Molecular Dynamics Study of the Microscopic Mechanical Balance at the Three-Phase Contact Line of Interfacial Nanobubble.

This study reveals the microscopic mechanical balance at the three-phase contact line (TPCL) of an interfacial nanobubble on a substrate with a wettability pattern using molecular dynamics simulations. The apparent contact angle was compared to that evaluated using Young's equation, in which the interfacial tensions were computed using a mechanical route. The comparison was conducted by changing the wettability of the substrate from hydrophilic to neutral while maintaining a hydrophobic region in the center of the substrate. When the wettability pattern pins the TPCL at the wettability boundary, the contact angle computed by Young's equation is larger than the apparent contact angle because a pinning force exists in the inward direction of the nanobubble. Conversely, on the surfaces where the wettability pattern does not pin the TPCL, the contact angle computed by Young's equation agrees with the apparent contact angle because the pinning force disappears. The distribution of principal stresses around the TPCL, which was visualized for the first time in this study, indicates that large compressive principal stresses exist between the liquid phase and the solid substrate interface, which pin the TPCL at the surface wettability boundary, and that the maximum principal stress occurs in the inward direction of the nanobubbles at the TPCL. The normalized pinning force estimated from the maximum principal stress is equivalent to that measured experimentally.

Enhanced prediction of renal function decline by replacing waist circumference with "A Body Shape Index (ABSI)" in diagnosing metabolic syndrome: a retrospective cohort study in Japan.

BACKGROUND: Abdominal obesity as a risk factor for diagnosing metabolic syndrome (MetS) is conventionally evaluated using waist circumference (WC), although WC does not necessarily reflect visceral adiposity. OBJECTIVE: To examine whether replacing WC with "A Body Shape Index (ABSI)", an abdominal obesity index calculated by dividing WC by an allometric regression of weight and height, in MetS diagnosis is useful for predicting renal function decline. SUBJECTS/METHODS: In total, 5438 Japanese urban residents (median age 48 years) who participated in a public health screening program for 4 consecutive years were enrolled. Systemic arterial stiffness was assessed by cardio-ankle vascular index (CAVI). The predictability of the new-onset renal function decline (eGFR < 60 mL/min/1.73 m2) by replacing high WC with high ABSI (ABSI ≥ 0.080) was examined using three sets of MetS diagnostic criteria: Japanese, IDF and NCEP-ATPIII. RESULTS: In Japanese and NCEP-ATPIII criteria, MetS diagnosed using ABSI (ABSI-MetS) was associated with significantly higher age-adjusted CAVI compared to non-MetS, whereas MetS diagnosed using WC (WC-MetS) showed no association. Kaplan-Meier analysis of the rate of new-onset renal function decline over 4 years (total 8.7%) showed remarkable higher rate in subjects with ABSI-MetS than in those without (log-rank test p < 0.001), but almost no difference between subjects with and without WC-MetS (p = 0.014-0.617). In gender-specific Cox-proportional hazards analyses including age, proteinuria, and treatments of metabolic disorders as confounders, ABSI-MetS (Japanese criteria for both sexes, IDF criteria for men) contributed independently to the new-onset renal function decline. Of these, the contribution of IDF ABSI-MetS disappeared after adjustment by high CAVI in the subsequent analysis. CONCLUSION: In this study, replacing WC with ABSI in MetS diagnostic criteria more efficiently predicted subjects at risk of renal function decline and arterial stiffening.

Calorie restriction in overweight males ameliorates obesity-related metabolic alterations and cellular adaptations through anti-aging effects, possibly including AMPK and SIRT1 activation.

