Translation reinitiation in c.453delC frameshift mutation of KCNH2 producing functional hERG K+ channels with mild dominant negative effect in the heterozygote patient-derived iPSC cardiomyocytes.

The c.453delC (p.Thr152Profs*14) frameshift mutation in KCNH2 is associated with an elevated risk of Long QT syndrome (LQTS) and fatal arrhythmia. Nevertheless, the loss-of-function mechanism underlying this mutation remains unexplored and necessitates an understanding of electrophysiology. To gain insight into the mechanism of the LQT phenotype, we conducted whole-cell patch-clamp and immunoblot assays, utilizing both a heterologous expression system and patient-derived induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) with 453delC-KCNH2. We also explored the site of translational reinitiation by employing LC/MS mass spectrometry. Contrary to the previous assumption of early termination of translation, the findings of this study indicate that the 453delC-KCNH2 leads to an N-terminally truncated hERG channel, a potential from a non-canonical start codon, with diminished expression and reduced current (IhERG). The co-expression with wildtype KCNH2 produced heteromeric hERG channel with mild dominant-negative effect. Additionally, the heterozygote patient-derived iPSC-CMs exhibited prolonged action potential duration and reduced IhERG, which was ameliorated with the use of a hERG activator, PD-118057. The results of our study offer novel insights into the mechanisms involved in congenital LQTS associated with the 453delC mutation of KCNH2. The mutant results in the formation of less functional N-terminal-truncated channels with reduced amount of membrane expression. A hERG activator is capable of correcting abnormalities in both the heterologous expression system and patient-derived iPSC-CMs.

Effects of changes in daily life attributed to COVID-19 on allergic diseases among Korean adolescents.

OBJECTIVE: The daily lives of adolescents have changed significantly because of COVID-19 pandemic. We investigated the effects of changes in daily life attributed to COVID-19 on allergic diseases among Korean adolescents. METHODS: Data from the 2021 Korea Youth Risk Behavior Survey were used. In total, 54,848 survey participants were included in the analysis. Allergic diseases included allergic rhinitis, atopic dermatitis, and asthma. Changes attributed to COVID-19 included family economic difficulties, physical activity, breakfast skipping frequency, alcohol consumption, smoking, and depressive moods. Chi-square tests and multiple logistic regression analyses were conducted to examine the impact of changes in daily life attributed to COVID-19 on allergic diseases. RESULTS: Among the Korean adolescents surveyed, 29.8% experienced a deterioration in their economic status due to COVID-19, 49.1% reported decreased physical activity, 2.8% reported increased alcohol consumption, 1.0% reported an increase in their smoking behavior, and 36.9% reported an increase in depressive moods. Those diagnosed with atopic dermatitis, allergic rhinitis, or asthma within the previous 12 months accounted for 17.1%, 6.2%, and 1.0% of the population, respectively. Adolescents who were significantly affected by COVID-19 in their daily lives were frequently diagnosed with allergic diseases within the last 12 months. CONCLUSION: Changes in daily life due to COVID-19, including decreased physical activity and increased depressive mood, were common in adolescents and were associated with an increased prevalence of allergic diseases. Since changes in daily life due to the pandemic may increase the burden of allergic disease, additional interventions for disease management should be considered.

Requirement of ß subunit for the reduced voltage-gated Na+ current of a Brugada syndrome patient having novel double missense mutation (p.A385T/R504T) of SCN5A.

Mutations within the SCN5A gene, which encodes the α-subunit 5 (NaV1.5) of the voltage-gated Na+ channel, have been linked to three distinct cardiac arrhythmia disorders: long QT syndrome type 3, Brugada syndrome (BrS), and cardiac conduction disorder. In this study, we have identified novel missense mutations (p.A385T/R504T) within SCN5A in a patient exhibiting overlap arrhythmia phenotypes. This study aims to elucidate the functional consequences of SCN5A mutants (p.A385T/R504T) to understand the clinical phenotypes. Whole-cell patch-clamp technique was used to analyze the NaV1.5 current (INa) in HEK293 cells transfected with the wild-type and mutant SCN5A with or without SCN1B co-expression. The amplitude of INa was not altered in mutant SCN5A (p.A385T/R504T) alone. Furthermore, a rightward shift of the voltage-dependent inactivation and faster recovery from inactivation was observed, suggesting a gain-of-function state. Intriguingly, the coexpression of SCN1B with p.A385T/R504T revealed significant reduction of INa and slower recovery from inactivation, consistent with the loss-of-function in Na+ channels. The SCN1B dependent reduction of INa was also observed in a single mutation p.R504T, but p.A385T co-expressed with SCN1B showed no reduction. In contrast, the slower recovery from inactivation with SCN1B was observed in A385T while not in R504T. The expression of SCN1B is indispensable for the electrophysiological phenotype of BrS with the novel double mutations; p.A385T and p.R504T contributed to the slower recovery from inactivation and reduced current density of NaV1.5, respectively.

