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1.  Diagnostic Patterns in the Evaluation of Patients Presenting with Syncope at the Emergency or Outpatient Department 
Yonsei Medical Journal  2012;53(3):517-523.
Patterns of syncope evaluation vary widely among physicians and hospitals. The aim of this study was to assess current diagnostic patterns and medical costs in the evaluation of patients presenting with syncope at the emergency department (ED) or the outpatient department (OPD) of a referral hospital.
Materials and Methods
This study included 171 consecutive patients with syncope, who visited the ED or OPD between January 2009 and July 2009.
The ED group had fewer episodes of syncope [2 (1-2) vs. 2 (1-5), p=0.014] and fewer prodromal symptoms (81.5% vs. 93.3%, p=0.018) than the OPD group. Diagnostic tests were more frequently performed in the ED group than in the OPD group (6.2±1.7 vs. 5.3±2.0; p=0.012). In addition, tests with low diagnostic yields were more frequently used in the ED group than in the OPD group. The total cost of syncope evaluation per patient was higher in the ED group than in the OPD group [823000 (440000-1408000) won vs. 420000 (186000-766000) won, p<0.001].
There were some differences in the clinical characteristics of patients and diagnostic patterns in the evaluation of syncope between the ED and the OPD groups. Therefore, a selective diagnostic approach according to the presentation site is needed to improve diagnostic yields and to reduce the time and costs of evaluation of syncope.
PMCID: PMC3343440  PMID: 22476994
Syncope; diagnosis; cost-benefit analysis
2.  A study of the relationship between clinical phenotypes and plasma iduronate-2-sulfatase enzyme activities in Hunter syndrome patients 
Korean Journal of Pediatrics  2012;55(3):88-92.
Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare lysosomal storage disorder caused by iduronate-2-sulfatase (IDS) deficiency. MPS II causes a wide phenotypic spectrum of symptoms ranging from mild to severe. IDS activity, which is measured in leukocyte pellets or fibroblasts, was reported to be related to clinical phenotype by Sukegawa-Hayasaka et al. Measurement of residual plasma IDS activity using a fluorometric assay is simpler than conventional measurements using skin fibroblasts or peripheral blood mononuclear cells. This is the first study to describe the relationship between plasma IDS activity and clinical phenotype of MPS II.
We hypothesized that residual plasma IDS activity is related to clinical phenotype. We classified 43 Hunter syndrome patients as having attenuated or severe disease types based on clinical characteristics, especially intellectual and cognitive status. There were 27 patients with the severe type and 16 with the attenuated type. Plasma IDS activity was measured by a fluorometric enzyme assay using 4-methylumbelliferyl-α-iduronate 2-sulphate.
Plasma IDS activity in patients with the severe type was significantly lower than that in patients with the attenuated type (P=0.006). The optimal cut-off value of plasma IDS activity for distinguishing the severe type from the attenuated type was 0.63 nmol·4 hr-1·mL-1. This value had 88.2% sensitivity, 65.4% specificity, and an area under receiver-operator characteristics (ROC) curve of 0.768 (ROC curve analysis; P=0.003).
These results show that the mild phenotype may be related to residual lysosomal enzyme activity.
PMCID: PMC3315624  PMID: 22474463
Hunter syndrome; Mucopolysaccharidosis II; Iduronate sulfatase; Genotype phenotype
3.  The Potential Role of Polymethyl Methacrylate as a New Packaging Material for the Implantable Medical Device in the Bladder 
BioMed Research International  2015;2015:852456.
Polydimethylsiloxane (PDMS) is used in implantable medical devices; however, PDMS is not a completely biocompatible material for electronic medical devices in the bladder. To identify novel biocompatible materials for intravesical implanted medical devices, we evaluated the biocompatibility of polymethyl methacrylate (PMMA) by analyzing changes in the levels of macrophages, macrophage migratory inhibitory factor (MIF), and inflammatory cytokines in the bladder. A ball-shaped metal coated with PMMA or PDMS was implanted into the bladders of rats, and after intravesical implantation, the inflammatory changes induced by the foreign body reaction were evaluated. In the early period after implantation, increased macrophage activity and MIF in the urothelium of the bladder were observed. However, significantly decreased macrophage activity and MIF in the bladder were observed after implantation with PMMA- or PDMS-coated metal in the later period. In addition, significantly decreased inflammatory cytokines such as IL-1β, IL-6, and TNF-α were observed with time. Based on these results, we suggest that MIF plays a role in the foreign body reaction and in the biocompatible packaging with PMMA for the implanted medical devices in the bladder.
PMCID: PMC4330953
4.  Analgesic effects of palonosetron in the intravenous propofol injection 
Korean Journal of Anesthesiology  2014;66(2):99-104.
Propofol is a good induction agent, but it has the disadvantage of causing pain on intravenous injection. The incidence of propofol-induced pain is approximately 70%. Palonosetron is a novel second-generation 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist. We presumed that palonosetron would be effective in reducing the occurrence of propofol-induced pain based on similar mechanisms to other 5-HT3 receptor antagonists.
