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The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor and its two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved for malignant melanoma, advanced non-small cell lung cancer, and advanced renal cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been reported in international Phase 3 studies and national post-marketing surveillance of nivolumab in Japan.This study analyzed five consecutive cases with thyroid dysfunction associated with nivolumab therapy. Second, it examined the mRNA and protein expressions of PD-L1 and PD-L2 by reverse transcription polymerase chain reaction and Western blotting.All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed within four weeks from the first administration of nivolumab and normalized within four weeks of onset in three of the five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients, and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism, and the other developed mild, transient hypothyroidism. In addition, it was verified that normal thyroid tissue expresses PD-L1 and PD-L2 mRNA and those proteins.In the present cases, nivolumab-induced thyrotoxicosis seemed to be associated with painless thyroiditis, while no patient with Graves' disease was observed. A transient and rapid course with subsequent hypothyroidism was observed in nivolumab-induced thyroiditis. In addition, it was verified that PD-L1 and PD-L2 are expressed in normal thyroid tissue. This suggests that nivolumab therapy reduces immune tolerance, even in normal thyroid tissue, and leads to the development of thyroiditis. Treating thyrotoxicosis with only supportive care and considering levothyroxine replacement therapy once subsequent hypothyroidism occurs is proposed. Further investigations are required to confirm whether glucocorticoid therapy and discontinuation of nivolumab therapy prevent subsequent hypothyroidism.

Objective: To investigate the significance of intra-abdominal fat area (IAFA) on new onset of individual components of the metabolic syndrome: high blood pressure, dyslipidemia, or hyperglycemia. Methods: We conducted a longitudinal study using checkup data of a hospital from 1994 to 2010. Of 25,255 subjects, we examined 1,380 Japanese, who underwent computed tomography to measure IAFA and had no metabolic syndrome components at baseline. Results: During 3.6 years of the mean follow-up period, one of metabolic syndrome components occurred in 752 subjects. Of three components, high blood pressure was more prevalent. The multiple Cox regression analysis disclosed that IAFA is significantly associated with onset of metabolic syndrome components (HR: 1.05 per 10 cm2, 95%CI: 1.03–1.07). This finding was independent of BMI, and significant even in non-obese individuals with body mass index

In this study, we evaluated the read-out signal quality from narrow track patterns, utilizing linearly arranged slender track patterns, while changing the track width from 10 to 0.1 μm and the pattern density from 200 nm line-and-space (L/S) to 120 nm L/S. To acquire narrow track readout signals, we adjusted the aperture’s in-plane position to cross a linear track at shallow angles of less than 1°, and we could successfully transform directly acquired signals into those of an aperture crossing tracks at a right angles. The results of an experiment utilizing a 10-μm-wide track (which is thought to represent an infinitely wide track) clarified that the stationary field was spread to an approximately 1.2–1.6 times larger region than the typical aperture size of 330 nm. The results also clarified that the “field spread” depended on the pattern density, that is, the case in which polarization direction θ equals 0 or 45°, and that the field spread increased monotonically as the line or space width became smaller. When the polarization direction equals 90°, the field spread had its local maximum when the line or space width was approximately 150 nm. An approximate prediction of the read-out signal amplitude was based on the rule that the signal amplitude was proportional to the net field spread that passed across the track pattern, and this prediction corresponded well to the experimental results, except when the interaction between the stationary field and the track side walls was not taken into account.

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial assessed cardiovascular outcomes in high-risk hypertensive patients receiving either candesartan or amlodipine. The aim of this study was to examine the role of pre-existing diabetes or obesity on these outcomes as a sub-analysis of the trial. We examined the influence of pre-existing diabetes on cardiovascular morbidity and mortality using a multivariate Cox regression model. The cardiovascular morbidity and mortality of candesartan and amlodipine were compared between subgroups with or without pre-existing diabetes or by body mass index (BMI) category, and new-onset diabetes was compared by BMI category. Pre-existing diabetes greatly increased the cardiovascular mortality and morbidity, regardless of the allocated drugs. Furthermore, all-cause mortality was significantly higher with amlodipine than with candesartan among patients with BMI >or=27.5 kg m(-2) (adjusted hazard ratio (HR)=0.32; range=0.13-0.75; P=0.009). New-onset diabetes occurred significantly less frequently with candesartan than with amlodipine, with an adjusted HR of 0.66 (P=0.043). Furthermore, the increase in new-onset diabetes was dependent on BMI among patients receiving amlodipine, whereas no such dependency was observed for candesartan (interaction P=0.016). In conclusion, preexisting diabetes increased the risk of experiencing a cardiovascular event among high-risk Japanese hypertensive patients. Candesartan treatment may suppress all-cause death and reduce the incidence of new-onset diabetes in patients with obesity.

OBJECTIVE Hypertensive patients have an increased risk of developing diabetes. Accumulating evidence suggests a close relation between metabolic disturbance and increased arterial stiffness. Here, we examined the association between pulse pressure and the risk of new-onset diabetes in high-risk Japanese hypertensive patients. RESEARCH DESIGN AND METHODS The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial examined the effects of candesartan and amlodipine on the incidence of cardiovascular events in 4,728 high-risk Japanese hypertensive patients. In the present study, we analyzed the relationship between pulse pressure at baseline and new-onset diabetes in 2,685 patients without diabetes at baseline (male 1,471; mean age 63.7 years; mean BMI 24.8 kg/m2) as a subanalysis of the CASE-J trial. RESULTS During 3.3 ± 0.8 years of follow-up, 97 patients (3.6%) developed diabetes. In multiple Cox regression analysis, pulse pressure was an independent predictor for new-onset diabetes (hazard ratio [HR] per 1 SD increase 1.44 [95% CI 1.15–1.79]) as were male sex, BMI, and additional use of diuretics, whereas age and heart rate were not. Plots of HRs for new-onset diabetes considering both systolic and diastolic blood pressure (DBP) revealed that a higher pulse pressure with a lower DBP, indicating that the increased pulse pressure was largely due to increased arterial stiffness, was strongly associated with the risk of new-onset diabetes. CONCLUSIONS Pulse pressure is an independent predictor of new-onset diabetes in high-risk Japanese hypertensive patients. Increased arterial stiffness may be involved in the development of diabetes.

