Endothelin, elastase, and endothelial dysfunction in pre-eclampsia.
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Biomedical subjects
Publications and source records attributed to W A Liston.
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OBJECTIVE: The aim of the study was to determine whether there was evidence of elastase containing neutrophils at the materno-fetal interface in women with pregnancy-induced hypertension (PIH). DESIGN: An observational prospective study. SETTING: The Simpson Memorial Maternal Pavilion Edinburgh. METHODS: Placentas were obtained at vaginal or abdominal delivery from 51 consecutive women, 23 had normal pregnancies (13 caesarean sections) and 28 had PIH (18 caesarean sections). An immunocytochemical technique was used to localize elastase containing neutrophils in the placenta, decidua and myometrium. MAIN OUTCOME MEASURES: The numbers of positively stained cells, estimated subjectively as minimal, moderate or heavy, in subchorionic plate, perivillous fibrin and decidua. RESULTS: In both normal and PIH pregnancies neutrophils were absent from the myometrium. However, elastase containing neutrophils were located in areas of fibrin in the subchorionic plate and around the villi although there was no significant difference between the normal and PIH group. Neutrophils were also located in the fibrin of the decidua and in this case the number was significantly greater in the PIH group than in the normal group and correlated with plasma urate. CONCLUSION: The release of neutrophil elastase in the decidua could contribute to the vascular damage evident in PIH.
OBJECTIVE: To determine whether any simple, purely genetic mechanism can account for susceptibility to pre-eclampsia. DESIGN: Six simple Mendelian models of inheritance were considered, and predictions concerning the incidence of pre-eclampsia in various family members of index cases were calculated for each genetic model. Data were then extracted from published family studies in which a suitable disease definition had been used, and compared to our theoretical expectations. RESULTS: Only one of the genetic models considered, in which both mother and fetus must express the same recessive gene to confer susceptibility, was consistent with the observed incidence values for relatives of index cases. This model was also consistent with the putative association with HLA-DR4, but could not account for the comparative rarity of pre-eclampsia in parous women. CONCLUSION: Homozygosity for a single recessive gene shared by mother and fetus, unlike five other genetic mechanisms tested, is consistent with published family studies in pre-eclampsia, and should be considered the best working hypothesis at present.
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A set of 21 early maternal serum samples (19 first-trimester and two at 14 weeks) from pregnancies resulting in a child with Down syndrome was matched for gestation and length of storage with 63 samples from unaffected pregnancies. The concentrations of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), human chorionic gonadotrophin (hCG), pregnancy-specific beta 1-glycoprotein (SP1), and placental alkaline phosphatase (PALP) were measured. The ratios of the medians for Down syndrome pregnancies compared with the medians for controls were AFP 0.71, uE3 0.67, hCG 1.43, SP1 0.79, and PALP 0.92. Although the differences between the medians for affected and unaffected pregnancies were not significant, the trends for AFP, uE3, and hCG confirm earlier findings on first-trimester samples.
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Full HLA-A,B and DR typing was carried out on 92 women with proteinuric pre-eclampsia, 80 of their husbands and 46 of their babies. The results were compared with corresponding data from 65 normotensive pregnancies involving primiparous women. The frequency of HLA-DR4 was increased in the pre-eclamptic women (RR 3.1; p less than 0.005) and in the babies of pre-eclamptic pregnancies (RR 2.6; p less than 0.03). The strongest association, however, was with sharing of HLA-DR4 between mother and fetus (RR 4.2; p = 0.01). There was no increase in HLA antigen sharing in general between spouses or maternal-fetal pairs in pre-eclampsia. Nor did pre-eclamptic women exhibit increased homozygosity in general at any HLA locus. We conclude that genetic susceptibility to pre-eclampsia depends at least partly on fetomaternal compatibility for a gene or genes associated with HLA-DR4.
56 women who had had proteinuric pre-eclampsia and who had parous sisters were studied. In first pregnancy, proteinuric pre-eclampsia was more common in the sisters than in the maternity hospital population (8/71 [11%] vs 41/1978 [2%]); the relative risk was 6.0. The frequency of HLA DR4 was higher in sisters with pregnancy-induced hypertension than in sisters with normotensive pregnancies (8/18 [44%] vs 10/54 [19%]) and more of them shared HLA DR4 with their spouses (4/14 [29%] vs 0/29). Genetic susceptibility to pre-eclampsia is associated with HLA DR4; it may be conferred by fetomaternal sharing of a single recessive HLA-linked gene.
