Abnormal placentation is the likely cause of the slow fetal growth and the high levels of circulating lipid peroxides found in severe pre-eclampsia. These peroxides are probably responsible for the high thromboxane:prostacyclin ratio found in this disease and may participate in the endothelial cell damage which is its most notable feature. Selenium (Se), because of its role in glutathione peroxidase, is suggested to be an important component of the removal system for these damaging peroxides. Serum-Se concentrations have therefore been measured in 19 pairs of pre-eclamptic women and matched controls. Infant birth-weights were recorded. No significant difference was found in the concentrations of Se in pre-eclamptic and control groups. Serum Se was found to be low in both groups. Birthweights were significantly lower in the pre-eclamptic group. The interpretation of serum-Se measurements from the third trimester of a pre-eclamptic pregnancy is complicated by the reduced fetal growth and probable lower Se take-up by the fetus in such a pregnancy. The merits of alternative measurements, such as total intravascular Se, placental Se, or samples from an earlier stage of gestation, are discussed. The importance of factors other than Se to the activity of glutathione peroxidase, and of other antioxidants to pre-eclamptic, is stressed.

Birth Weight↗

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Acetylation of arylamines by the placenta.

The N-acetylation of arylamines and hydrazines used as drugs may alter their pharmacological or toxicological activity. Arylamine N-acetyltransferase (NATs) are involved in drug metabolism, as they catalyse the N-acetylation of arylamine and mono-substituted hydrazine substrates. Placental metabolism regulates the nature of the chemicals which reach the developing fetus. The study of drug metabolism during pregnancy is important in determining the effect on the fetus of drugs administered to the mother and the maternal drug dose required, important if the treatment is to be effective. There are two forms of NAT in humans, NAT1 and NAT2, which are encoded at multi-allelic loci. There is inter-individual variation in both NAT1 and NAT2 activity, which has implications in drug dosage. Using a combination of enzyme activity measurements and Western blotting, this study has characterised the arylamine N-acetylation capabilities of placenta and cord blood. NAT1 activity in placenta and cord blood demonstrated inter-individual variation and the variation was in the range expected for adult NAT1 activity. The genotypes of both NAT1* and NAT2* were determined using DNA prepared using placental blood clots (maternal DNA) and cord blood (fetal DNA). The results indicate that placental NAT activity is an important factor when considering N-acetylation during pregnancy.

Acetylation↗

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The destruction of factor VIII clotting activity by thrombin and plasmin.

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Animals↗

PubMedDate not supplied

Current topic: pre-eclampsia and the placenta.

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Animals↗

PubMedDate not supplied

Syncytiotrophoblast membrane protein glycosylation patterns in normal human pregnancy and changes with gestational age and parturition.

The fetally derived syncytiotrophoblast in the placenta form the major interface with the maternal circulation. Cell surface N-linked oligosaccharides are known to influence cell-cell interactions in a variety of ways. The N-linked oligosaccharide component of the human syncytiotrophoblast membrane has been purified from term placentae, and its biochemical structure analysed. Ninety-five per cent of structures were complex N-linked oligosaccharides, with the remaining 5 per cent being of the oligomannose type. Seventy-two per cent of oligosaccharides were sialylated; 50 per cent having two or more sialic acid residues. Such a population of N-linked oligosaccharides would be expected to provide a surface which inhibits interactions between trophoblast and maternal leukocytes. The temporal changes in syncytiotrophoblast N-linked oligosaccharides from the end of the second, and through the third trimester (25-41 weeks) were analysed, as were the changes which occur during parturition. There was no change in the degree of sialylation of these structures. The only significant change was a 37 per cent decrease in core fucosylation of complex N-linked sugars during gestation (P less than 0.005). Women delivered by caesarean section at term, had significantly higher levels of fucosylation (equivalent to women with a gestational age of 31-36 weeks), than those who laboured at term. Present knowledge of core fucosylation of N-linked oligosaccharides is discussed in relation to trophoblast functioning.

Carbohydrate Sequence↗

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Purification of human cytotrophoblast from term amniochorion by flow cytometry.

Term cytotrophoblast do not express polymorphic MHC Class I antigens, unlike other fetal and maternal cells in the amniochorion/decidua. This allows cytotrophoblast to be isolated and purified from this tissue, utilizing 4E, a monoclonal antibody specific for HLA-B, which labels only non-trophoblast. We have developed a method using enzymic dispersion and Percoll gradient centrifugation, followed by flow cytometry, that yields, on average, a total of 5 X 10(6) term extravillous cytotrophoblast, 97 per cent pure. The availability of highly purified extravillous cytotrophoblast, for the first time, permits precise investigation of trophoblast function.

Antibodies, Monoclonal↗

PubMedDate not supplied

Antigenic heterogeneity of human cytotrophoblast and evidence for the transient expression of MHC class I antigens distinct from HLA-G.

Expression of MHC class I antigens on trophoblast populations in first trimester human chorionic villous tissue was assessed by immunohistology. Antibodies used were W6/32 which recognizes a non-polymorphic framework determinant of HLA- A, -B, -C, MHM5 specific for HLA-B, C and 4E and B23.1 which are specific for HLA-B. Syncytiotrophoblast and villous cytotrophoblast were negative with all the anti (HLA class I) antibodies tested. Interstitial trophoblast cells within the maternal decidua were identified with a new antibody, NDOG5, which is specific for extravillous cytotrophoblast. Double labelling showed that they bind W6/32 but not 4E, MHM5 or B23.1; consistent with the expression of the monomorphic HLA-G. In contrast the cytotrophoblast cells of the cell islands and cytotrophoblast shell, which also express the NDOG5 antigen, were positive with W6/32, 4E, MHM5 and B23.1. Cell column cytotrophoblast cells were negative with all four MHC class I antibodies. These results suggest that differentiation of cytotrophoblast from noninvasive to invasive forms is associated with transient expression of class I antigens other than HLA-G on cytotrophoblast shell and cell island cytotrophoblast.