Validation and Comparison of the Japanese Score and Other Scores in Patients with Nonvariceal Upper Gastrointestinal Bleeding: A Retrospective Study.

BACKGROUND: Various scoring systems have been developed to predict endoscopic intervention, mortality, and rebleeding in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB); however, they have not been sufficiently validated in Korea. Therefore, this study aimed to evaluate the usefulness of several scoring systems in Korea by validating and comparing the Japanese score and other scores in Korean people with NVUGIB. METHODS: The medical records of 1,368 patients with NVUGIB were reviewed to collect statistical, clinical, laboratory, and endoscopic data. The Japanese score, ABC score, Glasgow-Blatchford Bleeding Score (GBS), and MAP score were calculated retrospectively at a single research institution. These scores for predicting the need for endoscopic intervention, mortality, and rebleeding were calculated and evaluated using the area under the receiver operating characteristic curve. RESULTS: Of 1,368 patients, 88.5% required endoscopic intervention, 4.1% died within 30 days, and 12.6% experienced rebleeding. The Japanese score was effective for predicting endoscopic intervention, and the ABC score was best for predicting 30-day mortality. Sex, age, hematemesis, blood urea nitrogen, and American Society of Anesthesiologists score were found to be predictors of the need for endoscopic intervention. CONCLUSION: The Japanese score did not prove useful in Koreans with upper gastrointestinal bleeding. Additional research is needed due to the limitations of a retrospective study conducted in a single research institute.

A comparative study of scoring systems that accurately predict the prognosis of lower gastrointestinal bleeding.

PURPOSE: Lower gastrointestinal (GI) bleeding can be fatal; therefore, several scoring systems have been developed to predict its prognosis. We compared the mortality predictions and evaluated the usefulness of various scoring systems. METHODS: The medical records of 3794 patients who visited the emergency department with hematochezia between January 2016 and December 2021 were retrospectively reviewed. We calculated the areas under the receiver operating characteristic curves for 30-day mortality and prolonged hospital stay (≥ 10 days) based on the age, blood tests, and comorbidities (ABC); AIMS65; Glasgow-Blatchford; Oakland; Rockall (pre-endoscopy); and SHA2PE scores and compared the predictive accuracy of each score. RESULTS: Data for 963 patients (median age, 69 years; males, 54.5%; median hospital stay, 6 days) with colonoscopy-confirmed lower GI bleeding were analyzed. The 30-day mortality rate was 3.5%; the most common causes of lower GI bleeding were ischemic colitis and diverticulum bleeding in 19.3% and 19.2% of the cases, respectively. The AIMS65 and ABC scores were superior in predicting 30-day mortality (p < 0.001). The SHA2PE score was the most accurate predictor of prolonged hospital stay (p < 0.001). Through multivariate regression analysis, 30-day mortality was correlated with albumin level ≤ 3.0 g/dL, international normalized ratio > 1.5, blood urea nitrogen level ≥ 30 mg/dL, and systolic blood pressure (SBP) < 100 mmHg. A prolonged hospital stay was correlated with liver cirrhosis, hemoglobin ≤ 10 g/dL, albumin level ≤ 3.0 g/dL, and SBP < 100 mmHg. CONCLUSION: The recently developed scoring systems accurately predict lower GI bleeding prognosis, and their usefulness in clinical decision-making was confirmed.

Is colorectal endoscopic submucosal dissection safe and effective for 15-19-mm tumors?

