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Background and ObjectivesFemale patients tend to have greater disability and worse long-term outcomes after stroke than male patients. To date, the biological basis of sex difference in ischemic stroke remains unclear. We aimed to 1) assess sex differences in clinical manifestation and outcomes of acute ischemic stroke and 2) investigate whether the sex disparity is due to different infarct locations or different impacts of infarct in the same location.MethodsThis MRI-based multicenter study included 6,464 consecutive patients with acute ischemic stroke (ResultsMean (SD) age was 67.5 (12.6) years, and 2,641 (40.9%) were female patients. Percentage infarct volumes on diffusion-weighted MRI did not differ between female patients and male patients (median 0.14% vs. 0.14%, P=0.35). However, female patients showed higher stroke severity (NIHSS-score, median 4 vs. 3, P2) than male patients (adjusted-absolute-difference 4.5%; 95%-CI 2.0–7.0; PDiscussionFemale patients have more frequent middle cerebral artery disease and striatocapsular motor-pathway involvement with acute ischemic stroke, along with left parieto-occipital cortical infarcts showing greater severity for equivalent infarct volumes than in male patients. This leads to more severe initial neurological symptoms, higher susceptibility to neurological worsening, and less 3-month functional independence, when compared with male patients.

Background: To evaluate workload in emergency rooms (ERs) among clinical specialties including neurology and investigate characteristics of neurological consultations in ER.Methods: A nationwide survey was conducted to evaluate the number of specialists, resident physicians/surgeons, and emergency consultations of each clinical specialty in Korean tertiary referral hospitals from 2018 to 2019. Characteristics of neurological emergency consultations during the same period were investigated in one of the hospitals that participated.Results: A total of 23 hospitals were included. Four irrelevant clinical specialties were excluded. The number of neurology specialists and resident physicians were 12.5/hospital (4.1% of all specialists) and 6.4/hospital (3.4% of all resident physicians/surgeons), respectively, while the mean numbers of specialists and resident physicians or surgeons per clinical specialty were 13.7/hospital and 8.6/hospital, respectively. Neurological consultations accounted for 11.0% of all ER consultations for severe patients (Korean Triage and Acuity Scale level 1-3). Annual ER consultations for severe patients per neurology specialist was 274.1, which was only second to pediatrics (290.0). Annual ER consultations for severe patients per resident physician was 406.6 which was 1.6 times higher than the second highest (internal medicine, 247.0). Frequent conditions for neurological ER consultation were dizziness (24.8%), motor weakness (23.9%), headache (10.6%), dysarthria (9.9%), and seizures (7.7%). Frequent primary diagnoses were cerebrovascular diseases (29.0%) and episodic and paroxysmal disorders (24.9%).Conclusions: Workloads of neurology specialists for ER consultation were significantly heavy, and the workload of neurology resident physicians was the heaviest among all specialties. This should be considered in health care policies.

Background: Because Korea is the fastest aging country, the stroke incidence is increasing rapidly. We investigate the trend of the number of patients with acute stroke in recent years and estimate the burden of the neurologist to treat the acute stroke patient visited the emergency department.Methods: We requested a questionnaire survey to all teaching hospitals on the number of hospital beds, the number of stroke patients who visited the emergency department, the number of stroke patients in charge of the neurologist, and the number of days on duty of residents from 2016 to 2019.Results: Of 69 teaching hospitals, 41 hospitals answered the survey. The average hospital beds per hospital were increased annually from 909 to 916. The average patients who visited the emergency department with stroke and were in charged to neurologists were rapidly increased from 799 to 867 per hospital. In particular, the number of patients with hyperacute cerebral infarction requiring the thrombolytic administration or mechanical thrombectomy were rapidly increased from 105 to 131. On the other hand, the average number of residents per hospital was decreased from 5.1 to 4.8. Therefore, the days on duty per resident were increased from 74 to 77.Conclusions: The number of acute stroke patients, especially, hyperacute stroke required the rapid cooperation and high labor were increasing rapidly in recent years. However, because the number of residents were decreased, the burden was increasing. To improve the quality of acute stroke treatment, it is necessary to increase the number of residents.

OBJECTIVE We investigated (1) the associations of pre-stroke aspirin use with thrombus burden, infarct volume, hemorrhagic transformation, early neurological deterioration (END), and functional outcome, and (2) whether stroke subtypes modify these associations in first-ever ischemic stroke. METHODS This multicenter magnetic resonance imaging (MRI)-based study included 5,700 consecutive patients with acute first-ever ischemic stroke, who did not undergo intravenous thrombolysis or endovascular thrombectomy, from May 2011 through February 2014. Propensity score-based augmented inverse probability weighting was performed to estimate adjusted effects of pre-stroke aspirin use. RESULTS The mean age was 67 years (41% women), and 15.9% (n = 907) were taking aspirin before stroke. Pre-stroke aspirin use (vs nonuse) was significantly related to a reduced infarct volume (by 30%), particularly in large artery atherosclerosis stroke (by 45%). In cardioembolic stroke, pre-stroke aspirin use was associated with a ~50% lower incidence of END (adjusted difference = -5.4%, 95% confidence interval [CI] = -8.9 to -1.9). Thus, pre-stroke aspirin use was associated with ~30% higher likelihood of favorable outcome (3-month modified Rankin Scale score

