Clonal Hematopoiesis and Acute Ischemic Stroke Outcomes.

OBJECTIVE: The effect of clonal hematopoiesis of indeterminate potential (CHIP) on the manifestation and clinical outcomes of acute ischemic stroke (AIS) has not been fully elucidated. METHODS: Patients with AIS were included from a prospective registry coupled with a DNA repository. Targeted next-generation sequencing on 25 genes that are frequently mutated in hematologic neoplasms was performed. The prevalence of CHIP was compared between patients with AIS and age-matched healthy individuals. A multivariate linear or logistic regression model was used to assess the association among CHIP and stroke severity, hemorrhagic transformation, and functional outcome at 90 days. RESULTS: In total, 380 patients with AIS (mean age = 67.2 ± 12.7 years; 41.3% women) and 446 age-matched controls (mean age = 67.2 ± 8.7 years; 31.4% women) were analyzed. The prevalence of CHIP was significantly higher in patients with AIS than in the healthy controls (29.0 vs 22.0%, with variant allele frequencies of 1.5%, p = 0.024). PPM1D was found to be most significantly associated with incident AIS (adjusted odds ratio [aOR] = 7.85, 95% confidence interval [CI] = 1.83-33.63, p = 0.006). The presence of CHIP was significantly associated with the initial National Institutes of Health Stroke Scale (NIHSS) score (ß = 1.67, p = 0.022). Furthermore, CHIP was independently associated with the occurrence of hemorrhagic transformation (65/110 clonal hematopoiesis positive [CH+] vs 56/270 CH negative [CH-], aOR = 5.63, 95% CI = 3.24-9.77, p < 0.001) and 90-day functional disability (72/110 [CH+] vs 99/270 [CH-], aOR = 2.15, 95% CI = 1.20-3.88, p = 0.011). INTERPRETATION: CH was significantly associated with incident AIS. Moreover, particularly, sequence variations in PPM1D, TET2, and DNMT3A represent a new prognostic factor for AIS. ANN NEUROL 2023;94:836-847.

Age-related Variations in Patterns of Patent Foramen Ovale-Stroke versus Other Cryptogenic Stroke.

INTRODUCTION: Patent Foramen Ovale (PFO)-stroke, a form of cryptogenic stroke, has certain identifying clinical and imaging features. However, data describing this stroke type remains inconsistent. This study examined the potential variations in PFO-stroke features, depending on age. METHODS: From a hospital registry, cryptogenic stroke patients were retrospectively selected, and PFO-strokes identified by the presence of >10 microembolic signals (MES) on transcranial doppler (TCD) saline agitation test. Cryptogenic strokes were grouped according to age (<70 as young, >70 as elderly). Clinical and imaging variables of PFO-strokes and non-PFO strokes were compared, with and without age considered. RESULTS: Of the 462 cryptogenic patients, 30.5% (141/462) were PFO-strokes, while majority (321/462) had no PFO. When cryptogenic strokes were analyzed by age, the significant difference was noted in the lesion number, pattern, and side. A single (72.8% vs 57.9%, p=0.020) and a small single lesion (51.1% vs 35.5%, p=0.039) were frequently seen in the younger PFO-strokes than the non-PFO counterpart, while mixed territory lesions identified the elderly PFO-strokes (30.6% vs 8.9%, p=0.001). A multivariate logistic regression analysis of PFO-strokes further showed that age was independently associated with lesion side (OR 1.12 (1.05-1.20), p<0.001) and lesion number (OR 1.06 (1.02-1.10), p=0.005). CONCLUSIONS: Incorporating age-specific imaging criteria in the identification of PFO-strokes may be of additional value. Further, PFO may remain contributory to the stroke risk in the elderly, in association with vascular risk factors.

