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Verrucous carcinoma (VC) is a rare subtype of squamous cell carcinoma (SCC) characterized by its histological presentation as a low-grade tumor with no potential for metastasis, setting it apart from invasive SCC. However, distinguishing VC from its benign counterpart, verrucous hyperplasia (VH), is challenging due to their clinical and morphological similarities. Despite the importance of accurate diagnosis for determining treatment strategies, diagnosis of VH and VC relied only on lesion recurrence after resection. To address this challenge, we generated RNA profiling data from tissue samples of VH and VC patients to identify novel diagnostic markers. We analyzed differentially expressed (DE) mRNA and long non-coding RNA (lncRNA) in tissue samples from VH and VC patients. Additionally, ChIP-X Enrichment Analysis 3 (ChEA3) was conducted to identify the top five transcription factors potentially regulating the expression of DE mRNAs in VH and VC. Our analysis of mRNA and lncRNA expression profiles in VH and VC provides insights into the underlying molecular characteristics of these diseases and offers potential new diagnostic markers. The identification of specific DE genes and lncRNAs may enable clinicians to more accurately differentiate between VH and VC, leading to better treatment choices., Competing Interests: Declaration of competing interest No potential conflict of interest relevant to this article was reported., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite the growing necessity for government-led policy changes on clinical research ethics during pandemic, the scope of previous literature is limited to Korean government's pandemic response strategies or reflections of research ethics at the level of institutions and academic societies. This paper examines the proactive policy changes and responses by the South Korean government in addressing the challenges and issues of research ethics against the backdrop of the urgency of rapid development and emergency supply of medical products during the coronavirus disease 2019 (COVID-19) pandemic., Methods: We conducted searches of various government documents, using predetermined keywords related to research ethics and integrity during the COVID-19 pandemic. Only documents issued by governments or public institutions were included. A total of 24 documents were selected for analysis. They were divided into two phases: the first phase for urgent response (January 2020-February 2021) and the second phase (March 2021-February 2023) for long-term preparedness., Results: The Korean government recommended several measures of research governance to accelerate the ethical review of COVID-related research to be shortened less than one week: the joint operation of Institutional Review Boards (IRBs), exempted or expedited review by a special review committee, guidelines for urgent reviews, and designation of the Korean Academy of Medical Sciences as the supervising agency for the Clinical Trial Safety Support Institution as well as the Central IRB. It allowed temporary non-face-to-face methods for informed consent process (telephone explanations and a photo of the original signed consent) and clinical trials (telephone counselling and prescription, proxy prescription, and drug delivery and supply to clinical trial participants, and online ethics training)., Conclusion: As a result of South Korea's commitment to ethical principles in their pandemic response, the medical system did not experience collapses due to the pandemic, and pandemic research was conducted with careful ethical considerations. The pandemic ethics immunization during the Middle East respiratory syndrome epidemic in 2015 laid the foundation for prompt government initiatives that ensured both pandemic research ethics and pandemic response ethics., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: Exposure to perfluoroalkyl substances (PFAS) may increase the risk of liver disease by disrupting cholesterol and lipid synthesis/metabolism, leading to higher liver-enzyme concentrations. However, most studies assessing association between PFAS and liver enzymes focused on individual PFAS. Moreover, PFAS concentrations differ based on sex and obesity status, and it remains unclear whether these factors affect associations with liver function. Therefore, we examined the association between exposure to both individual and combined PFAS and liver-function biomarkers and assessed sex and obesity as effect modifiers in Korean adults., Methods: We measured serum concentrations of the five most abundant PFAS (PFOA, PFOS, PFHxS, PFDA, PFNA) and three liver enzymes (alanine transaminase [ALT], aspartate aminotransferase [AST], γ-glutamyl transferase [GGT]) in 1404 adults from the Korean National Environmental Health Survey Cycle 3, 2015-2017. We used linear regression to evaluate associations between individual PFAS and liver-function biomarkers, assessing sex and obesity as possible effect modifiers, and performed Bayesian kernel machine regression and quantile g-computation to evaluate the overall effect of PFAS mixture on biomarkers of liver function., Results: Among 1404 Korean adults, all five PFAS were detected. Geometric mean concentration was highest for PFOS (16.11 μg/L), followed by PFOA (5.83 μg/L), PFHxS (2.21 μg/L), PFNA (2.03 μg/L), and PFDA (1.06 μg/L). In multivariable linear regression, all PFAS were positively associated with ALT, AST, and GGT; 2-fold increase in each PFAS was associated with 3.4-8.6% higher ALT, 2.4-4.6% higher AST, and 4.6-11.1% higher GGT (all p < 0.05). Positive associations for PFOA, PFDA, and PFNA with AST were stronger in men, and positive associations for PFOS with ALT and GGT were stronger in women. Compared to obese participants, nonobese participants had higher average percent changes in each enzyme, particularly GGT, when individual PFAS concentration doubled. Additionally, increased exposure to PFAS mixtures was associated with higher ALT, AST, and GGT. In quantile g-computations, simultaneous quartile increase in all PFAS was significantly associated with 6.9% (95%CI: 3.7, 10.2) higher ALT, 4.5% (95%CI: 2.4, 6.6) higher AST, and 8.3% (95%CI: 3.7, 13.1) higher GGT levels, on average., Conclusions: Exposure to individual and combined PFAS is associated with higher liver enzymes in Korean adults, providing additional evidence for the association between PFAS exposure and risk of liver disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Stroke is the second leading cause of death in the world. Approximately 80% of strokes are ischemic in origin. Many risk factors have been linked to stroke, including an increased level of plasminogen activator inhibitor-1 (PAI-1). PAI-1 levels increase and remain elevated in blood during the acute phase of ischemic stroke, which can impair fibrinolytic activity, leading to coronary artery disease and arterial thrombotic disorders. Here, we present a case-control study of 574 stroke patients and 425 controls seen for routine health examination or treatment for nonspecific dizziness, nonorganic headache, or anxiety for positive family history of stroke at the Bundang Medical Center in South Korea. Polymorphisms in PAI-1 were identified by polymerase chain reaction/restriction fragment length polymorphism analysis using genomic DNA. Specifically, three variations (-675 4G>5G, 10692T>C, and 12068G>A) were linked to a higher overall prevalence of stroke as well as a higher prevalence of certain stroke subtypes. Haplotype analyses also revealed combinations of these variations (-844G>A, -675 4G>5G, 43G>A, 9785A>G, 10692T>C, 11053T>G, and 12068G>A) that were significantly associated with a higher prevalence of ischemic stroke. To the best of our knowledge, this is the first strong evidence that polymorphic sites in PAI-1 promoter and 3'-UTR regions are associated with higher ischemic stroke risk. Furthermore, the PAI-1 genotypes and haplotypes identified here have potential as clinical biomarkers of ischemic stroke and could improve the prognosis and future management of stroke patients.