Background and purpose The impact of fluid-attenuated inversion recovery hyperintense vessels (FHVs) on outcomes in patients ineligible for recanalization therapy with large-vessel occlusion (LVO) is unclear. We investigated the impact of FHVs determined using the FHV- Alberta Stroke Program Early CT Score (ASPECTS) on clinical outcomes in patients with LVO stroke of mild-to-moderate severity ineligible for recanalization therapy. Methods Sixty-eight consecutive patients with M1-middle cerebral artery occlusion who underwent magnetic resonance imaging within 24 hours of symptom onset and were ineligible for recanalization were included. Patients were dichotomized into a severe-FHV group (FHV-ASPECTS ≤4; n=33) and a mild-FHV group (FHV-ASPECTS >4; n=35), and multiple logistic regression analysis was used to examine the relationships of FHV scores with early neurological deterioration (END) and an unfavorable 3-month outcome (modified Rankin Scale score ≥3). Results Mean age was 66.2±13.5 years (mean±SD), and 30 (44%) were female. The severe-FHV group had a larger infarct volume (median, 5.5 mL vs. 3 mL) and more frequently exhibited the susceptibility vessel sign (30% vs. 3%) than the mild-FHV group. Ipsilateral old nonlacunar infarct was more frequent in the mild-FHV group than in the severe-FHV group (37% vs. 15%). The severe-FHV group had a fivefold higher risk of END (odds ratio [OR] 5.02, 95% confidence interval [CI] 1.36-18.45) and unfavorable outcome (OR 5.97, 95% CI 1.18-33.31, p=0.03) compared with the mild-FHV group. Conclusions Greater FHV extent was associated with higher risk of END and unfavorable outcome in patients with LVO stroke of mild-to-moderate severity.

AIM Preoperative factors predictive of permanent stoma creation were investigated in a long-term follow-up of patients with mid or low rectal cancer. METHOD We included patients who underwent radical resection for mid or low rectal cancer with available data for preoperative anal function measured by manometry and Faecal Incontinence Severity Index questionnaire between January 2005 and December 2015 in three tertiary referral hospitals. A permanent stoma was defined as a stoma present until the patient's last follow-up visit or death. Preoperative factors that predicted permanent stoma creation were analysed. RESULTS Over a median follow-up of 57.4 months (range 12-143 months), a permanent stoma was created in 144/577 (25.0%) patients, including 89 (15.4%) who underwent abdominoperineal resection, one (0.2%) who underwent Hartmann's operation without reversal, 15 (2.6%) with a diverting ileostomy at the time of initial sphincter-preserving surgery without undergoing stoma reversal, and 39 (6.8%) who underwent permanent ileostomy formation after sphincter-preserving surgery. Patients with permanent stoma creation had a shorter tumour distance from the anal verge (P

Background and Purpose Thrombectomy within 24 hours can improve outcomes in selected patients with a clinical-infarct mismatch. We devised an easy-to-use visual estimation tool that allows infarct volume estimation in centers with limited resources. Methods We identified 1,031 patients with cardioembolic or large-artery atherosclerosis infarction on diffusion-weighted images (DWIs) obtained before recanalization therapy and within 24 hours of onset, and occlusion of the internal carotid or middle cerebral artery. Acute DWIs were mapped onto a standard template and used to create visual reference maps with known lesion volumes, which were then used in a validation study (with 130 cases) against software estimates of infarct volume. Results The DWI reference map chart comprises 144 maps corresponding to 12 different infarct volumes (0.5, 1, 2, 3, 5, 7, 9, 11, 13, 15, 17, and 19 mL) in each of 12 template slices (Montreal Neurological Institute z-axis –15 to 51 mm). Infarct volume in a patient is estimated by selecting a slice with a similar infarct size at the corresponding z-axis level on the reference maps and then adding up over all slices. The method yielded good correlations to software volumetrics and was easily learned by both experienced and junior physicians, with approximately 1 to 2 minutes spent per case. The sensitivity, specificity, and accuracy for detecting threshold infarct volumes (90%). Conclusions We developed easy-to-use reference maps that allow prompt and reliable visual estimation of infarct volumes for triaging patients to thrombectomy in acute stroke.

Background and purpose We aimed to determine the relationships of 33 biomarkers of inflammation, oxidation, and adipokines with the risk of progression of symptomatic intracranial atherosclerotic stenosis (ICAS). Methods Fifty-two of 409 patients who participated in the TOSS-2 (Trial of Cilostazol in Symptomatic Intracranial Stenosis-2) showed progression of symptomatic ICAS in magnetic resonance angiography at 7 months after an index stroke. We randomly selected 20 patients with progression as well as 40 age- and sex-matched control patients. We serially collected blood samples at baseline, 1 month, and 7 months after an index stroke. Multiplex analysis of biomarkers was then performed. Results Demographic features and risk factors such as hypertension, diabetes, and smoking history were comparable between the two groups. Univariate analyses revealed that the levels of platelet-derived growth factor (PDGF)-AA [median (interquartile range)=1.64 (0.76-4.57) vs. 0.77 (0.51-1.71) ng/mL], PDGF-AB/BB [10.31 (2.60-25.90) vs. 2.35 (0.74-6.70) ng/mL], and myeloperoxidase [10.5 (7.5-22.3) vs. 7.8 (5.5-12.2) ng/mL] at 7 months were higher in the progression group. In the multivariate analysis using logistic regression, the PDGF AB/BB level at 7 months was independently associated with the progression of ICAS (p=0.02). Conclusions The PDGF-AB/BB level is associated with the progression of ICAS, and so may play a significant role in the progression of human ICAS.

We investigated whether left ventricular filling pressure is associated with arterial occlusion in patients with ischemic stroke related to atrial fibrillation (AF).Ninety-nine patients with AF-related stroke were included. Left ventricular filling pressure was assessed by E (early mitral inflow velocity)/e' (early diastolic velocity of the mitral valve annulus velocity) ratio based on tissue Doppler echocardiography. Arterial occlusion was evaluated by computed tomography or magnetic resonance angiography. In addition, the presence of a hyperdense middle cerebral artery sign (HMCAS) on noncontrast brain computed tomography, a marker of acute thrombus burden, was assessed. Multiple logistic regression was used to evaluate the association of E/e' with arterial occlusion and the HMCAS.The mean age was 73.2 (±10.2), and 56% were men. Thirty-six (36.4%) patients had arterial occlusion on imaging. E/e' ratios were independently associated with arterial occlusion with an odds ratio of 1.24 (per 1 increase, 95% confidence interval 1.11-1.38). The receiver operating characteristics curve demonstrated that E/e' ratios have an excellent discriminatory capacity in predicting arterial occlusion with an area under the curve of .77 (P .001). In addition, E/e' ratios were higher in patients with HMCAS than in those without (19.1 versus 14.0, P .001).E/e' ratios were associated with arterial occlusion in AF-related stroke and may play a role in identifying patients at high risk of severe stroke.

