Gaeun Kang

Regulation of Acetylation of Histone Deacetylase 2 by p300/CBP-Associated Factor/Histone Deacetylase 5 in the Development of Cardiac Hypertrophy

Rationale: Histone deacetylases (HDACs) are closely involved in cardiac reprogramming. Although the functional roles of class I and class IIa HDACs are well established, the significance of interclass crosstalk in the development of cardiac hypertrophy remains unclear. Objective: Recently, we suggested that casein kinase 2&agr;1–dependent phosphorylation of HDAC2 leads to enzymatic activation, which in turn induces cardiac hypertrophy. Here we report an alternative post-translational activation mechanism of HDAC2 that involves acetylation of HDAC2 mediated by p300/CBP-associated factor/HDAC5. Methods and Results: Hdac2 was acetylated in response to hypertrophic stresses in both cardiomyocytes and a mouse model. Acetylation was reduced by a histone acetyltransferase inhibitor but was increased by a nonspecific HDAC inhibitor. The enzymatic activity of Hdac2 was positively correlated with its acetylation status. p300/CBP-associated factor bound to Hdac2 and induced acetylation. The HDAC2 K75 residue was responsible for hypertrophic stress–induced acetylation. The acetylation-resistant Hdac2 K75R showed a significant decrease in phosphorylation on S394, which led to the loss of intrinsic activity. Hdac5, one of class IIa HDACs, directly deacetylated Hdac2. Acetylation of Hdac2 was increased in Hdac5-null mice. When an acetylation-mimicking mutant of Hdac2 was infected into cardiomyocytes, the antihypertrophic effect of either nuclear tethering of Hdac5 with leptomycin B or Hdac5 overexpression was reduced. Conclusions: Taken together, our results suggest a novel mechanism by which the balance of HDAC2 acetylation is regulated by p300/CBP-associated factor and HDAC5 in the development of cardiac hypertrophy.

Escitalopram treatment for depressive disorder following acute coronary syndrome: a 24-week double-blind, placebo-controlled trial.

OBJECTIVE Depression is common after acute coronary syndrome (ACS) and has adverse effects on prognosis. There are few evidence-based interventions for treating depression in ACS. This study investigated the efficacy and safety of escitalopram in treating depressive disorders identified 2-14 weeks after a confirmed ACS episode. METHOD A total of 217 patients with DSM-IV depressive disorders (121 major and 96 minor) and ACS were randomly assigned to receive escitalopram in flexible doses of 5-20 mg/d (n = 108) or placebo (n = 109) for 24 weeks. The study was conducted from 2007 to 2013. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS). Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), Clinical Global Impressions-Severity of Illness scale (CGI-S), Social and Occupational Functioning Assessment Scale (SOFAS), and World Health Organization Disability Assessment Schedule-12. Cardiovascular safety outcomes included echocardiography, electrocardiography, laboratory test, body weight, and blood pressure results. RESULTS Escitalopram was superior to placebo in reducing HDRS scores (mean difference = 2.3, P = .016, effect size = 0.38). Escitalopram was also superior to placebo in decreasing depressive symptoms evaluated by the MADRS, BDI, and CGI-S and in improving SOFAS functioning level. Escitalopram was not associated with any harmful changes in cardiovascular safety measures. Dizziness was significantly more frequently reported in the escitalopram group (P = .018), but there were no significant differences in any other adverse events. CONCLUSIONS These results indicate that escitalopram has clinically meaningful antidepressant effects with no evidence of reduced cardiovascular safety in depressive disorder following ACS. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00419471.

Effect of the allelic variant of alcohol dehydrogenase ADH1B*2 on ethanol metabolism.

