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Biomedical subjects

D G Watson

Publications and source records attributed to D G Watson.

At least 73 records · Page 4Linked to original sources
PubMed1994

Object recognition under sequential viewing conditions: evidence for viewpoint-specific recognition procedures.

In many computational approaches to vision it has been emphasised that object recognition involves the encoding of view-independent descriptions prior to matching to a stored object model, thus enabling objects to be identified across different retinal projections. In contrast, neurophysiological studies suggest that image descriptions are matched to less abstract, view-specific representations, resulting in more efficient access to stored object knowledge for objects presented from a view similar to a stored viewpoint. Evidence favouring a primary role for view-specific object descriptions in object recognition is reported. In a series of experiments employing line drawings of familiar objects, the effects of depth rotation upon the efficiency of object recognition were investigated. Subjects were required to identify an object from a sequence of very briefly presented pictures. The results suggested that object recognition is based upon the matching of image descriptions to view-specific stored representations, and that priming effects under sequential viewing conditions are strongly influenced by the visual similarity of different views of objects.

Adolescent↗
PubMed1994

Carrier-free 131I-meta-iodobenzylguanidine: comparison of production from meta-diazobenzylguanidine and from meta-trimethylsilylbenzylguanidine.

Meta-iodobenzylguanidine (MIBG) is a drug which is selectively accumulated by the uptake-1 process in adrenergic tissues. When labelled with 131I, it may be used for the targetted radiotherapy of tumours such as phaeochromocytoma and neuroblastoma. This paper describes the preparation of carrier-free 131I-MIBG by radioiodination of meta-diazobenzylguanidine, and compares this process with one involving iododesilylation of meta-trimethylsilylbenzylguanidine. Both processes result in the formation of carrier-free 131I-MIBG whose specific activity at greater than 3 x 10(16) Bq mol-1 is at least 100 times higher than that of commercially available 131I-MIBG for therapeutic use. The therapeutic use of 131I-MIBG with a higher than usual specific activity is predicted to result in a greater target-to-nontarget ratio, and therefore enhanced efficacy because of an increased therapeutic index. As the radiochemical yield of the process involving the metadiazobenzylguanidine intermediate is only 13%, compared with 98% for the iododesilylation reaction, the latter is the preferred synthetic route.

3-Iodobenzylguanidine↗
PubMed1994

Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness.

Lithium, an effective treatment for mania and the prevention of recurrent episodes of both mania and depression in patients with manic depressive illness, exerts multiple biochemical effects. However, any clinically relevant site of action of lithium must occur at therapeutic concentrations attained in the brain of patients and must account for the lag period accompanying onset of action as well as effects persisting beyond discontinuation of treatment. This monovalent cation acts as a potent uncompetitive inhibitor in the receptor-coupled breakdown of inositol phospholipids, resulting in a relative depletion of inositol and an alteration in the generation of diacylglycerol, an endogenous activator of protein kinase C. In our laboratory, we are examining the action of chronically administered lithium on posttranslational modification of specific phosphoproteins involved in regulating signal transduction in the brain. We have found that chronic, but not acute, administration of lithium in rats markedly reduces a major phosphoprotein substrate of protein kinase C in the hippocampus, an effect that persists beyond the cessation of lithium treatment. This protein, myristoylated alanine-rich C kinase substrate ("MARCKS"), is implicated in synaptic neurotransmission, calcium regulation, and cytoskeletal restructuring. These findings have relevance for the long-term action of lithium in stabilizing an underlying dysregulation in the brain and may move us closer to formulating a molecular basis of manic depressive illness.

Bipolar Disorder↗
PubMed1993

Identification and quantification of gamma-glutamyl conjugates of biogenic amines in the nervous system of the snail, Helix aspersa, by gas chromatography-negative-ion chemical ionisation mass spectrometry.