Background and Objective: Air pollution affects clinical course and prognosis of idiopathic pulmonary fibrosis (IPF). However, the effect of individual exposure to air pollutants on disease progression is unclear. We aimed to identify the effect of individual exposure to nitrogen dioxide (NO 2 ) and particulate matter (aerodynamic diameter ≤ 10 μm [PM 10 ]) on disease progression in patients with IPF., Methods: The serial lung function data of 946 IPF patients (mean age: 65.4 years, male: 80.9%) were analysed. Individual-level long-term exposures to NO 2 and PM 10 at the residential addresses of patients were estimated using a national-scale exposure prediction model, constructed based on air quality regulatory monitoring data. Progression was defined as a relative decline (≥10%) in forced vital capacity. Individual- and area-level covariates were adjusted in the primary analysis model., Results: Overall, 547 patients (57.8%) experienced progression during a median follow-up of 1.0 year (interquartile range: 0.4-2.6 years). In the primary model, a 10-ppb increase in NO 2 concentration was associated with a 10.5% increase in the risk of progression (hazard ratio [HR] = 1.105; 95% CI = 1.000-1.219) in patients with IPF. There was also an increasing trend of progression in patients with IPF according to the second to fourth quartiles of NO 2 (Q2 [HR = 1.299; 95% CI = 0.972-1.735], Q3 [1.409; 1.001-1.984], Q4 [1.598; 1.106-2.310]) compared to the first quartile. We found no association between PM 10 and progression in IPF patients., Conclusion: Our data suggest that increased individual exposure to NO 2 can increase the risk of progression in patients with IPF., (© 2022 Asian Pacific Society of Respirology.)

Background and Objective: Inflammation is an important factor in the development of aneurysm, and has been identified as a key characteristic predictive of rupture of intracranial aneurysm (IA). However, the role of inflammatory peripheral blood cell ratios in patients with IA has not been well delineated., Methods: A total of 1,209 patients, including 1,001 with unruptured IA and 208 with ruptured IA, were enrolled in this study. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), platelet-to-neutrophil ratio (PNR), and platelet-to-white-blood-cell ratio (PWR) were compared between ruptured and unruptured IA., Results: Compared with the ruptured IA group, the unruptured IA group had higher PNR {median, 65.96 [interquartile range (IQR) 48.95-85.05] vs. 37.78 (IQR, 23.17-54.05); p < 0.001} and PWR [median, 36.89 (IQR 29.38-44.56) vs. 22.39 (IQR, 16.72-29.29); p < 0.001]. In multivariate analysis, PNR and PWR were independently associated with ruptured IA ( p = 0.001 and p < 0.001, respectively). Unruptured IA subgroup analyses according to the PHASES scores showed that a higher PHASES score was associated with significantly higher NLR and erythrocyte sedimentation rate ( p < 0.001 and p = 0.025) and lower PNR and PWR ( p < 0.001 and p = 0.007)., Conclusions: We demonstrated that lower PNR and PWR levels are associated with ruptured IA and a higher PHASES score. Unlike many other inflammatory markers and bioassays, peripheral blood cell ratios are inexpensive and readily available biomarkers that may be useful for risk stratification in patients with cerebral aneurysm. However, a long-term prospective study is needed to clarify this matter., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Lee, Oh, Lee, Choo, Kim, Kim, Kim, Na and Heo.)

There has been increasing interest in the neurological impact of particulate matter (PM). However, its association with the incidence of Parkinson's disease (PD) remains unclear. We selected 313,355 participants satisfying inclusion criteria from the National Health Insurance Service-National Sample Cohort based on the nationwide population of South Korea, and followed them up from January 2007 through December 2015. Individual-level long-term PM exposure was assessed as the five time-varying average concentrations estimated for the previous 1, 2, 3, 4 and 5 years on each year (until censored or event occurred) at the district-level residential addresses of participants using a previously validated prediction model. Incident PD was defined as the first diagnosis accompanied by anti-PD medication prescription from 2007 through 2015. Time-varying Cox proportional hazards models were employed to estimate the hazard ratio (HR) of incident PD for long-term PM exposure, adjusting for individual- and area-level covariates. During the 8 years (2,745,389 person-years) of follow-up for a total of 313,355 participants (mean [range] age, 48.9 [19-87] years; 169,571 males [54.1%]), 2621 participants (0.8%) developed PD. The HR of incident PD per interquartile range (3.3 μg/m 3 ) increase in fine PM (PM 2.5 ) for the previous 1 year was 1.08 (95% confidence interval: 1.01-1.19). In subgroup-specific analyses, HRs for PM 2.5 were significant among older participants, males, participants living in metropolitan cities, ibuprofen users, and participants with comorbidities (HR: 1.10-1.20). Long-term exposure to PM 2.5 might play a role in PD development., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Recent epidemiological studies of air pollution have adopted spatially-resolved prediction models to estimate air pollution concentrations at people's homes. However, the benefit of these models was limited in many studies that used existing health data relying on incomplete addresses resulting from confidentiality concerns or lack of interest when designed., Objective: This simulation study aimed to understand the impact of incomplete addresses on health effect estimation based on the association between particulate matter with diameter ≤10 µm (PM 10 ) and low birth weight (LBW)., Methods: We generated true annual average concentrations of PM 10 at 46,007 mothers' homes and their LBW status, using the parameters obtained from our data analysis and a previous study in Seoul, Korea. Then, we hypothesized that mothers' address information is limited to the district and compared the properties of their health effect estimates of PM 10 with those using complete addresses. We performed this comparison across eight environmental scenarios that represent various spatial distributions of PM 10 and nine exposure prediction methods that provide different sets of predicted PM 10 concentrations of mothers., Results: We observed increased bias and root mean square error consistently across all environmental scenarios and prediction methods using incomplete addresses compared to complete addresses. However, the bias related to incomplete addresses decreased when we used population-representative exposures averaged to the district from predicted PM 10 at census tract centroids., Significance: Our simulation study suggested that individual exposure estimated by prediction approaches and averaged across population-representative points can provide improved accuracy in health effect estimates when complete address data are unavailable., Impact Statement: Our simulation study focused on a common and practical challenge of limited address information in air pollution epidemiology, and investigated its impact on health effect analysis. Cohort studies of air pollution have developed advanced exposure prediction model to allow the estimation of individual-level long-term air pollution concentrations at people's addresses. However, it is common that address information of existing health data is available at the coarse spatial scale such as city, district, and zip code area. Our findings can help understand the possible consequences of limited address information and provide practical guidance in achieving the accuracy in health effect analysis., (© 2022. The Author(s).)

Particulate matter (PM) air pollution has challenged the global community and the International Agency for Research on Cancer (IARC) classified airborne particulate matter as carcinogenic to humans. However, while most studies of cancer examined a single cancer type using different cohorts, few studies compared the associations of PM between different cancer types. We aimed to compare the association of long-term exposure to PM (PM 10 and PM 2.5 ) and cancer mortality across 17 different types of cancer using a population-based cohort in the Seoul Metropolitan Area (SMA), South Korea; Our study population includes 87,608 subjects (mean age: 46.58 years) residing in the SMA from the National Health Insurance Services-National Sample cohort (NHIS-NSC) and followed up for 2007-2015. We used the time-dependent Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of each cancer mortality per 10 μg/m 3 increase in PM concentrations, after adjusting for individual and areal characteristics. During eight years of follow-up, 1487 people died with any of 17 cancer types. Lung cancer death was the highest, followed by liver and stomach cancer. Although we did not find the association for all cancer types, possibly because of limited cancer cases, HRs of PM 2.5 were relatively high for lung, stomach, pancreas, non-Hodgkin's lymphoma, prostate, esophagus, oral and pharynx, and brain cancer mortality (HRs = 1.44-7.14). High HRs for pancreas, non-Hodgkin's lymphoma, esophagus, and oral and pharynx cancer were also seen for PM 10 ; our findings suggest PM air pollution as a potential risk factor of cancer mortality for upper digestive tracts, mouth, pancreas, and non-Hodgkin's lymphoma in a highly urbanized population with high exposure to PM for a long time.

