Injection barrel with a tapered structure for a low speed and small size cryogenic hydrogen pellet in medium-sized plasma fusion devices.

An injection barrel was designed and fabricated for a small size 0.8 mm cryogenic pellet with a low speed of 200-300 m/s in medium-sized plasma fusion devices. Pellet injection with pneumatic acceleration was examined using a conventional in situ technique. A tapered structure was applied in the downstream side of the injection barrel to satisfy the requirement of pellet speed reduction by expansion of the propellant gas. Shadowgraph and light gate measurements show that the intact pellets have speeds of 260 ± 30 m/s and a typical size of 1.1-1.2 mm. The pellet ablation code based on a neutral gas shielding model shows that the penetration depth of the measured pellet parameters does not cross the plasma center, even in medium-sized plasma devices such as the Heliotron J helical device. The injection barrel with a tapered structure developed in this study is feasible for low speed pellet injection.

Design of polarizers for a mega-watt long-pulse millimeter-wave transmission line on the large helical device.

The polarizer is one of the critical components in a high-power millimeter-wave transmission line. It requires full and highly efficient coverage of any polarization states, high-power tolerance, and low-loss feature. Polarizers with rounded shape at the edge of the periodic groove surface are designed and fabricated by the machining process for a mega-watt long-pulse millimeter-wave transmission line of the electron cyclotron resonance heating system in the large helical device. The groove shape of λ/8- and λ/4-type polarizers for an 82.7 GHz transmission line is optimally designed in an integral method developed in the vector theories of diffraction gratings so that the efficiency to realize any polarization state can be maximized. The dependence of the polarization states on the combination of the two polarizer rotation angles (Φλ/8, Φλ/4) is examined experimentally in a low-power test with the newly developed polarization monitor. The results show that the measured polarization characteristics are in good agreement with the calculated ones.

Power and polarization monitor development for high power millimeter-wave.

A new type monitor of power and polarization states of millimeter-waves has been developed to be installed at a miter-bend, which is a part of transmission lines of millimeter-waves, for electron cyclotron resonance heating on the Large Helical Device. The monitor measures amplitudes and phase difference of the electric field of the two orthogonal polarizations which are needed for calculation of the power and polarization states of waves. The power and phase differences of two orthogonal polarizations were successfully detected simultaneously.

Electron cyclotron beam measurement system in the Large Helical Device.

In order to evaluate the electron cyclotron (EC) heating power inside the Large Helical Device vacuum vessel and to investigate the physics of the interaction between the EC beam and the plasma, a direct measurement system for the EC beam transmitted through the plasma column was developed. The system consists of an EC beam target plate, which is made of isotropic graphite and faces against the EC beam through the plasma, and an IR camera for measuring the target plate temperature increase by the transmitted EC beam. This system is applicable to the high magnetic field (up to 2.75 T) and plasma density (up to 0.8 × 10(19) m(-3)). This system successfully evaluated the transmitted EC beam profile and the refraction.

Evaluation of animal models for intestinal first-pass metabolism of drug candidates to be metabolized by CYP3A enzymes via in vivo and in vitro oxidation of midazolam and triazolam.

1. To search an appropriate evaluation methodology for the intestinal first-pass metabolism of new drug candidates, grapefruit juice (GFJ)- and vehicle (tap water)-pretreated mice or rats were orally administered midazolam (MDZ) or triazolam (TRZ), and blood levels of the parent compounds and their metabolites were measured by liquid chromatography/MS/MS. A significant effect of GFJ to elevate the blood levels was observed only for TRZ in mice. 2. In vitro experiments using mouse, rat and human intestinal and hepatic microsomal fractions demonstrated that GFJ suppressed the intestinal microsomal oxidation of MDZ and especially TRZ. Substrate inhibition by MDZ caused reduction in 1'-hydroxylation but not 4-hydroxylation in both intestinal and hepatic microsomal fractions. The kinetic profiles of MDZ oxidation and the substrate inhibition in mouse intestinal and hepatic microsomal fractions were very similar to those in human microsomes but were different from those in rat microsomes. Furthermore, MDZ caused mechanism-based inactivation of cytochrome P450 3A-dependent TRZ 1'-hydroxylation in mouse, rat and human intestinal microsomes with similar potencies. 3. These results are useful information in the analysis of data obtained in mouse and rat for the evaluation of first-pass effects of drug candidates to be metabolized by CYP3A enzymes.

Reduction of Alzheimer's disease amyloid-ß in plasma by hemodialysis and its relation to cognitive functions.

