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Biomedical subjects

D Nicholls

Publications and source records attributed to D Nicholls.

17 recordsLinked to original sources
PubMed1991

Medicinal azides. Part 8. The in vitro metabolism of p-substituted phenyl azides.

1. A series of p-substituted aromatic azides was synthesized and their metabolism investigated in suspensions of mouse liver microsomes and mouse hepatocytes. Metabolite analysis was performed by h.p.l.c. 2. On incubation with microsomes under anaerobic conditions p-nitro, p-cyano- and p-chlorophenyl azide afforded metabolites which co-chromatographed with the respective aromatic amines. The rate at which p-nitrophenyl azide was metabolically reduced was approximately 20-fold that observed for p-cyano- and p-chlorophenyl azide. 3. Phenyl azide, p-methoxyphenyl azide and the aliphatic congener, phenethyl azide, did not furnish detectable amounts of metabolites on incubation with microsomes under anaerobic conditions. When phenyl azide and p-methoxyphenyl azide were incubated with hepatocytes or microsomes under aerobic conditions the resulting chromatograms furnished peaks which co-eluted with authentic p-hydroxyphenyl azide. 4. The microsomal reduction of p-nitrophenyl azide was dependent upon the presence of viable microsomes and NADPH, and on the absence of oxygen above the incubation medium.

Aerobiosis↗
PubMed1990

The release and uptake of excitatory amino acids.

In this article, David Nicholls and David Attwell describe recent advances in our understanding of the mechanisms by which excitatory amino acids are released from cells, and of the way in which a low extracellular glutamate concentration is maintained. Glutamate can be released from cells by two mechanism: either by Ca2(+)-dependent vesicular release or, in pathological conditions, by reversal of the plasma membrane uptake carrier. The contrasting pharmacology and ionic dependence of the glutamate uptake carriers in the vesicle membrane and in the plasma membrane explain how glutamate (but probably not aspartate) can function as a neurotransmitter, and why the extracellular glutamate concentration rises to neurotoxic levels in brain anoxia.

Animals↗
PubMed1988

Phorbol ester translocation of protein kinase C in guinea-pig synaptosomes and the potentiation of calcium-dependent glutamate release.

The distribution of protein kinase C activity and specific phorbol ester binding sites between soluble and particulate fractions of isolated guinea-pig cerebral cortical synaptosomes is examined following preincubation with phorbol esters. Half-maximal decrease in cytosolic activity requires 10 nM 4 beta-phorbol myristoyl acetate. Specific [3H]phorbol dibutyrate binding sites are translocated from cytoplasmic to particulate fractions in parallel with protein kinase C activity. Depolarization of the plasma membrane by 30 mM KCl does not cause translocation of protein kinase C. 1 microM 4 beta-phorbol myristoyl acetate and 1 microM 4 beta-phorbol didecanoate (but not 1 microM 4 alpha-phorbol didecanoate) enhance the release of glutamate from synaptosomes partially depolarized by 10 mM KCl; however, 4 beta-phorbol myristoyl acetate is ineffective at 20 nM. 1 microM 4 beta-phorbol myristoyl acetate slightly increases the cytosolic free Ca2+ concentration of polarized synaptosomes, but not that following partial depolarization. 4 beta-Phorbol myristoyl acetate causes a concentration-dependent increase in the Ca2+-dependent glutamate release induced by sub-optimal ionomycin concentrations, but is without effect on the release induced by maximal ionomycin. It is concluded that phorbol esters stereospecifically enhance the Ca2+-sensitivity of glutamate release, but that higher concentrations may be required than for protein kinase C translocation in the same preparation. Instead the enhancement may be related to the rapid inactivation of protein kinase C which occurs with phorbol esters.

Animals↗
PubMed1987

Blister beetle dermatosis in New Zealand.

Seventy-four New Zealand Army personnel with a distinctive bullous dermatosis caused by an endemic beetle are described. These are the first reported cases of this condition in New Zealand. The beetle, Thelyphassa lineata (Fabricius) belonging to the family Oedemeridae was shown to be a vesicant species, as skin contact induced blisters in volunteers. This is a previously unrecognised property of this species.

Animals↗
PubMed1985

Bioenergetic actions of beta-bungarotoxin, dendrotoxin and bee-venom phospholipase A2 on guinea-pig synaptosomes.

