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Adiponectin, an adipocyte-secreted protein, is known to have anti-atherogenic, anti-inflammatory and anti-diabetic properties and its serum levels are decreased in obesity, type 2 diabetes, and coronary artery disease. Several studies have been performed to investigate the association of genetic variations in the adiponectin with obesity, insulin resistance, and type 2 diabetes, but few studies were performed in association with coronary artery disease. Therefore we examined the associations between two single nucleotide polymorphisms (SNPs), +45T>G and +276G>T of the adiponectin gene, and coronary artery diseases (CAD). One hundred and fifty six subjects (mean age 57.4 yrs) were enrolled in which coronary angiograms were performed due to chest pain. Genotypings were done for two SNPs in the adiponectin gene by Taqman polymerase chain reaction (PCR) method. The presence of CAD was defined as a >50% reduction of coronary artery diameter. Among 156 subjects, the allele frequencies were 0.683 for G allele and 0.317 for T allele in SNP +276G>T and 0.705 for T allele and 0.295 for G allele in SNP +45T>G. Both genotypes were in compliance with Hardy-Weinberg equilibrium. No association with the presence of CAD was observed for adiponectin gene SNP276 and SNP45 (p = 0.954, p = 0.843). Also, no significant association was observed between the severity of CAD and either SNPs (p = 0.571, p = 0.955). Our study showed that SNP +276G>T and +45T>G in adiponectin gene were not associated with the presence of CAD. Further studies will be necessary to confirm the role of SNP 276G>T and 45T>G in the development of CAD.

Aims: We assessed whether the increased sequential changes in the fasting plasma glucose level (FPG) that is still within the normoglycemic range could be a predictor for future diabetes., Methods: A prospective cohort study was conducted with 5296 male employees, aged 31-44 years. A sequential change in the FPG level was defined as the first follow-up FPG level minus the baseline FPG level. The incident diabetes was assessed at annual examinations during the next 4.1 years. Cox proportional hazard analyses were performed., Results: During the 21,575.5 person-years follow-up among the 5,296 subjects, a total of 156 incident cases of type 2 diabetes occurred (116 cases among the 4,975 normoglycemic subjects and 40 cases among the 321 subjects with impaired fasting glucose). An increase in the FPG level from the baseline to the first follow-up, although still within the normoglycemic range (FPG<100 mg/dl), significantly predicted future diabetes: the multivariate hazard ratios associated with the sequential changes in the FPG of <-3, -3 to 3, 4-6, 7-9, and >9 mg/dl were 0.75, 1.00 (reference), 2.28, 3.28, and 6.10, respectively (p for trend <0.001)., Conclusions: The increase of the sequential changes in the FPG level that were within the normal glucose range was associated with a higher risk for developing diabetes. Thus, conducting assessment for the serial changes in the FPG level may help to identify the young, healthy, normoglycemic individuals at risk for type 2 diabetes.

This study was performed to evaluate the efficiency of simplified EM grid vitrification, skipping the step of removing the cryoprotectant (5.5M EG + 1.0M sucrose) droplet on the grid after loading oocytes, compared to conventional cryopreservation protocols for mouse mature oocytes. Firstly, the recovery, survival, fertilization and hatching rates of simplified EM grid vitrification were compared with those of the slow freezing method using 1.5M DMSO. Then, conventional EM grid vitrification was compared with simplified EM grid vitrification. Simplified EM grid vitrification showed higher survival, fertilization and hatching rates than those of the slow freezing method (85.6% vs. 63.2%; 51.0% vs. 22.3%; 38.7% vs. 12.5%, p < 0.01, respectively). Moreover, simplified EM grid vitrification showed higher recovery, survival and fertilization rates than those of conventional EM grid vitrification (100% vs. 95.0%, p=0.024; 90.0% vs. 78.9%, p=0.033; 56.7% vs. 38.7%, p=0.021, respectively). Hatching rate tended to be higher for simplified EM grid vitrification compared to conventional EM grid vitrification (41.1% vs. 24.1%). In conclusion, simplified EM grid vitrification is a convenient and efficient method for cryopreservation of mouse mature oocytes, compared to conventional EM grid vitrification and slow freezing methods.

Background: The authors previously described induction of spontaneous tissue generation by implanting a collagen matrix and a ligated pedicle (arteriovenous bundle) into a hollow porous chamber in vivo in the rabbit. They hypothesized that increased tissue volume could be obtained by the application of basic fibroblast growth factor (bFGF) and/or by increasing the chamber size and porosity., Methods: In rabbits, a saphenous arteriovenous pedicle and a collagen sponge were inserted into a porous chamber in the groin. Small-volume pore chambers (experiment 1, n = 7) and larger-volume, wider pore chambers (experiment 2, n = 13) were compared, and each was compared with and without bFGF. An additional three flaps of experiment 2 with bFGF were skin grafted, microsurgically transplanted to the ear, and evaluated at 6 months for stability., Results: All patent chambers grew tissue; chambers with bFGF were almost filled, and those without were only half-filled. Histomorphometric analysis confirmed a significant difference. The larger-volume, larger-pore chambers produced more than twice the volume of tissue as the smaller chambers did, and this was significant. Tissue volume in both the control and bFGF groups of experiment 2 was significantly greater than that in the respective groups of experiment 1. Histology, angiography, and scanning electron microscopy confirmed greater vascularity in the bFGF groups and demonstrated vascular connections penetrating the chamber pores linking with angiogenic sprouts, probably from the vasa vasorum of the pedicle, to contribute to new growth. Transplanted flaps survived and appeared normal 6 months later., Conclusions: Patent pedicles, bFGF, large pore size, and larger-volume chambers all seemed to contribute to increased tissue growth in this model. The tissue is stable long term.

Aims: Microalbuminuria is a risk factor for renal and cardiovascular disease. Recent studies have established this important relationship in patients with diabetes or hypertension, yet few studies have shown this relationship in healthy subjects. The purpose of this study is to examine the prevalence and the risk factors of microalbuminuria in normoglycemic, normotensive adults., Subjects and Methods: We examined the prevalence of microalbuminuria in the adults who voluntarily took part in a health examination program. As a cross-sectional study, we examined the risk factors of microalbuminuria in 4883 normoglycemic, normotensive healthy adults., Results: The prevalence of microalbuminuria was 2.8% in the normoglycemic, normotensive group (n=4883), 10.1% in the hypertensive group (n=1250), 16.0% in the diabetes group (n=455) and 5.4% in the total subjects (n=6588). The systolic blood pressure, high sensitive C-reactive protein (hsCRP) and insulin resistance were independently related with microalbuminuria on the logistic regression analysis. The odds ratio of microalbuminuria were 1.04 (1.02 - 1.05, 95% CI), 1.29 (1.10 - 1.51, 95% CI), and 1.83 (1.15 - 2.92, 95% CI), respectively., Conclusions: These finding suggest that the systolic blood pressure, hsCRP and insulin resistance are the independent risk factors for microalbuminuria in normoglycemic, normotensive adults.

The aims of this study were to determine if impaired fasting glucose should be redefined as a fasting plasma glucose (FPG) of 100 to 125 mg/dL (5.6-6.9 mmol/L) in Korea. A prospective cohort study was undertaken involving 13189 male workers aged 30 to 59 years who did not have medication for diabetes, a history of any cancer, or a fasting glucose level of 126 mg/dL or higher at the initial examination between January 1999 to December 2000. Subjects were reexamined at periodic annual health examination over a 5-year period. The receiver operating characteristic curve for predicting the future onset of diabetes was derived by plotting the sensitivity against 1 - specificity for a baseline FPG of less than 126 mg/dL. The age- and body mass index-adjusted incidence density of type 2 diabetes mellitus was examined according to the percentile of the distribution for the baseline FPG. The baseline FPG for predicting the future onset of diabetes at a point on the receiver operating characteristic curve that was closest to the ideal 100% sensitivity and 100% specificity was 92 mg/dL. There was a threshold for the age- and body mass index-adjusted incidence density of diabetes in the group with FPG of 93 to 95 mg/dL, at a mean of 93.9 mg/dL. Lowering the lower limit of impaired fasting glucose to 100 mg/dL (5.6 mmol/L) would optimize its sensitivity and specificity for predicting the future onset of diabetes in Korea.

