Jei Kim

Risk Factors and Stroke Mechanisms in Atherosclerotic Stroke Intracranial Compared With Extracranial and Anterior Compared With Posterior Circulation Disease

Background and Purpose— The aim of this study was to investigate differences in risk factors and stroke mechanisms between intracranial atherosclerosis (ICAS) and extracranial atherosclerosis (ECAS) and between anterior and posterior circulation atherosclerosis. Methods— A multicenter, prospective, Web-based registry was performed on atherosclerotic strokes using diffusionweighted magnetic resonance imaging and magnetic resonance angiography. Stroke mechanisms were categorized as artery-to-artery embolism, in situ thrombo-occlusion, local branch occlusion, or hemodynamic impairment. Results— Onethousand patients were enrolled from 9 university hospitals. Age (odds ratio [OR], 1.033; 95% confidence interval [CI], 1.018–1.049), male gender (OR, 3.399; 95% CI, 2.335–4.949), and hyperlipidemia (OR, 1.502; 95% CI, 1.117–2.018) were factors favoring ECAS (vs ICAS), whereas hypertension (OR, 1.826; 95% CI, 1.274–2.618; P=0.001) and diabetes mellitus (OR, 1.490; 95% CI, 1.105–2.010; P=0.009) were related to posterior (vs anterior) circulation diseases. Metabolic syndrome was a factor related to ICAS (vs ECAS) only in posterior circulation strokes (OR, 2.433; 95% CI, 1.005–5.890; P=0.007). Stroke mechanisms included arterytoartery embolism (59.7%), local branch occlusion (14.9%), in situ thrombo-occlusion (13.7%), hemodynamic impairment (0.9%), and mixed (10.8%). Anterior ICAS was more often associated with artery-to-artery embolism (51.8% vs 34.0%) and less often associated with local branch occlusion (12.3% vs 40.4%) than posterior ICAS (P<0.001). Conclusions— The prevalence of risk factors and stroke mechanisms differ between ICAS and ECAS, and between anterior and posterior circulation atherosclerosis. Posterior ICAS seems to be closely associated with metabolic derangement and local branch occlusion. Prevention and management strategies may have to consider these differences.

The expression of VEGF receptor genes is concurrently influenced by epigenetic gene silencing of the genes and VEGF activation.

Vascular endothelial growth factor (VEGF) activates the VEGF-VEGF receptor (VEGFR) signaling pathway in angiogenesis. Some cancer cell lines show decreased expression of the two VEGFRs, Flt-1 and KDR, even though VEGF is uniformly expressed in cancer cell lines. Promoter methylation is a well-known cause of epigenetic gene silencing in cancer cells. Although VEGF, Flt-1 and KDR have typical CpG islands in their promoter regions, the epigenetic transcriptional alterations of these genes have not yet been described. The present study evaluated the epigenetic gene silencing of VEGF and VEGFR genes in cancer tissues. We also analyzed whether the epigenetic alterations of VEGFR genes influence VEGFR expression concurrently with VEGF activation in cancer tissues. All cancer tissues we tested showed no methylation of VEGF, and variable promoter hypermethylation of Flt-1 and KDR. The promoter hypermethylation of Flt-1 and KDR was correlated with decreasing expression of the respective genes. In contrast, an increase in VEGF expression was positively correlated with Flt-1 and KDR expression in primary cancer tissues. The opposing influences of promoter methylation of VEGFR and increased VEGF expression concurrently influence Flt-1 and KDR expression in stomach cancer, colon cancer and hepatocellular carcinoma. The findings we observed showed that the epigenetic alteration developing in VEGFR genes might be an important factor to concurrently modulate expressions of the genes in addition to VEGF stimulation in cancer tissues. The epigenetic silencing of VEGFR genes should be considered in the activation of VEGF-VEGFR signaling pathway in the cancer cells.

Promoter methylation status of VEGF receptor genes: A possible epigenetic biomarker to anticipate the efficacy of intracellular-acting VEGF-targeted drugs in cancer cells

We evaluated whether the inhibitory effects of vascular endothelial growth factor (VEGF)-targeted drugs on the proliferation of cancer cells differed according to VEGF receptor (VEGFR) genes, Flt1 and KDR, promoter methylation status. Five hyper-VEGFR-methylation and six no-VEGFR-methylation cancer cells were used for the present study, together with human umbilical endothelial cells (HUVECs) as a control. No-VEGFR-methylation cancer cells showed higher expression of Flt1 and KDR than hyper-VEGFR-methylation cancer cells. Hyper-VEGFR-methylation cancer cells only showed increased expression and protein levels of Flt1 and KDR after treatment with the demethylase 5-aza-2’-deoxycytidine. Two drugs (a VEGF-specific-antibody, bevacizumab, and a KDR-specific-antibody) targeting extracellular VEGF-VEGFR signaling and two VEGF-specific-tyrosine kinase inhibitors (PTK/ZK and sunitinib) targeting intracellular VEGFR signaling were used in the cell proliferation assay. HUVECs showed dose- and time-dependent proliferation decrease with all tested drugs over a 72 h incubation period. No- or hyper-VEGFR-methylation cancer cells showed no significant proliferation differences after treatment with VEGF-specific-antibody or VEGFR2-specific-antibody. After PTK/ZK or sunitinib treatment, no-VEGFR-methylation cancer cells showed dose- or time-dependent decreases in proliferation. Hyper-VEGFR-methylation cancer cells also showed proliferation inhibition by VEGF-specific-tyrosine kinase inhibitors after demethylation of Flt1 and KDR. Proliferation inhibition synergistically increased after combination of demethylation with PTK/ZK in hyper-VEGF-methylation cancer cells. We observed that intracellular targeting of VEGF-VEGFR signaling could be more effective than extracellular targeting of the pathway in the suppression of proliferation of some cancer cells. In particular, the efficacy of intracellular targeting of VEGF-specific-tyrosine kinase inhibitors might be influenced by the epigenetic alteration of VEGFRs.

