Search

Background and aims Sarcopenia is associated with fibrotic burden in patients with chronic hepatitis B. We investigated the dynamic association between fibrosis changes and appendicular skeletal muscle mass during antiviral therapy in patients with chronic hepatitis B. Methods Between 2015 and 2018, chronic hepatitis B patients who received paired transient elastography to assess fibrotic burden in the liver and bioelectrical impedance analysis to assess appendicular skeletal muscle mass were recruited retrospectively. The sarcopenia index was calculated as total appendicular skeletal muscle mass/body mass index. Significant liver fibrosis was defined as a liver stiffness value≥8 kPa. Results In total, 223 (53.7%) received antiviral therapy, whereas 192 (46.3%) did not. Appendicular skeletal muscle mass decreased significantly in the antiviral therapy group (mean 21.16→21.00 kg, P = 0.01), but not in the non-antiviral therapy group (mean 20.77→20.64 kg, P = 0.134). In a subgroup with significant liver fibrosis, similar findings were observed (mean 20.73→20.54 kg in antiviral therapy group, P = 0.037; mean 21.39→21.07 kg in the non-antiviral therapy group, P = 0.097). Older age, male gender, higher body mass index, and higher aspartate aminotransferase were significantly associated with the increased risk of appendicular skeletal muscle mass reduction (≥5% from the baseline). Conclusions Appendicular skeletal muscle mass significantly decreased during antiviral therapy in patients with chronic hepatitis B patients.

Background and aims Sarcopenia leads to metabolic and vascular abnormalities. However, little is known regarding the independent relationship between skeletal muscle mass and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). This study aimed to evaluate the association between skeletal muscle mass and carotid atherosclerosis in men and women with T2DM. Methods In this cross-sectional study, a total of 8202 patients with T2DM were recruited from the Seoul Metabolic Syndrome cohort. Skeletal muscle mass was estimated using bioimpedance analysis, while skeletal muscle mass index (SMI, %) was defined as total skeletal muscle mass (kg)/body weight (kg) × 100. Both carotid arteries were examined by B-mode ultrasound. Carotid atherosclerosis was defined by having a carotid plaque or mean carotid intima-media thickness (IMT) ≥1.1 mm. Results Among the entire population, 4299 (52.4%) subjects had carotid atherosclerosis. The prevalence of carotid atherosclerosis increased with decreasing SMI quartiles for both sexes. The odds ratios for carotid atherosclerosis were 2.33 (95% confidence interval [CI], 1.17–4.63) and 2.24 (95% CI, 1.06–4.741) in the lowest versus highest SMI quartile in men and women, respectively, after the adjustment for clinical risk factors. In men, the risk of atherosclerosis increased linearly with decreasing SMI quartiles (p for trend = 0.036). Conclusions Low skeletal muscle mass was independently associated with the presence of carotid atherosclerosis in men and women with T2DM.

Gemigliptin is a potent, selective dipeptidyl peptidase (DPP)-4 inhibitor that does not require any dosage adjustment based on renal function. It is also known to have no apparent interaction with commonly used drugs. In the present study, we aimed to evaluate the glucose-lowering efficacy and safety of gemigliptin in post-transplant patients with type 2 diabetes mellitus (T2D).A total of 84 patients who were prescribed gemigliptin for more than 180 days after transplantation were analyzed retrospectively. Six-month changes in blood glucose and glycated hemoglobin (HbA1c) levels were checked to assess glycemic efficacy. Safety was evaluated by examining its influence on immunosuppressive treatment, as determined by the blood trough level and dosage of calcineurin inhibitors, as well as changes in parameters related to liver and renal function.Six months of gemigliptin treatment significantly lowered blood glucose level (HbA1c: 8.16 ± 1.69 to 7.44 ± 1.26%; P .001). There were no significant changes in blood trough levels of immunosuppressants, including tacrolimus, cyclosporine, and sirolimus. The dosage of immunosuppressants was also stable. In addition, there were no significant changes in the levels of liver enzymes and renal function during 6 months of treatment.Gemigliptin robustly lowered blood glucose levels without exerting any significant effect on immunosuppressive treatment, renal function, and liver enzymes in post-transplant patients with T2D.

Background Elucidation of the basic molecular mechanism of autophagy was a breakthrough in understanding various physiological events and pathogenesis of diverse diseases. In the fields of diabetes and metabolism, many cellular events associated with the development of disease or its treatment cannot be explained well without taking autophagy into account. While a grand picture of autophagy has been established, detailed aspects of autophagy, particularly that of selective autophagy responsible for homeostasis of specific organelles or metabolic intermediates, are still ambiguous and currently under intensive research. Scope of review Here, results from previous and current studies on the role of autophagy and its dysregulation in the physiology of metabolism and pathogenesis of diabetes are summarized, with an emphasis on the pancreatic β-cell autophagy. In addition to nonselective (bulk) autophagy, machinery and significance of selective autophagy such as mitophagy of pancreatic β-cells is discussed. Novel findings regarding autophagy types other than macroautophagy are also covered, since several types of autophagy or lysosomal degradation pathways other than macroautophagy coexist in pancreatic β-cells. Major conclusion Autophagy plays a critical role in cellular metabolism, homeostasis of the intracellular environment and function of organelles such as mitochondria and endoplasmic reticulum. Impaired autophagic activity due to aging, obesity or genetic predisposition could be a factor in the development of β-cell dysfunction and diabetes associated with lipid overload or human-type diabetes characterized by islet amyloid deposition. Modulation of autophagy of pancreatic β-cells is likely to be possible in the near future, which would be valuable in the treatment of diabetes associated with lipid overload or accumulation of islet amyloid., Highlights • Autophagy is critical for cellular metabolism, homeostasis and organelle function. • Impaired autophagic activity could predispose to β-cell dysfunction and diabetes. • Several types of autophagy coexist in pancreatic β-cells.

