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R A Lawrence

Publications and source records attributed to R A Lawrence.

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

Induction of intracellular glutathione in alveolar type II pneumocytes following BCNU exposure.

N,N'-bis(2-chloroethyl)-N-nitro-sourea (BCNU) is a potent inhibitor of glutathione reductase (GSSG-Red) activity in both tissues and cells. We examined the effects of treating alveolar type II cells with BCNU and found that a marked decrease in cellular GSSG-Red activity occurred in these cells associated with a time-dependent increase in cellular glutathione (GSH) concentrations. The increase in GSH was not found to be related to changes in cellular gamma-glutamyl transpeptidase activity, gamma-glutamylcysteine synthetase activity, nor increased intracellular transport of cystine. When the BCNU-exposed cells were incubated with hydrogen peroxide to produce oxidant stress, the cells exhibited increased susceptibility to oxidant damage when compared with controls, despite the fact that cellular concentrations of GSH were markedly elevated.

Animals↗
PubMed1994

Elimination of glutathione-induced protection from hyperbaric hyperoxia by acivicin.

Glutathione (GSH) administered intraperitoneally significantly prolongs the time to initial seizure and survival time of rats exposed to hyperbaric hyperoxia (HBO). Acivicin is an antitumor antibiotic that is an inhibitor of gamma-glutamyl transpeptidase (GGT), an enzyme necessary for the breakdown and transport across cell membranes of GSH. To determine whether acivicin treatment alters GSH-induced protection from HBO, rats were dosed with 25 mg/kg of acivicin or vehicle 1 h before O2 exposure at an inspired O2 fraction of 1.0 at 4 ATA. Immediately before exposure, rats received GSH (1 mmol/kg) or vehicle. Time to seizure and time to death were recorded during exposure by direct observation. In separate groups of rats on the same dosing schedule, plasma GSH, renal GGT, and brain GGT were measured 15 min after the GSH injection without HBO exposure and 100 min after the beginning of HBO exposure. Renal GGT was decreased to 2.5% of control and brain GGT to 37% of control in the acivicin-dosed rats. Plasma GSH increased 3-fold in rats given acivicin alone, 52-fold in rats given GSH alone, and 84-fold in rats receiving both acivicin and GSH. Rats dosed with GSH alone had significantly prolonged times to seizure and death compared with all other groups. Rats dosed with GSH after receiving acivicin were not protected from HBO despite the large increase in plasma GSH that occurred in these animals. GSH treatment did not increase tissue GSH in lung, liver, or brain at 160 or 200 min of exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effects of hyperoxia on rat diaphragm function.

The association of oxygen radical generation with impaired diaphragm performance has previously been reported after inspiratory resistive loading (IRL). We hypothesized that exposure of rats to normobaric hyperoxia (O2) could produce impaired diaphragm function because of free radical production. Sprague-Dawley rats were divided into four groups: 1) room air (control), 2) > 95% O2 for 24 h, 3) > 95% O2 for 48 h, and 4) > 95% O2 for 60 h. Each group was studied at rest after the O2 exposure and then after IRL. During IRL, the animals breathed through an inspiratory resistor until they were unable to sustain > 70% of the maximum airway pressure. Diaphragm samples were obtained for analysis of glutathione (GSH) and glutathione disulfide (GSSG) concentrations. In vitro isometric contractile properties were also determined, including maximal tetanic tension (Po) and maximal twitch tension (Pt), in GSSG content and in GSSG-to-GSH ratios. Hyperoxia for > 48 h resulted in significant decreases in Po and Pt and an increase in GSSG content and in GSSG-to-GSH ratios compared with other groups. Those same animals subjected to IRL showed a further decrease in Po and Pt. These data suggest that free radical generation may occur in the diaphragm during a hyperoxia exposure associated with activation of the GSH redox cycle and impairment of diaphragm function.

Airway Resistance↗
PubMed1994

Buthionine sulfoximine treatment impairs rat diaphragm function.

