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It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction.The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and60 (n = 3,176); and eGFR45 mL/Min/1.73 mThe baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR45 mL/Min/1.73 mHigher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR.

Neutron radiography can visualize heavy oil flows in metallic reactors used to upgrade heavy oils. Thus, we visualized heavy oil flows in a packed bed using real-time neutron radiography to support its capability and to offer basic experimental data necessary for verification and validation of numerical simulations. Atmospheric residue was used as the heavy oil sample and heavy oil and N2 gas were concurrently supplied into a packed bed from above a reactor simulating a trickle bed reactor. Reactor temperatures were set at either 100°C or 250°C to change heavy oil viscosity. The heavy oil flow rate was kept constant at 2.5 mL/min and the N2 gas flow rate was set at either 1 L/min or 3 L/min at 25°C. A series of neutron radiography experiments was conducted at the B-4 neutron imaging facility in the Kyoto University Research Reactor (KUR) with a thermal neutron flux of 5 × 107 n/cm2⋅s. We performed image processing for the neutron radiographs to calculate neutron beam attenuation and clarify flow behavior. Visualization results show differences in flow behavior depending on operating factors. Temperature had a particularly substantial effect on flow behavior because heavy oil viscosity depends strongly on temperature. The flows also showed different behaviors for 1 mm and 3 mm packed particle sizes because the void ratios in the packed bed, which were preliminarily observed by X-ray computational tomography (CT), change with particle size. Channeling flow was observed with 3 mm particles and a temperature of 250°C. Furthermore, this work suggests that neutron radiography can be used to investigate heavy oil flows in metallic reactors.

Two-phase flow through porous media must be well understood to develop a severe accident analysis code not only for light water reactor but also sodium-cooled fast reactor. When a core disruptive accident occurs in sodium-cooled fast reactor, the fuel inside the core become melted and interacts with the coolant. As a result, gas-liquid two-phase flow will be formed in the debris bed, which may have porous nature depending on the cooling process. In such condition, the local porosity and its distribution are very important to characterize two-phase flow field in the porous media. In this study, X-ray radiography was applied to measure the local porosity in the packed bed of spheres. The radial profiles were estimated from the chordal profiles measured by the X-ray method and compared with the previous porosity model. In addition, the void fraction radial profiles were also obtained in air-water two-phase flow.

Pulsed neutron transmission spectroscopy was applied to clarify a phase change phenomena of lead-bismuth eutectics (LBE). The melting and solidification behaviors of the LBE should be well understood to enhance the safety of an LBE-cooled accelerator driven system. In this study, the heating experiments were performed using a rectangular test section and LBE phase change process was visualized by the energy-resolved pulsed neutron imaging at BL22 RADEN facility in J-PARC and the solid/liquid interface was identified from the radiograph and Bragg edge information. The transient location of the interface was compared with measured temperature profiles and it would be useful to evaluate the LBE thermal properties., 8th International Topical Meeting on Neutron Radiography (ITMNR-8) Beijing, China, September 4-8, 2016

Supercritical water upgrading of heavy oil has attracted considerable attention, as the upgrading process can reduce the sulfur content and decrease the average molecular weight of the oil. Understanding the flow and mixing behavior of heavy oil in supercritical water is important to improve the process efficiency. We performed neutron radiography experiments to directly visualize the behavior of heavy oil in supercritical water. Atmospheric residue was used as a heavy oil sample, and the heavy oil and supercritical water were supplied countercurrently to a 1/2-inch tube reactor packed with Al2O3 particles with a diameter of 3 mm; the pressure and temperature were set to 25 MPa and 400°C. The behavior of the heavy oil in the supercritical water depended on the oil and water flow rates. This study demonstrates that neutron radiography is a feasible visualization technique for the investigation of heavy oil behavior in supercritical water.

In this work, CeO2 nanoparticles were synthesized hydrothermally with supercritical water using a tubular flow reactor with three different configurations and various flow rates of the feed solution and supercritical water, and the effects of the reactor configuration and the flow rates of the two streams on the size distributions of the synthesized nanoparticles were investigated. In addition, the flow and thermal fields in the reactors were calculated numerically under the experimental conditions using FLUENT software, where the numerical results for the flow and thermal fields were also verified by neutron radiography. Comparing the experimental results of nanoparticle synthesis with the numerical results, it was revealed that the size distributions of the synthesized nanoparticles could be explained well on the basis of the flow patterns and temperature distributions in the reactor, which depended on the reactor configuration and process conditions.

Background Although increased circulating levels of malondialdehyde-modified low-density lipoprotein (MDA-LDL) are associated with coronary artery disease (CAD), there is no direct evidence that increased MDA-LDL is a prognostic factor for CAD. Methods Forty-two patients (20 diabetic and 22 non-diabetic patients) who underwent percutaneous coronary intervention (PCI) were enrolled, and their baseline MDA-LDL levels were determined by immunoassay. Follow-up coronary angiography was performed at 2 to 7 months post-PCI. The patients were then divided into 2 groups, with in-stent restenosis (ISR) (n = 13) and without ISR (n = 29), and the baseline MDA-LDL levels were compared. We also studied 34 diabetics with CAD for up to 57 months until the onset of the next coronary event. Results In the diabetic patients, the mean MDA-LDL level was significantly higher in those with ISR than in those without ISR (151 +/− 61 vs. 90 +/− 26 U/l, p = 0.010). A baseline MDA-LDL value of 110 U/l for differentiating between diabetics with and without ISR was defined as the cut-off value. Kaplan–Meier analysis demonstrated that a circulating MDA-LDL of ≥ 110 U/l correlated significantly with a higher prevalence of cardiac events than MDA-LDL Conclusions Circulating MDA-LDL is a useful prognostic marker for future cardiac event in diabetic patients with CAD.