We investigated the clinical relevance of non-albumin proteinuria (NAP) in Korean patients with type 2 diabetes (T2D).We enrolled 883 T2D patients who had both their urinary albumin-to-creatinine ratio (uACR) and protein-to-creatinine ratio (uPCR) measured. We classified the patients into non-proteinuria (NP; uPCR150 mg/g and uACR30 mg/g), isolated NAP (iNAP; uPCR ≥150 mg/g and uACR30 mg/g), and albuminuria (uACR ≥30 mg/g) groups. The associations between uPCR, uACR, and several indices of glucose metabolism were investigated.The glucometabolic pathophysiology of iNAP (96 [10.9%]) group was more associated with a decrease in homeostatic model assessment (HOMA)-beta value (aOR 1.89 [95% CI, 1.21-2,96]) than with an increase in HOMA-insulin resistance (aOR 1.29 [95% CI, 0.83-2.01]). uPCR ≥150 mg/g was also found to have more consistent and stronger association with vascular complications than uACR ≥30 mg/g (aOR 1.44 [95% CI, 1.03-2.02] vs. 1.26 [95% CI, 0.89-1.79]).The nephropathy of iNAP may be mainly attributed to decreased beta cell function. Furthermore, uPCR might be a more sensitive urinary biomarker than uACR for the detection of vascular complications in T2D patients.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since vendredi 15 decembre 2017

Aims Recent evidence has shown that renal tubulointerstitial injuries play an important role in diabetic nephropathy. In this study, we evaluated the association between urinary N-acetyl-β- d -glucosaminidase (uNAG), an early renal tubular damage marker, and carotid artery atherosclerosis in patients with type 1 diabetes (T1D). Methods This was a cross-sectional study of 88 patients with T1D. Demographic and laboratory data; urinary indices, including urinary NAG-to-creatinine ratio (uNCR), and albumin-to-creatinine ratio (uACR); and carotid ultrasonography were investigated. Results Eighty-eight subjects were divided into three groups based on uNCR tertiles. Subjects belonging to the highest tertile of uNCR had the highest average mean and maximum carotid intima-media thickness (IMT). An elevated uNCR was also significantly correlated with increased average mean and maximum carotid IMT, whereas an elevated uACR was not. Even after adjusting for confounding factors, uNCR continued to be a meaningful predictive marker for increased average mean and maximum IMT. Conversely, the uACR could not predict carotid IMT after adjustment for confounding factors. Conclusions Elevated levels of uNAG are significantly associated with carotid artery atherosclerosis in patients with T1D independently of albuminuria, a marker of glomerular damage.

Aims We evaluated specific alterations in amino acids (AAs) profile in patients with type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) compared with healthy controls. In addition, we tried to find the mechanisms behind these AA alterations. Methods Twenty AAs, TNF-α, and IL-6 were analyzed in fasting serum samples from a total of 198 individuals (56 drug-naive patients with T2DM, 69 patients IFG, and 73 healthy controls). The C2C12 mouse myoblast cell lines were used to examine the changes of MAFbx and MuRF1 expressions, which are muscle specific E3 ligases acting as major mediators of skeletal muscle proteolysis, after development of insulin resistance induced by palmitate treatment. Results In addition to branched chain amino acids BCAAs, fasting serum AAs such as glutamic acid, lysine, phenylalanine, arginine, alanine, tyrosine, aspartic acid, were higher in patients with T2DM and intermediately elevated in patients with IFG compared with normoglycemic controls. These serum AA concentrations positively correlated with fasting glucose, homeostasis model assessment of insulin resistance (HOMA-IR), and pro-inflammatory cytokines. In addition, HOMA-IR and pro-inflammatory cytokines were two important independent predictors of serum AA levels. In vitro experiments showed that palmitate treatment in C2C12 myotubes induced insulin resistance, increased pro-inflammatory cytokine gene expression, and increased MAFbx gene and protein expression. Conclusions The increase in fasting serum AAs can be an early manifestation of insulin resistance. Increased muscle proteolysis induced by insulin resistance and inflammatory cytokines can be a possible mechanism for the rise in serum AA levels.

Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk. Among categories of NAFLD, hepatic fibrosis is most likely to affect mortality. Myocardial function and its energy metabolism are tightly linked, which might be altered by an insulin resistant condition such as NAFLD. We investigated whether hepatic steatosis and fibrosis were associated with myocardial dysfunction relative to myocardial glucose uptake.A total of 308 patients (190 without NAFLD, 118 with NAFLD) were studied in a tertiary care hospital. Myocardial glucose uptake was evaluated at fasted state using [Compared to those without NAFLD, patients with NAFLD had alterations in cardiac remodeling, manifested by increased left ventricular mass index, left ventricular end-diastolic diameter, and left atrial volume index (all p 0.05). Hepatic steatosis was significantly associated with left ventricular filling pressure (E/e' ratio), which reflects diastolic dysfunction (p for trend0.05). Those without NAFLD were more likely to have higher myocardial glucose uptake compared to those with NAFLD. Significant hepatic fibrosis was also correlated with diastolic dysfunction and impaired myocardial glucose uptake. Using multivariable linear regression, E/e' ratio was independently associated with hepatic fibrosis (standardized β = 0.12 to 0.27; all p 0.05). Association between hepatic steatosis and E/e' ratio was also significant (standardized β = 0.10 to 0.15; all p 0.05 excluding the model adjusted for adiposity).Hepatic steatosis and fibrosis are significantly associated with diastolic heart dysfunction. This association is linked with myocardial glucose uptake evaluated byNon-alcoholic fatty liver disease is associated with an increased risk of cardiovascular disease. More severe forms of non-alcoholic fatty liver disease, where hepatic fibrosis occurs, are linked to increased mortality. In this study, we have shown that hepatic steatosis and fibrosis are associated with subclinical myocardial dysfunction. This association is linked to altered myocardial glucose uptake.

