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Background: The gender disparity in cardiovascular disease (CVD) risk is greatest between young men and women. However, the causes of that are not fully understood. The objective of this study was to evaluate the relationship between insulin resistance and the presence of coronary artery calcium (CAC) to identify risk factors that may predispose young men and women to CVD., Methodology/principal Findings: Insulin resistance and CVD risk factors were examined in 8682 Korean men and 1829 women aged 30-45 years old. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR), and CAC was measured using computed tomography. Women were less likely to be insulin resistant (upper quartile of HOMA-IR, 18% vs. 27%, p<0.001) and had a lower prevalence of CAC (1.6% vs. 6.4%, p<0.001). Even when equally insulin resistant men and women were compared, women continued to have lower prevalence of CAC (3.1% vs. 7.2%, p = 0.004) and a more favorable CVD risk profile. Finally, after adjustment for traditional CVD risk factors, insulin resistance remained an independent predictor of CAC only in men (p = 0.03)., Conclusions/significance: Young women have a lower risk for CVD and a lower CAC prevalence compared with men. This favorable CVD risk profile in women appears to occur regardless of insulin sensitivity. Unlike men, insulin resistance was not a predictor of CAC in women in this cohort. Therefore, insulin resistance has less impact on CVD risk and CAC in young women compared with men, and insulin resistance alone does not explain the gender disparity in CVD risk that is observed at an early age.

Background and Aims: The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) reported reduced cardiovascular and all-cause mortality in patients with elevated C-reactive protein (CRP) and low LDL-cholesterol (LDL-C) levels treated with statins. The aims of this study were to determine the proportion of "JUPITER-eligible" Korean adults and to describe their characteristics., Methods and Results: As many as 15,154 subjects with serum LDL-C levels <130 mg/dL were selected among 28,851 middle-aged participants (men ≥ 50 years, women ≥ 60 years) who participated in a routine health check-up program. Among the participants with LDL-C less than 130 mg/dL, only 15% had CRP levels ≥2.0 mg/L (7.9% of original participants). Subjects were divided into four groups according to CRP levels (<0.5, ≥0.5 - <1.0, ≥1.0 - <2.0, and ≥2.0 mg/L). Mean HDL-C and apolipoprotein A1 levels decreased significantly as the mean CRP values increased. The insulin and homeostasis model of insulin resistance was significantly different according to CRP quartile. The number of subjects with metabolic syndrome and its components increased significantly as the mean CRP values increased., Conclusion: In this Asian population, few individuals with low LDL-C levels had CRP levels ≥2.0 mg/L. Elevated CRP levels were associated with components of atherogenic dyslipidemia and insulin resistance. Additional clinical trials should be designed and performed in different ethnic groups, as different CRP cut-off levels may be required in different ethnic groups., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: Withdrawal of opioids is usually associated with intolerable aversive symptoms. Our objective was to evaluate the efficacy of phenothiazine-type antipsychotics for reducing withdrawal symptoms during morphine abstinence., Methods: Adult NRL mice were rendered physically dependent on morphine by escalating the doses of subcutaneous morphine for 3 days. Withdrawal jumping was precipitated by a subcutaneous injection of naloxone (50 mg/kg) on day 4. In study I, on an equimolar basis, we compared the efficacy of six phenothiazine antipsychotics in saline on reducing morphine withdrawal symptoms. One hour before naloxone injection, the mice were assigned to receive intramuscular (i.m.) saline or one of the six phenothiazine-type antipsychotics (0.3 μmol/kg). After naloxone injection, the tested mouse was immediately placed in a transparent acrylic cylinder, and the severity of withdrawal symptoms was assessed, via a computer connected to the floor of the cylinder, by counting the number of the withdrawal jumps over a 30-minute interval. In study II, we performed a dose-response test in these six phenothiazine antipsychotics (0.03, 0.3, and 3 μmol/kg, i.m., for each test drug) on the inhibition of naloxone-precipitated morphine withdrawal jumping., Results: We found that all six phenothiazine-type antipsychotics attenuated the morphine withdrawal jumps, as compared with saline (p < 0.05). The effect is dose-dependent, with the potency ranking order as follows: fluphenazine ＝ triflupromazine > chlorpromazine ＝ perphenazine > promazine ＝ thioridazine (p < 0.05)., Conclusions: All six phenothiazine-type antipsychotics could attenuate morphine withdrawal symptoms; in particular, fluphenazine and triflupromazine may potentially be the more appropriate candidates for the treatment of morphine withdrawal symptoms., (Copyright © 2012. Published by Elsevier B.V.)

Objective: Ferritin concentrations are often increased in patients with metabolic syndrome and type 2 diabetes mellitus, but few reports have examined the associations between ferritin and atherosclerosis. We investigated whether any relationship between ferritin and coronary artery calcium score (CACS) >0 (as a marker of atherosclerosis) was independent of potential confounders, such as iron-binding capacity (transferrin), low-grade inflammation, and cardiovascular risk factors., Methods and Results: Data were analyzed from a South Korean occupational cohort of 12 033 men who underwent a cardiac computed tomography estimation of CACS and measurements of multiple cardiovascular risk factors. One-thousand three- hundred-fifteen of 12 033 (11.2%) subjects had a CACS >0. For people with a CACS >0, median (interquartile range) ferritin concentration was 196.8 (136.3-291.9) compared with 182.2 (128.1-253.6) in people with a CACS=0; P<0.001. In the highest ferritin quartile, 14.7% (442/3008) of subjects had a CACS >0 compared with 9.7% (292/3010) in the lowest quartile (P<0.0001). With increasing ferritin quartiles, there were also higher proportions of people with diabetes mellitus (P<0.0001), hypertension (P<0.0001), coronary heart disease (P=0.003), and a Framingham Risk Score >10% (P<0.0001). In logistic regression modeling with CACS >0 as the outcome, ferritin but not transferrin was independently associated with CACS >0 (odds ratio for highest quartile versus lowest quartile, 1.66 [95% CI, 1.3-1.98]; P=0.0001)., Conclusions: Increased ferritin concentrations are associated with the presence of a marker of early coronary artery atherosclerosis, independently of traditional cardiovascular risk factors including Framingham risk score, transferrin, preexisting vascular disease, diabetes mellitus, metabolic syndrome factors, and low-grade inflammation.

Background: Non alcoholic fatty liver disease (NAFLD) is associated with increased risk of type 2 diabetes and chronic liver disease but identifying patients who have NAFLD without resorting to expensive imaging tests is challenging. In order to help identify people for imaging investigation of the liver who are at high risk of NAFLD, our aim was to: a) identify easily measured risk factors at baseline that were independently associated with incident fatty liver at follow up, and then b) to test the diagnostic performance of thresholds of these factors at baseline, to predict or to exclude incident fatty liver at follow up., Methods: 2589 people with absence of fatty liver on ultrasound examination at baseline were re-examined after a mean of 4.4 years in a Korean occupational cohort study. Multi-variable logistic regression analyses were used to identify baseline factors that were independently associated with incident fatty liver at follow up. The diagnostic performance of thresholds of these baseline factors to identify people with incident fatty liver at follow-up was assessed using receiver operating characteristic (ROC) curves., Results: 430 incident cases of fatty liver were identified. Several factors were independently associated with incident fatty liver: increased triglyceride (per mmol/l increase) OR 1.378 [95%CIs 1.179, 1.611], p < 0.0001; glucose (per mmol/l increase) OR 1.215 [95%CIs 1.042, 1.416], p = 0.013; waist (per cm increase) OR 1.078 [95%CIs 1.057, 1.099], p < 0.001; ALT (per IU/L increase) OR 1.009 [95%CIs 1.002, 1.017], p = 0.016; and platelets (per 1x10⁹/L increase) OR 1.004 [1.001, 1.006], p = 0.001; were each independently associated with incident fatty liver. Binary thresholds of the five factors were applied and the area under the ROC curve for incident fatty liver was 0.75 (95%CI 0.72-0.78) for the combination of all five factors above these thresholds., Conclusion: Simple risk factors that overlap considerably with risk factors for type 2 diabetes allow identification of people at high risk of incident fatty liver at who use of hepatic imaging could be targeted.