The experimental studies on the accelerator-driven system (ADS) are being conducted for the basic research of nuclear transmutation analyses with the combined use of the core at the Kyoto University Critical Assembly (KUCA) and the fixed-field alternating gradient (FFAG; 100 MeV protons) accelerator, in the Kyoto University Research Reactor Institute. The ADS experiments with 100 MeV protons were carried out to investigate the neutronic characteristics of ADS, and the static and kinetic parameters were accurately analyzed through both the measurements and the Monte Carlo simulations of reactor physics parameters. An upcoming ADS at KUCA could be composed of highly-enriched uranium fueled and Pb–Bi zoned core, and the conversion analyses ( 237 Np and 241 Am) of nuclear transmutation could be conducted in ADS (hard spectrum core) at KUCA. Also, thermal hydraulics of liquid Pb–Bi are expected to be examined with the use of Pb–Bi test loop and test facilities for the investigation of Pb–Bi liquid characteristics from the viewpoints of single-phase heat transfer and two-phase flow.

The void fraction profile in a boiling channel is essential in analyzing convective flow boiling, where several investigations have been conducted. But due to the difficulty in the treatment of the non-thermodynamic equilibrium phenomena under subcooled conditions, the issues in comprehensive void fraction profile has not been solved, yet. To improve the understanding of these phenomena, detailed measurement results are required. In this investigation, by using five kinds of test sections, i.e. I.D.=3 mm L=400 mm, I.D.=5 mm L=200, 400, 1000 mm, and I.D.=10 mm L=400 mm, the void fraction was measured quantitatively over the whole length. For the measurements, thermal neutron radiography at the B-4 port of the Kyoto University Research Reactor was used. This facility is designed for the visualization of forced convective flow boiling in vertical tubes. To introduce the performance of this facility, this paper presents the measurement results of void fraction and the estimation results briefly., Proceedings of the 10th World Conference on Neutron Radiography (WCNR-10) Grindelwald, Switzerland October 5–10, 2014

Most mono-propellant thruster technologies were developed in the 1960s. Those basic principles and fundamental mechanisms, such as the catalyst and propellant, are still in use without major technical innovation. However, much remains to be clarified in terms of the mechanisms and quantitative limitations of the hydrazine decomposition phenomena inside the mono-propellant thruster. Therefore, in order to enhance the reliability of the propulsion systems, it should be promising to perform the direct observation of the physical and chemical phenomena occurring in the catalyst bed of the mono-propellant thruster. For that purpose, a visualization of the mono-propellant thruster was performed by using high frame-rate neutron radiography technique. The experiments were conducted at the Kyoto University Research Reactor and the hydrazine injection behavior to the catalyst bed was visualized clearly., Proceedings of the 10th World Conference on Neutron Radiography (WCNR-10) Grindelwald, Switzerland October 5–10, 2014

Adsorption refrigerator is one of the efficient tools for waste heat recovery, because the system is driven by heat at relative low temperature. However, the coefficient of performance is low due to its batch operation and the heat capacity of the adsorber. In order to improve the performance, it is important to optimize the configuration to minimize the amount of driving heat, and to clarify adsorption/desorption phenomena in transient conditions. Neutron radiography was applied to visualize and measure the adsorption amount distribution in an adsorber. The visualization experiments had been performed at the neutron radiography facility of E-2 port of Kyoto University Research Reactor. Activated carbon and ethanol were used as the adsorbent and refrigerant. From the acquired radiographs, adsorption amount was quantitatively measured by applying the umbra method using a checkered neutron absorber with boron powder. Then, transient adsorption and desorption processes of a rectangular adsorber with 84 mm in width, 50 mm in height and 20 mm in depth were visualized. As the result, the effect of fins in the adsorbent layer on the adsorption amount distribution was clearly visualized., Proceedings of the 10th World Conference on Neutron Radiography (WCNR-10) Grindelwald, Switzerland October 5–10, 2014

Gas-liquid two-phase flow in a narrow gap has been studied to develop a solid target cooling system for an accelerator driven system. Flow measurements are important to understand two-phase flow dynamics also in such a narrow channel. Although contact methods can measure detailed structure of two-phase flow, the intrusive effect on the flow becomes relatively larger in such a small channel. Therefore, non-intrusive measurement would be desirable. Neutron radiography (NRG) is one of the powerful tools for gas-liquid two-phase flow measurement and void fraction distribution can be estimated from the acquired images. However, the temporal resolution of NRG is about 100∼1, 000 Hz depending on the neutron flux and it should be increased to investigate flow dynamics. So the authors focused on a hybrid measurement of the NRG and a conductance liquid film sensor (LFS). The combination of these methods can complement the spatial and temporal information of the flow. In this study, the hybrid measurements were performed by NRG and LFS to visualize the detailed structure of narrow two-phase flow., Proceedings of the 10th World Conference on Neutron Radiography (WCNR-10) Grindelwald, Switzerland October 5–10, 2014

We have synthesized metal oxide nanoparticles through hydrothermal reaction at around 400 °C and 25 MPa by mixing the stream of metal ion solution at room temperature with another stream of supercritical water in a continuous flow-type reactor. In order to visualize the mixing behavior of the two streams, we performed neutron tomography measurements. By performing tomography measurements while rotating the mixing piece with supplying supercritical water and room temperature water, we succeeded in obtaining the three dimensional distribution of neutron attenuation. The results clearly showed how the two streams mix, which serves as a reference for numerical simulation.

Water distributions of a polymer electrolyte fuel cell (PEFC) with 9-parallel channels during operation were visualized using a neutron radiography facility at B4 port in KUR (Kyoto University Research Reactor). An imaging system with a neutron image intensifier (I.I.) was employed for reducing the exposure time, and the water distributions in the in-plane and through-plane directions in the PEFC were alternately obtained every 20 sec. The accumulation processes from the GDL to the channels were confirmed. Water accumulated in the GDL at the cathode and evacuation into the channels started around 5 min. Water tended to accumulate at the edge of the ribs, and accumulated as water drops in the channels. The size of the water drops grew up to 1 mm which was the same size as the channel width and height, and the cell voltage was decreased because the liquid drops disturbed the air supply.

