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Biomedical subjects

A Randall

Publications and source records attributed to A Randall.

At least 19 recordsLinked to original sources
PubMed2000

Modulation of the deactivation kinetics of a recombinant rat T-type Ca(2+) channel by prior inactivation.

Using patch clamp methods we have investigated the deactivation properties of the T-type Ca(2+) channel generated by expression of the rat alpha(1I) subunit in HEK293 cells. The amplitude of the repolarisation-induced tail current was strongly correlated (R=0. 998) with the current amplitude immediately prior to repolarisation. The rate of deactivation was voltage-dependent between -120 mV (tau(deact)=0.9+/-0.0 ms) and -60 mV (tau(deac)=3.3+/-0.5 ms). Interestingly, the rate of deactivation observed at -80 mV was clearly dependent on the level of inactivation induced immediately prior to repolarisation, with greater inactivation producing significantly slower deactivation. In contrast, the rate of deactivation appeared completely independent of the level of steady-state inactivation. Together these data indicate the presence of a tight relationship between the recent induction of inactivation of this T-type channel and its subsequent rate of deactivation.

Animals↗
PubMed2000

Potent inhibition of a recombinant low voltage-activated Ca(2+) channel by SB-209712.

T-type Ca(2+) currents were recorded in 2 mM Ca(2+) from HEK293 cells stably expressing the low voltage-activated Ca(2+) channel sub-unit alpha(1I). These currents were inhibited by the known Ca(2+) channel antagonist mibefradil with an IC(50) close to 1 microM. SB-209712 (1,6,bis¿1-[4-(3-phenylpropyl)piperidinyl]¿hexane), a compound originally developed as a high voltage-activated Ca(2+) channel blocker, proved to be a more potent T-type channel antagonist, exhibiting an IC(50) in the region of 500 nM. The antagonism produced by SB-209712 was reversed following drug removal and the observed antagonism exhibited little or no voltage-dependence with respect to either holding or test potential. These data indicate that SB-209712 is amongst the most potent known non-peptide T-type channel antagonists and thus may have some use in understanding the role of these channels in cellular function.

Animals↗
PubMed2000

Voltage- and time-dependent properties of the recombinant rat vanilloid receptor (rVR1).

Whole-cell voltage-clamp techniques were used to investigate the capsaicin-, voltage- and time-dependent properties of the rat vanilloid receptor (rVR1) stably expressed in human embryonic kidney (HEK) 293 cells. At a holding potential of -70 mV, application of capsaicin (0.03-30 microM) to HEK 293 cells expressing the rVR1 receptor led to the appearance of inward currents (EC50, 497 nM; Hill coefficient, nH, 2.85) which were reversibly antagonized by 10 microM capsazepine. Current-voltage relationships, determined using depolarizing or hyperpolarizing voltage ramps, had reversal potentials close to 0 mV, exhibited substantial outward rectification and possessed a region of negative slope conductance at holding potentials negative to around -70 mV. Further experiments indicated that the outward rectification and the region of negative slope conductance did not result from external block of the channel by either Ba2+, Ca2+ or Mg2+. During our characterization of rVR1, it became apparent that the rectification behaviour of this receptor was not entirely instantaneous as might be expected for a ligand-gated ion channel, but rather displayed clear time-dependent components. We characterized the kinetics of these novel gating properties in a series of additional voltage-step experiments. The time-dependent changes in rVR1-mediated conductance due to membrane depolarization or repolarization occurred with bi-exponential kinetics. On depolarization to +70 mV the time-dependent increase in outward current developed with mean time constants of 6.7 +/- 0.7 and 51.8 +/- 18.4 ms, with the faster time constant playing a dominant role (64.4 +/- 3.8 %). Similar kinetics also described the decay of 'tail currents' observed on repolarization. Furthermore, these time-dependent changes appeared to be unaffected by the removal of extracellular divalent cations and were not significantly voltage dependent. Our data reveal that rVR1 exhibits substantial time- and voltage-dependent gating properties that may have significance for the physiology of sensory transduction of nociceptive signals.

Action Potentials↗
PubMed2000

Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia.

