Background

Carotid cavernous fistula (CCF) is an abnormal communication between the carotid artery and the cavernous sinus. The pathogenesis of spontaneous CCF remains unclear, although sinus thrombosis is known to be a predisposing factor for dural arteriovenous fistula. Because spontaneous CCFs are mainly of the dural type, we considered that thrombogenic conditions, such as, protein S deficiency might be associated with CCF.

Case Report

A 42-year-old woman complained of conjunctival injection and retro-orbital pain that first appeared 1-month before visiting our hospital. She had no history of head trauma or intracranial surgery. Exophthalmos and chemosis were observed in her left eye, which also had lower visual acuity and higher intraocular pressure than the right eye. Magnetic resonance images and cerebral angiography revealed a left dural CCF. Her protein S was low, at 41% (normal range: 70-140%), but other hematologic values related to coagulation were normal. Her symptoms were relieved after initial transvenous coil embolization. However, a newly developed sixth-nerve palsy was detected 4 days after initial embolization. Follow-up angiography revealed a minimal shunt, and thus transvenous coil embolization was repeated. Two days later, the ophthalmoplegia started reducing, and 1-month later it had almost disappeared.

Conclusions

To the best of our knowledge, this is the first report of spontaneous dural CCF in a Korean patient with concurrent protein S deficiency. Interestingly, transient sixth-nerve palsy developed after transvenous coil embolization in this patient. This additional symptom caused by the residual fistula was relieved after additional transarterial embolization.

Purpose

Hemorrhagic metastatic brain tumors are not rare, but little is known about the surgical outcome following treatment. We conducted this study to determine the result of the surgical outcome of hemorrhagic metastatic brain tumors.

Materials and Methods

From July 2001 to December 2008, 21 patients underwent surgery for hemorrhagic metastatic brain tumors at our institution. 15 patients had lung cancer, 3 had hepatocellular carcinoma, and the rest had rectal cancer, renal cell carcinoma, and sarcoma. 20 patients had macroscopic hemorrhage in the tumors, and one patient had intracerebral hemorrhage surrounding the tumor. A retrospective clinical review was conducted focusing on the patterns of presenting symptoms and signs, as well as local recurrence following surgery.

Results

Among 21 hemorrhagic brain metastases, local recurrence developed in two patients. The 12 month progression free survival rate was 86.1%. Mean time to progression was 20.8 months and median survival time after surgery was 11.7 months.

Conclusion

The results of our study showed that hemorrhagic metastatic brain tumors rarely recurred after surgery. Surgery should be considered as a good treatment option for hemorrhagic brain metastasis, especially in cases with increased intracranial pressure or severe neurologic deficits.

Gliomas are the most common primary intracranial tumors. Their distinct ability to infiltrate into the extracellular matrix (ECM) of the brain makes it impossible to treat these tumors using surgery and radiation therapy. A number of different studies have suggested that hyaluronan (HA), the principal glycosaminoglycan (GAG) in the ECM of the brain, is the critical factor for glioma invasion. HA-induced glioma invasion was driven by two important molecular events: matrix metalloproteinase (MMP) secretion and upregulation of cell migration. MMP secretion was triggered by HA-induced focal adhesion kinase (FAK) activation, which transmits its signal through ERK activation and nuclear factor kappa B (NFκB) translocation. Another important molecular event is osteopontin (OPN) expression. OPN expression by AKT activation triggers cell migration. These results suggest that HA-induced glioma invasion is tightly regulated by signaling mechanisms, and a detailed understanding of this molecular mechanism will provide important clues for glioma treatment.

We report a patient with multiple simultaneous embolic infarctions with localized hemorrhagic conversion. A 75-year-old male patient had several silent microbleeds (SMBs) exclusively in the cerebral cortex, and underwent angioplasty and stenting for bilateral carotid stenosis. He subsequently experienced embolic infarctions in the cortex and the striatum: the cortical infarction, where an SMB had been present, showed hemorrhagic conversion, whereas the striatal infarction did not. This case suggests that SMBs are indicators of an underlying hemorrhage-prone state.

