bluuebunny/crossref_metadata_2025_split huggingface dataset:
Origins of congenital heart disease: An epidemiologic perspective
Authors: Miller Robert W. 
Published: June 2005

AbstractAs is true for laboratory or clinical research, epidemiology can either generate or test hypotheses about the origins of disease. In so doing with respect to cardiac anomalies, rubella virus was identified as an environmental cause and the role of genetics has been clarified. Microscopically visible chromosomal aberrations have been related to high rates of diverse cardiac defects in Turner's and autosomaltrisomy syndromes. Submicroscopic genetic defects may also produce heart anomalies, as in Marfan's syndrome. The role of inheritance in the production of cardiac malformations in general, however, appears to be small as indicated by studies of twins (only 1 of 6 series revealed an elevated concordance rate in identical pairs) or by studies of the effect of consanguinity. Yet a wide variety of congenital heart disease has been repeatedly found to occur excessively in families. Future research must evaluate whether these occurrences are determined pre‐ or postzygotically. By so doing the origins of sporadic cases may be elicited. The possibilities include submicroscopic chromosomal abnormalities, chemical or microbial agents that interfere with normal embryonic development, and combinations of these factors. Through the use of existing data resources epidemiologic research can help to identify the influence of each. Although computer technology has its value, etiologic insight, which can be tested by the epidemiologic method, seems more likely to come from observations made by physicians at the bedside.
Potentiation of the teratogenic effects of 5‐fluorouracil by natural pyrimidines I. Biological aspects
Authors: Wilson James G. , Jordan Robert L. , Schumacher Herbert 
Published: June 2005

AbstractThe uracil analogue 5‐fluorouracil (5‐FU) administered alone on day 9 of rat gestation was nonteratogenic at a dose of 10 mg/kg but highly teratogenic at 20 mg/kg. Simultaneous administration of the natural pyrimidine bases uracil (U) or thymine (Th) and the lower dose of 5‐FU was highly teratogenic and simultaneous administration of U or Th and the higher dose of 5‐FU was totally embryolethal, i.e., all litters resorbed before term. Uridine and thymidine given with 5‐FU had a similar effect but were less potent. The nucleotide thymidine monophosphate at greater than a molar equivalent dose failed to have this effect. The potentiative effect was reduced after a 1‐hour interval and virtually absent after a 3‐hour interval between injections of the analogue and natural base. When carbon tetrachloride was used to cause generalized damage to liver tissue a striking increase in teratogenic effect occurred, indicating that the intact liver tends to protect the embryo by catabolizing 5‐FU.Studies with 14C‐labeled 5‐FU showed that a significantly greater amount of 5‐FU reached the embryo when the analogue plus U was administered than when the analogue was given alone. It is assumed that nonspecific pyrimidine‐degrading enzymes in maternal liver were temporarily saturated by the combined concentrations of 5‐FU and U, and hence the effect was tantamount either to increasing the dose of teratogen or decreasing liver function. This supposed action by hepatic enzymes is supported by data presented in the following paper in this journal.
Potentiation of the teratogenic effects of 5‐fluorouracil by natural pyrimidines. II. Biochemical aspects
Authors: Schumacher Herbert J. , Wilson James G. , Jordan Robert L. 
Published: June 2005

AbstractThymine (Th), uracil (U), and the antimetabolite 5‐fluorouracil (5‐FU) are metabolized in vitro by rat liver enzyme systems present in the high‐speed supernatant soluble cell fraction. The data presented demonstrate that addition of either U or Th to such preparations or the use of livers from rats pretreated intraperitoneally with U or Th markedly decreases the ability of liver preparations to metabolize 5‐FU. These findings indicate that the decreased elimination from the body of a teratogenic dose of 5‐FU after treatment with an equimolar dose of U is due to the inhibition of metabolism of the antimetabolite in the maternal liver.The concomitant administration of the natural pyrimidines Th or U with 5‐FU resulted in prolonged high serum levels of the teratogen 5‐FU, which tended to enhance transfer to and uptake by the embryo. Since the embryo was unable to dispose of 5‐FU metabolically, prolonged high levels of 5‐FU would be expected to cause increased teratogenic effects. Studies with labeled 5‐FU revealed that most of the radioactivity found in the embryos was incorporated into RNA, with only about 30% in the TCA ex tract. Concomitant treatment of pregnant rats with 5‐FU and U had greater inhibitory effect on the incorporation of formate into the methyl group of DNA thymine in the embryo than treatment with 5‐FU alone. This treatment inhibited thymidylate synthetase more than an equimolar dose of 5‐FU alone. Neither treatment affected the high kinase activity of the embryo.
In vitro study of rat embryos. I. Effects of decreased oxygen on embryonic heart rate
Authors: Shepard Thomas H. , Tanimura Takashi , Robkin Maurice 
Published: June 2005

