The George Addlington Syme Oration: winds of change.
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Gynecology↗
Biomedical subjects
G C Liggins
Publications and source records attributed to G C Liggins.
Obstetric and paediatric collaboration to reduce morbidity after preterm birth.
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Adrenal Cortex Hormones↗
[Hormonal synergism, maturation of lung structure and surfactant production in the fetal sheep lung].
Simultaneous administration of cortisol, triiodothyronine, and prolactin but not of any of these hormones infused singly or in combination of two, increases pulmonary distensibility and stability to term values in fetal sheep of 125 days gestation. Similar results are obtained with thyrotropin-releasing hormone and cortisol. Measurements of elastin and collagen and discrepancies between concentrations of alveolar surfactant and lung distensibility and stability suggest that maturation of connective tissue plays an important part in fetal lung maturation.
Animals↗
Can the benefits of antepartum corticosteroid treatment be improved?
Although there is no doubt that antepartum corticosteroid treatment is effective in reducing the incidence of respiratory distress syndrome (RDS), the potential benefits cannot be fully realised for several reasons. Many patients deliver within 24 hours of the start of treatment because tocolytic treatment is withheld or ineffective. In other patients, contraindications to delayed delivery may exist. In addition, corticosteroids are relatively ineffective in the group of infants at greatest risk (less than 28 weeks). Marked improvements in benefit will be achieved by improved tocolytics (perhaps indomethacin and/or oxytocin analogues), by more precise methods of predicting and diagnosing preterm labour, and by methods that enhance the response to corticosteroids at very early gestational ages. In regard to the latter, there is encouragement from experimental work showing synergism of antepartum steroids with simultaneous TRH treatment and with neonatal instillation of surfactant.
Adrenal Cortex Hormones↗
Purification and characterization of a uterine phospholipase inhibitor that loses activity after labor onset in women.
Gravidin, a protein that inhibits release of arachidonic acid from human decidual cells, was purified from amniotic fluid. The protein has a molecular weight of 58 to 60 kilodaltons, an isoelectric point of 8.4, and physical characteristics that are indistinguishable from those of inhibitor II previously described. Activity was determined in a dispersed decidual cell system that released arachidonic acid in response to either histamine or calcium ionophore and in a cell-free assay of phospholipase A2. Protein purified from incubates of chorion obtained after the onset of labor was significantly less active than that from chorion obtained before the onset of labor.
Chorion↗
Phospholipases in the control of human parturition.
Prostaglandins play a key role in human labor in that prostaglandins can cause abortion or labor and prostaglandin antagonists can inhibit preterm labor. However, the factors determining prostaglandin synthesis and release in human pregnancy are uncertain. An increase in the synthesis of prostaglandins at the start of labor could result from either increased release of free arachidonic acid or removal of constraint on prostaglandin H synthase activity, or both. The points in the biosynthetic pathway of prostaglandins at which control could be exerted physiologically are examined, with emphasis on the phospholipases.
Annexins↗
Initiation of labour.
Since arachidonic acid is the obligatory substrate for the synthesis of prostaglandins, the regulation of arachidonic acid from phospholipid stores is likely to be pivotal in the release of prostaglandins and the initiation of labour. The hydrolysis of phospholipids to yield arachidonic acid is catalysed by phospholipases of which there are two of particular importance. Phospholipase C mediates the action of certain agonists including oxytocin and acts specifically on phosphatidyl-inositol resulting in the release of inositol phosphates. Phospholipase A2 is activated by a variety of physical and chemical agents (e.g. infection, trauma) that increase calcium concentrations in the cell; it releases arachidonic acid from phosphatidyl-choline and phosphatidyl-ethanolamine in particular. Factors influencing phospholipase activity are important in the mechanism initiating labour whether preterm or term. A specific chorionic protein (gravidin) that inhibits activity of phospholipase A2 during pregnancy but loses its activity at the onset of labour has been identified and characterised.
Animals↗
Transferrin stimulates proteoglycan accumulation by fetal lung cells in culture.
