Hye-Yeon Choi

Caspase‐2 primes cancer cells for TRAIL‐mediated apoptosis by processing procaspase‐8

Although caspase‐2 is believed to be involved in death receptor‐mediated apoptosis, the exact function, mode of activation, and regulation of caspase‐2 remain unknown. Here we show that protein kinase (PK) CK2 phosphorylates procaspase‐2 directly at serine‐157. When intracellular PKCK2 activity is low or downregulated by specific inhibitors, procaspase‐2 is dephosphorylated, dimerized, and activated in a PIDDosome‐independent manner. The activated caspase‐2 then processes procaspase‐8 monomers between the large and small subunits, thereby priming cancer cells for TNF‐related apoptosis‐inducing ligand (TRAIL)‐mediated apoptosis. The processed procaspase‐8 that is recruited to death‐inducing signaling complex by TRAIL engagement becomes fully activated, and cancer cells undergo apoptosis. PKCK2 activity is low in TRAIL‐sensitive cancer cell lines but high in TRAIL‐resistant cancer cell lines. Thus, downregulating PKCK2 activity is required for TRAIL‐mediated apoptosis to occur in TRAIL‐resistant cancer cells. Our data provide novel insights into the regulation, mode of activation, and function of caspase‐2 in TRAIL‐mediated apoptosis.

Improved Time Intervals by Implementation of Computerized Physician Order Entry-Based Stroke Team Approach

Background: The need for rapid evaluation and treatment of acute stroke patients has been well documented. A computerized physician order entry (CPOE) system can improve communication and provide immediate access to information, which may be useful for an effective team approach program targeted to reduce in-hospital time delays. Methods: To reduce the time from a patient’s arrival at the emergency department to thrombolysis, a team approach program using CPOE was developed, and its efficacy was investigated by comparing time intervals from arrival to evaluation and intravenous tissue-type plasminogen activator (tPA) treatment before and after the implementation of the program. Results: Among 379 consecutive patients who were screened as potential candidates for thrombolysis, 25 patients (6.6%) received tPA during a 1-year period after initiation of the program. Fourteen patients were treated with tPA in the previous year. After program implementation, time from arrival to computed tomography scan was reduced from 34 to 19 min (p = 0.01). Time to report of complete blood count was also shortened from 52 to 33 min (p < 0.01). Finally, time from arrival to tPA treatment was reduced by 23 min (from 79 to 56 min; p < 0.01). Onset-to-door time tended to be longer after the program implementation (from 41 to 60 min; p = 0.14). Conclusions: Implementation of the CPOE-based team approach program significantly reduced time from emergency department arrival to evaluations and treatment.

A Computerized In-Hospital Alert System for Thrombolysis in Acute Stroke

Background and Purpose— An effective stroke code system that can expedite rapid thrombolytic treatment requires effective notification/communication and an organized team approach. We developed a stroke code program based on the computerized physician order entry (CPOE) system and investigated whether implementation of this CPOE-based program is useful for reducing the time from arrival at emergency departments (ED) to evaluation steps and the initiation of thrombolytic treatment in various hospital settings. Methods— The CPOE-based program was implemented by 10 hospitals. Time intervals from arrival at the ED to blood tests, computed tomography scanning, and thrombolytic treatment during the 1-year period before and the 1-year period after the program implementation were compared. Results— Time intervals from ED arrival to evaluation steps were significantly reduced after implementation of the CPOE-based program. Times from ED arrival to CT scan, complete blood counts, and prothrombin time testing were reduced by 7.7 minutes, 5.6 minutes, and 26.8 minutes, respectively (P<0.001). The time from ED arrival to intravenous thrombolysis was reduced from 71.7±33.6 minutes to 56.6±26.9 minutes (P<0.001). The number of patients who were treated with thrombolysis increased from 3.4% (199/5798 patients) before the CPOE-based program to 5.8% (312/5405 patients) afterward (P<0.001). The CPOE implementation also improved the inverse relationship between onset-to-door time and door-to-needle time. Conclusions— The CPOE-based stroke code could be successfully implemented to reduce in-hospital time delay in thrombolytic therapy in various hospital settings. CPOE may be used as an efficient tool to facilitate in-hospital notification/communication and an organized team approach.

The frequency and risk of preclinical coronary artery disease detected using multichannel cardiac computed tomography in patients with ischemic stroke.

