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LATAR BELAKANG : Saat ini, berbagai tanaman asli Indonesia dikembangkan sebagai bahan perawatan luka untuk hasil penyembuhan yang lebih baik. Salah satunya, yaitu Moringa oleifera L., yang merupakan tanaman asli Indonesia serta berpotensi dapat membantu penyembuhan luka melalui regulasi jalur sitokin inflamasi, interleukin (IL)-1 dan IL-10. TUJUAN : Untuk mengetahui pengaruh pemberian ekstrak Moringa oleifera L. terhadap IL-1, IL-10, dan rasio IL-1: IL-10 di jaringan kulit, pada tikus dengan luka insisi. METODE : Penelitian ini menggunakan desain post test only controlled group dengan sampel berupa 15 tikus Wistar yang dilakukan luka insisi. Sampel dibagi menjadi 3 kelompok perlakuan: perawatan luka dengan framycetin sulphate (KP), krim ekstrak Moringa oleifera L. 15% (M), dan krim plasebo (KN). Pengukuran kadar IL-1, IL-10, dan rasio IL-1: IL-10 dilakukan pada hari ke-10 perlakuan melalui pengambilan jaringan. HASIL : Kadar IL-1 pada kelompok perlakuan (M) tidak berbeda bermakna dibanding KN dan KP (33,56±4,68 vs 40,92±27,32 vs 30,23±3,92 pg/mL, p=0,543). Kelompok KP memiliki IL-10 lebih tinggi dibandingkan kelompok M dan KN (113,95±9,38; 91,75±5,65 dan 94,93±2,39 pg/mL, p

Background: High-fat diet (HFD) and cigarette smoke exposure (CSE) have been used to induce atherosclerosis in wild-type (WT) rats however, their effectivity remains unclear.Objective: To confirm and compare the effectivity of HFD and CSE on both the histopathology of aorta and the level of malondialdehyde (MDA) in WT rats.Methods: Thirty-six WT Wistar rats were divided into four main groups (K0, K1, K2, and K3) and four subgroups (K3A, K3B, K3C, and K3D). The negative control group (K0) was fed with regular diet. Group K1 was treated with an intravenous adrenaline followed by high-fat diet (HFD), K2 was fed with regular diet and given CSE, while K3 was treated with a combination of CSE and HFD. The serum and cardiac MDA levels were measured using ELISA. Hematoxylin eosin and oil red O staining of aorta were done for measuring of the intima-media thickness (IMT) ratio and for counting of foam cells, respectively. Results: Both serum and cardiac tissue MDA levels in either K1, K2, or K3 were significant higher (p

Organizational structures that are more complex and innovative are starting to develop, especially in large companies but bring new challenges in their implementation. This study examines the implications of organizational structure changes on employee career opportunities and organizational citizenship behavior. This research was conducted at PT. XYZ is in the department of Human Resource Development (HRD) with a total population of 97 people, while the sample used is saturated. The method used is PLS-SEM using the SmartPLS software tool. As a result, organizational structure changes negatively affect organizational citizenship behavior but positively affect career opportunities. While career opportunities have a positive and significant effect on organizational citizenship behavior, on the other hand, career opportunities can indirectly affect organizational structure changes and organizational citizenship behavior in a positive and significant way.

Heart failure with reduced ejection fraction (HFrEF) due to ischemic heart disease (IHD) showed a progressive decline in left ventricular contractile function. However, no previous study has examined the left ventricular global longitudinal strain (LV GLS) parameter that represents LV contractile function. We investigated whether trimetazidine could improve the LV GLS value in patients with HFrEF due to IHD. We performed a double-blind, randomized controlled trial (RCT) including 26 patients with HFrEF due to stable IHD who were given modified-release trimetazidine 35 mg twice per day (n = 13) or placebo (n = 13) for 3 months in addition to standard medication. Left ventricular systolic function including GLS values was assessed at baseline and after 3 months using echocardiography. A total of 25 participants (13 control and 12 trimetazidine groups) were recruited with a baseline average age of 57.1 ± 10 years, and LV ejection fraction (LVEF) value of 34.6% ± 4.4%, and a GLS value of 7.4% ± 2.1%. Baseline clinical characteristics and echocardiogram were similar between the two groups. There was significant GLS improvement in the trimetazidine group (-6.9% ± 2.4% to -8.4% ± 2.6%, p = 0.000), but no significant differences were noted in the control group. The GLS improvement was significantly higher in the trimetazidine group than the control (1.5% + 0.9% vs. -0.7% + 1.7%, p = 0.001). No adverse drug reactions from the administration of trimetazidine in this study. Trimetazidine may improve GLS values in patients with HFrEF due to IHD.

The purpose of the study was to determine the effect of pricing on consumer purchasing decisions, to determine the effect of packaging on consumer purchasing decisions and to jointly determine the effect of pricing and packaging on consumer purchasing decisions. B in Serang City. This study uses quantitative research methods, data collection using research instruments, quantitative/statistical data analysis with the aim of testing the established hypothesis. The population in this study are consumers or visitors to Mr. Shop. B in Serang City who had made a purchase at Mr. Shop. B in Serang City. Based on the results of testing hypothesis 1, it shows that pricing has a significant effect on consumer purchasing decisions. B in Serang City, in this case, if the price fixing increases, the consumer's purchasing decisions will increase. The results of testing hypothesis 2 show that packaging has a significant effect on consumer purchasing decisions. B in Serang City, in this case, if the packaging increases, the consumer's purchasing decisions will increase. The results of the submission of hypothesis 3 show that pricing and packaging have a significant effect on consumer purchasing decisions. B in Serang City, this is if the pricing and packaging increase, the consumer's purchasing decisions will increase. Keywords: Pricing, Packaging and Consumer, Purchase Decisions

