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1.  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.
doi:10.1212/NXI.0000000000000134
PMCID: PMC4516398
2.  Protective activity ethanol extract of the fruits of Illicium verum against atherogenesis in apolipoprotein E knockout mice 
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/s12906-015-0750-0
PMCID: PMC4501282  PMID: 26174316
Atherosclerosis; ApoE-knockout mice; Inflammation; Hypercholesterolemia; Illicium verum
3.  Combined effect of bisphosphonate and recombinant human bone morphogenetic protein 2 on bone healing of rat calvarial defects 
Background
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.
Methods
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.
Results
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.
Conclusion
Low concentration bisphosphonate and rhBMP-2 have synergic effect on bone regeneration and this is result from the decreased activity of RANKL of osteoblast.
doi:10.1186/s40902-015-0015-3
PMCID: PMC4488498  PMID: 26161381
Bisphophonate; Bone morphogenetic protein 2; Bone regeneration; Histology; Alendronate
4.  The Clinical Utility of FDG PET-CT in Evaluation of Bone Marrow Involvement by Lymphoma 
Purpose
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.
Results
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).
Conclusion
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.
doi:10.4143/crt.2014.091
PMCID: PMC4506116  PMID: 25648095
Lymphoma; Positron-emission tomography; Bone marrow examination
5.  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.
Methods
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.
Results
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.
Conclusions
Accurate identification of the diverse nature of acute sensory myelitis may assist in patient care.
doi:10.3988/jcn.2015.11.3.227
PMCID: PMC4507376  PMID: 26174785
myelitis; acute; sensory; etiology
6.  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.
doi:10.1371/journal.pone.0131393
PMCID: PMC4488000  PMID: 26121574
7.  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.
doi:10.1038/ncomms8134
PMCID: PMC4479010  PMID: 25972078
8.  Non-Linear Concentration-Response Relationships between Ambient Ozone and Daily Mortality 
PLoS ONE  2015;10(6):e0129423.
Background
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.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0129423
PMCID: PMC4468145  PMID: 26076447
9.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1371/journal.pone.0129792
PMCID: PMC4466377  PMID: 26070207
10.  Korean research project on the integrated exposure assessment of hazardous substances for food safety 
Objectives:
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).
Methods:
We selected 4867 subjects of all ages throughout Korea. We conducted a food survey, dietary survey, biomonitoring, and health survey.
Results:
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.
Conclusions:
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.
doi:10.5620/eht.e2015004
PMCID: PMC4509523  PMID: 26184046
Food intake; Hazardous substances; Heavy metal; Integrated dietary exposure assessment; Survey design
11.  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.
doi:10.1007/s13139-013-0259-8
PMCID: PMC4028472  PMID: 24900156
Benign meningioma; Sphenoid bone; PET/CT; 18F-Fluorodeoxyglucose
12.  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
doi:10.3346/jkms.2015.30.6.770
PMCID: PMC4444479  PMID: 26028931
Pre-eclampsia; Proteomics; Spectrometry, Mass, Matrix-assisted Laser Desorption-ionization; Placenta; Blotting, Western
13.  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.
doi:10.3390/ijms160614158
PMCID: PMC4490545  PMID: 26110387
systemic lupus erythematosus; dendritic cells; type I interferon
14.  Utility of the Rio Score and Modified Rio Score in Korean Patients with Multiple Sclerosis 
PLoS ONE  2015;10(5):e0129243.
Objectives
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.
Methods
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.
Results
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.
Conclusions
We confirmed that RS and MRS at 6–15 months of IFNB therapy were useful for predicting poor responders over 3 years.
doi:10.1371/journal.pone.0129243
PMCID: PMC4444088  PMID: 26010897
15.  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.
doi:10.1126/science.aaa5267
PMCID: PMC4441202  PMID: 25814585
16.  Recalibration and Validation of the Charlson Comorbidity Index in Korean Incident Hemodialysis Patients 
PLoS ONE  2015;10(5):e0127240.
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0127240
PMCID: PMC4436150  PMID: 25984790
17.  Global variation in the effects of ambient temperature on mortality: a systematic evaluation 
Epidemiology (Cambridge, Mass.)  2014;25(6):781-789.
Background
Studies have examined the effects of temperature on mortality in a single city, country or region. However, less evidence is available on the variation in the associations between temperature and mortality in multiple countries, analyzed simultaneously.
Methods
We obtained daily data on temperature and mortality in 306 communities from 12 countries/regions (Australia, Brazil, Thailand, China, Taiwan, Korea, Japan, Italy, Spain, United Kingdom, United States and Canada). Two-stage analyses were used to assess the non-linear and delayed relationship between temperature and mortality. In the first stage, a Poisson regression allowing over-dispersion with distributed lag non-linear model was used to estimate the community-specific temperature-mortality relationship. In the second stage, a multivariate meta-analysis was used to pool the non-linear and delayed effects of ambient temperature at the national level, in each country.
