Identification of phenolic dermal sensitizers in a wound closure tape.

A latex-allergic patient presented with a severe local reaction to a non-latex wound closure bandage following surgery. Extracts of the bandage were analyzed by gas chromatograph-electron impact-mass spectrometry (GC EI-MS) in the total ion monitoring mode. Components were identified by their ion mass fingerprint and elution time as a corresponding standard from the GC column. The chemicals identified were 4,4'-thiobis-(6-tert-butyl-m-cresol) (TBBC), 6-tert-Butyl-m-cresol (BC), 2,4-di-tert-butylphenol (BP) and erucamide (EA). Sensitization potential of these chemicals was evaluated using two quantitative structure-activity relationship (QSAR) programs. The phenol 2,6-di-tert-butyl-4-(hydroxymethyl)phenol (BHP) was also included in the test series. It was initially thought to be present in the bandage but detectable levels could not be confirmed. The potential for TBBC to induce a sensitization response was predicted by both Derek for Windows and TOPKAT 6.2. The potential for BC and BP to induce a sensitization response was predicted by Derek for Windows, but not TOPKAT. BHP and EA were not predicted to be sensitizers by either QSAR program. Local lymph node assay (LLNA) analysis of the chemicals identified TBBC, BP, and BC as potential sensitizers with EC3 values between 0.2 and 4.5%. None of the animals exhibited body weight loss or skin irritation at the concentrations tested. In agreement with the toxicological modeling, BHP did not induce a sensitization response in the LLNA. Following a positive LLNA response, TBBC, BP, and BC were further characterized by phenotypic analysis of the draining lymph nodes. A positive LLNA result coupled with a lack of increase in B220(+)IgE(+) cell and serum IgE characterize these chemicals as Type IV sensitizers. These studies used a multidisciplinary approach combining clinical observation, GC-EI-MS for chemical identification, QSAR modeling of chemicals prior to animal testing, and the LLNA for determination of the sensitization potential of chemicals in a manufactured product.

Bacterial DNA does not increase serum corticosterone concentration or prevent increases induced by other stimuli.

Bacterial DNA containing unmethylated CpG motifs (CpG DNA) and other microbial molecules such as lipopolysaccharide (LPS) have a broad range of immune stimulatory effects, which may include many shared cell signaling pathways leading to enhanced cytokine production. Some cytokines activate the hypothalamic-pituitary-adrenal (HPA) axis, and their production is downregulated by products of the HPA axis (glucocorticoids). Because such interactions have practical implications in the clinical use of CpG DNA, the present study was done to examine the effects of CpG DNA and LPS on serum corticosterone concentrations. In contrast to LPS, administration of CpG DNA (DNA from Escherichia coli) (30-300 microg) alone did not significantly increase serum corticosterone concentrations 1 or 4 h after administration. Administration of CpG DNA to mice prior to LPS caused a synergistic increase in serum tumor necrosis factor-alpha (TNF-alpha), indicative of an immune stimulatory effect. LPS and TNF-alpha, however, induced similar levels of corticosterone with or without concomitant CpG DNA. Increasing doses of LPS caused peak corticosterone levels similar to those induced by LPS in combination with CpG DNA. Exogenous TNF-alpha administered in vivo induced comparable concentrations of corticosterone with or without CpG DNA. An alternative stressor (restraint) yielded similar levels of corticosterone with or without CpG DNA. These results indicate that CpG DNA does not induce corticosterone release or alter its release by other stimuli, indicating biologically important differences in its immune effect compared to those of LPS, and possibly reduced toxicity.

Toxicology of metam sodium.

Metam sodium is the third most commonly used agricultural pesticide (by weight) in the U.S. A spill of 19,000 gallons of metam sodium into the Sacramento River in 1991 clearly demonstrated that a major uncontrolled release can have adverse ecological and human health effects. Furthermore, this incident revealed that estimates of Reference Exposure Levels for the major breakdown product of metam sodium (methylisothiocyanate, MITC) were reasonable with regard to the induction of discomfort. In fact, the irritant properties of MITC seem to account for many of the most commonly reported symptoms in this incident. However, neurotoxicity may also account for some of these symptoms. There is evidence that metam sodium can act as a contact sensitizer in humans, inducing allergic dermatitis. It also may exacerbate or induce respiratory allergy (asthma). The ecological impact of routine use of metam sodium is not clear, but adverse effects on non-target plants have been inferred from modeling studies, and adverse effects on soil microbes have been observed. These issues deserve further study. Human health effects of occupational or routine environmental exposure to metam sodium are not known, but there is limited evidence for immunological (hypersensitivity) and developmental effects as well as irritation and associated symptoms. Animal studies suggest a potential for immunological, developmental, carcinogenic, and atherogenic effects. Metam sodium and some of its breakdown products have a wide variety of molecular and cellular actions that could explain the health effects noted here. However, further studies are needed to relate specific molecular or cellular actions to specific health effects.

Quantitative analysis of the neuroendocrine-immune axis: linear modeling of the effects of exogenous corticosterone and restraint stress on lymphocyte subpopulations in the spleen and thymus in female B6C3F1 mice.