Low concentrations of beta-bungarotoxin or bee-venom phospholipase A2 cause a progressive Ca2+-dependent increase in the proton permeability of the mitochondria within the synaptosomal cytosol, manifested as an increase in oligomycin-insensitive respiration and a partial depolarization of the mitochondrial membrane potential. This uncoupling appears to be a consequence of fatty acids liberated by phospholipase A2 activity at the plasma membrane, since it can be mimicked by the addition of oleate-albumin complexes, in which case there is no requirement for external Ca2+. Dendrotoxin does not affect the mitochondrial proton permeability in situ, but protects partially against the uncoupling action of beta-bungarotoxin. In contrast, this effect of bee-venom phospholipase A2 is unaffected by dendrotoxin. beta-Bungarotoxin, but not bee-venom phospholipase A2, induces a slow progressive depolarization of the plasma membrane. The action of beta-bungarotoxin at the plasma membrane appears not to be related to fatty acid production, since it is augmented rather than inhibited by raising albumin concentrations in the medium. It is concluded that beta-bungarotoxin has at least two actions on intact synaptosomes, both of which may involve interaction at the plasma membrane with a site common to dendrotoxin: first, a mitochondrial uncoupling mediated by fatty acids and, secondly, a depolarization at the plasma membrane.

Animals↗
PubMed1985

Calcium efflux and cycling across the synaptosomal plasma membrane.

Ca2+ efflux from intact synaptosomes is investigated. Net efflux can be induced by returning synaptosomes from media with elevated Ca2+ or high pH to a normal medium. Net Ca2+ efflux is accelerated when the Na+ electrochemical potential gradient is collapsed by veratridine plus ouabain. Under steady-state conditions at 30 degrees C, Ca2+ cycles across the plasma membrane at 0.38 nmol . min-1 . mg-1 of protein. Exchange is increased by 145% by veratridine plus ouabain, both influx and efflux being increased. Increased influx is probably due to activation of voltage-dependent Ca2+ channels, since it is abolished by verapamil. The results indicate that, at least under conditions of low Na+ electrochemical gradient, some pathway other than a Na+/Ca2+ exchange must operate in the plasma membrane to expel Ca2+.

Animals↗
PubMed1982

The role of phosphate in the regulation of the independent calcium-efflux pathway of liver mitochondria.

The rate of spontaneous efflux of Ca from liver mitochondria incubated in the absence of ATP and Mg increases with time and is associated with a synchronous collapse of membrane potential and with Pi efflux. In the presence of Mg and ATP the ruthenium-red-induced Ca efflux does not change with time. The activity of the Ca efflux pathway in Pi-depleted mitochondria is 15-fold greater than in mitochondria equilibrated with 3.3 mM Pi. 50% inhibition is caused by 0.3 mM Pi. The membrane potential is not affected by changes in Pi concentration, although the steady-state extra-mitochondrial free Ca concentration reflects the alterations in efflux rate. In the presence of Pi, the ruthenium-red-induced efflux rate is independent of the total matrix Ca content; however in Pi-depleted mitochondria, with acetate substituting as permeant anion, the efflux rate increases with total matrix Ca content. The lowered efflux rate in the presence of Pi is not due to a limitation in the rate of dissociation of the matrix Ca-phosphate complex. The efflux pathway is activated by a lowered membrane potential, but the relative effect of Pi is retained. Under the present conditions Na slightly inhibits the efflux rate. The lack of an effect of total matrix Ca content on the efflux rate in the presence of Pi is used as the basis of a highly accurate determination of the activity of the Ca uniporter as a function of external free Ca concentration.

Adenosine Triphosphate↗
PubMedDate not supplied

Multidisciplinary management of vascular access devices.

Many problems associated with the use of vascular access devices (VADs) can be circumvented with an organized, systematic approach to management. This paper describes an approach that includes several key components: 1) A nurse coordinator of parenteral therapy (CPT) follows all patients with a VAD; records demographic and clinical data on an ongoing basis; monitors complications and outcomes; serves as a consultant for VAD-related questions; develops policies, procedures, and guidelines for catheter care; and oversees inservice nursing and basic patient education. 2) A data coordinator enters all data into a data base management system, compiles complication and other statistics on a periodic basis, and retrieves selected data for specific purposes. 3) A VAD Committee, composed of the above two individuals, a nurse epidemiologist, and physicians representing medical oncology, hematology, transplantation, pediatrics, and surgery, meets monthly to collectively evaluate and assign cause for complications, consider new products, and discuss policy changes regarding VADs. As a result of this multidisciplinary process, responsibility and accountability for VAD insertion and care are appropriately placed, statistics on complications are compiled, and treatment and policy decisions are made. These outcomes have resulted in a significant reduction in complications, an increase in average catheter life, enhancement of quality assurance, and overall improved patient care.

Algorithms↗