Chorionic Villi↗

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The pathogenesis of pre-eclampsia.

Syncytiotrophoblast normally sheds redundant placental debris into the maternal circulation, a process, which depends on apoptosis. It is renewed from the underlying mononuclear cytotrophoblast. We propose that the continual clearance of this debris from the maternal circulation causes a systemic inflammatory response that is present in all pregnant women in the third trimester. Pre-eclampsia occurs when the systemic inflammatory response decompensates. This may occur if the burden of the debris is abnormally high, or if the woman's response to the process is excessive. There is evidence that oxidative stress in the placenta could lead to an overload of debris by stimulating apoptosis or necrosis or both. Such stress would be most likely with spiral artery disease either from deficient placentation or acute atherosis, In this model, deficient placentation is not the cause of pre-eclampsia but a powerfully predisposing condition.

Apoptosis↗

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Glutathione S-transferase GSTM1 and GSTT1 genotypes in ovarian cancer: association with p53 expression and survival.

The objective of this study was to determine whether the association between GSTM1 null/GSTTI null and survival in ovarian cancer is mediated by the influence of these genes on p53 expression. In 81 women with pure invasive ovarian cancer, GSTM1 null and GSTT1 null genotypes were identified using polymerase chain reaction and p53 expression was assessed using immunohistochemistry. The association of these factors with survival was examined using Cox's proportional hazards regression models. Performance status (P < 0.001), operative stage (P = 0.004), residual disease (P = 0.001), histologic subtype (P = 0.05), tumor grade (P = 0.007), and the combined GSTMI null/GSTTl null genotype (P = 0.023) were all individually associated with survival. p53 expression was not associated with survival (P = 0.45). In a multivariate analysis, the effects of GSTM1 null/GSTT1 null on survival were lost when residual disease and tumor grade were included. The effects of p53 expression on survival were unchanged when residual disease, tumor grade, operative stage, and performance score were included. GSTM1 null/GSTT1null did not influence the effects of p53 expression on survival and vice versa. The GSTM1 null/GSTT1 null genotype was associated with response to primary chemotherapy (P = 0.007) but p53 expression was not. We conclude that the association of GSTM1 null/GSTTl null with survival appears to be mediated through different mechanisms to p53 expression in ovarian cancer and in addition, may be a better predictor of outcome.

Adult↗

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Adhesion molecules of syncytiotrophoblast microvillous membranes inhibit proliferation of human umbilical vein endothelial cells.

It has been shown previously that syncytiotrophoblast microvillous membranes (STBM), isolated from normal or pre-eclampsia placentae, specifically inhibit the proliferation of cultured human umbilical vein endothelial cells (HUVEC) and disrupt the cell monolayer without causing cell death. We have previously shown that this anti-proliferative activity resides in a self-aggregating complex in which eight proteins, namely integrins alpha(5)(CD49e) and alpha(V)(CD51), dipeptidyl peptidase IV (DPP IV, CD26), alpha-actinin, transferrin receptor (TfR, CD71), transferrin, placental alkaline phosphatase (PLAP) and monoamine oxidase A (MAO-A) were identified. In the present study, we investigated which of these components causes the anti-proliferative activity of STBM. Antibodies against integrin alpha(5)and alpha(V)and DPP IV all reduced the STBM-induced inhibition of proliferation of HUVEC, which was also reversed by added fibronectin. A preparation of PLAP inhibited endothelial proliferation, but this was not due to enzymatic activity. The preparation was shown to be impure with more than 12 bands present on Coomassie blue stained SDS-PAGE gels. These included integrins alpha(5)and alpha(V), which could account, at least in part, for the inhibitory activity. We could not exclude, however, the possibility of other unidentified factors being involved. We conclude that adhesion molecules account for a major part of the anti-proliferative activity of STBM; these appear to compete for ligands in the extracellular matrix or serum with the appropriate receptors on HUVEC.

Actinin↗

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Comparative risk-benefit assessment of drugs used in the management of hypertension in pregnancy.

Antihypertensive treatment in pregnancy is needed to protect the mother from the dangers of severe hypertension (greater than or equal to 170/110mm Hg), particularly cerebral haemorrhage in the context of preeclampsia. There is no evidence that treatment of the hypertension confers any other benefit; the onset and progression of preeclampsia is neither prevented nor ameliorated. Therefore, there are no indications for treating mild-to-moderate hypertension (140 to 169/90 to 109mm Hg). Intravenous hydralazine and oral nifedipine are effective drugs to treat severe hypertension acutely, the latter having the advantage of ease of administration. For long term therapy, methyldopa is the only drug which has been fully assessed and shown to be safe for the neonate and infant. beta-Adrenoceptor antagonists are safe to use in the third trimester but cause significant intrauterine growth retardation when used for longer periods. ACE inhibitors are contraindicated and diuretics should be avoided. Although calcium antagonists appear to have much potential they require further assessment of their use in pregnancy.

Antihypertensive Agents↗