Unlike experimental studies indicating a neuroprotective property of uric acid, clinical studies have shown that elevated levels of uric acid are associated with a risk of ischemic stroke. However, the association of uric acid with cerebral hemorrhage has seldom been tested. We aimed to elucidate the association between uric acid and cerebral microbleeds (CMBs), a hemorrhage-prone cerebral microangiopathy. Seven hundred twenty-four patients with ischemic stroke who were consecutively admitted to our hospital were included in this study. We collected demographic, clinical, and laboratory data, including uric acid level, and examined the presence of CMBs using T2*-weighted gradient-echo MRI. We used logistic regression analysis to examine an independent association between uric acid and CMBs. Two-hundred twenty-six patients had CMBs (31.2%). After adjusting for possible confounders, elevated uric acid was independently associated with the presence of CMBs (the highest quartile vs. lowest quartile, adjusted odd ratio [OR], 1.98; 95% confidence interval [CI], 1.16–3.39). This association retained in patients with deep or infratentorial CMBs (with or without lobar CMBs) but not among those with lobar CMBs. In addition, this association was robust among patients with hypertension (the highest quartile vs. lowest quartile, adjusted OR, 2.74; 95% CI, 1.43–5.24). In contrast, we did not find the association in patients without hypertension. We demonstrated that serum uric acid is independently associated with the presence of CMBs. In particular, the relation between uric acid and CMBs was robust in hypertensive patients.

"Tumor-to-tumor" metastasis is a rare event; meningioma has been reported as the most common primary intracranial tumor to harbor cancer metastases. Several hypotheses have been previously proposed to explain this occurrence, but the exact mechanism by which these metastases develop into meningiomas is not yet understood. Magnetic resonance imaging and spectroscopy have been valuable diagnostic tools, but preoperative diagnosis of metastasis to meningioma remains highly difficult. We present a case report of a metastasis of non-small cell lung cancer into an intracranial meningioma.

Background and Purpose

The CHADS2 (an acronym for congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack or thromboembolism) score is a widely used system for estimating the risk of stroke in patients with atrial fibrillation. However, how the CHADS2 score is related to stroke severity and outcome in patients with strokes due to atrial fibrillation has not yet been elucidated.

Methods

We enrolled patients with atrial fibrillation who visited our stroke center within 7 days after the onset of acute ischemic stroke between October 2002 and September 2008. CHADS2 scores were categorized into three groups: 0 points, low risk; 1 or 2 points, intermediate risk; and 3-6 points, high risk. Poor neurological state was defined as follows: a National Institutes of Health Stroke Scale (NIHSS) score of ≥2, and a modified Rankin Scale (mRS) score of ≥3 at discharge. Mortality information was ascertained as at December 2008.

Results

A cohort of 298 patients with atrial-fibrillation-related stroke was included in this study. A high-risk CHADS2 score at admission was a powerful predictor of poor neurological outcome [for NIHSS: odds ratio (OR), 4.17; 95% confidence interval (CI), 1.76-9.87; for mRS: OR, 2.97; 95% CI, 1.23-7.16] after controlling for all possible confounders. In addition, a high-risk CHADS2 score was an independent predictor of all causes of death during the follow-up [hazard ratio (HR), 3.01; 95% CI, 1.18-7.65] and vascular death (HR, 12.25; 95% CI, 1.50-99.90).

Conclusions

Although the CHADS2 score was originally designed to distinguish patients with a future risk of stroke, our study shows that it may also be used to predict poor neurological outcome after atrial-fibrillation-related stroke.

Background and Purpose

The vertebral artery (VA) is important for the development of the transverse foramen (TF). Most studies of these structures have focused on anatomical anomalies. Therefore, we investigated quantitatively the association between the relative sizes of the TF and VA.