BACKGROUND: Calorie restriction (CR) is accepted as an experimental anti-aging paradigm. Several important signal transduction pathways including AMPK and SIRT1 are implicated in the regulation of physiological processes of CR. However, the mechanisms responsible for adaptations remain unclear in humans. SCOPE OF REVIEW: Four overweight male participants were enrolled and treated with 25% CR of their baseline energy requirements for 7weeks. Characteristics, including body weight (BW), body mass index (BMI), %fat, visceral fat area (VFA), mean blood pressure (MBP) and VO2 max, as well as metabolic parameters, such as insulin, lipid profiles and inflammatory makers and the expression of phosphorylated AMPK and SIRT1 in peripheral blood mononuclear cells (PBMNCs), were determined at baseline and then after 7weeks. In addition, we assessed the effects of the serum collected from the participants on AMPK and SIRT1 activation and mitochondrial biogenesis in cultured human skeletal muscle cells. MAJOR CONCLUSIONS: After CR, BW, BMI, %fat, VFA and MBP all significantly decreased, while VO2 max increased, compared to those at baseline. The levels of fasting insulin, free fatty acid, and inflammatory makers, such as interleukin-6 and visfatin, were significantly reduced, whereas the expression of phosphorylated AMPK and SIRT1 was significantly increased in PBMNCs collected after CR, compared to those at baseline. The skeletal muscle cells that were cultured in serum collected after CR showed an increase in AMPK and SIRT1 activity as well as mitochondrial biogenesis. GENERAL SIGNIFICANCE: CR is beneficial for obesity-related metabolic alterations and induces cellular adaptations against aging, possibly through AMPK and SIRT1 activation via circulating factors.

Low-Frequency Electroacupuncture Improves Insulin Sensitivity in Obese Diabetic Mice through Activation of SIRT1/PGC-1α in Skeletal Muscle.

Electroacupuncture (EA) has been observed to reduce insulin resistance in obesity and diabetes. However, the biochemical mechanism underlying this effect remains unclear. This study investigated the effects of low-frequency EA on metabolic action in genetically obese and type 2 diabetic db/db mice. Nine-week-old db/m and db/db mice were randomly divided into four groups, namely, db/m, db/m + EA, db/db, and db/db + EA. db/m + EA and db/db + EA mice received 3-Hz electroacupuncture five times weekly for eight consecutive weeks. In db/db mice, EA tempered the increase in fasting blood glucose, food intake, and body mass and maintained insulin levels. In EA-treated db/db mice, improved insulin sensitivity was established through intraperitoneal insulin tolerance test. EA was likewise observed to decrease free fatty acid levels in db/db mice; it increased protein expression in skeletal muscle Sirtuin 1 (SIRT1) and induced gene expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF1), and acyl-CoA oxidase (ACOX). These results indicated that EA offers a beneficial effect on insulin resistance in obese and diabetic db/db mice, at least partly, via stimulation of SIRT1/PGC-1α, thus resulting in improved insulin signal.

The Background of Calculating CAVI: Lesson from the Discrepancy Between CAVI and CAVI0.

Arterial stiffness is a good predictor of cardiovascular events. As a substitute for elastic modulus representing stiffness, pulse wave velocity (PWV) has been used for over a century as it is easy to measure; however, PWV is known to essentially depend on blood pressure at the time of measurement. The cardio-ankle vascular index (CAVI) is a relatively new index of global arterial stiffness of the origin of the aorta to the ankle arteries. The characteristic feature is its independency from blood pressure at the measuring time. Recently, a variant index CAVI0 was proposed, which was claimed to be a more accurate arterial stiffness index than CAVI, considering independency from blood pressure. The purpose of this review is to evaluate the properties of CAVI more precisely by comparing with CAVI0, and to confirm the true meaning of CAVI as an index of arterial stiffness. First, the properties of PWV depending on the blood pressure and the variation of PWV values in the cardiac cycle were analyzed. Then, we attempted to clarify the point at which the PWV, adopted in CAVI or in CAVI0, was measured in cardiac cycle. A comprehensive comparison of the clinical data of CAVI and CAVI0 showed that CAVI is more appropriate than CAVI0. In conclusion, CAVI is reconfirmed to be a reliable and useful index of blood pressure-independent arterial stiffness composed of both organic and functional stiffness.

