Search

AbstractThe physical data of the Large Helical Device (LHD) project have been serviced by the Analyzed Data Server system, and approximately 600 kinds of physical data are served. In order to execute simulation programs for the LHD experiment, one must gather sets of physical data. Because the Automatic Analyzed Server (AutoAna) calculates the physical data automatically, it eases the scientist’s task of collecting these physical data. The AutoAna has provided better computing environments for the scientists. Thus, the scientists, having recognized its benefits, make various requests as issues arise. In this paper, the authors introduce the current status of the AutoAna system.

We have successfully developed the apatite-fiber scaffold (AFS) with enhanced mechanical porosity for tissue engineering of bone and liver via two routes: i) use of two type of carbon beads with diameter of ~150 μm and ~20 μm and following ii) uniaxial pressing of the green compacts. Our Aim is to add vascular formation ability into the above AFS in order to maintain the regenerated tissues for a long time. In the present study, the AFSs with various porosities (68±2.4, 85±1.5, 89±0.6, 92±1.0%) were fabricated, and then loaded with vascular endothelial growth factor (VEGF). Drug release from VEGF-loaded AFSs with various porosities was examined by immersing them into phosphate buffer. The AFSs with the highest porosity (92%) could be released with the most VEGF among examined AFSs. In addition, we carried out preliminary study for the compatibility of vascular endothelial cells, M1 cells established by Matsuura et al. to the VEGF-loaded AFS (porosity: 92%), in order to account for the vascular formation into the pore of the AFS. The numbers of M1 cells cultured in/on the VEGF-loaded AFS were about 1.5 times that of VEGF-free AFS over a period of cell culture. These results demonstrate that the VEGF-loaded AFS with enhanced mechanical property have a good compatibility to the M1 cells as a model of vascular endothelial cells.

AbstractLarge Helical Device (LHD) experiments are executed with the collaboration of many universities in Japan. Therefore, remote participation plays an important role. In this paper, the authors introduce the current remote participation facilities for these experiments. National Institute for Fusion Science (NIFS) remote participation facilities fall into three categories. The first, remote access, allows direct access to the experimental network. This is the most flexible way to use computer resources remotely. For this purpose, virtual private network (VPN) service is available for coresearchers. In addition, several laboratories are connected directly via SINET3. Once researchers connect to the network, they can use the computer as if they are at the NIFS. The next is remote data reference. Users can view experimental data in a Web browser. Also, they can use a browser to retrieve basic information about experiments that is stored in a relational database. The last is video services. Remote researchers can use a videoconference system to communicate with researchers at the NIFS, and they can use Web browsers to watch the main monitor image displayed in the control room. For security reasons, the entire network is protected by a firewall, and one-time password authentication is used to realize secure VPN access.

AbstractThe data acquisition (DAQ) and management system of the Large Helical Device (LHD), named the LABCOM system, has been in development since 1995. The recently acquired data have grown to 7 gigabytes per shot, 10 times bigger than estimated before the experiment. In 2006 during 1-h pulse experiments, 90 gigabytes of data was acquired, a new world record. This data explosion has been enabled by the massively distributed processing architecture and the newly developed capability of real-time streaming acquisition. The former provides linear expandability since increasing the number of parallel DAQs avoids I/O bottlenecks. The latter improves the unit performance from 0.7 megabytes/s in conventional CAMAC digitizers to nonstop 110 megabytes/s in CompactPCI. The technical goal of this system is to be able to handle one hundred 100 megabytes/s concurrent DAQs even for steady-state plasma diagnostics. This is similar to the data production rate of the next-generation experiments, such as ITER. The LABCOM storage has several hundred terabytes of storage in double-tier structure: The first consists of tens of hard drive arrays, and the second some Blu-ray Disc libraries. Multiplex and redundant storage servers are mandatory for higher availability and throughputs. They together serve sharable volumes on Red Hat GFS2 cluster file systems. The LABCOM system is used not only for LHD but also for the QUEST and GAMMA10 experiments, creating a new Fusion Virtual Laboratory remote participation environment that others can access regardless of their location.

AbstractThe Large Helical Device (LHD) is the world’s largest heliotron-type device with l= 2, m= 10 continuous superconducting helical coils and three pairs of superconducting poloidal coils. The major and minor radii of the plasma are 3.6 to 3.9 and 0.6 to 0.65 m, respectively. A plasma with an elliptic cross section confined in the helical magnetic field rotates poloidally along the magnetic axis and has no axial symmetry. For the installation of various kinds of diagnostic instruments, large-sized ports are equipped. The diameter of the largest horizontal ports is 2410 mm, which enables us to easily access the full plasma cross section with multichannel viewing chords aligned parallel to one another. For the precise measurement of plasma quantities in a three-dimensional helical plasma, an extensive set of diagnostics has been developed with national and international collaborators and is routinely operated in LHD. The diagnostic system now consists of [approximately]50 measuring instruments and includes many challenging diagnostics that have been developed and operated for the study of LHD plasma confinement. These are classified as profile diagnostics, fluctuation diagnostics, and advanced diagnostics, some of which are selected for introduction in this article. In addition, diagnostics for the divertor and for energetic particles are discussed, along with topics that are somewhat unique to helical devices such as diagnosing three-dimensional phenomena and flux surface mapping. This large number of diagnostics in LHD rely on a data acquisition system that has broken world records for the amount of information accumulated in one shot. Finally, looking to the near future, countermeasures have been taken to protect diagnostics from the neutrons and gamma fluxes anticipated during deuterium-deuterium experiments, such as placing much of the diagnostic instrumentation behind a 2-m-thick concrete biological shield encompassing the LHD test cell.

Not Available

AbstractRemarkable progress to access the reactor-relevant regime has been made in a recent experiment in the Large Helical Device. Optimizing the rotational transform, the average beta value of 4.3%, which is the highest record among helical devices, was achieved. The high-performance plasma with a fusion triple product up to ~2.2 × 1019m−3·keV·s was sustained for >7 s by repetitive hydrogen pellet injection. With regard to steady-state operation, which is one of the key issues to realize a fusion reactor, discharges for >30 min were successfully sustained by ion cyclotron range of frequency heating with the aid of the magnetic axis swing technique to reduce the heat load to the plasma-facing component. In the discharge, the total input energy to the plasma reached 1.3 GJ, which also established a new record.