Methods

We recruited a consecutive series of subjects who underwent CT angiography to estimate the relative sizes of the VA and TF in axial source images. Two neurologists independently reviewed the axial CT images of 208 patients who had no history of transient ischemic attack or stroke. Averaged areas of the VA and TF were defined by the sum of the areas at each level from C3 to C6, divided by 4. Correlation analyses were adjusted for age, sex, and vascular risk factors.

Results

The mean age of the subjects was 53 years. The interobserver and intraobserver reliabilities of TF size were good. There was a linear relationship between the sizes of the VA and TF on each side (right side: r2=0.58, p<0.001; left side: r2=0.62, p<0.001). The area of the VA was significantly associated with that of the TF after adjusting for vascular risk factors.

Conclusions

The size of the VA is strongly and linearly correlated with the size of the TF. These findings suggest that measurement of the TF and VA with CT angiography is a reliable method for evaluating VA diseases, and may provide new insight into the differentiation between VA hypoplasia and atherosclerosis of the VA.

Objective

The objective of study is to evaluate the incidence of leptomeningeal carcinomatosis (LMC) in breast cancer patients with parenchymal brain metastases (PBM) and clinical risk factors for the development of LMC.

Methods

We retrospectively analyzed 27 patients who had undergone surgical resection (SR) and 156 patients with whole brain radiation therapy (WBRT) as an initial treatment for their PBM from breast cancer in our institution and compared the difference of incidence of LMC according to clinical factors. The diagnosis of LMC was made by cerebrospinal fluid cytology and/or magnetic resonance imaging.

Results

A total of 27 patients (14%) in the study population developed LMC at a median of 6.0 months (range, 1.0-50). Ten of 27 patients (37%) developed LMC after SR, whereas 17 of 156 (11%) patients who received WBRT were diagnosed with LMC after the index procedure. The incidence of LMC was significantly higher in the SR group compared with the WBRT group and the hazard ratio was 2.95 (95% confidence interval; 1.33-6.54, p<0.01). Three additional factors were identified in the multivariable analysis : the younger age group (<40 years old), the progressing systemic disease showed significantly increased incidence of LMC, whereas the adjuvant chemotherapy reduce the incidence.

Conclusion

There is an increased risk of LMC after SR for PBM from breast cancer compared with WBRT. The young age (<40) and systemic burden of cancer in terms of progressing systemic disease without adjuvant chemotherapy could be additional risk factors for the development of LMC.

Background

Lacunar infarctions account for up to 25% of all ischemic strokes and, thus, constitute a numerically important subgroup. It is important that the two pathogeneses of lacunar infarction, that is, small-vessel occlusion and branch atheromatous disease, be differentiated because prognoses and treatment strategies differ. The authors evaluated the presence of branch atheromatous plaque in parent arteries that supply lacunar infarcts by high-resolution magnetic resonance imaging (HR-MRI).

Methods

HR-MRI was performed in 15 patients with (1) a clinical presentation consistent with classical lacunar syndromes; (2) an acute lacunar infarction by diffusion-weighted imaging, measuring ≤20 mm in maximal diameter; (3) a magnetic resonance angiography showing a normal middle cerebral artery or basilar artery supplying the ischemic lesion, and (4) no other obvious etiology for small-vessel distribution ischemic stroke.

Results

The median time of vessel wall imaging after index events was 4 days (range, 2–15 days). Six of the 15 patients had a lacunar infarction in the middle cerebral artery territory, and 9 had a lesion in the basilar artery territory. HR-MRI detected underlying atheromatous plaques in 9 patients (60%) with a lacunar infarction. In these 9 patients, asymptomatic intracranial atherosclerotic stenosis was more frequent compared to patients without branch atheromatous plaque (55.6 vs. 16.7%). In pontine infarctions, ischemic lesions that extended to the pial base of the pons were more frequent in patients with branch atheromatous plaques (83.3 vs. 33.3%), and all the ischemic lesions and atheromatous plaques were on the same side (right, n = 2; left, n = 4). All plaques responsible for acute symptomatic lacunar infarction were enhanced in contrast-enhanced T1-weighted HR-MR images.