This study aimed to evaluate the clinical significance of urine protein to creatinine ratio (uPCR) in relation to the cardiovascular risk associated with carotid artery intima-media thickness (cIMT) progression in subjects with type 2 diabetes (T2D) and normoalbuminuria.In this retrospective longitudinal study on T2D, we recruited 927 participants with normoalbuminuria (urine albumin to creatinine ratio [uACR] 30 mg/g) whose cIMT was measured at baseline and after at least 1 year, and whose initial uPCR and uACR data were available.Higher initial uPCR was positively correlated with a greater increment in maximal cIMT (β = 0.074, p = 0.028), and this correlation was significant even after adjusting for multiple confounding factors (β = 0.074, p = 0.046). High baseline uPCR was an independent predictive factor for the increased risk of maximal cIMT progression in a simple logistic regression model (OR, 1.41; 95% CI, [1.08-1.86]; p = 0.013). Even after adjusting for several confounding variables, higher uPCR was significantly associated with a higher risk of cIMT progression (OR, 1.48; 95% CI, [1.08-2.03]; p = 0.014).These results suggest that high uPCR may be a useful predictive marker for the progression of carotid artery atherosclerosis, even in subjects with T2D and without albuminuria.

Although sarcopenia is associated with metabolic disorders, its influence on albuminuria has not been determined. The aim of this study was to identify the relationship between sarcopenia and albuminuria in the general population.This was a population-based, cross-sectional study using a nationally representative sample of 2326 subjects aged ≥20years from the Korea National Health and Nutrition Examination Surveys of 2008-2011. Appendicular skeletal muscle (ASM) measured by dual-energy X-ray absorptiometry was used to assess sarcopenia, which was defined as ASM divided by body mass index, as recommended by the international consensus meeting of the National Institutes of Health. Albuminuria was defined as an albumin-to-creatinine ratio of ≥30mg/g using random spot urine samples.A total of 385 (16.5%) subjects were classified as having albuminuria. Sarcopenic subjects showed a higher proportion of albuminuria than subjects without sarcopenia (odds ratios [ORs]=2.17-3.26, all P0.05) after stratification based on the presence of hypertension, diabetes, or metabolic syndrome and a higher homeostasis model assessment of insulin resistance (all P0.001). The albuminuria risk was comparable between insulin-sensitive subjects with sarcopenia and insulin-resistant subjects with preserved muscle mass. A multiple logistic regression analysis also demonstrated that sarcopenia was independently associated with albuminuria (OR=1.61, 95% confidence interval [CI]=1.04-2.48, P0.05). The association between sarcopenia and albuminuria remained strong in the elderly population (ORs=1.80-2.68, P0.05), whereas it lost its significance in the younger age group. Furthermore, the risk of albuminuria was much higher in sarcopenic obese subjects than in other groups (OR=4.90, 95% CI=3.23-7.43, P0.001).Sarcopenia was associated with an increased risk of albuminuria independent of hypertension, diabetes, and metabolic syndrome. Sarcopenia and obesity had a synergistic impact on the increased risk of albuminuria. This suggests that sarcopenic obesity as well as sarcopenia alone may be considered as novel risk factors for albuminuria.

Oxidative stress is important for the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a chronic disease that ranges from hepatic steatosis to nonalcoholic steatohepatitis (NASH). The nuclear factor erythroid 2-related factor 2-Kelch-like ECH associated protein 1 (Nrf2-Keap1) pathway is essential for cytoprotection against oxidative stress. In this study, we found that oxidative stress or inflammatory biomarkers and TUNEL positive cells were markedly increased in NASH patients compared to normal or simple steatosis. In addition, we identified that the hepatic mRNA levels of Nrf2 target genes such as Nqo-1 and GSTA-1 were significantly increased in NASH patients. Ezetimibe, a drug approved by the Food and Drug Administration for the treatment of hypercholesterolemia, improves NAFLD and alleviates oxidative stress. However, the precise mechanism of its antioxidant function remains largely unknown. We now demonstrate that ezetimibe activates Nrf2-Keap1 pathway which was dependent of autophagy adaptor protein p62, without causing cytotoxicity. Ezetimibe activates AMP-activated protein kinase (AMPK), which in turn phosphorylates p62 (p-S351) via their direct interaction. Correspondingly, Ezetimibe protected liver cells from saturated fatty acid-induced apoptotic cell death through p62-dependent Nrf2 activation. Furthermore, its role as an Nrf2 activator was supported by methione- and choline- deficient (MCD) diet-induced NASH mouse model, showing that ezetimibe decreased the susceptibility of the liver to oxidative injury. These data demonstrate that the molecular mechanisms underlying ezetimibe's antioxidant role in the pathogenesis of NASH.

