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Biomedical subjects

E M Wallace

Publications and source records attributed to E M Wallace.

At least 55 records · Page 3Linked to original sources
PubMed1999

Amniotic fluid levels of dimeric inhibins, pro-alpha C inhibin, activin A and follistatin in Down's syndrome.

OBJECTIVE: In the second trimester of pregnancy, inhibin A is significantly increased in maternal serum and decreased in amniotic fluid in Down's syndrome pregnancies compared to normal. We wished to further evaluate the levels of inhibin A, inhibin B, pro-alpha C inhibin, activin A and the binding protein follistatin in amniotic fluid in Down's syndrome and control pregnancies. DESIGN: Case-matched control study. PATIENTS: 29 Down's syndrome and 290 chromosomally normal control pregnancies were identified from records and amniotic fluid, collected at second trimester amniocentesis, retrieved from routine storage for analysis. MEASUREMENTS: Inhibin A, inhibin B, pro-alpha C inhibin, total activin A and follistatin were measured using sensitive and specific enzyme linked immunosorbent assays. RESULTS: The median (10th-90th percentiles) amniotic fluid inhibin A level in the control pregnancies increased from 334 (122-553) ng/l at 14 weeks' to 695 (316-1475) ng/l at 19 weeks' gestation. The corresponding figures for inhibin B and the alpha-subunit precursor inhibin pro-alpha C were 632 (185-1354) and 2062 (1237-3381) ng/l, respectively at 14 weeks' and 2439 (748-5307) and 3115 (2021-6567) ng/l, respectively at 19 weeks' gestation. Total activin A increased from 3795 (1554-5296) at 14 weeks' to 5086 (3059-8224) at 18 weeks' gestation. Expressed as multiples of the median (MoM) the median (95% CI) amniotic fluid levels of inhibin A, inhibin B, pro-alpha C inhibin and acitivin A in the Down's syndrome samples were 0.77 (0.59-0.85), 0.94 (0.63-1.23), 0.77 (0.49-0.84) and 0.77 (0.53-0.87), respectively. Compared to controls the levels of inhibin A, pro-alpha C inhibin and activin A were significantly lower in Down's syndrome pregnancies (P < 0.01, Mann-Whitney U test). Follistatin levels in the controls declined slightly from 2106 (1421-3538) ng/l at 14 weeks' to 1600 (1281-2543) ng/l at 18 weeks' gestation. Levels in the Downs' syndrome pregnancies were similar to controls. CONCLUSIONS: The data suggest that the production, secretion or metabolism of the inhibin alpha- and beta A-subunits is altered in Down's syndrome pregnancies in the second trimester.

Activins↗
PubMed1998

Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme.

Endothelin-1 is the most potent peptidic vasoconstrictor discovered to date. The final step of posttranslational processing of this peptide is the conversion of its precursor by endothelin-converting enzyme-1 (ECE-1), a metalloprotease which displays high amino acid sequence identity with neutral endopeptidase 24.11 (NEP) especially at the catalytic center. A series of potent and selective arylacetylene-containing ECE-1 inhibitors have been prepared. (S, S)-3-Cyclohexyl-2-[[5-(2, 4-difluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]amino] propio nic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit ECE-1 and NEP with IC50 values of 14 nM and 2 microM, respectively. Similarly, (S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3- yny l]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide, had IC50's of 33 nM and 6.5 microM for ECE-1 and NEP, respectively. Slight modification of the aryl moiety was found to have dramatic effects on ECE-1/NEP selectivity. The 2-fluoro dipeptide analogue, (S, S)-2-[[5-(2-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (40), showed a 72-fold selectivity for ECE-1 over NEP, while the 3-fluoro dipeptide analogue, (S, S)-2-[[5-(3-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (22), was equipotent for ECE-1 and NEP. Several of these inhibitors were shown to be potent in blocking ET-1 production in vivo as demonstrated by the big ET-1-induced pressor response in rats. These potent inhibitors are the most selective for ECE-1 reported to date and are envisaged to have a variety of therapeutic applications.

Acetylene↗
PubMed1998

Inhibin A and pro-alpha C inhibin in Down syndrome and normal pregnancies.

