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1.  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
2.  Diamond Nanogel-Embedded Contact Lenses Mediate Lysozyme-Dependent Therapeutic Release 
ACS Nano  2014;8(3):2998-3005.
Temporarily implanted devices, such as drug-loaded contact lenses, are emerging as the preferred treatment method for ocular diseases like glaucoma. Localizing the delivery of glaucoma drugs, such as timolol maleate (TM), can minimize adverse effects caused by systemic administration. Although eye drops and drug-soaked lenses allow for local treatment, their utility is limited by burst release and a lack of sustained therapeutic delivery. Additionally, wet transportation and storage of drug-soaked lenses result in drug loss due to elution from the lenses. Here we present a nanodiamond (ND)-embedded contact lens capable of lysozyme-triggered release of TM for sustained therapy. We find that ND-embedded lenses composed of enzyme-cleavable polymers allow for controlled and sustained release of TM in the presence of lysozyme. Retention of drug activity is verified in primary human trabecular meshwork cells. These results demonstrate the translational potential of an ND-embedded lens capable of drug sequestration and enzyme activation.
PMCID: PMC4004290  PMID: 24506583
nanomedicine; contact lens; nanodiamond; drug delivery; biomaterials
3.  Crystal structure of UbiX, an aromatic acid decarboxylase from the psychrophilic bacterium Colwellia psychrerythraea that undergoes FMN-induced conformational changes 
Scientific Reports  2015;5:8196.
The ubiX gene of Colwellia psychrerythraea strain 34H encodes a 3-octaprenyl-4-hydroxybenzoate carboxylase (CpsUbiX, UniProtKB code: Q489U8) that is involved in the third step of the ubiquinone biosynthesis pathway and harbors a flavin mononucleotide (FMN) as a potential cofactor. Here, we report the crystal structures of two forms of CpsUbiX: an FMN-bound wild type form and an FMN-unbound V47S mutant form. CpsUbiX is a dodecameric enzyme, and each monomer possesses a typical Rossmann-fold structure. The FMN-binding domain of UbiX is composed of three neighboring subunits. The highly conserved Gly15, Ser41, Val47, and Tyr171 residues play important roles in FMN binding. Structural comparison of the FMN-bound wild type form with the FMN-free form reveals a significant conformational difference in the C-terminal loop region (comprising residues 170–176 and 195–206). Subsequent computational modeling and liposome binding assay both suggest that the conformational flexibility observed in the C-terminal loops plays an important role in substrate and lipid bindings. The crystal structures presented in this work provide structural framework and insights into the catalytic mechanism of CpsUbiX.
PMCID: PMC4316190  PMID: 25645665
4.  Molecular Basis for SMC Rod Formation and Its Dissolution upon DNA Binding 
Molecular Cell  2015;57(2):290-303.
SMC condensin complexes are central modulators of chromosome superstructure in all branches of life. Their SMC subunits form a long intramolecular coiled coil, which connects a constitutive “hinge” dimerization domain with an ATP-regulated “head” dimerization module. Here, we address the structural arrangement of the long coiled coils in SMC complexes. We unequivocally show that prokaryotic Smc-ScpAB, eukaryotic condensin, and possibly also cohesin form rod-like structures, with their coiled coils being closely juxtaposed and accurately anchored to the hinge. Upon ATP-induced binding of DNA to the hinge, however, Smc switches to a more open configuration. Our data suggest that a long-distance structural transition is transmitted from the Smc head domains to regulate Smc-ScpAB’s association with DNA. These findings uncover a conserved architectural theme in SMC complexes, provide a mechanistic basis for Smc’s dynamic engagement with chromosomes, and offer a molecular explanation for defects in Cornelia de Lange syndrome.
Graphical Abstract
•Prokaryotic Smc-ScpAB complexes form rod-like structures•Binding of ATP and DNA induces a rod-to-ring transition in prokaryotic condensin•The condensin hinge is rigidly anchored to its coiled coil•The rod-like conformation is a conserved feature of SMC protein dimers
Soh et al. show that the rod-like conformation is a conserved architectural scheme of SMC complexes. Upon ATP-induced binding to DNA, the juxtaposed coiled coils of prokaryotic Smc-ScpAB adopt an open conformation to expose a DNA binding site at the inner surface of the hinge domain.