This study was performed to understand how chlorpyrifos (CHL) affects zebrafish (Danio rerio) embryos and adults, by exposing this model organism to various concentrations of the insecticide. The 96-h acute toxicity test to determine the effect of CHL on adult zebrafish yielded a LC50 of 709.43μg/L(-1). Small molecular weight proteins less than 25kDa and phospholipids were analyzed with MALDI-TOF MS/MS in order to compare expression patterns, revealing that some peaks were dramatically altered after CHL treatment. Whereas no acute toxicity was detected in the embryo toxicity test, malformation of zebrafish larvae was observed, with many individuals harboring curved spines. In an angiogenesis test on larvae of transgenic zebrafish, CHL did not have an inhibitory effect. Relative gene expression analyses using real-time polymerase chain reaction (RT-PCR) of DNA from zebrafish embryos revealed that different subtypes of cytochrome P450 (CYP450), such as CYP1A and CYP3A, were significantly up-regulated in response to CHL at a concentration of 400μg/L(-1) compared to the control. The expression level of NR1I2, a CYP gene transcriptional regulator, UGT1a1, and MDR1 were all up-regulated in the CHL-treated embryos. Finally, the expression level of acetylcholinesterase (AChE) and catalase (CAT) decreased, whereas that of superoxide dismutase (SOD) did not differ significantly. Our results suggest that the up-regulation of metabolic enzymes including CYP450 and MDR1 may be involved in CHL resistance in zebrafish.

Objective Cilostazol, a phosphodiesterase 3, has been widely used in patients with arterial disease and is known to have additional beneficial effects on dyslipidemia. However, the effect of cilostazol on hepatic steatosis has not been fully elucidated. We investigated the effect of cilostazol on hepatic ABCA1 expression and hepatic steatosis in diet-induced obesity mice model. Methods Hepatic ABCA1 expression and lipid accumulation were analyzed in HepG2 cell lines treated with cilostazol. Male C57BL/6 mice were randomly divided into three groups: (1) fed normal chow diet with vehicle; (2) fed high-fat diet (HFD) with vehicle; (3) fed HFD with cilostazol. Cilostazol (30 mg/kg) was orally administered once daily for 9 weeks. Results Cilostazol significantly enhanced ABCA1 expression and restored ABCA1 expression reduced by palmitate in HepG2 cells. Cilostazol treatment ameliorated lipid accumulation induced by palmitate, and this effect was diminished when ABCA1 or LRP1 was silenced by small interference RNA. After silencing of LRP1, ABCA1 expression was decreased in HepG2 cells. Cilostazol significantly enhanced hepatic ABCA1 expression and decreased hepatic fat in HFD-fed mice. Hepatic expression of cleaved caspase-3 and PARP1 was also decreased in HFD-fed mice treated with cilostazol. Conclusions Cilostazol ameliorated hepatic steatosis and increased ABCA1 expression in the hepatocytes. Enhancing ABCA1 expression with cilostazol represents a potential therapeutic avenue for treatment of hepatic steatosis.

Background & Aims Although sarcopaenia is associated with obesity-related comorbidities, its influence on non-alcoholic fatty liver disease (NAFLD) or steatohepatitis has not been fully determined. We aimed to investigate the direct relationship between sarcopaenia and NAFLD or steatohepatitis in the general population. Methods We conducted a cross-sectional study using nationally representative samples of 15,132 subjects from the Korea National Health and Nutrition Examination Surveys 2008–2011. Subjects were defined as having NAFLD when they had higher scores from previously validated NAFLD prediction models such as the hepatic steatosis index, comprehensive NAFLD score and NAFLD liver fat score. BARD and FIB-4 scores were used to define advanced fibrosis in subjects with NAFLD. The skeletal muscle index (SMI) [SMI(%)=total appendicular skeletal muscle mass (kg)/weight (kg)×100] measured by dual-energy X-ray absorptiometry was used to diagnose sarcopaenia with cut points of 32.2% for men and 25.5% for women. Results SMI was inversely correlated with all NAFLD predicting scores (Ps p Conclusions Sarcopaenia is associated with increased risks of NAFLD and advanced fibrosis, independent of obesity or metabolic control.

Although several sulphonylureas are widely used in type 2 diabetes (T2D), their differential impacts on long-term major kidney outcomes remain unclear. This study aimed to investigate the effects of the two most commonly prescribed sulphonylureas, glimepiride and gliclazide, on kidney outcomes in patients with T2D.A total of 4486 patients treated with either glimepiride or gliclazide for more than 2 years were followed for up to 5.5 years (median: 4.7 years). A propensity score based on baseline characteristics was used to match 1427 patients treated with glimepiride with 1427 gliclazide-treated patients; incidences of end-stage renal disease (ESRD) and sustained doubling of creatinine to132.6 μmol/L (1.5mg/dL) were also compared.In the matched cohort with 12,122 person-years of follow-up, there was no significant difference between groups in risk of ESRD [hazard ratio (HR): 0.57, 95% confidence interval (CI): 0.29-1.12] or doubling of creatinine (HR: 0.74, 95% CI: 0.44-1.26), although there was a trend towards higher risks in the glimepiride group. Subgroup analyses showed that, compared with glimepiride, gliclazide was associated with a lower risk of doubling of creatinine in patients with preserved renal function (glomerular filtration rate ≥ 60 mL/min/1.73 m(2), HR: 0.21, 95% CI: 0.04-0.99) and good glycaemic control (HbA1c7%, HR: 0.35, 95% CI: 0.14-0.86), and in older subjects (≥ 62 years, HR: 0.52, 95% CI: 0.27-0.99).In a real-life setting, there was no significant difference in clinical outcomes of kidney disease for patients treated with glimepiride vs gliclazide. However, gliclazide appeared to protect against renal complication progression in certain populations.