BACKGROUND/AIMS: Rapid removal of plasma amyloid-ß (Aß) by blood purification may serve as a peripheral Aß sink from the brain for Alzheimer's disease therapy. We investigated the reduction of plasma Aß during hemodialysis and cognitive states. METHODS: Aß concentrations and Mini-Mental State Examinations (MMSE) were investigated in 37 hemodialysis patients (68.9 ± 4.1 years). RESULTS: The dialyzers effectively removed Aß(1-40) and Aß(1-42), 63.9 ± 14.4 and 51.6 ± 17.0% at 4 h dialysis, resulting in the reduction of Aßs in whole-body circulation by 51.1 ± 8.9 and 32.7 ± 12.0%, respectively. Although the plasma Aßs before dialysis (750.8 ± 171.3 pg/ml for Aß(1-40)) were higher than those reported for Alzheimer's disease patients, the cognitive states of hemodialysis patients were relatively normal, especially of longer dialysis vintages. CONCLUSIONS: Dialyzers effectively reduced Aßs in whole-body circulation. Repeated rapid decrease of plasma Aßs might maintain cognitive state.

Collective Thomson scattering of a high power electron cyclotron resonance heating beam in LHD (invited).

Collective Thomson scattering (CTS) system has been constructed at LHD making use of the high power electron cyclotron resonance heating (ECRH) system in Large Helical Device (LHD). The necessary features for CTS, high power probing beams and receiving beams, both with well defined Gaussian profile and with the fine controllability, are endowed in the ECRH system. The 32 channel radiometer with sharp notch filter at the front end is attached to the ECRH system transmission line as a CTS receiver. The validation of the CTS signal is performed by scanning the scattering volume. A new method to separate the CTS signal from background electron cyclotron emission is developed and applied to derive the bulk and high energy ion components for several combinations of neutral beam heated plasmas.

Separate evaluation of intestinal and hepatic metabolism of three benzodiazepines in rats with cannulated portal and jugular veins: comparison with the profile in non-cannulated mice.

Pharmacokinetic analyses of three kinds of benzodiazepines--midazolam (MDZ), triazolam (TRZ) and alprezolam (APZ)--were performed in rats with cannulated portal and jugular veins. Each drug was administered to the double-cannulated rats, and pharmacokinetic data for the parent drugs and their 1'- and 4-hydroxylated metabolites were compared with those obtained in non-cannulated mice. In bioavailability, the drugs ranked APZ >> TRZ = MDZ in rats, and APZ > TRZ >> MDZ in mice, with the values for MDZ remarkably different between rats and mice (19% in rats versus 2.3% in mice). In contrast, hepatic availability (Fh) was similar (APZ > TRZ > MDZ) in both species. Highly significant relationships were found between the ratio of the area under the plasma concentration-time curve (AUC) for the parent drugs in portal blood (AUC(por)) to that in systemic blood (AUC(sys)) and Fh in rats and mice. The double-cannulated rat is useful for estimating the hepatic availability of drug candidates by determining the AUC values for the parent drugs in portal and systemic blood samples.

Real-time feedback control of millimeter-wave polarization for LHD.

Electron cyclotron heating (ECH) is widely used in magnetic fusion devices, and the polarization of the injected millimeter-wave beams plays a crucial role in the propagation and absorption of the beam energy by the plasma. This polarization can be adjusted by grating mirror polarizers placed in the transmission lines which carry the microwaves from the power source to the plasma. In long-pulse devices such as the Large Helical Device (LHD) and ITER, it is desirable to track changes in the plasma and adjust the polarization of the ECH in real time such as to keep the absorption as high as possible and avoid shine-through which may lead to overheating of vessel components. For this purpose a real-time feedback control scheme is envisioned in which a measure of the absorption efficiency can be used to adjust the orientation of the polarizing mirrors toward an optimum. Such a setup has been tested in a low-power test stand as preparation for future implementation in the LHD ECH system. It is shown that a simple search algorithm is efficient and can in principle be used to control either the absorption efficiency or the linear polarization angle.

The observation of nonlinear ion cyclotron wave excitation during high-harmonic fast wave heating in the large helical device.

A wave detector, a newly designed magnetic probe, is installed in the large helical device (LHD). This wave detector is a 100-turn loop coil with electrostatic shield. Comparing a one-loop coil to this detector, this detector has roughly constant power coupling in the lower frequency range of 40 MHz, and it can easily detect magnetic wave in the frequency of a few megahertz. During high-harmonic fast wave heating, lower frequency waves (<10 MHz) were observed in the LHD for the first time, and for the power density threshold of lower frequency wave excitation (7.5 MHz) the power density of excited pumped wave (38.47 MHz) was approximately -46 dBmHz. These lower frequencies are kept constant for electron density and high energy particle distribution, and these lower frequency waves seem to be ion cyclotron waves caused by nonlinear wave-particle interaction, for example, parametric decay instability.

Design of collective Thomson scattering system using 77 GHz gyrotron for bulk and tail ion diagnostics in the large helical device.

