The case of a girl with a deficiency of adenine phosphoribosyltransferase (A-PRTase activity was 0.45 nMol/mg Prot/hr), repeated urolithiasis, and symptoms of renal failure from 1976 to 1978, is reported here, although, she has been free from symptoms since 1979. Crystals have been observed in her urinary sediment even during the asymptomatic period. Furthermore, the urinary calculi and the crystals were recognized as 2,8-dihydroxyadenine. The excretion of 2,8-dihydroxyadenine crystals in the urine has been inhibited by administration of allopurinol to the patient. These findings suggest the possibility that the escalation of this disease into renal insufficiency can be prevented by early discovery of this disease through detection of 2,8-dihydroxyadenine crystals in the urinary sediment through use of a screening test.
A guinea pig with skin-like heteroplasia in the right cornea was found in a stock of the Hartley strain. Histological examination showed that a part of the corneal epithelium together with the anterior half of the corneal stroma was re-placed with a skin-like structure but the posterior half of the stroma and corneai endothelium remained intact. The pathogenesis of this heteroplasia is discussed from the point of corneal morphogenesis, with special reference to epithelial-mesenchymal interaction.
The effects of starvation were studied on the fetus and alkaline phophatase (ALP) of the placenta and intestine in pregnant rats. The following results were obtained. 1) Starvation from day 17 to 20 of pregnancy decreased the weight of maternal organs (liver, intestine), and the placental and fetal weights decreased in rats starved during late pregnancy (day 1 7-20). 2) The degree of ossification decreased in the fetuses derived from dams starved during late pregnancy, but no gross or visceral malformations were observed in any group. 3) Total placental ALP activity of the dams starved during late pregnancy decreased, and its reaction constant (Km) increased to 13 mM from 4 mM of the control value, but ALP activity of the maternal organs and placenta from dams starved during early pregnancy (day 7-10) was almost the same as the control value. 4) The inhibitory effect of 1-phenylalanine against placental ALP activity in rats starved during late pregnancy increased to 27 mM from the 21 mM of the control value. Based on these data, the relationship between placental ALP activity and SFD production resulting from starvation of pregnant rats was discussed.
The present study in an innovative manner using anencephalic fetuses as model established that the corticosteroid production is important and a prerequisite to pulmonary maturation. This was found out by subjecting amniotic fluid to phospholipid (lectihin and sphingomyelin) analysis in hydramniotic pregnancies who gave birth to anencephalic babies where hypothalamo-hypophyseal adreno cortical axis is reported to be defective.
Reproductive medicine has progressed and many clinically important problems have been resolved. However, the mechanism of fertilization, which is the most basic and fundamental phenomenon in human reproduction, has not yet been clarified. We have investigated the morphological and functional characteristics of the human oocyte in vivo and in vitro. Observations of the human oocyte at or before fertilization in vitro including ultrastructual changes will be discussed.
During the past decade several chromosome surveys on newborn infants in North America and Europe have been reported. Recently two or three surveys including ours were reported in Japan. The incidence of chromosomal aberrations in newborn infants based on these reports are presented. The screening methods for chromosomal aberrations for newborn infants, the limitations of these screening methods, and the transition of some clinical manifestations on newborn infants with chromosomal aberrations are discussed.
Recent cytogenetic studies on spontaneous and induced abortuses indicate by implication that almost half of the fertilized ova are chromosomally abnormal and that 90% of the abnormals are eliminated before the pregnancy is recognized. Around 5% of conceptuses at the beginning of clinically recognizable pregnancy are chromosomally abnormal. Of these 5%, half are autosomal trisomies involving chromosomes 2 through 22. Trisomy 1 has never been encountered. Among the trisomies, trisomy 16 is most frequent accounting for 30% of all trisomies, trisomies 21 and 22 are next common, being 10% each, and trisomies 13 and 18 each take 5%. Monosomy X is found 19% of all abnormals, triploidy is 17% and tetraploidy 5%. More than 90% of such abnormal conceptuses later abort spontaneously, most of them during the first trimester of pregnancy. Thus, only 0.6% of liveborns are chromosomally abnormal. Prenatal selection rates of these chromosome abnormalities are: trisomy 21 : 77%, trisomy 18 : 94%, trisomy 13 : 96%, monosomy X : 99% and triploidy : 99.8%. Most of the abortuses with lethal chromosome abnormalities are either an empty sac or a totally disorganized embryo. They stop to develop at 6 weeks of embryonic age or earlier. On the other hand, apparently normal fetuses are occasionally found among conceptuses with trisomy 21, monosomy X and tri ploidy. In conclusion, spontaneous abortions are an efficient device for the elimination of abnormal conceptuses.