Eighty patients were randomized to either Group N (0.9% sodium chloride [normal saline] 2 ml, n = 40) or Group P (palonosetron 0.075 mg, 2 ml, n = 40). Patients were intravenously given a 2 ml pretreatment solution, containing either palonosetron 0.075 mg or normal saline. Following pretreatment with 2 ml of palonosetron 0.075 mg or normal saline, we manually occluded venous drainage midarm with the help of an assistant. One minute later, we released the occlusion of venous drainage. This was followed by a 5-second propofol injection at 25% of the total calculated doses. Patients were then interviewed about whether or not they experienced propofol-induced pain.
Overall, the incidence of propofol-induced pain was 60% in the normal saline group and 27.5% in the palonosetron group. No patients in the palonosetron group experienced severe pain. The incidence of propofol-induced pain was significantly lower in the palonosetron group compared to the normal saline group (P < 0.01).
Following pretreatment with palonosetron, 72.5% of patients experienced a decrease in the occurrence of propofol-induced pain.
PMCID: PMC3948450  PMID: 24624266
Injections; Pain; Palonosetron; Propofol
5.  Voxel-wise lp-ntPET for detecting localized, transient dopamine release of unknown timing. Sensitivity analysis and application to cigarette smoking in the PET scanner 
Human brain mapping  2014;35(9):4876-4891.
The lp-ntPET (“linear parametric ntPET”) model estimates time-variation in endogenous neurotransmitter levels from dynamic PET data. The pattern of dopamine change over time may be an important element of the brain’s response to addictive substances such as cigarettes or alcohol. We have extended the lp-ntPET model from the original ROI-based implementation to be able to apply the model at the voxel-level. The resulting endpoint is a dynamic image, or movie, of transient neurotransmitter changes. Simulations were performed to select threshold values to reduce the false positive rate when applied to real 11C-raclopride PET data. We tested the new voxel-wise method on simulated data and finally, we applied it to 11C-raclopride PET data of subjects smoking cigarettes in the PET scanner. In simulation, the temporal precision of neurotransmitter response was shown to be similar to that of ROI-based lp-ntPET (standard deviation ~3 min). False positive rates for the voxel-wise method were well controlled by combining a statistical threshold (the F-test) with a new spatial (cluster-size) thresholding operation. Sensitivity of detection for the new algorithm was greater than 80 % for the case of short-lived dopamine changes that occur in sub-regions of the striatum as might be the case with cigarette smoking. Finally, in 11C-raclopride PET data, dopamine movies reveal for the first time that different temporal patterns of the dopamine response to smoking may exist in different sub-regions of the striatum. These spatio-temporal patterns of neurotransmitter change created by voxel-wise lp-ntPET may serve as novel biomarkers for addiction and/or treatment efficacy.
PMCID: PMC4303353  PMID: 24700424
lp-ntPET; time-varying parameters; dopamine; sensitivity; voxel analysis; nicotine
6.  Anthocyanin Induces Apoptosis of DU-145 Cells In Vitro and Inhibits Xenograft Growth of Prostate Cancer 
Yonsei Medical Journal  2014;56(1):16-23.
To investigate the effects of anthocyanins extracted from black soybean, which have antioxidant activity, on apoptosis in vitro (in hormone refractory prostate cancer cells) and on tumor growth in vivo (in athymic nude mouse xenograft model).
Materials and Methods
The growth and viability of DU-145 cells treated with anthocyanins were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis was assessed by DNA laddering. Immunoblotting was conducted to evaluate differences in the expressions of p53, Bax, Bcl, androgen receptor (AR), and prostate specific antigen (PSA). To study the inhibitory effects of anthocyanins on tumor growth in vivo, DU-145 tumor xenografts were established in athymic nude mice. The anthocyanin group was treated with daily oral anthocyanin (8 mg/kg) for 14 weeks. After 2 weeks of treatment, DU-145 cells (2×106) were inoculated subcutaneously into the right flank to establish tumor xenografts. Tumor dimensions were measured twice a week using calipers and volumes were calculated.
Anthocyanin treatment of DU-145 cells resulted in 1) significant increase in apoptosis in a dose-dependent manner, 2) significant decrease in p53 and Bcl-2 expressions (with increased Bax expression), and 3) significant decrease in PSA and AR expressions. In the xenograft model, anthocyanin treatment significantly inhibit tumor growth.
This study suggests that anthocyanins from black soybean inhibit the progression of prostate cancer in vitro and in a xenograft model.
PMCID: PMC4276751  PMID: 25510742
Prostatic neoplasms; anthocyanins; apoptosis
7.  An Extremely Rare Case of Gastric Subepithelial Tumor: Gastric Endometriosis 
Clinical Endoscopy  2015;48(1):74-77.