Background/aims: We have a limited understanding of the effect of nonalcoholic fatty liver disease (NAFLD) on the development of type 2 diabetes., Methods: The study subjects included male who had received biennial medical check-ups between 2005 and 2009 and who had been diagnosed with fatty liver disease. The subjects with sustained NAFLD (FL, n=107) and sustained non-NAFLD (NFL, n=1,054) were followed to determine the development of type 2 diabetes., Results: In the FL group, there were more subjects with impaired fasting glucose (IFG), type 2 diabetes and high HOMA-IR than there were in the NFL group during the 5-year follow-up period (32.7 vs. 17.6%, 1.9 vs. 0.3%, 17.9 vs. 5.2% respectively, p<0.05). The FL group showed a higher risk than NFL group for abnormal glucose metabolism as determined using IFG (odds ratio [OR], 2.13; confidence interval [CI], 1.36 to 3.35), type 2 diabetes (OR, 7.63; 95% CI, 1.03 to 56.79) and high HOMA-IR (OR, 3.25; 95% CI, 1.79 to 5.91) and metabolic parameters such as body mass index (OR, 3.35; 95% CI, 1.87 to 6.02), triglyceride (OR, 3.05; 95% CI, 1.92 to 4.86) and fasting blood sugar (OR, 2.18; 95% CI, 1.39 to 3.41)., Conclusions: Sustained NAFLD appears to be associated with an increased risk for the development of type 2 diabetes and deterioration of metabolic parameters in non-obese, non-diabetic Korean men.

Background: Increased low-density lipoprotein cholesterol (LDL) concentration is associated with increased risk of coronary heart disease (CHD) but a substantial risk of cardiovascular disease often remains after LDL concentrations have been treated to target. Apolipoprotein B (apo B) is the major apolipoprotein contained within atherogenic lipoproteins such as LDL, and apo B is a more reliable indicator of cardiovascular risk than LDL concentration., Aim and Methods: Our aim was to develop a formula for calculating apo B using lipid biochemistry measurements that are commonly available in clinical practice. We examined the clinical and laboratory data from 73,047 Koreans who underwent a medical health check that included apolipoprotein B concentration. The study sample was randomly divided into a training set for prediction model building and a validation set of equal size. Multivariable linear regression analysis was used to develop a prediction model equation for estimating apo B and to validate the developed model., Results: The best results for estimating apo B were derived from an equation utilising LDL and triglyceride (TG) concentrations [ApoB = -33.12 + 0.675*LDL + 11.95*ln(tg)]. This equation predicted the apo B result with a concordance correlation coefficient (CCC and 95%CIs) = 0.936 (0.935,0.937))., Conclusion: Our equation for predicting apo B concentrations from routine analytical lipid biochemistry provides a simple method for obtaining precise information about an important cardiovascular risk marker.

Background: Reduced lung function is associated with incident insulin resistance and diabetes. The aim of this study was to assess the relationship between lung function and incident type 2 diabetes in Korean men., Methods: This study included 9,220 men (mean age: 41.4 years) without type 2 diabetes at baseline who were followed for five years. Subjects were divided into four groups according to baseline forced vital capacity (FVC) (% predicted) and forced expiratory volume in one second (FEV1) (% predicted) quartiles. The incidence of type 2 diabetes at follow-up was compared according to FVC and FEV1 quartiles., Results: The overall incidence of type 2 diabetes was 2.2%. Reduced lung function was significantly associated with the incidence of type 2 diabetes after adjusting for age, BMI, education, smoking, exercise, alcohol, and HOMA-IR. Both FVC and FEV1 were negatively associated with type 2 diabetes (P < 0.05). In non-obese subjects with BMI < 25, the lowest quartile of FVC and FEV1 had a significantly higher odds ratio for type 2 diabetes compared with the highest quartile after adjusting for age and BMI (2.15 [95% CI 1.02-4.57] and 2.19 [95% CI 1.09-4.42])., Conclusions: Reduced lung function is independently associated with the incidence of type 2 diabetes in Korean men.

Our aim is to develop nanostructured lipid carriers (NLCs) for loading the apomorphine diester prodrugs, diacetyl apomorphine (DAA) and diisobutyryl apomorphine (DIA), into the brain. NLCs were prepared using sesame oil/cetyl palmitate as the lipid matrices. Experiments were performed with the objective of evaluating the physicochemical characteristics, drug release, safety and brain-targeting efficacy of the NLCs. The size of regular NLCs (N-NLCs) was 214 nm. The addition of Forestall (FE) and polyethylene glycol (PEG) to the NLCs (P-NLCs) increased the particle diameter to 250 nm. The zeta potentials of N-NLCs and P-NLCs were respectively shown to be - 21 and 48 mV. Diester prodrugs were more lipophilic and more chemically stable than the parent apomorphine. The hydrolysis study indicated that the prodrugs underwent bioconversion in plasma and brain extract, with DAA exhibiting faster degradation than DIA. Sustained release was achieved through the synergistic effect of integrating strategies of prodrugs and NLCs, with the longer carbon chain showing the slower release (DIA < DAA). None of the NLCs tested here exhibited a toxicity problem according to the examination of neutrophil lactate dehydrogenase (LDH) release and hemolysis. Results of a bioimaging study in mice showed that P-NLCs largely accumulated in the brain. The distribution duration of the fluorescent dye in the brain region was also prolonged by the nanocarriers.

Aims: To know which MS criteria best predict the presence of NAFLD and the prevalences of metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) diagnosed ultrasonographically among pre-diabetic and diabetic subjects based on three different MS criteria (IDF, ATP III, WHO)., Methods: Subjects were screened and those with a fasting serum glucose level ≥100 mg/dL were further tested with a 75 g oral glucose tolerance test. And those who were newly diagnosed as having pre-diabetes or diabetes were evaluated for MS and NAFLD. We compared the risk ratios of NAFLD among three MS criteria using multivariate and multiple logistic regression analyses., Results: A total of 1365 subjects (977 males, mean age 48.4±9.5 years) were analyzed. The WHO criteria produced the highest prevalence of MS in both the pre-diabetic (49.8%) and diabetic (58.9%) groups. The IDF criteria produced the highest odds ratio for NAFLD in both pre-diabetic (3.89 [95% CI 2.75-5.51]) and diabetic (5.53 [95% CI 3.21-9.52]) groups., Conclusions: The prevalence of MS depends on the set of diagnostic criteria used. IDF criteria best predicts the presence of NAFLD. The presence of NAFLD should be considered as a component of the diagnostic criteria for MS., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: There is controversy about the specific pathophysiology of metabolic syndrome (MS) but several authors have argued that hyperinsulinemia is a key feature of the cluster. We aimed to assess whether the baseline insulin levels could predict the development of MS in a well characterised cohort of otherwise healthy adults who were followed over a five year period., Methods: We identified 2, 350 Koreans subjects who did not have MS in 2003 and who were followed up in 2008. The subjects were divided into 4 groups according to the baseline quartiles of fasting insulin, and the predictors of the incidence of MS were analyzed using multivariate regression analysis., Results: Over the follow up period, 8.5% of the cohort developed MS. However, 16.4% of the subjects in the highest quartile of the insulin levels developed MS. In a model that included gender, age, the smoking status, the exercise level, alcohol consumption and the systolic blood pressure, the subjects in the highest quartile of the insulin levels had more than a 5 times greater risk of developing MS compared that of the subjects in the lowest quartile. This predictive importance remained significant even after correcting for all the individual features of MS., Conclusions: These data suggest that high baseline fasting insulin levels are independent determinants for the future development of MS.

Objective: Omentin-1 is a novel adipokine that increases insulin sensitivity and is expressed in visceral adipose tissue. The aim of this study was to determine the metabolic parameters that influence plasma omentin-1 levels in women with polycystic ovary syndrome (PCOS)., Design and Methods: A cross-sectional study was performed in 87 women with PCOS and 53 body mass index (BMI)-matched healthy controls including 39 non-obese, normal-weight (NW) PCOS women with normal glucose tolerance (NGT) and 44 BMI- and homeostasis model assessment (HOMA)-matched controls. Indices of insulin sensitivity, metabolic variables, circulating androgen levels, serum adiponectin, and omentin-1 levels were measured. A 75 g oral glucose tolerance test was performed in all participants., Results: Plasma omentin-1 levels were significantly lower in women with PCOS compared with those in BMI-matched controls (P<0.001). A significantly lower level of plasma omentin-1 was observed in non-obese women with PCOS and NGT compared with that in BMI- and HOMA-matched controls (P<0.001). Omentin-1 level was negatively correlated with BMI, indices of insulin sensitivity, and circulating androgens and was associated with greater 2 h postprandial glucose, C-peptide, and insulin levels compared with fasting values. Within the NW and NGT groups, omentin-1 levels remained negatively correlated with BMI, 2 h postprandial C-peptide, and circulating androgens and demonstrated a negative linear trend according to quartile of free testosterone (P=0.028)., Conclusions: Plasma levels of omentin-1 were reduced in non-obese women with PCOS and NGT. Postprandial hyperinsulinemia and hyperglycemia contributed more to lower omentin-1 levels than did fasting values in the setting of PCOS. Increased androgen levels contributed to decreased omentin-1 levels in women with PCOS.