Background: C-reactive protein (CRP) is known as an emerging recognized marker of the potential risk of myocardial infarction and stroke, and several studies have reported higher incidences of cardiovascular events during the winter months. Here, we investigated seasonal CRP variations using a high-sensitivity immunoradiometric assay in apparently healthy Koreans., Methods: This study included 18,445 apparently healthy Koreans (12,064 men and 6381 women, 47.2 (11.5) years of age). Anthropometric indices of adiposity, metabolic variables, blood pressure (BP), and several cardiovascular risk factors were measured. High sensitivity CRP testing was performed by immunonephelometry., Results: The mean (SD) CRP level in the study population was 1.66 (2.15) mg/L, and mean (SD) CRP levels in the spring, summer, fall and winter were 1.76 (2.30) mg/L, 1.51 (1.94) mg/L, 1.61 (2.08) mg/L, and 1.76 (2.30) mg/L, respectively. After adjusting for age, sex, diabetes, hypertension, regular exercise, smoking, and body mass index, the odds ratios of an elevated CRP in the spring, fall and winter season were 1.196 (95% CI, 1.024-1.396 p = 0.024), 1.086 (95% CI, 0.943-1.250 p = 0.251) and 1.258 (95% CI, 1.088-1.456 p = 0.002), respectively, as compared with the summer season., Conclusions: Our results indicate a highly significant seasonal variation in CRP levels, with higher values during winter and spring than in summer. Elevated plasma CRP levels can be related to an increased risk of cardiovascular events, which are more prominent during the winter months. To further elucidate this relationship additional studies are needed.

Buprenorphine is a promising new pharmacotherapy for the management of physical dependence to opioids. The aim of the study was to evaluate the duration of action of several novel depots of buprenorphine in the treatment of physical dependence to morphine in mice. Following intramuscular injection, the duration of action of several novel oil-based depots of buprenorphine base in morphine-dependent mice were evaluated. The traditional dosage form of buprenorphine hydrochloride in saline was used as control. We found that the depot of buprenorphine base in sesame oil produced a dose-related long-lasting effect. On an equimolar basis of 6 micromol kg(-1), its effect was 5.7-fold longer than that of buprenorphine hydrochloride in saline. When prepared in several other oleaginous vehicles (castor oil, cottonseed oil, peanut oil and soybean oil), buprenorphine base also produced a long-lasting effect, which was similar to buprenorphine base in sesame oil. In conclusion, buprenorphine base, when prepared in oleaginous vehicles and injected intramuscularly in mice, produced a long-lasting effect on physical dependence to morphine.

The increment for the prevalence of diabetes mellitus and impaired glucose tolerance warrants lowering the cutoffs of normoglycemia to help predict the future development of diabetes. The aim of this study was to find out whether insulin resistance and high-sensitivity C-reactive protein (hsCRP), a nontraditional cardiovascular risk factor, were related to the fasting glucose level, even in normoglycemic range that was categorized by the newly recommended criteria by the American Diabetes Association. Among the participants undergoing medical checkup program at Kangbuk Samsung Hospital, 10059 subjects (5535 men and 4524 women; mean age, 45 years) with normal fasting glucose levels, as defined by the newly recommended criteria (<5.6 mmol/L), were enrolled in this study. The blood pressures, body mass index (BMI), fasting blood glucose, fasting insulin, lipid batteries, and hsCRP levels were checked. The homeostatic model assessment-insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check indexes (QUICKI) were calculated. All subjects were subdivided into 4 groups according to the fasting glucose level. The HOMA-IR, QUICKI, and log-transformed (log) hsCRP, or log(hsCRP), level significantly increased according to the increment in fasting glucose, and these associations were consistent after adjustment for age and BMI, except for the log(hsCRP) (P = .124 after adjustment). Log(hsCRP) increased as the HOMA-IR increased and as the QUICKI decreased, and when multiple regression analysis was done with log(hsCRP) as the dependent variable, age, high BMI, male sex, high HOMA-IR, hypertriglyceridemia, and low high-density lipoprotein cholesterol were the significant predictor for log(hsCRP). In conclusion, the insulin resistance indexes and hsCRP increased gradually even in the normal fasting glucose range, as categorized by the newly recommended criteria for abnormal fasting glucose levels, supporting the rationale for expanding the range of fasting hyperglycemia.

Intravenous infusion of norepinephrine is usually effective and safe to maintain adequate cerebral perfusion pressure for the management of posttraumatic intracranial hypertension. We report the case of a 17-year-old woman who suffered from traumatic intracranial bleeding and hypotension; she developed rhabdomyolysis, myoglobinuria and acute renal failure after receiving high dose norepinephrine postoperatively. Hemodialysis was begun 3 days after the onset of myoglobinuria when acute renal failure was noted, despite aggressive fluid supplementation and alkaline diuresis. After aggressive treatment and dialysis, the patient's myoglobinuria and rhabdomyolysis gradually declined. Her kidneys eventually regained normal function. We consider that systemic hypotension may have been the leading cause for development of rhabdomyolysis, and vasoconstrictors such as norepinephrine aggravated this. We emphasise the potentially devastating consequences of rhabdomyolysis when a large dose of norepinephrine is given for the treatment of hypotension during cerebral perfusion pressure-guided management.

From December 2002 to January 2004, 30 patients (20 men and 10 women; mean age 36.8 years [+/- 14.9 years]) with preoperative Glasgow Coma Scale scores of 8 or less underwent emergency haematoma evacuation surgery and continuous intracranial pressure (ICP), cerebral perfusion pressure (CPP) and mean arterial blood pressure monitoring to determine ICP and CPP thresholds to predict patient outcomes. Receiver-operating characteristic (ROC) curves were plotted. Using the ROC curve, the diagnostic accuracy is given by the area under the curve and at the point on the curve farthest from the diagonal, which indicates the threshold value. The results showed that the initial ICP for unfavourable outcomes was 47.4 +/- 21.4 mmHg, resulting in a CPP of 22.8 +/- 12.83 mmHg. The initial ICP for favourable outcomes was 26.4 +/- 10.1 mmHg, resulting in a CPP of 48.8 +/- 13.4 mmHg. The CPP had the largest area under the ROC curve in all stages of the operation, corresponding to intraoperative CPP thresholds of 37 mmHg (initial), 51.8 mmHg (intraoperative) and 52 mmHg (after scalp closure). The ROC curve analysis showed that CPP was a better predictor of outcome than ICP.

The aims of the present study were to (1) examine the range of values for insulin sensitivity measures such as fasting serum insulin, homeostasis model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI) and (2) to identify cutoffs for indirect indexes of insulin sensitivity such as insulin, HOMA, and QUICKI that confer increased risk of metabolic syndrome in a large sample of Korean adults. The total number of study subjects involved was 83186. All of them presented for a routine health status checkup at the Kangbuk Samsung Hospital between January 2003 and December 2004, and none of them was currently taking medication for hypertension, diabetes, or dyslipidemia. We used 3 measures of insulin sensitivity: the fasting serum insulin, the HOMA, and the QUICKI. The age- and sex-adjusted prevalence of metabolic syndrome was examined by tenths of the distribution of each index of insulin. The fasting serum insulin, HOMA, and QUICKI were compared by using receiver operating characteristic curves. The fasting serum insulin ranged from 1.71 to 70.40 microU/mL, with the 25th percentile = 5.97, the median = 7.69, and the 75th percentile = 9.82. The HOMA ranged from 0.34 to 17.72, with the 25th percentile = 1.33, the median = 1.74, and the 75th percentile = 2.27. The QUICKI ranged from 0.112 to 0.202, with the 25th percentile = 0.146, the median = 0.152, and the 75th percentile = 0.158. The insulin, HOMA, and QUICKI values at the point on the receiver operating characteristic curve closest to the ideal of 100% sensitivity and 100% specificity for detecting the presence of metabolic syndrome were 9.7 microU/mL, 2.43, and 0.145, respectively. In conclusion, these findings describe the spectrum of insulin sensitivity in Korean adults. This study is the first attempt to determine cutoff values for indirect indexes of insulin sensitivity such as insulin, HOMA, and QUICKI that confer an increased risk of metabolic syndrome. These findings may be useful for evaluating insulin resistance, particularly in epidemiological studies.

