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Objective: This study was undertaken to determine the excess risk of antithrombotic‐related bleeding due to cerebral small vessel disease (SVD) burden. Methods: In this observational, prospective cohort study, patients with cerebrovascular or cardiovascular diseases taking oral antithrombotic agents were enrolled from 52 hospitals across Japan between 2016 and 2019. Baseline multimodal magnetic resonance imaging acquired under prespecified conditions was assessed by a central diagnostic radiology committee to calculate total SVD score. The primary outcome was major bleeding. Secondary outcomes included bleeding at each site and ischemic events. Results: Of the analyzed 5,250 patients (1,736 women; median age = 73 years, 9,933 patient‐years of follow‐up), antiplatelets and anticoagulants were administered at baseline in 3,948 and 1,565, respectively. Median SVD score was 2 (interquartile range = 1–3). Incidence rate of major bleeding was 0.39 (per 100 patinet‐years) in score 0, 0.56 in score 1, 0.91 in score 2, 1.35 in score 3, and 2.24 in score 4 (adjusted hazard ratio [aHR] for score 4 vs 0 = 5.47, 95% confidence interval [CI] = 2.26–13.23), that of intracranial hemorrhage was 0.11, 0.33, 0.58, 0.99, and 1.06, respectively (aHR = 9.29, 95% CI = 1.99–43.35), and that of ischemic event was 1.82, 2.27, 3.04, 3.91, and 4.07, respectively (aHR = 1.76, 95% CI = 1.08–2.86). In addition, extracranial major bleeding (aHR = 3.43, 95% CI = 1.13–10.38) and gastrointestinal bleeding (aHR = 2.54, 95% CI = 1.02–6.35) significantly increased in SVD score 4 compared to score 0. Interpretation: Total SVD score was predictive for intracranial hemorrhage and probably for extracranial bleeding, suggesting the broader clinical relevance of cerebral SVD as a marker for safe implementation of antithrombotic therapy. ANN NEUROL 2024;95:774–787 [ABSTRACT FROM AUTHOR]

Background: Haploinsufficiency of cytotoxic T‐lymphocyte antigen 4 (CTLA4) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and diverse autoimmune disorders. Although central nervous system lesions have been described in patients with CTLA4 insufficiency, there have been few reports in the field of neurology. Case presentation: A 23‐year‐old man was referred to Saga University Hospital (Saga, Japan) with dizziness and abnormal head magnetic resonance imaging showing hyperintensity in the left cerebellar hemisphere. He was diagnosed with immune thrombocytopenia and hypogammaglobulinemia at age 8 years. He had repeated mild upper respiratory infections. Neurological events had occurred four times, with a long spinal lesion extending over three vertebral segments. High‐dose intravenous methylprednisolone was effective for acute attacks, and low‐dose prednisolone prevented relapses for 7 years. When he reached the age of 37 years, he developed severe diarrhea and immune cytopenia, and lost 6 kg in half a year. It was suspected that the patient had primary immunodeficiency due to his history of recurrent infections, hypogammaglobulinemia and severe diarrhea. Genome sequencing showed a heterozygous CTLA4 variant in exon 2. Abatacept therapy with prednisolone and cyclosporine was effective for diarrhea and autoimmune cytopenia. Conclusions: A patient with CTLA4 variant might develop multiple central nervous system lesions including longitudinally‐extended spinal cord lesions. As there is effective targeted immunotherapy, a complete immunological work‐up is required for early diagnosis when a patient presents with central nervous system lesions and multi‐organ symptoms. [ABSTRACT FROM AUTHOR]

Strategic links between Japan and Europe during the Cold War were limited. During this period the IISS helped bridge the gap between the two, exposing its membership base to the international affairs of Asia and Japan and providing Japanses scholars, strategists and diplomats with a platform from which to amplify their voices in the West. Analyses by these experts often appeared in IISS publications, but the Institute also gained key insights through its well-established conferences and lecture series. These initiatives illuminated Japanese strategic thinking and perspectives on contemporary critical issues in Japan's and Asia's foreign, security and defence policy. This Adelphi book, through its collection of earlier analysis, helps the reader to understand the evolution of Japanese strategic thought from the 1960s until today, and shines a light on the continuities and changes in this thinking. New, original analysis of the material seeks to identify areas where such thinking was prescient and remains relevant to the contemporary strategic environment, and other areas where predictions failed or assumptions were proved wrong. These new essays were also informed by interviews of Japanese senior scholars and diplomats who spent time with the IISS. This book seeks to frame, educate and guide strategic thinking on the most pressing issues of today, both in and outside Japan and Asia, and will be of great interest to analysts, practitioners and students of international affairs. [ABSTRACT FROM AUTHOR]