In near-field optical recording, the combination of a triangular aperture and a polarized illuminating light is thought to be one of the most promising breakthroughs for improving both spatial resolution and signal-to-noise ratio. In light of this, we have already fabricated a triangular-aperture mounted optical head slider and demonstrated its superior performance while clarifying the influence of the polarization direction on the spatial resolution in the circumferential direction. When the polarization direction was perpendicular to the bottom side (which is parallel to the slider trailing edge) of the aperture, the highest spatial resolution and signal contrast were obtained, in spite of the usage of a fairly large aperture, indicating the presence of clear readout signal waveforms corresponding down to 100 nm line-and-space (L/S) patterns. In this study, we tried to experimentally clarify the influence of the polarization direction of the illuminating light on an aperture's field spread in the radial direction. In order to concretely evaluate the field spread, we prepared 1-mm-long linearly arranged (in the circumferential direction) L/S patterns on a metal-layered medium, and a piezo-electric actuator combined positioner. Intersecting the aperture at two portions of the tracks, directly acquired signal waveforms could be successfully transformed into the waveforms that would be obtained if the aperture had crossed the track at right angles. The field spreads in the radial direction were estimated to be approximately 250 nm when the polarization direction was perpendicular to the bottom side. In contrast, when the polarization direction was 45 degrees, the stationary field spread in the radial direction was estimated to be approximately 350 - 370 nm. It could be confirmed experimentally that both the highest spatial resolution in the circumferential direction and the smallest field spread in the radial direction were realized with the combination of the triangular aperture and the illuminating polarized light whose direction was perpendicular to the bottom side. Based on these results, the signal-to-noise ratio will be evaluated and discussed in the future with respect to the above-mentioned optimum aperture structure and conditions.

Heat-assisted magnetic recording (HAMR) technology needs a light delivery system with an incorporated near-field transducer (NFT) as a minute heat generator. A novel system for light delivery with a triangular spot size converter (SSC) and an optical fiber is proposed. The advantages of using a triangular SSC are optical efficiency and integration tolerance between the optical fiber and the NFT. It also has good affinity to conventional head fabrication process. The optical fiber enables flexible laser location. It was confirmed that fabricated triangular SSC can propagate light and reduce beam spot. Computer simulations and experiments demonstrated possibility of integration of light delivery system between NFT, SSC, and optical fiber. Flyability of a pico slider with an optical fiber was also demonstrated. It shows that the optical fiber does not have a big impact on flyability below 10 nm flying height and off-track vibration.

The continual advancement of the digital network society demands higher density and higher data transfer rates for all sorts of data storage. Optical memory based on the “near-field” principle is considered one of the most promising ones because it has no apparent physical density limit such as that due to the thermal instability encountered in magnetic recording. In light of this, we have previously demonstrated the superior readout performance of an optical head slider which is mounted on a non-circular aperture, specifically a triangular aperture having a bottom side size of 330 nm irradiated by polarized light, with this scheme indicating a clear signal response corresponding to a 70-nm-long single slit pattern. In order to fully realize the superior potential of the triangular aperture’s high spatial resolution and high signal output, it is essential to minimize aperture-to-medium spacing. In this paper, we introduce a protruded aperture mounted on a 1.5-mm-long miniaturized optical head slider whose aperture protrudes approximately 20 nm from an air-bearing surface level based on nano-step lithography technology. Utilizing a triangular aperture of 140 nm per side, a readout experiment was carefully performed at an aperture-to-medium spacing down to approximately 30 nm, corresponding to a circumferential velocity of 2.18 m/s. The influence of the incident light’s polarization direction (in relation to the bottom side of the triangular aperture) on the readout signals was evaluated by flying the aperture above a chromium patterned medium having single-space or line-and-space patterns whose line lengths ranged from 300 to 50 nm.

Optical memory based on the “near-field” principle is considered one of the most promising technological breakthroughs because it has no apparent physical density limit such as that due to the thermal instability encountered in magnetic recording. In light of this, we have demonstrated the superior readout performance of an optical head slider mounted on a triangular aperture with a typical side size of 140 nm irradiated by polarized light. With this scheme, we have indicated a clear signal response corresponding to a 150-nm line-and-space (L/S) pattern. In this paper, we introduce a protruded aperture mounted on a 1.5-mm-long miniaturized optical head slider whose aperture protrudes approximately 25 nm from an air-bearing surface. Utilizing a triangular aperture irradiating polarized violet laser light, we performed a readout experiment at an aperture-to-medium spacing down to approximately 29 nm. A clear readout signal was obtained corresponding to the pattern down to 100-nm line width, in spite of the usage of a fairly large side size of 330 nm. We also evaluated the influence of the incident light’s polarization direction on the readout signals while changing the line width of the L/S patterns from 300 to 100 nm. A polarization direction perpendicular to the bottom side of the aperture provided both higher spatial resolution and better signal contrast. We also observed a “spike phenomenon” when the aperture passed through the boundaries between the metal portion and the space (or line-and-space) portion. We believe this phenomenon is the cause of the enhancement or suppression of specific L/S pattern or period signals.

