Yoshiaki Shiokawa

Middle cerebral artery occlusion: correlation of computed tomography and angiography with clinical outcome.

The clinical outcome of 40 cases with middle cerebral artery (MCA) occlusion was examined in relation to the site of occlusion and the findings on computed tomography (CT). Patients were treated conservatively without surgery. A few had decompressive craniotomy when necessary. Outcome in 7 (18%) was good, in 6 (15%) moderate, and in 15 (38%) severe; 12 (30%) died by the follow-up at 3 months. In cases with occlusion at the origin of the MCA, hypodensity on CT scan was usually localized to the basal ganglia, presumably because of collateral circulation through the anterior cerebral arteries; the outcome in these patients was not always favorable. Cases with occlusion of the trunk or branch vessels always showed marked CT hypodensity, and clinical outcome was poor. To assess quantitatively the extent of collateral circulation, the conduction time of contrast medium from the intracranial siphon (IC) to the insular portion of the MCA (M2) through the anterior cerebral arteries was calculated on serial carotid angiograms obtained within 24 hours after stroke onset. An IC-M2 time of 5 seconds was a critical indicator of whether extensive CT hypodensity would develop (the rule of 5 seconds). Furthermore, this method predicted the appearance and extent of infarction before CT revealed hypodensity. The significance of acute reconstructive surgery is also discussed.

Clinicopathological Study of Intracranial Fusiform and Dolichoectatic Aneurysms Insight on the Mechanism of Growth

BACKGROUND AND PURPOSE Intracranial fusiform aneurysms can be divided into 2 clinically different subtypes: acute dissecting aneurysms and chronic fusiform or dolichoectatic aneurysms. Of these 2, the natural history and growth mechanism of chronic fusiform aneurysms remains unknown. METHODS A consecutive series of 16 patients with chronic fusiform aneurysms was studied retrospectively to clarify patient clinical and neuroradiological features. Aneurysm tissues were obtained from 8 cases and were examined to identify histological features that could correspond to the radiological findings. RESULTS Four histological features were found: (1) fragmentation of internal elastic lamina (IEL), (2) neoangiogenesis within the thickened intima, (3) intramural hemorrhage (IMH) and thrombus formation, and (4) repetitive intramural hemorrhages from the newly formed vessels within thrombus. IEL fragmentation was found in all cases, which suggests that this change may be one of the earliest processes of aneurysm formation. MRI or CT detected IMH, and marked contrast enhancement of the inside of the aneurysm wall (CEI) on MRI corresponded well with intimal thickening. Eight of 9 symptomatic cases but none of 7 asymptomatic cases presented with both radiological features. CONCLUSIONS Data suggest that chronic fusiform aneurysms are progressive lesions that start with IEL fragmentation. Formation of IMH seems to be a critical event necessary for lesions to become symptomatic and progress, and this can be monitored on MRI. Knowledge of this possible mechanism of progression and corresponding MRI characteristics could help determine timing of surgical intervention.

Cloning and characterization of a human brain Na+-independent transporter for small neutral amino acids that transports d-serine with high affinity

We isolated a cDNA for the human homologue of system asc transporter Asc-1 from human brain. The encoded protein designated as hAsc-1 (human Asc-1) exhibited 91 % sequence identity to mouse Asc-1. Consistent with mouse Asc-1, hAsc-1 required 4F2 heavy chain for its functional expression in Xenopus oocytes. hAsc-1 exhibited the properties of amino acid transport system asc which transports small neutral amino acids in a Na(+)-independent manner. hAsc-1 transported D-serine at high affinity with a K(m) value of 22.8 microM. In brain, 2.0 kb mRNA was highly expressed. hAsc-1 gene was mapped to human chromosome 19, region q12-q13.1. Because of the high-affinity transport with the K(m) value close to the physiological concentration of D-serine, together with the high levels of expression in brain, hAsc-1 is proposed to play significant roles in the D-serine mobilization in brain.