The Large Helical Device is a heliotron device with L = 2 and M = 10 continuous helical coils with a major radius of 3.5–4.1 m, a minor radius of 0.6 m and a toroidal field of 0.5–3 T, which is a candidate among toroidal magnetic confinement systems for a steady state thermonuclear fusion reactor. There has been significant progress in extending the plasma operational regime in various plasma parameters by neutral beam injection with a power of 13 MW and electron cyclotron heating (ECH) with a power of 2 MW. The electron and ion temperatures have reached up to 10 keV in the collisionless regime, and the maximum electron density, the volume averaged beta value and stored energy are 2.4 × 1020 m−3, 4.1% and 1.3 MJ, respectively. In the last two years, intensive studies of the magnetohydrodynamics stability providing access to the high beta regime and of healing of the magnetic island in comparison with the neoclassical tearing mode in tokamaks have been conducted. Local island divertor experiments have also been performed to control the edge plasma aimed at confinement improvement. As for transport study, transient transport analysis was executed for a plasma with an internal transport barrier and a magnetic island. The high ion temperature plasma was obtained by adding impurities to the plasma to keep the power deposition to the ions reasonably high even at a very low density. By injecting 72 kW of ECH power, the plasma was sustained for 756 s without serious problems of impurities or recycling.

One of the main objectives of LHD is to extend the plasma confinement database for helical systems and to demonstrate such extended plasma confinement properties to be sustained in the steady state. Among the various plasma parameter regimes, the study of confinement properties in the collisionless regime is of particular importance. Electron cyclotron resonance heating (ECRH) has been extensively used for these confinement studies of LHD plasma from the initial operation. The system optimizations including the modification of the transmission and antenna system are performed with special emphasis on the local heating properties. As a result, a central electron temperature of more than 10?keV with an electron density of 0.6 × 1019?m?3is achieved near the magnetic axis. The electron temperature profile is characterized by a steep gradient similar to those of an internal transport barrier observed in tokamaks and stellarators. The 168?GHz ECRH system demonstrated efficient heating at densities more than 1.0 × 1020?m?3. The continuous wave ECRH system is successfully operated to sustain a 756?s discharge.

AbstractRecent progress in the Large Helical Device (LHD) experiment during the last 2 yr is reviewed. The LHD has been extending its operational regime toward fusion-relevant conditions while taking advantage of the net-current-free heliotron concept employing a superconducting coil system. Heating capability has exceeded 10 MW, and the central ion and electron temperatures have reached 7 and 10 keV, respectively. The maximum values of beta and pulse length have been extended to 3.2% and 150 s, respectively. Several encouraging physics observations have been obtained, i.e., simultaneous achievement of the mitigation of the magnetohydrodynamic instability criteria and good confinement, and formation of an internal transport barrier. The initial results have been obtained using a local island divertor, which shows the possibility of particle control at the plasma edge.

Characteristics of MHD instabilities and their impacts on plasma confinement are studied in current free plasmas of the Large Helical Device. Spontaneous L–H transition is often observed in high beta plasmas close to 2% at low toroidal fields (B_t  0.75 T). The stored energy starts to rise rapidly just after the transition accompanying the clear rise in the electron density but quickly saturates due to the growth of the m = 2/n = 3 mode (m and n: poloidal and toroidal mode numbers), the rational surface of which is located in the edge barrier region, and edge localized mode (ELM) like activities having fairly small amplitude but high repetition frequency. Even in low beta plasmas without L–H transitions, ELM-like activities are sometimes induced in high performance plasmas with a steep edge pressure gradient and transiently reduce the stored energy up to 10%. Energetic ion driven MHD modes such as Alfvén eigenmodes (AEs) are studied in a very wide range of characteristic parameters (the averaged beta of energetic ions, 〈β_b∥〉, and the ratio of energetic ion velocity to the Alfvén velocity, V_b∥/V_A), of which range includes all tokamak data. In addition to the observation of toroidicity induced AEs (TAEs), coherent magnetic fluctuations of helicity induced AEs (HAEs) have been detected for the first time in NBI heated plasmas. The transition of a core-localized TAE to a global AE (GAE) is also observed in a discharge with temporal evolution of the rotational transform profile, having a similarity to the phenomenon observed in a reversed shear tokamak. At low magnetic fields, bursting TAEs transiently induce a significant loss of energetic ions, up to 40% of injected beams, but on the other hand play an important role in triggering the formation of transport barriers in the core and edge regions.

The structure of the radial electric field and heat transport at the magnetic island in the large helical device (LHD) are investigated by measuring the radial profile of the poloidal flow with charge exchange spectroscopy and measuring the time evolution of the electron temperature with ECE. A vortex-like plasma flow along the magnetic flux surface inside the magnetic island is observed when the n/m = 1/1 external perturbation field becomes large enough to increase the magnetic island width above a critical range (15–20% of minor radius) in LHD. This convective poloidal flow results in a non-flat space potential inside the magnetic island. The sign of the curvature of the space potential (∂²Φ/∂r², where Φ is the space potential) depends on the radial electric field at the boundary of the magnetic island. The heat transport inside the magnetic island is studied with a cold pulse propagation technique. The experimental results show the existence of radial electric field shear at the boundary of the magnetic island and a reduction in heat transport at the boundary and inside the magnetic island.

Standard diagnostics for fundamental plasma parameters and for plasma physics are routinely utilized for daily operation and physics studies in the large helical device (LHD) with high reliability. Diagnostics for steady-state plasma are under intensive development, especially for T_e, n_e (yttrium–aluminium garnet (YAG) laser Thomson, CO₂ laser polarimeter), data acquisition in steady-state and heat-resistant probes. To clarify the plasma properties of the helical structure, two- or three-dimensional diagnostics are being aggressively developed: tangential cameras (fast SX TV, photon counting CCD, H_α TV); tomography (tangential SX CCD, bolometer); imaging (bolometer, ECE, reflectometer). Divertor and edge physics are important key issues for steady-state operation. Diagnostics for neutral flux (H_α array, Zeeman spectroscopy) and n_e (fast scanning probe, Li beam probe, pulsed radar reflectometer) are also in advanced stages of development. In addition to these, advanced diagnostics are being intensively developed in LHD through domestic and international collaborations.

