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Cerebral collaterals is crucially important in the pathophysiology of acute ischemic stroke and associated with outcome after reperfusion therapy. We explored the effectiveness of collateral augmentation treatment with a combination of acetazolamide (ACZ) and head-down tilt (HDT) in the transient middle cerebral artery occlusion (MCAO) rat model. Transient MCAO was induced in all animals for 1.5 h, followed by reperfusion for 22.5 h. Seventy-two male Wistar rats were divided into four treatment groups: control, ACZ, HDT, and combination. Twenty sham rats, which underwent surgery, were randomly allocated to these groups. Twenty-four hours after MCAO or sham surgery, we measured the infarction volume, brain edema (aquaporin-4 [AQP4], and brain water content), and neurological deficits (Garcia and Longa tests). Collateral augmentation treatments were associated with reduced infarction volume, less brain edema, and better neurological outcomes compared with untreated animals. More specifically, ACZ and HDT treatments resulted in small infarction volumes, and HDT was associated with a low AQP4 expression and improved neurological score, while the combination of ACZ and HDT improved neurological scores and reduced brain water content. This study shows that collateral augmentation treatments are associated with a better stroke prognosis compared with untreated animals after transient MCAO. The combination of ACZ and HDT seems to have some synergistic effect, but was not proven to be superior to HDT treatment alone.

Even after extensive standard evaluation, the probable cause of stroke in some patients remains unclear; this condition is defined as cryptogenic stroke (CS). The prognosis of patients with CS is largely undetermined. We investigated whether higher brachial-ankle pulse wave velocities (baPWVs) can predict poor functional outcomes at 3 months after stroke onset in these patients. We investigated patients with CS with first-ever acute cerebral infarction who underwent baPWV measurements. The stroke subtypes were classified using the Trial of ORG 10172 in Acute Stroke Treatment classification. Poor functional outcomes were defined as modified Rankin Scale scores of2 at 3 months after stroke onset. In total, 595 patients with CS were included; among them, 360 were men (60.5%). Their mean age was 65.0 ± 12.4 years. One-hundred-eleven patients (18.7%) had poor functional outcomes. In the multivariable logistic regression analysis, the cutoff baPWV value based on the receiver-operating characteristic curve was1968 cm/s, which was determined as a strong independent predictor (OR 3.159, 95% CI 1.487-6.715, p = 0.003). The OR of the cutoff value was higher in the patients with CS with initial National Institutes of Health Stroke Scale (NIHSS) scores of ≥5 (OR 4.252, 95% CI 1.596-11.324, p = 0.004); that in the patients with initial NIHSS scores of5 was not significant (OR 1.671, 95% CI 0.620-4.505, p = 0.310). baPWV measurement during the acute stroke phase might be useful in identifying patients with CS at high risks of having a poor neurological prognosis.

The relationship between liver fibrosis and the occurrence of ischemic stroke is unknown. We investigated the correlation between liver fibrosis assessed with transient elastography (TE) and the risk of ischemic stroke.Between April 2013 and August 2014, patients with acute ischemic stroke and subjects who underwent a health check-up were included in the study. Liver fibrotic burden was assessed with TE in all participants. The degree of liver fibrosis was compared between groups by using various multiple logistic regression models and propensity-score matched analyses.Two hundred ninety-five patients with ischemic stroke (stroke group) and 1942 subjects with health check-up (control group) were included. The mean liver stiffness (LS) on TE (5.6 vs. 4.1 kPa) and the proportion of significant fibrosis (8 kPa) (9.2% vs. 1.8%) were significantly higher in the stroke than in the control group (all p0.05). These trends were observed regardless of body mass index, the degree of hepatic steatosis, and metabolic syndrome (all p0.05). The adjusted odds ratio (OR) for ischemic stroke was 1.268 (95% confidence intervals [CI] 1.183-1.358) per 1 kPa increase and 12.033 (95% CI 5.180-27.948) for significant fibrosis, compared with no fibrosis (all p 0.05). Propensity-score matched analysis also confirmed that liver fibrosis was independently associated with the risk of ischemic stroke (OR 1.804 [95% CI 1.461-2.230] per 1 kPa increase, 13.184 [95% CI 3.127-55.645] for significant fibrosis, compared with no fibrosis; all p0.001).The degree of liver fibrosis, assessed with TE, was significantly associated with the risk of ischemic stroke.

