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Biomedical subjects

T H Shepard

Publications and source records attributed to T H Shepard.

At least 73 records · Page 4Linked to original sources
PubMed1986

Bowel migration in the normal fetus: US detection.

Ten fetuses underwent ultrasound scanning at 7-10 weeks gestational (postmenstrual) age. In all cases, an echogenic mass measuring 0.5-1.0 cm was demonstrated within the base of the umbilical cord at its insertion into the fetal abdomen. No area with echogenicity characteristic of the small bowel was identified within the lower part of the fetal abdomen. All fetuses were reexamined 4-12 weeks later, at which time the mass in the umbilical cord was no longer seen, and normal fetal bowel was visualized in the lower abdominal cavity of the fetus. This sequence of findings appears to represent the sonographic demonstration of normal fetal bowel migration early in gestation and should not be confused with defects of the abdominal wall such as omphalocele or gastroschisis.

Abdominal Muscles↗
PubMed1986

Pathogenesis of congenital defects associated with Turner's syndrome: the role of hypoalbuminemia and edema.

Studies of prenatal fetuses with 45,X Turner syndrome have allowed for plausible hypotheses of how their pitting edema may lead to production of the associated congenital defects found in the condition. Hypoalbuminemia in these fetuses which are only about one-sixth the levels found in newborns and one-third the level in "control" fetuses may explain the edema. Malformation of the ear, hairline, neck webbing, nipples, coarctation, nails and horseshoe kidney can be related to embryonic and fetal deformation from edema.

Abnormalities, Multiple↗
PubMed1986

Human teratogenicity.

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Abnormalities, Drug-Induced↗
PubMed1985

The effect of oxygen concentration on the teratogenicity of salicylate, niridazole, cyclophosphamide, and phosphoramide mustard in rat embryos in vitro.

Comparisons were made of rat embryos cultured at 5% or 20% oxygen in the presence of salicylate (SAL), cyclophosphamide (CP), niridazole (NDZ), or phosphoramide mustard (PM). Multiple regression analyses were used to compare the effects of drug concentration, oxygen concentration, and the product of drug times oxygen concentration on malformation incidence, viability, and protein content of embryos cultured for 24 hours. Drug concentration significantly affected malformation incidence or severity and protein content (P less than 0.001) for the four drugs tested. Oxygen concentration significantly affected protein content for the four compounds (P less than 0.001) but affected malformation incidence only with NDZ. Furthermore, the interaction of oxygen concentration and drug concentration significantly affected the malformation incidence in the presence of NDZ (P less than 0.001), and protein content (P less than 0.001) and viability (P less than 0.001) in the presence of CP. The pattern of significant effects of the independent variables (drug concentration, oxygen concentration, and drug times oxygen concentration) is consistent with the hypotheses of oxygen-dependent metabolism (or lack of metabolism) of the drugs in question. NDZ, which is thought to be converted to reactive intermediates by an oxygen-inhibited nitroreductase, was more toxic at reduced oxygen tension. CP, which is activated by an oxygen-dependent P-450 system, was more toxic with increased oxygen tension. Significant effects of the independent variables on embryos exposed to SAL or PM were consistent with the effects on control embryos, notably, increased protein content with increased oxygen.

Abnormalities, Drug-Induced↗
PubMed1985

Effects of 3-methylcholanthrene and phenobarbital on the capacity of embryos to bioactivate teratogens during organogenesis.

Pregnant Sprague-Dawley rats were divided into four groups and given ip injections of 3-methylcholanthrene (MC) in corn oil, corn oil only, phenobarbital (PB) in Hank's balanced salt solution (HBSS), or HBSS only. Maternal animals were killed on Day 10 of gestation, and embryos from each group were explanted in medium containing cyclophosphamide (CP), 2-acetylaminofluorene (AAF), or dimethylsulfoxide vehicle. After a 24-hr culture period, embryos from dams treated with HBSS, corn oil, or PB/HBSS exhibited no increase in abnormalities (as compared with controls) when either CP or AAF were added to the media. However, embryos transplacentally preexposed to MC and subsequently treated during culturing with AAF (but not CP) exhibited striking increases in malformation incidence. Commonly observed malformations included abnormally open neural tubes, abnormal flexure rotation, and prosencephalic defects. Homogenates of Day 10 embryos transplacentally preexposed to MC exhibited readily measurable oxidative biotransformation of AAF as assessed with HPLC. Biotransformation of AAF by embryos from the other three groups was virtually undetectable. Incorporation of exogenously supplemented bioactivating systems from livers of mature animals indicated that postmitochondrial supernatant fractions (S-9) from male, MC-pretreated rats effectively catalyzed the conversion of AAF (but not CP) to embryotoxic metabolites. Conversely, hepatic S-9 from adult, male, PB-pretreated rats was highly effective in converting CP (but not AAF) to embryotoxic metabolites. The results indicated the inducerspecific occurrence of embryonic bioconversion of AAF to embryotoxic metabolites via MC-inducible, P-450-dependent, embryonic enzyme systems.