Comparison of Cardio-Ankle Vascular Index (CAVI) and CAVI0 in Large Healthy and Hypertensive Populations.

AIM: The cardio-ankle vascular index (CAVI) represents the blood pressure-independent arterial stiffness from the origin of the aorta to the ankle. CAVI0 has been proposed as a variant index. We aimed to clarify the difference between CAVI and CAVI0 among large populations, and to explore reasons of the difference. METHODS: The subjects were 5,293 Japanese healthy and 3,338 hypertensive people. Simple and multiple regression analyses were performed using age, sex, body mass index, systolic, and diastolic blood pressure (Pd) as variables. Sub-group analysis was performed by sex and age. The CAVI values with and without adjustment by reference pressure were also compared. RESULTS: CAVI had a positive correlation with Pd, while CAVI0 had a negative correlation with Pd in the healthy population. The CAVI values of the hypertensive group were higher than those of healthy group in both men and women, but the CAVI0 values in women of the hypertensive group in the 30-39 age group was significantly lower than that of the corresponding healthy group. Differences of CAVI values with or without modification using the reference pressure were 1.09%±1.38% for the healthy group and 3.68%±1.66% for the hypertensive group. CONCLUSION: CAVI showed the expected values, but CAVI0 showed inexplicable results in the healthy and hypertensive populations. The differences were due to the strong dependency of CAVI0 on Pd. Differences of CAVI values with or without reference pressure were negligible. These results indicate that CAVI obtained by the VaSera system is appropriate, but CAVI0 is not.

Coefficients in the CAVI Equation and the Comparison Between CAVI With and Without the Coefficients Using Clinical Data.

AIM: The Cardio-Ankle Vascular Index (CAVI) is a stiffness index of the arterial tree from the origin of the aorta to the ankle, independent of blood pressure at the time of measurement. The CAVI equation includes the coefficients "a" and "b" to adjust it to the value of Hasegawa's pulse wave velocity, which is compensated for at 80 mmHg of diastolic pressure. To verify this adjustment with the coefficients, the clinical significance of CAVI and CAVI without the coefficients (haß) were compared in both an epidemiological study and an acute clinical study. METHODS: In the epidemiological study, the significances of CAVI and haß among people with or without coronary risks such as hypertension, dyslipidemia, hyperglycemia, and abnormal electrocardiography change, were compared. In the acute clinical study, nitroglycerin was administered to subjects in a control group and to coronary artery disease patients, observing CAVI and haß values over a 20-min period. RESULTS: There was no discrepancy in terms of statistically significant differences between CAVI and haß among subjects with or without risk factors. Furthermore, there was also no discrepancy in terms of statistically significant differences between CAVI and haß during the changes of those values following nitroglycerin administration over a 20-min period. CONCLUSION: In both the epidemiologic and clinical studies, there was no discrepancy in terms of significant differences between CAVI and haß. These results suggest that both are valid as indices of stiffness of the arterial tree from the origin of the aorta to the ankle.

Severe electrolytes disorders with the interstitial kidney alterations in the patient with the history of total thyroidectomy and parathyroidectomy: possible role of vitamin D deficiency.

Vitamin D plays vital role for the health, and its deficiency has been implicated in the diverse pathological conditions such as hypomagnesemia and abnormal immune system. Here, we present a case of severe electrolytes disorders (hypokalemia and hypomagnesemia etc.) and kidney damages associated with vitamin D deficiency.

Anagliptin ameliorates albuminuria and urinary liver-type fatty acid-binding protein excretion in patients with type 2 diabetes with nephropathy in a glucose-lowering-independent manner.

