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1.  The First Fellow of American College of Surgeons to Come to Korea: Dr. Alfred Irving Ludlow 
Yonsei Medical Journal  2015;56(5):1171-1173.
PMCID: PMC4541643  PMID: 26256956
2.  An Outbreak of Middle East Respiratory Syndrome Coronavirus Infection in South Korea, 2015 
Yonsei Medical Journal  2015;56(5):1174-1176.
PMCID: PMC4541644  PMID: 26256957
3.  Cancer Cell Line Panels Empower Genomics-Based Discovery of Precision Cancer Medicine 
Yonsei Medical Journal  2015;56(5):1186-1198.
Since the first human cancer cell line, HeLa, was established in the early 1950s, there has been a steady increase in the number and tumor type of available cancer cell line models. Cancer cell lines have made significant contributions to the development of various chemotherapeutic agents. Recent advances in multi-omics technologies have facilitated detailed characterizations of the genomic, transcriptomic, proteomic, and epigenomic profiles of these cancer cell lines. An increasing number of studies employ the power of a cancer cell line panel to provide predictive biomarkers for targeted and cytotoxic agents, including those that are already used in clinical practice. Different types of statistical and machine learning algorithms have been developed to analyze the large-scale data sets that have been produced. However, much work remains to address the discrepancies in drug assay results from different platforms and the frequent failures to translate discoveries from cell line models to the clinic. Nevertheless, continuous expansion of cancer cell line panels should provide unprecedented opportunities to identify new candidate targeted therapies, particularly for the so-called "dark matter" group of cancers, for which pharmacologically tractable driver mutations have not been identified.
PMCID: PMC4541646  PMID: 26256959
Targeted therapy; cancer genomics; biomarker; personalized medicine
4.  Outcome and Complications in Surgical Treatment of Lumbar Stenosis or Spondylolisthesis in Geriatric Patients 
Yonsei Medical Journal  2015;56(5):1199-1205.
Development of anesthesiology and improvement of surgical instruments enabled aggressive surgical treatment even in elderly patients, who require more active physical activities than they were in the past. However, there are controversies about the clinical outcome of spinal surgery in elderly patients with spinal stenosis or spondylolisthesis. The purpose of this study is to review the clinical outcome of spinal surgery in elderly patients with spinal stenosis or spondylolisthesis. MEDLINE search on English-language articles was performed. There were 39685 articles from 1967 to 2013 regarding spinal disease, among which 70 dealt with geriatric lumbar surgery. Eighteen out of 70 articles dealt with geriatric lumbar surgery under the diagnosis of spinal stenosis or spondylolisthesis. One was non-randomized prospective, and other seventeen reports were retrospective. One non-randomized prospective and twelve out of seventeen retrospective studies showed that old ages did not affect the clinical outcomes. One non-randomized prospective and ten of seventeen retrospective studies elucidated postoperative complications: some reports showed that postoperative complications increased in elderly patients, whereas the other reports showed that they did not increase. Nevertheless, most complications were minor. There were two retrospective studies regarding the mortality. Mortality which was unrelated to surgical procedure increased, but surgical procedure-related mortality did not increase. Surgery as a treatment option in the elderly patients with the spinal stenosis or spondylolisthesis may be reasonable. However, there is insufficient evidence to make strong recommendations regarding spinal surgery for geriatric patients with spinal stenosis and spondylolisthesis.
PMCID: PMC4541647  PMID: 26256960
Spinal surgery; geriatric patient; spinal stenosis; spondylolisthesis
5.  Prognostic Impacts of Metastatic Site and Pain on Progression to Castrate Resistance and Mortality in Patients with Metastatic Prostate Cancer 
Yonsei Medical Journal  2015;56(5):1206-1212.
To investigate predictors of progression to castration-resistant prostate cancer (CRPC) and cancer-specific mortality (CSM) in patients with metastatic prostate cancer (mPCa).
Materials and Methods
A retrospective analysis was performed on 440 consecutive treatment-naïve patients initially diagnosed with mPCa between August 2000 and June 2012. Patient age, body mass index (BMI), Gleason score, prostate-specific antigen (PSA), PSA nadir, American Joint Committee on Cancer stage, Visual Analogue Scale pain score, Eastern Cooperative Oncology Group performance score (ECOG PS), PSA response to hormone therapy, and metastatic sites were assessed. Cox-proportional hazards regression analyses were used to evaluate survivals and predictive variables of men with bone metastasis stratified according to the presence of pain, compared to men with visceral metastasis.
Metastases were most often found in bone (75.4%), followed by lung (16.3%) and liver (8.3%) tissues. Bone metastasis, pain, and high BMI were associated with increased risks of progression to CRPC, and bone metastasis, pain, PSA nadir, and ECOG PS≥1 were significant predictors of CSM. During the median follow-up of 32.0 (interquartile range 14.7-55.9) months, patients with bone metastasis with pain and patients with both bone and visceral metastases showed the worst median progression to CRPC-free and cancer-specific survivals, followed by men with bone metastasis without pain. Patients with visceral metastasis had the best median survivals.