PURPOSE: The outcomes of colorectal endoscopic submucosal dissection (ESD) in 15-19-mm tumors are unclear. This study compared the effectiveness and safety of colorectal ESD for 15-19-mm tumors and tumors exceeding that size. METHODS: From August 2018 to December 2020, 213 cases of colorectal tumors removed by colorectal ESD at a tertiary hospital were enrolled in this study. The cases were divided into two groups according to the pathologically measured size of the resected lesion: an intermediate group (15-19 mm, n = 62) and a large group (≥ 20 mm, n = 151). The en bloc resection rate, complete resection rate, and complications were investigated retrospectively. RESULTS: The en bloc resection rate was significantly higher in the intermediate than large group (100% vs. 94%, p = 0.049), and the mean total procedure time was shorter in the intermediate than large group (29.2 [Formula: see text] 12.6 vs. 48.4 [Formula: see text] 28.8 min, p < 0.001). However, the mean procedure speed was significantly lower in the intermediate than large group (0.25 [Formula: see text] 0.10 vs. 0.28 [Formula: see text] 0.11 cm2/min, p = 0.031). The complete resection rate, post-procedural bleeding, and perforation rate were not significantly different between the two groups. In multivariate analyses, the total procedure time and mean procedure speed were significantly associated with lesion size. CONCLUSION: Colorectal ESD of 15-19-mm lesions is effective, and has a shorter procedure time and higher en bloc resection rate than the same procedure for larger lesions.

Lower socioeconomic status associated with higher tuberculosis rate in South Korea.

BACKGROUND: Tuberculosis is an infectious disease influenced by social factors rather than a simple infectious disease. In this study, we investigated the relationship between tuberculosis rates and socioeconomic status. METHODS: This study was conducted using data of the 49,483 participants of the Korean National Health and Nutrition Examination Survey (KNHANES) VI-VIII (2013-2021). The relationships between tuberculosis rates and the quartiles of monthly household income and education level were examined using a multivariate logistic regression analysis. RESULTS: The KNHANES data revealed that the prevalence of tuberculosis as substantially related to monthly household income (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.1-32.0 for lowest vs. highest incomes) and education level (OR, 3.8; 95% CI, 1.2-12.0 for 10-12 years vs. ≥13 years; OR, 4.1; 95% CI, 1.2-14.8 for ≤ 6 years vs. ≥13 years). Furthermore, current tuberculosis treatment was significantly related to monthly household income and education level. CONCLUSION: There were substantial correlations between tuberculosis rates and socioeconomic status in South Korea.

The growth status of North Korean refugee adolescents in South Korea: comparison with South Korean adolescents.

AIM: To assess the growth status of North Korean refugee adolescents (NKRA) living in South Korea (SK) and compare their growth status with that of SK adolescents (SKA). SUBJECTS AND METHODS: NKRA were interviewed from 2017 to 2020, whereas the data for SKA were from the 2016 to 2018 Korea National Health and Nutrition Examination Surveys. SKA and NKRA were matched by age and gender in a 3:1 ratio and 534 SKA and 185 NKRA were enrolled. RESULTS: After adjusting for the covariates, NKRA had greater prevalences of thinness (odds ratio [OR], 11.5; 95% confidence interval [CI], 2.9-45.6) and obesity (OR, 12.0; 95% CI, 3.1-46.1) than SKA, but were not of short stature. In comparison with SKA in low-income families, NKRA had similarly greater prevalences of thinness and obesity, but not of short stature. As the length of stay of NKRA in SK increased, the prevalence of short stature and thinness did not decrease, while the prevalence of obesity increased significantly. CONCLUSION: Although they had lived in SK for several years, NKRA had greater prevalences of thinness and obesity than SKA and the prevalence of obesity increased significantly with the length of stay in SK.

Anti-Inflammatory Effects of Alphitolic Acid Isolated from Agrimonia coreana Nakai Extracts Are Mediated via the Inhibition of ICRAC Activity in T Cells.

