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Biomedical subjects

M E Kelly

Publications and source records attributed to M E Kelly.

At least 127 records · Page 7Linked to original sources
PubMed1986

Neuropharmacological manipulations with MPTP.

Studies have been carried out in the rodent and marmoset to assess (i) the selectivity of MPTP action to the nigrostriatal system, (ii) the possibility that melanin pigmentation may influence the actions of MPTP, (iii) whether the metabolites of MPTP may contribute to its actions on dopamine cells, (iv) the site(s) of action of MPTP in the brain, (v) the mechanism(s) of action of MPTP and whether it is possible to prevent the damaging effects of MPTP/metabolites on the brain dopamine systems. The peripheral administration of MPTP in the mouse causes depletions of dopamine and its metabolites in both the striatal and limbic systems: this action is similar in both white and pigmented mice. The MAO-B inhibitor deprenyl was shown to antagonize the actions of MPTP, and its metabolite formed via oxidation through MAO, MPP+, was shown to disrupt striatal dopamine function as determined behaviorally (as motor impairment) or biochemically (as loss of dopamine and its metabolites) when injected into the cerebral ventricles of mouse or infused into the substantia nigra of rat brain. MPTP and MPP+ act in the midbrain to interfere with dopamine cell functioning, and studies in both the rodent and marmoset are presently analyzing possible additional actions in forebrain regions. It is therefore proposed that the neurotoxic action of MPTP, effected via its metabolite MPP+, may not be selective for the nigrostriatal system. Nevertheless, the nature and profile of neurotoxicity effected by MPTP and, in particular, MPP+ should ensure continuing analyses of the relevance of such action to an understanding of the etiology of, treatment of, and even the possible prevention of Parkinson's disease in man.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

The neurotoxic actions of 1-methyl-4-phenylpyridine (MPP+) are not prevented by deprenyl treatment.

1-Methyl-4-phenylpyridine (MPP+) injected into the cerebral ventricles (ICV) of mouse caused depletions of striatal dopamine (DA)(-42%), 3,4-dihydroxyphenylacetic acid (DOPAC) (-34%) and homovanillic acid (HVA) (-16%) content without significant reductions in levels of noradrenaline (NA), serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). When deprenyl was administered before MPP+, striatal DA and its metabolites were further depleted, and striatal NA and 5-HT levels also were reduced. Further, whilst ICV MPP+ alone failed to influence the biochemistry of the limbic areas (nucleus accumbens plus tuberculum olfactorium), in the presence of deprenyl MPP+ caused 20-40% reductions in levels of limbic NA, DA, DOPAC, HVA, 5-HT and 5-HIAA. Therefore, deprenyl treatment does not prevent the neurotoxic actions of MPP+; indeed, a more extensive neurotoxicity for MPP+ is revealed in the presence of this monoamine oxidase inhibitor.

1-Methyl-4-phenylpyridinium↗
PubMed1985

An isolated mammalian brainstem-spinal cord preparation suitable for the investigation of descending control of motor activity.

An in vitro, hemisected brainstem-spinal cord preparation which allows bulbo-spinal interactions to be investigated, has been developed using 25-33 g golden hamsters. Spinal reflexes showing both monosynaptic and polysynaptic components were recorded from the lumbar ventral roots following stimulation of the corresponding dorsal roots. Trains of conditioning stimuli delivered to the caudal region of the medulla caused inhibition of the monosynaptic component and potentiation of the polysynaptic component of the spinal reflex.

Animals↗
PubMed1985

Biochemical correlates of motor changes caused by the manipulation of dopamine function in the substantia nigra of the mouse.

2-Di-n-propylamino-5,6-dihydroxytetralin, injected bilaterally into the substantia nigra of the mouse, caused dose-dependent motor inhibition which was associated with decreased levels of DOPAC and increased levels of dopamine in the striatum. (-)Sulpiride, injected into the substantia nigra, antagonised the locomotor depression although the partial antagonism of the elevation in the level of dopamine in the striatum and of the reduction in levels of DOPAC did not achieve significance. The specificity of the action of tetralin on dopamine receptors was shown by the failure of prazosin and yohimbine to antagonise the locomotor depression induced by tetralin and the reduction in levels of DOPAC. The selectivity of the action of tetralin for the dopamine system was shown by its failure to affect levels of noradrenaline, serotonin and 5-hydroxyindoleacetic acid in the striatum. The injection of tetralin into the substantia nigra also caused biochemical changes in limbic areas (nucleus accumbens and tuberculum olfactorium), where the levels of dopamine and DOPAC were elevated, and in the frontal cortex where the levels of DOPAC were reduced. These changes were antagonised by a concomitant injection of (-)sulpiride into the substantia nigra. It is concluded that the action of dopamine agonists in the midbrain can decrease the functional activity in the ascending dopaminergic pathways.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Comparative cost of myocardial revascularization: percutaneous transluminal angioplasty and coronary artery bypass surgery.