Metastatic spread and pain patterns confer different prognosis in patients with mPCa. Bone may serve as a crucial microenvironment in the development of CRPC and disease progression.
PMCID: PMC4541648  PMID: 26256961
Bone; metastasis; pain; prostate cancer; viscera
6.  Characteristics and Survival of Breast Cancer Patients with Multiple Synchronous or Metachronous Primary Cancers 
Yonsei Medical Journal  2015;56(5):1213-1220.
Newly developed extra-mammary multiple primary cancers (MPCs) are an issue of concern when considering the management of breast cancer survivors. This study aimed to investigate the prevalence of MPCs and to evaluate the implications of MPCs on the survival of breast cancer patients.
Materials and Methods
A total of 8204 patients who underwent surgery at Severance Hospital between 1990 and 2012 were retrospectively selected. Clinicopathologic features and survival over follow-up periods of ≤5 and >5 years were investigated using univariate and multivariate analyses.
During a mean follow-up of 67.3 months, 962 MPCs in 858 patients (10.5%) were detected. Synchronous and metachronous MPCs were identified in 23.8% and 79.0% of patients, respectively. Thyroid cancer was the most prevalent, and the second most common was gynecologic cancer. At ≤5 years, patients with MPCs were older and demonstrated significantly worse survival despite a higher proportion of patients with lower-stage MPCs. Nevertheless, an increased risk of death in patients with MPCs did not reach statistical significance at >5 years. The causes of death in many of the patients with MPCs were not related to breast cancer. Stage-matched analysis revealed that the implications of MPCs on survival were more evident in the early stages of breast disease.
Breast cancer patients with MPCs showed worse survival, especially when early-stage disease was identified. Therefore, it is necessary to follow screening programs in breast cancer survivors and to establish guidelines for improving prognosis and quality of life.
PMCID: PMC4541649  PMID: 26256962
Breast cancer; metachronous; multiple primary neoplasms; survival; synchronous
7.  Analysis of Dysphagia Patterns Using a Modified Barium Swallowing Test Following Treatment of Head and Neck Cancer 
Yonsei Medical Journal  2015;56(5):1221-1226.
The purposes of this study were to evaluate specific dysphagia patterns and to identify the factors affecting dysphagia, especially aspiration, following treatment of head and neck cancer.
Materials and Methods
A retrospective analysis of 57 patients was performed. Dysphagia was evaluated using a modified barium swallow (MBS) test. The MBS results were rated on the 8-point penetration-aspiration scale (PAS) and swallowing performance status (SPS) score.
Reduced base of the tongue (BOT) retraction (64.9%), reduced laryngeal elevation (57.9%), and cricopharyngeus (CP) dysfunction (47.4%) were found. Reduced BOT retraction was correlated with clinical stage (p=0.011) and treatment modality (p=0.001). Aspiration in 42.1% and penetration in 33.3% of patients were observed. Twenty-four patients had PAS values over 6, implying aspiration. Forty-one patients had a SPS score of more than 3, 25 patients had a score greater than 5, and 13 patients had a SPS score of more than 7. Aspiration was found more often in patients with penetration (p=0.002) and in older patients (p=0.026). In older patients, abnormal swallowing caused aspiration even in those with a SPS score of more than 3, irrespective of stage or treatment, contrary to younger patients. Tube feeders (n=20) exhibited older age (65.0%), dysphagia/aspiration related structures (DARS) primaries (75.0%), higher stage disease (66.7%), and a history of radiotherapy (68.8%).
Reduced BOT retraction was the most common dysphagia pattern and was correlated with clinical stage and treatment regimens including radiotherapy. Aspiration was more frequent in patients who had penetration and in older patients. In contrast to younger patients, older patients showed greater risk of aspiration even with a single abnormal swallowing irrespective of stage or treatment.
PMCID: PMC4541650  PMID: 26256963
Head and neck cancer; dysphagia; modified barium swallow; radiotherapy; aspiration
8.  Effect of Triflusal on Primary Vascular Dysregulation Compared with Aspirin: A Double-Blind, Randomized, Crossover Trial 
Yonsei Medical Journal  2015;56(5):1227-1234.
Primary vascular dysregulation (PVD) is a condition in which the response to cold temperature or external stimuli is abnormal. We investigated whether triflusal use results in amelioration of PVD symptoms and improvement of several related parameters compared with aspirin.
Materials and Methods
Eighty-eight PVD patients (54% female, 56±8 years) were randomly selected to receive either triflusal (300 mg, b.i.d.) or aspirin (150 mg, b.i.d.) for a period of 6 weeks followed by crossover. PVD was defined as both red-blood-cell standstill in video-assisted microscopic capillaroscopy during cold stimulation using carbon dioxide gas and a score of more than 7 points in a validated questionnaire. Efficacy of treatment was assessed by 1) cold intolerance symptom severity (CISS) score, 2) finger Doppler indices, and 3) indocyanine green perfusion imaging.