Isolated systolic hypertension (ISH) reflects atherosclerosis. Studies reported hypertension prevalence among diabetes mellitus (DM); however, limited studies provided community prevalence. Present study aimed to explore ISH prevalence among DM in Indonesia. This study obtained data from the 2018 Indonesian basic health survey. The DM category was determined by fasting plasma glucose (PG) level ≥126 mg/dL or 2-hours postprandial and random PG level ≥200 mg/dL or previously diagnosed by a doctor. ISH is categorized if systolic blood pressure is≥140 mmHg and diastolic blood pressure is 90 mmHg. This study also explored the subject's determinants, i.e., compliance, demography, and lipid profile. A Chi-square and Binary logistic regression were used to determine the association. The study included 3,911 DM individuals and disclosed the prevalence of ISH 17.5%. ≥65 years old (OR=13.61 95%CI: 3.297-19.365) and 45-64 years old OR=4.59 95%CI: 3.297-6.383)), high HDL-cholesterol (OR=0.77; 95%CI: 0.626-0.936), and longer DM duration (OR=2.89; 95%CI: 2.405-3.474), all together were related to the ISH. Subjects with the oldest age category, i.e., ≥65 years old, had the highest OR. Older DM individuals with low HDL-C and longer DM duration were related to the ISH, suggesting lipid profile treatments, mainly the HDL-C, is a pivotal effort to delay ISH.

Background: Double coronary culprit lesions in ST-segment elevation myocardial infarction (STEMI) is uncommon. Despite successful primary percutaneous coronary intervention (PPCI) in all culprit lesions, the clinical outcome remains unfavorable and the possible factors for the outcome are not fully understood.Cases Presentation: We reported four cases of double culprit lesions STEMI underwent PPCI. Patient A, a 62 y.o. male with extensive anterior-inferior STEMI, had total occlusion (TO) at both proximal left anterior descending (LAD) and mid right coronary artery (RCA). Patient B, a 42 y.o. male with extensive anterior-inferior STEMI, had subtotal occlusion (STO) at proximal RCA and TO at proximal LAD. Both of them had RBBB ECG pattern. Patient C, a 67 y.o. male with inferior STEMI had 90% thrombus occlusion at proximal–mid LAD and TO at proximal RCA. Patient D, a 65 y.o. male with anteroseptal STEMI, had STO at proximal LAD and 80% thrombus occlusion at mid left circumflex. The cardiomyocyte infarction biomarkers increased in all patients. Although all of them underwent successful PPCI in all of culprit lesions, they suffered from acute heart failure and two of them experienced recurrent ventricular arrhythmia episodes. One of them (patient A) died two days post PPCI. He was only patient who suffering from total occlusion in LAD and RCA with TIMI thrombus 5 and experienced a total atrioventricular block post-PPCI.Conclusion: STEMI with coronary double culprits have severe clinical outcome, regardless of the successful PCI. The degree of coronary occlusions might be linked to the patient clinical outcome.

Background: Atherosclerosis is related to hypercholesterolaemia and inflammation. Edamame is one of the soybeans with high levels of genistein which protects the formation of atherosclerosis. Purpose: This research aimed to evaluate the effects of genistein-rich edamame on LDL, hs-CRP, Neutrophil-Lymphocyte Ratio (NLR) and Monocyte-Lymphocyte Ratio (MLR) on atherosclerosis-induced mice. Method: This research is a true experimental study with posttest only-controlled group design. Thirty male rats were divided randomly into five groups: negative control group without any intervention, positive control group with atherosclerosis induction, first intervention group with edamame extract supplementation, second intervention group with genistein-rich edamame extract supplementation, and third intervention group treated with atorvastatin. After 28 days, serum LDL, hs-CRP, LDL and MLR were measured. Results: There were significant differences (p

Latar Belakang: Jumlah CD4 merupakan parameter penting pada penderita HIV dan berhubungan dengan peningkatan risiko disfungsi sistolik. Hingga saat ini, korelasi antara jumlah CD4 dengan parameter global longitudinal strain (GLS) sebagai indikator fungsi sistolik subklinis masih belum jelas. Metode: Penelitian ini merupakan studi observasional dengan metode belah lintang. GLS ventrikel kiri diperiksa menggunakan ekokardiografi dua dimensi. Jumlah CD4 baseline dan nadir diperoleh dari rekam medis sedangkan jumlah CD4 aktual dan CD4 percentage (CD4%) diperiksa menggunakan metode flow cytometry. Hasil: Total 37 pasien HIV asimptomatik mengikuti penelitian dengan rerata umur 31,95± 7,54 tahun dan median durasi penggunaan ARV adalah 34 bulan. Median CD4 baseline dan CD4 nadir adalah 272 sel/uL dan 223 sel/uL, sedangkan rerata CD4 aktual dan CD4% adalah 516,08±252,03 sel/uL dan 19,66±7,97 %. Semua subyek penelitian memiliki fungsi sistolik normal. Rerata GLS ventrikel kiri adalah 17,02±0,71. GLS ventrikel kiri berkorelasi positif dengan CD4 aktual (r=0,43; p=0,008) dan CD4% (r=0,349; p=0,034). Penderita HIV dengan jumlah CD4 aktual ?400 sel/uL memiliki GLS ventrikel kiri yang lebih baik dibandingkan dengan yang