Endometriosis is a disease characterized by the presence of endometrial tissue outside of the uterine cavity. It is common in women of childbearing age, and is most frequently located in the pelvic cavity. Approximately 10% of endometriosis cases occur outside of the pelvic cavity in locations such as the intestines, genitourinary system, kidneys, lungs, and skin. However, there have been few reports of endometriosis in the stomach. Here, we report a rare case of endometriosis that presented as a subepithelial stomach tumor.
PMCID: PMC4323438
Endometriosis; Stomach; Subepithelial tumor
8.  Systematic Review of Surgical Approaches for Adrenal Tumors: Lateral Transperitoneal versus Posterior Retroperitoneal and Laparoscopic versus Robotic Adrenalectomy 
Background. Laparoscopic lateral transperitoneal adrenalectomy (LTA) has been the standard method for resecting benign adrenal gland tumors. Recently, however, laparoscopic posterior retroperitoneal adrenalectomy (PRA) has been more popular as an alternative method. This systematic review evaluates current evidence on adrenalectomy techniques, comparing laparoscopic LTA with PRA and laparoscopic adrenalectomy with robotic adrenalectomy. Methods. PubMed, Embase, and ISI Web of Knowledge databases were searched systematically for studies comparing surgical outcomes of laparoscopic LTA versus PRA and laparoscopic versus robotic adrenalectomy. The studies were evaluated according to the PRISMA statement. Results. Eight studies comparing laparoscopic PRA and LTA showed that laparoscopic PRA was superior or at least comparable to laparoscopic LTA in operation time, blood loss, pain score, hospital stay, and return to normal activity. Conversion rates and complication rates were similar. Six studies comparing robotic and laparoscopic adrenalectomy found that outcomes and complications were similar. Conclusion. Laparoscopic PRA was more effective than LTA, especially in reducing operation time and hospital stay, but there was no evidence showing that robotic adrenalectomy was superior to laparoscopic adrenalectomy. Cost reductions and further technical advances are needed for wider application of robotic adrenalectomy.
PMCID: PMC4281398  PMID: 25587275
9.  Clinicopathologic significance of expression of nuclear factor-κB RelA and its target gene products in gastric cancer patients 
AIM: To assess the prognostic significance of nuclear factor-κB (NF-κB) and its target genes in gastric cancer.
METHODS: The tumor tissues of 115 patients with gastric cancer were immunohistochemically evaluated using monoclonal antibodies against NF-κB RelA. Preoperative serum levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6) were assessed via enzyme-linked immuno-sorbent assay. C-reactive protein (CRP) and serum amyloid A (SAA) were measured via immunotrubidimetry.
RESULTS: Positive rate of NF-κB RelA was 42.6%. NF-κB RelA expression in tumor tissues was also related to serum levels of IL-6 (P = 0.044) and CRP (P = 0.010). IL-6, SAA, CRP were related to depth of invasion, VEGF and SAA were correlated with lymph node metastasis. IL-6, VEGF, SAA and CRP were related to the stage. Univariate analysis demonstrated that immunostaining of NF-κB RelA, levels of IL-6, VEGF, SAA were significantly related with both disease free survival and overall survival (OS). Multivariate analysis verified that NF-κB RelA [hazard ratio (HR): 3.40, P = 0.024] and SAA (HR: 3.39, P = 0.045) were independently associated with OS.
CONCLUSION: Increased expression of NF-κB RelA and high levels of serum SAA were associated with poor OS in gastric cancer patients.
PMCID: PMC3442213  PMID: 23002344
Nuclear factor-κB; Vascular endothelial growth factor; Interleukin-6; C-reactive protein; Serum amyloid A; Stomach; Carcinoma
10.  Pseudotumor of the Omentum Associated with Migration of the Ingested Crab-Leg 
Journal of Korean Medical Science  2012;27(5):569-571.
Foreign body ingestion is not uncommon in clinical practice, and it may occasionally lead to penetration injuries. Emergency physicians and radiologists sometimes fail to obtain complete histories including ingestion and may overlook the possibility of foreign body-induced complications. Herein, we report a case of stomach antrum perforation due to foreign body migration. We were unaware of the patient's history of eating the Korean delicacy "Kanjang-gaejang," which is raw crab seasoned with soy sauce. Several imaging diagnostic modalities had suggested the possibility of a malignant mass in the gastrocolic ligament area. During the operation, a crab leg was discovered as the cause of an intra-abdominal abscess. The patient underwent an antrectomy, a vagotomay, and a transverse colon wedge resection. We present this unusual case of a pseudotumorous lesion caused by ingestion of Kanjang-gaejang.
PMCID: PMC3342553  PMID: 22563227
Foreign Bodies; Crab; Perforation; Stomach; Pseudotumor
11.  Knockdown of anterior gradient 2 expression extenuates tumor-associated phenotypes of SNU-478 ampulla of Vater cancer cells 
BMC Cancer  2014;14(1):804.