Background: The interindividual variability for the development of collaterals in coronary artery disease is dependent on the hypoxic induction level of VEGF. To determine whether the hypoxic induction of VEGF is controlled by the transcription of HIF-1 (alpha), the VEGF and HIF-1 (alpha) m-RNA levels were correlated to hypoxia in monocytes harvested from patients with coronary artery disease., Methods: The collateral scoring system used was modified from the TIMI system. The mononuclear cell layer of the patients' blood was cultured in hypoxia (1% O2, 5% CO2, 94%N2) and normoxia (5% CO2, 95% room air) for 17 hours. The VEGF and HIF-1 (alpha) mRNA levels were measured using a RT-PCR technique. We calculated the fold inductionsof VEGF, HIF-1 (alpha) mRNA with hypoxia by dividing the hypoxic and the normoxic values., Results: We found significantly higher hypoxic inductions of VEGF m-RNA in patients with collaterals compared to patients with no collaterals. However, there was no differencein the hypoxic inductions of HIF-1 (alpha) between the two groups (VEGF m-RNA mean fold inductions 3.71 +/- 3.30 versus 1.65 +/- 0.62, p=0.012, HIF-1(alpha) mRNA 1.42 +/- 0.58 versus 1.20 +/- 0.39, p=0.165)., Conclusions: We concluded that the interindividual variability in the hypoxic inductions of VEGF m-RNA in monocytes in patients is not controlled by the transcriptional levels of HIF-1 (alpha) with hypoxia. These findings suggest that a mechanism such as the post-transcriptional modification of HIF-1(alpha) is involved in the hypoxic inductions of VEGF.

Background: Apolipoprotein B (apo B) has been reported to be a better predictor of coronary artery disease than cholesterol indices. The objectives of this study were to evaluate concordances/discordances between cholesterol indices and apo B and to assess the factors that influence them., Methods: For this study, 11 816 individuals (6965 males, 4851 females), none of whom had a past history of coronary artery disease, were selected from among visitors to the health promotion center at Kangbuk Samsung Hospital between January and December 2002. We assessed concordances between the biochemical indices of atherogenicity and evaluated factors associated with discordances., Results: Apo B and various cholesterol indices were correlated, although concordance fell within the range 47%-56%. Multinomial logistic regression analysis showed an increasing risk of a disproportionately higher apo B than LDL-cholesterol in males, the elderly, smokers, individuals with metabolic syndrome, in those with high HDL-cholesterol or triglyceride (TG) concentrations or larger waist circumferences, and in those with low total cholesterol (TC)., Conclusions: The introduction of apo B to standard lipid profile testing could improve the evaluation of risk factors of coronary artery disease and aid more accurate assessment of the effects of cholesterol-lowering therapy, particularly in males, the elderly, smokers, or in individuals with metabolic syndrome, high HDL-cholesterol, high TGs, larger waist circumferences, or low TC.

The expanded blastocysts, developed from 2PN-stage embryos, are generally divided into three categories: a good blastocyst containing a large and distinguishable inner cell mass (ICM), a blastocyst with a small and distinct ICM, and a blastocyst with a poorly defined ICM. In this study, we introduce methods for the derivation of human embryonic stem cells (hESCs) depending on the quality of the blastocysts. An immunosurgical method was used for the good expanded blastocysts. This method, however, raises the probability of ICM loss in cases of hESC derivation from blastocysts with smaller or indistinct ICMs. Furthermore, this method is also associated with a risk of the contamination of the hESCs with animal pathogens. To overcome these shortcomings, the partial- or whole-embryo culture method was used. For blastocysts with no visible ICM, the whole-embryo culture method was used to establish hESCs via the seeding of the entire blastocyst without its zona pellucida directly on a STO feeder layer. However, trophectodermal overgrowth tends to hinder the expansion of the ICM during the initial steps of hESC derivation. Therefore, the partial-embryo culture method was developed to establish hESCs from blastocysts with smaller ICMs. The surgical isolation of the region containing the ICM with an ultra-fine glass pipette alleviates trophectoderm overgrowth. This method is also applicable to blastocysts with large and distinct ICMs, and the efficiency of this method is comparable to that of the immunosurgical method.

Background: Associations between hyperuricemia, cardiovascular diseases and diabetes have been reported, but few of the studies have been conducted in the Korean population. The present study examined a Korean adult population with respect to the relationships between serum uric acid concentrations and hypertension, insulin resistance, and the risk factors of metabolic syndrome., Methods and Results: A total of 53,477 subjects were divided into 4 groups according to serum uric acid quartiles. The incidence of hypertension in all subjects was higher in the first quartile than in the third plus fourth quartile (odds ratio (OR) 1.192, p < 0.001). Homeostasis model assessment index was found to be associated with serum uric acid concentration in all subjects (OR 1.193, p < 0.001), and the serum uric acid concentration was positively correlated with the risk factors of metabolic syndrome. In addition, the number of metabolic syndrome variables increased as serum uric acid concentration increased., Conclusions: Serum uric acid concentration was found to be independently correlated with hypertension, insulin resistance and the risk factors of metabolic syndrome. In addition, even those with a serum uric acid concentration in the normal range showed an increased risk of metabolic syndrome as serum uric acid concentration increased.

Objective: The purpose of this study is to evaluate the prevalence of Helicobacter pylori (H. pylori) infection and its association with cardiovascular risk factors in healthy Korean adults. In 58981 subjects who participated in health screening program, the proportion of seropositive subjects for H. pylori and its association with cardiovascular risk factors was evaluated., Results: A total of 70.9% of participants were tested positive for the H. pylori antibody. The seropositivity was highest in the age group of 50 and 60 years old. More male subjects tended to be infected with H. pylori (p<0.05) than female subjects except for the age group of 50s. H. pylori seropositive subjects tended to be older than seronegative subjects (41.5 vs. 39.2 years old). After adjusting for age, H. pylori-seropositive group showed higher mean values for total cholesterol, triglyceride, low-density lipoprotein (LDL)-cholesterol, apolipoprotein B and lower values for high-density lipoprotein (HDL)-cholesterol, apolipoprotein A1 (p<0.05). In univariate correlation analysis, age, total cholesterol, LDL-cholesterol and apolipoprotein B were positively correlated and HDL-cholesterol and apolipoprotein A1 were negatively correlated with H. pylori immunoglobulin G (IgG) titers (p<0.05). The multiple analysis of covariance analysis (MANCOVA) for the H. pylori infection status showed triglyceride, HDL-cholesterol and apolipoproteins associated with H. pylori infection significantly (p<0.05). In the analysis performed only in the H. pylori-seropositive group, no difference between the groups with and without peptic ulcer were shown according to the risk factors except HDL-cholesterol (p=0.031)., Conclusions: H. pylori infection is prevalent in Korean adults and is associated with cardiovascular risk factors, especially with triglyceride, HDL-cholesterol and apolipoproteins, independently from the presence of peptic ulcer. This is in line with the previous study results in which H. pylori infection per se might be one of the factors affecting atherosclerosis through modulation of lipid profiles, which needs further research.

The aim of this study was to assess the effects of iontophoresis and electroporation on transdermal delivery of nalbuphine (NA) and its two novel prodrugs: nalbuphine benzoate (NAB) and sebacoyl dinalbuphine ester (SDN) from solutions as well as from hydrogels. Hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) were used in hydrogel formulations to evaluate their feasibility for delivery of NA and its prodrugs. Application of iontophoresis or electroporation significantly enhanced the in vitro permeation of NA and its prodrugs. The enhancement effect was more pronounced after applying iontophoresis. The combination of two electrically assisted methods enhanced the delivery of NA; however, no such enhancement was observed for the permeation of NAB and SDN. Hydrogels containing low concentration HPC did not affect the passive as well as electrically assisted permeation of NA and its prodrugs. The increase of hydrogel concentration as well as molecular weight significantly decreased the electrically assisted permeation of NA, whereas the permeation of NAB and SDN remained unchanged. For the electrically assisted permeation from CMC-based hydrogels, the reduced permeation from higher percentage of CMC hydrogels may be attributed the viscosity effect as well as the ion competition effect. The above results demonstrated that lipophilicity and molecular size, as well as hydrogel compositions had significant effects on skin permeation of NA, NAB and SDN via passive diffusion or under the electric field.