There is no consensus on the relationship between high blood pressure (BP) and incident diabetes mellitus (DM). Therefore, the aim of the current study was to investigate the independent association between BP and incident DM and identify the metabolic components that influence incident DM in Korean subjects. The current study included 14 054 non-diabetic subjects (mean age of 41 years) at the start of the study who were followed for an average of 5 years. We measured the risk for incident DM according to the subjects' baseline BP. Subjects were separated into three groups as follows: normotensive (<120/80 mm Hg), pre-hypertensive (120/80 mm Hg ≤BP <140/90 mm Hg) and hypertensive (≥140/90 mm Hg). The overall incidence of DM was 1.8% (246 subjects), comprising 0.9% of the normotensive group, 1.9% of the pre-hypertensive group and 4.0% of the hypertensive group (P<0.01). Within the hypertensive group, subjects with high body mass index (BMI) and high fasting-glucose levels were 40 times more likely to develop DM compared with those with low BMI and low glucose levels (0.3 vs. 13.2%, P=0.001). The risk for incident DM was significantly higher in the hypertensive group compared with that in the normotensive group (OR 3.41 vs. 1.00, P<0.0001). However, the significance disappeared after making adjustments for the baseline BMI and fasting glucose levels (OR 1.18 vs. 1.00, P=0.83). We found that the significance of high BP in predicting incident DM was influenced by the baseline BMI and fasting glucose levels of the subjects.

Background: The relationships between insulin level and indexes of insulin resistance (IR) to predict incident hypertension have been explored only in cross-sectional or prospective studies with small numbers of patients. We investigated whether plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA(IR)) are associated with the onset of hypertension in a population of apparently healthy and relatively lean Korean adults., Methods: We selected 10,894 of 15,638 subjects who were normotensive at baseline during general health status evaluations in 2003 and 2008. The baseline and follow-up examinations included analyses of fasting glucose, insulin level, and lipid profile. Alcohol consumption, smoking status, exercise habits, and education level were also evaluated using a standard questionnaire., Results: Of the 10,894 subjects, hypertension developed in 881 (8.1%) during the ensuing 5 years. Incident hypertension was more common among older subjects than it was in younger subjects and was associated with a high baseline body mass index (BMI). In multivariable logistic models, elevated serum insulin, and HOMA(IR) were associated with an increased risk of incident hypertension in both sexes. In a multivariable analysis using quartiles of insulin and HOMA(IR), the odds ratio (OR) for incident hypertension was the highest in the highest quartile of insulin and HOMA(IR). The highest quartile of insulin and HOMA(IR) was associated with a 1.5-1.7 times increased risk of incident hypertension., Conclusions: This 5-year follow-up study provides evidence that both a high circulating insulin level and HOMA(IR) are significant risk factors for the development of hypertension in a relatively lean and healthy population.

Diester prodrugs of apomorphine, diacetyl apomorphine (DAA), and diisobutyryl apomorphine (DIA) were synthesized, and their partition coefficients, capacity factor (log K'), enzymatic hydrolysis, and in vitro permeation across nude mouse skin were characterized. The lipophilicity of the diesters was between that of apomorphine HCl and the apomorphine base. The prodrugs were chemically stable, but enzymatically unstable in esterase medium, skin homogenate, and human plasma. DAA showed a faster hydrolysis in plasma compared to DIA. Total fluxes (nmol/cm(2)/h) of the parent drug and prodrug were significantly greater after topical treatment with the diesters in aqueous solutions (water, 30% polyethylene glycol in water, and 30% glycerol in water) compared to treatment with HCl and base forms of apomorphine. DIA flux from deionized water was 51 nmol/cm(2)/h, which exceeded the flux of apomorphine HCl by 10-fold. The extent of parent drug regeneration after topical application ranged 51-88% and 34-61% for DAA and DIA, respectively, depending on the vehicles selected. Permeation measurements using intact and stratum corneum-stripped skins demonstrated that the viable epidermis/dermis was an important barrier to prodrug permeation. Nano-sized lipid emulsions were also used as carriers for apomorphine and its prodrugs. Diester prodrugs exhibited superior skin permeation compared to the parent drug when formulated into the emulsions. DAA and DIA fluxes from lipid emulsions were 11- and 3-fold higher than that of apomorphine HCl. The results in the present work suggest the feasibility of diester prodrugs for the transdermal delivery of apomorphine., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Context: Although fatty liver and insulin resistance are known to be associated, the relationship between the two in the development of type 2 diabetes mellitus (T2DM) is unclear., Objective: We investigated the 5-yr risk of developing T2DM in individuals diagnosed with fatty liver using ultrasound and stratified by insulin sensitivity using quartiles of fasting insulin concentration., Design and Methods: We examined the clinical and laboratory data of 11,091 Koreans who had a medical evaluation including fasting insulin concentration and abdominal ultrasound at baseline and had a follow-up after 5 yr., Results: At baseline, 27% of the population had fatty liver. Almost half (47%) of the individuals with fatty liver had baseline insulin concentration in the highest quartile compared with 17% in those without fatty liver (P < 0.001). Regardless of baseline insulin concentration, individuals with fatty liver had significantly (P < 0.001) more baseline clinical and metabolic abnormalities, including higher glucose and triglyceride concentration and lower high-density lipoprotein cholesterol concentration. In addition, regardless of baseline insulin concentration, individuals with fatty liver had a significantly increased risk for incident T2DM compared with those without fatty liver [crude odds ratio, 5.05 (95% confidence interval, 2.08-12.29) in the lowest insulin quartile and 6.34 (3.58-11.21) in the highest quartile]. In individuals in the highest insulin quartile, the odds ratio for developing T2DM remained significant even after multivariate adjustment including baseline glucose concentration [2.42 (1.23-4.75)]., Conclusion: Although associated with insulin resistance, fatty liver diagnosed by ultrasound appears to independently increase the risk of T2DM.

Prehypertension is associated with oxidative stress and increased arterial stiffness. While plasma homocysteine levels are associated with increased pulse wave velocity in hypertensive individuals, there is no report regarding this relationship in prehypertensives. Homocysteine levels and brachial-ankle pulse wave velocity (baPWV) were investigated in 4177 prehypertensives (3178 men, mean age 53 ± 11 years) with ankle-brachial indexes (ABIs) greater than 0.95 who had visited the Kangbuk Samsung Health Promotion Center. The subjects were subdivided into two groups according to baPWV; group I (1720 subjects) was defined as subjects with a baPWV of 1366 cm/sec or lower, while group II (2457 subjects) included subjects with a baPWV greater than 1366 cm/sec. Subjects were also divided into four quartile groups depending on homocysteine level. Homocysteine levels in group II were found to be significantly higher than those in group I. There were significant differences in baPWV value among the four quartile groups (quartile I, 1411 ± 213.9 cm/sec; quartile II, 1436 ± 223.3 cm/sec; quartile III, 1460 ± 220.4 cm/sec; quartile IV, 1494 ± 251.3 cm/sec; p-value <0.001). In multivariate regression models, the increasing quartile groups of homocysteine had higher odds ratios (ORs) for increased baPWV compared to that of the lowest quartile group (OR [95% confidence interval (CI)] in the second, third, and highest quartiles: 1.41 [1.12-1.77], 1.65 [1.30-2.10], and 1.82 [1.42-2.33], respectively, p < 0.001), irrespective of confounding factors. This study indicates an independent relationship between circulating homocysteine level and arterial stiffness in prehypertensives, suggesting that circulating homocysteine level could be a useful biomarker of subclinical target organ damage in prehypertensives.

Background: insulin resistance is known to be the most important pathogenic factor in the development of nonalcoholic fatty liver disease. We performed a prospective study to analyze the associations of baseline and changes in fasting insulin levels with future development of nonalcoholic fatty liver disease in nondiabetic adults over a 5-year period., Methods: this study was performed in 4954 subjects who did not have diabetes or nonalcoholic fatty liver disease and who participated in a health checkup program in both 2003 and 2008. The presence of nonalcoholic fatty liver disease was defined by ultrasonographic examination. Subjects were divided into 4 groups according to the baseline quartiles of fasting insulin and dichotomized fasting insulin levels at baseline and after 5 years: low-low, low-high, high-low, high-high., Results: after 5 years, 644 subjects (13%) developed nonalcoholic fatty liver disease. The odds ratio (OR) for development of nonalcoholic fatty liver disease increased as the quartiles of the baseline fasting insulin levels increased from the first to the fourth quartile (1.00 vs. 0.99, 1.44, 1.65, respectively). The OR for nonalcoholic fatty liver disease was 2.5-fold higher in the high-high group and 1.6-fold higher in the low-high group compared with that of the low-low group. The OR for nonalcoholic fatty liver disease increased as the quartile of changes in fasting insulin level over the 5-year period increased., Conclusion: high baseline and continuously increasing fasting insulin levels were the independent determinants for future development of nonalcoholic fatty liver disease during a 5-year follow-up in nondiabetic healthy adults., (2011 Elsevier Inc. All rights reserved.)