PMCID: PMC4306524  PMID: 25557547
5.  Heat-related mortality risk model for climate change impact projection 
We previously developed a model for projection of heat-related mortality attributable to climate change. The objective of this paper is to improve the fit and precision of and examine the robustness of the model.
We obtained daily data for number of deaths and maximum temperature from respective governmental organizations of Japan, Korea, Taiwan, the USA, and European countries. For future projection, we used the Bergen climate model 2 (BCM2) general circulation model, the Special Report on Emissions Scenarios (SRES) A1B socioeconomic scenario, and the mortality projection for the 65+-year-old age group developed by the World Health Organization (WHO). The heat-related excess mortality was defined as follows: The temperature–mortality relation forms a V-shaped curve, and the temperature at which mortality becomes lowest is called the optimum temperature (OT). The difference in mortality between the OT and a temperature beyond the OT is the excess mortality. To develop the model for projection, we used Japanese 47-prefecture data from 1972 to 2008. Using a distributed lag nonlinear model (two-dimensional nonparametric regression of temperature and its lag effect), we included the lag effect of temperature up to 15 days, and created a risk function curve on which the projection is based. As an example, we perform a future projection using the above-mentioned risk function. In the projection, we used 1961–1990 temperature as the baseline, and temperatures in the 2030s and 2050s were projected using the BCM2 global circulation model, SRES A1B scenario, and WHO-provided annual mortality. Here, we used the “counterfactual method” to evaluate the climate change impact; For example, baseline temperature and 2030 mortality were used to determine the baseline excess, and compared with the 2030 excess, for which we used 2030 temperature and 2030 mortality. In terms of adaptation to warmer climate, we assumed 0 % adaptation when the OT as of the current climate is used and 100 % adaptation when the OT as of the future climate is used. The midpoint of the OTs of the two types of adaptation was set to be the OT for 50 % adaptation.
We calculated heat-related excess mortality for 2030 and 2050.
Our new model is considered to be better fit, and more precise and robust compared with the previous model.
PMCID: PMC3890078  PMID: 23928946
Heat-related mortality; Excess deaths; Climate change; Projection; Adaptation
6.  Finite Element Analysis for Comparison of Spinous Process Osteotomies Technique with Conventional Laminectomy as Lumbar Decompression Procedure 
Yonsei Medical Journal  2014;56(1):146-153.
The purpose of this study was to evaluate and compare the biomechanical behavior of the lumbar spine after posterior decompression with the spinous process osteotomy (SPiO) technique or the conventional laminectomy (CL) technique using a finite element (FE) model.
Materials and Methods
Three validated lumbar FE models (L2-5) which represented intact spine and two decompression models using SPiO and CL techniques at the L3-4 segment were developed. In each model, the ranges of motion, the maximal von Mises stress of the annulus fibrosus, and the intradiscal pressures at the index segment (L3-4) and adjacent segments (L2-3 and L4-5) under 7.5 Nm moments were analyzed. Facet contact forces were also compared among three models under the extension and torsion moments.
Compared to the intact model, the CL and SPiO models had increased range of motion and annulus stress at both the index segment (L3-4) and the adjacent segments under flexion and torsion. However, the SPiO model demonstrated a reduced range of motion and annulus stress than the CL model. Both CL and SPiO models had an increase of facet contact force at the L3-4 segment under the torsion moment compared to that of the intact model. Under the extension moment, however, three models demonstrated a similar facet contact force even at the L3-4 model.
Both decompression methods lead to postoperative segmental instability compared to the intact model. However, SPiO technique leads to better segmental stability compared to the CL technique.
PMCID: PMC4276748  PMID: 25510758
Lumbar spinal stenosis; spinous process osteotomies; conventional laminectomy; finite element model
7.  Oral Disease-Modifying Therapies for Multiple Sclerosis 
Classical multiple sclerosis (MS) treatments using first-line injectable drugs, although widely applied, remain a major concern in terms of therapeutic adherence and efficacy. New oral drugs recently approved for MS treatment represent significant advances in therapy. The oral route of administration clearly promotes patient satisfaction and increases therapeutic compliance. However, these drugs may also have safety and tolerability issues, and a thorough analysis of the risks and benefits is required. Three oral drugs have been approved by regulatory agencies for MS treatment: fingolimod, teriflunomide, and dimethyl fumarate. This article reviews the mechanisms of action, safety, and efficacy of these drugs and two other drugs that have yielded positive results in phase III trials: cladribine and laquinimod.