MRI of intracranial subependymoma : report of a case

SummarySubependymoma is a rare, benign intraventricular tumour and a case of septum pellucidum origin examined with CT and MR is reported. Well demarcated non-enhancing mass with multiple small intratumoral cysts is demonstrated on CT and MR images. The differential diagnosis from ependymoma has some therapeutic implications but may not be possible by CT or MRI.

Efficacy of early administration of escitalopram on depressive and emotional symptoms and neurological dysfunction after stroke: a multicentre, double-blind, randomised, placebo-controlled study.

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-Åsberg 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.

Establishment of Government-Initiated Comprehensive Stroke Centers for Acute Ischemic Stroke Management in South Korea

Background and Purpose— In 2008, the Ministry of Health and Welfare of South Korea initiated the Regional Comprehensive Stroke Center (CSC) program to decrease the incidence and mortality of stroke nationwide. We evaluated the performance of acute ischemic stroke management after the Regional CSC program was introduced. Methods— The Ministry of Health and Welfare established 9 Regional CSCs in different provinces from 2008 to 2010. All Regional CSCs have been able to execute the critical processes independently for stroke management since 2011. The Ministry of Health and Welfare was responsible for program development and financial support, the Regional CSC for program execution, and the Korea Centers for Disease Control and Prevention for auditing the execution. We analyzed prospectively collected data on the required indices from 2011 and repeated the analysis the following year for comparison. Results— After the Regional CSCs were established, the first brain image was taken within 1 hour from arrival at the emergency room for all patients with stroke; the length of hospital stay decreased from 14 to 12 days; for the rapid execution of thrombolysis, the first brain image was taken within 12 minutes; intravenous and intra-arterial thrombolysis were started within 40 and 110 minutes, respectively, after emergency room arrival; and the hospital stay of thrombolytic patients decreased from 19 to 15 days. Conclusions— The Regional CSC program has improved the performance of acute stroke management in South Korea and can be used as a model for rapidly improving stroke management.

T cell subsets in chronic hepatitis B and the effect of prednisolone withdrawal and interferon alpha - 2b

Objectives The evaluations of the pathogenetic roles of cell mediated immunity and of the preventive effect for disease progression with interferon(IFN) treatment in patients with chronic active hepatitis-B(CAH-B) are the objectives of this study. Methods Thirty-two patients with CAH-B were treated with interferon α-2b(IFN α-2b) with prednisolone withdrawal and 30 control patients were treated with conventional hepatotonics for 6 months. Peripheral total T cell fractions and T cell subsets of the patients with CAH-B, treated with IFNα-2b with prednisolone withdrawal, were examined 1 month before administration of prednisolone, and compared with 12 normal controls for assessing the potential role of cellular immunity in the development of CAH-B. To estimate the effectiveness of IFN therapy for the patients with CAH-B, levels of various liver function tests, HBsAg, anti-HBs, HBeAg, anti-HBe, HBV DNA, anti-HCV and others were assessed for the treatment group and compared with control patients at pre- and post-treatment period each. Results The value of CD4 was significantly lower in patients with CAH-B than normal controls(36.3±7.7% vs 42.1±5.7%, p<0.05) and the value of CD8 was significantly higher in patients with CAH-B than normal controls(30.6±10.3% vs 24.3±5.2%, p<0.05) before prednisolone administration. The patients in responder group (n=26) had significantly lower CD4 cells compared with normal controls, but non-responders (n=6) did not have. The levels of liver function test (LFT) in the patients with IFN α-2b treatment with, prednisolone withdrawal were not different from the control patient group at pretreatment, but significantly lower than control patient group’s after treatment, regardless of response to IFN α-2b treatment with prednisolone withdrawal. Conclusions The cellular immunity of the host may have a potential role in the pathogenesis of chronicity of hepatitis B infection. IFN α-2b treatment with prednisolone withdrawal may be regarded as one of the effective treatment modalities for the inhibition of disease progression in patients with CAH-B.