Background: Insulin resistance (IR) is associated with a significant increase in the risk of coronary artery disease (CAD). The serum apolipoprotein B and Apo A1/Apo B ratio are important markers of CAD. The aim of this study was to assess the association of the serum Apo B and Apo A1/Apo B ratio, with insulin resistance in apparently healthy normoglycemic Koreans., Methods: From the individuals that participated in medical screening at the health promotion center of Kangbuk Samsung Hospital, between January and December 2002, a total of 7427 participants (4356 men, 3071 women) were enrolled in this study. All participants had no personal histories of diabetes, with normal fasting glucose levels. The clinical characteristics and biochemical parameters of the subjects were assessed., Results: The Apo B, total cholesterol/high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C)/high-density lipoprotein-cholesterol showed positive correlations with metabolic syndrome and insulin resistance (p<0.001). The Apo A1, Apo A1/Apo B, LDL/Apo B and HDL/Apo A1 showed negative correlations with metabolic syndrome and insulin resistance (p<0.001)., Conclusion: These data suggest that insulin resistance may be associated with the serum Apo B and Apo A1/Apo B ratio in non-diabetic, normoglycemic subjects. Thus, further study may be needed to determine whether medical intervention is inevitable or not in these type of subjects.

We describe a case of situational syncope induced by belching. The patient showed severe syncope with a high-degree atrioventricular block just after belching, but has not experienced syncope or dizziness over a 3-month follow-up after permanent pacemaker implantation.

Background: Men with a prolonged corrected QT (QTc) interval have an increased risk of cardiovascular mortality and sudden death, even in healthy individuals. In addition, prolonged QTc is a predictor of mortality in diabetics. However, the relationship between insulin resistance and QTc is not clarified in non-diabetic healthy people. The present study was performed to observe the association between QTc and insulin resistance in Korean non-diabetic subjects., Methods and Results: In the current study there was a total of 874 subjects (520 men, 354 women, mean age: 45.9+/-11.0 years) who underwent a medical check-up at the health promotion center at Kangbuk Samsung Hospital from January 2002 to May 2002. Age, sex, height, body weight, blood pressure, blood cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), fasting insulin, and fasting glucose levels were measured. The QT intervals were corrected using Bazett's formula (QTc = QT/square root of RR). Homeostasis model assessments (HOMA) were performed to assess the correlation between insulin resistance indices and the QTc interval. The mean QTc interval was significantly longer in females (417+/-24 ms) than in males (402+/-23 ms) (p < 0.001). After adjusting the variables related to the QTc interval, the differences in QTc between men and women were statistically significant (p < 0.001). A significant positive correlation was found between QTc and age, glucose, and blood pressure in male subjects. Female subjects showed positive correlation between QTc and age, glucose, blood pressure, total cholesterol, low-density lipoprotein cholesterol, triglyceride, fasting insulin, and the HOMA index, and a negative correlation between QTc and HDL-C. Multiple regression analysis showed that in men, age (beta = 0.480, p < 0.001) and diastolic blood pressure (beta = 0.280, p < 0.001) were predictors of QTc. In women, age (beta = 0.321, p = 0.008), diastolic blood pressure (beta = 0.324, p = 0.006) and HOMA index (beta = 3.508, p = 0.033) were predictors of QTc., Conclusions: The present study of Korean healthy subjects shows that QTc was more prolonged in females than in males. In normoglycemic female subjects, insulin resistance was an independent determinant of the prolongation of QTc.

OPG (osteoprotegerin) is an inhibitor of osteoclastogenesis and recent work suggests it has a role in atherosclerosis. Therefore we measured serum OPG levels in patients with coronary artery disease, compared the serum OPG levels among the different groups according to the number of stenotic vessels and determined whether there was any correlation with aortic calcification, LV (left ventricular) mass index and serum CRP (C-reactive protein) levels. Subjects (n=100; mean age, 57 years) who underwent coronary angiograms were enrolled. Blood pressure, body mass index, fasting blood glucose, lipid profiles and CRP levels were measured and the LV mass indices were calculated using ECGs. Serum OPG levels were measured by ELISA. The presence of calcification in the aortic notch was checked by a chest X-ray. The subjects were divided into four groups according to the number of stenotic vessels. The mean serum OPG levels increased significantly as the number of stenotic vessels increased, and the mean serum OPG levels were higher in the group with three-vessel disease compared with the groups with no- or one-vessel disease. The mean serum CRP level was significantly higher in the group with three-vessel disease compared with the groups with no-, one- and two-vessel disease. Age and LV mass index showed significant positive correlations with serum OPG levels, although significance was lost after an adjustment for age. Serum CRP levels were positively correlated with serum OPG levels even after an adjustment for age. There were no differences in serum OPG levels according to the presence of fasting hyperglycaemia or aortic calcification. In conclusion, serum OPG level was related to the severity of stenotic coronary arteries and serum CRP levels. LV mass indices showed no significant correlation with OPG levels. The precise mechanism for the role of OPG in atherosclerosis needs to be investigated further.

Objectives: This study was performed to determine whether an increase in abdominal obesity is an independent risk factor for impaired fasting glucose and type 2 DM., Methods: Among 24, 212 adults over 30 years who undertook comprehensive medical screening examinations from Jan to Dec 1999, in a university hospital in Seoul, a total of 11, 183 subjects were selected who had no DM at baseline and who were followed up more than once by Dec 2002. The average follow up period was 2.4 (+/-0.5) years. DM was defined as having a fasting glucose level &gt; or = 126mg/dl, and impaired fasting glucose as showing a fasting glucose level between 110 and 125 mg/dl. Body weight, height and waist circumference (WC) were simultaneously measured with blood sampling. The relative risks (RRs) for DM and impaired fasting glucose by WC were calculated using Cox proportional hazard model. Ageadjusted rates were estimated by direct standardization using a reference population of 2000 from 30 to 80 years., Results: The average age of the subjects was 41.7 (+/- 7.0) years; males 41.2 (+/-6.5) and females 45.6 (+/-9.2). RRs for type 2 DM by WC with the reference group of WC &lt; 80cm were as follows: 2.66 (95%, CI 0.55~12.8) for WC of 80~89cm in men, 5.92 (95%, CI 1.08~32.3) for WC &gt; or = 90 cm in men, and 2.64 (95%, CI 0.23~29.8) for WC of 80~89cm in females. RRs for impaired fasting glucose by WC were 3.03 (95%, CI 2.18~4.22) for WC 80~89cm in men, 6.10 (95%, CI 4.25~8.75) for WC &gt; or = 90cm in men, and 1.56 (95%, CI 0.43~5.67) for WC 80~89cm in women, and 8.08 (95%, CI 2.22~29.4) for WC &gt; or = 90cm in females. These results remained significant after adjustment for age, BMI and fasting glucose concentrations at baseline in both sexes. Annual increment of more than 1 cm in WC was associated with the development of DM and impaired fasting glucose independently of age, sex, BMI, or presence of abdominal obesity., Conclusions: In Korean adults, abdominal obesity increased the risk for the development of type 2 diabetes and impaired fasting glucose. This result supports many other prospective studies suggesting abdominal obesity as a risk factor for type 2 diabetes.

We prepared a series of alginate and Pluronic-based solutions as the in situ gelling vehicles for ophthalmic delivery of pilocarpine. The rheological properties, in vitro release as well as in vivo pharmacological response of polymer solutions, including alginate, Pluronic solution, and alginate/Pluronic solution, were evaluated. The optimum concentration of alginate solution for the in situ gel-forming delivery systems was 2% (w/w) and that for Pluronic solution was 14% (w/w). The mixture of 0.1% alginate and 14% Pluronic solutions showed a significant increase in gel strength in the physiological condition; this gel mixture was also found to be free flowing at pH 4.0 and 25 degrees C. Both in vitro release and in vivo pharmacological studies indicated that the alginate/Pluronic solution retained pilocarpine better than the alginate or Pluronic solutions alone. The results demonstrated that the alginate/Pluronic mixture can be used as an in situ gelling vehicle to increase ocular bioavailability.