PMCID: PMC4302185  PMID: 25628732
multiple sclerosis; oral drug; clinical trial; treatment
8.  Recent Advances in Endoscopic Papillectomy for Ampulla of Vater Tumors: Endoscopic Ultrasonography, Intraductal Ultrasonography, and Pancreatic Stent Placement 
Clinical Endoscopy  2015;48(1):24-30.
Since it was first described nearly three decades ago, endoscopic papillectomy (EP) has been utilized as a less invasive, alternative therapy for adenoma of the major duodenal papilla. In this article, we review the recent advances in EP, especially those pertaining to endoscopic ultrasonography (EUS), intraductal ultrasonography (IDUS), and pancreatic stent placement for the prevention of postpapillectomy pancreatitis. Because EUS and IDUS have similar diagnostic accuracies, either modality can be used for the preprocedural evaluation of ampullary tumors. Nevertheless, further technical refinements are required for a more precise evaluation. Given the paucity of data on the usefulness of EUS and/or IDUS during follow-up after EP, a well-designed study is warranted. Furthermore, pancreatic stent placement appears to have a protective effect against postpapillectomy pancreatitis; however, a prospective, randomized, controlled study with a larger number of patients is needed to assess this finding. Moreover, since pancreatic stent placement after EP is not always successful, various novel techniques have been developed to ensure reliable stent placement. Despite the recent advances in EP, further technical refinements and studies are needed to confirm their efficacy.
PMCID: PMC4323428
Ampulla of Vater; Ampullary tumors; Endoscopic resection; Endoscopic papillectomy
9.  Gastrointestinal stromal tumors (GISTs) of the stomach: a multicenter, retrospective study of curatively resected gastric GISTs 
The standard treatment for primary localized gastric gastrointestinal stromal tumor (GIST) is surgical resection. The clinical behavior of gastric GIST after surgical resection is extremely variable. We conducted a multicenter, retrospective study of gastric GISTs patients who underwent curative surgical resection to evaluate clinical features and the prognosis of surgically treated gastric GISTs.
We performed a retrospective study on 406 consecutive patients who underwent curative resections for localized gastric GIST at four university hospitals in Daegu, Korea, between March 1998 and March 2012. The retrospectively collected medical records were reviewed with respect to clinical parameters including age, gender, tumor location, surgical approach, and recurrence.
There were 406 patients: 157 males (38.7%) and 249 females (61.3%), with a mean age of 60.8 ± 10.8 (standard deviation) years. The mean tumor size was 4.9 cm (range, 0.3-29 cm). Curative surgical resection was performed in all patients without tumor rupture or spillage. Laparoscopic wedge resections were performed in 156 patients (38.4%) and open resections in 250 patients (61.6%). The tumor size of the laparoscopic wedge resection group was smaller than that of open resection group (3.45 cm vs. 5.46 cm; P < 0.001). There were 11 recurrent cases (2.7%). No recurrence was observed in patients who underwent laparoscopic wedge resections.
Gastric GISTs had a low recurrence rate after curative resection in our series. Laparoscopic gastric wedge resection is feasible for treating gastric GISTs in selected patients.
PMCID: PMC4255548  PMID: 25485237
Gastrointestinal stromal tumors; Stomach; Prognosis; Laparoscopy
10.  Structure-activity relationships of the intramolecular disulfide bonds in coprisin, a defensin from the dung beetle 
BMB Reports  2014;47(11):625-630.
Defensins, which are small cationic molecules produced by organisms as part of their innate immune response, share a common structural scaffold that is stabilized by three disulfide bridges. Coprisin is a 43-amino acid defensin-like peptide from Copris tripartitus. Here, we report the intramolecular disulfide connectivity of cysteine-rich coprisin, and show that it is the same as in other insect defensins. The disulfide bond pairings of coprisin were determined by combining the enzymatic cleavage and mass analysis. We found that the loss of any single disulfide bond in coprisin eliminated all antibacterial, but not antifungal, activity. Circular dichroism (CD) analysis showed that two disulfide bonds, Cys20-Cys39 and Cys24-Cys41, stabilize coprisin’s α-helical region. Moreover, a BLAST search against UniProtKB database revealed that coprisin’s α-helical region is highly homologous to those of other insect defensins. [BMB Reports 2014; 47(11): 625-630]
PMCID: PMC4281341  PMID: 24393527
Antimicrobial peptide; Circular dichroism; Coprisin; disulfide connectivity; Insect defensin
11.  Anti-inflammatory Effects of Schisandra chinensis (Turcz.) Baill Fruit Through the Inactivation of Nuclear Factor-κB and Mitogen-activated Protein Kinases Signaling Pathways in Lipopolysaccharide-stimulated Murine Macrophages 
Journal of Cancer Prevention  2014;19(4):279-287.