OBJECTIVE: The objective of this study is to elucidate the effect of anagliptin on glucose/lipid metabolism and renoprotection in patients with type 2 diabetic nephropathy. METHODS: Twenty-five patients with type 2 diabetic nephropathy received anagliptin 200 mg/day for 24 weeks, and 20 patients who were switched to anagliptin from other dipeptidyl peptidase-4 (DPP-4) inhibitors were analyzed regarding primary and secondary endpoints. The primary endpoint was change in hemoglobin A1c (HbA1c) during treatment with anagliptin. Additionally, we evaluated changes in lipid data (low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglyceride), blood pressure (BP), urinary albumin to creatinine ratio (UACR), liver-type fatty acid-binding protein to creatinine ratio (ULFABP) and renal function (estimated glomerular filtration rate and serum cystatin C) as secondary endpoints. RESULTS: After switching to anagliptin from other DPP-4 inhibitors, the levels of HbA1c in the 20 participants showed no significant change, 7.5%±1.2% at 24 weeks compared with 7.3%±0.9% at baseline. The levels of the log10-transformed UACR were significantly reduced from 1.95±0.51 mg/g creatinine (Cr) at baseline to 1.76±0.53 mg/g Cr at 24 weeks after anagliptin treatment (p<0.01). The percentage change in the UACR (Δ%UACR) from baseline to 24 weeks was also significantly lower by -10.6% (p<0.001). Lipid data, systolic BP and renal function were not changed during anagliptin treatment. Additionally, ULFABP in eight participants, who had ≥5 µg/g Cr at baseline, was significantly decreased from baseline (8.5±2.8 µg/g Cr) to 24 weeks (3.1±1.7 µg/g Cr, p<0.01) after anagliptin treatment, and the percentage change in the ULFABP during anagliptin treatment was -58.1% (p<0.001). CONCLUSIONS: Anagliptin induced no significant change in HbA1c, lipid data, systolic BP and renal function. However, anagliptin reduced the UACR and ULFABP, although without a corresponding change in HbA1c, indicating direct action of anagliptin on renoprotection in patients with type 2 diabetic nephropathy.

Restoration of the Hypothalamic-pituitary-adrenal Response to Hypoglycemia in Type 2 Diabetes by Avoiding Chronic Hypoglycemia.

An impaired ability to sense and respond to drug-induced hypoglycemia is a common and serious complication in diabetic patients. The hypothalamic-pituitary-adrenal (HPA) axis activity plays a critical role in the counterregulatory response to hypoglycemia. We herein report a case that experienced restoration of a blunted HPA axis by avoiding hypoglycemia with the use of the DPP-4 inhibitor sitagliptin.

Extraction of the Density Fluctuations in Diatomic Fluids Around the Critical Points Using Molecular Dynamics Simulation.

The objective in this study is the investigation of the principle of corresponding state for the density fluctuation around the critical points of non-polar diatomic fluids. In this paper, we conducted Molecular Dynamics (MD) simulation for the extraction of the fluctuation structure around the critical points of 2-Center-Lennard-Jones (2CLJ) fluids, which have anisotropy depending on the molecular elongation. As a result, in the 2CLJ fluids which have comparatively shorter molecular elongations, the principle of corresponding state can be satisfied because almost all density fluctuations in each elongation showed the similar values. On the other hand, some of the results suggested that the 2CLJ fluids which have the longer elongation decrease the density fluctuation although the further detailed investigation is necessary.

Ambulatory blood pressure level rather than dipper/nondipper status predicts vascular events in type 2 diabetic subjects.

