Sail Chun

Effects of α-Lipoic Acid on the Plasma Levels of Asymmetric Dimethylarginine in Diabetic End-Stage Renal Disease Patients on Hemodialysis: A Pilot Study

Background/Aim: Endothelial dysfunction due to reduced nitric oxide (NO) availability precedes the development of atherosclerosis. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is not only a cause of endothelial dysfunction, but also a predictor of the cardiovascular outcome in end-stage renal disease (ESRD) patients on hemodialysis (HD). α-Lipoic acid (ALA), a strong antioxidant, increases NO-mediated vasodilation in diabetic patients. We investigated whether ALA could decrease the plasma level of ADMA in diabetic ESRD patients on HD. Methods: Fifty patients undergoing HD three times per week were randomized to a treatment group receiving ALA 600 mg/day for 12 weeks or a control group. We measured the plasma levels of cholesterol, albumin, high-sensitivity C-reactive protein, oxidized low-density lipoprotein, hemoglobin A1c, and ADMA in both groups at baseline and at 12 weeks. Results: In the control group, the levels of total cholesterol, serum albumin, high-sensitivity C-reactive protein, oxidized low-density lipoprotein, hemoglobin A1c, and ADMA did not change. In the treatment group, the plasma levels of ADMA decreased significantly from a median of 1.68 (range 0.45–3.78) µM to a median of 1.31 (range 0.25–3.19) µM (p = 0.001). Conclusion: Considering that ADMA is an independent risk factor for cardiovascular outcome in ESRD patients, ALA may have the potential of a beneficial effect in them, in part by decreasing the plasma level of ADMA.

Inflammatory and Hemostatic Biomarkers Associated With Early Recurrent Ischemic Lesions in Acute Ischemic Stroke

BACKGROUND AND PURPOSE Early recurrent ischemic lesions (ERILs) on diffusion-weighted imaging after acute ischemic stroke have been suggested as a potential marker of early recurrent stroke. We hypothesized that biomarkers of inflammation or coagulation may be associated with the pathogenesis of ERILs and sought to investigate whether these biomarkers provide prognostic information on the risk of development of ERILs independently of clinical and imaging variables. METHODS This prospective study enrolled 153 consecutive patients with acute ischemic stroke who underwent diffusion-weighted imaging within 24 hours and subsequently at 5 days after onset and whose plasma or serum for biomarkers (C-reactive protein, fibrinogen, d-dimer, tissue plasminogen activator, and plasminogen activator inhibitor-1) were collected within 24 hours of onset. Those receiving thrombolysis or interventional therapy were excluded. ERILs were defined as new ischemic lesions on 5-day diffusion-weighted imaging separate from the index stroke lesions, which were not accompanied by subsequent recanalization. RESULTS ERILs were observed in 37 patients (24.2%). In univariate analysis, shorter time from onset to initial MRI (P=0.013), initial acute multiple infarcts (P<0.001), initial larger infarct volume (P=0.005), stroke subtype (P<0.001), elevated d-dimer (P=0.028), and anticoagulation after admission (P=0.001) were associated with ERILs. In multivariate analysis, initial acute multiple infarcts (OR, 16.60; 95% CI, 5.73 to 48.08), large artery atherosclerosis (OR, 4.62; 95% CI, 1.51 to 14.11), and log d-dimer (OR, 3.20; 95% CI, 1.14 to 9.00) remained independent predictors of ERILs. CONCLUSIONS These data suggest that elevated d-dimer level reflecting increase of thrombin generation and fibrin turnover may be an independent factor predicting ERILs.

Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: a prospective case-control study.

We performed the present prospective case-control study to evaluate whether the plasma concentrations of phthalate esters are elevated in women with advanced-stage endometriosis in a Korean population. Measuring plasma levels of monoethylhexyl phthalate and di-(2-ethylhexyl) phthalate in 97 women with advanced-stage endometriosis and 169 control women by liquid chromatography-tandem mass spectrometry, we found that the concentrations of monoethylhexyl phthalate, as well as di-(2-ethylhexyl) phthalate, are significantly higher in those with advanced-stage endometriosis, which supports the hypothesis that exposure to phthalate might play a role in the establishment of endometriosis.

Tacrolimus Concentrations in Relation to CYP3A and ABCB1 Polymorphisms Among Solid Organ Transplant Recipients in Korea