Background: Atherosclerosis is a systemic disease. Many ischemic stroke patients may have concomitant coronary artery disease (CAD). Detection and treatment of preclinical CAD in stroke patients may improve long-term outcome and survival because CAD is a major cause of death during follow-up in stroke patients. However, association between coronary and cerebral artery atherosclerosis in stroke patients has not fully been investigated. This study aimed at examining the frequency and high-risk groups of CAD in ischemic stroke patients. Methods: Consecutive patients who were admitted due to acute ischemic stroke between July 2006 and June 2010 were prospectively enrolled in this study. A total of 1,304 patients who underwent MSCT coronary angiography and cerebral angiography were included in this study. By using 64-multislice computed tomography coronary angiography, we investigated the frequency of CAD and association between coronary and cerebral artery atherosclerosis in terms of location and burden (severity and extent) in stroke patients. We also sought to identify high-risk groups for CAD among stroke patients. Results: The frequency of significant (≧50%) CAD was 32.3% and the frequency of any degree of CAD was 70.1%. Diabetes mellitus, serum levels of total cholesterol, high-density lipoprotein cholesterol and triglyceride, and significant stenosis of the extracranial carotid, intracranial vertebral and basilar arteries were independently associated with CAD. However, no association was found between CAD and significant stenosis of the anterior, middle and posterior cerebral arteries. The association between CAD and cerebral atherosclerosis was stronger with increased severity and extent of cerebral atherosclerosis. When compared to patients with <2 risk factors and without significant cerebral atherosclerosis, those with multiple (≧2) risk factors and atherosclerosis in both the carotid and the vertebrobasilar arteries had very high risks of CAD [odds ratio (OR) 8.36; 95% confidence interval (CI) 4.15–16.87]. The risk was also high in patients with multiple risk factors and atherosclerosis in either the carotid or the vertebrobasilar artery (OR 4.13; 95% CI 2.62–6.51), and in those with <2 risk factors but atherosclerosis in both the carotid and the vertebrobasilar arteries (OR 3.40; 95% CI 1.22–9.47). Conclusions: A substantial portion of stroke patients had preclinical CAD, and there was a clear relationship between coronary and cerebral artery atherosclerosis in terms of location and burden. The risk of CAD was particularly high in stroke patients with multiple risk factors and atherosclerosis of the carotid and/or vertebrobasilar arteries.

Transoesophageal echocardiography in patients with acute stroke with sinus rhythm and no cardiac disease history

Background Transoesophageal echocardiography (TOE) is the gold standard for detecting potential cardiac sources of embolism (PCSE). However, the role of TOE in patients with ischaemic stroke with normal sinus rhythm (NSR) and no cardiac disease remains uncertain. Methods The authors retrospectively analysed 1833 consecutive patients with ischaemic stroke with NSR and no history of cardiac disease who were examined by TOE. The authors investigated the frequency of PCSE and aortic plaques detected in these patients. Determination of high- and medium-risk PCSE was based on the Trial of ORG 10172 in the Acute Stroke Treatment classification. The authors also determined how the proportions of stroke subtypes and treatment strategies based on current guidelines have been changed after TOE. Results PCSE and/or aortic plaques were detected in 753 (41.1%) of 1833 patients. After TOE, a total of 355 PCSE (45 high-risk PCSE and 310 medium-risk PCSE) were found in 323 patients (17.6%). Aortic plaques were found in 502 patients (27.4%). Among these, complex aortic plaques, which are significant sources of embolism, were found in 157 patients (8.5%). Changes in treatment strategies for secondary prevention based on the current guidelines would have been necessary in 63 patients (3.4 %) after TOE examination. Conclusion Potential embolic sources from the heart and aorta can be detected by TOE examination in many patients with stroke with NSR and no cardiac disease, which enables a better determination of stroke mechanisms.

Etiology of aseptic meningitis and clinical characteristics in immune-competent adults

Viral meningitis is the most common cause of aseptic meningitis. Use of the polymerase chain reaction (PCR) has increased the ability to determine the etiology of viral meningitis. This study used PCR analysis to evaluate the etiology of aseptic meningitis in 177 previously healthy adults over a 5‐year period, as well as analyzing the clinical characteristics, cerebrospinal fluid (CSF) findings, and prognosis according to each etiology. The most frequent cause of aseptic meningitis was enterovirus (EV), followed by varicella zoster virus (VZV). Patients with EV meningitis were significantly younger than those with VZV meningitis. The percentage of lymphocytes in white blood cell counts and protein concentrations in the CSF differed significantly among patients with EV, VZV and meningitis of undetermined etiology. Younger age and lower percentage of lymphocyte and protein level in CSF analysis may be suggestive of EV meningitis. Further prospective studies are warranted to identify the correlations between the clinical characteristics and the etiologies of meningitis. J. Med. Virol. 88:175–179, 2016.

The clinical syndrome and etiological mechanism of infarction involving the nucleus prepositus hypoglossi.

