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1.  Essential Engagement of Toll-Like Receptor 2 in Initiation of Early Protective Th1 Response against Rough Variants of Mycobacterium abscessus 
Infection and Immunity  2015;83(4):1556-1567.
Although Mycobacterium abscessus (M. abscessus) is becoming more prevalent in patients without overt immunodeficiency, little is known about the factors that contribute to disease susceptibility. This study was undertaken to investigate how Toll-like receptor 2 (TLR2) functionally contributes to the generation of protective immunity against M. abscessus in a morphotype-specific manner. We found that Tlr2−/− mice were extremely susceptible to an intravenous (i.v.) model of infection by M. abscessus rough variants, displaying uncontrolled infection in the lungs and a significantly lower survival rate than with wild-type (WT) mice. This uncontrolled infection resulted from failures in the following processes: (i) production of the crucial cytokines gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 12p70 (IL-12p70); (ii) early infiltration of neutrophils, monocytes, and dendritic cells (DCs) in the lungs of Tlr2−/− mice; (iii) rapid influx of CD4+ and CD8+ T cells; and (iv) the expansion of memory/effector T cells. Notably, systemic administration of M. abscessus culture filtrate-treated syngeneic DCs from WT mice greatly strengthened immune priming in vivo, resulting in a dramatic reduction in bacterial growth and improved long-term survival in Tlr2−/− mice, with a recovery of protective immunity. Our findings demonstrate that TLR2 is an essential contributor to instructive and effector immunity during M. abscessus infection in a morphotype-specific manner.
PMCID: PMC4363419  PMID: 25644006
2.  Green Tea Epigallocatechin-3-Gallate Suppresses Autoimmune Arthritis Through Indoleamine-2,3-Dioxygenase Expressing Dendritic Cells and the Nuclear Factor, Erythroid 2-Like 2 Antioxidant Pathway 
The activity of one of the major catechins in Green Tea, the polyphenol (−)-epigallocatechin-3-gallate (EGCG), has been shown to have a variety of health benefits. Recent studies suggest that EGCG can modulate both the innate and adaptive arms of the immune system. The goal of the current studies was to examine the immunomodulatory effects and mechanisms of action of EGCG on experimental arthritis in mice.
EGCG (10 mg/kg) was administered by oral gavage after CIA induction, while control mice were administered phosphate buffered saline (PBS). Disease mechanisms were studied in both groups of mice. Phenotypes were examined using repeated measure analysis of variance (ANOVA) and data from in vitro and ex vivo experiments were analyzed for significance using the Mann-Whitney U test.
EGCG treatment ameliorated clinical symptoms and reduced histological scores in arthritic mice. Serum type-II collagen-specific immunoglobulin (Ig) IgG2a antibodies were significantly lower in EGCG-fed mice compared to PBS-treated mice. EGCG significantly suppressed T cell proliferation and relative frequencies of CD4 T cells, CD8 T cells and B cell subsets including marginal zone B cells, T1 and T2 transitional B cells, while increasing the frequency of CD4+ Foxp3+ regulatory T cells (Tregs) and indoleamine‐2,3‐dioxygenase (IDO) expression by CD11b+ dendritic cells (DC). Splenic CD11b+ DC from EGCG fed mice induced an increased frequency of Tregs via an IDO-dependent mechanism in in vitro cultures. Importantly, joint homogenates from EGCG-fed mice exhibited significantly increased levels of Nuclear Factor, Erythroid 2-Like 2 (Nrf-2) and Heme oxygenase-1 (HO-1) compared with PBS-fed mice.
This is the first report of upregulation of the Nrf-2 antioxidant pathway in EGCG-mediated immunoregulation. EGCG ameliorated experimental arthritis in mice by eliciting IDO-producing DCs, increasing frequencies of T regs and inducing the activation of the Nrf-2 antioxidant pathway. It remains to be established whether EGCG is useful for the prevention and treatment of rheumatoid arthritis and other inflammatory disorders.
PMCID: PMC4570740  PMID: 26379475
Green Tea (−)-epigallocatechin-3-gallate (EGCG); Collagen-induced arthritis; Regulatory T cells; Nrf-2 signaling pathway
3.  Comparison of scleral buckling and vitrectomy using wide angle viewing system for rhegmatogenous retinal detachment in patients older than 35 years 
BMC Ophthalmology  2015;15:121.
To compare scleral buckling (SB) and pars plana vitrectomy (PPV) using a wide angle viewing system (WAVS) for uncomplicated phakic rhegmatogenous retinal detachment (RRD).
The medical records of patients with uncomplicated phakic RRD were retrospectively reviewed. Eyes with pseudophakic or attached fovea were excluded. Patients treated with SB were classified as group B, and PPV using WAVS as group V. Primary success rate, visual acuity (VA), macular complications, and sustained subretinal fluid (SRF) were compared between groups.