Routine Use of Intravenous Low-Dose Recombinant Tissue Plasminogen Activator in Japanese Patients General Outcomes and Prognostic Factors From the SAMURAI Register

Background and Purpose— A retrospective, multicenter, observational study was conducted to document clinical outcomes and to identify outcome predictors in patients treated with low-dose intravenous recombinant tissue plasminogen activator (0.6 mg/kg alteplase), which was approved in Japan in 2005, within 3 hours of stroke onset. Methods— Consecutive patients with stroke treated with recombinant tissue plasminogen activator in 10 Japanese stroke centers were included. Results— A total of 600 patients (377 men, 72±12 years old) were studied. Median National Institutes of Health Stroke Scale scores decreased from 13 before recombinant tissue plasminogen activator to 8 at 24 hours later. Symptomatic intracerebral hemorrhage within 36 hours with a ≥1-point increase from the baseline National Institutes of Health Stroke Scale score developed in 23 patients (3.8%; 95% CI, 2.6% to 5.7%). At 3 months, 43 patients had died (7.2%; 5.4% to 9.5%), and 199 patients (33.2%; 29.5% to 37.0%) had a modified Rankin Scale score ≤1. Analysis of 399 patients with a premorbid modified Rankin Scale score ≤1 who met the criteria of the European license (≤80 years old, an initial National Institutes of Health Stroke Scale score ≤24, etc) showed that 40.6% (35.9% to 45.5%) had a 3-month modified Rankin Scale score ≤1. After multivariate adjustment, younger age, lower initial National Institutes of Health Stroke Scale score, absence of internal carotid artery occlusion, higher Alberta Stroke Program Early CT Score on CT, and absence of intravenous antihypertensives just before recombinant tissue plasminogen activator were independently related to a 3-month modified Rankin Scale score ≤1. Congestive heart failure and hyperglycemia were independently related to mortality. Conclusions— Three-month outcomes of patients receiving low-dose intravenous recombinant tissue plasminogen activator therapy in the present study were similar to those from postmarketing surveys using 0.9 mg/kg alteplase.

Reduced Estimated Glomerular Filtration Rate Is Associated with Stroke Outcome after Intravenous rt-PA: The Stroke Acute Management with Urgent Risk-Factor Assessment and Improvement (SAMURAI) rt-PA Registry

Background: The aim of this study was to determine whether renal dysfunction affects the outcome of stroke patients treated with recombinant tissue plasminogen activator (rt-PA). Methods: A retrospective, multicenter, observational study was conducted to identify the effects of underlying risk factors on intravenous rt-PA therapy using 0.6 mg/kg alteplase in 10 stroke centers in Japan. Consecutive stroke patients with a premorbid modified Rankin Scale (mRS) score ≤3 who received rt-PA were studied. Renal dysfunction was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 on admission. The outcome measures were any intracerebral hemorrhage (ICH) and symptomatic ICH within the initial 36 h; favorable (mRS 0–1) outcome, poor outcome (mRS 4–6) and mortality at 3 months. Results: Of a total of 578 patients (372 men; 64.4%, 71.4 ± 11.7 years old), renal dysfunction was present in 186 patients (32.2%). These patients were older and more commonly had hypertension, atrial fibrillation, prior ischemic heart disease and prior use of antithrombotic agents than patients without renal dysfunction. ICH (27.4 vs. 16.6%) and symptomatic ICH (8.1 vs. 2.6%) was more common in patients with renal dysfunction than in those without. At 3 months, patients with renal dysfunction had higher median mRS scores than those without (3 vs. 2). After multivariate adjustment for established outcome predictors, renal dysfunction was related to any ICH (odds ratio 1.81, 95% confidence interval 1.16–2.84), symptomatic ICH (2.64, 1.10–6.56), poor outcome (1.55, 1.01–2.38), and mortality (2.94, 1.38–6.42). Conclusions: Reduced eGFR was associated with early ICH and 3-month unfavorable outcome in stroke patients receiving intravenous rt-PA.

