official journal of Congeital Anomalies Research Association of Japan
Online ISSN : 2433-1503
Print ISSN : 0037-2285
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Congenital Anomalies
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  • 1989 Volume 29 Issue 4 Pages 275-294
    Published: 1989
    Released: July 22, 2021
    JOURNALS OPEN ACCESS
    ABSTRACT The developmental process of cerebellar hypoplasia was investigated in homozygous (j/j) Gunn rats (born from heterozygous (+/j) mothers) with hereditary hyperbilirubinemia by light microscopy of Epon-embedded sections and Golgi preparations, electron microscopy and immunofluorescence with anti-S100 protein immune serum. No abnormalities were found in the cerebellar cortex at postnatal day 1. But at day 3, some Purkinje cells contained whorled membranous inclusions,. enlarged Golgi cisternae and vesicles, and/or dilated endoplasmic reticulum. Membranous inclusions filled the cytoplasm of a large number of Purkinje cells at day 10. These severely damaged Purkinje cells died and disappeared by day 30. The remaining Purkinje cells contained only a few membranous inclusions at day 30. At the adult stage, membranous inclusions were no longer detected in the remaining Purkinje cells. In these Purkinje cells, the dendrites were poorly developed and primitive synaptic junctions with parallel fibers were occasionally found on the dendritic shafts even at the adult stage. The perisomatic processes were often present on the remaining Purkinje cell soma from day 18 to the adult stage and were in synaptic contact with climbing fibers. The external granular layer was thinner in j/j than in +/j rats without hyperbilirubinemia at days 12 and 15 and disappeared at day 18 in j/j rats, i.e., earlier inj/j than in +/j rats. The molecular layer was thinner at day 10 and became slightly thicker thereafter. Cells in the molecular layer were scarce after day 12. The internal granular layer was thinner after day 12. An insufficient number of cells in the internal granular layer was apparent after day 12. Bergmann glia cells were hypertrophied after day 10 and filled the spaces where Purkinje cells had dis- appeared. Subsequently, Bergmann fibers and astrocytes in the internal granular layer were hypertrophied after day 15. Thus, in the developmental process of cerebellar hypoplasia in j/j Gunn rats, Purkinje cell damage preceded the histogenetic abnormalities of the cortex including astrocytic changes.
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  • 1989 Volume 29 Issue 4 Pages 295-308
    Published: 1989
    Released: July 22, 2021
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    ABSTRACT Pregnant female rats of the Fischer344 (F344/Du Crj) strain were ex- posed to gamma-ray radiation of 1.46Gy on day 15 of gestation (vaginal plug = day 0). When male offspring of control and irradiated dams matured, they were trained with various avoidance conditioning paradigms. In the avoidance acquisition paradigm in which one of the tone-on and lights-off signals was presented with predetermined random sequences, the irradiated group had lower overall rates of active avoidance responding than controls. In the go/no-go (active-passive) discrimination avoidance paradigm after rats learned only active avoidance responses to these two different signals, irradiated rats established stable active avoidance rates under the go (tone-on) signal, while they decreased gradually the rate of passive avoidance responding to the no-go (lights-off) signal as the amount of discrimination training increased. In the standard avoidance acquisition paradigm in which only the lights-off signal was used, the irradiated group also was inferior in active avoidance learning to controls. However, the irradiated group showed a high level of anticipatory responding, which was maintained in avoidance conditioning paradigms even though no shock-avoidance contingency was operating. These results indicated that poor associative ability for the warning signal and the shock might result in the active avoidance learning deficits in irradiated rats, and that active responding was more persistent and passive responding declined due to response excitation within a shock paradigm over the subsequent further training.
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  • 1989 Volume 29 Issue 4 Pages 309-320
    Published: 1989
    Released: July 22, 2021
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    ABSTRACT Evaluation of data on the frequency of severe mental retardation among prenatally exposed survivors of the atomic bombing of Hiroshima and Nagasaki, and the performance of such survivors on intelligence tests and in school has shown the most striking effects on the developing brain of exposure to ionizing radiation to occur among those individuals exposed in the 8th through the 15th, and the 16th through the 25th week after fertilization. This is true under the earlier T65DR and the newer DS86 systems of dosimetry. Seizure data have also revealed a significant effect of radiation in the 8-15 week period after fertilization. Although the observed frequency of severe mental retardation in the 8-15 week period can be satisfactorily described by a linear no-threshold model with both dosimetries, there is some suggestion of a threshold in the low dose region with the DS86 uterine absorbed doses but not with the T65DR fetal absorbed doses. However, the location and even the existence of a threshold in these weeks after fertilization is difficult to demonstrate statistically with the DS86 uterine absorbed doses. If the threshold is estimated using all 19 cases of mental retardation within these weeks, the lower bound of the confidence interval of the estimate includes zero, and thus a threshold cannot be convincingly established. However, when we exclude two probable nonradiation-related cases of Down’s syndrome, the results suggest a threshold with a lower bound in the 0.10-0.20 Gy region. Both dosimetries indicate a threshold in the dose-response function for mental retardation in the 16-25 week period, probably in the 0.23-0.70 Gy interval. The seizure data provide no persuasive evidence of a threshold in the 8-15 week period after fertilization; the 95% lower bound of the estimate of the threshold includes zero. Finally, although the mean IQ scores, and the mean school performances in the low dose region are similar to the values in the control group, particularly so with doses under 0.10 Gy, evidence for a threshold is not compelling.