Review of the literature revealed that about 190 different types of autosomal abnormalities had been described by the end of 1981. Newer types of abnormalities and also larger number of cases with unusual structural rearrangements are to be described by the use of newer techniques. In the past 3 years, 5 cases of inv dup, one dir dup, two dup (dir or inv) and 7 psu dic were detected in the author's laboratory, although only one case each of inv dup, dup and psu dic were found during the preceding 7 years. The incidence of both inv dup and psu dic may be much higher than what is generally believed. It is also noteworthy that in all 3 cases of de novo translocation and in 2 of 4 cases of complex rearrangements, a small deletion was detected (Table 2). The association of a small deletion with an apparently balanced rearrangement might be much common phenomenon than what is generally believed. According to Nakagome et al. (1976) and Nakagome (1980), the Cd-band technique (Eiberg, 1974) reveales only a functioning kinetochore. Chromosomes of 11 aged individuals (66-87 years) were examined with this technique and compared with 11 controls. It was found that the number of Cd-negative chromosomes was significantly increased in the aged individuals (Table 3). They were most frequently observed in the C group, however, they were also increased in the D group and were detected in all other groups of chromosomes.
Monitoring systems or services primarily aiming to check unusual outbreak at the earliest time of its occurance are widely applied in the various branch of present society. The movement of human vital events, however, shifts slowly and the level of unusual incidence seems to be rather low compared with in other branches of human society. Therefore, national statistical service on birth defects started in 1950s, which gradually moved to the monitoring service including epidemiological intelligence for 1960s. In 1974, scientists of 13 countries created a clearinghouse service of information of their monitoring systems at the occasion of meeting of European Teratology Society Then discussions were down at the 31st WHO General Assembly in 1978. They reported as follows: it was recognized that the birth defects contribute to early mortality and detract the quality of life in all societies. There is a need for further information about it in particular their relation to environmental hazards. European Community recently started to establish her own project "EURO-CAT" study, involving 18 designated institutions to monitor outbreak of birth defects within Europe. From the first yearbook of the International Clearinghouse for Birth Defects Monitoring Systems printed in 1982, several recent topics in this field; femur reduction deformity in Alps-Rhone, France; Down syndrome by type, Ebstein heart anomaly; multiple malformation classification method, and so forth are discussed.
The author attended the 22nd Annual Meeting of the Teratology Society and the 3rd International Conference on Limb Development and Regeneration held in June and July, 1982. The following topics learned at these meetings and during the travel between the meetings are reviewed. 1) Current models in limb and vertebra development. The positional information theory by Wolpert is briefly explained together with the polar coordinate model by French et al and the clock and wavefront model by Cooke and Zeeman. 2) Importance of extracellular matrices in limb and vertebra morphogenesis. Distribution of hyaluronate in the developing limb and vertebral column has been claimed as an important factor controlling mesenchymal condensation. The role of fibronectin in cell migration and cell to cell interaction is another interesting topic. 3) Effects of vitamin A on limb and vertebra morphogenesis. Recent findings in experiments using regenerating urodele limbs and developing chick wing buds suggest that vitamin A disturbs "positional values" in the developing limb. 4) Vascular lesions as a pathogenetic event in limb and vertebra teratogenesis. Hypervitaminosis A has been shown to induce vascular aberrations, leading to limb and vertebra malformations. Fluid dynamics in the developing limb and vertebral column should further be investigated. 5) Intrauterine treatments of limb and vertebra malformations. Trials of intrauterine treatments of limb and vertebra malformations induced in monkeys are in progress at the Pregnancy Research Branch, NICHD, NIH. Teratologists should pay attention to the development in this field.
This paper reviews some uses and limitations of current methods for detecting and identifying teratogenic agents in man. Although both human epidemiology and animal testings (in vivo and in vitro) are essential in studies of human teratogenesis, they still have limitations and problems. The proposals for implementing new approaches to the problems are as follows: 1. Recognize the limitations of the present systems for detecting teratogenic agents in man. 2. Monitoring and surveillance systems should be used to test hypotheses as well as to monitor the sudden increase in the frequency of specific malformations. 3. Some in vitro techniques have been developed recently for assessing teratogenic effects of chemicals. In vitro techniques are important tools for elucidating mechanisms of teratogenesis, although they may not replace screening tests in vivo. 4. The role of clinicians is of major importance for detecting and identifying human teratogens.