Schisandrae Fructus, the dried fruit of Schisandra chinensis (Turcz.) Baill. (Magnoliaceae), is widely used in traditional medicine for the treatment of a number of chronic inflammatory diseases. This study examined the anti-inflammatory effects of Schisandrae Fructus ethanol extract (SF) on the production of pro-inflammatory substances in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages.
To measure the effects of SF on pro-inflammatory mediator and inflammatory cytokine’s expression and production in RAW 264.7 cells, we used the following methods: cell viability assay, Griess reagent assay, enzyme-linked immunosorbent assay, reverse transcriptase-polymerase chain reaction, Western blotting analysis and immunofluorescence staining.
Stimulation of the RAW 264.7 cells with LPS caused an elevated production of nitric oxide (NO), tumor necrosis factor α (TNF-α) and interleukin (IL)-1β, which was markedly inhibited by the pretreatment with SF without causing any cytotoxic effects. SF also inhibited the expression of inducible NO synthase, TNF-α, and IL-1β protein and their mRNAs in LPS-stimulated RAW 264.7 cells. Furthermore, SF attenuated LPS-induced nuclear translocation of nuclear factor-κB (NF-κB) by reducing inhibitory-κB degradation, and reduced the phosphorylation of mitogen-activated protein kinases (MAPKs), implying that SF regulated LPS-induced NF-κB-dependent inflammatory pathways through suppression of MAPKs activation.
SF may be useful for the treatment of various inflammatory diseases.
PMCID: PMC4285959  PMID: 25574463
Schisandra chinensis; Anti-inflammation; Nuclear factor-kappa B; Mitogen-activated protein kinases
12.  Total Anomalous Pulmonary Venous Return in Siblings 
Total anomalous pulmonary venous return (TAPVR) is a rare and critical congenital vascular anomaly that requires an early operation. However, initial symptoms of TAPVR may be non-specific, and cardiovascular findings may be minimal. The heart may not be enlarged and there is often no cardiac murmur. Without cardiac murmur, these symptoms are similar to those of respiratory distress syndrome in newborns. Therefore, a high degree of suspicion and an early diagnosis of TAPVR are important. This condition generally occurs without a family history and has a low recurrence rate, but several familial cases, including siblings, have been reported worldwide. Additionally, several chromosomal or gene abnormalities associated with TAPVR have been reported. In the case presented here, two brothers with a 6-year age gap were diagnosed with TAPVR. Surgery was performed without cardiac or neurological complications. This is the first report on TAPVR in siblings in Korea.
PMCID: PMC4286644  PMID: 25580197
Total anomalous pulmonary venous return; TAPVR; Sibling
13.  Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone agonist with or without growth hormone 
There is controversy surrounding the growth outcomes of treatment with gonadotropin-releasing hormone agonist (GnRHa) in central precocious puberty (CPP). We analyzed height preservation after treatment with GnRHa with and without growth hormone (GH) in girls with CPP.
We reviewed the medical records of 82 girls with idiopathic CPP who had been treated with GnRHa at Severance Children's Hospital from 2004 to 2014. We assessed the changes in height standard deviation score (SDS) for bone age (BA), and compared adult height (AH) with midparental height (MPH) and predicted adult height (PAH) during treatment in groups received GnRHa alone (n=59) or GnRHa plus GH (n=23).
In the GnRHa alone group, the height SDS for BA was increased during treatment. AH (160.4±4.23 cm) was significantly higher than the initial PAH (156.6±3.96 cm) (P<0.001), and it was similar to the MPH (159.9±3.52 cm). In the GnRHa plus GH group, the height SDS for BA was also increased during treatment. AH (159.3±5.33 cm) was also higher than the initial PAH (154.6±2.55 cm) (P<0.001), which was similar to the MPH (158.1±3.31 cm). Height gain was slightly higher than that in the GnRHa alone group, however it statistically showed no significant correlation with GH treatment.