Supercritical water is used in various chemical reaction processes including hydrothermal synthesis of metal oxide nano-particles, oxidation, chemical conversion of biomass and plastics. Density of the super critical water is much less than that of the sub-critical water. By using neutron radiography, Peterson et al. have studied salt precipitation processes in supercritical water and the flow pattern in a reverse-flow vessel for salt precipitation, and Balasko et al. have revealed the behaviour of supercritical water in a container. The nano-particles were made by mixing the super critical flow and the sub critical water solution. In the present study, neutron radiography was applied to the flow visualization of the super and sub critical water mixture in a T-junction made of stainless steel pipes for high pressure and temperature conditions to investigate their mixing process. Still images by a CCD camera were obtained by using the neutron radiography system at B4 port in KUR.

To clarify the usefulness of protein-sparing modified formula diet in obese type 2 diabetic patients, the effects of partial use of formula diet on weight reduction and changes in related metabolic variables, and the improving rates of risk factors per 1% body weight reduction, were compared with those of conventional subcaloric diet.Obese patients [BMI25 kg/m²] with diabetic mellitus were randomly assigned to a low-caloric diet with partial use of formula diet group (FD, n = 119) and a conventional low-caloric diet group (CD, n = 110). Subjects in FD took one pack of formula diet (MicroDiet®, 240 kcal/pack) in place of one of three daily low-caloric meals for 24 weeks. Total daily calorie prescribed was same.Weight reduction was greater in FD than in CD (week 24: -3.5 vs -1.4 kg; all p0.001). Systolic blood pressure decreased significantly only in FD. HbA1c reduction was greater in FD than in CD. HDL-cholesterol increased significantly more in FD than in CD (week 24: +2.8 vs. +0.6 mg/dl, p0.001). Among several improving rates (%) of risk factors/1% body weight reduction, those of HbA1c at weeks 16 and 24, triglyceride at week 8 and HDL-cholesterol at week 24, were significantly higher in FD than CD. Doses of sulfonylurea and thiazolidinedione were significantly decreased in FD than in CD.Partial use of formula diet was much more effective in reducing body weight, and also in improving coronary risk factors than conventional diet in part due to reduced body weight through decreased energy diet intake and due to dietary composition of the formula diet.

LR11/SorLA, a receptor interacting with CD87 on monocytes and macrophages, is highly expressed on human immature hematopoietic stem cells. However, it is unknown whether LR11 is expressed on premature leukemic cells, and whether the levels of circulating soluble LR11 (sLR11) shed from leukemic cells correlate with disease state.The expression of LR11 on leucocytes and leukemic cells was examined by flow cytometry. Serum sLR11 levels were measured by ELISA in patients with various hematological diseases, including 43 acute myeloid leukemia (AML) and 23 acute lymphoblastic leukemia (ALL) patients. Data were subjected to statistical analysis for validation of sLR11 levels and patients' clinical data.LR11 is specifically expressed in monocytes, and surface levels on leukemic cells are highly induced in both AML and ALL. sLR11 levels of acute leukemia patients were significantly increased (P0.001) (ALL, 73.5±93.5 ng/ml; AML, 26.8±29.1 ng/ml) in comparison to controls (9.2±3.3 ng/ml). Patients with AML and ALL in remission showed significantly decreased sLR11 levels to below 20 ng/ml.LR11 and its released soluble form are strongly elevated in acute leukemias. Remarkably, this increase in circulating sLR11 levels is ameliorated at complete remission.

Neutrons are effectively scattered by hydrogen atoms and have high permeability in heavier elements including Fe, Cr, and Ni. Therefore, neutron radiography should enable the detection of differences in water density in a stainless-steel reactor. To test this, we performed neutron radiography on a tubular flow reactor for supercritical hydrothermal synthesis and visualized the mixing behavior of supercritical water and room-temperature water at a T-junction. The results showed that the difference in density between supercritical water and room-temperature water, as well as how the density changed during mixing, was clearly visualized. The partitioned flow in the side tube was also visualized while feeding room-temperature water. The results indicated the importance of buoyancy forces, as discussed by others in previous reports.

Compared to other statins, pitavastatin is a highly potent 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor and an efficient hepatocyte low-density lipoprotein-cholesterol (LDL-C) receptor inducer. Its characteristic structure (heptenoate as the basic structure, a core quinoline ring and side chains that include fluorophenyl and cyclopropyl moieties) provides improved pharmacokinetics and significant LDL-C-lowering efficacy at low doses. Unlike other statins, the cyclopropyl group on the pitavastatin molecule appears to divert the drug away from metabolism by cytochrome P450 (CYP) 3 A4 and allows only a small degree of clinically insignificant metabolism by CYP2C9. As a result, pitavastatin is minimally metabolized; most of the bioavailable fraction of an oral dose is excreted unchanged in the bile and is reabsorbed by the small intestine ready for enterohepatic recirculation. This process probably accounts for pitavastatin's increased bioavailability relative to most other statins and contributes to its prolonged duration of action. In addition to its potent LDL-C-lowering efficacy, a number of pleiotropic benefits that might lead to a reduction in residual risk have been suggested in vitro. These include beneficial effects on endothelial function, stabilisation of the coronary plaque, anti-inflammatory effects and anti-oxidation. With regard to the clinical safety and efficacy of pitavastatin, the Phase IV Collaborative study of Hypercholesterolemia drug Intervention and their Benefits for Atherosclerosis prevention (CHIBA study) showed similar changes in lipid profile with pitavastatin and atorvastatin in Japanese patients with hypercholesterolemia. However, a subgroup analysis of the CHIBA study showed that pitavastatin produced more significant changes from baseline in LDL-C, TG, and HDL-C in patients with hypercholesterolemia and metabolic syndrome. The clinical usefulness of pitavastatin has been further demonstrated in a number of Japanese patient groups with hypercholesterolemia, including those with insulin resistance, low levels of high-density lipoprotein-cholesterol (HDL-C), high levels of C-reactive protein, and chronic kidney disease. Finally, the Japan Assessment of Pitavastatin and AtorvastatiN in Acute Coronary Syndrome (JAPAN-ACS) study showed that pitavastatin induces plaque regression in patients with ACS, which suggests potential benefits for pitavastatin in reducing CV risk.