The use of triflusal resulted in a greater improvement in CISS score (44.5±18.4 vs. 51.9±16.2; p<0.001) and in mean radial peak systolic velocity (69.8±17.2 vs. 66.1±16.4; p=0.011) compared to aspirin. Furthermore, significant differences were also observed in perfusion rates on indocyanine green perfusion imaging between triflusal and aspirin (45.6±25.8 vs. 51.6±26.9; p=0.020).
Triflusal was more effective and demonstrated a more consistent impact on the improvement of symptoms and blood flow in patients with PVD than aspirin.
PMCID: PMC4541651  PMID: 26256964
Primary vascular dysregulation; triflusal; finger Doppler; endothelin-1; microvascular circulation
9.  Clinical and Angiographic Predictors of Microvascular Dysfunction in ST-Segment Elevation Myocardial Infarction 
Yonsei Medical Journal  2015;56(5):1235-1243.
We aimed to discover clinical and angiographic predictors of microvascular dysfunction using the index of microcirculatory resistance (IMR) in patients with ST-segment elevation myocardial infarction (STEMI).
Materials and Methods
We enrolled 113 patients with STEMI (age, 56±11 years; 95 men) who underwent primary percutaneous coronary intervention (PCI). The IMR was measured with a pressure sensor/thermistor-tipped guidewire after primary PCI. The patients were divided into three groups based on IMR values: Low IMR [<18 U (12.9±2.6 U), n=38], Mid IMR [18-31 U (23.9±4.0 U), n=38], and High IMR [>31 U (48.1±17.1 U), n=37].
The age of the Low IMR group was significantly lower than that of the Mid and High IMR groups. The door-to-balloon time was <90 minutes in all patients, and it was not significantly different between groups. Meanwhile, the symptom-onset-to-balloon time was significantly longer in the High IMR group, compared to the Mid and Low IMR groups (p<0.001). In the high IMR group, the culprit lesion was found in a proximal location significantly more often than in a non-proximal location (p=0.008). In multivariate regression analysis, age and symptom-onset-to-balloon time were independent determinants of a high IMR (p=0.013 and p=0.003, respectively).
Our data suggest that age and symptom-onset-to-balloon time might be the major predictors of microvascular dysfunction in STEMI patients with a door-to-balloon time of <90 minutes.
PMCID: PMC4541652  PMID: 26256965
Microvascular dysfunction; ST-segment elevation myocardial infarction; index of microcirculatory resistance; doorto-balloon time; symptom-onset-to-balloon time
10.  eNOS3 Genetic Polymorphism Is Related to Post-Ablation Early Recurrence of Atrial Fibrillation 
Yonsei Medical Journal  2015;56(5):1244-1250.
Previous studies have demonstrated an association between eNOS polymorphisms and atrial fibrillation (AF). We sought to determine whether eNOS polymorphisms are associated with AF recurrence after a radiofrequency catheter ablation (RFCA).
Materials and Methods
A total of 500 consecutive patients (56±11 years, 77% male) with paroxysmal (68%) or persistent (32%) AF who underwent RFCA and 500 age, gender-matched controls were genotyped for the eNOS3 single nucleotide polymorphism (rs1799983). AF recurrence was monitored according to 2012 ACC/AHA/ESC guidelines.
The frequencies of the rs1799983 variant alleles (T) in the case and control group were not significantly different (OR 1.05, 95% CI 0.75-1.46, p=0.798). AF patients with rs1799983 variants were more likely to have coronary artery disease or stroke than those without genetic variant at this gene (31.0% vs. 17.3%, p=0.004). During mean 17 months follow-up, early recurrence of AF (ERAF; within 3 months) and clinical recurrence (CR) of AF were 31.8% and 24.8%, respectively. The rs1799983 variant was associated with higher risk of ERAF (OR 1.71, 95% CI 1.06-2.79, p=0.028), but not with CR. ERAF occurred earlier (11±16 days) in variant group than those without variant allele (20±25 days, p=0.016). A multiple logistic regression analysis showed that presence of the rs1799983 variant (OR 1.75, 95% CI 1.07-2.86, p=0.026) and persistent AF were independent predictors for ERAF after AF ablation.
The rs1799983 variant of the eNOS3 gene was associated with ERAF, but not with CR, after RFCA. eNOS3 gene variants may have a potential role for stratification of post-ablation management.
PMCID: PMC4541653  PMID: 26256966
Atrial fibrillation; eNOS gene; catheter ablation; recurrence
11.  In silico Screening of Chemical Libraries to Develop Inhibitors That Hamper the Interaction of PCSK9 with the LDL Receptor 
Yonsei Medical Journal  2015;56(5):1251-1257.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) and promotes degradation of the LDLR. Inhibition of PCSK9 either by reducing its expression or by blocking its activity results in the upregulation of the LDLR and subsequently lowers the plasma concentration of LDL-cholesterol. As a modality to inhibit PCSK9 action, we searched the chemical library for small molecules that block the binding of PCSK9 to the LDLR.
Materials and Methods
We selected 100 chemicals that bind to PCSK9 where the EGF-AB fragment of the LDLR binds via in silico screening of the ChemBridge chemical library, using the computational GOLD algorithm analysis. Effects of chemicals were evaluated using the PCSK9-LDLR binding assay, immunoblot analysis, and the LDL-cholesterol uptake assay in vitro, as well as the fast performance liquid chromatography assay for plasma lipoproteins in vivo.