Activation of the glutathione (GSH) redox cycle with production of glutathione disulfide (GSSG) has been shown to occur in the diaphragm during inspiratory resistive loading (RB). Buthionine sulfoximine (BSO) lowers tissue GSH by irreversibly inhibiting the rate-limiting synthesis enzyme gamma-glutamylcysteine synthetase. We investigated the effects of BSO on rat diaphragm function, both at rest and after a period of RB. Rats in the RB groups underwent inspiratory RB until they were unable to sustain 70% of their maximal airway pressure. A portion of the diaphragm was analyzed for GSH and GSSG levels, and measurements of in vitro contractile properties included contraction times, maximal tetanic tension (Po), maximal twitch tension (Pt), and force frequency curves. BSO treatment produced a profound depletion of diaphragmatic GSH. Neither BSO nor RB alone significantly altered diaphragm contractile properties at this load of RB. But, in BSO-RB rats, there was a significant decrease in Pt, Po, and tetanic tension at all frequencies of stimulation compared with those in other groups. These data reveal that animals treated with BSO followed by inspiratory resistive loading exhibit marked diaphragm impairment, suggesting that GSH may play an important role in protecting the diaphragm from the stress induced by this resistive breathing protocol.

Analysis of Variance↗
PubMed1994

The anatomy of violence.

The aim of this article is to analyse the causes and background of violence in the light of the increasing incidence internationally of both group and interpersonal violence. The author classifies violence according to types and causes. Comparative statistics are quoted to illustrate the incidence of violence in the author's experience and in some other countries. Indications are that violence is multifactorial in aetiology and suggestions are made how the incidence of violence may be reduced.

Cultural Characteristics↗
PubMed1993

Stage and isotype specific immune responses in a rat model of filariasis.

Inbred PVG rats infected with 100 Brugia pahangi infective larvae (L3) divide into rats that develop microfilaraemic infection (Mf+), and those that remain microfilaria negative (Mf-). All rats had high levels of specific IgG to adult worm and L3 extracts, however, after the onset of microfilaraemia, Mf+ rats had significantly higher levels of IgG to Mf extract. Mf+ rats recognized several antigenic components of each developmental extract that were not responded to by Mf- rats. In particular Mf+ rats recognized a triplet of proteins of 61-67 kD in microfilarial extract from day 74 post infection onwards. This indicated that these proteins were stage specific to Mf and Mf- rats had not been exposed to Mf rather than Mf absence being due to a protective antibody response. Analysis of the immunoglobulin isotype usage during infection revealed that each isotype was independent both in its period of induction and the developmental stage to which it responded. The predominant isotypes responding throughout infection were IgG1, IgG2a and IgM. Specific IgG2b and IgG2c were elevated early in infection but after the onset of microfilaraemia antibody of these subclasses was suppressed. The antigenic profiles recognized on immunoblots by IgG1, IgG2a and IgM were very similar.

Animals↗
PubMed1993

Diaphragmatic function after resistive breathing in vitamin E-deficient rats.

The effects of vitamin E deficiency on diaphragm function were studied at rest and after resistive breathing (RB) in Sprague-Dawley rats (wt 300-400 g). The animals were pair fed a vitamin E-deficient diet (E-def) or a matched vitamin E-sufficient diet (E-suf). Each diet group was then further subdivided into a group that breathed unimpeded (control) and a second group that breathed through an inspiratory resistor until the animals were unable to sustain 70% of their maximum airway pressure. Diaphragm samples were obtained for analysis of thiobarbituric acid-reactive substances, glutathione (GSH) concentrations, and glutathione disulfide (GSSG) concentrations. In vitro isometric contractile studies were also performed and included twitch (Pt) and maximum tetanic (Po) tensions, force-frequency curves, fatigue index, and recovery index. Pt was significantly reduced in the E-suf RB group as well as both of the E-def groups. Po was also significantly reduced in both E-def groups. The E-def rats subjected to RB showed a significant decrease in tension at both high and low frequencies compared with the E-suf rats. Concentrations of diaphragm thiobarbituric acid-reactive substances were significantly increased in both E-def groups. RB in both E-suf and E-def rats resulted in increases in diaphragm concentrations of GSSG and decreases in the GSH/GSSG ratios. We conclude that reduction of contractile function, lipid peroxidation, and activation of the GSH redox cycle occur with RB and that these effects are significantly increased in the presence of vitamin E deficiency.