To clarify which parameter, diurnal pattern of blood pressure (BP) or level of BP variability, has the stronger predictive value for fatal and nonfatal vascular events, vital status after a mean (+/-SD) follow-up period of 86+/-46 months was determined in 392 type 2 diabetic subjects without any history of vascular disease, in whom the 24-h BP profile had been monitored between 1988 and 1998. After the exclusion of 28 subjects who died during the follow-up period of causes unrelated to diabetes, 364 subjects were recruited for further analysis. A total of 147 first events, including 50 fatal vascular events and 97 nonfatal vascular events, were recorded during the follow-up period. The rates of various vascular events increased with both reduced nocturnal falls in systolic BP (SBP) and levels of all ambulatory BP parameters. The ambulatory BP parameter showing the largest area under the receiver operating characteristic curve (ROCAUC) for fatal events was the mean 24-h pulse pressure (PP), and that for nonfatal events was the mean nighttime SBP; both exceeded the respective values of nocturnal fall in SBP. Furthermore, when dipper and nondipper diabetic subjects were divided into subgroups based on the 24-h PP (54.3 mmHg) and the nighttime SBP (116.5 mmHg) cut-off points derived from the ROC analyses, Kaplan-Meier plots showed that the diabetic subgroups with high ambulatory BP levels had worse outcomes, independent of dipper/nondipper status. Finally, these parameters were applied to the Cox model with the values of nocturnal fall in SBP and other confounding factors, and results showed that mean 24-h PP and mean nighttime SBP predicted fatal and nonfatal vascular events, respectively, more strongly than nocturnal fall in SBP in type 2 diabetic subjects. These findings therefore suggest that ambulatory BP levels in type 2 diabetic subjects have a higher predictive value for organ damage and death compared with diurnal BP patterns or dipper/nondipper status.

Three ileus cases associated with the use of dipeptidyl peptidase-4 inhibitors in diabetic patients.

Dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antidiabetic drugs that increase incretin hormone levels to enhance blood sugar level-dependent insulinotropic effects, suppress glucagon action, and reduce bowel motility. These incretin effects are ideal for blood sugar control. However, the safety profile of DPP-4 inhibitors is not yet established. Herein, we present three cases of ileus, considered to be closely related to the use of DPP-4 inhibitors, in diabetic patients. Each of the three patients exhibited some risk of a deficiency in bowel movement; the onset of ileus was within 40 days after strengthened inhibition of DPP-4. The use of a DPP-4 inhibitor could be safe, although the cases presented herein enable us to inform the scientific community to some of the potential adverse effects of the use of DPP-4 inhibitors in select populations.

Carotid atherosclerosis mediated by visceral adiposity and adipocytokines in type 2 diabetic subjects.

The aim of this study was to verify the possible association of visceral fat accumulation with carotid atherosclerosis in order to identify the practical and feasible determinants for each parameter of atherosclerosis in type 2 diabetic subjects. The subjects were 151 diabetic (DM) and age-matched 83 nondiabetic subjects (C), without atherosclerotic disease. Visceral fat area (VFA) on a CT scan at the umbilicus level was measured. Ambulatory 24-h blood pressure (BP) was recorded. Stiffness index beta, intima-media thickness (IMT) and plaque formation of carotid arteries were measured by ultrasonography. Insulin sensitivity was estimated by homeostasis model assessment (HOMA). Serum levels of adiponectin and tumor necrosis factor (TNF)-alpha were determined. Male gender, HOMA, serum non-HDL-Cholesterol (Chol) and TNF-alpha/adiponectin ratio were higher, and VFA was larger in DM than in C. The IMT, stiffness index beta and plaque formation in DM were more pronounced than in C, even after adjusting for age, sex and 24-h systolic BP (sBP). VFA was positively correlated with TNF-alpha/adiponectin ratio and serum non-HDL-Chol in DM. Furthermore, multiple regression analysis revealed that, in DM, serum non-HDL-Chol was associated with IMT, VFA probably via an increase in TNF-alpha/adiponectin ratio was associated with stiffness index beta, and 24-h sBP, HOMA and VFA were associated with plaque formation independently of age and sex, respectively, although any association was not observed in C. Thus, we conclude that visceral fat-associated alterations in adipokines may be mediating the development and progression of atherosclerosis in type 2 diabetic subjects, compared with nondiabetic subjects.

A lack of increase in high molecular weight-adiponectin in macroalbuminuric subjects with metabolic syndrome may exert renal and atherosclerotic risks.