A consecutive series of 78 patients having percutaneous transluminal coronary angioplasty for single vessel coronary artery disease and 85 patients having single vessel coronary artery bypass graft surgery were followed up prospectively for 1 year. Days in hospital and angiographic and revascularization procedures were counted in the two groups of patients and total cost of care for 12 months was calculated using current billing levels. Angioplasty was initially successful in 74% of patients; because of initial failure in 26% and late restenosis in 18%, bypass surgery was ultimately needed in 23 of 78 patients having coronary angioplasty. Nevertheless, total cost of care per patient was 43% lower for those having angioplasty as an initial procedure for single vessel coronary artery disease.

Adult↗
PubMed1985

Sequence determination of the capsid protein gene and flanking regions of tobacco etch virus: Evidence for synthesis and processing of a polyprotein in potyvirus genome expression.

The nucleotide sequence of the 3'-terminal portion of the tobacco etch virus (TEV) genome was determined. The 2324-nucleotide sequence represented approximately one-fourth of the TEV genome and included the capsid protein gene and flanking regions. An open reading frame of 2135 nucleotides and an untranslated region of 189 nucleotides adjacent to a polyadenylate tract were identified. The sequence began within an open reading frame, indicating that the initiation codon was upstream of the available sequence data. The sequence of the 20 NH(2)-terminal amino acids of the TEV capsid protein was established chemically. An identical amino acid sequence, predicted from the nucleotide sequence, was located, commencing at amino acid - 263. These data indicated that maturation of the capsid protein required a post-translational cleavage of a larger protein precursor, with a probable cleavage site between the amino acids glutamine and glycine.

Journal Article↗
PubMed1985

Modification of dyskinesias following the intrastriatal injection of prostaglandins in the rodent.

The abilities of prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2 alpha to antagonize striatal dopamine function were assessed following bilateral and unilateral injections into the striata of the rat and guinea-pig. Three tests were used to assess the effects of the bilateral injections, ability to antagonize dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin (0.025 mg kg-1 s.c.), ability to antagonize stereotyped behaviour induced by apomorphine (0.5 or 2 mg kg-1 s.c.) and ability to induce catalepsy. Asymmetry/circling behaviour revealed on challenge with apomorphine (0.25 mg kg-1 s.c.) was measured following unilateral injection into the striatum. In the rat, dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin was antagonized by PGE1 (0.001-1 micrograms) and PGE2 (0.00001-1 micrograms) but not by PGD2 or PGF2 alpha (1 microgram). Stereotyped behaviour induced by apomorphine was not antagonized by any of the prostaglandins. A weak catalepsy was induced by PGE1 (1 microgram only), PGE2 (0.001-1 micrograms) and PGD2 (0.001-1 micrograms) but not by PGF2 alpha. Asymmetry and circling behaviour was only observed following the unilateral injection into the striatum of PGE1 and PGD2 (0.01-1 microgram) and challenge with apomorphine. In the guinea-pig the actions of PGE1 and E2 were compared with those of PGF2 alpha. Dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin was antagonized by bilateral injections into the striatum of PGE2 (0.001-1 microgram), but not PGE1 (0.5 micrograms) and PGF2 alpha (1 microgram) but not PGE, (0.5 micrograms) and PGF2 alpha (1 microgram). Similar injections of PGE1, E2 and F2 alpha, all failed to antagonize apomorphine-induced stereotyped behaviour, or to induce catalepsy. PGE, (0.01-0.5 fig) and PGE2 (0.002-1 pg), but not PGF2 alpha, caused asymmetry following unilateral injection into the striatum and peripheral challenge with apomorphine. 5 It is concluded that the major effect in the striatum of the prostaglandins of the E series is to antagonize dyskinetic biting; this action is not shared by other prostaglandins tested, and does not reflect a generalised ability to antagonize striatal dopamine function. It is suggested that the actions of the prostaglandins to modify differentially dopamine-dependent behaviours from the striatum may reflect activity at a site subsequent to the dopamine receptor.

