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1.  Effect of Vestibulosympathetic Reflex and Baroreflex on Expression of pERK in the Nucleus Tractus Solitarius following Acute Hypotension in Conscious Rats 
Control of blood pressure is maintained by the interaction between the arterial baroreflex and vestibulosympathetic reflex during postural changes. In this study, the contributions of vestibular receptors and baroreceptors to the maintenance of blood pressure following acute hypotension were compared in terms of phosphorylated extracellular regulated protein kinase (pERK) expression in the nucleus tractus solitaries (NTS). Expression of pERK in the NTS was measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) 5, 10, 20, and 40 min following acute hypotension induced by sodium nitroprusside (SNP) infusion. Expression of pERK increased significantly in the NTS in the control group following SNP infusion, and the expression peaked at 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than in control group. The BL group showed a relatively higher reduction in pERK expression than the SAD group, and the pERK expression in the NTS was localized to the caudal portion of the nuclei in the BL and SAD groups. These results suggest that the vestibular receptors may play a key role in maintaining blood pressure following acute hypotension; thus, the vestibular system may contribute to compensate for orthostatic hypotension.
doi:10.4196/kjpp.2014.18.4.353
PMCID: PMC4146639  PMID: 25177169
Baroreceptor; Hypotension; Nucleus tractus solitarius; pERK; Vestibular receptor
2.  Contrast-Induced Nephropathy in Patients Undergoing Intravenous Contrast-Enhanced Computed Tomography in Korea: A Multi-Institutional Study in 101487 Patients 
Korean Journal of Radiology  2014;15(4):456-463.
Objective
To evaluate the prevalence of known risk factors for contrast-induced nephropathy (CIN) and their association with the actual occurrence of CIN in patients undergoing intravenous contrast-enhanced computed tomography (CECT) in Korea.
Materials and Methods
Patients who underwent CECT in 2008 were identified in the electronic medical records of 16 tertiary hospitals of Korea. Data on demographics, comorbidities, prescriptions and laboratory test results of patients were collected following a standard data extraction protocol. The baseline renal function was assessed using the estimated glomerular filtration rate (eGFR). We identified the prevalence of risk factors along the eGFR strata and evaluated their influence on the incidence of CIN, defined as a 0.5 mg/dL or 25% increase in serum creatinine after CECT.
Results
Of 432425 CECT examinations in 272136 patients, 140838 examinations in 101487 patients met the eligibility criteria for analysis. The mean age of the participants was 57.9 ± 15.5 years; 25.1% of the patients were older than 70 years. The prevalence of diabetes mellitus was 11.9%, of hypertension 13.7%, of gout 0.55% and of heart failure was 1.7%. Preventive measures were used in 40238 CECT examinations (28.6%). The prevalence of risk factors and use of preventive measures increased as the renal function became worse. A CIN was occurred after 3103 (2.2%) CECT examinations, revealing a significant association with decreased eGFR, diabetes mellitus, and congestive heart failure after adjustment.
Conclusion
Risk factors for CIN are prevalent among the patients undergoing CECT. Preventive measures were seemingly underutilized and a system is needed to improve preventive care.
doi:10.3348/kjr.2014.15.4.456
PMCID: PMC4105808  PMID: 25053905
Contrast-induced nephropathy; Contrast-enhanced computed tomography; Prevalence; Risk factor
3.  Cardioprotective effects of angiotensin III against ischemic injury via the AT2 receptor and KATP channels 
Physiological Reports  2013;1(6):e00151.
Angiotensin III (Ang III) has similar effects on blood pressure and aldosterone secretion as Ang II, but cardioprotective effects are also proposed. In this study, we investigated whether Ang III protects the heart against ischemia/reperfusion (I/R) injury. After sacrificing Sprague-Dawley rats, the hearts were perfused with Krebs–Henseleit buffer for a 20 min preischemic period with and without Ang III followed by 20-min global ischemia and 50-min reperfusion. Pretreatment with Ang III (1 μmol/L) improved an increased postischemic left ventricular end-diastolic pressure (LVEDP) and a decreased postischemic left ventricular developed pressure (LVDP) induced by reperfusion compared to untreated hearts. Ang III markedly decreased infarct size and lactate dehydrogenase levels in effluent during reperfusion. Ang III increased coronary flow and the concentrations of atrial natriuretic peptide in coronary effluent during reperfusion. Pretreatment with Ang II type 2 receptor (AT2R) antagonist or ATP-sensitive K+ channel (KATP) blocker for 15 min before ischemia attenuated the improvement of LVEDP, LVDP, and ±dP/dt induced by Ang III. Ang III treatment increased Mn-superoxide dismutase, catalase, and heme oxygenase-1 protein levels, which was attenuated by pretreatment with AT2R antagonist or KATP blocker. Ang III treatment also decreased Bax, caspase-3, and caspase-9 protein levels, and increased Bcl-2 protein level, which were attenuated by pretreatment with AT2R antagonist or KATP blocker. These results suggest that the cardioprotective effects of Ang III against I/R injury may be partly related to activating antioxidant and antiapoptotic enzymes via AT2R and KATP channels.
doi:10.1002/phy2.151
PMCID: PMC3871466  PMID: 24400153
Angiotensin III; apoptosis; atrial natriuretic peptide; Bax; Bcl-2; caspase-3; caspase-9; catalase; heart; heme oxygenase-1; ischemia; KATP channel; superoxide dismutase
4.  Epigenetic Changes of Serotonin Transporter in the Patients with Alcohol Dependence: Methylation of an Serotonin Transporter Promoter CpG Island 
Psychiatry Investigation  2010;8(2):130-133.