The gamma-glutamyl conjugates of p-octopamine and dopamine were identified unambiguously for the first time and quantified in a single cerebral ganglion or pleural plus pedal ganglia of the snail, Helix aspersa, by gas chromatography-negative-ion chemical ionisation mass spectrometry. A new method was used for synthesis of gamma-glutamylamine standards. The concentration of gamma-glutamyltyramine was found to be low in the tissues, therefore it was used as an internal standard. The gamma-glutamylamines were extracted with water and derivatised with pentafluoropropionic anhydride and trifluoroethanol. Under negative-ion chemical ionisation conditions, the trifluoroethyl and pentafluoropropionyl derivatives produced significant ions which were sufficiently abundant to be suitable for selective ion monitoring. The method had a limit of detection of ca. 80 pg of gamma-glutamyl conjugate per tissue and calibration curves were linear over the range examined.

Animals↗
PubMed1993

The determination of hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls.

5- and 6-Hydroxydopamine, which we had earlier identified as naturally occurring amines in human urine, were quantified in Parkinson's patients treated with L-DOPA, Parkinson's patients whose treatment did not include L-DOPA and in age matched controls. Analysis was carried out by GC-MS of the ditrifluoromethylbenzoyl-trimethylsilyl (DTFMB-TMS) derivatives of the compounds. The concentrations of 5- and 6-hydroxydopamine in the urine of DOPA treated Parkinson's patients were significantly higher than the concentrations from patients not treated and from normal controls. Urinary dopamine levels were greatly elevated in DOPA treated Parkinson's patients while p-tyramine levels were suppressed. No marked differences were seen between the three groups in terms of the urinary concentrations of any of the other amines measured.

Biogenic Monoamines↗
PubMed1993

Analysis of biogenic amines in plasma of hypertensive patients and a control group.

Procedures were developed for the determination of 17 circulating amines using gas chromatography-negative ion chemical ionisation mass spectrometry. The amines were quantified against their appropriate deuterated isotopomers. The mean concentrations and ranges of catecholamines and trace amines were high compared with previous studies. In comparison with nonhypertensives, plasma from hypertensives had higher concentrations of the following amines: noradrenaline (t = 4.0%); normetanephrine (t = 6.1%) and metanephrine (t = 1.9%). There were no significant differences between 5HT levels in plasma from hypertensives and controls. The following trace amines could be detected in variable amounts in plasma: p-tyramine, m-tyramine, p-octopamine, m-octopamine, p-synephrine, m-synephrine, and salsolinol. The trace amines melatonin, N-acetyl 5HT, tryptamine, 6-hydroxymelatonin and 5-methoxytryptamine could not be detected in plasma with limits of detection lying in the range 20-100 pg ml-1.

Biogenic Amines↗
PubMed1993

Assay of certain oral contraceptive formulations by gas chromatography-mass spectrometry-selected ion monitoring.

The combined technique of gas chromatography--mass spectrometry--selected ion monitoring (GC-MS-SIM) has been employed for the nanogram level determination of ethinyloestradiol, mestranol, norgestrel and norethisterone in various oral contraceptive formulations. Steroids were assayed as their DMES-or methoxime DMES ether derivatives in the presence of ethisterone as the internal standard. The method is accurate, specific and suitable for single tablet assay.

Contraceptives, Oral, Hormonal↗
PubMed1992

Chronic lithium administration alters a prominent PKC substrate in rat hippocampus.

The therapeutic effect of lithium in the treatment of bipolar disorder exhibits a significant delay in the onset of action and a persistence of efficacy beyond abrupt discontinuation of treatment. Lithium is known to alter receptor-coupled phosphoinositide second messenger pathway in brain, resulting in indirect changes in an endogenous activator of protein kinase C (PKC). Such evidence has suggested that PKC may be involved in the mechanism of action of lithium in the brain. PKC represents a site wherein long-term regulatory changes in cell function occur through the phosphorylation of specific phosphoproteins involved in processes including neurotransmitter release and receptor activation. In studies of rats exposed to lithium, however, we have found no significant effects of chronic administration on the relative activity, subcellular distribution, or activation of PKC in hippocampus. We did find a major reduction in the in vitro PKC mediated phosphorylation of two major substrates, 83 kDa and 45 kDa, in hippocampus of rats exposed to chronic lithium and maintaining clinically relevant therapeutic levels in brain. Using immunoblot analysis we have identified a known myristoylated alanine-rich C kinase substrate (MARCKS) at 83 kDa. In vivo levels of MARCKS in hippocampus were found to be significantly reduced after chronic lithium exposure. These findings persist in animals withdrawn from lithium, but are not apparent following acute treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Determination of acidic metabolites of biogenic amines in human aqueous humour by gas chromatography--negative ion chemical ionisation mass spectrometry.