In the first four years of the LHD experiment, several encouraging results have emerged, the most significant of which is that MHD stability and good transport are compatible in the inward shifted axis configuration. The observed energy confinement at this optimal configuration is consistent with ISS95 scaling with an enhancement factor of 1.5. The confinement enhancement over the smaller heliotron devices is attributed to the high edge temperature. We find that the plasma with an average beta of 3% is stable in this configuration, even though the theoretical stability conditions of Mercier modes and pressure driven low-n modes are violated. In the low density discharges heated by NBI and ECR, internal transport barrier (ITB) and an associated high central temperature (>10 keV) are seen. The radial electric field measured in these discharges is positive (electron root) and expected to play a key role in the formation of the ITB. The positive electric field is also found to suppress the ion thermal diffusivity as predicted by neoclassical transport theory. The width of the externally imposed island

Energy confinement and heat transport of net-current-free NBI heated plasmas in the large helical device (LHD) are discussed with emphasis on density and power deposition profile dependences. Although the apparent density dependence of the energy confinement time has been demonstrated in a wide parameter range in LHD, the loss of this dependence has been observed in the high density regime under specific conditions. Broad heat deposition due to off-axis alignment and shallow penetration of neutral beams degrades the global energy confinement while the local heat transport maintains a clear temperature dependence, lying between Bohm and gyro-Bohm characteristics. The central heat deposition tends towards an intrinsic density dependence like τE∝(n¯e/P)0.6 from the state where density dependence is lost. The broadening of the temperature profile due to the broad heat deposition profile contrasts with the invariant property that has been observed widely as profile resilience or stiffness in tokamak experiments. The confinement improvement as a result of the inward shift of the magnetic axis is obvious in the core region, which emphasizes the improvement of transport because of the geometry being unfavourable for the central heating of NBI in this configuration. The edge pressure, clearly, does not depend on the magnetic axis position. Unlike a tokamak H-mode, the edge pressure is determined by transport and can be increased by increasing the heating power.

Significant progress has been made with ion cyclotron range of frequencies (ICRF) heating in the Large Helical Device. This is mainly due to better confinement of the helically trapped particles and less accumulation of impurities in the region of the plasma core. During the past two years, ICRF heating power has been increased from 1.35 to 2.7 MW. Various wave-mode tests were carried out using minority-ion heating, second-harmonic heating, slow-wave heating and high-density fast-wave heating at the fundamental cyclotron frequency. This fundamental heating mode extended the plasma density range of effective ICRF heating to a value of 1×1020 m−3. This use of the heating mode was its first successful application in large fusion devices. Using the minority-ion mode gave the best performance, and the stored energy reached 240 kJ using ICRF alone. This was obtained for the inward-shifted magnetic axis configuration. The improvement associated with the axis-shift was common for both bulk plasma and highly accelerated particles. For the minority-ion mode, high-energy ions up to 500 keV were observed by concentrating the heating power near the plasma axis. The confinement properties of high-energy particles were studied for different magnetic axis configurations, using the power-modulation technique. It confirmed that with the inward-shifted configuration the confinement of high-energy particles was better than with the normal configuration. By increasing the distance of the plasma to the vessel wall to about 2 cm, the impurity influx was sufficiently reduced to allow sustainment of the plasma with ICRF heating alone for more than 2 min.

The behaviour of high-energy ions accelerated by an ion cyclotron range of frequency (ICRF) electric field in the large helical device (LHD) is discussed. A better confinement performance of high-energy ions in the inward-shifted magnetic axis configuration was experimentally verified by measuring their energy spectrum and comparing it with the effective temperature determined by an electron slowing down process. In the standard magnetic axis configuration a saturation of the measured tail temperature was observed as the effective temperature was increased. The ratio between these two quantities is a measure of the quality of transfer efficiency from high-energy ions to a bulk plasma; when this efficiency was compared with Monte Carlo simulations the results agreed fairly well. The ratio of the stored energy of the high-energy ions to that of the bulk plasma was measured using an ICRF heating power modulation method; it was deduced from phase differences between total and bulk plasma stored energies and the modulated ICRF heating power. The measured high energy fraction agreed with that calculated using the injected ICRF heating power, the transfer efficiency determined in the experiment and the confinement scaling of the LHD plasma.

The most important finding in the Large Helical Device (LHD) experiments so far is that an inward-shifted configuration exhibits good plasma performance with a scaling similar to that of ELMy H-mode tokamaks. The inward-shifted configuration has been predicted to have unfavourable magnetohydrodynamic (MHD) properties, even though it has significantly better particle-orbit properties. However, no serious confinement degradation due to the MHD activities was observed, resolving favourably the potential conflict between stability and confinement. Neoclassical transport loss can be suppressed even in a low-collisionality regime, and in this way the inward-shifted configuration was shown to make the LHD plasma properties favourable. Then, it is very important to realize more improved plasma performance and higher temperature plasmas for extending the plasma-parameter regime in order to obtain data that can be extrapolated to a reactor. In the fifth campaign in 2001–2002, an increase in the heating power achieved an electron temperature T_e of over 10 keV and an ion temperature T_i of 5 keV. A T_e profile, which is characteristic of internal transport barriers, was also observed when the electron cyclotron resonance heating power was highly focused on the centre of the plasma sustained by neutral beam injection.

The superconducting machine LHD has conducted long pulse experiments for four years to achieve long-duration plasmas with high performance. The operational regime was largely extended in discharge duration and plasma density. In this paper, the plasma characteristics, in particular, plasma performance and impurity behaviour in long pulse discharges are described. Confinement studies show that global energy confinement times are comparable to those in short pulse discharges. Long sustainment of high performance plasma, which is equivalent to the previous achievement in other devices, was demonstrated. Long pulse discharges enabled us to investigate impurity behaviour in a long timescale. Intrinsic metallic impurity accumulation was observed in a narrow density window (2–3×10¹⁹ m⁻³) only for hydrogen discharges. Impurity transport study by using active impurity pellet injection shows a long impurity confinement time and an inward convection in the impurity accumulation window, which is consistent with the intrinsic impurity behaviour. The pulsed neon gas injection experiment shows that the neon penetration into the plasma core is caused by the inward convection due to radial electric field. Finally, impurity accumulation control with an externally induced magnetic island at the plasma edge was demonstrated.