The vanilloid receptor-1 (VR1) is a ligand-gated, non-selective cation channel expressed predominantly by sensory neurons. VR1 responds to noxious stimuli including capsaicin, the pungent component of chilli peppers, heat and extracellular acidification, and it is able to integrate simultaneous exposure to these stimuli. These findings and research linking capsaicin with nociceptive behaviours (that is, responses to painful stimuli in animals have led to VR1 being considered as important for pain sensation. Here we have disrupted the mouse VR1 gene using standard gene targeting techniques. Small diameter dorsal root ganglion neurons isolated from VR1-null mice lacked many of the capsaicin-, acid- and heat-gated responses that have been previously well characterized in small diameter dorsal root ganglion neurons from various species. Furthermore, although the VR1-null mice appeared normal in a wide range of behavioural tests, including responses to acute noxious thermal stimuli, their ability to develop carrageenan-induced thermal hyperalgesia was completely absent. We conclude that VR1 is required for inflammatory sensitization to noxious thermal stimuli but also that alternative mechanisms are sufficient for normal sensation of noxious heat.

Adenosine Triphosphate↗
PubMed1999

Millennium pay

Explore the source record for details and available documents.

Journal Article↗
PubMed1999

Professional training. Learning the hard way.

An audit of nursing, midwifery and physiotherapy training commissioned by a consortium of trusts in Sussex showed diverging views on the relevance of courses. Many nursing students wanted more practical experience. Two-thirds of students reported financial hardship and a third were working at the same time as studying.

Attitude of Health Personnel↗
PubMed1996

Prognostic value of plasma fibrinogen concentration in patients with unstable angina and non-Q-wave myocardial infarction (TIMI IIIB Trial)

Inflammation may play an important role in acute coronary syndromes. We studied the prognostic value of fibrinogen, an acute-phase protein directly involved in thrombotic process, measured serially in 1,473 patients with unstable angina and non-Q-wave myocardial infarction participating in the Thrombolysis in Myocardial Infarction IIIB trial. Overall, no association was found between baseline (pretreatment) fibrinogen and in-hospital (< or = 10 days) myocardial infarction (p=0.70) and death (p=0.64); however, patients with spontaneous ischemia (p=0.004) and the combined unsatisfactory outcome of death, myocardial infarction, and spontaneous ischemia (p=0.003) had higher fibrinogen concentrations than those without these events. This association was confined to patients with unstable angina. A baseline fibrinogen concentration > or = 300 mg/dl was associated with a modest trend toward an increased risk of death, myocardial infarction, or spontaneous ischemia (odds ratio 1.61, 95% confidence interval 1.02 to 2.52; p=0.04). Elevation of fibrinogen, a readily measurable acute-phase protein, at the time of hospital admission is associated with coronary ischemic events and a poor clinical outcome in patients with unstable angina.

Angina, Unstable↗
PubMed1996

Changes in action potential duration alter reliance of excitatory synaptic transmission on multiple types of Ca2+ channels in rat hippocampus.

It has been established that multiple types of Ca2+ channels participate in triggering neurotransmitter release at central synapses, but there is uncertainty about the nature of their combined actions. We investigated synaptic transmission at CA3-CA1 synapses of rat hippocampal slices and asked whether the dependence on omega-CTx-GVIA-sensitive N-type channels and omega-Aga-IVA-sensitive P/Q-type Ca2+ channels can be altered by physiological mechanisms. The reliance on multiple types of Ca2+ channels was not absolute but depended strongly on the amount of Ca2+ influx through individual channels, which was manipulated by prolonging the presynaptic action potential with the K+ channel blocker 4-aminopyridine (4-AP) and by varying the extracellular Ca2+ concentration ([Ca2+]o). We quantified the influence of spike broadening on Ca2+ influx through various Ca2+ channels by imposing mock action potentials on voltage-clamped cerebellar granule neurons. In field recordings of the EPSP in hippocampal slices, action potential prolongation increased the EPSP slope by 2-fold and decreased its reliance on either N-type or P/Q-type Ca2+ channels. The inhibition of synaptic transmission by N-type channel blockade was virtually eliminated in the presence of 4-AP, but it could be restored by lowering [Ca2+]o. These results rule out a scenario in which a significant fraction of presynaptic terminals rely solely on N-type channels to trigger transmission. The change in sensitivity to the neurotoxins with 4-AP could be explained in terms of a nonlinear relationship between Ca2+ entry and synaptic strength, which rises steeply at low [Ca2+]o, but approaches saturation at high [Ca2+]o. This relationship was evaluated experimentally by varying [CA2+]o in the absence and presence of 4-AP. One consequence of this relationship is that down-modulation of presynaptic Ca2+ channels by various modulators would increase the relative impact of spike broadening greatly.