Alprostadil↗
PubMed1984

Unilateral striatal dopamine denervation: reduced motor inhibitory effects of dopamine antagonists revealed in models of asymmetric and circling behaviour.

Circling and asymmetric behaviours to apomorphine (dopamine agonist/antagonist) challenge were studied in rats with unilateral striatal electrolesions or 6-hydroxydopamine (6-OHDA) lesions, each induced by combined lesions at 3 striatal locations, to allow an assessment of drug action on 'normal' receptors in the intact striatum or 'supersensitive' receptors in the lesioned striatum respectively. The minimally effective dose of 6-OHDA (given in the presence of DMI and tranylcypromine) to cause functional change was 3 X 8 micrograms, with 3 X 32 micrograms providing maximal change. Electrolesions were shown histologically to be confined to striatal tissue, and dopamine depletions caused by 6-OHDA were selective for the striatum. Temporal differences were recorded for onset of asymmetry and circling behaviour, both between behaviours and between lesions. Thus, asymmetry developed during the 2nd-4th days after 6-OHDA lesion but circling developed more abruptly on postoperative days 10-12. In contrast, both asymmetry and circling behaviours were apparent from the first day following electrolesion. The dose-dependent effects of apomorphine were apparent at much lower doses in 6-OHDA lesioned than electrolesioned rats. This potency difference was also demonstrated for two further dopamine agonists, 2-di-n-propylamino-5,6-dihydroxytetralin and SK & F 38393. In contrast, the agonist-induced asymmetric and circling behaviours of electrolesioned rats were some 9-44 times more sensitive than those of 6-OHDA lesioned rats to antagonism by the neuroleptic agents haloperidol, alpha-flupenthixol and oxiperomide, although tiapride antagonism was very similar in both the electrolesioned and 6-OHDA-lesioned rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

The antidyskinetic action of dihomo-gamma-linolenic acid in the rodent.

The antidyskinetic action of dihomo-gamma-linolenic acid (DHLA) was assessed against dyskinesias induced in the guinea-pig by dopamine injected into the striatum (200 micrograms bilateral 2 h after nialamide, 75 mg kg-1, i.p.) and in the guinea-pig and rat by 2-di-n-propylamino-5, 6-dihydroxytetralin (tetralin), 0.025 mg kg-1, s.c. Dopamine and tetralin-induced dyskinesias in the guinea-pig were reduced or abolished by DHLA given i.p., 30-100 mg kg-1, given once daily for 5-10 days. Tetralin-induced dyskinesias were antagonized by DHLA given orally to the guinea-pig (50-200 mg kg-1, 5 days) or in the diet to the rat (approximately 200 mg kg-1 daily for 10-14 days). DHLA injected into the striatum (2.5-20 micrograms bilateral, 2-4 days) also antagonized tetralin-induced dyskinesias in the rat. The antidyskinetic action of DHLA given i.p. to the guinea-pig could be antagonized by aspirin or eicosa-5,8,11,14-tetraynoic acid (100 mg kg-1 i.p. daily, starting 2 days before a 5 day treatment with DHLA). Aspirin (25-100 mg kg-1, i.p.) dose-dependently antagonized the antidyskinetic activity of 5 and 20 micrograms DHLA given bilaterally into the striatum (2 days). DHLA (100 mg kg-1 i.p.) given daily for 10 days or approximately 200 mg kg-1 DHLA (daily for 10-14 days given in the diet) administration to the rat failed to modify the stereotyped behaviour induced by apomorphine, 0.5 or 2 mg kg-1 s.c., to induce catalepsy, or to modify the cataleptic effects of haloperidol 0.25 or 1 mg kg-1 i.p. 7 It is suggested that the selective inhibition of dyskinesias in the rodent by DHLA may reflect a striatal effect with a dependency on conversion to prostaglandins.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1983

The production of asymmetry and circling behaviour following unilateral, intrastriatal administration of neuroleptic agents: a comparison of abilities to antagonise striatal function.