BACKGROUND It has been known that ADH1B*2 allele has a protective effect against the development of alcohol dependence. However, the protection mechanism is still unknown. We investigated whether ADH1B gene polymorphism affects ethanol (EtOH) metabolism. METHODS In a parent study, we conducted a randomized crossover trials on 24 healthy male subjects who were selected by genotyping: 12 with ALDH2*1/*1 (active form) and 12 with ALDH2*1/*2 (inactive form). In the present study, the 24 subjects were reclassified into 2 groups of 11 with ADH1B*1/*2 and 13 with ADH1B*2/*2 according to the ADH1B genotypes. Each subject was administered 1 of 3 doses of EtOH (0.25, 0.5, 0.75 g/kg) or a placebo in 4 trials. After the administration of alcohol, blood EtOH and acetaldehyde concentrations were measured 9 times over 4 hours. RESULTS In the case of EtOH, the area under the concentration-time curve from 0 to 4 hours (AUC0-4 ) and the peak blood concentration of EtOH (Cmax ) in subjects with ADH1B*2/*2 were significantly higher than those in subjects with ADH1B*1/*2 at all 3 dosages before stratifying by ALDH2 genotype. However, after stratifying by ALDH2 genotype, a statistically significant difference between ADH1B*2/*2 and ADH1B*1/*2 was found only at the 0.5 g/kg dosage regardless of ALDH2 genotype. In the case of acetaldehyde, the AUC0-4 and Cmax of acetaldehyde of ADH1B*2/*2 after administration of 0.25 g/kg alcohol and the AUC0-4 of acetaldehyde of ADH1B*2/*2 at 0.5 g/kg were significantly higher than corresponding values of ADH1B*1/*2 only in the group of ALDH2*1/*2. CONCLUSIONS Our findings indicate that the blood EtOH concentrations of ADH1B*2/*2 group are higher than those of ADH1B*1/*2 group regardless of ALDH2 genotype, and the blood acetaldehyde concentrations of ADH1B*2/*2 are also higher than those of ADH1B*1/*2 only in the ALDH2*1/*2 group. To our knowledge, this is the first report to demonstrate the association of ADH1B*2 allele with blood EtOH and acetaldehyde levels in humans, and these results suggest that higher blood EtOH and acetaldehyde concentrations in ADH1B*2/*2 may constitute the mechanism of protection against alcoholism by ADH1B*2/*2.

Associations between serum lipid levels and suicidal ideation among Korean older people.

INTRODUCTION There have been inconsistent reports on the relationships between lipids and suicidality, and studies conducted in older adults are rare. This study examined associations between serum lipid levels and suicidal ideation in an older population. METHODS This study used data obtained from a representative Korean sample of 4265 people age 65 years or older who completed a self-administered questionnaire about suicidal ideation over the last year. The fasting serum concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured and categorized into lower, intermediate (reference), and upper quartiles. A complex sample logistic regression stratified by gender was performed to determine the associations between serum lipid levels and suicidal ideation after controlling for covariates including age, education, marital status, current smoking, alcohol drinking, body mass index, hypertension, diabetes, diagnosed depression, antidepressant use, and lipid-lowering therapies. RESULTS In this study, the prevalence of suicidal ideation in an older Korean population was 22.9% (SE=0.9%). The prevalence was significantly higher in women than in men, 27.7% (1.2%) vs. 15.9% (1.1%) respectively. After adjusting for covariates, lower triglyceride levels were significantly associated with a decreased risk of suicidal ideation (OR=0.65; 95% CI=0.43-0.99) among men but no significant associations were observed among women. Additionally, there were no significant associations between any other measure of cholesterol levels and suicidal ideation in either men or women. LIMITATIONS Cross-sectional design cannot infer temporality or the effects of changes in variables. CONCLUSIONS These results support the association between lower triglyceride levels and a reduced risk of suicidal ideation among Korean men over 65. Further studies are necessary to investigate gender difference and the biological mechanism.

Caffeine counteracts impairments in task-oriented psychomotor performance induced by chlorpheniramine: a double-blind placebo-controlled crossover study.

