Biomedical subjects
H Kalter
Publications and source records attributed to H Kalter.
The validation of interviews for estimating morbidity.
Health interview surveys have been widely used to measure morbidity in developing countries, particularly for infectious diseases. Structured questionnaires using algorithms which derive sign/symptom-based diagnoses seem to be the most reliable but there have been few studies to validate them. The purpose of validation is to evaluate the sensitivity and specificity of brief algorithms (combinations of signs/symptoms) which can then be used for the rapid assessment of community health problems. Validation requires a comparison with an external standard such as physician or serological diagnoses. There are several potential pitfalls in assessing validity, such as selection bias, differences in populations and the pattern of diseases in study populations compared to the community. Validation studies conducted in the community may overcome bias caused by case selection. Health centre derived estimates can be adjusted and applied to the community with caution. Further study is needed to validate algorithms for important diseases in different cultural settings. Community-based studies need to be conducted, and the utility of derived algorithms for tracking disease frequency explored further.
Five-decade international trends in the relation of perinatal mortality and congenital malformations: stillbirth and neonatal death compared.
The relation between long-term temporal trends in stillbirth and neonatal death rates and the congenital malformation frequencies in such deaths were analysed, using data from hospital-based European, USA, and Canadian reports published from 1950. In the last 50 years the overall perinatal mortality rate has fairly steadily improved, decreasing by 65-80%. This was accomplished by the control of some serious problems of early life. However, lingering disorders form an ever larger proportion of the causes of perinatal mortality. Among the prominent of these are congenital malformations, accounting for nearly 30% of perinatal deaths at present. However, this figure conceals important differences between stillbirths and early neonatal deaths. For example, although stillbirth and early neonatal mortality rates have decreased to similar extents during these years, congenital malformations, which were almost equally frequent causes of death in both of them at the beginning of this period, are now about twice as common in early neonatal (one week) deaths as in stillbirths. Other differences between them are in birthweight-related malformation frequencies and in characteristic arrays of malformations. The significance of these patterns and of some geographical variations, and the likelihood of continuing improvement in the stillbirth and early neonatal mortality rates are discussed.
Analysis of the syndrome of congenital malformations induced in genetically defined mice by acute riboflavin deficiency.
The role of genetics in the expression of a complex syndrome of teratologically induced congenital malformations was examined by the use of three inbred strains and 15 related crosses of mice. The syndrome, which included various limb, brain, orofacial, gastrointestinal, and miscellaneous malformations, was induced by an intense riboflavin deficiency produced by feeding the antagonist galactoflavin during midgestation. Analyses of the data showed that, although all three strains shared the major and most other features of the syndrome, there occurred in its manifestation vast quantitative and qualitative differences among them, in which they were resembled by their related crosses such as to constitute strain-specific malformation patterns. The results can be regarded as typifying an animal counterpart of human situations, the three strains representing in toto the mouse family, each strain individually exhibiting the variety that occurs between siblings in expressing a single syndrome.
Retinoic acid vs. excess vitamin A.
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More on the use of the terms kill and sacrifice in animal research.
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Decreased maternal serum magnesium concentration and adverse fetal outcome in insulin-dependent diabetic women.
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Diabetes and spontaneous abortion: a historical review.
The recent claims that there is an increased frequency of spontaneous abortion in diabetic pregnancies prompted a reexamination of this question. More than 50 articles published in 1950 to 1986 containing relevant information provided the data for this purpose. In 8041 American and European, otherwise uninterrupted diabetic pregnancies ascertained through hospital records, mostly not specified as to the time at first examination and the interval covered, there occurred 10.0% +/- 0.3% spontaneous abortions. The frequency was significantly greater (12.7% +/- 0.7%), however, in the 1890 pregnancies observed during specifically stated extended periods. The records are marred by the lack of control pregnancies and the great absence of information regarding the variables and confounding factors that influence the spontaneous abortion rate. Nevertheless, since the results are very similar to those found in general clinical material it is most probable that there is no excess of spontaneous abortion in diabetic pregnancy. The recent claims of such an increase may have been based on the pregnant women in these studies being seen earlier and being closely examined for longer periods than has usually been the case and to the enrollment in the studies of women with unrepresentatively great risk of reproductive mishap.
Diabetes and spontaneous abortion.
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Experimental teratological studies with the mouse CNS mutations cranioschisis and delayed splotch.
Teratological experiments were made with a recessive mouse gene (cranioschisis) causing exencephaly and a semidominant gene (delayed splotch) causing spina bifida. In studies with the cranioschisis gene administration of warfarin and thyroxine resulted in frequencies of exencephaly significantly below that expected of a recessive trait, perhaps indicating selective elimination of abnormal conceptuses. Studies with the delayed splotch gene tested the hypothesis that offspring with a hereditary defect of neural-tube closure have other, unexpressed CNS defects, which may be elicited by teratological impulses. This proposition was decisively upheld by administering 5-bromo-2'-deoxyuridine, cadmium sulfate and retinoic acid, as these treatments all caused significantly greater frequencies of induced exencephaly in offspring with spina bifida than in their genetically normal littermates.