A set of chemicals were found that decreased the binding of PCSK9 to the EGF-AB fragment of the LDLR in a dose-dependent manner. They also increased the amount of the LDLR significantly and subsequently increased the uptake of fluorescence-labeled LDL in HepG2 cells. Additionally, one particular molecule lowered the plasma concentration of total cholesterol and LDL-cholesterol significantly in wild-type mice, while such an effect was not observed in Pcsk9 knockout mice.
Our findings strongly suggest that in silico screening of small molecules that inhibit the protein-protein interaction between PCSK9 and the LDLR is a potential modality for developing hypercholesterolemia therapeutics.
PMCID: PMC4541654  PMID: 26256967
PCSK9; in silico; protein-protein interaction; LDL receptor; hypercholesterolemia; inhibitor
12.  Clinical Features of Obstructive Sleep Apnea That Determine Its High Prevalence in Resistant Hypertension 
Yonsei Medical Journal  2015;56(5):1258-1265.
Resistant hypertension (HTN) occurs in 15-20% of treated hypertensive patients, and 70-80% of resistant hypertensive patients have obstructive sleep apnea (OSA). The characteristics of resistant HTN that predispose patients to OSA have not been reported. Therefore, we aimed to determine the clinical, laboratory, and polysomnographic features of resistant HTN that are significantly associated with OSA.
Materials and Methods
Hypertensive patients (n=475) who underwent portable polysomnography were enrolled. The patients were categorized into controlled (n=410) and resistant HTN (n=65) groups. The risk factors for the occurrence of OSA in controlled and resistant hypertensive patients were compared, and independent risk factors that are associated with OSA were analyzed.
Out of 475 patients, 359 (75.6%) were diagnosed with OSA. The prevalence of OSA in resistant HTN was 87.7%, which was significantly higher than that in controlled HTN (73.7%). Age, body mass index, neck circumference, waist circumference, and hip circumference were significantly higher in OSA. However, stepwise multivariate analyses revealed that resistant HTN was not an independent risk factor of OSA.
The higher prevalence and severity of OSA in resistant HTN may be due to the association of risk factors that are common to both conditions.
PMCID: PMC4541655  PMID: 26256968
Resistant hypertension; sleep apnea; polysomnography; obesity; body mass index
13.  Comparison of Second- and Third-Generation Cephalosporin as Initial Therapy for Women with Community-Onset Uncomplicated Acute Pyelonephritis 
Yonsei Medical Journal  2015;56(5):1266-1273.
This study examined the clinical effectiveness of parenteral cefuroxime and cefotaxime as empirical antibiotics for treating hospitalized women with uncomplicated acute pyelonephritis (APN).
Materials and Methods
This study was based on the clinical and microbiologic data of 255 hospitalized women with APN. Of these 255 women, 144 patients received cefuroxime and 111 received cefotaxime.
There were no marked differences in the demographic features, clinical characteristics, and treatment duration between the populations of the cefuroxime and cefotaxime groups. The rates of defervescence showed no significant differences in the two groups at 48, 72, 96, and 120 hours. The clinical cure rates observed at the follow-up visit 4 to 14 days after the completion of antimicrobial therapy were not statistically different between the cefuroxime and cefotaxime groups [94.9% (129 of 136) versus 98.0% (100 of 102), respectively; p=0.307], and the microbiological cure rates were also not significantly different [88.3% (91 of 103) versus 95.0% (76 of 80), respectively; p=0.186]. The median hospitalization periods in the cefuroxime and cefotaxime groups were 7 (6-8) and 7 (6-8) days (p=0.157), respectively. Microbiological success rates after 72-96 hours of initial antimicrobial therapy were also not statistically different in the cefuroxime and cefotaxime groups, 89.4% (110 of 123) versus 94.9% (93 of 98; p=0.140).
Cefuroxime, a second-generation cephalosporin, is an appropriate antibiotic option for the initial treatment of uncomplicated APN and its efficacy does not differ from cefotaxime, a third-generation cephalosporin, in the initial parenteral therapy for community-onset APN.
PMCID: PMC4541656  PMID: 26256969
Pyelonephritis; E. coli; cefotaxime; cefuroxime
14.  IL-10 Polymorphisms and Tuberculosis Susceptibility: An Updated Meta-Analysis 
Yonsei Medical Journal  2015;56(5):1274-1287.
The association of interleukin-10 (IL-10) polymorphisms (-1082G/A, -819C/T, -592A/C) and interleukin-6 (IL-6) poly-morphisms (-174G/C) with tuberculosis (TB) risk has been widely reported. However, the results are controversial. To clarify the role of these polymorphisms in TB, we performed a meta-analysis of all available and relevant published studies.
Materials and Methods
Based on comprehensive searches of the PubMed, Medline, Embase, Web of Science, Elsevier Science Direct and Cochrane Library database, we identified outcome data from all articles estimating the association between IL-10 and IL-6 polymorphisms and TB risk.
