Relationship Between Earlobe Crease and Brachial-ankle Pulse Wave Velocity in Non-hypertensive, Non-diabetic Adults in Korea

OBJECTIVES: Several studies have found a significant association between the presence of earlobe crease (ELC) and cardiovascular disease (CVD). Brachial-ankle Pulse Wave Velocity (baPWV) is a non-invasive and useful measure of arterial stiffness predicting cardiovascular events and mortality. However, few studies have reported the relationship between ELC and baPWV as a new measure of arterial stiffness. the purpose of this study was to determine whether ELC is related to baPWV in non-diabetic, non-hypertensive, and apparently healthy Korean adults. METHODS: A cross-sectional study was conducted on 573 non-hypertensive, non-diabetic Korean adults aged 20-80 yr. Subjects were stratified into three groups according to gender and menopausal status. baPWV was measured by an automatic waveform analyser. the association between ELC and baPWV was assessed by multiple linear regression analysis after adjusting for conventional cardiovascular disease risk factors including age, gender, blood pressure, lipid profile, and smoking status etc. RESULTS: the overall frequency of ELC was 19.02% and the subjects with ELC showed significantly higher mean baPWV (p<0.0001). Multiple linear regression of subjects revealed that the presence of ELC was independently associated with baPWV (male, p<0.0001; premenopausal female p=0.0162; postmenopausal female p=0.0208). CONCLUSION: ELC had a significant correlation with baPWV, independently controlling for other classical cardiovascular risk factors in adults aged 20 yr or older. ELC is an important surrogate marker of increased arterial stiffness as measured by baPWV in Korean adults.ope

The Effect of Stimulation Frequency on the Ionic Currents in Single Atrial Cells of the Rabbit

In single atrial cells isolated from rabbit hearts the calcium current and [Caj-dependent transient outward current were recorded using the whole-cell clamp technique and the effect of stimulation frequency on these currents was investigated. Voltage dependent transient outward current, which contributes the initial, rapid repolarization phase of the action potential and is frequency-dependent, was also investigated. Increasing the stimulation frequency from O. 025 Hz to 1 Hz had no effect on the calcium current and [Caj-dependent transient outward current and greatly inhibited voltage-dependent transient outward current. The amplitude of voltage dependent transient outward current increased as the membrane potential became depolarized, its steady-state inactivation spans the voltage range -70 mV to -10 mVand steady-state activation curve -30 mV to 30 mV. Within the range of the resting membrane potential (at -70 mV), the voltage-dependent recovery time constant was 1. 3 s. The reversal potential was about -50 mV. Voltage-dependent transient outward current was inhibited by K-channel blockers and not inhibited by modulation of [Cali. From the above findings, it is concluded that due to the amplitude and voltage-dependent recovery time constant which were the basic mechanisms for frequency-dependency, the voltage- dependent transient outward current contributes the initial, rapid repolarization phase and changed the action potential configuration according to stimulation frequency in the rabbit atrium

Role of TNFR-related 2 mediated immune responses in dextran sulfate sodium-induced inflammatory bowel disease

Previous work has suggested that the LIGHT-TR2 costimulatory pathway plays a role in the acute and chronic stages of dextran sulfate sodium (DSS)-induced colitis [Steinberg et al. (2008); Wang et al. (2005)]. To clarify the role of TNFR-related 2 (TR2) signaling in the maintenance of intestinal homeostasis, we generated a TR2 knock-out (KO) mouse. Using DSS to induce colitis, we compared the colitic symptoms and pathological changes in wild type (WT) and TR2 KO mice, and the production of cytokines by the diseased colons. We also studied the role of TR2 in suppressing innate and adaptive immunity in the DSS model. TR2 deficient mice were characterized by reduced symptoms of intestinal inflammation compared with wildtype mice, and reduced production of cytokines. We therefore generated a monoclonal antibody against mouse TR2 which was specific to TR2 and capable of blocking TR2 signals. With this antibody, we demonstrated that antagonizing TR2 during the development of DSS-induced colitis reduced the symptoms of inflammation. Our findings suggest that TR2 is an important mediator in colitis, and may serve as a therapeutic target in inflammatory bowel disease

