Hyun Goo Kang

Magnetic Resonance Imaging in Acute Ischemic Stroke Treatment

Although intravenous administration of tissue plasminogen activator is the only proven treatment after acute ischemic stroke, there is always a concern of hemorrhagic risk after thrombolysis. Therefore, selection of patients with potential benefits in overcoming potential harms of thrombolysis is of great importance. Despite the practical issues in using magnetic resonance imaging (MRI) for acute stroke treatment, multimodal MRI can provide useful information for accurate diagnosis of stroke, evaluation of the risks and benefits of thrombolysis, and prediction of outcomes. For example, the high sensitivity and specificity of diffusion-weighted image (DWI) can help distinguish acute ischemic stroke from stroke-mimics. Additionally, the lesion mismatch between perfusion-weighted image (PWI) and DWI is thought to represent potential salvageable tissue by reperfusion therapy. However, the optimal threshold to discriminate between benign oligemic areas and the penumbra is still debatable. Signal changes of fluid-attenuated inversion recovery image within DWI lesions may be a surrogate marker for ischemic lesion age and might indicate risks of hemorrhage after thrombolysis. Clot sign on gradient echo image may reflect the nature of clot, and their location, length and morphology may provide predictive information on recanalization by reperfusion therapy. However, previous clinical trials which solely or mainly relied on perfusion-diffusion mismatch for patient selection, failed to show benefits of MRI-based thrombolysis. Therefore, understanding the clinical implication of various useful MRI findings and comprehensively incorporating those variables into therapeutic decision-making may be a more reasonable approach for expanding the indication of acute stroke thrombolysis.

Cross-linking of 4-1BB activates TCR-signaling pathways in CD8+ T lymphocytes

Cross-linking of 4-1BB, a member of the TNFR family, increased tyrosine phosphorylation of TCR-signaling molecules such as CD3ε, CD3ζ, Lck, the linker for activation of T cells, and SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76). In addition, incubation of activated CD8+ T cells with p815 cells expressing 4-1BBL led to redistribution of the lipid raft domains and Lck, protein kinase C-θ, SLP-76, and phospholipase C-γ1 (PLC-γ1) on the T cell membranes to the areas of contact with the p815 cells and recruitment of 4-1BB, TNFR-associated factor 2, and phospho-tyrosine proteins to the raft domains. 4-1BB ligation also caused translocation of TNFR-associated factor 2, protein kinase C-θ, PLC-γ1, and SLP-76 to detergent-insoluble compartments in the CD8+ T cells, and cross-linking of 4-1BB increased intracellular Ca2+ levels apparently by activating PLC-γ1. The redistribution of lipid rafts and Lck, as well as translocation of PLC-γ1, and degradation of IκB-α in response to 4-1BB were inhibited by disrupting the formation of lipid rafts with methyl-β-cyclodextrin. These findings demonstrate that 4-1BB is a T cell costimulatory receptor that activates TCR-signaling pathways in CD8+ T cells.

Conversion of Alloantigen-Specific CD8+ T Cell Anergy to CD8+ T Cell Priming through In Vivo Ligation of Glucocorticoid-Induced TNF Receptor

In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD toward aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cell anergy. Functionally active donor CD8+ T cells produced high levels of IFN-γ and had an elevated CTL activity against host Ags. In in vitro MLR, anergic responder CD8+ T cells were generated, and DTA-1 stimulated the activation of these anergic CD8+ T cells. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, were responsible for the DTA-1-mediated conversion of cGVHD to aGVHD. These results indicate that donor CD8+ T cell anergy is a restriction factor in the development of aGVHD and that in vivo ligation of GITR prevents CD8+ T cell anergy by activating donor CD8+ T cells that otherwise become anergic. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD vs aGVHD and as a target for therapeutic intervention in a variety of related diseases.