The phase I trial is the first step in administering a drug to humans, but it has no therapeutic purpose. Under the absence of therapeutic purpose, healthy volunteers demonstrated different motivations, unlike the actual patients participating in trials. There were many reported motivations, such as financial motivation, contributing to the health science, accessing ancillary health care benefits, scientific interest or interest in the goals of the study, meeting people, and general curiosity. The aim of this study was to identify the motivation and characteristics of healthy volunteers participating in phase I trials in the Republic of Korea. We gave surveys to 121 healthy volunteers to study their demographic characteristics and the reasons of participation. We identified whether the decision to participate in the research was influenced by demographic factors and whether the perception and attitudes toward the research were influenced by the characteristics of the healthy volunteers. After completion of the first survey, 12 healthy volunteers who had participated in a phase I clinical trial were selected to answer the second interview. According to our survey, most healthy volunteers were unmarried men and economically dependent. Most of them participated in the study because of financial reward. The most important factor to measure financial reward was the research period. Also, 43% of the volunteers were university students, 42% answered "university graduation" and 55% were residing in family-owned houses. Many healthy volunteers were found to be living in family homes and to have a student status or lack of economic independence. Results of the survey showed that 64% of respondents indicated having more than one clinical trial participation. In-depth interviews showed that healthy volunteers had diverse motivation to participate in research and that healthy volunteer perceive the clinical trial positively. The main motivation for healthy volunteers' participation in research was "financial reward." Healthy volunteers also considered research schedules, processes, and safety, and had a positive perception of clinical trials, but they thought that the public has a negative perception.

Alzheimer's disease (AD) animal studies have reported that mesenchymal stem cells (MSCs) have therapeutic effects; however, clinical trial results are controversial. Neprilysin (NEP) is the main cleavage enzyme of β -amyloid (A β ), which plays a major role in the pathology and etiology of AD. We evaluated whether transplantation of MSCs with NEP gene modification enhances the therapeutic effects in an AD animal model and then investigated these pathomechanisms. We manufactured NEP gene-enhanced human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and intravenously transplanted them in A β 1-42 -injected AD animal models. We compared the differences in behavioral tests and immunohistochemical assays between four groups: normal, A β 1-42 injection, naïve hUC-MSCs, and NEP-enhanced hUC-MSCs. Both naïve and NEP-enhanced hUC-MSC groups showed significant improvements in memory compared to the A β 1-42 injection group. There was no significant difference between naïve and NEP-enhanced hUC-MSC groups. There was a significant decrease in Congo red, BACE-1, GFAP, and Iba-1 and a significant increase in BDNF, NeuN, and NEP in both hUC-MSC groups compared to the A β 1-42 injection group. Among them, BDNF, NeuN, GFAP, Iba-1, and NEP showed more significant changes in the NEP-enhanced hUC-MSC group than in the naïve group. After stem cell injection, stem cells were not found. Extracellular vesicles (EVs) were equally observed in the hippocampus in the naïve and NEP-enhanced hUC-MSC groups. However, the EVs of NEP-enhanced hUC-MSCs contained higher amounts of NEP as compared to the EVs of naïve hUC-MSCs. Thus, hUC-MSCs affect AD animal models through stem cell-released EVs. Although there was no significant difference in cognitive function between the hUC-MSC groups, NEP-enhanced hUC-MSCs had superior neurogenesis and anti-inflammation properties compared to naïve hUC-MSCs due to increased NEP in the hippocampus by enriched NEP-possessing EVs. NEP gene-modified MSCs that release an increased amount of NEP within EVs may be a promising therapeutic option in AD treatment., Competing Interests: There are no conflicts of interest to declare for all authors., (Copyright © 2021 HyeJu Jeong et al.)

Purpose: The aim of this study was to determine whether gender influences the prediction of health-related quality of life (HRQoL) in persons with newly diagnosed epilepsy (NDE)., Methods: This was a 1-year longitudinal study. Persons with NDE were assessed with the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), the Hospital Anxiety Depression Scale (HADS), the Stigma Scale, and the Rosenberg Self-esteem Scale. An analysis of covariance (ANCOVA) with interaction terms was used., Results: Among 134 adults with NDE, there were no gender differences in the scores of the QOLIE-31 and its subscales. A multivariate linear regression analysis showed that the HADS-anxiety scores at diagnosis (p = 0.005) and seizure recurrence after diagnosis (p = 0.050) negatively predicted QOLIE-31 scores in persons with NDE. There were significant effects of the gender interaction with seizure recurrence (F = 8.745, p = 0.004, partial eta 2  = 0.066) and antiepileptic drug (AED) polytherapy (F = 6.320, p = 0.013, partial eta 2  = 0.049) in the adjusted model. Specifically, seizure recurrence negatively predicted the QOLIE-31 scores only in men. By contrast, AED polytherapy negatively predicted the QOLIE-31 scores only in women., Conclusions: There are gender differences in certain epilepsy-related factors predicting HRQoL at 1 year in persons with NDE., Competing Interests: Conflicts of interest The authors declare no conflicts of interest in relation to this study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Although outdoor air pollution including particulate matter (PM) was classified as carcinogenic to humans based on accumulating epidemiological evidence, these findings were suggested mostly from low-dose environments in North America and Europe. We aimed to examine the association of long-term exposure to PM ≤ 10 and 2.5 μm in diameter (PM 10 and PM 2.5 ) and nitrogen dioxide (NO 2 ) with lung cancer incidence using a population-based cohort in the Seoul Metropolitan Area (SMA), South Korea. Our study included 83,478 people residing in the SMA and followed up for 2007-2015 from the National Health Insurance Service-National Sample Cohort. This cohort was constructed based on the National Health Insurance database that contains sociodemographic and medical information under universal health coverage. Individual long-term concentrations of PM 10 , PM 2.5 , and NO 2 were estimated at people's district-level and annually-updated residential addresses for the previous 5 years by using previously-validated prediction models. We applied a time-dependent Cox proportional hazards model and estimated hazard ratios (HRs) per 10 μg/m 3 and 10 ppb increases in PM and NO 2 , respectively, after adjusting for individual characteristics. During 9 years of follow-up, 489 lung cancer new cases occurred (714,012 person-year). The adjusted HRs for PM 10 were greater than 1 but statistically non-significant (HR = 1.15; 95% CI = 0.88-1.52). We also did not find associations for PM 2.5 and NO 2 . Despite null associations for the total population, our subgroup analysis suggested associations with PM in family members with cancer (PM 10 : HR = 2.59, 95% CI = 1.26-5.32; PM 2.5 : 5.55, 1.09-27.91) and in those who have smoked more than 1 pack per day (1.77, 0.96-3.25; 3.81, 1.00-14.44) or for less than 20 years (2.81; 1.13-7.07; 2.02, 0.21-19.23). Our study based on a highly urbanized population exposed to relatively high air pollution provides no evidence of the association between PM and lung cancer incidence in the total population but indicates the potential susceptibility in heavy smokers for relatively short periods and family members of cancer patients. Future studies should re-examine the association using improved exposure assessment and extended population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ambient air pollution is associated with the prognosis of idiopathic pulmonary fibrosis (IPF) patients. We aimed to identify the impacts of individual exposure to particulate matter with a 50% cut-off aerodynamic diameter of 10 μm (PM 10 ) and nitrogen dioxide (NO 2 ) on IPF patients' mortality.1114 patients (mean age 65.7 years; male 80.5%) diagnosed with IPF between 1995 and 2016 were included in this study. Individual-level long-term concentrations of PM 10 and NO 2 at residential addresses of patients were estimated using a national-scale exposure prediction model. The effect of PM 10 and NO 2 on mortality was estimated using a Cox proportional hazards model adjusted for individual- and area-level covariates.The median follow-up period was 3.8 years and 69.5% of the patients died or underwent lung transplantation. When adjusted for individual- and area-level covariates, a 10 ppb increase in NO 2 concentration was associated with a 17% increase in mortality (hazard ratio (HR) 1.172, 95% CI 1.030-1.344; p=0.016). When IPF patients were stratified by age (≥65 versus <65 years) or by sex, NO 2 was a significant prognostic factor for mortality in the elderly (HR 1.331, 95% CI 1.010-1.598; p=0.010). When stratified by age and sex jointly, NO 2 showed the stronger association with mortality in elderly males (HR 1.305, 95% CI 1.072-1.598; p=0.008) than in other groups. PM 10 was not associated with IPF mortality in all patients and in subgroups stratified by age or sex.Our findings suggest that increased exposure to NO 2 can increase the risk of mortality in patients with IPF, specifically in elderly males., Competing Interests: Conflict of interest: H-Y. Yoon has nothing to disclose. Conflict of interest: S-Y. Kim has nothing to disclose. Conflict of interest: O-J. Kim has nothing to disclose. Conflict of interest: J.W. Song has nothing to disclose., (Copyright ©ERS 2021.)