Background: Central obesity stands for the corner-stone of cardio-metabolic health, while nitric oxide (NO) is a major regulator of cardiovascular function. To day, the correlation between serum NO metabolites nitrate/nitrite and the obesity components in young adults remains elusive. Thus, this current study was conducted to know the correlation between serum NO metabolites levels and body fat percentage, waist circumference (WC) as well as body mass index (BMI) in young adults with central obesity.Materials and Methods: A cross-sectional study was conducted in Riau, Indonesia, involving 79 young adults aged 18-25 years, composing of 39 and 40 subjects with and without central obesity, respectively. Anthropometric measurements were performed to assess WC and BMI. Body fat percentage was measured using bioelectrical impedance analysis and serum NO metabolites levels were assessed using Griess methods.Results: Levels of serum NO metabolites were significant higher in the subjects with central obesity (168.41±12.64 μmol/L) than that of normal subjects (70.57±44.99 μmol/L, p

Serum uric acid (UA) is taken up by endothelial cells and reduces the level of nitric oxide (NO) by inhibiting its production and accelerating its degradation. Cytosolic and plasma xanthine oxidase (XO) generates superoxide and also decreases the NO level. Thus, hyperuricemia is associated with impaired endothelial function. Hyperuricemia is often associated with vascular diseases such as chronic kidney disease (CKD) and cardiovascular disease (CVD). It has long been debated whether hyperuricemia is causally related to the development of these diseases. The 2020 American College of Rheumatology Guideline for the Management of Gout (ACR2020) does not recommend pharmacological treatment of hyperuricemia in patients with CKD/CVD. In contrast, the Japanese Guideline on Management of Hyperuricemia and Gout (JGMHG), 3rdedition, recommends pharmacological treatment of hyperuricemia in patients with CKD. In a FREED study on Japanese hyperuricemic patients with CVD, an XO inhibitor, febuxostat, improved the primary composite endpoint of cerebro-cardio-renovascular events, providing a rationale for the use of urate-lowering agents (ULAs). Since a CARES study on American gout patients with CVD treated with febuxostat revealed increased mortality, ACR2020 recommends switching to different ULAs. However, there was no difference in the mortality of Japanese patients between the febuxostat-treated group and the placebo or allopurinol-treated groups in either the FEATHER or FREED studies.

Serum uric acid level above 7 mg/dl is defined as hyperuricemia, which gives rise to the monosodium urate (MSU), causing gout and urolithiasis. Hyperuricemia is an independent risk factor as well as a marker for hypertension, heart failure, atherosclerosis, atrial fibrillation, and chronic kidney disease. MSU crystals, soluble uric acid (UA), or oxidative stress derived from xanthine oxidoreductase (XOR) might be plausible explanations for the association of cardio-renovascular diseases with hyperuricemia. In macrophages, MSU activates the Nod-like receptor family, pyrin domain containing 3(NLRP3) inflammasome, and proteolytic processing mediated by caspase-1 with enhanced interleukin (IL)-1β and IL-18 secretion. Soluble UA accumulates intracellularly through UA transporters (UAT) in vascular and atrial myocytes, causing endothelial dysfunction ad atrial electrical remodeling. XOR generates reactive oxygen species (ROS) that lead to cardiovascular diseases. Since it remains unclear whether asymptomatic hyperuricemia could be a risk factor for cardiovascular and kidney diseases, European and American guidelines do not recommend pharmacological treatment for asymptomatic patients with cardio-renovascular diseases. The Japanese guideline, on the contrary, recommends pharmacological treatment for hyperuricemia with CKD to protect renal function, and it attaches importance of the cardio-renal interaction for the treatment of asymptomatic hyperuricemia patients with hypertension and heart failure.

Background: Iron overload can cause DNA oxidation which increase TGF β1, type 1 fibrilarprotein and myocardium fibrosis. Myocardium fibrosis is the main cause of death on the state of iron overload. The iron influx towards the cell during iron overload is still unknown, some research suggested LTCC acts as iron influx. This research aims to investigate the role of azelnidipine as type L calcium channel blocker, lowering TGF β1, collagen and myocardium fibrosis. Method: The research subjects consisted of 25 male Balb-C mice(8 weeks, 30-40mg) divided into 5 groups. Group 1 (NaCl+S) 0,3 cc Na Cl 0,9% (I.P) and drug solvent (Aquabidest, CMC and Nipagin) orally. Group 2Fe+S) 0.3 cc 1,5 mg Fe+sucrose (Venofer®) (I.P) and drug solvent (Aquabidest, CMC and Nipagin) orally. Group 3 (Fe+Dfx) 1,5 mg Fe+sucrose (Venofer®) (I.P) and deferasirox 20 mg/kg body weight/day orally, group 4 (Fe+Azl) 1,5 mg Fe+sucrose (Venofer®) (I.P) and azelnidipine 14 mg/day orally and group 5 (Fe+Dfx-Azl) 1,5 mg Fe+sucrose (Venofer®) (I.P) and mixture of deferasirox 20 mg/kg body weight/day and azelnidipine 14 mg/day orally. Fe-sucorse was diluted with NaCl 0.9 %. Intraperitoneal injection were administered intermittently for 60 days of treatment. Result: The highest Expression of TGF β, collagen I and fibrosis area fractions are in group Fe+S. The result of Post Hoc test between 2 treatment groups indicated that there were no difference in TGF β expression between groups NaCl+S with Fe+Dfx (P>0.05) , Fe+Dzl (P>0.05). There are no significant in collagen expression between groups NaCl+S with Fe+Dfx (P > 0.05) ,Fe+Dzl (P>0.05). Conclusion: Azelnidipine, LTCC have roles on the influx of iron into the myocardium, lowering TGF β, collagen Iexpressionsand myocardium fibrosis. Bangladesh Journal of Medical Science Vol.19(2) 2020 p.223-228