A single bout of exercise increases the rate of muscle glucose transport (GT) by both insulin-independent and insulin-dependent mechanisms. The purpose of this study was to determine whether high-fat diet (HFD) feeding interferes with the metabolic activation induced by moderate-intensity endurance exercise. Rats were fed an HFD or control diet (CD) for 4 weeks and then exercised on a treadmill for 1 hour (19 m/min, 15% incline). Insulin-independent GT was markedly higher in soleus muscle dissected immediately after exercise than in muscle dissected from sedentary rats in both dietary groups, but insulin-independent GT was 25% lower in HFD-fed than in CD-fed rats. Insulin-dependent GT in the presence of submaximally effective concentration of insulin (0.9 nmol/L) was also higher in both dietary groups in muscle dissected 2 hours after exercise, but was 25% lower in HFD-fed than in CD-fed rats. Exercise-induced activation of 5'adenosine monophosphate-activated protein kinase, a signaling intermediary leading to insulin-independent GT and regulating insulin sensitivity, was correspondingly blunted in the HFD group. High-fat diet did not affect glucose transporter 4 content or insulin-stimulated Akt phosphorylation. Our findings provide evidence that an HFD impairs the effects of short-term endurance exercise on glucose metabolism and that exercise does not fully compensate for HFD-induced insulin resistance in skeletal muscle. Although the underlying mechanism is unclear, reduced 5'adenosine monophosphate-activated protein kinase activation during exercise may play a role.

Rho-associated kinase (ROCK) regulates reorganization of actin cytoskeleton. During adipogenesis, the structure of filamentous actin is converted from long stress fibers to cortical actin, suggesting that the ROCK is involved in adipogenesis. Two ROCK isoforms have been identified: ROCK-I and ROCK-II. However, pharmacological inhibitors of ROCK cannot distinguish two ROCK isoforms. In the present study, we examined the role of ROCK in adipogenesis and actin cytoskeleton using genetic and pharmacological approaches. Y-27632, which inhibits the activity of both ROCK isoforms, enhanced adipogenesis through the up-regulation of adipogenic transcription factors in 3T3-L1 cells. Furthermore, Y-27632 restored inhibition of adipogenesis by lysophosphatidic acid, which activates Rho. Regarding actin cytoskeleton, Y-27632 disrupted stress fibers in 3T3-L1 preadipocytes. Next, we analyzed adipogenesis of mouse embryonic fibroblasts (MEFs) derived from ROCK-I and ROCK-II knock-out mice, respectively. Adipogenesis of ROCK-II (-/-) MEFs was markedly enhanced compared with wild-type MEFs while that of ROCK-I (-/-) MEFs was not. In contrast to pharmacological approaches, no obvious alteration was found in actin cytoskeleton of ROCK-II (-/-) MEFs compared with wild-type MEFs. In 3T3-L1 cells, knockdown of ROCK-II by RNA interference enhanced the expression of adipogenic transcription factors while that of ROCK-I did not. Moreover, Y-27632 inhibited IRS-1 serine phosphorylation and enhanced Akt phosphorylation in 3T3-L1 preadipocytes. Similarly, Akt phosphorylation in ROCK-II (-/-) MEFs was augmented compared with wild-type MEFs. In conclusion, inhibition of ROCK-II, not ROCK-I, enhances adipogenesis accompanied by the up-regulation of adipogenic transcription factors. Augmentation of insulin signaling may contribute to the enhancement of adipogenesis.

Notch signaling regulates cell fate determination in various tissues. We have reported the generation of mice with a pancreas-specific knockout of Rbp-j using Pdx.cre mice. Those mice exhibited premature endocrine and ductal differentiation. We now generated mice in which the Rbp-j gene was inactivated in Ptf1a-expressing cells using Ptf1a.cre mice. The timing of the Cre-mediated deletion in Rbp-j(f/f) Ptf1a.cre mice is 1 day later than that in Rbp-j(f/f) Pdx.cre mice. In Rbp-j(f/f) Ptf1a.cre mouse pancreases, at E13.5, the reduced Hes1 expression was accompanied by reduced epithelial growth, but premature endocrine cell differentiation was minimal. At E15.5, Pdx1 expression was repressed and acinar cell differentiation was reduced, but an increase in acinar cell proliferation was observed during the perinatal period. Our study indicates that, in addition to its role in preventing premature differentiation of early endocrine cells, Rbp-j regulates epithelial growth, Pdx1 expression, and acinar cell differentiation during mid-pancreatic development.

SummaryLittle is known about the role of the central melanocortin system in the control of fuel metabolism in peripheral tissues. Skeletal muscle AMP-activated protein kinase (AMPK) is activated by leptin and serves as a master regulator of fatty acid β-oxidation. To elucidate an unidentified role of the central melanocortin system in muscle AMPK regulation, we treated conscious, unrestrained mice intracerebroventricularly with the melanocortin agonist MT-II or the antagonist SHU9119. MT-II augmented phosphorylation of AMPK and its target acetyl-CoA carboxylase (ACC) independent of caloric intake. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by the coadministration of SHU9119 or in KKAy mice, which centrally express endogenous melanocortin antagonist. Importantly, high-fat-diet-induced attenuation of AMPK/ACC phosphorylation in leptin-overexpressing transgenic mice was not reversed by central leptin but was markedly restored by MT-II. Our data provide evidence for the critical role of the central melanocortin system in the leptin-skeletal muscle AMPK axis and highlight the system as a therapeutic target in leptin resistance.