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At eight weeks of pregnancy a couple were informed that the prospective father's mother had died of Huntington's disease (HD). There were no living affected members in the immediate family to confirm the diagnosis. By inspection of the local genetic register, it was established that it was indeed HD segregating in the extended family. Genotyping of the prospective mother and father, the father's unaffected father, and his unaffected maternal grandmother was carried out using a battery of polymorphic DNA markers, including a new probe which has a very low recombination rate with the HD locus. Analysis of DNA from a chorionic villus sample taken at 10 weeks of pregnancy showed that the fetus must have inherited a chromosome from its father's affected mother. Its risk of developing HD was 47%. If the genotype of the unaffected maternal grandmother was taken into account, the risk was reduced to 42%. Neither risk was considered acceptable by the prospective parents and the pregnancy was terminated at 12 weeks' gestation. Prospects for future pregnancies are good, with a 50% chance of having a child whose risk of inheriting the HD gene is less than 1.5%. In retrospect it was noted that although genotyping of the maternal grandmother had refined the fetal risk, it had also nearly contributed to an inadvertent and unwanted predictive test for HD on the father. This case makes the point that in prenatal exclusion testing, linkage information must be generated with considerable care.
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Full HLA-A, B and DR types were obtained for 22 families (mothers, fathers and neonates) associated with severe (proteinuric) pre-eclampsia, 21 families associated with mild pre-eclampsia, and 132 families associated with normal pregnancies. There was an increased frequency of DR4 (relative risk 3.6: p less than 0.003, uncorrected) in both neonates and mothers of the severe pre-eclampsia families when compared to the normotensive controls. There were no significant differences between either pre-eclampsia group and controls in HLA antigen homozygosity, HLA antigen sharing or in lymphocytotoxin production.
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Two case histories are described with conflicting implications for the etiopathogenesis of pre-eclampsia. In both, typical proteinuric pre-eclampsia developed despite a history of previous normotensive pregnancy. In the first case, the disease was associated with a change of husband, consistent with the view that pre-eclampsia arises from an inadequate maternal immune response to paternal antigens inherited by the fetus. The second case, however, concerned a woman who developed pre-eclampsia for the first time in her third pregnancy by the same reproductive partner. We conclude that either more than one underlying cause can result in the clinical syndrome of pre-eclampsia, or that pre-eclampsia is caused by an environmental factor. The possibility that pre-eclampsia may be initiated by an infectious agent is briefly explored in the light of the clinical histories described and well-established epidemiological, clinical and laboratory data.
Several studies have supported the hypothesis that the maternal immune response to incompatible paternal HLA antigens present on the conceptus may influence pregnancy outcome. In order to relate feto-maternal histocompatibility directly to pregnancy course and characteristics, complete HLA-A, B and DR types were obtained from 132 healthy family groups consisting of mothers, fathers and neonates. The distribution of feto-maternal HLA compatibility was heavily skewed towards incompatibility, with 90% of fetuses being mismatched at 2 or 3 loci. There was no segregation distortion of paternal haplotypes, however, and the number of feto-maternal mismatches was close to that expected theoretically. More than 2% of the neonates were perfectly HLA-A, B and DR compatible with their mothers. The degree of feto-maternal HLA disparity showed no significant correlation with sex of neonate, birthweight, placental weight, maternal plasma alpha-fetoprotein or parity of the mother. Feto-maternal HLA disparity did, however, correlate significantly with maternal lymphocytotoxin production, even after allowance was made for parity (P less than 0.01). We conclude that feto-maternal HLA compatibility per se does not have a major influence on pregnancy outcome, and in particular is unlikely to predispose to spontaneous abortion; so an absence of antigen sharing between spouses experiencing recurrent spontaneous abortions should not be regarded in itself as a contraindication to offering immunotherapy to such couples.
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Amniocentesis was performed at 19 weeks' gestation on a patient with two sequential serum alphafetoprotein values above 2 times median. Ultrasound examination suggested a possible sacrococcygeal teratoma. However, both amniotic fluid alphafetoprotein and acetylcholinesterase were normal, and the patient elected to continue her pregnancy. At 24 weeks fetal demise was confirmed, and prostaglandin induction of labour produced a macerated female fetus with a large sacrococcygeal teratoma.