To visualize boiling two-phase flow at high heat flux by using neutron radiography, a new neutron radiography facility was developed in the B-4 beam hole of KUR. The B-4 beam hole is equipped with a supermirror neutron guide tube with a characteristic wavelength of 1.2 A, whose geometrical parameters of the guide tube are: 11.7 m total length and 10 mm wide ×74 mm high beam cross-section. The total neutron flux obtained from the KUR supermirror guide tube is about 5×10 7 n/cm 2 s with a nominal thermal output of 5 MW of KUR, which is about 100 times what is obtainable with the conventional KUR neutron radiography facility (E-2 beam hole). In this study a new imaging device, an electric power supply (1200 A, 20 V), and a thermal hydraulic loop were installed. The neutron source, the beam tube, and the radiography rooms are described in detail and the preliminary images obtained at the developed facility are shown.

We aimed at elucidating the roles of transforming growth factor (TGF)-β and Smad3 signaling in adipocyte differentiation (adipogenesis) and in the pathogenesis of obesity. TGF-β/Smad3 signaling in white adipose tissue (WAT) was determined in genetically obese (ob/ob) mice. The effect of TGF-β on adipogenesis was evaluated in mouse embryonic fibroblasts (MEF) isolated both from WT controls and Smad3 KO mice by Oil red-O staining and gene expression analysis. Phenotypic analyses of high-fat diet (HFD)-induced obesity in Smad3 KO mice compared to WT controls were performed. TGF-β/Smad3 signaling was elevated in WAT from ob/ob mice compared to the controls. TGF-β significantly inhibited adipogenesis in MEF, but the inhibitory effects of TGF-β on adipogenesis were partially abolished in MEF from Smad3 KO mice. TGF-β inhibited adipogenesis independent from the Wnt and β-catenin pathway. Smad3 KO mice were protected against HFD-induced insulin resistance. The size of adipocytes from Smad3 KO mice on the HFD was significantly smaller compared to the controls. In conclusion, the TGF-β/Smad3 signaling pathway plays key roles not only in adipogenesis but also in development of insulin resistance.

Deficiency of Smad3, an intracellular mediator of TGF-β, was shown to significantly accelerate re-epithelialization of the colonic mucosa. This study was performed to investigate the molecular mechanisms by which Smad3 controls colonic epithelial cell proliferation and crypt formation. Smad3(ex8/ex8) C57BL/6 mice were used in this study and wild-type littermates served as controls. The number of proliferating cells in the isolated colonic epithelium of Smad3(-/-) mice was significantly increased compared to that in wild-type littermates. Protein levels of the cell cycle inhibitors p21 and p27 were significantly decreased, while that of c-Myc was increased in the isolated colonic epithelium from Smad3(-/-) mice. In the colonic tissue of wild-type mice, cell proliferation was restricted to the bottom of the crypts in accordance with nuclear β-catenin staining, whereas proliferating cells were located throughout the crypts in Smad3(-/-) mice in accordance with nuclear β-catenin staining, suggesting that Smad3 is essential for locating proliferating cells at the bottom of the colonic crypts. Notably, in Smad3(-/-) mice, there was loss of EphB2 and EphB3 receptor protein expression, critical regulators of proliferating cell positioning, while EphB receptor protein expression was confirmed at the bottom of the colonic crypts in wild-type mice. These observations indicated that disturbance of the EphB/ephrin B system brings about mispositioning of proliferating cells in the colonic crypts of Smad3(-/-) mice. In conclusion, Smad3 is essential for controlling number and positioning of proliferating cells in the colonic crypts and contributes to formation of a "proliferative zone" at the bottom of colonic crypts in the normal colon.

Background JELIS was a large-scale clinical trial that investigated the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD). In this paper, the data of patients registered in JELIS were analysed to compare the incidence of CAD between patients with impaired glucose metabolism (IGM) and normoglycemic (NG) patients. The effect of EPA on the incidence of CAD in patients with IGM was also assessed. Methods The 18,645 hypercholesterolemic patients registered in JELIS were divided into two groups. One group consisted of patients with IGM ( n = 4565), which included the patients who had diabetes mellitus and patients who had a fasting plasma glucose of 110 mg/dL or higher, either at the time of registration or after 6 months. The other group consisted of NG patients ( n = 14,080). CAD incidence of the two groups over the average 4.6-year follow-up period was compared, and the effect of EPA was assessed. Results Compared to NG patients, IGM patients had a significantly higher CAD hazard ratio (1.71 in the non-EPA group and 1.63 in the EPA group). The treatment with EPA resulted in a 22% decrease in the CAD incidence ( P = 0.048) in IGM patients and an 18% decrease ( P = 0.062) in NG patients. Conclusions It was found that the CAD risk in IGM patients is higher than in NG patients, and that highly purified EPA is very effective in decreasing the incidence of CAD among Japanese IGM patients, even though the intake of fish is high.

To investigate the relation between cardiovascular events and blood pressure or blood glucose control during long-term treatment with candesartan cilexetil in Japanese patients with hypertension and diabetes mellitus.During a planned 3-year follow-up period, five surveys were performed (at registration, after 6 months, and after 1-3 years).Among 17,622 patients registered nationwide, 16,869 were available for safety evaluation and 16,860 for efficacy evaluation. The actual mean follow-up period was 29 months, and the annual incidence of primary cardiovascular events was 17.4/1000 persons. After 3 years, 18.0% of the patients had a blood pressure130/80 mmHg, while 45.4% had a hemoglobin A(1c)6.5%. Compared with these patients showing good control of hypertension and/or diabetes, the incidence of cardiovascular events was significantly higher in patients with poor control.These findings emphasize the importance of tight blood pressure and glycemic control in hypertensive patients with diabetes. In addition, the target blood pressure (130/80 mmHg) in the 2004 Japanese Hypertension Management Guidelines and the target hemoglobin A(1c) (6.5%) in the Japanese Treatment Guide for Diabetes were supported.