Background: The human nucleus prepositus hypoglossi (NPH), which is known to be a neural integrator of horizontal eye movement, may also serve vestibular function. The present study investigated the clinical spectrum and etiological mechanism of isolated, small infarctions involving the NPH area demonstrated on MRI. Methods: The subjects of this study were 18 consecutive patients with a small infarction involving the NPH that was demonstrated by diffusion-weighted MRI. We assessed their clinical features according to the level involved (pons or medulla oblongata) and determined etiological mechanisms that may cause infarction in this region. Results: Vertigo and nausea/vomiting were the presenting symptoms in all patients. Sixteen patients showed truncal ataxia (contralateral falls in 11 patients and bilateral falls in 3). Gaze-evoked nystagmus was observed in 13 patients. In addition to those NPH-related symptoms, ipsi- lateral peripheral facial palsy and horizontal gaze palsies, including internuclear ophthalmoplegia and horizontal conjugate gaze palsy, were commonly associated with pontine lesions, and dysphagia was common in medullary lesions. Ten out of 18 patents showed significant stenosis (≧50%) of the relevant vertebral artery. Two patients had aortic atheroma >4 mm, and 1 patient had atrial fibrillation. Conclusions: Clinical features of vertigo, contralateral falls and gaze-evoked nystagmus are suggestive of an NPH lesion. Accompanying signs of ipsilateral facial palsy of the peripheral type and/or horizontal gaze palsies are highly specific for a pontine NPH lesion. Large-artery atherosclerosis was the most common causative mechanism of infarctions involving the NPH area.

Process Improvement to Enhance Existing Stroke Team Activity Toward More Timely Thrombolytic Treatment

Background and Purpose Process improvement (PI) is an approach for enhancing the existing quality improvement process by making changes while keeping the existing process. We have shown that implementation of a stroke code program using a computerized physician order entry system is effective in reducing the in-hospital time delay to thrombolysis in acute stroke patients. We investigated whether implementation of this PI could further reduce the time delays by continuous improvement of the existing process. Methods After determining a key indicator [time interval from emergency department (ED) arrival to intravenous (IV) thrombolysis] and conducting data analysis, the target time from ED arrival to IV thrombolysis in acute stroke patients was set at 40 min. The key indicator was monitored continuously at a weekly stroke conference. The possible reasons for the delay were determined in cases for which IV thrombolysis was not administered within the target time and, where possible, the problems were corrected. The time intervals from ED arrival to the various evaluation steps and treatment before and after implementation of the PI were compared. Results The median time interval from ED arrival to IV thrombolysis in acute stroke patients was significantly reduced after implementation of the PI (from 63.5 to 45 min, p=0.001). The variation in the time interval was also reduced. A reduction in the evaluation time intervals was achieved after the PI [from 23 to 17 min for computed tomography scanning (p=0.003) and from 35 to 29 min for complete blood counts (p=0.006)]. Conclusions PI is effective for continuous improvement of the existing process by reducing the time delays between ED arrival and IV thrombolysis in acute stroke patients.

Alberta Stroke Program Early CT Score in the Prognostication after Endovascular Treatment for Ischemic Stroke: A Meta-analysis

Purpose The Alberta Stroke Program Early CT Score (ASPECTS) was devised to quantify the extent of early ischemic changes in the middle cerebral artery territory on brain CT. We performed a systematic review and meta-analysis of studies that presented clinical outcomes and baseline ASPECTS in ischemic stroke patients managed with endovascular methods to validate the use of ASPECTS for risk prognostication. Materials and Methods We searched the MEDLINE, EMBASE, and Cochran databases for observational or interventional studies that reported clinical outcomes and baseline ASPECTS in ischemic stroke patients treated with endovascular methods. Data were pooled to perform a meta-analysis for comparisons of clinical outcomes between high and low ASPECTS patients. Results A meta-analysis of 13 studies (six observational and seven interventional) revealed favorable outcomes (mRS sore 0-2 at 90 days) for high baseline ASPECTS (odds ratio=2.22; 95% CI: 1.74-2.86). Conclusion High ASPECTS is a predictor of favorable outcome after endovascular therapy for ischemic stroke.

Cortex-sparing infarctions in patients with occlusion of the middle cerebral artery

Background In patients with a middle cerebral artery (MCA) occlusion, the involvement of the cortex may be affected by the presence of leptomeningeal anastomoses between the cerebral arteries. Methods The authors enrolled consecutive patients with acute infarctions in the MCA territory and MCA occlusion on angiographic studies. Infarct patterns were classified into three categories based on the extent of cortical surface involvement: total cortex (TC), partial cortex (PC) and no cortex (NC). The authors analysed the infarction patterns by stroke subtype, and investigated factors that resulted in cortex sparing. Results Out of 73 total patients, cortex-sparing infarctions were seen in 53 patients (72.6%, NC in 39 (53.5%) and PC in 14 (19.1%)). The extent of cortical involvement differed according to stroke subtype (p=0.036). TC was more frequent (42.9% vs 22.2%), and PC was less frequent (10.7% vs 27.9%, p=0.037) in cardioembolism than large-artery atherosclerosis. However, the proportion of patients with complete cortical sparing (NC) was similar between cardioembolism and large-artery atherosclerosis (46.4% vs 49.9%). In the upstream of leptomeningeal collateral arteries, the extent of cortical involvement was associated with significant stenosis of the ipsilateral anterior or posterior cerebral artery (p=0.011). Conclusion This study suggests that pre-existing arteriolar connections, which may cover almost entire cortical surfaces of the MCA territory, exist in many patients. The findings also suggest that the extent of cortical involvement is different between stroke subtypes, and is critically affected by the status of upstream collateral arteries.