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Biomedical subjects

R A Lawrence

Publications and source records attributed to R A Lawrence.

At least 91 records · Page 5Linked to original sources
PubMed1992

Diphosphoryl lipid A protects rats from lethal hyperoxia.

Bacterial endotoxin has been shown to protect rats from lethal hyperoxia. The structure of endotoxin contains diphosphoryl lipid A (DPL) as the lipid backbone stripped of protein and polysaccharides. DPL is the component of the endotoxin molecule that has been demonstrated (in previous studies) to be responsible for the immunologic, mitogenic, pyrogenic, and lethal properties of endotoxin. Monophosphoryl lipid A (MPL) is a nonpyrogenic, nontoxic modification of the DPL molecule that retains its immunostimulatory and mitogenic properties. We hypothesized that DPL may be the actual active component of endotoxin that protects rats from lethal hyperoxia. We also hypothesized that the protection from hyperoxia that is afforded by the DPL component may be related to endogenous release of tumor necrosis factor alpha which should allow MPL to also be protective. To test these hypotheses, we performed a series of experiments in which rats were treated with endotoxin, DPL, MPL or vehicle and exposed to room air or hyperoxia. We found that DPL and endotoxin both protected rats from lethal hyperoxia, but MPL alone was not protective. Even though MPL was not protective, DPL and MPL both increased endogenous release of tumor necrosis factor alpha early after injection (peak DPL level, 3619 +/- 1500 pg/ml, peak MPL level, 4038 +/- 500 pg/ml). Protection in both the endotoxin- and DPL-treated animals was associated with increases in lung antioxidant enzyme activities. We concluded that DPL protect rats from hyperoxia but that MPL is not protective in spite of its immunostimulatory and mitogenic effects.

Animals↗
PubMed1991

Immunological tolerance: The key feature in human filariasis?

Filariasis is a widespread tropical disease caused by a group of nematode parasites that can survive for many years in immunocompetent hosts. The paradox of filariasis has always been the inverse association between parasite density, in terms of circulating microfilariae in the blood, and severe pathology. In this review, Rick Maizels and Rachel Lawrence argue that microfilariae and adult parasites induce a form of immunological tolerance which prevents both parasite elimination and progression to disease. The breakdown of this unresponsiveness is seen as the critical step towards pathogenesis. However, not every exposed individual progresses through infection to disease. The authors discuss evidence for protective immunity acting on antigens from the mosquito-borne infective larva, and propose that this stage represents a vulnerable target outside the scope of tolerance and pathogenesis. Stage-specific larval antigens, to which asymptomatic hosts are known to respond, may therefore represent the most effective and safe choice for an anti filarial vaccine.

Journal Article↗
PubMed1991

Effects of age on rat glutathione metabolism.

The authors hypothesized that rat plasma or tissue glutathione metabolism could change with age due to possible decreases in glutathione-related enzyme activities. To test this hypothesis, the authors measured plasma and tissue concentrations of glutathione and glutathione-related enzymes. Animals were 3 months, 12 months, or 24 months old at the time of experiments. Plasma glutathione was found to be significantly increased in both the 12-month-old and 24-month-old groups compared to the 3-month-old rats. Tissue enzyme measurements showed no significant differences between the groups in lung or liver glutathione peroxidase or glutathione S-transferase. gamma-Glutamyl transpeptidase activity was significantly decreased in kidney and lung with aging. Decreases in tissue gamma-glutamyl transpeptidase activity occur with age; this may contribute to increases in plasma glutathione concentrations.

Age Factors↗
PubMed1991

Allopurinol-induced effects in premature baboons with respiratory distress syndrome.