Using two enzyme-linked immunosorbent assays specific for inhibin A and pro-alpha C inhibin, levels of the two proteins were assessed in maternal serum from 43 Down syndrome and 300 chromosomally normal pregnancies at 15-17 weeks' gestation. Compared to the control pregnancies, both inhibin A and pro-alpha C inhibin were significantly elevated in the Down syndrome pregnancies with median levels, expressed as multiples of the normal median, of 1.53 MoM and 1.34 MoM, respectively (P < 0.001 and P = 0.046 compared to controls). Levels of inhibin A and pro-alpha C inhibin were weakly but significantly correlated in both the control and the Down syndrome sera (r = 0.25, P < 0.0001; r = 0.4, P = 0.008, respectively). These data suggest that the mechanism(s) underlying the elevated inhibin levels observed in Down syndrome may affect the regulation of both the inhibin alpha- and beta A-subunits.

Down Syndrome↗
PubMed1998

Clinical presentation of uterine fibroids.

It is often accepted that fibroids cause a variety of female reproductive problems, such as menorrhagia, pain, infertility, pregnancy loss and pregnancy complications. Understandably, therefore, many 'successful' medical or surgical interventions have been proposed. However, while fibroids are certainly commonly associated with these conditions, it remains unclear whether this is coincidental, because of the high prevalence of fibroids, or causal. In particular, this chapter explores the roles of fibroids in menorrhagia, discussing possible pathophysiological mechanisms and the utility of medical and surgical management. Similarly, the relationship between fibroids and infertility is examined, concluding that fibroids are not causative in the vast majority of cases and thereby questioning the effectiveness of myomectomy as a treatment for infertility. The use of hormone replacement therapy in post-menopausal women with existing fibroids is also discussed, concluding that this is generally safe and appropriate. In pregnancy, it is a commonly held tenet that uterine fibroids enlarge and that they are associated with various adverse outcomes such as miscarriage, placental abruption, fetal growth retardation and Caesarean section. This chapter evaluates the available evidence for this and concludes that, as with infertility, the role of fibroids has been exaggerated. Nonetheless, pregnancy management options are discussed.

Female↗
PubMed1998

Evaluation of serum inhibin A as a surveillance marker after conservative management of tubal pregnancy.

Tubal pregnancy is now commonly managed by laparoscopic salpingostomy or systemic methotrexate. A disadvantage of such conservative management is the need for appropriate follow-up, with serial measurement of serum concentrations of human chorionic gonadotrophin (HCG), to exclude persistent ectopic pregnancy (PEP). Concentrations of inhibin A, also a placental product, are significantly increased during pregnancy and the half-life of inhibin A is significantly shorter than that of HCG. To assess the suitability of inhibin A as a marker of PEP, we studied 16 women who had undergone surgery for a tubal pregnancy, measuring HCG and inhibin during follow-up. The mean +/- SEM time taken to achieve non-pregnant concentrations of inhibin A was significantly shorter than for HCG (4.2 +/- 0.8 days versus 21.6 +/- 4.4 days respectively; P < 0.001 Wilcoxon signed rank test). However, in all women the inhibin A concentration increased rapidly after reaching a nadir, reflecting the return of ovarian function, complicating the interpretation of results. In four women inhibin A was almost undetectable preoperatively, while the corresponding HCG concentration was high. These data suggest that inhibin A will not be a useful marker for PEP but that it may provide a more accurate preoperative assessment of trophoblast viability than HCG, thereby improving management.

Adult↗
PubMed1998

Follistatin and activin A in extra-embryonic coelomic and amniotic fluids and maternal serum in early pregnancy.

Follistatin is a specific binding protein which controls bioavailability of activins and inhibins which have an important role in fetal development. In the first trimester of pregnancy bioactive dimeric inhibins are found at high concentrations in the extra-embryonic coelomic fluid, but the distribution of follistatin and activins is not known. We have used recently developed immunoassays for follistatin, activin A and activin AB to determine their presence in the intrauterine compartments during early pregnancy. Follistatin was present in highest concentrations in the extra-embryonic coelomic fluid (11.72 +/- 1.70 ng/ml; median +/- SEM), with less in maternal serum (6.35 +/- 4.58) and lowest amounts in amniotic fluid (0.97 +/- 0.52). Follistatin concentrations in extra-embryonic coelomic fluid were highly correlated with both dimeric inhibin isoforms. Activin A was present in only barely detectable amounts in some samples of extra-embryonic coelomic fluid (41% of samples) and maternal serum (26%) and was undetectable in all amniotic fluid samples. Activin AB was undetectable in all compartments. The presence of follistatin in the amniotic and extra-embryonic coelomic fluids may regulate the availability of bioactive activins and inhibins which are released into the intrauterine compartments during the development of the fetus and placenta in early pregnancy.

Activins↗
PubMed1998

Thyroxine abuse: an unusual case of thyrotoxicosis in pregnancy.