Animals↗
PubMed1993

Diethylmaleate produces diaphragmatic impairment after resistive breathing.

Formation of oxygen-derived free radicals and activation of the glutathione (GSH) redox cycle has been associated with impaired rat diaphragm performance. Diethylmaleate (DEM) given intraperitoneally irreversibly conjugates with GSH, resulting in marked decreases in tissue concentrations of GSH. We have investigated the effects of acute GSH depletion by DEM on diaphragmatic function during resistive breathing (RB) in the rat. The experimental groups were 1) control, 2) DEM alone, 3) RB, and 4) DEM with RB (DEM + RB). RB was obtained by inspiratory RB until the rats were unable to sustain 70% of maximum airway opening pressure. A portion of the diaphragm was frozen for biochemical assays, and the rest of the diaphragm was prepared for measurement of in vitro contractile properties, including maximum tetanic tension, twitch tension, force-frequency curves, and contraction times. DEM treatment produced a profound depletion of GSH in the DEM and DEM + RB groups. Neither DEM nor RB alone significantly altered diaphragm contractile properties. In DEM + RB rats, however, there was a significant decrease in maximum tetanic tension, twitch tension, and tetanic tension. These data reveal that DEM produced an acute depletion of GSH in the diaphragm without impairment of the muscle in nonstressed rats. In the presence of DEM-induced GSH depletion, RB did result in marked diaphragm impairment. The depletion of GSH and the subsequent impairment in diaphragm contractility after RB suggest that GSH may play an important role in protecting the diaphragm against oxidative stress associated with RB.

Animals↗
PubMed1993

Day care and teenage mothers: nurturing the mother-child dyad.

Children of adolescent mothers do not fare well cognitively or behaviorally over time. Both short-term and long-term studies corroborate these findings. Our preliminary data help us focus on the vulnerabilities and strengths of young mothers in their interactions with their children. We suggest, on the basis of these preliminary data, that intervention be directed toward nurturing the young mother and her infant or child in a day-care setting so that she can better learn to nurture her child. The gains to young mothers and children as well as to society will be substantial if we can decrease the very distressing morbidity observed long-term in the children of adolescent mothers.

Adolescent↗
PubMed1992

Investigation of the prostaglandin E (EP-) receptor subtype mediating relaxation of the rabbit jugular vein.