The role of transferrin in growth and the formation of extracellular matrix was investigated by comparing its effects on proteoglycan metabolism and cell proliferation in primary cultures of fetal rat lung fibroblasts and Type II epithelial cells. Transferrin specifically stimulated the accumulation of dermatan/chondroitin sulfate proteoglycans associated with the cells and matrix in a dose-dependent manner (0-200 micrograms/ml, r = .850 in fibroblasts and r = .810 in Type II cells). This effect was not due to increased synthesis since there was a corresponding decrease in proteoglycans and their degradation products released into the medium. The effect is probably mediated via an action on the proteoglycan core protein, since there was no effect of transferrin on enzyme activity promoting glycosaminoglycan synthesis on the synthetic initiator beta-D-xyloside. The effect of transferrin on proteoglycan distribution was not a secondary effect caused by changes in collagen synthesis and was not linked to cell proliferation or the concentration of Fe3+ ions in the culture medium.
Animals↗
Effects of corticosteroids, prostaglandin E2, and beta-agonists on adenylate cyclase activity in fetal rat lung fibroblasts and type II epithelial cells.
The effect of glucocorticoids on the response of adenylate cyclase in fetal rat lung fibroblast and Type II epithelial cell cultures to beta-agonists and prostaglandin E2 (PGE2) was investigated. There was significant stimulation of cyclic AMP synthesis by adrenalin in both fibroblasts and Type II cells, which was potentiated in a dose-dependent manner by cortisol. Stimulation of adenylate cyclase by PGE2 (10-1000 nM) was demonstrated in fibroblasts but not in Type II cells. The response to PGE2 was stimulated by pretreatment with cortisol only in fibroblasts (p less than .01), and no latent response to PGE2 was evident in Type II cells after cortisol treatment. These experiments suggest that both cell types isolated from late gestation fetal lung contain active beta-agonist and glucocorticoid receptors that synergize in raising intracellular cyclic AMP, which has multiple effects, including surfactant secretion from Type II cells. Since the adenylate cyclase response to PGE2 and its enhancement by glucocorticoids occurred only in fibroblasts, it is concluded that the reported effects of PGE2 on surfactant release are not mediated via raised intracellular cyclic AMP in Type II cells.
Adenylyl Cyclases↗
Morphometric analyses of the effects of thyrotrophin releasing hormone and cortisol on the lungs of fetal sheep.
Morphometric analyses of ovine fetal lung parenchyma were undertaken in order to elucidate the roles of pituitary, thyroid and adrenocortical hormones in promoting the structural changes underlying the increased distensibility and stability present in mature fetal lungs. Twenty-six Romney fetuses were treated with either cortisol for 84 h from 125 days (4), pulsatile TRH for 6.5 days from 122 days (4), cortisol and TRH (12), or 0.9% NaCl solution (6). The left lungs were used for physiological studies (distensibility, V40) and the right lungs were prepared for electron microscopy. Using 32 regions of lung parenchyma per fetus, volume density, surface density and arithmetic mean thickness of the alveolar walls were calculated using point and intersection counts. Of the three regimens, treatment with TRH + cortisol (exposure to raised concentrations of cortisol, T3 and prolactin) induced significantly greater lung distensibility, the largest potential alveolar air space (62% of the parenchyma), the greatest alveolar surface area (113.7 mm2/mm3 x 10(-3)) and the thinnest alveolar walls (6.7 microns). We conclude that cortisol, T3 and prolactin act synergistically to promote maturational changes in the alveolar wall. While cortisol plays the major role, T3 and prolactin enhance the ability of the immature lung to respond to the cortisol.
Animals↗
The effect of cortisol on thyroid hormone kinetics in the ovine fetus.
The mechanism underlying the association of rising concentrations of circulating triiodothyronine (T3) with the prepartum surge in the concentration of cortisol was investigated in 11 fetal sheep. The concentrations and metabolic clearance rates of T3 and thyroxine (T4) were measured prior to and following a continuous intravascular infusion of cortisol (1 mg/h for 84 h). Mean plasma T3 concentrations increased 10-fold following cortisol infusion whereas the concentrations of T4 either remained stable or exhibited a variable decline. Cortisol induced a 5-fold decrease in the metabolic clearance rate of T3 and a 6-fold increase in that of T4. The corresponding mean production rates of T3 and T4 increased significantly although the magnitude of the change varied between fetuses. We conclude that the prepartum rise in plasma T3 concentrations is likely to be a consequence of both a decreased metabolic clearance of T3 and increased peripheral conversion of T4 to T3 caused by rising concentrations of cortisol in fetal plasma.