Background: Large artery disease (LAD), cardioembolism (CE), and small vessel disease (SVD) are well-established causes of ischemic stroke. Although a founder variant of RNF213 has been regarded a genetic susceptibility for Moyamoya disease (MMD) and certain types of intracranial atherosclerotic stenosis (ICAS), correlations between RNF213 variants and ischemic stroke with SVD remain largely unknown., Objectives: This study aimed to characterize the associations of four RNF213 polymorphisms (4448G>A, 4810G>A, 4863G>A, and 4950G>A) with ischemic stroke subtypes in Koreans., Methods: Genetic data from 529 stroke patients were analyzed and compared to 424 age- and sex-matched controls. Genetic variants of RNF213, as obtained from the Human Gene Mutation Database, were analyzed in the study subjects using the polymerase chain reaction restriction fragment length polymorphism assay. We investigated four single-nucleotide polymorphisms of RNF213 to elucidate their association with ischemic stroke [LAD, (n = 192), SVD (n = 145) and CE (n = 51)]., Results: The RNF213 4950G>A genotype was observed more frequently in cerebral stroke patients and was more strongly associated with SVD than LAD (P = 0.014). RNF213 4448/4950 in combination with G-A was higher in SVD patients. However, the RNF213 4863/4950 allele combination was associated with increased risk of SVD and LAD. These results confirmed that RNF213 4950GA+AA variants were more frequent in ischemic stroke, especially in SVD, and that RNF213 G-G-G-A and G-G-G-A (4448/4810/4863/4950) haplotype sequences play a role in LAD and CE as well as SVD., Conclusions: Our data reported that the RNF213 4950G>A genotypes and several RNF213 (4448/4810/4863/4950) haplotypes were associated with ischemic stroke in Koreans.

Thymidylate synthase (TS) is a key gene involved in the repair of DNA damage and DNA synthesis that plays an important role in vascular development and recovery. In particular, TS gene polymorphisms play a major role in the progression of vascular disease and cancer metastasis. Therefore, the aim of this study was to investigate the association of three TS polymorphisms (1100T>C [rs699517], 1170A>G [rs2790], and 1494ins/del [rs151264360]) with ischemic stroke and silent brain infarction (SBI) in Koreans. A total of 1299 participants (507 stroke patients, 383 SBI patients, and 409 controls) were enrolled in the study. Genotyping of the three TS polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. To examine the association between TS gene polymorphisms and the diseases, we performed statistical analyses, including multivariable logistic regression and Fisher's exact tests. We found that TS 1100T>C and 1170A>G genotypes were strongly associated with ischemic stroke and SBI susceptibility. More specifically, the TS 1100T>C polymorphism was associated with the likelihood of ischemic stroke (TT vs. CC: AOR = 2.151, 95% CI = 1.275-3.628, P = 0.004) and SBI (TT vs. TC+CC: AOR = 1.443, 95 % CI = 1.009-2.063, P = 0.045). In contrast, the TS 1170A > G polymorphism exhibited lower correlation with the risk of stroke (AA vs. GG: AOR = 0.284, 95% CI = 0.151-0.537, P < 0.0001) and SBI (AA vs. GG: AOR = 0.070, 95% CI = 0.016-0.298, P = 0.0002). Furthermore, we confirmed that the TS 1100T>C polymorphism was synergistic with low folic acid levels (AOR = 6.749, P < 0.0001). Altogether, these results suggest that TS 1100T>C and 1170A > G polymorphisms are associated with the risk of ischemic stroke and SBI, and our study provides the first evidence that 3'-UTR variants in TS are potential biomarkers in ischemic stroke and SBI.

Background: Mounting evidence implicates an association between ambient air pollution and impaired reproductive potential of human. Our study aimed to assess the association between air pollution and ovarian reserve in young, infertile women., Methods: Our study included 2276 Korean women who attended a single fertility center in 2016-2018. Women's exposure to air pollution was assessed using concentrations of particulate matter (PM 10 and PM 2.5 ), nitrogen dioxide (NO 2 ), carbon monoxide (CO), sulfur dioxide (SO 2 ), and ozone (O 3 ) that had been collected at 269 air quality monitoring sites. Exposure estimates were computed for 1, 3, 6, and 12 months prior to the ovarian reserve tests. Anti-Müllerian hormone (AMH) ratio (defined as an observed-to-expected AMH based on age) and low AMH (defined as < 0.5 ng/mL) were employed as indicators of ovarian reserve. We included a clustering effect of 177 districts in generalized estimating equations approach. A secondary analysis was conducted restricting the analyses to Seoul residents to examine the association in highly urbanized setting., Results: The mean age was 36.6 ± 4.2 years and AMH level was 3.3 ± 3.1 ng/mL in the study population. Average AMH ratio was 0.8 ± 0.7 and low AMH was observed in 10.3% of women (n=235). The average concentration of six air pollutants was not different between the normal ovarian reserve and low AMH groups for all averaging periods. In multivariable models, an interquartile range (IQR)-increase in 1 month-average PM 10 was associated with decrease in AMH ratio among total population (β= -0.06, 95% confidence interval: -0.11, 0.00). When we restrict our analysis to those living in Seoul, IQR-increases in 1 and 12 month-average PM 2.5 were associated with 3% (95% CI: -0.07, 0.00) and 10% (95% CI: -0.18, -0.01) decrease in AMH ratio. The ORs per IQR increase in the six air pollutants were close to null in total population and Seoul residents., Conclusions: In a cohort of infertile Korean women, there was a suggestive evidence of the negative association between ambient PM concentration and ovarian reserve, highlighting the potential adverse impact of air pollution on women's fertility.