Recent experimental results in the Large Helical Device have indicated that a large pressure gradient can be formed beyond the stability criterion for the Mercier (high-n) mode. While the stability against an interchange mode is violated in the inward-shifted configuration due to an enhancement of the magnetic hill, the neoclassical transport and confinement of high-energy particle are, in contrast, improved by this inward shift. Mitigation of the unfavourable effects of MHD instability has led to a significant extension of the operational regime. Achievements of the stored energy of 1 MJ and the volume-averaged beta of 3% are representative results from this finding. A confinement enhancement factor above the international stellarator scaling ISS95 is also maintained around 1.5 towards a volume-averaged beta, ⟨β⟩, of 3%. Configuration studies on confinement and MHD characteristics emphasize the superiority of the inward-shifted geometry to other geometries. The emergence of coherent modes appears to be consistent with the linear ideal MHD theory; however, the inward-shifted configuration has reduced heat transport in spite of a larger amplitude of magnetic fluctuation than the outward-shifted configuration. While neoclassical helical ripple transport becomes visible for the outward-shifted configuration in the collisionless regime, the inward-shifted configuration does not show any degradation of confinement deep in the collisionless regime (ν*<0.1). The distinguished characteristics observed in the inward-shifted configuration help in creating a new perspective of MHD stability and related transport in net current-free plasmas. The first result of the pellet launching at different locations is also reported.

The experimental results from the Large Helical Device (LHD) heliotron / torsatron of the first two years are reviewed. The world's largest superconducting helical coils have been driven up to 2.9 Tesla on the axis which is close to the designed value (3 T). The obtained plasma performances are better than those predicted by the database from the medium-size helical devices. These improvements are attributed mainly to the optimization of a magnetic field configuration which can be controlled by shifting the magnetic axis inward than that of standard case. This configuration improves particle orbits of trapped high energy ions resulting in success of ICRF heating in LHD. Efforts have also been made on steady state plasma operation, and long pulse discharges more than one minute have been achieved both by ICRF and NBI. It should be noted that the feature of no current-disruption in helical plasma makes the discharges easy.

OBJECTIVE: Graves' ophthalmopathy (GO), resulting from the inflammation of retro-orbital tissue, is one of the major complications of Graves' disease (GD). We investigated the clinical usefulness of the measurement of retinal blood flow (RBF) in the evaluation of GO and its activity. MEASUREMENT: RBF was quantitated by pulsed Doppler mode at just below the branch of central retinal artery, from which the resistance index (RI) was calculated. PATIENTS: Forty-seven euthyroid GD patients and 70 gender- and age-matched normal controls were measured for RI to investigate the effect of GO on RBF. To investigate the effect of hyperthyroidism, 20 GD patients were measured for RI changes during antithyroid drug (ATD) therapy. Furthermore, 17 GD patients with clinically overt GO were measured for RI changes during treatment with glucocorticoid plus retro-orbital radiation. RESULTS: RI and exophthalmos showed a significant positive correlation in 47 treated euthyroid GD patients without clinically overt GO (r=0.307, P<0.05), but not in 70 age- and sex-matched normal subjects (r=0.185, P=0.161). Furthermore, RI, but not exophthalmos, significantly correlated with serum TSH receptor antibodies, an indicator for the disease activity of GO. ATD therapy significantly reduced RI in GD patients from 0.719+/-0.041 in the hyperthyroid state to 0.661+/-0.051 in the euthyroid state, but not to the levels observed in normal subjects having the similar exophthalmos (0.640+/-0.049). The fractional reduction of RI during ATD therapy significantly correlated with those of pulse pressure and ultrasonographic distensibility in carotid artery, but not with those of serum vascular injury markers. In 17 GD patients with clinically overt GO, all four patients having adipose tissue enlargement but not extraocular muscle hypertrophy (inactive GO) showed RI within the mean +/- 1 s.d. for treated GD patients without GO. In the other 13 GD patients having extraocular muscle hypertrophy (active GO), four and eight patients showed RI outside mean +/- 2 s.d. and mean +/- 1 s.d. respectively. Treatment with glucocorticoid plus radiation moved RI in 8 out of 10 patients toward the mean values of GD patients without GO, in spite of little improvement of exophthalmos. CONCLUSIONS: It was suggested that GD patients showed altered retinal hemodynamics, possibly resulting either from the cardiovascular effect of hyperthyroidism or from retro-orbital inflammation, particularly in extraocular muscle.

The GLUT4 glucose transporter resides mostly in perinuclear membranes in unstimulated 3T3-L1 adipocytes and is acutely translocated to the cell surface in response to insulin. Using a novel method to purify intracellular GLUT4-enriched membranes, we identified by mass spectrometry the intermediate filament protein vimentin and the microtubule protein alpha-tubulin as components of these membranes. Immunoelectron microscopy of the GLUT4-containing membranes also revealed their association with these cytoskeletal proteins. Disruption of intermediate filaments and microtubules in 3T3-L1 adipocytes by microinjection of a vimentin-derived peptide of the helix initiation 1A domain caused marked dispersion of perinuclear GLUT4 to peripheral regions of the cells. Inhibition of the microtubule-based motor dynein by brief cytoplasmic acidification of cultured adipocytes also dispersed perinuclear GLUT4 and inhibited insulin-stimulated GLUT4 translocation to the cell surface. Insulin sensitivity was restored as GLUT4 was again concentrated near the nucleus upon recovery of cells in physiological buffer. These data suggest that GLUT4 trafficking to perinuclear membranes of cultured adipocytes is directed by dynein and is required for optimal GLUT4 regulation by insulin.

Based on recent studies showing that phospholipase D (PLD)1 is associated with intracellular membranes and promotes membrane budding from the trans-Golgi, we tested its possible role in the membrane trafficking of GLUT4 glucose transporters. Using immunofluorescence confocal microscopy, expressed Myc epitope-tagged PLD1 was found to associate with intracellular vesicular structures by a mechanism that requires its N-terminal pleckstrin homology domain. Partial co-localization with expressed GLUT4 fused to green fluorescent protein in both 3T3-L1 adipocytes and Chinese hamster ovary cells was evident. Furthermore, microinjection of purified PLD into cultured adipocytes markedly potentiated the effect of a submaximal concentration of insulin to stimulate GLUT4 translocation to cell surface membranes. Insulin stimulated PLD activity in cells expressing high levels of insulin receptors but no such insulin effect was detected in 3T3-L1 adipocytes. Taken together, these results are consistent with the hypothesis that PLD1 associated with GLUT4-containing membranes acts in a constitutive manner to promote the mechanism of GLUT4 translocation by insulin.