Orexins and melanin-concentrating hormone (MCH) as orexigenic neuropeptides are present in the lateral hypothalamus, and their receptors are distributed in the cerebral cortex and hippocampus. In the present study, the regulatory effects of orexin-A, orexin-B and MCH on neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) expressions were examined in primary cortical neuron cultures using quantitative real-time PCR. Both orexin-A and orexin-B on 6-day exposure significantly increased the NT-3 mRNA at concentrations of 0.01, 0.1 and 1microM. Orexin-A and B at 1microM led to an increase of twofold or more over the control. However, no such NT-s mRNA increase occurred with exposure to MCH at the same concentrations as orexins. The mRNA expression of BDNF was significantly increased only by orexin-B at 1microM. These findings suggest that orexins, but not MCH, may be an inducer of NT-3 in the cerebral cortex.

Aims To compare the efficacy and safety of pitavastatin and atorvastatin in Japanese patients with hypercholesterolemia. Methods and results Japanese patients with total cholesterol (TC)≥220mg/dL were randomized to receive pitavastatin 2mg ( n =126) or atorvastatin 10mg ( n =125) for 12 weeks. The primary endpoint was percent change from baseline in non-HDL-C level after 12 weeks of treatment. Reduction of non-HDL-C by pitavastatin treatment (39.0%, P =0.456 vs. atorvastatin) was non-inferior to that by atorvastatin (40.3%). Both pitavastatin and atorvastatin also significantly reduced LDL-C by 42.6% and 44.1%, TC by 29.7% and 31.1%, and TG by 17.3% and 10.7%, respectively, at 12 weeks without intergroup differences. HDL-C showed a significant increase at 12 weeks with pitavastatin treatment (3.2%, P =0.033 vs. baseline) but not with atorvastatin treatment (1.7%, P =0.221 vs. baseline). Waist circumference, body weight and BMI were significantly correlated with percent reduction of non-HDL-C in the atorvastatin group, whereas pitavastatin showed consistent reduction of non-HDL-C regardless of the body size. In patients with metabolic syndrome, LDL-C was reduced significantly more in patients receiving pitavastatin when compared with those receiving atorvastatin. AST, ALT and γGTP increased significantly in patients receiving atorvastatin but not in those receiving pitavastatin. Both treatments were well tolerated. Conclusion Pitavastatin 2mg and atorvastatin 10mg are equally effective in improving the lipid profile and were well tolerated in Japanese patients with hypercholesterolemia.

Hyper-responsiveness of plasma cortisol to vasopressin has been demonstrated in ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH) and some adrenal adenomas with Cushing's syndrome (CS). However, the clinical significance of hyper-responsiveness of plasma cortisol to vasopressin has not been investigated systematically in adrenal nodule(s). The aim of this study was to clarify the prevalence of hyper-responsiveness of plasma cortisol to vasopressin (vasopressin responder) and their clinical characteristics in terms of hormonal secretion using vasopressin-loading test in the patients with adrenal nodule(s) except pheochromocytomas. A vasopressin-loading test was performed on 61 consecutive patients with adrenal nodules (CS: 33, aldosterone-producing adenoma: 10, non-functional tumor: 18). Vasopressin responders were observed in 36.1% of adrenal nodule(s), 42.4% of CS and 28.5% of non-CS. In responders with CS, eight patients had bilateral nodules that were diagnosed as AIMAH, and the remaining six patients had a unilateral nodule. These patients had lower plasma cortisol than non-responders at both morning (P0.01) and midnight (P0.05), as well as the morning following overnight dexamethasone suppression at 1mg (P0.05) and 8mg (P0.05). Hyper-responsiveness of the adrenal gland to vasopressin resulting in enhanced plasma cortisol was frequently observed among patients with adrenal nodule(s). The vasopressin responders among the patients with adrenal nodule(s) frequently had CS with low autonomous cortisol secretion.

Japan EPA Lipid Intervention Study (JELIS) was a large-scale clinical trial examining the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemic patients. Herein, we focused on risk factors other than low-density lipoprotein cholesterol (LDL-C) to investigate the effects of EPA on CAD among JELIS primary prevention cases.Hypercholesterolemic patients on statin therapy but without evidence of CAD (n=14,981) were randomly assigned to an EPA group (n=7503) or a control group (n=7478). The relationships between incident CAD, the number of CAD risk factors (hypercholesterolemia; obesity; high triglyceride (TG) or low high-density lipoprotein cholesterol (HDL-C); diabetes; and hypertension) and EPA treatment were investigated.For the control and EPA groups combined, a higher number of risk factors was directly associated with an increased incidence of CAD. Incidence was lower for the EPA group than for the control group regardless of the numbers of risk factors. Compared to patients with normal serum TG and HDL-C levels, those with abnormal levels (TGor=150 mg/dL; HDL-C40 mg/dL) had significantly higher CAD hazard ratio (HR: 1.71; 95% CI: 1.11-2.64; P=0.014). In this higher risk group, EPA treatment suppressed the risk of CAD by 53% (HR: 0.47; 95% CI: 0.23-0.98; P=0.043).Multiple risk factors besides cholesterol are associated with markedly increased incidence of CAD. High TG with low HDL-C represents a particularly potent risk factor. EPA was effective in reducing the incidence of CAD events for patients with this dyslipidemic pattern, suggesting that EPA may be especially beneficial in patients who with abnormal TG and HDL-C levels.