The near-field principle combined with thin-film gas-lubricated slider bearing technology is thought to be one of the most promising breakthroughs to overcome the difficult optical diffraction limit (or wavelength shortening limit), which governs traditional optical recording performance. In light of this, we have demonstrated high linear density (150 nm pattern length) and high speed 10 MHz readout signals using the combination of a tapered circular aperture and a planar lens mounted on a quartz slider, flying above a metal patterned medium. In order to further improve both the spatial resolution and signal-to-noise ratio of this device, it is essential to minimize the spacing and laser power throughput of an aperture. Also investigated was the effectiveness of a non-circular aperture, which has approximately triangular configuration in combination with polarized light in simultaneously improving spatial resolution and increasing signal output. In this paper, we confirmed the predicted effectiveness on more practical condition of both high speed and compactness of head construction using a sub-micrometer size non-circular aperture, which was mounted on a 1.5-mm-long miniaturized optical head slider, flying above a ROM medium having sub-100-nm-long chromium patterns. The influence of the electric-field direction of the incident light and aperture to medium spacing on the readout signal are carefully evaluated by flying the aperture at spacing down to less than 50 nm.

Insulinoma is the most common cause of fasting hypoglycemia resulting from autonomous insulin hypersecretion. A 59-year-old woman who had previously had an insulinoma and had undergone a partial pancreatectomy was admitted to our hospital because of recurrence of hypoglycemia after 27 years. She had two unusual endocrinological features: 1) the serum insulin response to intravenous secretin injection was not impaired, and 2) the serum C-peptide levels and ratios of serum C-peptide to insulin were relatively low. Two pancreatic tumors were readily detectable by computed tomography (CT) and magnetic resonance imaging (MRI). The selective arterial calcium injection (SACI) test showed a hyperinsulinemic response by calcium administration to the gastroduodenal artery. A partial pancreatectomy was done and her hypoglycemia disappeared. Histology revealed that the tumors were composed of monotonous, small round cells that were positive for both insulin and cathepsin B. As previous in vitro studies have shown that C-peptide can be metabolized within human insulinoma cells by proteolytic cleavage by cathepsin B, our patient's low serum C-peptide levels might have been caused by degradation of C-peptide by cathepsin B. According to the data from the literature, the molar ratio of serum C-peptide to insulin is generally decreased in patients with insulinoma than normal subjects. This case highlights the need for careful interpretation of C-peptide levels and the intravenous secretin injection test in the diagnosis of insulinoma.

The regulations for the human use of advanced therapy medical products such as gene and cell therapy products have evolved in accordance with advance of clinical experience, scientific knowledge, and social acceptance to these technologies. In Japan, two laws, the Pharmaceuticals and Medical Devices (PMD) Act and the Act on the Safety of Regenerative Medicine (ASRM), were enacted in November 2014. The PMD Act defines regenerative medical products for the first time and introduces a system for the conditional and time-limited marketing authorization of regenerative medical products. Under ASRM, the responsibilities of medical institutions to ensure the safety and provide transparency of such medical technologies are described. Amendments to accompanying guidelines for these two Acts are currently in preparation. It is expected that the new legislative frameworks will promote the timely development of new products and technologies, to bring safe and effective regenerative medicines to Japanese patients.

The regulations for the human use of advanced therapy medical products such as gene and cell therapy products have evolved in accordance with advance of clinical experience, scientific knowledge, and social acceptance to these technologies. In Japan, two laws, the Pharmaceuticals and Medical Devices (PMD) Act and the Act on the Safety of Regenerative Medicine (ASRM), were enacted in November 2014. The PMD Act defines regenerative medical products for the first time and introduces a system for the conditional and time-limited marketing authorization of regenerative medical products. Under ASRM, the responsibilities of medical institutions to ensure the safety and provide transparency of such medical technologies are described. Amendments to accompanying guidelines for these two Acts are currently in preparation. It is expected that the new legislative frameworks will promote the timely development of new products and technologies, to bring safe and effective regenerative medicines to Japanese patients.

Recent rapid progress in a digital network society necessitates storage devices with higher-density and faster transfer rates. In optical storage, a novel recording principle is eagerly awaited that will drastically improve recording density without being restricted by a wavelength shortening limit or a numerical aperture (NA) limit of the optics utilized. Storage based on the “near-field” principle is thought to be one of the most promising breakthroughs for overcoming various limitations governing traditional optical recording. We have already proposed an integrated optical head slider assembly that relies on the novel near-field principle for its operation; it is mounted on a minute tapered aperture and has a planar focusing lens and a micro silicon mirror. Readout signals corresponding to a 200-nm-long bit have demonstrated a frequency band up to approximately 10 MHz, using a chromium patterned medium. In this study, we have investigated the accuracy of the tracking characteristics of an aperture-mounted head slider by using linearly arranged 1-mm-long line-and-space patterns. Based on the step or inverse step responses that occur when an aperture flies obliquely across the linearly arranged pattern region boundary, we present a simple method of predicting accurate tracking characteristics in detail, and also by using a 350-nm line-and-space pattern signal, we were able to predict both tracking characteristics and tracking sensitivities of arbitrary wide tracks to a track width of 100 nm.

This paper reports on the results of comparing different types of tensile testing methods that are used to evaluate thin-film properties. We tested the same material fabricated on a single wafer using different testing techniques at five different research institutions. The testing methods were different in the way the specimen was gripped. Materials tested were single-crystal silicon (SCS), polysilicon, nickel, and titanium films. Specimens with three different shapes were processed through the same fabrication steps. The tensile strength, fracture strain, and Young's modulus of the films were measured and compared. The measured values of the mechanical properties of all the testing methods were in good agreement with each other, thus demonstrating their accuracy.

The internal stress of sputtered titanium thin films was optimized for Micro Electro Mechanical System (MEMS) applications and the strength properties of the films were investigated. Low internal stress was obtained for 0.5-μm thick films by controlling the argon gas flow rate and for 1.0-μm thick films using the multiple deposition process. The Young's modulus, tensile strength, and maximum elongation of the titanium films were measured using a thin film tensile tester with an electrostatic force grip system. The tested films were 0.5 or 1.0 μm thick, 20 or 50 μm wide, and 100 or 500 μm in gauge length. The averages of the Young's modulus and the tensile strength were 90 and 0.65–0.8 GPa, respectively. A large maximum strain was observed, showing slip along the maximum shear stress directions, which will enable more reliable MEMS devices.

