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Current tocolytic protocols rely largely on the use of beta-mimetics to induce myometrial quiescence and delay delivery. Unfortunately, the rapid transplacental passage and poor receptor specificity of the commonly used beta-mimetics results in widespread activation of intrauterine and extrauterine beta 1 and beta 2 receptors. The use of beta-mimetics is associated with a range of well-recognized and potentially dangerous side effects for mother and fetus. The value of continued use of beta-agonists after obtaining uterine quiescence also has been the subject of recent debate. In this article we have attempted to explore the biochemical and molecular rationale for the use of alternative therapeutic modalities in the treatment and prevention of PTL. In the light of the current view that the term "preterm labor" covers a considerable diversity of causes, we propose that a range of treatment regimes should be chosen on the basis of the diagnosis and classification of the patient according to the their particular condition. Although the measurement of several biochemical parameters have been suggested to be of use in predicting PTL, we believe that a panel of diagnostic indicators (e.g., free or total CRH, IL-6, extracellular matrix proteases, fetal fibronectin) is more likely to provide useful diagnostic information on which appropriate treatment modalities can be selected (Table 1). Because of the complex and interactive nature of the mechanisms operating within the intrauterine environment to regulate myometrial activation and uterotonin production, we speculate that a combination of tocolytics, anti-inflammatory agents, uterotonic antagonists, and receptor blockers is likely to be more effective than a monotherapeutic approach, which focuses on only one facet of the process of uterine activation for pharmacologic intervention. For example, the use of antibiotics, PGHS inhibitors, and/or beta-mimetics might be an appropriate first line of treatment for infection-associated PTL in extreme prematurity. If it is successful, this treatment might be followed by longer term use of a progestagen and/or NO donor to maintain myometrial quiescence until closer to term. Alternatively, use of progesterone or oxytocin antagonists may be effective in augmenting the actions of beta-mimetics while reducing their side effects, whereas other combinations may be useful as long-term prophylactics in women with a high risk of developing PTL. Improvements continue in our diagnostic ability to correctly identify the different causes of preterm labor. We anticipate that careful selection of differing combinations of therapeutic options will result in significant reductions in the morbidity, mortality, and healthcare costs associated with preterm birth.

Serum concentrations of immunoreactive inhibin (ir-inhibin) and human chorionic gonadotrophin (HCG) have been measured during the first trimester in a longitudinal study of pregnant women attending a recurrent miscarriage clinic. In 30 singleton pregnancies (Group 1) that continued successfully to term, the median concentration of ir-inhibin initially declined from 1,140 pg/mL at week 4-5 then rose back to comparable values between weeks 7 and 10 but to decline again to reach the significantly lower level of 840 pg/mL (p < 0.01) at week 15-16. Serum levels of HCG showed the classical profile of normal pregnancy reaching a median peak value of 65,600 IU/L (1st IRP) at week 8-9. In 7 pregnancies that miscarried but earlier had evidence on ultrasound of an active fetal heart, HCG levels in the first 9 weeks were consistently below the 10th percentile for Group 1 pregnancies (p < 0.001). Levels of ir-inhibin were also suppressed but to a lesser extent. In 6 of 7 a fetal pregnancies, HCG levels during the first 9 weeks were again markedly subnormal. The levels of ir-inhibin varied between high normal and subnormal. In none of the pregnancy groups was a correlation found between ir-inhibin and HCG concentrations. In a single pregnancy with an anencephalic fetus, while levels of ir-inhibin and HCG were not depressed, peak values were not reached until week 12. The study shows that the level of ir-inhibin in the maternal serum in early pregnancy is of little value as a prognostic indicator of pregnancy outcome. It confirms that a subnormal HCG level is a useful predictor of early pregnancy failure.