Seventy-two eyes were included in group B and 57 eyes in group V. Group B had better preoperative VA (1.38 ± 0.87 vs 1.84 ± 0.97 in LogMAR, P = 0.010), but worse final VA (0.51 ± 0.48 vs 0.30 ± 0.23, P = 0.012) than group V. The primary success rate of 94.7 % in group V was higher than 77.8 % in group B (P = 0.010). Final success rate was 100 % in both groups. There was no significant difference in macular complications between groups (P = 0.087). Sustained SRF was found in 22 eyes in group B (38.6 %), while only two eyes in group V exhibited sustained SRF (2.8 %, P < 0.001).
Pars plana vitrectomy using WAVS was more efficacious than SB for treating uncomplicated phakic RRD.
PMCID: PMC4566311  PMID: 26362540
4.  Prognostic Value of Volume-Based Metabolic Parameters Measured by 18F-FDG PET/CT of Pancreatic Neuroendocrine Tumors 
To date, the prognostic value of 18F-FDG PET/CT for patients with pancreatic neuroendocrine tumors (PNETs) has not been well characterized. We investigated the prognostic value of volumetric parameters using 18F-FDG PET/CT in this patient population.
We retrospectively reviewed 20 cases of pathologically proven PNET in patients who had undergone pre-therapeutic 18F-FDG PET/CT. PET parameters including maximum and average standardized uptake values (SUVmax, SUVave), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor were measured using a threshold SUV to determine the boundaries of the tumors. Univariate and multivariate survival analyses were performed with adjustments for PET parameters and other clinical values.
The median clinical follow-up was 22.3 (range, 1.2–95.4) months. Cancer-related death occurred in 5 of 20 patients (25 %). Patients had clinical or pathological stages of I in seven patients, II in six patients, III in three patient, and IV in four patients. According to the WHO histological classification of subtypes, 3 patients exhibited well-differentiated PNETs, 13 patients had well-differentiated endocrine carcinomas, and 4 had poorly differentiatedendocrine carcinomas. Univariate analysis showed that tumor size (p = 0.028), AJCC stage (p = 0.009), T stage (p = 0.028), M stage (p = 0.029), treatment modality (p = 0.045), MTV (p = 0.003) and TLG (p = 0.027) were significant predictors of overall survival. On multivariate analysis, MTV (HR = 10.859, p = 0.031) was a significant independent predictor of overall survival along with the AJCC stage (HR = 11.556, p = 0.027).
In patients with PNETs, the MTV of the primary tumor as measured by 18F-FDG PET/CT along with the AJCC stage may be a significant independent prognostic factor for overall survival.
PMCID: PMC4145103  PMID: 25177374
18F-FDG PET/CT; Pancreatic neuroendocrine tumor; Metabolic tumor volume; Total lesion glycolysis; Prognosis
5.  IL-12p40 Homodimer Ameliorates Experimental Autoimmune Arthritis 
IL-23 is the key cytokine that induces the expansion of Th17 cells. It is composed of p19 and p40 subunits of IL-12. The p40 subunit binds competitively to the receptor of IL-23 and blocks its activity. Our aim was to assess the preventive and therapeutic effect of the IL-12p40 homodimer (p40)2 subunit in autoimmune arthritis animal models. In the current study, using IL-1R antagonist–knockout mice and a collagen-induced arthritis model, we investigated the suppressive effect of (p40)2 on inflammatory arthritis. We demonstrated that the recombinant adenovirus-expressing mouse (p40)2 model prevented the development of arthritis when given before the onset of arthritis. It also decreased the arthritis index and joint erosions in the mouse model if transferred after arthritis was established. (p40)2 inhibited the production of inflammatory cytokines and Ag-specific T cell proliferation. It also induced CD4+CD25+Foxp3 regulatory T (Treg) cells in vitro and in vivo, whereas the generation of retinoic acid receptor–related organ receptor γt and Th17 cells was suppressed. The induction of Treg cells and the suppression of Th17 cells were mediated via activated STAT5 and suppressed STAT3. Our data suggest that (p40)2 suppressed inflammatory arthritis successfully. This could be a useful therapeutic approach in autoimmune arthritis to regulate the Th17/Treg balance and IL-23 signaling.
PMCID: PMC4574520  PMID: 26324771
6.  Clays as dietary supplements for swine: A review 
Clays are crystalline, hydrated aluminosilicate molecules composed of alkali and alkaline earth cations along with small amounts of various other elements. The best-known are montmorillonite, smectite, illite, kaolinite, biotite and clinoptilolite. The molecules in these clays are arranged in three-dimensional structures creating internal voids and channels capable of trapping a wide variety of molecules. As a result of this structure, clay minerals are regarded as a simple and effective tool for the prevention of the negative effects of many toxic compounds. Dietary supplementation with clays has been shown to improve weight gain and feed conversion in pigs. Where improvements in performance have been noted, one of the most likely explanations for the improvement is the fact clays increase nutrient digestibility. Clays reduce the speed of passage of feed along the digestive tract which allows more time for digestion. Feeding clays also causes morphological changes in the intestinal mucosa such as an increase in villus height and an increase in the villus height to crypt depth ratio. These changes increase the surface area of the gastrointestinal tract thus increasing nutrient digestibility. Several studies have indicated that feeding clay reduces the incidence, severity and duration of diarrhea in pigs. The mechanism for the reduction in diarrhea is likely due to increases in the numbers of Bifidobacteria and Lactobacillus and decreases in Clostridia and E. coli in the small intestine of pigs fed clays. In addition, the numbers of pigs born alive and weaned, birth weight and weaning weight have been shown to be higher for sows fed clays. Several studies have indicated that clays can help mitigate the effects of mycotoxins. The aim of the present review is to focus on the various clays which have been given attention in recent research and to discuss their potential to improve pig performance.