This retrospective observational study was performed to investigate electroencephalogram abnormalities in clozapine-treated patients with refractory schizophrenia or bipolar disorder. The electroencephalogram and plasma clozapine and norclozapine levels in 71 patients were measured on the same day. Fifty-nine patients (85.9%) had a diagnosis of schizophrenia, and 12 patients (14.1%) had a diagnosis of bipolar disorder. The mean daily clozapine dose was 242.9 ± 105.5 mg (range 25-500 mg), and the mean plasma clozapine and norclozapine levels were 429.4 ± 264.1 and 197.8 ± 132.6 ng/ml, respectively. Twenty-five patients (35.2%) were taking valproate in combination with clozapine. electroencephalogram abnormalities were found in 51 (71.8%) patients. No patient reported clinical seizures. Plasma clozapine level was significantly associated with electroencephalogram abnormalities and was identified as a significant predictor of electroencephalogram abnormalities in a logistic regression analysis. The plasma norclozapine levels of patients taking both clozapine and valproic acid were significantly lower than those of patients treated with clozapine alone. These results demonstrate that electroencephalogram abnormalities are closely correlated with plasma clozapine levels. Valproate reduced plasma norclozapine levels. Simultaneous monitoring of electroencephalogram and plasma clozapine levels was useful for adjusting clozapine doses, improving clinical efficacy, and preventing the side effects of clozapine treatment.

Background Cerebral small vessel disease (SVD) is comprised of lacunes, cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), and enlarged perivascular space (EPVS). We investigated the cumulative effect of SVD on 3-month functional outcome following ischemic stroke using the total SVD score. Methods The total SVD score of 477 acute ischemic stroke patients with adequate brain MRI was analyzed. We used multivariable ordinal logistic regression analysis to investigate the independent impact of total SVD score on ordinal modified Rankin Scale (mRS) score at 3-month after ischemic stroke. Results Mean age was 66±14 years, and 61% were men. The distribution of the total SVD score from 0 to 4 was 27%, 24%, 26%, 16%, and 7%, respectively. The proportion of mRS scores 2 or greater was 16% and 47% in total SVD score 0 and 4, respectively. Multivariable ordinal logistic regression analysis results showed that compared with the total SVD score of 0, total SVD scores of 2, 3, and 4 were independently associated with higher mRS scores with adjusted odds ratios (95% confidence intervals) of 1.68 (1.02–2.76), 2.24 (1.25–4.00), and 2.00 (1.02–4.29). Lacunes, CMBs, WMHs but not EPVS were associated with mRS scores at 3 months. However, the impact of each SVD marker on stroke outcome was smaller than that of the total SVD score. Conclusion We found an independent association between total SVD scores and functional outcome at 3 months following ischemic stroke. The total SVD score may be useful for stratification of patients who are at a high-risk of unfavorable outcomes.

ObjectiveTo define the role and risks associated with white matter hyperintensity (WMH) load in a stroke population with respect to recurrent stroke and mortality after ischemic stroke.MethodsA total of 7,101 patients at a network of university hospitals presenting with ischemic strokes were followed up for 1 year. Multivariable Cox proportional hazards model and competing risk analysis were used to examine the independent association between quartiles of WMH load and stroke recurrence and mortality at 1 year.ResultsOverall recurrent stroke risk at 1 year was 6.7%/y, divided between 5.6%/y for recurrent ischemic and 0.5%/y for recurrent hemorrhagic strokes. There was a stronger association between WMH volume and recurrent hemorrhagic stroke by quartile (hazard ratio [HR] 7.32, 14.12, and 33.52, respectively) than for ischemic recurrence (HR 1.03, 1.37, and 1.61, respectively), but the absolute incidence of ischemic recurrence by quartile was higher (3.8%/y, 4.5%/y, 6.3%/y, and 8.2%/y by quartiles) vs hemorrhagic recurrence (0.1%/y, 0.4%/y, 0.6%/y, and 1.3%/y). All-cause mortality (10.5%) showed a marked association with WMH volume (HR 1.06, 1.46, and 1.60), but this was attributable to nonvascular rather than vascular causes.ConclusionsThere is an association between WMH volume load and stroke recurrence, and this association is stronger for hemorrhagic than for ischemic stroke, although the absolute risk of ischemic recurrence remains higher. These data should be helpful to practitioners seeking to find the optimal preventive/treatment regimen for poststroke patients and to individualize risk-benefit ratios.

Background White matter hyperintensities ( WMHs ) are commonly asymmetric between hemispheres but for unknown reasons. We investigated asymmetric WMHs associated with lacunar infarcts. Methods and Results A total of 267 consecutive patients with small first‐ever supratentorial infarcts (≤20 mm) were included. None had a relevant vascular stenosis. WMH asymmetry was measured based on the hemispheric difference of a modified Scheltens scale score (≥3 defined as asymmetric). We analyzed the association of the hemispheric WMH asymmetry with old silent lacunar infarcts or acute lacunar infarcts. We compared lesion frequency maps between groups and generated t‐statistics maps. The mean age of patients was 64 years, and 63% were men. Asymmetric WMH was more than 3‐fold as frequent ( P WMHs , an acute lacunar infarct was more likely to be located in the left (versus right) hemisphere (74% versus 26%, P WMHs , an acute lacunar infarct was more likely to be located on the right (versus left) hemisphere (81% versus 19%, P WMHs was associated with acute and silent lacunes on the same side. Conclusions These are the first data to show that asymmetric WMH s are associated with both old silent lacunar infarcts and acute lacunar infarcts ipsilateral to the greatest WMH burden. This suggests that the hemisphere with relatively large WMHs is more vulnerable to ischemia.