In CPP girls treated with GnRHa, the height SDS for BA was increased, and the AH was higher than the initial PAH. Combined GH treatment showed a limited increase in height gain.
PMCID: PMC4316408  PMID: 25654068
Central precocious puberty; Gonadotropin-releasing hormone; Growth hormone; Treatment outcome
14.  Risk factors for latent tuberculosis infection in close contacts of active tuberculosis patients in South Korea: a prospective cohort study 
BMC Infectious Diseases  2014;14(1):566.
The diagnosis and treatment of latent tuberculosis infection (LTBI) have become mandatory to reduce the burden of tuberculosis worldwide. Close contacts of active TB patients are at high risk of both active and LTBI. The aim of this study is to identify the predominant risk factors of contracting LTBI, persons in close contact with TB patients were recruited. This study also aimed to compare the efficacy of the tuberculin skin test (TST) and QuantiFERON®-TB GOLD (QFT-G) to diagnose LTBI.
Close contacts of active pulmonary TB patients visiting a hospital in South Korea were diagnosed for LTBI using TST and/or QFT-G. The association of positive TST and/or QFT-G with the following factors was estimated: age, gender, history of Bacillius Calmette-Guerin (BCG) vaccination, history of pulmonary TB, cohabitation status, the acid-fast bacilli smear status, and presence of cough in source cases.
Of 308 subjects, 38.0% (116/305) were TST positive and 28.6% (59/206) were QFT-G positive. TST positivity was significantly associated with male gender (OR: 1.734; 95% CI: 1.001-3.003, p =0.049), history of pulmonary TB (OR: 4.130; 95% CI: 1.441-11.835, p =0.008) and household contact (OR: 2.130; 95% CI: 1.198-3.786, p =0.01) after adjustment for confounding variables. The degree of concordance between TST and QFT-G was fair (70.4%, κ =0.392).
A prevalence of LTBI among close contacts of active pulmonary TB patients was high, and prior TB history and being a household contact were risk factors of LTBI in the study population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0566-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4237765  PMID: 25404412
Tuberculin test; Interferon-gamma release tests; Latent tuberculosis; Independent living; Tuberculosis, pulmonary
15.  House-plant placement for indoor air purification and health benefits on asthmatics 
Some plants were placed in indoor locations frequented by asthmatics in order to evaluate the quality of indoor air and examine the health benefits to asthmatics.
The present study classified the participants into two groups: households of continuation and households of withdrawal by a quasi-experimental design. The households of continuation spent the two observation terms with indoor plants, whereas the households of withdrawal passed the former observation terms with indoor plants and went through the latter observation term without any indoor plants.
The household of continuation showed a continual decrease in the indoor concentrations of volatile organic compounds (VOCs) during the entire observation period, but the household of withdrawal performed an increase in the indoor concentrations of VOCs, except formaldehyde and toluene during the latter observation term after the decrease during the former observation term. Peak expiratory flow rate (PEFR) increased in the households of continuation with the value of 13.9 L/min in the morning and 20.6 L/ min in the evening, but decreased in the households of withdrawal with the value of -24.7 L/min in the morning and -30.2 L/min in the evening in the first experimental season. All of the households exhibited a decrease in the value of PEFR in the second experimental season.
Limitations to the generalizability of findings regarding the presence of plants indoors can be seen as a more general expression of such a benefit of human-environment relations.
PMCID: PMC4258716  PMID: 25384387
Asthma; Formaldehyde; Health; House-plant; Indoor air quality; Volatile organic compounds
16.  Dohaekseunggi-tang extract inhibits obesity, hyperlipidemia, and hypertension in high-fat diet-induced obese mice 
Dohaekseunggi-tang (DHSGT) is a traditional plant-based medicine prescribed to promote blood circulation and to treat obesity and hypertension. The present study aimed to identify potential anti-obesity activities of DHSGT extract.
Anti-obesity, anti-hyperlipidemic, and anti-hypertensive effects of orally-administered DHSGT extract were evaluated in high-fat diet- (HFD)-induced obese mice. Serum biochemistry profiles and expression of diverse metabolic regulatory gene mRNAs in mouse visceral fat were assessed by RT-PCR. The effects of DHSGT on angiotensin-1 converting enzyme (ACE) and pancreatic lipase activities were determined using in vitro inhibition assays.
