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Background and ObjectivesWhite matter hyperintensities (WMHs) are reportedly increased in moyamoya disease (MMD); however, their clinical importance is not well-established owing to their pathophysiologic heterogeneity by distribution. This study aimed to evaluate the burden and pattern of WMHs and its clinical implications in the MMD trajectory.MethodsAdult patients with MMD without significant structural lesions were 1:1 propensity score-matched with healthy controls for sex and vascular risk factors. The total, periventricular, and subcortical WMH volumes were segmented and quantified fully automatically. WMH volumes were detrended by age and compared between the 2 groups. MMD severity based on Suzuki stage and future ischemic events were assessed for their association with WMH volumes.ResultsA total of 161 pairs of patients with MMD and controls were analyzed. MMD significantly correlated with increased total WMH volume (B [standard error], 0.126 [0.030];p< 0.001), periventricular WMH volume (0.114 [0.027];p< 0.001), and periventricular-to-subcortical ratio (0.090 [0.034];p= 0.009). In the MMD subgroup (n = 187), advanced MMD had an independent association with the total WMH volume (0.120 [0.035];p< 0.001), periventricular WMH volume (0.110 [0.031];p< 0.001), and periventricular-to-subcortical ratio (0.139 [0.038];p< 0.001). Periventricular WMH volume (adjusted hazard ratio [95% confidence interval], 5.12 [1.26–20.79]) and periventricular-to-subcortical ratio (3.80 [1.51–9.56]) were associated with future ischemic events in patients with medically followed up MMD. However, no demonstrable association was found between subcortical WMH volume and MMD, MMD severity, or future ischemic events.DiscussionPeriventricular WMHs, but not subcortical WMHs, may represent the main pathophysiology of MMD. Periventricular WMHs may be used as a marker for ischemic vulnerability in patients with MMD.

Introduction: Although the association between vertebral artery or posterior inferior cerebellar artery dissection and lateral medullary infarction (LMI) has been established, the actual prevalence of dissection among patients with LMI may still be underestimated. Methods: Consecutive patients with acute pure LMI admitted between 2010 and 2021 were included. High-resolution vessel wall MRI (VWMRI) and/or transfemoral cerebral angiography (TFCA) were performed in a part of patients and were regarded as gold standard tests for diagnosis of dissection. Factors associated with definite dissection based on VWMRI or TFCA findings were assessed. Risk scoring for dissection was created based on multivariate logistic regression and applied to estimate the number of possible dissection. Results: Eighty-seven LMI patients were eligible and 47 (54.0%) of them underwent VWMRI (n=43) and/or TFCA (n=7). Among these 47 cases, 24 were definite dissection. Three out of 40 patients without gold standard tests were diagnosed with definite dissection based on conventional MRI findings. Preceding headache and normal body weight were independently associated with dissection in LMI patients. A risk scoring which includes age, body mass index, and headache predicted dissection with 91.7% sensitivity and 69.6% specificity (area under the receiver operating characteristic curve, 0.889; 95% confidence intervals, 0.802-0.977) in our population. Additional nine out of 37 patients without gold standard tests nor diagnosis of definite dissection in conventional MRI could be considered as possible dissection based on the scoring. Definite and possible dissections together comprised 41.4% (n=36) of LMI in our study. Conclusions: Arterial dissection may be more prevalent among LMI patients than reported before. Thorough diagnostic effort for dissection is necessary based on scrutinizing risk stratification.

Introduction: White matter hyperintensities (WMH) are reportedly increased in moyamoya disease (MMD); however, their clinical importance is not well-established owing to their pathophysiological heterogeneity by distribution. This study aimed to evaluate the burden and pattern of WMH and its clinical implications in the MMD trajectory. Methods: Adult MMD patients without significant structural lesions were 1:1 propensity score-matched with healthy controls for sex and vascular risk factors. The total, periventricular, and subcortical WMH volumes were segmented and quantified fully automatically. WMH volumes were detrended by age and compared between the two groups. MMD severity based on Suzuki stage and future ischemic events were assessed for their association with WMH volumes. Results: A total of 190 pairs of patients with MMD and controls were analyzed. MMD significantly correlated with increased total (B, 0.086; standard error [SE], 0.027; p=0.002) and periventricular WMH volumes (B, 0.079; SE, 0.025; p=0.002). In the MMD subgroup, advanced MMD had an independent positive association with the total (B, 0.124; SE, 0.034; p Conclusions: Periventricular WMH, but not subcortical WMH, may represent the main pathophysiology of MMD. Periventricular WMH may be used as a marker for ischemic vulnerability in patients with MMD.

