Rejection of first-set skin allografts in man. the microvasculature is the critical target of the immune response.

Recent reports of microvascular injury in delayed hypersensitivity skin reactions prompted us to reexamine the pathogenesis of first-set skin allograft rejection in man using morphologic techniques that allowed both extensive vessel sampling and unequivocal evaluation of microvascular endothelium. We here report that widespread microvascular damage is a characteristic, early consequence of the cellular immune response to first-set human skin allografts and is qualitatively similar to, but substantially more extensive than, that occurring in delayed hypersensitivity reactions. Microvascular damage in invariably preceded significant epithelial necrosis and affected initially and primarily those venules, arterioles, and small veins enveloped by lymphocytes. Vessels of both the allograft itself and the underlying graft bed (recipient tissue) were equally affected. These data suggest that endothelial cells of the microvasculature are the critical target of the immune response in first-set vascularized skin allograft rejection in man and that rejection can be attributed largely to ischemic infarction resulting from extensive microvascular damage. Other mechanisms, such as direct cellular contacts between infiltrating lymphocytes and epithelium, apparently played only a minor role. The findings presented here indicate that the rejection of first-set vascularized skin allografts, though induced by immunologically specific mechanisms, is primarily effected by final pathways that are relatively nonspecific and that may cause damage to both foreign and host vessels and cells. Rather than contradicting studies demonstrating the exquisite specificity of allograft rejection in other systems, these findings provide a further example of the heterogeneity of the cellular immune response. Recognition of the critical role of immunologically mediated microvascular injury may prove important both for an understanding of the biology of allograft rejection and for strategies aimed at prolonging allograft survival.

The microvasculature is the critical target of the immune response in vascularized skin allograft rejection.

Vascularized first set human skin allografts were rejected largely by a process of extensive and progressive microvascular damage leading to ischemia and infarction. Microvascular injury was associated with a cellular immune response. However, vessel damage was at least in part immunologically nonspecific because vessels of the graft bed (host tissue) were damaged as well as those of the graft itself. We conclude that the microvascular endothelium is the critical target of the immune response in vacularized skin allografts in man, and that this sequence of events--primary vascular damage followed by ischemic infarction--may have significance in a variety of experimental and clinical settings.

Recurrent idiopathic membranous glomerulonephritis.

This study reports the clinical and pathological findings in a patient with recurrent membranous glomerulonephritis following transplantation of an HLA-identical kidney. Such a recurrence has been previously reported only once, although membranous glomerulonephritis is a common cause of nephrotic syndrome in adults. This case confirms that membranous glomerulonephritis may occasionally recur following renal transplantation and demonstrates that immunofluorescence and electron microscopic studies may be necessary to distinguish recurrent, membranous glomerulonephritis from the membranous changes frequently seen with chronic rejection. In light of the apparent low incidence of recurrent membranous glomerulonephritis, renal transplantation remains an excellent therapeutic option in this disease.

Serum magnesium. A CAP survey--1975.

The results of the 1975 CAP Comprehensive Chemistry Survey of serum magnesium are presented. More than 1,260 laboratories participated in this survey. The most commonly used method for the measurement of serum magnesium concentrations is atomic absorption spectrophotometry. Colorimetric dye methods (Rapid-Stat (TM) kits, the Dupont ACA and titan yellow) follow in popularity. Variation in precision was lowest with atomic absorption and highest with titan yellow methods. All three of the dye-binding methods demonstrated either consistently negative or consistently positive biases when compared with the weighted mean concentration. The differences between the mean concentrations obtained by the dye-binding methods and atomic absorption spectrophotometry are statistically analyzed, and several conclusions are presented. As demonstrated by this survey and at the concentrations measured, the estimation of serum magnesium by any of the commonly used methods, except titan yellow, is clinically appropriate.

Serum lithium. A CAP survey perspective.

Lithium data from the 1975 College of American Pathologists Comprehensive Chemistry Survey program have been analyzed. The results have been organized into five method-dependent groups: four variations on emission flame spectrophotometry, and one group containing all manual atomic absorption methods. The bias observed between flame emission and atomic absorption methods was correlated with the sample mean. In addition, three paired specimens were analyzed by mean comparison. This study indicates that atomic absorption methods have a negative bias, but an apparent correlation with the sample mean indicates the probability of standardization error between the methods. This may be related to a protein depression effect and may be due to differences in viscosity between aqueous standards and serum-based samples. Both atomic absorption and flame emission methods demonstrate variability that is clinically satisfactory.

Evaluation of surgical therapy by cost-benefit analysis.