4-1BB cross-linking enhances the survival and cell cycle progression of CD4 T lymphocytes

4-1BB, a T cell co-stimulatory receptor, prolongs the survival and multiplication of CD4 T cells. Cross-linking 4-1BB stimulated expression of the anti-apoptotic genes bcl-XL and bcl-2, as well as of cyclins D2 and E, and inhibited expression of the cyclin-dependent kinase (cdk) inhibitor p27kip1. Ova-activated CD4 T cells of 4-1BB-deficient/DO11.10 TCR transgenic mice survived less well and underwent less expansion than cells of wild type DO11.10 TCR transgenic mice. These findings demonstrate that 4-1BB is a co-stimulatory molecule for CD4 T cell survival and expansion in vivo.

Risk Factors Associated With the Presence of Unruptured Intracranial Aneurysms

Background and Purpose— With the increased investigation of cerebral arteries using magnetic resonance angiography in the general population, the detection of unruptured intracranial aneurysms (UIAs) has increased. Understanding the distribution and factors associated with UIAs might be helpful for understanding the pathomechanism. Methods— Subjects who underwent magnetic resonance angiography with a health examination at the Health Screening and Promotion Center were enrolled. The incidence and risk factors of UIAs (age, sex, hypertension, diabetes mellitus, smoking, alcohol, and coronary artery disease) were investigated by comparing patients with and without UIAs. These risk factors were also investigated by the UIA location, distal internal carotid artery, anterior cerebral artery and middle cerebral artery (MCA), MCA bifurcation, anterior and posterior communicating artery, and posterior circulation. Results— Among 187 166 subjects who received health examination, 18 954 underwent magnetic resonance angiography. Of them, 367 (1.93%) had UIAs. Age (odds ratio [OR], 1.02; P=0.003), women (OR, 2.00; P<0.001), hypertension (OR, 2.21; P<0.001), smoking (OR, 1.66; P=0.001), and coronary artery disease (OR, 0.23; P<0.001) were independently associated with the presence of UIAs. Hypertension was associated with most UIAs, except for those located at sidewalls (anterior cerebral artery and MCA). MCA aneurysms were associated with old age and smoking. Distal internal carotid artery, posterior communicating artery, and MCA-bifurcation aneurysms were associated with female sex. Anterior communicating artery aneurysms were associated with smoking and alcohol. Posterior circulation UIAs were only associated with hypertension. Coronary artery disease was negatively associated with anterior circulation aneurysms. Conclusions— The risk factors for UIAs differ by their location, compared with the control. Interestingly, the presence of coronary artery disease was protective against the presence of UIAs.

Histologic features of acute thrombi retrieved from stroke patients during mechanical reperfusion therapy

Background The histologic features of thrombus may differ according to the stroke subtypes. However, in acute reperfusion therapy, fibrin-specific thrombolytics are used based on the assumption that all thrombi are alike. Aims The histologic characteristics of thrombi were compared between patients with different stroke etiologies. Methods Between April 2010 and March 2012, we analyzed thrombi retrieved from acute stroke patients during mechanical thrombectomy. All thrombi were analyzed using component-specific stains such as Martius scarlet blue for fibrins and immunostaining with CD42b antibody for platelets. The stroke subtypes were determined based on the Trial of ORG 10172 in Acute Stroke Treatment classification. Results Among 36 patients, 22 were diagnosed with cardioembolism, 8 with atherothrombosis, and 6 with undetermined etiology. In arteriogenic thrombi, red blood cells were most abundant (56.9 ± 12.2%), and the platelets covered the fibrin layers or were localized at the edge or periphery of the thrombus. In cardiogenic thrombi, fibrin was most abundant (39.5 ± 13.5%), and platelets were clustered within the rich fibrin. Red blood cells proportion was greater in arteriogenic thrombi than in cardiogenic thrombi (p < 0.001), whereas fibrin proportion was greater in cardiogenic thrombi than in arteriogenic thrombi (p = 0.003). Of six patients with undetermined etiology, the thrombi in five showed histologic features and composition similar to that of cardiogenic thrombi. Conclusions Acute thrombi showed different histologic features according to the stroke etiology. The distribution of platelets and proportion of red blood cells and fibrin were major distinguishing factors between stroke subtypes.