Background: Altered lipid profile is a well-known manifestation of thyroid dysfunction. Recently, serum Lp(a) and C-reactive protein (CRP) have emerged as new cardiovascular risk factors, but studies on changes of these markers with respect to thyroid function status have produced variable results. To better understand the effects of thyroid dysfunction on the development of atherosclerosis, we investigated plasma CRP and lipid profiles such as apoA1, apoB, and Lp(a) in cases with differing severities of thyroid dysfunction., Methods: Fifty four patients with hyperthyroidism, 35 patients with subclinical hyperthyroidism, 33 patients with overt hypothyroidism, 190 patients with subclinical hypothyroidism and 100 age- and sex-matched healthy control subjects were evaluated. Serum high sensitivity (hs)-CRP and Lp(a) were measured by immunonephelometry., Results: No significant differences were found in serum hs-CRP, Lp(a), HDL-C or ApoA1 in different thyroid function groups. Serum total cholesterol and LDL-C levels were significantly lower in cases of hyperthyroidism than in cases of overt hypothyroidism, subclinical hypothyroidism or subclinical hyperthyroidism, or in healthy control subjects (p <0.01). Serum triglyceride levels were higher in overt hypothyroidism than in hyperthyroidism or healthy controls (p <0.05). Serum apoB levels were significantly lower in hyperthyroidism than in overt hypothyroidism, subclinical hypothyroidism or in healthy control subjects (p <0.01). These differences were consistently significant after adjustment for age and BMI., Conclusions: Serum CRP and Lp(a) levels, risk factors for atherosclerosis, were not found to be significantly affected by the degree of thyroid dysfunction. Increased risk of atherosclerosis in hypothyroidism does not appear to be associated with non-traditional cardiovascular risk factors, such as serum CRP, Lp(a) or apoA1 levels.

Background: C-reactive protein (CRP), very sensitive acute phase reactant, is an important marker of coronary artery disease. However, the relationship between insulin resistance and CRP has not been thoroughly studied. We observed the association between CRP, insulin resistance and metabolic syndrome as defined by the ATP III report, and thus identified the role of CRP in the relation to insulin resistance., Methods: Seven hundred and sixty-seven subjects (436 men, 331 women) who underwent a medical check-up at health promotion center in a University Hospital during March 2002, aged 20-84 years, were included in this study. The components of metabolic syndrome as defined by the ATP III report and high sensitivity CRP levels were analyzed, and Homeostasis model assessment index (HOMA) and quantitative insulin sensitivity check index (QUICKI) were calculated., Results: The mean concentrations of CRP in subjects according to the presence of 0, 1, 2, 3, 4, or 5 components of metabolic syndrome as defined by ATP III were 0.64, 0.95, 1.14, 1.19, 2.40, and 2.53 mg/l, respectively. The mean concentrations of CRP were significantly higher in subjects with a high insulin resistance (higher HOMA index and lower QUICKI) than in those with a low insulin resistance. Significant positive correlations were identified between CRP and BMI, waist circumference, triglyceride, blood pressure, glucose and HOMA index. A significant negative correlation was found between CRP and HDL cholesterol or QUICKI., Conclusion: These results suggest that metabolic syndrome and insulin resistance are associated with systemic inflammatory response, which plays an important pathogenic role in atherosclerosis., (Copyright 2004 Elsevier Ireland Ltd.)

Background: There is some controversy about the role of insulin resistance (IR) in the regulation of blood pressure (BP). Moreover, a large study of the association between BP and IR has not been conducted in normal glucose tolerance Asians. The present study investigated the relationships between IR, body mass index (BMI) and waist circumference and BP in normoglycemic Koreans., Methods and Results: Anthropometric indices of adiposity, metabolic variables (fasting serum insulin and a homeostasis model assessment (HOMA) index of insulin sensitivity), BP and several cardiovascular risk factors were measured during a cross-sectional survey of 49,076 normoglycemic Korean subjects. A high BP was defined as a systolic BP >/=140 mmHg or a diastolic BP >/=90 mmHg. The prevalence of high BP by HOMA grading was 0.985 (95% confidence interval (CI) 0.857-1.132, p=0.835), 1.180 (95% CI 1.032-1.350, p=0.016), 1.289 (95% CI 1.129-1.472, p<0.001), and 1.540 (95% CI 1.341-1.768, p<0.001) times higher in subjects in the second, third, fourth, and fifth quintiles, respectively, compared with those in the first quintile. In addition, age, sex, waist circumference and BMI were found to be significantly associated with a high BP., Conclusion: IR, BMI and waist circumference are independently correlated with high BP in normoglycemic Koreans.

Objectives: The purpose of the present study was to investigate the relationships between blood pressure (BP), insulin resistance as determined by a homeostasis model (HOMA-IR), and body fat distribution., Methods: Anthropometric indices of adiposity, metabolic variables (fasting serum insulin and a homeostasis model assessment [HOMA] index of insulin sensitivity), BP and several cardiovascular risk factors were measured during a cross sectional survey of 53477 apparently healthy Korean subjects who requested a health status check. Hypertension was defined as a systolic BP > or = 140 mmHg or a diastolic BP > or = 90 mmHg and we excluded the subjects taking BP-lowering medication., Results: Systolic and diastolic blood pressure (SBP, DBP) were positively and significantly associated with age, body mass index, waist circumference, and waist/hip ratio. In addition, SBP and DBP were positively associated with fasting serum insulin levels and the HOMA index. By multiple regression analysis age, waist circumference, body mass index, HOMA index and female sex were independently associated with either increased SBP or DBP. When the population is divided into quintiles according to insulin resistance (measured by HOMA analysis) prevalence of hypertension in the second, third, fourth and fifth quintiles compared to subjects in the first quintile are 1.004(95% CI 0.875-1.152, p = 0.957), 1.200(95% CI 1.052-1.369, p = 0.007), 1.312(95% CI 1.151-1.494 p < 0.001 ), and 1.603(95% CI 1.408-1.825 p < 0.001). In addition age, sex, body mass index and waist circumference were found to be significantly associated with hypertension., Conclusion: Our results showed that insulin resistance, body mass index and waist circumference are independent risk factors of a high BP in Koreans.

Background: Inflammation has been demonstrated to be an important risk factor for the development of cardiovascular disease (CVD). The relationship of the peripheral leukocyte count to the severity of stable angina remains to be clarified. The present study analyzed the relationship of the peripheral leukocyte count to the severity of stable angina determined by coronary angiography., Methods: The data from 108 patients with stable angina, and 92 subjects with normal coronary angiograms were reviewed, and the role of the peripheral leukocyte count as a risk factor for stable angina evaluated. In addition, the correlation of the peripheral leukocyte count and the severity of stable angina, as assessed by the Gensini's score in the stable angina group, were analyzed., Results: Age, the prevalence of hypertension and diabetes, and the fasting blood sugar were significantly higher, and the HDL was lower in the stable angina than the control group. A multivariate analysis showed that a peripheral leukocyte count over 6,800/mm3 was an independent variable, but with no statistical significance (p=0.067), and diabetes (OR=3.02, 95% CI: 1.29-7.02) and old age (OR=3.62, 95% CI: 1.3-9.87) were independent risk factors for stable angina. A positive correlation between peripheral leukocyte count and Gensini's score was noted in the stable angina group even after adjusting for age, fasting blood sugar, blood pressure and lipid profiles (R2=0.198, p=0.015)., Conclusion: An increased peripheral leukocyte count is considered not so much an indicator of the pathogenesis of stable angina, but as a predictor for disease progression. Furthermore, it is considered that the above correlation will be helpful in screening high-risk groups that require relatively active interventional therapy.