1. Prostaglandin E2 (PGE2) relaxes circular smooth muscle of the rabbit isolated jugular vein at very low concentrations (mean pIC50 against histamine-induced contraction = 9.34). This effect is not blocked by the EP1-receptor antagonist, AH 6809 (2 microM). 2. From a group of prostaglandin E analogues examined, 16,16-dimethyl PGE2, misoprostol, 11-deoxy PGE2-1-alcohol and 11-deoxy PGE1 were highly potent relaxant agents, whereas 17-phenyl-omega-trinor PGE2, MB 28767 and butaprost had low potency and sulprostone and oxoprostol were virtually inactive. 3. Comparison of the jugular vein data with published data for inhibitory agonist potencies on the cat trachea (EP2 preparation) and the field-stimulated guinea-pig vas deferens (EP3) indicates that the EP-receptor in the rabbit jugular vein is closest to the EP2 subtype. However, the correlation is not entirely convincing. For example, butaprost, 16,16-dimethyl PGE2 and 11-deoxy PGE1 are of similar potency on the cat trachea, whereas butaprost is about 300 times less potent than the other two analogues on the jugular vein. The existence of more than one EP2-receptor appears possible. 4. It was felt that the activity of butaprost required further investigation in view of the claim that it is a specific EP2-receptor agonist. We have shown that butaprost has very low inhibitory activity on the guinea-pig vas deferens, a very sensitive EP3-receptor containing preparation. However, on the chick ileum, the original EP3 preparation, butaprost showed potent contractile activity (pEC25 approximately 8.0).In addition, its maximum response was lower than that of PGE2; lower maxima were also found for sulprostone, MB 28767 and oxoprostol, but not for ICI 80205, 16,16-dimethyl PGE2 and 17-phenyl-omega-trinor PGE2. The maximal response to a combination of either sulprostone and butaprost or sulprostone and PGE2 was similar to that achieved by PGE2 alone. Analysis of the interaction between sulprostone and PGE2 appears to exclude a partial agonist action for sulprostone. Furthermore neither sulprostone nor butaprost appear to have inhibitory activity on the ileum. AH 6809 at 2 pM produced only a small shift of the PGE2 log concentration-response curve.5. It is likely that contraction of the longitudinal smooth muscle of the chick ileum is mediated by (at least) two EP-receptor subtypes; activation of only one receptor system does not induce the maximum response (i.e. the acetylcholine maximum) of the preparation. One receptor could be an EP3 subtype, at which sulprostone exerts a selective agonist action. The other receptor is unlikely to be an EP, subtype, because of the high agonist potency of butaprost, the low agonist potency of iloprost, and the low antagonist potency of AH 6809. An alternative hypothesis is that the chick ileum contains a novel EP-receptor subtype in addition to an EP3-receptor.

Animals↗
PubMed1992

Characterization of receptors involved in the direct and indirect actions of prostaglandins E and I on the guinea-pig ileum.

1. A study of the effects of prostaglandin E2 (PGE2) and eleven synthetic analogues on the guinea-pig isolated ileum preparation has revealed three distinct contractile actions, each associated with a different prostaglandin E (EP-) receptor subtype. In addition, PGI2 (prostacyclin) and its stable analogues can activate prostaglandin I (IP-) receptors to elicit both contraction and relaxation of the ileum. 2. Two of the PGE actions involve direct stimulation of the smooth muscle, being unaffected by 1 microM morphine treatment. One action is blocked by AH 6809 at micromolar concentrations and ICI 80205 and 16,16-dimethyl PGE2 are particularly potent agonists. Activation of EP1-receptors appears to be involved. The second action is unaffected by AH 6809; sulprostone and MB 28767 are potent agonists. Comparison with agonist potency rankings on the guinea-pig vas deferens indicates that EP3-receptors may be involved. 3. The third PGE effect and the stimulant PGI effect are blocked by morphine, indicating enteric neurones and/or sensory nerve terminals as sites of action. EP2-receptors may be involved in the PGE action, in view of the marked effect of morphine on the contractile actions of misoprostol, 11-deoxy PGE2-1-alcohol, 11-deoxy PGE1 and butaprost, all of which show some selectivity for EP2-receptors. The PGI action is most easily studied with cicaprost (EC25 = 1.3 nM), since iloprost, carbacyclin and to a lesser extent PGI2 also have agonist activity at EP1-receptors. 4. The contractile action of 17-phenyl-omega-trinor PGE2 on the ileum is unaffected by morphine. Since this analogue shows only weak agonist activity on the rabbit jugular vein (EP2 preparation) and guinea-pig vas deferens (EP3), it may be a more useful standard agonist than PGE2 in EPl1-receptor studies.5. In the presence of morphine and AH 6809, cicaprost inhibits histamine-induced contractions (IC25 = 22 nM). PGI2 and iloprost show mixed inhibitory/potentiating actions, whereas carbacyclin only potentiates histamine contractions. This IP-receptor-mediated inhibition may account for the bell-shaped log concentration-response curve of cicaprost (no inhibitors present) and the very marked block of iloprostinduced contractions by AH 6809.6. We have found no evidence for either IP-receptors mediating direct contraction or EP-receptors mediating inhibition of the ileum longitudinal smooth muscle, as has been suggested in the literature.7. In view of the complexity of prostanoid action on the guinea-pig ileum we feel that the preparation must be used with caution to ascertain the EPl agonist or antagonist potencies of novel compounds.