Current status and role of antiphospholipid antibody testing in cryptogenic stroke.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: Among 2947 patients, 606 (20.6%) were tested for aPLs and 129 (21.3%) were positive. Physicians tended to perform aPL testing in patients aged <50 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 aged <50 years rather than in older patients, even among cryptogenic stroke patients. The two age groups had similar positivity rates of >40% (<50 years: 43.2%; ≥50 years: 40.4%; p = 0.92) and their antibody profiles were similar. CONCLUSIONS: 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.

Ultrasmall polymer-coated cerium oxide nanoparticles as a traumatic brain injury therapy.

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.

Drinking Patterns and Risk of Ischemic Stroke in Middle-Aged Adults: Do Beneficial Drinking Habits Indeed Exist?

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 <5 d/wk; drinker group II, ≤30 g/d and ≥5 d/wk; drinker group III, >30 g/d and <5 d/wk; and drinker group IV, >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 <5 d/wk (drinker groups I and III) had a significantly lower risk of ischemic stroke (group I hazard ratio, 0.71 [95% CI, 0.59-0.85]; group III hazard ratio, 0.80 [95% CI, 0.68-0.93]) during the first 7 years from the baseline, while other drinker groups showed no such differences. However, the effect of drinking patterns on ischemic stroke risk was attenuated after the first 7 years. 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.

Gamma-glutamyl transferase predicts future stroke: A Korean nationwide study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

Ceria Nanoparticles Synthesized With Aminocaproic Acid for the Treatment of Subarachnoid Hemorrhage.

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 Ce3+ to Ce4+ 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<0.001) and neurological outcomes (modified Garcia score: 12.1±0.5 in the ceria nanoparticles group versus 4.4±0.5 in the control group; P<0.001) of the animals with SAH. 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.

Prediction of Stroke Subtype and Recanalization Using Susceptibility Vessel Sign on Susceptibility-Weighted Magnetic Resonance Imaging.

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<0.01) and length (P=0.01) were larger in the cardioembolism group. The SVS diameter was larger in the recanalization group (thrombolysis in cerebral infarction ≥2b) than in the nonrecanalization group (P=0.04). Multivariable analysis revealed that the SVS diameter was an independent predictor of cardioembolism (adjusted odds ratio, 1.97; 95% confidence interval, 1.34-2.90; P<0.01). There was no significant association between the SVS volume and the recanalization status (adjusted odds ratio, 1.003; 95% confidence interval, 0.999-1.006; P=0.12). The optimal cutoff value of the SVS diameter for the cardioembolism was 5.5 mm (sensitivity, 45.6%; specificity, 93.8%). CONCLUSIONS: Increased SVS diameter on susceptibility-weighted magnetic resonance imaging may predict cardioembolism. No clear association was found between SVS volume and endovascular recanalization.

Supernumerary phantom limb in a patient with basal ganglia hemorrhage - a case report and review of the literature.

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.

Ceria-Zirconia Nanoparticles as an Enhanced Multi-Antioxidant for Sepsis Treatment.

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.

Targeted Metabolomic Biomarkers for Stroke Subtyping.

BACKGROUND AND PURPOSE: Ischemic stroke is a heterogeneous disease with various etiologies. The current subtyping process is complicated, time-consuming, and costly. Metabolite-based biomarkers have the potential to improve classification and deliver optimal treatments. We here aimed to identify novel, targeted metabolomics-based biomarkers to discriminate between large-artery atherosclerosis (LAA) and cardioembolic (CE) stroke. METHODS: We acquired serum samples and clinical data from a hospital-based acute stroke registry (ischemic stroke within 3 days from symptom onset). We included 346 participants (169 LAA, 147 CE, and 30 healthy older adults) and divided them into training and test sets. Targeted metabolomic analysis was performed using quantitative and quality-controlled liquid chromatography with tandem mass spectrometry. A multivariate regression model using metabolomic signatures was created that could independently distinguish between LAA and CE strokes. RESULTS: The training set (n = 193) identified metabolomic signatures that were different in patients with LAA and CE strokes. Six metabolomic biomarkers, i.e., lysine, serine, threonine, kynurenine, putrescine, and lysophosphatidylcholine acyl C16:0, could discriminate between LAA and CE stroke after adjusting for sex, age, body mass index, stroke severity, and comorbidities. The enhanced diagnostic power of key metabolite combinations for discriminating between LAA and CE stroke was validated using the test set (n = 123). CONCLUSIONS: We observed significant differences in metabolite profiles in LAA and CE strokes. Targeted metabolomics may provide enhanced diagnostic yield for stroke subtypes. The pathophysiological pathways of the identified metabolites should be explored in future studies.

