Fc-saxatilin inhibits VEGF-induced permeability by regulating claudin-5 expression in human brain microvascular endothelial cells

The disruption of the blood-brain barrier influences the degree of brain damage and prognosis in cerebral ischemia or other brain diseases accompanied by inflammation. Vascular endothelial growth factor (VEGF) released during brain ischemia or inflammation has been implicated in the breakdown of the blood-brain barrier by increasing endothelial permeability. Saxatilin, a disintegrin-containing RGD motif, has been reported to disaggregate platelets via interactions with platelet integrins and to have a thrombolysis effect. Additionally, the Fc-saxatilin fusion protein reduces vascular leakage in cerebral ischemia in mice. In this study, we show that Fc-saxatilin prevents VEGF-induced permeability in human brain microvascular endothelial cells (HBMECs). The activation of Src and Fak, downstream signaling proteins of VEGF in the induction of endothelial permeability, was inhibited by Fc-saxatilin in HBMECs. The downregulation of a tight junction protein, claudin-5, at the protein and mRNA levels by VEGF was recovered by Fc-saxatilin. Our findings suggest that Fc-saxatilin attenuates VEGF-induced endothelial permeability via the regulation of downstream signaling, and this may contribute to its protective effect against vascular leakage in the ischemic brain.ope

Pathophysiologic and Therapeutic Perspectives Based on Thrombus Histology in Stroke

Recent advances in endovascular thrombectomy have enabled the histopathologic analysis of fresh thrombi in patients with acute stroke. Histologic analysis has shown that the thrombus composition is very heterogeneous between patients. However, the distribution pattern of each thrombus component often differs between patients with cardiac thrombi and those with arterial thrombi, and the efficacy of endovascular thrombectomy is different according to the thrombus composition. Furthermore, the thrombus age is related to the efficacy of reperfusion therapy. Recent studies have shown that neutrophils and neutrophil extracellular traps contribute to thrombus formation and resistance to reperfusion therapy. Histologic features of thrombi in patients with stroke may provide some clues to stroke etiology, which is helpful for determining the strategy of stroke prevention. Research on thrombus may also be helpful for improving reperfusion therapy, including the development of new thrombolytic agents.ope

Updated Korean Clinical Practice Guidelines on Decompressive Surgery for Malignant Middle Cerebral Artery Territory Infarction

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Immediate Anticoagulation for Acute Cardioembolic Stroke is Still Popular in Selective Cases in Korea

BACKGROUND: Although current guidelines do not recommend immediate anticoagulation therapy (IAC) for acute ischemic stroke, judicious debates are still lingering on whether it might be done for acute cardioembolic stroke (ACES). We surveyed current practice patterns of anticoagulation therapy for ACES in Korea, and analyzed their related factors. METHODS: Using a web-based system, all neurology staffs of training hospitals in Korea surveyed about when and how they commenced anticoagulation therapy in the hypothetical cases with ACES. RESULTS: Of the 359 subjects invited, 281 responded to the e-mail, of whom 76 abstained from participating. The number of participants was therefore 205 (57.1%). Although a few physicians (4.4%) always performed IAC and some (10.7%) never did, most physicians made different decisions according to infarct size and presence of hemorrhagic transformation (HTr): IAC was performed more often in cases with medium-sized or small infarct than large one (68.2% vs. 35.9%, P<0.001), and in cases without HTr (68.6% vs. 34.9%, P<0.001). The most common method of administration was 'heparin followed by warfarin' (68.2%), and then 'warfarin alone' or 'warfarin with aspirin'. If IAC was not commenced, it resumed most commonly between 1 and 2 weeks after the onset (44.0%). CONCLUSION: Quite many neurologists in Korea did IAC in selective ACES, e.g. small sized infarction without HTr. Further studies are needed to prove the efficacy of IAC therapy in this selective population.ope

Rapid Differential Endogenous Plasminogen Activator Expression After Acute Middle Cerebral Artery Occlusion

BACKGROUND AND PURPOSE: During focal cerebral ischemia, the microvascular matrix (ECM), which participates in microvascular integrity, is degraded and lost when neurons are injured. Loss of microvascular basal lamina antigens coincides with rapid expression of select matrix metalloproteinases (MMPs). Plasminogen activators (PAs) may also play a role in ECM degradation by the generation of plasmin or by MMP activation. METHODS: The endogenous expressions of tissue-type plasminogen activator (tPA), urokinase (uPA), and PA inhibitor-1 (PAI-1) were quantified in 10-microm frozen sections from ischemic and matched nonischemic basal ganglia and in the plasma of 34 male healthy nonhuman primates before and after middle cerebral artery occlusion (MCA:O). RESULTS: Within the ischemic basal ganglia, tissue uPA activity and antigen increased significantly within 1 hour after MCA:O (2P<0.005). tPA activity transiently decreased 2 hours after MCA:O (2P=0.01) in concert with an increase in PAI-1 antigen (2P=0.001) but otherwise did not change. The transient decrease in free tPA antigen was marked by an increase in the tPA-PAI-1 complex (2P<0.001). No significant relations to neuronal injury or intracerebral hemorrhage were discerned. CONCLUSIONS: The rapid increase in endogenous PA activity is mainly due to significant increases in uPA, but not tPA, within the ischemic basal ganglia after MCA:O. This increase and an increase in PAI-1 coincided with latent MMP-2 generation and microvascular ECM degeneration but not neuronal injury.ope

Focused Update of 2009 Korean Clinical Practice Guidelines for the Antiplatelet Therapy in Secondary Prevention of Stroke