2-Acetylaminofluorene↗
PubMed1985

Embryotoxic drugs.

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Abnormalities, Drug-Induced↗
PubMed1983

A selection of candidate compounds for in vitro teratogenesis test validation.

The Consensus Workshop on In Vitro Teratogenesis Testing recommended that test validation be facilitated by a listing of agents with defined teratogenicity; subsequently, a panel was convened to review and select such agents. This communication established a list of 47 compounds or conditions which demonstrate a wide range of teratogenicity in vivo. The agents were chosen primarily on the strength of the literature base denoting their in vivo effects. The tables note a number of general biological and toxicological characteristics for each agent, and the details of representative in vivo teratology studies are summarized and referenced. This list is intended to serve as a base for in vitro teratogenesis test validation and should prove useful in developing and identifying those systems which will contribute to a more effective testing program.

Abnormalities, Drug-Induced↗
PubMed1983

Iron deficiency in the rat: biochemical studies of fetal metabolism.

The effects of dietary-induced iron deficiency on fetal and maternal metabolism were studied in the rat. Concentrations of phenylalanine, but not tyrosine, were significantly elevated in plasma from iron-deficient maternal and fetal rats at day 20 of gestation with individual fetal plasma levels of phenylalanine as high as 10 mg per 100 ml. Concentrations of total 5-hydroxyindole compounds were significantly decreased in brain tissue from iron-deficient fetuses (day 20 of gestation), suggesting that synthesis of the compounds may be inhibited by iron deficiency. Mitochondrial NADH oxidase activity was markedly decreased (60%) in homogenates of fetuses at day 14 of gestation and may account for the high fetal resorption rate and small fetal size observed in the rat in iron deficiency.

Animals↗
PubMed1983

A kinetic analysis of rat embryo response to cyclophosphamide exposure in vitro.

Day 10 rat embryos were exposed in vitro to a teratogenic dose of cyclophosphamide (25 micrograms/ml) in the presence of a metabolic system (activated CP) for varying lengths of time and then were recultured in drug-free medium. Development was assessed after a total of 24-26 hours of culture. Exposure periods of 2.5 hours or less had no significant effects on growth, incidence of malformed embryos, mitotic index, or necrotic index when compared to control cultures from which cofactors for metabolic activation were omitted. Embryos exposed to activated CP for 5 hours and then recultured in drug-free medium for 19-21 hours were indistinguishable from embryos exposed to activated CP continuously over a 24-26-hour period. These embryos are characterized by retarded growth as well as abnormalities of the prosencephalon, mandibular arches, limbs, and tail. Histological examination of embryos exposed to activated CP for 5 hours and immediately fixed revealed a decrease in the mitotic index and an increase in the necrotic index of the neuroepithelium and the surrounding mesenchyme of the prosencephalon. Our findings indicate that a 5-hour exposure to activated CP during day 10 of rat gestation is sufficient to produce the molecular lesions necessary to elicit the teratogenic effects of cyclophosphamide.

Abnormalities, Drug-Induced↗
PubMed1983

Fetal iron balance in the rat.

