Sakharov and genetic science in the Soviet Union.
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Genetics↗
Biomedical subjects
M Melnick
Publications and source records attributed to M Melnick.
Editorial: Sakharov and genetic science in the Soviet Union.
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Genetics↗
Corticosteroid-induced abnormality in fetal mice and H-2 haplotype: evidence of a cytoplasmic effect.
Different strains of H-2 congenic mice have different susceptibilities to corticosteroid-induced fetal loss and cleft palate. Applying this knowledge, we tested the null hypothesis, which assumes that there are no statistically significant differences in the frequency of abnormality among various types of treated backcross offspring and, thus, no evidence of a cytoplasmic effect. In the present study this null hypothesis was frequently, but not consistently, rejected. Therefore, there was some evidence of a cytoplasmic effect. One possible explanation of these results is seen when one considers the phenotypic effects of "gene-gene interaction" between variant H-2 genotypes and an invariant mitochondrial genotype.
Abnormalities, Drug-Induced↗
H-2 haplotype and the embryotoxicity of serum from nonpregnant congenic mice.
Previous studies revealed a significant association between genes at or near the H-2 complex and fetal loss. Reasoning that the maternal serum might contain one or more unknown factors that are harmful to early embryonic or fetal development, or both, we performed an embryotoxicity screen using chick embryos and serum from nonpregnant C57BL/10Sn (H-2b) and B10.A/SnSg (H-2a) congenic mice. Serum from the strain with the higher frequency of fetal loss (C57BL/10 Sn) yielded a significantly greater frequency of chick abnormality, specifically neural tube malformation and death, than the serum from the strain with the lower frequency of fetal loss (B10.A/SnSg). Further, the C57BL/10 Sn serum demonstrated a highly significant dose-response. These results suggest that analogous studies may be profitable with women who have a history of chronic fetal wastage and/or offspring with neural tube defects.
Animals↗
Peer oppression in the Soviet Union.
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Emigration and Immigration↗
The effects of long-term fetal constraint in vitro on the cranial base and other skeletal components.
Recently it was suggested that some cases of premature closure of the sagittal suture in humans may be due to fetal head constraint. Using various modifications of the procedure for long-term shell-less cultivation of chick embryos, we sought to test the hypothesis that fetal head constraint may result in abnormalities of the cranial base and other skeletal structures of the head. Our experiments with various sized containers demonstrate that fetal constraint is associated with both deformation and malformation of the craniofacial skeleton, including the cranial base, squamosal, columella (stapes), and mandible. The severity of both deformation and malformation appears to be a function of the degree of fetal constraint. If, as some suggest, abnormality of the cranial base is the primary anomaly in craniosynostosis, then our results tend to support the fetal constraint hypothesis as one explanation of simple craniostenosis.
Animals↗
Maternal influences on congenital craniofacial malformations.
Congenital craniofacial malformations represent an extremely complex biomedical problem area. The complexity includes early detection, diagnosis, treatment, habilitation, and, of course, prevention. The genetic and environmental issues which appear to interact and result in congenital malformations are becoming better understood. Rapid advances in mouse and human immunogenetics indicate several possible explanations as to why some individuals acquire certain birth defects whereas other individuals do not express congenital malformations. Recent discoveries concerning the major histocompatibility complex (MHC) and associations with a number of human malformations have stimulated interesting speculations concerning genetic and environmental factors which might be responsible for predispositions to congenital malformations. Of particular interest is the possible function of the major histocompatibility complex of the mother during early stages of embryogenesis and how this assembly of genes may confer susceptibility to environmentally induced birth defects in mouse and human reproduction.
Abnormalities, Drug-Induced↗
Localization of H-2Kk in developing mouse palates using monoclonal antibody.
Using monoclonal antibodies to H-2Kk antigen, we sought to develop a reproduceable method of in situ localization in embryonic tissue and to determine whether there are specific patterns of H-2 localization in time and space in the developing palatal tissues of B10.A(H-2a) embryonic mice, with and without corticosteroid pretreatment at 12 days gestation. Our procedure employs ethanol-glacial acetic acid fixation, paraplast embedding, and enzymatic predigestion with purified hyaluronidase and neuraminidase. H-2 antigens were detected in palatal mesenchyme as well as basement membranes but not in oral or nasal epithelium. The pattern of distribution in mesenchyme of untreated embryos changed with progressive shelf development vertical leads to horizontal leads to epithelial fusion leads to epithelial seam degeneration leads to mesenchymal confluence. Although the palatal shelves of treated embryos remained vertical, corticosteroid treatment does not appear to alter the detectable spatiotemporal distribution of H-2 antigens in developing palates of embryonic B10.A mice.
Animals↗
Scientists as targets in the Soviet Union.
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Science↗
Corticosteroid-induced cleft lip in mice: a teratologic, topographic, and histologic investigation.