The mechanism of cardiac-troponin elevation after exercise remains unclear. Studies have reported that leucocyte ratios are related to coronary artery disease. The present study explored the relationship between leucocyte ratios, exercise intensity, and post-exercise cardiac-troponin I (cTnI) levels. Ninety-two participants in a long-distance cycling tour were included in this study. Baseline and post-exercise blood samples were collected to determine cTnI concentrations. Biochemical parameters and leucocyte ratios were measured at baseline. Exercise intensity was examined by recording the heart rate (HR). Exercise intensity was determined as the percentage of peak HR to maximal predicted HR. Based on clinical cutoff points of the cTnI assay, cTnI levels were defined as

Background: Coronary collateral circulation (CCC) is linked to myocardial remodeling severity in patients with chronic ischaemic heart disease (IHD). However its effect on left ventricular reverse remodeling (LVRR) in patients with chronic IHD underwent coronary artery bypass surgery (CABG) has never been reported. Purpose of this study was to investigate the effect of CCC grade on the LVRR event in patients with chronic IHD underwent CABG. Methods: This prospective cohort study was performed in patients with chronic IHD underwent CABG. The CCC was classified using Rentrop collateral score, i.e low CCC grade (Rentrop score 0 and 1) and high CCC grade (Rentrop score 2 and 3). LVRR event was defined as a reduction in left ventricular end systolic volume (LVESV) of 10% or more, measured by a 3D echocardiography at 1.5 months post CABG compared to the baseline before CABG. Results: A total of 22 patients (81.8% male) with mean of age 58.6 years old were enrolled. LVRR occurred in 50% patients. LVRR event was significantly higher in the patients with high CCC grade than the low CCC grade patients (p=0.009). The high CCC grade increased LVRR event independently (odds ratio=26.67; relative risk=6.93). Conclusions: High coronary collateral circulation may increase left ventricular reverse remodeling event in patients with chronic ischemic heart disease underwent coronary artery bypass surgery. Keywords: coronary collateral circulation; left ventricular reverse remodeling; chronic ischaemic heart disease; coronary artery bypass surgery; 3D echocardiography.

Background: To date, the mechanisms of post-exercise cardiac troponin elevation are debatable. Previous studies have reported that oxidative stress happens after extended exercise. Objectives: This study purposed to establish the association between the elevation of malondialdehyde (MDA), which is a marker of oxidative stress, and cardiac troponin-I (cTn-I) after prolonged cycling. Methods: Ninety-two males in Indonesian cycling tours participated in the present study. Baseline and post-exercise blood specimens were obtained to define MDA and cTn-I levels. The elevations of MDA and cTn-I were determined as positive differences of post-cycling MDA and cTn-I levels to the baseline, respectively. Results: Eighty-eight participants (age, mean = 45.3 years old, [SD]:11.47; body mass index (BMI), mean=24.2 kg/m2, [SD]: 3.03) finished the cycling tours. Subjects’ characteristics were comparable based on the touring category, except for the family history of coronary artery disease, high-density lipoprotein cholesterol level, neutrophil count, resting heart rate, exercise intensity, and cTn-I elevation. MDA significantly escalated at the level of 210.90 µmol/mL at post-exercise, from 190.18 µmol/mL at baseline. cTn-I also increased at the level of 13.65 ng/dL from 5.16 ng/dL. The elevation of MDA was related to the elevation of cTn-I. Elevation of cTn-I after prolonged cycling was contributed by elevation of MDA and exercise intensity. Conclusions: The present findings support existing confirmation that cTn-I elevation after prolonged exercise is related to oxidative stress and exercise intensity.

The present study aimed to explore the prevalence of isolated systolic hypertension (ISH) and its risk factors among diabetes mellitus (DM) subjects in the community setting study in Indonesia. This cross-sectional study extracted secondary data from basic health survey (Riset Kesehatan Dasar; RISKESDAS) conducted in 2018. DM subjects were defined based on fasting blood glucose level ≥ 126 mg/dL or 2 hours postprandial and random blood glucose level ≥ 200 mg/dL or previously had been diagnosed by a doctor; while ISH was determined based on systolic blood pressure ≥ 140 mmHg and diastolic blood pressure < 90 mmHg. We also observed the subject’s characteristics, such as demography, lipid profile, and subject’s compliance. Data were then analyzed using Chi-square and Binary logistic regression. Study involved 3,911 DM subjects, revealed the overall prevalence of ISH 17.5%. Age category of 35-44 years old (POR= 10.80; 95%CI: 2.595-44.957), 45-54 years old (POR=22.81; 95%CI: 5.616-92.677), 55-64 years old (POR=46.12; 95% CI: 11.393-186.720); 65-74 years old (POR= 81.82; 95% CI: 20.110-332.868); ≥75 years old (POR=109.64; 95% CI: 26.373-455.789), low HDL cholesterol (POR= 0,80; 95% CI: 0.653-0.972); duration of DM (POR= 1.73; 95% CI: 1.257-2.389) were associated with the ISH. The prevalence of ISH among DM subjects was 17.5%. Older DM subjects, low HDL cholesterol, and duration of DM were associated with the ISH, suggesting that modification lipid profile, especially the HDL cholesterol level, is an important measure to delay ISH in elderly and long-duration DM subjects.