Anterior gradient 2 (AGR2) has been implicated in tumor-associated phenotypes such as cell viability, invasion and metastasis in various human cancers. However, the tumor promoting activity of AGR2 has not yet been determined in biliary tract cancers. Thus, we examined the expression of AGR2 and its tumor-promoting activity in biliary tract cancer cells in this study.
Expression of AGR2 mRNA and protein was analyzed by real time RT-PCR and western blotting, respectively. MTT assay was employed to measure cell viability and pulsed BrdU incorporation by proliferating cells was monitored by flow cytometry. Soft agar colony formation assay and transwell invasion assay were employed to determine anchorage-independent growth and in vitro invasion of the tumor cells, respectively. In vivo tumor formation was examined by injection of tumor cells into immunocompromised mice subcutaneously. Statistical analysis was performed with 2-tailed unpaired Student’s t-test for continuous data and with one-way ANOVA for multiple group comparisons. Bonferroni tests were used for post hoc 2-sample comparisons.
AGR2 mRNA was detected in SNU-245, SNU-478, and SNU-1196 cell lines, and its protein expression was confirmed in SNU-478 and SNU-245 cell lines by western blot analysis. Knockdown of AGR2 expression with an AGR2-specific short hairpin RNA (shRNA) in SNU-478, an ampulla of Vater cancer cell line resulted in decreased cell viability and in decreased anchorage-independent growth by 98%. The AGR2 knockdown also increased the sensitivity of the cells to chemotherapeutic drugs, including gemcitabine, 5-fluorouracil and cisplatin. In addition, SNU-478 cells expressing AGR2-shRNA failed to form detectable tumor xenografts in nude mice, whereas control cells formed tumors with an average size of 179 ± 84 mm3 in 3 weeks. Overexpression of AGR2 in SNU-869 cells significantly increased cell viability through enhanced cell proliferation and the number of Matrigel™-invading cells compared with AGR2-negative SNU-869 cells.
Our findings implicate that AGR2 expression augments tumor-associated phenotypes by increasing proliferative and invasive capacities of the ampulla of Vater cancer cells.
PMCID: PMC4228270  PMID: 25367337
AGR2; Tumor promotion; SNU-478; SNU-869; Biliary tract cancer; Ampulla of Vater
12.  Importance of the Time Interval between Bowel Preparation and Colonoscopy in Determining the Quality of Bowel Preparation for Full-Dose Polyethylene Glycol Preparation 
Gut and Liver  2014;8(6):625-631.
The quality of bowel preparation (QBP) is the important factor in performing a successful colonoscopy. Several factors influencing QBP have been reported; however, some factors, such as the optimal preparation-to-colonoscopy time interval, remain controversial. This study aimed to determine the factors influencing QBP and the optimal time interval for full-dose polyethylene glycol (PEG) preparation.
A total of 165 patients who underwent colonoscopy from June 2012 to August 2012 were prospectively evaluated. The QBP was assessed using the Ottawa Bowel Preparation Scale (Ottawa) score according to several factors influencing the QBP were analyzed.
Colonoscopies with a time interval of 5 to 6 hours had the best Ottawa score in all parts of the colon. Patients with time intervals of 6 hours or less had the better QBP than those with time intervals of more than 6 hours (p=0.046). In the multivariate analysis, the time interval (odds ratio, 1.897; 95% confidence interval, 1.006 to 3.577; p=0.048) was the only significant contributor to a satisfactory bowel preparation.
The optimal time was 5 to 6 hours for the full-dose PEG method, and the time interval was the only significant contributor to a satisfactory bowel preparation.
PMCID: PMC4215448  PMID: 25368750
Quality of bowel preparation; Colonoscopy; Time interval
13.  Ribes fasciculatum var. chinense Attenuated Allergic Inflammation In Vivo and In Vitro 
Biomolecules & Therapeutics  2014;22(6):547-552.
Ribes fasciculatum var. chinense MAX. (R. fasciculatum) has traditionally been used in Korea to treat inflammatory diseases. However, the exact mechanism that accounts for the anti-inflammatory effect of R. fasciculatum is not completely understood. We aimed to ascertain the pharmacological effects of R. fasciculatum on both compound 48/80- or histamine-induced scratching behaviors and 2, 4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) in mice. Additionally, to find a possible explanation for the anti-inflammatory effects of R. fasciculatum, we evaluated the effects of R. fasciculatum on the production of inflammatory mediators in LPS-stimulated macrophage cells. Treatment of R. fasciculatum significantly reduced compound 48/80- or histamine-induced the pruritus in mice. R. fasciculatum attenuated the AD symptoms such as eczematous, erythema and dryness and serum IgE levels in AD model. Additionally, R. fasciculatum inhibited the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The maximal rates of TNF-α and IL-6 inhibition by R. fasciculatum (1 mg/ml) were approximately 32.12% and 46.24%, respectively. We also showed that R. fasciculatum inhibited the activation of nuclear factor-kappa B in LPS-stimulated macrophages. Collectively, the findings of this study provide us with novel insights into the pharmacological actions of R. fasciculatum as a potential molecule for use in the treatment of allergic inflammatory diseases.