Introduction: Alteration of the gastrointestinal (GI) tract by resection or bypass surgery might affect the absorption of both warfarin and direct oral anticoagulants (DOACs). The clinical trials of DOACs excluded individuals with altered GI tract, hence there are limited pharmacokinetic data for them. Only several cases have been reported suggesting atrial fibrillation-related stroke due to reduced absorption of DOACs after GI surgery. We aimed to investigate the efficacy of warfarin and DOACs who underwent GI surgery using nationwide population-based data. Methods: This was a retrospective cohort study using claim-based national data from 2013 to 2020 from Korean Health Insurance Review and Assessment Service (HIRA). Patients with nonvalvular AF (NVAF) taking oral anticoagulants (OACs) were included. The patients taking OACs due to other indications than NVAF were excluded. Cox proportional hazard models with time-varying covariates were used to investigate the impact of GI surgery in patients taking warfarin and DOACs. Results: Of the 311,782 patients (mean age 72, male 56.7%) with NVAF, 3,807 underwent GI surgery. Warfarin and DOACs were prescribed in 14.3% and 85.7% of the patients, respectively. Overall, warfarin was associated with a higher risk of ischemic stroke compared with DOACs (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.44-1.59). In the GI surgery group, the hazard ratio for ischemic stroke for warfarin compared with DOACs was 2.70 (95% CI, 1.63-4.45, Figure). In the no GI surgery group, warfarin also had a higher risk of ischemic stroke compared with DOACs (HR 1.51, 95% CI 1.44-1.59). Among DOAC-treated patients, GI surgery was not associated with a risk of ischemic stroke (HR 0.87, 95% CI 0.67-1.12). Conclusions: DOACs were more effective for stroke prevention than warfarin in patients with NVAF whose GI tracts were altered due to previous surgery. GI surgery did not affect the risk of stroke in patients with NVAF taking DOAC.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) has been linked with incident cardiovascular disease and its outcome. However, the association between CHIP and acute ischemic stroke is not yet fully elucidated. Methods: This retrospective, observational cohort study included 366 acute ischemic stroke patients from a single center prospective stroke registry and 4,628 general population control (age over 40 years old). We compared the prevalence of CHIP between stroke patients and control groups. A multivariable linear or logistic regression model was used to assess the association between CHIP and initial stroke severity, hemorrhagic transformation and functional disability at 90-day (modified Rankin scale score >1) after stroke. The contribution of individual CHIP driving genes was also evaluated. Results: When comparing the acute ischemic stroke patients (N=366) and the general population (N=4,628), the prevalence of CHIP was significantly higher in stroke patients than in the general population (32.0% vs. 13.9% with variant allele frequencies of 1.5%, p Conclusion: CHIP was obviously increased in ischemic stroke patients. Furthermore, CHIP was significantly associated with stroke severity, hemorrhagic transformation, and functional disability at 90 days.

Although it is not recognized as essential to test for antiphospholipid antibody (aPL) in stroke of unknown cause, aPL-related stroke may account for a considerable number of cryptogenic strokes. We aimed to assess the current status and diagnostic value of aPL testing in cryptogenic stroke patients.Consecutive patients admitted with acute ischemic stroke were examined to confirm the factors associated with performing aPL testing and with positive aPL test results in real-world practice. Cryptogenic stroke patients were separately examined in the same manner. The antibody profiles of cryptogenic stroke patients with aPL positivity were compared by age.Among 2947 patients, 606 (20.6%) were tested for aPLs and 129 (21.3%) were positive. Physicians tended to perform aPL testing in patients aged50 years and in cryptogenic stroke patients. Cryptogenic stroke was a strong predictor of positive aPL results (adjusted odds ratio 3.70, 95% confidence interval 2.38-5.76). However, aPL positivity did not differ by age in stroke patients. Among 283 cryptogenic stroke patients, 136 (48.1%) were tested for aPLs and 56 (41.2%) were positive. aPL tests were performed predominantly in patients aged50 years rather than in older patients, even among cryptogenic stroke patients. The two age groups had similar positivity rates of40% (50 years: 43.2%; ≥50 years: 40.4%; p = 0.92) and their antibody profiles were similar.A significant number of patients with cryptogenic stroke had positive aPL results regardless of age. aPL testing may offer additional diagnostic opportunities in cryptogenic stroke patients, and thus may reduce the incidence of cryptogenic stroke.

