Teratogenic and embryotoxic activity of several 2,4-diaminopyrimidine derivatives

The degree of teratogenic and embryotoxic effects is dependent not only on the period of gestation and the agent dosage but also on the chemical structure of its molecule. In the series of derivatives of 2,4-diamino-5-phenylpyrimidine with different length of the alkul radical in the 6 position the preparation with ethyl group has the greatest injuring effect. Thus, the structural distinctions in the molecules of pharmacological agents are responsible for the selective toxicity of drugs in relation to mammalian embryos.     

The cytogenetic disorders in the people who took part in the cleanup of the sequelae at the Chernobyl Atomic Electric Power Station and who lived continuously in areas with an unfavorable ecological situation

Cytogenetic disturbances are manifested now in persons who liquidated aftereffects of the Chernobyl disaster. The character and course of the disturbances depend on the ecological conditions of the region where liquidators live at present. Examination of a group of liquidators with nerve-psychopathologic disorders and accompanying somatic pathology has revealed the presence of cytogenetic disturbances, mainly of the chromosome aberration type. At the same time, in persons who live under conditions of high environment pollution with ejections of industrial enterprises, the number of chromatid aberrations increases, which may be a result of action of chemical mutagens. A tight correlation is revealed between the level of cytogenetic disorders in lymphocytes and expressivity of the secondary immunodeficiency. Elimination of lymphocytes with unstable chromosome aberration is delayed when ecological pollution of the biosphere reaches the high level.     

Clinical trials comparing two treatment policies: which aspects of the treatment policies make a difference?

We discuss pragmatic clinical trials with survival endpoints in which subjects commonly change treatment during follow-up. Suppose that an intention-to-treat (ITT) analysis shows a significant difference between the randomized groups. We may want to ask questions about the reason for such a difference in outcome between randomized groups: for example, was the difference due to different policies for change to a third more beneficial regime? We address such questions using the semi-parametric accelerated life models of Robins, which exploit the randomization assumption fully and avoid direct comparisons of possibly differently selected subgroups. No assumption is made about the relationship of treatment actually prescribed to prognosis. A sensitivity analysis, using a range of plausible values for the causal effect of a covariate, estimates the contrasts between randomized groups that would have been observed if the covariate had universally been 0. The main technical problem is in dealing with censoring, for the method requires different degrees of recensoring for different values of the causal effect, and this can lead to estimates of low precision. The methods are applied to a randomized comparison of two anti-hypertensive treatments in which approximately half the subjects changed treatment during follow-up. Various time-dependent covariates, representing patterns of side-effects and treatments, are used in the model. We find that the observed difference in cardiovascular deaths between the randomized groups cannot be explained in this way by their different covariate patterns.     

Effect of the vascular endothelium on norepinephrine-induced contractions in uterine radial arteries from the nonpregnant and pregnant human uterus

OBJECTIVE: Our purpose was to investigate the role of the endothelium in the human uterine arterial response to norepinephrine in the nonpregnant and pregnant states. STUDY DESIGN: Tissue was obtained from six pregnant and six nonpregnant women undergoing cesarean section or hysterectomy. Uterine radial arteries were isolated and subjected to norepinephrine dose-response curves with and without intact endothelium. RESULTS: Responses were obtained over a dose range of 10(-8) to 10(-4) norepinephrine. Initially there was no difference between vessels from pregnant and nonpregnant patients, but removal of the endothelium significantly increased the response in vessels from pregnant women. Addition of nitro-L-arginine methyl ester when the endothelium was intact did not alter the dose-response curves. CONCLUSIONS: In pregnancy human uterine radial arteries are more sensitive to norepinephrine than during the nonpregnant state. This increase is countered by an endothelium-derived relaxing factor. The factor is unlikely to be nitric oxide.     

Designing flexibility into memory systems

This paper describes two techniques which can be used to improve the flexibility of modern microcomputer systems. The first is the idea of a ‘processor-configured’ system, whereby the memory and peripheral interfaces may have their structure logically altered by a single from the processor card, so that they match the wordlength of the processor used. The technique may be applied to existing bus standards with a minimum of modification, and then allows 8-bit and 16-bit processor cards to be exchanged on the system with a minimum of inconvenience, and without compromising performance. The second technique, of ‘shadow-ROM’, is not new, but is not yet widely used in personal computer systems. The system described, using most significant address page switching, is a particularly flexible one.     