Objective
Psychiatric disorders such as depression, anxiety and alcohol dependence are associated with serotonin metabolism. We assessed the methylation level of the serotonin transporter (5-HTT) promoter region in control and alcohol dependent patients.
Methods
Twenty seven male patients who met the Diagnostic and Statistical Manual of Mental Disorder IV (DSM-IV) criteria for alcohol dependence were compared with fifteen controls. Polymerase chain reaction (PCR) assays of bisulfate-modified DNA were designed to amplify a part of the CpG island in the 5HTT gene. Pyrosequencing was performed and the methylation level at seven CpG island sites was measured.
Results
We found no differences in the methylation patterns of the serotonin transporter linked promoter region (5-HTTLPR) between alcohol-dependent and control subjects.
Conclusion
Our negative finding may be because 5-HTT epigenetic variation may not affect the expression for 5-HTT or there may be other methylation site critical for its expression. To find out more conclusive result, repeating the study in more methylation sites with a larger number of samples in a well-controlled setting is needed.
doi:10.4306/pi.2011.8.2.130
PMCID: PMC3149107  PMID: 21852989
Serotonin transporter region (5-HTTLPR); Methylation; Alcohol dependence
5.  Identification of Pax3 and Zic1 targets in the developing neural crest 
Developmental biology  2013;386(2):473-483.
The neural crest (NC) is a multipotent population of migratory cells unique to the vertebrate embryo, contributing to the development of multiple organ systems. Transcription factors pax3 and zic1 are among the earliest genes activated in NC progenitors, and they are both necessary and sufficient to promote NC fate. In order to further characterize the function of these transcription factors during NC development we have used hormone inducible fusion proteins in a Xenopus animal cap assay, and DNA microarray to identify downstream targets of Pax3 and Zic1. Here we present the results of this screen and the initial validation of these targets using quantitative RT-PCR, in situ hybridization and morpholinos-mediated knockdown. Among the targets identified we found several well-characterized NC-specific genes, including snail2, foxd3, gbx2, twist, sox8 and sox9, which validate our approach. We also obtained several factors with no known function in Xenopus NC, which represent novel regulators of NC fate. The comprehensive characterization of Pax3 and Zic1 targets function in the NC gene regulatory network, are essential to understanding the mechanisms regulating the emergence of this important cell population.
doi:10.1016/j.ydbio.2013.12.011
PMCID: PMC3933997  PMID: 24360908
Xenopus; Neural crest; Pax3; Zic1; Microarray; Gene regulatory network
6.  Non-Contact Respiratory Rate Measurement Validation for Hospitalized Patients 
This paper presents the first clinical results for validating the accuracy of respiratory rate obtained for hospitalized patients using a non-contact, low power 2.4 GHz Doppler radar system. Twenty-four patients were measured in this study. The respiratory rate accuracy was benchmarked against the respiratory rate obtained using Welch Allyn Propaq Encore model 242, the Embla Embletta system with Universal XactTrace respiratory effort sensor and Somnologica for Embletta software, and by counting chest excursions. The 95% limits of agreement between the Doppler radar and reference measurements fall within +/−5 breaths per minute.
doi:10.1109/IEMBS.2009.5332635
PMCID: PMC4313750  PMID: 19963625
7.  Rapid Increase of Health Care Utilization and Cost due to Benign Prostatic Hyperplasia in Korean Men: Retrospective Population-based Analysis Using the Health Insurance Review and Assessment Service Data 
Journal of Korean Medical Science  2015;30(2):180-185.
Using the Korean public health insurance database, we analyzed patients diagnosed as benign prostatic hyperplasia (BPH) from 2004 to 2008. Age and year-specific amount and seasonal variation of hospital visits (HV), duration of treatment (DT), the total and per capita amount of insurance payment (TAIP, PCIP) were evaluated. A total of 12,088,995 HV were studied. Total HV increased 1.7 times and DT almost doubled in 2008 compared to those in 2004. HV, DT, and TAIP showed linearly increasing patterns year by year. In a time series analysis, HV increased in winter and demonstrated seasonality in a 12-month cycle. In a Poisson regression analysis, the annual variations of HV, DT, TAIP, and PCIP were different by age groups. In patients older than 40 yr, HV significantly increased 1.10-1.16 times compared to that of the previous year. DT markedly increased in their 60s and 80s patients. The rate of increase in PCIP was steeper in patients 50 yr and older than in the others.Health care utilization due to BPH was rapidly increasing in Korea and it was remarkable in the elderly population. Seasonal variation of HV demonstrated that health care utilization increased in winter.