Collective Thomson scattering (CTS) system is expected to be a strong diagnostic tool for measuring thermal and fast ion distribution function at a local point inside plasmas. The electron cyclotron resonance heating system using a gyrotron at the frequency range of 77 GHz has been installed at the large helical device (LHD). The feasibility of CTS system using the 77 GHz gyrotron is assessed in terms of scattering spectrum and a background noise of the electron cyclotron emission, which affect the signal to noise ratio, with the realistic plasma parameters and incident port locations of LHD. Based on the calculated scattering spectra for bulk and tail fast ion diagnostics, the scattering radiation receiver system with gyrotron frequency feedback circuit is proposed to avoid the frequency chirping.

Effects of premedication with fentanyl and midazolam on mask induction of anaesthesia of dogs with sevoflurane.

Fourteen beagles were used to determine the effects of fentanyl and midazolam as a premedicant for mask induction of anaesthesia with sevoflurane. The drugs were administered to each dog in a randomised cross-over design with a seven-day washout period between experiments. After a 15-minute equilibration period, a treatment consisting of fentanyl (10 mug/kg bodyweight) and midazolam (0.2 mg/kg) was given either intravenously or intramuscularly. Anaesthesia was then induced by the use of a facemask with sevoflurane in 100 per cent oxygen at a flow rate of 4 l/minute. Vaporiser settings were increased by 0.8 per cent at 15-second intervals until the value corresponding to 4.8 per cent sevoflurane was achieved. The time to the onset and cessation of involuntary movements, loss of the palpebral reflex, negative response to tail-clamp stimulation, and endotracheal intubation and cardiopulmonary variables were measured. Both the treatments with tentanyl and midazolam resulted in a shorter and smoother induction of anaesthesia than treatment with saline, and the cardiopulmonary changes were smaller and milder.

Detection of new anti-neutral glycosphingolipids antibodies and their effects on Trk neurotrophin receptors.

We screened sera from patients with various neurological disorders for the presence of anti-neutral glycosphingolipids antibodies and only found them in sera from relapsing polychondritis with limbic encephalitis patients. Neutral glycosphingolipids are resident in membrane lipid rafts where high affinity nerve growth factor (NGF) receptor, Trk is co-localized. Therefore, we examined whether these antibodies influence the action of NGF in NGF-responsive cells. The results strongly suggest that these antibodies enhance NGF-induced Trk autophosphorylation and neurite outgrowth as well as neurofilament M expression. These data strongly indicate that these anti-neutral glycosphingolipids antibodies have a functional impact on NGF-Trk-mediated intracellular signal transduction pathway.

Dynamic behavior of individual cells in developing organotypic brain slices revealed by the photoconvertable protein Kaede.

In recent years, advances in optical imaging methods have facilitated the visualization of events in the developing cortex. In particular, the introduction of DNA encoding fluorescent protein into cells of the embryonic brain allows the visualization of progenitor cells; slice preparations of the cortex then allow the monitoring of the behavior of transfected cells in the context of the living cerebral wall by time-lapse microscopy. Such approaches have provided substantial information about the patterns of neuronal migration. However, as these techniques label large numbers of cells in the ventricular zone (VZ), it is difficult to follow individual cell shape changes or cell behaviors within the VZ, where neuron production and initial migration take place. Here, we report a unique method using the photoconvertable fluorescent protein Kaede, which emits green fluorescence and shifts to emitting red fluorescence upon radiation with UV. Using this method, we were able to follow the behavior of a particular pair of daughter cells among neighboring Kaede-positive cells in the SVZ of mouse brain slices. The spindle shape progenitor divided into two multipolar-shaped daughter cells. The cell-cell borders of daughter cells were clearly visualized, and easily describe the position and distance between two or more cells. The photoconvertable property of Kaede offers a powerful cell marking tool to identify the precise morphology and migratory behaviors of individual cells within living cortical slices.

Sawtooth oscillation in current-carrying plasma in the large helical device.

Sawtooth oscillations have been observed in current-carrying helical plasmas by using electron-cyclotron-emission diagnostics in the Large Helical Device. The plasma current, which is driven by neutral beam injection, reduces the beta threshold of the sawtooth oscillation. When the central q value is increased due to the plasma current, the core region crashes, and, when it is decreased, the edge region crashes annularly. Observed rapid mixture of the plasma in the limited region suggests that these sawtooth crashes are reconnection phenomena. Unlike previous experiments, no precursor oscillation has been observed.

Island dynamics in the large-helical-device plasmas.

In the Large Helical Device plasma discharges, the size of an externally imposed island with mode number ( n/m = 1/1) decreases substantially when the plasma is collisionless ( nu(*)< approximately 1) and the beta is finite ( > approximately 0.1%) at the island location. For the collisional plasmas with finite beta, on the other hand, the size of the island increases. However, there is a threshold in terms of the vacuum island size below which the island enlargement is not seen.