Leukoaraiosis or white matter hyperintensities are frequently observed on magnetic resonance imaging of stroke patients. We investigated how white matter hyperintensity volumes affect stroke outcomes, generally and by subtype. In total, 5035 acute ischaemic stroke patients were enrolled. Strokes were classified as large artery atherosclerosis, small vessel occlusion, or cardioembolism. White matter hyperintensity volumes were stratified into quintiles. Mean age (± standard deviation) was 66.3 ± 12.8, 59.6% male. Median (interquartile range) modified Rankin Scale score was 2 (1-3) at discharge and 1 (0-3) at 3 months; 16.5% experienced early neurological deterioration, and 3.3% recurrent stroke. The Cochran-Mantel-Haenszel test with adjustment for age, stroke severity, sex, and thrombolysis status showed that the distributions of 3-month modified Rankin Scale scores differed across white matter hyperintensity quintiles (P < 0.001). Multiple ordinal logistic regression analysis showed that higher white matter hyperintensity quintiles were independently associated with worse 3-month modified Rankin Scale scores; adjusted odds ratios (95% confidence interval) for the second to fifth quintiles versus the first quintile were 1.29 (1.10-1.52), 1.40 (1.18-1.66), 1.69 (1.42-2.02) and 2.03 (1.69-2.43), respectively. For large artery atherosclerosis (39.0%), outcomes varied by white matter hyperintensity volume (P = 0.01, Cochran-Mantel-Haenszel test), and the upper three white matter hyperintensity quintiles (versus the first quintile) had worse 3-month modified Rankin Scale scores; adjusted odds ratios were 1.45 (1.10-1.90), 1.86 (1.41-2.47), and 1.89 (1.41-2.54), respectively. Patients with large artery atherosclerosis were vulnerable to early neurological deterioration (19.4%), and the top two white matter hyperintensity quintiles were more vulnerable still: 23.5% and 22.3%. Moreover, higher white matter hyperintensities were associated with poor modified Rankin Scale improvement: adjusted odds ratios for the upper two quintiles versus the first quintile were 0.66 (0.47-0.94) and 0.62 (0.43-0.89), respectively. For small vessel occlusion (17.8%), outcomes tended to vary by white matter hyperintensitiy volume (P = 0.10, Cochran-Mantel-Haenszel test), and the highest quintile was associated with worse 3-month modified Rankin Scale scores: adjusted odds ratio for the fifth quintile versus first quintile, 1.98 (1.23-3.18). In this subtype, worse white matter hyperintensities were associated with worse National Institute of Health Stroke Scale scores at presentation. For cardioembolism (20.6%), outcomes did not vary significantly by white matter hyperintensity volume (P = 0.19, Cochran-Mantel-Haenszel test); however, the adjusted odds ratio for the highest versus lowest quintiles was 1.62 (1.09-2.40). Regardless of stroke subtype, white matter hyperintensities were not associated with stroke recurrence within 3 months of follow-up. In conclusion, white matter hyperintensity volume independently correlates with stroke outcomes in acute ischaemic stroke. There are some suggestions that stroke outcomes may be affected by leukoaraiosis differentially depending on stroke subtypes, to be confirmed in future investigations.

A dual-broadband Spidron fractal tapered slot antenna is proposed for radar applications in the S and X bands. Dual-Spidron fractal patches are symmetrically arranged adjacent to each other, and a slot is etched from the central section of the patch to form a feeding slot. A microstrip-to-slotline transition is used to excite the tapered aperture of the Spidron fractal patch. The proposed antenna is fabricated and tested, and has compact dimensions of 35.8 mm × 24 mm (0.358 λ 0 × 0.24 λ 0). The measured −10 dB reflection bandwidths for the lower and upper frequency bands are 39.42% (2.75–4.10 GHz) and 34.74% (7.85–11.15 GHz), respectively. The measurements also indicate that the proposed antenna exhibits two types of radiation patterns, namely, a near omni-directional pattern in the lower band and a directional pattern in the upper band. The measured peak gains range from 0.4 to 2.97 dBi in the lower band and from 1.42 to 5.52 dBi in the upper band.

Objective: To measure the impact of cerebral white matter hyperintensity (WMH) burden on the outcomes of stroke in general, and stroke subtype specifically. Methods: A total of 3814 acute ischemic stroke patients were prospectively enrolled from 11 stroke centers. WMH volume on MRI were quantified and categorized into quintiles. First, the impact of WMH on 3-month modified Rankin scale (mRS) in the entire patient population was studied, and in each stroke type that was determined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Then, we analyzed inter-group differences by: initial NIH stroke scale at admission, early neurological deterioration during the first 3 weeks after stroke onset, and functional recovery as well as stroke recurrence during the 3-month period following the initial infarct. Results: Mean age was 67.1 ± 12.9, and 58.7% were men. In large artery atherosclerosis (LAA) stroke, top two WMH quintiles were independently associated with mRS at 3months. However, only the highest quintile was associated with mRS at 3 months in small vessel occlusion (SVO) and cardioembolism (CE). WMHs were independently associated with initial neurological severity in SVO stroke, but not in other subtypes. WMHs were related with early neurological deterioration only in LAA stroke. Regardless of stroke subtypes, WMHs were not associated with stroke recurrence. Higher WMH volume was independently associated with poor functional recovery in LAA stroke but not in CE subtype. Conclusion: To our knowledge, this is the first study to demonstrate that WMH volume is an independent predictor of outcomes for certain types of stroke subtypes.