We assessed serum levels of total- and HMW-adiponectin as well as carotid intima-media thickness (IMT) in relation to the levels of albuminuria in subjects with and without metabolic syndrome (MS). Consecutive 291 subjects were enrolled in this study. Waist circumference (WC) was measured and MS was diagnosed according to the Japanese criteria. Urinary albumin/creatinine ratio (ACR) was determined, and then divided into three stages; normo-, micro- and macroalbuminuria. Of all subjects, 95 were defined as having MS (MS+) and the other 196 were not (MS-). There was no significant difference in age between MS+ and MS- groups. The prevalence of micro- and macroalbuminuria was about twice as high in the MS+ than in the MS-. Although there was no difference in the WC among normo-, micro- and macroalbuminuric subjects in both MS+ and MS-, serum HMW-adiponectin levels and the HMW/total-adiponectin ratio in the macroalbuminuric MS- were significantly higher than that in the normo- and microalbuminuric MS-. However, these parameters did not change with an increase in urinary ACR among MS+. IMT was greatest in macroalbuminuric MS+ when compared with other groups. Multiple regression analysis revealed that HMW/total-adiponectin ratio is associated with urinary ACR independent of age, gender and presence of MS. We concluded that increased serum HMW-adiponectin by unknown mechanisms, at abstract least independent of WC, might help protect against renal and atherosclerosis risks in macroalbuminuric MS-.

AST-120 (Kremezin) initiated in early stage chronic kidney disease stunts the progression of renal dysfunction in type 2 diabetic subjects.

There is little clinical evidence when AST-120 should be prescribed for subjects with early stage overt diabetic nephropathy. We therefore designed a prospective, randomized, controlled study for subjects with type 2 diabetes (serum creatinine <1.5mg/dl and urinary protein >0.5g/day) in November, 2001. The primary end point was defined as exceeding 2mg/dl of serum creatinine, and the secondary end point was defined as introducing a hemodialysis. Twenty-two subjects were selected, and after excluding 6 drop-out subjects, 16 subjects (10 in the control group; 6 in the KRM group) finally entered the study. Mean follow-up periods were 37 and 34 months in the control and KRM groups, respectively. There was no difference in clinical characteristics including renal dysfunction at baseline between the two groups. There was a significant reduction in urinary indoxyl sulfate at month 12 in the KRM group than in the control group. A significant difference was observed in changes in mean levels of serum creatinine versus time between the two groups. The primary end points were counted in 7 (70%) of the control subjects, while only 1 (17%) of the KRM group, and the Kaplan-Meier analysis was statistically significant. Although 4 (40%) of the control group and 1 (17%) of the KRM group were initiated hemodialysis as the secondary end point, the difference did not reach a statistical significance. Thus, we concluded that administration of AST-120 initiated in early stage overt diabetic nephropathy stunts the progression of renal dysfunction.

Insulin resistance is associated with reduced nocturnal falls of blood pressure in normotensive, nonobese type 2 diabetic subjects.

To assess the relationship between insulin resistance and ambulatory blood pressure (BP) pattern, we determined glucose infusion rate (GIR) as a marker of insulin resistance using a glucose clamp method, and measured 24-h BPs in 25 normotensive, nonobese type 2 diabetic subjects. They were divided into two groups: 11 dippers and 14 nondippers. Clinical characteristics were similar in the two groups except for orthostatic fall in systolic BP. The median GIR level was significantly lower in nondippers than in dippers (P < 0.05). Spearman's rank correlation revealed that the GIRs were negatively correlated with the systolic, diastolic and mean BPs during nighttime (P < 0.05 or less), but not with daytime or whole day BPs. Moreover, based on a logistic regression analysis, the GIR as well as orthostatic fall in systolic BP discriminated independently between dippers and nondippers. Thus, our results suggest that insulin resistance is associated with decreased nocturnal BP fall in type 2 diabetic subjects.