Graphical Abstract
doi:10.3346/jkms.2015.30.2.180
PMCID: PMC4310945  PMID: 25653490
Prostatic Hyperplasia; Epidemiology; Insurance Claim Review
8.  Improvement of Antibody Responses by HIV Envelope DNA and Protein Co-Immunization 
Vaccine  2013;32(4):507-513.
Background
Developing HIV Envelope (Env) vaccine components that elicit durable and protective antibody responses is an urgent priority, given the results from the RV144 trial. Optimization of both the immunogens and vaccination strategies will be needed to generate potent, durable antibodies. Due to the diversity of HIV, an effective Env-based vaccine will most likely require an extensive coverage of antigenic variants. A vaccine co-delivering Env immunogens as DNA and protein components could provide such coverage. Here, we examine a DNA and protein co-immunization strategy by characterizing the antibody responses and evaluating the relative contribution of each vaccine component.
Method
We co-immunized rabbits with representative subtype A or B HIV gp160 plasmid DNA plus Env gp140 trimeric glycoprotein and compared the responses to those obtained with either glycoprotein alone or glycoprotein in combination with empty vector.
Results
DNA and glycoprotein co-immunization was superior to immunization with glycoprotein alone by enhancing antibody kinetics, magnitude, avidity, and neutralizing potency. Importantly, the empty DNA vector did not contribute to these responses. Humoral responses elicited by mismatched DNA and protein components were comparable or higher than the responses produced by the matched vaccines.
Conclusion
Our data show that co-delivering DNA and protein can augment antibodies to Env. The rate and magnitude of immune responses suggest that this approach has the potential to streamline vaccine regimens by inducing higher antibody responses using fewer vaccinations, an advantage for a successful HIV vaccine design.
doi:10.1016/j.vaccine.2013.11.022
PMCID: PMC3926420  PMID: 24280279
HIV; Envelope-based vaccine; DNA+protein co-immunization; neutralizing antibodies
10.  Amelioration of Hypercholesterolemia by an EGFR Tyrosine Kinase Inhibitor in Mice with Liver-Specific Knockout of Mig-6 
PLoS ONE  2014;9(12):e114782.
Mitogen-inducible gene 6 (Mig-6) is a negative feedback inhibitor of epidermal growth factor receptor (EGFR) signaling. We previously found that Mig-6 plays a critical role in the regulation of cholesterol homeostasis and in bile acid synthesis. In this study, we investigated the effects of EGFR inhibition to identify a potential new treatment target for hypercholesterolemia. We used a mouse model with conditional ablation of the Mig-6 gene in the liver (Albcre/+Mig-6f/f; Mig-6d/d) to effectively investigate the role of Mig-6 in the regulation of liver function. Mig-6d/d mice were treated with either the EGFR inhibitor gefitinib or statin for 6 weeks after administration of a high-fat or standard diet. We then compared lipid profiles and other parameters among each group of mice. After a high-fat diet, Mig-6d/d mice showed elevated serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and glucose, characteristics resembling hypercholesterolemia in diabetic patients. We observed decreases in serum levels of lipids and glucose in high-fat-diet-fed Mig-6d/d mice after 6 weeks of treatment with gefitinib or statin. Furthermore gefitinib-treated mice showed significantly greater decreases in serum levels of total, HDL and LDL cholesterol compared with statin-treated mice. Taken together, these results suggest that EGFR inhibition is effective for the treatment of hypercholesterolemia in high-fat-diet-fed Mig-6d/d mice, and our findings provide new insights into the development of possible treatment targets for hypercholesterolemia via modulation of EGFR inhibition.
doi:10.1371/journal.pone.0114782
PMCID: PMC4259477  PMID: 25486251
11.  Pulmonary Vein to Esophageal Fistula after Staged Hybrid Totally Thoracoscopic Surgical and Percutaneous Radiofrequency Catheter Ablation: A Case Report 
A case of a fistula running from the pulmonary vein to the esophagus after a staged hybrid procedure combining total thoracoscopic ablation and percutaneous radiofrequency catheter ablation has not been reported previously. We describe such a case in a 37-year-old man who was successfully treated by surgery.