PMCID: PMC4546348  PMID: 26301092
Animal production; Clay; Clinoptilolite; Feed additive; Montmorillonite; Zeolite
7.  Does Temperature Modify the Effects of Rain and Snow Precipitation on Road Traffic Injuries? 
Journal of Epidemiology  2015;25(8):544-552.
There are few data on the interaction between temperature and snow and rain precipitation, although they could interact in their effects on road traffic injuries.
The integrated database of the Korea Road Traffic Authority was used to calculate the daily frequency of road traffic injuries in Seoul. Weather data included rain and snow precipitation, temperature, pressure, and fog from May 2007 to December 2011. Precipitation of rain and snow were divided into nine and six temperature range categories, respectively. The interactive effects of temperature and rain and snow precipitation on road traffic injuries were analyzed using a generalized additive model with a Poisson distribution.
The risk of road traffic injuries during snow increased when the temperature was below freezing. Road traffic injuries increased by 6.6% when it was snowing and above 0°C, whereas they increased by 15% when it was snowing and at or below 0°C. In terms of heavy rain precipitation, moderate temperatures were related to an increased prevalence of injuries. When the temperature was 0–20°C, we found a 12% increase in road traffic injuries, whereas it increased by 8.5% and 6.8% when it was <0°C and >20°C, respectively. The interactive effect was consistent across the traffic accident subtypes.
The effect of adverse weather conditions on road traffic injuries differed depending on the temperature. More road traffic injuries were related to rain precipitation when the temperature was moderate and to snow when it was below freezing.
PMCID: PMC4517993  PMID: 26073021
injuries; precipitation; snow; traffic accidents; weather
8.  Estimation of the Biological Half-Life of Methylmercury Using a Population Toxicokinetic Model 
Methylmercury is well known for causing adverse health effects in the brain and nervous system. Estimating the elimination constant derived from the biological half-life of methylmercury in the blood or hair is an important part of calculating guidelines for methylmercury intake. Thus, this study was conducted to estimate the biological half-life of methylmercury in Korean adults. We used a one-compartment model with a direct relationship between methylmercury concentrations in the blood and daily dietary intake of methylmercury. We quantified the between-person variability of the methylmercury half-life in the population, and informative priors were used to estimate the parameters in the model. The population half-life of methylmercury was estimated to be 80.2 ± 8.6 days. The population mean of the methylmercury half-life was 81.6 ± 8.4 days for men and 78.9 ± 8.6 days for women. The standard deviation of the half-life was estimated at 25.0 ± 8.6 days. Using the direct relationship between methylmercury concentrations in blood and methylmercury intake, the biological half-life in this study was estimated to be longer than indicated by the earlier studies that have been used to set guideline values.
PMCID: PMC4555264  PMID: 26264017
biological half-life; dietary exposure; methylmercury; one-compartment toxicokinetic model; population model
9.  Mortality risk attributable to high and low ambient temperature: a multicountry observational study 
Lancet (London, England)  2015;386(9991):369-375.
Although studies have provided estimates of premature deaths attributable to either heat or cold in selected countries, none has so far offered a systematic assessment across the whole temperature range in populations exposed to different climates. We aimed to quantify the total mortality burden attributable to non-optimum ambient temperature, and the relative contributions from heat and cold and from moderate and extreme temperatures.
We collected data for 384 locations in Australia, Brazil, Canada, China, Italy, Japan, South Korea, Spain, Sweden, Taiwan, Thailand, UK, and USA. We fitted a standard time-series Poisson model for each location, controlling for trends and day of the week. We estimated temperature–mortality associations with a distributed lag non-linear model with 21 days of lag, and then pooled them in a multivariate metaregression that included country indicators and temperature average and range. We calculated attributable deaths for heat and cold, defined as temperatures above and below the optimum temperature, which corresponded to the point of minimum mortality, and for moderate and extreme temperatures, defined using cutoffs at the 2·5th and 97·5th temperature percentiles.
We analysed 74 225 200 deaths in various periods between 1985 and 2012. In total, 7·71% (95% empirical CI 7·43–7·91) of mortality was attributable to non-optimum temperature in the selected countries within the study period, with substantial differences between countries, ranging from 3·37% (3·06 to 3·63) in Thailand to 11·00% (9·29 to 12·47) in China. The temperature percentile of minimum mortality varied from roughly the 60th percentile in tropical areas to about the 80–90th percentile in temperate regions. More temperature-attributable deaths were caused by cold (7·29%, 7·02–7·49) than by heat (0·42%, 0·39–0·44). Extreme cold and hot temperatures were responsible for 0·86% (0·84–0·87) of total mortality.
