Virus-associated immunopathology: animal models and implications for human disease. 1. Effects of viruses on the immune system, immune-complex diseases, and antibody-mediated immunologic injury

The tissue damage caused by virus infection has been traditionally explained by the ability of viruses to multiply in cells and thereby injure or destroy them. Recent evidence suggests, however, that lesions may also be caused by the host''s immune response to viral antigens and that the immune system itself may be perturbed by some viruses. This memorandum reviews recent developments in viral immunopathology, with special reference to animal model systems, and indicates the possible relevance of the new concepts and techniques for certain diseases of man. Certain viruses, notably the leukaemia viruses and some of those causing persistent infections, depress the host''s ability to mount an antibody response to antigens, while other viruses may enhance the antibody response. Cell-mediated immunity may also be depressed. Another immunopathological manifestation of virus infection is immune-complex disease. When viruses or their antigens persist in the circulation they combine with specific antibody, and the resulting complexes lodge in various sites, especially the kidney. Further combination with complement leads to the release of tissue-damaging substances. A third condition associated with virus infection is antibody-mediated immunologic injury. Both oncogenic and non-oncogenic viruses frequently induce new antigens on the surface of the cells they invade. When antibody attaches to these antigens in the presence of complement, the cells are destroyed.     

Non-Mendelian developmental defects: animal models and implications for research into human disease

The major groups of malformations in man are polygenic in origin but this review deals only with defects due to non-Mendelian factors. Animal models that help in identifying the causes and in understanding the numerous and often subtle mechanisms of human malformations are of particular value. Many chemicals, physical agents, and nutritional deficiencies affect experimental species but few are teratogenic for domestic animals and even fewer for man. The known fetopathic viruses of animals and man cross the placenta to cause chronic, nonlethal fetal damage without harm to the mother. Ionizing radiations are teratogenic for all species and hyperthermia for many, but the role of the latter in human development is uncertain. The identification of more animal species with spontaneous or induced defects comparable to those found in man and of additional causative teratogens will increase the resources available for research into the causes and mechanisms of abnormal development in man. No animal species is ideal in teratological research but each has its virtues. This report comments on the present status of research in teratology and the trends that might profitably be followed in the future.     

S-Adenosyl-L-methionine and alcoholic liver disease in animal models: implications for early intervention in human beings.

In patients with severe alcoholic liver disease (i.e., cirrhosis), a deficiency of S-adenosylmethionine (SAMe) develops as a result of decreased SAMe synthetase activity. Whether a sizeable SAMe depletion occurs already at earlier stages of alcoholic liver disease has been the subject of debate. To address this issue, rats were fed alcohol (or isocaloric carbohydrate) in Lieber-DeCarli liquid diets containing adequate amounts of protein, vitamins, and lipotropic factors, including methionine. Alcohol feeding resulted in hepatic steatosis (without fibrosis) and unchanged SAMe synthetase activity, yet SAMe concentration was already greatly decreased. This most likely resulted from oxidative stress associated with the metabolism of alcohol and the induction of cytochrome P4502E1 (CYP2E1), which generates free radicals. Indeed, the decrease in hepatic SAMe correlated with parameters of oxidative stress, such as increased 4-hydroxynonenal (measured by gas chromatography-mass spectrometry) and diminished glutathione (GSH). Decreased GSH, occurring as a result of excessive GSH consumption caused by the oxidative stress, probably generated by enhanced utilization of SAMe, a precursor of GSH, thereby explaining the depletion of SAMe. In view of the known differences between rodents and primates in the metabolism of lipotropes, my colleagues and I have also studied the interaction between alcohol and SAMe in baboons and found again that, at early stages preceding the development of cirrhosis, there was already a significant lowering of hepatic SAMe concentration, associated with a striking oxidative stress documented by decreased levels and accelerated turnover of GSH. This was associated with increased lipid peroxidation and damage to cellular membranes, including those of the mitochondria, assessed by electron microscopy. Oral administration of SAMe resulted in its hepatic repletion with a corresponding attenuation of the ethanol-induced oxidative stress and liver injury, with significantly less GSH depletion, less increases in plasma aspartate aminotransferase (AST) levels, less leakage of mitochondrial glutamic dehydrogenase into the plasma, and fewer megamitochondria. In conclusion, (1) both in rodents and in non-human primates, significant SAMe depletion occurs already at early stages of alcoholic liver disease, despite the consumption of adequate diets; (2) the decreased hepatic SAMe concentration and the associated liver lesions, including mitochondrial injury, can be corrected with SAMe supplementation; and (3) accordingly, therapeutic administration of SAMe should be the subject of a comprehensive clinical trial to assess its capacity to attenuate early stages of alcoholic liver injury in human beings.     

The economic implications of animal diseases and disease control at the national level.

The authors examine the economic implications of animal diseases and control programmes at the national level, including the role of government in animal health, the effect of regulations and the use of cost-benefit analysis. Special attention is paid to the role of economic analysis in government decision-making processes. Economics provides a framework for gathering information and for the presentation of that information in a methodical manner, thereby providing a method for the decision maker to examine policy alternatives. In addition, assumptions underlying the analysis must be clearly laid out and explained by the person undertaking the analysis. Economic reasons for government intervention in animal health programmes include externalities, natural monopolies, public goods, coordination failure, information failure and distribution issues. An integrated holistic approach that includes national and international policy objectives is outlined in the paper. In the approach outlined, government coordinates the activities of stakeholders in animal health, including producers, consumers and researchers.     