The results indicated significant association of the allele model, heterozygous model and dominant model of IL-6 -174G/C polymorphism with decreased risk of TB. In the stratified analysis by ethnicity, significantly increased risk was observed for IL-10 -1082G/A polymorphism in Europeans under recessive model, for IL-10 -819C/T polymorphism in Asians under heterozygous model and dominant model and IL-10 -592A/C polymorphism in Asians under Allele model, homozygous model and recessive model. Moreover, significantly decreased risk of TB was associated with Asians for IL-6 -174C/G polymorphism in allele model, heterozygous model and dominant model. We also performed the analyses by sample types in IL-10 -1082G/A polymorphism, and observed significantly increased TB risk in mixed group under homozygous model.
The results suggested that the IL-10 -1082G/A polymorphism is associated with increased TB risk in Europeans, while IL-10 -819C/T and IL-10 -592A/C polymorphisms in Asians. However, IL-6 -174G/C polymorphism might be a genetic risk factor that decreases TB susceptibility in Asians.
PMCID: PMC4541657  PMID: 26256970
IL-10; IL-6; polymorphism; tuberculosis; susceptibility; meta-analysis
15.  Nonalcoholic Fatty Liver Disease Is Associated with the Presence and Morphology of Subclinical Coronary Atherosclerosis 
Yonsei Medical Journal  2015;56(5):1288-1295.
In this study, we aimed to evaluate whether nonalcoholic fatty liver disease (NAFLD) was associated with the presence and morphology of coronary atherosclerotic plaques shown by multidetector computed tomography (MDCT) in asymptomatic subjects without a history of cardiovascular disease.
Materials and Methods
We retrospectively enrolled 772 consecutive South Korean individuals who had undergone both dualsource 64-slice MDCT coronary angiography and hepatic ultrasonography during general routine health evaluations. The MDCT studies were assessed for the presence, morphology (calcified, mixed, and non-calcified), and severity of coronary plaques.
Coronary atherosclerotic plaques were detected in 316 subjects (40.9%) by MDCT, and NAFLD was found in 346 subjects (44.8%) by hepatic ultrasonography. Subjects with NAFLD had higher prevalences of all types of atherosclerotic plaque and non-calcified, mixed, and calcified plaques than the subjects without NAFLD. However, the prevalence of significant stenosis did not differ between groups. After adjusting for age, smoking status, diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, NAFLD remained a significant predictor for all types of coronary atherosclerotic plaque [odds ratio (OR): 1.48; 95% confidence interval (CI): 1.05-2.08; p=0.025] in binary logistic analysis, as well as for calcified plaques (OR: 1.70; 95% CI: 1.07-2.70; p=0.025) in multinomial regression analysis.
Our study demonstrated that NAFLD was significantly associated with the presence and the calcified morphology of coronary atherosclerotic plaques detected by MDCT. Further prospective clinical studies are needed to clarify the exact physiopathologic role of NAFLD in coronary atherosclerosis.
PMCID: PMC4541658  PMID: 26256971
Nonalcoholic fatty liver disease; subclinical coronary atherosclerosis; metabolic syndrome; multidetector computed tomography
16.  Serum Dickkopf-1 as a Biomarker for the Diagnosis of Hepatocellular Carcinoma 
Yonsei Medical Journal  2015;56(5):1296-1306.
Dickkopf-1 (DKK-1) is a Wnt/β-catenin signaling pathway inhibitor. We investigated whether DKK-1 is related to progression in hepatocellular carcinoma (HCC) cells and HCC patients.
Materials and Methods
In vitro reverse-transcription polymerase chain reaction (RT-PCR), wound healing assays, invasion assays, and ELISAs of patient serum samples were employed. The diagnostic accuracy of the serum DKK-1 ELISA was assessed using receiver operating characteristic (ROC) curves and area under ROC (AUC) analyses.
RT-PCR showed high DKK-1 expression in Hep3B and low in 293 cells. Similarly, the secreted DKK-1 concentration in the culture media was high in Hep3B and low in 293 cells. Wound healing and invasion assays using 293, Huh7, and Hep3B cells showed that DKK-1 overexpression promoted cell migration and invasion, whereas DKK-1 knock-down inhibited them. When serum DKK-1 levels were assessed in 370 participants (217 with HCC and 153 without), it was significantly higher in HCC patients than in control groups (median 1.48 ng/mL vs. 0.90 ng/mL, p<0.001). The optimum DKK-1 cutoff level was 1.01 ng/mL (AUC=0.829; sensitivity 90.7%; specificity 62.0%). Although DKK-1 had a higher AUC than alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) (AUC=0.829 vs. 0.794 and 0.815, respectively), they were statistically similar (all p>0.05). When three biomarkers were combined (DKK-1 plus AFP plus DCP), they showed significantly higher AUC (AUC=0.952) than single marker, DKK-1 plus AFP, or DKK-1 plus DCP (all p<0.001).
DKK-1 might be a key regulator in HCC progression and a potential therapeutic target in HCC. Serum DKK-1 could complement the diagnostic accuracy of AFP and DCP.