AbstractTo study directly the effects of hypoxia on the mammalian embryo, rat embryos at the 14‐, 22‐, and 35‐somite stages were explanted into the in vitro system of New. The initial heart rates in the three groups did not differ. With hypoxia the 22‐ and 35‐somite embryos responded with a prompt heart‐rate drop but no significant effect was found in the 14‐somite embryos. Irreversible sludging of yolksac circulation was associated with death in the older embryos.
Transplacental infection of rats and hamsters induced by oral and parenteral inoculations of H‐1 and rat viruses (RV)
Authors: Kilham Lawrence , Margolis George 
Published: June 2005

AbstractAn aim of the present investigations was to use recently isolated strains of H‐1 and RV, which had been subjected to a minimum of laboratory passages, to induce transplacental infection orally in order to replicate natural infections in rats, the natural hosts, as well as in hamsters, which are subject to “spontaneous” infection with these agents. H‐1 virus had a remarkable ability to penetrate both the gut wall and placental barrier and infect fetuses within 24 hours of oral inoculation of pregnant hamsters, whereas such infections could be induced in rats only by parenteral inoculation. However, rats were susceptible to fetal infection with RV given orally. The pathogenesis of infection was somewhat different with the two viruses. RV, in contradistinction to H‐1, proliferated in maternal organs and possibly in the placenta for several days before invading the fetus. Both H‐1 and RV were alike in being transported in the blood in close association with erythrocytes. All fetuses invaded by either agent developed widespread infections prior to death as shown by the presence of intranuclear inclusions and cytolytic effects. Placentas remained intact and viable even after resorption of attached fetuses. The health of all mother animals was unaffected. One special strain — HHP — was the only RV strain to induce transplacental infection orally in hamsters. The various attributes of these parvoviruses that make them particularly favorable agents for the study of transplacental infections are discussed.
Prolonged gestation in the rat and its usefulness in experimental teratology
Authors: Barrow Mark V. , Rowland Carol A. 
Published: June 2005

AbstractAfter ascertaining that intrauterine growth and maturation continue when pregnancy is prolonged with progesterone in Sprague‐Dawley rats this technique was combined with the teratogens chlorcyclizine, vitamin A, and β‐aminopropionitrile (BAPN), to study the effects of 2 to 3 extra days of intrauterine growth on various abnormalities. Females were killed on day 21 or, if treated with progesterone, on day 24 of gestation. Untreated animals served as controls.In the day‐24 chlorcyclizine group, edema and hydronephrosis were either as severe as or more marked than in the day‐21 group and the testes remained near the kidneys rather than descending deep into the pelvis. Vertebral calcification, usually not present on day 21, had occurred by day 24. These findings suggest that edema, hydronephrosis, and undescended testes were probably permanent defects, whereas lack of calcification was due to delay in occurrence. The smaller dose of vitamin A produced facial abnormalities ranging from marked underdevelopment of the mandible to relative prognathism in day‐21 fetuses but mostly prognathism in day‐24 fetuses; whereas the higher dose produced severe underdevelopment of the jaws and decrease of skeletal calcification in young of both age groups. Severe limb malformations, noted in day‐21 fetuses after high doses of vitamin A, were not grossly altered by prolonging pregnancy. BAPN‐induced limb malformations and gibbus deformities noted on day 21 were still present on day 24.
Tooth anomalies in the oral‐facial‐digital syndrome
Authors: Lauterstein Aubrey M. , Pruzansky Samuel 
Published: June 2005