4-Aminopyridine↗
PubMed1995

Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons.

The diversity of Ca2+ channel types in rat cerebellar granule neurons was investigated with whole-cell recordings (5 mM external Ba2+). Contributions of five different high-voltage-activated Ca2+ channel current components were distinguished pharmacologically. Nimodipine-sensitive L-type current and omega-CTx-GVIA-sensitive N-type current contributed 15 and 20% of the total current, respectively. The bulk of the remaining current (46%) was inhibited by omega-Aga-IVA. The current blocked by this toxin was further subdivided into two components, P-type and Q-type, on the basis of differences in their inactivation kinetics and sensitivity to omega-Aga-IVA. P-Type current was noninactivating during 0.1 sec depolarizations, half-blocked at about 1-3 nM omega-Aga-IVA, and contributed approximately 11% of the total current; Q-type current was prominently inactivating, half-blocked at approximately 90 nM omega-Aga-IVA, and comprised 35% of the total current. Both P- and Q-type currents were potently inhibited by the Conus magus toxin omega-CTx-MVIIC. A current component resistant to all of the aforementioned blockers (R-type) displayed more rapid inactivation than the other components and constituted 19% of the total current. The Q-type current, the largest of the current components in the granule neurons, resembles currents that can be generated in Xenopus oocytes by expression of cloned alpha 1A subunits.

Animals↗
PubMed1994

The vaccination status of aboriginal children in the North Coast Health Region of New South Wales.

OBJECTIVE: To determine the vaccination status of Aboriginal children resident in the North Coast Health Region of NSW. DESIGN: Cross-sectional descriptive study. SETTING AND PARTICIPANTS: The vaccination status of Aboriginal children aged 4 months to 11 years and resident in selected villages/isolated communities, small and large towns in the North Coast Health Region of NSW was determined by review of vaccination records. Data were obtained from general practitioners, the Aboriginal Health Service, Community Health Centres and Local Government Councils. MAIN OUTCOME MEASURES: Vaccination status according to the childhood immunisation schedule recommended by the National Health and Medical Research Council, defined as fully or partially documented, with a generous lag time. RESULTS: The study population comprised 1179 children--55% of the estimated Aboriginal population under 12 years of age in the North Coast Health Region. Data collection on Sabin vaccine was incomplete and was not included in the analysis. Of 1094 children whose records were analysed, 9% had fully documented and 27% fully or partially documented evidence of up-to-date vaccinations. For measles vaccination, 28% of children aged 18 months or more had fully documented and 35% fully or partially documented evidence of vaccination. There was no fully documented evidence of any vaccinations for 52% of children. CONCLUSION: The vaccination status of Aboriginal children in the North Coast Health Region is poor. The 1989-1990 National Health Survey showed overall vaccination rates for NSW and Australia to be more than twice those found for this population.

Child↗
PubMed1994

Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission.

Several types of calcium channels found in the central nervous system are possible participants in triggering neurotransmitter release. Synaptic transmission between hippocampal CA3 and CA1 neurons was mediated by N-type calcium channels, together with calcium channels whose pharmacology differs from that of L- and P-type channels but resembles that of the Q-type channel encoded by the alpha 1A subunit gene. Blockade of either population of channels strongly increased enhancement of synaptic transmission with repetitive stimuli. Even after complete blockade of N-type channels, transmission was strongly modulated by stimulation of neurotransmitter receptors or protein kinase C. These findings suggest a role for alpha 1A subunits in synaptic transmission and support the idea that neurotransmitter release may depend on multiple types of calcium channels under physiological conditions.

Animals↗
PubMed1992

The health debate USA.

The debate about the future of health care in the USA is raging. Newspaper headlines reveal horror stories of the cost or inaccessibility of health care. Every day, someone announces new plans or ideas for tackling the problems. Alan Randall, a Harkness Fellow, visited the USA in 1991.

Delivery of Health Care↗