Decreased Estimated Glomerular Filtration Rate and Proteinuria and Long-Term Outcomes After Ischemic Stroke: A Longitudinal Observational Cohort Study.

BACKGROUND: It remains unclear how chronic kidney disease and its underlying pathological conditions, kidney dysfunction, and kidney damage, are associated with cardiovascular outcomes. This study aimed to determine whether kidney dysfunction (ie, decreased estimated glomerular filtration rate), kidney damage (ie, proteinuria), or both are associated with the long-term outcomes after ischemic stroke. METHODS: A total of 12 576 patients (mean age, 73.0±12.6 years; 41.3% women) with ischemic stroke who were registered in a hospital-based multicenter registry, Fukuoka Stroke Registry, between June 2007 and September 2019, were prospectively followed up after stroke onset. Kidney function was assessed by estimated glomerular filtration rate and categorized into G1: ≥60 mL/(min·1.73 m2), G2: 45-59 mL/(min·1.73 m2), and G3: <45 mL/(min·1.73 m2). Kidney damage was evaluated by proteinuria using a urine dipstick test and classified into P1: -, P2: ±/1+, and P3: ≥2+. Hazard ratios and 95% CI for events of interest were estimated by a Cox proportional hazards model. Long-term outcomes included recurrence of stroke and all-cause death. RESULTS: During the median follow-up of 4.3 years (interquartile range, 2.1-7.3 years), 2481 patients had recurrent stroke (48.0/1000 patient-years) and 4032 patients died (67.3/1000 patient-years). Chronic kidney disease was independently associated with increased risks of stroke recurrence and all-cause death even after adjustment for multiple confounding factors, including traditional cardiovascular risk factors. Both estimated glomerular filtration rate and proteinuria were independently associated with increased risks of stroke recurrence (multivariable-adjusted hazard ratio [95% CI], G3: 1.22 [1.09-1.37] versus G1, P3: 1.25 [1.07-1.46] versus P1) and death (G3: 1.45 [1.33-1.57] versus G1, P3: 1.62 [1.45-1.81] versus P1). In subgroup analyses, effect modifications were found in the association of proteinuria with death by age and stroke subtype. CONCLUSIONS: Kidney dysfunction and kidney damage were independently, but differently, associated with increased risks of recurrent stroke and all-cause death.

Prospective study of adoptive activated αßT lymphocyte immunotherapy for refractory cancers: development and validation of a response scoring system.

BACKGROUND AIMS: This prospective clinical study aimed to determine the efficacy and prognostic factors of adoptive activated αßT lymphocyte immunotherapy for various refractory cancers. The primary endpoint was overall survival (OS), and the secondary endpoint was radiological response. METHODS: The authors treated 96 patients. Activated αßT lymphocytes were infused every 2 weeks for a total of six times. Prognostic factors were identified by analyzing clinical and laboratory data obtained before therapy. RESULTS: Median survival time (MST) was 150 days (95% confidence interval, 105-191), and approximately 20% of patients achieved disease control (complete response + partial response + stable disease). According to the multivariate Cox proportional hazards model with Akaike information criterion-best subset selection, sex, concurrent therapy, neutrophil/lymphocyte ratio, albumin, lactate dehydrogenase, CD4:CD8 ratio and T helper (Th)1:Th2 ratio were strong prognostic factors. Using parameter estimates of the Cox analysis, the authors developed a response scoring system. The authors then determined the threshold of the response score between responders and non-responders. This threshold was able to significantly differentiate OS of responders from that of non-responders. MST of responders was longer than that of non-responders (317.5 days versus 74 days). The validity of this response scoring system was then confirmed by internal validation. CONCLUSIONS: Adoptive activated αßT lymphocyte immunotherapy has clinical efficacy in certain patients. The authors' scoring system is the first prognostic model reported for this therapy, and it is useful for selecting patients who might obtain a better prognosis through this modality.

Sex Differences in Long-Term Functional Decline after Ischemic Stroke: A Longitudinal Observational Study from the Fukuoka Stroke Registry.