Agrimonia pilosa Ledeb., an important medicinal herb in traditional East Asian medicine, is primarily used to treat abdominal pain, dysentery, and hemostasis. There are ten other reported species of Agrimonia plants, including Agrimonia coreana Nakai-a naturally growing species in South Korea-and Agrimonia eupatoria Linn. Although recent studies have isolated numerous active constituents and investigated their effects, the medicinal utility of this herb is not yet fully explored. Through patch-clamp recording, a previous study reported that Agrimonia plant extracts inhibit the function of Ca2+ release-activated Ca2+ channels (CRACs). Herein, we aimed to identify and isolate the main compounds in A. coreana responsible for CRAC inhibition while assessing the anti-inflammatory effects mediated by this inhibition. We demonstrated for the first time that alphitolic acid isolated from A. coreana has a dose-dependent inhibitory effect on CRAC activity and, thus, an inhibitory effect on intracellular calcium increase. Furthermore, analysis of human CD4+ T cell proliferation via the carboxyfluorescein diacetate succinimidyl ester method revealed that alphitolic acid inhibited T cell proliferation in a concentration-dependent manner. Our findings provide a theoretical basis for the potential therapeutic use of alphitolic acid in the treatment of inflammatory diseases.

Association between alcohol and bone mineral density in a Mendelian randomization study: the Dong-gu study.

INTRODUCTION: Many previous studies have reported a positive relationship between alcohol and bone mineral density (BMD). However, the causality between alcohol and BMD has not been fully evaluated. MATERIALS AND METHODS: This study enrolled 8892 participants from the Dong-gu study. Mendelian randomization (MR) using two-stage least-squared regression was used to evaluate the association between the genetically predicted amount of alcohol consumption per day and BMD. The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism was used as instrumental variables for alcohol consumption. Age, smoking history, and BMI were adjusted in the multivariate model. RESULTS: Self-reported alcohol consumption was positively related to total hip and lumbar spine BMD in both sexes. In multivariate Mendelian randomization analysis, the genetically predicted amount of alcohol consumption was positively associated with both total hip and lumbar spine BMD in men. Total hip BMD and lumbar spine BMD increased by 0.004 g/cm2 (95% confidence interval [CI] 0.002-0.007) and 0.007 g/cm2 (95% CI 0.004-0.011) with doubling of alcohol consumption. However, in women, genetically predicted alcohol consumption was not significantly associated with BMD. CONCLUSION: In our MR study, genetically predicted alcohol consumption was positively associated with BMD in men. This result suggests that the association between alcohol consumption and BMD is causal.

Higher expression of KCNK10 (TREK-2) K+ channels and their functional upregulation by lipopolysaccharide treatment in mouse peritoneal B1a cells.

Innate-like CD5+ B1a cells localized in serous cavities are activated by innate stimuli, such as lipopolysaccharide (LPS), leading to T cell-independent antibody responses. Although ion channels play crucial roles in the homeostasis and activation of immune cells, the electrophysiological properties of B1a cells have not been investigated to date. Previously, in the mouse B cell lymphoma cells, we found that the voltage-independent two-pore-domain potassium (K2P) channels generate a negative membrane potential and drive Ca2+ influx. Here, we newly compared the expression and activities of K2P channels in mouse splenic follicular B (FoB), marginal zone B (MZB), and peritoneal B1a cells. Next-generation sequencing analysis showed higher levels of transcripts for TREK-2 and TWIK-2 in B1a cells than those in FoB or MZB cells. Electrophysiological analysis, using patch clamp technique, revealed higher activity of TREK-2 with the characteristic large unitary conductance (~ 250 pS) in B1a than that in FoB or MZB cells. TREK-2 activity was further increased by LPS treatment (>2 h), which was more prominent in B1a than that in MZB or FoB cells. The cytosolic Ca2+ concentration of B cells was decreased by high-K+-induced depolarization (ΔRKCl (%)), suggesting the basal Ca2+ influx to be driven by negative membrane potential. The LPS treatment significantly increased the ΔRKCl (%) in B1a, though not in FoB and MZB cells. Our study was the first to compare the K2P channels in mouse primary B cell subsets, elucidating the functional upregulation of TREK-2 and augmentation of Ca2+ influx by the stimulation of Toll-like receptor 4 in B1a cells.

Thermosensitivity of the voltage-dependent activation of calcium homeostasis modulator 1 (calhm1) ion channel.

Calcium homeostasis modulator 1 (calhm1) proteins form an outwardly rectifying nonselective ion channel having exceedingly slow kinetics and low sensitivity to voltage that is shifted by lowering extracellular Ca2+ ([Ca2+]e). Here we found that physiological temperature dramatically facilitates the voltage-dependent activation of the calhm1 current (Icalhm1); increased amplitude (Q10, 7-15) and fastened speed of activation. Also, the leftward shift of the half-activation voltage (V1/2) was similary observed in the normal and lower [Ca2+]e. Since calhm1 is highly expressed in the brain and taste cells, the thermosensitivity should be considered in their electrophysiology.