Mouse models of myelin diseases

Dys- and demyelination are the common endpoints of several inherited diseases of glial cells, which elaborate myelin and which maintain the myelin sheath very much like an "external" cellular organelle. Whereas some of the genes that are affected by mutations appear to be glial-specific, other genes are expressed in many cell types but their defect is restricted to oligodendrocytes or Schwann cells. Many of the disease genes and their encoded proteins have been studied with the help of mouse models, and a number of different molecular pathomechanisms have emerged which have been summarized in Figure 8. Some of the new concepts in the field, which have been addressed in this review, have only emerged because similar pathomechanisms were discovered for different myelin proteins. Mouse models have clearly helped to address both, the molecular pathology of myelin diseases and the normal function of myelin genes, but as discussed in this review, these questions turned out to be very different. Despite the progress in understanding the role of the abundant myelin proteins, there also remain a number of open questions that concern, among other things, the initial axon-glia recognition, the assembly process of the myelin sheath, and the long-term interaction of axons with their myelinating glia. Finally, animal models of human neurological diseases should not be restricted to the study of pathology, but they should also contribute to the development of experimental treatments. It is encouraging that a few attempts have been made.     

Morphologic disturbance of lung maturation in fetuses of alloxan diabetic rabbits

Maturation of lungs was studied morphologically in fetuses of does made diabetic with alloxan. The lungs of fetuses of does treated with alloxan 24 h after mating appeared to be less mature than control lungs, as shown by significant decrease in areal density of air space (p < 0.01) and by increases in areal density of alveolar epithelium and capillaries (p < 0.02). In alloxan fetuses, ultrastructural techniques revealed that type II cells had 10 times the control value for areal density of glycogen (p < 0.01) and 2.5 times that of rough endoplasmic reticulum (p < 0.05), but the proportion of type II cells and the number of lamellar bodies per type II cell profile were similar in both groups. Ultrastructural examination of capillaries demonstrated that their migration and the fusion of their basement membrane with that of alveolar epithelium did not occur as frequently in alloxan fetuses as in control fetuses. Biochemically, the lungs of alloxan fetuses contained significantly more glycogen and protein (p < 0.01) than control lungs, but the deoxyribonucleic acid was similar. The alloxan fetuses had a disturbance of lung structural maturation that was consistent with our previous findings of delayed functional maturation without accompanying change in disaturated phosphatidylcholine levels and ratio of lecithin to sphingomyelin.     

Current situation and control strategies for resurgence of diphtheria in newly independent states of the former Soviet Union

Since 1990, an epidemic of diphtheria has spread throughout the newly independent states of the former Soviet Union, and by 1995 a total of 47 808 cases were reported. During the early stages of the epidemic, adequate control measures were not taken and vaccine was in short supply; possible contributing factors to the spread of the epidemic are the presence of highly susceptible child and adult populations, socioeconomic instability, population movement, and a deteriorating health infrastructure. Although WHO views the epidemic as an International public-health emergency and, together with UNICEF and the International Red Cross, has formulated a strategy to combat the epidemic, the necessary funds have not been made fully available. Current vaccination recommendations also need to be reviewed to ensure that population immunity will be adequate to prevent any resurgence of diphtheria in Europe and North America.     

Reducing cancer risk among Native American adolescents

BACKGROUND: This article discusses the development, implementation, and preliminary testing of an intervention to reduce cancer risks through tobacco use prevention and dietary modification among Native American youth in the Northeastern United States. METHODS: The intervention outcome study includes a research design and outcome measurement instruments. In collaboration with Native American communities, reservations, and organizations in the Northeastern United States, implementation of the design quantifies the separate and combined effects of a tobacco use prevention and a dietary modification intervention. RESULTS: Native American youths in the tobacco prevention intervention and in the combined tobacco and dietary intervention increased their knowledge of tobacco facts and their awareness of the motives of tobacco advertising, and showed higher ratings for an ability to resist peer pressure and to refuse offers of tobacco use between pretest and posttest. Youths in the combined intervention were significantly less apt to report smoking of any kind. Youths in the tobacco use prevention-only condition reported significantly less smoking than their counterparts in the dietary modification-only condition and control condition on 4 of 8 measurement items. As for dietary variables, pretest to posttest measurement scores showed that, after receiving the curriculum, youths in the dietary modification intervention and in the combined intervention improved their knowledge of the health implications of consuming dietary fat, fiber, fruits, and vegetables. Youths in the dietary modification and combined intervention also improved their scores of knowledge related to cancer risk-reducing nutritional practices, cultural dietary habits, and healthy food choices available for Native American cultures. Youths in the dietary modification-only condition report significantly increasing their consumption of complex carbohydrates and significantly decreasing their fat intake between pretest and posttest occasions. CONCLUSIONS: Data from this longitudinal study suggest the value of the FACETS curriculum for helping Native American youth reduce their risks for cancer associated with tobacco use and dietary preference and consumption patterns. In particular, results indicate the enhanced effects of the combined tobacco use prevention and dietary modification intervention for preventing tobacco use and for improving youths' knowledge and attitudes with regard to tobacco use and diet. Further, the study demonstrates the value of collaborating with Native American organizations to design a cancer risk-reducing curriculum and to implement tests of that curriculum.