INTRODUCTION: Data on sex differences in poststroke functional status for a period longer than 1 year based on large cohorts are sparse. This study aimed to determine whether there are sex differences in long-term functional decline after ischemic stroke. METHODS: We tracked functional status for 5 years among 3-month survivors of acute ischemic stroke and compared outcomes between women and men using a large-scale hospital-based stroke registry in Fukuoka, Japan. Functional status was assessed using the modified Rankin Scale (mRS). Functional dependency was defined as an mRS score of 3, 4, or 5. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals of outcomes after adjusting for possible confounders. RESULTS: A total of 8,446 patients (71.9 ± 12.5 years, 3,377 (40.0%) female patients) were enrolled in this study. Female sex was associated with a higher risk of functional dependency at 5 years poststroke even when adjusting for age, 3-month mRS score, and other confounding factors (multivariable-adjusted OR vs. men, 1.56 [95% confidence interval, 1.26-1.93]). This significant association of female sex with higher dependency at 5 years was also found among patients who were independent at 3 months poststroke. Subgroup analysis showed that increased risk of functional dependency in female patients was more marked in patients aged ≥75 years than in those aged <75 years (p for heterogeneity = 0.02). Conversely, female sex was associated with a lower risk of death. No sex difference was observed in stroke recurrence during 5 years poststroke. DISCUSSION/CONCLUSION: This longitudinal observational study suggests that female sex was independently associated with an increased risk of functional decline in the chronic phase of stroke, especially in older patients. There was no sex difference in 5-year stroke recurrence, and thus, other factors might be involved in more significant deterioration of functional status in female survivors of ischemic stroke. Further studies are needed to elucidate underlying causes of sex differences in long-term functional decline after stroke.

Day-by-Day Blood Pressure Variability in the Subacute Stage of Ischemic Stroke and Long-Term Recurrence.

BACKGROUND AND PURPOSE: This study aimed to determine whether variability of day-by-day blood pressure (BP) during the subacute stage of acute ischemic stroke is predictive of long-term stroke recurrence. METHODS: We analyzed 7665 patients (mean±SD age: 72.9±13.1 years; women: 42.4%) hospitalized for first-ever ischemic stroke in 7 stroke centers in Fukuoka, Japan, from June 2007 to November 2018. BP was measured daily during the subacute stage (4-10 days after onset). Its mean and coefficient of variation (CV) values were calculated and divided into 4 groups according to the quartiles of these BP parameters. Patients were prospectively followed up for recurrent stroke or all-cause death. The cumulative event rate was calculated with the Kaplan-Meier method. We estimated the hazard ratios and 95% confidence intervals of the events of interest after adjusting for potential confounders and mean BP values using Cox proportional hazards models. The Fine-Gray model was also used to account for the competing risk of death. RESULTS: With a mean (±SD) follow-up duration of 3.9±3.2 years, the rates of recurrent stroke and all-cause death were 3.9 and 9.9 per 100 patient-years, respectively. The cumulative event rates of recurrent stroke and all-cause death increased with increasing CVs of systolic BP and diastolic BP. The systolic BP CV was significantly associated with an increased risk of recurrent stroke after adjusting for multiple confounders and mean BP (hazard ratio [95% CI] for fourth quartile versus first quartile, 1.26 [1.05-1.50]); the risk of recurrent stroke also increased with an increasing systolic BP CV for nonfatal strokes (1.26 [1.05-1.51]) and when death was regarded as a competing risk (1.21 [1.02-1.45]). Similar associations were observed for the diastolic BP CV. CONCLUSIONS: Day-by-day variability of BP during the subacute stage of acute ischemic stroke was associated with an increased long-term risk of recurrent stroke.

Associations Between Adherence to Evidence-Based, Stroke Quality Indicators and Outcomes of Acute Reperfusion Therapy.

BACKGROUND: Quality indicators (QIs) are an accepted tool for measuring a hospital's performance in routine care. We examined national trends in adherence to the QIs developed by the Close The Gap-Stroke program by combining data from the health insurance claims database and electronic medical records, and the association between adherence to these QIs and early outcomes in patients with acute ischemic stroke in Japan. METHODS: In the present study, patients with acute ischemic stroke who received acute reperfusion therapy in 351 Close The Gap-Stroke-participating hospitals were analyzed retrospectively. The primary outcomes were changes in trends for adherence to the defined QIs by difference-in-difference analysis and the effects of adherence to distinct QIs on in-hospital outcomes at the individual level. A mixed logistic regression model was adjusted for patient and hospital characteristics (eg, age, sex, number of beds) and hospital units as random effects. RESULTS: Between 2013 and 2017, 21 651 patients (median age, 77 years; 43.0% female) were assessed. Of the 25 defined measures, marked and sustainable improvement in the adherence rates was observed for door-to-needle time, door-to-puncture time, proper use of endovascular thrombectomy, and successful revascularization. The in-hospital mortality rate was 11.6%. Adherence to 14 QIs lowered the odds of in-hospital mortality (odds ratio [95% CI], door-to-needle <60 min, 0.80 [0.69-0.93], door-to-puncture <90 min, 0.80 [0.67-0.96], successful revascularization, 0.40 [0.34-0.48]), and adherence to 11 QIs increased the odds of functional independence (modified Rankin Scale score 0-2) at discharge. CONCLUSIONS: We demonstrated national marked and sustainable improvement in adherence to door-to-needle time, door-to-puncture time, and successful reperfusion from 2013 to 2017 in Japan in patients with acute ischemic stroke. Adhering to the key QIs substantially affected in-hospital outcomes, underlining the importance of monitoring the quality of care using evidence-based QIs and the nationwide Close The Gap-Stroke program.