The immunologic phenotype of thrombi is associated with future vascular events after cerebral infarction.

BACKGROUND: Thrombi retrieved from patients with acute ischemic stroke may contain prognostic information. OBJECTIVE: To investigate the relationship between the immunologic phenotype of thrombi and future vascular events in patients with a stroke. METHODS: This 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. RESULTS: A 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). CONCLUSIONS: The immunological phenotype of thrombi could provide prognostic information after stroke.

Global hyperperfusion after successful endovascular thrombectomy is linked to worse outcome in acute ischemic stroke.

Patients with stroke may develop hyperperfusion after a successful endovascular thrombectomy (EVT). However, the relationship between post-EVT hyperperfusion and clinical outcomes remains unclear and requires further clarification. We reviewed consecutive patients with anterior circulation occlusion who were successfully recanalized with EVT. Based on post-EVT arterial spin-labeling images, hyperperfusion was categorized as follows: global hyperperfusion (GHP), increased cerebral blood flow (CBF) in ≥ 50% of the culprit vessel territory; focal hyperperfusion (FHP), increased CBF in < 50% of the culprit vessel territory; no hyperperfusion (NHP), no discernible CBF increase. Factors associated with hyperperfusion were assessed, and clinical outcomes were compared among patients under different hyperperfusion categories. Among 131 patients, 25 and 40 patients developed GHP and FHP, respectively. Compared to other groups, the GHP group had worse National Institutes of Health Stroke Scale score (GHP vs. NHP/FHP, 18.1 ± 7.4 vs. 12.3 ± 6.0; p < 0.001), a larger post-EVT infarct volume (98.9 [42.3-132.7] vs. 13.5 [5.0-34.1] mL; p < 0.001), and a worse 90-day outcome (modified Rankin Scale, 3 [1-4] vs. 2 [0-3]; p = 0.030). GHP was independently associated with infarct volume (B = 0.532, standard error = 0.163, p = 0.001), and infarct volume was a major mediator of the association of GHP with unfavorable outcomes (total effect: ß = 0.176, p = 0.034; direct effect: ß = 0.045, p = 0.64; indirect effect: ß = 0.132, p = 0.017). Patients presenting with post-EVT GHP had poorer neurological prognosis, which is likely mediated by a large infarct volume.

Characteristics and Clinical Implication of White Matter Lesions in Patients With Adult Moyamoya Disease.

BACKGROUND AND OBJECTIVES: White 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. METHODS: Adult 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. RESULTS: A 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. DISCUSSION: Periventricular 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.

Presence of Embolic Source and Outcome in Central Retinal Artery Occlusion.

OBJECTIVES: The etiology of central retinal artery occlusion (CRAO) is unclear in approximately 50% of patients, suggesting pathomechanical heterogeneity; moreover, little is known about outcomes according to etiology. This study investigated whether the presence of an embolic source affects outcome in CRAO. METHODS: CRAO patients within 7 days of symptom onset were retrospectively enrolled. Clinical parameters, including initial and 1-month visual acuity, CRAO subtype, and brain images, were reviewed. CRAO etiology was categorized as CRAO with or without an embolic source (CRAO-E+ and CRAO-E-). Visual improvement was defined as a decrease in logarithm of the minimum angle of resolution ≥0.3 at 1 month. RESULTS: A total of 114 patients with CRAO were included. Visual improvement was noted in 40.4% of patients. Embolic sources were identified in 55.3% of patients, and visual improvement group rather than no improvement group was more commonly associated with the presence of an embolic source. In multivariable logistic regression analysis, CRAO-E+ independently predicted visual improvement (odds ratio 3.00, 95% CI 1.15-7.81, p = 0.025). DISCUSSION: CRAO-E+ was found to be associated with a better outcome. CRAO-E+ may be more prone to recanalization than that CRAO-E-.