Preparation of large Cu3Sn single crystal by Czochralski method

Cu3Sn was recently predicted to host topological Dirac fermions, but related research is still in its infancy. The growth of large and high-quality Cu3Sn single crystals is, therefore, highly desired to investigate the possible topological properties. In this work, we report the single crystal growth of Cu3Sn by Czochralski (CZ) method. Crystal structure, chemical composition, and transport properties of Cu3Sn single crystals were analyzed to verify the crystal quality. Notably, compared to the mm-sized crystals from a molten Sn flux, the cm-sized crystals obtained by the CZ method are free from contamination from flux materials, paving the way for the follow-up works

High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells

<p>Abstract</p> <p>Background</p> <p>Clevudine is a nucleoside analog reverse transcriptase inhibitor that exhibits potent antiviral activity against hepatitis B virus (HBV) without serious side effects. However, mitochondrial myopathy has been observed in patients with chronic HBV infection taking clevudine. Moreover, the development of diabetes was recently reported in patients receiving long-term treatment with clevudine. In this study, we investigated the effects of clevudine on mitochondrial function and insulin release in a rat clonal β-cell line, INS-1E.</p> <p>Methods</p> <p>The mitochondrial DNA (mtDNA) copy number and the mRNA levels were measured by using quantitative PCR. MTT analysis, ATP/lactate measurements, and insulin assay were performed.</p> <p>Results</p> <p>Both INS-1E cells and HepG2 cells, which originated from human hepatoma, showed dose-dependent decreases in mtDNA copy number and cytochrome c oxidase-1 (Cox-1) mRNA level following culture with clevudine (10 μM-1 mM) for 4 weeks. INS-1E cells treated with clevudine had reduced total mitochondrial activities, lower cytosolic ATP contents, enhanced lactate production, and more lipid accumulation. Insulin release in response to glucose application was markedly decreased in clevudine-treated INS-1E cells, which might be a consequence of mitochondrial dysfunction.</p> <p>Conclusions</p> <p>Our data suggest that high-dose treatment with clevudine induces mitochondrial defects associated with mtDNA depletion and impairs glucose-stimulated insulin secretion in insulin-releasing cells. These findings partly explain the development of diabetes in patients receiving clevudine who might have a high susceptibility to mitochondrial toxicity.</p

Pharmacokinetic Modeling of Bepotastine for Determination of Optimal Dosage Regimen in Pediatric Patients with Allergic Rhinitis or Urticaria

Bepotastine, a second-generation antihistamine for allergic rhinitis and urticaria, is widely used in all age groups but lacks appropriate dosing guidelines for pediatric patients, leading to off-label prescriptions. We conducted this study to propose an optimal dosing regimen for pediatric patients based on population pharmacokinetic (popPK) and physiologically based pharmacokinetic (PBPK) models using data from two previous trials. A popPK model was built using NONMEM software. A one-compartment model with first-order absorption and absorption lag time described our data well, with body weight incorporated as the only covariate. A PBPK model was developed using PK-Sim software version 10, and the model well predicted the drug concentrations obtained from pediatric patients. Furthermore, the final PBPK model showed good concordance with the known properties of bepotastine. Appropriate pediatric doses for different weight and age groups were proposed based on the simulations. Discrepancies in recommended doses from the two models were likely due to the incorporation of age-dependent physiological factors in the PBPK model. In conclusion, our study is the first to suggest an optimal oral dosing regimen of bepotastine in pediatric patients using both approaches. This is expected to foster safer and more productive use of the drug

A Population Pharmacokinetic and Pharmacodynamic Model of CKD-519

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that is being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition, the exposure of CKD-519 was highly varied, depending on food and dose. For highly variable exposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study aimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519 and to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results from multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects. The results showed that a 3-compartment with Erlang&rsquo;s distribution, followed by the first-order absorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and time was incorporated into the model (NONMEM version 7.3). After the PK model development, the CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the turnover model, including the placebo effect. According to PK-PD simulation results, 200 to 400 mg of CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof of concept studies in patients with dyslipidemia