AbstractThe relation of alveolar clefts to morphogenesis of teeth in the line of the cleft was explored. The oral‐facial‐digital (OFD) syndrome is a unique experiment of nature wherein the position of the cleft is posterior to where it occurs in the more common types of cleft. In the latter the cleft occurs anterior to the maxillary canine and affects the number and form of the lateral incisor. In the OFD syndrome the cleft occurs posterior to the canine with duplicate canines, sometimes “T”‐shaped, occurring on either side of the alveolar cleft. These findings suggest a common timespace relation between alveolar clefting and tooth‐bud formation, probably occurring in the sixth week of embryonic life.
Teratogenic effects of carotid ligation on the developing dentition of the rhesus monkey
Authors: Kraus Bertram S. , Myers Ronald E. , Clark Gerald R. 
Published: June 2005

AbstractThe common carotid arteries and jugular veins were bilaterally ligated in three rhesus monkey fetuses, each of 65 days gestational age, which were then restored to the uterus and allowed to reach full term. At birth the animals were killed and the tooth crowns were extracted. There were numerous morphological abnormalities of the crown and in many instances the crowns were markedly smaller than those of a nonligated series of full term offspring. Several types of the abnormalities were similar to those observed in human subjects afflicted with cleft lip and/or palate, Down syndrome (“Mongolism”), and rubella syndrome. Since rhesus monkey and human dental crowns have many developmental and morphological traits in common the use of this animal as an experimental model in the investigation of normal and abnormal crown development is indicated.
Growth of postimplantation mouse embryos cultured in a serum‐supplemented, chemically defined medium
Authors: Clarkson S. G. , Doering J. V. , Runner M. N. 
Published: June 2005

AbstractThe isolated mammalian embryo is a relatively unexploited developmental system for studying early somite stages: the embryonic period of greatest susceptibility to teratogenesis. The mouse embryo offers sufficient advantages for such studies that a short‐term culture procedure was adapted for early postimplantation stages (Witschi stages 14 or 15 corresponding to one to 12 somites). Criteria for growth in vitro demonstrated that quantitative determinations of DNA, RNA and protein content consistently correlated with morphological end points.A medium comprising 20% rat serum in Waymouth's MB 752/1 supported better development and net macromolecular synthesis than did media containing 0, 10 or 100% rat serum. Embryos in the 20% serum‐supplemented medium approximately doubled their nucleic acid and protein contents during 22 hours in culture. This increase corresponds to roughly 60% of the growth of embryos in vivo and should permit biochemical investigations to be made of the early effects of teratogenic treatments.
Resorption in guinea pigs as estimated by counting corpora lutea: The problem of twinning
Authors: Hoar Richard M. 
Published: June 2005

AbstractNormal pregnant guinea pigs were killed on gestation days 12–20 and examined for implantation sites and resorbing embryos. Their ovaries were removed and serially sectioned, and the functioning corpora lutea counted for comparison with the number of conceptuses.It was found that a single corpus luteum was associated with two implantation sites with a frequency of 9.55%. Embryonic loss prior to implantation was 12.6% and the value for resorption following implantation varied from 5.8 to 7.2% depending on the time of killing and the method employed for determining resportion. A count of functioning corpora lutea facilitated the determination of embryonic loss prior to implantation, but offered little advantage over simpler techniques for determining resorption after implantation.
Correlation of embryonic movement with palate closure in mice
Authors: Walker Bruce E. 
Published: June 2005

AbstractPrevious experiments on palate development led to the hypothesis that neck extension and movements of the lower jaw and tongue are necessary for palate closure. To see if such movements existed at the appropriate developmental stage living embryos were studied at the time of normal palate closure. Spinal cord sections were performed on pregnant mice to permit laparotomy without sedating the embryos, the mice were partially submerged in warm saline, and embryonic movements were observed and photographed. Onset of movement coincided temporally with the onset of palate closure. In addition to movements of limbs and trunk, movements of neck, lower jaw, and tongue were also seen. Activity of embryos could be detected within the intact uterus as well as after removal from the uterus and membranes, and was inhibited by ether. The movements appeared to be spontaneous. These observations are consistent with the hypothesis that the mechanism of palate closure involves muscular movements by the embryo.
Studies of the growth‐inhibitory action of cortisone on chick embryos
Authors: Badran Amado , Provenza D. Vincent 
Published: June 2005