ß-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke.

Background and Purpose: Little is known about how ß-cell dysfunction affects clinical outcome after ischemic stroke. We examined whether ß-cell function is associated with clinical outcome after acute ischemic stroke and if so, whether insulin resistance influences this association in a prospective study of patients with acute stroke. Methods: A total of 3590 nondiabetic patients with acute ischemic stroke (mean age, 71 years) were followed up for 3 months. ß-Cell function was assessed using the homeostasis model assessment for ß-cell function (HOMA-ß). Study outcomes were poor functional outcome (modified Rankin Scale score, 3­6) and stroke recurrence at 3 months after stroke onset and neurological deterioration (≥2-point increase in the National Institutes of Health Stroke Scale score) at discharge. Logistic regression analysis was used to evaluate the association between quintile levels of serum HOMA-ß and clinical outcomes. Results: The age- and sex-adjusted odds ratios for poor functional outcome and neurological deterioration increased significantly with decreasing HOMA-ß levels (P for trend, <0.001 and 0.001, respectively). These associations became more prominent after adjustment for HOMA-insulin resistance and were substantially unchanged even after further adjustment for other confounders, namely, body mass index, dyslipidemia, hypertension, estimated glomerular filtration rate, stroke subtype, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy (odds ratio [95% CI] for the first versus fifth quintile of HOMA-ß, 3.30 [2.15­5.08] for poor functional outcome and 10.69 [4.99­22.90] for neurological deterioration). Such associations were not observed for stroke recurrence. In stratified analysis for the combination of HOMA-ß and HOMA-insulin resistance levels, lower HOMA-ß and higher HOMA-insulin resistance levels were independently associated with increased risks of poor functional outcome and neurological deterioration. Conclusions: Our findings suggest that ß-cell dysfunction is significantly associated with poor short-term clinical outcome independently of insulin resistance in nondiabetic patients with acute ischemic stroke.

Pre-Stroke Cholinesterase Inhibitor Treatment Is Beneficially Associated with Functional Outcome in Patients with Acute Ischemic Stroke and Pre-Stroke Dementia: The Fukuoka Stroke Registry.

INTRODUCTION: Pre-stroke dementia is significantly associated with poor stroke outcome. Cholinesterase inhibitors (ChEIs) might reduce the risk of stroke in patients with dementia. However, the association between pre-stroke ChEI treatment and stroke outcome remains unresolved. Therefore, we aimed to determine this association in patients with acute ischemic stroke and pre-stroke dementia. METHODS: We enrolled 805 patients with pre-stroke dementia among 13,167 with ischemic stroke within 7 days of onset who were registered in the Fukuoka Stroke Registry between June 2007 and May 2019 and were independent in basic activities of daily living (ADLs) before admission. Primary and secondary study outcomes were poor functional outcome (modified Rankin Scale [mRS] score: 3-6) at 3 months after stroke onset and neurological deterioration (≥2-point increase in the NIH Stroke Scale [NIHSS] during hospitalization), respectively. Logistic regression analysis was used to evaluate associations between pre-stroke ChEI treatment and study outcomes. To improve covariate imbalance, we further conducted a propensity score (PS)-matched cohort study. RESULTS: Among the participants, 212 (26.3%) had pre-stroke ChEI treatment. Treatment was negatively associated with poor functional outcome (odds ratio: 0.68 [95% confidence interval: 0.46-0.99]) and neurological deterioration (0.52 [0.31-0.88]) after adjusting for potential confounding factors. In the PS-matched cohort study, the same trends were observed between pre-stroke ChEI treatment and poor functional outcome (0.61 [0.40-0.92]) and between the treatment and neurological deterioration (0.47 [0.25-0.86]). CONCLUSIONS: Our findings suggest that pre-stroke ChEI treatment is associated with reduced risks for poor functional outcome and neurological deterioration after acute ischemic stroke in patients with pre-stroke dementia who are independent in basic ADLs before the onset of stroke.

Measuring Quality of Care for Ischemic Stroke Treated With Acute Reperfusion Therapy in Japan　- The Close The Gap-Stroke.