The purpose of this study was to establish an economic and efficient method to screen total PCBs and total dioxins (PCDDs+PCDFs+Co-PCBs) in the highly exposed people in Japan. In this paper, we suggest use of total PCBs in human blood to represent other persistent organic pollutants, especially dioxins. Twenty blood samples were collected from Japanese volunteers. Total PCBs and total dioxins (PCDDs+PCDFs+Co-PCBs) were detected from all twenty blood samples. We carried out detailed analysis of correlation between concentration of total PCBs and each dioxin congener with both measured value and TEQ calculated value. The mean concentration of total PCBs was 250 ng g-fat(-1), and the mean concentration of total dioxins was 37 ng g-fat(-1) or 40 pg TEQ g-fat(-1). Correlations between the total PCBs (ng g-fat(-1)) and the total measured dioxins (ng g-fat(-1)), and between the total PCBs (ng g-fat(-1)) and the total dioxin TEQ calculated value (pg-TEQ g-fat(-1)) were 0.95 and 0.90, respectively. It became clear that the concentrations of total PCBs in human blood is a good indicator of the concentrations of total dioxins in Japan. If a mass screening is conducted on women of reproductive age in order to detect highly exposed women, it is possible that women with the highest contamination may be treated in order to decrease the levels of these chemicals before pregnancy. In conclusion, measurement of total PCBs concentration is useful for exposure assessment of dioxins in human blood.

The increased population of TLR2/TNF-alpha co-expressing adipocytes is associated with the development of insulin resistance. We have herein shown the significance of low-dose growth hormone (GH) supplementation for the regulation of TLR2 and TNF-alpha expressions in visceral fat using different kinds of mouse models fed with a high-fat diet. Low-dose GH supplementation reduced the increased population of TLR2/TNF-alpha co-expressing adipocytes in high-fat fed mice. The neutralization of IGF-1 abolished the effect of GH supplementation on the TLR2 expression using GH-overexpressing mice. IGF-1, but not GH, inhibited the FFA-induced TLR2 and TNF-alpha expression in 3T3-L1 cells. Finally, low-dose GH supplementation reduced the TLR2 expression without an obvious change in the visceral fat volume in ob/ob mice. These results indicate that low-dose GH supplementation possibly inhibits the high-fat induced change of the adipocytes to TLR2/TNF-alpha co-expressing cells through the action of IGF-1.

Advanced glycation end products (AGEs), among the most important causes of atherosclerosis in diabetes mellitus, stimulate the proliferation of smooth muscle cells (SMCs). Smooth muscle cells are central in the formation of atherosclerotic lesions, where they show both increased migration and accelerated proliferation. In investigating how AGEs stimulate SMC proliferation, we focused on protein tyrosine phosphatase, especially Src homology 2-containing protein tyrosine phosphatase (SHP2), which is considered important in regulating cell proliferation. Advanced glycation end products increased activity of SHP2 in the membrane fraction of rat aortic SMCs compared with control bovine serum albumin (P < .05). Upon characterizing the genomic and promoter structure of SHP2, we detected nuclear factor-kappaB (NF-kappaB) binding sites in the promoter area. Advanced glycation end product stimulation increased luciferase activity in cells transfected with SHP2 promoter region including NF-kappaB binding sites (P < .05) and increased SHP2 expression (P < .05). These data indicate that AGE stimulation appears to activate NF-kappaB. Activated NF-kappaB binds to sites on the SHP2 promoter, resulting in increased SHP2 expression, SHP2 activity, and, ultimately, SMC proliferation. It suggests that AGE stimulation induces SMC proliferation via SHP2, underscoring the importance of control of AGE for suppressing macroangiopathy in diabetes mellitus.

Advanced glycation end products (AGE) have been observed in various pathological conditions especially in diabetes mellitus. However, it is unclear as to whether AGE are involved in insulin resistance in adipose tissues. In this study, we examined the effects of AGE on insulin sensitivity in adipocytes by examining the effects of AGE and its mechanisms on the glucose uptake in adipocytes and adipocyte differentiation. Glucose-, glyceraldehyde-, or glycolaldehyde-derived AGE inhibited the differentiation of 3T3-L1 cells. These AGE also inhibited the glucose uptake in the absence or presence of insulin, which were completely prevented by antibody against AGE or receptor for AGE (RAGE). The AGE increased the intracellular reactive oxygen species (ROS) generation in 3T3-L1 adipocytes, and the effects of AGE on glucose uptake were completely reversed by the treatment with an anti-oxidant, N-acetylcysteine. The AGE also induced the expression of monocyte chemoattractant protein-1, which has been implicated in the development of obesity-associated glucose intolerance, in 3T3-L1 adipocytes. Our present study suggests that AGE-RAGE interaction inhibits the glucose uptake through the overgeneration of intracellular ROS, thus indicating that it is involved in the development of obesity-related insulin resistance.

The relationship between adipocytes and infiltrated macrophages in fat tissue is important for the pathogenesis of insulin resistance through the activation of cytokines. Peroxisome proliferator-activated receptors (PPARs) play a role in the regulation of cytokine secretion in these cells. We studied the effect of the PPARalpha activation of macrophages on the modulation of the tumor necrosis factor alpha (TNFalpha) expression in adipocytes using a cell culture system. A conditioned medium of lipopolysaccharide (LPS)-stimulated RAW264.7 cells, a macrophage cell line, induced the level of TNFalpha mRNA in 3T3-L1 adipocytes. This effect was inhibited by the addition of neutralizing antibody against interleukin 6 (IL-6) in the conditioned medium or the preincubation of RAW264.7 cells with a specific PPARalpha agonist, K-111 (2,2-dichloro-12-(4-chlorophenyl)dodecanoic acid). K-111 reduced both the IL-6 production and mRNA expression in RAW264.7 cells, and its effect was stronger than that of rosiglitazone, a PPARgamma agonist. The activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway and nuclear factor kappa B (NF-kappaB) subunits of p65 was significantly inhibited by K-111. The blocking of IL-6 production through the SAPK/JNK pathway or by transfection with siRNA specific for IL-6 abolished the inhibitory effect of K-111 on the TNFalpha expression in the 3T3-L1 adipocytes. As a result, the IL-6 produced by RAW264.7 cells is an inducer of TNFalpha expression in 3T3-L1 adipocytes, and the IL-6 secretion is inhibited by the activation of PPARalpha. The PPARalpha activators may suppress the pathogenetical secretion of TNFalpha in the adipocytes through the functional modulation of the infiltrated macrophages.