Most of the temperature-related mortality burden was attributable to the contribution of cold. The effect of days of extreme temperature was substantially less than that attributable to milder but non-optimum weather. This evidence has important implications for the planning of public-health interventions to minimise the health consequences of adverse temperatures, and for predictions of future effect in climate-change scenarios.
UK Medical Research Council.
PMCID: PMC4521077  PMID: 26003380
10.  Update on biomarkers in neuromyelitis optica 
Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO. However, whether AQP4-IgG levels correlate with disease activity, severity, response to therapy, or long-term outcomes is unclear. Moreover, biomarkers for patients with seronegative NMO have yet to be defined and validated. Collaborative international studies hold great promise for establishing and validating biomarkers that are useful in therapeutic trials and clinical management. In this review, we discuss known and potential biomarkers for NMO.
PMCID: PMC4516398
11.  Protective activity ethanol extract of the fruits of Illicium verum against atherogenesis in apolipoprotein E knockout mice 
Illicium verum Hook. fil. Illiciaceae (Illicium v.) has been traditionally used in herbal medicine for treating many inflammatory diseases, including skin inflammation and rheumatism. We investigated its use as a preventive agent against inflammatory and vascular diseases in a murine model of atherosclerosis using apolipoprotein E-knockout (ApoE−/−) mice fed on a high-fat diet (HFD).
We investigated the effect of Illicium v. on cytotoxicity, NF-κB activity, and adhesion molecule expression in TNF-α – stimulated HASMCs (Human Aortic smooth muscle cells). ApoE−/−mice, fed a HFD and treated daily for 12 weeks by oral administration of either Illicium v. (100 or 200 mg/kg) or atorvastatin (10 mg/kg), were evaluated for atherosclerotic lesions and inflammatory responses by performing Oil red O and iNOS staining, respectively. Expression of inflammatory cytokines (i.e., NF-κB, TNF-α, IL-1β, COX, IκB-α, Iκκ-α/β) and adhesion molecules in the aorta were measured by western blot analysis.
In TNF-α-stimulated HASMCs, Illicium v. treatment decreased NF-κB transcriptional activity, and NF-κB protein levels were reduced in a dose-dependent manner over a range of 10–100 μg/mL Illicium v. Also, Illicium v. attenuated the expression of adhesion molecules that are responsible for inflammation in these cells. In animal experiments, treatment with Illicium v. or atorvastatin counteracted the characteristic changes in body weight, blood pressure, and lipid levels seen in HFD-fed ApoE−/− mice. In addition, Illicium v. treatment reduced aortic atherosclerotic plaque lesions and the immunoreactivity of iNOS activation. The aortic expression of inflammatory adhesion molecules and cytokines (TNF-α, IL-1β, NF-κB, COX, IκB-α, Iκκ-α/β), which is characteristic of HFD-fed ApoE−/− mice, was attenuated by 12-week treatment with daily oral administration of Illicium v. or atorvastatin, and the most potent effect was seen with the herbal tincture.
The beneficial effects of Illicium v. are consistent with a significant decrease in the iNOS-mediated inflammatory response, resulting in reduction of inflammation-associated gene expression. Treatment with Illicium v. may be the basis of a novel therapeutic strategy for hyperlipidemia-atherosclerosis.
PMCID: PMC4501282  PMID: 26174316
Atherosclerosis; ApoE-knockout mice; Inflammation; Hypercholesterolemia; Illicium verum
12.  Combined effect of bisphosphonate and recombinant human bone morphogenetic protein 2 on bone healing of rat calvarial defects 
This study aimed to investigate new bone formation using recombinant human bone morphogenetic protein 2 (rhBMP-2) and locally applied bisphosphonate in rat calvarial defects.
Thirty-six rats were studied. Two circular 5 mm diameter bony defect were formed in the calvaria using a trephine bur. The bony defect were grafted with Bio-Oss® only (group 1, n = 9), Bio-Oss® wetted with rhBMP-2 (group 2, n = 9), Bio-Oss® wetted with rhBMP-2 and 1 mM alendronate (group 3, n = 9) and Bio-Oss® wetted with rhBMP-2 and 10 mM alendronate (group 4, n = 9). In each group, three animals were euthanized at 2, 4 and 8 weeks after surgery, respectively. The specimens were then analyzed by histology, histomorphometry and immunohistochemistry analysis.
There were significant decrease of bone formation area (p < 0.05) between group 4 and group 2, 3. Group 3 showed increase of new bone formation compared to group 2. In immunohistochemistry, collagen type I and osteoprotegerin (OPG) didn’t show any difference. However, receptor activator of nuclear factor κB ligand (RANKL) decreased with time dependent except group 4.
Low concentration bisphosphonate and rhBMP-2 have synergic effect on bone regeneration and this is result from the decreased activity of RANKL of osteoblast.