BACKGROUND: In Japan there is no consensus on how to efficiently measure quality indicators (QIs), defined as a standard of care, for acute ischemic stroke (AIS). Using information from a health insurance claims database and electronic medical records, we evaluated the feasibility and validity of measuring QIs for AIS patients who received intravenous recombinant tissue plasminogen activator (IV rt-PA) or endovascular therapy (EVT).Methods and Results:AIS patients receiving rt-PA or EVT between 2013 and 2015 were identified. We selected 17 AIS QI measures for primary stroke centers (PSCs) and 8 for comprehensive stroke centers (CSCs). Defined QIs were calculated for each hospital and then averaged. In total, the data of 8,206 patients (rt-PA 83.7%, EVT 34.9%) from 172 hospitals were obtained. Median National Institute of Health Stroke Scale score at admission was 14, and 37.7% of the patients were functionally independent at discharge. All target QIs were successfully measured with fewer missing values, and the accuracy of preset data was about 90%. Adherence rates were low (<50%) in 5 QI measures among PSCs, including door-to-needle time ≤1 h, and in 1 QI measure among CSCs (door-to-brain and vascular imaging time ≤30 min). CONCLUSIONS: Measuring QIs for AIS by this novel approach was feasible and reliable in the provision of a national benchmark.

Smoking Status and Functional Outcomes After Acute Ischemic Stroke.

Background and Purpose- Smoking is an established risk factor for stroke; however, it is uncertain whether prestroke smoking status affects clinical outcomes of acute ischemic stroke. This study aimed to elucidate the association between smoking status and functional outcomes after acute ischemic stroke. Methods- Using a multicenter hospital-based stroke registry in Japan, we investigated 10 825 patients with acute ischemic stroke hospitalized between July 2007 and December 2017 who had been independent before stroke onset. Smoking status was categorized into those who had never smoked (nonsmokers), former smokers, and current smokers. Clinical outcomes included poor functional outcome (modified Rankin Scale score ≥2) and functional dependence (modified Rankin Scale score 2-5) at 3 months. We adjusted for potential confounding factors using a logistic regression analysis. Results- The mean age of patients was 70.2±12.2 years, and 37.0% were women. There were 4396 (42.7%) nonsmokers, 3328 (32.4%) former smokers, and 2561 (24.9%) current smokers. The odds ratio (95% CI) for poor functional outcome after adjusting for confounders increased in current smokers (1.29 [1.11-1.49] versus nonsmokers) but not in former smokers (1.05 [0.92-1.21] versus nonsmokers). However, among the former smokers, the odds ratio of poor functional outcome was higher in those who quit smoking within 2 years of stroke onset (1.75 [1.15-2.66] versus nonsmokers). The risk of poor functional outcome tended to increase as the number of daily cigarettes increased in current smokers (P for trend=0.002). All these associations were maintained for functional dependence. Conclusions- Current and recent smoking is associated with an increased risk of unfavorable functional outcomes at 3 months after acute ischemic stroke. Registration- URL: http://www.fukuoka-stroke.net/english/index.html. Unique identifier: 000000800.

Anticoagulation and Risk of Stroke Recurrence in Patients with Embolic Stroke of Undetermined Source Having No Potential Source of Embolism.

BACKGROUND: This study aimed to determine whether use of oral anticoagulants (OACs) was associated with a reduced risk of recurrent stroke compared with use of antiplatelets (APs) in patients with embolic stroke of undetermined source (ESUS) having no potential source of embolism. METHODS: Of 8,790 patients with acute ischemic stroke registered at 7 centers in the Fukuoka Stroke Registry from June 2007 to May 2017, we included 681 patients (mean age 69.7 [SD 14.1] years, 48.3% men) who experienced ESUS without a potential source of embolism and received OAC alone or AP alone. We estimated hazard ratios (HRs) and 95% confidential intervals (CIs) of recurrent ischemic stroke or any stroke after discharge using a Cox proportional hazards model and Fine and Gray model. RESULTS: During a mean follow-up of 3.4 (SD 1.7) years, event rates of recurrent ischemic stroke were 4.4 per 100 person-years in 489 patients treated with AP and 2.0 per 100 person-years in 192 patients treated with OAC. OAC use was associated with a reduced risk of recurrent ischemic stroke, even after adjusting for potential confounding factors (multivariable-adjusted HR [95% CI], 0.42 [0.23-0.80]) and when additionally considering death as a competing risk (0.45 [0.24-0.85]). The reduced risk of recurrent ischemic stroke was still observed in patients treated with OAC (0.32 [0.15-0.67]) in reference to propensity score-matched patients treated with AP. These associations were maintained for all types of stroke, including ischemic and hemorrhagic stroke. CONCLUSIONS: This nonrandomized observational study suggests that anticoagulation therapy might be associated with a reduced risk of recurrent stroke compared with antiplatelet therapy in patients with ESUS in whom no potential source of embolism was identified. Further study should be performed in consideration of a potential source of embolism even in patients with ESUS.

