Search PubMed⌕ Search

Biomedical subjects

G Edwards

Publications and source records attributed to G Edwards.

At least 109 records · Page 6Linked to original sources
PubMed1997

Adhesion molecules involved in macrophage responses to Wallerian degeneration in the murine peripheral nervous system.

When a peripheral nerve is damaged the severed axon undergoes Wallerian degeneration. The distal nerve is infiltrated by large numbers of monocyte-derived macrophages which participate in the phagocytosis of degenerating myelin. In other tissues, adhesion molecules play a crucial role in leukocyte recruitment during inflammation. Blood-borne cells enter damaged tissue by interacting with adhesion molecules expressed on activated endothelium. Having crossed the endothelium, leukocytes must adhere and migrate within the tissue. We investigated the adhesion molecules involved in both stages of the macrophage response to transection of one sciatic nerve of BALB/c mice. By injecting monoclonal antibodies in vivo, before and after peripheral nerve injury, we showed that intercellular adhesion molecule-1 (ICAM-1) and integrins alpha4beta1 (VLA-4) and alphaMbeta2 (type 3 complement receptor) are unlikely to be involved in the transendothelial migration of monocytes responding to peripheral nerve degeneration. We also studied the adhesion of macrophages within the endoneurium, using an in vitro adhesion assay. Macrophages showed much greater levels of adhesion to cryostat sections of transected nerves than to control nerves. This increased adhesion was partially inhibited by antibodies to the beta1-integrin chain, and more strongly inhibited by the extracellular matrix molecules fibronectin and collagen. Adhesion was unaffected by laminin-1 and by antibodies to other adhesion molecules, including alpha4beta1- and alpha5beta1-integrins. Thus we conclude that monocyte entry into a degenerating peripheral nerve is independent of alphaLbeta2/alphaMbeta2-ICAM-1 or alpha4beta1/VCAM-1 interactions, and that adhesion within the endoneurium is mediated in part by a beta1-integrin other than alpha4beta1 or alpha5beta1.

Animals↗
PubMed1997

Alcohol policy and the public good.

Despite a diversity of cultural, social and economic experiences with alcohol at national level, a broad unity of purpose is emerging within the alcohol problems perspective. The scientific basis for that perspective finds its support in a sustained international research effort. With the publication in 1994 of the WHO report "Alcohol Policy and the Public Good", that perspective has been given persuasive empirical underpinning and a sharp focus. Essentially the problems perspective suggests that the target for public policy is the prevention or alleviation of population-wide alcohol-related problems, with problems broadly defined. The test for any policy within this arena is then whether it contributes to the achievement of that target. The perspective is thus rational, empirical, rooted in the traditions of public health, and readily intelligible to the ordinary citizen. Key conclusions emanating from "Alcohol Policy and the Public Good" are summarized. That text is rounded off by the challenging assertion that "Drinking problems are not carried by an uncontrollable tide. With public will, and on the evidence, they are capable of amelioration." A positive response to that challenge by the nations of Europe is both necessary and feasible.

Alcohol Drinking↗
PubMed1997

Infection with Plasmodium berghei alters benzodiazepine receptor in rat brain.

The purpose of this study was to assess the effect of malaria infection on benzodiazepine binding in rat brain. Young male Wistar rats were infected with the rodent parasite Plasmodium berghei, while age-matched control rats (n = 5) received normal saline intraperitoneally. Parasitemia was determined in blood of infected animals. Animals were killed after two weeks, and synaptosomal brain membrane homogenate was prepared from cerebral cortex. Membrane homogenate was incubated in duplicate with 3H-flunitrazepam (0.2-10 nM in buffer, pH 7.4) and binding parameters determined. The number of receptors (Bmax) was decreased marginally but significantly (P = 0.047) in malaria-infected (MI) rats (MI rats: 1.12 +/- 0.1 pmol.mg-1 protein; control rats: 1.42 +/- 0.08 pmol.mg-1 protein) while binding affinity (Kd) was not altered (MI rats: 1.18 +/- 0.3 nM; control rats: 1.02 +/- 0.15 nM). These results suggest that malaria may be associated with decreased benzodiazepine activity.

Animals↗
PubMed1996

Modulation of membrane currents and mechanical activity by niflumic acid in rat vascular smooth muscle.