doi:10.5090/kjtcs.2014.47.6.560
PMCID: PMC4279838  PMID: 25551082
Pulmonary veins; Esophageal fistula
12.  Pathophysiologic and Transcriptomic Analyses of Viscerotropic Yellow Fever in a Rhesus Macaque Model 
Infection with yellow fever virus (YFV), an explosively replicating flavivirus, results in viral hemorrhagic disease characterized by cardiovascular shock and multi-organ failure. Unvaccinated populations experience 20 to 50% fatality. Few studies have examined the pathophysiological changes that occur in humans during YFV infection due to the sporadic nature and remote locations of outbreaks. Rhesus macaques are highly susceptible to YFV infection, providing a robust animal model to investigate host-pathogen interactions. In this study, we characterized disease progression as well as alterations in immune system homeostasis, cytokine production and gene expression in rhesus macaques infected with the virulent YFV strain DakH1279 (YFV-DakH1279). Following infection, YFV-DakH1279 replicated to high titers resulting in viscerotropic disease with ∼72% mortality. Data presented in this manuscript demonstrate for the first time that lethal YFV infection results in profound lymphopenia that precedes the hallmark changes in liver enzymes and that although tissue damage was noted in liver, kidneys, and lymphoid tissues, viral antigen was only detected in the liver. These observations suggest that additional tissue damage could be due to indirect effects of viral replication. Indeed, circulating levels of several cytokines peaked shortly before euthanasia. Our study also includes the first description of YFV-DakH1279-induced changes in gene expression within peripheral blood mononuclear cells 3 days post-infection prior to any clinical signs. These data show that infection with wild type YFV-DakH1279 or live-attenuated vaccine strain YFV-17D, resulted in 765 and 46 differentially expressed genes (DEGs), respectively. DEGs detected after YFV-17D infection were mostly associated with innate immunity, whereas YFV-DakH1279 infection resulted in dysregulation of genes associated with the development of immune response, ion metabolism, and apoptosis. Therefore, WT-YFV infection is associated with significant changes in gene expression that are detectable before the onset of clinical symptoms and may influence disease progression and outcome of infection.
Author Summary
Yellow fever virus causes ∼200,000 infections and 30,000 deaths annually in Africa and South America. Although this is an important human pathogen, the basis of yellow fever disease severity remains poorly understood. Rhesus macaques are susceptible to yellow fever and develop similar symptoms as severe as those observed in humans. In this study, we characterized disease progression in this model and observed a profound loss of lymphocytes that preceded the appearance of serum markers of virus-induced liver pathology. This change might provide an early indicator of fatal yellow fever. In addition, we also identified significant changes in gene expression in white blood cells that occur before any measurable disease symptoms and these genetic signatures may provide future targets for antiviral therapeutics and better diagnostics.
doi:10.1371/journal.pntd.0003295
PMCID: PMC4238990  PMID: 25412185
13.  Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits 
Journal of Virology  2014;88(22):12949-12967.
ABSTRACT
Identifying characteristics of the human immunodeficiency virus type 1 (HIV-1) envelope that are effective in generating broad, protective antibodies remains a hurdle to HIV vaccine design. Emerging evidence of the development of broad and potent neutralizing antibodies in HIV-infected subjects suggests that founder and subsequent progeny viruses may express unique antigenic motifs that contribute to this developmental pathway. We hypothesize that over the course of natural infection, B cells are programmed to develop broad antibodies by exposure to select populations of emerging envelope quasispecies variants. To test this hypothesis, we identified two unrelated subjects whose antibodies demonstrated increasing neutralization breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in both subjects. We compared the immunogenicity of envelope vaccines derived from time points obtained during and after broadening of neutralization activity within these subjects. Rabbits were coimmunized four times with selected multiple gp160 DNAs and gp140-trimeric envelope proteins. The affinity of the polyclonal response increased as a function of boosting. The most rapid and persistent neutralization of multiclade tier 1 viruses was elicited by envelopes that were circulating in plasma at time points prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later envelope variants. These data have implications for vaccine development in describing a target time point to identify optimal envelope immunogens.
IMPORTANCE Vaccine protection against viral infections correlates with the presence of neutralizing antibodies; thus, vaccine components capable of generating potent neutralization are likely to be critical constituents in an effective HIV vaccine. However, vaccines tested thus far have elicited only weak antibody responses and very modest, waning protection. We hypothesized that B cells develop broad antibodies by exposure to the evolving viral envelope population and tested this concept using multiple envelopes from two subjects who developed neutralization breadth within a few years of infection. We compared different combinations of envelopes from each subject to identify the most effective immunogens and regimens. In each subject, use of HIV envelopes circulating during the early development and maturation of breadth generated more-potent antibodies that were modestly cross neutralizing. These data suggest a new approach to identifying envelope immunogens that may be more effective in generating protective antibodies in humans.
doi:10.1128/JVI.01812-14
PMCID: PMC4249069  PMID: 25210191
14.  Exonic Variants Associated with Development of Aspirin Exacerbated Respiratory Diseases 
PLoS ONE  2014;9(11):e111887.