BackgroundThrombi retrieved from patients with acute ischemic stroke may contain prognostic information.ObjectiveTo investigate the relationship between the immunologic phenotype of thrombi and future vascular events in patients with a stroke.MethodsThis study included patients with acute ischemic stroke who underwent endovascular thrombectomy at Chung-Ang University Hospital in Seoul, Korea, between February 2017 and January 2020. Laboratory and histological variables were compared between patients with and without recurrent vascular events (RVEs). Kaplan–Meier analysis followed by the Cox proportional hazards model was used to identify factors related to RVE. Receiver operating characteristic (ROC) analysis was conducted to evaluate the performance of the immunologic score by combining immunohistochemical phenotypes to predict RVE.ResultsA total of 46 patients were included in the study with 13 RVEs (mean±SD age, 72.8±11.3 years; 26 (56.5%) men). Thrombi with a lower percentage of programmed death ligand-1 expression (HR=11.64; 95% CI 1.60 to 84.82) and a higher number of citrullinated histone H3 positive cells (HR=4.19; 95% CI 0.81 to 21.75) were associated with RVE. The presence of high-mobility group box 1 positive cell was associated with reduced risk of RVE, but the association was lost after adjustment for stroke severity. The immunologic score, which consists of the three immunohistochemical phenotypes, showed good performance in predicting RVE (area under the ROC curve, 0.858; 95% CI 0.758 to 0.958).ConclusionsThe immunological phenotype of thrombi could provide prognostic information after stroke.

Background and Purpose: Although it has been reported that the amount of alcohol consumption has a J-shaped association with ischemic stroke, it is unclear whether differences in drinking patterns affect this relationship. We aimed to clarify the impact of drinking patterns on ischemic stroke in midlife. Methods: We used data from the National Health Insurance Service-National Sample Cohort, which is a large-sized, standardized population cohort in Korea. Five different drinking patterns were defined by combining the frequency of alcohol consumption and quantity of alcohol consumed per occasion, that is, abstainers, not drinking alcohol; drinker group I, ≤30 g/d and 30 g/d and 30 g/d and ≥5 d/wk. The association between the drinking patterns and ischemic stroke occurrence was analyzed using the Cox proportional hazard model. Results: A total of 152 469 middle-aged participants (mean age, 50.2 years; 72 285 men [47.4%]) were eligible for the analyses. The median follow-up time was 9.0 years. Compared with abstainers, those who drank Conclusions: Reduced risk of ischemic stroke was observed in middle-aged participants with specific drinking patterns, but it was limited to the earlier period. Physicians should be cautious in educating patients on alcohol consumption, considering the long-term association between drinking patterns and ischemic stroke.

No medication has been approved for secondary injuries after traumatic brain injury (TBI). While free radicals are considered a major mediator of secondary injury, conventional antioxidants only have modest clinical efficacy. Here, we synthesized CX201 consisting of core cerium oxide nanoparticles coated with 6-aminocaproic acid and polyvinylpyrrolidone in aqueous phase. CX201 with 3.49 ± 1.11 nm of core and 6.49 ± 0.56 nm of hydrodynamic diameter showed multi-enzymatic antioxidant function. Owing to its excellent physiological stability and cell viability, CX201 had a neuroprotective effect in vitro. In a TBI animal model, an investigator-blinded randomized experiment showed a single intravenously injected CX201 significantly improved functional recovery compared to the control. CX201 reduced lipid peroxidation and inflammatory cell recruitment at the damaged brain. These suggest ultrasmall CX201 can efficiently reduce secondary brain injuries after TBI. Given the absence of current therapies, CX201 may be proposed as a novel therapeutic strategy for TBI.