Animals↗
Arterial gas tensions and hemoglobin concentrations of the freely diving Weddell seal.
Heart rate, body temperature, arterial blood gas tensions, pHa and hemoglobin concentrations were measured during and after free diving of the Weddell seal (Leptonychotes weddelli), beneath the fast ice of McMurdo Sound, Antarctica. To examine arterial nitrogen tensions (PaN2), 47 samples of arterial blood were obtained from 4 seals diving up to 23 min to depths of 230 m. Peak arterial nitrogen tensions between 2000 and 2500 mmHg were recorded at depths of 40-80 m during descent, indicating that the seal's lung collapses by 25-50 m. Then arterial blood nitrogen tensions slowly decreased to about 1500 mmHg near surfacing. Thus during diving alveolar collapse and redistribution of blood nitrogen allow the seal to avoid nitrogen narcosis and decompression sickness. The arterial PO2 (PaO2) at rest (78 +/- 13 mmHg, mean +/- SD) increased with diving compression to a maximum measured value of 232 mmHg and then rapidly decreased to 25-35 mmHg. The lowest diving PaO2 was 18 mmHg just before the seal surfaced from a 27-min dive. A consistent increase of arterial hemoglobin concentrations occurred during each dive. We suggest that an extension of the sympathetic outflow of the diving reflex caused profound contraction of the Weddell seal's spleen.
Animals↗
Protective metabolic mechanisms during liver ischemia: transferable lessons from long-diving animals.
During periods of O2 lack in liver of seals, mitochondrial respiration and adenosine triphosphate (ATP) synthesis are necessarily arrested. During such electron transfer system (ETS) arrest, the mitochondria are suspended in functionally protected states; upon resupplying O2 and adenosine diphosphate (ADP), coupled respiration and ATP synthesis can resume immediately, implying that mitochondrial electrochemical potentials required for ATP synthesis are preserved during ischemia. A similar situation occurs in the rest of the cell since ion gradients also seem to be maintained across the plasma membrane; with ion-specific channels seemingly relatively inactive, ion fluxes (e.g., K+ efflux and Ca++ influx) can be reduced, consequently reducing ATP expenditure for ion pumping. The need for making up energy shortfalls caused by ETS arrest is thus minimized, which is why anaerobic glycolysis can be held in low activity states (anaerobic ATP turnover rates being reduced in ischemia to less than 1/100 of typical normoxic rates in mammalian liver and to about 1/10 the rates expected during liver hypoperfusion in prolonged diving). As in many ectotherms, an interesting parallelism (channel arrest coupled with a proportionate metabolic arrest at the level of both glycolysis and the ETS) appears as the dominant hypoxia defense strategy in a hypoxia-tolerant mammalian organ.
Animals↗
Oxytocin stimulates the release of arachidonic acid and prostaglandin F2 alpha from human decidual cells.
Oxytocin at a physiological concentration stimulated the immediate release of free arachidonic acid from dispersed human decidual cells in a perfusion system. This indicates that oxytocin activates phospholipase(s) thus enhancing prostaglandin synthesis. The effect of oxytocin on the release of [3H]-arachidonic acid from decidual cells of women in labor was significantly greater (1036 +/- 207, mean dpm +/- SEM, n = 23) than from those of women not-in-labor (505 +/- 121 dpm, n = 12) or with endometrial cells of non-pregnant women (711 +/- 210 dpm, n = 18), and correlates well with reported oxytocin receptor concentrations in these tissues. These new findings are consistent with a role for endogenous oxytocin in stimulating prostaglandin synthesis at the onset of parturition.
Arachidonic Acid↗
Synergistic hormonal effects on lung maturation in fetal sheep.