PMCID: PMC4256035  PMID: 25489423
Ribes fasciculatum; Inflammatory mediators; Nuclear factor-kappa B; Macrophage; Allergic inflammation
14.  Gastric Squamous Papilloma in a 52-Year-Old Female Patient 
Clinical Endoscopy  2014;47(6):571-574.
A papilloma is a benign epithelial lesion characterized by finger-like projections of tissue lined by an overgrowth of squamous cells and a core of connective tissue. We report a case of squamous papilloma on the cardia in a 52-year-old asymptomatic female. Endoscopy showed a 1-cm sized is polyp with hyperemic change originating from the cardia adjacent to the esophagogastric junction, the biopsy of which suggested a diagnosis of squamous papilloma. Endoscopic mucosal resection was performed to obtain a definite diagnosis and the polyp was completely removed. The histological result was compatible with squamous papilloma, and its surrounding tissues showed foveolar epithelium, which suggested a stomach origin. This is the first report of endoscopic resection of a gastric squamous papilloma. Squamous papilloma should be considered in the differential diagnosis of a gastric polyp, especially one in the cardia. As the prognostic value of a squamous papilloma is not well known, we recommend endoscopic resection to treat a gastric squamous papilloma, when possible.
PMCID: PMC4260108  PMID: 25505726
Papilloma; Stomach; Endoscopic resection; Polyps
15.  Effects of KH-204 on the expression of heat shock protein 70 and germ cell apoptosis in infertility rat models 
Idiopathic infertility is a significant number of causes of male infertility. Empirical treatments are used for idiopathic male infertility, and antioxidant supplementation is a kind of management of oxidative stress related infertility. We investigated the antioxidant effects of the modified Ojayeonjonghwan (KH-204) in a rat model of cryptorchidism.
Male rats were divided into four groups (n = 8 in each): a normal control group, a cryptorchidism-induced control group and two cryptorchidism-induced groups treated p.o. with either 200 or 400 mg/kg, KH-204 for 4 weeks. The testes and epididymides from rats in all groups were removed, weighed and subjected to histological examination and semen analysis after surgery. Oxidative stress was assessed by measuring 8-hydroxy-20-deoxyguanosine (8-OHdG), superoxide dismutase (SOD) and heat shock protein (HSP) levels. Apoptosis was determined using a terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling assay.
Treatment with the multi-herbal medicine KH-204 (1) increased the mean weight of the cryptorchid testes; (2) restored sperm counts, motility and germinal cell layer thickness; (3) decreased levels of 8-OHdG and increased levels of SOD; and (4) decreased HSP70 levels and apoptosis.
KH-204 reduces the oxidative stress in an experimental rat model of cryptorchidism, and it may alleviate HSP expression and germ cell apoptosis.
PMCID: PMC4197240  PMID: 25269420
Infertility, male; Phytotherapy; Spermatozoa; Antioxidants
16.  Association between Blood Lipid Levels and Personality Traits in Young Korean Women 
PLoS ONE  2014;9(9):e108406.
Abnormal lipid levels are important etiological factors associated with the development of atherosclerosis and with increased cardiovascular morbidity and mortality. Lipid levels are also influenced by lifestyle and behavioral factors, which suggests that personality traits might be related to abnormal lipid profiles. Studies on personality traits and lipid levels are relatively scarce in Korea. Therefore, the objective of this study was to examine the association between lipid levels and personality traits in young Korean women. A total of 1,701 young Korean women [mean age  = 24.9±4.6 years (range 17–39)] who volunteered for personality trait evaluation were recruited for this study. Lipid levels, including total cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride, were measured in all subjects after an overnight fast, and a low density lipoprotein (LDL) cholesterol level was calculated. The study population was divided into abnormal and normal lipid level groups according to the clinical criteria. Personality traits were measured using the Revised NEO Personality Inventory for the Five-Factor Model of personality. High neuroticism was associated with low HDL cholesterol levels. Low extraversion and openness were associated with high levels of triglyceride. At the facet level, the association between personality and lipid levels were generally consistent. Angry hostility, self-consciousness, vulnerability to stress, activity, and straightforwardness were associated with HDL cholesterol levels. Activity, positive emotion, aesthetics, actions, and deliberation were associated with triglyceride. When applying clinical criteria, conscientiousness was less likely to have abnormal total cholesterol levels. Our results showed that the women with the low HDL cholesterol levels are like to be more neurotic and the hyperglycemic women are prone to lower extraversion and openness in Korea. Understanding the associations between blood lipid levels and personality traits may have a beneficial effect for the managing of dyslipidemia.
PMCID: PMC4182467  PMID: 25268499
17.  An optimal transition time to extracorporeal cardiopulmonary resuscitation for predicting good neurological outcome in patients with out-of-hospital cardiac arrest: a propensity-matched study 
Critical Care  2014;18(5):535.