Development of Quality Indicators of Stroke Centers and Feasibility of Their Measurement Using a Nationwide Insurance Claims Database in Japan　­ J-ASPECT Study ­

BACKGROUND: We aimed to develop quality indicators (QIs) related to primary and comprehensive stroke care and examine the feasibility of their measurement using the existing Diagnosis Procedure Combination (DPC) database. METHODS AND RESULTS: We conducted a systematic review of domestic and international studies using the modified Delphi method. Feasibility of measuring the QI adherence rates was examined using a DPC-based nationwide stroke database (396,350 patients admitted during 2013-2015 to 558 hospitals participating in the J-ASPECT study). Associations between adherence rates of these QIs and hospital characteristics were analyzed using hierarchical logistic regression analysis. We developed 17 and 12 measures as QIs for primary and comprehensive stroke care, respectively. We found that measurement of the adherence rates of the developed QIs using the existing DPC database was feasible for the 6 QIs (primary stroke care: early and discharge antithrombotic drugs, mean 54.6% and 58.7%; discharge anticoagulation for atrial fibrillation, 64.4%; discharge antihypertensive agents, 51.7%; comprehensive stroke care: fasudil hydrochloride or ozagrel sodium for vasospasm prevention, 86.9%; death complications of diagnostic neuroangiography, 0.4%). We found wide inter-hospital variation in QI adherence rates based on hospital characteristics. CONCLUSIONS: We developed QIs for primary and comprehensive stroke care. The DPC database may allow efficient data collection at low cost and decreased burden to evaluate the developed QIs.

Association Between Onset-to-Door Time and Clinical Outcomes After Ischemic Stroke.

BACKGROUND AND PURPOSE: The role of early hospital arrival in improving poststroke clinical outcomes in patients without reperfusion treatment remains unclear. This study aimed to determine whether early hospital arrival was associated with favorable outcomes in patients without reperfusion treatment or with minor stroke. METHODS: This multicenter, hospital-based study included 6780 consecutive patients (aged, 69.9±12.2 years; 63.9% men) with ischemic stroke who were prospectively registered in Fukuoka, Japan, between July 2007 and December 2014. Onset-to-door time was categorized as T0-1, ≤1 hour; T1-2, >1 and ≤2 hours; T2-3, >2 and ≤3 hours; T3-6, >3 and ≤6 hours; T6-12, >6 and ≤12 hours; T12-24, >12 and ≤24 hours; and T24-, >24 hours. The main outcomes were neurological improvement (decrease in National Institutes of Health Stroke Scale score of ≥4 during hospitalization or 0 at discharge) and good functional outcome (3-month modified Rankin Scale score of 0-1). Associations between onset-to-door time and main outcomes were evaluated after adjusting for potential confounders using logistic regression analysis. RESULTS: Odds ratios (95% confidence intervals) increased significantly with shorter onset-to-door times within 6 hours, for both neurological improvement (T0-1, 2.79 [2.28-3.42]; T1-2, 2.49 [2.02-3.07]; T2-3, 1.52 [1.21-1.92]; T3-6, 1.72 [1.44-2.05], with reference to T24-) and good functional outcome (T0-1, 2.68 [2.05-3.49], T1-2 2.10 [1.60-2.77], T2-3 1.53 [1.15-2.03], T3-6 1.31 [1.05-1.64], with reference to T24-), even after adjusting for potential confounding factors including reperfusion treatment and basal National Institutes of Health Stroke Scale. These associations were maintained in 6216 patients without reperfusion treatment and in 4793 patients with minor stroke (National Institutes of Health Stroke Scale ≤4 on hospital arrival). CONCLUSIONS: Early hospital arrival within 6 hours after stroke onset is associated with favorable outcomes after ischemic stroke, regardless of reperfusion treatment or stroke severity.

Adverse Influence of Pre-Stroke Dementia on Short-Term Functional Outcomes in Patients with Acute Ischemic Stroke: The Fukuoka Stroke Registry.