The concentrations of acidic metabolites derived from the biogenic amines o-, m-, and p-tyramines (o-, m-, and p-hydroxyphenylacetic acids), p-octopamine/p-synephrine (p-hydroxymandelic acid), and dopamine (homovanillic acid and 3,4-dihydroxyphenylacetic acid) were measured in human aqueous humour obtained from patients undergoing elective surgery for cataract removal or for trabeculectomy as a treatment for chronic open-angle glaucoma. There were no clear differences in the pattern of metabolism of neurotransmitters between the two groups. An unexpected finding was that the o-tyramine metabolite, o-hydroxyphenylacetic acid, was present in aqueous humour.

Acids↗
PubMed1991

Determination of (-)-bunolol and its metabolite, dihydro-(-)-bunolol, in human aqueous humour by gas chromatography-negative ion chemical ionisation mass spectrometry.

(-)-Bunolol (LB) was applied to the human eye in a commercially available eye drop formulation. LB and its metabolite, dihydro-(-)-bunolol (DHLB) were identified and quantified in human aqueous humour. The compounds were analysed as their trimethylsilyl-pentafluorobenzamide derivatives using gas chromatography-negative ion chemical ionisation mass spectrometry. In the case of DHLB the corresponding 2H3-labelled isotopomers were used as internal standards and LB was quantified against its methoxime derivative. Calibration curves for LB and DHLB against internal standards were linear with correlation coefficients 0.994 and 0.996, respectively. Replicate analyses of a pooled sample of aqueous humour containing LB and DHLB gave standard errors of the mean of +/- 9.8 and +/- 2.4% for the concentrations of LB and DHLB, respectively. The practical limit of detection of the method was ca. 30 pg for LB and ca. 100 pg for DHLB. The derivatization procedure was also satisfactory for the analysis of a number of other beta-blockers which are used in ophthalmological practice.

Aqueous Humor↗
PubMed1991

Biogenic amines: their occurrence, biosynthesis and metabolism in the locust, Schistocerca gregaria, by gas chromatography-negative-ion chemical ionisation mass spectrometry.

Extraction-derivatisation techniques have been developed for the unambiguous identification of biogenic amines, and their putative amino acid precursors and metabolites (both major and minor), in single ventral thoracic nerve cords of the locust. Schistocerca gregaria, by the use of gas chromatography-negative-ion chemical ionisation mass spectrometry with selected ion monitoring. In addition the configuration of that enantiomer of p-octopamine present in the thoracid nervous system of the locust was established as R using the chiral derivatisation reagent, (-)-heptafluorobutyrylphenylalanyl chloride.

Acetylation↗
PubMed1991

The analysis of thiocarbamides by gas chromatography/negative-ion chemical-ionization mass spectrometry.

Thiocarbamides were converted to their di-N-pentafluorobenzyl (PFB) derivatives and analysed by gas chromatography/negative-ion chemical-ionization mass spectrometry with methane as reagent gas. The PFB derivatives of the 2-thiouracils gave mass spectra in which the ion current was carried largely by an ion arising from [M-PFB]-. The derivative was used in the determination of the uptake and metabolism of thiocarbamides by cultures of melanoma cells.

Gas Chromatography-Mass Spectrometry↗
PubMed1991

Measurement of urinary medium chain acyl glycines by gas chromatography--negative ion chemical ionization mass spectrometry.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an inborn error of fatty acid metabolism, which is difficult to diagnose, partly because of its unpredictable clinical presentation. A specific diagnostic marker is an increased excretion of certain medium chain acyl glycines. A sensitive and specific method has been developed for the extraction, derivatization, identification and quantitation of urinary medium chain acyl glycines by gas chromatography-negative ion chemical ionization mass spectrometry (GC-NICIMS). The following series of standard acyl glycines has been synthesized and characterized: hexanoyl, octanoyl, 3-phenylpropionyl and suberyl and their respective isotopomers (using 13C2-glycine; for use as internal standards). The range of excretion of these compounds in normal subjects has been established using this method and increased excretion of acyl glycines, particularly hexanoyl, 3-phenylpropionyl and suberyl was successfully demonstrated in three MCAD deficient subjects from one family.