Prolonged conventional cardiopulmonary resuscitation (CCPR) is associated with a poor prognosis in out-of-hospital cardiac arrest (OHCA) patients. Alternative methods can be needed to improve the outcome in patients with prolonged CCPR and extracorporeal cardiopulmonary resuscitation (ECPR) can be considered as an alternative method. The objectives of this study were to estimate the optimal duration of CPR to consider ECPR as an alternative resuscitation method in patients with CCPR, and to find the indications for predicting good neurologic outcome in OHCA patients who received ECPR.
This study is a retrospective analysis based on a prospective cohort. We included patients ≥ 18 years of age without suspected or confirmed trauma and who experienced an OHCA from May 2006 to December 2013. First, we determined the appropriate cut-off duration for CPR based on the discrimination of good and poor neurological outcomes in the patients who received only CCPR, and then we compared the outcome between the CCPR group and ECPR group by using propensity score matching. Second, we compared CPR related data according to the neurologic outcome in matched ECPR group.
Of 499 patients suitable for inclusion, 444 and 55 patients were enrolled in the CCPR and ECPR group, respectively. The predicted duration for a favorable neurologic outcome (CPC1, 2) is < 21 minutes of CPR in only CCPR patients. The matched ECPR group with ≥ 21 minutes of CPR duration had a more favorable neurological outcome than the matched CCPR group at 3 months post-arrest. In matched ECPR group, younger age, witnessed arrest without initial asystole rhythm, early achievement of mean arterial pressure ≥ 60 mmHg, low rate of ECPR-related complications, and therapeutic hypothermia were significant factors for expecting good neurologic outcome.
ECPR should be considered as an alternative method for attaining good neurological outcomes in OHCA patients who required prolonged CPR, especially of ≥ 21 minutes. Younger or witnessed arrest patients without initial asystole were good candidates for ECPR. After implantation of ECPR, early hemodynamic stabilization, prevention of ECPR-related complications, and application of therapeutic hypothermia may improve the neurological outcome.
PMCID: PMC4189722  PMID: 25255842
18.  The genome sequence of the Antarctic bullhead notothen reveals evolutionary adaptations to a cold environment 
Genome Biology  2014;15(9):468.
Antarctic fish have adapted to the freezing waters of the Southern Ocean. Representative adaptations to this harsh environment include a constitutive heat shock response and the evolution of an antifreeze protein in the blood. Despite their adaptations to the cold, genome-wide studies have not yet been performed on these fish due to the lack of a sequenced genome. Notothenia coriiceps, the Antarctic bullhead notothen, is an endemic teleost fish with a circumpolar distribution and makes a good model to understand the genomic adaptations to constant sub-zero temperatures.
We provide the draft genome sequence and annotation for N. coriiceps. Comparative genome-wide analysis with other fish genomes shows that mitochondrial proteins and hemoglobin evolved rapidly. Transcriptome analysis of thermal stress responses find alternative response mechanisms for evolution strategies in a cold environment. Loss of the phosphorylation-dependent sumoylation motif in heat shock factor 1 suggests that the heat shock response evolved into a simple and rapid phosphorylation-independent regulatory mechanism. Rapidly evolved hemoglobin and the induction of a heat shock response in the blood may support the efficient supply of oxygen to cold-adapted mitochondria.
Our data and analysis suggest that evolutionary strategies in efficient aerobic cellular respiration are controlled by hemoglobin and mitochondrial proteins, which may be important for the adaptation of Antarctic fish to their environment. The use of genome data from the Antarctic endemic fish provides an invaluable resource providing evidence of evolutionary adaptation and can be applied to other studies of Antarctic fish.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0468-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4192396  PMID: 25252967
19.  Vav3, a GEF for RhoA, Plays a Critical Role under High Glucose Conditions 
Endocrinology and Metabolism  2014;29(3):363-370.
The role of small GTPase molecules is poorly understood under high glucose conditions.
We analyzed the expression pattern of Vav3 in skeletal muscle C2C12 cells under high glucose culture condition with reverse transcription-polymerase chain reaction and Western blot analysis. We also measured glucose uptake using isotope-labelled glucose.
We showed that expression of Vav3 (a guanine nucleotide exchange factor for RhoA) increased. mRNA and protein levels in skeletal muscle C2C12 cells under high glucose conditions. The AMP-activated protein kinase (AMPK) activator AMPK agonist 5-aminoimidazole-4-carboxy-amide-1-d-ribofuranoside (AICAR) suppressed high glucose-induced Vav3 induction. In addition, exposure of cells to high glucose concentration increased the phosphorylation of PAK-1, a molecule downstream of RhoA. The phosphorylation of paxillin, a downstream molecule of PAK-1, was also increased by exposure to high glucose. Phosphorylation of these molecules was not observed in the presence of AICAR, indicating that AMPK is involved in the RhoA signal pathway under high glucose conditions. Knock down of Vav3 enhances metformin-mediated glucose uptake. Inhibition of AMPK blocked the increases of Vav3 knock down-induced glucose uptake. Metformin-mediated Glut4 translocation was also increased by Vav3 knock-down, suggesting that Vav3 is involved in metformin-mediated glucose uptake.