Summary Background Mood and emotional disturbances are common in patients with stroke, and adversely affect the clinical outcome. We aimed to evaluate the efficacy of early administration of escitalopram to reduce moderate or severe depressive symptoms and improve emotional and neurological dysfunction in patients with stroke. Methods This was a placebo controlled, double-blind trial done at 17 centres in South Korea. Patients who had had an acute stroke within the past 21 days were randomly assigned in a 1:1 ratio to receive oral escitalopram (10 mg/day) or placebo for 3 months. Randomisation was done with permuted blocks stratified by centre, via a web-based system. The primary endpoint was the frequency of moderate or severe depressive symptoms (Montgomery-Asberg Depression Rating Scale [MADRS] ≥16). Endpoints were assessed at 3 months after randomisation in the full analysis set (patients who took study medication and underwent assessment of primary endpoint after randomisation), in all patients who were enrolled and randomly assigned (intention to treat), and in all patients who completed the trial (per-protocol analysis). This trial is registered with ClinicalTrials.gov, number NCT01278498. Findings Between Jan 27, 2011, and June 30, 2014, 478 patients were assigned to placebo (n=237) or escitalopram (n=241); 405 were included in the full analysis set (195 in the placebo group, 210 in the escitalopram group). The primary outcome did not differ by study group in the full analysis set (25 [13%] patients in the placebo group vs 27 [13%] in the escitalopram group; odds ratio [OR] 1·00, 95% CI 0·56–1·80; p>0·99) or in the intention-to-treat analysis (34 [14%] vs 35 [15%]; OR 1·01, 95% CI 0·61–1·69, p=0·96). The study medication was generally well tolerated; the most common adverse events were constipation (14 [6%] patients who received placebo vs 14 [6%] who received escitalopram), muscle pain (16 [7%] vs ten [4%]), and insomnia (12 [5%] vs 12 [5%]). Diarrhoea was more common in the escitalopram group (nine [4%] patients) than in the placebo group (two [1%] patients). Interpretation Escitalopram did not significantly reduce moderate or severe depressive symptoms in patients with acute stroke. Funding Dong-A Pharmaceutical and Ministry for Health, Welfare, and Family Affairs, South Korea.

Although early neurological deterioration (END) during the acute stroke period is known to be directly associated with poor short- and long-term outcomes, few studies have investigated the ability to predict END. The aim of this study was to investigate whether there are differences in the occurrence of END according to the ischemic stroke predictive risk score (iScore), which was developed to predict short- and long-term mortality.We collected data from 2150 consecutive ischemic stroke patients who were admitted to 3 study hospitals between January 2012 and June 2014. END was defined as an increase (≥4) in the National Institutes of Health Stroke Scale score within the first 72 hours of stroke onset. We calculated the 30-day iScore for each patient to determine the relationship between the iScore and occurrence of END.Among 2150 patients, END was observed in 146 patients (6.8%). There was a positive correlation between the iScore and occurrence of END. After adjusting for potential confounders, the iScore was independently associated with END (odds ratio: 1.217 per 20-point increase in iScore, 95% confidence interval: 1.121-1.321, P .001). There was good correlation between observed and expected outcomes predicted by the iScore (Pearson correlation coefficient: r = .950, P .001).The iScore can predict the risk of END development within the acute stroke stage.

Purpose There are various patterns in determining the choice of the first-line antithrombotic agent for acute stroke with non-valvular atrial fibrillation. We investigated the efficacy and safety of non-vitamin K oral anticoagulants as first-line antithrombotics for patients with acute stroke and non-valvular atrial fibrillation. Materials and Methods Patients with non-valvular atrial fibrillation and ischemic stroke or transient ischemic attack within 24 h from stroke onset were included. On the basis of the first regimen used and the regimen within 7 days after admission, the study population was divided into three groups: 1) antiplatelet switched to warfarin (A-W), 2) antiplatelet switched to NOAC (A-N), and 3) NOAC only (N only). We compared the occurrence of early neurologic deterioration, symptomatic intracranial hemorrhage, systemic bleeding, and poor functional outcome at 90 days. Results Of 314 included patients, 164, 53, and 97 were classified into the A-W, A-N, and N only groups, respectively. Early neurologic deterioration was most frequently observed in the A-W group (9.1%), followed by the A-N (5.7%) and N only (1.0%) groups (p = 0.017). Multivariable analysis adjusting for potential confounders demonstrated that the N only group was independently associated with a lower rate of early neurologic deterioration (odds ratio [OR] 0.104, 95% CI 0.013-0.831) or poor functional outcome at 90 days (OR 0.450, 95% CI 0.215-0.940) than the A-W group. However, the rate of symptomatic intracranial hemorrhage or any systemic bleeding event did not differ among the groups. Conclusion Using non-vitamin K oral anticoagulants as the first-line regimen for acute ischemic stroke may help prevent early neurologic deterioration without increasing the bleeding risk.