Targeting metabolic syndrome (MetS) in early chronic kidney disease (CKD) is essential to reduce cardiovascular complications. We compared the association of kidney function estimated by two glomerular filtration rate (GFR) equations with MetS in community population.We analyzed 12,700 participants from 2009 to 2010 the Korea National Health Survey data. GFR was estimated using the CKD Epidemiology Collaboration equation (GFR(CKD-EPI)) and the Modification of Diet in Renal Disease study equation (GFR(MDRD)).The prevalence of MetS increased from the highest GFR category (105 ml/min/1.73 m(2)) to the lowest (60 ml/min/1.73 m(2)) using both equations (GFR(CKD-EPI), 14.1% to 62.3%; GFR(MDRD), 18.4% to 62.9%). Participants reclassified to higher GFR(CKD-EPI) category (upward) from GFR(MDRD) had lower prevalence of MetS than those moved downward (Net reclassification improvement 13.7%, P0.001). Compared with GFR ≥105 ml/min/1.73 m(2), mildly impaired GFR(CKD-EPI) (75-89 ml/min/1.73 m(2)) was independently associated with increased odds of MetS (OR 1.30, 95% CI 1.09-1.56, P=0.003) in multivariate analysis, whereas GFR(MDRD) was not (OR 1.08, 95% CI 0.92-1.27, P=0.344).Compared with GFR(MDRD), GFR(CKD-EPI) showed better association with prevalence of MetS, particularly in normal to mildly impaired GFR range. GFR(CKD-EPI) may improve risk stratification of individuals with MetS according to kidney function in community-based population.

Objective The clinical significance of the measurement of serum PCSK9 (proprotein subtilisin kexin type 9) is not well defined. This study investigated the association between serum PCSK9 levels and atherosclerosis assessed by carotid intima media thickness (IMT) in hypertensive patients. Methods A total of 126 hypertensive patients over the age of 45 were enrolled. The maximum carotid IMT (max-IMT) and the mean carotid IMT (mean-IMT) were measured at the time of enrollment. Clinical and laboratory parameters including serum PCSK9 were analyzed. Results Patients were divided into tertiles based on serum PCSK9 levels. After adjusting for age, sex, total cholesterol, HDL-cholesterol and triglyceride, max-IMT was significantly increased in the highest tertile of serum PCSK9 (0.969 ± 0.033 vs 0.959 ± 0.033 vs 1.077 ± 0.033 mm, respectively; P = 0.026). Mean-IMT showed a tendency to increase across the tertile groups (0.773 ± 0.025 vs 0.790 ± 0.026 vs 0.856 ± 0.025 mm, respectively; P = 0.059). Multivariate regression analysis revealed that serum PCSK9 was independently associated with carotid IMT (max-IMT: β = 0.212, P = 0.016; mean-IMT: β = 0.184, P = 0.04). Conclusion The present study is the first to report the association between serum PCSK9 levels and carotid IMT in hypertensive patients. These results suggest that serum PCSK9 may have a certain role in early pathogenesis of atherosclerosis.

Since the Superconducting Quantum Interference Device (SQUID) is the most sensitive magnetic field detector, it is widely used for measuring very weak biomagnetic signals, such as a Magnetocardiography (MCG). However, because the SQUID is easily affected by environmental magnetic noises, it is often used as a form of gradiometer suppressing spatially homogeneous field noises. The characteristic of the SQUID gradiometer mainly depends on the distance between the connected coils, that is, a baseline. Accordingly, in order to fabricate a gradiometer, the investigation of a proper baseline for the MCG signal is necessary. For the investigation, however, various gradiometers having different baselines have to be fabricated and tested, which required too much cost and effort. In this study, we suggest a simple simulation method to investigate the performance of a SQUID gradiometer depending on the baseline. In addition, in order to verify the reliability of our simulation, we fabricated wire wound axial first-order gradiometers (50 mm, 70 mm, and 100 mm baseline) and a second-order gradiometer (50 mm baseline) and compared the characteristics of the measured gradiometer signal with the simulated signal.

Leptin and adiponectin are hormones secreted from adipocytes that have important roles in metabolism and energy homeostasis. This review evaluates the effects of leptin and adiponectin on β-cell function by analyzing and compiling results from human clinical trials and epidemiologic studies as well as in vitro and in vivo experiments. Leptin has been shown to inhibit ectopic fat accumulation and thereby prevent β-cell dysfunction and protect the β-cell from cytokine- and fatty acid-induced apoptosis. However, leptin suppresses insulin gene expression and secretion as well as glucose transport into the β-cell. Adiponectin stimulates insulin secretion by enhancing exocytosis of insulin granules and upregulating the expression of the insulin gene; however, this effect depends on the prevailing glucose concentration and status of insulin resistance. In addition, adiponectin has antiapoptotic properties in β-cells. Available evidence concerning the role of these adipokines on insulin secretion, insulin gene expression, and apoptosis is not always entirely consistent; and many fundamental questions remain to be answered by future studies.

Brain-computer interface (BCI) is a developing, novel mode of communication for individuals with severe motor impairments or those who have no other options for communication aside from their brain signals. However, the majority of current BCI systems are based on visual stimuli or visual feedback, which may not be applicable for severe locked-in patients that have lost their eyesight or the ability to control their eye movements. In the present study, we investigated the feasibility of using auditory steady-state responses (ASSRs), elicited by selective attention to a specific sound source, as an electroencephalography (EEG)-based BCI paradigm. In our experiment, two pure tone burst trains with different beat frequencies (37 and 43 Hz) were generated simultaneously from two speakers located at different positions (left and right). Six participants were instructed to close their eyes and concentrate their attention on either auditory stimulus according to the instructions provided randomly through the speakers during the inter-stimulus interval. EEG signals were recorded at multiple electrodes mounted over the temporal, occipital, and parietal cortices. We then extracted feature vectors by combining spectral power densities evaluated at the two beat frequencies. Our experimental results showed high classification accuracies (64.67%, 30 commands/min, information transfer rate (ITR) = 1.89 bits/min; 74.00%, 12 commands/min, ITR = 2.08 bits/min; 82.00%, 6 commands/min, ITR = 1.92 bits/min; 84.33%, 3 commands/min, ITR = 1.12 bits/min; without any artifact rejection, inter-trial interval = 6s), enough to be used for a binary decision. Based on the suggested paradigm, we implemented a first online ASSR-based BCI system that demonstrated the possibility of materializing a totally vision-free BCI system.