Conclusions

HR-MRI results enabled underlying symptomatic branch atheromatous disease to be detected in lacunar infarction patients. The experience gained during this study indicates that HR-MRI better delineates intracranial arterial lesions, suggesting that its use will lead to a further understanding of the mechanisms involved in stroke.

Objectives

Rhinomanometry is a widely accepted method for objective assessment of nasal patency. However, few studies have reported the values of otherwise healthy population for nasal resistance in East Asians. The purpose of this study was to measure normal total nasal resistance (TNR) values in a large sample of Korean adults and to reveal parameters contributing to TNR values.

Methods

Subjects were enrolled from a cohort of the Korean Genome and Epidemiology Study. They were evaluated by anthropometry, questionnaire, and active anterior rhinomanometry at transnasal pressures of 100 and 150 Pascal (Pa).

Results

The study sample consisted of 2,538 healthy subjects (1,298 women and 1,240 men) aged 20 to 80 years. Normal reference TNR values were 0.19±0.08 Pa/cm3/second at 100 Pa and 0.22±0.09 Pa/cm3/second at 150 Pa. The TNR of women was significantly higher than that of men (P<0.0001). TNR decreased with increasing age in both genders (P<0.05). In women, lower body weight was related to increasing TNR. In men, current smokers had higher TNR than ex-smokers and never smokers.

Conclusion

The results of the present study provide information regarding the values of otherwise healthy population of TNR and parameters associated with TNR in Korean adults.

Objective

The Histoculture Drug Response Assay (HDRA), which measures chemosensitivity using minced tumor tissue on drug-soaked gelfoam, has been expected to overcome the limitations of in vitro chemosensitivity test in part. We analyzed interim results of HDRA in malignant gliomas to see if the test can deserve further clinical trials.

Methods

Thirty-three patients with malignant gliomas were operated and their tumor samples were examined for the chemosensitivity to 10 chosen drugs by HDRA. The most sensitive chemotherapy regimen among those pre-established was chosen based on the number of sensitive drugs or total inhibition rate (IR) of the regimen. The response was evaluated by 3 month magnetic resonance image.

Results

Among 13 patients who underwent total resection of the tumor, 12 showed no evidence of disease and one patient revealed progression. The response rate in 20 patients with residual tumors was 55% (3 complete and 8 partial responses). HDRA sensitivity at the cut-off value of more than one sensitive drug in the applied regimen showed a sensitivity of 100%, specificity of 60% and predictability of 70%. Another cut-off value of >80% of total IR revealed a sensitivity of 100%, specificity of 69%, and predictability of 80%. For 12 newly diagnosed glioblastoma patients, median progression-free survival of the HDRA sensitive group was 21 months, while that of the non-sensitive group was 6 months (p=0.07).

Conclusion

HDRA for malignant glioma was inferred as a feasible method to predict the chemotherapy response. We are encouraged to launch phase 2 clinical trial with chemosensitivity on HDRA.

Background

Cerebral microbleeds (MBs) are understood as an important radiologic marker of intracerebral hemorrhage. We sought to investigate the temporal changes of MBs and clinical factors associated with the changes using long-term follow-up MRI.

Methods/Principal Findings

From October 2002 to July 2006, we prospectively enrolled patients with stroke or transient ischemic attack, and followed-up their brain MRIs with an interval >12 mo. We compared demographic factors, vascular risk factors, laboratory findings, and radiologic factors according to the presence or changes of MBs. A total of 224 patients successfully completed the follow-up examinations (mean, 27 months). Newly developed MBs were noted in 10 patients (6.8%) among those without MBs at baseline (n = 148), and in those with MBs at baseline (n = 76), the MB count had decreased in 11 patients (14.5%), and increased in 41 patients (53.9%). The estimated annual rate of change of MB numbers was 0.80 lesions per year in all patients, a value which became greater in those patients who exhibited MBs at baseline (MBs≥5, 5.43 lesions per year). Strokes due to small vessel occlusion and intracerebral hemorrhage, as well as white matter lesions were independently associated with an increased MB count, whereas the highest quartile of low-density lipoprotein (LDL) cholesterol was associated with a decreased MB count.