Objectives: A cross-sectional analysis was conducted in healthy, nondiabetic Korean adults to assess the prevalence of nonalcoholic fatty liver disease (NAFLD), to compare the prevalence of NAFLD across different glycemic ranges as assessed by glycosylated hemoglobin (HbA1c), and to examine the impact of NAFLD on insulin resistance in relation to HbA1c levels., Methods: After rigorous exclusion criteria, the final number of subjects who participated in a comprehensive health status checkup program was 99,969. All subjects were classified into four categories with respect to HbA1c level (≤4.9, 5.0-5.4, 5.5-5.9, and 6.0-6.4%). We estimated the odds ratio (OR) for prevalence of NAFLD according to the categorized level of HbA1C and evaluated the association of NAFLD with the homeostatic model assessment of insulin resistance (HOMA-IR) in relation to the HbA1c level., Results: Twenty-eight percent (n=28,130, 40.2% of the men, 10.3% of the women) of the study subjects had NAFLD. Men had a 5.83-fold (95% confidence interval 5.63-6.05) increased risk for having NAFLD than did women. The risk for NAFLD increased with increasing level of HbA1c (OR 1.44, 2.62, and 7.18) when compared with the lowest quartile (HbA1C≤4.9%). HOMA-IR increased in the NAFLD subjects as the level of HbA1c increased. The magnitude of association of HOMA-IR with HbA1c level was greater in NAFLD subjects than in non-NAFLD subjects (P<0.001 for interaction). These associations were consistent even after adjustment for body mass index and other metabolic components., Conclusions: NAFLD had an association with HbA1c level and insulin resistance in nondiabetic individuals, and these associations were independent of obesity and other metabolic components.

The aim of this study was done to assess the association of lung function with insulin resistance (IR), systemic inflammation, and metabolic syndrome (MetS). In 9,581 apparently healthy non-smoking male adults, pulmonary function, fasting glucose, insulin, lipid profiles and serum high-sensitivity C-reactive protein (hs-CRP) levels were measured, and homeostatic model assessment (HOMA) was used to assess IR. The presence of MetS was defined according to the AHA/NHLBI criteria. The prevalence of MetS was 19.3%. The odds ratio of MetS for restrictive ventilatory pattern was 1.55 (95% confidence interval, 1.12-2.14), and that for obstructive ventilatory pattern was 1.39 (0.66-2.94) after adjustment for confounders. When subjects were divided in 4 groups according to quartiles of FVC or FEV(1) (% predicted [pred]), HOMA-IR significantly increased as the FVC or FEV(1) (% predicted [pred]) decreased. Individuals in the lowest FVC or FEV(1) quartile had the highest hs-CRP level. Prevalence of MetS increased as FVC or FEV(1) (% predicted [pred]) quartiles decreased. The abdominal obesity, hs-CRP and HOMA-IR were the independent predictors for the lowest FVC and FEV(1) (% predicted [pred]) even after adjustment for confounders. These results indicate that MetS, IR, and systemic inflammation are important risk factors for reduced lung function in nonsmoking Korean males.

Background/aims: This study evaluated the relationship between hyperuricemia and nonalcoholic fatty liver disease (NAFLD) by comparing the incidence rates of NAFLD in relation to serum uric acid levels in apparently healthy subjects during a 5-year period., Methods: Among 15,638 healthy Korean subjects who participated in a health-screening program in 2003 and 2008, respectively, 4954 subjects without other risk factors were enrolled in this study. We compared the incidence rates of NAFLD in 2008 with respect to baseline uric acid levels., Results: In 2003, serum uric acid levels were categorized into the following quartiles: 0.6-3.9, 3.9-4.8, 4.8-5.9, and 5.9-12.6 mg/dL. The incidence of NAFLD in 2008 increased with the level of baseline uric acid (5.6%, 9.8%, 16.2%, and 20.9%, respectively; p<0.05). Multiple logistic regression analysis demonstrated that hyperuricemia was associated with the development of NAFLD. When compared to the subjects in quartile 1, the odds ratio (OR) for the incidence of NAFLD for quartiles 2, 3, and 4 were 1.53 (95% confidence interval [CI], 1.09-2.16; p=0.014], 1.69 (95% CI, 1.17-2.44; p=0.005), and 1.84 (95% CI, 1.25-2.71; p=0.002), respectively., Conclusions: High serum uric acid levels appear to be associated with an increased risk of the development of NAFLD.

Background and Objectives: The correlation between brain natruretic peptide (BNP) level and cardiac autonomic function has been studied in type 2 diabetic patients. However, there is limited data from patients with normal systolic function. We evaluated the association between heart rate recovery (HRR) representing autonomic dysfunction and three plasma BNP levels: pre-exercise, post-exercise, and change during exercise in patients with normal systolic function., Subjects and Methods: Subjects included 105 patients with chest pain and normal systolic function. HRR was defined as the difference between the peak heart rate and the rate measured two minutes after completion of a treadmill exercise test. We measured plasma BNP levels before exercise, 5 minutes after completion of exercise, and during exercise (absolute value of difference between pre- and post-exercise BNP levels)., Results: Patients with abnormal HRR values (

Background: Several studies have reported the role of N-acetylcysteine on the prevention of contrast induced nephropathy (CIN) with conflicting results. To date, the effect of acetylcysteine on cystatin C-based CIN has not been described. This study was designed to examine the incidence of cystatin C-based CIN and investigate the effect of N-acetylcysteine on the prevention of CIN after coronary angiography (CAG)., Methods: We conducted a prospective, randomized trial on 166 patients (80 patients in N-acetylcysteine group and 86 patients in control group) that underwent elective CAG with apparently normal renal function. Serum cystatin C and creatinine concentrations were measured before, and at 24 and 48 h after CAG., Results: The overall incidence of cystatin C-based CIN among all study subjects was 10.2% (5.0% in N-acetylcysteine group and 15.1% in control group, p<0.05) and that of serum creatinine-based CIN was 6% (3.8% in N-acetylcysteine group and 8.1% in control group, p=NS). Kappa analysis between cystatin C-based CIN and serum creatinine-based CIN showed a substantial agreement (k=0.64). Multivariate logistic regression analysis showed that N-acetylcysteine administration was independently protective against the development of cystatin C-based CIN (Odd ratio[95% confidence interval] 0.255[0.066 to 0.994]) but there was a trend toward protection against that of serum creatinine-based CIN., Conclusions: This study suggests that in patients with apparently normal renal function, prophylactic oral N-acetylcysteine administration is effective at preventing cystatin C-based CIN development after elective coronary angiography and/or intervention, and that serum cystatin C might be a more sensitive marker of the early CIN than serum creatinine., (Copyright 2008 Elsevier Ireland Ltd. All rights reserved.)

The aim of this study was to develop and characterize lipid nanoparticle systems for the transdermal delivery of buprenorphine and its prodrugs. A panel of three buprenorphine prodrugs with ester chains of various lengths was synthesized and characterized by solubility, capacity factor (log K'), partitioning between lipids and water and the ability to penetrate nude mouse skin. Colloidal systems made of squalene (lipid emulsion, LE), squalene + Precirol (nanostructured lipid carriers, NLC) and Precirol (solid lipid nanoparticles, SLN) as the lipid core material were prepared. Differential scanning calorimetry showed that the SLN had a more-ordered crystalline lattice in the inner matrix compared to the NLC. The particle size ranged from 220-300 nm, with NLC showing the smallest size. All prodrugs were highly lipophilic and chemically stable, but enzymatically unstable in skin homogenate and plasma. The in vitro permeation results exhibited a lower skin delivery of drug/prodrug with an increase in the alkyl chain length. SLN produced the highest drug/prodrug permeation, followed by the NLC and LE. A small inter-subject variation was also observed with SLN carriers. SLN with soybean phosphatidylcholine (SLN-PC) as the lipophilic emulsifier showed a higher drug/prodrug delivery across the skin compared to SLN with Myverol, a palmitinic acid monoglyceride. The in vitro permeation of the prodrugs occurred in a sustained manner for SLN-PC. The skin permeation of buprenorphine could be adjusted within a wide range by combining a prodrug strategy and lipid nanoparticles.

