Background and Methods Maternal-infant transmission is the primary means by which young children become infected with human immunodeficiency virus type 1 (HIV). We conducted a randomized, double-blind, placebo-controlled trial of the efficacy and safety of zidovudine in reducing the risk of maternal-infant HIV transmission. HIV-infected pregnant women (14 to 34 weeks' gestation) with CD4+ T-lymphocyte counts above 200 cells per cubic millimeter who had not received antiretroviral therapy during the current pregnancy were enrolled. The zidovudine regimen included antepartum zidovudine (100 mg orally five times daily), intrapartum zidovudine (2 mg per kilogram of body weight given intravenously over a one-hour period, then 1 mg per kilogram per hour until delivery), and zidovudine for the newborn (2 mg per kilogram orally every six hours for six weeks). Infants with at least one positive HIV culture of peripheral-blood mononuclear cells were classified as HIV-infected. Results From April 1991 through Decemb...

Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group.

Substantial advances in our understanding of placental function have resulted from recent establishment of in vitro approaches, such as cell culture, and application of molecular methods to study placental steroidogenesis. Insight into the processes of placental cell differentiation and hormonal function has been gained from culture of relatively pure preparations of cytotrophoblast. Various factors, e.g. cAMP and peptide growth factors, have been shown to have striking effects on progesterone and estrogen formation by placental tissue under in vitro conditions. Using advanced molecular approaches, the genes governing specific enzymes critical to placental steroidogenesis have been identified. Regulation of the mRNAs encoding specific enzyme peptides and thus expression of the genes by factors, such as cAMP, have been elucidated by Northern analysis and other techniques. It is critical that these contemporary approaches continue to be implemented aggressively to further elucidate placental function. However, it is clear from a survey of the literature, particularly of the past decade, that the vast majority of investigation in the area has been conducted in vitro. It is essential to determine whether the factors that have been observed to regulate placental endocrine function in vitro are operable in vivo. It is only with in vivo study that the dynamics of steroidogenesis and the complex functional relationships between placenta, fetus, and mother will be uncovered and understood. It is increasingly evident that the regulation of placental steroidogenesis involves autocrine and/or paracrine mechanisms, similar to those integral to hormone biosynthesis within other reproductive organs, e.g. ovary and testis. For example, as discussed above, estrogen regulates LDL uptake and P-450scc, and thus apparently is involved in generating substrate for progesterone production within the placenta. Conversely, progesterone has effects on 17 beta-hydroxysteroid oxidoreductase and thus the metabolism of estradiol, while androgens exert marked inhibitory effects on placental progesterone formation, at least in vitro. Not surprisingly, the regulation of placental progesterone and estrogen formation also is multifactorial. Thus, aromatase activity is stimulated synergistically by cAMP and phorbol esters, an effect that is suppressed by peptide growth factors. Therefore, the autocrine/paracrine and multifactorial regulation of hormone biosynthesis that has been relatively well documented in other tissues should be recognized as important in the primate placenta. Finally, the basic mechanisms underlying regulation of steroidogenesis within the fetoplacental unit during primate pregnancy appear similar, in important ways, to those of widely used laboratory animals, such as the rat and rabbit.(ABSTRACT TRUNCATED AT 400 WORDS)

Placental steroid hormone biosynthesis in primate pregnancy.

Amaranth seeds are rich in protein with a high nutritional value, but little is known about their bioactive compounds that could benefit health. The objectives of this research were to investigate the presence, characterization, and the anticarcinogenic properties of the peptide lunasin in amaranth seeds. Furthermore, to predict and identify other peptides in amaranth seed with potential biological activities. ELISA showed an average concentration of 11.1 µg lunasin equivalent/g total extracted protein in four genotypes of mature amaranth seeds. Glutelin fraction had the highest lunasin concentration (3.0 µg/g). Lunasin was also identified in albumin, prolamin and globulin amaranth protein fractions and even in popped amaranth seeds. Western blot analysis revealed a band at 18.5 kDa, and MALDI-TOF analysis showed that this peptide matched more than 60% of the soybean lunasin peptide sequence. Glutelin extracts digested with trypsin, showed the induction of apoptosis against HeLa cells. Prediction of other...

Bioactive peptides in amaranth (Amaranthus hypochondriacus) seed.

We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital-parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.

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Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate

Both estradiol and progesterone may act locally to modulate ovarian function in various species. This study examined the distribution of estradiol and progesterone receptors (ER and PR, respectively) within the primate ovary throughout the menstrual cycle. Ovaries were collected from rhesus or cynomolgus monkeys during the early, mid-, and late (n = 3-6/stage) follicular and luteal phases of the cycle. The tissues were processed for indirect immunocytochemical localization of receptors with specific monoclonal antibodies against ER (H222 and D75) and PR (JZB39). Specific immunocytochemical staining, as determined by comparing adjacent tissue sections incubated with either receptor antibodies or a nonspecific antibody, was exclusively nuclear. Both ER and PR were localized in the germinal epithelium of ovaries at all stages of the cycle. ER was not detected in any other ovarian structure (i.e. stroma, follicles, interstitial tissue, or corpora lutea) regardless of the stage of development. However, ER was detected in other estrogen-responsive tissues, e.g. the oviduct of the monkey and corpora lutea of the pseudopregnant rabbit. In the monkey ovary, PR was detected in stromal and interstitial tissues as well as theca interna and externa of healthy and atretic follicles at all stages of the cycle. The granulosa cells of some primordial and primary follicles demonstrated staining for PR. However, the granulosa layer of follicles that developed beyond the primary stage were consistently negative for PR. Only the granulosa layer of large preovulatory follicles that showed signs of luteinization after the LH surge showed staining for PR equivalent to that in the theca. Monkey corpora lutea exhibited specific nuclear staining for PR. Moreover, the percentage of receptor-positive nuclei in the corpus luteum varied (P less than 0.05) between the early (28 +/- 3%), mid (48 +/- 1%)-, and late (4 +/- 2%) luteal phase of the cycle. Nonfunctional (serum progesterone less than 0.5 ng/ml) regressing corpora lutea did not exhibit for staining for PR. Luteal cells that were PR positive also contained histochemically detectable 3 beta-hydroxysteroid dehydrogenase. These data are consistent with the concept of a receptor-mediated autocrine or paracrine role for progestins, but not estrogens in the gametogenic and endocrine functions of the primate ovary throughout the menstrual cycle.