BackgroundPrevious studies reported recurrent SARS-CoV-2 RNA positivity in individuals who had recovered from COVID-19 infections. However, little is known regarding the systematic review of recurrent SARS-CoV-2 RNA positivity. The current study conducted a systematic review and meta-analysis, aimed to estimate the incidence of recurrent SARS-CoV-2 RNA positivity after recovery from COVID-19 and to determine the factors associated with recurrent positivity.MethodsWe searched the PubMed, MedRxiv, BioRxiv, the Cochrane Library, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry for studies published to June 12, 2020. Studies were reviewed to determine the risk of bias. A random-effects model was used to pool results. Heterogeneity was assessed using I2.ResultsFourteen studies of 2,568 individuals were included. The incidence of recurrent SARS-CoV-2 positivity was 14.81% (95% confidence interval [CI]: 11.44–18.19%). The pooled estimate of the interval from disease onset to recurrence was 35.44 days (95% CI: 32.65–38.24 days), and from the last negative to recurrent positive result was 9.76 days (95% CI: 7.31–12.22 days). Patients with younger age (mean difference [MD]=-2.27, 95% CI: -2.95 to -1.80) and a longer initial illness (MD=8.24 days; 95% CI: 7.54 – 8.95; I2=98.9%) were more likely to experience recurrent SARS-CoV-2 positivity, while patients with diabetes (RR=0.52; 95% CI: 0.30-0.90; I2=53%), severe disease (RR=0.54; 95% CI: 0.35-0.84; I2=70%), and a low lymphocyte count (RR=0.58; 95% CI: 0.39 – 0.86; I2=48%) were less likely to experience recurrent SARS-CoV-2 positivity.ConclusionsThe incidence of recurrent SARS-CoV-2 positivity was 14.81%. The estimated interval from disease onset to repeat positivity was 35.44 days, and the estimated interval from the last negative result to recurrent positive result duration was 9.76 days.

The establishment of subcritical fluid application for zingiberene extraction was studied by employing water as a green solvent. The zingiberene content was observed by using Liquid Chromatography-Mass Spectrofotometry and regarding to the independent variable of temperature, extraction time, ginger-solvent ratio and aging time. By applying subcritical water, the critical value of zingiberene content obtained was 0.036%. This value was approached by the surface modeling of alpha for rotatability design which performed at 125  C, 20 min of extraction time, 0.08 of ginger to solvent ratio and 9 min of aging time of extraction parameters. The surface modeling was validated by plotting the observed and predicted value of zingiberene content and evidenced by the value of R-square at 0.76.

Latar Belakang: Gagal jantung merupakansalah satu masalah kesehatan masyarakat global dengan jumlah penderita yang diperkirakan terus mengalami peningkatan. Meskipun terdapat kemajuan dalam tata kelolanya, gagal jantung masih memiliki prognosis yang buruk. Vitamin D merupakan mikronutrien yang berpengaruh terhadap prognosis pasien gagal jantung kronik. Saat ini belum ada data mengenai kadar vitamin D serum pada pasien gagal jantung kronik yang dirawat pada populasi Indonesia. Tujuan penelitian ini adalah untuk mengetahui kadar vitamin D serum pada pasien gagal jantung kronik yang menjalani rawat inap.Metode: Penelitian observasional pada pasien gagal jantung kronik yang dirawat di RSUP. Dr. Kariadi Semarang mulaibulan November 2017 sampaiJanuar1 2018. Pemeriksaan kadar vitamin D serum [25(OH)D] dilakukan dengan metode chemiluminescence immunoassay (CLIA).Hasil: Sebanyak 102 pasien (median usia 55 (22–65) tahun) yang terlibat, terdapat 69 sampel yang memenuhi kriteria seleksi. Median fraksi ejeksi ventrikel kiri adalah 35 (10-76)%. Median kadar vitamin D serum adalah 47.25 (14.25–143.02) nmol/L.Yang menarik, 88,4% pasien menunjukkan kadar vitamin D lebih rendah dari yang direkomendasikan. Dibandingkan dengan pasien dengan kadar vitamin D normal, pasien dengan kadar rendah tersebut lebih sering disertai denganhipertensi atau diabetes, berjenis kelamin perempuan, dan memiliki riwayat rawat inap ulang yang lebih sering.Kesimpulan: Defisiensi vitamin D serum dialami olehsebagian besar pasien gagal jantung kronik yang dirawat. Data ini menunjukkan perlunya pengukuran kadar vitamin D pada pasien gagal jantung kronik dengan hipertensi, diabetes, jenis kelamin wanita dan rawat inap ulang.Kata Kunci : Gagal jantung, defisiensi vitamin D, rawat inap

Total-Cholesterol(TC) to HDL-Cholesterol(HDL-C) ratio in athletes is well-known better than sedentary people. However, there is lack of information about comparison of TC/HDL-C in different groups of cyclists based on cycling touring characteristics and anthropometry parameters. This study was to compare TC/HDL-C ratio among groups based on type of tour participated in cyclists population.Eighty-eight participants were recruited in this cross-sectional study. Mean differences of parameters between groups analyzed by One-Way Anova test and independent t-test, while multivariate analyses was done by binary logistic-regression. P value

Local anesthetics (LAs) inhibit endoplasmic reticulum-associated protein degradation, however the mechanisms remain elusive. Here, we show that the clinically used LAs pilsicainide and lidocaine bind directly to the 20S proteasome and inhibit its activity. Molecular dynamic calculation indicated that these LAs were bound to the β5 subunit of the 20S proteasome, and not to the other active subunits, β1 and β2. Consistently, pilsicainide inhibited only chymotrypsin-like activity, whereas it did not inhibit the caspase-like and trypsin-like activities. In addition, we confirmed that the aromatic ring of these LAs was critical for inhibiting the proteasome. These LAs stabilized p53 and suppressed proliferation of p53-positive but not of p53-negative cancer cells.

Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations in UMOD that encodes uromodulin. Topiroxostat, a novel non-purine analog, selectively inhibits xanthine oxidase and reduces the serum uric acid levels and the urinary albuminuria.Genomic DNA of a patient was extracted from peripheral white blood. Exons and flanking sequences of UMOD were amplified by PCR with primers. Mutation analysis was performed by direct sequencing of the PCR products. The wild-type and mutant uromodulin were expressed in HEK293 cells and analyzed by western blotting, immunoprecipitation, immunofluorescence, and flow cytometry.We identified an FJHN patient who carried a novel UMOD mutation G335A (C112Y). The levels of both cytosolic and secreted C112Y protein were significantly decreased compared with the wild-type, whereas the level of ubiquitination was higher in C112Y than that in the wild type. The half-life of C112Y was shortened and it was restored by a proteasome inhibitor MG132. Immunofluorescence revealed decreased levels of C112Y in the Golgi apparatus and on the plasma membrane. Expression of C112Y induced cellular apoptosis as revealed by flow cytometry. Apoptosis induced by C112Y was suppressed by topiroxostat.C112Y causes its protein instability resulting cellular apoptosis which could be suppressed with topiroxostat.

Cardiac arrhythmogenesis is regulated by channel proteins whose protein levels are in turn regulated by the ubiquitin-proteasome system (UPS). We have previously reported on UPS impairment induced by E334K cardiac myosin-binding protein C (cMyBPC), which causes hypertrophic cardiomyopathy (HCM) accompanied by arrhythmia. We hypothesized that UPS impairment induced by E334K cMyBPC causes accumulation of cardiac channel proteins, leading to electrophysiological dysfunction. Wild-type or E334K cMyBPC was overexpressed in HL-1 cells and primary cultured neonatal rat cardiac myocytes. The expression of E334K cMyBPC suppressed cellular proteasome activities. The protein levels of K(v)1.5, Na(v)1.5, Hcn4, Ca(v)3.2, Ca(v)1.2, Serca, RyR2, and Ncx1 were significantly higher in cells expressing E334K cMyBPC than in wild type. They further increased in cells pretreated with MG132 and had longer protein decays. The channel proteins retained the correct localization. Cells expressing E334K cMyBPC exhibited higher Ca(2+) transients and longer action potential durations (APDs), accompanied by afterdepolarizations and higher apoptosis. Those augments of APD and Ca(2+) transients were recapitulated by a simulation model. Although a Ca(2+) antagonist, azelnidipine, neither protected E334K cMyBPC from degradation nor affected E334K cMyBPC incorporation into the sarcomere, it normalized the APD and Ca(2+) transients and partially reversed the levels of those proteins regulating apoptosis, thereby attenuating apoptosis. In conclusion, UPS impairment caused by E334K cMyBPC may modify the levels of channel proteins, leading to electrophysiological dysfunction. Therefore, UPS impairment due to a mutant cMyBPC may partly contribute to the observed clinical arrhythmias in HCM patients.

β-Galactosidase deficiency is a group of lysosomal lipid storage disorders with an autosomal recessive trait. It causes two clinically different diseases, G(M1) -gangliosidosis and Morquio B disease. It is caused by heterogeneous mutations in the GLB1 gene coding for the lysosomal acid β-galactosidase. We have previously reported the chaperone effect of N-octyl-4-epi-β-valienamine (NOEV) on mutant β-galactosidase proteins. In this study, we performed genotype analyses of patients with β-galactosidase deficiency and identified 46 mutation alleles including 9 novel mutations. We then examined the NOEV effect on mutant β-galactosidase proteins by using six strains of patient-derived skin fibroblast. We also performed mutagenesis to identify β-galactosidase mutants that were responsive to NOEV and found that 22 out of 94 mutants were responsive. Computational structural analysis revealed the mode of interaction between human β-galactosidase and NOEV. Moreover, we confirmed that NOEV reduced G(M1) accumulation and ameliorated the impairments of lipid trafficking and protein degradation in β-galactosidase deficient cells. These results provided further evidence to NOEV as a promising chaperone compound for β-galactosidase deficiency.

BACKGROUND AND PURPOSE The expression of voltage-dependent K+ channels (Kv) 1.5 is regulated by members of the heat shock protein (Hsp) family. We examined whether the heat shock transcription factor 1 (HSF-1) and its inducer geranylgeranylacetone (GGA) could affect the expression of Kv1.5 channels and its anchoring protein, synapse associated protein 97 (SAP97).

Denaturing high-performance liquid chromatography (DHPLC), which has recently been developed as an automated method to detect mutations, is at least ten times less expensive than the direct sequencing method; however, its sensitivity and specificity for cardiac myosin-binding protein C (MYBPC3) gene mutations in hypertrophic cardiomyopathy have not been reported yet. A mutation analysis of exons 1 to 35 of MYBPC3 gene from 20 Japanese patients with hypertrophic cardiomyopathy was performed using DHPLC and direct sequencing. Compared to direct sequencing, the sensitivity and specificity of DHPLC were 87.5% and 97.42%, respectively. Its positive and negative predictive values were 41.18% and 99.74%. The positive and negative likelihood ratios were 33.95 and 0.13, and the prevalence was 2.02%. DHPLC showed high sensitivity and specificity for detecting MYBPC3 gene mutations in hypertrophic cardiomyopathy. The use of this complementary sequencing method should reduce the cost of detection of MYBPC3 gene mutations, and could be used to screen patients with hypertrophic cardiomyopathy.