Cerebral small vessel diseases (SVDs) are related to stroke or cognitive dysfunction. n-3-polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) represent possible disease-modifying factors for cardiovascular disease or dementia. Our hypothesis was that a low proportion of plasma FAs would be associated with cerebral SVDs. We prospectively enrolled 220 patients with a first-episode cerebral infarction within 7 days after symptom onset. The composition of plasma FAs was analyzed by gas chromatography methods. The presence and burden of cerebral microbleeds (CMBs), high-grade white matter changes (HWCs), high-grade perivascular spaces (HPVSs), and asymptomatic lacunar infarctions (ALIs) were investigated. The mean proportion (± SD) was 2.0 ± 0.7 for EPA, 8.9 ± 1.5 for DHA, and 12.0 ± 2.1 for ∑ n-3-PUFAs. In total, 46 (20.9%) patients had CMBs, 64 (29.1 %) had HWCs, 57 (25.9%) had HPVSs, and 65 (29.5%) had ALIs. In univariate analyses, CMBs, HWCs, and HPVSs were each negatively correlated with the proportion of EPA, DHA, and ∑ n-3-PUFAs. In the multivariate analysis, a lower proportion of EPA, DHA and ∑ n-3-PUFAs was associated with the presence of CMBs, HWCs and HPVS, but not ALIs. Total SVDs score was inversely correlated with the proportion of EPA, DHA and ∑ n-3-PUFAs. Overall, we found an association between low proportions of plasma n-3-PUFAs and cerebral SVDs pathologies. Further studies are needed to explore the association and potential therapeutic role of FAs in cerebral SVDs.

The ankle-brachial blood pressure index (ABI) is an established clinical test for assessment of peripheral arterial disease and an indicator of generalized atherosclerosis. We investigated whether low ABI is associated with long-term functional outcome in patients with acute cerebral infarction.We included 775 patients with acute cerebral infarction who were admitted within 7 days from stroke onset and had completed an ABI measurement during admission. Poor functional outcome was defined as a modified Rankin Scale of more than 2 at three months from stroke onset. The association between low ABI and poor functional outcome was analyzed using logistic regression analysis.A low ABI (0.9) was present in 10.1% of patients. At three months from stroke onset, 16.9% of patients showed poor functional outcome (mRS2). After adjusting for conventional cardiovascular risk factors and the presence of cerebral atherosclerosis, a low ABI was independently associated with poor functional outcome (odds ratio 2.523, 95% CI 1.330-4.785, p = 0.005).The presence of a low ABI was associated with an increased risk of poor functional outcome in patients with acute cerebral infarction. Screening for low ABI among stroke patients may be necessary to identify individuals at increased risk of poor functional outcome. Proper and individualized treatment for patients with a low ABI may improve long-term functional outcome following acute cerebral infarction.

Background Atrial fibrillation (AF), which is the most common etiology of cardioembolic stroke, may be accompanied by other cardiac sources of embolism. The heterogeneity and multiplicity of the cardiac sources of embolism may influence stroke severity via formation of thrombi with heterogenous compositions, ages, and sizes. We investigated among stroke patients with AF whether stroke severity is different between patients with concomitant potential cardiac sources of embolism and those without. Methods The subjects for this study were consecutive patients with cerebral infarction and AF who underwent transesophageal echocardiography during a 10-year period. The definitions and determination of high- and medium-risk potential cardiac sources of embolism were based on the Trial of Org 10172 in Acute Stroke Treatment classification. Initial stroke severity and infarct sizes were compared between patients with concomitant potential cardiac sources of embolism and those without. Results Of the 266 patients enrolled, 181 (68.0%) had one or more concomitant potential cardiac sources of embolism. Left atrial thrombus and spontaneous echo contrast were most common. Patients with concomitant potential cardiac sources of embolism had a higher median score on the initial National Institute of Health Stroke Scale (6 vs. 3, p = 0.005) and a larger infarction diameter (45.4 ± 31.3 mm vs. 35.5 ± 26.6 mm, p = 0.002) than those without. Occlusion of the symptomatic arteries was more frequently detected in patients with concomitant potential cardiac sources of embolism. Conclusions Stroke patients with AF frequently had concomitant potential cardiac sources of embolism, and strokes were more severe in them.