Background and aims: We explored the association between the total small vessel disease score obtained from baseline magnetic resonance imaging and subsequent cerebro-cardiovascular events in neurologically healthy Japanese adults. Methods: The presence of small vessel disease features, including lacunae, cerebral microbleeds, white matter changes, and basal ganglia perivascular spaces on magnetic resonance imaging, was summed to obtain a "total small vessel disease score" (range, 0–4). After excluding participants with previous stroke or ischemic heart disease, intracranial artery stenosis (≥50%), or cerebral aneurysm (≥4 mm), a total of 1349 participants (mean age, 57.7 years; range, 22.8–85.0 years; 46.9% male) were classified into three groups by total small vessel disease score: 0 (n = 984), 1 (n = 269), and ≥2 (n = 96). Cerebro-cardiovascular events (i.e., any stroke, transient ischemic attack, ischemic heart disease, acute heart failure, and aortic dissection) were defined as the primary end point. The hazard ratio (HR) of events during follow-up was calculated using Cox proportional hazards modeling with adjustments for age, sex, hypertension, diabetes mellitus, and smoking. Cumulative event-free rates were estimated using the Kaplan–Meier method. Results: During follow-up (mean, 6.7 years), 35 cerebro-cardiovascular (16 cerebrovascular) events were identified. Higher small vessel disease score was associated with increased risk of cerebro-cardiovascular events (HR per unit increase, 2.17; 95% confidence interval, 1.36–3.46; P = 0.001). Events were more frequent among participants with higher score (P < 0.001, log-rank test). Conclusions: This study offered additional evidence for the clinical relevance of total small vessel disease score, suggesting the score as a promising tool to predict the risk of subsequent vascular events even in healthy populations. [ABSTRACT FROM AUTHOR]

Simple Summary: We pathologically compared the cerebral infarction (CI) status in autopsy cases with and without malignancy focusing on the status of intracranial Mönckeberg's atherosclerosis. Most of Mönckeberg's atherosclerosis were found in the basal ganglia. Its prevalence in CI cases with malignancy was significantly higher than in malignancy cases without CI and was apparently higher than CI cases without malignancy. The results indicated that Mönckeberg's atherosclerosis was frequently found in the basal ganglia of CI patients with malignancy and that intracranial Mönckeberg's atherosclerosis is a potential risk factor for CI in patients with advanced stage malignancy. Cerebral infarction (CI) severely affects the prognosis of patients with malignancy. The aim of the study was to compare the pathology of CI between cases with and without malignancy focusing on intracranial Mönckeberg's atherosclerosis. Among 778 autopsy cases of craniotomy, 53 cases of "cerebral infarction without malignancy group" (CI group), 50 cases of "malignant tumor without CI group" (MT group), and 39 cases of "cerebral infarction with malignancy group" (CM group) were identified. Mönckeberg's atherosclerosis was mainly found in the basal ganglia and its prevalence in the CM group (38.5%) was significantly higher than in the MT group (12.0%, p = 0.005), and apparently higher than in the CI group (18.9%, p = 0.057). The CI group was significantly older, had higher BMIs, and a greater prevalence of hypertension and atrial fibrillation compared to the CM group. In addition, the prevalence of chronic renal disease was significantly lower in the CM group (2.6%, p = 0.012) than in the CI group (20.8%). Our results indicated that Mönckeberg's atherosclerosis was often found in the basal ganglia of CM cases and that intracranial Mönckeberg's atherosclerosis is a potential risk factor for CI in patients with advanced stage malignancy. [ABSTRACT FROM AUTHOR]

