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Biomedical subjects

T H Shepard

Publications and source records attributed to T H Shepard.

At least 91 records · Page 5Linked to original sources
PubMed1983

Bioactivation of thalidomide by a monkey liver fraction in a rat limb culture system.

The effect of thalidomide on a rat limb bud system has been studied in vitro. Thalidomide and adult monkey liver supernatants activated with cofactors for the mixed function monooxygenase system inhibited growth. Similar preparations from the rat did not inhibit growth. Planimetric measures of the surface area of limb buds were found to correlate closely with their protein contents. The ability to compare metabolizing systems from different mammals may be useful in extrapolating teratologic data between different species.

Animals↗
PubMed1982

Vaginal spermicides and miscarriage seen primarily in the emergency room.

Among 813 women who had obtained a vaginal spermicide within 48 weeks of the estimated date of fertilization (EDF), 47 (5.8%) had an early miscarriage. Among women who had obtained oral contraceptives, 35/1,127 (3.1%) miscarried, and among women who obtained neither, 140/4,231 (3.3%) miscarried. The risk ratio estimate comparing spermicide users with nonusers was 1.8 (90% confidence interval 1.4, 2.3). The association was strongest among women who had obtained a spermicide within 12 weeks of the EDF. Examination of abortus material revealed that the association with spermicides was strongest among those where an abnormal fetus was present.

Abnormalities, Drug-Induced↗
PubMed1982

The in vitro teratogenicity of cyclophosphamide in rat embryos.

When Day 10 rat embryos were grown in culture containing cyclophosphamide, an hepatic microsomal fraction (S-9), and cofactors for monooxygenation, they developed characteristic malformations. When a fixed volume of CP was added to cultures the number of malformed embryos was increased and their growth decreased dependent upon the S-9 concentration. In one group of experiments S-9 was prepared from animals which had been pretreated with either phenobarbital (PB) or 3-methylcholanthrene (MCA). All embryos cultured with CP by S-9 from animals pretreated with polychlorinated biphenyls (Aroclor 1254) microliter/ml) was used. No malformations were seen under the same conditions when MCA-induced S-9 (0.25-12.5 microliter/ml) was substituted. The teratogenic activation of CP by S-9 from animals pretreated with polychlorinated biphenyls (Aroclor 1254) was inhibited in vitro by the addition of either metyrapone or carbon monoxide. Embryos which were exposed to CP (25 mg/kg) in vivo on Day 10 were indistinguishable from embryos treated in vitro. All developed characteristic defects and had significant decreases in growth parameters when compared to control litters receiving only vehicle. No histological differences were seen between embryos treated in vivo or in vitro. These data provide further evidence that the teratogenicity of CP is dependent upon one or more maternal P450 monooxygenase systems.

Abnormalities, Drug-Induced↗
PubMed1982

Sodium salicylate teratogenicity in vitro.

Rat embryos were exposed to sodium salicylate in vitro at concentrations comparable to those used to produce terata in vivo. Embryos treated with 400, 600, or 800 micrograms Na salicylate/ml were compared with embryos treated with an equimolar concentration of NaCl. When compared to growth of the controls, a significant dose-dependent decrease in growth parameters was observed. The incidence of abnormal embryos characterized by generalized swelling (particularly in the area of the rhombencephalon) was also dose dependent. This study demonstrates the teratogenicity of salicylate in the rat independent of maternal factors.

Abnormalities, Drug-Induced↗
PubMed1982

Detection of human teratogenic agents.

Criteria for definition of a human teratogen are similar to Koch's postulates and include (1) presence of the agent during the critical period of development, (2) production of congenital defects by the agent in an experimental animal, and (3) evidence that the agent acts directly on the embryo or fetus. Examples of how teratogens have been identified through specific syndrome identification and by application of experimental animal information are given. Hyperthermia, an example of the latter, is discussed in some detail. Certain bias factors that confound epidemiologic studies are discussed. A system for detection an prevention of human teratogenicity is proposed. The system is based on the integration of three data bases: (1) the exposed parent-child pair, (2) the chemical and biologic effects of the agent, and (3) identification of specific exposure syndromes.

Congenital Abnormalities↗
PubMed1981

The teratogenicity of cytochalasin D and its inhibition by drug metabolism.

Pregnant rats received intraperitoneal injections of cytochalasin D (CD) on gestational days 7-11. Doses of 400 micrograms/kg were only minimally and nonsignificantly teratogenic, leading to 2 exencephalic fetuses among the 111 fetuses delivered. By contrast, embryos exposed to CD in vitro on day 10 showed significant frequencies of neural tube abnormalities when exposed to CD concentrations at or above 3.1 ng/ml. These embryos also exhibited significantly decreased protein, somite counts, and crown-rump lengths. In order to understand this apparent discrepancy between the teratogenicity of CD in vivo and in vitro we performed experiments to determine whether drug metabolism could inhibit the teratogenicity in vitro. Male rats were pretreated with a mixture of polychlorinated biphenyls as cytochrome P-450 inducers, and their livers were used to prepare a microsome-rich fraction (S-9). This S-9 fraction, plus a source of reducing equivalents (NADPH), significantly inhibited the teratogenicity of CD. The teratogenicity was restored by the omission of NADPH, and was partially restored with the addition of carbon monoxide. These results led us to conclude that the teratogenic effect of CD can be inhibited by drug metabolism in vitro; additionally, it is likely that some or all of this drug metabolism may depend on cytochrome P-450. We further speculate that CD may be inactivated in vivo by these same systems, explaining the discrepancy between the teratogenicity of CD in vivo and in vitro.

Animals↗
PubMed1981

Low-birth-weight and congenital rubella syndrome: effect of gestational age at time of maternal rubella infection.

