Potent inhibitors of secretory phospholipase A2: synthesis and inhibitory activities of indolizine and indene derivatives

Phospholipase A2 is an enzyme which hydrolyzes the sn-2 position of certain cellular phospholipids. The liberated lysophospholipid and arachidonic acid are precursors in the biosynthesis of various biologically active products. As human nonpancreatic sPLA2 is present in high levels in the blood of patients in several pathological conditions, the potent sPLA2 inhibitors have been suggested to be useful drugs. Here we describe the synthesis, structure-activity relationship, and inhibitory activities of indolizine and indene derivatives. 1-(Carbamoylmethyl)indolizine derivatives and 1-oxamoylindolizine derivatives exhibited very potent inhibitory activity. The former was unstable to air oxidation, but the latter exhibited an improvement both in stability and in potency. Some compounds approached the stoichiometric limit of the chromogenic assay.     

JSFR key technology evaluation on fuel handling system

A simplified fuel handling system design for the demonstration Japan sodium-cooled fast reactor (JSFR) has been proposed. Fast Reactor Cycle Technology Development project phase I results of key technology evaluations on a pantograph fuel handling machine (FHM), a fuel transfer pot with two core component positions, dry spent fuel cleaning and minor actinide-bearing fresh fuel shipping cask are summarized. A full-scale FHM mockup has been fabricated and tested in the air accumulating performance and seismic tolerance data. A mockup fuel transfer pot with fins and chromium carbide coating has been fabricated and tested with sodium accumulating heat transfer performance data. Several sodium cleaning tests using a dummy subassembly has been conducted accumulating cleaning performance data. For fresh fuel shipping cask, a design tool for evaluation of heat transfer capability has been developed and a helium gas cask shows cooling capability of minor actinide-bearing fresh fuel. Those experimental and analytical efforts have shown that key technologies to develop simplified fuel handling system are matured enough to proceed large-scale sodium experiments and conceptual design study for the demonstration JSFR.     

A particle method for elastic and visco-plastic structures and fluid-structure interactions

A new particle method is proposed for elastic and visco-plastic structures based on the concept of MPS (Moving Particle Semi-implicit) method which was developed for fluid dynamics. Particle interaction models for differential operators are prepared in MPS method. The government equations of elastic structures are interpreted into interactions among particles. These interactions are equivalent to those of normal and tangential springs. Therefore the present particle method is simple and corresponding physical meaning is clear. Model for visco-plastic structure is represented to replace these elastic springs into visco-plastic ones. Elements or grids are not necessary. A tensile plate and a cantilever beam as elastic structures are analyzed by the present method. The results are in good agreement with theoretical solutions. Visco-plastic analysis for creep deformation and fracture of a cracked plate is also carried out and the result is in good agreement with an experiment. The present particle method for elastic structures is combined with MPS method for fluid-structural interaction problems. Since both methods are based on the same particle modeling in Lagrangian coordinates, large deformation of the interfaces can be easily analyzed. Water falling on a cantilever beam is analyzed by the combined method. Crash of water and resultant displacement of the beam are successfully analyzed. Structural analysis in a breakwater is carried out with wave propagation. The calculated pressure distribution on the breakwater is in good agreement with a theory. Received 21 November 2000     

Preparation and characterization of dicesium tetravalent plutonium hexanitrate

In experiments on U crystallization in a dissolver solution containing Cs, there is concern that Cs and Pu(IV) nitrate complex are deposited on the UNH crystal in the dissolver solution at the time of the U crystallization. The characteristics of generation of Cs and Pu(IV) nitrate complex with dissolver solution of MOX fuel were examined. This complex was obtained as a precipitate by mixing dissolver solution of MOX fuel and CsNO₃ solution, and was identified as dicesium tetravalent plutonium hexanitrate, Cs₂Pu(NO₃)₆ by concentration analysis and XRD. The precipitate has a tendency to be generated at high HNO₃ concentrations. Thermal analysis shows that the precipitate is stable below 245 °C, and a weight loss of 10.29 ± 0.23% is observed between 245 and 297 °C. This result indicates the decomposition of Cs₂Pu(NO₃)₆ to Cs₂PuO₂(NO₃)₄. With these properties, the UNH crystal should melt at the condition between 60 and 100 °C and be separable from the Cs complex by filtration. This suggests a new method of crystal purification allowing higher decontamination of UNH crystal in the U crystallization process.     