Aspirin-exacerbated respiratory disease (AERD) is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC) for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA), and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (210-1) were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p = 3.40×10−8) in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954) showed the best AUC of 0.75 (asymptotic p-value of 7.94×10−21), with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be “probably damaging” to the structure and function of the protein, with a high score of ‘1’. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.
doi:10.1371/journal.pone.0111887
PMCID: PMC4221198  PMID: 25372592
15.  Comparison of putative circulating cancer stem cell detection between the hepatic portal system and peripheral blood in colorectal cancer patients 
Purpose
The present pilot study was conducted to detect putative cancer stem cell (CSC) from the hepatic portal system and peripheral blood in the colorectal cancer patients and to compare them to healthy donor and diverticulitis patients.
Methods
Laboratory study was performed to identify the expression of cell surface markers, epithelial cell adhesion molecule (EpCAM), cytokeratin (CK) 18, CK20, CD44, and CD133, on several colon cancer cell lines. Clinical pilot study was conducted to detect putative circulating CSC as EpCAM+CD133+ cell in colorectal cancer (n = 10), diverticulitis (n = 5), and four healthy donors, by using flow cytometry. Blood was drawn from the hepatic portal system and peripheral vein.
Results
On laboratory study, EpCAM was expressed in whole colon cancer cell lines, and CD44 and CD133 were simultaneously expressed in 50% of the cell lines with stemness phenotype, but CK18 and CK20 were not expressed in most of the cell lines. On clinical study, the mean EpCAM+CD133+ cell counts of 11.6/105 in the hepatic portal system were somewhat lower than 15.4/105 in peripheral vein (P = 0.241). As for diverticulitis patients, EpCAM+CD133+ cells were also detected to have steeper dropped to near zero, after the surgery.
Conclusion
The numbers of putative CSC were not statistically different between the detection sites of the portal vein and peripheral vein in the colon cancer patients. Therefore, we may not have benefitted by getting the cells from the hepatic portal system. In addition, the CD133+EpCAM+ cells in the colon cancer patients might contain normal stem cells from cancer inflammation similar to diverticulitis.
doi:10.4174/astr.2014.87.5.232
PMCID: PMC4217260  PMID: 25368848
Cancer stem cell; Hepatic portal system; Colorectal cancer; CD133; EpCAM
16.  COMP-Angiopoietin1 Potentiates the Effects of Bone Morphogenic Protein-2 on Ischemic Necrosis of the Femoral Head in Rats 
PLoS ONE  2014;9(10):e110593.
Angiogenesis is considered essential for proper bone regeneration. The purpose of this investigation was to determine if a combined therapy of bone morphogenetic protein-2 (BMP-2) and cartilage oligomeric matrix protein angiopoietin-1 (COMP-Ang1) can potentiate the therapeutic effect of BMP-2 in a rat model of ischemic necrosis of the femoral head (INFH). INFH was surgically induced in the femoral head of rats, and the animals were divided into the following groups: 1) a sham-operated group (sham group), 2) a bovine serum albumin-injected group (BSA group), 3) a BMP-2-injected group (BMP-2 group), and 4) a COMP-Ang1 and BMP-2-injected group (COMP-Ang1 + BMP-2 group) (n = 20/group). Radiologic, histologic, and histomorphometric assessments were performed to assess femoral head morphology, vascular density, and bone resorption activity. Western blots and immunohistochemical staining were performed to evaluate production of BMP-related signaling proteins in C3H10T1/2 cells and tissues. Real-time RT-PCR was performed to investigate expression of the target integrin gene, and the effect of integrin on C3H10T1/2 cells was determined using a cell adhesion assay. Radiographs obtained six weeks after injection revealed better preservation of the architecture of the femoral head in the COMP-Ang1 + BMP-2 group compared with the BSA and BMP-2 groups. Histological findings indicated increased trabecular bone and vascularity and decreased osteoclast bone resorption activity in the COMP-Ang1 + BMP-2 group compared with those in the BSA and BMP-2 groups. The combination of COMP-Ang1 and BMP-2 increased phosphorylation of Smad1/3/5, p38, and Akt. Increased integrin α3 and β1 mRNA expression in the COMP-Ang1 + BMP-2 group promoted cell adhesion. These results suggest that COMP-Ang1 preserved the necrotic femoral head through the potentiation of BMP-2 signaling pathways and angiogenesis. Combination treatment with COMP-Ang1 and BMP-2 may be a clinically useful therapeutic application in INFH.
doi:10.1371/journal.pone.0110593
PMCID: PMC4201557  PMID: 25329960
17.  Factors influencing on difficulty with laparoscopic total extraperitoneal repair according to learning period 
Purpose
Laparoscopic total extraperitoneal (TEP) repair of inguinal hernia is technically challenging enough to build high barrier to entry. The purpose of this study was to identify clinical factors influencing technical difficulty with laparoscopic TEP according to learning period.
Methods
We conducted a retrospective study of 112 adult patients who underwent laparoscopic TEP for unilateral inguinal hernia from January 2009 to September 2013. A technically difficult case was defined as the 70th percentiles or more in the distribution curve of operative time, major complication, or open conversion.