Small versus Large Ruptured Intracranial Aneurysm: Concerns with the Site of Aneurysm

Background: Although size is one of the strongest predictors, small aneurysms often rupture. We compared the characteristics of small and large ruptured intracranial aneurysms (RIAs) according to their location to find the factors associated with small RIAs in each location. Methods: Patients with subarachnoid hemorrhage due to saccular RIAs were consecutively enrolled. The sizes were dichotomized as small (<5 mm) or large, and the location was classified as paraclinoid-distal internal carotid artery, sidewalls of anterior or middle cerebral artery (MCA; sidewall), MCA-bifurcation, anterior or posterior communicating artery (Acom or Pcom, respectively), and posterior circulation RIAs. Independent factors associated with small RIAs compared to large RIAs were investigated in each location. Results: Small RIAs were observed in 384 of 791 patients (48.5%), and were most commonly located at Acom (17.1%) followed by Pcom (9.0%) and sidewalls (7.2%). Female sex (OR 3.038; 95% CI 2.099-4.395), young age (OR 0.971; 95% CI 0.958-0.985), hypertension (OR 1.412; 95% CI 1.033-1.930) and multiple aneurysms (OR 1.942; 95% CI 1.335-2.824) were associated with small RIAs. By location, sidewall aneurysms (OR 2.183; 95% CI 1.049-4.542) were associated with small RIAs, whereas MCA-bifurcation (OR 0.318; 95% CI 0.168-0.599) and Pcom aneurysms (OR 0.511; 95% CI 0.277-0.944) were associated with large RIAs. The presence of multiple aneurysms (OR 4.69; 95% CI 1.45-21.19) was associated with small RIAs at sidewalls, and young age, female sex, hypertension and the presence of bilateral A1 (OR 1.85; 95% CI 1.09-3.13) were associated with small RIAs at Acom. Acom RIAs with bilateral A1 was smaller than those with unilateral A1 (4.7 ± 2.1 vs. 5.8 ± 2.6 mm; p < 0.001). Conclusions: Intracranial aneurysms which rupture below 5 mm are not uncommon, and the factors associated with small-sized RIAs differ according to location. Sidewall aneurysms, with multiple aneurysms and Acom aneurysms with bilateral A1 may rupture even at small size.

Intracranial arterial disease in CADASIL patients

BACKGROUND Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the involvement of cerebral small arteries. Although cerebral large artery disease has been reported in CADASIL patients, the prevalence and location of relevant cerebral arterial disease have not been elucidated. In this study, we aim to characterize infarctions associated with cerebral large artery disease in CADASIL patients. METHODS We retrospectively reviewed 49 consecutive symptomatic patients with genetically confirmed CADASIL, who visited the Asan Medical Center between December 2002 and December 2013. Infarctions located within the territory of a relevant, large cerebral artery were identified with the use of magnetic resonance imaging and magnetic resonance angiography. Patients with or without territorial patterns associated with large artery disease were compared. RESULTS Out of a total of 49 patients, 23 patients had cerebral infarction. Among these, seven had infarction associated with cerebral large artery disease. The corresponding vascular lesions were located in the intracranial arteries in all seven patients. There were no differences between patients with or without territorial infarction in terms of vascular risk factors, microbleeds, white matter changes, or mutations involving cysteine. A literature review illustrates that symptomatic intracranial diseases are present in CADASIL patients at least in East Asia. CONCLUSION Infarction in association with intracranial arterial disease may be a manifestation of CADASIL. Further studies are needed to elucidate the pathologic characteristics and to see whether this occurs exclusively in East Asia.

Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation–Related Mild Ischemic Stroke: A Randomized Clinical Trial

Importance In atrial fibrillation (AF)–related acute ischemic stroke, the optimal oral anticoagulation strategy remains unclear. Objective To test whether rivaroxaban or warfarin sodium is safer and more effective for preventing early recurrent stroke in patients with AF-related acute ischemic stroke. Design, Setting, and Participants A randomized, multicenter, open-label, blinded end point evaluation, comparative phase 2 trial was conducted from April 28, 2014, to December 7, 2015, at 14 academic medical centers in South Korea among patients with mild AF-related stroke within the previous 5 days who were deemed suitable for early anticoagulation. Analysis was performed on a modified intent-to-treat basis. Interventions Participants were randomized 1:1 to receive rivaroxaban, 10 mg/d for 5 days followed by 15 or 20 mg/d, or warfarin with a target international normalized ratio of 2.0-3.0, for 4 weeks. Main Outcomes and Measures The primary end point was the composite of new ischemic lesion or new intracranial hemorrhage seen on results of magnetic resonance imaging at 4 weeks. Primary analysis was performed in patients who received at least 1 dose of study medications and completed follow-up magnetic resonance imaging. Key secondary end points were individual components of the primary end point and hospitalization length. Results Of 195 patients randomized, 183 individuals (76 women and 107 men; mean [SD] age, 70.4 [10.4] years) completed magnetic resonance imaging follow-up and were included in the primary end point analysis. The rivaroxaban group (n = 95) and warfarin group (n = 88) showed no differences in the primary end point (47 [49.5%] vs 48 [54.5%]; relative risk, 0.91; 95% CI, 0.69-1.20; P = .49) or its individual components (new ischemic lesion: 28 [29.5%] vs 31 of 87 [35.6%]; relative risk, 0.83; 95% CI, 0.54-1.26; P = .38; new intracranial hemorrhage: 30 [31.6%] vs 25 of 87 [28.7%]; relative risk, 1.10; 95% CI, 0.70-1.71; P = .68). Each group had 1 clinical ischemic stroke, and all new intracranial hemorrhages were asymptomatic hemorrhagic transformations. Hospitalization length was reduced with rivaroxaban compared with warfarin (median, 4.0 days [interquartile range, 2.0-6.0 days] vs 6.0 days [interquartile range, 4.0-8.0]; P < .001). Conclusions and Relevance In mild AF-related acute ischemic stroke, rivaroxaban and warfarin had comparable safety and efficacy. Trial Registration clinicaltrials.gov Identifier: NCT02042534

ATP-sensitive K+ channels maintain resting membrane potential in interstitial cells of Cajal from the mouse colon

&NA; To investigate the role of ATP‐sensitive K+(KATP) channels on pacemaker activity in interstitial cells of Cajal (ICC), whole‐cell patch clamping, RT‐PCR, and intracellular Ca2+([Ca2+]i) imaging were performed in cultured colonic ICC. Pinacidil (a K+ channel opener) hyperpolarized the membrane and inhibited the generation of pacemaker potential, and this effect was reversed by glibenclamide (a KATP channel blocker). RT‐PCR showed that Kir 6.1 and SUR2B were expressed in Ano‐1 positive colonic ICC. Glibenclamide depolarized the membrane and increased pacemaker potential frequency. However, 5‐hydroxydecanoic acid (a mitochondrial KATP channel blocker) had no effects on pacemaker potentials. Phorbol 12‐myristate 13‐acetate (PMA; a protein kinase C activator) blocked the pinacidil‐induced effects, and PMA alone depolarized the membrane and increased pacemaker potential frequency. Cell‐permeable 8‐bromo‐cyclic AMP also increased pacemaker potential frequency. Recordings of spontaneous intracellular Ca2+([Ca2+]i) oscillations showed that glibenclamide increased the frequency of [Ca2+]i oscillations. In small intestinal ICC, glibenclamide alone did not alter the generation of pacemaker potentials, and Kir 6.2 and SUR2B were expressed in Ano‐1 positive ICC. Therefore, KATP channels in colonic ICC are activated in resting state and play an important role in maintaining resting membrane potential.