These results demonstrate that Vav3 is involved in the process of metformin-mediated glucose regulation.
PMCID: PMC4192823  PMID: 25309796
AMP-activated protein kinases; Diabetes; High glucose; Metformin; Vav3
20.  Bariatric Surgery Improves the Cavernosal Neuronal, Vasorelaxation, and Contraction Mechanisms for Erectile Dysfunction As Result of Amelioration of Glucose Homeostasis in a Diabetic Rat Model 
PLoS ONE  2014;9(8):e104042.
Bariatric surgery is an effective treatment option for both obesity and obesity-related type 2 diabetes mellitus (T2DM). However, little is known regarding the effects of bariatric surgery on erectile dysfunction among patients with T2DM. Therefore, we investigated whether bariatric surgery would lead to structural and biochemical changes in the corpus cavernosum.
Material and Method
Twenty-five male Otsuka Long-Evans Tokushima Fatty rats were assigned to either a control group (sham operation, n = 10) or a bariatric surgery group (gastric bypass surgery, n = 15). Four weeks after the operation, each group of rats was evaluated with an oral glucose tolerance test (OGTT). The penile intracavernous pressure was measured for erectile functional analysis. Histologic evaluation of the tissue was performed with Masson's trichrome staining. Endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), Rho kinase, and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels in the corpus cavernosum were assayed by using western blot and ELISA.
The mean body weight of the bariatric surgery group was lower than the control group (p = 0.002). The postoperative OGTT result was lower in the bariatric surgery group than in the control group (p = 0.014), and this was lower than the preoperative value (p = 0.037). The intracavernous pressure/mean arterial pressure ratio was higher in the bariatric surgery group compared to the control group (p = 0.021), and a higher cavernosum smooth muscle/collagen ratio was observed in the bariatric surgery group compared to the control group (p = 0.025). Likewise, the expression of eNOS and nNOS was higher in bariatric surgery group than in the control group (p = 0.027 and p = 0.008, respectively). Decreased expression of Rho kinase and levels of 8-OHdG were observed in the bariatric surgery group (p = 0.032).
In this animal model, bariatric surgery appears to ameliorate T2DM-related metabolic dysfunction leading to structural and biochemical changes in the corpus cavernosum, and thus, results in improvement of erectile dysfunction associated with T2DM.
PMCID: PMC4138031  PMID: 25137300
21.  Creating Dynamic Images of Short-lived Dopamine Fluctuations with lp-ntPET: Dopamine Movies of Cigarette Smoking 
We describe experimental and statistical steps for creating dopamine movies of the brain from dynamic PET data. The movies represent minute-to-minute fluctuations of dopamine induced by smoking a cigarette. The smoker is imaged during a natural smoking experience while other possible confounding effects (such as head motion, expectation, novelty, or aversion to smoking repeatedly) are minimized.
We present the details of our unique analysis. Conventional methods for PET analysis estimate time-invariant kinetic model parameters which cannot capture short-term fluctuations in neurotransmitter release. Our analysis - yielding a dopamine movie - is based on our work with kinetic models and other decomposition techniques that allow for time-varying parameters 1-7. This aspect of the analysis – temporal-variation- is key to our work. Because our model is also linear in parameters, it is practical, computationally, to apply at the voxel level. The analysis technique is comprised of 5 main steps: pre-processing, modeling, statistical comparison, masking and visualization. Preprocessing is applied to the PET data with a unique ‘HYPR’ spatial filter 8 that reduces spatial noise but preserves critical temporal information. Modeling identifies the time-varying function that best describes the dopamine effect on 11C-raclopride uptake. The statistical step compares the fit of our (lp-ntPET) model 7 to a conventional model 9. Masking restricts treatment to those voxels best described by the new model. Visualization maps the dopamine function at each voxel to a color scale and produces a dopamine movie. Interim results and sample dopamine movies of cigarette smoking are presented.
PMCID: PMC4046621  PMID: 23963311
Neurotransmission; transient; dopamine release; PET; modeling; linear; time-invariant; smoking; F-test; ventral-striatum
22.  Production of CMAH Knockout Preimplantation Embryos Derived From Immortalized Porcine Cells Via TALE Nucleases 
Although noncancerous immortalized cell lines have been developed by introducing genes into human and murine somatic cells, such cell lines have not been available in large domesticated animals like pigs. For immortalizing porcine cells, primary porcine fetal fibroblasts were isolated and cultured using the human telomerase reverse transcriptase (hTERT) gene. After selecting cells with neomycin for 2 weeks, outgrowing colonized cells were picked up and subcultured for expansion. Immortalized cells were cultured for more than 9 months without changing their doubling time (~24 hours) or their diameter (< 20 µm) while control cells became replicatively senescent during the same period. Even a single cell expanded to confluence in 100 mm dishes. Furthermore, to knockout the CMAH gene, designed plasmids encoding a transcription activator-like effector nuclease (TALENs) pairs were transfected into the immortalized cells. Each single colony was analyzed by the mutation-sensitive T7 endonuclease I assay, fluorescent PCR, and dideoxy sequencing to obtain three independent clonal populations of cells that contained biallelic modifications. One CMAH knockout clone was chosen and used for somatic cell nuclear transfer. Cloned embryos developed to the blastocyst stage. In conclusion, we demonstrated that immortalized porcine fibroblasts were successfully established using the human hTERT gene, and the TALENs enabled biallelic gene disruptions in these immortalized cells.