Results
The rate of body mass index (BMI) above 25 kg/m2 was significantly higher in the difficult group than the nondifficult group in the learning period of laparoscopic TEP (57.9% vs. 26.8%, respectively, P = 0.020). However, in the experience period, it revealed no statistical difference with technical difficulty (31.3% vs. 33.3%, respectively, P = 0.882). In multivariate analysis, BMI (≥25 kg/m2) was identified as a significant independent factor for technical difficulty with laparoscopic TEP in the learning period (odds ratio, 4.572; P = 0.015).
Conclusion
Patient's BMI (≥25 kg/m2) can create technical difficulty with laparoscopic TEP only in the learning period, but not in the experience period. Therefore BMI could be applied as one of the guidelines for patient selection, especially for surgeons in the learning curve of laparoscopic TEP.
doi:10.4174/astr.2014.87.4.203
PMCID: PMC4196429  PMID: 25317416
Body mass index; Inguinal hernia; Laparoscopy; Learning curve; Herniorrhaphy
18.  Platycarya strobilacea S. et Z. Extract Has a High Antioxidant Capacity and Exhibits Hair Growth-promoting Effects in Male C57BL/6 Mice 
This study was conducted to evaluate the effects of Platycarya strobilacea S. et Z. (PSE) extract on mouse hair growth and to determine the mechanism of action of PSE. PSE was purchased and its antioxidant activities, such as electron donating ability, total polyphenol content, and flavonoid content were tested. Toxicity during topical treatment was determined by the CCK-8 assay, a cell viability test. Fifteen 4-week-old male C57BL/6 mice were assigned to receive one of three treatments: dimethyl sulfoxide (negative control), minoxidil (positive control) or PSE. Test materials were topically applied to the shaved dorsal skin of each mouse daily for 3 weeks. After 21 days, we observed skin tissue hair follicle morphology and length, mast cell number, and stem cell factor (SCF) expression using hematoxylin and eosin (H&E), toluidine blue, and immunohistochemical staining, respectively. Furthermore, the expression of cytokines involved in hair growth [i.e., insulin-like growth factor (IGF)-1, keratinocyte growth factor (KGF), and transforming growth factor (TGF)-β1] was determined by PCR. PSE was found to have very high antioxidant activity. The cell viability rate of PSE-treated mice was markedly higher than that of mice in the control group. We also observed an increase in hair follicle length, strong SCF staining, and a decrease in mast cell number in the PSE group. In addition, PSE-treated mice had higher IGF-1 and KGF expression and lower TGF-β1 expression than mice in the minoxidil-treated group. These results suggest that topical application of PSE promotes hair growth by intensifying SCF, suppressing mast cell production, and increasing hair growth-promoting cytokine expression.
doi:10.3746/pnf.2014.19.3.136
PMCID: PMC4195618  PMID: 25320710
Platycarya strobilacea S. et Z.; hair growth; hair growth factors; antioxidant activity; C57BL/6 mouse
19.  A study of docetaxel and irinotecan in children and young adults with recurrent or refractory Ewing sarcoma family of tumors 
BMC Cancer  2014;14(1):622.
Background
Patients with Ewing sarcoma family of tumors (ESFT) who are resistant even to salvage chemotherapy, have dismal prognoses and few therapeutic options. Because the docetaxel/irinotecan (DI) combination has not been previously evaluated in ESFT, we prospectively evaluated its use in patients with recurrent or refractory ESFT.
Methods
Patients aged <30 years with ESFT, who failed ≥ third-line therapy, were eligible. They received docetaxel 100 mg/m2 intravenously on day 1, and irinotecan 80 mg/m2 on days 1 and 8, of a 21-day cycle up to 15 cycles or until disease progressed. The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS) and safety.
Results
We enrolled nine patients (median age: 13 years); four were male. Two patients had recurrent disease and seven had progressive disease. This group had undergone a median of four prior chemotherapy regimens (range: 3-6), and received a total of 51 DI cycles (median: three cycles/per person; range: 1-15 cycles). The nine patients showed one complete response (CR), two partial responses (PRs), one stable disease, and five progressive diseases, for an ORR (CR + PR) of 3/9 (33.3%). Two patients with PR achieved CR with subsequent surgery. Overall median PFS was 2.2 months (range: 0.5-16.9 months). All nine patients had grade 4 neutropenia (100%); grade 3 diarrhea or grade 2/3 neuropathy each occurred in two patients (22%). All toxicities were manageable without serious morbidities or treatment-related mortality.
Conclusions
The DI combination may be effective and tolerable for patients with heavily pre-treated ESFT.
Trial registration
NCT01380275. Registered June 21, 2011.
doi:10.1186/1471-2407-14-622
PMCID: PMC4155244  PMID: 25164234
Docetaxel; Irinotecan; Recurrent; Refractory; Ewing sarcoma family of tumors
20.  Risk Factor Analysis May Provide Clues to Diarrhea Prevention in Outdoor-Housed Rhesus Macaques (Macaca mulatta) 
American journal of primatology  2013;75(8):872-882.