AMPO‐Japan Asia Quarterly Review, Voices from the Japanese Women's Movement. London: M. E. Sharpe, 1996. ISBN 1–56324–726–7. Eva‐Marie Kröller, Allan Smith, Joshua Mostow and Robert Kramer (eds), Pacific Encounters: The Production of Self and Other. Vancouver: Institute of Asian Research, University of British Columbia, 1997. ISBN 0–88865–165–1, Can$19.95. Glenn D. Hook, Militarization and Demilitarization in Contemporary Japan. London and New York: Routledge, 1996. xvi + 256pp. ISBN 0–415–02274–6, £50.00 (hbk). Gary Rodan, Kevin Hewison and Richard Robison (eds), The Political Economy of South‐East Asia: An Introduction. Melbourne: Oxford University Press, 1997. ISBN 0–19–550654–5, £34.00 (hbk). ISBN 0–19–553736‐X, £15.99 (pbk). John Gerard Ruggie, Constructing the World Polity: Essays on International Institutionalization. London: Routledge, 1997. xiii + 312pp. ISBN 0–415–09990–0, $75.00; £50.00 (hbk); ISBN 0–415–09991–9, $22.99; £16.99 (pbk) Linda Weiss, The Myth of the Powerless State: Governing the Economy in a Global Era. Cambridge: Polity Press, 1998. 260pp. ISBN 0–7456–1581–3. [ABSTRACT FROM PUBLISHER]

(1) Background: Pericytes are involved in intraplaque neovascularization of advanced and complicated atherosclerotic lesions. However, the role of pericytes in human carotid plaques is unclear. An unstable carotid plaque that shows high-intensity signals on time-of-flight (TOF) magnetic resonance angiography (MRA) is often a cause of ischemic stroke. The aim of the present study is to examine the relationship between the pericytes in intraplaque neovessels and MRA findings. (2) Methods: A total of 46 patients with 49 carotid artery stenoses who underwent carotid endarterectomy at our hospitals were enrolled. The patients with carotid plaques that were histopathologically evaluated were retrospectively analyzed. Intraplaque hemorrhage was evaluated using glycophorin A staining, and intraplaque neovessels were evaluated using CD34 (Cluster of differentiation) stain as an endothelial cell marker or NG2 (Neuron-glial antigen 2) and CD146 stains as pericyte markers. Additionally, the relationships between the TOF-MRA findings and the carotid plaque pathologies were evaluated. (3) Results: Of the 49 stenoses, 28 had high-intensity signals (TOF-HIS group) and 21 had iso-intensity signals (TOF-IIS group) on TOF-MRA. The density of the CD34-positive neovessels was equivalent in both groups. However, the NG2- and CD146-positive neovessels had significantly higher densities in the TOF-HIS group than in the TOF-IIS group. (4) Conclusion: The presence of a high-intensity signal on TOF-MRA in carotid plaques was associated with intraplaque hemorrhage and few pericytes in intraplaque neovessels. These findings may contribute to the development of new therapeutic strategies focusing on pericytes. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Japan's Changing China Policy," by Michael J. Green and Benjamin L. Shelf that was published in the Summer 1996 issue.

Background: Dual-energy computed tomography (DE-CT) can differentiate between hemorrhage and iodine contrast medium leakage following mechanical thrombectomy (MT) for acute ischemic stroke (AIS). We determined whether subarachnoid hemorrhage (SAH) and subarachnoid iodine leakage (SAIL) on DE-CT following MT were associated with malignant brain edema (MBE)., Methods: We analyzed the medical records of 81 consecutive anterior circulation AIS patients who underwent MT. SAH or SAIL was diagnosed via DE-CT performed immediately after MT. We compared the procedural data, infarct volumes, MBE, and modified Rankin scale 0-2 at 90 days between patients with and without SAH and between patients with and without SAIL. Furthermore, we evaluated the association between patient characteristics and MBE., Results: A total of 20 (25%) patients had SAH and 51 (63%) had SAIL. No difference in diffusion-weighted imaging (DWI)-infarct volume before MT was observed between patients with and without SAH or patients with and without SAIL. However, patients with SAIL had larger DWI-infarct volumes 1 day following MT than patients without SAIL (95 mL vs 29 mL; p=0.003). MBE occurred in 12 of 81 patients (15%); more patients with SAIL had MBE than patients without SAIL (22% vs 3%; p=0.027). Severe SAIL was significantly associated with MBE (OR, 12.5; 95% CI, 1.20-131; p=0.006), whereas SAH was not associated with MBE., Conclusion: This study demonstrated that SAIL on DE-CT immediately after MT was associated with infarct volume expansion and MBE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis., Methods: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression., Results: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome., Discussion: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Objectives: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet)., Methods: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use., Results: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years)., Interpretation: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)