Results
The temperatures associated with the lowest mortality were around the 75th percentile of temperature in all the countries/regions, ranging from 66th (Taiwan) to 80th (UK) percentiles. The estimated effects of cold and hot temperatures on mortality varied by community and country. Meta-analysis results show that both cold and hot temperatures increased the risk of mortality in all the countries/regions. Cold effects were delayed and lasted for many days, while hot effects appeared quickly and did not last long.
Conclusions
People have some ability to adapt to their local climate type, but both cold and hot temperatures are still associated with the risk of mortality. Public health strategies to alleviate the impact of ambient temperatures are important, in particular in the context of climate change.
doi:10.1097/EDE.0000000000000165
PMCID: PMC4180721  PMID: 25166878
18.  The effect of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of cilostazol and its active metabolites in healthy Korean subjects 
AIMS
The primary objective of this study was to evaluate the effects of Ginkgo biloba extracts (GBE) on the pharmacokinetics of cilostazol and its metabolites. The secondary objective was to assess the effect of GBE on the pharmacodynamics of cilostazol.
METHODS
A randomized, double-blind, two-way crossover study was conducted with 34 healthy Korean subjects. All subjects were given an oral dose of cilostazol (100 mg) plus GBE (80 mg) or cilostazol (100 mg) plus placebo twice daily for 7 days. Plasma concentrations of cilostazol and its active metabolites (3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol) were measured using liquid chromatography–tandem mass spectroscopy on day 7 for pharmacokinetic assessment. The adenosine diphosphate-induced platelet aggregation and bleeding time were measured at baseline and on day 7 for pharmacodynamic assessment.
RESULTS
The geometric mean ratios of area under the concentration–time curve for dosing interval for cilostazol plus GBE vs. cilostazol plus placebo were 0.96 (90% confidence interval, 0.89–1.03; P = 0.20) for cilostazol, 0.96 (90% confidence interval, 0.90–1.02; P = 0.30) for 3,4-dehydrocilostazol and 0.98 (90% confidence interval, 0.93–1.03; P = 0.47) for 4′-trans-hydroxycilostazol. The change of aggregation after administration of cilostazol plus GBE seemed to be 1.31 times higher compared with cilostazol plus placebo, without statistical significance (P = 0.20). There were no significant changes in bleeding times and adverse drug reactions between the treatments.
CONCLUSIONS
Co-administration of GBE showed no statistically significant effects on the pharmacokinetics of cilostazol in healthy subjects. A large cohort study with long-term follow-up may be needed to evaluate the possible pharmacodynamic interaction between cilostazol and GBE, given that there was a remarkable, but not statistically significant, increase in inhibition of platelet aggregation.
doi:10.1111/bcp.12236
PMCID: PMC4004402  PMID: 24001154
cilostazol; Ginkgo biloba extracts; herb–drug interaction; pharmacodynamics; pharmacokinetics
19.  Changes in the Pulmonary Function Test after Radioactive Iodine Treatment in Patients with Pulmonary Metastases of Differentiated Thyroid Cancer 
PLoS ONE  2015;10(4):e0125114.
Objective
Pulmonary function test (PFT) is a useful tool for an objective assessment of respiratory function. Impaired pulmonary function is critical for the survival and quality of life in patients with pulmonary metastases of solid cancers including thyroid cancer. This study aimed to evaluate clinical factors associated with severely impaired pulmonary function by serial assessment with PFT in patients with pulmonary metastasis of differentiated thyroid cancer (DTC) who received radioactive iodine treatment (RAIT).
Patients
This retrospective study enrolled 31 patients who underwent serial PFTs before and after RAIT for pulmonary metastasis of DTC. We evaluated the risk factors for severe impairment of pulmonary function.
Results
The median age of the patients was 44.1 years and 18 of them were female patients. Severe impairment of pulmonary function was observed in five patients (16%) after a median of three RAITs (cumulative I-131 activity = 20.4 GBq). These patients were older and more frequently had mild impairment of baseline pulmonary function, respiratory symptoms, or progressive disease compared with patients with stable pulmonary function. Neither cumulative dose nor number of RAIT was associated with decreased pulmonary function. Coexisting pulmonary diseases, presence of respiratory symptoms, and metastatic disease progression were significantly associated with severe decrease in forced vital capacity during follow-up (p =.047, p =.011, and p =.021, respectively).
Conclusions
Pulmonary function was severely impaired during follow-up in some patients with pulmonary metastasis of DTC after a high-dose RAITs. Neither the number of RAIT nor the cumulative I-131 activity was associated with decreased pulmonary function. Serial PFT might be considered for some high-risk patients during follow-up.
doi:10.1371/journal.pone.0125114
PMCID: PMC4414613  PMID: 25923702
22.  HbA1c variability and the risk of microalbuminuria in patients with type 1 diabetes 
doi:10.1186/1687-9856-2015-S1-P9
PMCID: PMC4428784
HbA1c variability; microalbuminuria; type 1 diabetes
23.  Neural Substrates of Motor and Non-Motor Symptoms in Parkinson’s Disease: A Resting fMRI Study 
PLoS ONE  2015;10(4):e0125455.