Conclusion

During the follow-up period, most of MBs showed dynamic temporal change. Symptomatic or asymptomatic small vessel diseases appear to act as risk factors while in contrast, a high level of LDL cholesterol may act as a protective factor against MB increase.

Background

Sphingosylphosphorylcholine (SPC) acts as a potent lipid mediator and signaling molecule in various cell types. In the present study, we investigated the effects of SPC on melanogenesis and SPC-modulated signaling pathways related to melanin synthesis.

Methods

Melanin production was measured in Mel-Ab cells. A luciferase assay was used to detect transcriptional activity of the MITF promoter. Western blot analysis was performed to examine SPC-induced signaling pathways.

Results

SPC produced significant hypopigmentation effects in a dose-dependent manner. It was found that SPC induced not only activation of Akt but also stimulation of mTOR, a downstream mediator of the Akt signaling pathway. Moreover, SPC decreased the levels of LC3 II, which is known to be regulated by mTOR. Treatment with the mTOR inhibitor rapamycin eliminated decreases in melanin and LC3 II levels by SPC. Furthermore, we found that the Akt inhibitor LY294002 restored SPC-mediated downregulation of LC3 II and inhibited the activation of mTOR by SPC.

Conclusions

Our data suggest that the mTOR signaling pathway is involved in SPC-modulated melanin synthesis.

Objective

This paper presents data from a retrospective study of endoscopic third ventriculostomy (ETV) in patients with shunt malfunction and proposes a simple and reasonable post-operative protocol that can detect ETV failure.

Methods

We enrolled 19 consecutive hydrocephalus patients (11 male and 8 female) who were treated with ETV between April 2001 and July 2010 after failure of previously placed shunts. We evaluated for correlations between the success rate of ETV and the following parameters : age at the time of surgery, etiology of hydrocephalus, number of shunt revisions, interval between the initial diagnosis of hydrocephalus or the last shunt placement and ETV, and the indwelling time of external ventricular drainage.

Results

At the time of ETV after shunt failure, 14 of the 19 patients were in the pediatric age group and 5 were adults, with ages ranging from 14 months to 42 years (median age, 12 years). The patients had initially been diagnosed with hydrocephalus between the ages of 1 month 24 days and 32 years (median age, 6 years 3 months). The etiology of hydrocephalus was neoplasm in 7 patients; infection in 5; malformation, such as aqueductal stenosis or megacisterna magna in 3; trauma in 1; and unknown in 3. The overall success rate during the median follow-up duration of 1.4 years (9 days to 8.7 years) after secondary ETV was 68.4%. None of the possible contributing factors for successful ETV, including age (p=0.97) and the etiology of hydrocephalus (p=0.79), were statistically correlated with outcomes in our series.

Conclusion

The use of ETV in patients with shunt malfunction resulted in shunt independence in 68.4% of cases. Age, etiology of hydrocephalus, and other contributing factors were not statistically correlated with ETV success. External ventricular drainage management during the immediate post-ETV period is a good means of detecting ETV failure.

Objective

Incomplete recovery from facial palsy has a long-term impact on the quality of life, and medical options for the sequelae of Bell's palsy are limited. Invasive treatments and physiotherapy have been employed to relieve symptoms, but there is limited clinical evidence for their effectiveness. Acupuncture is widely used on Bell's palsy patients in East Asia, but there is insufficient evidence for its effectiveness on Bell's palsy sequelae. The objective is to evaluate the efficacy and safety of acupuncture in patients with sequelae of Bell's palsy.

Method/Design

This study consists of a randomized controlled trial with two parallel arms: an acupuncture group and a waitlist group. The acupuncture group will receive acupuncture treatment three times per week for a total of 24 sessions over 8 weeks. Participants in the waitlist group will not receive any acupuncture treatments during this 8 week period, but they will participate in the evaluations of symptoms at the start of the study, at 5 weeks and at 8 weeks after randomization, at which point the same treatment as the acupuncture group will be provided. The primary outcome will be analyzed by the change in the Facial Disability Index (FDI) from baseline to week eight. The secondary outcome measures will include FDI from baseline to week five, House-Brackmann Grade, lip mobility, and stiffness scales.