Status of human monkeypox: clinical disease, epidemiology and research

Monkeypox, a vesiculo-pustular rash illness, was initially discovered to cause human infection in 1970 through the World Health Organization (WHO)-sponsored efforts of the Commission to Certify Smallpox Eradication in Western Africa and the Congo Basin. The virus had been discovered to cause a nonhuman primate rash illness in 1958, and was thus named monkeypox. The causative agents of monkeypox and smallpox diseases both are species of Orthopoxvirus. Orthopoxvirus monkeypox, when it infects humans as an epizootic, produces a similar clinical picture to that of ordinary human smallpox. Since 1970, extensive epidemiology, virology, ecology and public health research has enabled better characterization of monkeypox virus and the associated human disease. This work reviews the progress in this body of research, and reviews studies of this "newly" emerging zoonotic disease.     

Anticipatory problem solving: models for clinical practice and research

Summary Problem solving that anticipates a client's future is a fundamental component of primary care. However, adequate models for clinical practice and for research are needed. A paradigm of anticipatory care conceptualized as an interpersonal problem solving process is used as a framework for critical analysis of existing models and for the specification of conceptual and practical bases of new models of anticipatory care. The paper addresses questions concerning problem solving for the model of anticipatory guidance presented by the American Public Health Association and the model developed by Caplan, and the models of preparatory communication developed by Janis and by Leventhal and Johnson. The questions that are used to critique existing models and to specify new ones deal with identification and specification of issues for anticipatory care; its goals, functions, and intended outcomes; appraisal of readiness to participate in and worthwhileness of anticipatory care; the characteristic features of a model's solution phases and strategies of preparation; and the evaluation of the adequacy of anticipatory care.     

Mathematical models of complex dose-response relationships: implications for experimental design in psychopharmacologic research.

We develop a mathematical model to account for the complex relationship between drug dose and clinical response in psychopharmacologic research. The model specifies relationships among drug dose, drug bioavailability, pharmacokinetic factors, course moderators, clinical response and the heterogeneity of the disorder, and allows for the derivation of results that have implications for experimental design in psychopharmacologic research. These results form the basis for computer simulations which indicate that random assignment to two fixed doses is more powerful and less sensitive to heterogeneity than assignment to clinically determined doses. Fixed dose designs, however, tend to overestimate the magnitude of drug bioavailability-clinical response relationships. Clinically determined dose designs are useful in some experimental situations; their effectiveness is enhanced by systematically reducing the clinically determined dose. Larger dose reductions improve the ability to detect bioavailability-clinical response relationships.     

Climate change: effects on animal disease systems and implications for surveillance and control

Climate driven and other changes in landscape structure and texture, plus more general factors, may create favourable ecological niches for emerging diseases. Abiotic factors impact on vectors, reservoirs and pathogen bionomics and their ability to establish in new ecosystems. Changes in climatic patterns and in seasonal conditions may affect disease behaviour in terms of spread pattern, diffusion range, amplification and persistence in novel habitats. Pathogen invasion may result in the emergence of novel disease complexes, presenting major challenges for the sustainability of future animal agriculture at the global level. In this paper, some of the ecological mechanisms underlying the impact of climatic change on disease transmission and disease spread are further described. Potential effects of different climatic variables on pathogens and host population dynamics and distribution are complex to assess, and different approaches are used to describe the underlying epidemiological processes and the availability of ecological niches for pathogens and vectors. The invasion process can disrupt the long-term co-evolution of species. Pathogens adhering to an r-type strategy (e.g. RNA viruses) may be more inclined to encroach on a novel niche resulting from climate change. However, even when linkage between disease dynamics and climate change are relatively strong, there are other factors changing disease behaviour, and these should be accounted for as well. Overall vulnerability of a given ecosystem is a key variable in this regard. The impact of climate-driven changes varies in different parts of the world and in the different agro-climatic zones. Perhaps priority should go to those geographical areas where the integrity of the ecosystem is most severely affected and the adaptability, in terms of robustness and sustainability of response, relatively low.     

Ethical and legal implications of the new genetics: issues for discussion.

The so-called 'new genetics,' a phrase sometimes associated with The Human Genome Initiative, poses no really new ethical problems, but exacerbates old ones. The issues of most concern to geneticists and their patients are summarized under the eleven headings below. These issues emerged from a 19-nation study of ethics and genetics in 1985-86 and from preliminary work on a forthcoming 36-nation study by the same authors.     

社区家庭照护患者的老年综合征研究

该文介绍老年病学的核心技术——老年综合评估及其在老年医疗照护体系中的应用,包括老年综合评估的概念、发展历程、主要内容、适应人群、评估工具、工作方式、评估的医疗目标和非医疗目标,讨论了老年综合评估在老年病医院、护理院、社区、家庭等老年医疗照护机构的应用,建议老年综合评估与我国的医疗卫生体系相结合,完善我国的老年医疗照护体系,更好地为老年病人服务。     

Expanding the definition of disability: implications for planning, policy, and research.

Disability remains an area that is difficult to define and measure. Rheumatoid arthritis (RA), with its greater impact on women than on men, is one example of this. People with RA are limited in many areas besides paid work, so to measure this disability only in terms of paid work greatly underestimates its impact on people's lives, particularly those of women. This article reviews the major definitions of disability and reports the results of a national study assessing disability in both family and paid work roles. Both areas reveal high rates of disability among RA patients. The study concludes that measuring disability only in terms of paid work seriously underestimates its prevalence among women. These results have important implications for health policy because the greatest needs of the disabled may be, not in income replacement programs, such as Social Security disability programs, but rather in fortifying family and other care services that would enable people with RA to maintain higher levels of function in all domains of life.