Unlike cleft palate, relatively few teratogens have been found to induce cleft lip in mice. The present study was designed to assess the teratologic, topographic (SEM), and histologic effects on lip morphogenesis following the administration of triamcinolone hexacetonide on the eighth day of gestation. The frequency of cleft lip in treated A/J mice was found to be more than three times greater than the spontaneous frequency in untreated controls. Comparable studies with other murine strains suggest no association between the cleft lip response and either a maternal effect or the H-2 complex. Affected A/J embryos showed a severe reduction in the size of the lateral nasal processes; affected embryos also demonstrated localized cell type-specific alterations, particularly in the epithelia and at the interface between epithelium and mesenchyme.
Abnormalities, Drug-Induced↗
The association of H-2 haplotype with implantation, survival, and growth of murine embryos.
Using three congenic strains, C57BL/10Sn(H-2b), B10.A/SnSg(H-2a), and B10.D2/nSn(H-2d), we sought to investigate the possible association of H-2 haplotype with the number of implants, fetal survival, and fetal weight, as well as to analyze the possible effects of hybrid vigor and maternal-fetal histoincompatibility in primigravidae mice. The results of this study indicate a significant association between genes at or near the H-2 complex and both fetal loss and fetal weight, but not the number of implants. Haplotype variation accounted for 14 percent of the variation in fetal loss and 20 percent of the variation in fetal weight. With the exception of fetal loss, there was no evidence of a maternal effect. There was also no clear evidence of hybrid vigor or histoincompatibility effects for any of the three variables studied. In summary, the data suggests that particular allelic variants at or near the H-2 complex confer some selective advantage as measured by differential fetal survival and fetal growth.
Animals↗
Corticosteroid-induced cleft palate in mice and H-2 haplotype: maternal and embryonic effects.
This report confirms and expands on the original preliminary observations made by Bonner and Slavkin that corticosteroid-induced cleft palate in mice is associated with H-2 haplotype. Using three congenic strains, B10, B10.A, and B10.D2, our studies demonstrate that B10.A (H-2a) is most susceptible and B10.D2(H-2d) is least susceptible, B10(H-2b) being intermediate. Variation in fetal loss among strains accounts for less than 1 percent of the variation in cleft-palate frequency among strains; variation in H-2 haplotype, however, accounts for more than 60 percent of the variation in cleft-palate frequency. With regard to all possible reciprocal F1 hybrids, our results indicate that while there is a significant maternal effect, maternal haplotype can account for only 11 percent of the variation in cleft-palate frequency among crosses. Embryonic haplotype accounts for 17 percent of the variation, which is indicative of an important embryonic effect. Finally, our studies suggest that susceptibility to corticosteroid-induced cleft palate is associated with the K end of the H-2 complex.
Adrenal Cortex Hormones↗
Spatiotemporal patterns of fibronectin distribution during embryonic development. I. Chick limbs.
It has been suggested that an extracellular matrix - and cell surface - associated glycoprotein, fibronectin, plays a role in the positioning of cells in morphogenesis and in the maintenance of orderly tissue organization. In the present study the appearance and distribution of fibronectin during in ovo chick limb development has been investigated by indirect immunofluorescence techniques in H.H. stages 20-30. Fibronectin is not detectable until just prior to the transition from the morphogenetic to the cytodifferentiation phase of development. Beginning at H.H. stage 25, successive nonrandom patterns of fibronectin detection and distribution, which resemble the subsequent cartilaginous elements, precede overt chondrogenesis as detected by Alcian blue staining. This corresponds to the onset of the cytodifferentiation phase of limb development. As the accumulation of acidic proteoglycan increases in the cartilage matrix and the mesenchymal cells become more round in appearance, the presence of detectable fibronectin decreases and is ultimately seen only in the perichondria and basement membrane. However, predigestion of developed cartilage tissue with testicular hyaluronidase, prior to fibronectin staining, indicated that fibronectin remains a major constituent of cartilage matrix and is apparently masked by cartilage-specific proteoglycans. This study of chick limb development is consistent with the hypothesis that fibronectin may be a molecule that facilitates the spatial organization of cartilaginous primordia cytodifferentiation.
Animals↗
Spatiotemporal patterns of fibronectin distribution during embryonic development. II. Chick branchial arches.