Background: Recent clinical evidence supports the early initiation of aspirin and clopidogrel combination for patients with minor stroke or high-risk transient ischemic attack (TIA) to prevent stroke recurrence. However, some of the patients still experience early neurological deterioration (END) despite optimal antithrombotic treatment. We investigated clinical and laboratory variables related to END after optimal antithrombotic treatment among the patients with non-cardioembolic stroke or TIA. Methods: The patients with minor neurological deficit who received aspirin and clopidogrel within 24 hours after symptom onset were selected from the prospective stroke registries of Seoul National University and Chung-Ang University Hospital, in Seoul, Korea. The END due to ischemic stroke (END_IS) was defined as two or more national institute health stroke scale increase within 5 days after stroke which us due to stroke progression or recurrence. Included patients were divided into two groups according to the presence of END_IS and demographic and laboratory variables were compared between the two groups. Multivariable logistic regression analysis was performed to assess the independent predictors of the END. Results: During the study period from January 2015 to January 2021, 33 (8.7%) out of 380 patients experienced END_IS. In multivariate analysis, independent predictors of END_IS were the presence of intracranial artery stenosis ≥ 50% (odds ratio [OR] 2.922, [95% CI, 1.342-6.364], p=0.007), higher initial NIHSS score, (OR 1.502 [95% CI 1.120-2.015], p=0.007), previous use of statin (OR 0.282 [95% CI 0.080-0.990], p=0.007) and higher serum D-dimer level (OR 1.408 [95% CI, 1.074-1.847], p=0.048). Conclusions: Intracranial artery stenosis, stroke severity, previous statin use, and D-dimer level were the independent predictors of END_IS after dual-antiplatelet treatment in patients with minor stroke. Future studies are necessary to develop an additional therapeutic strategy for the at-risk patient group.

Background and purpose The recent successes of the DAWN and DEFUSE 3 trials have extended the therapeutic time window for endovascular treatment (EVT). Accordingly, an increased care burden and clinical benefit for patients with acute stroke in the emergency room are expected. It is necessary to evaluate and respond to these changes in order to provide the best care to patients. Methods Data of patients with acute stroke or transient ischemic attack treated at Seoul National University Hospital between October 2010 and September 2016 were reviewed. To estimate the increased workload associated with the revised guidelines, clinical candidates of acute stroke based on the initial history and examination findings and eligible patients for early stroke intervention were selected. Additionally, the data of eligible patients who received EVT more than 6 hours after the onset were reviewed. Results The serial addition of intravenous thrombolysis, EVT within 6 hours, and EVT beyond 6 hours to the guidelines resulted in 506 (19.8%), 588 (23.0%), and 718 (28.0%) clinical candidates, respectively, and 329 (12.8%), 365 (14.3%), and 389 (15.2%) eligible patients out of 2,561 patients with stroke. Compared to applying the previous stroke guidelines, the number of clinical candidates increased by 130 (22.1%), whereas the number of eligible patients for early stroke intervention increased by only 24 (6.6%). Seven of the 24 eligible patients received off-label EVT and showed significantly improved neurological outcomes at discharge. Conclusions Notwithstanding the small number of subjects in this study, providing EVT to eligible patients beyond 6 hours may improve their neurological outcomes.

This chapter describes the vascular complications of diabetes. Persistent hyperglycemia damages endothelial cells throughout the vascular system. Hyperglycemic injury of large vessels and small vessels advance to macro- and microvascular complications, respectively. Ischemic stroke is a macrovascular complication; in other words, patients with stroke who have diabetes are likely to have other diabetic vascular complications as well. In addition, apart from its effects on mortality and morbidity, macro- and microvascular complications influence the management of patients with stroke. Therefore, stroke physicians should be able to deal with vascular complications when they treat patients with diabetes rather than referring all patients to endocrinologists. Macrovascular complications involve a medium- or large-sized vessels and manifest as atherosclerosis. Atherosclerotic progression is accelerated under hyperglycemic conditions and leads to cardiovascular diseases, which is a top cause of death in patients with diabetes. Microvascular complications arise from injuries of small vessels including capillaries and small arterioles. Classic diabetic microvascular complications include diabetic retinopathy, nephropathy, and neuropathy. Intensive glycemic control may help reduce vascular damage and is an important strategy in preventing and delaying microvascular complications. However, the advantage of intensive glycemic control for avoiding macrovascular complications is controversial: patients with longer diabetes duration and higher cardiovascular risks conferred no benefit. Moreover, the risk of hypoglycemia should be considered in intensive glycemic control. Accordingly, the glycemic target should be individualized weighing the risk of hypoglycemia. Early use of antidiabetics with cardioprotective benefits (GLP-1 RAs or SGLT2 inhibitors) may be considered for patients with cardiovascular risk factors, including ischemic stroke.