Background. Cytochrome P450 3A (CYP3A) and the drug transporter P-glycoprotein (P-gp) affect the bioavailability of tacrolimus, the most commonly used immunosuppressive agent in organ transplant recipients. We have determined the genotypic frequencies of the CYP3A and ATP-binding cassette sub-family B member 1 (ABCB1) genes, which encode the CYP3A and P-gp proteins, respectively, in Korean organ transplant recipients and donors, and have assessed the influence of CYP3A and ABCB1 polymorphisms on tacrolimus concentrations. Methods. Using chip-based MALDI-TOF mass spectrometry, 506 solid organ transplant recipients and 62 corresponding of liver transplant donors were genotyped for CYP3A4*6, CYP3A4*18, CYP3A5*3, CYP3A5P1*3, ABCB1 c.2677G>A/T, and ABCB1 c.3435C>T alleles, and their steady-state blood concentrations of tacrolimus were measured. Results. Frequencies of variant alleles among the transplant recipients were CYP3A5*3 76.8%, CYP3A5P1*3 75.9%, ABCB1 c.2677A/T 52.8%, ABCB1 c.3435T 36.9%, CYP3A4*18 1.9%, and CYP3A4*6 0.3%. The CYP3A5P1*3 allele was strongly linked to the CYP3A5*3 allele (r2=0.816). Patients with the CYP3A5*3 and CYP3A5P1*3 alleles showed higher blood tacrolimus concentrations per adjusted dose ratio than did patients with wild-type alleles, among both liver transplant donors and renal transplant recipients. Conclusion. The CYP3A5 genotype of the liver is considered to show the most important association with tacrolimus concentrations. Ultimately, genotyping for CYP3A5 may help optimal individualization of immunosuppressive drug therapy for patients undergoing solid organ transplantation.

Effects of total cholesterol and triglyceride on the percentage difference between the low-density lipoprotein cholesterol concentration measured directly and calculated using the Friedewald formula.

Abstract Background: We elucidate how the triglyceride (TG) and total cholesterol (TC) concentrations affect the percentage difference (%ΔLDL) between the low-density lipoprotein cholesterol (LDL-C) concentration evaluated by direct measurement (DLDL-C) and calculated using the Friedewald formula (FLDL-C), under conditions allowing the calculation. Methods: Serum concentrations of TC, TG, high-density lipoprotein cholesterol (HDL-C), and DLDL-C were measured and the FLDL-C and %ΔLDL were calculated for 38,243 Koreans who had TG values <4.52 mmol/L. The DLDL-C was measured using the homogeneous Kyowa Medex assay (Kyowa, Tokyo, Japan). The %ΔLDL was calculated using the equation: [(FLDL-C–DLDL-C)/DLDL-C]×100. Results: The mean %ΔLDL-C was –9.1±6.4%. The %ΔLDL differed by more than ±5% in 75.4% of the subjects, and the FLDL-C was lower than the DLDL-C in 96.3%. The mean %ΔLDL-C for the group with the highest TG and lowest TC was 11.8-fold that for the group with the lowest TG and highest TC. Conclusions: Under conditions satisfying the requirements of the Friedewald formula, the DLDL-C and FLDL-C differed significantly over the concentration ranges of both TC and TG. In an evaluation of patients with hyperlipidemia, the Friedewald calculation may underestimate the risk for coronary heart disease. Clin Chem Lab Med 2008;46:371–5.

The effects of green tea ingestion over four weeks on atherosclerotic markers

Background: The objective of this study was to evaluate the effects of green tea ingestion over four weeks on atherosclerotic biological markers. Methods: After a one-week baseline period, 12 healthy male volunteers aged 28-42 years drank 600 mL of green tea dailyfor four weeks. Lipid profile, oxidized low-density lipoprotein (ox-LDL), total antioxidant capacity (TAC), C-reactive protein (CRP) and soluble cell adhesion molecules were measured at baseline and after two and four weeks ingestion of green tea. Results: There was no significantchange in the concentrations of lipid profile, TAC, CRP, soluble intercellular adhesion molecule-1 (sICAM-1), or soluble E-selectin after ingestion of green tea. The levels of ox-LDL and soluble vascular cell adhesion molecule-1 (sVCAM-1) were significantly decreased after four weeks of green tea ingestion (Wilcoxon signed rank test, P=0.006). Conclusions: The results of this study suggest an in vivo anti-oxidative effect for green tea and an influence of green tea on atherosclerotic biological markers. The effect of green tea seen on ox-LDL and sVCAM-1provides a potential mechanism for the cardiovascular benefits of regular ingestion of green tea.

Homocysteine-lowering therapy or antioxidant therapy for bone loss in Parkinson's disease.

We investigated whether homocysteine (Hcy)‐ lowering therapy or an antioxidant prevented bone loss in Parkinsons disease (PD) patients taking levodopa. Forty‐two PD patients with low bone mineral density (BMD) taking levodopa were randomly assigned to Hcy‐lowering therapy (5 mg folate and 1500 μg vitamin B12 daily), α‐lipoic acid (α‐LA) therapy (1200 mg daily), or control groups. Primary outcomes were BMD changes from baseline to 12 months. Secondary outcomes were changes in Hcy level, and C‐telopeptide (CTX) levels at 12 months. Forty‐one patients completed the study. Hcy‐lowering therapy resulted in significantly greater BMD changes at the lumbar spine (4.4%), total femur (2.8%), and femur shaft (2.8%) than control (P = 0.005–0.023). BMD changes in the α–LA therapy group were similar to those of the control group, but changes at the trochanter (4.6%) were significantly greater in the α–LA therapy group than in the control group after adjustment for body mass index changes. Hcy concentrations decreased to 35.2% ± 13.4% in the Hcy‐lowering therapy group, but increased in other groups. Serum CTX levels at 12 months tended to be lower in the Hcy‐lowering group (0.442 ± 0.024 ng/mL) than control group (0.628 ± 0.039 ng/mL) (P = 0.159). This small trial suggests that Hcy‐lowering therapy may prevent bone loss in PD patients taking levodopa.