Congenital malformations (second of two parts).
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Medical progress. Congenital malformations: etiologic factors and their role in prevention (first of two parts).
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Congenital malformations of the central nervous system and transplacental carcinogenesis: modification of ethylnitrosourea-induced brain tumors in rats by pretreatment with methylazoxymethanol.
X-irradiation of rat fetuses prior to exposing them transplacentally to the neurotropic carcinogen ethylnitrosourea (ENU) greatly reduces the frequency of offspring that develop neurogenic tumors. Since the tumor inhibition may have been related to the teratogenic effects of the irradiation of the fetal brain, it was of interest to learn whether another means of causing such brain damage would also interfere with the development of ENU-induced neurogenic tumors. For this purpose methylazoxymethanol (MAM), known to produce microencephaly, was used. Pregnant Sprague-Dawley rats were injected i.p. with 20 or 30 mg MAM/kg on the 15th day of gestation and 10 mg ENU/kg on the 16th or 20th day of gestation, or with either chemical alone. The offspring were observed during their life-span for the appearance of neurogenic tumors. MAM produced the expected microencephaly, but when administered alone caused no neurogenic tumors. ENU had no effect on brain size; and when administered alone produced high rates of offspring with neurogenic tumors (68 and 72% after treatment on the earlier and later day of gestation, respectively). The combined treatments resulted in significantly reduced frequencies of brain tumors, but did not modify the frequencies of non-brain tumors. The treatments caused relatively little or no excess pre- and postnatal mortality and for the most part had little effect on postnatal growth. Mean time of appearance of neurogenic tumors and mean number of neurogenic tumors per affected animal were unchanged by the dual treatments. There were no sex differences in tumor frequency, latency, or multiplicity. As noted, MAM reduced cerebral hemisphere size, but did not affect spinal cord size. The site of tumor inhibition by MAM thus appears to be correlated with the site of teratogenic damage. Nevertheless, various considerations led us to conclude that reduced number of target cells does not entirely explain the modifications in the frequency of tumors caused by MAM.
Dose-response studies with genetically homogeneous lines of mice as a teratology testing and risk-assessment procedure.
Current teratology testing procedures are mainly focused on qualitative considerations and, hence, largely ignore the variability in responsiveness to exogenous agents that may exist within species. An example is given of a test using genetically homogeneous lines of animals, which shows how extensive intraspecies variability can be. Pregnant females of six strains of mice were given single doses of 12.5 to 1200 mg/kg cortisone acetate by four routes on 4 days of gestation. The frequency of cleft palate and of fetal resorption were evaluated for their dose-response relations. The range of responses was extremely wide; in one series the malformation ED50 of the most responsive strain was about 16 times greater than that of the least responsive one. By indicating that a range of sensitivities may be possessed by species, and by approximating the limits of that range, inbred lines can reveal mild degrees of responsiveness that are frequently overlooked in using outbred stocks, and hence are of value in assessing risk.
A compendium of the genetically induced congenital malformations of the house mouse.
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The natural elimination of sporadically malformed mouse embryos.
Female A/JKt mice greater than or equal to 250 days old had litters with significantly larger fetal resorption rates and offspring with significantly smaller frequencies of sporadic malformations [cleft lip +/- palate (CLP) and open eyelid (OL)] than females < 250 days old. The OL frequency was reduced in litters with resorption as well as in those without, and thus was apparently associated with advanced maternal age per se; whereas the CLP frequency was reduced only in litters with resorption. It seems therefore that the frequency of CLP was reduced in the offspring of older females by preferential elimination and that of OL by another means, perhaps failure to express a tendency.
Dose-related reduction by prenatal x-irradiation of the transplacental neurocarcinogenicity of ethylnitrosourea in rats.
Pregnant Sprague-Dawley rats were X-irradiated on the 16th day of gestation with 5 to 250 rads and given i.p. injections 4 days later with 10 mg ethylnitrosourea per kg. The offspring were observed over their life span for the appearance of neurogenic tumors. The frequency of animals surviving beyond 4 weeks of age that developed tumors was inversely related to X-ray dose. About 15% developed tumors after exposure to the largest doses, 39 to 46% after the intermediate doses, and 58 to 65% after the smallest doses; 69% tumors occurred after treatment with ethylnitrosourea alone. The reductions in tumor frequency were not due to the increased mortality rate of tumor-prone animals, either before or after the onset of tumor appearance. Mean offspring weight at 4 weeks and 4 months of age was inversely related to X-ray dose but was not significantly different in those animals later developing tumors from that in animals remaining tumor free. Mean time of tumor appearance and mean number of tumors per affected animal were unrelated to tumor frequency. It does not seem that the destruction of target cells is by itself sufficient to explain the results.