It has recently been demonstrated with the chick limb in ovo that successive nonrandom patterns of fluorescent staining with specific antibodies to fibronectin indicate the cartilagenous primordia prior to overt chondrogenesis. Given the apparent nonequivalence of embryonic cartilages, the purpose of this study was to determine whether this phenomenon was unique to developing chick limbs or is a more general characteristic of chondrogenesis. The appearance and distribution of fibronectin during chick first and second branchial arch development in ovo was investigated by indirect immunofluorescence techniques in H.H. stages 15-26. Fibronectin can be detected in early stages in areas presumed to be composed mainly of ectomesenchyme. During later stages of development, successive nonrandom patterns of fibronectin distribution appear to precede overt chondrogenesis as demonstrated by alcian blue staining. Pretreatment of cartilage with testicular hyaluronidase, prior to fibronectin staining, revealed that fibronectin was still present, suggesting that it was masked by proteoglycans. Fibronectin was also detected in the developing membrane bones of the mandible. The nonrandom patterning of fibronectin distribution in ovo in chick branchial arches and limb buds, respectively derived from neural crest and somatic mesoderm, were similar. It appears that specific patterns of fibronectin distribution were characteristic of chondrogenesis, regardless of the embryonic origin of the cartilage. This phenomenon may prove to be an extremely useful probe for early developmental skeletal abnormalities.
Animals↗
Scanning electron microscopy of teeth in dominant osteogenesis imperfecta: support for genetic heterogeneity.
Scanning electron microscopic studies were performed on 25 deciduous and permanent teeth from members of 7 kindreds with dominant nonlethal osteogenesis imperfects (OI). Two families had normal teeth on clinical and radiological examination; five families had blue or brown opalescent teeth with specific radiologic findings. Enamel surfaces and prism organization were normal on all teeth. On fractured surfaces, the dentin tubules of normal teeth from patients with OI were evenly distributed and coursed regularly to the dentin-enamel junction. Opalescent teeth had few tubules and those present were short, narrow, and tortuous. Dentin calcification fronts of normal teeth were composed of many nodules with regularly spaced openings on their surfaces. Calcification fronts of opalescent teeth were composed of irregularly spaced, small nodules, which varied greatly in size and the nodules lacked tubule openings on their surfaces. The results of this study support the concept that at least two dominant forms of OI exist--one in which all individuals with IO have normal teeth, and the other in which all with OI have blue or brown opalescent teeth with characteristic changes on SEM.
Dental Enamel↗
Cleft lip+/-cleft palate: an overview of the literature and an analysis of Danish cases born between 1941 and 1968.
In recent years there has been some controversy over the analytical designs and the meaning of varying results with regard to studies of facial clefting and other common congenital malformations. Regardless, it is still unclear as to the nature of the genetic and environmental components of the etiology as well as the nature of the relevant pathogenetic mechanisms. Despite claims to the contrary, the predictions of a particular multifactorial/threshold inheritance (MF/T) model delineated by Carter [1977d] and others are not well supported by studies worldwide. The present study population consists of 1,895 persons born in Denmark with cleft lip with or without cleft palate (CL +/- P) between 1941 and 1968. A test of the MF/T predictions revealed the following: 1) the incidence of CL +/- P in siblings was 40 X greater than that in the general population 2) the risk to siblings of CL +/- P females was not significantly different from the risk to siblings of CL +/- P males; 3) recurrence risk for siblings of CL +/- P probands was dependent upon the proband's cleft type; 4) only 0.4% of the variation in risk to the siblings born after the proband could be accounted for by the number of previously affected siblings; 5) the consanguinity rate was 6 times less than the general population rate; 6) heritability estimates from siblings and parents by sex suggest, either the presence of significant dominance effects, or a common sibling environment component in the etiology of the disorder. Further, testing with a multiple-sex threshold method, designed and provided us by [Kidd and Spence, 1976] revealed that neither the MF/T nor single-major locus with random environmental variation provided a good fit. In light of recent experimental mouse and human data, an alternative model of monogenic-dependent susceptibility to a variety of teratogens is discussed.
Cleft Lip↗
Dentin dysplasia type I: a scanning electron microscopic analysis of the primary dentition.
Dentin dysplasia type I (DD-I) is a rare autosomal dominant disorder which affects both the deciduous and permanent dentitions. The affected deciduous and permanent teeth have short conical roots with sharp, apical constrictions and frequently periapical radiolucencies in the absence of caries. Apical to a thin layer of normal coronal dentin are large, calcified, dentin masses which nearly obliterate the pulp chamber and canals. Presented here are light microscopic and scanning electron microscopic observations of deciduous teeth from three unrelated persons with the disorder. In general, the deciduous teeth had (1) normal enamel, (2) a thin layer of normal dentin adjacent to the dentinoenamel junction, (3) a crescent-shaped pulpal remnant below the normal dentin, (4) dysplastic dentin masses (ranging from atubular to a few small tubules) between which are spaces presumed to previously have contained smaller remnants of the original mesenchymal dental papilla, and (5) root dentin, which is dysplastic throughout. The SEM-defined phenotype, however, was noticeably variable among all three persons. Based on the current concepts of tooth morphogenesis, it is most likely that the abnormal root morphology of DD-I teeth is secondary to the abnormal differentiation and/or function of the ectomesenchymally derived odontoblasts.
Adult↗