PMCID: PMC4040627  PMID: 24866481
CMAH knockout; immortalization; somatic cell nuclear transfer; transcription activator-like effector nuclease
23.  Relationship between pregnancy rate and serum progesterone concentration in cases of porcine embryo transfer 
Journal of Veterinary Science  2014;15(1):167-171.
The level of P4 at the time of embryo transfer (ET) is important. P4 concentrations and numbers of corpora lutea for 126 recipients were evaluated. Nuclear transfer embryos were transferred into 126 surrogates. 11 maintained their pregnancy until full-term delivery, 17 miscarried, and implantation failed in 98 animals. P4 levels in the full-term group were significantly different from those of the pigs that aborted or in which implantation failed (p < 0.05). However, the numbers of corpora lutea were not significantly different. These findings indicate that the concentration of progesterone can be an important factor for successful ET in pigs.
PMCID: PMC3973761  PMID: 24378584
corpus luteum; pregnancy; progesterone; somatic cell nuclear transfer
24.  Resistin Knockout Mice Exhibit Impaired Adipocyte Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) Expression 
Diabetes  2013;62(2):471-477.
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that also plays a regulatory role in fat metabolism. In 3T3-L1 cells, resistin was demonstrated to be a key mediator of GIP stimulation of lipoprotein lipase (LPL) activity, involving activation of protein kinase B (PKB) and reduced phosphorylation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK). The current study was initiated to determine whether resistin has additional roles in GIP-regulated adipocyte functions. Analysis of primary adipocytes isolated from Retn−/−, Retn+/−, and Retn+/+ mice found that GIP stimulated the PKB/LKB1/AMPK/LPL pathway and fatty acid uptake only in Retn+/+ adipocytes, suggesting that GIP signaling and/or GIP responsiveness were compromised in Retn+/− and Retn−/− adipocytes. GIP receptor (GIPR) protein and mRNA were decreased in Retn+/− and Retn−/− adipocytes, but resistin treatment rescued LPL responsiveness to GIP. In addition, genes encoding tumor necrosis factor (TNF), TNF receptor 2 (TNFR2), and the signaling proteins stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK), were downregulated, and phosphorylated levels of SAPK/JNK/c-Jun were decreased in Retn−/− mice. Chromatin immunoprecipitation assays were used to identify a 12-O-tetradecanoylphorbol-13-acetate (TPA)-response element (TRE-III) responsible for c-Jun–mediated transcriptional activation of Gipr. Blunted GIP responsiveness in Retn+/− and Retn−/− adipocytes was therefore largely due to the greatly reduced GIPR expression associated with decreased c-Jun–mediated transcriptional activation of Gipr.
PMCID: PMC3554369  PMID: 23002036
25.  Impact of Enzyme Replacement Therapy on Linear Growth in Korean Patients with Mucopolysaccharidosis Type II (Hunter Syndrome) 
Journal of Korean Medical Science  2014;29(2):254-260.
Hunter syndrome (or mucopolysaccharidosis type II [MPS II]) arises because of a deficiency in the lysosomal enzyme iduronate-2-sulfatase. Short stature is a prominent and consistent feature in MPS II. Enzyme replacement therapy (ERT) with idursulfase (Elaprase®) or idursulfase beta (Hunterase®) have been developed for these patients. The effect of ERT on the growth of Korean patients with Hunter syndrome was evaluated at a single center. This study comprised 32 patients, who had received ERT for at least 2 yr; they were divided into three groups according to their ages at the start of ERT: group 1 (<6 yr, n=14), group 2 (6-10 yr, n=11), and group 3 (10-20 yr, n=7). The patients showed marked growth retardation as they got older. ERT may have less effect on the growth of patients with the severe form of Hunter syndrome. The height z-scores in groups 2 and 3 revealed a significant change (the estimated slopes before and after the treatment were -0.047 and -0.007, respectively: difference in the slope, 0.04; P<0.001). Growth in response to ERT could be an important treatment outcome or an endpoint for future studies.
Graphical Abstract
PMCID: PMC3924006  PMID: 24550654
Mucopolysaccharidosis II; Hunter Syndrome; Enzyme Replacement Therapy; Growth; Elaprase; Hunterase

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