We investigated the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the stability of Kv1.5 channel protein. The expression and function of Kv1.5 (Kv1.5-FLAG) in transfected African green monkey kidney fibroblast cells as well as rat atrium were estimated by immunoblotting, immunoprecipitation, immunofluorescence and patch-clamp techniques. Both EPA and DHA immediately blocked Kv1.5 channel current in a dose-dependent manner, accompanied by reduction of their phosphorylation. Chronic treatment (for 12 h) with EPA at lower concentrations (0.3-10 muM) increased the level of Kv1.5-FLAG protein as well as Kv1.5 channel current without changes in its gating kinetics, prolonging its half-life; in contrast, both EPA and DHA at higher concentrations (30-100 muM) decreased the expression of Kv1.5-FLAG. EPA at the higher concentrations also decreased mRNA of Kv1.5 and synapse-associated protein 97 expression. EPA at the lower concentrations increased Kv1.5 expression in the endoplasmic reticulum, Golgi apparatus and cell membrane. EPA-induced increase of Kv1.5 channel expression and current was abolished by pretreatment with the protein transport inhibitor brefeldin A or colchicines, and by the Kv1.5 channel blocker 4-aminopyridine. Oral administration of EPA (30 mg/kg) increased the level of endogenous Kv1.5 in rat atria. These results indicate that chronic treatment with EPA at lower concentrations stabilizes Kv1.5 channel protein in the endoplasmic reticulum and Golgi apparatus thereby enhancing the Kv1.5 channel current on the cell membrane.

The ubiquitin-proteasome system is responsible for the disappearance of truncated cardiac myosin-binding protein C, and the suppression of its activity contributes to cardiac dysfunction. This study investigated whether missense cardiac myosin-binding protein C gene (MYBPC3) mutation in hypertrophic cardiomyopathy (HCM) leads to destabilization of its protein, causes UPS impairment, and is associated with cardiac dysfunction. Mutations were identified in Japanese HCM patients using denaturing HPLC and sequencing. Heterologous expression was investigated in COS-7 cells as well as neonatal rat cardiac myocytes to examine protein stability and proteasome activity. The cardiac function was measured using echocardiography. Five novel MYBPC3 mutations -- E344K, DeltaK814, Delta2864-2865GC, Q998E, and T1046M -- were identified in this study. Compared with the wild type and other mutations, the E334K protein level was significantly lower, it was degraded faster, it had a higher level of polyubiquination, and increased in cells pretreated with the proteasome inhibitor MG132 (50 microM, 6 h). The electrical charge of its amino acid at position 334 influenced its stability, but E334K did not affect its phosphorylation. The E334K protein reduced cellular 20 S proteasome activity, increased the proapoptotic/antiapoptotic protein ratio, and enhanced apoptosis in transfected Cos-7 cells and neonatal rat cardiac myocytes. Patients carrying the E334K mutation presented significant left ventricular dysfunction and dilation. The conclusion is the missense MYBPC3 mutation E334K destabilizes its protein through UPS and may contribute to cardiac dysfunction in HCM through impairment of the ubiquitin-proteasome system.

The aim of this study was to elucidate the mechanisms for regulations of cardiac Kv1.5 channel expression. We particularly focused on the role of heat shock proteins (Hsps). We tested the effects of Hsps on the stability of Kv1.5 channels using biochemical and electrophysiological techniques: co-expression of Kv1.5 and Hsp family proteins in mammalian cell lines, followed by Western blotting, immunoprecipitation, pulse-chase analysis, immunofluorescence and whole-cell patch clamp. Hsp70 and heat shock factor 1 increased the expression of Kv1.5 protein in HeLa and COS7 cells, whereas either Hsp40, 27 or 90 did not. Hsp70 prolonged the half-life of Kv1.5 protein. Hsp70 was co-immunoprecipitated and co-localized with Kv1.5-FLAG. Hsp70 significantly increased the immunoreactivity of Kv1.5 in the endoplasmic reticulum, Golgi apparatus and on the cell membrane. Hsp70 enhanced Kv1.5 current of transfected cells, which was abolished by pretreatment with brefeldin A or colchicine. Thus, Hsp70, but not other Hsps, stabilizes functional Kv1.5 protein.

We report a novel action of intracellular adenosine monophosphate (AMP) to inhibit β-adrenergic signaling in isolated rat ventricular myocytes. Extracellular application of adenosine or AMP suppressed isoproterenol (Iso)-induced prolongation of action potential duration (APD). This effect was completely abolished by an A 1 -receptor antagonist, DPCPX. Intracellular application of AMP, but not adenosine, attenuated Iso-induced APD prolongation. Iso-induced increases in the L-type Ca 2+ current (I Ca,L ) were also inhibited by intracellular AMP. These inhibitory effects were not affected by either DPCPX or glibenclamide. In vitro, AMP directly inhibited PKA activity via binding to its regulatory subunit. These results suggest that intracellular AMP attenuates β-adrenergic signaling by directly inhibiting PKA activity, independently of A 1 -purinergic receptor.