As many studies showed the spatial heterogeneity in the association between particulate matter (PM) air pollution and low birth weight (LBW), few studies focused on the variation of local associations at the national scale and related areal characteristics. This study aimed to explore different approaches to estimating local effects of PM with an aerodynamic diameter ≤10 μm (PM 10 ) on LBW across 235 districts in South Korea, to investigate the spatial pattern of local associations, and to examine the relationship with local socio-demographic and environmental characteristics. LBW was identified in 5,692,650 mothers from birth certificate data for 2001-2013. We estimated individual annual-average concentrations of PM 10 at centroids of mothers' residential districts by using a previously-validated prediction model. Then, we estimated district-specific odds ratios of LBW for PM 10 using modified geographically weighted logistic regression. Here, we applied four approaches with different neighborhood definitions: the distance-based approach within 20- and 40-km bandwidth and the hybrid approach replacing with adjacent districts for urban districts <100 km 2 . In addition, we compared district-specific socioeconomic indicators and emission estimates across three groups of districts that showed significantly positive, no, and significantly negative associations. Medians of district-specific estimates of four approaches were similar to the global estimate and between each other. However, their variability differed with some unreasonably high estimates when a small distance was applied as the neighborhood definition, although spatial pattern was generally similar among the four. The hybrid approach based on the different neighborhood definition by urban and rural areas provided stable risk estimates. Higher risk districts in rural areas were found in more socioeconomically-deprived areas, whereas urban areas showed higher risk districts when their air pollution emissions were higher. Our approach and findings will help identify high risk areas and enhance understanding of geographic determinants., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Implant surface decontamination is a challenging procedure for therapy of peri-implant disease. This study aimed to compare the effectiveness of decontamination on oral biofilm-contaminated titanium surfaces in Er:YAG laser, Er, Cr:YSGG laser, and plastic curette., Methodology: For oral biofilms formation, six participants wore an acrylic splint with eight titanium discs in the maxillary arch for 72 hours. A total of 48 contaminated discs were distributed among four groups: untreated control; decontamination with plastic curettes; Er, Cr:YSGG laser; and Er:YAG laser irradiation. Complete plaque removal was estimated using naked-eye and the time taken was recorded; the residual plaque area was measured and the morphological alteration of the specimen surface was observed by scanning electron microscopy. The total bacterial load and the viability of adherent bacteria were quantified by live or dead cell labeling with fluorescence microscopy., Results: The mean treatment time significantly decreased based on the treatment used in the following order: Er:YAG, Er, Cr:YSGG laser, and plastic curettes (234.9±25.4 sec, 156.1±12.7 sec, and 126.4±18.6 sec, P=0.000). The mean RPA in the Er, Cr:YSGG laser group (7.0±2.5%) was lower than Er:YAG and plastic curettes groups (10.3±2.4%, 12.3±3.6%, p=0.023). The viable bacteria on the titanium surface after Er, Cr:YSGG laser irradiation was significantly lower compared to the decontamination with plastic curette (P=0.05) but it was not significantly different from the Er:YAG laser irradiation., Conclusion: We found that Er:YAG laser and Er, Cr:YSGG laser irradiation were effective methods for decontaminations without surface alterations.

A recent study of the ischemic stroke described the roles played by miRNAs in the downregulation of specific cell-cycle gene expression and it is thought to require the development of biomarkers for the prognostic of ischemic stroke. Here, we hypothesized that four miRNA polymorphisms ( miR-10a , miR-27a , miR-34b /c, and miR-300 ) may affect stroke susceptibility and mortality. Blood samples were collected from 530 patients and 403 controls. Genetic polymorphisms were detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis and real-time PCR. We found that the miR-300 rs12894467 TC genotype and the dominant model (AOR: 2.069, p -value: 0.017; AOR: 1.931, p -value: 0.027) were significantly associated with an increased risk for the ischemic stroke subtype. In Cox proportional hazard regression models, the miR-10a rs3809783 A>T and miR-34b/c rs4938723 T>C polymorphisms were associated with the mortality rates among ischemic stroke patients. We found that a miR-300 polymorphism was associated with increased ischemic stroke susceptibility among the Korean population. Additionally, polymorphisms in miR-10a and miR-34b/c were associated with the increased or decreased mortality of ischemic stroke patients. This study marks the first report of an association between ischemic stroke and miRNA polymorphisms ( miR-10a A>T, miR - 27a T>C, miR-34b/c T>C, and miR-300 T>C) in the Korean population.

Ischemic stroke is a complicated disease which is affected by environmental factors and genetic factors. In this field, various studies using whole-exome sequencing (WES) have focused on novel and linkage variants in diverse diseases. Thus, we have investigated the various novel variants, which focused on their linkages to each other, in ischemic stroke. Specifically, we analyzed the N-methylpurine DNA glycosylase ( MPG ) gene, which plays an initiating role in DNA repair, and the nitrogen permease regulator-like 3 ( NPRL3 ) gene, which is involved in regulating the mammalian target of rapamycin pathway. We took blood samples of 519 ischemic stroke patients and 417 controls. Genetic polymorphisms were detected by polymerase chain reaction (PCR), real-time PCR, and restriction fragment length polymorphism (RFLP) analysis. We found that two NPRL3 polymorphisms (rs2541618 C>T and rs75187722 G>A), as well as the MPG rs2562162 C>T polymorphism, were significantly associated with ischemic stroke. In Cox proportional hazard regression models, the MPG rs2562162 was associated with the survival of small-vessel disease patients in ischemic stroke. Our study showed that NPRL3 and MPG polymorphisms are associated with ischemic stroke prevalence and ischemic stroke survival. Taken together, these findings suggest that NPRL3 and MPG genotypes may be useful clinical biomarkers for ischemic stroke development and prognosis.

Background: While many studies reported the association between long-term exposure to particulate matter air pollution (PM) and cardiovascular disease (CVD), few studies focused on incidence with relatively high-dose exposure using a nationwide cohort. This study aimed to investigate the association between long-term exposure to PM 10 and PM 2.5 and incidence of CVD in a nationwide and population-based cohort in South Korea where the annual average concentration of PM 2.5 is above 20 μg/m 3 ., Methods: We selected 196,167 adults in the National Health Insurance Service-National Sample Cohort (NHIS-NSC) constructed based on the entire South Korean population. Incidence of four CVD subtypes including ischemic heart disease (IHD), myocardial infarction, heart failure, and stroke, and total CVD including all four was identified as the first diagnosis for 2007-2015. To assess individual exposures, we used annually-updated district-level residential addresses and district-specific PM concentrations predicted by a previously developed universal kriging prediction model. We computed individual-level long-term PM concentrations for four exposure windows: previous 1, 3, and 5 year(s) and 5 years before baseline. We applied time-dependent Cox proportional hazards models to estimate hazard ratios (HRs) of incident CVDs per 10 μg/m 3 increase in PM 10 and PM 2.5 after adjusting for individual- and area-level characteristics., Results: During 1,578,846 person-year, there were 33,580 cases of total incident CVD. Average PM 10 and PM 2.5 concentrations for the previous 5 years were 52.3 and 28.1 μg/m 3 , respectively. A 10 μg/m 3 increase in PM 2.5 exposed for the previous 5 years was associated with 4 and 10% increases in the incidence of total CVD (95% confidence interval: 0-9%) and IHD (4-16%), respectively. HRs tended to be higher with earlier exposure for IHD and more recent exposure for stroke. The estimated shape of the concentration-response relationship showed non-linear patterns. We did not find evidence of the association for PM 10 ., Conclusions: Using a population-based nationwide cohort exposed to relatively high PM concentration, this study confirmed the association between PM 2.5 and CVD incidence that was reported in previous studies mostly with low-dose environments. The magnitude and the shape of the association were generally consistent with previous findings.

Although intravenous administration of mesenchymal stem cells (MSCs) is effective for experimental stroke, low engraftment and the limited functional capacity of transplanted cells are critical hurdles for clinical applications. C-C motif chemokine ligand 2 (CCL2) is associated with neurological repair after stroke and delivery of various cells into the brain via CCL2/CCR2 (CCL2 receptor) interaction. In this study, after CCL2-overexpressing human umbilical cord-derived MSCs (hUC-MSCs) were intravenously transplanted with mannitol in rats with middle cerebral arterial occlusion, we compared the differences between four different treatment groups: mannitol + CCL2-overexpressing hUC-MSCs (CCL2-MSC), mannitol + naïve hUC-MSCs (M-MSC), mannitol only, and control. At four-weeks post-transplantation, the CCL2-MSC group showed significantly better functional recovery and smaller stroke volume relative to the other groups. Additionally, we observed upregulated levels of CCR2 in acute ischemic brain and the increase of migrated stem cells into these areas in the CCL2-MSC group relative to the M-MSC. Moreover, the CCL2-MSC group displayed increased angiogenesis and endogenous neurogenesis, decreased neuro-inflammation but with increased healing-process inflammatory cells relative to other groups. These findings indicated that CCL2-overexpressing hUC-MSCs showed better functional recovery relative to naïve hUC-MSCs according to the increased migration of these cells into brain areas of higher CCR2 expression, thereby promoting subsequent endogenous brain repair.