The metabolic syndrome represents an aggregation of cardiovascular risk factors including obesity, raised blood pressure, impaired glucose tolerance, and dyslipidemia that are associated with increased incidence of arteriosclerosis. Evidence accumulated indicates that the visceral fat accumulation is essential in the development of the syndrome. To investigate the prevalence of the metabolic syndrome in Japan, we analyzed cross-sectional data from 3574 middle aged Japanese (2947 men and 627 women, aged 40-59 years) in a large company, whose visceral fat accumulation was assessed by computed tomography. We employed receiver operation characteristic analysis to identify the optimal visceral fat area (VFA) value that has the sensitivity and the specificity to predict the presence of at least two components of the syndrome in an individual. The sensitivities and the specificities for men were 0.67 and 0.60 at VFA of 100 cm2, and for women, 0.73 and 0.70 at VFA of 65 cm2, respectively. Waist circumferences that corresponded to the VFA cutoff were 86.0 cm for men, and 77.0 cm for women. Using 100 cm2 in men and 65 cm2 in women as the criteria of visceral adiposity, the prevalence of the metabolic syndrome was 25.5% in men and 11.0% in women. Although obesity is less prevalent than in western countries, the metabolic syndrome is substantially widespread in Japan. (Communicated by Hiroo IMURA, M.J.A.)

The present experiments were designed to characterize the mechanisms involved in the corticotropin releasing factor (CRF)-induced activation of central sympatho-adrenomedullary outflow in rats. Intracerebroventricularly (i.c.v.) administered CRF and urocortin (0.5, 1.5 and 3.0 nmol/animal) effectively and dose-dependently elevated plasma levels of adrenaline and noradrenaline, and the effect of urocortin was almost the same as that of CRF. The elevation of catecholamines induced by CRF and urocortin (1.5 nmol/animal) was reduced by CP-154,526(butyl-ethyl-(2,5-dimethyl-7-(2,4,6trimethylphenyl)-7H-pyrrolo [2,3-d] pyrimidin-4-yl]amine), a selective CRF1 receptor antagonist, in a dose dependent manner (1.2 and/or 2.4 micromol/animal, i.c.v.), and abolished by indomethacin (1.2 micromol/animal, i.c.v.), an inhibitor of cyclooxygenase. Furegrelate (1.8 micromol/animal, i.c.v.), an inhibitor of thromboxane A2 synthase, abolished the CRF-induced elevation of adrenaline, but had no effect on the evoked release of noradrenaline. These results suggest that activation of brain CRF1 receptor facilitates the central sympathetic and adrenomedullary outflow in distinct central pathways in rats; brain thromboxane A2 is involved in the central adrenomedullary outflow; an active metabolite of arachidonic acid other than thromboxane A2 (probably prostaglandin E2) may be involved in the central sympathetic outflow.

Some kinds of dielectric fluids as dibutyl decannedioate generate jet flow between electrodes. One of the authors calls the fluids ECf (Electro-conjugate Fluids), which are considered as smart fluids. The authors propose a micro motor by making use of ECF. In our previous paper, a rotor electrode(RE)-type micro ECF motor have been reported In the paper, fabrication of micro ECF motors having I.D.ø3mm, I.D.ø4mm, I.D.ø8mm is described. On the RE-type micro ECF motor, some pairs of electrodes are located on the surface of a cylindrical rotor. The rotor can rotates with the reaction force caused by ECF jets. By making use of the ECF jet's reaction force, micro motors are easily realized. In this paper, fabrication of a micro ECF motor having I.D.ø2mm is described. Also, Basic characteristics such as rotational velocity are experimentally examined.

We characterized nicotinic acetylcholine receptor-mediated noradrenaline release from the isolated, vascularly perfused rat stomach. The stomach was perfused via the coeliac artery with Krebs-Ringer solution at a constant flow rate of 4 ml per minute. Endogenous noradrenaline released into the perfusate was electrochemically measured using high-performance liquid chromatography. Nicotinic receptor agonists were applied once into the perfusion medium for 2 min and nicotinic receptor antagonists were administered throughout the experiments. The (-)-nicotine (3x10(-5) M)-induced noradrenaline release was abolished by tetrodotoxin and hexamethonium and partially blocked by dihydro-beta-erythroidine (up to 10(-5) M) (a relatively selective antagonist of alpha4beta2 nicotinic receptors) and abolished by mecamylamine (10(-5) M) (a relatively selective antagonist of alpha3beta4 nicotinic receptors), but not influenced by alpha-bungarotoxin (3x10(-7) M) or alpha-conotoxin ImI (10(-6) M) (antagonists of alpha7 nicotinic receptors). (+/-)-Epibatidine (3x10(-7) M) (a very potent, but non-selective agonist) and (-)-cytisine (3x10(-4) M) (an agonist of beta4 nicotinic receptors) effectively evoked the release of noradrenaline, while (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-amine (RJR-2403) (up to 10(-4) M) (an agonist of alpha4beta2 nicotinic receptors) had no effect. The potency of these agonists was as followed; (+/-)-epibatidine(-)-nicotine(-)-cytisineRJR -2403. These results are compatible with the published view that alpha3beta4 nicotinic receptors are predominant in other parts of the autonomic nervous system. These receptors (probably located on the gastric sympathetic ganglia) are involved in the release of noradrenaline from the rat stomach.