AbstractA histological study of the action of cortisone on developing chick embryo tibial cartilage revealed that the chondrocytes were smaller and the intercellular substance was diminished. Autoradiographic experiments demonstrated less accumulation of 35S in the diaphysis of cortisone‐treated cartilage, but not in the metaphysis or epiphysis.
Teratogenic effects of vincristine in three lines of mice
Authors: Joneja M. , Ungthavorn S. 
Published: June 2005

AbstractPregnant DBA/2J, C3H/HeJ, and ICR/Ha mice were injected intraperitoneally with vincristine sulfate on day 9 of gestation. The mothers were killed on day 17 and the fetuses were examined for various defects. A high incidence of fetal mortality, congenital anomalies, and growth retardation was induced in all three types of mice. DBA's were most susceptible to the teratogenic effects of the drug. Anomalies involved the central nervous system, eyes, limbs, tail and ribs, and most fetuses had more than one anomaly. Most of the types of anomalies observed were similar to those reported in rats, but dose required to produce malformations was much higher than that reported for rats, hamsters and monkeys.
Congenital defects in guinea pigs: Prenatal retardation of brain growth of guinea pigs following hyperthermia during gestation
Authors: Edwards M. J. 
Published: June 2005

AbstractHyperthermia was induced in pregnant guinea pigs for 1 hour on 2, 4, or 8 consecutive days between days 4 and 67 of gestation. Mean newborn brainweight was reduced substantially and incidence of micrencephaly increased following hyperthermia on 4 or 8 successive days during days 15 to 32, and apparently to a lesser degree following exposure on days 39 to 46, and 53 to 60 of gestation. Maternal hyperthermia at other than these periods was associated with little or no reduction in mean brainweight or increase in incidence of micrencephaly. Following hyperthermia on 2 successive days during days 14 to 31 of gestation the incidence of micrencephaly was increased and mean brainweight decreased in offspring from females heat stressed on days 16–17, 20–21, 22–23, and 24–25. The effects of hyperthermia on brain growth were most marked on days 20–21 or 22–23. Following 1 hour of maternal heat stress on day 21 of gestation, brainweight of newborn animals was reduced if maternal body temperature was elevated more than 2.5°C above normal. For each 1°C elevation in body temperature above this level brainweight was reduced by approximately 8.4% compared with control values.
Congenital eye defects in the mouse. II. The influence of litter size, litter spacing, and suckling of offspring on risk of eye defects in C57BL mice
Authors: Pierro Louis J. , Spiggle Jean 
Published: June 2005

AbstractEye defects including corneal capacity, microphthalmia, cataract, and anophthalmia occur spontaneously in C57BL mice. Breeding experiments with substrain C57BL/10ChPr described in the present report indicated that the probability of inclusion of animals with eye defects in litters subsequent to the first is influenced by litter spacing, litter size, and suckling of offspring. Second and third litters were as likely to include progeny with eye defects as were first litters if they resulted from matings taking place after weaning of the previous litter or if the mother was prevented from suckling her previous litter. If the gestation period overlapped with suckling of young from a previous litter the resulting litter contained fewer offspring and animals with eye defects were less likely to be included. Reduction in litter size appeared to result from embryonic losses prior to the time of implantation. The prevalence of overlap between gestation and suckling of young, in matings used for stock maintenance, led to an apparent decline with increasing litter rank in the frequency of litters that included progeny with eye defects.
A model in comparative teratogenesis. II. Response to 5‐fluoro‐2‐deoxycytidine at successive stages in organogenesis of mice of strains C57BL/6JHanFfm and C57BL/10JFfm– + ld
Authors: Fränz J. , Degenhardt K.‐H. 
Published: June 2005