Background and Objective: The blood neutrophil/lymphocyte ratio (NLR) is a marker of peripheral inflammation, with a high NLR associated with an increased risk of cardiovascular events and poor prognosis in ischemic stroke. However, few data are available on the differential impact of the blood NLR on different silent cerebral vascular pathologies, including cerebral large-artery atherosclerosis (LAA) and cerebral small-vessel disease (CSVD), in neurologically healthy individuals. Methods: We evaluated cardiovascular risk factors, brain magnetic resonance imaging (MRI), and MR angiography of 950 individuals without any neurological diseases. The study participants were divided into three groups according to NLR tertile (low, middle, and high). The presences of extracranial (EC) and intracranial (IC) atherosclerosis were considered to indicate LAA on brain MR angiography. The presences of silent lacunar infarction (SLI) and cerebral white matter hyperintensities (WMHs) were analyzed as indices of CSVD on brain MRI. Results: In univariate analysis, the high NLR tertile group showed a high prevalence of old age, hyperlipidemia, and renal dysfunction and higher fasting glucose. Multivariable logistic regression analysis revealed that indices of LAA (EC atherosclerosis [odds ratio: 1.88; 95% confidence interval: 1.14-3.09; p = 0.01] and IC atherosclerosis [odds ratio: 1.87; 95% confidence interval: 1.15-3.06; p = 0.01]) were more prevalent in the highest NLR tertile group than in the lowest NLR tertile group after adjustment for cardiovascular risk factors. However, no significant differences were found in the prevalence of CSVD indices (SLI and WMHs) among the three NLR tertile groups. Conclusions: A high NLR is associated with the development of cerebral LAA but not CSVD., (Copyright © 2020 Chung, Lee, Choi, Kim, Kim, Kim, Oh and Kim.)

In this study, we developed a low-cost, high-precision vehicle navigation system for deep urban multipath environments using time-differenced carrier phase (TDCP) measurements. Although many studies are being conducted to navigate autonomous vehicles using the global positioning system (GPS), it is difficult to obtain accurate navigation solutions due to multipath errors in urban environments. Low-cost GPS receivers that determine the solution based on pseudorange measurements are vulnerable to multipath errors. We used carrier phase measurements that are more robust for multipath errors. Without correction information from reference stations, the limited information of a low-cost, single-frequency receiver makes it difficult to quickly and accurately determine integer ambiguity of carrier phase measurements. We used TDCP measurements to eliminate the need to determine integer ambiguity that is time-invariant and we combined TDCP-based GPS with an inertial navigation system to overcome deep urban multipath environments. Furthermore, we considered a cycle slip algorithm for its accuracy and a multi-constellation navigation system for its availability. The results of dynamic field tests in a deep urban area indicated that it could achieve horizontal accuracy of at the submeter level.

Silent brain infarction (SBI) is a cerebral infarction identified through brain imaging. In particular, studies have shown that the presence of SBI in elderly patients increases their risk of cognitive dysfunction, impairment and dementia. However, little research has been published on the relevance of SBI to these risks for the Korean population. The association between potassium voltage‑gated channel subfamily Q member 2 (KCNQ2), transcription factor 4 (TCF4) and regulator of G‑protein signaling 18 (RGS18) genotypes and SBI were investigated using whole‑exome sequencing and PCR restriction fragment length polymorphism (RFLP) analysis. The study population included 407 patients with SBI (171 males) and 401 control subjects (172 males). Genotyping was performed using PCR RFLP. Interestingly, TCF4 rs9957668T>C polymorphisms were associated with SBI prevalence [TT vs. CC: adjusted odds ratio (AOR), 1.815, 95% confidence intervals (CI), 1.202‑2.740; TT vs. TC+CC: AOR, 1.492, 95% CI, 1.066‑2.088; TT+TC vs. CC: AOR, 1.454, 95% CI, 1.045‑2.203]. The combination of KCNQ2 rs73146513A>G and TCF4 rs9957668T>C genotypes was associated with increasing SBI prevalence (AG/CC: AOR, 3.719, 95% CI, 1.766‑7.833; AA/CC: AOR, 3.201, 95% CI, 1.387‑7.387). The present study showed that TCF4 rs9957668T>C polymorphisms may be risk factors for SBI. Therefore, the TCF4 rs9957668T>C polymorphism may serve as a biomarker for increased risk of SBI in the Korean population.

Intracranial major artery stenosis/occlusion (ICASO) is the major cause of ischemic stroke. Recent studies have suggested that variants of RNF213 , a susceptibility gene for moyamoya disease (MMD), are also related to non-MMD ICASO. Regarding the predominant involvement of steno-occlusion on anterior circulation in MMD, we hypothesized that the ICASO distribution pattern (anterior/posterior) in non-MMD may differ according to RNF213 variants. This study analyzed 1024 consecutive Korean subjects without MMD who underwent computed tomography angiography (CTA) or magnetic resonance angiography (MRA). We evaluated four single nucleotide polymorphisms (SNPs) in the exon region of RNF213 : 4448G > A (rs148731719), 4810G > A (rs112735431), 4863G > A (rs760732823), and 4950G > A (rs371441113). Associations between RNF213 variants and anterior/posterior ICASO were examined using multivariate logistic regression analysis. Anterior ICASO was present in 23.0% of study subjects, and posterior ICASO was present in 8.2%. The GA genotype of RNF213 4810G > A (adjusted odds ratio (AOR) [95% confidence interval (CI)], 2.39 [1.14-4.87] compared to GG; p = 0.018) and GA genotype of RNF213 4950G > A (AOR [95% CI], 1.71 [1.11-2.63] compared to GG; p = 0.015) were more frequent in subjects with anterior ICASO. The genotype frequency of RNF213 4863G > A differed significantly according to the presence of posterior ICASO. Further investigations of the functional and biological roles of RNF213 will improve our understanding of the pathomechanisms of ICASO and cerebrovascular disease.

Elevated blood pressure (BP) has been proposed as a possible pathophysiological mechanism linking exposure to ambient air pollution and the increased risk of cardiovascular mortality and morbidity. In this study, we investigated the hourly relationship between ambient air pollutants and BP. BP measurements were extracted from the electronic health record database of the Seoul National University Bundang Hospital from February 2015 to June 2017. A total of 98,577 individual BP measurements were matched to the hourly levels of air pollutants. A generalized additive model was constructed for hour lags of 0-8 of air pollutants adjusting for age, sex, meteorological variables, and time trend. Systolic BP was shown to be significantly lower at 2-4 hours and 3-5 hours after increased levels of SO 2 and CO, respectively (0.24 mmHg and 0.26 mmHg for an interquartile range, respectively). In contrast, O 3 and NO 2 were associated with significantly increased systolic BP at 3-5 lag hours and at 0-2 lag hours, respectively. BP elevation in association with O 3 and NO 2 was shown to be significantly greater in hypertensive patients than normotensive subjects. Our findings suggest that short-term exposure to air pollution may be associated with elevated BP.