Trial registration

Current Controlled-Trials ISRCTN43104115; registration date: 06 July 2010; the date of the first patient's randomization: 04 August 2010

Objectives

Anthropometric abnormalities of the mandible and neck may contribute to snoring in non-obese Asians. The study evaluated the clinical implications of mandible and neck measurements in non-obese Asian snorers.

Methods

The external mandible and neck measurements (neck circumference, two lengths of neck, mandibular body angle, and lengths of mandibular ramus and body) were compared between snorers and non-snorers in a sample of 2,778 non-obese Koreans (1,389 males, 1,389 females) aged 40 to 69 years (mean, 48.47±7.72 years).

Results

The overall prevalence of snoring was 64.7% (899/1,389) and 48.3% (671/1,389) in non-obese male and female subjects, respectively. In non-obese males, snorers had significantly a greater neck circumference (P<0.0001) and shorter mandibular body length (P=0.0126) than non-snorers. In non-obese females, snorers had significantly greater neck circumferences (P=0.0165), compared with non-snorers. However, there were no statistically significant differences in other variables between non-snorers and snorers.

Conclusion

Anthropometric abnormalities of the mandible and neck, including thick neck circumference in both genders and small mandible size in males, may be relevant contributing factors to snoring in non-obese Asian snorers.

Objectives

The aim of this study was to investigate optimal continuous positive airway pressure (CPAP) level, to examine the factors affecting optimal CPAP level, and to develop a predictive equation for optimal CPAP level in Korean patients with obstructive sleep apnea syndrome (OSAS).

Methods

A total of 202 patients with OSAS who underwent successful manual titration for CPAP treatment were included in this study. Correlations between the optimal CPAP level and baseline data including anthropometric and polysomnographic variables were analyzed. A predictive equation for optimal CPAP level was developed based on anthropometric and polysomonographic data.

Results

The mean optimal CPAP level in 202 patients with OSAS was 7.8±2.3 cm H2O. The mean optimal CPAP level in the mild, moderate, and severe OSAS groups was 6.0±1.3, 7.4±1.9, and 9.1±2.1 cm H2O, respectively. The apneahypopnea index (AHI) (r=0.595, P<0.001), arousal index (r=0.542, P<0.001), minimal SaO2 (r=-0.502, P<0.001), body mass index (BMI) (r=0.494, P<0.001), neck circumference (r=0.265, P<0.001), and age (r=-0.164, P=0.019) were significantly correlated with optimal CPAP level. The best predictive equation according to stepwise multiple linear regression analysis was: Optimal CPAP level (cm H2O)=0.681+(0.205×BMI)+(0.040×AHI). Forty-two percent of the variance in the optimal CPAP level was explained by this equation (R2=0.42, P<0.001).

Conclusion

A predictive equation for optimal CPAP level in Korean patients with OSAS was developed using AHI and BMI, which can be easily measured during the diagnostic process.

Objective

The aim of this report is to provide accurate nationwide epidemiologic data on primary central nervous system (CNS) tumors in Korea. Despite its importance, there are no accurate statistics on primary CNS tumors in Korea. We analyzed primary CNS tumors diagnosed in 2005 from the nationwide registry.

Methods

Data on primary CNS tumors diagnosed in 2005 were collected from the Korean Central Cancer Registry and the Korean Brain Tumor Society. Crude and age-standardized rates were calculated in terms of gender, age, and histological type. Tumors of uncertain histology were investigated individually at the corresponding hospitals and had their diagnoses confirmed.

Results

A total of 5,692 patients diagnosed with primary CNS tumors in 2005 were included in this study. CNS tumors occurred in females more often than in males (female to male, 1.43 : 1). The most common tumor was meningioma (31.2%). Glioblastoma accounted for 30.7% of all gliomas, and 19.3% of all malignant primary CNS tumors. In children under 19 years of age, both germ cell tumor and embryonal/primitive/medulloblastoma were the most common tumors.