Objectives: The association between parity and risk of hemorrhagic stroke (HS) remains to be clarified. This study assessed the association of parity with the overall risk of HS and compared its contribution to intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH).Methods: We used a database from a nationwide multicenter case-control study, in which 471 female cases with incident HS were matched at 1:2 with 942 community or hospital controls. A total of 459 HS cases and 918 controls with information on parity were included. Parity was categorized as 0–1, 2, 3, and ≥4. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by conditional logistic regression. As potential confounders, age, history of hypertension, history of diabetes, family history of stroke, smoking status, alcohol consumption, educational status, age at menarche, and use of oral contraceptives were included in the models.Results: Compared with nullipara and unipara, women with parity of 2, 3, and ≥4 had significantly higher risk for total HS, ICH, and SAH, respectively. Each additional parity increased the ORs of HS (adjusted OR for total HS = 1.27 [95% CI 1.14–1.41]; adjusted OR for SAH = 1.34 [95% CI 1.13–1.58]; adjusted OR for ICH = 1.27 [95% CI 1.08–1.48]). Likelihood ratio test for trends showed a significantly increased risk with increasing parity for total HS and for both types of HS (ptrend < 0.05 in all analyses).Conclusions: Increased number of childbirths may be related to an increased risk of both intracerebral hemorrhage and subarachnoid hemorrhage.

Objective— There is hope that molecular imaging can identify vulnerable atherosclerotic plaques. However, there is a paucity of clinical translational data to guide the future development of this field. Here, we cross-correlate cathepsin-B or matrix metalloproteinase-2/-9 molecular optical imaging data of human atheromata or emboli with conventional imaging data, clinical data, and histopathologic data. Methods and Results— Fifty-two patients undergoing carotid endarterectomy (41 atheromata) or carotid stenting (15 captured emboli) were studied with protease-activatable imaging probes. We show that protease-related fluorescent signal in carotid atheromata or in emboli closely reflects the pathophysiologic alterations of plaque inflammation and statin-mediated therapeutic effects on plaque inflammation. Inflammation-related fluorescent signal was observed in the carotid bifurcation area and around ulcero-hemorrhagic lesions. Pathologically proven unstable plaques had high cathepsin-B–related fluorescent signal. The distribution patterns of the mean cathepsin-B imaging signals showed a difference between the symptomatic vs asymptomatic plaque groups. However, the degree of carotid stenosis or ultrasonographic echodensity was weakly correlated with the inflammatory proteolytic enzyme-related signal, suggesting that molecular imaging yields complimentary new information not available to conventional imaging. Conclusion— These results could justify and facilitate clinical trials to evaluate the use of protease-sensing molecular optical imaging in human atherosclerosis patients.

The ketogenic diet (KD) remains a therapy in search of explanation although it is an established treatment of intractable epilepsy. Recent studies suggest that the KD may be both anticonvulsant and antiepileptogenic. Epileptic seizures have been shown to stimulate the proliferation rate of neuronal progenitor cells in adult animals, which may be related to epileptogenesis. It is known that calorie restriction (CR) increases neurogenesis. The KD was originally formulated to reproduce the biochemical changes seen upon fasting (extreme CR). Thus, we investigated the effects of the KD on neurogenesis after kainic acid (KA)-induced seizures in mice. In the present study, quantitative analysis of BrdU labeling revealed a significant increase in the proliferation rate of neuronal progenitor cells after KA-induced seizures in the KD-fed mice. This finding may provide a clue to explain how the KD exerts antiepileptogenic effects although further studies are mandatory to elucidate the relationship between seizure-induced neurogenesis augmented by the KD and its antiepileptogenic properties. In conclusion, our results suggest that the KD enhances neurogenesis, which may be related to its beneficial effects on epilepsy.

Background and Purpose: A recent study showed that cardiogenic emboli might flow more frequently into the right hemisphere, whereas atheromatous aortic arch emboli might flow more frequently into the left hemisphere. We tried to 1) see if cardioembolic (CE) infarct volume would be larger in the right hemisphere than in the left hemisphere, and 2) depict anatomical regions showing CE vs. large artery atherosclerotic (LAA) infarction-related right-left propensity. Methods: In this study on carotid artery territory CE (n = 694) vs. LAA (n = 1162) acute ischemic stroke patients who were enrolled consecutively from 11 nationwide stroke centers, we quantitatively registered diffusion magnetic resonance imaging lesions onto the Montreal Neurologic Institute brain template. Results: In patients with bilateral CE stroke (n = 163), right hemispheric infarct size was about two times bigger than the contralateral left hemispheric infarct size (p = 0.002). However, in patients with either unilateral (n = 925) or bilateral (n = 184) LAA stroke, there was no significant difference in the right vs. left hemispheric infarct size between the right vs. left unilateral infarct groups or within the bilateral infarct group (all p > 0.05). In patients with unilateral CE stroke (n = 510), there was no significant difference in the infarct size between the groups with right vs. left hemispheric lesions. Age and infarct volume-adjusted p-value maps of the CE vs. LAA stroke patients, which were corrected for multiple comparisons, revealed the brain regions with a significantly higher infarct frequency in CE stroke than in LAA stroke. The significant clusters were observed only in the right hemisphere, encompassing both the superior and inferior division middle cerebral artery territories, particularly in the pial and corticosubcortical regions including the claustrum and insula. Conclusion: The present multi-center quantitative magnetic resonance imaging study confirms the ‘right > left’ propensity of CE (vs. LAA) stroke.

Medical complications are an important clinical problem after acute stroke and present potential barriers to optimal recovery. Pneumonia has been estimated to occur in one third of all stroke victims and is the most common respiratory complication. Moreover, a recent study showed that pneumonia increases the risk of 30-day mortality. In patients with acute stroke, most stroke deaths after the first week and before 30 days were reported to be due to complications of immobility (ie, pneumonia or pulmonary embolism). Because pneumonia is critical in the functional status and prognosis, rapid assessment of a high-risk patient of pneumonia is needed. Some studies found that the neurologic deficit as rated on the National Institutes of Health stroke scale (NIHSS) was correlated with pneumonia and observed that dysphagia and mechanical ventilation were also associated with pneumonia. Stroke patients with paralysis and those with impaired level of consciousness also had had higher rates of pneumonia. Despite the abundant studies of several important risk factors, no grading scale for development of pneumonia after acute stroke is yet used. The purpose of this study was to define a clinical grading scale for pneumonia, which is predictive of incidence of pneumonia development and can be rapidly and accurately assessed at the early time after stroke onset.