Serotonin transporter gene polymorphisms may be associated with poststroke neurological recovery after escitalopram use

Objective Selective serotonin reuptake inhibitors (SSRIs) putatively improve neurological recovery after stroke. We aimed to investigate whether serotonin transporter (SERT) gene polymorphisms are related to the responsiveness to SSRIs in the poststroke neurological recovery. Methods This was a post hoc analysis of the EMOTION study (ClinicalTrials.gov NCT01278498), a randomised, placebo-controlled, double-blind trial examining the efficacy of escitalopram on emotional and neurological disturbances after acute stroke. Patients with no/minimal disability initially (modified Rankin Scale (mRS) 0–1) were excluded. Of the participants, 301 underwent genetic studies of the STin2 (a variable number tandem repeat (VNTR) in intron 2) (STin2 12/10 and STin2 12/12 genotypes) and 5-HTTLPR (a variable-length repeat in the promoter region) polymorphisms of SERT. We explored whether neurological function (National Institutes of Health Stroke Scale (NIHSS) score and mRS) at 3 months would differ according to SERT polymorphisms within each treatment arm (escitalopram and placebo). Results Among the escitalopram users (n=159), neurological function in subjects with STin2 12/10 (n=29) improved significantly more than that in STin2 12/12 carriers (n=130) at 3 months. After adjusting for age, initial NIHSS and depression, STin2 12/10 independently predicted a good clinical outcome (mRS 0–1) (OR 2.99, 95% CI 1.04 to 8.58) at 3 months. However, differences between STin2 polymorphisms were not shown in the placebo group (n=142). 5-HTTLPR polymorphisms were not associated with neurological recovery in any treatment group. Conclusion STin2 VNTR polymorphisms may be associated with poststroke neurological recovery after SSRI therapy. Further studies are needed to identify the role of serotonin in neurological recovery after stroke.

Impacts of Rapid Recanalization and Collateral Circulation on Clinical Outcome after Intraarterial Thrombolysis

Background and Purpose Rapid recanalization might improve clinical outcomes after intraarterial thrombolysis (IAT) for acute ischemic stroke patients with collateral circulation. We determined whether rapid recanalization and collateral circulation affect clinical outcomes after IAT. Methods We retrospectively evaluated the clinical and radiological data of 134 consecutive patients who underwent IAT for intracranial artery occlusion. The interval from symptom onset to recanalization after IAT (onset-to-recanalization time) as an estimate of the probability of good clinical outcome (modified Rankin scale 0-2) was calculated in patients with collateral circulation in the ischemic hemisphere, which was rated poor (0/1 American Society of Interventional and Therapeutic Neuroradiology criteria) or good (2-4). Changes in National Institute of Health Stroke Scale (NHISS) score before and after IAT and modified Rankins scale scores 3 months after discharge were compared with respect to onset-to-recanalization time. Results In patients with good collateral circulation, the estimated onset-to-recanalization time for a 0.5 probability of a good clinical outcome was 347 minutes; with poor collateral circulation, it was 172 minutes for a 0.2 probability of good clinical outcome. Outcome analyses according to onset-to-recanalization time showed patients recanalized <6 hours had lower NHISS scores (<4.5, 4.5-6, >6 hours of onset-to-recanalization time, and non-recanalization: 5.1, 6.9, 11.9, and 19.8, respectively) at discharge and higher percentages of good clinical outcome (69%, 66.7%, 21.9%, and 0%, respectively) 3 months after IAT. Conclusions The time window to expect a high probability of a good clinical outcome after IAT is highly dependent on the collateral circulation.

High red blood cell composition in clots is associated with successful recanalization during intra-arterial thrombectomy

We evaluated the composition of individual clots retrieved during intra-arterial thrombectomy in relation to recanalization success, stroke subtype, and the presence of clot signs on initial brain images. We analyzed clot and interventional data from 145 retrieval trials performed for 37 patients (69.5±14.0 years, 20 men, large artery atherosclerosis, n = 7; cardioembolism, n = 22; undetermined etiology, n = 8) who had undergone intra-arterial thrombectomy. Rates of clot retrieval and successful recanalization (Arterial Occlusive Lesion score of 2–3) for separate retrieval trials were evaluated. The area occupied by red blood cell (RBC), fibrin/platelets, and white blood cell (WBC) was measured from digitized images of hematoxylin-eosin stained clots. Compositional differences were compared according to recanalization success, stroke subtype, and the presence of hyperdense clot sign on initial computed tomography and/or blooming artifact on magnetic resonance image. Of the 145 total retrieval trials (3.4±2.4 times per patient), clot was retrieved in 93 trials (64%), while recanalization was successful in 73 (50%). Fibrin/platelets (63%) occupied the greatest area in retrieved clots, followed by RBCs (33%) and WBCs (4%). Clots retrieved from successful recanalization exhibited higher RBC composition (37%) than those retrieved from non-recanalization trials (20%, p = 0.001). RBC composition was higher in cardioembolic stroke (38%) rather than large artery atherosclerosis (23%) and undetermined etiology (26%, p = 0.01). Clots exhibiting clot signs (40%) had higher RBC composition than those without clot signs (19%, p = 0.001). RBC-rich clots were associated with successful recanalization of intra-arterial thrombectomy, cardioembolic stroke, and the presence of clot-signs on initial brain images.