Cortisol has minimal effects on lung maturation in fetal sheep before 130 days gestation. To test whether there is enhancement of cortisol action by other hormones, cortisol (F), triiodothyronine (T3), epinephrine (E), prolactin (PRL), and epidermal growth factor (EGF), alone or in combination, were infused into fetal sheep for 84 h between 124 and 128 days gestation. A mixture of F + T3 + PRL, but not any combination of two hormones, increased both distensibility [1.71 +/- 0.12 (SE) ml of air/g wet wt at 40 cmH2O, V40] and stability (1.16 +/- 0.09 ml of air per g wet wt at 5 cmH2O, V5) to near full-term values, above values resulting from treatment with F alone (0.91 +/- 0.12 and 0.43 +/- 0.09 ml/g, P less than 0.01). Only F had an effect when given alone, V40 increasing (P less than 0.05). Treatment with F + T3 (0.81 +/- 0.18 ml/g) and F + E (0.77 +/- 0.07 ml/g) increased V5 above values obtained with F alone (P less than 0.05). Alveolar saturated phosphatidylcholine (SPC) was higher after treatment with F + T3 (161 +/- 52 micrograms/g), F + T3 + PRL (156 +/- 53 micrograms/g, P less than 0.05), and F + E (113 +/- 40 micrograms/g, P = 0.07) than after F (12 +/- 3 micrograms/g). We conclude that F, T3, and PRL have a synergistic effect on the development of distensibility and stability of the ovine fetal lung.
Animals↗
Synergism of cortisol and thyrotropin-releasing hormone in lung maturation in fetal sheep.
The effects of fetal infusions of cortisol and thyrotropin-releasing hormone (TRH) singly and together on pressure-volume relationships and saturated phosphatidylcholine (SPC) concentrations in the lungs were studied in 28 fetal sheep delivered at 128 days of gestation. Four groups each of 7 fetuses were infused with either saline (for 156 h), TRH (25 micrograms/h in 60-s pulses for 156 h), TRH (for 156 h) combined with cortisol (1 mg/h for 84 h), or cortisol (for 84 h). Cortisol had no effect on SPC concentrations, whereas both TRH and cortisol plus TRH increased the concentration of SPC in lavage fluid but not lung tissue. Neither cortisol nor TRH significantly affected lung distensibility [V40; 0.64 +/- 0.04 and 0.57 +/- 0.10 (SE) ml/g, respectively, vs. 0.41 +/- 0.03 ml/g in controls] or stability (V5; 0.24 +/- 0.01 and 0.35 +/- 0.07 ml/g vs. 0.24 +/- 0.03 ml/g), whereas treatment with a combination of the two hormones was associated with a fourfold increase in V40 (1.70 +/- 0.16 ml/g) and V5 (1.03 +/- 0.15 ml/g). Since raised concentrations of cortisol, triiodothyronine, and estradiol-17 beta (treatment with cortisol) had no effect on V40 and V5, whereas similar hormonal changes associated with elevated prolactin levels (treatment with cortisol plus TRH) had marked effects, we conclude that prolactin plays an essential part in the synergism of cortisol and TRH.
Animals↗
Thyroid hormone kinetics during late pregnancy in the ovine fetus.
The factors responsible for the changes in the plasma concentrations of thyroid hormones in the ovine fetus in late pregnancy were investigated by making serial measurements of the concentrations, metabolic clearance rates and production rates of T3 and T4 in 17 fetuses. The concentrations of T3 in fetuses of 135-145 days gestational age were four times higher than in those of 110-125 days but the concentrations of T4 were unchanged. The metabolic clearance rate of T3 halved over this period whereas that of T4 rose slightly. The production rate of T3 more than doubled and of T4 increased slightly but not significantly. We conclude that the concentration of T4 shows little change with increasing gestational age because the trends in metabolic clearance rates and production rates are weak and in the same direction. The sharp rise in the concentration of T3 is attributable to a fall in metabolic clearance rate coupled with a rise in production rate.
Animals↗
Anticardiolipin antibodies: their presence as a marker for lupus anticoagulant in pregnancy.
A solid phase ELISA was developed to investigate the association between anticardiolipin antibodies and lupus anticoagulant in pregnancy. Twenty-seven pregnant women with a history of recurrent fetal losses or systemic lupus erythematosus (SLE) were tested for the presence of lupus anticoagulant, anticardiolipin antibodies, antinuclear antibodies (ANA) and anti-single-stranded DNA antibodies. Nineteen women with a total of 49 previous unsuccessful pregnancies were found to have lupus anticoagulant and anticardiolipin antibodies. Three women who had suffered four fetal deaths from six pregnancies had anticardiolipin antibodies without lupus anticoagulant. Cardiolipin antibodies were not detected in the remaining five patients. This assay for measuring anticardiolipin antibodies appears to provide a simple and inexpensive method of identifying women at risk of fetal death from the adverse effects of lupus anticoagulant.
Abortion, Habitual↗