Granulocyte colony-stimulating factor (G-CSF) has been used in the treatment of neutropenia in hematologic disorders. The neuroprotective and anti-inflammatory effects of G-CSF were reported in various neurological disease models. In this study, we examined whether G-CSF induces functional recovery after intracerebral hemorrhage (ICH). ICH was induced using collagenase injection in adult rats. Either G-CSF (50 microg/kg, i.p.) or saline was given from 2 h after ICH and every 24 h for 3 days. 72 h after ICH induction, the rats were sacrificed for histological analysis and measurement of brain edema. Behavioral tests were performed before and 1, 7, 14, 21, 28, and 35 days after ICH. We also measured the blood-brain barrier (BBB) permeability using Evans blue dye injection method. G-CSF-treated rats recovered better on rotarod and limb placing tests, starting from 14 days throughout 5 weeks after ICH. The brain water content and BBB permeability of G-CSF-treated group decreased in the lesioned hemispheres compared with those of ICH-only group. In G-CSF-treated group, the number of TUNEL+, myeloperoxidase+, and OX42+ cells was smaller than that of ICH-only group in the periphery of hematoma. These findings suggest that G-CSF induces long-term sensorimotor recovery after ICH with reduction of brain edema, inflammation, and perihematomal cell death.

Neural stem cells are considered as a candidate for cell replacement therapy in various neurological diseases. To investigate whether human neural stem cells can migrate into the adult ischemic rat brain, we transplanted immortalized human neural 'tem-like' cells intravenously 24 h after focal cerebral ischemia. The intravenously injected human neural stem-like cells were found around the infarcted area, differentiated into neurons and astrocytes in the lesioned areas, and survive up to 56 days after transplantation. The number of the injected cells increased between 7 and 14 days after transplantation with incorporating BrdU. Our findings show that intravenously injected human neural stem-like cells may incorporate into the ischemic brain, and undergo proliferation responding to the endogenous mitotic signal during the acute period of focal ischemia.

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood–injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.

Diffusion-weighted imaging (DWI) has demonstrated a focal area of cytotoxic oedema during partial status epilepticus (PSE). However, vasogenic oedema related to the breakdown of the blood-brain-barrier (BBB) and ictal hyperperfusion could be the predominant DWI findings in the epileptogenic area during PSE. We report a case of PSE with ictal aphasia, right hemiparesis, and repetitive focal motor seizure of the right side. T2-weighted image (T2WI) and apparent diffusion coefficient (ADC) maps obtained during PSE showed an increased signal in the left temporo-parietal area, indicative of vasogenic oedema. EEG documented the ictal activities and single photon emission tomography (SPECT) showed asymmetrically increased perfusion in the corresponding area. Follow-up T2WI, DWI, and ADC maps obtained 3 months later showed the disappearance of the previous abnormalities. However, T2WI showed cortical atrophy and newly developed white matter changes in the corresponding area. This case shows that DWI findings may be variable during PSE, dependent on the predominance of cytotoxic and vasogenic oedema.

Brief or prolonged seizures induce various patterns of plasticity. Axonal or dendritic remodelling and development of ectopic granule cells have been described in the hilus and molecular layer of the adult rodent hippocampus. Hippocampal cell proliferation also occurs after seizures. However, whether the seizure-induced cell proliferation plays a pathological or reparative role in the epileptic brain is unknown. In this study, we attempted to suppress the seizure-induced cell proliferation with the antimitotic agent cytosine-b-D-arabinofuranoside (Ara-C) and to examine the development of spontaneous recurrent seizures (SRS). Experimental status epilepticus was induced with pilocarpine, and Ara-C or vehicle alone was infused continuously with an osmotic minipump. SRS were video-monitored. BrdU immunohistochemistry was used for the spatial and temporal analysis of hippocampal cell proliferation, and double labelling with NeuN, calbindin and GFAP antibodies was performed for the differentiation of BrdU-positive cells. Timm staining was also performed for evaluation of mossy fibre sprouting (MFS). With continuous Ara-C infusion, the likelihood of developing SRS was decreased and, during the latent period, the development of ectopic granule cells in the hilus and new glia in the CA1 area was reduced when compared with the vehicle-infused group, while MFS was not altered. The results suggest that the hippocampal cell proliferation plays a pro-epileptogenic role rather than a compensatory role, and that the epileptogenic process may be associated with the generation of new glia in the CA1 area and/or new neurons in the dentate gyrus, particularly the ectopically located hilar granule cells.

Background: Carbon monoxide (CO) is a common cause of poisoning, and its sequelae include a progressive (25%) and a delayed relapsing form (75%). We report the diffusion-weighted MRI (DWI) findings in the delayed relapsing form of CO poisoning and characterize the types of edema. Methods: From November 1, 2000 to June 1, 2003, 5 consecutive patients (2 men, 3 women, range of age: 54–67 years), who had the delayed relapsing type of CO poisoning, underwent DWI, conventional MRI, MR angiography and SPECT. CO poisoning was diagnosed by the presence of a typical clinical history, an abnormally increased level of serum carboxyhemoglobin and MRI findings. Apparent diffusion coefficient (ADC) values were measured in all of the abnormal lesions with visual inspection of DWI and T2-weighted echo-planar imaging. Results: DWI showed high signal intensities in bilateral periventricular white matter, in the splenium of the corpus callosum, in internal capsules, and brainstem showing moderately decreased ADC values. In the globus pallidus, the ADC values were rather increased with low signal intensities on DWI. Brain SPECT showed decreased perfusion in bilateral white matter and some parts of the cerebral cortex, which correlated well with the DWI findings. Conclusions: We suggest that prominent, symmetric restricted diffusion can occur in periventricular white matter, brainstem, and corpus callosum after the delayed relapsing type of CO poisoning. Delayed cytotoxic edema can occur in this setting, which provides a new guidance for the pathogenesis of CO poisoning and the differential diagnosis of white matter diseases.

