Clinical Research

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This article has no abstract; the first 100 words appear below. From June 5 to 7, 1979, I attended a conference entitled "Clinical Research: Elements for a prognosis" at the University of Chicago Center for Policy Study. Conferences on the relation between public policy and medical practice, pedagogy, or research are so common these days that one might wonder why this one is singled out for special notice. I should like to call special attention to the manner in which this conference was planned (by Richard L. Landau, Daniel X. Freedman, and Leon I. Goldberg). Since this conference was much more productive than most, I commend the organizers' style to others . . . Robert J. Levine, M.D. Yale University School of Medicine New Haven, CT 06510 *The authors and titles of these papers are: Arley T. Bever, Jr, Ph.D.: A quantitative assessment of fundamental and targeted research at NIAMDD; Paul B. Beeson, M.D.: How to foster the gain in knowledge about disease; Sidney Udenfriend, Ph.D.: Improving the scientific base of clinical medicine by facilitating collaboration between academia, the pharmaceutical industry, and government; Michael R. Sonnenreich, J.D.: Encumbrances to fundamental clinical research; Robert J. Levine, M.D.: The impact of institutional review boards on clinical research; and Scott N. Swisher, M.D.: Manpower training for fundamental clinical research.
 
To identify correlates of external funding for research, a mail survey of the membership of the American Federation for Clinical Research was conducted. Data were collected from 2,642 respondents on research training environment, current work environment, current sources and amounts of external research support, and probability of remaining in research. Respondents reported that they worked 62.4 +/- 20.4 hours per week, and that their dominant activities were research (37% of time), clinical responsibilities (20%), teaching (15%), and administration (13%). Nearly two-thirds reported some external research funding, including 1,371 (52%) individuals who received support as principal investigators from federal agencies. In multivariate analyses, the probability of having federal or nonprofit foundation support was positively correlated with the number of hours per week devoted to research, the number of grants submitted in the previous two years, the amount of research training during fellowship, and the presence of PhD degree recipients in the research training environment; and negatively correlated with the number of hours per week of clinical, teaching, and administrative activities, and having a PhD degree. In contrast, corporate support was positively correlated with the number of hours of total work per week, but negatively correlated with the amount of time currently devoted to research. Respondents who reported that their probability of remaining in research was decreasing had fewer months of research training, greater clinical responsibilities, and less external research support. We conclude that federal and nonprofit foundation support but not corporate support are positively correlated with the adequacy of research training and the amount of time currently devoted to research, and negatively correlated with clinical responsibilities.
 
The immunologic abnormalities in AIDS are on the one hand selective and distinctive and on the other hand broad and heterogeneous. The common denominator of the immune defects in AIDS patients is a quantitative and qualitative defect in the T4 inducer/helper subset of T cells. However, AIDS patients also manifest a remarkable abnormality of B cell function characterized by a polyclonal activation of B cells with spontaneous secretion of Ig and increased spontaneous proliferation. This likely explains the hypergammaglobulinemia that is consistently seen in AIDS patients. Furthermore, the spontaneous polyclonal activation of the B cells is accompanied by a refractoriness to be novo stimuli rendering them defective in their ability to mount a humoral response to a new antigen. AIDS patients also manifest defects in T cell and NK cell-mediated cytotoxicity, both of which are at least partially corrcted by IL-2 in vitro. Finally, monocyte funection is also abnormal in AIDS. The recent demonstration that the T4 lymphocytotropic retrovirus HTLV-III is likely the underlying and primary etiologic agent in AIDS is entirely compatible with the immunologic defects observed in this syndrome.
 
This paper reviews our studies of cardiovascular dysfunction in septic shock that were performed during the past ten years in the Medical Intensive Care Unit (ICU) and animal laboratories at the National Institutes of Health (NIH). By simultaneously studying septic shock in both humans and we were able to extrapolate data from the laboratory to the clinical setting and thus examine the pathophysiology of the cardiovascular changes in this disease.
 