Both an angiotensin II receptor blocker, losartan (CAS 124750-99-8) and a serum urate lowering agent, benzbromarone (CAS 3562-84-3) exert a uricosuric action by inhibiting urate transporter 1 (URAT1). A recent clinical trial indicated that losartan could reduce the level of serum urate in hypertensive patients treated with urate lowering agents, suggesting the different mode of action of losartan from benzbromarone. In the present study, the effect of losartan and benzbromarone on the level of URAT1 mRNA was determined in transfected HEK293 cells. Losartan caused a significant reduction of its mRNA level, whereas it was not affected by benzbromarone. These results indicate that losartan decreases the level of human URAT1 mRNA, which may underlie the uricosuric action of losartan in hypertensive patients treated with serum urate lowering agents.

Apoptosis appears to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM). We have previously reported 3 HCM patients carrying the E334K MYBPC3, and that heterologous expression of E334K cMyBPC in cultured cells induced apoptosis. The purpose of this study was to identify pharmacological agents that would inhibit apoptosis in HL-1 cardiomyocytes expressing E334K cMyBPC.E334K cMyBPC expression in cells increased levels of pro-apoptosis (p53, Bax and cytochrome c) and decreased levels of anti-apoptosis (Bcl-2 and Bcl-XL). While the beta blocker carvedilol (1 μM) normalized the level of p53 and Bcl-2 and the calcium channel blocker (CCB) bepridil (0.5 μM) normalized that of Bcl-2, both the CCB azelnidipine (1 μM) and the angiotensin receptor blocker (ARB) olmesartan (10 μM) normalized those of p53, Bax, cytochrome c, and Bcl-XL. Among those proteins, cytochrome c was the one which showed the highest degree of change. Both azelnidipine (0.1 μM) and olmesartan (1 μM) reduced the level of cytochrome c by 40.2 ± 4.3% and 31.3 ± 5.1%, respectively. The CCB amlodipine and the ARB valsartan reduced it only by 19.1 ± 2.1% and 20.1 ± 5.2%, respectively. Flow cytometric analysis and annexin V staining showed that treatment of cells with azelnidipine (0.1 μM) plus olmesartan (0.3 μM) or that with amlodipine (0.1 μM) plus valsartan (0.3 μM) reduced the number of apoptotic cells by 35.8 ± 10.5% and 18.4 ± 3.2%, respectively.Azelnidipine plus olmesartan or amlodipine plus valsartan inhibited apoptosis of HL-1 cells expressing E334K cMyBPC, and the former combination was more effective than the latter.

BACKGROUND The prion protein (PrP) has been reported to serve as a surface maker for isolation of cardiomyogenic progenitors from murine embryonic stem (ES) cells. Although PrP-positive cells exhibited automaticity, their electrophysiological characteristics remain unresolved. The aim of the present study was therefore to investigate the electrophysiological properties of PrP-positive cells in comparison with those of HCN4p-or Nkx2.5-positive cells. METHODS AND RESULTS Differentiation of AB1, HCN5p-EGFP and hcgp7 ES cells into cardiac progenitors was induced by embryoid body (EB) formation. EBs were dissociated and cells expressing PrP, HCN4-EGFP and/or Nkx2.5-GFP were collected via flow cytometry. Sorted cells were subjected to reverse transcriptase-polymerase chain reaction, immunostaining and patch-clamp experiments. PrP-positive cells expressed mRNA of undifferentiation markers, first and second heart field markers, and cardiac-specific genes and ion channels, indicating their commitment to cardiomyogenic progenitors. PrP-positive cells with automaticity showed positive and negative chronotropic responses to isoproterenol and carbamylcholine, respectively. Hyperpolarization-activated cation current (I(f)) was barely detectable, whereas Na(+) and L-type Ca(2+) channel currents were frequently observed. Their spontaneous activity was slowed by inhibition of sarcoplasmic reticulum Ca(2+) uptake and release but not by blocking I(f). The maximum diastolic potential of their spontaneous firings was more depolarized than that of Nkx2.5-GFP-positive cells. CONCLUSIONS PrP-positive cells contained cardiac progenitors that separated from the lineage of sinoatrial node cells. PrP can be used as a marker to enrich nascent cardiac progenitors.

Background: Development of biological pacemaker is a potential treatment for bradyarrhythmias. Pacemaker cells could be extracted from differentiated embryonic stem (ES) cells based on their specific cell marker hyperpolarization-activated cyclic nucleotide-gated (HCN)4. The goal of this study was to develop a method of identification, isolation, and characterization of pacemaking cells derived from differentiated ES cells with GFP driven by HCN4 promoter. Methods and Results: Polymerase chain reaction (PCR) screening and southern blot analysis revealed that HCN4p-EGFP trans-gene was stably integrated into the chromosome of mouse AB1 ES cells. RT-PCR and immunostaining results showed similar expression of the specific cardiac pacemaker markers of the HCN4p-EGFP ES cells and its parental AB1 ES cell lines. Although HCN4p-EGFP trans-gene may have slight effect on the general mesodermal differentiation, it had no effect on the pluripotency of ES cells, on the transcription of cardiac specific factors and cardiac contractile proteins, and on the capability of ES cells to differentiate into pacemaker cells. Electrophysiological study indicated that HCN4p-GFP-positive cells revealed the spontaneous action potential, which was slowed by the treatment with 2 mM Cs+, and expressed the hyperpolarization-activeted cation current If encoded by HCN4 gene. Conclusion: By the approach of using stable transfectant of HCN4p-EGFP gene, the identification, isolation, and characterization of ES cell-derived pacemaking cells could be carried out. PACE 2010; 33:290–303)