To test the hypothesis that administration of allopurinol could modify the response to prolonged hyperoxia in premature baboons (140 days gestation) with respiratory distress syndrome, we evaluated physiological, pathological, and lung biochemical parameters in groups of premature baboons treated with mechanical ventilation and exposed to various amounts of oxygen for 6 days. Three groups of experimental animals were studied, including animals that received oxygen as needed to maintain arterial oxygen between 60 and 80 Torr [inspiratory O2 concentration- (FIO2) PRN], animals that received 100% oxygen continuously but also received allopurinol intravenously at a dose of 10 mg.kg-1.day-1 (FIO2-1.0 + allopurinol), and animals that received 100% oxygen continuously and the vehicle for allopurinol administration (FIO2-1.0). Pathological examinations of the experimental animals showed evidence of lung injury in both 100% oxygen-exposed groups, but the allopurinol-treated animals had findings more compatible with the FIO2-PRN group, with relatively few macrophages or polymorphonuclear lymphocytes being present in lung tissue. Lungs of animals treated with allopurinol were also more distensible and had a trend toward decreased lung water compared with the FIO2-1.0 group. Allopurinol-treated animals were able to induce lung glutathione concentrations and glutathione-related and antioxidant enzyme activities compared with the normoxic control (FIO2-PRN) group. Ventilator pressure requirements were also decreased in the allopurinol-treated animals compared with the FIO2-1.0 controls after 42 h. These data suggest that treatment of hyperoxia-exposed premature baboons with allopurinol for the first 6 days of life results in significant changes in lung responses and antioxidant defenses compared with vehicle-treated baboons exposed to 100% oxygen for the same time period.

Allopurinol↗
PubMed1991

Dental needs assessment survey: three Florida counties.

Dental needs assessment surveys were completed in three Florida counties (1987 - Lee County), (1988 - Pasco County) and (1989 - St. Lucie County). The data collected were then compared with the results from the national caries prevalence surveys in 1979-80 and 1986-87, by individual county and with the combined three-county total. Visual tactile examinations were done using the Radlike criteria for the DMFS index and the WHO Treatment Needs Index. Schools were selected based on the percent of students enrolled in the free or reduced lunch program and by geographic distribution. Although there were age group differences within individual counties, the combined data showed every age group except the seven year olds at a lower DMFS mean level than the data from the 1986-87 national survey for Region IV. The differences range from -.20 surfaces in 8-year-olds to -.57 surfaces in 13-year-olds. None of the differences were statistically significant from the national surveys. This indicates that these small scale surveys are a reliable method for needs assessment.

Adolescent↗
PubMed1989

Breastfeeding and medical disease.

Breastfeeding is an important opportunity for both mother and infant. There are nutritional, immunologic, infection protection, and psychological reasons to preserve lactation when illness intervenes. The internist will have patients with acute self-limited disease who are breastfeeding and patients with chronic long-term illness who wish to breastfeed their infants. The internist will need to consider the breastfeeding and the infant when planning treatment. The risk of treatment to the infant versus the great benefits of breastfeeding in most cases will support continuing breastfeeding. This article discusses the key considerations in managing the lactating woman with an illness.

Bacterial Infections↗
PubMed1989

EP 171: a high affinity thromboxane A2-mimetic, the actions of which are slowly reversed by receptor blockade.

1. Replacement of the four-carbon omega-terminus in 9,11-endoxy-10a-homo prostaglandin H2 with a p-fluorophenoxy group produces a compound (EP 171) with very high agonist potency at TP-receptors. 2. On six isolated smooth muscle preparations EP 171 was 33-167 times more potent as a TP-receptor agonist than U-46619 (11,9-epoxymethano PGH2); EC50 values ranged from 45 to 138 pM. The actions of EP 171 were difficult to study because of their slow onset and offset. For example, on the guinea-pig trachea the time required for 50% reversal of EP 171-induced contractions during washout was about 3 h. 3. On the pig pulmonary artery, a more rapidly responding preparation, it was possible to show that the TP-receptor antagonist EP 092 blocked the contractile actions of EP 171 and U-46619 to similar extents: pA2 = 8.09 and 8.15 respectively. 4. EP 171 was also a very potent activator of human blood platelets, being about 90 times more potent than U-46619. Both shape change (0.1 nM) and aggregation (1 nM) were slow in onset, a profile not previously observed for a thromboxane A2-mimetic. 5. When potencies at TP-, EP1-(guinea-pig fundus) and FP-(dog iris sphincter) receptors were compared, EP 171 showed a higher specificity as a TP-receptor agonist than either STA2 or U-46619. These studies also showed that contrary to earlier reports, the guinea-pig fundus does contain TP-receptors mediating muscle contraction. However, the maximal response due to activation of TP-receptors was only about 35% of the PGE2 maximum. 6. Established responses to EP 171 were slowly reversed following addition of a high concentration of a TP-receptor antagonist (EP 092, GR 32191 or BM 13177). Faster reversals of three less potent 16-p-halophenoxy prostanoids and U-46619 were obtained. Half-times for offset (and onset) of agonist action appeared to correlate with potency rather than with lipophilicity. 7. Competition between the agonists and a radio iodinated PTA2 derivative ([125I]-PTA-OH) for binding to TP-receptors on intact human platelets was studied. IC50 values correlated well with aggregating potency, EP 171 having the lowest IC50 of 2.9 nM. The true Ki for EP 171 may be about 1 nM if both its racemic nature and reduction of initial free ligand concentration due to TP-receptor binding are taken into account. 8. It is concluded from a comparison of agonist potency rankings that subclassification of the TP-receptor is not warranted at this time. The factors that may be responsible for the slow kinetics of EP 171 action are discussed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Functional and ligand binding studies suggest heterogeneity of platelet prostacyclin receptors.