BACKGROUND: Dementia and stroke are major causes of disability in the elderly. However, the association between pre-stroke dementia and functional outcome after stoke remains unresolved. We aimed to determine this association in patients with acute ischemic stroke. METHODS: Among patients registered in the Fukuoka Stroke Registry from June 2007 to May 2015, 4,237 patients with ischemic stroke within 24 h of onset, who were functionally independent before the onset, were enrolled in this study. Pre-stroke dementia was defined as any type of dementia that was present prior to the index stroke. Primary and secondary study outcomes were poor functional outcome (modified Rankin Scale 3-6) at 3 months after the stroke onset and neurological deterioration (≥2-point increases on the National Institutes of Health Stroke Scale score during hospitalization), respectively. For propensity score (PS)-matched cohort study to control confounding variables for pre-stroke dementia, 318 pairs of patients with and without pre-stroke dementia were also selected on the basis of 1:1 matching. Multivariable logistic regression models and conditional logistic regression analysis were used to quantify associations between pre-stroke dementia and study outcomes. RESULTS: Of all 4,237 participants, 347 (8.2%) had pre-stroke dementia. The frequencies of neurological deterioration and poor functional outcome were significantly higher in patients with pre-stroke dementia than in those without pre-stroke dementia (neurological deterioration, 16.1 vs. 7.1%, p < 0.01; poor functional outcome, 63.7 vs. 27.1%, p < 0.01). Multivariable analysis showed that pre-stroke dementia was significantly associated with neurological deterioration (OR 1.67; 95% CI 1.14-2.41; p < 0.01) and poor functional outcome (OR 2.91; 95% CI 2.17-3.91; p < 0.01). In the PS-matched cohort study, the same trends were observed between the pre-stroke dementia and neurological deterioration (OR 2.60; 95% CI 1.17-5.78; p < 0.01) and between the dementia and poor functional outcome (OR 3.62; 95% CI 1.89-6.95; p < 0.01). CONCLUSIONS: Pre-stroke dementia was significantly associated with higher risks for poor functional outcome at 3 months after stroke onset as well as for neurological deterioration during hospitalization in patients with acute ischemic stroke.

Isolated and repeated stroke-like episodes in a middle-aged man with a mitochondrial ND3 T10158C mutation: a case report.

BACKGROUND: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, is the most common phenotype of mitochondrial disease. It often develops in childhood or adolescence, usually before the age of 40, in a maternally-inherited manner. Mutations in mitochondrial DNA (mtDNA) are frequently responsible for MELAS. CASE PRESENTATION: A 55-year-old man, who had no family or past history of mitochondrial disorders, suddenly developed bilateral visual field constriction and repeated stroke-like episodes. He ultimately presented with cortical blindness, recurrent epilepsy and severe cognitive impairment approximately 6 months after the first episode. Genetic analysis of biopsied biceps brachii muscle, but not of peripheral white blood cells, revealed a T10158C mutation in the mtDNA-encoded gene of NADH dehydrogenase subunit 3 (ND3), which has previously been thought to be associated with severe or fatal mitochondrial disorders that develop during the neonatal period or in infancy. CONCLUSION: A T10158C mutation in the ND3 gene can cause atypical adult-onset stroke-like episodes in a sporadic manner.

Short-Term Exposure to Fine Particulate Matter and Risk of Ischemic Stroke.

BACKGROUND AND PURPOSE: There is a strong association between ambient concentrations of particulate matter (PM) and cardiovascular disease. However, it remains unclear whether acute exposure to fine PM (PM2.5) triggers ischemic stroke events and whether the timing of exposure is associated with stroke risk. We, therefore, examined the association between ambient PM2.5 and occurrence of ischemic stroke. METHODS: We analyzed data for 6885 ischemic stroke patients from a multicenter hospital-based stroke registry in Japan who were previously independent and hospitalized within 24 hours of stroke onset. Time of symptom onset was confirmed, and the association between PM (suspended PM and PM2.5) and occurrence of ischemic stroke was analyzed by time-stratified case-crossover analysis. RESULTS: Ambient PM2.5 and suspended PM at lag days 0 to 1 were associated with subsequent occurrence of ischemic stroke (ambient temperature-adjusted odds ratio [95% confidence interval] per 10 µg/m3: suspended PM, 1.02 [1.00-1.05]; PM2.5, 1.03 [1.00-1.06]). In contrast, ambient suspended PM and PM2.5 at lag days 2 to 3 or 4 to 6 showed no significant association with stroke occurrence. The association between PM2.5 at lag days 0 to 1 and ischemic stroke was maintained after adjusting for other air pollutants (nitrogen dioxide, photochemical oxidants, or sulfur dioxide) or influenza epidemics and was evident in the cold season. CONCLUSIONS: These findings suggest that short-term exposure to PM2.5 within 1 day before onset is associated with the subsequent occurrence of ischemic stroke.

Causes of Ischemic Stroke in Patients with Non-Valvular Atrial Fibrillation.