OBJECTIVE: We assessed the effects of atherosclerosis on the glomerular filtration rate (GFR) in patients with type 2 diabetes and who had micro- or normoalbuminuria. RESEARCH DESIGN AND METHODS: A total of 61 Japanese patients with type 2 diabetes were recruited from inpatients of Osaka City University Hospital. They ranged in age from 40 to 69 years (28 men and 33 women). Each subject collected a 24-h urine sample for quantitative analysis of albumin. Absence of albuminuria was defined as a urinary albumin excretion level of <30 mg/24 h (n = 36) and microalbuminuria as a level of 30-300 mg/24 h. The GFR was estimated using 99mTc diethylenetriamine pentaacetic renogram method. As indexes of atherosclerosis, we measured the intimal-medial thickness (IMT) and distensibility of the carotid artery using high-resolution B-mode ultrasonagraphy and an echo-tracking system. We measured the resistance index (RI) of the renal interlobar arteries by pulsed Doppler sonography. RESULTS: The clinical characteristics of type 2 diabetic patients with and without microalbuminuria did not differ except for duration of diabetes, which was longer in the patients with microalbuminuria. GFR also did not differ between the patients with and without microalbuminuria. GFR was significantly correlated with the patient's age (r = -0.256, P < 0.05), carotid IMT (r = -0.326, P < 0.05), carotid stiffness beta (r = -0.449, P < 0.001), and renal arterial RI (r = -0.365, P < 0.05). In multiple regression analysis, independent factors associated with GFR were carotid IMT (R2 = 0.108, P = 0.0102), carotid stiffness beta (R2 = 0.208, P = 0.0003), and renal artery RI (R2 = 0.130, P = 0.0043). CONCLUSIONS: The decline in GFR in type 2 diabetic patients in the early stages of nephropathy may be due in part to atherosclerosis.

Abstract:: Osteoblast deficit plays a principal role in the development of diabetic osteopenia. We have previously reported that high glucose conditions impair the function of osteoblast-like MG-63 cells. This study was performed to assess the sensitivity of osteoblasts to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in patients with type 2 diabetes without insulin deficiency or overt diabetic complications. During stimulation with 1,25(OH)2D3 at 2.0 mg/day for 6 consecutive days in 9 type 2 diabetic patients, serum levels of bone alkaline phosphatase (BALP), osteocalcin (OC) and the carboxyterminal propeptide of type 1 procollagen, and the urinary excretion of pyridinoline and deoxypyridinoline (DPYR), were monitored. As parameters of glycemic control, the mean level of fasting plasma glucose (mFPG) throughout the 1,25(OH)2D3 stimulation test and the level of HbA1C were used. 1,25(OH)2D3 increased serum 1,25(OH)2D significantly by day 2, which was followed by a significant reduction in the serum level of intact parathyroid hormone. The maximal increment of serum OC adjusted for that of 1,25(OH)2D was negatively correlated with both mFPG and HbA1C levels (p50.05). Furthermore, the magnitude of 1,25(OH)2D3-induced bone resorption, as reflected by the maximal increase in urinary DPYR excretion, was negatively correlated with the mFPG level (p50.05). Basal BALP tended to be negatively correlated with HbA1C, although not to a significant extent. In conclusion, our findings would indicate that poor glycemic control impairs the responses of osteoblasts and osteoclasts to 1,25(OH)2D3 in normo-insulinemic type 2 diabetic patients.

The suppressive mechanisms of T cells induced by water-soluble fraction of mouse seminal vesicle fluid (WSF-SVF) were investigated to clarify its immunological roles in the reproductive immunity. WSF-SVF inhibited the blastogenic responses to concanavalin A (Con A) or phytohemagglutinin (PHA) of T cells. Pretreatment of splenocytes with WSF-SVF did not suppress the blastogenesis of splenocytes to Con A when treated cells were washed before cultures. WSF-SVF did not inhibit the proliferation of Con A-activated splenocytes, that of listeria-immune splenocytes to listerial antigen and growth of tumor cells (Yac 1 cells, Ehrlich ascites carcinoma cells, EL 4 cells). Listerial antigenspecific immune response was not observed when mice were immunized with both listerial antigen and WSF-SVF, whereas it was observed when mice were immunized with only listerial antigen. WSF-SVF also significantly inhibited allogenic MLR. WSF-SVF did not adsorb Con A, and its suppressive activity was rather enhanced by heating at 56d`C for 30 min. These results suggest that WSF-SVF inhibits the stage of sensitization of T cells with antigen or stimulant, such as mitogen nonspecifically, without adsorption to antigen or mitogen, and its substance is stable.

An anomalous geomagnetic sudden commencement (SC) occurred on March 24, 1991. It is characterized by an exceptionally large and sharp impulse observed in its initial part along the noon meridian in middle and low latitudes. The analysis of the SC was made by using high time resolution digital data from the 210° Meridian Magnetometer Chain in the west Pacific, Sub-Auroral Magnetometer Network (SAMNET) in the United Kingdom and southern Scandinavia, the EISCAT Magnetometer Cross in northern Scandinavia and Svalbard, and Canopus in Canada together with other ground and satellite (GOES 6, GOES 7, CRRES, and GMS) data. The results of the analysis suggest that the pulse observed at lower-latitude ground stations was caused by the propagation of a strong magnetospheric compression of short duration (less than l min) which has never been observed before this event. The HF Doppler observation in Kyoto near local noon seems to be consistent with existence of the bipolar electric field associated with the propagating compressional magnetic pulse. The SAMNET stations and CRRES in the early morning also detected positive pulses which delays 30–50 s from the pulses in noon sector. Although the delay in the peak time of the pulse observed on the ground is consistent with ionospheric hydromagnetic wave propagation from the dayside to the nightside with finite speed, the initial onset time of the pulse on the ground was almost simultaneous everywhere suggesting the existence of an “almost instantaneous” propagation mode below the ionosphere.