Background Supernumerary phantom limb (SPL) is a rare neurologic phenomenon, in which a patient misperceives an extra limb in addition to the original set of limbs. We report a case of SPL in a patient with a right basal ganglia hemorrhage and review the previous literature about this peculiar phenomenon. Case presentation Two days after the event of a right basal ganglia hemorrhage, a 78-year-old male reported a phantom arm protruding from his left shoulder. He could not see or touch the phantom arm but he felt the presence of an addition arm lateral to his paretic arm. Pain or sensory discomfort were absent in either the paretic arm or the phantom arm. He stated that he could intentionally move the phantom arm independent of his paretic arm. The examination showed that the passive movement of his paretic arm did not elicit any movement of his phantom arm. We diagnosed the SPL as a complication of the hypertensive basal ganglia hemorrhage and treated him with anti-hypertensive medications. His phantom arm persisted for 3 weeks, and it gradually faded away. Conclusion SPL had been reported as a rare complication of various types of cerebral lesions. Right hemispheric lesions were most frequently associated with the SPL. Considering the intentional movement of the phantom arm, we deduced that the SPL might result from the impairment of the sensory feedback system for both internal body image and motor movement.

Supplemental Digital Content is available in the text., Background and Purpose— The susceptibility vessel sign (SVS) is a hypointense signal visualized because of the susceptibility effect of thrombi, sensitively detected on susceptibility-weighted magnetic resonance imaging. The relationship of SVS parameters with the stroke subtype and recanalization status after endovascular treatment remains uncertain. Methods— The data from 89 patients with acute stroke caused by anterior circulation infarcts who underwent susceptibility-weighted magnetic resonance imaging before endovascular treatment were examined. Independent reviewers, blinded to the stroke subtype and recanalization status, measured the SVS diameter, length, and estimated volume. The intra- and interrater agreements of the SVS parameters were assessed. Results— The SVS was identified in 78% of the patients. SVS was more commonly associated with cardioembolism than with noncardioembolism (P=0.01). The SVS diameter (P

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with a high mortality rate, for which there currently is no effective treatment. A perihematomal edema caused by an intense inflammatory reaction is more deleterious than the hematoma itself and can result in neurological deterioration and death. Ceria nanoparticles (CeNPs) are potent free radical scavengers with potential for biomedical applications. As oxidative stress plays a major role in post-ICH inflammation, we hypothesized that CeNPs might protect against ICH. To test this hypothesis, core CeNPs were synthesized using a modified reverse micelle method and covered with phospholipid-polyethylene glycol (PEG) to achieve biocompatibility. We investigated whether our custom-made biocompatible CeNPs have protective effects against ICH. The CeNPs reduced oxidative stress, hemin-induced cytotoxicity, and inflammation in vitro. In a rodent ICH model, intravenously administered CeNPs were mainly distributed in the hemorrhagic hemisphere, suggesting that they could diffuse through the damaged blood–brain barrier. Moreover, CeNPs attenuated microglia/macrophage recruitment around the hemorrhagic lesion and inflammatory protein expression. Finally, CeNP treatment reduced the brain edema by 68.4% as compared to the control. These results reveal the great potential of CeNPs as a novel therapeutic agent for patients with ICH.

Background and purpose Gamma-glutamyl transferase (GGT) is reported to be associated with stroke independently of the conventional risk factors. However, the underlying mechanism remains to be identified. This study focused on atrial fibrillation (AF), which also reportedly has a close association with GGT. Methods Acute ischemic stroke patients who were admitted to the Seoul National University Hospital within 7 days of stroke onset were analyzed. Multinomial logistic regression was performed to assess the relationship between GGT and cardioembolic stroke. Mediation analysis based on binary logistic regression was used to determine whether AF mediates the relationship between GGT and cardioembolic stroke. Results AF was found in 132 (15.0%) of 880 eligible patients with acute ischemic stroke, and 270 (30.7%) patients were categorized as cardioembolic stroke. High GGT levels in acute ischemic stroke patients was associated with cardioembolic stroke [odds ratio (OR)=3.42, 95% CI=1.59-7.37], but not with large-artery atherosclerosis stroke (OR=1.10, 95% CI=0.54-2.23). Approximately half (53.9%) of the total effect of GGT levels on cardioembolic stroke was mediated by AF. Conclusions The GGT level was significantly associated with cardioembolic stroke via AF. The results obtained in the present study may explain why GGT is associated with stroke.