The effects of niflumic acid on whole-cell membrane currents and mechanical activity were examined in the rat portal vein. In freshly dispersed portal vein cells clamped at -60 mV in caesium (Cs+)-containing solutions, niflumic acid (1-100 microM) inhibited calcium (Ca2+)-activated chloride currents (IC1(Ca)) induced by caffeine (10 mM) and by noradrenaline (10 microM). In a potassium (K+)-containing solution and at a holding potential of - 10 mV, niflumic acid (10-100 microM) induced an outward K+ current (IK(ATP)) which was sensitive to glibenclamide (10-30 microM). At concentrations < 30 microM and at a holding potential of -2 mV, niflumic acid had no effect on the magnitude of the caffeine- or noradrenaline-stimulated current (IBK(Ca)) carried by the large conductance, Ca(2+)-sensitive K+ channel (BKCa). However, at a concentration of 100 microM, niflumic acid significantly inhibited IBK(Ca)) evoked by caffeine (10 mM) but not by NS1619 (1-(2'-hydroxy-5'-trifluoromethylphenyl)-5-trifluoromethyl-2(3 H) benzimidazolone; 20 microM). In Cs(+)-containing solutions, niflumic acid (10-100 microM) did not inhibit voltage-sensitive Ca2+ currents. In intact portal veins, niflumic acid (1-300 microM) inhibited spontaneous mechanical activity, an action which was partially antagonised by glibenclamide (1-10 microM), and contractions produced by noradrenaline (10 microM), an effect which was glibenclamide-insensitive. It is concluded that inhibition of ICl(Ca) and stimulation of IK(ATP) both contribute to the mechano-inhibitory actions of niflumic acid in the rat portal vein.

Adrenergic alpha-Agonists↗
PubMed1996

A role in migration for the alpha V beta 1 integrin expressed on oligodendrocyte precursors.

Myelination of the CNS requires the migration of oligodendrocyte precursors throughout the CNS from restricted regions within the ventricular and subventricular zones. In light of the significant effects of cell-extracellular matrix (ECM) interactions on cell migration in other developing systems, we have analyzed the role of integrins in oligodendrocyte precursor migration. We have shown previously that oligodendrocyte precursors in vitro express a limited repertoire of integrins, including alpha 6 beta 1, alpha v beta 3, and that differentiation is associated with downregulation of alpha v beta 1 and upregulation of alpha v beta 5. Using a migration assay based on the movement of cells away from an agarose drop containing a high-density cell suspension, we find that RGD peptides (that block alpha v but not alpha 6 integrins) and anti-beta 1 antibodies block migration on an astrocyte-derived ECM, whereas anti-beta 3 antibodies have little effect. These results suggest that alpha v beta 1 but not alpha 6 beta 1 plays a role in oligodendrocyte precursor migration, and this is confirmed by the use of blocking monoclonal antibodies that distinguish these two integrins. In keeping with the results of others, we find that differentiated oligodendrocytes lose migratory potential and that the timing of this loss correlates with downregulation of alpha v beta 1. Taken together with the work of others showing that ECM ligands for alpha v beta 1 are expressed within the CNS, we propose that this integrin plays a significant role in the migration of oligodendrocyte precursors in vivo and that its downregulation during differentiation could be an important factor regulating the migratory phenotype of these cells.

Animals↗
PubMed1996

Sensible drinking.

Explore the source record for details and available documents.

Alcohol Drinking↗
PubMed1996

A 1-year prospective study of burns in an Irish paediatric burns unit.

Burns are the fourth leading cause of injury death in children in the USA, accounting for 1300 paediatric deaths annually. The majority of paediatric burns mortality and morbidity result from simple domestic accidents that are preventable. A prospective study of paediatric burns from 1 January 1992 to 1 January 1993 was undertaken at our burns unit to outline the profile of the Irish paediatric burns problem. A total of 336 burns were referred to our unit over the 12 months (80 per cent self-referrals, 15 per cent tertiary referrals from district hospitals and 5 per cent GP referrals). Sixteen per cent (57) of the patients required admission and 33 per cent (112) required prolonged dressings as outpatients. Mortality and morbidity rates were comparable to other centres at 1.8 per cent and 39 per cent respectively. The demographic analysis of the patient population was similar to that seen in other studies from developed countries but there were some notable differences. First, there was an alarmingly high incidence of serious sunburn injuries, especially among young infants. Most parents were unaware of the association between childhood sunburn and the development of skin cancer in later life. Second, 90 per cent of the accidents occurred in the home and almost all were preventable. A parent or guardian was present in 87 per cent of cases but parental knowledge of the appropriate first aid measures was poor. It is suggested that a public health education campaign on this issue would help in reducing the incidence and severity of paediatric burn injuries in Ireland.