Seventy-five percent of rhesus macaques at national primate research centers are housed outside. Annually, 15–39% of these animals experience diarrhea and require veterinary treatment for dehydration, electrolyte imbalance, or weight loss. An estimated 21–33% of these patients will die or be euthanized. Many studies have explored the various infectious etiologies of non-human primate diarrhea. However, there is little published information on diarrhea incidence rates and risk factors in outdoor-housed rhesus macaques. Without this information, it is challenging to determine endemic and epidemic diarrhea levels, or to develop and evaluate mitigation strategies. Using electronic medical records, we conducted a retrospective cohort study to calculate diarrhea incidence rates for rhesus macaques (N = 3,181) housed in three different outdoor housing types (corrals, shelters, and temporary housing) at the Oregon National Primate Research Center between November 1, 2009 and October 31, 2010. With multiple logistic regression analysis, we determined the relative risk of housing type, sex, and age on development of diarrhea. Diarrhea incidence and mortality in our population was lower than many published ranges. Type of outdoor housing, age, and previous diarrhea episode were positively correlated with diarrhea risk. Younger animals in smaller shelters and temporary housing had a greater risk of acquiring diarrhea, with juvenile animals (0.7–3.9 years) having the highest mortality rate. Sex was not a risk factor, but adult females with diarrhea were more likely to develop life-threatening complications than adult males. We also constructed a predictive model for diarrhea-associated mortality using Classification and Regression Tree. Findings from this study will be used to develop and evaluate mitigation strategies in our outdoor-housed population and to provide a foundation for genetic susceptibility and immune function testing.
doi:10.1002/ajp.22150
PMCID: PMC3956043  PMID: 23568382
rhesus; diarrhea; risk; morbidity; mortality; classification; tree
21.  Neuropathic Pain Model of Peripheral Neuropathies Mediated by Mutations of Glycyl-tRNA Synthetase 
Journal of Korean Medical Science  2014;29(8):1138-1144.
Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. Previous studies have found that, according to CMT patients, neuropathic pain is an occasional symptom of CMT. However, neuropathic pain is not considered to be a significant symptom associated with CMT and, as a result, no studies have investigated the pathophysiology underlying neuropathic pain in this disorder. Thus, the first animal model of neuropathic pain was developed by our laboratory using an adenovirus vector system to study neuropathic pain in CMT. To this end, glycyl-tRNA synthetase (GARS) fusion proteins with a FLAG-tag (wild type [WT], L129P and G240R mutants) were expressed in spinal cord and dorsal root ganglion (DRG) neurons using adenovirus vectors. It is known that GARS mutants induce GARS axonopathies, including CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). Additionally, the morphological phenotypes of neuropathic pain in this animal model of GARS-induced pain were assessed using several possible markers of pain (Iba1, pERK1/2) or a marker of injured neurons (ATF3). These results suggest that this animal model of CMT using an adenovirus may provide information regarding CMT as well as a useful strategy for the treatment of neuropathic pain.
Graphical Abstract
doi:10.3346/jkms.2014.29.8.1138
PMCID: PMC4129208  PMID: 25120326
Charcot-Marie-Tooth Disease; Neuralgia; Glycyl-tRNA Ligase; ATF3 Protein Mouse; Microglia; Adenoviridae
22.  SPA0355 attenuates ischemia/reperfusion-induced liver injury in mice 
Hepatic ischemia/reperfusion (I/R) injury leads to oxidative stress and acute inflammatory responses that cause liver damage and have a considerable impact on the postoperative outcome. Much research has been performed to develop possible protective techniques. We aimed to investigate the efficacy of SPA0355, a synthetic thiourea analog, in an animal model of hepatic I/R injury. Male C57BL/6 mice underwent normothermic partial liver ischemia for 45 min followed by varying periods of reperfusion. The animals were divided into three groups: sham operated, I/R and SPA0355 pretreated. Pretreatment with SPA0355 protected against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and reduced parenchymal necrosis and apoptosis. Liver synthetic function was also restored by SPA0355 as reflected by the prolonged prothrombin time. To gain insight into the mechanism involved in this protection, we measured the activity of nuclear factor-κB (NF-κB), which revealed that SPA0355 suppressed the nuclear translocation and DNA binding of NF-κB subunits. Concomitantly, the expression of NF-κB target genes such as IL-1β, IL-6, TNF-α and iNOS was significantly downregulated. Lastly, the liver antioxidant enzymes superoxide dismutase, catalase and glutathione were upregulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde. Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.
doi:10.1038/emm.2014.48
PMCID: PMC4150932  PMID: 25104735
23.  Postprandial glucose-lowering effects of fermented red ginseng in subjects with impaired fasting glucose or type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial 
Background
Red ginseng is prepared by steaming raw ginseng, a process believed to increase the pharmacological efficacy. Further bioconversion of red ginseng through fermentation is known to increase its intestinal absorption and bioactivity, and bioconversion diminishes the toxicity of red ginseng’s metabolite. This study was conducted to investigate the effects of daily supplementation with fermented red ginseng (FRG) on glycemic status in subjects with impaired fasting glucose or type 2 diabetes.