BACKGROUND: Oral anticoagulants (OACs) reduce the incidence of embolic events associated with non-valvular atrial fibrillation (NVAF); however, ischemic stroke can still occur in such patients. Although there are various causes of ischemic stroke in patients with NVAF, their medication status at onset has scarcely been studied. This retrospective study aimed to determine the underlying causes of ischemic stroke in patients with NVAF in relation to pre-stroke anticoagulation. METHODS: Among Japanese patients with acute ischemic stroke enrolled in the Fukuoka Stroke Registry from June 2007 to May 2013, 1,302 patients with NVAF who had been hospitalized within 24 h of onset were included in this study, and their backgrounds, pre-stroke use of OACs and prothrombin time-international normalized ratio (PT-INR) on admission were investigated. Strokes were regarded as being non-cardioembolic (CE) type when causes other than NVAF had been identified. The sub-therapeutic range (TR) for warfarin was defined according to Japanese guidelines for pharmacotherapy of atrial fibrillation. RESULTS: Atrial fibrillation had been diagnosed prior to onset of stroke in 704 of 1,302 patients (54%). However, it had not been detected before or on admission, but identified later during hospitalization in 270 patients (21%). Of the patients who had atrial fibrillation on admission but had not been diagnosed as having it, 108 (8%) had not received any medication before onset of stroke and 220 (17%) had received medications other than OACs. OACs had been administered to 415 (59%) of the patients with known atrial fibrillation. The proportion of pre-stroke CHADS2 or CHA2DS2-VASc scores ≥1 ranged from 93 to 99% depending on whether atrial fibrillation had been diagnosed or anticoagulation therapy administered before stroke onset. The PT-INR was in the sub-TR on admission in 283 of 399 patients (71%) receiving warfarin. Male sex, smoking and previous stroke were more prevalent in patients with values within or over the TR of PT-INR than in those in the sub-TR. Non-CE stroke was more prevalent in patients with values above the lower therapeutic limit of the recommended PT-INR than in those in the sub-TR (p < 0.001). The number of CE strokes was much smaller in patients with high admission PT-INR values; this was not observed for non-CE ischemic strokes (p < 0.001). CONCLUSIONS: In the clinical setting, under-diagnosis, underuse and sub-therapeutic doses of OACs are major causes of ischemic stroke in patients with NVAF. However, non-CE ischemic strokes may develop in patients receiving therapeutic doses of warfarin.

Influence of Statin Pretreatment on Initial Neurological Severity and Short-Term Functional Outcome in Acute Ischemic Stroke Patients: The Fukuoka Stroke Registry.

BACKGROUND: Statins have neuroprotective effects against ischemic stroke. However, associations between pre-stroke statin treatment and initial stroke severity and between the treatment and functional outcome remain controversial. This study aimed at determining these associations in ischemic stroke patients. METHODS: Among patients registered in the Fukuoka Stroke Registry from June 2007 to October 2014, 3,848 patients with ischemic stroke within 24 h of onset, who had been functionally independent before onset, were enrolled in this study. Ischemic stroke was classified as cardioembolic or non-cardioembolic infarction. Primary and secondary study outcomes were mild neurological symptoms defined as a National Institutes of Health Stroke Scale score of ≤4 on admission and favorable functional outcome defined as a modified Rankin Scale score of ≤2 at discharge, respectively. Multivariable logistic regression models were used to quantify associations between pre-stroke statin treatment and study outcomes. RESULTS: Of all 3,848 participants, 697 (18.1%) were taking statins prior to the stroke. The frequency of mild neurological symptoms was significantly higher in patients with pre-stroke statin treatment (64.1%) than in those without the treatment (58.3%, p < 0.01). Multivariable analysis showed that pre-stroke statin treatment was significantly associated with mild neurological symptoms (OR 1.31; 95% CI 1.04-1.65; p < 0.01). Sensitivity analysis in patients with dyslipidemia (n = 1,998) also showed the same trend between pre-stroke statin treatment and mild neurological symptoms (multivariable-adjusted OR 1.26; 95% CI 0.99-1.62; p = 0.06). In contrast, the frequency of favorable functional outcome was not different between patients with (67.0%) and without (65.3%) the treatment (p = 0.40). Multivariable analysis also showed no significant association between pre-stroke statin treatment and favorable functional outcome (OR 1.21; 95% CI 0.91-1.60; p = 0.19). Continuation of statin treatment, however, was significantly associated with favorable functional outcome among patients with pre-stroke statin treatment (multivariable-adjusted OR 2.17; 95% CI 1.16-4.00; p = 0.02). CONCLUSIONS: Pre-stroke statin treatment in ischemic stroke patients was significantly associated with mild neurological symptoms within 24 h of onset. Pre-stroke statin treatment per se did not significantly influence the short-term functional outcome; however, continuation of statin treatment during the acute stage of stroke seems to relate with favorable functional outcome for patients with pre-stroke statin treatment.