Accidents, Home↗
PubMed1996

Investigation of the effects of 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) on membrane currents in rat portal vein.

1. The effects of 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) were investigated on evoked and spontaneous currents in freshly-isolated cells from the rat portal vein by use of conventional whole-cell recording and perforated-patch techniques. 2. At a holding potential of -60 mV in potassium-free, caesium-containing solutions, NPPB (10 microM) inhibited calcium (Ca)-sensitive chloride currents (ICl(Ca)) evoked by caffeine (10 mM) and by noradrenaline (10 microM) by 58% and 96%, respectively. 3. At a holding potential of -2 mV in potassium (K)-containing solutions, NPPB (10 microM) inhibited charybdotoxin-sensitive K-currents (IBK(Ca)) induced by noradrenaline (10 microM) and acetylcholine (10 microM) by approximately 90%. In contrast, IBK(Ca) induced by caffeine (10 mM) was unaffected in the presence of NPPB (10 microM). Conversely, IBK(Ca) elicited by caffeine (2 mM) was reduced by approximately 50% whereas IBK(Ca) evoked by noradrenaline (50 microM) was not significantly inhibited by NPPB. 4. In K-containing solutions, NPPB (10 microM) abolished spontaneous transient outward currents (STOCs) and induced a slowly-developing outward K-current. Bath application of glibenclamide (10 microM) abolished the outward current but did not antagonize the inhibitory effects of NPPB on STOCs or on IBK(Ca) evoked by noradrenaline. 5. In caesium-containing solutions, NPPB (30 microM) inhibited voltage-sensitive Ca-currents. 6. In Ca-free, K-containing solutions and in the presence of glibenclamide (5 microM), IBK(Ca) induced by 20 microM NS1619 was enhanced by NPPB (10 microM). 7. It is concluded that NPPB inhibits agonist-induced ICl(Ca) in rat portal vein smooth muscle. However, this agent also inhibits agonist-evoked IBK(Ca) and STOCs. Moreover, NPPB inhibits voltage-sensitive Ca-currents and stimulates a glibenclamide-sensitive K-current and IBK(Ca). The effects of this agent on evoked ICl(Ca) and IBK(Ca) and on STOCs probably involves an inhibitory action on intracellular Ca-stores.

Acetylcholine↗
PubMed1996

Effects of cytochrome P450 inhibitors on EDHF-mediated relaxation in the rat hepatic artery.

1. The possibility that the endothelium-derived hyperpolarising factor (EDHF) in the rat hepatic artery is a cytochrome P450 mono-oxygenase metabolite of arachidonic acid was examined in the present study. In this preparation, acetylcholine elicits EDHF-mediated relaxations in the presence of the nitric oxide (NO) synthase and cyclo-oxygenase inhibitors N omega-nitro-L-arginine (L-NOARG) and indomethacin, respectively. 2. 17-Octadecynoic acid (17-ODYA, 50 microM), a suicide-substrate inhibitor of the cytochrome P450 mono-oxygenases responsible for the production of 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acids (EETs), had no effect on acetylcholine-induced relaxations in the presence of L-NOARG (0.3 mM) plus indomethacin (10 microM). Furthermore, 5,6-, 8,9-, 11,12- and 14,15- EETs failed to relax arteries without endothelium in the presence of L-NOARG plus indomethacin. 3. Proadifen and clotrimazole, which are inhibitors of several isoforms of cytochrome P450 mono-oxygenases, inhibited acetylcholine-induced relaxations in the presence of L-NOARG plus indomethacin. The concentration of acetylcholine which caused half-maximal relaxation was about 3 and 30 times higher in the presence than in the absence of clotrimazole (3 microM) and proadifen (10 microM), respectively. The maximal relaxation was reduced by proadifen but not by clotrimazole. Proadifen (10 microM) also inhibited acetylcholine-induced hyperpolarization in the presence of L-NOARG plus indomethacin. 4. In the presence of 30 mM K+ plus indomethacin (10 microM), acetylcholine induced an L-NOARG-sensitive relaxation mediated via release of NO. Under these conditions, proadifen (10 microM) shifted the acetylcholine concentration-response curve 6 fold to the right without affecting the maximal relaxation. Clotrimazole (3 microM) was without effect on these responses. The relaxant actions of the NO donor, 3-morpholino-sydnonimine, were unaffected by proadifen (10 microM). 5. The relaxant effects of the opener of ATP-sensitive potassium channels, levcromakalim, were abolished by proadifen (10 microM) and strongly attenuated by clotrimazole (3 microM). Proadifen (10 microM) also abolished the hyperpolarization induced by levcromakalim (1 microM). 6. The lack of effect of 17-ODYA on relaxations mediated by EDHF, together with the failure of extracellularly-applied EETs to produce relaxation, collectively suggest that EDHF is not an EET in the rat hepatic artery. It seems likely that inhibition of ion channels in the smooth muscle rather than reduced EDHF formation in the endothelium offers a better explanation for the actions of the cytochrome P450 inhibitors proadifen and clotrimazole.