Methods
This study was a four-week long, randomized, double-blind, placebo-controlled trial. Forty-two subjects with impaired fasting glucose or type 2 diabetes were randomly allocated to two groups assigned to consume either the placebo or fermented red ginseng (FRG) three times per day for four weeks. Fasting and postprandial glucose profiles during meal tolerance tests were assessed before and after the intervention.
Results
FRG supplementation led to a significant reduction in postprandial glucose levels and led to an increase in postprandial insulin levels compared to the placebo group. There was a consistently significant improvement in the glucose area under the curve (AUC) in the FRG group. However, fasting glucose, insulin, and lipid profiles were not different from the placebo group.
Conclusion
Daily supplementation with FRG lowered postprandial glucose levels in subjects with impaired fasting glucose or type 2 diabetes.
Trial registration
ClinicalTrials.gov: NCT01826409
doi:10.1186/1472-6882-14-237
PMCID: PMC4227112  PMID: 25015735
Fermented red ginseng; Type 2 diabetes; Impaired fasting glucose; Postprandial glucose
24.  Prevalence and Predictors of Polypharmacy among Korean Elderly 
PLoS ONE  2014;9(6):e98043.
Objective
Polypharmacy is widespread in the elderly because of their multiple chronic health problems. The objective of this study was to investigate the prevalence and predictors associated with polypharmacy in a nationally representative sample of Korean elderly individuals.
Methods
We used the Korea Health Insurance Review and Assessment Service – National Patient Sample (HIRA-NPS) data from 2010 and 2011. We used information on 319,185 elderly patients (aged 65 years or older) between January 1, 2010 and December 31, 2011 from the HIRA-NPS database. We defined ‘polypharmacy’ as the concurrent use of 6 medications or more per person, ‘major polypharmacy’ as 11 medications or more, and ‘excessive polypharmacy’ as 21 medications or more. The frequency and proportion (%) and their 95% confidence intervals were presented according to the polypharmacy definition. Polypharmacy was visualized by the Quantum Geographic Information Systems (QGIS) program to describe regional differences in patterns of drug use. Multivariate ordinal logistic regression was performed to estimate odds ratios (ORs) and their 95% confidence intervals (CI) to investigate the risk factors for polypharmacy.
Results
Of the Korean elderly studied, 86.4% had polypharmacy, 44.9% had major polypharmacy and 3.0% had excessive polypharmacy. Polypharmacy was found to be primarily concentrated in the Southwest region of the country. Significant associations between polypharmacy and the lower-income Medical Aid population (OR = 1.52, 95% CI 1.47, 1.56) compared with National Health Insurance patients was observed.
Conclusions
Nationwide efforts are needed for managing polypharmacy among Korean elderly patients. In particular, a national campaign and education to promote appropriate use of medicines for the Medical Aid population is needed.
doi:10.1371/journal.pone.0098043
PMCID: PMC4051604  PMID: 24915073
25.  Association Analysis of TEC Polymorphisms with Aspirin-Exacerbated Respiratory Disease in a Korean Population 
Genomics & Informatics  2014;12(2):58-63.
The tyrosine-protein kinase Tec (TEC) is a member of non-receptor tyrosine kinases and has critical roles in cell signaling transmission, calcium mobilization, gene expression, and transformation. TEC is also involved in various immune responses, such as mast cell activation. Therefore, we hypothesized that TEC polymorphisms might be involved in aspirin-exacerbated respiratory disease (AERD) pathogenesis. We genotyped 38 TEC single nucleotide polymorphisms in a total of 592 subjects, which comprised 163 AERD cases and 429 aspirin-tolerant asthma controls. Logistic regression analysis was performed to examine the associations between TEC polymorphisms and the risk of AERD in a Korean population. The results revealed that TEC polymorphisms and major haplotypes were not associated with the risk of AERD. In another regression analysis for the fall rate of forced expiratory volume in 1 second (FEV1) by aspirin provocation, two variations (rs7664091 and rs12500534) and one haplotype (TEC_BL2_ht4) showed nominal associations with FEV1 decline (p = 0.03-0.04). However, the association signals were not retained after performing corrections for multiple testing. Despite TEC playing an important role in immune responses, the results from the present study suggest that TEC polymorphisms do not affect AERD susceptibility. Findings from the present study might contribute to the genetic etiology of AERD pathogenesis.
doi:10.5808/GI.2014.12.2.58
PMCID: PMC4099349  PMID: 25031568
aspirin-exacerbated respiratory disease; aspirin-tolerant asthma; Tec protein tyrosine kinase; genetic polymorphisms; haplotypes

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