Eating disorders and the associated behavioural problems and drug abuse are uncommon in pregnancy. When they do occur they are often unrecognized because of denial but when significant may pose a risk to both the mother and her fetus. This case illustrates a number of problems that may be encountered in women with eating disorders in pregnancy, including prolonged and recurrent metabolic disturbances and diuretic abuse. In particular it illustrates the derangements of thyroid function seen in pregnant women with eating disorders and reminds us that when a cause for thyrotoxicosis remains obscure, thyroxine abuse should be considered and explored.

Adult↗
PubMed1998

Haematological effects of betamethasone treatment in late pregnancy.

To assess the maternal haematological effects of betamethasone administered in late pregnancy, an automated full blood count was performed before and daily for 5 days after betamethasone in 25 women with a singleton pregnancy between 23 and 33 weeks' gestation. From a mean (+/- SD) baseline level of 11.0+/-2.2 x 10(9)/L, the total white cell count increased significantly to 13.2+/-2.9 x 10(9)/L and 13.5+/-3.1 x 10(9)/L on the first and second day after treatment respectively, returning to baseline on day 3 (p<0.0001, ANOVA). These changes represented a mean increase in the neutrophil count of 35% and a mean decrease in the lymphocyte count of 23%. While there was considerable intersubject variation in the extent of the changes, this study has quantified the leucocytosis induced by betamethasone in late pregnancy, information that may assist with the clinical evaluation of a woman at risk of preterm delivery.

Adult↗
PubMed1998

Evolution of an inhibin A ELISA method: implications for Down's syndrome screening.

The development of a sensitive and specific enzyme-linked immunoassay (ELISA) for inhibin A stimulated the observation that inhibin A was a useful prenatal marker of Down's syndrome. Modifications of that ELISA, in terms of preassay sample treatment, detection methods and standard preparation, were subsequently introduced to improve assay performance and reduce costs. These modified formats have been validated and reported. We describe the modifications in detail, explaining the rationale for each, and report the results of a study directly comparing the various ELISA formats in terms of assay performance when applied to clinical samples and ability to differentiate between normal and Down's syndrome pregnancies. A format involving sample pretreatment with sodium dodecylsulphate at 100 degrees C was found to give better assay performance and a modest improvement in discrimination between Down's syndrome samples and controls, and we recommend this format for use by other investigators.

Down Syndrome↗
PubMed1998

Inhibin-B and pro-alphaC-containing inhibins in amniotic fluid from chromosomally normal and Down syndrome pregnancies.

In second-trimester Down syndrome pregnancies, levels of inhibin-A (the alpha-betaA dimer) in maternal serum and amniotic fluid (AF) are significantly higher and lower than in normal pregnancy, respectively. Since AF also contains inhibin-B (the alpha-betaB dimer) and precursor inhibins, we have examined whether the secretion of these inhibin isoforms may also be altered in association with Down syndrome. AF from 45 Down syndrome and 150 chromosomally normal pregnancies between 16 and 19 weeks' gestation were analysed, blinded to whether the sample was from a Down syndrome or a normal pregnancy. The median (10th-90th percentiles) inhibin-B level in the control pregnancies increased from 310.0 (80.8-1112.5) pg/ml at 16 weeks to 459.5 (193.7-1386.8) pg/ml at 19 weeks' gestation. The corresponding figures for precursor inhibins (pro-alphaC inhibins) were 541.8 (206.9-1322.8) pg/ml at 16 weeks and 1391.8 (433.3-2652.6) pg/ml at 19 weeks. Expressed as multiples of the median (MOM), the levels of inhibin-B and pro-alphaC inhibins in the Down syndrome samples were 0.85 and 0.79, respectively. Neither was significantly different from the controls. These data suggest that, of the three inhibin subunits, abnormal production or secretion of the inhibin betaA-subunit may underlie the decreased inhibin-A levels previously observed in Down syndrome. Confirmation of this by quantitative assessment of the inhibin subunit messenger ribonucleic acids would now be useful.

Amniocentesis↗
PubMed1997

Physiological relationships between inhibin B, follicle stimulating hormone secretion and spermatogenesis in normal men and response to gonadotrophin suppression by exogenous testosterone.