This study was designed to clarify which vascular carrier, the arteriovenous shunt loop or the arteriovenous bundle, has more potential as a vascular carrier for an artificial skin flap in rats. An arteriovenous shunt loop was constructed between the femoral artery and vein using an interpositional artery (group I) or vein (group II) graft. For arteriovenous bundle groups, the femoral artery and vein were used and subdivided into two groups: distal ligation type (group III) and flow-through type (group IV). The vascular pedicle was wrapped with an artificial dermis and implanted beneath the inguinal skin for 4 weeks. For the control group, a folded sheet of artificial dermis without any vascular carrier was embedded. In experiment 1, the volumes of generated tissue within the artificial dermis were measured in the experimental and control groups (n = 5 in each group). In experiment 2, the origin of new blood vessels sprouting from the arteriovenous shunt loop and arteriovenous bundle were evaluated histologically. The volume of generated tissue in the shunt groups was significantly greater than that in the bundle groups (p < 0.01). However, the bundle groups also showed a great potential for producing new tissue. Serial histological studies showed that new capillaries were derived not only from the vasa vasorum of the femoral vessels but directly from the femoral vein in both the shunt and the bundle groups. This "sprouting" was extensively exhibited in the group III. Although the arteriovenous shunt loop showed a greater potential for producing new tissue and capillaries, the distal ligation type of bundle was thought to be an effective and practical vascular carrier for producing a tissue-engineered skin flap.

Background: Thyroid abnormalities affect a considerable portion of the population, and overt hypothyroidism is associated with an elevated risk of cardiovascular disease and adverse changes in blood lipids. Subclinical hypothyroidism is also associated with an increase risk of cardiovascular disease. So, we undertook this study to investigate the prevalence of overt and subclinical thyroid disorders and their associations with cardiovascular risk factors., Methods: This study involved 66,260 subjects (43,588 men, 22,672 women; between 20-80 years of age, mean age 41.5 +/- 9.6). Serum free thyroxine (FT4), thyroid stimulating hormone (TSH), total cholesterol, low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were measured by RIA using commercial kits. High sensitivity C-reactive protein (hsCRP) levels were determined by nephelometry., Results: The prevalences of overt thyrotoxicosis, subclinical thyrotoxicosis, overt hypothyroidism and subclinical hypothyroidism were 5/1000 (334 subjects), 6.4/1000 (426 subjects), 1.6/1000 (108 subjects), and 6.4/1000 (375 subjects). Mean plasma total cholesterol and LDL-C were elevated in overt hypothyroidism than in normal controls (202.1 mg/dL and 121.8 mg/dL versus 197.1 mg/dL and 120.1 mg/dL, respectively) (p < 0.05). In subclinical hypothyroidism, mean total cholesterol and LDL-C levels were also elevated (201.9 mg/dL and 123.7 mg/dL) (p = 0.015, p = 0.047). Waist-to-hip ratio (WHR) was lower in overt thyrotoxicosis and higher in hypothyroidism., Conclusion: The prevalence of thyroid dysfunction in Korea is not significantly different from that reported by other countries. It was also age dependent and higher in women, but this elevation in women was lower than expected. Patients with hypothyroidism exhibited higher waist-to-hip ratios, an index of obesity. Patients with subclinical hypothyroidism exhibited elevated atherogenic parameters (Total cholesterol, LDL-C). Therefore screening and treatment for subclinical hypothyroidism may be warranted due to its adverse effects on lipid metabolism.

Background: C-reactive protein (CRP), one of the hepatic acute phase reactants, has been associated with decreased endothelium-dependent relaxation, a potential risk factor for hypertension. However, the relationship between CRP and hypertension has not been well elucidated. The aim of this study is to assess whether circulating levels of CRP are independently related to essential hypertension., Methods: We evaluated the relationship between high sensitivity CRP with blood pressure (BP) and several cardiovascular risk factors in a cross-sectional survey of 8347 apparently healthy Korean persons. The CRP was measured by nephelometry., Results: The subjects consisted of 4813 men and 3534 women, aged >/=20 years. Mean (SD) age and CRP level of the population were 47.1 (11.5) years and 1.12 (1.72) mg/L. Overall hypertension prevalence was 34%. There was a significant positive association between BP and the CRP level (P <.0001). After adjustment for age, sex, fasting blood sugar, triglyceride, low-density lipoprotein, body mass index, waist-hip ratio, high-density lipoprotein, the prevalence of hypertension by CRP was 1.267 (95% confidence interval [CI] 1.079-1.487, P =.004), 1.253 (95% CI 1.062-1.477, P =.007), and 1.451 (95% CI 1.231-1.711, P <.001) times higher in subjects in the second, third, and fourth quartiles of CRP, as compared to subjects in the first quartile., Conclusions: Our results suggest that the CRP level may be an independent risk factor for the development of hypertension in Korean persons. However, because of the cross-sectional nature of our study, this finding should be confirmed in prospective cohort studies, aimed at elucidating the role of CRP in the prediction, diagnosis, and management of hypertension.

The objective of this work was to study the in vitro characteristics as well as in vivo pharmacokinetic performance of a series nalbuphine (NA) prodrug-loaded microspheres. An oil-in-water solvent evaporation method was used to incorporate the various NA prodrugs into poly(D,L-lactide-co-glycolide) (PLGA)-based microspheres. The morphology of microspheres under the scanning electron microscopy (SEM) revealed a spherical shape with smooth surface. Drug release rates for the microspheres were found to be a function of prodrug hydrophilicity, with higher drug release rates for microspheres loaded with more hydrophilic prodrugs. The release profiles fit well to the Baker and Lonsdale's spherical matrix model, suggesting the drug release from microspheres was consistent with a diffusion mechanism. The in vivo pharmacokinetic studies after s.c. injection of microspheres into rabbits showed sustained plasma NA-time profiles, with approximately 104.7, 67.2, and 41.0% relative bioavailability for microspheres loaded with nalbuphine propionate (NAP), nalbuphine pivalate (NPI), and nalbuphine decanoate (NDE), respectively. The in vitro release characteristics correlated well with the in vivo pharmacokinetic profiles. The results indicated that the prodrug hydrophilicity had significant effects on the in vitro as well as in vivo drug release kinetics. The present study demonstrates the feasibility of using biodegradable polymeric microspheres for controlled delivery of NA prodrugs.

Under ultrasound exposure, the stability of plasmid DNA protected by polymer-based gene delivery system is an important factor for achieving optimal transfection into cells. We have evaluated the effectiveness of various polymer-based plasmid DNA delivery systems, which are interactive polymers and cationic polymers, to avoid shear degradation induced by ultrasound exposure. Alternatively, it is shown that sonication of plasmid DNA for exposure time as low as 10s resulted in total DNA fragmentation and the loss of transfection potency in NIH/3T3 cells. Among these polymer-based plasmid DNA delivery systems, only cationic polymers had the ability to provide the protection of plasmid DNA from ultrasonic degradation as indicated by the reservation in supercoiled circular (SC) and open circular (OC) forms of plasmid DNA on the agarose gel electrophoresis. The DNA stability protected by cationic polymers decreased after ultrasound exposure in 1M sodium chloride solution. Also, higher molecular weight of cationic polymers and sufficient cationic polymer/DNA weight ratios are essential to prevent DNA from degradation under ultrasound exposure in aqueous or salt solution. These results suggest that the protective mechanism by cationic polymers is due to the attractive bonding between cationic polymer and negative plasmid DNA. Whereas, DNA condensation alone provoked by the addition of polyethylene glycols was not sufficient to resist the DNA fragmentation induced by ultrasound exposure.

The aim of this study was to assess the effects of electroporation on transdermal permeation of nalbuphine (NA) and its prodrugs. The permeation characteristics were investigated under various electrical factors and skin barriers to elucidate the mechanisms involved in transdermal delivery of NA and its prodrugs by skin electroporation. The in vitro permeation studies were performed using side-by-side diffusion cells. The various electrical factors investigated were pulse voltage, pulse duration and pulse number; the different skin barriers studied were intact hairless mouse skin, stratum corneum (SC)-stripped skin, delipid skin as well as furry Wistar rat skin. The prodrugs were fully converted to parent drug after skin permeation. Application of electroporation significantly enhanced transdermal permeation of NA and its prodrugs. The enhancement ratios were highest for NA and the four prodrugs showed the similar permeability after electroporation. The permeation amounts of NA and its prodrugs may be increased by application of higher pulse voltage, pulse duration as well as pulse number. Various kinetics and mechanisms were observed for the permeation of the hydrophilic NA and lipophilic nalbuphine enanthate through different skin barriers by applying electroporation. This study demonstrated that electroporation may enhance and control transdermal permeation of NA and its prodrugs. The results also indicated that the physicochemical properties of prodrug had significant effects on kinetics as well as mechanisms of transdermal permeation by electroporation.