We previously reported that gamma delta T cells appeared and could play a protective role early in infections with intracellular bacteria such as Listeria monocytogenes, Mycobacterium bovis BCG, and Salmonella choleraesuis. To extend these findings to virus infection, we examined the developmental sequence of gamma delta T cells in bronchoalveolar lavage during the course of Sendai virus infection in C57BL/6 mice. To produce a natural but nonlethal infection course as far as possible, we used a sublethal dose of a wild-type virus which had not been subjected to serial passages in a chicken embryo, hence retaining full virulence for mice. Virus titers in lungs reached a peak on day 6 and then decreased to an undetectable level by day 10. This time course of virus reproduction was immediately and coincidentally followed by the developmental course of gamma delta T cells, in which the cell number peaked on day 7 and then decreased to a marginal level by day 10. On the other hand, the alpha beta T-cell number continued to increase until day 10 and remained at a high level thereafter. The early-appearing gamma delta T cells were CD4-, CD8-, IL-2R alpha- beta+, CD44+, Mel-14-, and LFA-1 alpha/beta+ in phenotype and used V gamma 1/2 and V gamma 4 and V delta 3, V delta 4, V delta 5, and V delta 6. The gamma delta T cells were responding to macrophages from infected mice when the cells were cultured in vitro. Furthermore, the expression of endogenous heat shock protein (hsp) was infection specific, and its level appeared to correlate with the gamma delta T-cell development. These results suggest that the early recruitment of gamma delta T cells, which proliferate in response to endogenous hsp+ cells, is also characteristic of this virus infection, although this view appears to be contradictory to earlier reports.

The effect of mouse seminal vesicle fluid (SVF) on blastogenic response of splenocytes to mitogens was investigated. SVF significantly suppressed blastogenic response of splenocytes to concanavalin A and phytohemagglutinin in a dose-dependent manner, but blastogenic response to lipopolysaccharide was suppressed only at low, although significant, levels, even at high concentrations of SVF. Extensive dialysis did not reduce the capacity of SVF to inhibit blastogenesis of splenocytes. For elucidation of the mechanisms of suppression of blastogenic response, interleukin-2 (IL-2)-dependent cells were cultured in the presence of IL-2 and various concentrations of SVF. The presence of SVF did not inhibit the proliferative response of IL-2-dependent cells to IL-2. These results suggest that the suppression of blastogenic response of T lymphocytes to mitogens in seminal plasma is caused by an undialyzable component (or components) derived from seminal vesicle and is attributable to the alteration of receptors for mitogens or of IL-2 receptors that are expressed on stimulation by mitogens.

Effects of tolbutamide on the activity of hepatic phosphoenolpyruvate carboxykinase (PEPCK), a rate limiting enzyme in gluconeogenesis, was examined using rat hematoma (H4IIE) cells. Tolbutamide inhibited PEPCK activity induced by cAMP in a time- and dose-dependent manner. Tolbutamide effect was rapidly exerted and insulin-independent. The inhibitory effect of 5 mM tolbutamide corresponded with that of 10−7 M insulin. These results suggest the possibility that tolbutamide plays a significant role on amelioration of the deranged glucose metabolism in the liver through repression of gluconeogenesis, primarily due to the inhibition of PEPCK activity.Copyright 1993, 1999 Academic Press

Plasma leptin level is known to correlate with the degree of obesity. To determine the influences of renal fuction and insulin resistance on plasma leptin concentrations, we measured plasma leptin concentrations and performed the euglycaemic hyperinsulinaemic clamp studies in 57 patients with non-insulin-dependent diabetes mellitus with a wide range of renal function. In simple regression analyses, plasma leptin concentration showed significant positive correlations with percentage of body fat measured by dual energy X-ray absorptiometry, body mass index, waist to hip ratio and fasting plasma insulin. Leptin level was higher in females than males. Multiple regression analyses indicated that percent body fat, waist to hip ratio, plasma insulin, gender and renal function (1/creatinine), but not insulin sensitivity, were significant and independent determinants of plasma leptin level. These results suggest that plasma leptin level is regulated or affected by multiple factors including renal function. Insulin resistance appeared to increase leptin levels indirectly by raising plasma insulin. [Diabetologia (1997) 40: 676–679]Plasma leptin level is known to correlate with the degree of obesity. To determine the influences of renal fuction and insulin resistance on plasma leptin concentrations, we measured plasma leptin concentrations and performed the euglycaemic hyperinsulinaemic clamp studies in 57 patients with non-insulin-dependent diabetes mellitus with a wide range of renal function. In simple regression analyses, plasma leptin concentration showed significant positive correlations with percentage of body fat measured by dual energy X-ray absorptiometry, body mass index, waist to hip ratio and fasting plasma insulin. Leptin level was higher in females than males. Multiple regression analyses indicated that percent body fat, waist to hip ratio, plasma insulin, gender and renal function (1/creatinine), but not insulin sensitivity, were significant and independent determinants of plasma leptin level. These results suggest that plasma leptin level is regulated or affected by multiple factors including renal function. Insulin resistance appeared to increase leptin levels indirectly by raising plasma insulin. [Diabetologia (1997) 40: 676–679]

OBJECTIVE: We studied the relationship between vasoconstrictor changes in foot arteries (pedal, metatarsal, and digital arteries) and autonomic neuropathy in diabetic patients to estimate the degrees of sympathetic dysfunction. RESEARCH DESIGN AND METHODS: Sixty-two patients and nineteen age-matched control subjects were studied. The resistance index (RI) and pulsatility index (PI) were measured as vascular hemodynamic parameters using Doppler sonography, and the increases in these hemodynamic parameters (%RI and %PI) from rest to a deep breath were measured as indexes of the degrees of sympathetic vasoconstrictor function. Cardiovascular autonomic function tests (AFTs) were performed and the score was compared to %RI and %PI values obtained. RESULTS: Of the 62 diabetic patients, 51 had various degrees of autonomic neuropathy. Both %RI and %PI in the diabetic patients were significantly less than those in the control subjects for all foot arteries tested (all P < 0.001). There were strongly inverse correlations between the %RI and %PI of foot arteries and the AFT score (r = -0.556 to -0.846, P < 0.0001). The %RI of the digital artery was the most strongly correlated with AFT score (r = -0.846, P < 0.0001) among foot arteries tested. The abnormality of sympathetic vasoconstriction was detectable in the majority of the diabetic patients with the early phase of autonomic neuropathy (%RI: 89.5%; %PI: 94.5%). CONCLUSIONS: We conclude that the %RI of the digital artery is a useful and reliable sympathetic function test of early phase in diabetic patients.

