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Biomedical subjects

J Millar

Publications and source records attributed to J Millar.

At least 91 records · Page 5Linked to original sources
PubMed1989

Neocortical epileptogenesis in vitro: studies with N-methyl-D-aspartate, phencyclidine, sigma and dextromethorphan receptor ligands.

Slices of rat neocortex have been used to study the role of N-methyl-D-aspartate (NMDA) receptors in the induction of epileptiform activity. The NMDA antagonist potency of a range of compounds with putative anticonvulsant activity has been compared with their ability to reduce epileptiform activity in this tissue. Epileptiform activity was induced by the omission of magnesium from the bathing medium. Competitive and noncompetitive phencyclidine-like NMDA antagonists reduced such spontaneous and stimulus-evoked epileptiform bursts and after potentials. Similar epileptiform activity induced by the addition of proconvulsant drugs, e.g. gamma-aminobutyric acidA antagonists, potassium channel blockers or carbachol was reduced by ketamine and/or D-2-amino-5-phosphonovaleric acid. In magnesium-free medium, the frequency of spontaneous bursts and the number of afterpotentials per burst were reduced in parallel. There was a good correlation (r greater than 0.9) between their potencies against NMDA depolarizations and against epileptiform bursts (MK-801 [(+)-5-methyl-10,11- dihydro-5H-dibenzvo[a,d]cyclohepten-5,10-imine] greater than thienylcyclohexylpiperidine phencyclidine greater than 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid greater than cyclazocine greater than D-2-amino-5-phosphonovaleric acid greater than dextrorphan greater than SKF10,047 (N-allylnormetazocine) greater than ketamine greater than dextromethorphan = or greater than pentazocine). Sigma and dextromethorphan receptor ligands (e.g. ditolyguanidine, carbetapentane and phenytoin), whereas inactive as NMDA antagonists, reduced epileptiform activity by decreasing the number of afterpotentials per burst with less effect on the burst frequency. The quisqualate/kainate antagonist, FG9041 (6,7-dinitro-quinoxaline-2,3-dione), only reduced spontaneous bursts at doses which also reduced NMDA. Our results imply a central role for NMDA receptors in epileptogenesis in neocortical slices.

Animals↗
PubMed1989

Part-time women general practitioners--workload and remuneration.

A postal questionnaire survey was conducted comparing the workload and remuneration of part-time women principals in group practices in the Northern and Oxford regions. Part time was defined as receiving less than a full profit share at parity. Of 501 women principals 308 (62%) responded of whom 146 (47%) were part-time. Respondents were asked to record aspects of workload over a four-week period for themselves and their full-time partner who did the most sessions within the practice. The results showed that although two-thirds of the part-timers had 50% or less of a full profit share, part-time principals overall did about 76% of the daytime clinical work (surgeries and home visits) done by their full-time partners, excluding specialized clinics. The lower the profit share the wider this discrepancy. Although 33% of the respondents did not out-of-hours work, the remainder did more than their profit share would indicate. Twenty per cent of the 116 principals with 40% or more of a full profit share and 57% of the 30 principals with less than 40% of a full profit share felt that their share was unfair. Lack of involvement in practice business and feeling that opinions did not carry equal weight were associated with feelings of unfairness.

Female↗
PubMed1988

Stimulated limbic and striatal dopamine release measured by fast cyclic voltammetry: anatomical, electrochemical and pharmacological characterisation.

Fast cyclic voltammetry at carbon fibre microelectrodes was used to monitor stimulated release of electroactive species simultaneously in both caudate and nucleus accumbens. The released species was identified as dopamine in both nuclei on the basis of anatomical, electrochemical and pharmacological criteria. Dopamine release in the nucleus accumbens was consistently evoked at more ventromedial stimulation sites than for caudate. In both nuclei, release was reduced or abolished by alpha-methyl-p-tyrosine and Ro 4-1284. Pargyline, cocaine and GBR 12909 potentiated release while desipramine had no effect. In conjunction with the electrochemical data, the results indicate that dopamine is the sole species detected in caudate and accumbens following stimulation of the median forebrain bundle.

Animals↗
PubMed1988

Diffusion and uptake of dopamine in rat caudate and nucleus accumbens compared using fast cyclic voltammetry.

Fast cyclic voltammetry was used in the caudate and nucleus accumbens of anaesthetised rats to study the release and reuptake of dopamine following stimulation of the median forebrain bundle. Dopamine uptake was significantly slower in accumbens than caudate, indicating a lower number of functional uptake sites. This implies that dopamine may be able to diffuse further from its sites of release in nucleus accumbens than in caudate and thus may have a neuromodulator role in this region.

Animals↗
PubMed1988

Basic instrumentation for fast cyclic voltammetry.

Fast cyclic voltammetry is a new voltammetric technique which has been especially useful for measurements of dopamine release in vivo. This paper describes methods for the construction of a basic fast cyclic voltammetric amplifier, and the associated apparatus necessary to carry out fast cyclic voltammetric experiments.

Amplifiers, Electronic↗
PubMed1988

Actions of dopamine antagonists on stimulated striatal and limbic dopamine release: an in vivo voltammetric study.