Background
Recently, non-motor symptoms of Parkinson’s disease (PD) have been considered crucial factors in determining a patient’s quality of life and have been proposed as the predominant features of the premotor phase. Researchers have investigated the relationship between non-motor symptoms and the motor laterality; however, this relationship remains disputed. This study investigated the neural connectivity correlates of non-motor and motor symptoms of PD with respect to motor laterality.
Methods
Eight-seven patients with PD were recruited and classified into left-more-affected PD (n = 44) and right-more affected PD (n = 37) based on their MDS-UPDRS (Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale) motor examination scores. The patients underwent MRI scanning, which included resting fMRI. Brain regions were labeled as ipsilateral and contralateral to the more-affected body side. Correlation analysis between the functional connectivity across brain regions and the scores of various symptoms was performed to identify the neural connectivity correlates of each symptom.
Results
The resting functional connectivity centered on the ipsilateral inferior orbito-frontal area was negatively correlated with the severity of non-motor symptoms, and the connectivity of the contralateral inferior parietal area was positively correlated with the severity of motor symptoms (p < 0.001, |r| > 0.3).
Conclusions
These results suggest that the inferior orbito-frontal area may play a crucial role in non-motor dysfunctions, and that the connectivity information may be utilized as a neuroimaging biomarker for the early diagnosis of PD.
doi:10.1371/journal.pone.0125455
PMCID: PMC4409348  PMID: 25909812
24.  MRI characteristics of neuromyelitis optica spectrum disorder 
Neurology  2015;84(11):1165-1173.
Since its initial reports in the 19th century, neuromyelitis optica (NMO) had been thought to involve only the optic nerves and spinal cord. However, the discovery of highly specific anti–aquaporin-4 antibody diagnostic biomarker for NMO enabled recognition of more diverse clinical spectrum of manifestations. Brain MRI abnormalities in patients seropositive for anti–aquaporin-4 antibody are common and some may be relatively unique by virtue of localization and configuration. Some seropositive patients present with brain involvement during their first attack and/or continue to relapse in the same location without optic nerve and spinal cord involvement. Thus, characteristics of brain abnormalities in such patients have become of increased interest. In this regard, MRI has an increasingly important role in the differential diagnosis of NMO and its spectrum disorder (NMOSD), particularly from multiple sclerosis. Differentiating these conditions is of prime importance because early initiation of effective immunosuppressive therapy is the key to preventing attack-related disability in NMOSD, whereas some disease-modifying drugs for multiple sclerosis may exacerbate the disease. Therefore, identifying the MRI features suggestive of NMOSD has diagnostic and prognostic implications. We herein review the brain, optic nerve, and spinal cord MRI findings of NMOSD.
doi:10.1212/WNL.0000000000001367
PMCID: PMC4371410  PMID: 25695963
25.  Constitutional multicenter bank linked to Sasang constitutional phenotypic data 
Background
Biobanks are more important in medical area because they can give researchers data for demonstrating and validating their research. In this study, we developed a biobank called the Korea Constitutional Multicenter Bank (KCMB) based on Sasang Constitutional Medicine (SCM). The aim of the KCMB was a foundation to providing the scientific basis of SCM.
Methods
The KCMB has been constructed since 2006 in 24 Korean medical clinics with collection of questionnaire data, physical measurements and biological information comprised the results from blood test and DNA analyses. All participants were prescribed Sasang Constitution (SC)-specific herbal remedies for the treatment, and showed improvement of original symptoms as confirmed by Korean medicine doctor. Collected data went through de-identification process using the electronic case report form system. For calculation of several SC type specific tendencies, we used the direct standardization and Chi-square tests.
Results
The KCMB collected clinical information from 3,711 study participants (1,353 men and 2,358 women) aged more than 10 years. The mean age (± standard deviation) was 47.1 (±16.6) and 47.7 (±15.8) years for men and women respectively. After applying the direct standardization, the estimated constitutional distributions for the SC types were as follows: 39.2% for Tae-eumin(TE), 27.1% for Soeumin(SE), 33.7% for Soyangyin(SY), and non-zero but below 0.1% for Taeyangyin(TY). The estimated distribution of TE was about 10% less, while that of SY and SE were slightly more than the distribution reported by Jema Lee established the SCM. Based on the participants’ medical history within the KCMB, each SC type had notably different frequencies for some diseases such as hypertension, diabetes, hyperlipidemia, stroke, and obesity (P < 0.001).
Conclusions
The KCMB may serve to verify and validate SCM theories and practices. It may also provide new insights into SCM mechanisms. The results from many studies using the KCMB data are of great importance and value for making decisions in healthcare policy and developing novel therapies.
doi:10.1186/s12906-015-0553-3
PMCID: PMC4378550  PMID: 25887924
Biobank; Sasang Constitutional Medicine; Sasang Constitution

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