The aim of this update of Korean clinical practice guidelines for stroke is to provide timely evidence-based recommendations on the antiplatelet therapy in secondary prevention of stroke. Evidence-based recommendations are included for the use of antiplatelet agents for noncardioembolic stroke. Changes in the guidelines necessitated by new evidence will be continuously reflected in the new guidelineope

Long-Term Changes in Post-Stroke Depression, Emotional Incontinence, and Anger

Background and purpose: Long-term changes in post-stroke depression (PSD), post-stroke emotional incontinence (PSEI), and post-stroke anger (PSA) have rarely been studied. Methods: This is a sub-study of EMOTION, a randomized, placebo-controlled trial, that examined the efficacy of escitalopram on PSD, PSEI, and PSA in patients with stroke. We interviewed patients at the long-term period (LTP) using predefined questionnaires: Montgomery-Åsberg depression rating scale (MADRS) for PSD, modified Kim's criteria for PSEI, and Spielberger trait anger scale for PSA. Additionally, the ENRICHD Social Support Instrument (ESSI) for the social support state and the modified Rankin Scale (mRS) were measured. We investigated the changes in and factors behind PSD, PSEI, and PSA at LTP. Results: A total of 222 patients were included, and the median follow-up duration was 59.5 months (interquartile range, 50 to 70). Compared to the data at 6 months post-stroke, the prevalence of PSEI (11.7% at 6 months, 6.3% at LTP; P=0.05) and mean anger score (21.62, 16.24; P<0.01) decreased, while the prevalence of PSD (35.6%, 44.6%; P=0.03) and mean MADRS (6.16, 8.67; P<0.01) increased at LTP. ESSI was associated with PSD and PSA, but not with PSEI. The effect of the baseline National Institutes of Health Stroke Scale score on PSD decreased over time. The effect of low social support on PSD was greater than that of mRS at LTP. Conclusions: The prevalence and degree of PSD significantly increased, while those of PSEI and PSA decreased at LTP. PSD in this stage appeared to be more closely associated with a lack of social support than patients' physical disabilities.ope

2011 Update of Scientific Statement for the Primary Prevention of Stroke: Dyslipidemia and Inflammation

BACKGROUND: This scientific statement is intended to provide a systematic review of new evidences in dyslipidemia and inflammation for primary stroke prevention. METHODS: Using a structured literature search, we identified major observational studies, clinical trials, meta-analyses, and updated major guidelines published between July 2007 and November 2010. In addition to the brief summary of earlier evidences employed in the first edition of Korean clinical practice guideline for primary prevention of stroke, we summarized the newly identified evidences. RESULTS: For dyslipidemia, observational studies further support a strong association between ischemic stroke and high total and low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol. Two clinical trials and 6 meta-analyses confirm statin efficacy for primary prevention of stroke in high risk patients. Efficacy of other lipid-lowering agents is not established. For inflammation, inflammatory markers might help to identify patients having high risk for stroke or cardiovascular event and to decide whether statin therapy is indicated, but its usefulness for broad population needs to be confirmed. CONCLUSIONS: Writing committee will continue to keep an eye on upcoming evidences to timely update the guideline for primary stroke prevention in dyslipidemia and inflammation.ope

Focused Update of 2009 Korean Clinical Practice Guidelines for the Surgical or Interventional treatment of Extracranial Carotid Artery Stenosis in Secondary Prevention of Stroke

Since the publication of the first edition of Korean clinical practice guidelines of secondary stroke prevention, encouraging data from recent large clinical trials and meta-analysis have led us to consider many therapeutic options in the treatment of symptomatic extracranial carotid stenosis. Accordingly, the writing group of Clinical Research Center for Stroke decided to provide recent views on the therapeutic revascularization of extracranial carotid stenosis, and timely evidence-based recommendations. In this updated version, new evidences about carotid angioplasty/stenting, treatment timing, and perioperative preparation are given, and qualifying conditions for operator are elucidated. This refinement was based on current consensus between Korean Society of Intravascular Neurosurgery, Korean Society of Interventional Neuroradiology, and Korean Society of Cerebrovascular Surgery and approved by Korean Stroke Society, Korean Neurological Association, and Korean Society of Geriatric Neurology. These recommendations are subject to future correction based on new evidences from ongoing and future studiesope

Current Status and Problems of Stroke Units in Korea: Results of a Nationwide Acute Care Hospital Survey by the Korean Stroke Society

Background: The patients who received organized inpatient care are more likely to survive and to be independent. The benefit is most apparent in units based in a discrete ward, stroke unit (SU). The observed benefit is sufficiently large to warrant efforts of widespread implementation of SU care. The Korean Stroke Society surveyed acute stroke care hospitals to know the density and the distribution of SU in Korea. Methods: One hundred-sixty one acute care hospitals were selected among those included in the 5th Quality Audit in 2014 by the Health Insurance Review and Assessment Service of Korea. A senior director of stroke service in each hospital was chosen and asked about the current status of acute stroke care including SU and major obstacles to establish SU in each hospital. Results: The results of the questionnaire revealed the shortage of a total SU number and markedly uneven distribution of SU between rural and urban area. Most hospitals indicated the absence of the insurance reimbursement for medical service in SU, which served as the fundamental cause of lack of skilled manpower for establishing SU. Conclusions: The state-of-the-art SU, which is properly certified or designated, should be spread out more evenly in Korea for the optimal treatment of public regardless of a residential district. Government should encourage and support for the establishment of SU, which is an important first step toward making it reality.ope