Buprenorphine is a promising drug for the treatment of chronic pain and opioid dependence. The aim of the present work was to evaluate the feasibility of lipid nanoparticles with different oil/fatty ester ratios for injection of buprenorphine. To improve the release properties and analgesic duration of the drug, ester prodrugs were also incorporated into the nanoparticles for evaluation. Linseed oil and cetyl palmitate were respectively chosen as the liquid lipid and solid lipid in the inner phase of the nanoparticulate systems. Differential scanning calorimetry (DSC) was performed, and the particle size, zeta potential, molecular environment, and lipid/water partitioning were determined to characterize the state of the drug/prodrug and lipid modification. The in vitro release kinetics were measured by a Franz assembly. DSC showed that systems without oil (solid lipid nanoparticles, SLNs) had a more ordered crystalline lattice in the inner matrix compared to those with oil (nanostructured lipid carriers, NLCs and lipid emulsion, LE). The mean diameter of the nanoparticles ranged between 180 and 200nm. The in vitro drug/prodrug release occurred in a delayed manner in decreasing order as follows: SLN>NLC>LE. It was found that the release rate was reduced following an increase in alkyl ester chains in the prodrugs. The in vivo antinociception was examined by a cold ethanol tail-flick test in rats. Compared to an aqueous solution, a prolonged analgesic duration was detected after an intravenous injection of buprenorphine-loaded SLNs and buprenorphine propionate (Bu-C3)-loaded NLCs (with 10% linseed oil in the lipid phase). The Bu-C3 in NLCs even showed a maximum antinociceptive activity for 10h. In vitro erythrocyte hemolysis and lactate dehydrogenase (LDH) release from neutrophils demonstrated a negligible toxicity of these carriers. Our results indicate the feasibility of using lipid nanoparticles, especially SLNs and NLCs, as parenteral delivery systems for buprenorphine and its prodrugs.

Objective: We investigated the incidence of the metabolic syndrome and assessed the effect of smoking status and weight change on incident metabolic syndrome., Research Design and Methods: This study included 4,542 men without metabolic syndrome at baseline who were followed for an average of 3 years. Subjects were divided into four categories according to smoking status at baseline and at the 3-year follow-up., Results: The overall incidence of metabolic syndrome was 10.6%: 8.0% in nonsmokers, 7.1% in new smokers, 17.1% in ex-smokers, and 13.9% in sustained smokers (P < 0.001). In a multivariate regression model, ex-smokers had significantly increased odds for incident metabolic syndrome with a mean 1.45 (95% CI 1.06-1.98) compared with sustained smokers. This was no longer significant after including weight change., Conclusions: Smoking cessation within 3 years may be a higher risk factor for incident metabolic syndrome than sustained smoking, indicating that weight control in ex-smokers is critical to attenuate the additional risk for incident metabolic syndrome.

To compare the prevalence of the metabolic syndrome (MS) using 3 definitions (World Health Organization [WHO], Adult Treatment Panel [ATP III], and International Diabetes Foundation [IDF]) in Korean subjects, we reviewed 6,196 participants (3,436 men and 2,760 women; mean age 51 +/- 11 and 49 +/- 12 years) who underwent a general health status evaluation and had findings of MS components, including serum insulin and microalbuminuria. The prevalence of the MS according to the WHO, ATP III, and IDF definitions (male and female) was 17.1% and 10.3%, 26% and 19.3%, and 22% and 25.4%, respectively. The degrees of agreement according to the k statistics (WHO and IDF, WHO and ATP III, and IDF and ATP III) were modest in both genders. The diagnosis of the MS was associated with a high odds ratio for nonalcoholic fatty liver disease but with a significantly varying prevalence of a Framingham risk score of >10%. The MS was seen in 10% to 30% of otherwise healthy middle-age Korean subjects presenting for health screening and the prevalence varied widely according to the criteria of its definition. The effect of the diagnosis of the MS in terms of cardiovascular risk varies significantly according to the criteria used. In conclusion, a universally accepted definition of the MS is needed for clinical and population-based studies.

Background: Nonalcoholic fatty liver disease (NAFLD) has been linked to cardiovascular disease (CVD) but it is largely unknown if such a relationship between NAFLD and CVD risk relates to severity of liver disease or if it is independent. We aimed to study the severity of NAFLD in a well characterized non-obese population and to compare this to prevalence of CVD risk factors and Framingham risk score., Methods: This study included 30,172 subjects. Based on the presence or absence of steatosis on ultrasound and serum alanine aminotransferase (ALT), subjects were divided into controls, an increased serum ALT group without steatosis and a group with presumed nonalcoholic fatty liver disease (NAFLD), which included a steatosis alone group and a group with presumed nonalcoholic steatohepatitis (NASH) with steatosis and an elevated ALT., Results: The odds ratio for 10-year risk by total Framingham risk scores > or =10% was 5.3 times higher in NASH groups. The prevalence of diabetes, hypertension, elevated CRP and metabolic syndrome were all increased up to 15-fold over controls, independent of age, BMI, smoking and exercise habits. Overall CVD risk was significantly greater in NASH than in either steatosis or raised ALT alone., Conclusion: Young, non-obese subjects with NAFLD are at significantly increased CVD risk, especially those with NASH. As well as specific therapy for liver disease, a diagnosis of NAFLD should lead to targeted risk assessment and risk factor modification.

Background/purpose: Silent infarcts (SIs) are commonly found on brain computed tomography (CT) or magnetic resonance imaging (MRI) among elderly subjects, but their risk factors and impact on outcome in stroke patients are unknown. We evaluated the prevalence, risk factors and impact of SIs on the outcome of patients admitted with first-ever ischemic stroke or transient ischemic attack (TIA)., Methods: A prospective study of 446 patients admitted consecutively to the neurology service with a diagnosis of TIA or stroke between July 2003 and June 2005, including 226 without any history of prior TIA or stroke. All patients underwent brain CT on the day of admission to the hospital. Risk factors analyzed included age, history of hypertension, diabetes mellitus, cardiovascular disease or stroke, smoking habit and alcohol use. Cholesterol and triglyceride levels were measured on the second day of admission. We monitored these patients for 24 months after stroke onset., Results: The frequency of SIs among the 226 patients with first-ever stroke or TIA was 20%. Most of the SIs were small and deep. Small-artery disease was more frequently observed in patients with SIs. Age, hypertension, diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, alcohol use, smoking habits and atrial fibrillation did not significantly differ between patients with SIs and those without SIs. During the 24-month follow-up period, the frequency of recurrent stroke was higher in patients with SIs than those without SIs. The mortality rate was higher in patients without SIs than those with SIs. The interval from stroke onset to rehospitalization was shorter in patients without SIs than in those with SIs., Conclusion: The study showed a higher frequency of small artery disease in patients with SIs. First-ever stroke patients with SIs should be considered at high risk for recurrent stroke.

Objectives: Adipocyte fatty acid-binding protein (A-FABP), also known as aP2 or FABP4, is abundantly expressed in adipocytes and plays a role in glucose homeostasis. We analyzed the relationship between the coronary artery disease and serum FABP4 levels in Korean adults., Methods: In a total of 234 Korean adults, in whom coronary angiograms were performed, anthropometric measurements were done and fasting glucose and lipid profiles were measured. Serum FABP4 levels were measured using ELISA. The presence of metabolic syndrome was diagnosed according to American Heart Association/National Heart, Lung and Blood Institute (AHA/NHBL) criteria with body mass index (BMI) substituted for waist circumference., Results: Among the subjects, 31.6% had diabetes, 46.9% had metabolic syndrome, and mean log (FABP4) levels showed significantly higher levels in subjects with diabetes. Among the subjects, 42.4% had normal coronary vessel, 34.6% had 1-vessel disease, 13.7% had 2-vessel disease, and 9.4% had 3-vessel disease. Among the parameters, mean age, fasting glucose, and log (FABP4) levels increased significantly as the numbers of stenotic vessel increased from normal to 3-vessel disease, and for FABP4, these significances showed a consistent trend for difference after adjustment for age, gender, BMI, and fasting glucose (P=0.072). Mean log (FABP4) level showed lower values in subjects taking aspirin, and higher values in subjects taking statin and anti-hypertensive drugs., Conclusions: Serum FABP4 levels increased as the numbers of stenotic coronary artery increased, although these differences were attenuated after adjustment for age and fasting glucose levels. Various anti-atherogenic medications showed different effects on the serum FABP4 levels, which need further investigation.

This study was performed to evaluate the relationship between serum phosphate levels and cardiovascular risk factors and metabolic syndrome components in a cross-sectional survey. Plasma phosphate was measured by immunoturbidimetry in 46,798 subjects over 20 years of age with an estimated GFR>or=60 mL/(min 1.73 m(2)) who participated in a health-check survey at the Kangbuk Samsung Hospital in South Korea. The median plasma phosphate level was 3.49+/-0.44 mg/dL and the mean estimated GFR was 77.46+/-8.51 mL/(min 1.73 m(2)). We found that serum phosphate levels had a positive correlation with total cholesterol, HDL-C, lipoprotein a, apolipoprotein A1, calcium, and albumin. In addition, serum phosphate levels had a negative correlation with age, body mass index, uric acid, fasting glucose, insulin, HOMA-IR, HS-CRP, triglyceride levels, systolic blood pressure, diastolic blood pressure, and waist circumference (P<0.001). In conclusion, we found that a high phosphate level is correlated with cardiovascular disease while a lower phosphate level is correlated with metabolic syndrome. Serum phosphate levels that were too high or too low correlated with cardiovascular risk factors and elements of metabolic syndrome, respectively, showing that it may be important to maintain an appropriate level of phosphate for the prevention of cardiovascular events and metabolic syndrome.

