Biomedical subjects

G Millicovsky

Publications and source records attributed to G Millicovsky.

13 recordsLinked to original sources

PubMed1995

Spina bifida: role of neural tissue damage during pregnancy in producing spinal paralysis.

Spina bifida is one of the most common human birth defects. In fetuses with open spina bifida, the spinal cord remains exposed to the amniotic fluid (AF) throughout gestation. Results of prenatal examinations suggest that affected fetuses exhibit leg movement until the third trimester but become paralyzed later in pregnancy, several months after the initial spinal cord defect occurred. Clinical observations suggest that after the initial defect in neural tube closure, the spinal cord may be subjected to continuous, progressive damage related to contact with the AF. We urge clinicians and scientists to test the AF damage hypothesis by studying prenatal fetal activity in humans and through experimental studies. If this hypothesis is correct, the onset of spinal paralysis in affected fetuses may be prevented by protecting the spinal cord tissues before major nerve damage occurs. If the course of this disease process could be altered, both the patient and family would benefit from the reduction in the misery of the disabling neurologic condition as well as from the acute and long-term cost of medical care.

Amniotic Fluid↗

PubMed1994

Comparison of craniofacial growth after rigid fixation with autogenous bone plates and with metal plates.

This study was undertaken to determine whether rigid fixation using autogenous cranial bone grafts restricts craniofacial growth less than metal plates in 7-week-old Yorkshire pigs. A rectangular 10 x 20 mm segment of bone centered on the right coronal suture was resected. Animals were randomly assigned to one of three experimental groups: (1) rigid fixation across the defect using the bone graft rotated 90 degrees and attached with four microscrews; (2) rigid fixation across the defect using two microplates attached with four microscrews; or (3) no rigid fixation, with four microscrews placed to serve as radiologic markers. All animals were followed up with serial radiographs, and 8 months after the surgery direct measurements were performed on dry skull preparations. The greatest lengths were in the control group, followed by the bone plate and then the metal plate groups, but these differences were not statistically significant. The cranial width was significantly greater in the bone plate group, suggesting that a growth center may have been reoriented.

Animals↗

PubMed1985

Normal and abnormal development of the lip and palate.

Largely because fusion of the lip and the palate are developmental weak points, common facial clefts may arise in a great many ways, both experimentally and in man. However, we believe that the vast majority of human clefts have similar origins with minor variations. One must always question the appropriateness of animal models. Apparently appropriate animal models are giving us considerable insight into the manner in which genetic and environmental factors alter development and how they interact with one another in the developing embryo. These studies help us understand the nature of the multifactorial threshold concept as it applies to cleft lip and cleft palate, and they emphasize the potential importance of even "minor" environmental factors in determining on which side of the threshold for clefting an individual embryo may fall.

Animals↗

PubMed1984

Craniofacial development: the possible mechanisms for some malformations.

Normal craniofacial development is reviewed and some mechanisms in the fusion of mammalian facial 'processes' are discussed. The manipulation of environmental factors and effects of teratogens are related to genetic susceptibility of animal models, and extrapolated to craniofacial malformations in man.

Abnormalities, Drug-Induced↗

PubMed1984

Teratologic evaluation of ethylene glycol monobutyl ether in Fischer 344 rats and New Zealand white rabbits following inhalation exposure.

Timed-pregnant Fischer 344 rats and New Zealand White rabbits were exposed to ethylene glycol monobutyl ether vapors by inhalation on gestational days 6 through 15 (rats) or 6 through 18 (rabbits) at concentrations of 0, 25, 50, 100 or 200 ppm. The animals were sacrificed on gestational day 21 (rats) or 29 (rabbits). In rats, exposure to 200 or 100 ppm resulted in maternal toxicity (clinical signs, decreased body weight and weight gain, decreased absolute and relative organ weights, decreased food and water consumption and evidence of anemia), embryotoxicity (increased number of totally resorbed litters and decreased number of viable implantations per litter) and fetotoxicity (reductions in skeletal ossification). No increase in fetal malformations was observed in any exposure group relative to controls. At 50 or 25 ppm, there was no maternal, embryo or fetal toxicity (including malformations) in rats. In rabbits, exposure to 200 ppm resulted in maternal toxicity (apparent exposure-related increases in deaths and abortions, clinical signs, decreased weight during exposure and reduced gravid uterine weight at sacrifice) and embryotoxicity (reduced number of total and viable implantations per litter). No treatment-related fetotoxicity was seen. No treatment-related increased in fetal malformations or variations were seen at any exposure concentration tested. There was no evidence of maternal, embryo, or fetal toxicity (including malformations) at 100, 50 or 25 ppm in rabbits.