1. This study describes attempts to compare prostacyclin (IP-) receptors in human, pig, horse, rabbit and rat platelets and in circular muscle of human, rabbit and dog mesenteric and pig gastroepiploic arteries. Three stable prostacyclin analogues, iloprost, cicaprost and 6a-carba-prostacyclin (6a-carba-PGI2) and a prostaglandin endoperoxide analogue EP 157 (previously shown to mimic prostacyclin on human platelets) were used. 2. Our main conclusion is that prostacyclin receptors on human, pig and horse platelets are similar in nature, but distinct from those on rabbit and rat platelets. Functional studies (inhibition of aggregation) showed that iloprost and cicaprost always had similar potencies whereas 6a-carba PGI2 was much more potent than EP 157 on rabbit and rat platelets (300 and 1000 fold on a molar basis) compared with human, pig and horse platelets (2, 7 and 7 fold respectively). Measurement of initial rates of cyclic AMP production confirmed these orders of potency. 3. Although pig platelets were quite sensitive to inhibition by EP 157 (threshold = 10 nM in some experiments), maximal inhibition of aggregation was not always achieved (20 microM). EP 157 also produced only small elevations of cyclic AMP and inhibited rises in cyclic AMP induced by iloprost. It is possible that EP 157 has a lower efficacy than iloprost at the IP-receptor and on pig platelets it can sometimes act as a partial agonist. 4. Human, pig and horse platelet membranes bound [3H]-iloprost at 30 degrees C and this binding was inhibited by the four prostanoids. On human and pig membranes the order of potency was cicaprost = iloprost greater than 6a-carba PGI2 greater than EP 157. The order of potency may be similar on horse platelet membranes, but the analysis is complicated by the presence of a second component of [3H]-iloprost binding that is inhibited by iloprost and 6a-carba PGI2 but not by cicaprost. This binding may be due to the presence of an EP1-receptor, since iloprost and 6a-carba PGI2 but not cicaprost are known to have potent EP1-receptor agonist actions on smooth muscle preparations. IC50 values for cicaprost inhibition on human, pig and horse membranes were 110, 90 and 165 nM respectively. The need for IP-receptor radioligands of greater specificity is apparent from these studies. 5. Minimal binding of [3H]-iloprost to rabbit and rat platelet membranes was obtained at 30 degrees C. Lowering the incubation temperature to 4 degrees C and ensuring that the temperature did not rise during the filtration process increased binding and allowed inhibition curves to be obtained. The results suggest a lower binding affinity for [3H]-iloprost, associated with a higher dissociation rate for the radioligand-receptor complex. IC50 values for cicaprost were 900nm for rabbit and 640nm for rat platelets. In a similar manner to horse platelet membranes, the presence of a second binding site for [3H]-iloprost was detected on rabbit platelet membranes. 6. Sensitivity to the relaxant action of iloprost on the arterial smooth muscle preparations decreased in the order: human mesenteric, dog mesenteric, rabbit mesenteric, pig gastro-epiploic. Cicaprost was always slightly more potent than iloprost (1.2-2.8 fold). On the pig vessel preparation 6a-carba PGI2 did not produce complete relaxation. The possibility that this is due to an opposing contractile action mediated via EP1 or EP3 receptors is discussed. 7. EP 157 relaxed the human, pig and rabbit arterial preparations at concentrations 100-200 times those of iloprost. This correlates well with its IP-receptor agonist potency on human, pig and horse platelets. The results obtained with EP 157 further demonstrate the potential difficulties in separating platelet inhibitory and vasodilator properties of prostacyclin mimetics in man.