Introduction: Although it has been reported that amount of alcohol consumption has J-shaped association with ischemic stroke, it is yet to be concluded whether difference in drinking pattern affects the relationship. Given that drinking pattern may vary even among individuals with similar drinking amount, it is necessary to further assess the association between drinking pattern and ischemic stroke. Methods: The National Health Insurance Service-National Sample Cohort is a large-sized, standardized population cohort in Korea, which consists of randomly selected 2% of Koreans considering demographic characteristics. Drinking pattern was defined in 5 categories by frequency and quantity per occasion. Participants who reported to have rarely or never drunken alcohol were classified as abstainers. Those who drank less than 5 days per week were defined as social drinkers or episodic heavy drinkers, depending on whether the amount of alcohol consumed at one occasion exceeded a bottle of Soju (60g of alcohol). In the same way, participants drinking 5 days or more a week were classified as daily modest drinkers or daily heavy drinkers. We analyzed the relationship between drinking pattern and ischemic stroke occurrence. Results: A total of 286,256 eligible participants (mean age, 45 years; 148,985 men [52.0%]) were analyzed. Median follow-up period was 9.0 years. As reported in previous studies, social drinking had protective effect for ischemic stroke (HR, 0.88; 95% CI, 0.81-0.96). In participants who drink more, however, the drinking pattern influenced the results. Drinking modest amount of alcohol everyday significantly elevated the risk of ischemic stroke (HR, 1.16; 95% CI, 1.01-1.33), whereas episodic heavy drinking did not (HR, 0.90; 95% CI, 0.76-1.07). Conclusions: Risk of ischemic stroke may be influenced by drinking pattern. Particularly, daily modest drinkers may be at higher risk for ischemic stroke compared with intermittent excessive drinkers.

Background and Purpose— Despite early aneurysm repair and aggressive management for complications, subarachnoid hemorrhage (SAH) results in at least 25% mortality rate and 50% persistent neurological deficit. We investigated whether ceria nanoparticles which have potent antioxidative activities can protect against subarachnoid hemorrhage via attenuating fatal brain injuries. Methods— Uniform, 3 nm, water-dispersed ceria nanoparticles were prepared from short sol-gel reaction of cerium (III) ions with aminocaproic acid in aqueous phase. SAH was induced by endovascular perforation of middle cerebral artery of rats. A single dose of ceria nanoparticles (0.5 mg Ce/kg) or saline control was randomly administered intravenously at an hour post-SAH. Neuronal death, macrophage infiltration, SAH grade, and brain edema were evaluated at 72 hours. Mortality and neurological function were assessed for 14 days. Results— The obtained ceria nanoparticles with high Ce 3+ to Ce 4+ ratio demonstrated potent antioxidative, cytoprotective, and anti-inflammatory activities in vitro. In rodent SAH models, the severity of hemorrhage was comparable between the ceria nanoparticles- and saline-treated groups. However, ceria nanoparticles significantly reduced neuronal death, macrophage infiltration, and brain edema after SAH. Ceria nanoparticles successfully improved survival rates (88.2% in the ceria nanoparticles group versus 21.1% in the control group; P P Conclusions— Ceria nanoparticles, totally synthesized in aqueous phase using aminocaproic acid, demonstrated promising results against SAH via potent antioxidative, neuroprotective and anti-inflammatory activities. Given the obvious limitations of current therapies for SAH, ceria nanoparticles can be a potential therapeutic agent which might result in a paradigm shift in SAH treatment.

Systemic inflammatory response syndrome (SIRS) is self-destructive and uncontrollable inflammatory response of the whole body triggered by infection, trauma, or a variety of severe injuries. Although reactive oxygen species play a pivotal role in the development of SIRS, the trials with conventional antioxidants have failed to improve patient outcome. Ceria nanoparticles (CeNPs) have potent, autocatalytic reactive oxygen species scavenging activities, which may have sufficient therapeutic effects for SIRS. Herein, 3 nm CeNPs are fabricated totally in aqueous phase by using 6-aminohexanoic acid (6-AHA) and their Ce3+ to Ce4+ ratio is increased to enhance antioxidative properties. The obtained 6-AHA-CeNPs demonstrate strong antioxidative and anti-inflammatory effects in various biofluids and inflammatory cells. In SIRS animal models, 6-AHA-CeNPs are demonstrated to reduce multiple organ injuries and inflammation. Moreover, 6-AHA-CeNPs decrease mortality and improve clinical scores of SIRS models. These findings suggest that 6-AHA-CeNPs have potential as a therapeutic nanomedicine for SIRS.