Cylindrical roller bearings are being developed which can operate over 300°C and greater than three million DN for innovative gas-generators. Under such severe conditions, it is necessary for retainers to be frictionless, lightweight and strong. After preliminary testing, SiC particle reinforced aluminum alloy composite appeared to have good friction and wear properties. It's specific gravity is about one-third of the present material in use, silver-coated SAE4340. In the course of the study, two different friction and wear tests were conducted to investigate the optimum volume fraction of SiC. The results indicated that the most efficient volume fraction was 20vol%. The tensile strength of Al-20vol%SiC was about 140MPa at 300°C. Based on the results of FEM analysis, 140MPa is considered sufficient to endure any stress concentration caused by tensile hoop stresses up to four million DN. Presented at the 54th Annual Meeting Las Vegas, Nevada May 23–27, 1999

1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration.

Two novel bioelectrical impedance analysis (BIA) methods have been developed recently for evaluation of intra-abdominal fat accumulation. Both methods use electrodes that are placed on abdominal wall and allow evaluation of intra-abdominal fat area (IAFA) easily without radiation exposure. Of these, "abdominal BIA" method measures impedance distribution along abdominal anterior-posterior axis, and IAFA by BIA method(BIA-IAFA) is calculated from waist circumference and the voltage occurring at the flank. Dual BIA method measures impedance of trunk and body surface at the abdominal level and calculates BIA-IAFA from transverse and antero-posterior diameters of the abdomen and the impedance of trunk and abdominal surface. BIA-IAFA by these two BIA methods correlated well with IAFA measured by abdominal CT (CT-IAFA) with correlatipn coefficient of 0.88 (n = 91, p0.0001) for the former, and 0.861 (n = 469, p0.01) for the latter. These new BIA methods are useful for evaluating abdominal adiposity in clinical study and routine clinical practice of metabolic syndrome and obesity.

Objective To elucidate early change of intra-abdominal fat in response to calorie restriction in patients with obesity by weekly evaluation using a dual bioelectrical impedance analysis (Dual BIA) instrument. Methods For 67 Japanese patients with obesity, diabetes, or metabolic syndrome, intra-abdominal fat area (IAFA), initially with both Dual BIA and computed tomography (CT), and in subsequent weeks of calorie restriction, with Dual BIA were measured. Results IAFA by Dual BIA (Dual BIA-IAFA) correlated well with IAFA by CT (CT-IAFA) in obese patients (r = 0.821, P < .0001, n = 67). Ten males and 9 females (age 49.0 ± 14.4 years, BMI 33.2 ± 7.3 kg/m2) lost more than 5% of baseline body weight (BW) in 3 weeks, and their Dual BIA-IAFA, BW, and WC decreased by 18.9%, 5.3%, and 3.8%, respectively (P < .05, ANCOVA). Conclusion Dual BIA instrument could detect the weekly change of Dual BIA-IAFA under calorie restriction in obese patients and demonstrated a substantially larger change of IAFA compared with changes of BW and WC in early weeks. This observation corroborates the significance of evaluating IAFA as a biomarker for obesity, and indicates the clinical usefulness of the Dual BIA instrument.

To elucidate early change of intra-abdominal fat in response to calorie restriction in patients with obesity by weekly evaluation using a dual bioelectrical impedance analysis (Dual BIA) instrument.For 67 Japanese patients with obesity, diabetes, or metabolic syndrome, intra-abdominal fat area (IAFA), initially with both Dual BIA and computed tomography (CT), and in subsequent weeks of calorie restriction, with Dual BIA were measured.IAFA by Dual BIA (Dual BIA-IAFA) correlated well with IAFA by CT (CT-IAFA) in obese patients (r = 0.821, P.0001, n = 67). Ten males and 9 females (age 49.0 ± 14.4 years, BMI 33.2 ± 7.3 kg/m2) lost more than 5% of baseline body weight (BW) in 3 weeks, and their Dual BIA-IAFA, BW, and WC decreased by 18.9%, 5.3%, and 3.8%, respectively (P.05, ANCOVA).Dual BIA instrument could detect the weekly change of Dual BIA-IAFA under calorie restriction in obese patients and demonstrated a substantially larger change of IAFA compared with changes of BW and WC in early weeks. This observation corroborates the significance of evaluating IAFA as a biomarker for obesity, and indicates the clinical usefulness of the Dual BIA instrument.

The purpose of the current study was to evaluate the influence of light sources on the mechanical properties and wear characteristics of indirect composite materials. The two composite materials used were Estenia CB and Epricord. The three laboratory polymerization units used, of which the wavelength range was 400-500 nm, were Hyper LII (two metal halide lamps of 4.82 mW/cm(2)), α-Light II (one halogen lamp and two fluorescent tubes of 3.60 mW/cm(2)), and Labolight LV-II (three fluorescent tubes of 0.63 mW/cm(2)). Three-body wear test was performed using indirect composite plate specimens, a gold alloy antagonist, and a polymer slurry. Wear depths of Estenia CB polymerized with Hyper LII, α-Light II, and Labolight LV-II were 5.7, 18.5, and 64.2 µm respectively, whereas those of Epricord were 12.9, 18.7, and 48.5 µm respectively. Results showed that, after 100,000 cycles of localized loading, high-intensity light sources were effective in enhancing the wear resistance of both composite materials.