Acetylcholine↗
PubMed1996

Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein.

1. The effects of the cytochrome P450 inhibitors, proadifen, clotrimazole and 17-octadecynoic acid (17-ODYA) on K-currents in freshly-isolated single cells derived from rat portal vein and on mechanical activity in whole veins were studied. 2. When cells were stepped from -90 mV to a series of test potentials (from -80 to +50 mV), a delayed rectifier current (IK(V)) and an A-type current (IK(A)) could be identified. Proadifen (10 microM), clotrimazole (30 microM) and 17-ODYA (5 microM) each inhibited IK(V) but had little effect on IK(A). 3. When cells were held at -10 mV to inactivate the time-dependent K-currents, IK(V) and IK(A), levcromakalim (3 microM) induced a time-independent outward K-current (IK(ATP)) which was totally inhibited by clotrimazole (30 microM) and almost fully inhibited by proadifen (10 microM). 17-ODYA (5 microM) had no effect on IK(ATP) and exerted only a minor inhibitory action on this current at 20 microM. 4. 17-ODYA (5 microM) potentiated current flow through the large conductance, Ca-sensitive K-channel (BKCa). In contrast, proadifen (10 microM) had no effect on IBK(Ca) whereas clotrimazole (30 microM) exerted a small but significant inhibitory action. 5. Proadifen (10 microM) and clotrimazole (30 microM) each inhibited the magnitude but increased the frequency of spontaneous contractions in whole portal veins. 17-ODYA (5 microM) had no effect on spontaneous contractions but these were inhibited when the concentration of 17-ODYA was increased to 50 microM. 6. The spasmolytic effect of levcromakalim on spontaneous contractions was antagonized by proadifen (10-30 microM) in a concentration-dependent manner but 17-ODYA (up to 50 microM) was without effect. 7. These results in portal vein show that cytochrome P450 inhibitors exert profound effects on a variety of K-channel subtypes. This suggests that enzymes dependent on this cofactor may be important regulators of K-channel activity in smooth muscle. The relevance of these findings for the identification of the pathway involved in the synthesis of the endothelium-derived hyperpolarizing factor is discussed.

Animals↗
PubMed1996

Pharmacological characterization of the inwardly-rectifying current in the smooth muscle cells of the rat bladder.

1. In freshly-isolated single cells of the rat bladder detrusor, outwardly-rectifying and inwardly-rectifying membrane currents were identified by the whole-cell voltage-clamp technique. 2. The inwardly-rectifying current (IIR) exhibited features of a cation current permeable to both K+ and Na+ but it was unaffected by changes in extracellular Ca2+. It had an activation threshold close to -60 mV and an estimated reversal potential of -29 mV. 3. IIR activated slowly with a voltage-sensitive time-constant of 69 ms at -140 mV and 209 ms at -100 mV but did not exhibit time-dependent inactivation. 4. IIR was unaffected by tetraethylammonium (up to 20 mM) but it was reduced by extracellular Ba2+ (1 mM) and by extracellular Cs+ (1 mM). 5. IIR was reduced by terikalant (100 microM) and markedly inhibited by ciclazindol (100 microM) although at these concentrations, both agents also reduced outward currents. 6. IIR was inhibited by ZD7288 (10-100 microM) in a concentration-dependent manner. At concentrations up to 30 microM, ZD7288 did not reduce the magnitude of outward currents but these were inhibited by 100 microM ZD7288. 7. In strips of bladder detrusor, spontaneous mechanical activity was increased by ZD7288 (0.3-100 microM) and by ciclazindol (0.3-100 microM) but was unaffected by glibenclamide (1-10 microM). 8. It is concluded that IIR closely resembles the hyperpolarization-activated current Ih, previously described in the smooth muscle of rabbit jejunum and in a variety of other cell types. This current may play an important role in modulating detrusor excitability but this could not be confirmed using the inhibitors ZD7288 and ciclazindol.

Animals↗