Background: The clinical significance of cerebral white matter hyperintensities (WMH) on brain magnetic resonance imaging (MRI) has recently increased, and recognized now as a risk factor for future stroke and dementia. High levels of plasma homocysteine (Hcyt) are associated with cerebral WMH. Recent studies suggest a different anatomy and physiology in the arteriolar system may be supplied to the periventricular and deep subcortical white matter. We hypothesize that plasma Hcyt levels have differing impacts on periventricular WMH (PVWMH) than on deep subcortical WMH (DSWMH). Methods: We evaluated plasma Hcyt levels from 937 neurologically healthy participants. The severity of PVWMH and DSWMH was evaluated by the use of a manual grading scale. Moderate to severe PVWMH and DSWMH levels were defined when the Fazekas score was two or three, respectively. Predominant PVWMH (pred-PVWMH) and predominant DSWMH (pred-DSWMH) were defined as having a difference of Fazekas score between PVWMH and DSWMH of two or more. Other confounding variables including age, sex, vascular risk factors, and estimated glomerular filtration rate (eGFR) were also analyzed. Results: Logistic regression revealed that, after adjusting for the confounding variables, PVWMH was associated with old age, hypertension, diabetes mellitus, low eGFR, and high plasma Hcyt levels. DSWMH was associated with old age, hypertension, and hypercholesterolemia but not with plasma Hcyt levels. Plasma Hcyt levels were associated with pred-PVWMH but not with pred-DSWMH. Conclusions: High plasma Hcyt levels are strongly associated with the development of PVWMH but not DSWMH. Our results suggest the possibility that different pathogeneses exist for PVWMH and DSWMH and that dysregulated Hcyt metabolism associated with the development of PVWMH., (Copyright © 2019 Lee, Woo, Chung, Choi, Kim, Kim and Oh.)

Epidermal inflammation is caused by various bacterial infectious diseases that impair the skin health. Feruloylserotonin (FS) belongs to the hydroxycinnamic acid amides of serotonin, which mainly exists in safflower seeds and has been proven to have anti-inflammatory and antioxidant activities. Human epidermis mainly comprises keratinocytes whose inflammation causes skin problems. This study investigated the protective effects of FS on the keratinocyte with lipopolysaccharides (LPS)-induced human HaCaT cells and elucidated its underlying mechanisms of action. The mechanism was investigated by analyzing cell viability, PGE 2 levels, cell apoptosis, nuclear factor erythroid 2-related factor 2 (Nrf2) translocation, and TLR4/NF-κB pathway. The anti-inflammatory effects of FS were assessed by inhibiting the inflammation via down-regulating the TLR4/NF-κB pathway. Additionally, FS promoted Nrf2 translocation to the nucleus, indicating that FS showed anti-oxidative activities. Furthermore, the antioxidative and anti-inflammatory effects of FS were found to benefit each other, but were independent. Thus, FS can be used as a component to manage epidermal inflammation due to its anti-inflammatory and anti-oxidative properties.

Background: Atrial fibrillation is a common cardiac arrhythmia and an important risk factor for stroke and cardiovascular morbidity. However, there is limited evidence regarding the association of air pollution with atrial fibrillation. This study aimed to compare the short-term and long-term effects of air pollution on atrial fibrillation., Design: A nationwide cohort from the Korean general population., Methods: Different analytical approaches were used for short-term and long-term effects. For the analysis of short-term effects, the daily incidence of emergency admissions for atrial fibrillation was identified. The relationship of atrial fibrillation with air pollutants, including PM 2.5 (particulate matter ≤ 2.5 μm in aerodynamic diameter), PM 10 , carbon monoxide, sulphur dioxide, nitrogen dioxide and ozone, was analysed using a time-series analysis. The long-term effects of air pollution were analysed for subjects aged ≥30 years who resided in Seoul between 2007 and 2015 and had no history of atrial fibrillation., Results: During the study period, 1137 emergency visits were identified in Seoul as being associated with atrial fibrillation. A 10-μg/m 3 increase in ambient PM 2.5 was shown to significantly increase emergency admissions by 4.5% at lag day 3 ( p  = 0.038). No other pollutants showed a significant relationship with emergency atrial fibrillation admission. Among 124,010 residents in Seoul, 1903 developed atrial fibrillation at a median follow-up of 9.5 years (1.95 per 1000 person-years). Long-term exposure to air pollution had no significant impact on atrial fibrillation occurrence ( p  = 0.830 for PM 2.5 )., Conclusion: This study suggests that short-term exposure to PM 2.5 triggers atrial fibrillation. However, we found no evidence linking atrial fibrillation with long-term exposure to air pollution.

This study investigated the anti-inflammatory effects of mixed extracts of Achyranthes japonica Nakai (AJ) and Aralia continentalis Kitagawa (AC) (ratios of 1:2, 1:3, 1:5, 2:1, 3:1 and 5:1) on RAW264.7 macrophages and evaluated the anti-inflammatory effects of the mixed extracts of AJ and AC by measuring IL-1 β , IL-6, and TNF α using the ELISA kit assay. In particular, the formation of nitric oxide (NO) was found to decrease in the group treated with the combined extracts of AJ and AC at all ratios. In particular, extracts of ratio of 2:1 (AJ:AC) deceased the formation of NO level that is approximately 60% of the group treated with only lipopolysaccharide (LPS). Also, extracts of ratio of 2:1 (AJ:AC) reduced the production of IL-1 β , IL-6, TNF α and PGE2 with statistical significance. Volunteers over the age of 50 who complain of discomfort in knee joints were selected as the experimental subjects. The subjects took daily administration of 2000 mg of the combined extracts of ratio of 2:1 (AJ:AC) for 12 weeks. A survey (VAS (Visual Analog Scale), WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index)) was conducted after the 12 weeks of oral administration. The experimental group showed the change between each visit and baseline time compared with the control group. In the intention-to-treat (ITT) analysis, VAS score and WOMAC stiffness score decreased significantly. And the WOMAC total score and function score tended to decrease. In the per-protocol (PP) analysis, the WOMAC stiffness score was significantly decreased and the VAS and WOMAC total and function scores were decreased. There was no significant difference in all parameters of ITT and PP in radiological examinations.

The pathogenesis of Alzheimer's disease (AD) is associated with an increased inflammatory response via activated microglia and astrocytes. In the present study, we investigated whether treatment with the anti-tumor necrosis factor alpha (TNF-α) monoclonal antibody adalimumab can improve cognitive function and reduce AD pathology in Aβ 1-40 -injected animal models of AD, as well as the mechanisms underlying the effects of treatment. Aβ 1-40 -injected mice treated with adalimumab exhibited significant improvements in memory relative to mice injected with Aβ 1-40 alone, as well as decreases in beta secretase-1 (BACE1) protein expression and Aβ 1-40 plaques. In addition, adalimumab treatment significantly attenuated neuronal damage and neuroinflammation in Aβ 1-40 -injected mice. Aβ 1-40 -induced decreases in brain-derived neurotrophic factor (BDNF) expression were also attenuated by treatment with adalimumab. Our experiments further verified that the effects of adalimumab are mediated by nuclear factor kappa B (NF-κB) p65 signalling. Serine 536 residues of NF-κB p65, which is phosphorylated by TNF-α, increased along with the degradation of inhibitor of κB (IκB) in the hippocampus of Aβ-injected mice, although these effects were again attenuated by adalimumab. Furthermore, Aβ 1-40 -induced increases in TNF-α and interleukin (IL)-6 expression were decreased by treatment with adalimumab. Our results indicate that adalimumab may be clinically useful in human patients with AD., (Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Acute stroke alters the systemic immune response as can be observed in peripheral blood; however, the molecular mechanism by which microRNA (miRNA) regulates target gene expression in response to acute stroke is unknown. We performed a miRNA microarray on the peripheral blood of 10 patients with acute ischemic stroke and 11 control subjects. Selected miRNAs were quantified using a TaqMan assay. After searching for putative targets from the selected miRNAs using bioinformatic analysis, functional studies including binding capacity and protein expression of the targets of the selected miRNAs were performed. The results reveal a total of 30 miRNAs that were differentially expressed (16 miRNAs were upregulated and 14 miRNAs were downregulated) during the acute phase of stroke. Using prediction analysis, we found that miR-340-5p was predicted to bind to the 3'-untranslated region of the arginase-1 (ARG1) gene; a luciferase reporter assay confirmed the binding of miR-340-5p to ARG1. miR-340-5p was downregulated whereas ARG1 mRNA was upregulated in peripheral blood in patients experiencing acute stroke. Overexpression of miR-340-5p in human neutrophil and mouse macrophage cell lines induced downregulation of the ARG1 protein. Transfection with miR-340-5p increased nitric oxide production after LPS treatment in a mouse macrophage cell line. Our results suggest that several miRNAs are dynamically altered in the peripheral blood during the acute phase of ischemic stroke, including miR-340-5p. Acute stroke induces the downregulation of miR-340-5p, which subsequently upregulates ARG1 protein expression.