We have recently revealed that the thymus is the organ showing the highest expression of thromboxane (TX) A2 receptor in mice. In this study, thymic cell populations expressing the receptor were identified, and the effects of a TXA2 agonist on these cells were examined. Radioligand binding using a TXA2 receptor-specific radioligand revealed a single class of binding sites in the thymocytes with an affinity and specificity identical to those reported for the TXA2 receptor. The receptor density in these cells was comparable to that seen in blood platelets. This receptor is most highly expressed in CD4-8- and CD4+8+ immature thymocytes, followed by CD4+8- and CD4-8+ cells. The receptor density in splenic T cells was less than one fifth of that in CD4+8+ cells and no binding activity was detectable in splenic B cells. The addition of a TXA2 agonist, STA2, to thymocytes induced the disappearance of the CD4+8+ cells in a time- and concentration-dependent manner and caused DNA fragmentation. These changes were blocked by a specific TXA2 antagonist, S-145. These results demonstrate that TXA2 induces apoptotic cell death in immature thymocytes by acting on the TXA2 receptor on their cell surface and suggest a role for the TXA2/TXA2 receptor system in the thymic micro-environment.

The human thromboxane A2 gene, present as a single copy, spans over 15 kilobases (kb) and contains 3 exons divided by 2 introns. The first intron, intron 1, exists in the 5'-noncoding region, 83 base pairs upstream from the ATG start site and is 6.3 kb long. Intron 2 with a length of 4.3 kb is located at the end of the sixth transmembrane region, thereby separating it from the downstream coding sequences including the seventh transmembrane region and the 3'-untranslated region. By rapid amplification of 5'-cDNA ends, transcription initiation sites starting in two different putative promoter regions were determined. In the 5'-flanking region of these transcription initiation sites, no typical TATA box exists. The major promoter, the promoter region I, contains four potential SP-1 binding sites and several potential binding sites for other transcription factors. By polymerase chain reaction analysis, a small portion of the RNA transcribed from this gene was shown to contain an additional 115-base pair long noncoding exon, exon 1b, which is located in intron 1. No additional exon in intron 2 was detectable, indicating that a single type of thromboxane A2 receptor protein is encoded by this gene. Chromosomal localization was carried out by fluorescence in situ hybridization of cloned genomic DNA to the metaphase chromosome. The gene was assigned to 19p13.3 of human chromosome.

A cDNA clone for the mouse thromboxane A2 receptor was isolated from mouse lung cDNA library. The cDNA has a 1,023 base pair open reading frame which encodes a protein of 341 amino acid residues. STA2 and U-46619 induced inward current in Xenopus laevis oocytes injected with the transcript of the clone. Specific binding of [3H]S-145 was found in membranes of COS-1 cells transfected with the cDNA (Kd = 3.3 nM) and was displaced with unlabeled prostaglandins and thromboxane analogues in the order of S-145 greater than STA2 greater than U-46619 greater than PGD2 greater than PGF2 alpha = PGE2. Northern blot analysis demonstrated that thromboxane A2 receptor mRNA is expressed abundantly in thymus, spleen and lung.

Adipose tissue plays an important role in energy balance and metabolism and is the major target for insulin-sensitizing peroxisome proliferator-activated receptor (PPAR) gamma agonists. The angiotensin II type 1 receptor blocker telmisartan, a partial agonist of PPAR-gamma, has been demonstrated to improve insulin sensitivity. However, there is uncertainty about the sites of its action. Here, we demonstrate that treatment with telmisartan (3 mg/kg p.o.) for 7 weeks decreased plasma glucose levels in oral glucose and insulin tolerance tests and the index of the homeostasis model assessment of insulin resistance in A-ZIP/F-1 transgenic mice, an animal model of lipodystrophy. These effects were accompanied by decreases in circulating triglyceride and fatty acid levels. However, this treatment did not affect body weight and plasma adiponectin, leptin, and corticosterone levels. In A-ZIP/F-1 mouse liver the transcripts encoding PPAR-gamma and its downstream lipogenic genes were highly up-regulated, consistent with increased hepatic triglyceride content and lipid droplet accumulation. Telmisartan reversed these effects and also down-regulated mRNAs encoding gluconeogenic genes. Thus, the present findings are consistent with a novel mode of insulin-sensitizing action of telmisartan, involving an adipose tissue-independent pathway. Telmisartan-elicited down-regulation of hepatic expression of PPAR-gamma-regulated lipogenic genes is associated with amelioration of fatty liver.

Obesity is closely associated with development of hypertension. Adipose tissue produces molecules of renin-angiotensin system, which contribute to metabolic as well as cardiovascular disorders that develop in obesity. CASE-J Study demonstrated the usefulness of angiotensin receptor blockade in preventing new onset diabetes in obese hypertensive patients.

Obesity is recognized as a disease when it is associated with current or future health problems. The association of obesity with hypertension, glucose intolerance, and lipid metabolism disorder is diagnosed as metabolic syndrome since it tends to cause arteriosclerotic diseases. Obesity is important since it is pandemic throughout the earth. In this review we explain the concept and classification of obesity. We discuss the disease basis of obesity and metabolic syndrome, especially from the standpoint of adipotoxicity.

Light delivery with spot size converter (SSC) and optical fiber for heat assisted magnetic recording is proposed. It has an advantage in optical efficiency and integration tolerance. SSC was fabricated and confirmed its operation. Fly-ability of pico slider with optical fiber was also demonstrated.