Thyroid hormone has many effects on the heart and cardiovascular system. Thyrotoxicosis is associated with increased cardiovascular morbidity and mortality, primarily due to heart failure and thromboembolism. However, the relationship between thyroid hormone excess and the cardiac complications of angina pectoris and myocardial infarction remains largely speculative. Moreover, few studies have been reported on the effect of thyroid hormone levels within normal range on coronary artery disease (CAD). Therefore we examined the association of thyroid function with coronary artery diseases in euthyroid angina patients. Total 192 subjects (mean age; 60.8 yrs) were enrolled in which coronary angiograms were performed due to chest pain. We measured free thyroxine (FT(4)), thyroid stimulating hormone (TSH), serum lipid levels and high-sensitivity C-reactive protein (hsCRP) levels and analyzed their association with the presence of CAD. Serum FT(4) levels were higher in patients with CAD compared with the patients without CAD (1.31 +/- 0.30 vs 1.20 +/- 0.23, p = 0.006), and high FT(4) level was associated with the presence of multi-vessel disease. Multivariate analysis showed that age (odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01-1.07, p = 0.007), hypertension (OR 2.04; 95% CI 1.06-3.90, p = 0.036) and FT(4) (OR 4.23; 95% CI 1.12-15.99, p = 0.033), were the determinants for CAD. The relative risk (RR) for CAD in highest tertile of FT(4) showed increased risk compared with the lowest tertile (RR 1.98; 95% CI 0.98-3.99, p<0.001). Our study showed that FT(4) levels were associated with the presence and the severity of CAD. Also, this study suggests that elevated serum FT(4) levels even within normal range could be a risk factor for CAD. Further studies will be necessary to confirm the relationship of thyroid function and CAD.

Long-acting analgesia is critical for patients suffering from long-acting pain. The purpose of this study was to develop lipid emulsions as parenteral drug delivery systems for morphine and its ester prodrugs. Morphine prodrugs with various alkyl chain lengths, including morphine propionate (MPR), morphine enanthate (MEN), and morphine decanoate (MDE), were synthesized. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were quickly hydrolyzed to the parent drug when exposed to esterase and plasma. Lipid emulsions were prepared using phosphatidylethanolamine (PE) as an emulsifier, while squalene was used as an inner oil phase. Drug release was found to be a function of the drug/prodrug lipophilicity, with a lower release rate for more-lipophilic drug/prodrugs. The inclusion of morphine and its prodrugs into lipid emulsions retarded their release. Lipid emulsions, which incorporated cholesterol, generally exhibited a drug/prodrug release comparable to that of emulsions without co-emulsifiers. Pluronic F68 (PF68) further slowed down the release of morphine and its prodrugs from the emulsions. The antinociceptive activity through the parenteral administration of these emulsions was examined using a cold ethanol tail-flick study. Compared with an aqueous solution, a prolonged analgesic duration was detected after application of the drug/prodrug emulsions. Incorporation of co-emulsifiers such as PF68 and cholesterol further increased the duration of action. The combination of prodrug strategy and lipid emulsions may be practically useful for improving analgesic therapy with morphine.

Background: Recent studies have challenged the original definition of microalbuminuria when used to assess the risk of coronary heart disease or death. However, no large study has been conducted on Asian subjects regarding this topic to date. Therefore, we investigated the relationship between albuminuria below 17 microg/mg and other cardiovascular risk factors in apparently healthy Korean men., Methods: We enrolled 2474 men with albuminuria below 17 microg/mg to participate in this study. We evaluated a variety of cardiovascular risk factors as well as the urine albumin creatinine ratio (UACR). The subjects were stratified into five groups by their UACR values and comparisons were made among the five groups., Results: The comparisons showed that the UACR was progressively higher in subjects with a larger waist circumference and BMI as well as higher values for: serum triglyceride, glucose, hsCRP, and the systolic BP, in addition to a higher prevalence of diabetes and metabolic syndrome. When we excluded subjects with hypertension and diabetes, the results were similar., Conclusions: Our findings suggest that low grade albuminuria in Korean men was associated with a variety of cardiovascular risk factors, and this finding was unchanged when we excluded subjects with diabetes and hypertension. Further studies are warranted to evaluate the clinical implications of our findings.

Plasma total homocysteine (tHcy) is an independent risk factor for cardiovascular disease and increased tHcy levels have been reported to be a novel risk factor of atherosclerotic disease. The aim of this study was to assess the association of the metabolic syndrome components with plasma (tHcy) level. Total 722 participants (284 men, 438 women) from the medical checkup program were enrolled in this study. The clinical characteristics and biochemical parameters of the subjects were assessed and the tHcy levels were compared according to the components of metabolic syndrome diagnosed by Adult Treatment Panel (ATP) III guideline and International Diabetes Federation (IDF) criteria. Among the components, groups with larger waist circumference and higher fasting blood glucose levels showed significantly higher tHcy level than the counterparts. Although statistically insignificant, mean concentrations of tHcy was higher in subjects with metabolic syndrome defined by both criteria. In multiple regression analysis, age, sex and systolic blood pressure were the independent determinants of tHcy level. In conclusion, tHcy level was not associated with metabolic syndrome defined by either criteria in Korean subjects.

Objective: Recent studies suggest a lower risk for overweight/obesity in moderate alcohol drinkers. However, the validity of this relationship and its impact on the putative benefits of alcohol consumption on cardiovascular disease (CVD) risk has not been well evaluated., Research Design and Methods: We assessed the impact of BMI on the relationship between alcohol consumption and CVD risk factors (blood pressure, lipid panel, and glucose and insulin concentrations) in 27,030 healthy Korean men with no major comorbidities or medication intake seen in a large urban Korean hospital., Results: BMI and overweight prevalence increased linearly with alcohol intake (P < 0.001). Alcohol intake was also positively associated with blood pressure and triglyceride, HDL, and fasting glucose concentrations (P < 0.001) and negatively associated with LDL and insulin concentrations (P < 0.001). With nondrinkers as the reference group, the odds ratio for having insulin in the top quartile also declined linearly when adjusted for age, BMI, smoking, and exercise, with the heaviest drinkers (>40 g/day) having an odds ratio of 0.71 (95% CI 0.62-0.82) (P < 0.001). The relationship between alcohol and CVD risk factors was similar in normal-weight and overweight individuals., Conclusions: Alcohol intake is associated with increasing BMI and several metabolic abnormalities, including higher fasting glucose. Paradoxically, it is also associated with lower insulin concentrations. The clinical significance of these findings needs further investigation.

Aims: With increasing prevalence of diabetes mellitus and metabolic syndrome (MS), the importance of early detection of insulin resistance is emphasized. However, a simple and practical method of measurement is not readily available. Therefore, we examined the sensitivity and specificity of HbA(1c) for predicting impaired fasting glucose (IFG) and MS and its association with cardiovascular risk factors, particularly in the normal range of HbA(1c) levels in non-diabetic Korean subjects., Methods: In 40,155 participants (median age 40 years) participating in a medical check-up programme, analysis of the distribution of HbA(1c) and its association with various cardiovascular risk factors was performed. In 22,465 selected participants, an analysis was conducted of the ability of HbA(1c) to predict MS and IFG. Anthropometric measurements were made in all subjects and fasting glucose, lipid profiles and HbA(1c) were measured. The presence of MS was defined according to the definitions of the Adult Treatment Panel III (ATP III) guideline and the new International Diabetes Federation (IDF) guideline. Patients with diabetes were excluded from the study., Results: The incidence of MS was 12.2% according to ATP III criteria and 7.6% according to IDF criteria. When subjects were grouped by quartile of HbA(1c), cardiovascular risk factors significantly increased as the HbA(1c) increased. An HbA(1c) of 5.45% predicted the presence of MS (ATP III: sensitivity/specificity 57.4/64.3%, area under the curve 64.8%; IDF: sensitivity 60.2/63.4%, area under the curve 66.1%) and fasting blood glucose > or = 5.6 mmol/l (sensitivity/specificity 53.7/70%, area under the curve 66.1%). When the analyses were done separately by gender, female subjects showed higher cut-off of HbA(1c) for the prediction of MS (5.55% for both ATP III and IDF criteria)., Conclusions: HbA(1c) increased as cardiovascular risk factors increased and HbA(1c) of 5.45% predicted the presence of MS. HbA(1c) might be a predictive measure of IFG and MS, and also cardiovascular risk factors in the Korean population.