Animals↗
PubMed1992

Endothelial cell cystine uptake and glutathione increase with N,N-bis(2-chloroethyl)-N-nitrosourea exposure.

Glutathione (gamma-glutamylcysteinylglycine, GSH) is an important cellular antioxidant. In typical cultured cell preparations GSH synthesis is limited by the availability of intracellular cysteine. Because extracellular cystine is the chief source of intracellular cysteine in cultured cells, increasing cystine transport can result in increased intracellular GSH. Depletion of GSH or exposure to oxidants has been shown to stimulate cystine transport in bovine pulmonary endothelial cells and other cell types. BCNU [N,N-bis(2-chloroethyl)-N-nitrosourea] is a potent inhibitor of glutathione reductase (GSSG-Red). We examined the effects of BCNU on cystine uptake by bovine pulmonary artery endothelial cells (BPAEC). We hypothesized that blocking GSSG-Red could result in increased cellular uptake of cystine to replenish decreases in GSH caused by oxidation. Levels of BCNU between 0.005 and 0.05 mM added to the cell culture medium inhibited GSSG-Red at 2, 4, and 24 h after addition. BCNU treatment resulted in concentration-dependent increases in both cystine uptake and GSH levels after 24 h of exposure. The increases in uptake were specific for cystine and glutamate and were sodium independent, suggesting induction of a xc(-)-like transport system. No intracellular accumulation of GSSG was measured nor was any significant depletion of GSH noted at any time of BCNU exposure.

Animals↗
PubMed1992

Resistive breathing activates the glutathione redox cycle and impairs performance of rat diaphragm.

Free radical activation and lipid peroxidation have been described in skeletal muscle during strenuous exercise. We hypothesized that oxygen radicals could also be formed in the diaphragm muscle during strenuous resistive breathing and that these radicals might affect diaphragm function. Seven control and 12 experimental male Sprague-Dawley rats were studied. Six experimental animals were subjected to resistive breathing (RB) alone and six animals received 15 min of mechanical ventilatory support (MV) after the resistive breathing period. Inspiratory resistance was adjusted to maintain airway opening pressure at 70% maximum in both groups until exhaustion. Diaphragm samples were obtained for analysis of thiobarbituric acid-reactive substances (TBAR), reduced glutathione (GSH), and glutathione disulfide (GSSG). In vitro isometric contraction times, twitch (Pt) tension and maximum tetanic (Po) tension, force-frequency curves, fatigue index, and recovery index were measured. In RB and MV compared with controls, there were significant decreases in Pt and Po. Diaphragm TBAR concentrations were increased in MV compared with controls or RB. GSSG-to-total glutathione ratio was increased in RB and MV compared with controls. Production of free radicals during RB and MV may represent an important mechanism of diaphragmatic injury that could contribute to the decline in contractility.

Airway Resistance↗
PubMed1992

The medico-legal, social and ethical implications of surrogate parenthood.

Infertility has existed for thousands of years and treatment has evolved with the advance of medical science. Surrogate parenthood was effected previously by sexual intercourse, but AIH, AID and GIFT have rendered this practice obsolete. The terms surrogate mother, partial and full surrogacy are defined. Medico-legal, social and ethical arguments for and against surrogacy are discussed. References are made to varying national attitudes as to the desirability of legalizing surrogate parenthood and the implications for commissioning parents, the surrogate mother and adequate counselling are considered.

Contracts↗