Possible Role of Phthalate in the Pathogenesis of Endometriosis: In Vitro, Animal, and Human Data

CONTEXT Although phthalates were shown to have several negative effects on reproductive function in animals, its role in the pathogenesis of endometriosis remains to be elucidated. OBJECTIVE We aimed to investigate the in vitro and in vivo effects of di-(2-ethylhexyl)-phthalate (DEHP) and to compare the urinary levels of several phthalate metabolites between women with and without endometriosis. DESIGN For experimental studies, we used endometrial cell culture and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models. We also performed a prospective case-control study for human sample analyses. SETTING The study was conducted at an academic center. MAIN OUTCOME MEASURES The activities of matrix metalloproteinase (MMP)-2 and 9, cellular invasiveness, phosphorylation of extracellular signal-regulated kinase (Erk), and expression of p21-activated kinase 4 were analyzed in endometrial cells treated with DEHP. The implant size was compared between NOD/SCID mice fed with and without DEHP. Urinary concentrations of several phthalate metabolites were compared between women with and without endometriosis. RESULTS In vitro treatment of endometrial cells with DEHP led to significant increases of MMP-2 and 9 activities, cellular invasiveness, Erk phosphorylation, and p21-activated kinase 4 expression. The size of the endometrial implant was significantly larger in the NOD/SCID mice fed with DEHP compared with those fed with vehicle. The urinary concentration of mono (2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-oxohexyl) phthalate, and mono (2-ethyl-5-carboxyphentyl) phthalate were significantly higher in women with endometriosis compared with controls. CONCLUSION These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells.

Relationship between Serum Total Cholesterol Level and Serum Biochemical Bone Turnover Markers in Healthy Pre- and Postmenopausal Women

Background. The presence of common risk factors suggests that there is a relationship between osteoporosis and cardiovascular disease, possibly via dyslipidemia and inflammation. We investigated the relationships among the lipid profile, the inflammation marker high-sensitivity C-reactive protein (hsCRP), bone turnover markers, and bone mineral density (BMD) to assess the correlation between osteoporosis and cardiovascular disease and identify factors predicting osteoporosis. Methods. The study included 759 Korean women older than 20 years of age. The BMD, serum lipid profile, and levels of hsCRP, cross-linked C-terminal peptide (CTX), and osteocalcin were measured. We compared the serum biomarkers between groups with normal and low BMD and assessed the correlations between the levels of bone turnover markers and the lipid profile and hsCRP level. Results. The concentrations of CTX, osteocalcin, and total cholesterol were significantly higher in the low BMD group than in the normal BMD group in premenopausal women group. However, hsCRP was not correlated with these parameters. Multivariate logistic regression analysis revealed that TC (OR, 1.647; 95% CI, 1.190–2.279) and osteocalcin (OR, 1.044; 95% CI, 1.002–1.088) had an increased risk of low BMD in premenopausal women. Conclusions. These results indicate that total cholesterol concentration is correlated with the levels of bone turnover markers, suggesting that it might predict osteoporosis in premenopausal women.

Comparison of the MDRD Study and CKD-EPI Equations for the Estimation of the Glomerular Filtration Rate in the Korean General Population: The Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-1), 2010

Background: We compared the accuracy of the Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in Korean patients and evaluated the difference in CKD prevalence determined using the two equations in the Korean general population. Methods: The accuracy of the two equations was evaluated in 607 patients who underwent a chromium-51-ethylenediaminetetraacetic acid GFR measurement. Additionally, we compared the difference in CKD prevalence determined by the two equations among 5,822 participants in the fifth Korea National Health and Nutrition Examination Survey, 2010. Results: Among the 607 subjects, the median bias of the CKD-EPI equation was significantly lower than that of the MDRD study equation (0.9 vs. 2.2, p=0.020). The accuracy of the two equations was not significantly different in patients with mGFR <60 mL/min/1.73m2; however, the accuracy of the CKD-EPI equation was significantly higher than that of the MDRD study equation in patients with GFR ≥60 mL/min/1.73m2. The prevalences of the CKD stages 1, 2 and 3 in the Korean general population were 47.56, 49.23, and 3.07%, respectively, for the MDRD study equation; and were 68.48, 28.89, and 2.49%, respectively, for the CKD-EPI equation. Conclusions: These data suggest that the CKD-EPI equation might be more useful in clinical practice than the MDRD study equation in Koreans.