Objective: Nonalcoholic fatty liver disease (NAFLD) is emerging as a major health problem in parallel with an increasing prevalence of obesity. Insulin resistance and abdominal and overall adiposity are closely associated with NAFLD; however, the interplay between them in the relationship with NAFLD is unclear, especially in nondiabetic individuals., Research Design and Methods: Abdominal ultrasound, hepatitis serology, and measurements of fasting plasma insulin (FPI), lipid concentrations, overall obesity (BMI), and abdominal obesity (waist circumference) were performed in 56,249 Korean subjects., Results: After rigorous exclusion criteria, 36,654 nondiabetic subjects (54% male) were enrolled. Subjects were divided into control (no fatty liver on ultrasound, serum alanine aminotransferase [ALT] <30 units/l [men] or <19 units/l [women]), fatty liver with normal ALT (FL-NALT), and fatty liver with a high ALT (FL-HALT) groups. After adjusting for age, BMI, and waist circumference, FPI and ratio of triglycerides to HDL cholesterol (TG/HDL-C ratio) were significantly higher in the FL-NALT than in the control group and even higher in the FL-HALT group. Odds ratios for the presence of FL-HALT with increasing quartiles of FPI and TG/HDL-C ratio were increased five- to sevenfold over those of the control group, independent of age, BMI, and waist circumference., Conclusions: In this large population of individuals of Korean ancestry, results indicate that while overall (BMI) and abdominal (waist circumference) overweight/obesity are associated with features of NAFLD, surrogate estimates of insulin resistance, FPI concentration, and TG/HDL-C ratio predict NAFLD independently of age, BMI, and waist circumference.

Background: Subjects with high normal blood pressure (BP: systolic, 130-139 mmHg or diastolic, 85-89 mmHg) have higher cardiovascular risks compared with individuals with normal BP (systolic BP, 120-129 mmHg or diastolic BP, 80-84 mmHg). In the present study the prevalence of microalbuminuria and cardiovascular risk factors, as well as factors that influence microalbuminuria, were assessed in 2 groups of subjects with prehypertension., Methods and Results: Of 2,678 prehypertensive subjects (1,689 men, 989 women), none had a history of diabetes or hypertension. Urine albumin excretion was measured by an immunoradiometric assay in a morning urine sample. The prevalence of microalbuminuria in the high normal BP group was higher than in the normal BP group (4.9% vs 2.8%, p=0.009). Subjects with high normal BP were older, and had higher prevalence of males and metabolic syndrome; larger waist circumference and body mass index, higher levels of triglycerides, fasting blood glucose, uric acid and ferritin, and lower levels of high-density lipoprotein-cholesterol were more common in subjects with high normal BP than in those with normal BP. Multiple logistic regression analysis showed that the high normal BP category had an independently significant association with microalbuminuria (odds ratio=1.692, 95% confidence interval 1.097-2.611)., Conclusions: Subjects with high normal BP have greater risk factors for cardiovascular disease, including microalbuminuria, than those with normal BP. Further investigations are needed to ascertain whether more positive treatment strategies for the early prevention of cardiovascular disease might be needed for individuals with high normal BP.

Background: Cardiovascular events are known to occur more frequently in patients with a high morning surge in blood pressure (BP), but the correlation between a morning BP surge and corrected QT dispersion (QTc) has not been confirmed to date., Methods and Results: The correlation between the morning BP surge and QTc was studied in 82 patients recently diagnosed with high BP (47 males, 35 females). Twenty-four-hours BP monitoring was conducted to classify patients into dipper (n=45) or nondipper (n=37) groups according to the degree of nocturnal BP reduction. QTc was found to be significantly longer in the nondippers compared with the dippers (36.1+/-17.2 vs 47.6+/-20.7, p<0.001). In addition, there was a significant increase in the end-diastolic interventricular septum thickness (IVSd), left ventricular posterior wall thickness in diastole (PWT) and left ventricular mass index (LVMI) in the nondippers vs the dippers (respectively, 0.93+/-0.09 vs 1.03+/-0.05, p<0.001, 0.94+/-0.09 vs 1.01+/-0.04, p<0.01, 109.7+/-12.8 vs 129.1+/-20.9, p<0.001). QTc had a significant positive correlation with nighttime BP, IVSd, PWT, and LVMI, but negatively correlated with the nocturnal BP reduction rate. These results were maintained even after adjusting for age and gender. However, a significant correlation between the morning BP surge and QTc was not confirmed., Conclusion: In the present nondipper hypertensive patients, QTc, nighttime BP, LVMI, and wall thickness were significantly greater than in the dipper patients. However, there was no significant correlation between the morning BP surge and QTc.

Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K'). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and approximately 75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, alpha-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation.

Background: Several studies have reported that plasma brain natriuretic peptide (BNP) levels are increased in patients with chronic atrial fibrillation (AF). The objective of this study was to assess the factors influencing plasma BNP levels in patients with chronic AF and preserved left ventricular (LV) systolic function., Methods: Transthoracic echocardiography was performed in 104 patients (48 men, 56 women; mean age, 63.9+/-10.7 years) with chronic AF. At the same time, plasma BNP levels were measured with a Triage kit (Biosite, San Diego, CA)., Results: Women, long duration of AF, and hypertension were more prevalent in the highest quartile group of BNP levels than in the lowest quartile of BNP. Significant correlations were observed between plasma BNP levels and the following: mitral E velocity (r=0.343), mitral annular E' velocity (r=-0.402), ratio of mitral E velocity and mitral annular E' velocity (r=0.487), left atrial(LA) size (r=0.653), LA volume index (r=0.775), right atrial (RA) volume index (r=0.563), maximal velocity (V(max)) of mitral regurgitation (MR) (r=0.448), tricuspid regurgitation (TR) V(max) (r=0.532) and LV mass index (r=0.581). In stepwise multiple linear regression analysis, LA volume index (beta=0.326, p<0.001), LV mass index (beta=0.395, p<0.001) and duration of AF (beta=0.492, p<0.001) independently predicted plasma BNP levels in the study subjects. The patients with increased LA volume index exhibited a longer duration of AF, larger RA volume index and LV mass index, higher MR V(max), TR V(max) and plasma BNP level., Conclusions: LA volume index, LV mass index and duration of AF are independent predictors of plasma BNP levels in patients with chronic AF and preserved LV systolic function.

Purpose: There are few prospective data on the incidence of metabolic syndrome. The goals of this study were to define the incidence of and specific risk factors for metabolic syndrome (MetS) in Korean male workers 30 to 39 years of age., Methods: A prospective cohort study was undertaken involving 4,779 male workers, 30 to 39 years of age, who did not take medication for dyslipidemia or have a history of any malignancy at study entry. Subjects were reexamined annually at a university hospital in Seoul, Korea, over a 3-year period between 2002 to August 2005. A modified National Cholesterol Education Program definition of MetS with body mass index was used instead of waist circumference. Cox proportional hazards models were used to calculate adjusted hazard ratios in separate models for MetS., Results: At the end of the 3-year follow-up period, MetS developed in 708 individuals. The unadjusted incidence density of MetS was 70.5 (95% CI, 65.3 approximately 75.37), and the age-adjusted incidence density of MetS was 76.9 per 1,000 person-years (95% CI, 67.8 approximately 86.1). Among a variety of candidate risk factors, uric acid, weight change, gamma-glutamyltranspeptidase, and alanine aminotransferase were independent risk predictors for MetS., Conclusions: The high-incidence density of this MetS in Korea may be an indicator of future increases in diabetes and cardiovascular disease.

Recent versions of the criteria for diagnosing the metabolic syndrome have emphasized the superiority of abdominal obesity, as measured by waist circumference (WC), in identifying individuals at increased risk for cardiovascular disease (CVD). On the other hand, there is evidence that body mass index (BMI), an estimate of overall obesity, fulfills this function as effectively as does WC. The present analysis was performed to compare the relative use of these 2 indices of obesity to identify multiple CVD risk factors. The study population consisted of 19584 apparently healthy men and women of Korean ethnicity, and the CVD risk factors measured included fasting plasma concentrations of the following variables: glucose, insulin, total, low-density lipoprotein, and high-density lipoprotein cholesterol, triglycerides, apolipoproteins A-I and B, and high-sensitivity C-reactive protein. The univariate relationships between the 2 indices of obesity and the 9 CVD risk factors were relatively modest (the highest r value was 0.45), but they were all statistically significant, and the magnitude of the relationships between the CVD risk factors and BMI and WC were comparable. When multivariate analysis was performed, adjusting for age and either BMI or WC, each index of obesity continued to have an independent relationship, albeit reduced in magnitude, with the CVD risk factors. These findings suggest that measurements of BMI provide as much clinical insight as do determinations of WC in identifying multiple CVD risk factors in a large population of apparently healthy Korean men and women, and that the use of both indices would provide the most information.