OBJECTIVE: To investigate the association between arterial wall stiffness indexes beta of the common carotid artery (CCA) and the femoral artery (FA) and insulin resistance in NIDDM subjects in a cross-sectional study. RESEARCH DESIGN AND METHODS: We evaluated the arterial stiffness indexes beta of CCA and FA using an ultrasonic phase-locked echo-tracking system in 60 NIDDM subjects attending the diabetes center in Osaka City University Hospital, compared with 120 age- and sex-matched control subjects. Insulin sensitivity indexes were evaluated using a euglycemic-hyperinsulinemic clamp. RESULTS: Stiffness indexes beta of both CCA and FA were significantly higher in NIDDM subjects than in control subjects (CCA 18.1 +/- 0.9 vs. 11.7 +/- 0.3, respectively, P < 0.001; FA 35.7 +/- 2.3 vs. 23.7 +/- 0.8, respectively, P < 0.001). The mean insulin sensitivity index in NIDDM subjects was 4.69 +/- 0.29 mg.kg-1.min-1.mU-1.l. The stiffness indexes beta of both CCA and FA were inversely correlated with insulin sensitivity indexes (CCA r = -0.393, P = 0.002; FA r = -0.329, P = 0.010), as well as with age, duration of diabetes, and mean blood pressure. In stepwise multiple regression analyses, insulin sensitivity index and duration of diabetes were identified as significant independent variables for stiffness indexes beta in both CCA and FA (CCA R2 = 0.249, P = 0.0003; FA R2 = 0.336, P < 0.001). CONCLUSIONS: Arterial stiffness indexes beta of CCA and FA were associated with insulin resistance in NIDDM subjects.

Leptin is a newly found hormone secreted by adipocytes that regulates food intake, thermogenesis, and body fat. We measured plasma leptin levels in 103 patients with chronic renal failure treated by hemodialysis and 167 age- and gender-matched healthy control subjects to examine the impact of renal failure on plasma leptin levels and the influence of leptin on body composition measured by dual-energy X-ray absorptiometry. Hemodialysis patients showed a significant decrease in both body fat mass and lean body mass compared with those of the control subjects. Plasma leptin was significantly elevated in the hemodialysis group over the controls. In both groups, leptin was higher in female than male subjects, and it correlated positively with percent body fat. The subjects were divided into six categories according to percent body fat, and plasma leptin levels were compared between the two groups in the same category. Leptin of hemodialysis patients was significantly higher than that of the control subjects in the percent body fat categories of 30 or greater, whereas there was no statistically significant difference in leptin concentrations in the lower percent body fat categories. This was also true in the comparison in each gender, and leptin levels in female subjects showed a more remarkable difference between the hemodialysis and control groups in obese categories. Multiple regression analysis in all subjects indicated that plasma leptin levels were independently affected by percent body fat, plasma insulin concentration, gender, and renal failure. The positive impact of renal failure on leptin remained significant in the subjects with percent body fat of 30 or greater in the multiple regression model, whereas it was no longer significant in the remaining lean subjects. In multiple regression analysis of factors affecting fat mass index and lean mass index, leptin level was selectively associated with fat mass index, but not with lean mass index, regardless of percent body fat ranges. These results indicate that renal failure is an important factor affecting plasma leptin levels, especially in obese female subjects, and that hyperleptinemia was closely related to fat mass but not to lean body mass in hemodialysis patients. (Am J Kidney Dis 1998 Apr;31(4):655-61)

Small‐cell carcinoma of the endometrium is a rare neoplasm, and its aggressive behavior has been reported. We report a case of small‐cell carcinoma occurring primarily in the endometrium of a 62‐year‐old woman with postmenopausal vaginal bleeding and lower abdominal pain. The excised uterus showed a necrotic polypoid mass and histologically displayed an endometrial small‐cell carcinoma. Immuno‐histochemically, the tumor cells were positive for cytokeratin, the epithelial membrane antigen, neuron‐specific enolase, and chromogranin, but were negative for the leukocyte common antigen and Grimelius stain. Ultrastructural analysis revealed the presence of dense core granules in the cytoplasm of tumor cells. The patient died 2 months after surgery because of aggressive behavior of the tumor. We wish to distinguish small‐cell carcinoma of the endometrium from conventional epithelial tumors of the endometrium, because of the former's distinctive histopathologic, immunohistochemical, and ultrastructural characteristics.

Abstract:  Rhabdomyosarcoma (RMS) is occasionally found in the female genital tract, and mostly appears as one of the heterologous mesenchymal components in uterine carcinosarcoma designated as malignant mixed müllerian tumour (MMMT). We examined the biological properties of a pure rhabdomyosarcoma (RMS) cell line designated FU-MMT-3, which was newly established from a surgical specimen taken from a patient with uterine MMMT. We also evaluated c-myc and MYCN gene amplification in three RMS cell lines (including FU-MMT-3) derived from three MMMTs by Southern blot analysis. FU-MMT-3 cells were propagated continuously for 57 serial passages over a 2-year period in vitro. FU-MMT-3 was able to produce tumours demonstrating pure RMS in athymic nude mice. Cytogenetically, FU-MMT-3 showed a triploidy pattern, with complex karyotypic abnormalities including trisomy of chromosome 8. All three RMS cell lines, including FU-MMT-3, showed amplification of the c-myc gene (approximately fourfold to eightfold), while no cell lines demonstrated MYCN gene amplification. FU-MMT-3 is considered to provide a useful system for the study of the biological behaviour of RMS in MMMTs. Extra copies of chromosome 8 and c-myc gene amplification may be associated with the rhabdomyoblastic differentiation in MMMT.