Oral DHSGT treatment reduced obese HFD C57BL/6 J mouse body weight, liver and adipose tissue mass, adipocyte size, and blood pressure versus untreated HFD mice. DHSGT also decreased serum total cholesterol, LDL-cholesterol, triglyceride, glucose, and leptin concentrations, and increased HDL-cholesterol and adiponectin levels in HFD mice. Furthermore, DHSGT markedly increased mRNA expression of peroxisome proliferator activated receptor-gamma, uncoupling protein-2, and adiponectin in visceral adipose tissue of HFD mice. In vitro tests revealed that DHSGT effectively inhibited porcine pancreatic lipase and ACE activities, with IC50 values of 7.58 mg/ml and 0.56 mg/ml, respectively.
These results validate traditional knowledge and suggest that DHSGT may be potentially useful for managing hyperlipidemia, hyperglycemia, hypertension, and obesity.
PMCID: PMC4193160  PMID: 25280587
Angiotensin-1 converting enzyme; Body weight; Dohaekseunggi-tang; High-fat diet; Pancreatic lipase; Visceral adipose tissue
17.  Role of NADH: quinone oxidoreductase-1 in the tight junctions of colonic epithelial cells 
BMB Reports  2014;47(9):494-499.
NADH:quinone oxidoreductase 1 (NQO1) is known to be involved in the regulation of energy synthesis and metabolism, and the functional studies of NQO1 have largely focused on metabolic disorders. Here, we show for the first time that compared to NQO1-WT mice, NQO1-KO mice exhibited a marked increase of permeability and spontaneous inflammation in the gut. In the DSS-induced colitis model, NQO1-KO mice showed more severe inflammatory responses than NQO1-WT mice. Interestingly, the transcript levels of claudin and occludin, the major tight junction molecules of gut epithelial cells, were significantly decreased in NQO1-KO mice. The colons of NQO1-KO mice also showed high levels of reactive oxygen species (ROS) and histone deacetylase (HDAC) activity, which are known to affect transcriptional regulation. Taken together, these novel findings indicate that NQO1 contributes to the barrier function of gut epithelial cells by regulating the transcription of tight junction molecules. [BMB Reports 2014;47(9): 494-499]
PMCID: PMC4206724  PMID: 24393524
Barrier dysfunction of epithelial cells; Chromosome condensation; Claudin-1; Gut epithelial cell tight junction; Gut inflammation; Histone acetylation/deacetylation; NQO1 knockout mice; Occludin; Transcription
18.  Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway 
Molecules and Cells  2013;36(3):267-272.
Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach. LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G12/13 signaling.
PMCID: PMC3887977  PMID: 23912594
FAK; G12/13; LGR5; NFkappaB; Rho
19.  A Longitudinal Brain Magnetic Resonance Imaging Study of Neuromyelitis Optica Spectrum Disorder 
PLoS ONE  2014;9(9):e108320.
Brain involvement is commonly seen in patients with neuromyelitis optica spectrum disorder (NMOSD). However, little is known about the chronic changes of acute brain lesions on MRI over time. Here, our objective was to evaluate how acute brain MRI lesions in NMOSD changed on follow-up MRI. We reviewed the MRIs of 63 patients with NMOSD who had acute brain lesions and follow-up MRI over an interval of at least 3 months. Of the 211 acute brain lesions, 24% of lesions disappeared completely on T2-weighed images (WI) and a decrease in size ≥50% on T2-WI was observed in 58% of lesions on follow-up MRI. However, 47% of lesions revealed focal T1-hypointensity and, in particular, 18% showed focal cystic changes. Cystic changes were observed most commonly in corticospinal tract and corpus callosal lesions whereas the vast majority of lesions in the cerebellum, basal ganglia and temporal white matter resolved completely. MRI remission on T2-WI occurred in 82% of lesions, while approximately half of the lesions presented foci of T1-hypointensity, which may be considered a severe tissue injury over time. The extent of brain injury following an acute brain lesion in NMOSD may depend on the location of the lesion.
PMCID: PMC4178152  PMID: 25259647
20.  Ordinary kriging approach to predicting long-term particulate matter concentrations in seven major Korean cities 
Cohort studies of associations between air pollution and health have used exposure prediction approaches to estimate individual-level concentrations. A common prediction method used in Korean cohort studies is ordinary kriging. In this study, performance of ordinary kriging models for long-term particulate matter less than or equal to 10 μm in diameter (PM10) concentrations in seven major Korean cities was investigated with a focus on spatial prediction ability.