Federal spending must be reduced across the board if this country is to remain economically viable. Biomedical research must be prepared to share its portion of this burden. To alleviate the pains of austerity, realistic priorities must be delineated in all segments of federal spending and efficient cost-productivity ratios should be evident in most supported programs. Priorities should be set by the experts in a particular field. In biomedical research, these priorities should probably be based primarily on data relating to the goals of this discipline, i.e., the betterment of both the quantity and quality of life. This would include evaluating data relative to the prevalence of any given disease and the influence of particular diseases on life expectancy and disability. Setting of priorities is the only answer to the problem posed when demand for funds exceeds the supply. Researchers must demonstrate the relevance of their work through greater interaction of academia with society. Though perhaps distasteful, a substantial element of mission-oriented research will be necessary. Public and congressional leaders must be convinced that basic medical research provides the foundation for future delivery of health care. The latter cannot be allowed to expand at the expense of the former, since neither could then thrive. Monetary support to biomedical research should not be subject to drastic and intermittent change but should be predictable, stable, and based on realistic longrange planning, even if at reduced levels of funding. Finally, unpleasant as it may be to some, medical schools will have to continue their increasing involvement in providing health care. Hopefully, this function will provide a broader bridge between basic research and medical practice, and both will be supported by a strong commitment to excellence in medical education.
 
Analysis of the difficult problem of investigators' access to patients' charts suggested to us a difference between the situations in which former patients and current patients are the focus of the screening. After consideration of a number of options, we settled on a procedure of informing patients in a general way at the time of admission about the possibility that their charts might be screened, and allowing them to decline to be involved in that process. Early results of an evaluation of the procedure suggest reason for optimism that it will be successful in meeting its intended aims, but more prolonged follow-up will be required to determine the effect of obtaining consent for screening on patients' attitudes and on the conduct of biomedical research.
 
Basic and clinical science have interacted in the analysis of androgen action to provide insight into sexual differentiation during embryogenesis and the process of virilization during postnatal life. As a consequence, our understanding as to how the male and female phenotypes develop has been revolutionized. In addition, the unraveling of androgen action has provided insight into the operation of other hormonal systems. The importance of androgen physiology for these advances stems from several distinctive features. The metabolism of androgens has served as a paradigm for the elucidation of extraglandular hormone formation and for the analysis of complex hormonal interaction at the cellular level. Although essential for reproduction, androgens are not critical for the life of individuals; thus, mutations that either block or enhance androgen action are compatible with life. Androgens play a central role in the embryonic differentiation of their own target tissues and hence in the development of the male phenotype; as a consequence, mutations that impair androgen action have a high rate of ascertainment. The receptor protein and many of the enzymes critical for androgen action are expressed in cultured skin fibroblasts; spontaneous mutations that influence these functions and cause human disease can, therefore, be characterized in vitro. Because the gene for the androgen receptor protein is X-linked and hence expressed in the hemizygous state, disorders of the androgen receptor appear to be relatively common in man and animals. Thus, while many aspects of androgen action are still unexplained, phenotypic sexual differentiation is the best understood aspect of embryogenesis, and major insight has been obtained into several disorders of human intersex.
 
Through this presentation, I have attempted to highlight some of the work that has been carried out in my laboratory over the past four years. We have strived to take a systemic approach to the study of the structure, function, and regulation of adenosine receptors and the transmembrane signalling processes that they activate. Much remains to be learned.
 
In this essay we will briefly describe some recent findings concerning the biochemical nature of these receptors, their mechanisms of activation and coupling to effectors, and recent discoveries about the ways in which their function is regulated. This information provides the framework for attempts to devise strategies for ultimately regulating plasma membrane receptor function for therapeutic gain.
 
Several biomedical advances from fetal research which are recent accomplishments and some others which are potential accomplishments in the next few years are reviewed. Bans on one or another category of fetal research can slow some of these advances drastically. Wide differences of opinion exist, especially concerning the involvement of a fetus in research before or after induced abortion and the participation of the dying, nonviable fetus as a research subject. Nonetheless, fetal research has solved problems of fetal health and can contribute to the understanding of many other biological phenomena. This calls for concerted efforts to find ways that fetal research can continue to benefit the human fetus and other human beings within an ethical and legal framework agreed upon by the majority of people in our society.
 
Specialization has been construed to be central to the problem of the allocation of medical manpower in the United States. I would like to begin by challenging this supposition which is implicit in the health manpower legislation now under discussion.
 
Top-cited authors
Thomas J Kipps
  • University of California, San Diego
Erik Ranheim
  • University of Wisconsin–Madison
Michael S Hendryx
  • Indiana University Bloomington
Douglas S Wakefield
  • University of Missouri
Peter Michael Elias
  • University of California, San Francisco