Background: Peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear hormone receptor family, which is involved in the differentiation of adipose tissue, is reported to be associated with the pathogenesis of type 2 diabetes mellitus, insulin resistance and atherosclerosis. Whether the prevalence of coronary artery disease (CAD) is associated with Pro12Ala polymorphism in exon B of PPAR-gamma was investigated in Korean adults., Methods and Results: The study was conducted in 267 subjects (158 males, 109 females, mean age 58 years) who underwent coronary angiography because of chest pain. Cardiovascular risk factors, such as blood pressure, body mass index (BMI), fasting blood sugar and serum lipid profiles, were assessed in all subjects, who were divided into 4 groups according to the number of stenosed coronary arteries: normal, 1-vessel, 2-vessel and 3-vessel disease. Genotyping of Pro12Ala polymorphism was done with real-time polymerase chain reaction. Allelic frequency for proline was 0.955 and 0.045 for alanine, which was in Hardy-Weinberg equilibrium (p=0.74). One hundred and seventeen subjects (43.8%) had normal coronary arteries, 88 (33%) had 1-vessel disease, 39 (14.6%) had 2-vessel disease and 23 (8.6%) had 3-vessel disease. When the cardiovascular risk factors were compared among the 4 groups, there were no meaningful differences except for age and FBG levels, which were significant even after adjustment for age and BMI. There were no significant differences in the prevalence or severity of CAD according to the different genotypes of Pro12Ala, and in logistic regression analysis Pro12Ala polymorphism was not a predictor for CAD., Conclusions: There was no significant association between Pro12Ala polymorphism in exon B of PPAR-gamma and prevalence or severity of CAD in Korean adults. Further studies on the correlation between Pro12Ala polymorphism and CAD should be carried out in a larger Korean population in the future.

Background: Serum iron plays an important role in the oxidation of low-density lipoprotein (LDL) cholesterol, it induces inflammatory reactions and it is positively related to coronary heart disease. An increase of the inflammatory marker, C-reactive protein (CRP), is a risk factor for future cardiac events. Hence, we examined the association of the cardiovascular disease risk factors and serum ferritin with CRP., Methods: This study was performed on 808 subjects (465 males and 343 females). CRP levels >3.0 mg/L, serum ferritin levels >200 ng/mL, total cholesterol levels >200 mg/dL and LDL-cholesterol levels >160 mg/dL were all considered as elevated. High-density lipoprotein cholesterol levels <40 mg/dL were considered as low., Results: In the group with low LDL-cholesterol, no correlation was detected between serum ferritin and hsCRP [odds ratio (OR) = 1.68, 95% confidence interval (CI) = 0.81-3.48, p = 0.144]. However, a correlation was detected in the group with elevated LDL-cholesterol (OR = 11.21, 95% CI = 1.14-110.27, p = 0.032). In addition, when the interaction term was added to the assessment of the correlation between the elevated hsCRP and LDL-cholesterol, the strong correlation of hsCRP and serum ferritin was confirmed (p = 0.002)., Conclusions: Oxidation of LDL-cholesterol by serum ferritin may play a role in the inflammatory reaction and for the increased hsCRP. Future prospective studies may be required to assess whether reducing the serum ferritin and CRP levels via medical intervention and life style modification would be helpful for preventing cardiovascular disease.

This study investigates the submicron lipid emulsion as a potential parenteral drug delivery system for nalbuphine and its ester prodrugs. Submicron emulsions were prepared using egg phospholipid as the main emulsifier, various co-emulsifiers were also incorporated, including Brij 30, Brij 98, and stearylamine. Squalene as the oil phase formed stable emulsions with small particles. Drug release was affected by incorporating various co-emulsifiers and drugs with various lipophilicity. The loading of nalbuphine into lipid emulsions resulted in the slower and sustained release of nalbuphine. Lipid emulsions containing Brij 98 could further enhance the release of prodrugs as compared to the aqueous solution (control) especially for nalbuphine enanthate (NAE). Hemolysis caused by the interaction between erythrocytes and lipid emulsions was investigated. Brij 30 and Brij 98 could shield the hemolytic activity of phospholipids in the oil/water interface, decreasing the acute toxicological potential of the emulsions. The in vivo analgesic activity of various emulsions was examined by a cold ethanol tail-flick test. The analgesic duration and potency were significantly increased by incorporating nalbuphine and NAE into Brij 98-containing emulsions. There was no need for nalbuphine benzoate (NAB) to show a controlled delivery manner by encapsulating into emulsions, since NAB itself could prolong the analgesic duration of nalbuphine due to the slow enzyme degradation. The in vivo analgesic activity correlated well to the profiles of in vivo pharmacokinetic profiles. The study demonstrates the feasibility of using submicron lipid emulsion as the parenteral drug delivery system for nalbuphine and its prodrugs.

B-type brain natriuretic peptide (BNP) levels increase during myocardial ischemia. Here, the authors undertook to evaluate the correlation between changes in plasma BNP levels during exercise and the presence and severity of coronary artery disease (CAD). The study subjects consisted of 159 hospitalized patients with a normal systolic function. Patients were allocated to a control group (N = 101, comprising patients with coronary artery stenosis of < 50%) or to a CAD group (N = 58, comprising patients with stenosis of > or = 50% or a greater coronary artery lesion). In addition, the CAD group was further subdivided into a single-vessel disease (VD) subgroup (N = 31) and a multi-VD subgroup (N = 27). All 159 study subjects underwent coronary angiography (CAG), and plasma BNP levels were measured before and immediately after exercise. A comparative study of BNP levels in the control and CAD groups before and after exercise revealed that BNP levels in the CAD group were significantly higher [22.4 (5.0-28.5) vs. 54.3 (13.1-74.6), P = 0.000; 35.0 (6.2-37.6) vs. 82.5 (23.2-102.8) pg/mL, P = 0.002, respectively]. Changes in BNP levels during exercise in the CAD group tended to be greater than in the control group, but without significance [12.6 (0-13.6) vs. 28.3 (2.8-25.5) pg/mL; P = 0.083]. Subgroup analysis showed that BNP levels tended to be positively related to the proportion of disease vessels, but statistical significance was only found between the control and multi-VD subgroup. Summarizing, this study shows that BNP level changes caused by exercise are closely related with the presence of CAD in patients with a normal systolic function. However, the relationship between these level changes and CAD severity requires further evaluation.

The Klotho knockout mouse is thought to be a good animal model for human aging. Recent studies have reported on the association of KLOTHO gene mutation with cardiovascular disease in humans. We observed the frequencies of single nucleotide polymorphisms, that is, G-395A in the promoter region, C1818T in exon 4, and a functional variant, KL-VS, of KLOTHO gene in Koreans, and we investigated their relationships with the presence of coronary artery disease (CAD) in patients who had undergone coronary angiograms. A total of 274 subjects who underwent coronary angiograms because of chest pain were enrolled, and their blood pressure, body mass index, fasting blood glucose level, and lipid profiles were measured. Genotypings were performed on samples of their blood with real-time polymerase chain reaction. Two single nucleotide polymorphisms, G-395A and C1818T, complied with Hardy-Weinberg equilibrium. For the KL-VS genotype, 1 homozygote subject for the adverse allele was detected among the entire population (GG for F352V and CC for C370S). When the subjects were classified into 4 groups according to the number of stenotic vessels, there were no differences among the mean values of the cardiovascular risk factors, except for age and the fasting blood glucose levels, which showed a significant difference between that of the normal and the diseased vessel groups. There were no differences in the prevalence of CAD according to the genotypes of the G-395A polymorphism; however, for the C1818T polymorphism, those subjects with the T allele showed a lower prevalence of CAD than those with the CC genotype. When the subjects were divided into 2 groups according to age, in the group younger than 60 years, T allele carriers of the C1818T polymorphism showed a lower prevalence of CAD than did the noncarriers. In the group older than 60 years, A allele carriers of the G-395A polymorphism showed a lower prevalence of CAD than did the noncarriers. On the haplotype analysis, the GG-CC haplotype showed an increased risk for CAD with an odds ratio of 2.594 (95% confidence interval, 1.385-4.858; P = 0.003). Differential effects of age were observed in the association of KLOTHO G-395A and C1818T polymorphisms with CAD in Koreans. The KL-VS variant seems to be rarely found in the Korean population. These results infer the possibility of the KLOTHO gene being a candidate gene of atherosclerosis in humans, and further research on this topic needs to be done.