Neuroimaging features of antiphospholipid antibody-related stroke compared with atrial fibrillation-related stroke.

Recognizing the lesion pattern of antiphospholipid antibody-related stroke (aPL-stroke) may contribute to establishing the cause in patients with cryptogenic stroke. We aimed to describe the neuroimaging features of aPL-stroke compared with atrial fibrillation-related stroke (AF-stroke), a major hidden cause of cryptogenic stroke. Using a prospective stroke registry, we identified consecutive aPL- and AF-stroke patients without other potential causes of stroke. Neuroimaging features based on diffusion-weighted imaging and angiographic findings at admission were compared. A total of 56 and 333 patients were included in the aPL- and AF-stroke groups, respectively. aPL-stroke patients more often presented with single small lesions (aPL-stroke, 30.4% vs. AF-stroke, 7.5%, p < 0.001), while the predominant pattern in AF-stroke patients was large territorial lesions (26.8% vs. 56.5%, p < 0.001). aPL-stroke patients had smaller infarct volume (1.58 mL [0.45; 9.41] vs. 11.32 mL [2.82; 33.08], p < 0.001) and less experience of relevant artery occlusion (17.9% vs. 54.7%, p < 0.001). The proportion of multi-territory lesions, an embolic pattern, was similar between the two groups (28.6% vs. 22.8%, p = 0.44). In comparison only including patients with multi-territory lesions as well, aPL-stroke patients showed small lesion dominance and smaller infarct volume. Multivariate analyses showed independent associations between mild neuroimaging features (small lesion prevalence, smaller infarct volume, and absence of relevant artery occlusion) and aPL-stroke. Patterns of small lesion prevalence, small infarct volume, and absence of relevant artery occlusion were suggestive of aPL-stroke rather than AF-stroke. Cryptogenic stroke patients with such neuroimaging features may benefit from aPL testing for a precise diagnosis.

Accessible chromatin structure permits factors Sp1 and Sp3 to regulate human TGFBI gene expression.

Transforming growth factor beta 1-induced (TGFBI) protein is an extracellular matrix (ECM) protein that is associated with other ECM proteins and functions as a ligand for various types of integrins. In this study, we investigated how human TGFBI expression is regulated in lung and breast cancer cells. We observed that the TGFBI promoter in A549 and MBA-MD-231 cells, which constitutively express TGFBI, existed in an open chromatin conformation associated with transcriptionally permissive histone modifications. Moreover, we found that TGFBI expression required Sp1 transcription elements that can bind transcription factors Sp1 and Sp3 in vitro. Occupancy of the TGFBI promoter by Sp1 and Sp3 in vivo was only observed in TGFBI-expressing cells, indicating that open chromatin conformation might facilitate the binding of Sp1 and Sp3 to the TGFBI promoter region. TGFBI promoter activity was impaired when Sp1 elements were mutated, but was increased when Sp1 or Sp3 factors was overexpressed. Furthermore, Sp1 inhibition in vivo by mithramycin A, as well as knockdown of Sp1 and/or Sp3 expression by short interfering RNA, significantly reduced TGFBI mRNA and protein levels. Thus, our data demonstrated that the expression of TGFBI is well correlated with chromatin conformation at the TGFBI promoter, and that factors Sp1 and Sp3 are the primary determinants for the control of constitutive expression of TGFBI gene.

Effects of Gamma-Glutamyl Transferase on Stroke Occurrence Mediated by Atrial Fibrillation.

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.

The Clinical Benefit and Care Burden of Extending the Window of Endovascular Thrombectomy for Stroke in the Emergency Room.

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.