Association between Alcohol Consumption and Serum Cortisol Levels: a Mendelian Randomization Study.

BACKGROUND: Several studies have reported conflicting results regarding the relationship between alcohol consumption and cortisol levels. However, the causality between alcohol consumption and cortisol levels has not been evaluated. METHODS: This study examined 8,922 participants from the Dong-gu Study. The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism was used as an instrumental variable for alcohol consumption. The association between the genetically predicted alcohol consumption and cortisol level was evaluated with Mendelian randomization (MR) using two-stage least squares regression. RESULTS: Alcohol consumption was positively associated with the serum cortisol level in both sexes in the observational analysis. In the MR analysis, the genetically predicted alcohol consumption was positively related to the cortisol level in men, with cortisol levels increasing by 0.18 µg/dL per drink per day. However, there was no relationship in women in the MR analysis. CONCLUSION: The predicted alcohol consumption according to the ALDH2 rs671 polymorphism was positively related to the cortisol levels, suggesting a causal relationship between alcohol consumption and cortisol levels.

Impact of High-Dose Irradiation on Human iPSC-Derived Cardiomyocytes Using Multi-Electrode Arrays: Implications for the Antiarrhythmic Effects of Cardiac Radioablation.

Cardiac radioablation is emerging as an alternative option for refractory ventricular arrhythmias. However, the immediate acute effect of high-dose irradiation on human cardiomyocytes remains poorly known. We measured the electrical activities of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) upon irradiation with 0, 20, 25, 30, 40, and 50 Gy using a multi-electrode array, and cardiomyocyte function gene levels were evaluated. iPSC-CMs showed to recover their electrophysiological activities (total active electrode, spike amplitude and slope, and corrected field potential duration) within 3-6 h from the acute effects of high-dose irradiation. The beat rate immediately increased until 3 h after irradiation, but it steadily decreased afterward. Conduction velocity slowed in cells irradiated with ≥25 Gy until 6-12 h and recovered within 24 h; notably, 20 and 25 Gy-treated groups showed subsequent continuous increase. At day 7 post-irradiation, except for cTnT, cardiomyocyte function gene levels increased with increasing irradiation dose, but uniquely peaked at 25-30 Gy. Altogether, high-dose irradiation immediately and reversibly modifies the electrical conduction of cardiomyocytes. Thus, compensatory mechanisms at the cellular level may be activated after the high-dose irradiation acute effects, thereby, contributing to the immediate antiarrhythmic outcome of cardiac radioablation for refractory ventricular arrhythmias.

Increased inward rectifier K+ current of coronary artery smooth muscle cells in spontaneously hypertensive rats; partial compensation of the attenuated endothelium-dependent relaxation via Ca2+ -activated K+ channels.

Endothelium-dependent vasorelaxation is partly mediated by small-conductance (SK3) and intermediate-conductance Ca2+ -activated K+ channels (SK4) in the endothelium that results in endothelium-dependent hyperpolarization (EDH). Apart from the electrical propagation through myoendothelial gap junctions, the K+ released from the endothelium facilitates EDH by increasing inward rectifier K+ channel (Kir) conductance in smooth muscle cells. The EDH-dependent relaxation of coronary artery (CA) and Kir current in smooth muscle cells (CASMCs) of hypertensive animals are poorly understood despite the critical role of coronary flow in the hypertrophic heart. In spontaneously hypertensive (SHR) and control (WKY) rats, we found attenuation of the CA relaxation by activators of SK3 and SK4 (NS309 and 1-EBIO) in SHR. In isolated CASMCs, whole-cell patch-clamp study revealed larger IKir in SHR than WKY, whereas the myocytes of skeletal and cerebral arteries showed smaller IKir in SHR than WKY. While the treatment with IKir inhibitor (0.1 mmol/L Ba2+ ) alone did not affect the WKY-CA, the SHR-CA showed significant contractile response, suggesting relaxing influence of the higher IKir in the CASMCs of SHR. Furthermore, the attenuation of NS309-induced relaxation of CA by the combined treatment with 0.1 mmol/L Ba2+ was more prominent in SHR than WKY. Our study firstly shows a distinct increase of IKir in the CASMCs of SHR, which could partly compensate for the attenuated relaxation via endothelial SK3 and SK4.