Cost-benefit analysis (CBA) is described briefly, emphasizing the contribution this technique can make in justifying health care programs vying with other costly public programs for support. Costs and benefits of two surgical diagnostic techniques are outlined briefly as illustrations of the analysis. The first analyzes routine intraoperative cholangiography indicating the slight benefits that accrue from its use in terms of mortality and hospital expense. A more complicated example is an analysis of a policy of universal annual uterine cervical smears in asymptomatic women for cancer prevention where, granted the assumptions of the model, the costs minus the benefits of the program are estimated to be $565,000/beneficiary/year. The average beneficiary will gain 22 years of life at an average cost/year of about $26,000. The two examples are presented primarily as illustrations of a methodology which is being applied widely in medicine and public policy planning. Second, the marshalling of facts in CBA of a policy of annual uterine smears is of interest to those concerned with the justification of this screening procedure.

Successful pregnancy renal transplantation.

Pregnancy in a renal homograft recipient resulted in the delivery of a 2770-g male fetus by classic cesarean section. Renal function remained stable throughout the gestation. The fetoplacental unit was monitored by the concurrent assay of 24-hour urinary estrogen excretion and human placental lactogen (hPL) in light of the spuriously low estrogen levels often found in these patients on chronic glucocorticoid immunosuppression.

Cost-benefit analysis of surgery. Current accomplishments and limitations.

The general principles of cost-benefit analysis are applicable to health care issues, which are in particular need of carefully detailed study at a time when health care expenditures are increasing and when there is competition for scarce resources. There are limitations to such analyses, particularly in the evaluation of the many intangible values so important in the costs and benefits of health care. As examples of the methodology, a simplified cost-benefit analysis is presented for cholecystectomy for silent gallstones in terms of an individual patient, and a more complex analysis is presented for a national program for renal transplantation or chronic hemodialysis for end-stage renal disease. Finally, costs of intensive care support are presented. These examples illustrate advantages and disavantages of a revealing type of analysis that will be applied with increasing frequency to future health care issues.

Professional uncertainty and the problem of supplier-induced demand.

This paper discusses the puzzling problem of large differences in per capita use of certain common surgical procedures among neighboring populations, which by all available measures are quite similar in need for and access to services. The evidence reviewed here supports the hypothesis that variations occur to a large extent because of differences among physicians in their evaluation of patients (diagnosis) or in their belief in the value of the procedures for meeting patient needs (therapy). This hypothesis, which we call the professional uncertainty hypothesis, is germane to current controversies concerning the nature and extent of supplier influence on the demand for medical services. It is also important because of its implications for health regulatory policy. Our plan is to (1) review the relevance of the hypotheses for the supplier-induced demand controversy; (2) review the epidemiologic evidence on the nature and causes of variation; (3) examine patterns of use of common surgical procedures to illustrate the importance of supplier influence on utilization; and (4) consider some of the implications of the professional uncertainty hypotheses for public policy.

Cost-benefit and cost-effective analysis in surgery.

Cost-benefit analysis and cost-effective analysis are formal analytical methods to provide a rational, objective means of comparing total costs with total benefits or of comparing effects in the selection of competing programs for financial support. The use of these techniques in the medical field is a relatively recent development and can aid in future cost containment.

Ectopic pregnancy: incidence and review of determinant factors.

The incidence of ectopic pregnancies has been expressed in various ways that are not comparable and provide widely differing estimates due to individual definitions of the denominator. Population-based data are presented based on a count of all ectopic pregnancies reported in short stay hospitals in Maine, Rhode Island, and Vermont in 1974-1976. The incidence is 40 per 10(5) female population age 14-44 and is more consistent across 80 hospital service areas than other gynecological diagnoses. The data do not reveal an increasing incidence over these 3 years in contrast to national surveys based on a longer period of observation. A review of determinant factors for ectopic pregnancy is presented, and current theories concerning the etiology, changes in contraceptive practices, innovations in sterilization procedures, or advances in diagnosis do not appear individually or collectively to explain the increasing incidences reported by others. Further basic biologic and epidemiologic research is needed to determine causes and trends in this principal cause of first trimester mortality among pregnant women.

Papanicolaou cervical smears for screening in asymptomatic women.

The annual Papanicolaou smear as a screening test for cervical cancer is evaluated on the basis of cost-effectiveness, predictive value, and other factors of patient selection and comparative trends in mortality rate before and after the introduction of screening programs. For the asymptomatic woman at normal risk for cancer, Papanicolaou smears are recommended only once every five years, although symptomatic or high-risk women should still maintain an annual screening schedule.

An overview of hospital gynecologic practice.

Table 1 presents an overview of current gynecologic practice in hospitals as illustrated by three New England states. We believe the balance of diagnoses and operations displayed are reasonably typical of practice elsewhere in the United States. However, since operative rates are lower in New England than in other parts of the country, the proportions of women undergoing hysterectomy or a sterilization procedure will be somewhat higher elsewhere. The general issue of variation in rates of diagnoses and operations is presented; professional uncertainty is a fact which may account for the variation. Further controlled studies are urgently needed to decrease this element of uncertainty and to distinguish too much diagnosis and treatment from too little. Ultimately, nothing less will meet the standards of the best care for patients or satisfy health insurance or government programs that premiums or taxes are supporting an appropriate level of health care.