AbstractTen mg/kg 5‐fluoro‐2‐deoxycytidine (FCdR) was given intraperitoneally to pregnant mice of the inbred C57BL/6JHanFfm and C57BL/10JFfm‐ + ld strains once at successive stages of organogenesis. Near‐term fetuses were analyzed for gross and skeletal malformations. The following observations were made. (1) The critical period for eye defects occurred at stages IV–X with a maximum response at stages VIII:18 for C57BL/10− + ld and IX for C57BL/6. Females were more often affected than males, and right eyes more often than left. (2) The critical period for the vertebral column was at stages VI–XII with maximum response at stages IX–XI for vertebral bodies and neural arches and IX for ribs. (3) Limb primordia reacted at stages VIII:18–XII, with two peaks of maximum response at stages IX and XI. (4) Skull primordia reacted at stages VI–IX with no clear peak of maximum response. The types of malformations were described. They were found to be nonspecific for FCdR. Strain differences regarding times of maximum response were explained by the different rates of intrauterine development. Concerning the sporadic malformations seen in controls and at a higher rate and severity in the experimental series, it was concluded that FCdR changed the threshold for these genetically determined defects.
Variations in development of the caudal neural tube in human embryos (Horizons XIV–XXI)
Authors: Lemire Ronald J. 
Published: June 2005

AbstractEight human embryos of Streeter's Horizons XIV to XXI were examined with respect to variations in caudal neural tube development after closure of the posterior neuropore in Horizon XII. A major aspect of this development appears to be a process of “canalization” (accessory lumens coalescing from the differentiating caudal neural cell mass), which corresponds to such occurrences in the chick and rat. Some degree of obliteration of the central canal was found in four embryos.The relation of these observations to clinical entities is discussed. There is suggestive evidence that open lesions of the spine may be associated with failure of closure of the posterior neuropore. In contrast, normal‐skin covered lesions probably arise from neural tube formed from the differentiating caudal cell mass after Horizon XII. This hypothesis could explain the distribution of lesions seen in newborn children.
A maternal effect on the frequency of spontaneous cleft lip in the A/J mouse
Authors: Davidson J. G. , Fraser F. C. , Schlager G. 
Published: June 2005

AbstractFemale mice of the inbred C57BL/6 strain were crossed to males of the A/J strain. F1 females were backcrossed to A/J males, the backcross females were crossed to A/J males, and so on for six backcross generations. In each generation a reciprocal backcross was obtained by crossing the hybrid males with A/J females. The following conclusions were drawn: (1) Spontaneous resorption in the C57BL/6 strain is determined in part by genes, recessive to their alleles in the A/J strain, which act in the mother, rather than the fetus. (2) The predisposition to spontaneous cleft lip in the A/J strain shows multifactorial inheritance. In the backcrosses, where the picture is not complicated by the maternal effect, the frequency of cleft lip reached the A/J level only in the sixth backcross. (3) In each backcross generation (hybrid mother) the cleft lip frequency was lower than in the genetically similar reciprocal backcross (A/J mother); thus the A/J mother contributes to the fetal susceptibility to cleft lip, either by providing an appropriate uterine environment or by not providing a factor, present in the C57BL strain, that decreases susceptibility to cleft lip.
Morphology and embryology of duplicitas posterior mice
Authors: Center Elizabeth M. 
Published: June 2005

AbstractThe duplicitas posterior syndrome, which involves both duplication and reduction of structures in the posterior region of the mouse, was investigated with reference to the morphology and embryology of its various manifestations. The four principal categories of external anomalies are (a) reduction of a hindleg, (b) reduction of a hindleg and development of an extra leg, (c) duplication of hindlimbs, and (d) kinking of the tail. The skeletal elements of the hindlimb girdle and vertebral column caudal to the thoracic region are involved. Various abnormalities of the urinary tract, male genital tract, and posterior end of the hindgut also occur. It appears from study of embryological stages of 10 to 16 days' gestation that the primary definitive effect is on the caudal end of the neural tube. Bifurcation of and apparent budding off from the primary neural tube of an accessory neural tube with accompanying limb and tail involvement are found. This doubling process may be preceded by prior subdivision of chordamesodermal tissues. The abnormalities of the urogenital and hindgut tissues are probably secondary to the duplication of axial and appendicular elements. Genetic tests indicated that the syndrome has a multifactorial basis, probably involving at least two recessive genes.