Abnormalities, Drug-Induced↗

PubMed1983

Effect of phenytoin on maternal heart rate in A/J mice: possible role in teratogenesis.

Phenytoin (diphenylhydantoin, Dilantin, PHT), an anticonvulsant and antiarrhythmic drug, is teratogenic to A/J mice, producing an increased incidence of cleft lip with or without cleft palate [CL(P)] and cardiac defects. Although its mechanism of teratogenic action remains unclear, one possibility may involve uterine ischemia resulting from an exaggerated depressant effect on maternal cardiovascular function. To test this hypothesis, the heart rate response of susceptible A/J and resistant C57Bl/6J mice was monitored following intraperitoneal injection of doses of PHT of known teratogenic potential. Heart rate (HR) was obtained electrocardiographically from unanesthetized, pregnant mice on day 10 of gestation via previously implanted subcutaneous electrodes. The HR of A/J mice was significantly depressed relative to vehicle-injected controls following doses of 40, 60, and 75 mg/kg, with the greatest effect occurring in the high-dose group. In C57Bl/6J mice, the HR response of the group treated with 75 mg/kg was not different from that of the vehicle-treated controls. At the same dose level, the depression of HR of A/J mice was significantly greater in magnitude and duration than that of C57Bl/6J mice. A proposed maternally mediated mechanism of CL(P) in A/J mice involving low placental/embryonic oxygen delivery is discussed. The results of the present study indicate the potential significance that changes in maternal physiology may have on embryonic development.

Abnormalities, Drug-Induced↗

PubMed1982

Developmental alterations associated with spontaneous cleft lip and palate in CL/Fr mice.

Cleft lip with or without associated cleft palate [CL(P)], one of the most common human malformations, is believed to be caused by a combination of genetic and environmental factors. To study the morphological manifestations of genetic factors in this interaction, we compared the embryonic development of the CL/Fr mouse strain (with a mean incidence of 36% spontaneous CL(P) in our colony) with that of the C57B1/6J mouse strain (with no CL(P) in our colony). Results from our scanning electron microscopic study demonstrated that, when compared with C57B1/6J embryos, CL/Fr embryos have several developmental differences including: 1) altered facial geometry, 2) depressed ability of the surface epithelium of primary-palate primordia to participate in the fusion process, and 3) variable hypoplasia of the lateral nasal prominences. We suggest that all of these alterations may contribute to the pathogenesis of CL(P) in the CL/Fr mouse strain.

Animals↗

PubMed1981

Effects of hydroxyurea on hemodynamics of pregnant rabbits: a maternally mediated mechanism of embryotoxicity.

Hydroxyurea is a cytotoxic agent used in the management of chronic granulocytic leukemia. This compound is teratogenic and embryolethal in various animal species, and has been widely used in experimental studies aimed at understanding the possible mechanisms of drug-induced malformations. Previous studies from our laboratory have demonstrated that maternal subcutaneous injections of hydroxyurea produce immediate circulatory alterations in rabbit embryos similar to those observed subsequent to uterine artery occlusion. The present study was designed to investigate the possibility that the embryolethal and teratogenic properties of hydroxyurea might be due to alterations in maternal hemodynamics, i.e., constriction of the uterine vasculature, resulting in exposure of the embryo to uterine ischemia at critical stage of in utero development. This study demonstrates that hydroxyurea significantly alters blood pressure and heart rate and produces significant uterine vasoconstriction. The resulting reductions in uterine blood flow (77%) elicited by hydroxyurea may be associated with its immediate embryotoxicity.

Abnormalities, Drug-Induced↗

PubMed1981

Maternal hyperoxia greatly reduces the incidence of phenytoin-induced cleft lip and palate in A/J mice.

The A/J mouse has been used to study the teratogenic affects of phenytoin. The developmental abnormalities produced in offspring of this model are similar to some of the malformations observed in cases of human "fetal hydantoin syndrome." Placing pregnant A/J mice in a hyperoxic chamber after phenytoin injection greatly reduces the incidence of phenytoin-induced cleft lip and palate. These results suggest that phenytoin may affect embryonic development indirectly by altering maternal physiology. This maternally mediated mechanism, and the protection against it afforded by hyperoxia, has general implications for the effects of maternal toxicity on teratogenesis.

Abnormalities, Drug-Induced↗

PubMed1981

Hyperoxia and hypoxia in pregnancy: simple experimental manipulation alters the incidence of cleft lip and palate in CL/Fr mice.