PMCID: PMC4541659  PMID: 26256972
Dickkopf-1; hepatocellular carcinoma; biomarker
17.  TWIK-Related Spinal Cord K+ Channel Expression Is Increased in the Spinal Dorsal Horn after Spinal Nerve Ligation 
Yonsei Medical Journal  2015;56(5):1307-1315.
The TWIK-related spinal cord K+ channel (TRESK) has recently been discovered and plays an important role in nociceptor excitability in the pain pathway. Because there have been no reports on the TRESK expression or its function in the dorsal horn of the spinal cord in neuropathic pain, we analyzed TRESK expression in the spinal dorsal horn in a spinal nerve ligation (SNL) model.
Materials and Methods
We established a SNL mouse model by using the L5-6 spinal nerves ligation. We used real-time polymerase chain reaction and immunohistochemistry to investigate TRESK expression in the dorsal horn and L5 dorsal rot ganglion (DRG).
The SNL group showed significantly higher expression of TRESK in the ipsilateral dorsal horn under pain, but low expression in L5 DRG. Double immunofluorescence staining revealed that immunoreactivity of TRESK was mostly restricted in neuronal cells, and that synapse markers GAD67 and VGlut2 appeared to be associated with TRESK expression. We were unable to find a significant association between TRESK and calcineurin by double immunofluorescence.
TRESK in spinal cord neurons may contribute to the development of neuropathic pain following injury.
PMCID: PMC4541660  PMID: 26256973
TRESK protein; rat; neuralgia; pain
18.  Effect of Subthalamic Deep Brain Stimulation on Levodopa-Induced Dyskinesia in Parkinson's Disease 
Yonsei Medical Journal  2015;56(5):1316-1321.
To evaluate the effect of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on levodopa-induced peak-dose dyskinesia in patients with Parkinson's disease (PD).
Materials and Methods
A retrospective review was conducted on patients who underwent STN DBS for PD from May 2000 to July 2012. Only patients with levodopa-induced dyskinesia prior to surgery and more than 1 year of available follow-up data after DBS were included. The outcome measures included the dyskinesia subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) part IV (items 32 to 34 of UPDRS part IV) and the levodopa equivalent daily dose (LEDD). The patients were divided into two groups based on preoperative to postoperative LEDD change at 12 months after the surgery: Group 1, LEDD decrease >15%; Group 2, all other patients. Group 2 was further divided by the location of DBS leads.
Of the 100 patients enrolled, 67 were in Group 1, while those remaining were in Group 2. Twelve months after STN DBS, Groups 1 and 2 showed improvements of 61.90% and 57.14%, respectively, in the dyskinesia subscore. Group 1 was more likely to experience dyskinesia suppression; however, the association between the groups and dyskinesia suppression was not statistically significant (p=0.619). In Group 2, dyskinesia was significantly decreased by stimulation of the area above the STN in 18 patients compared to stimulation of the STN in 15 patients (p=0.048).
Levodopa-induced dyskinesia is attenuated by STN DBS without reducing the levodopa dosage.
PMCID: PMC4541661  PMID: 26256974
Deep brain stimulation; dyskinesias; Parkinson disease; subthalamic nucleus
19.  Ivy Sign on Fluid-Attenuated Inversion Recovery Images in Moyamoya Disease: Correlation with Clinical Severity and Old Brain Lesions 
Yonsei Medical Journal  2015;56(5):1322-1327.
Leptomeningeal collateral, in moyamoya disease (MMD), appears as an ivy sign on fluid-attenuated inversion-recovery (FLAIR) images. There has been little investigation into the relationship between presentation of ivy signs and old brain lesions. We aimed to evaluate clinical significance of ivy signs and whether they correlate with old brain lesions and the severity of clinical symptoms in patients with MMD.
Materials and Methods
FLAIR images of 83 patients were reviewed. Each cerebral hemisphere was divided into 4 regions and each region was scored based on the prominence of the ivy sign. Total ivy score (TIS) was defined as the sum of the scores from the eight regions and dominant hemispheric ivy sign (DHI) was determined by comparing the ivy scores from each hemisphere. According to the degree of ischemic symptoms, patients were classified into four subgroups: 1) nonspecific symptoms without motor weakness, 2) single transient ischemic attack (TIA), 3) recurrent TIA, or 4) complete stroke.
TIS was significantly different as follows: 4.86±2.55 in patients with nonspecific symptoms, 5.89±3.10 in patients with single TIA, 9.60±3.98 in patients with recurrent TIA and 8.37±3.39 in patients with complete stroke (p=0.003). TIS associated with old lesions was significantly higher than those not associated with old lesions (9.35±4.22 vs. 7.49±3.37, p=0.032). We found a significant correlation between DHI and motor symptoms (p=0.001).
Because TIS has a strong tendency with severity of ischemic motor symptom and the presence of old lesions, the ivy sign may be useful in predicting severity of disease progression.
PMCID: PMC4541662  PMID: 26256975
Moyamoya disease; FLAIR; MRI; ivy sign; old lesion; supraclinoid carotid stenosis
20.  Influence of Parent Artery Segmentation and Boundary Conditions on Hemodynamic Characteristics of Intracranial Aneurysms 
Yonsei Medical Journal  2015;56(5):1328-1337.