Characterization of GTPase-activating proteins for the function of the Rho-family small GTPases in the fission yeast Schizosaccharomyces pombe.

BACKGROUND: The small GTPase Rho1 has been shown to regulate the organization of the actin cytoskeleton and formation of the cell wall in the fission yeast Schizosaccharomyces pombe. Activity of Rho1 must be precisely regulated in vivo, since both increases and decreases in its activity affect cell growth and shape. Thus, it is important to clarify the mechanism by which the activity of Rho1 is regulated in vivo. RESULTS: Seven genes encoding putative GAPs, GTPase-activating proteins, for the function of the Rho-family proteins were isolated from S. pombe. After disruption of these genes, rga1+ was found to play important roles in cell growth and morphogenesis. In rga1 null cells, delocalized F-actin patches and extraordinary thickening of the cell wall and the septum were observed. On the other hand, over-expression of Rga1 produced shrunken or dumpy cells. The phenotype of the rga1 null cells or the Rga1-over-expressing cells was similar to that of cells containing abnormally high or low Rho1 activity, respectively. Moreover, direct association of Rga1 with Rho1 was shown. Rga1 was localized to the cell ends and septum where Rho1 is known to function. CONCLUSIONS: In S. pombe, Rga1 is involved in the F-actin patch localization, cell morphogenesis, regulation of septation, and cell wall synthesis, probably functioning as a GAP for the function of Rho1.

Effects of nitrous oxide on mask induction of anesthesia with sevoflurane or isoflurane in dogs.

OBJECTIVE: To determine the effects of nitrous oxide (N2O) on the speed and quality of mask induction with sevoflurane or isoflurane in dogs. ANIMALS: 7 healthy Beagles. PROCEDURE: Anesthesia was induced with sevoflurane or isoflurane delivered in 100% oxygen or in a 2:1 mixture of N2O and oxygen via a face mask. Each dog received all treatments with at least 1 week between treatments. Initial vaporizer settings were 0.8% for sevoflurane and 0.5% for isoflurane (0.4 times the minimum alveolar concentration [MAC]). Vaporizer settings were increased by 0.4 MAC at 15-second intervals until settings were 4.8% for sevoflurane and 3.0% for isoflurane (2.4 MAC). Times to onset and cessation of involuntary movements, loss of the palpebral reflex, negative response to tail-clamp stimulation, and endotracheal intubation were recorded, and cardiopulmonary variables were measured. RESULTS: Administration of sevoflurane resulted in a more rapid induction, compared with isoflurane. However, N2O had no effect on induction time for either agent. Heart rate, mean arterial blood pressure, cardiac output, and respiratory rate significantly increased and tidal volume significantly decreased from baseline values immediately after onset of induction in all groups. Again, concomitant administration of N2O had no effect on cardiopulmonary variables. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of N2O did not improve the rate or quality of mask induction with sevoflurane or isoflurane. The benefits provided by N2O attributable to concentrating and second gas effects appear minimal in healthy dogs when low solubility inhalation agents such as isoflurane and sevoflurane are used for mask induction.

Tyrosine phosphorylation of the catalytic subunit p110 of phosphatidylinositol-3 kinase induced by HMG-CoA reductase inhibitor inhibits its kinase activity in L6 myoblasts.

Previous studies from this laboratory have shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (HCRI) causes apoptotic cell death of a muscle cell-derived cell line, L6 myoblasts, by involving the phosphatidylinositol-3 (PI-3) kinase pathway and tyrosine phosphorylation of several cellular proteins, although the relationship between PI-3 kinase pathway and tyrosine phosphorylation responses remained to be elucidated. Here, we show that HCRI induces tyrosine phosphorylation of catalytic subunit p110 of PI-3 kinase as early as 5 min after addition of HCRI into culture medium. We could not detect the tyrosine phosphorylation of the regulatory subunit p85 of PI-3 kinase under the present experimental conditions. Concomitantly, the kinase activity toward PI in p110 immunoprecipitates was decreased with a similar time course. Furthermore, both herbimycin A and genistein, potent inhibitors of tyrosine kinase activity, inhibited HCRI-induced inhibition of PI-3 kinase activity as well as HCRI-induced apoptotic cell death. Once the catalytic subunit p110 becomes tyrosine-phosphorylated, the regulatory subunit p85 appears to be dissociated from the catalytic subunit, because we observed a decreasing amount of p85 regulatory subunits in p110 immunoprecipitates in response to HCRI treatment. These results strongly suggest the novel function of tyrosine phosphorylation of catalytic subunit p110 of PI-3 kinase in the regulation of its kinase activity. The tyrosine phosphorylation of these catalytic subunits may play an important role in the intracellular signal transduction of apoptotic cell death. To our knowledge, this is the first report that tyrosine phosphorylation of p110 catalytic subunit acts as a negative regulator of its kinase activity.