This study aimed to evaluate the effects of chlorpheniramine on psychomotor performance and the counteracting effects of caffeine on those sedative antihistamine actions. Sixteen healthy young men participated in this study. Using a double-blind placebo-controlled crossover design, each subject was administered one of the following conditions in a random order with a one-week interval: ‘placebo-placebo’, ‘4 mg of chlorpheniramine-placebo’, ‘placebo-200 mg of caffeine’ or ‘4 mg of chlorpheniramine-200 mg of caffeine’. Before and after the treatments, psychomotor functions were assessed using a battery of tests. Additionally, subjective responses were assessed using a visual analogue scale (VAS). Psychomotor performance changed over time in different ways according to the combination of study medications. In the ‘chlorpheniramine-placebo’ condition, reaction times of the compensatory tracking task were significantly impaired compared with the other three conditions. In addition, the number of omission errors of the continuous performance test were significantly greater compared with the ‘placebo-caffeine’ condition. However, the response pattern of the ‘chlorpheniramine-caffeine’ condition was not significantly different from that of the ‘placebo-placebo’ condition. Changes of VAS for sleepiness were significantly greater in the ‘chlorpheniramine-placebo’ condition compared with the other three conditions. In conclusion, chlorpheniramine significantly increases subjective sleepiness and objectively impairs psychomotor performance. However, caffeine counteracts these sedative effects and psychomotor impairments.

Associations between sleep duration and abnormal serum lipid levels: data from the Korean National Health and Nutrition Examination Survey (KNHANES)

BACKGROUND Shorter or longer sleep duration has been reported to be associated with abnormal serum lipid levels, but the findings have been inconsistent. This study examined associations between sleep duration and abnormal serum lipid levels in a Korean adult population. METHODS This study used the data of 13,609 people aged ≥20 years from the Korean National Health and Nutrition Examination Survey (KNHANES) in 2010-2012. Sleep duration was classified into five groups: ≤5, 6, 7 (reference category), 8, and ≥9 hours. The serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride were measured and defined in terms of abnormal serum lipid levels. Multiple logistic regressions were performed to determine the associations between sleep duration and abnormal serum lipid levels. The covariates included age, sex, education, marital status, current smoking, alcohol consumption, physical activity, body mass index, hypertension, diabetes, depressive symptoms, and stress level. RESULTS Self-reported sleep duration of ≤5 hours was significantly associated with high TC and high LDL-C levels in unadjusted models, but after adjusting for age and sex, the statistical significance disappeared. On the other hand, after adjusting for covariates, self-reported sleep duration of ≥9 h was significantly associated with low HDL-C levels (odds ratio = 1.30; 95% confidence interval = 1.09-1.54). CONCLUSIONS These findings suggest that longer sleep duration is associated with low HDL-C levels among Korean adults.

Relationships between high-density lipoprotein cholesterol and depressive symptoms: Findings of the Korean National Health and Nutrition Examination Survey (KNHANES)

Although serum cholesterol has been associated with late-life depression, few studies on the associations between lipids and depression among middle-aged adults have been performed. This study examined associations between serum lipid levels and depressive symptoms in Korean middle-aged adults. We used data from 8207 participants aged 40-64 years who completed a questionnaire about their experience of depressive symptoms over the last year as part of the 2010-2012 Korean National Health and Nutrition Examination Survey. Higher HDL-C levels were significantly associated with an elevated risk of depressive symptoms (OR=1.32; 95% CI=1.09-1.60) after adjusting for other covariates.

Usefulness of Age-Stratified N-Terminal Prohormone of Brain Natriuretic Peptide for Diagnosing Kawasaki Disease