Effect Modification of Acetaldehyde Dehydrogenase 2 rs671 Polymorphism on the Association between Alcohol Intake and Blood Pressure: the Dong-gu Study.

BACKGROUND: Elevated blood pressure is a major preventable cause of cardiovascular diseases. Alcohol consumption is a well-known risk factor of elevated blood pressure. The aldehyde dehydrogenase 2 (ALDH2) polymorphism is common in Eastern Asians, and inactive ALDH2 genotypes are associated with both avoiding alcohol consumption and aldehyde accumulation. Therefore, this study assessed the associations between alcohol consumption and hypertension and blood pressure according to the ALDH2 genotypes. METHODS: This study consists of 8,526 participants in the Dong-gu Study. Multivariate logistic regression was used to calculate the odds ratio (OR) according to alcohol consumption after stratifying by gender and ALDH2 genotypes. Multivariate linear regression was performed to estimate the systolic blood pressure (SBP) and diastolic blood pressure (DBP) according to the amount of alcohol consumed. RESULTS: In men, alcohol consumption was positively associated with both SBP and DBP in active ALDH2 carriers, but not in inactive ALDH2 carriers. In active ALDH2 carriers, compared to non-drinkers, the OR of hypertension was 1.16 (95% confidence interval [CI], 0.91-1.49) for < 1 drink/day, and 1.44 (95% CI, 1.15-1.80) for ≥ 1 drink/day in men. With each 1 drink/day increase, SBP and DBP increased by 3 and 1 mmHg in men, respectively. There was no significant association between ALDH2 genotypes and hypertension and blood pressure in women. CONCLUSION: ALDH2 genotype modified the association between alcohol consumption and blood pressure in men. There was a positive relationship between alcohol consumption and blood pressure in active ALDH2 carriers, but no significant relationship in inactive ALDH2 carriers.

The novel high-frequency variant of TRPV3 p.A628T in East Asians showing faster sensitization in response to chemical agonists.

TRPV3, a member of the thermosensitive Ca2+-permeable TRPV channel subfamily expressed in skin and sensory nerves, is also activated by chemical agonists such as 2-aminoethyl diphenylborinate (2-APB). Repetitive stimuli induce sensitization of TRPV3 activation, characterized by the cumulative increase in current amplitude and linearization of current-voltage relation (I/V curve). Through genomic analysis of various populations, we found non-rare TRPV3 mutation (p.A628T) in East Asian people with an allele frequency of 0.249 while 0.007 in Caucasian. Slope conductance of unitary channel was not different between WT and p.A628T. Whole-cell patch clamp study of wildtype TRPV3 (WT) and p.A628T overexpressed in HEK293T cells showed similar sensitization by the repetitive increase in temperature from 23 to 37 °C, while slightly higher sensitization to 43 °C in p.A628T. In contrast, the repetitive application of 2-APB (10 µM) or carvacrol (100 µM) induced faster sensitization in p.A628T than WT. However, 1 µM farnesyl pyrophosphate, an intrinsic lipid metabolite agonist, induced similar level of slow activations in WT and p.A628T. In Fura-2 microspectrofluorimetry, the 2-APB pulses induced a faster increase of [Ca2+]c in p.A628T than WT. In terms of ionic selectivity of channels, WT and p.A628T showed similar Ca2+ permeability (PCa/PNa) calculated from the reversal potential of I/V curves. Taken together, p.A628T shows faster sensitization to chemical agonists that are reflected as higher [Ca2+]c signaling. Based on the intriguing pharmacological sensitivity, the physiological implications of p.A628T in the East Asian population require further investigation.

Serum level vitamin D and parathyroid hormone, and mortality, with or without chronic kidney disease.