Inhibin has been postulated to be secreted by Sertoli cells in response to follicle stimulating hormone (FSH) and in turn to exert an inhibitory effect on FSH production. We have investigated this relationship using an assay specific for dimeric inhibin B. A total of 56 normal men received 200 mg testosterone enanthate (TE) i.m. weekly, for 65 +/- 1 weeks in a trial of hormonal male contraception. Before treatment a significant negative correlation between inhibin B and FSH concentration (r = 0.49, P < 0.001) was observed. During TE treatment, luteinizing hormone (LH) and FSH were rapidly suppressed. This was followed by a parallel decline in inhibin B and sperm concentration. During the early recovery phase, inhibin B concentrations remained suppressed in men who showed a delay in resumption of spermatogenesis, despite higher FSH concentrations. Inhibin B returned to pretreatment concentrations after 24 weeks recovery, when the inverse relationship with FSH was restored. Our results showed the expected inverse physiological relationship between inhibin B and FSH in normal men, with a decline during TE treatment and alpha subsequent resumption of the inverse relationship during recovery. These data clearly support the hypothesis that inhibin B plays a physiological role in the feedback control of FSH secretion, and reflects FSH-stimulated Sertoli cell function.

Adult↗
PubMed1997

Antenatal corticosteroid prescribing: setting standards of care.

OBJECTIVE: Despite widespread recognition that prenatal administration of corticosteroids dramatically reduces perinatal mortality and morbidity, clinical practice in this area remains less than ideal. We therefore reviewed our practice to identify reasons for this and to determine attainable standards of care. DESIGN: Retrospective case record review. SETTING: Level three maternity unit in Edinburgh, UK. POPULATION: All women admitted at gestations of 24 to 34 weeks and 6 days inclusive, and all women receiving corticosteroids in one institution, over a 10-month period. MAIN OUTCOME MEASURES: The number and clinical features of women delivering before and after 35 weeks of pregnancy who had received corticosteroids. RESULTS: Seven hundred and two women were admitted during the study period; case records were available for 688 of these. One hundred and ninety-two women (28%) delivered before 35 weeks of gestation, of whom 123 (64%) had received dexamethasone. Of 69 women who received no steroids 30 (43%) were in hospital for more than 24 hours before delivery. Overall, 29% of women receiving dexamethasone delivered after 35 weeks of gestation and 42 (24%) women treated with dexamethasone received more than one course. While the grade of admitting doctor did not affect prescribing, there were other significant differences that may help guide future practice. CONCLUSIONS: This study provides some guidance for optimising corticosteroid prescribing and for the development of clinical practice guidelines. Approximately 80% of women should be able to receive at least some corticosteroids prior to delivery before 35 completed weeks of pregnancy.

Delivery, Obstetric↗
PubMed1997

Maternal serum inhibin-A and free beta-hCG concentrations in trisomy 21 pregnancies at 10 to 14 weeks of gestation.

OBJECTIVE: To determine the relation between maternal serum inhibin-A and free beta-hCG concentrations in chromosomally normal pregnancies and to compare the two biochemical markers for their sensitivity in identifying trisomy 21 pregnancies. SAMPLE: Inhibin-A and free beta-hCG were measured in maternal serum samples from 800 chromosomally normal singleton pregnancies at 10 to 14 weeks of gestation and 76 singleton pregnancies with fetal trisomy 21. RESULTS: In the normal group maternal serum inhibin-A was significantly associated with both maternal weight and gestational age (F = 11.2, P < 0.0001). In pregnancies with trisomy 21 the maternal serum inhibin-A and free beta-hCG concentrations were significantly increased (mean difference inhibin = 0.51 SD, F = 18, P < 0.0001 and mean difference free beta-hCG = 1.13 SD, F = 80, P < 0.0001). For a 5% false positive rate, the sensitivity of maternal serum free beta-hCG in identifying pregnancies with trisomy 21 was 28.9% compared with 12.8% for maternal serum inhibin-A. Delta inhibin-A was significantly associated with delta-free beta-hCG (r = 0.345, P < 0.01) and the deviation from the normal mean for free beta-hCG was significantly greater than the deviation for inhibin-A (t = 4.0, P < 0.0001). For a 5% false positive rate, the sensitivity achieved by combining information from delta inhibin-A and delta free beta-hCG was similar to the sensitivity of free beta-hCG alone (30.3% compared with 28.9%). CONCLUSION: At 10 to 14 weeks of gestation fetal trisomy 21 is associated with increased maternal serum inhibin-A and free beta-hCG levels. However, the degree of elevation of inhibin-A is less than that of free beta-hCG, and there is a significant association between levels of the two proteins. The sensitivity for trisomy 21 achieved with the combination of maternal serum inhibin-A and free beta-hCG is not significantly different from that achieved with maternal serum free beta-hCG alone.

Adolescent↗
PubMed1997

Dexamethasone-induced leucocytosis in pregnancy.