Measurement of visceral fat accumulation is essential for the diagnosis of obesity. Currently, the visceral fat area (VFA) obtained from the abdominal cross-sectional image measured by X-ray CT is used as the gold standard. However it has problems of complexity, cost, and X-ray exposure. On the other hand, the waist circumference is used as a simple index, but it is indirect method and is affected by subcutaneous fat. Bioelectrical impedance analysis (BIA) is a proven method practically used to measure total body fat, and is the most suitable for the measurement of visceral fat accumulation. For the latter purpose, we developed a new simple measurement system using dual current pathways bioelectrical impedance analysis (dual-BIA). This proposed system measures imped ance reflecting the subcutaneous fat volume (SFV) and the fat free volume (FFV) in the abdomen by passing current via respective pathways. Regarding to measure these two imped ance values we adopted the four electrodes method. The VFA was calculated by using these two impedance values and abdominal body shape data to minimize the influence of FFV and SFV. We compared the VFA measured by dual-BIA system with that measured by X-ray CT in 98 subjects, and found a high correlation coefficient (r=0.888, p

We have previously demonstrated the therapeutic usefulness of leptin in lipoatrophic diabetes and insulin-deficient diabetes in mouse models and could also demonstrate its dramatic effects on lipoatrophic diabetes in humans. The aim of the present study was to explore the therapeutic usefulness of leptin in a mouse model of type 2 diabetes with increased adiposity.To generate a mouse model mimicking human type 2 diabetes with increased adiposity, we used a combination of low-dose streptozotocin (STZ, 120 microg/g body weight) and high-fat diet (HFD, 45% of energy as fat). Recombinant mouse leptin was infused chronically (20 ng [g body weight](-1) h(-1)) for 14 days using a mini-osmotic pump. The effects of leptin on food intake, body weight, metabolic variables, tissue triacylglycerol content and AMP-activated protein kinase (AMPK) activity were examined.Low-dose STZ injection led to a substantial reduction of plasma insulin levels and hyperglycaemia. Subsequent HFD feeding increased adiposity and induced insulin resistance and further augmentation of hyperglycaemia. In this model mouse mimicking human type 2 diabetes (STZ/HFD), continuous leptin infusion reduced food intake and body weight and improved glucose and lipid metabolism with enhancement of insulin sensitivity. Leptin also decreased liver and skeletal muscle triacylglycerol content accompanied by an increase of alpha2 AMPK activity in skeletal muscle. Pair-feeding experiments demonstrated that leptin improved glucose and lipid metabolism independently of the food intake reduction.This study demonstrates the beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity, indicating the possible clinical usefulness of leptin as a new glucose-lowering drug in humans.

Dysregulation of tissue-specific intracellular glucocorticoid reactivation is implicated in obesity and related metabolic diseases in humans. The ratio of end products of glucocorticoid metabolism in fresh urine sample, tetrahydrocortisol (THF) + allo-tetrahydrocortisol (allo-THF) vs. tetrahydrocortisone (THE), i.e., the urinary ratio is regarded as an index of the systemic balance underlying intracellular glucocorticoid metabolism, where the enzymes, 11β-hydroxysteroid dehydrogenase type 1 and type 2 as well as 5α- and 5β-reductase are involved in a tissue-specific manner.To explore the clinical implications of the urinary ratio in obesity and related metabolic diseases, the urinary ratio was determined by gas chromatography and mass spectrometry.The urinary ratio was shown to be constant and reproducible in the same individuals. The ratio was found to inversely correlate with BMI (P0.01), waist circumference (P0.01), and liver transaminase (P0.05) in a large cohort of ∼200 Japanese subjects. This finding suggests that the systemic balance underlying intracellular glucocorticoid reactivation was suppressed in obesity and liver dysfunction. Consistent with this notion, the ratio was decreased in patients with non-alcoholic steatohepatitis (P0.01). The urinary ratio was not altered in patients with type 2 diabetes on a 2-month mild calorie restriction. In contrast, the ratio was significantly reduced in patients who responded to the anti-diabetic pioglitazone (P0.01).The present study provides novel evidence that the urinary ratio reflects the facet of adipose tissue and liver function in humans, thereby offering a unique opportunity to evaluate obesity-related diseases.

Increased activity of intracellular glucocorticoid reactivating enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in obese adipose tissue contributes to adipose dysfunction. As recent studies have highlighted a potential role of preadipocytes in adipose dysfunction, we tested the hypothesis that a variety of metabolic stress mediated by ceramide or AMP-activated protein kinase (AMPK) would regulate 11beta-HSD1 in preadipocytes. The present study is the first to show that 1) expression of 11beta-HSD1 in 3T3-L1 preadipocytes was robustly induced when cells were treated with cell-permeable ceramide analogue C(2) ceramide, bacterial sphingomyelinase, and sphingosine 1-phosphate, 2) 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)-induced activation of AMPK augmented the expression and enzyme activity of 11beta-HSD1, and 3) these results were reproduced in human preadipocytes. We demonstrate for the first time that C(2) ceramide and AICAR markedly induced the expression of CCAAT/enhancer-binding protein (C/EBP) beta and its binding to 11beta-HSD1 promoter. Transient knockdown of C/EBPbeta protein by small interfering RNA markedly attenuated the expression of 11beta-HSD1 induced by C(2) ceramide or AICAR. The present study provides novel evidence that ceramide- and AMPK-mediated signaling pathways augment the expression and activity of 11beta-HSD1 in preadipocytes by way of C/EBPbeta, thereby highlighting a novel, metabolic stress-related regulation of 11beta-HSD1 in a cell-specific manner.

Simple measurement of visceral fat accumulation is essential for diagnosis and treatment of metabolic syndrome. Bioelectrical impedance method is most suitable for theses measurements. However, measuring visceral fat volume without the influence of subcutaneous fat has been difficult because of the low spatial resolution of bioelectrical impedance method. In the present study, we have developed a simple method for the measurement of visceral fat accumulation using visceral fat bioelectrical impedance analysis (VF-BIA). For VF-BIA, an electric current (250 μA, 50 kHz) was applied to electrodes bilaterally fixed on the hands and feet, and the voltage was measured between six pairs of electrodes placed around the trunk at the umbilical level. The impedance reflects the total amount of abdomen fat, in addition to obtain the impedance of the body surface which reflects the amount of subcutaneous fat, the voltage induced by applying electric current to the electrodes placed on the body surface around the trunk at the umbilical level was measured with electrodes between the stimulating electrodes. Regarding to measure these two impedance values we adopted the four electrodes method.