PMCID: PMC4488498  PMID: 26161381
Bisphophonate; Bone morphogenetic protein 2; Bone regeneration; Histology; Alendronate
13.  The Clinical Utility of FDG PET-CT in Evaluation of Bone Marrow Involvement by Lymphoma 
Bone marrow biopsy is a standard method for the evaluation of bone marrow infiltration by lymphoma; however, it is an invasive and painful procedure. Fluorodeoxyglucose positron emission tomography–computed tomography (FDG PET-CT) is a noninvasive imaging technique with the potential to detect bone marrow involvement by lymphoma.
Materials and Methods
We retrospectively reviewed medical records of lymphoma patients. All patients were examined by FDG PET-CT and iliac crest bone marrow biopsy for initial staging work-up.
The study population comprised 94 patients (median age, 60 years; 56 males) with Hodgkin’s lymphoma (n=8) or non-Hodgkin’s lymphoma (n=86). Maximum standardized uptake values on the iliac crest of patients with lymphoma infiltrated bone marrow were significantly higher than those of patients with intact bone marrow (2.2±1.2 g/mL vs. 1.3±0.4 g/mL; p=0.001). The calculated values for FDG PET-CT during evaluation of bone marrow involvement were as follows: sensitivity 50%, specificity 96%, positive predictive value 80%, negative predictive value 85%, and positive likelihood ratio (LR+) 11.7. The value of LR+ was 16.0 in patients with aggressive subtypes of non-Hodgkin’s lymphoma (NHL).
FDG PET-CT could not replace bone marrow biopsy due to the low sensitivity of FDG PET-CT for detection of bone marrow infiltration in lymphoma patients. Conversely, FDG PET-CT had high specificity and LR+; therefore, it could be a useful tool for image-guided biopsy for lymphoma staging, especially for aggressive subtypes of NHL. In addition, unilateral bone marrow biopsy could be substituted for bilateral bone marrow biopsy in lymphoma patients with increased FDG uptake on any iliac crest.
PMCID: PMC4506116  PMID: 25648095
Lymphoma; Positron-emission tomography; Bone marrow examination
14.  The Etiological Spectrum of Acute Sensory Myelitis 
Background and Purpose
Acute myelitis patients exhibiting only sensory deficits upon initial presentation are not commonly encountered in clinical practice, but they definitely exist. Since acute sensory myelitis has not been investigated previously, this study evaluated the etiological spectrum of the condition with the aim of describing the clinical characteristics thereof.
Patients with acute myelitis who presented at the Ewha Womans University Medical Center (during 1999-2012) and the National Cancer Center (during 2005-2014) with only sensory symptoms as first clinical features were enrolled in this study. Their medical records, electrophysiological and laboratory data, and MRI findings were analyzed retrospectively.
Of a total of 341 acute myelitis patients, 52 (15%) were identified as having acute sensory myelitis. The male-to-female ratio of these patients was 35:17, and their age at the onset of the condition was 41.7±10.5 years (mean±SD; range, 24-72 years). Acute sensory myelitis developed in patients with multiple sclerosis (MS; 14%), neuromyelitis optica spectrum disorder (NMOSD; 17%), and acute myelitis associated with concurrent systemic diseases including Behçet's disease and cancer (6%). Despite detailed evaluation, the etiology of 33 patients with acute myelitis could not be determined. Longitudinally extensive transverse myelitis on spinal MRI and progression of the sensory level were observed most commonly in NMOSD patients (89% and 78%, respectively); however, these patients did not exhibit sensory dissociation. Residual negative sensory symptoms were observed more frequently in NMOSD patients (33%) than in those with acute myelitis of unknown cause (24%) or MS (14%). During the long-term follow-up (4.7±2.7 years) of patients who did not undergo maintenance immunotherapy, a monophasic clinical course was common in those with acute myelitis of unknown cause (76%), but not in NMOSD or MS patients.
Accurate identification of the diverse nature of acute sensory myelitis may assist in patient care.
PMCID: PMC4507376  PMID: 26174785
myelitis; acute; sensory; etiology
15.  Elderly Peritoneal Dialysis Compared with Elderly Hemodialysis Patients and Younger Peritoneal Dialysis Patients: Competing Risk Analysis of a Korean Prospective Cohort Study 
PLoS ONE  2015;10(6):e0131393.
The outcomes of peritoneal dialysis (PD) in elderly patients have not been thoroughly investigated. We aimed to investigate the clinical outcomes and risk factors associated with PD in elderly patients. We conducted a prospective observational nationwide adult end-stage renal disease (ESRD) cohort study in Korea from August 2008 to March 2013. Among incident patients (n = 830), patient and technical survival rate, quality of life, and Beck’s Depression Inventory (BDI) scores of elderly PD patients (≥65 years, n = 95) were compared with those of PD patients aged ≤49 years (n = 205) and 50~64 years (n = 192); and elderly hemodialysis (HD) patients (n = 315). The patient death and technical failure were analyzed by cumulative incidence function. Competing risk regressions were used to assess the risk factors for survival. The patient survival rate of elderly PD patients was inferior to that of younger PD patients (P<0.001). However, the technical survival rate was similar (P = 0.097). Compared with elderly HD patients, the patient survival rate did not differ according to dialysis modality (P = 0.987). Elderly PD patients showed significant improvement in the BDI scores, as compared with the PD patients aged ≤49 years (P = 0.003). Low albumin, diabetes and low residual renal function were significant risk factors for the PD patient survival; and peritonitis was a significant risk factor for technical survival. Furthermore, low albumin and hospitalization were significant risk factors of patient survival among the elderly. The overall outcomes were similar between elderly PD and HD patients. PD showed the benefit in BDI and quality of life in the elderly. Additionally, the technical survival rate of elderly PD patients was similar to that of younger PD patients. Taken together, PD may be a comparable modality for elderly ESRD patients.
