Prediction of pre-eclampsia by uterine artery Doppler imaging: relationship to gestational age at delivery and small-for-gestational age.

OBJECTIVES: To determine the relationship between pre-eclampsia, small-for-gestational age (SGA) and gestational age at delivery, and the effect of this relationship on the prediction of pre-eclampsia by uterine artery Doppler imaging. METHODS: This was a multicenter prospective Doppler study of the uterine artery at 22-24 weeks of gestation in unselected women with singleton pregnancies. RESULTS: In the 30,639 pregnancies examined, the median uterine artery pulsatility index (PI) was 1.0 and the 95(th) centile was 1.58. In 614 (2%) cases the woman developed pre-eclampsia and in this group there was an inverse significant association between the gestational age at delivery and prevalence of SGA (r = - 0.99, P < 0.0001), and between the gestational at delivery and mean uterine artery PI (r = - 0.51, P < 0.0001) and prevalence of mean uterine artery PI above the 95(th) centile (r = - 0.99, P < 0.0001). The mean uterine artery PI was above the 95(th) centile in 77.2% of women who developed pre-eclampsia requiring delivery before 34 weeks, in 35.9% of those delivering at 34-37 weeks and in 21.9% of those delivering after 37 weeks. The respective percentages were 82.3%, 46.9% and 28.8% for those with pre-eclampsia and SGA, and 43.8%, 21.2% and 8.4% for those with SGA but without pre-eclampsia. CONCLUSIONS: Pre-eclampsia requiring early delivery is more likely to be associated with SGA than less severe pre-eclampsia in women who deliver at term. Doppler ultrasound assessment of the uterine arteries is more effective in identifying pre-eclampsia requiring preterm than term delivery.

Partitioning of a-factor analogues into membranes: analysis of binding and importance for biological activity.

Analogues of the a-factor mating pheromone of the yeast Saccharomyces cerevisiae were used to measure interactions of the pheromones with lipid vesicles and with isolated yeast membranes. The binding of the analogues of a-factor to vesicles and to membranes was best described as a partitioning of the pheromones into the lipid phase. The partitioning was enhanced by the negative surface potential of the membranes and was well described by the Gouy-Chapman theory of diffuse double layers. From the analysis of the binding of the pheromones to synthetic vesicles of known surface potential, effective charges and intrinsic partition coefficients were obtained for the pheromones. The information was used in subsequent experiments with yeast membranes to determine the intrinsic partition coefficients of the a-factor analogues and the charge density of the yeast membranes. Derivatives of a-factor with different alkyl chains in place of the normal C-terminal farnesyl displayed biological activity that paralleled the degree of partitioning of the pheromones into vesicles. Demethylation of the C-terminus decreased the partition coefficient by 6-fold and decreased the biological activity of the pheromone by greater than 2500-fold. The results show that a-factor can effectively partition into membrane bilayers and that the partitioning is probably involved in the subsequent recognition of the pheromone by the a-factor receptor.

Synthesis and biological activity of fluorescent yeast pheromones.

The mating pheromones of Saccharomyces cerevisiae and derivatives of these pheromones have been synthesized and tested for biological activity in a solution-phase assay. The effects of native alpha-factor and a-factor on the growth of target cells in these assays were identical. A derivative of alpha-factor in which the amino terminus was modified with the fluorescent probe, 6-amino-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)hexanoyl, was only slightly less active than the unmodified pheromone. Derivatives of a-factor that contain various alkyl groups in place of the farnesyl moiety of the native pheromone were also synthesized and tested for biological activity. A derivative in which the farnesyl moiety is substituted with an unbranched decyl group exhibited activity identical to that of the natural pheromone, whereas a derivative that contains an unbranched pentyl group exhibited significantly lower biological activity than native a-factor. The derivatives of a-factor have in addition been modified to incorporate 6-amino-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) at the terminus of the alkyl chains. A derivative with the probe attached to a decyl chain displayed activity similar to that of the native pheromone, whereas the same modification on a pentyl chain produced a derivative with very low activity. The fluorescence spectra of the modified alpha-factor and a-factors were measured in methanol, aqueous solution, and aqueous solution containing phospholipid vesicles. The fluorescence of the probes depends on the environment of the pheromones and can be used to monitor the association of the pheromones with the lipid bilayer.