A Randomized Controlled Trial of Hydrocortisone Against Hyponatremia in Patients With Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— Hyponatremia is common after aneurysmal subarachnoid hemorrhage (SAH). It is caused by natriuresis, which induces osmotic diuresis and decreases blood volume, contributing to symptomatic cerebral vasospasm (SCV). Hypervolemic therapy to prevent SCV will not be efficient under this condition. We conducted a randomized controlled trial to assess the efficacy of hydrocortisone, which promotes sodium retention in the kidneys. Methods— Seventy-one SAH patients were randomly assigned after surgery to treatment with either a placebo (n=36) or 1200 mg/d of hydrocortisone (n=35) for 10 days and tapered thereafter. Both groups underwent hypervolemic therapy. The primary end point was the prevention of hyponatremia. Results— Hydrocortisone prevented excess sodium excretion (P=0.04) and urine volume (P=0.04). Hydrocortisone maintained the targeted serum sodium level throughout the 14 days (P<0.001), and achieved the management protocol with lower sodium and fluid (P=0.007) supplementation. Hydrocortisone kept the normal plasma osmolarity (P<0.001). SCV occurred in 9 patients (25%) in the placebo group and in 5 (14%) in the hydrocortisone group. No significant difference in the overall outcome was observed between the 2 groups. Conclusions— Hydrocortisone overcame excess natriuresis and prevented hyponatremia. Although there was no difference in outcome, hydrocortisone supported efficient hypervolemic therapy.

Pretreatment ASPECTS on DWI predicts 3-month outcome following rt-PA: SAMURAI rt-PA Registry

Objective: To evaluate whether the pretreatment Alberta Stroke Programme Early CT Score (ASPECTS) assessed using diffusion-weighted imaging (DWI) predicts stroke outcomes at 3 months following IV recombinant tissue-type plasminogen activator (rt-PA) therapy. Methods: Stroke patients treated with rt-PA (0.6 mg/kg alteplase) in 10 stroke centers in Japan were retrospectively studied. ASPECTS was assessed on DWI just prior to rt-PA injection. The primary outcome was a modified Rankin Scale (mRS) score of 0–2 at 3 months. Secondary outcomes included death at 3 months and symptomatic intracerebral hemorrhage (sICH) within 36 hours. Results: For the 477 patients (316 men, 71 ± 11 years old) enrolled, the median NIH Stroke Scale score was 13 (interquartile range 7–18.5), the median ASPECTS on DWI was 8 (7–10), and sICH was identified in 15 patients (3.1%). At 3 months, 245 (51.4%) had an mRS score of 0–2, and 29 (6.1%) had died. Patients with an mRS score of 0–2 had higher median ASPECTS (9; interquartile range 8–10) than other patients (8; 6–9, p < 0.001). Using receiver operating characteristic curves, the optimal cutoff ASPECTS to predict an mRS score of 0–2 was ≥7. On multivariate regression analysis, ASPECTS ≥7 was related to an mRS score of 0–2 (odds ratio 1.85; 95% confidence interval 1.07–3.24), ASPECTS ≤4 was related to death (3.61; 1.23–9.91), and ASPECTS ≤5 was related to sICH (4.74; 1.54–13.64). Conclusion: ASPECTS on DWI was independently predictive of functional and vital outcomes at 3 months, as well as sICH within 36 hours, following rt-PA therapy for stroke patients.

Systolic Blood Pressure After Intravenous Antihypertensive Treatment and Clinical Outcomes in Hyperacute Intracerebral Hemorrhage The Stroke Acute Management With Urgent Risk-Factor Assessment and Improvement-Intracerebral Hemorrhage Study