The in-vitro permeation of buprenorphine across skin was investigated to assess the effects of iontophoresis and electroporation on drug permeation from solutions as well as from hydrogels. Iontophoresis (0.3 mA cm(-2)) increased the buprenorphine permeation from solution by a factor of 14.27 as compared with passive diffusion; the application of electroporation increased the buprenorphine permeation from solutions by a factor of 8.45. The permeation experiments using cellulose membrane and stratum corneum (SC)-stripped skin as permeation barriers suggested that the enhancement with iontophoresis was primarily due to strong electrophoretic drift of buprenorphine molecules, whereas the enhancement seen with electroporation was mainly attributed to the creation of transient aqueous pores in the SC layer. Application of high-voltage pulses followed by iontophoresis resulted in a shorter permeation onset time from both solutions and hydrogels as compared with iontophoresis or electroporation alone. The charge repulsion between buprenorphine and chitosan vehicles as well as the competition effects of counter-ions for carboxymethylcellulose (CMC)-based polymers may account for the different permeation rates under electrical field. This study demonstrates the feasibility of using hydrogels for delivery of buprenorphine under the application of iontophoresis or electroporation, separately or together.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are a group of kinases that play an important role in proliferation and differentiation. In megakaryocyte-like human erythroleukemia (HEL) cells, ERK2 was found to be predominantly expressed and strongly activated by prostaglandin (PG) E(2), thrombin, and epinephrine. On the other hand, adenosine, ADP, ATP, and UTP did not significantly increase ERK1/2 phosphorylation. However, of the agonists tested, only ADP was able to stimulate thymidine uptake. Pretreatment with pertussis toxin abolished the PGE(2) response but had less of an effect on thrombin. PGE(2)- and thrombin-induced ERK1/2 activation was mimicked by 4-beta-phorbol-12-myristate-13-acetate and ionomycin and blocked by mitogen-activated protein kinase kinase inhibitor 1,4 diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene but displayed differential sensitivity to protein kinase C inhibitor bisindolylmaleimide I and Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Analogs of cAMP or agents that stimulate cAMP production were either weak or ineffective activators. Further studies indicate that the effect of thrombin was blocked by the phosphoinositide 3-kinase inhibitor wortmannin but not by agents inhibiting tyrosine kinase activity. On the contrary, herbimycin, but not wortmannin, attenuated the effect of PGE(2). Collectively, these results indicate that ERK1/2 are selectively activated by G protein-coupled receptors and not functionally associated with proliferation in HEL cells. ERK1/2 activation in response to PGE(2) and thrombin is mediated by distinctive types of G proteins and is differentially regulated by multiple pathways, including calcium mobilization, protein kinase C, phosphoinositide 3-kinase, and tyrosine kinases.

The objective of this work was to assess the in vitro characteristics, in vivo pharmacokinetics and in vivo pharmacodynamics of nalbuphine propionate (NAP)-loaded microspheres. An oil-in-water solvent evaporation method was used to incorporate NAP into poly (d,l-lactide-co-glycolide) (PLGA)-based microspheres. The morphology of the microspheres were evaluated using scanning electron microscopy which showed a spherical shape with smooth surface. A prolonged in vitro drug release profile was observed, with approximately 71.1% of incorporated drug released in 96 h. The release profile fit well to the Baker and Lonsdale's spherical matrix model, suggesting the release of NAP from microspheres was consistent with a diffusion mechanism. The in vivo pharmacokinetic studies after subcutaneous injection of NAP-loaded microsphere showed a sustained plasma nalbuphine (NA)-time profile, with 100% relative bioavailability comparing to the AUC obtained after intravenous injection. The in vitro release pattern correlated well with the in vivo pharmacokinetic profile. The pharmacodynamic studies evaluated using paw pressure model also showed a prolonged pharmacological response after injection of microspheres. A linear correlation between the percent analgesic effect and the logarithm of plasma NA concentration was obtained, suggesting the pharmacological response can be reflected by plasma drug concentration. This correlation may be utilized for evaluating the pharmacological responses of various NA and its prodrug-based formulations with known plasma NA concentrations.

The objective of this study was to evaluate the in vitro transdermal permeation of nalbuphine hydrochloride (CAS 23277-43-2) (NA) and nalbuphine pivalate (NAP), a novel prodrug of NA, from different hydrogel formulations under passive diffusion as well as iontophoresis. Various concentrations of polymers, including polyvinylpyrrolidone (PVP) and hydroxypropyl cellulose (HPC) were used in the hydrogel formulations. The passive permeation rate of NA was affected by the polymer concentrations, which can be attributed to different viscosities of the hydrated formulations; whereas the passive permeation rate of NAP was not influenced by the various polymer concentrations. Iontophoresis significantly increased the permeation rates of NA and NAP from various hydrogel formulations through skin; the enhancement ratios were higher for NA in all the formulations studied. The iontophoretic permeation rates of NA were slightly decreased by the incorporation of polymers; however, the transdermal flux and membrane potential were independent of polymer concentrations for both NA and NAP, demonstrating that the polymer concentrations in the hydrogel formulations did not have significant effects on the iontophoretic permeation of NA and NAP.

The major purpose of this study is to develop and characterize a series of carbopol- and pluronic-based solutions as the in situ gelling vehicles for ophthalmic drug delivery. The rheological properties, in vitro release as well as in vivo pharmacological response of various polymer solutions, including carbopol, pluronic and carbopol/pluronic solution, were evaluated. It was found that the optimum concentration of carbopol solution for the in situ gel forming delivery systems was 0.3% (w/w), and that for pluronic solution was 14% (w/w). The mixture of 0.3% carbopol and 14% pluronic solutions showed a significant enhancement in gel strength in the physiological condition; this gel mixture was also found to be free flowing at pH 4.0 and 25 degrees C. The rheological behaviors of carbopol/pluronic solution were not affected by the incorporation of pilocarpine hydrochloride. Both the in vitro release and in vivo pharmacological studies indicated that the carbopol/pluronic solution had the better ability to retain drug than the carbopol or pluronic solutions alone. The results demonstrated that the carbopol/pluronic mixture can be used as an in situ gelling vehicle to enhance the ocular bioavailability.

The in vitro transport of nalbuphine (NA) and its prodrugs across various skins was investigated in order to assess the effects of prodrug lipophilicity on passive as well as iontophoretic permeation. The passive diffusion of NA and its prodrugs increased with the drug lipophilicity. Iontophoresis significantly increased the transport of NA and its prodrugs; the enhancement ratio was highest for NA and decreased as the drug lipophilicity increased. Measurements using intact and stratum corneum (SC)-stripped skins showed that the SC was the major skin diffusion barrier for the passive permeation of NA and nalbuphine pivalate (NAP). The iontophoretic permeation of NA and NAP across intact and SC-stripped skins indicated that the SC layer was not rate-limiting for the permeation of NA, but remained the rate-limiting barrier for transdermal permeation of NAP. Permeation studies using SC-stripped and delipidized skins suggested that the intercellular pathway was the predominant route for the passive permeation of NA and NAP as well as the iontophoretic permeation of NAP across the SC. The relative rates of passive and iontophoretic permeation across Wistar rat skins demonstrated that a significant amount of NA may permeate skin via the appendageal routes, whereas NAP permeated predominantly through the lipid matrix.

The effect of low frequency ultrasound (20 kHz) on the permeation of clobetasol 17-propionate (CP) through skin (sonophoresis) was studied. The ultrasound was applied at either continuous or discontinuous modes and at different intensities. The results showed that low frequency ultrasound significantly enhanced the permeability of CP across hairless mouse skin in vitro. Delivering the same amount of ultrasonic energy in different modes of application markedly influenced the flux and skin residual of CP. The on/off discontinuous ultrasound had greater enhancement on CP permeation than the continuous ultrasound. The results of skin histopathology and permeation experiment using various membranes demonstrate that both disordering of stratum corneum and convective flow resulted from the cavitation effect were responsible for sonophoretic enhancement of CP. The permeation of CP through hair follicles and sweat ducts was susceptible to the application of ultrasound.