We obtained hourly PM10 data for 2010 at 226 urban-ambient monitoring sites in South Korea and computed annual average PM10 concentrations at each site. Given the annual averages, we developed ordinary kriging prediction models for each of the seven major cities and for the entire country by using an exponential covariance reference model and a maximum likelihood estimation method. For model evaluation, cross-validation was performed and mean square error and R-squared (R2) statistics were computed.
Mean annual average PM10 concentrations in the seven major cities ranged between 45.5 and 66.0 μg/m3 (standard deviation=2.40 and 9.51 μg/m3, respectively). Cross-validated R2 values in Seoul and Busan were 0.31 and 0.23, respectively, whereas the other five cities had R2 values of zero. The national model produced a higher crossvalidated R2 (0.36) than those for the city-specific models.
In general, the ordinary kriging models performed poorly for the seven major cities and the entire country of South Korea, but the model performance was better in the national model. To improve model performance, future studies should examine different prediction approaches that incorporate PM10 source characteristics.
PMCID: PMC4178540  PMID: 25262773
Exposure prediction; Health effect; Kriging; Long-term exposure; Particulate matter
21.  Clinical significance of NQO1 polymorphism and expression of p53, SOD2, PARP1 in limited-stage small cell lung cancer 
Background: Small cell lung cancer (SCLC) is one of highly aggressive cancers with poor prognosis. Unfortunately, there are as yet no molecular targets that can be exploited to prolong survival in patients with SCLC. This study aimed to investigate possible molecular markers associated with prognosis in limited-stage small cell lung cancer (LS-SCLC). Methods: The demographic and clinical data for LS-SCLC patients treated in a tertiary care hospital between January 2008 and December 2012 were retrospectively reviewed. NQO1 polymorphism and the expression of p53, SOD2, PARP1 were examined in biopsy specimens, and the factors affecting prognosis were identified. Results: 79 patients with LS-SCLC having available pathologic tissues were analyzed. 84.8% of them received both chemotherapy and radiotherapy. NQO1 polymorphism was detected in 60.0% (45/79; heterozygous in 26 patients, homozygous in 19 patients). Over-expression of p53, SOD2, PARP1 was seen in 45.6% (36/79), 38.0% (30/79) and 41.8% (33/79) of the patients, respectively. The univariate Cox proportional hazards model revealed that serum lactate dehydrogenase (LDH) levels and PARP1 expression were associated with disease progression. In the multivariate analysis, only PARP1 expression was a significant independent prognostic factor for progression-free survival (hazard ratio: 0.494; 95% CI, 0.267-0.913, P = 0.025). Conclusions: PARP1 expression is correlated with longer progression-free survival in LS-SCLC requiring further studies to clarify the precise role of PARP1 and the relevance of PARP1-targeted therapy.
PMCID: PMC4230145  PMID: 25400754
Small cell lung cancer; NQO1 polymorphism; PARP1; prognosis
22.  Effects of Air Pollution on Asthma Hospitalization Rates in Different Age Groups in Metropolitan Cities of Korea 
Air quality, atmosphere, & health  2013;6(3):10.1007/s11869-013-0195-x.
Many studies have shown associations between air pollution and asthma admissions in Korea, but have not reported whether these effects differ by age classification. The purpose of this study was to determine whether air pollution effects on asthmatic hospital admissions are different by three age groups (years): children (less than 15), adults (15–64; reference group), and the elderly (over 65). Daily time-series data from seven metropolitan cities in South Korea were analyzed in two stages. In the first stage, relative asthma morbidity rates associated with air pollution were estimated for each city and age group, using semi-parametric log-linear regression. In the second stage, estimates from all seven cities were combined by age group using Bayesian hierarchical modeling. The effects of exposure to particulate matter <10 micrometers in aerodynamic diameter (PM10), carbon monoxide (CO) and nitrogen dioxide (NO2) varied significantly by age groups. Using adults as the referent, the relative rate (RR) of asthma admissions with 10μg/m3 increase of PM10 is 1.5% (95%CI: 0.1–2.8%) lower for children, and 1.3% (95% CI: 0.7–1.9%) higher for the elderly; RR with 1ppm increase of CO is 1.9% (95% CI: 0.3–3.8%) lower for children; RR with 1ppb increase of NO2(1ppb) is 0.5% (95% CI: 0.3–0.7%) higher for the elderly. No significant age group difference in relative rate was found for ozone or sulfur dioxide.