Overexpression of c-met proto-oncogene associated with chromophilic renal cell carcinoma with papillary growth

The in vitro antiviral activity against picornaviruses (rhinovirus serotype 1B and 14, and poliovirus type 2) of new synthetic 3-hydroxyflavones, 3-acetoxyflavones, and substituted cinnamic and benzoic acid flavon-3-yl esters was evaluated. The maximum non-toxic concentration of compounds was determined in a human cell line (HeLa) suitable for the replication of the three viruses. Their antiviral potency was measured by a plaque reduction assay. Generally, rhinoviruses exhibited a higher sensitivity to the new flavonoids than poliovirus. Flavones, with sterically small substituents in position 3, showed good activity against both rhinoviruses tested. However, the introduction of bulky substituents in the same position resulted in analogues with a higher toxicity and often with a lower efficacy.     

Novel action of a piperazine derivative on the end-plate of the frog

The effects of a piperazine derivative, trimetazidine (1-(2, 3, 4-trimethoxybenzyl) piperazine dihydrochloride) on the frog end-plate membrane were studied. Action and resting membrane potentials and the input resistance of muscle fibers were not affected by trimetazidine (82-165 muM). Under these conditions, the frequency of the miniature endplate potentials was unchanged while its amplitude was slightly decreased. The amplitude of acetylcholine (ACh) potentials were markedly and reversibly decreased after application of trimetazine (82-165 muM). The dose response curve of the end-plate membrane to ACh showed a non-competitive type of blockade. Trimetazidine (165 muM) not only decreased the amplitude of the end-plate currents (EPC) recorded from the glycerinated muscles using a voltage clamp technique, but also drastically shortened its time course. Under these conditions, the falling phase of the EPC became completely voltage insensitive. The equilibrium potential for the EPC slightly shifted to a more negative value in the presence of trimetazine (165 muM). Coefficient of variation of EPC was increased by Trimetazidine (165 mum), indicating a decrease in the quantal content of the EPC. The rate of desensitization of the end-plate to ACh was facilitated and the rate of decrease in EPC amplitude during tetanic stimulation became voltage sensitive by the action of trimetazidine (133 muM). It is concluded that trimetazidine mainly acts on the postsynaptic membrane with a weak presynaptic action. The agent seems to block a step subsequent to the interaction of ACh with its receptor, which presumably involves changes in the ion conductance of the membrane and is responsible for the voltage sensitivity of the response.     

Purification of uranium products in crystallization system for nuclear fuel reprocessing

Uranium crystallization system has been developed to establish an advanced aqueous reprocessing for fast breeder reactor (FBR) fuel cycle. In the crystallization system, most part of uranium in dissolved solution of spent FBR-MOX fuels is separated as uranyl nitrate hexahydrate (UNH) crystals by a cooling operation. The targets of U yield and decontamination factor (DF) on the crystallization system are decided from FBR cycle performance and plutonium enrichment management. The DF is lowered by involving liquid and solid impurities on and in the UNH crystals during crystallization. In order to achieve the DF performance (more than 100), we discuss the purification technology of UNH crystals using a Kureha Crystal Purifier (KCP). Results show that more than 90% of uranium in the feed crystals could be recovered as the purified crystals in all test conditions, and the DFs of solid and liquid impurities on the purified UNH crystals are more than 100 under longer residence time of crystals in the column of KCP device. The purification mechanism is mainly due to the repetition of sweating and recrystallization in the column under controlled temperature.     

Positivity for antinuclear antibody in patients with advanced rheumatoid arthritis

Some patients with rheumatoid arthritis (RA) as well as those with other collagen diseases are positive for antinuclear antibody (ANA). We investigated the frequency of positivity for ANA in 104 patients with RA and evaluated the clinical features and laboratory data in the ANA-positive and -negative groups. The presence of ANA in sera was studied by indirect immunofluorescence using HEp-2 cells as the antigen substrate. Sera with a positive fluorescence at a dilution of 1:20 were considered to be positive for ANA. Of the 104 patients, 39 (37.5%) were positive for ANA. The staining pattern in the positive cases varied, but most were speckled (64.1%) and homogeneous (48.7%). A small number showed a nucleolar (20.5%) or a centromere (10.3%) pattern. None showed a shaggy pattern. The ANA titer was lower in RA patients compared with those with other collagen-related diseases such as systemic lupus erythematosus or progressive systematic sclerosis. None of the patients positive for ANA with either a nucleolar or centromere staining pattern had progressive systemic sclerosis or the CREST syndrome. One patient each had Raynaud's phenomenon and pulmonary fibrosis. There was no correlation between ANA positivity and indicators of joint inflammation. The prevalence of ANA positivity in patients with advanced or prolonged disease was higher than those with early stages or short durations. There was no correlation with drug therapy.