The major purpose of this work was to study the effect of various liposome formulations on the iontophoretic transport of enoxacin through excised rat skin. The electrochemical stability of these liposomes was also evaluated. The encapsulation percentage of enoxacin was significantly enhanced after 6 h incubation in an electric field; whereas the fusion of liposomes was inhibited by application of electric current. The results of iontophoretic drug transport showed that the permeability of enoxacin released from liposomes was higher compared with that of free drug. The iontophoretic permeability of enoxacin released from liposomes increased with a decrease in the fatty acid chain length of the phospholipid, which may be due to the different phase transition temperatures of the phospholipids. Incorporation of charged phospholipid resulted in an alteration of the transdermal behavior of enoxacin: the iontophoretic permeation as well as the amount of enoxacin partitioned in skin was greatly reduced after incorporation of stearylamine in liposomes, which can be attributed to the competitive ion effect. The enoxacin released from stratum corneum-based liposomes showed the highest amount of enoxacin partitioned into skin depot. The results of employing cathodal iontophoresis on negative charged liposomes suggested that the liposomal vesicles or phospholipids may carry enoxacin into deeper skin strata via the follicular route.

Preoperative planning of craniofacial synostosis can be achieved through the use of two- or three-dimensional (3D) computed tomography (CT) images and by 3D solid models. The advantage of using 3D models was evaluated by calculating the amount of blood transfused and the operating time for 36 craniosynostosis procedures, 21 planned with 3D models and 15 with CT images performed in the past 7 years. The use of 3D models reduced both blood loss and operating time for fronto-orbital advancement with reshaping, LeFort III advancement, and LeFort IV minus Glabellar advancement; blood loss for fronto-orbital advancement without reshaping; and operating time for total cranial reshaping.

An actinomycete, strain YC75T, which produced bafilomycin-like antifungal compounds, was identified as a member of the genus Kitasatospora on the basis of morphological and chemotaxonomic characteristics. The strain produced the aerial and fragmenting vegetative mycelia consisting of straight chains of 20 or more smooth-surfaced spores. Submerged spores were formed in tryptic soy broth. No soluble pigments were formed. Whole-cell hydrolysates contained glucose and mannose, but not galactose. The 16S rDNA sequence of YC75T was compared with those of the other representative kitasatosporae and streptomycetes. Strain YC75T formed a significant monophyletic clade with Kitasatospora phosalacinea. The levels of DNA relatedness between strain YC75T and representatives of the genus Kitasatospora ranged from 16 to 59% including K. phosalacinea (28 and 40%). It is clear from polyphasic evidence that the isolate should be classified as Kitasatospora cheerisanensis sp. nov., whose type strain is YC75T (= KCTC 2395T). The presence of galactose in whole-cell hydrolysates may not be a stable chemical marker for the genus Kitasatospora.

The objective of this study was to evaluate the in vitro and in vivo transdermal iontophoresis of various diclofenac sodium polymer formulations. The excised rat skin, human skin as well as cellulose membrane were used to examine the in vitro drug permeation whereas the microdialysis technique was used to monitor the drug concentration in vivo. Polymer solutions based on polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) binary system showed higher drug permeability than that of single polymer vehicle. The effect of formulations on drug permeation through cellulose membrane was quite different from those through rat skin and human skin, which can be explained by the different permeation pathways between them. It appeared to be a membrane-controlled mechanism but not the vehicle matrix-controlled mechanism for diclofenac hydrogels when using skin as the diffusion barrier. The recovery of diclofenac sodium in the in vivo microdialysis was approximately 80-90%, indicating this technique can be used in the intradermal drug monitoring. For all the polymer formulations tested, there was a good relationship between the in vitro and in vivo drug permeation. A synergistic effect on drug permeation was observed when transdermal iontophoresis combined with the pretreatment of cardamom oil as a permeation enhancer.

The objective of this work was to assess the effects of drug solubility and loading percent, as well as Carbopol 934/hydroxypropylcellulose (CP/HPC) ratio, on drug release and mucoadhesive performance of the nalbuphine prodrug loaded buccal disks. Drug release rates for the disks were found to be a function of drug solubility, with higher drug release rates for disks loaded with more hydrophilic prodrugs and an increased amount of beta-cyclodextrin. The drug release rates increased with loading percents for nalbuphine hydrochloride, whereas an opposite drug release trend was observed for disks loaded with nalbuphine enanthate, which can be explained by the diffusional drug release mechanism. The CP/HPC ratio affected release rates of nalbuphine enanthate, whereas the ratio had no impact on the release of nalbuphine hydrochloride. Within the 2 days of experiment time, all formulations attached well to the porcine buccal tissues, indicating those formulation variables had no influence on the mucoadhesive performance of CP/HPC-based buccal disks.

The benign osteoblastoma is rarely seen as a tumor of the facial bone in infancy or early childhood. Only five cases with nasal involvement have been reported in the literature. The authors present a case of osteoblastoma of the nasal cavity, the nasal bone, the ethmoid sinus, and the anterior cranial base. This 3-year-old girl presented with a tumor surrounding the left medial canthus. Imaging studies, including x-ray films, computerized tomography scans, magnetic resonance images, a (99m)Tc-scintigram, and angiograms, confirmed the location of the tumor. A biopsy specimen of tumor was obtained intranasally and the pathological diagnosis was an osteoblastic tumor suggestive of osteoblastoma. Although the tumor margin was well defined on the radiological images, it was difficult to determine the exact margin during the operation. Therefore, it is important to show how to excise the tumor completely under direct view. With the use of a "dismasking flap," it was possible to resect the benign osteoblastoma completely from the nasal cavity, even though it extended into the orbit, the maxilla, and the anterior cranial base.

Investigations on the chromosomal inversion polymorphism were conducted on a Korean (Taenung) natural population of D. melanogaster during the period 1978 to 1992. A total of 66 different endemic and cosmopolitan inversions were found on both major chromosome pairs II and III. Some of them proved to be rare cosmopolitan types (2LKA, 2LNS, 2LF, 2RCy, 3LM, 3RKI, and 3RK), while others were endemics. The distribution of breakpoints for endemic and rare cosmopolitan inversions are not random along the two autosome arms. With respect to frequency changes, the 15-year survey revealed that five of the cosmopolitan types (2Lt, 2RNS, 3LP, 3RC, and 3RMo) exhibit cyclical frequency changes, whereas gene arrangement 3RP shows relatively stable frequencies. Tests for correlations between gene arrangement frequencies and several climatic variables gave no clear evidence for such relationships. Only one correlation coefficient out of 64 was statistically significant.

We characterized the effect of hydroxypropyl methylcellulose (HPMC)/lactose ratio and HPMC viscosity grade (molecular weight) on solute release and swelling of matrix tablets. We used a semiquantitative optical imaging method to monitor the swelling of matrices with HPMC content from 20% to 80% (w/w) and four viscosity grades. Several aspects of the swelling process common to all formulations were revealed: (i) swelling is anisotropic with a preferential expansion in the axial direction, (ii) swelling is isotropic with respect to the gel layer thickness and composition in both axial and radial directions, (iii) the gel layer develops in three stages, and (iv) water penetration is Fickian in nature and essentially constant for all formulations. We monitored simultaneously drug, lactose, and HPMC release. Lactose and drug release rates were superimposed, indicating a similar diffusional release mechanism and no interaction with HPMC. The strong dependence of HPMC release on viscosity grade is explained on the basis of the concept of polymer disentanglement concentration. We analyzed drug release rates using a model for a reservoir-type release system that incorporates swelling kinetics. HPMC/lactose ratio modulates drug release rate by altering drug diffusivity, a function of gel composition. In contrast, HPMC viscosity grade impacts matrix dissolution and gel layer thickness development below a critical molecular weight. For slowly dissolving matrices containing high viscosity grade (> 4000 cps) HPMC, similar drug release rates are observed mainly due to the same drug diffusivity as a result of the identical gel composition and thickness. For fast dissolving matrices (< or = 100 cps) swelling inhomogeneity is proposed as being responsible for a higher apparent drug diffusivity and release rate.