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  • 1989 Volume 29 Issue 4 Pages 321-332
    Published: 1989
    Released: July 22, 2021
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    ABSTRACT This paper described three major epidemiological approaches to explore etiological clues to and risk factors for human congenital malformations, taking cleft lip and/or palate as an example. (1) An analysis of mortality statistics demonstrated an apparently downward trend of infant mortality from cleft lip and/or palate over the recent three decades in Japan. This particular finding was found to be plausibly ascribable to changing clinical assignment of causes of death from “cleft lip and/or palate” to “congenital heart diseases” or “multiple anomalies, syndromes or chromosome abnormalities”, when previous reports on incidence rate and autopsy series were examined. (2) A case-control study of 194 infants with cleft lip and/or palate (cases) and 194 normal infants (controls), who were matched to cases for sex, maternal age to within one year, birth order and residential area, yielded the following major findings. (a) A significantly increased risk was associated with parental highest educational attainment of less than 19 years, parental occupation of unskilled/service workers, positive family history of cleft lip and/or palate, positive past history of artificial abortion, maternal smoking habits at first trimester, and maternal episodes at first trimester of suffering from any diseases and of ingesting any drugs. (b) A significantly decreased risk was linked with frequent maternal intake at first trimester of such animal proteins as meats, fishes and shells, eggs and milk. (c) Maternal drinking habits and radiation exposures, and frequent maternal ingestion of Japanese/black tea were not associated. (d) Maternal coffee drinking at first trimester significantly elevated the risk, but turned to be unrelated when maternal smoking habits were statistically corrected. (3) A cohort study of approximately 10,000 pregnants, which is on- going from April 1989 in Nagoya and aims to disclose the associations of parental life-style habits with general pregnancy outcomes including major congenital malformations, was briefly discussed.
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  • 1989 Volume 29 Issue 4 Pages 333-344
    Published: 1989
    Released: July 22, 2021
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    ABSTRACT Modern industrialization has introduced harmful metals into our environment, and there has been a good deal of speculation that heavy metals can cause teratogenesis. In fact many metals have been confirmed to have em- bryotoxicity in experimental animals, but only a few elements (e.g., mercury, lead, etc.) are known to be human teratogens. Liquid metallic mercury is hardly absorbed from the gastrointestinal tract. Inorganic mercury is also poorly absorbed, i.e., around 2% of ingested mercuric chloride is absorbed. Uptake of inorganic mercury by the fetus is very low. An experiment using mice revealed that a significant proportion of mercury is blocked in the yolk sack. Among the organic mercury compounds, the most accumulated knowledge pertains to methylmercury compounds. Methyl- mercury is efficiently absorbed through the intestinal tract and skin. It crosses the human placenta with infantile blood levels in excess of the mother’s blood, giving rise to a higher risk for the fetus. Pathological features of children’s brains affected by prenatal methylmercury exposure are the outcome of disturbances in the development of the brain; microcephaly, dilated lateral ventricles, as well as derangement in the fundamental structuring of gray matter as the result of abnormal neuronal migration. Degeneration of already formed nerve cells is involved in some cases. Lead has been shown to pass through the human placenta readily, and the concentration in the umbilical cord blood is 80-90 % as high as that in the maternal blood. A large cohort study suggests that increased exposure to lead from the environment in the prenatal and early postnatal periods results in the deficit of mental development. Teratogenicity of many metal compounds such as aluminum, cadmium, chromium, indium, nickel, platinum, tellurium, thallium, ytterbium and zinc salts has been confirmed in experimental animals. Some metalloids (e.g., arsenic, selenium and lithium) appear to have teratogenic potential for humans.
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  • 1989 Volume 29 Issue 4 Pages 345-351
    Published: 1989
    Released: July 22, 2021
    JOURNALS OPEN ACCESS
    ABSTRACT The molecular events that guide pattern formation during embryonic development have been difficult to characterize in mammals, partly because of the difficulty in drawing a molecular connection between the phenotype of a dysmorphic mutation and the specific gene in which that mutation occurs. However, recent advances for recombinant DNA technique have made it possible to approach and clone the genes involved in the developmental process. The experimental insertion of retroviral or molecularly cloned DNA into mouse embryos to produce transgenic mice is one such approach that has led to information on phenotypes of dysmorphic mutation at the molecular level. During a series of transgenic experiment we obtained a developmental mutant that showed an autosomal dominant trait characterized by a short snout. The primary come of this dysmorphism was a developmental defect in the first branchial arch. The transgene was integrated into the chromosome 13. One fragment flanking the insertion site was highly conserved in mammals.
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  • 1989 Volume 29 Issue 4 Pages 353-362
    Published: 1989
    Released: July 22, 2021
    JOURNALS OPEN ACCESS
    ABSTRACT This review discusses the pathogenesis of spina bifida and describes the microscopic appearance of the initial pathological features and their further development in the spinal cords. The embryos and fetuses were derived from pregnant mice given orally 60, 40 or 0 mg/kg of retinoic acid in olive oil on day 8 of gestation and killed one, two or 10 days later. Separation of the primary neural fold from the secondary neural tube was seen in 9- and 10-day-old embryos in which the caudal end of the neuroepithelium was disorganized and the posterior neuropore was open; underneath it, the secondary neural tissue was seen. At term, fetuses showed spina bifida, including myeloschisis, myelocele and diplomyelia. The cord lesions were located between the third lumbar and second coccygeal levels. Thus, the differentiation and development of the spinal cord proceeds as in chick and human embryos, and the spinal cord caudal to the third lumbar level originates from both neuroepithelium and mesenchyme-like cells while that caudal to the third sacral level originates from mesenchyme-like cells only.
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