Acyl-CoA Dehydrogenases↗
PubMed1991

The analysis of 5-fluorouracil in human plasma by gas chromatography-negative ion chemical ionization mass spectrometry (GC-NICIMS) with stable isotope dilution.

5-Fluorouracil (5-FU) was extracted from plasma and converted to its di-N-ditrifluoromethylbenzyl (DTFMBz) derivative by treatment with DTFMBzBr. Under negative ion chemical ionization (NICI) conditions the derivative yielded a mass spectrum in which most of the ion current was carried by the M(-)-DTFMBz ion (m/z 355). Selected ion monitoring enabled detection of this derivative in amounts less than 1 pg, and the practical limit of detection for 5-FU extracted from plasma was ca 400 pg ml-1. 5-FU was quantified by adding a fixed amount of [15N2]5-FU to samples of plasma before extraction, and comparing the ratio of the ions of m/z 355 and 357 against a calibration curve constructed over the concentration range under investigation. The method was used to measure the variation in the concentration of 5-FU with time during continuous infusion of the drug via three, different protocols in patients with hepatic tumour.

Fluorouracil↗
PubMed1991

A mutant CHO-K1 strain with resistance to Pseudomonas exotoxin A and alphaviruses fails to cleave Sindbis virus glycoprotein PE2.

RPE.40, a mutant CHO-K1 strain selected for resistance to Pseudomonas exotoxin A, is defective in the production of infectious alphaviruses, although viruses are taken in and processed normally (J. M. Moehring and T. J. Moehring, Infect. Immun. 41:998-1009, 1983). To determine the cause of this defect, the synthesis of Sindbis virus proteins was examined. RPE.40 cells produced and glycosylated structural glycoprotein precursors PE2 and immature E1 normally. Mature E1 was formed, but PE2 was not cleaved to E2 and E3. PE2 instead was modified to a higher-molecular-weight form (PE2') in which the high-mannose oligosaccharides were processed to the complex form without proteolytic cleavage. The data suggest that the cleavage which produces E2 occurs within the trans-Golgi or in post-Golgi elements and is closely associated with the addition of sialic acid residues to the asparagine-linked oligosaccharides. RPE.40 cells make and release noninfectious Sindbis virions that contain PE2' and no detectable E2. These virions can be converted to an infectious form by treatment with trypsin. A defect in an intracellular endopeptidase activity in RPE.40 cells is postulated. Comparison of two Sindbis virus strains showed that the requirement for E2 in the virion to ensure infectivity is strain specific.

ADP Ribose Transferases↗
PubMed1991

Muscarinic receptor regulation and protein kinase C: sites for the action of chronic lithium in the hippocampus.

Regulation of muscarinic receptor activity in critical regions of the limbic system may represent a site for the therapeutic action of lithium. Muscarinic receptors in the hippocampus are coupled to phosphoinositide (PI) hydrolysis and the generation of the second messengers inositol (1,4,5) trisphosphate [Ins (1,4,5)P3] as well as diacylglycerol (DAG), which can directly activate protein kinase C (PKC). Since lithium may affect the regeneration of critical receptor-coupled pools of phosphatidylinositol 4,5-bisphosphate, studies in our laboratory have investigated the effects of chronic lithium on the regulation of the muscarinic receptor response. We have recently demonstrated that, following chronic administration of atropine in control and chronic lithium animals, there is an up-regulation of muscarinic receptor binding sites in the hippocampus; however, a concomitant sensitization of the carbachol-stimulated PI response is observed only in control animals. We have so far detected no effects of either in vitro or in vivo lithium on muscarinic receptor interactions with G proteins. However, we have observed a reduction in the in vitro phosphorylation of a major PKC phosphoprotein substrate in the rat hippocampus, following chronic lithium treatment. This effect may be related to long-lasting changes in regulation of receptor activity.

Animals↗