Nitric oxide (NO.) has been implicated in the process of cerebral ischemia/reperfusion injury. We have examined the production of NO., as reflected by nitrite (NO2-) + nitrate (NO3-) accumulation, from synaptosomes isolated from neonatal or adult rat brain and subjected to a period of glucose and oxygen deprivation. There was a significant increase in the amount of NO2- + NO3- production from adult synaptosomes under these conditions, whereas there was no difference compared to control in the production of NO2- + NO3- from the neonatal synaptosomes. The total antioxidant status of the synaptosomes at these different stages of brain development was found to be the same. These data suggest that the vulnerability of the adult brain to ischemia/reperfusion injury may be associated with the production of NO. from nerve terminals. The ratios of antioxidant capacity to NO. production under such conditions have been shown here to be different between the neonatal and adult nerve terminals. Thus the well documented resistance of neonatal brain to ischemia/reperfusion injury may involve the neonatal nerve terminal being under less oxidative stress than the adult.

The effects of hypoxia, aglycaemia, and hypoxia-aglycaemia on intrasynaptosomal free Ca2+ concentration ([Ca2+]i) have been investigated in rat brain synaptosomes prepared from animals aged 5, 10, 15, 20, 25, and 60 days. After 60 min of hypoxia there was no significant difference, when compared with controls, in basal [Ca2+]i or [Ca2+]i following depolarisation in all of the ages studied. Following 60 min of aglycaemia there was no significant difference from controls in [Ca2+]i of synaptosomes prepared from pups of < or = 20 days, although a significant rise in [Ca2+]i was seen in preparations from animals > 20 days old. Sixty minutes of hypoxia-aglycaemia led to a significant rise in [Ca2+]i only in preparations from animals 15-60 days old. With both aglycaemia and hypoxia-aglycaemia a progressive increase in the magnitude of the rise in [Ca2+]i was seen with development. These data suggest increases in [Ca2+]i in adult nerve terminals following prolonged aglycaemia and hypoxia-aglycaemia but no change following prolonged hypoxia. In contrast, no significant changes in [Ca2+]i values were apparent in neonatal nerve terminals under any of these conditions. In control synaptosomes with glucose and oxygen freely available, a decrease in resting and depolarised [Ca2+]i during development was seen, suggesting a change in calcium homeostasis within the nerve terminal as the brain develops. It is suggested that the mechanism underlying the relative resistance to ischaemic damage of neonatal brain as compared with adult brain may be related to the regulation of calcium at the nerve ending.

The effect of specific irreversible inhibitors of complexes I, III, IV and V of the mitochondrial respiratory chain, (rotenone, myxothiazol, cyanide and oligomycin, respectively) on mitochondrial N-acetylaspartate production, and its relationship to oxidative phosphorylation (ATP production and oxygen consumption) were investigated in isolated rat brain mitochondria. Mitochondrial N-acetylaspartate production, ATP production and oxygen consumption were all significantly decreased in the presence of each of the inhibitors used compared with control incubations, and correlated positively with each other. It is postulated that decreased N-acetylaspartate levels seen in disease states by 1H NMR spectroscopy in vivo may reflect primarily an impaired mitochondrial energy production rather than neuronal cell loss.

The postnatal development of the complexes of the electron transport chain in mitochondria isolated from rat brain synaptosomes was investigated. Synaptosomal brain mitochondria were isolated from rats aged 10-60 days, and the activities of mitochondrial complex I, complex II-III, complex IV and complex V were measured. There was a significant increase in the activity of II-III from day 10 to day 15 and complex IV from day 10 to day 21, thereafter the activities of complexes I-III and IV did not change significantly. The activity of complex I did not change significantly during the period 10-60 days post partum. In synaptic mitochondria, complex V activity was higher than in non-synaptic mitochondria, whereas the activity of complex I was lower than in non-synaptic mitochondria. These data show that the complexes of the respiratory chain within synaptic mitochondria have activities different from those of non-synaptic mitochondria and may have major implications for the relative susceptibility of mitochondria in different brain cell types to neurotoxins such as MPP+, hypoxic/ischaemic damage and oxidative stress.