Sex differences in short-term outcomes after acute ischemic stroke: the fukuoka stroke registry.

BACKGROUND AND PURPOSE: Variable sex differences in clinical outcomes after stroke have been reported worldwide. This study aimed to elucidate whether sex is an independent risk factor of poor functional outcome after acute ischemic stroke. METHODS: Using the database of patients with acute stroke registered in the Fukuoka Stroke Registry in Japan from 1999 to 2013, 6236 previously independent patients with first-ever ischemic stroke who were admitted within 24 hours of onset were included in this study. Baseline characteristics were assessed on admission. Study outcomes included neurological improvement, neurological deterioration, and poor functional outcome (modified Rankin Scale score, 3-6 at discharge). Logistic regression analyses were performed to evaluate the association between sex and clinical outcomes. RESULTS: Overall, 2398 patients (38.5%) were women. Severe stroke (National Institutes of Health Stroke Scale score, ≥8) on admission was more prevalent in women than in men. The frequency of neurological improvement or deterioration during hospitalization was not different between the sexes. After adjusting for possible confounders, including age, stroke subtype and severity, risk factors, and poststroke treatments, it was found that female sex was independently associated with poor functional outcome at discharge (odds ratio, 1.30; 95% confidence interval, 1.08-1.57). There was heterogeneity of the association between sex and poor outcome according to age: women had higher risk of poor outcome than men among patients aged ≥70 years, but no clear sex difference was found in patients aged <70 years. CONCLUSIONS: Female sex was associated with the risk of poor functional outcome at discharge after acute ischemic stroke.

Nox4 is a major source of superoxide production in human brain pericytes.

BACKGROUND: Pericytes are multifunctional cells surrounding capillaries and postcapillary venules. In brain microvasculature, pericytes play a pivotal role under physiological and pathological conditions by producing reactive oxygen species (ROS). The aims of this study were to elucidate the source of ROS and its regulation in human brain pericytes. METHODS: The expression of Nox enzymes in the cells was evaluated using RT-PCR and western blot. Superoxide production was determined by superoxide dismutase-inhibitable chemiluminescence. Silencing of Nox4 was performed using RNAi, and cell proliferation was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. RESULTS: Nox4 was predominant among the Nox family in human brain pericytes. Membrane fractions of cells produced superoxide in the presence of NAD(P)H. Superoxide production was almost abolished with diphenileneiodonium, a Nox inhibitor; however, inhibitors of other possible superoxide-producing enzymes had no effect on NAD(P)H-dependent superoxide production. Pericytes expressed angiotensin II (Ang II) receptors, and Ang II upregulated Nox4 expression. Hypoxic conditions also increased the Nox4 expression. Silencing of Nox4 significantly reduced ROS production and attenuated cell proliferation. CONCLUSION: Our study showed that Nox4 is a major superoxide-producing enzyme and that its expression is regulated by Ang II and hypoxic stress in human brain pericytes. In addition, Nox4 may promote cell growth.

Impact of the 1425G/A polymorphism of PRKCH on the recurrence of ischemic stroke: Fukuoka Stroke Registry.

BACKGROUND: Epidemiologic studies have elucidated that the 1425G/A single-nucleotide polymorphism (rs2230500 single-nucleotide polymorphism) in exon 9 of the protein kinase C eta (PRKCH) gene is an independent risk factor for ischemic stroke: stroke incidence is significantly higher in the subjects with AA than those with AG or GG genotype. However, its impact on stroke recurrence remains unknown. The aim of the present study was to clarify whether the polymorphism is also a risk factor for recurrent stroke in patients with acute ischemic stroke. METHODS: We enrolled 2418 consecutive patients with acute and first-ever ischemic stroke and investigated the 1425G/A polymorphism of PRKCH. Patients were followed up for a median of 733 days. The association between the polymorphism and stroke recurrence was investigated using the Cox proportional hazard model. RESULTS: In the enrolled patients, the GG genotype was the most prevalent (63%), followed by AG (32%) and AA genotypes (5%). Recurrent stroke occurred in 302 patients during the follow-up period. Kaplan-Meier analyses revealed no difference in the rate of recurrent stroke after first-ever stroke among the 3 genotypes. The incidence of recurrent stroke was not significantly different in patients with AA (hazard ratio [HR] 1.02, 95% confidence interval .59-1.64, P=.94) or AG (HR .89, 95% confidence interval .69-1.14, P=.36) genotypes compared with those with the GG genotype after adjusting for multiple confounders. CONCLUSIONS: The 1425G/A polymorphism in PRKCH is not a significant predictor of stroke recurrence in patients with acute ischemic stroke during a 2-year follow-up period.