The purpose of this study is to explore the influence of segmentation of the upstream and downstream parent artery and hemodynamic boundary conditions (BCs) on the evaluated hemodynamic factors for the computational fluid dynamics (CFD) analysis of intracranial aneurysms.
Materials and Methods
Three dimensional patient-specific aneurysm models were analyzed by applying various combinations of inlet and outlet BCs. Hemodynamic factors such as velocity pattern, streamline, wall shear stress, and oscillatory shear index at the systolic time were visualized and compared among the different cases.
Hemodynamic factors were significantly affected by the inlet BCs while there was little influence of the outlet BCs. When the inlet length was relatively short, different inlet BCs showed different hemodynamic factors and the calculated hemodynamic factors were also dependent on the inlet length. However, when the inlet length (L) was long enough (L>20D, where D is the diameter of inlet section), the hemodynamic factors became similar regardless of the inlet BCs and lengths. The error due to different inlet BCs was negligible. The effect of the outlet length on the hemodynamic factors was similar to that of the inlet length.
Simulated hemodynamic factors are highly sensitive to inlet BCs and upstream parent artery segmentation. The results of this work can provide an insight into how to build models and to apply BCs for more accurate estimation of hemodynamic factors from CFD simulations of intracranial aneurysms.
PMCID: PMC4541663  PMID: 26256976
Intracranial aneurysms; hemodynamic factors; parent artery segmentation; boundary conditions; computational fluid dynamics
21.  Focal Lymphocytic Thyroiditis Nodules Share the Features of Papillary Thyroid Cancer on Ultrasound 
Yonsei Medical Journal  2015;56(5):1338-1344.
It is often difficult to discriminate focal lymphocytic thyroiditis (FLT) or adenomatous hyperplasia (AH) from thyroid cancer if they both have suspicious ultrasound (US) findings. We aimed to make a predictive model of FLT from papillary thyroid cancer (PTC) in suspicious nodules with benign cytologic results.
Materials and Methods
We evaluated 214 patients who had undergone fine-needle aspiration biopsy (FNAB) and had shown thyroid nodules with suspicious US features. PTC was confirmed by surgical pathology. FLT and AH were confirmed through more than two separate FNABs. Clinical and biochemical findings, as well as US features, were evaluated.
Of 214 patients, 100 patients were diagnosed with PTC, 55 patients with FLT, and 59 patients with AH. The proportion of elevated thyrotropin (TSH) levels (p=0.014) and thyroglobulin antibody (Tg-Ab) or thyroid peroxidase antibody (TPO-Ab) positivity (p<0.001) in the FLT group was significantly higher than that in the PTC group. Regarding US features, absence of calcification (p=0.006) and "diffuse thyroid disease" (DTD) pattern on US (p<0.001) were frequently seen in the FLT group. On multivariate analysis, Tg-Ab positivity, presence of a DTD pattern on US, and absence of calcification in nodules were associated with FLT with the best specificity of 99% and positive predictive value of 96%. In contrast, a taller than wide shape of nodules was the only variable significant for differentiating AH from PTC.
Suspicious thyroid nodules with cytologic benign results could be followed up with US rather than repeat FNAB, if patients exhibit Tg-Ab positivity, no calcifications in nodules, and a DTD pattern on US.
PMCID: PMC4541664  PMID: 26256977
Differential diagnosis; focal lymphocytic thyroiditis; papillary thyroid cancer
22.  Image Settings Affecting Nuchal Translucency Measurement Using Volume NT™ Software 
Yonsei Medical Journal  2015;56(5):1345-1351.
To evaluate the effects of the deviation from the mid-sagittal plane, fetal image size, tissue harmonic imaging (THI), and speckle reduction filter (SRF) on the measurement of the nuchal translucency (NT) thickness using Volume NT™ software.
Materials and Methods
In 79 pregnant women, NT was measured using Volume NT™. Firstly, the three-dimensional volumes were categorized based on the angle of deviation in 10° intervals from the mid-sagittal plane. Secondly, the operator downsized the fetal image to less than 50% of the screen (Method A) and by magnifying the image (Method B). Next, the image was magnified until the fetal head and thorax occupied 75% of the screen, and the NT was measured (Method C). Lastly, NT values were acquired with THI and SRF functions on, with each function alternately on, and with both functions off.
The mean differences in NT measurements were -0.09 mm (p<0.01) between two-dimensional (2D) and a deviation of 31-40° and -0.10 mm (p<0.01) between 2D and 41-50°. The intraclass correlation coefficients (ICC) for 2D-NT and NT according to image size were 0.858, 0.923, and 0.928 for methods A, B, and C, respectively. The ICC for 2D-NT and NT with respect to the THI and SRF were 0.786, 0.761, 0.740, and 0.731 with both functions on, THI only, SRF only, and with both functions off, respectively.
NT measurements made using Volume NT™ are affected by angle deviation from the mid-sagittal plane and fetal image size. Additionally, the highest correlation with 2D-NT was achieved when THI and SRF functions were used.