Levels of vitamin D and parathyroid hormone (PTH) are closely associated with renal function. We evaluated the associations among 25-hydroxyvitamin D (25OHD) levels, PTH levels, and mortality, and whether these associations varied by renal function. We used data from the Dong-gu Study, a population-based cohort in Korean adults. We analyzed the associations among intact PTH, 25OHD levels and mortality in 8580 participants. Hazard ratios (HRs) for mortality were calculated using Cox proportional hazards regression after adjusting for age, sex, month of sampling, lifestyle, and comorbidities. We also evaluated the effects of chronic kidney disease (CKD). A total of 860 deaths occurred during the follow-up period of 7.6 years. Compared to the first 25OHD quartile, the HRs of the second, third, and fourth quartiles were 0.96 [95% confidence interval (CI) 0.79-1.16], 0.84 (95% CI 0.68-1.02), and 0.71 (95% CI 0.57-0.89), respectively. The association between intact PTH levels and mortality varied by renal function, and was both nonlinear and significant only in subjects with CKD. Compared to the second intact PTH quartile in such subjects, the HRs for the first, third, and fourth quartiles were 1.61 (95% CI 0.92-2.81), 1.97 (95% CI 1.17-3.31), and 2.19 (95% CI 1.33-3.59), respectively. In conclusion, we demonstrated that low serum levels of 25OHD are associated with an increased risk of mortality. Serum levels of intact PTH are nonlinearly associated with mortality only in subjects with CKD, with the lowest risk for mortality being evident in the second quartile.

The Association between the Apolipoprotein E Gene Polymorphism and All-cause Mortality in the Korean Population.

BACKGROUND: Apolipoprotein E (APOE) gene polymorphism is associated with neurodegenerative and cardiovascular diseases. Although the effects of the gene differ by ethnic group, few studies have examined Asians. Therefore, the association between APOE polymorphism and mortality in Koreans was evaluated in this study. METHODS: This study population included participants from the Dong-gu and Namwon Studies. APOE genotypes were categorized as E2 (E2/E2 and E2/E3), E3 (E3/E3), and E4 (E3/E4 and E4/E4). Multivariate Cox proportional hazard models were constructed using the E3 allele as a reference. RESULTS: In the model adjusting for study site, age, gender, and lifestyle, the hazard ratio (HR) of mortality for those with the E4 allele was 1.08 (95% confidence interval [CI], 0.97-1.20), while that for those with the E2 allele was 0.84 (95% CI, 0.74-0.96). After adjusting for blood lipids to evaluate their mediating effects, the HRs of mortality for those with E4 and E2 alleles were 1.08 (95% CI, 0.97-1.20) and 0.80 (95% CI, 0.70-0.92), respectively. These associations were more evident in younger groups, with HRs of 0.70 (95% CI, 0.52-0.92) for the E2 allele and 1.25 (95% CI, 1.03-1.53) for the E4 allele. CONCLUSION: In two large population-based cohort studies, the E2 allele was associated with a lower risk of mortality compared with the E3 allele, whereas the E4 genotype was not associated with mortality in Koreans.

Sevoflurane, Propofol and Carvedilol Block Myocardial Protection by Limb Remote Ischemic Preconditioning.

The effects of remote ischemic preconditioning (RIPC) in cardiac surgery have been inconsistent. We investigated whether anesthesia or beta-blockers interfere with RIPC cardioprotection. Fifty patients undergoing cardiac surgery were randomized to receive limb RIPC (four cycles of 5-min of upper arm cuff inflation/deflation) in the awake state (no-anesthesia; n = 17), or under sevoflurane (n = 17) or propofol (n = 16) anesthesia. In a separate crossover study, 11 healthy volunteers received either carvedilol or no medication prior to RIPC. Plasma dialysates were obtained and perfused through an isolated male Sprague⁻Dawley rat heart subjected to 30-min ischemia/60-min reperfusion, following which myocardial infarct (MI) size was determined. In the cardiac surgery study, pre-RIPC MI sizes were similar among the groups (39.7 ± 4.5% no-anesthesia, 38.9 ± 5.3% sevoflurane, and 38.6 ± 3.6% propofol). However, post-RIPC MI size was reduced in the no-anesthesia group (27.5 ± 8.0%; p < 0.001), but not in the anesthesia groups (35.7 ± 6.9% sevoflurane and 35.8 ± 5.8% propofol). In the healthy volunteer study, there was a reduction in MI size with RIPC in the no-carvedilol group (41.7 ± 4.3% to 30.6 ± 8.5%; p < 0.0001), but not in the carvedilol group (41.0 ± 4.0% to 39.6 ± 5.6%; p = 0.452). We found that the cardioprotective effects of limb RIPC were abolished under propofol or sevoflurane anesthesia and in the presence of carvedilol therapy.