Birth weights of 42 full-term patients with congenital rubella syndrome were analyzed. All of these infants were products of pregnancies in which the exact dates of the maternal first day of last menstrual period and of the time of onset of the mothers' rubella rash were known. The range of time of maternal rubella associated with low-birth-weight was in the gestational age interval from 16 to 100 days. Low-birth-weight may have a relationship with time of maternal rubella rather than with the type of defects, i.e., cataract, heart disease, and deafness.

Female↗
PubMed1980

The effect of high doses of retinoic acid on prenatal craniofacial development in Macaca nemestrina.

Eight pregnant Macaca nemestrina were administered from 7.5 to 10 mg/kg retinoic acid by mouth from day 20 to 44 of gestation. All fetuses exhibited craniofacial abnormalities. The craniofacial complex was studied in detail utilizing gross photography, silver nitrate impregnation, radiography, alizarin staining, and histologic processing. Nearly all the bones of the craniofacial complex were affected; the zygomatic bone and the mandible were most severely altered. Premature fusion of the coronal suture occurred in all the specimens, and there was a clockwise rotation of the craniofacial complex on right lateral view. In general, the bones of the affected fetus were smaller and less well developed than in the control specimen. The abnormal specimens in the present investigation resembled the Treacher-Collins syndrome in humans, and may be the result of defective neural crest cell migration in the first and second branchial arches.

Abnormalities, Drug-Induced↗
PubMed1980

The Down syndrome in the fetus.

A significant number of fetuses with the Down syndrome are spontaneously lost before birth; however, very few such fetuses have been described. In the present study, 13 fetuses of 127--180 mm in crown-rump length were examined following amniocentesis diagnosis of trisomy 21 and therapeutic abortion. Four features, i.e., simian crease, clinodactyly, septal heart defects, and decreased size, were found to be relatively common in trisomy 21 fetuses as compared to controls. Other features were found to be less useful in identification. We conclude that the presence of two of the four features noted above is suggestive of trisomy 21 in the fetus.

Dermatoglyphics↗
PubMed1980

Teratogenic effects of retinoic acid in pigtail monkeys (Macaca nemestrina). II. Craniofacial features.

The teratogenic effects of retinoic acid, the alcohol-soluble acid form of vitamin A, on the craniofacial complex of 11 macaque (Macaca nemestrina) whose mothers had received the compound from days 20 to 44 are described. The fetuses ranged in gestational age from 81 to 185 days and exhibited features of the so-called retinoic acid syndrome (RAS). The syndrome includes both craniofacial defects and postcranial anomalies of the musculoskeletal and urogenital systems. The craniofacial anomalies were described with reference to gross external appearance and radiographic observations. The most frequent findings were cleft palate, malformed ears, hypertelorism, exophthalmos, hypoplasia of the bone of the mid-face and mandible, a curvature of the inferior border of the mandible, retrognathia, and distortion of the cranium. Lateral cephalograms on nine animals of the RAS sample were measured using six linear dimensions which define the cranial base, face height, palatal length, and mandibular length. The measurements were plotted relative to normal curves which describe growth of the dimensions through the macaque fetal period. For their age, the abnormal animals were small in the craniofacial region. The same measurements were then plotted relative to the size of the fetus, to investigate the possibility of a differential response of the various craniofacial areas to the teratogen. Mandibular length and anterior cranial base were the most reduced dimensions, followed by anterior and posterior face height, with palatal length the least affected. Comparison of the features of the RAS syndrome in the macaque fetus with those reported for various human mandibulofacial dysostosis syndromes yields similarities, but there are enough differences to indicate that the syndromes are not identical in the two species. The utility of the approach used, wherein several craniofacial dimensions of the abnormal are assessed relative to normal growth curves and relative to body size, is emphasized.

Abnormalities, Drug-Induced↗
PubMed1980

Reproductive studies in the iron-deficient rat.

Severe iron-deficient anemia was produced in the rat by diet. Controls consisted of animals raised on the same diet but injected with iron intraperitoneally. The deficient rats were bred and found to have normal numbers of corpora leutea of pregnancy and implantation sites. Resorptions were very common, and only about 25% of the deficient fetuses were viable on day 20. The peak mortality occurred on about day 12 of gestation. The viable fetuses were smaller than the controls, and a predominance of females was found. More eye defects occurred in the deficient groups, but a significantly increased gross defect rate over controls did not occur. The deficient maternal hemoglobins dropped during pregnancy, and the maternal and fetal hemoglobins on day 20 of gestation averaged 4.5 and 4.7 gm/dl, respectively. Partial treatment of the deficient animals by iron injection on days 0 and 7, or on day 7, prevented embryonic and fetal loss and partially corrected both fetal and maternal hemoglobin concentrations.

Anemia, Hypochromic↗
PubMed1979

Urethral obstruction malformation complex: a cause of abdominal muscle deficiency and the "prune belly".

Abdominal muscle deficiency with a "prune belly" abdomen as been a major feature of the so-called prune belly syndrome, which has been regarded as a specific entity, although the etiology and developmental pathology are not understood. We present evidence that abdominal muscle deficiency is an etiologically nonspecific anatomic defect which is secondary to fetal abdominal distention of various causes. One of the more common causes is urethral obstruction with consequent early bladder distention, causing abdominal distention and other anomalies, a constellation of findings which we have termed the urethral obstruction malformation complex. This interpretation of the etiology of most cases of prune belly syndrome accounts for the male predominance, the observed variability in severity, and the lack of a defined mode of inheritance. Recurrence risk figures need to be redefined for each specific obstructing lesion of the urethra. The possibility of early prenatal diagnosis and management of fetuses with urethral obstruction needs further study.

Abdominal Muscles↗