Visceral adipose tissue has emerged as a key organ contributing to the development of coronary artery disease (CAD). However, defining central obesity by waist circumference (WC) may underestimate visceral adiposity in lean patients. The aim of this study was to investigate the relationship between visceral adiposity and severity of CAD in subjects with normal WC.Among 365 patients with documented CAD, 90 male subjects with normal WC (90 cm) were selected and their visceral fat areas (VFA) were examined using computed tomography. Lipid profiles and levels of adipokines including lipocalin-2, high molecular weight adiponectin, and monocyte chemoattractant protein (MCP)-1 were measured. Patients were divided into tertiles based on VFA at the L4 vertebra level.Patients with single-vessel disease had significantly lower VFA than those with multi-vessel disease (P0.05; 86.0 vs. 97.5 vs. 99.6 cm(2) for single- , double- , and triple-vessel diseases, respectively). Positive association between the extent of CAD and VFA was clearly demonstrated and logistic regression analysis showed that subjects in the upper tertile for VFA had a 4.5-fold higher risk of having multi-vessel disease compared with those in the lowest tertile (P0.05; odds ratio=4.51; 95% confidence interval=1.10-18.45). Circulating levels of lipocalin-2 and MCP-1 were significantly higher in the upper tertiles of VFA.Increased visceral adiposity is significantly associated with the severity of CAD, even in subjects without central obesity as determined by WC measurements. Abnormalities in adipokine regulation may provide a novel mechanistic connection between visceral adiposity and associated cardiovascular complications.

Hyperglycemia-induced oxidative stress is known to play an important role in the development of several diabetic complications, including atherosclerosis. Although a number of antioxidants are available, none have been found to be suitable for regulating the oxidative stress response and enhancing antioxidative defense mechanisms. In this study, we evaluated the effects of magnesium lithospermate B (LAB) against oxidative stress. We also endeavored to identify the target molecule of LAB in vascular smooth muscle cells (VSMCs) and the underlying biochemical pathways related to diabetic atherosclerosis. Modified MTT and transwell assays showed that the increased proliferation and migration of rat aortic VSMCs in culture with high glucose was significantly inhibited by LAB. LAB also attenuated neointimal hyperplasia after balloon catheter injury in diabetic rat carotid arteries. To determine molecular targets of LAB, we studied the effects of LAB on aldose reductase (AR) activity, O-GlcNAcylation, and protein kinase C (PKC) activity in VSMCs under normoglycemic or hyperglycemic conditions and showed the improvement of major biochemical pathways by LAB. Potential involvement of the nuclear factor erythroid 2-related factor-2 (Nrf2) – antioxidant responsive element (ARE)-NAD(P)H: quinone oxidoreductase-1 (NQO1) pathway was assessed using siRNA methods. We found that LAB activates the NQO1 via the Nrf2-ARE pathway, which plays an important role in inhibition of the major molecular mechanisms that lead to vascular damage and the proliferation and migration of VSMCs. Together, these findings demonstrate that the induction of the Nrf2-ARE-NQO1 pathway by LAB could be a new therapeutic strategy to prevent diabetic atherosclerosis.

Ginseng has been reported to ameliorate hyperglycemia in experimental and clinical studies; however, its mechanism of action remains unclear. In this study, we investigated the metabolic effects and putative molecular mechanisms of Korean red ginseng (KRG, Panax ginseng) in animal models for type 2 diabetes mellitus (T2DM) and peripheral insulin-responsive cell lines. Korean red ginseng was administered orally at a dose of 200 mg/(kg d) to Otsuka Long-Evans Tokushima fatty rats for 40 weeks. Initially, chronic administration of KRG reduced weight gain and visceral fat mass in the early period without altering food intake. The KRG-treated Otsuka Long-Evans Tokushima fatty rats showed improved insulin sensitivity and significantly preserved glucose tolerance compared with untreated control animals up to 50 weeks of age, implying that KRG attenuated the development of overt diabetes. KRG promoted fatty acid oxidation by the activation of adenosine monophosphate-activated protein kinase (AMPK) and phosphorylation of acetyl-coenzyme A carboxylase in skeletal muscle and cultured C2C12 muscle cells. Increased expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, nuclear respiratory factor-1, cytochrome c, cytochrome c oxidase-4, and glucose transporter 4 by KRG treatment indicates that activated AMPK also enhanced mitochondrial biogenesis and glucose utilization in skeletal muscle. Although these findings suggest that KRG is likely to have beneficial effects on the amelioration of insulin resistance and the prevention of T2DM through the activation of AMPK, further clinical studies are required to evaluate the use of KRG as a supplementary agent for T2DM.

By suitably bio-functionalizing the surfaces, magnetic nanoparticles are able to bind specific biomolecules, and may serve as vectors for delivering bio-entities to target tissues. In this work, the synthesis of bio-functionalized magnetic nanoparticles with two kinds of bio-probes is developed. Here, the stem cell is selected as a to-be-delivered bio-entity and infarcted myocardium is the target issue. Thus, cluster designation-34 (CD-34) on stem cell and creatine kinase-MB (CK-MB) (or troponin I) on infarcted myocardium are the specific biomolecules to be bound with bio-functionalized magnetic nanoparticles. In addition to demonstrating the co-coating of two kinds of bio-probes on a magnetic nanoparticle, the feasibility of manipulation on bio-functionalized magnetic nanoparticles by external magnetic fields is investigated.

