde blood flow may be observed in the vertebral artery and is associated with progressive ipsilateral proximal subclavian or innominate artery stenosis. The subclavian steal phenomenon is more prevalent in the left subclavian artery (LSA). The purpose of this study was to analyze the correlation between the degree of LSA stenosis and pulse Doppler waveforms of the left vertebral artery (LVA). Methods:A retrospective analysis of LVA waveforms was performed in 22 cases with LSA proximal stenosis before the origin of the LVA in conventional angiograms. The degree of LSA stenosis was classified into 5 groups (Results:A statistically significant correlation (R2 = 0.646, p < 0.0001) was found between the degree of LSA stenosis and the LVA waveform. Conclusions:The pattern analysis of LVA pulse Doppler waveforms seems to be useful in determining the degree of LSA stenosis.