I have studied the clinical and roentgenological features of congenital hand anomalies. Many clinical findings have shown that failure of formation of parts, partial necrosis of mesenchyme, does not lead to the typical split hand (oligodactyly). Abnormality of the number of digits, polydactyly or split hand, may be due to abnormal distribution and arrangement of mesenchyme, which may be induced by disorder of the ectoderm. However, we may say that failure of formation of parts is responsible for brachydactyly, atypical split hand and radial deficiency. The critical period of radial ray deficiency may be earlier than the period of webbing or union of the digital rays. The critical period of webbing or union of the digital rays may be a little earlier than the period of mesenchymal condensation; and in the same period, a split hand can be formed as a result of union of the digital rays. If necrosis of the mesenchymal tissues were a dominant feature of split hand and syndactyly, these hand anomalies would be accompanied by hypoplastic abnormality in the proximal portion as is the case in symbrachy-dactyly or atypical split hand.
Spinal malformations experimentally induced in rats were observed and compared with congenital spinal anomalies of human being which are not infrequently seen in orthopedic clinic. These model animals were expected to suggest the reasonable way of classification of varieties of congenital spinal deformity, associated anomalies hidden in or out of skeletal system, chronological changes of the malformed spine in the postnatal growing age and the suitable manner of therapeutic management of the individual cases. Clinical material is limited mainly to the postural deformity due to congenital vertebral anomaly, including scoliosis and kyphosis. The study is definitely informative to clarify many of these problems, but low and inconstant incidence of spinal anomalies in the drug-treated rats, high mortality rate of these malformed offsprings etc. are the remaining difficulties.
Of 103 spina bifida 74 patients were reviewed with 19 drop out and 10 deaths. Spina bifida were divided into three types clinically by the appearence, ie, myelomeningocele, meningocele and spina bifida occulta with lipoma or dimple. The orthopedic problems were discussed about the deformities and ability of walking. One third of myelomeningocele have the severe orthopedic problems, although all of the other types of spina bifida are able to walk. But the deformities of the lower extremities were seen in about 50 to 70% in the meningocele and spina bifida occulta with lipoma or dimple.
Eight hundred and eighty-six cases with gastrointestinal anomaly were devided into eleven categories and analysed from the teratological viewpoints. They are esophageal atresia, intestinal atresia and stenosis, midgut malrotation, Hirschsprung's disease, imperforate anus, hypertrophic pyloric stenosis, neonatal gastric rupture, diaphragmatic hernia, abdominal wall anomalies (omphalocele, gastroschisis, prune belly and exstrophic cloaca), biliary atresia and choledochal cyst. There were high rate of low birth weight in esophageal atresia, abdominal wall anomaly and imperforate anus. These three anomalie also frequently combined with malformation of the other system including vertebra and limbs. Down's syndrome frequently combined with duodenal atresia (in 29%), Hirschsprung's disease, imperforate anus and diaphragmatic hernia of special type (Morgagni's hernia and hiatal hernia) but rarely combined with inguinal hernia in our series. We had three cases of esophageal atresia occurred in trisomy-18, on which a radical operation was not performed. Hirschsprung's disease and hypertrophic pyloric stenosis had large birth weight in average and had low incidence of combined anomaly including vertebra and limbs, contrary to the fact that the two are known as hereditary disease. Among 48 esophageal atresias and 250 anorectal malformations we have encountered 7 cases which have the both. In the seven cases three belonged to the complete form of VATER association, which were succumbed in all and were described in the details. The other four were VATE in one, ATER in one and ATE in two. Special attention should be paid on the sacral deformity in the baby with imperforate anus. One case of anal stenosis was treated by bougie but constipation was persisted. Anterior sacral meningocele (S-2) was diagnosed by digital examination and X-CT at eight months of age. A successful resection of the presacral meningocele was performed with complete recovery. Two cases with imperforate anus of high type had severe deformity of the sacrum accompanied with urinary incontinence. A radical pull through operation was carried out on the two cases with excellent result in regard to the bowel habits.