In the present study, we investigated the roles of cyclic adenosine monophosphate (cAMP), intracellular calcium, glucocorticoids, protein kinase-C and gonadotrophin-releasing hormone (GnRH) in regulating human chorionic gonadotrophin (hCG), inhibin and activin production in cultured human term placental trophoblast cells. Inhibin and hCG were measured in conditioned media by radioimmunoassay, while putative forms of inhibin and activin were characterized by western blotting using affinity-purified antisera directed against the inhibin alpha- and beta A-subunits. Inhibin and hCG secretion were stimulated by dexamethasone (0.2 microM), GnRH (5-25 microM), calcium ionophore A23187 (0.2-1 microM), phorbol-12-myristate-13-acetate (22 nM) and epinephrine (1 microM), with increasing response over successive 24-h treatment periods. Two molecules Mr approximately 30 and 32 kDa appeared to be the predominant dimeric forms of inhibin secreted by the cells, while 26 kDa activin was present in excess over inhibin. Large amounts of 40-44 kDa protein were detected by the alpha-directed antisera only, which may be a form of the inhibin alpha-subunit precursor protein. Secretion of activin was responsive to phorbol ester-mediated stimulation but not to the presence of GnRH or elevated cAMP concentrations. The divergence in maternal serum inhibin and hCG concentrations during late pregnancy remains unexplained by these findings.

The contribution of the fetus to inhibin production in human pregnancy is unclear. Previous studies have reported inhibin concentrations in cord blood but on limited sample numbers. The present study is a more extensive examination of sex differences in immunoreactive inhibin and steroidal hormones in term umbilical cord blood. Venous serum concentrations of inhibin were found to be significantly higher in males (mean +/- SD 2,168 +/- 914 pg/ml, n = 62) than in females (1,761 +/- 951 pg/ml, n = 63) (p < 0.01). Male concentrations of total testosterone (p < 0.005), free testosterone (p < 0.005), and estradiol (p < 0.05) were also significantly higher. The concentration of dehydroepiandrosterone sulphate (DHEAS) and the sex hormone-binding globulin (SHBG) capacity were similar in males and females. Multivariate regression analysis showed that the inhibin concentration in males correlated with the testosterone concentration and in females it correlated not only with testosterone concentration but also with gestational age at delivery and SHBG capacity (all p < 0.001). Inhibin concentrations in cord arterial serum in a subgroup of 24 males and 31 females were higher than in the venous serum in both sexes but the differences were not statistically significant. Concentrations of DHEAS determined in 22 female cord arterial blood samples (6.0 +/- 2.5 mumol/l) were significantly higher than the venous concentrations (5.2 +/- 1.8 mumol/l) (p < 0.05). Inhibin did not correlate with DHEAS either in their arterial serum concentrations or in the arteriovenous concentration differences. The findings of this study are consistent with the placenta being the principal source of inhibin circulating in the human fetus in late pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

The relation of childhood and early adolescent social experiences with young women's concern over physical appearance (appearance anxiety) in late adolescence and early adulthood was examined. Female under-graduates completed questionnaires assessing appearance anxiety and a questionnaire assessing childhood and early adolescent experiences hypothesized to relate to appearance anxiety as well as current behaviors hypothesized to reflect it. The results suggest that appearance anxiety in women is related to reported negative social experiences in childhood and early adolescence. These experiences were suggested to lead to dissatisfaction with their childhood and early adolescent appearances which in turn was related to appearance anxiety in late adolescence and early adulthood. Appearance anxiety was also found to be related to current social experiences. The most obvious manifestation of appearance anxiety in young women was relatively greater reported attention to improving their appearance.

We describe a method for the measurement of plasma dehydroepiandrosterone sulphate (DHAS) which incorporates a Triton X-100 solubilised preparation of human placental steroid sulphatase as a hydrolysing agent and a direct radioimmunoassay of liberated DHA using a specific antiserum. The hydrolysis procedure is carried out at 50 degrees C for 1 h and an assay run can be completed in 4 h. As determined by the method, plasma concentrations of DHAS in 32 normal adult men (ages 23-58 yr) had a mean value +/- SD of 5.5 +/- 1.89 mumol/l. For 30 normal adult cyclic women (ages 22-35 yr) the mean plasma concentration of DHAS +/- SD was 3.1 +/- 1.35 mumol/l which was significantly lower (P less than 0.01) than found for men. Plasma DHAS concentration were also measured in 50 hirsute female patients. The mean value +/- SD was 5.03 +/- 2.52 mumol/l which was significantly higher (P less than 0.01) than the value for the normal female group. Some 42% of the hirsute patients had DHAS concentrations above the upper 95% probability limit of the normal range for premenopausal women.