Antagonists of cannabinoid CB1 receptor (CB1, CNR1) promote weight loss and decrease hyperglycemia in patients with type 2 diabetes. While the endocannabinoid system may modulate islet hormone secretion, the cell-type expressing CB1 receptor in islets has not been fully resolved. In this study, we verified receptor gene expression in rodent islets and cell lines and examined the distribution of CB1 receptor in mouse, rat, and human islets by confocal immunofluorescence (IF) microscopy. IF demonstrated CB1 receptor was present in beta-cell lines, but co-localized solely with somatostatin in the islet delta-cells of Zucker rats, C57BL/6 mice, and humans; no CB1 receptor expression was observed in alpha-, beta-, or pp-cells. Similarly, a rat somatostatinoma cell line, MSL-G2-Tu6, was found to express CB1 receptor. We also found monoacylglycerol lipase (MAGL) to be expressed in delta-cells and fatty acid amide hydrolase (FAAH) to be expressed in alpha-cells. The specific expression of CB1 in delta-cells suggests that the ECS may play a role in modulating islet hormone secretion. As there are some differences between our findings and previous reports, further studies, including detailed physiological studies of the effects of the ECS on islet function, are warranted.

The effects of mechanical vibrations on critical heat flux (CHF) are examined in this study at atmospheric pressure in vertical annulus tube under electrically heated condition. Vibration of heating rod was increased as flow regime changed from subcooled region to bubbly region. CHF was increased by mechanical vibration up to 16.4%. Vibration amplitude was one of the effective parameters on CHF enhancement. It seems to come from turbulence increasing and increment of deposition of droplet from the liquid film by vibration. Vibration is an effective method for heat transfer enhancement as well as CHF enhancement.

Heart failure is associated with advanced age and insulin resistance and is thought to be exacerbated by cardiac fibrosis. Plasminogen activator inhibitor type-1 (PAI-1) has been strongly implicated as a determinant of fibrosis in diverse organs and tissues. Its concentration is increased in blood, and its expression is increased in vessel walls in association with insulin resistance. Accordingly, we sought to determine whether expression of PAI-1 in the heart increases as a function of age of 10 week old and 20 week old normal and insulin resistant transgenic mice thereby potentially predisposing to heart failure. Results obtained indicate that PAI-1 content increases significantly in the heart as a function of age by more than 60%. The increases are much greater than those that can be accounted for by the modest, and statistically insignificant increases in the concentrations of PAI-1 in plasma that were observed to occur as a function of age as well. Thus, PAI-1 increases in the heart is a function of age, occurs in insulin resistant and non-insulin resistant mice, and may contribute to fibrosis predisposing to heart failure associated with advanced age, particularly when insulin resistance is present.

We propose independent component analysis (ICA) as a pre-process for synthetic aperture magnetometry (SAM) in magnetocardiogram. SAM is a very useful method for source current imaging. However, SAM cannot separate one source from the others when there are time-correlated multi-sources, especially for successively active sources. The proposed method compensates the intrinsic drawback of SAM with ICA, which is feasible for 3-D imaging of the myocardial current distribution of specific temporal features. By using our method, we successfully localized an accessory pathway of a patient suffering from the WPW syndrome.

► Seven flavonol glycosides were isolated from Sicyos angulatus. ► All flavonols were identified as 3,7-O-glycosides of quercetin and kaempferol. ► These flavonoids were first time isolated from the genus Sicyos. ► These flavonoids showed differences with other genera of same tribe the Sicyeae. ► Four of the seven flavonoids have various biological activities.

In order to gain an understanding of the relationship between critical heat flux (CHF) and flow-induced vibration (FIV), an experimental investigation was carried out with vertical round tube at the atmosphere. In the both condition of departure from nucleate boiling (DNB) and the liquid film dryout (LFD), CHF increases up to 12.6% with vibration intensity, represented by vibrational Reynolds number ( Re v ). CHF enhancement by tube vibration seems to come from the reinforced flow turbulent mixing and the increment of deposition of droplet into the liquid film. Based on the experimental results, an empirical correlation is proposed for the prediction of CHF enhancement ratio. The correlation predicts the CHF enhancement ratio ( E n ) with reasonable accuracy, with an average error rate of 4.5 and 26.5% for RMS. Vibration is an effective method for heat transfer enhancement as well as CHF. Nonetheless, the risk of system failure by FIV has made it very difficult to take advantage of vibration in heat transfer facilities. Therefore, it is necessary to find out optimal fuel design enhancing the CHF but preventing FIV damage in an acceptable vibration range.

To achieve the liver-directed expression in sufficient amounts of therapeutic genes for successful and safe gene therapy, natural liver-specific promoters can be used to direct the expression of therapeutic genes in the liver, whereas strong viral enhancers were used to obtain sufficient amounts of expressed therapeutic gene products. However, very often use of either the former or the latter does not guarantee both potent and liver-specific therapeutic gene expression. Here we conglomerate them and thus create a potent tissue-specific promoter by characterizing and using the liver-type pyruvate kinase proximal promoter (LPKPP) harboring its TATA box and a HNF-1alpha binding site. Alone it hardly activated its reporter gene expression in non-hepatocytes or hepatocytes. However, in the presence of the SV40 viral enhancer (SV40VE), which is active in multiple cell types, it was able to potently activate its reporter gene expression specifically in hepatocytes. The tissue-specific activation of the LPKPP by the viral enhancer was attributed to HNF-1alpha binding to the LPKPP. Taken together, these results support the idea that the constitutively active SV40VE could be used to activate the LPKPP in a tissue-specific manner in the presence of HNF-1alpha. To our knowledge, this is the first study to utilize HNF-1alpha and its binding site, in the context of the LPKPP, to generate a basal promoter that is transcriptionally activated potently in a tissue-specific manner by a viral enhancer that is active in multiple cell types.