Immunocytochemical localization of estradiol and progesterone receptors in the monkey ovary throughout the menstrual cycle.

The inhibition of the pregnenolone Δ5–3Β-hydroxysteroid dehydrogenase-Δ5-4 isomerase systems in microsomes of human placenta or corpus luteum of pregnancy has been investigated using three steroidal substances: 2Α-cyano- 4,4,17Β-trimethylandrost-5-en-17Α-ol-3-one (cyanoketone), 2- hydroxymethylene, 17Α-methyl-5Α-androstan-17Β-ol-3-one (oxymetholone), and estradiol 17Β. The inhibition is of the competitive type with the synthetic steroids. The apparent Ki’s are approximately 0.3xl0-5 M and 0.2xI0-5 m for cyanoketone in the placental and ovarian systems, respectively, and the apparent Ki produced by oxymetholone is 0.6x10-6 m in the ovarian system, however, that for the placental system is much smaller, 5.5xl0-8 M. Approximately 50% inhibition was obtained in both systems with 2–5xl0-5 M estradiol-17Β. Oxymetholone may be useful for the inhibition of corpora luteal function in women.

Inhibition of the Pregnenolone Δ5–3β-Hydroxysteroid Dehydrogenase-Δ5-4 Isomerase Systems of Human Placenta and Corpus Luteum of Pregnancy

The determination of urinary 17-ketosteroids has limited applications in the understanding and diagnosis of the nature of endocrine disorders associated with mild hirsutism and virilism in the female, because a very large number of these patients excretes 17-ketosteroids well within the normal range. Recent experience of Finkelstein, Forchielli and Dorfman (1) suggests that in these cases the blood levels and nature of the circulating androgens may be very important. Earlier indirect evidence (2-12) and the more recent isolation and partial identification of sulfates of dehydroisoandrosterone, androsterone, and etiocholanolone by Baulieu (13) indicate that 17-ketosteroids are present in plasma mainly in the form of esters. Direct estimation of these conjugated steroids in plasma offers distinct advantages: the alteration of the steroid molecule which occurs with certain types of hydrolysis as well as possible problems of incomplete hydrolysis can be circumvented. Also, information concerning the physiological significance of the steroid conjugating mechanisms may be gained through direct qualitative and quantitative estimation of these conjugates. The present paper describes a convenient method, using quantitative paper chromatography, for the estimation of dehydroisoandrosterone and androsterone sulfates (DHIA-SO and Andro-SO4) in plasma.

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Quantitative paper chromatography of conjugated 17-ketosteroids in plasma.

A double isotope derivative method for the estimation of pregnenolone (3β-hydroxypregn-5-en-20-one) sulfate in plasma is described. Acetic-1-14C-anhydride is used as reagent and 7α-3H-ammonium pregnenolone sulfate as indicator. Multiple chromatographies before and after acetylation and recrystallization to constant 3H/14C are used to achieve purification. The mean recovery of the indicator is 9 ± 4%. The average absolute deviation of paired samples is 1.5 μg/100 ml. Pregnenolone sulfate can be measured in plasma throughout normal pregnancy. Values are as high as reported values for progesterone. A gradient is shown between fetal and maternal compartments (F > M) and between umbilical artery and umbilical vein (A >V).

Pregnenolone sulfate in human pregnancy plasma.

Monkeys with excellent reproductive histories were immunized with the laminin peptides YIGSR, RGD, IKVAV, and YD, a control sequence with no known biological function. Sera from the YIGSR-immunized monkey became toxic, causing neural tube defects in whole rat embryo cultures, and this monkey experienced fetal loss after immunization. Sera from the RGD-immunized monkey also became embryotoxic in culture after immunization, but this monkey appeared to become infertile as she failed to initiate a pregnancy for at least 2 years after immunization. In contrast, embryos cultured on sera from the IKVAV- or YD-immunized monkeys were predominantly normal and both monkeys completed successful pregnancies. Antibody levels to the respective peptides or to laminin were not predictive of embryotoxicity, but antibody binding to homogenized yolk sacs as well as to yolk sacs of cultured embryos was associated with sera embryotoxicity and reproductive outcomes in vivo. These observations suggested that the laminin sequences YIGSR and RGD may play a role in immune-mediated reproductive failure by reacting directly with embryonic tissue and could provide a basis for identifying individuals at risk for both spontaneous abortion and infertility.

https://www.pnas.org/content/pnas/92/15/6818.full.pdf

Suzanne H. Conrad

Papers

Inhibition of the Pregnenolone Δ5–3β-Hydroxysteroid Dehydrogenase-Δ5-4 Isomerase Systems of Human Placenta and Corpus Luteum of Pregnancy

Quantitative paper chromatography of conjugated 17-ketosteroids in plasma.

Pregnenolone sulfate in human pregnancy plasma.

Reproduction and sera embryotoxicity after immunization of monkeys with the laminin peptides YIGSR, RGD, and IKVAV.

Pregnenolone sulfate-an efficient precursor for the placental production of progesterone.