The discovery of the neurogenesis, migration and differentiation of neural stem cells in experimental models of stroke reveals a potential new facet of recovery after stroke that may translate into new treatments for stroke and other neurological disorders. New neurons are regenerated and functional recovery is enhanced with neural stem cell transplantation in stroke. In this review, we summarize the recent experiences about intravenous transplantation of human neural stem cells in various stroke models.

Background and Purpose— We aimed to generate rigorous graphical and statistical reference data based on volumetric measurements for assessing the relative severity of white matter hyperintensities (WMHs) in patients with stroke. Methods— We prospectively mapped WMHs from 2699 patients with first-ever ischemic stroke (mean age=66.8±13.0 years) enrolled consecutively from 11 nationwide stroke centers, from patient (fluid-attenuated-inversion-recovery) MRIs onto a standard brain template set. Using multivariable analyses, we assessed the impact of major (age/hypertension) and minor risk factors on WMH variability. Results— We have produced a large reference data library showing the location and quantity of WMHs as topographical frequency-volume maps. This easy-to-use graphical reference data set allows the quantitative estimation of the severity of WMH as a percentile rank score. For all patients (median age=69 years), multivariable analysis showed that age, hypertension, atrial fibrillation, and left ventricular hypertrophy were independently associated with increasing WMH (0–9.4%, median=0.6%, of the measured brain volume). For younger (≤69) hypertensives (n=819), age and left ventricular hypertrophy were positively associated with WMH. For older (≥70) hypertensives (n=944), age and cholesterol had positive relationships with WMH, whereas diabetes mellitus, hyperlipidemia, and atrial fibrillation had negative relationships with WMH. For younger nonhypertensives (n=578), age and diabetes mellitus were positively related to WMH. For older nonhypertensives (n=328), only age was positively associated with WMH. Conclusions— We have generated a novel graphical WMH grading (Kim statistical WMH scoring) system, correlated to risk factors and adjusted for age/hypertension. Further studies are required to confirm whether the combined data set allows grading of WMH burden in individual patients and a tailored patient-specific interpretation in ischemic stroke-related clinical practice.

Background and Purpose: Studies on the molecular pathways involved in the progression of intracranial large artery atherosclerosis are rare. We aimed to study the relationship between biomarkers and the risk of progression of symptomatic intracranial large artery atherosclerosis. Methods: Of 409 patients in Trial of cilostazol in symptomatic intracranial stenosis-2 (TOSS-2) study, 52 patients showed progression of symptomatic intracranial large artery atherosclerosis on MRA after 7 months. We selected 20 patients with progression and 40 age- and sex- matched control patients. We collected blood sample initially, one month and 7 month after infarction, and multiplex analysis of biomarkers including interleukin-1,2,6,8,10, soluble CD40ligand, TNF alpha, PDGF, soluble ICAM, E-selectin and VCAM , MMP-2,3,9, SOD1,2,3 and adipokines, were performed. Results: Demographic features such as age, sex, hypertension, diabetes and smoking history were not different between both groups. On univariate analysis, 7 month PDGF-AA (3053 ± 2896 pg/ml, vs 1444±1548 pg/ml), PDGF-AB/BB (15304.0±15634 pg/ml vs 5627±8656 pg/ml) level and MPO(25.7±33.9vs 9.9±8.7ng/ml) were higher in progression group. On multivariate analysis using logistic model, 7 month PDGF AA is independent prognostic factor for progression of intracranial large artery atherosclerosis (p=0.012). Conclusion: PDGF-AB/BB level is associated with progression of symptomatic intracranial large artery atherosclerosis.

Background and Purpose— Predictors of progression of intracranial atherosclerotic stenosis have not been clearly identified. We investigated whether poststroke changes in lipid profiles would affect the prognosis of symptomatic intracranial atherosclerotic stenosis. Methods— This is a substudy of Trial of cilOstazol in Symptomatic intracranial Stenosis 2 (TOSS-2). From 10 centers we enrolled 230 subjects with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or basilar artery. At baseline and 7 months after stroke, subjects underwent MR angiogram and assessment of cardiovascular risk factors including lipoprotein levels. Progression of intracranial atherosclerotic stenosis was determined by comparing stenosis on the baseline and follow-up MR angiograms. Results— Cilostazol treatment was more frequently seen in the nonprogression group (109 of 198 [55.1%]) than in the progression group (11 of 32 [34.4%]). At 7 months after stroke when compared with baseline, low-density lipoprotein cholesterol and total cholesterol levels decreased in both groups. However, only nonprogressors showed increase in high-density lipoprotein cholesterol levels between baseline and follow-up. Changes in apolipoprotein B/apolipoprotein A-I levels were not different between the groups, although apolipoprotein B/A-I at 7 months was higher in progressors than in nonprogressors. Remnant lipoprotein cholesterol levels decreased in nonprogressors, whereas they did not change in progressors. In multivariable analyses, after adjusting for cilostazol treatment and remnant lipoprotein cholesterol reduction or apolipoprotein B/A-I at 7 months, high-density lipoprotein cholesterol elevation remained as a significant predictor for the nonprogression. Conclusions— This is the first prospective multicenter study to demonstrate that high-density lipoprotein cholesterol elevation, along with remnant lipoprotein cholesterol reduction and low apolipoprotein B/A-I, is associated with prevention of angiographic progression of symptomatic intracranial atherosclerotic stenosis. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00130039.