The effect of intramuscular dexamethasone administration in late pregnancy on the maternal peripheral white cell count was examined in 20 women. The mean total white cell count increased from a baseline of 11.3 x 10(9)/L (SD 2.3) to 16.2 x 10(9)/L (SD 4.6) on day 1, normalising thereafter. This 43% increase represented composite changes in the neutrophil and lymphocyte counts which, on average, increased by 62% and decreased by 22%, respectively. It is concluded that prenatal dexamethasone induces a significant neutrophilia on the first day following administration. This information may be helpful when monitoring for infection.

Adolescent↗
PubMed1997

Maternal serum inhibin-A in pregnancies complicated by insulin dependent diabetes mellitus.

We have examined whether insulin dependent diabetes mellitus (IDDM) affects maternal serum levels of inhibin-A, a recently described prenatal marker of Down's syndrome, by comparing levels in 169 women with IDDM with levels in 432 nondiabetic pregnant women between 15 and 20 weeks of gestation. There was a small but significant increase in the inhibin-A level in the diabetic women only when levels were corrected for maternal weight: median MoM 1.17 (P < 0.01 vs controls, Student's t test). The underlying mechanism for this elevation in pregnancies complicated by IDDM currently remains obscure.

Biomarkers↗
PubMed1997

Dimeric inhibins in amniotic fluid, maternal serum, and fetal serum in human pregnancy.

Using new specific and sensitive enzyme-linked immunosorbent assays for inhibin A and inhibin B, we measured these proteins in amniotic fluid (AF), maternal serum (MS), and umbilical cord serum in normal pregnancies. Inhibin A levels in AF rose from a median (10-90th percentile) level of 615 (158.2-1124.6) pg/mL at 14 weeks to 1336.0 (489.4-2084.1) pg/mL at 20 weeks, and inhibin B rose from 216.6 (67.4-554.6) to 1078.2 (439.3-2482.2) pg/mL over the same period. In MS, inhibin A levels fell from a median (10-90th percentile) level of 177.5 (101.4-290.7) pg/mL at 10 weeks to a nadir of 111.9 (59.5-200.3) pg/mL at 17 weeks, rising again to 180.3 (74.1-327.2) pg/mL at 20 weeks. No inhibin B was detectable in MS. In 47 pairs of matched samples (14-16 weeks gestation) there was no correlation of inhibin A levels in AF with those in MS (r = 0.19; P > 0.05). In 45 term umbilical cord serum samples, no dimeric inhibin was detectable in serum from female babies, but inhibin B was detectable in male sera; the median (10-90th percentile) concentration was 167.4 (111.2-224.8) pg/mL. These data suggest that for the gestation periods studied, although the placenta secretes inhibin A, another source, probably the fetal membranes, secretes both inhibin A and inhibin B. Further, the presence of inhibin B in male fetuses is consistent with a testicular origin, suggesting that inhibin B may be important in the development of the fetal hypothalamo-pituitary-testicular axis.

Amniocentesis↗
PubMed1997

Effects of chemotherapy-induced testicular damage on inhibin, gonadotropin, and testosterone secretion: a prospective longitudinal study.

To investigate the role of inhibin in the control of follicle-stimulating hormone (FSH) secretion, we have measured levels of immunoreactive inhibin (ir-inhibin), inhibin B, Pro-alpha C containing inhibins, FSH, luteinizing hormone (LH), and testosterone in twelve men with hematological malignancies before, during, and after chemotherapy. Inhibin B levels fell significantly by 1 month from a mean +/- SE baseline level of 273.2 +/- 32.8 pg/mL, reaching a nadir of 52.6 +/- 15.3 pg/mL at 4 months (P < 0.0001). FSH levels increased within the first month from a baseline level of 3.9 +/- 0.6 IU/L, reaching a peak level of 22.4 +/- 3.3 IU/L at 4 months (P < 0.0001). FSH and inhibin B were significantly and inversely correlated (r = 0.69, P < 0.0001). Pro-alpha C containing inhibin levels increased significantly (P < 0.05) at 3 months and were significantly and positively correlated with FSH (r = 0.38, P = 0.002). LH levels increased significantly but to a much lesser extent than FSH, the increase becoming evident only 4 months after treatment commenced (P < 0.03). Levels of ir-inhibin and testosterone remained unchanged throughout the study. These data provide strong support to the hypothesis that inhibin B is the physiologically important form of inhibin in men, negatively regulating FSH secretion at the pituitary. Furthermore, they suggest that FSH stimulates inhibin alpha-subunit secretion by the testis.

Adult↗