Cytokine production in fat tissue plays a key role in insulin resistance. The aim of study is to know the phenotypic changes of adipocytes with high fat-induced insulin resistance. High fat intake induced the expression of tumor necrosis factor alpha (TNFalpha) in visceral fat tissue as well as development of insulin resistance. Analysis of the gene expression profiles in adipocytes showed that high fat intake induced the expression of toll-like receptor 2 (TLR2) in addition to TNFalpha. Flow cytometry analysis revealed the presence of adipocytes co-expressing TLR2 and TNFalpha (TLR2/TNFalpha-adipocytes), and the number of TLR2/TNFalpha-adipocytes in visceral fat tissues was increased by high fat intake compared to that in subcutaneous fat tissues. Free fatty acids increased TNFalpha expression in 3T3-L1 adipocytes through TLR2 signals. These results indicate that TLR2/TNFalpha-adipocytes possibly cause the induction of TNFalpha expression in visceral fat tissues, being associated with the development of high fat-induced insulin resistance.

Summary Background Epidemiological and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids protects against mortality from coronary artery disease. We aimed to test the hypothesis that long-term use of eicosapentaenoic acid (EPA) is effective for prevention of major coronary events in hypercholesterolaemic patients in Japan who consume a large amount of fish. Methods 18 645 patients with a total cholesterol of 6·5 mmol/L or greater were recruited from local physicians throughout Japan between 1996 and 1999. Patients were randomly assigned to receive either 1800 mg of EPA daily with statin (EPA group; n=9326) or statin only (controls; n=9319) with a 5-year follow-up. The primary endpoint was any major coronary event, including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-fatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting. Analysis was by intention-to-treat. The study was registered at ClinicalTrials.gov, number NCT00231738. Findings At mean follow-up of 4·6 years, we detected the primary endpoint in 262 (2·8%) patients in the EPA group and 324 (3·5%) in controls—a 19% relative reduction in major coronary events (p=0·011). Post-treatment LDL cholesterol concentrations decreased 25%, from 4·7 mmol/L in both groups. Serum LDL cholesterol was not a significant factor in a reduction of risk for major coronary events. Unstable angina and non-fatal coronary events were also significantly reduced in the EPA group. Sudden cardiac death and coronary death did not differ between groups. In patients with a history of coronary artery disease who were given EPA treatment, major coronary events were reduced by 19% (secondary prevention subgroup: 158 [8·7%] in the EPA group vs 197 [10·7%] in the control group; p=0·048). In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18%, but this finding was not significant (104 [1·4%] in the EPA group vs 127 [1·7%] in the control group; p=0·132). Interpretation EPA is a promising treatment for prevention of major coronary events, and especially non-fatal coronary events, in Japanese hypercholesterolaemic patients.

An adiabatic upward co-current air–water two-phase flow in a vertical large diameter pipe (inner diameter, D: 0.2 m, ratio of pipe length to diameter, L/D: 60.5) was experimentally investigated under various inlet conditions. Flow regimes were visually observed, carefully analyzed and classified into five, i.e. undisturbed bubbly, agitated bubbly, churn bubbly, churn slug and churn froth. Void fraction, bubble frequency, Sauter mean diameter, interfacial area concentration (IAC) and interfacial direction were measured with four-sensor optical probes. Both the measured void fraction and the measured IAC demonstrated radial core-peak distributions in most of the flow regimes and radial wall peak in the undisturbed bubbly flow only. The bubble frequency also showed a wall-peak radial distribution only when the bubbles were small in diameter and the flow was in the undisturbed bubbly flow. The Sauter mean diameter of bubbles did not change much in the radial direction in undisturbed bubbly, agitated bubbly and churn bubbly flows and showed a core-peak radial distribution in the churn slug flow due to the existence of certain amount of large and deformed bubbles in this flow regime. The measurements of interfacial direction showed that the main and the secondary bubbly flow could be displayed by the main flow peak and the secondary flow peak, respectively, in the probability density function (PDF) of the interfacial directional angle between the interfacial direction and the z-axis, ηzi. The local average ηzi at the bubble front or rear hemisphere ( η zi F and η zi R ) reflected the local bubble movement and was in direct connection with the flow regimes. Based on the analysis, the authors classified the flow regimes in the vertical large diameter pipe quantitatively by the cross-sectional area-averaged ηzi at bubbly front hemisphere ( η zi F ¯ ). Bubbles in the undisturbed bubbly flow moved in a vertical way with some swerving motions and those in other flow regimes moved along the lateral secondary flow with an averaging net upward velocity.

The vertebrate Polycomb Group (PcG) genes encode proteins that form large multimeric and chromatin-associated complexes implicated in the stable repression of developmentally essential genes. Rnf110 and Phc2 are shown to be components of mammalian PcG multimeric complexes in HeLa cells. Here we report defects in Peyer's patch (PP) development in Rnf110 mutant mice, which is synergically exaggerated by Phc2 mutation. PP development involves a series of inductive interactions and subsequent differentiation and proliferation between lymphoid and mesenchymal cells in late gestational stage. Rnf110 and Phc2 mutations impair development of PP anlagen by affecting proliferation of lymphoid lineage cells populated in PP anlagen in gene-dosage dependent manner. We suggest that PcG complexes may act to mediate certain inductive signals maybe through IL-7Rα to allow sufficient proliferation of lymphoid inducer cells during PP organogenesis.