Background This study aimed to describe patterns of long-term antithrombotic use in acute ischemic stroke (AIS) patients with non-valvular atrial fibrillation (NVAF) in Korea and their impacts on clinical events before introduction of non-vitamin K antagonist oral anticoagulants (NOAC) into practice in 2015. Methods Patients with NVAF who were admitted due to the AIS and discharged no later than 2008 were enrolled retrospectively. Data were collected at 11 time points during the first 3 years of follow-up. The primary outcome event was a composite of stroke recurrence, major bleeding, and death. Vitamin K antagonist (VKA) users were categorized into a well-controlled INR group and a poorly-controlled INR group (modified TTR ≥47.0% vs

Vascular smooth muscle cell (VSMC) proliferation and migration in response to platelet-derived growth factor (PDGF) play an important role in the development of atherosclerosis and restenosis. Recent evidence indicates that PDGF increases intracellular levels of reactive oxygen species in VSMCs and that both PDGF-induced VSMC proliferation and migration are reactive oxygen species-dependent. Danshen is a representative oriental medicine used for the treatment of vascular disease. Previously, we reported that magnesium lithospermate B, an active component of Danshen, is a potent antioxidant. Thus we investigated the therapeutic potential of magnesium lithospermate B in neointimal formation after carotid artery injury in rats along with its effects on the PDGF signaling pathway for stimulating VSMC proliferation and migration in vitro. PDGF is dimeric glycoprotein composed of two A or two B chains. In this study, we used PDGF-BB, which is one of the isoforms of PDGF (i.e., PDGF-AA, PDGF-BB, and PDGF-AB). Our results demonstrated that magnesium lithospermate B directly scavenged reactive oxygen species in a xanthine/xanthine oxidase system and reduced PDGF-BB-induced intracellular reactive oxygen species generation in VSMCs. In a rat carotid artery balloon injury model, magnesium lithospermate B treatment (10 mg/kg/day, i.p) showed a significant effect on the prevention of neointimal formation compared with vehicle treatment. In cultured VSMCs, magnesium lithospermate B significantly attenuated PDGF-BB-induced cell proliferation and migration as measured by 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide (MTT) assay and transwell migration assays, respectively. Further, magnesium lithospermate B inhibited PDGF-BB-induced phosphorylation of phospatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways by scavenging reactive oxygen species. Together, these data indicated that magnesium lithospermate B, a potent reactive oxygen species scavenger, prevented both injury-induced neointimal formation in vivo and PDGF-BB-induced VSMC proliferation and migration in vitro, suggesting that magnesium lithospermate B may be a promising agent to prevent atherosclerosis and restenosis following angioplasty.

Brain edema is a leading cause of death after stroke. Cytotoxic edema, which is most severe in astrocytes, begins within a few minutes of adenosine triphosphate depletion and reflects the ultimate infarct size. Vasogenic edema is caused by uncontrolled fluid leakage from the blood to the brain parenchyma through a weakened blood-brain barrier (BBB) and contributes to an actual net volume increase of the brain, which often leads to death. Recent research on ischemia-induced injury mechanisms of the microvasculature has led to the disclosure of the mechanisms and cellular pathways leading to BBB breakdown. In addition, the introduction of magnetic resonance imaging to clinical practice has enabled the evaluation of edema severity in stroke patients and differentiation between cytotoxic and vasogenic edema. Free radicals exert their deleterious actions during both cytotoxic and vasogenic edema. They can contribute to BBB disruption directly and can also trigger molecular pathways related to the dysfunction of ion transporters in the cell membrane and those related to increased vascular permeability. The development of effective therapeutic strategies aimed at reducing brain edema based on targeting specific molecular pathways involved may reduce death and disability from stroke.

Matrix metalloproteinase (MMP)-2 and MMP-9 were analyzed by gelatin zymography and an enzyme-linked immunosorbent assay (ELISA) in a cerebrospinal fluid (CSF) from patients with tuberculous meningitis (n=24), acute aseptic meningitis (n=23) and the control (n=10). The MMP-2 and MMP-9 levels were significantly higher in the samples from the tuberculous meningitis patients than those from either the aseptic meningitis patients or the controls. In tuberculous meningitis, the patients with late neurologic complications had higher MMP-2 and MMP-9 levels than those without. The persistent increase in the MMP-2 and MMP-9 levels was associated with the development of complications following tuberculous meningitis. Inhibiting the MMPs may be an effective strategy for preventing or reducing the complications in tuberculous meningitis.

To determine whethr oxygen free radicals are involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, the effect of dimethylthiourea (DMTU), an effective hydroxyl radical scavenger, on MPTP-induced changes of [3H]dopamine uptake was investigated in rat striatal slices. The uptake of [3H]dopamine was decreased by MPTP treatment, and DMTU prevented the MPTP-induced decreases of [3H]dopamine uptake in a dose-dependent manner. The highest dose of DMTU used in this study completely prevented the MPTP-induced decrease of [3H]dopamine uptake. These results indicate that free radicals play a major role in the pathogenetic mechanism of MPTP-induced neurotoxicity.