This paper describes alterations in the incidence of cleft lip and palate in CL/Fr mice subsequent to experimental manipulation of maternal respiratory oxygen levels during a critical period of pregnancy. Only a few previous studies have shown that the incidence of some "genetically determined" malformations in mammals can be decreased by environmental procedures. In addition to demonstrating a decreased incidence of cleft lip and palate subsequent to maternal hyperoxia on gestational days 10 and 11 in a genetically susceptible strain, the results of the present study show that hypoxia at this time increases the incidence of cleft lip and palate.

Animals↗

PubMed1981

Active role of embryonic facial epithelium: new evidence of cellular events in morphogenesis.

Epithelial cells of the C57B1/6J mouse embryo participate in a temporal sequence of events associated with the approximation, fusion and consolidation of components of the facial primordia into a definitive structure. These cells lose their surface microvilli, and after a brief period of quiescence they begin to fill the grooves separating facial constituents by producing a series of surface projections that increase in size and complexity as the process of fusion nears termination. Cessation of surface activity and the restoration of epithelial microville indicate the end of the temporal sequence. Significantly, the epithelial cells of primary palates of embryos with genetically-and phenytoin-induced cleft lip remain unchanged and do not participate in fusion. This epithelial sequence has not been described previously and we suggest that all of its steps may be critical to the normal development of the mammalian face.

Animals↗

PubMed1980

Cardiovascular alterations in rabbit embryos in situ after a teratogenic dose of hydroxyurea: an in vivo microscopic study.

The early cardiovascular (CV) responses of New Zealand white rabbit embryos in situ subsequent to maternal SC injection with hydroxyurea (HU) were analyzed by in vivo microscopic methods. Laparotomies were performed on gestational day 12, and the gravid uteri were exteriorized. The embryos were exposed by careful incisions of the uterine wall and reflection of the extraembryonic membranes. Temperature, water, and electrolyte homeostasis were maintained throughout all procedures. Maternal injection with HU at a teratogenic level (750 mg HU/kg) caused alterations in the embryonic CV system as early as 2 minutes post-treatment. Typically, within 4 minutes the embryonic craniofacial region responded with dilations of the anterior cardinal vein (ACV) and its tributaries. The ensuing pathological events included petechial hemorrhages and hematomas in the forebrain, postocular region, mandibular and nasal processes, and apparent collapse of the vasculature in the forelimb bud. Many embryos exhibited pericardial hemorrhage within 9 minutes. The most severely affected embryos displayed cardiac tamponade and stasis of blood flow through the cardiac chambers. In contrast, control embryos, which received either no drug treatment of SC injection of saline at various osmolarities and pH's, demonstrated none of the CV changes reported above, even after 120 minutes. Low doses of HU (500 mg/kg) produced only ACV dilations in some embryos by 30 minutes. Histologic analysis of HU embryos confirmed the in vivo microscopic observations. The drastic CV derangements exhibited by many embryos may be one of the causes for the high resorption rates associated with the treatment. Furthermore, since teratogenic doses of HU produce immediate hemorrhages and hematomas in the embryos in the same craniofacial areas which are later deformed in the term fetus, it is possible that the teratogenic action of this drug may be related to the initial vascular embryopathies.

Animals↗

PubMed1980

Differential embryonic cardiovascular responses to acute maternal uterine ischemia: an in vivo microscopic study of rabbit embryos with either intact or clamped umbilical cords.

The effects of acute episodes of maternal uterine ischemia on the cardiovascular system of New Zealand white rabbit embryos were studied by in vivo microscopic methods. On gestational day 12, gravid uteri were surgically externalized, and the walls of the implantation sites were carefully incised and reflected to reveal the embryos. Throughout all procedures, temperature, water, and electrolyte homeostasis were preserved. The embryos within each litter were divided into two groups: 1) two randomly selected embryos whose umbilical cords were clamped, and 2) the remaining embryos of the litter whose umbilical cords were uncompromised. Uterine ischemia was induced by clamping all uterine arterial and venous channels. Occlusion of the maternal uterine vessels produced severe uterine cyanosis within 1-2 min. The embryos whose umbilical cords were not clamped exhibited severe cardiovascular derangements beginning within 3-4 min. In contrast, the embryos whose umbilical cords were clamped (thereby interrupting both umbilical and vitelline circulations) had no observable cardiovascular alterations. The absence of effects in embryos with clamped umbilical cords suggests that acute episodes of hypoxia are well tolerated by young embryos. In contrast, the rapid appearance of cardiovascular derangements after interruption of maternal uterine circulation in embryos with unclamped umbilical cords emphasizes the idea that even brief intervals of uterine ischemia are deleterious to the rabbit embryo.

Animals↗