Conclusion

This article is the first nationwide primary CNS tumor epidemiology report in Korea. Data from this study should provide valuable information regarding the understanding of primary CNS tumors epidemiology in Korea.

Spontaneous tonsillar hemorrhage from infectious causes is extremely rare and post-tonsillectomy hemorrhage, although also relatively rare, is an unavoidable complication of the procedure. Hemorrhage in association with tonsillitis or tonsillectomy is potentially dangerous and can be life threatening. We report here the presentation and management of a 42-yr-old man with severe spontaneous hemorrhage from infected tonsils and post-tonsillectomy hemorrhage. We suggest that if attempts to control the bleeding are not successful or if severe spontaneous tonsillar hemorrhage occurs repeatedly or a malignancy is suspected, tonsillectomy and close postoperative follow up is recommended.

Viral contamination in environmental samples can be underestimated because a single cell line might reproduce only some enteric viruses and some enteric viruses do not exhibit apparent cytopathic effects in cell culture. To overcome this problem, we evaluated a cell culture-PCR assay based on a combination of A549 and Buffalo green monkey kidney (BGMK) cell lines as a tool to monitor infectious adenoviruses and enteroviruses in river water. Water samples were collected 10 times at each of four rivers located in Gyeonggi Province, South Korea, and then cultured on group 1 cells (BGMK cells alone) and group 2 cells (BGMK and A549 cells). Reverse transcription and multiplex PCR were performed, followed by phylogenetic analysis of the amplicons. Thirty (75.0%) of the 40 samples were positive for viruses based on cell culture, and the frequency of positive samples grown on group 2 cells (65.0%) was higher than the frequency of positive samples grown on group 1 cells (50.0%). The number of samples positive for adenoviruses was higher with A549 cells (13 samples) than with BGMK cells (one sample); the numbers of samples positive for enteroviruses were similar with both types of cells. By using phylogenetic analysis, adenoviral amplicons were grouped into subgenera A, C, D, and F, and enteroviral amplicons were grouped into coxsackieviruses B3 and B4 and echoviruses 6, 7, and 30, indicating that A549 and BGMK cells were suitable for recovering a wide range of adenoviral and enteroviral types. The cell culture-PCR assay with a combination of A549 and BGMK cells and molecular identification could be a useful tool for monitoring infectious adenoviruses and enteroviruses in aquatic environments.

Radiation is a core part of therapy for malignant glioma and is often provided following debulking surgery. However, resistance to radiation occurs in most patients, and the underlying molecular mechanisms of radio-resistance are not fully understood. Here, we demonstrated that microRNA 21 (miR-21), a well-known onco-microRNA in malignant glioma, is one of the major players in radio-resistance. Radio-resistance in different malignant glioma cell lines measured by cytotoxic cell survival assay was closely associated with miR-21 expression level. Blocking miR-21 with anti-miR-21 resulted in radio-sensitization of U373 and U87 cells, whereas overexpression of miR-21 lead to a decrease in radio-sensitivity of LN18 and LN428 cells. Anti-miR-21 sustained γ-H2AX DNA foci formation, which is an indicator of double-strand DNA damage, up to 24 hours and suppressed phospho-Akt (ser473) expression after exposure to γ-irradiation. In a cell cycle analysis, a significant increase in the G2/M phase transition by anti-miR-21 was observed at 48 hours after irradiation. Interestingly, our results showed that anti-miR-21 increased factors associated with autophagosome formation and autophagy activity, which was measured by acid vesicular organelles, LC3 protein expression, and the percentage of GFP-LC3 positive cells. Furthermore, augmented autophagy by anti-miR-21 resulted in an increase in the apoptotic population after irradiation. Our results show that miR-21 is a pivotal molecule for circumventing radiation-induced cell death in malignant glioma cells through the regulation of autophagy and provide a novel phenomenon for the acquisition of radio-resistance.