PMCID: PMC4488000  PMID: 26121574
16.  Green fluorescent protein nanopolygons as monodisperse supramolecular assemblies of functional proteins with defined valency 
Nature Communications  2015;6:7134.
Supramolecular protein assemblies offer novel nanoscale architectures with molecular precision and unparalleled functional diversity. A key challenge, however, is to create precise nano-assemblies of functional proteins with both defined structures and a controlled number of protein-building blocks. Here we report a series of supramolecular green fluorescent protein oligomers that are assembled in precise polygonal geometries and prepared in a monodisperse population. Green fluorescent protein is engineered to be self-assembled in cells into oligomeric assemblies that are natively separated in a single-protein resolution by surface charge manipulation, affording monodisperse protein (nano)polygons from dimer to decamer. Several functional proteins are multivalently displayed on the oligomers with controlled orientations. Spatial arrangements of protein oligomers and displayed functional proteins are directly visualized by a transmission electron microscope. By employing our functional protein assemblies, we provide experimental insight into multivalent protein–protein interactions and tools to manipulate receptor clustering on live cell surfaces.
Supramolecular protein assemblies can provide novel nano-architectures with diverse structures and functions. Here, the authors report a fabrication strategy for a series of monodisperse protein oligomers, which allows valency-controlled display of various functional proteins.
PMCID: PMC4479010  PMID: 25972078
17.  Non-Linear Concentration-Response Relationships between Ambient Ozone and Daily Mortality 
PLoS ONE  2015;10(6):e0129423.
Ambient ozone (O3) concentration has been reported to be significantly associated with mortality. However, linearity of the relationships and the presence of a threshold has been controversial.
The aim of the present study was to examine the concentration-response relationship and threshold of the association between ambient O3 concentration and non-accidental mortality in 13 Japanese and Korean cities from 2000 to 2009.
We selected Japanese and Korean cities which have population of over 1 million. We constructed Poisson regression models adjusting daily mean temperature, daily mean PM10, humidity, time trend, season, year, day of the week, holidays and yearly population. The association between O3 concentration and mortality was examined using linear, spline and linear-threshold models. The thresholds were estimated for each city, by constructing linear-threshold models. We also examined the city-combined association using a generalized additive mixed model.
The mean O3 concentration did not differ greatly between Korea and Japan, which were 26.2 ppb and 24.2 ppb, respectively. Seven out of 13 cities showed better fits for the spline model compared with the linear model, supporting a non-linear relationships between O3 concentration and mortality. All of the 7 cities showed J or U shaped associations suggesting the existence of thresholds. The range of city-specific thresholds was from 11 to 34 ppb. The city-combined analysis also showed a non-linear association with a threshold around 30-40 ppb.
We have observed non-linear concentration-response relationship with thresholds between daily mean ambient O3 concentration and daily number of non-accidental death in Japanese and Korean cities.
PMCID: PMC4468145  PMID: 26076447
18.  Factors that Predict Negative Results of QuantiFERON-TB Gold In-Tube Test in Patients with Culture-Confirmed Tuberculosis: A Multicenter Retrospective Cohort Study 
PLoS ONE  2015;10(6):e0129792.
Interferon-γ release assays such as the QuantiFERON-TB Gold In-Tube Test (QFT-GIT) are designed to detect Mycobacterium tuberculosis infections, whether latent or manifesting as disease. However, a substantial number of persons with culture-confirmed tuberculosis (TB) have negative QFT-GITs. Information on host factors contributing to false-negative and indeterminate results are limited.
A multicenter retrospective cohort study was performed with 1,264 culture-confirmed TB patients older than 18 years who were subjected to the QFT-GIT at one of the six hospitals between May 2007 and February 2014. Patients with human immunodeficiency virus infection were excluded. Clinical and laboratory data were collected in South Korea.
Of all patients, 87.6% (1,107/1,264) were diagnosed with pulmonary TB and 12.4% (157/1,264) with extrapulmonary TB. The rate of negative results was 14.4% (182/1,264). The following factors were highly correlated with false-negative results in the QFT-GIT: advanced age (age ≥ 65 years, odds ratio [OR] 1.57, 95% confidence interval [CI] 1.03–2.39), bilateral disease as determined by chest radiography (OR 1.75, 95% CI 1.13–2.72), malignancy (OR 2.42, 95% CI 1.30–4.49), and lymphocytopenia (total lymphocyte count < 1.0 × 109/L, OR 1.86, 95% CI 1.21–2.87).
