Prospects for 4-laser white-light sources

This paper describes a series of simulation experiments designed to demonstrate the feasibility of using solid-state lasers in white-light mixtures. The mixed-laser sources are evaluated in terms of the luminous efficacy of the radiation (LER) as well as different measures of colour performance. The latter include the CIE colour rendering index (R_a) and the IES colour fidelity index (R_f) as well as a selection of additional parameters in the two systems. Optimization of the mixtures is achieved by the use of purpose-designed differential evolution algorithms. The best results to date (with four real laser wavelengths) are R_f of 84 with LER 364?lm/W, which indicate the feasibility of the mixed-laser approach to provide highly efficient, energy-saving light sources. These prospects will be further enhanced by potential future developments in semiconductor lasers, with the possibility of producing R_f of 86 with LER of 380?lm/W.     

Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase

The kinase inhibitors SB 203580 and PD 98059 have been reported to be specific inhibitors of the 38- and 42/44-kDa mitogen-activated protein kinase (MAPK) pathways, respectively. In this study, the two inhibitors were found to decrease platelet aggregation induced by low concentrations of arachidonic acid, suggesting that they also interfere with the metabolism of arachidonic acid to thromboxane A2. In support of this, SB 203580 and PD 98059 inhibited the conversion of exogenous [3H]arachidonic acid to [3H]thromboxane in intact platelets. Measurement of platelet cyclooxygenase-1 activity following immunoprecipitation revealed that SB 203580 and PD 98059 are direct inhibitors of this enzyme. Both compounds were shown to inhibit purified cyclooxygenase-1 and -2 by a reversible mechanism. In addition, SB 203580 (but not PD 98059) inhibited platelet aggregation induced by prostaglandin H2 and the conversion of prostaglandin H2 to thromboxane A2 in intact platelets. SB 203580 also inhibited this pathway in platelet microsome preparations, suggesting a direct inhibitory effect on thromboxane synthase. These results demonstrate that direct effects of the two kinase inhibitors on active arachidonic acid metabolites have to be excluded before using these compounds for the investigation of MAPKs in signal transduction pathways. This is of particular relevance to studies on the regulation of cytosolic phospholipase A2 as these two MAPKs are capable of phosphorylating cytosolic phospholipase A2, thereby increasing its intrinsic activity.     

Two residues that may ligate Ca2+ in transmembrane domain six of the plasma membrane Ca(2+)-ATPase

In order to identify Ca2+ ligands in the putative transmembrane domain 6 of the plasma membrane Ca2+ pump, amino acids Asn879, Met882, Asp883, and Ser887 were singly altered. Asn879, Met882, and Asp883 were chosen because the corresponding amino acids have been proposed as Ca2+ ligands in the sarcoplasmic reticulum Ca2+ pump (Clarke, D. M., Loo, T. W., and MacLennan, D. H. (1990) J. Biol. Chem. 265, 6262-6267). For the alterations, a fully active truncated version of the pump was used, because the interaction of Ca2+ with the pump could be studied without interference from calmodulin binding. The mutants at Asn and Asp did not carry out ATP-supported Ca2+ uptake and formed no acylphosphate from [gamma-32P]ATP, suggesting that, like the corresponding amino acids in the sarcoplasmic reticulum Ca2+ pump, these two are Ca2+ ligands. However, all the mutants at the position of Met882 showed some activity. Indeed, the Met882--> Ile mutant was fully active at a saturating Ca2+ concentration and only the K1/2 for Ca2+ activation was shifted slightly upward. Converting the Met to Thr (which is the corresponding residue in the sarcoplasmic reticulum Ca2+ pump) reduced the activity to 20% of the wild type, further emphasizing the differences between the two Ca2+ pumps. The mutant Ser887--> Ala was expressed in greater amounts than, and had a specific activity about 50% higher than, the wild type, indicating that this serine also could not be a Ca2+ ligand and could not replace the missing Thr at position Met882.     

The new age of liver transplantation

The advent of cyclosporin A for immunosuppression (IS) in liver transplantation (LTx) in the early 1980s heralded a new age for LTx, resulting in widespread application, rapidly expanding indications, relaxation of restrictions in donor selection and advances in the preservation of liver grafts and management of LTx operations. Liver transplantation, together with the transplantation of other organs (kidney, pancreas, heart, heart-lung, intestine), became possible. In Australia, around 125 LTx (22% in children) are performed each year. Indications are: primary sclerosing cholangitis; primary biliary cirrhosis; auto-immune hepatitis; chronic viral hepatitis; biliary atresia; metabolic disorders; fulminant hepatic failure (FHF); alcoholic cirrhosis; and malignancy (cancer, CA). Since 1965, 810 patients underwent LTx and 70 (9%) re-Tx. Patient survivals at 1, 5 and 9 years post-Tx are 80, 74 and 66%, respectively. Patients with primary diseases that recur in the LTx (hepatitis B and CA) do less well following LTx, with 5-year survival rates of 55 and 40%, respectively). Recent developments include: increasing the availability of donor organs by the use of living donors, 'split' cadaveric donor (CD) grafts, 'marginal' and non-heart-beating CD grafts and xenografts; expanding the indications for LTx; development of effective liver support systems for patients with FHF; the treatment of diabetics with liver failure with islet Tx (at the time of LTx); more effective immunosuppression; and methods to diminish recurrent disease in LTx. Some understanding of the unique 'tolerogenic' capabilities of the liver has come with the recognition of 'two-way microchimerism'. The satisfactory 5-9 year outcomes for patients underline the cost-effectiveness of LTx.     

Contrasting effects of D- and L-(E)-4-(3-phosphono-2-propenyl)piperazine-2-carboxylic acid as anticonvulsants and as inhibitors of potassium-evoked increases in hippocampal extracellular glutamate and aspartate levels in freely moving rats

Microdialysis experiments performed in the dorsal hippocampus of freely moving rats showed that L-(E)-4-(3-phosphono-2-propenyl)piperazine-2-carboxylic acid (L-CPPene) is 10 times as potent as D-CPPene in inhibiting potassium-induced increases in extracellular levels of aspartate and glutamate. In control experiments, two 100 mM KCl stimuli (S1 and S2) applied for 10 min each (separated by a 40-min recovery period) produced substantial (300-500%) increases in the extracellular levels of aspartate, glutamate, taurine, and GABA and a 50% decrease in the glutamine level. S2/S1 ratios in the control groups were 0.67 (aspartate), 0.78 (glutamate), 0.83 (GABA), and 0.85 (taurine). In the experimental groups, D- or L-CPPene was applied via the probe during the second potassium stimulus (S2). L-CPPene (25 or 250 microM) produced selective suppression of potassium-induced increases of extracellular glutamate (S2/S1 ratio: 0.25) and aspartate (S2/S1 ratio: 0.20) levels, whereas 250 microM D-CPPene was required to inhibit the extracellular aspartate and glutamate increases. Neither enantiomer of CPPene affected the potassium-induced increases of GABA and taurine or the decrease in extracellular glutamine concentration. An additional study comparing the anticonvulsant potencies of D- and L-CPPene was performed using audiogenic DBA/2 mice. The anticonvulsant potency of D-CPPene, as assessed against sound-induced seizures in DBA/2 mice, was an order of magnitude higher than that of L-CPPene [ED50 clonic phase (intraperitoneal, 45 min): 1.64 mumol/kg and 16.8 mumol/kg, respectively]. We attribute the anticonvulsant action of D-CPPene to its antagonist action at the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)