PMCID: PMC3821782  PMID: 24223075
23.  Biomechanical Analysis of Fusion Segment Rigidity Upon Stress at Both the Fusion and Adjacent Segments: A Comparison between Unilateral and Bilateral Pedicle Screw Fixation 
Yonsei Medical Journal  2014;55(5):1386-1394.
The purpose of this study was to investigate the effects of unilateral pedicle screw fixation on the fusion segment and the superior adjacent segment after one segment lumbar fusion using validated finite element models.
Materials and Methods
Four L3-4 fusion models were simulated according to the extent of decompression and the method of pedicle screws fixation in L3-4 lumbar fusion. These models included hemi-laminectomy with bilateral pedicle screw fixation in the L3-4 segment (BF-HL model), total laminectomy with bilateral pedicle screw fixation (BF-TL model), hemi-laminectomy with unilateral pedicle screw fixation (UF-HL model), and total laminectomy with unilateral pedicle screw fixation (UF-TL model). In each scenario, intradiscal pressures, annulus stress, and range of motion at the L2-3 and L3-4 segments were analyzed under flexion, extension, lateral bending, and torsional moments.
Under four pure moments, the unilateral fixation leads to a reduction in increment of range of motion at the adjacent segment, but larger motions were noted at the fusion segment (L3-4) in the unilateral fixation (UF-HL and UF-TL) models when compared to bilateral fixation. The maximal von Mises stress showed similar patterns to range of motion at both superior adjacent L2-3 segments and fusion segment.
The current study suggests that unilateral pedicle screw fixation seems to be unable to afford sufficient biomechanical stability in case of bilateral total laminectomy. Conversely, in the case of hemi-laminectomy, unilateral fixation could be an alternative option, which also has potential benefit to reduce the stress of the adjacent segment.
PMCID: PMC4108828  PMID: 25048501
Unilateral pedicle screw fixation; lumbar fusion surgery; adjacent segment degeneration; finite element model
24.  Risk Factors for Death during Pulmonary Tuberculosis Treatment in Korea: A Multicenter Retrospective Cohort Study 
Journal of Korean Medical Science  2014;29(9):1226-1231.
The data regarding risk factors for death during tuberculosis (TB) treatment are inconsistent, and few studies examined this issue in Korea. The purpose of this study was to evaluate baseline prognostic factors for death during treatment of adult patients with pulmonary TB in Korea. A multicenter retrospective cohort study of 2,481 patients who received TB treatment at eight hospitals from January 2009 to December 2010 was performed. Successful treatment included cure (1,129, 45.5%) and treatment completion (1,204, 48.5%) in 2,333 patients (94.0%). Unsuccessful treatment included death (85, 3.4%) and treatment failure (63, 2.5%) occurred in 148 patients (6.0%). In multivariate analysis, male sex, anemia, dyspnea, chronic heart disease, malignancy, and intensive care unit (ICU) admission were significant risk factors for death during TB treatment. Therefore, male sex, anemia, dyspnea, chronic heart disease, malignancy, and ICU admission could be baseline prognostic factors for death during treatment of adult patients with pulmonary TB in Korea.
Graphical Abstract
PMCID: PMC4168175  PMID: 25246740
Tuberculosis, Pulmonary; Therapeutics; Mortality, Korea
25.  A case of thyrotoxic periodic paralysis as initial manifestation of Graves' disease in a 16-year-old Korean adolescent 
Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism, with recurrent muscle paralysis and hypokalemia that are caused by an intracellular shift of potassium. TPP is relatively common in Asian males, but is extremely rare in children and adolescents, even for those of Asian descent. We describe a 16-year-old Korean adolescent presenting with a two-week history of episodic leg weakness in the morning. He showed sinus tachycardia, lower leg weakness, and hypokalemia. Thyroid function test showed hyperthyroidism, and thyroid ultrasonography revealed a diffuse enlarged thyroid with increased vascularity, consistent with Graves' disease. He was treated with β-adrenergic blocker and antithyroid drugs. He has been symptom free for one year, as his hyperthyroidism has been controlled well with antithyroid drugs. TPP should be considered in children and adolescents with acute paralysis of the lower extremities and hypokalemia.
PMCID: PMC4208265  PMID: 25346923
Thyrotoxic periodic paralysis; Graves' disease; Adolescent; Korean

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