Consequently, QFT-GIT results need to be interpreted with caution in patients with these host risk factors such as the elderly, bilateral disease on chest radiography, or malignancy, or lymphocytopenia.
PMCID: PMC4466377  PMID: 26070207
19.  Korean research project on the integrated exposure assessment of hazardous substances for food safety 
This survey was designed to conduct the first nationwide dietary exposure assessment on hazardous substances including the intakes of functional food and herbal medicine. In this paper, we introduced the survey design and the results of the dietary exposure status and internal exposure levels of lead (Pb), cadmium (Cd), and mercury (Hg).
We selected 4867 subjects of all ages throughout Korea. We conducted a food survey, dietary survey, biomonitoring, and health survey.
Pb and Cd were the highest (median value) in the seaweed (94.2 μg/kg for Pb; 594 μg/kg for Cd), and Hg was the highest in the fish (46.4 μg/kg). The dietary exposure level (median value) of Pb was 0.14 μg/kg body weight (bw)/d, 0.18 μg/kg bw/d for Cd, and 0.07 μg/kg bw/d for Hg. Those with a blood Pb level of less than 5.00 μg/dL (US Centers for Disease Control and Prevention, reference value for those 1 to 5 years of age) were 99.0% of all the subjects. Those with a blood Cd level with less than 0.30 μg/L (German Federal Environmental Agency, reference value for non-smoking children) were 24.5%. For those with a blood Hg level with less than 5.00 μg/L (human biomonitoring I, references value for children and adults, German Federal Environmental Agency) was 81.0 % of all the subjects.
The main dietary exposure of heavy metals occurs through food consumed in a large quantity and high frequency. The blood Hg level and dietary exposure level of Hg were both higher than those in the European Union.
PMCID: PMC4509523  PMID: 26184046
Food intake; Hazardous substances; Heavy metal; Integrated dietary exposure assessment; Survey design
20.  Primary Benign Intraosseous Meningioma on 18F-FDG PET/CT Mimicking Malignancy 
We present a case of primary benign intraosseous meningioma in the sphenoid bone mimicking malignancy. A 44-year-old female patient who had a protruding right eye and headache came to our hospital. MRI showed a large, destructive, heterogeneously well-enhancing soft tissue mass in the right sphenoid bone suggesting malignancy. 18F-FDG PET/CT showed a hypermetabolic mass in the same site with an SUVmax of 9.1 The pathological diagnosis by surgery revealed that this tumor was a WHO grade I transitional meningioma. This case suggests that primary benign intraosseous meningioma may show high 18F-FDG uptake mimicking a malignancy.
PMCID: PMC4028472  PMID: 24900156
Benign meningioma; Sphenoid bone; PET/CT; 18F-Fluorodeoxyglucose
21.  The Proteomic Analysis of Human Placenta with Pre-eclampsia and Normal Pregnancy 
Journal of Korean Medical Science  2015;30(6):770-778.
Preeclampsia is one of the most important and complexed disorders for women's health. Searching for novel proteins as biomarkers to reveal pathogenesis, proteomic approaches using 2DE has become a valuable tool to understanding of preeclampsia. To analyze the proteomic profiling of preclamptic placenta compared to that of normal pregnancy for better understanding of pathogenesis in preeclampsia, placentas from each group were handled by use of proteomics approach using 2DE combined with MALDI-TOF-MS. The 20 spots of showing differences were analysed and identified. Among differentially expressed protein spots Hsp 27 and Hsp 70 were selected for validation using Western blot analysis. In preeclamptic placenta 9 differentially expressed proteins were down-regulated with Hsp 70, serum albumin crystal structure chain A, lamin B2, cytokeratin 18, actin cytoplasmic, alpha fibrinogen precursor, septin 2, dihydrolipoamide branched chain transacylase E2 and firbrinogen beta chain. The 11 up-regulated proteins were fibrinogen gamma, cardiac muscle alpha actin proprotein, cytokeratin 8, calumenin, fibrinogen fragment D, F-actin capping protein alpha-1 subunit, Hsp 27, Hsp 40, annexin A4, enoyl-CoA delta isomerase and programmed cell death protein 6. The western blot analysis for validation also showed significant up-regulation of Hsp 27 and down-regulation of Hsp 70 in the placental tissues with preeclmaptic pregnancies. This proteomic profiling of placenta using 2DE in preeclampsia successfully identifies various proteins involved in apoptosis, mitochondrial dysfunction, as well as three Hsps with altered expression, which might play a important role for the understanding of pathogenesis in preeclampsia.
Graphical Abstract
PMCID: PMC4444479  PMID: 26028931
Pre-eclampsia; Proteomics; Spectrometry, Mass, Matrix-assisted Laser Desorption-ionization; Placenta; Blotting, Western
22.  A Plasmacytoid Dendritic Cells-Type I Interferon Axis Is Critically Implicated in the Pathogenesis of Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is characterized by the generation of immune responses to various nuclear components. Impaired clearance of apoptotic cells and loss of tolerance to self-antigens are involved both in the initiation and in the propagation of the disease. Dendritic cells (DCs) are key factors in the balance between autoimmunity and tolerance and play a role linking innate and adaptive immunity. DCs, particularly plasmacytoid DCs (pDCs), are the main source of type I interferon (IFN) cytokines, which contribute to the immunopathogenesis of SLE. There is accumulating evidence that pDCs and type I IFN cytokines take the leading part in the development of SLE. In this review, we discuss recent data regarding the role of pDCs and type I IFN cytokines in the pathogenesis of SLE and the potential for employing therapies targeting against aberrant regulation of the pDC-type I IFN axis for treating SLE.