Animals↗
PubMed1989

Effects of hyperoxia and vitamin E on the fatty acid composition of rat lung microsomes and mitochondria.

Peroxidation of lung membrane lipids in vitro produces very specific changes in lung membrane fatty acid content with some fatty acids being affected more than others. We performed a series of experiments to determine the changes occurring in fatty acid composition in lung microsomes and mitochondria during an in vivo hyperoxic exposure. Hyperoxia did produce specific changes in the relative content of fatty acids present in lung microsomes and mitochondria of both vitamin E-supplemented and vitamin E-deficient rats. Changes were noted to occur in saturated and polyunsaturated fatty acids. The total amount of lung lipids extractable in the microsomal fractions decreased after hyperoxia in both the vitamin E-supplemented and the vitamin E-deficient animals with no changes occurring in extraction of lung mitochondrial total lipids. Decreases in lung mitochondrial fatty acids caused by hyperoxia occurred in the same fatty acids in both the vitamin E-supplemented and the vitamin E-deficient animals with few polyunsaturated fatty acids (PUFA) being affected. Decreases in lung microsomal fatty acids occurring during hyperoxia were different in the vitamin E-supplemented animals from those in the vitamin E-deficient animals with many more PUFA decreasing in the vitamin E-deficient group. The greatest number of PUFA found to decrease after hyperoxia when comparing all the different groups occurred in the microsomal fraction of the vitamin E-deficient rats. These data suggest that vitamin E-deficient animals have increased peroxidation of lung microsomal PUFA or a decrease in production of lung microsomal PUFA in vivo during a hyperoxic exposure.

Animals↗
PubMed1989

Breast-feeding.

The pediatrician plays a crucial role in the success of breast-feeding by providing well-researched, practical advice and support to the lactating woman, beginning in the prenatal period and continuing until total weaning. The pediatrician can provide much needed support and affirmation when the mother is sabotaged by well-meaning friends and relatives who are misinformed about the value or techniques of breast-feeding. Mothers state that their pediatrician is the most important member of the support team but also the one most apt to obstruct success with inappropriate advice. An understanding of lactation as a physiologic process will provide a sound basis for anticipatory guidance.

Breast↗
PubMed1988

BCNU-induced protection from hyperbaric hyperoxia: role of glutathione metabolism.

To explore the role of the glutathione oxidation-reduction cycle in altering the sensitivity of rats to the effects of hyperbaric hyperoxia, we administered N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU) to decrease tissue glutathione reductase activity. We then exposed these animals and their matched vehicle-treated controls to 100% O2 at 4 ATA. Animals that received BCNU and were immediately exposed to hyperbaric O2 showed enhanced toxicity by seizing earlier in the exposure than controls. Animals that received BCNU 18 h before the hyperbaric O2 exposure were paradoxically protected from the effects of the exposure with a prolongation of their time to initial seizure and a marked increase in their survival time during the exposure. Tissue glutathione concentrations were also measured in the various groups and the hyperbaric O2 exposure produced marked decreases in hepatic glutathione levels in all control animals. In animals treated with BCNU 18 h before exposure, hepatic glutathione concentrations also decreased, but the concentrations had significantly increased during the 18-h waiting period, allowing these animals to maintain hepatic levels in the normal range even during their hyperbaric exposures. We conclude that treatment of rats with BCNU 18 h before exposure to hyperbaric hyperoxia results in enhanced protection of the animals during the exposure.