Maternal and fetal iron balance through pregnancy was examined in the rat. The 20th day was selected for detailed study because of the peak iron requirements at that time. The standard diet provided a borderline iron supply to the fetus due to the limited availability of its iron for absorption. When a more available form of iron was used, normal fetal development occurred over a range of dietary iron content from 16 to 2500 mg/kg. At a level of 5 to 8 mg/kg, there was attrition of placental tissues with frequent fetal death and resorption. When the iron-deficient pregnancy was sustained, both maternal and fetal iron deficiency were present. At progressively higher levels of dietary iron, feto-placental iron content was constant despite a progressive increase in maternal iron stores. Fetal iron supply appeared to be determined primarily by plasma iron concentration, and, at normal levels, about 25% of transferrin iron passing through the uterine vasculature, was removed by the intact placentas. Low levels of plasma iron resulted in damage to fetal tissues and reduced the capacity of placental tissues to take up iron. At high levels of plasma iron, plasma iron turnover initially increased 5-fold over basal levels in nonpregnant animals due to increased placental uptake. However, with continued hyperferremia, uptake was regulated so as to maintain fetal iron at a normal level. A comparison of these data with human iron requirements explained the occurrence of both maternal and fetal iron deficiency in the rat, but only maternal iron deficiency in the human.

Animals↗
PubMed1983

Studies of hemoglobin expression in erythroid cells of early human fetuses using anti-gamma- and anti-beta-globin chain fluorescent antibodies.

Cells from early human fetuses were analyzed for gamma- and beta-globin expression by means of monospecific and monoclonal anti-gamma- and anti-beta-chain antibodies. We found that gamma-chain synthesis in embryonic (yolk sac) nucleated cells is either absent or it is below the threshold of sensitivity of the fluorescent antibody method (about 0.1 pg of hemoglobin per cell or less). In the earliest embryo studied (38 days old) all the liver-origin erythroid cells were labeled intensely by the anti-gamma-chain monoclonal. The majority of the liver-origin erythroblasts in a 45-day-old fetus were labeled with the anti-beta-chain monoclonal. These findings suggest that beta-gene expression is present in the earliest fetus in which globin expression was studied immunochemically. Histochemical and immunochemical staining of early fetal livers clearly shows that this organ is infiltrated by embryonic erythroblasts of hematogenous origin. The coexistence of embryonal and liver-origin erythroid cells in the early fetuses makes biochemical and molecular analyses of erythropoiesis in these fetuses uninformative unless care is taken to separate the two populations from each other with density methods.

Erythropoiesis↗
PubMed1983

A review of limb defects in a large fetus collection.

Although a considerable number of papers have been published dealing with the frequency and variety of genetic and nongenetic limb defects in newborns and to a lesser extent among embryos, little has been published about the range of limb defects among spontaneously aborted middle and late-term fetuses. This study reports on 133 limb defects from the Central Laboratory for Human Embryology (CLHE), Seattle, Washington. These constitute 34.1% of the total defective specimens in the collection and 5.4% of the total collection population. It is proposed that 30% of the limb defects described indicate a definite recurrence risk, 27% do not indicate recurrence, and the recurrence risk for 43% is unknown. The most interesting findings from this study include the observation that reduction defects affect predominantly the preaxial side of the upper limb and that addition defects (polydactyly) affect predominantly the postaxial side of the lower limb. The observation in relation to reduction defects agrees with U.S. newborn studies. The observation in relation to polydactyly is exactly opposite the studies of Latin American newborns and Japanese embryos.

Anencephaly↗
PubMed1983

Teratology testing: I. Development and status of short-term prescreens. II. Biotransformation of teratogens as studied in whole embryo culture.

The development and role of short-term prescreening tests have been described and discussed in the first section. In the second section we have summarized the results of studies of the biotransformation and bioactivation of teratogens in a whole embryo culture system. The effect of adding a hepatic monooxygenase with or without cofactors or inhibitors gives information on the phase I bioactivation of teratogens. The growth retardation and defect rate can be correlated with the concentration of teratogen added. Four teratogens (cyclophosphamide, chlorambucil, rifampicin, and 2-acetylaminofluorene) were bioactivated in vitro by a liver monooxygenase system; one (cytochalasin D) was inactivated and seven others were active without bioactivation. Those that were active without bioactivation were sodium salicylate, niridazole, phosphoramide mustard, acrolein, 4-hydroperoxycyclophosphamide, 4-ketocyclophosphamide, ethanol, and acetaldehyde. These results establish that biotransformational variables must be considered if mass-screening programs are to have any validity.

Animals↗