Unconstrained development of gamma interferon (IFN-gamma)-secreting natural killer (NK) cells and T helper (Th) 1 cells is central to protection against Listeria monocytogenes. In contrast, interleukin 4 (IL-4) is considered harmful. IL-12 produced by infected macrophages promotes, and IL-4 interferes with, protective antilisterial immunity. The liver NK T lymphocytes, which are a potent source of IL-4, are downregulated at an intermediate stage of listeriosis. Here we demonstrate that endogenous IL-12 participates in the control of IL-4-producing liver NK T lymphocytes during listeriosis. The effects of L. monocytogenes infection on IL-4-producing liver NK T lymphocytes were reversed by antibody neutralization of IL-12 but not of IFN-gamma or tumor necrosis factor alpha (TNF-alpha). IL-4 production by liver NK T lymphocytes was virtually unaffected by heat-killed L. monocytogenes (HKL). Viable L. monocytogenes markedly increased the numbers of IL-12 producers in livers in parallel with an increase in macrophage numbers, whereas HKL failed to do so with similar efficiency. These results indicate that in the liver endogenous IL-12 improves protective immunity against listeriosis by downregulating IL-4-producing NK T lymphocytes. Moreover, our findings that HKL have a low level of IL-12-inducing activity and fail to control IL-4-producing NK T lymphocytes in the liver are consistent with the lesser protective capacity of HKL compared to that of live listeriae.

Numerous microbial pathogens, including Listeria monocytogenes, enter the host through the intestine. Although relatively little is known about the biological functions of intestinal intraepithelial lymphocytes (i-IEL), they are generally considered a first line of defense against intestinal infections. In the mouse, the vast majority of i-IEL express the CD8 coreceptor either as a CD8 alpha/alpha homodimer or as a CD8 alpha/beta heterodimer. The CD8 receptor of T-cell receptor TcR gamma/delta i-IEL is exclusively homodimeric, whereas the CD8-expressing TcR alpha/beta i-IEL segregate into equal fractions of CD8 alpha/alpha and CD8 alpha/beta cells. We infected beta 2-microglobulin (beta 2m)+/- mice (possessing all i-IEL populations) and beta 2m -/- mutant mice (lacking all CD8 alpha/beta + i-IEL and having few CD8 alpha/alpha + TcR alpha/beta i-IEL) with L. monocytogenes per os and determined their biological functions after TcR ligation with monoclonal antibodies. Cytolytic activities of TcR alpha/beta and TcR gamma/delta i-IEL from beta 2m +/- mice were not influenced by intestinal listeriosis. Cytolytic activities of TcR alpha/beta i-IEL were impaired in uninfected beta 2m -/- mice, but this reduction was reestablished as a consequence of intestinal listeriosis. Frequencies of gamma interferon (IFN-gamma)-producing TcR alpha/beta i-IEL in uninfected beta 2m -/- mice were reduced, compared with that in their heterozygous controls. Equally low frequencies of IFN-gamma-producing TcR gamma/delta i-IEL in beta 2M +/- and beta 2m-/- mutants were found. Listeriosis increased frequencies of INF-gamma-producing TcR alpha/beta and TcR gamma/delta i-IEL in both mouse strains. Most remarkably, the proportion of IFN-gamma-producing TcR gamma/delta i-IEL was elevated 10-fold in listeria-infected beta 2M -/- mice. Our findings show that the beta 2m-independent CD8 beta- i-IEL expressing either TcR alpha/beta or TcR gamma/delta are stimulated by intestinal listeriosis independent of regional beta 2m expression. We conclude that the three major CD8+ i-IEL populations are stimulated by intestinal listeriosis and that CD8 beta- i-IEL compensate for the total lack of CD8 beta+ i-IEL in beta 2M -/- mutant mice. Hence, in contrast to the peripheral immune system, which crucially depends on CD8 alpha/beta + TcR alpha/beta lymphocytes, the mucosal immune system can rely on additional lymphocytes expressing the CD8 alpha/alpha homodimer.

In the liver, an unusual T lymphocyte population exists with the intriguing phenotype CD4+NK1+ TCR alpha beta int. Thus far, functions of these lymphocytes remained elusive. Recently, however, CD4+NK1+ liver T lymphocytes have been shown to produce cytokines. Here we show that sorted CD4+NK1+ liver lymphocytes from naive mice lyse target cells after TCR alpha beta or CD3, but not TCR gamma delta, engagement. Liver lymphocytes from beta 2-microglobulin-deficient gene disruption mutant mice failed to express such cytolytic activities and in vivo treatment with anti-NK1.1 mAb or anti-CD4 mAb, but not anti-CD8 mAb, markedly reduced target cell lysis. In vivo administration or rIL-12 impaired TCR alpha beta-mediated target cell lysis by liver lymphocytes. A similar down-regulation of cytolytic activities was observed with liver lymphocytes from mice infected with Listeria monocytogenes or Mycobacterium bovis BCG, which are potent IL-12 inducers. We anticipate (i) that cytolytic CD4+NK1+ T lymphocytes contribute to immunosurveillance of inflammatory processes in the liver and (ii) that they are influenced by IL-12.

To elucidate the relationship between the virulence of intracellular bacterium and its ability to induce gamma/delta T cells in the host during infection, we examined the differences in appearance of gamma/delta T cells in mice infected with Salmonella choleraesuis virulent strain RF-1 carrying a virulence plasmid of 50 kb, and with avirulent strain 31N-1 cured of the 50-kb plasmid. The number of gamma/delta T cells in the peritoneal cavity was increased to a significant level on day 3 after an intraperitoneal infection with a sublethal dose (5 x 10(4) colony-forming units) of avirulent strain 31N-1. On the other hand, no increase in the number of gamma/delta T cells was evident in the peritoneal cavity at any stage after infections with various doses of virulent strain RF-1, although the numbers of the bacteria were drastically increased. Similar to that seen in the peritoneal cavity, the number of gamma/delta T cells in the liver was significantly increased after an intraperitoneal infection with avirulent strain 31N-1 but not with virulent strain RF-1. The early appearing gamma/delta T cells during salmonellosis with avirulent stain 31N-1, which preferentially used V gamma 1/V delta 6, showed blastogenesis in response to purified protein derivative (PPD) derived from Mycobacterium tuberculosis. The gamma/delta T cells also responded to the peritoneal adherent cells in mice infected with avirulent strain 31N-1 6 d previously, which expressed a high level of endogenous heat-shock protein (hsp) homologous to the mycobacterial 65-kD hsp. The expression of the hsp, however, was not prominent in the adherent cells in mice infected with virulent strain RF-1. These results suggest that the gamma/delta T cells specific for PPD may play important roles in host defense against murine salmonellosis, and that the virulence of Salmonella may be inversely correlated with its ability to induce endogenous hsp in the infected macrophages, which in turn stimulate the gamma/delta T cells in the host during salmonellosis.