Background: Conventional stroke registries contain alphanumeric text-based data on the clinical status of stroke patients, but this format captures imaging data in a very limited form. There is a need for a new type of stroke registry to capture both text- and image-based data. Methods and Results: We designed a next-generation stroke registry containing quantitative magnetic resonance imaging (MRI) data, ‘DUIH_SRegI’, developed a supporting software package, ‘Image_QNA’, and performed experiments to assess the feasibility and utility of the system. Image_QNA enabled the mapping of stroke-related lesions on MR onto a standard brain template and the storage of this extracted imaging data in a visual database. Interuser and intrauser variability of the lesion mapping procedure was low. We compared the results from the semi automatic lesion registration using Image_QNA with automatic lesion registration using SPM5 (Statistical Parametric Mapping version 5), a well-regarded standard neuroscience software package, in terms of lesion location, size and shape, and found Image_QNA to be superior. We assessed the clinical usefulness of an image-based registry by studying 47 consecutive patients with first-ever lacunar infarcts in the corona radiata. We used the enriched dataset comprised of both image-based and alphanumeric databases to show that diffusion MR lesions overlapped in a more posterolateral brain location for patients with high NIH Stroke Scale scores (≧4) than for patients with low scores (≤3). In April 2009, we launched the first prospective image-based acute (≤1 week) stroke registry at our institution. The registered data include high signal intensity ischemic lesions on diffusion, T2-weighted, or fluid attenuation inversion recovery MRIs, and low signal intensity hemorrhagic lesions on gradient-echo MRIs. An interim analysis at 6 months showed that the time requirement for the lesion registration (183 consecutive patients, 3,226 MR slices with visible stroke-related lesions) was acceptable at about 1 h of labor per patient by a trained assistant with physician oversight. Conclusions: We have developed a novel image-based stroke registry, with database functions that allow the formulation and testing of intuitive, image-based hypotheses in a manner not easily achievable with conventional alphanumeric stroke registries.

Objective Few studies have investigated if exercise by itself has anti-atherosclerotic effects, without combining interventions with a low-fat diet. We studied the effects of exercise as a stand-alone intervention on preexisting atheromata by measuring not only plaque size but also the levels of plaque-destabilizing matrix-metalloproteinase (MMP) activity in vivo . Methods and results We used near-infrared fluorescent (NIRF) molecular imaging with an MMP-2/9 activatable NIRF probe to visualize the inflammatory protease activity within preexisting atheromata of 17-week-old ApoE −/− mice on: (a) normal chow diet (NCD), (b) Western diet (WD), and (c) WD with treadmill exercise for 10 weeks. We also measured tissue levels of aortic lipid peroxidation (LPO) and plasma levels of glucose/lipid/cytokine profiles. Exercise did not attenuate growth of preexisting atheromatous plaques. However, exercise strongly decreased proteolytic activity in plaques for animals on WD, with levels decreasing almost to NCD levels. Exercise was associated with decreased aortic LPO levels and increased blood adiponectin/leptin levels; however, exercise did not affect WD-consumption/weight-gain or improve blood glucose/lipid profiles. Conclusions Exercise training reduced aortic MMP activity in mice with preexisting atheromata, even though they remained on a high fat diet and plaque-growth was not attenuated.

Rehabilitation after a stroke is very important because it has beneficial effects on brain function, including the promotion of plasticity. However, an optimal time window for rehabilitation interventions after hemorrhagic stroke has not been clearly defined. The aim of this study was to determine whether early exercise training initiated 24 h after an intracerebral hemorrhage (ICH) might enhance neurologic recovery more than exercise initiated 1 week after ICH without hematoma expansion and edema volume increase. We subjected adult male Sprague–Dawley rats to experimental ICH by the intrastriatal administration of bacterial collagenase. The rats were randomly divided into the following 2 groups: early training group (treadmill exercise started 24 h post-ICH; n = 18) and late training group (treadmill exercise started 1-week post-ICH; n = 18). Two weeks after surgery we performed neurologic tests (rota-rod, modified limb-placing, and adhesive-dot removal tests), and measured hematoma volumes and brain water content. In the late training group, compared with the pre-ICH performance on the rota-rod test (98.3 ± 69.4 s), the animals had significantly worse performance after the post-ICH rehabilitation (40.5 ± 52.6 s; p t -test). In the early training group however, the motor performance after the post-ICH rehabilitation (56.4 ± 73.5 s) was not significantly different from the baseline pre-ICH performance (79.8 ± 33.9 s; p = 0.24). There were no significant differences between the two groups with respect to the other neurologic tests. Early exercise did not increase hematoma size or brain water content. Early treadmill training could be performed safely, and enhanced motor recovery in a rat model of ICH. Further studies are required to translate the results into clinical significance.

Inflammation in atherosclerotic plaques causes plaque vulnerability and rupture, leading to thromboembolic complications. Cathepsin B (CatB) proteases secreted by macrophages play a major role in plaque inflammation. We used a CatB-activatable near-infrared fluorescence (NIRF) imaging agent to demonstrate the inflammatory component in mice atheromata and the atherosclerosis-modulating effects of atorvastatin or glucosamine treatments. Apolipoprotein E knockout mice ( n = 35) were fed normal chow, a Western diet, a Western diet + atorvastatin, a Western diet + glucosamine, or a Western diet + atorvastatin + glucosamine for 14 weeks. Twenty-four hours after the intravenous injection of a CatB-activatable probe, ex vivo NIRF imaging of the aortas and brains was performed, followed by histology. The CatB-related signal, observed in the aortas but not in the cerebral arteries, correlated very well with protease activity and the presence of macrophages on histology. Animals on Western diets could be distinguished from animals on a normal diet. The antiatherosclerotic effects of atorvastatin and glucosamine could be demonstrated, with reduced CatB-related signal compared with untreated animals. Plaque populations were heterogeneous within individuals, with some plaques showing a high and others a lower CatB-related signal. These differences in signal intensity could not be predicted by visual inspection of the plaques but did correlate with histologic evidence of inflammation in every case. This suggests that vulnerable inflamed plaques can be identified by optical molecular imaging.