Background and Purpose— Blood pressure (BP) lowering is often conducted as part of general acute management in patients with acute intracerebral hemorrhage. However, the relationship between BP after antihypertensive therapy and clinical outcomes is not fully known. Methods— Hyperacute (<3 hours from onset) intracerebral hemorrhage patients with initial systolic BP (SBP) >180 mm Hg were included. All patients received intravenous antihypertensive treatment, based on predefined protocol to lower and maintain SBP between 120 and 160 mm Hg. BPs were measured every 15 minutes during the initial 2 hours and every 60 minutes in the next 22 hours (a total of 30 measurements). The mean achieved SBP was defined as the mean of 30 SBPs, and associations between the mean achieved SBP and neurological deterioration (≥2 points’ decrease in Glasgow Coma Score or ≥4 points’ increase in National Institutes of Health Stroke Scale score), hematoma expansion (>33% increase), and unfavorable outcome (modified Rankin Scale score 4–6 at 3 months) were assessed with multivariate logistic regression analyses. Results— Of the 211 patients (81 women, median age 65 [interquartile range, 58–74] years, and median initial National Institutes of Health Stroke Scale score 13 [8–17]) enrolled, 17 (8%) showed neurological deterioration, 36 (17%) showed hematoma expansion, and 87 (41%) had an unfavorable outcome. On multivariate regression analyses, mean achieved SBP was independently associated with neurological deterioration (odds ratio, 4.45; 95% confidence interval, 2.03–9.74 per 10 mm Hg increment), hematoma expansion (1.86; 1.09–3.16), and unfavorable outcome (2.03; 1.24–3.33) after adjusting for known predictive factors. Conclusions— High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.

Guidelines for the intravenous application of recombinant tissue-type plasminogen activator (alteplase), the second edition, October 2012: a guideline from the Japan Stroke Society.

In Japan, intravenous alteplase, a recombinant tissue-type plasminogen activator (rt-PA), was approved for an indication of ischemic stroke in 2005 on the basis of the results of a clinical trial with a unique dose of the drug (0.6 mg/kg). The Japan Stroke Society published the guidelines for intravenous application of rt-PA and organized training sessions for proper use all over Japan in an effort to promote the safe, widespread use of intravenous alteplase. Seven years following its approval, clinical experience with intravenous alteplase has accumulated, additional evidence of intravenous alteplase has been found in Japan and overseas, and the medical environment has substantially changed, including approvals for new drugs and medical devices. Notably, the use of alteplase in the extended therapeutic time window (within 4.5 hours of symptom onset) became covered by insurance in Japan in August 2012. To address these changing situations, we have decided to prepare the revised guidelines. In preparing the second edition, we took care to make its contents more practical by emphasizing information needed in clinical practice. While the first edition was developed with emphasis on safety in light of limited clinical experience with intravenous alteplase in Japan in 2005, this second edition is a substantial revision of the first edition mainly in terms of eligibility criteria, on the basis of accumulated evidence and the clinical experience.

ENHANCED TUMOR GROWTH ELICITED BY L-TYPE AMINO ACID TRANSPORTER 1 IN HUMAN MALIGNANT GLIOMA CELLS

OBJECTIVE To study the expression and function of L-type amino acid transporter 1 (LAT1), a major catalytic subunit of system L that is responsible for the transport of large neutral amino acids, including most essential amino acids, in concert with the covalently bound 4F2 heavy chain, and is implicated in tumorigenesis. METHODS Human glioma cell lines and tumor specimens were analyzed for LAT1 expression using Western blotting and reverse transcription polymerase chain reaction analysis. The rate of neutral amino acid uptake was measured using L-[C]leucine. The proliferation and apoptosis rates were analyzed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide and terminal deoxynucleotidyl transferase-mediated nick end-labeling assays, respectively, on inhibition of system L by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. The effects on proliferation and tumor growth caused by exogenously overexpressed LAT1 were similarly analyzed. RESULTS LAT1 was expressed in most human high-grade gliomas and glioma cell lines at various levels, with more ubiquitous expression of 4F2 heavy chain. Glioma cells with high LAT1 expression exhibited a marked increase in the uptake rate of L-[C]leucine. 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid treatment not only suppressed deoxyribonucleic acid synthesis in association with the up-regulation of the cyclin-dependent kinase inhibitor p21 but also enhanced apoptosis with caspase activation, thereby exerting both cytostatic and cytocidal effects in glioma cells with high LAT1 expression levels. Furthermore, overexpression of LAT1 in glioma cells with low endogenous LAT1 expression significantly enhanced the rates of tumor cell growth in athymic mice. CONCLUSION LAT1, the major transporter of system L, is frequently expressed at higher levels in high-grade gliomas than in low-grade gliomas and brain tissues, and it may play an important role in enhancing the rates of tumor cell proliferation and growth in vivo.