PMCID: PMC4490545  PMID: 26110387
systemic lupus erythematosus; dendritic cells; type I interferon
23.  Utility of the Rio Score and Modified Rio Score in Korean Patients with Multiple Sclerosis 
PLoS ONE  2015;10(5):e0129243.
Early identification of suboptimal responders to multiple sclerosis (MS) treatment is critical for optimizing therapeutic decisions. The Rio score (RS) and modified Rio score (MRS) were developed to discriminate the responses to interferon-beta (IFNB) treatment in MS patients. This study was performed to evaluate the utility of RS and MRS in daily clinical practice in Korea.
This was a real-world setting, multicenter, retrospective study of MS patients treated with IFNB from 10 hospitals in Korea. We investigated whether the RS and MRS at the early stage of IFNB therapy could predict treatment responses over 3 years. Suboptimal treatment responses at 3 years were defined as the presence of clinical relapse and/or EDSS progression and/or patients who had been treated with INFB for at least for 1 year and therapy was switched due to perceived treatment failure during the 2 years of follow-up.
Seventy patients (50 females and 20 males) were enrolled; 92% (12/13) of patients with high RS and 86% (12/14) of patients with high MRS (score 2 or 3) were suboptimal responders, whereas 93% (53/57) of patients with low RS and 93% (52/56) patients with low MRS (score 0 or 1) showed optimal responses. New active lesions on MRI with clinical relapse in high RS and MRS were the most common combination in suboptimal responders.
We confirmed that RS and MRS at 6–15 months of IFNB therapy were useful for predicting poor responders over 3 years.
PMCID: PMC4444088  PMID: 26010897
24.  Spring-loaded unraveling of a single SNARE complex by NSF in one round of ATP turnover 
Science (New York, N.Y.)  2015;347(6229):1485-1489.
During intracellular membrane trafficking, N-ethylmaleimide-sensitive factor (NSF) and alpha-soluble NSF attachment protein (α-SNAP) disassemble the soluble NSF attachment protein receptor (SNARE) complex for recycling of the SNARE proteins. The molecular mechanism by which NSF disassembles the SNARE complex is largely unknown. Using single-molecule fluorescence spectroscopy and magnetic tweezers, we found that NSF disassembled a single SNARE complex in only one round of adenosine triphosphate (ATP) turnover. Upon ATP cleavage, the NSF hexamer developed internal tension with dissociation of phosphate ions. After latent time measuring tens of seconds, NSF released the built-up tension in a burst within 20 milliseconds, resulting in disassembly followed by immediate release of the SNARE proteins. Thus, NSF appears to use a “spring-loaded” mechanism to couple ATP hydrolysis and unfolding of substrate proteins.
PMCID: PMC4441202  PMID: 25814585
25.  Recalibration and Validation of the Charlson Comorbidity Index in Korean Incident Hemodialysis Patients 
PLoS ONE  2015;10(5):e0127240.
Weights assigned to comorbidities to predict mortality may vary based on the type of index disease and advances in the management of comorbidities. We aimed to develop a modified Charlson comorbidity index (CCI) in incident hemodialysis patients (mCCI-IHD), thereby improving risk stratification for mortality.
Data on 24,738 Koreans who received their first hemodialysis treatment between 2005 and 2008 were obtained from the Korean Health Insurance dataset. The mCCI-IHD score were calculated by summing up the weights which were assigned to individual comorbidities according to their relative prognostic significance determined by multivariate Cox proportional hazards model. The modified index was validated in an independent nationwide prospective cohort (n=1,100).
The Cox proportional hazards model revealed that all comorbidities in the CCI except ulcers significantly predicted mortality. Thus, the mCCI-IHD included 14 comorbidities with re-assigned severity weights. In the validation cohort, both the CCI and the mCCI-IHD were correlated with mortality. However, the mCCI-IHD showed modest but significant increases in c statistics compared with the CCI at 6 months and 1 year. The analyses using continuous net reclassification improvement revealed that the mCCI-IHD improved net mortality risk reclassification by 24.6% (95% CI, 2.5-46.7; P=0.03), 26.2% (95% CI, 1.0-51.4; P=0.04) and 42.8% (95% CI, 4.9-80.8; P=0.03) with respect to the CCI at 6 months and 1 and 2 years, respectively.
The mCCI-IHD facilitates better risk stratification for mortality in incident hemodialysis patients compared with the CCI, suggesting that it may be a preferred index for use in clinical practice and the statistical analysis of epidemiological studies.
PMCID: PMC4436150  PMID: 25984790

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