Endosulfine α (ENSA) is an endogenous ligand of the sulfonylurea receptor 1 (SUR1) that can stimulate insulin secretion by pancreatic β cells. Originally, an intronless gene coding for this protein was assigned to Chr. 14q, but more recent information available in public databases indicated the position of ENSA on 1q21. We show here that the 1q21 locus represents the expressed gene consisting of 6 exons, whereas the locus on Chr. 14q is apparently a pseudogene. The ENSA gene on 1q21 produces several alternatively spliced transcripts, and is located within a region linked with T2DM in diverse populations including the Pima Indians. We analyzed ENSA in this Native American population and identified seven variants, which fall into three linkage disequilibrium groups. Analysis of representative markers in over 1200 Pima Indians did not reveal any significant association with T2DM, or with differences in insulin action and insulin secretion in a subset of approximately 270 non-diabetic subjects. In addition, we did not detect any significant correlation of skeletal muscle ENSA transcript levels with differences in insulin action in 49 non-diabetic subjects. We conclude that sequence alterations in ENSA are an unlikely cause for the linkage of T2DM with 1q21–q23 in the Pima Indians.

We have previously reported that the serum level of epidermal growth factor receptor (EGFR) was significantly elevated in 38 cervical carcinoma patients. The levels of mutant p53 protein were determined in the serum of the same cohort (invasive or recurrent carcinoma: 26, carcinoma in situ (CIS): 12) and 18 controls using ELISA. The median serum level for mutant p53 in cervical carcinoma patients (0.11 ng/ml; range, 0-2.66 ng/ml) demonstrated no significant difference compared to that of controls (0.14 ng/ml; range, 0-0.34 ng/ml) (P=0.324). Serum mutant p53 showed positive elevation in 5 patients with invasive or recurrent carcinoma (19%) and 1 with CIS (8%). A significant correlation was found between EGFR and mutant p53 levels (r=0.668; P

Effects of heating rate on the temperature profile of the thermal explosion mode of combustion synthesis and on the homogeneity of the reaction product are investigated. Analysis of the temperature profile using a simple mathematical model indicated that a significant fraction of reactants is consumed during the precombustion duration, forming intermetallic compounds at the reactant interface, which was confirmed experimentally. The relationship between the parameters measured from the temperature profile and the degree of conversion of reactants to products is discussed.

Epidermis-origin hemolymph protein (EOHP) was identified and purified from the last instar larval hemolymph of Galleria mellonella by anion exchange chromatography, chromatofocusing chromatography, and Sephadex G-100. The EOHP has a native molecular mass of 47 kDa and is composed of one subunit. The isoelectric point of the EOHP was determined to be 5.3. The amino acid composition of the EOHP was rich in aspartic acid, glutamic acid and lysine, but poor in tyrosine, methionine, and tryptophan. EOHP is present in hemolymph over the period from the 4th instar larvae to the adult stage examined. Concentration of EOHP is high during the larval stage but gradually decreased during the developmental stage from pupal to adult stage. EOHP is present in the cuticle, fat bodies and trachea but not in hemocytes, fore gut, mid gut and hind gut.

Background . Human amnion has useful biomedical applications because it contains a large amount of human collagen fibers. We prepared purified human collagen membrane (HCM) from human amnion and used it to develop a new sheet by combining it with synthetic bioabsorbable polyglycolic acid (PGA) mesh. We evaluated its efficacy in preventing air leakage from the lungs of dogs. Methods . In 20 dogs, HCM-PGA sheet (n = 5), sheets using fibrin glue with a separate application method (n = 5), a mixed application method (n = 5), and fibrin glue alone (n = 5), were used as dressing materials after partial lung resection. Results . The HCM-PGA sheet using fibrin glue with a separate application method was shown to be significantly more effective by an air leakage pressure test than the other three methods. These results indicate that the HCM-PGA sheet is useful for preventing air leakage from the lung. Conclusions . The HCM-PGA sheet is more effective than conventional fibrin glue for controlling postoperative air leakage.

A substantial percentage of patients have undiagnosed diabetes. We investigated the demographic characteristics and cardiometabolic profiles of subjects with undiagnosed diabetes.A cross-sectional study with nationally representative samples of 25490 subjects aged ≥ 20 years from the KHNANES 2008 to 2011, which applied a complex, multistage, probability proportional to size sampling design. Subjects were categorized as having normal glucose (n = 16880), impaired fasting glucose (n = 5771), undiagnosed diabetes (n = 713), or diagnosed diabetes (n = 2126). Hyper low-density lipoprotein cholesterolemia was individually evaluated by the 2004 Adult Treatment Panel III guidelines and predicted risk of cardiovascular disease was estimated from the Framingham model.Among overall subjects with diabetes, the prevalence of undiagnosed diabetes was markedly increased in younger adults compared to older adults (49% in diabetic subjects50 years vs 23% in diabetic subjects ≥50 years, P.001), suggesting significant discrepancies in age-based screening. Patients with undiagnosed diabetes were also more likely to have undiagnosed or uncontrolled hypertension and hyper-low-density lipoprotein cholesterolemia. Individuals with undiagnosed diabetes had a significantly higher predicted 10-year Framingham cardiovascular disease risk than those with diagnosed diabetes (11% vs 8% in50 years, 33% vs 30% in ≥50 years; both P.001). Patients with undiagnosed diabetes were also more likely to have multiple cardiovascular risk factors including obesity, smoking and uncontrolled hypertension.People with undiagnosed diabetes have a higher predicted risk for cardiovascular disease compared to those with diagnosed diabetes. Intensive screening for diabetes in younger adults should be stressed in public healthcare to reduce the burden of modifiable cardiometabolic risk among individuals with undiagnosed diabetes.