PMCID: PMC4541665  PMID: 26256978
Volume NT™ software; nuchal translucency; angle deviation; image size; tissue harmonic imaging; speckle reduction filter
23.  Screening Ultrasound in Women with Negative Mammography: Outcome Analysis 
Yonsei Medical Journal  2015;56(5):1352-1358.
To show the results of an audit of screening breast ultrasound (US) in women with negative mammography in a single institution and to analyze US-detected cancers within a year and interval cancers.
Materials and Methods
During the year of 2006, 1974 women with negative mammography were screened with US in our screening center, and 1727 among them had pathologic results or any follow up breast examinations more than a year. We analyzed the distribution of Breast Imaging Reporting and Data System (BI-RADS) category and the performance outcome through follow up.
Among 1727 women (age, 30-76 years, median 49.5 years), 1349 women (78.1%) showed dense breasts on mammography, 762 (44.1%) had previous breast US, and 25 women (1.4%) had a personal history of breast cancers. Test negatives were 94.2% (1.627/1727) [BI-RADS category 1 in 885 (51.2%), 2 in 742 (43.0%)]. The recall rate (=BI-RADS category 3, 4, 5) was 5.8%. Eight cancers were additionally detected with US (yield, 4.6 per 1000). The sensitivity, specificity, and positive predictive value (PPV1, PPV2) were 88.9%, 94.6%, 8.0%, and 28.0%, respectively. Eight of nine true positive cancers were stage I or in-situ cancers. One interval cancer was stage I cancer from BI-RADS category 2.
Screening US detected 4.6 additional cancers among 1000. The recall rate was 5.8%, which is in lower bound of acceptable range of mammography (5-12%), according to American College of Radiology standard.
PMCID: PMC4541666  PMID: 26256979
Breast neoplasms, diagnosis; breast neoplasms, ultrasonography; cancer screening
24.  Noninfectious Complications of Peritoneal Dialysis in Korean Children: A 26-Year Single-Center Study 
Yonsei Medical Journal  2015;56(5):1359-1364.
The aim of this study was to investigate noninfectious complications of peritoneal dialysis (PD), including mechanical and metabolic complications, at a single center in Korea.
Materials and Methods
We analyzed data from 60 PD patients aged ≤18 years (40 boys and 20 girls) during the period between 1986 and 2012. The collected data included gender, age, causes of PD, incidence of noninfectious complications, and treatment for the complications.
The mean duration of PD therapy was 28.7±42.1 months (range 1-240 months). The most common cause of end-stage renal disease was glomerular disease (43.3%). There were no statistically significant differences between patients with and without mechanical complications regarding gender, age at the start of PD, and total duration of PD. Outflow failure was the most common catheter-related complication (14.3%), followed by leakage (10.0%) and hernia (8.6%). Metabolic complications, such as hyperglycemia and hypokalemia, were observed in three of 16 patients. The frequency of noninfectious complications of PD in our study was comparable with those in previous pediatric studies. PD was switched to hemodialysis (HD) in only three patients.
Our results indicate that noninfectious complications of PD are common, though they hardly lead to catheter removal or HD in pediatric patients on PD.
PMCID: PMC4541667  PMID: 26256980
Peritoneal dialysis; noninfectious complication; children
25.  Changes of Heart Rate Variability during Methylphenidate Treatment in Attention-Deficit Hyperactivity Disorder Children: A 12-Week Prospective Study 
Yonsei Medical Journal  2015;56(5):1365-1371.
The aim of this study was to clarify the relationship between the autonomic nervous system and attention deficit hyperactivity disorder (ADHD) rating scales and to evaluate the usefulness of heart rate variability (HRV) as a psychophysiological biomarker for ADHD.
Materials and Methods
Subjects were recruited from outpatients in the Department of Child and Adolescent Psychiatry at the Korea University Medical Center from August 2007 to December 2010. Subjects received methylphenidate. Time- and frequency-domain analyses of HRV, the Korean ADHD rating scale (K-ARS), and computerized ADHD diagnostic system were evaluated before treatment. After a 12-week period of medication administration, we repeated the HRV measurements and K-ARS rating.
Eighty-six subjects were initially enrolled and 37 participants completed the 12-week treatment and HRV measurements subsequent to the treatment. Significant correlations were found between the K-ARS inattention score and some HRV parameters. All of the HRV parameters, except the standard deviations of the normal-to-normal interval, very low frequency, and low frequency to high frequency, showed a significant positive correlation between baseline and endpoint measures in completers. High frequency (HF) and the square root of the mean squared differences of successive normal-to-normal intervals (RMSSD), which are related to parasympathetic vagal tone, showed significant decreases from baseline to endpoint.
The HRV test was shown to be reproducible. The decrease in HF and RMSSD suggests that parasympathetic dominance in ADHD can be altered by methylphenidate treatment. It also shows the possibility that HRV parameters can be used as psychophysiological markers in the treatment of ADHD.
PMCID: PMC4541668  PMID: 26256981
Attention deficit hyperactivity disorder; heart rate variability; methylphenidate; autonomic nervous system

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