The p53 tumor suppressor function can be compromised in many tumors by the cellular antagonist HDM2 and human papillomavirus oncogene E6 that induce p53 degradation. Restoration of p53 activity has strong therapeutic potential. Here, we identified TSC-22 as a novel p53-interacting protein and show its novel function as a positive regulator of p53. We found that TSC-22 level was significantly down-regulated in cervical cancer tissues. Moreover, over-expression of TSC-22 was sufficient to inhibit cell proliferation, promote cellular apoptosis in cervical cancer cells and suppress growth of xenograft tumors in mice. Expression of also TSC-22 enhanced the protein level of p53 by protecting it from poly-ubiquitination. When bound to the motif between amino acids 100 and 200 of p53, TSC-22 inhibited the HDM2- and E6-mediated p53 poly-ubiquitination and degradation. Consequently, ectopic over-expression of TSC-22 activated the function of p53, followed by increased expression of p21Waf1/Cip1 and PUMA in human cervical cancer cell lines. Interestingly, TSC-22 did not affect the interaction between p53 and HDM2. Knock-down of TSC-22 by small interfering RNA clearly enhanced the poly-ubiquitination of p53, leading to the degradation of p53. These results suggest that TSC-22 acts as a tumor suppressor by safeguarding p53 from poly-ubiquitination mediated-degradation.

Aberrant miR-21 expression is closely associated with cell proliferation, anti-apoptosis, migration, invasion, and metastasis in various cancers. However, the regulatory mechanism of miR-21 biogenesis is largely unknown. Here, we demonstrated that the tumor suppressor PTEN negatively regulates the expression of oncogenic miR-21 at the post-transcriptional level. Moreover, our results suggest that PTEN plays such a role through the indirect interaction with the Drosha complex. To elucidate how PTEN regulates pri- to pre-miR-21 processing, we attempted to find PTEN-interacting proteins and identified an RNA-regulatory protein, RNH1. Using the sensor to monitor pri-miR-21 processing, we demonstrated that RNH1 is necessary and sufficient for pri-miR-21 processing. Moreover, our results propose that the nuclear localization of RNH1 is important for this function. Further analysis showed that RNH1 directly interacts with the Drosha complex and that PTEN blocks this interaction. Taken together, these results suggest that the PTEN-mediated miR-21 regulation is achieved by inhibiting the interaction between the Drosha complex and RNH1, revealing previously unidentified role of PTEN in the oncogenic miR-21 biogenesis.

Background

Delayed arrival at hospital is one of the major obstacles in enhancing the rate of thrombolysis therapy in patients with acute ischemic stroke. Our study aimed to investigate factors associated with prehospital delay after acute ischemic stroke in Korea.

Methods

A prospective, multicenter study was conducted at 14 tertiary hospitals in Korea from March 2009 to July 2009. We interviewed 500 consecutive patients with acute ischemic stroke who arrived within 48 hours. Univariate and multivariate analyses were performed to evaluate factors influencing prehospital delay.

Results

Among the 500 patients (median 67 years, 62% men), the median time interval from symptom onset to arrival was 474 minutes (interquartile range, 170-1313). Early arrival within 3 hours of symptom onset was significantly associated with the following factors: high National Institutes of Health Stroke Scale (NIHSS) score, previous stroke, atrial fibrillation, use of ambulance, knowledge about thrombolysis and awareness of the patient/bystander that the initial symptom was a stroke. Multivariable logistic regression analysis indicated that awareness of the patient/bystander that the initial symptom was a stroke (OR 4.438, 95% CI 2.669-7.381), knowledge about thrombolysis (OR 2.002, 95% CI 1.104-3.633) and use of ambulance (OR 1.961, 95% CI 1.176-3.270) were significantly associated with early arrival.

Conclusions

In Korea, stroke awareness not only on the part of patients, but also of bystanders, had a great impact on early arrival at hospital. To increase the rate of thrombolysis therapy and the incidence of favorable outcomes, extensive general public education including how to recognize stroke symptoms would be important.