Animals↗
PubMed1988

Glutathione disulfide formation occurring during hypoxia and reoxygenation of rat lung.

To study changes in glutathione redox status as an indicator of oxidant stress during hypoxia and reoxygenation, we perfused isolated rat lungs with a high or low oxygen perfusate and measured the release of total glutathione and glutathione disulfide (GSSG) into the perfusate. Lungs were perfused for a 20-minute baseline period with a perfusate equilibrated with 95% O2 and 5% CO2 and ventilated with a 95% O2 and 5% CO2 gas mixture. Only very low amounts of oxygen were measurable in this hypoxic perfusate. The lungs were then perfused from a second reservoir containing perfusate equilibrated with 95% N2 and 5% CO2 and ventilated with a 95% N2 and 5% CO2 gas mixture. After the period of hypoxia, the lungs were reperfused with the 95% O2 and 5% CO2 equilibrated perfusate and ventilated with a 95% O2 and 5% CO2 gas mixture for the remainder of the experiment. Glutathione was measured in the perfusate serially throughout the experiment, and lactic dehydrogenase (LDH) was also measured to assess cell membrane rupture during the infusion. GSSG release remained stable in the baseline and hypoxic period but rose significantly in the reoxygenation period, to concentrations approximately two times basal release. Lung tissue concentrations of GSSC also rose in the reoxygenation period. Decreasing lung glutathione reductase activity by pretreating animals with 1,3-bis-2-chloroethyl)-1-nitrosourea (BCNU) increased GSSG release into the perfusate during reoxygenation. We conclude that GSSG formation and release is increased in the lung during the reoxygenation period after lung hypoxia, suggesting the presence of hydroperoxide and free radical metabolism. These data support the hypothesis that alterations in lung metabolism occur during hypoxia that allow free GSSG formation and release during the reintroduction of oxygen.

Animals↗
PubMed1988

A comparison of energy expenditure during rowing and cycling ergometry.

Metabolic and cardiorespiratory responses of healthy adults were compared at similar incremental power outputs during a variable-resistance rowing exercise and a fixed-resistance cycle ergometer exercise. Repeated measurements of power (watts), VEBTPS, VO2 STPD, and HR were obtained on 60 men and 47 women ranging in age from 20 to 74 yr. Average maximal power output for the men was significantly higher (P less than 0.05) for cycling than rowing: 207 +/- 5.2 W vs 195 +/- 58 W (mean +/- SE). A similar difference was also observed for women favoring cycling: 135 +/- 4.1 W vs 126 +/- 4.9 W (mean +/- SE). VEBTPS, VO2 STPD, and HR were significantly higher at all power increments during the rowing graded exercise test (RGXT) when compared with the same exercise intensity during the cycle graded exercise test (CGXT). Consistent linearity was found between VEBTPS and VO2 STPD and between HR and VO2 STPD for both exercises. The linear relationship between VEBTPS and VO2 STPD for men during RGXT was r = 0.976, P less than 0.001, slope = 44.6 +/- 1.03, and for women during RGXT it was r = 0.990, P less than 0.001, slope = 19.6 +/- 0.36. The relationship between HR and VO2 STPD for men during rowing was r = 0.989, P less than 0.001, slope = 29.1 +/- 0.76, and for women during rowing it was r = 0.971, P less than 0.001, slope = 35.7 +/- 0.89. The linear relationship between VEBTPS and VO2 STPD for men during CGXT was r = 0.991, P less than 0.001, slope = 31.1 +/- 0.98, and for women it was r = 0.959, P less than 0.991, slope = 29.6 +/- 0.87. The relationship between HR and VO2 STPD for men during CGXT was r = 0.997, P less than 0.001, slope = 28.1 +/- 0.83, and for women it was r = 0.990, R less than 0.001, slope = 35.9 +/- 0.96. Results indicated that energy costs for rowing ergometry was significantly higher than cycle ergometry at all comparative power outputs including maximum levels. It was concluded that rowing ergometry could be an effective alternative activity for physical fitness and exercise rehabilitation programs.

Adult↗