Background and aims: Despite early aneurysm repair and aggressive management for complications, subarachnoid hemorrhage (SAH) results in at least 25% mortality rate and 50% persistent neurologic deficit. Thus, a novel therapeutic agent that directly targets brain damages after SAH is strongly required. For this purpose, we developed aminocaproic acid stabilized ceria nanoparticles (Amicar-CeNPs), which have incomparable anti-oxidative activity and biocompatibility. Methods: Uniform water-dispersed Amicar-CeNPs were prepared from short sol-gel reaction of cerium (III) ions in aqueous phase with aminocaproic acid. SAH was induced by endovascular perforation of middle cerebral artery of rats. A single dose of Amicar-CeNPs (0.5mg/kg) or saline control were randomly administered intravenously at an hour post-SAH. Neuronal death, macrophage infiltration, SAH grade and brain water content were evaluated at 72 hours. Mortality and neurologic function were assessed for 14 days. Results: Amicar-CeNPs, 3-nm in size and with high Ce 3+ to Ce 4+ ratio, demonstrated very potent anti-oxidative, cytoprotective, and anti-inflammatory activities in vitro. In rodent SAH model, Amicar-CeNPs significantly reduced neuronal death (1.1% vs. 90.1%; P Conclusions: Amicar-CeNPs, totally synthesized in aqueous phase, demonstrated very promising results against SAH via potent anti-oxidative, neuroprotective and anti-inflammatory activities. Given the obvious limitations of current therapies for SAH, Amicar-CeNPs are strongly required to be tested in SAH patients as an investigational new drug.

Background: Alcohol consumption is associated with negative consequences including liver disease, major trauma and various cancers. However, a paradoxical beneficial effect of alcohol has been documented for cardiovascular disease in a large meta-analysis. On the other hand, a similar relationship has not been consistently documented or modest for the risk of stroke due to its heterogeneity in subtypes and pathophysiology. In this context, more comprehensive approaches using a representative dataset and composite outcomes are required to clarify the differential effects of alcohol on cardio-cerebrovascular disease (CCVD). Methods: The Korean National Health Insurance Service (NHIS) is the sole provider of full-coverage health insurance for Korean citizens. NHIS-National Sample Cohort (NHIS-NSC) was a standardized cohort representative of Korean population. Based on biennial health exam at 2003 and 2004, we investigated the relationship between alcohol consumption and the incidence of CCVDs [ischemic stroke (IS), hemorrhagic stroke (HS) and myocardial infarction (MI)] and all-cause mortality until 2013, using multivariable Cox proportional hazards models. Results: Among 204,557 participants (median follow up, 9.1 years), the following events were observed: IS 3,274; HS 1,056; MI 1,065 ; and all-cause mortality 8,771 cases. The hazards for IS and MI remained below the null point for the moderate alcohol consumption, but the risk for HS increased in heavy drinkers. In composite outcome indices, moderate consumption was associated with a lower risk for CCVD and all-cause mortality; however, the risk for all-cause mortality was significantly elevated in cases of heavy drinkers. Conclusions: Alcohol consumption was associated with a decreased risk of both CCVD, specifically ischemic vascular disease, and all-cause mortality at moderate dose, but this protective relationship was offset by an increase in the risk for HS and mortality at heavy dose.

Introduction: Recent studies have consistently reported that gamma-glutamyl transferase (GGT) is correlated with higher risk of stroke independent of stroke risk factors and alcohol intake. However, it remains to be further elucidated why GGT is associated with stroke. To clarify the question, we focused on atrial fibrillation (AF), which has also been noted to have a close relationship with GGT. Hypothesis: GGT may be associated with cardioembolic stroke through AF. Methods: From a prospective stroke registry of Seoul National University Hospital, acute ischemic stroke patients who had checked GGT within 7 days from the admission were selected for analysis. The binary logistic regression was used to investigate the relationship between GGT, AF, and cardioembolic stroke. Results: Among 958 eligible patients, 134 patients (13.99%) had AF and 269 (28.08%) patients were classified as cardioembolism according to the TOAST system. GGT was significantly associated with AF in ischemic stroke patients (Adjusted OR, 2.43; 95% CI, 1.32-4.52). Patients with elevated GGT were more likely to be assigned to cardioembolism compared to other TOAST classifications, after adjustment for all potential confounders except for AF (OR, 2.14; 95% CI, 1.31-3.52). When an additional adjustment for AF was made, the increasing trend in OR according to increasing GGT quartile was lost and the association between GGT and cardioembolism was considerably attenuated, although the relationship remained significant (OR, 1.79; 95% CI, 1.01-3.2). Conclusions: GGT showed significant correlation with cardioembolic stroke, potentially owing in large part to its relationship with AF. It may be a possible answer to explain the association between GGT and stroke.