The abilities of typical and atypical neuroleptic agents to antagonise at striatal dopamine receptors were determined in the rat. Neuroleptic agents were injected unilaterally into the striatum and asymmetric body posturing/circling behaviour (always ipsilateral to the side of neuroleptic injection) assessed (1) to neuroleptic challenge alone (vehicle injected into the contralateral striatum), (2) as that revealed after neuroleptic challenge by peripherally administered apomorphine or (3) by dopamine injection into the contralateral striatum. Unilateral intrastriatal fluphenazine (1-5 micrograms), cis- and trans-flupenthixol (1-20 micrograms), haloperidol (0.5-5 micrograms), thioridazine (5-10 micrograms), clozapine (1-5 micrograms), tiapride (1-5 micrograms), metoclopramide (1-10 micrograms), (+)-sulpiride (20 micrograms) and piperoxan (10 micrograms) each failed, alone, to cause any postural asymmetry/circling. However, ipsilateral asymmetry was induced by unilateral intrastriatal (-)-sulpiride (1-5 micrograms). In contrast, ipsilateral asymmetry developed when the intrastriatal injection of all neuroleptic agents (excepting (+)-sulpiride and trans-flupenthixol) was followed by peripheral challenge with apomorphine: effective neuroleptic doses were all in the range 0.5-10 micrograms, although (-)-sulpiride was effective at 0.001-0.1 microgram. Active circling was only recorded for (-)-sulpiride and tiapride. The striatal imbalance caused by (-)-sulpiride could be revealed by apomorphine for 24 h, although other intrastriatal neuroleptic responses persisted for 6-8 h. The abilities of all neuroleptic agents to cause striatal imbalance could also be revealed by injecting dopamine into the contralateral striatum (at a dose which alone did not cause any asymmetric motor responding). These intrastriatal injection approaches are forwarded as valuable techniques for determining striatal dopamine antagonist activity in the rodent.

Animals↗
PubMed1983

Does contralateral circling involve action of drugs on hyposensitive striatal dopamine receptors in the hemisphere contralateral to denervation?

Rats receiving unilateral intrastriatal injections of 6-hydroxydopamine (6-OHDA) (3 x 16 micrograms, in the presence of tranylcypromine and desmethylimipramine (DMI), resulting in 84% dopamine depletion) exhibited contralateral asymmetry and circling behaviour on peripheral challenge with apomorphine or on unilateral intrastriatal injection of dopamine (into the denervated striatum) (resulting in a stable response after 8 days). The denervated striatum was markedly more sensitive to the effects of dopamine than the normal striatum, although dopamine failed to elicit a response from an intact striatum opposite to a denervation by 6-OHDA. Following unilateral striatal electrolytic lesions (resulting in a stable response after 6-8 days) the rats exhibited ipsilateral asymmetry and circling after the apomorphine challenge. Again, the striata opposite to the lesion failed to mediate a response to dopamine. The contralateral responses to apomorphine observed in animals lesioned with 6-OHDA were not enhanced when an electrolytic lesion was subsequently placed in the intact striatum, nor were the ipsilateral responses of lesioned rats to apomorphine enhanced when 6-OHDA was subsequently injected into the opposite striatum. All asymmetric and circling responses were sensitive to neuroleptics. Thus, it is concluded that a unilateral striatal lesion produced by 6-OHDA or electrolytic lesion can cause reduced functional dopaminergic activity in the opposing striatum. This dopaminergic hyposensitivity would facilitate a contralateral response initiated by hypersensitive mechanisms in the denervated striatum.

Animals↗
PubMed1981

Proposals and current practices in quality control.

The current status of quality control in clinical laboratories is discussed, and selected new techniques for quality control and presented from the literature of the last six years. The concept of quality control is broadened beyond the running of control materials for validation of test runs. Methods for recognition, identification, and reduction of both process error are presented. Examples are presented of improvements utilizing graphic techniques, manipulation of control and check sample sera, statistical techniques for interpretation of trends, quality control action rules for the detection of out-of-control situations and method evaluation.

Analysis of Variance↗
PubMed1979

Imipramine for aspermia after lymphadenectomy.

During radical retroperitoneal lymphadenectomy the hypogastric sympathetic plexus is necessarily partially sacrificed, with resultant failure of part of the ejaculatory mechanism and aspermia. We have observed this condition to be reversible with imipramine.

Adult↗