Despite much progress in microRNA (miRNA) research, information regarding the association between miRNAs and venous thromboembolism (VTE), especially in Asian patients, remains limited. This case-control study sought to determine the correlation between the presence of polymorphisms in the genes encoding the miRNAs miR-146a, miR-149, miR-196a2, miR-499, and VTE in Korean patients. We observed no statistically significant differences in the genotype frequency of miRNA polymorphisms between 300 control individuals and 203 VTE patients. However, we observed a significant association between three allelic combinations of miRNA polymorphisms and VTE risk. Overall, our findings suggest that specific miRNA polymorphisms are associated with the risk of VTE in a Korean population.

Several studies have demonstrated the beneficial effect of mesenchymal stem cells (MSCs) on intracerebral hemorrhage (ICH). Enhancement of the therapeutic efficacy of MSCs in ICH is necessary, considering the diseases high association with mortality and morbidity. Various preconditioning methods to enhance the beneficial properties of MSCs have been introduced. We suggested apocynin, a well-known nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, as a novel preconditioning regimen to enhance the therapeutic efficacy of MSCs in ICH. Rat ICH models were made using bacterial collagenase. 24 h after ICH induction, the rats were randomly divided into apocynin-preconditioned MSC-treated (Apo-MSC), naïve MSC-treated and control groups. Hematoma volume, brain edema, and degenerating neuron count were compared at 48 h after the ICH induction. The expression of tight junction proteins (occludin, zona occludens [ZO]-1) were also compared. Hematoma size, hemispheric enlargement and degenerating neuron count were significantly lower in the Apo-MSC group than in the naïve MSC group ( p = 0.004, 0.013 and 0.043, respectively), while the expression of occludin was higher ( p = 0.024). Apocynin treatment enhances the therapeutic efficacy of MSCs in ICH in the acute stage, through the improvement of the beneficial properties of MSCs, such as neuroprotection and the reinforcement of endovascular integrity of cerebral vasculature.

Purpose: We investigated factors contributing to anxiety and depressive symptoms over a 1-year period in Korean adults with new-onset epilepsy., Methods: This longitudinal multicenter study included adults diagnosed with epilepsy within 12 months of a first seizure. Using stepwise regression analyses, we determined whether Hospital Anxiety Depression Scale (HADS) scores could be predicted by demographic, clinical, and psychosocial variables at baseline and at 12 months., Results: Of 141 patients included at baseline, 63 (44.7%) and 60 (42.6%) had Hospital Anxiety Depression Scale-Anxiety (HADS-A) and Hospital Anxiety Depression Scale-Depression (HADS-D) scores >7, respectively. Of 98 patients who completed the 12-month study, the corresponding figures decreased to 32.7% and 36.7%, respectively. Higher HADS-A scores both at baseline and 12 months were predicted by higher neuroticism, stigma, and lower self-esteem (p < 0.05). Higher HADS-D scores at baseline were predicted by higher neuroticism, lower self-esteem, marital status, and lower extroversion (p < 0.05) whereas those at 12 months were predicted by self-esteem, seizure recurrence, and age at epilepsy onset (p < 0.05). Neuroticism or self-esteem was the strongest predictor of psychological distress., Conclusions: Anxiety and depressive symptoms are common at the time of diagnosis in Korean adults with new-onset epilepsy. While these decrease over time, they remained high 12 months after epilepsy diagnosis. Psychological factors, particularly neuroticism and self-esteem, may be the most important risk factors. Epilepsy variables, such as seizure recurrence and age at onset, may also be important factors for depressed mood at 12 months., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Global cerebral ischemia (GCI) is a major obstacle for cardiac arrest survival. Recent studies have suggested the possibility of mesenchymal stem cell (MSC) as a novel therapeutic option for GCI, but these results were limited to the neuroprotective effects of MSCs. Therefore, we aimed to investigate specific characteristics of neurogenesis after transient GCI, and to assess the effect of MSC on these characteristics., Methods: Adult male Sprague-Dawley rats were subjected to 7 min of transient GCI and randomized into 7 groups: baseline, MSC, and control administered groups, to be analyzed at 2, 3, and 4 weeks after GCI, respectively. The same interventions were repeated for sham operated animals. Rats were euthanized at the designated time after GCI., Results: A comparison of GCI and sham groups without MSC treatment, showed that the counts of bromodeoxyuridine (BrdU)- and doublecortin (DCX)-positive cells were significantly increased in the GCI group at 1 week after insult, but the trend was reversed at 3 weeks after insult. The counts of BrdU-, Ki67- and DCX-positive cells and the intensity of zinc translocator 3 (ZnT3) were all significantly higher in the MSC-treated group than those in the control group at 3 weeks after GCI. The count of NeuN-positive cells in the hippocampus was significantly increased in the MSC group at 4 weeks after GCI., Conclusions: GCI induces transient neurogenesis, followed by an anergic state. MSC may counteract this anergy of neurogenesis and result in an increase in intact neurons in later stages., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: We assessed the association between periodontal disease status and metabolic syndrome (MetS) and its individual components in Korean adults over 50 years old., Material and Methods: In the Dong-gu study, 5078 men and women aged over 50 years were included. They underwent a questionnaire survey, physical assessment, biochemical assessment and periodontal assessment. The percentages of sites with periodontal probing depth ≥4 mm, and clinical attachment loss ≥4 mm were recorded for each participant. Periodontal disease was also classified by the Centers for Disease Control and Prevention/American Academy of Periodontology definition of periodontitis and the American Academy of Periodontology definition (1999). MetS was defined by the 2009 guidelines of the International Diabetes Federation. This study used multivariate negative binominal regression analysis to assess the association between the severity of periodontitis and MetS, after age, smoking habits, alcohol consumption and physical activity related factors were adjusted for., Results: Prevalence of MetS was 32.3%, 36.2% and 45.9% among men with no or mild, moderate and severe periodontitis, respectively. The severity of periodontitis was positively associated with the prevalent MetS in men but not in women. In men, severe periodontitis showed a higher risk of MetS than those with no or mild periodontitis (relative risk 1.43, 95% confidence interval 1.17-1.73) after adjusting for confounders. Periodontal probing depth was positively associated with the prevalence of MetS in both genders. In the analysis separated by individual MetS components, periodontitis severity was positively associated with hypertriglyceridemia and low high-density lipoprotein cholesterol in men, while positively associated with low high-density lipoprotein cholesterol and abdominal obesity in women., Conclusion: Increasing the severity of periodontitis was associated with the risk of prevalent MetS in Korean adults. This result confirmed that periodontal inflammation might be a contributive factor of MetS., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)