The nature and severity of menopausal symptoms are highly variable among women. Polymorphisms of the estrogen receptor-beta (ERbeta) gene, such as cytosine-adenine (CA) dinucleotide repeats in intron 5, have been implicated in various diseases.We investigated the possible role of a CA dinucleotide repeat polymorphism in intron 5 of the ERbeta gene in the occurrence of menopausal and premenstrual symptoms.Fifty-one postmenopausal Japanese women were interviewed about premenstrual symptoms, menopausal symptoms, and use of hormone replacement therapy. Menopausal symptoms were divided into vasomotor, psychological, and musculoskeletal symptoms, and summary scores were created on the basis of severity. CA repeat polymorphism of the ERbeta gene was examined using denaturing high-performance liquid chromatography with the WAVE DNA Fragment Analysis System (Transgenomic Inc., Omaha, Nebraska).The number of CA repeats of the ERP gene ranged from 14 to 25, and subjects could be divided into 3 groups: those withor =17 repeats, or extremely short (E); 18 to 21 repeats, or short (S); andor =22 repeats, or long (L). Four genotypes of CA repeats (EL, SS, SL, and LL) were found among the subjects, with SL being the most common. Relative to subjects with the SL genotype, women with SS had a 7.0-fold increased risk of vasomotor symptoms (odds ratio [OR] = 7.0; 95% CI, 1.25-39.15; P0.05), a 13.0-fold higher risk of psychological symptoms (OR = 13.0; 95% CI, 1.44-117.2; P0.01), and a 7.6-fold increased risk of premenstrual symptoms (OR = 7.6; 95% CI, 1.61-35.9; P = 0.01). The EL genotype was associated with an increased risk of vasomotor symptoms (P0.05), depression (P0.01), and premenstrual symptoms (P0.01).CA repeat polymorphism of the ERbeta gene may be associated with menopausal and premenstrual symptoms. Premenstrual symptom scores were significantly related to menopausal symptom scores.

This paper aimed to improve the four-sensor probe methodology for the multi-dimensional two-phase flow measurement. We theoretically derived the interfacial measurement theorem relating the local instantaneous interfacial velocity to local measurable velocities of the multi-sensor probe in the improvement. Based on this theorem, theoretical measurement methods for the local instantaneous interfacial normal direction and the local time-averaged interfacial area concentration (IAC) using the four-sensor probe were presented. An interface-pairing signal-processing scheme was proposed to identify the same interfaces from the sequential signals detected by different sensors. The practical application of the improved IAC methodology to the two-phase flow in a vertical large diameter pipe showed that the four-sensor probes (together with the interface-pairing signal-processing scheme) could effectively measure the local time-averaged IACs with high effective interface percentages not only in the one-dimensional two-phase flow but also in the multi-dimensional two-phase flow. The measurement error analysis indicated that the errors from the bubble deformation and velocity variation due to the sensor piecing were negligible if we only applied the multi-sensor probe to the two-phase flow with the bubbles having much larger size than the sensor diameter. The total error from both the escaped and missing bubbles in the void fraction and IAC measurements was estimated at about 15.75% in the two-phase flow in a pool.

High-resolution high frame-rate neutron radiography system was developed. To achieve the high resolution, various combinations of imaging devices such as a fluorescent converter, high-speed video camera, and image intensifier were tested. Gen III image intensifier (GaAsP) combined with high-resolution high-speed video camera produced good-quality images. By using the new imaging system, measurement error of instantaneous void fraction and decay characteristics of fluorescent converter were estimated. In addition, the imaging system was applied to 3-D measurement of spherical particle position, which enables to measure 3-D velocity field combined with Particle Tracking Velocimetry.

A test section simulating the HANARO fuel channel was constructed and a two-phase flow pattern was examined. D 2 O was used as the working liquid and air was used to simulate the vapor. The high-speed neutron radiography technique was applied for the test and it was performed at a beam facility of HANARO called ENF (Ex-core Neutron-irradiation Facility). The flow pattern was also investigated with the ultrasonic technique and the results were compared with those from the neutron radiography images.

Liquid metal two-phase flows in metallic vessels were studied by using high frame-rate neutron radiography. Both a bubble column and a gas-lift loop arrangement have been considered. Liquid velocity field of two-phase flow in a flat bubble column with rectangular cross-section was measured precisely by the particle tracking velocimetry. In a gas-lift loop, simultaneous measurements of void fraction by using high frame-rate neutron radiography and four-sensor probe were also performed to observe the bubble-probe interaction. Asymmetric Abel inversion was applied to compare the radial void fraction profiles. Measured radial void fraction profiles obtained by neutron radiography and electrical conductivity probe agreed well with each other. From these measurements, the measurement error and basic characteristics of gas–liquid metal two-phase flow were clarified.

Neutron radiography and electrical four-sensor conductivity probe method were applied to measurement of liquid–metal two-phase flow. Visualization and measurements of nitrogen gas–molten lead bismuth two-phase flow were performed by using neutron radiography technique. Simultaneous measurements of void fraction by using high-frame-rate neutron radiography and four-sensor probe were also performed to observe the bubble–probe interaction. At the same experimental conditions, four-sensor probe was applied to the measurements of interfacial area concentration in radial direction. From the visualization of the two-phase flow, it turned out that cap bubbles or elongated slug bubbles were dominant at the superficial gas velocity of 1.1–38.3 cm/s and no stable Taylor bubbles were detected in this experiment. Measured radial void fraction profiles obtained by neutron radiography and electrical conductivity probe agreed well with each other. From these measurements, the measurement error and basic characteristics of gas–liquid–metal two-phase flow were clarified.

Peroxisome proliferator-activated receptors (PPARs) regulate the vascular cell functions as well as systemic lipid and glucose metabolism. Here, we studied the effect of TAK-559, a newly developed potent activator both for PPARalpha and gamma, on the vascular cell recruitment. TNF-alpha- or interleukin-1beta (IL-1beta)-induced THP-1 cell attachment to cultured endothelial cells was significantly reduced in the presence of 10 microM TAK-559 (P0.05). The secretion of monocyte chemoattractant protein-1 (MCP-1) from endothelial cells is reduced by 36% in the presence of 10 microM TAK-559, accompanied with the decreased mRNA expression in the cells. The proliferation and migration of cultured smooth muscle cells (SMCs) were significantly decreased in the presence of TAK-559 (P0.05). TAK-559-treated hypercholesterolemic rabbits showed the significant reduction of intimal thickning after balloon catheterization by 51% compared with control (P0.05), although the plasma lipid and glucose level was not changed between them. The numbers of macrophage and SMCs were decreased to 34% and 49% in the hyperplastic intima of arteries from TAK-559-treated rabbits compared to those from control, respectively. These results suggest that the PPARalpha and gamma activator inhibits the recruitment of macrophages and SMCs in intima, possibly leading to the reduction of intimal hyperplasia in hypercholesterolemia.