Background The current guideline recommends moderate‐ to vigorous‐intensity physical activity ( PA ) at least 40 min/day for 3 to 4 days/week. Although recent evidence has demonstrated that low‐dose PA could reduce cardiovascular mortality, the relationship between low‐dose PA and the risk of stroke remains uncertain. Methods and Results Using data from a nation‐wide sample cohort in Korea, we examined 336 326 individuals who received a general health examination between 2009 and 2010. Level of PA was assessed using a questionnaire for weekly PA frequencies regarding 3 intensity categories: light, moderate, and vigorous. Moderate‐ to vigorous‐intensity PA ( MVPA ) was classified into 4 frequency categories: none, 1 to 2, 3 to 4, or ≥5 times/week. Cox proportional hazard models were constructed to estimate the risk of stroke. During the average follow‐up of 3.6 years, 2213 stroke cases occurred. MVPA was none in 50%, 1 to 2 times/week in 20%, 3 to 4 times/week in 13%, and ≥5 times/week in 18% of the cohort. Individuals with MVPA 1 to 2 times/week had a 16% reduced risk of stroke (adjusted hazard ratio, 0.84; 95% confidence interval, 0.73–0.96) compared with those with no MVPA . The population attributable fraction of no MVPA was 12%, which was the second most important risk factor for a stroke after hypertension. Conclusions Even 1 to 2 times a week of MVPA might be beneficial to prevent a first‐ever stroke in the general population, although a quantitative validation of the questionnaire is needed. From a public health perspective, we need to encourage inactive people to start exercising with more‐achievable goals.

Although gamma-glutamyl transferase (GGT) is generally regarded as an alternative biomarker for alcohol consumption, its independent role in vascular diseases emerged recently. However, its role in stroke remains unknown. The aim of this study is to clarify the impact of GGT on stroke in a large-sized, national, standardized population cohort in Korea.In Korea, the National Health Insurance Service (NHIS) provides full-coverage health insurance service for all citizens. Using data from the NHIS, the NHIS-National Sample Cohort was designed by randomly selecting 2% of Koreans, carefully considering demographic characteristics. We analyzed eligible individuals from this standardized cohort. The Cox proportional hazards model was used for the study investigating the relationship between GGT and stroke.Among the 456,100 eligible participants, 7,459 patients (1.64%) developed stroke as follows: 5,789 ischemic strokes, 1,046 intracerebral hemorrhages (ICHs), and 624 subarachnoid hemorrhages. GGT was independently correlated with increased risk of stroke after adjustment for alcohol consumption and stroke risk factors (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.29-1.51). The risks of both ischemic stroke (HR = 1.45, 95% CI = 1.32-1.58) and ICH (HR = 1.46, 95% CI = 1.18-1.80) were significantly elevated with increasing GGT. Despite some effect modifications by sex, age, and alcohol, the risk of total stroke and ischemic stroke in association with GGT remained significant in all subgroups.In a standard Korean population, GGT was a novel biomarker predicting stroke risk, independently from alcohol consumption and other risk factors. Ann Neurol 2018;83:375-386.

The two oxidation states of ceria nanoparticles, Ce3+ and Ce4+ , play a pivotal role in scavenging reactive oxygen species (ROS). In particular, Ce3+ is largely responsible for removing O2- and . OH that are associated with inflammatory response and cell death. The synthesis is reported of 2 nm ceria-zirconia nanoparticles (CZ NPs) that possess a higher Ce3+ /Ce4+ ratio and faster conversion from Ce4+ to Ce3+ than those exhibited by ceria nanoparticles. The obtained Ce0.7 Zr0.3 O2 (7CZ) NPs greatly improve ROS scavenging performance, thus regulating inflammatory cells in a very low dose. Moreover, 7CZ NPs are demonstrated to be effective in reducing mortality and systemic inflammation in two representative sepsis models. These findings suggest that 7CZ NPs have the potential as a therapeutic nanomedicine for treating ROS-related inflammatory diseases.