1. Fast cyclic voltammetry at carbon fibre microelectrodes was used to study the effects of several dopamine antagonists upon stimulated dopamine release in the rat striatum and nucleus accumbens. 2. In both nuclei, stimulated dopamine release was increased by D2-receptor-selective and mixed D1/D2-receptor antagonists. The D1-selective antagonist SCH 23390 had no effect. 3. Striatal and limbic dopamine release were elevated by cis- but not trans-flupenthixol. 4. The 'atypical' neuroleptics (clozapine and thioridazine) did not cause a selective elevation of dopamine release in the limbic terminal region, whereas the non-antipsychotic drug metoclopramide increased dopamine release more in striatum than nucleus accumbens. 5. We conclude from this study that striatal and limbic dopamine release are under the control of a stereoselective dopamine D2-autoreceptor on the nerve terminal and that atypical neuroleptics do not show a limbic-selective effect at this receptor after acute administration.

Animals↗
PubMed1988

A comparison between the in vivo and in vitro activity of five potent and competitive NMDA antagonists.

1. Phosphonate analogues of glutamate have been tested and compared as N-methyl-D-aspartate (NMDA) antagonists in electrophysiological and binding experiments. The compounds tested were three established NMDA antagonists: D-2-amino-5-phosphonopentanoate (D-AP5), DL-2-amino-7-phosphonoheptanoate (DL-AP7), 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), and two novel putative NMDA antagonists: 3-(2-carboxypiperidin-4-yl)propyl-1-phosphonate (CPPP) and 3-(2-carboxy-piperidin-4-yl)methyl-1-phosphonate (CPMP). 2. When administered electrophoretically to rat spinal neurones in vivo, these compounds were found to be selective NMDA antagonists with little effect on excitations evoked by quisqualate and kainate. CPMP and CPPP were approximately equipotent with CPP and about 5 times more potent than D-AP5. 3. Following systemic administration, 2-5 mg kg-1 i.v. of CPP, CPMP and CPPP reduced NMDA-evoked excitations by 70-100% whereas 50-100 mg kg-1 of D-AP5 and DL-AP7 produced a similar effect. The onset of the effects required 20-30 min and lasted more than six hours. 4. On bath application to cortical wedges, the IC50 values (microM) for antagonism of 40 microM NMDA were: CPP, 0.64 +/- 0.06 (mean +/- s.e.mean; n greater than 4); CPMP, 1.65 +/- 0.13; CPPP 0.89 +/- 0.09; D-AP5, 3.7 +/- 0.32; DL-AP7, 11.1 +/- 2.1; and DL-AP4 and DL-AP6 were inactive at 100 microM. 5. In binding studies with [3H]-CPP, the Ki values (nM) were: CPP, 446 + 150 (mean + s.e.mean; n > 3); CPMP, 183 + 74 and CPPP, 179 +/- 13 whereas against NMDA (lO microM)-stimulated [3H]- TCP (thienylcyclohexylpiperidine) binding the ICjo values (microM) for CPMP and CPPP respectively were 5.6 + 2.7 and 4.5 + 2.2. 6. Systemic administration of CPPP and CPMP, at doses sufficient to antagonize NMDA, also reduced cardiovascular responses to 5-hydroxytryptamine (Bezold-Jarisch reflex). This illustrates a role for NMDA receptors in central cardiovascular control. 7. The results indicate the systemic doses of piperidine and piperazine analogues of D-AP5 which may be used for assessing the role ofNMDA receptors in central synaptic function.

2-Amino-5-phosphonovalerate↗
PubMed1987

Accommodation of rat nigrostriatal dopamine neurones to high frequency electrical stimulation of the median forebrain bundle: in vivo voltammetric data.

The frequency response of nigrostriatal neurones to electrical stimulation of the median forebrain bundle was investigated in vivo using high-speed cyclic voltammetry to measure the evoked striatal dopamine overflow. It was found that the nerves could follow 25-50 Hz stimulation for at least 10 s, whereas the neurones were unable to respond to high frequencies (100-200 Hz) for more than 1-3 s. Accommodation, due to incomplete re-equilibration of ionic fluxes between successive stimuli, provides a possible explanation for these findings.

Adaptation, Physiological↗
PubMed1987

Inhibition of bombesin-induced mitogenesis by pertussis toxin: dissociation from phospholipase C pathway.

Prior incubation of quiescent cultures of Swiss 3T3 cells with pertussis toxin selectively inhibited the stimulation of DNA synthesis induced by peptides of the bombesin family. While pertussis toxin blocked mitogenesis at an early stage in the action of the peptide, the toxin did not impair the rapid stimulation of polyphosphoinositide breakdown, Ca2+ mobilization or activation of protein kinase C promoted by bombesin. Thus, inhibition of bombesin-induced mitogenesis by pertussis toxin can be dissociated from inactivation of the phospholipase C signalling pathway.

Animals↗
PubMed1987

Cytogenetic follow-up studies of recipients of T-cell depleted allogeneic bone marrow.

Serial cytogenetic studies of bone marrow and blood cells were made in leukaemic patients who had received an allogeneic bone marrow graft from a donor of unlike sex. The donor marrow was treated with the monoclonal antibody Campath-1 before infusion. The persistence of a significant proportion of dividing recipient cells in marrow and blood was observed after grafting. These recipient cells showed evidence of radiation damage of both the stable and unstable types. More than one transient clone of chromosomally abnormal recipient cells was observed in three cases. The differences between the cytogenetic findings in patients receiving donor marrow from which T cells have been removed and those cases previously studied in our Leukaemia Unit who had received untreated donor marrow are discussed.

Adolescent↗