N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was recently reported as a biomarker for diagnosing Kawasaki disease (KD). The basal NT-proBNP level, however, gradually decreases with age. We investigated the usefulness of an age-stratified cutoff value of NT-proBNP for diagnosing KD. All the patients enrolled in this study visited Chonnam National University Hospital between December 2007 and March 2016. The KD groups consisted of 214 patients with complete KD and 129 patients with incomplete KD. The control group included 62 children with simple febrile illness but without heart disease. Laboratory data including NT-proBNP level were evaluated. Each group was divided into subgroups according to patient age (<6 months, 6–12 months, 12–24 months, and >24 months), and different cutoff values of NT-proBNP were calculated. The cutoff values of NT-proBNP used to diagnose total KD and incomplete KD were 762 and 762 pg/mL (<6 months), 310 and 310 pg/mL (6–12 months), 326 and 326 pg/mL (12–24 months), and 208 and 137 pg/mL (>24 months), respectively. In conclusion, age-stratified NT-proBNP is a useful biomarker for the differential diagnosis of KD in patients with a simple febrile illness.

Associations between serum lipid levels and depressive symptom in a Korean older population.

Depression is a frequent cause of emotional suffering in later life and significantly decreases quality of life in older adults. Serum cholesterol has been reported to be associated with depression in late life, but the findings have been inconsistent (Olusi and Fido, 1996; Aijanseppa et al., 2002; Kim et al., 2004; Ancelin et al., 2010). Furthermore, only a few studies have investigated the association between lipid and depression in Asian populations. This study examined associations between serum lipid levels and depressive symptom in a Korean older population using a nationally representative survey. Depression Inventory: T0=16; T1=15.25; T2=16.75). Figure 1 summarizes the main results of the study. Behavioral disturbances and in particular depression showed a global decrease: the most part of PWD improved in psychological outcomes showing a positive trend. This trend underlined a possible relationship between the improvement and AMT treatment. Cognitive profile showed a slight worsening at T1 in all PWD and a small increase of MMSE scores can be observed at T2. Considering the shortness of the intervention and the kind of music therapy approach, significant changes in cognitive domains were not looked for. Significant results were obtained on FC in anxiety and burden reduction in which all subjects showed a remarkable improvement at T1 and sometimes also at follow-up. Also in depression symptom, the most part of FC slightly improved. These preliminary data proved the effects of AMT approach both on PWD and their FC, in particular on behavioral and psychological symptoms. The intervention was perceived by FC as an important support in the management of PWDs’ behavioral and communicative disturbances. Thus, sonorous-music and nonverbal communication led by a trained music therapist can be considered a possible way to promote the relationship between PWD and FC reducing their feeling of frustration and the burden caused by management disease. Future studies focusing on stronger research methodology (randomized controlled trials) and assessment are needed to confirm these results and to implement AMT approach as an effective nonpharmacological intervention for PWD/FC couples.

A Randomized, Double-Blind Pilot Study of Dose Comparison of Ramosetron to Prevent Chemotherapy-Induced Nausea and Vomiting

Purpose. This study was conducted to determine the optimal dose titration of ramosetron to prevent the Rhodes Index of Nausea, Vomiting, and Retching (RINVR). Methods. Patients treated with folic acid, 5-fluorouracil, and oxaliplatin were randomized into three groups (0.3 mg, 0.45 mg, and 0.6 mg ramosetron before chemotherapy). The pharmacokinetics and pharmacodynamics using RINVR were evaluated. Results. Seventeen, 15, and 18 patients received ramosetron at doses of 0.3 mg, 0.45 mg, and 0.6 mg, respectively. T max (h), C max (ng/mL), and AUClast (ng·h/mL) were associated with dose escalation significantly, showing a reverse correlation with the RINVR during chemotherapy. Acute CINV was observed in four patients (22.2%), two patients (14.3%), and one (5.6%) patient and a delayed CINV on day 7 was found in eight (47%), three (21.4%), and five (27.8%) patients in each group. The complete response rate was increased with dose escalation (35.3%, 50.0%, and 72.2% in each group) and also showed the tendency for decreasing moderate-to-severe CINV. Conclusions. This study shows a trend regarding the dose-response relationship for ramosetron to prevent CINV, including delayed emesis. It suggested that dose escalation should be considered in patients with CINV in a subsequent cycle of chemotherapy, and an individual approach using RINVR could be useful to monitor CINV.