The effects of exogenous corticosterone and restraint stress on the number and percentage of lymphocyte subpopulations in the spleen and thymus were evaluated. The data were used to generate linear models that describe the relationship between these parameters and the area under the corticosterone concentration vs time curve (AUC). Comparison of the models revealed that the number of nucleated cells in the spleen was decreased similarly by exogenous corticosterone and restraint (at equivalent corticosterone AUC values). However, exogenous corticosterone caused a greater decrease in cell number in the thymus than it did in the spleen. Corticosterone preferentially depleted CD4+CD8+ cells in the thymus, whereas the same corticosterone exposure produced by restraint stress did not. In the spleen, cell number for all major cell types was decreased by both treatments, but there were minor differences in the change in percentage of some subpopulations induced by exogenous corticosterone as compared to restraint. The models derived here provide quantitative data that indicate the magnitude of corticosterone and stress-induced effects on lymphocyte populations in the spleen and thymus. These results have mechanistic implications, and they may be useful in future efforts to extrapolate from mouse to human by completing a risk assessment parallelogram.

Modeling and predicting selected immunological effects of a chemical stressor (3,4-dichloropropionanilide) using the area under the corticosterone concentration versus time curve.

Many chemicals and drugs can induce a neuroendocrine stress response that can be immunosuppressive. Mathematical models have been developed that allow prediction of the immunological impact of such stress responses in mice on the basis of exposure to the important stress-related mediator corticosterone. The area under the corticosterone concentration vs. time curve (AUC) has been used as an indicator of cumulative corticosterone exposure in these modeling studies. In the present study, an immunotoxicant known to induce a stress response, 3,4-dichloropropionanilide (propanil), was evaluated to determine if corticosterone AUC values are related to suppression of immunological parameters in mice treated with this chemical. Linear relationships between corticosterone AUC values and suppression of the following parameters were noted in B6C3F1 female mice: thymus cellularity and thymus subpopulation percentages, splenic subpopulation percentages, natural killer cell activity, MHC class II protein expression, and IgG1 and IgG2a antibody responses to antigen. Linear models derived in previous studies using mice treated with exogenous corticosterone or with restraint stress effectively predicted the immunological effects of 3, 4-dichloropropionanilide on the basis of corticosterone AUC values. The models derived using immobilization stress were more effective (r(2) for observed vs. predicted = 0.90) than the models derived using mice treated with exogenous corticosterone (r(2) for observed vs. predicted = 0.65). This was expected, because most stressors induce a variety of immunomodulatory mediators, not just corticosterone. These findings have implications for risk assessment in immunotoxicology.

Health services research in a quick and dirty world: the New York City hospital occupancy crisis.

In 1987/1988, New York City experienced an unexpected health care crisis: a severe and prolonged communitywide shortage of inpatient hospital beds. A rapid rise in hospital occupancy rates dramatically ended a long-term decline in hospital utilization and left health care providers and policymakers baffled about both cause and remedy. This article describes the course of a short-term, intensive, midcrisis study that unraveled the reasons for the high occupancy rates. As a case study for a research effort that successfully yielded valid and timely results, this article illuminates the research design and methodological decisions that lay behind the findings and discusses the implications of those decisions. Key to the success of the study were a mandate to diagnose the crisis, a statewide patient discharge data base, our previous hands-on experience with that data base, active support for the study from the community of health care providers, and strong results.

How will changes in physician payment by Medicare influence laboratory testing?

In-office laboratory testing offers physicians an opportunity to increase their incomes through the potential profit available from technical services. This financial incentive for in-office testing has been altered by Medicare limits on physician payment, legislative changes in physicians' ability to bill Medicare for laboratory tests, and technological advances in office laboratory equipment. While restrictions on payment may make laboratory testing relatively less profitable than other technical services offered in the physician's office, in-office laboratory testing still offers potential financial benefit to physicians, particularly if they can influence the demand for tests. Economic theory suggests that physicians may be able to increase the demand for their services, including laboratory testing, but empirical data are not conclusive. As Medicare and other third-party payers consider fundamental reform in physician payment, the effect of different payment schemes on physicians' use of laboratory tests may have important consequences for physicians' income, the quality of care, patients' access to care, and the cost of the Medicare program.

Which hospital services are most overused? Results from a medical audit.

When we assessed the extent of unnecessary ordering of clinical services by medical house staff at a large university hospital, 21% of services were judged to be unwarranted. Most overordered were nuclear medicine services, followed by laboratory tests. Because of their large volume, clinical laboratory services accounted for 78% of all unwarranted orders. Unwarranted use of hospital services is substantial and variable among physicians and services. This study confirms the value of medical record reviews for documenting the need for and guiding the course of hospital cost-containment programs.

Lessons for teaching cost containment.

Increasing financial restrictions on hospitals by the federal government and changing physician reimbursement procedures make it more important to control the use of medical care resources by physicians. A prospective controlled study was made of an educational program for the medical and surgical house staffs and for medical students designed to reduce unneeded orders for low cost, high volume ancillary and nursing services. The program was comprised of six mutually reinforcing components: lectures, medical record audits and reviews, group feedback in the form of cost summaries containing information on unnecessary ordering, hospital price booklets, current patient bills, and pertinent journal articles. Operating at a time of retrospective hospital cost reimbursement, the program achieved only modest reductions in the residents' and students' use of hospital services and no substantive effect upon hospital costs. However, the program participants accepted the program enthusiastically. Several factors crucial to such educational cost containment programs were identified. The authors believe that experience with the program has valuable lessons for other hospitals initiating cost-control efforts.

The failure of physician education as a cost containment strategy. Report of a prospective controlled trial at a university hospital.

To test the hypothesis that physician education is an effective strategy to reduce total hospital costs, we evaluated three educational interventions at a large university hospital. This prospective controlled study spanned two academic years and involved 1,663 patients and 226 house staff. In the first year, weekly lectures on cost containment (medicine and surgery) and audit with feedback (medicine only) both failed to produce a significant change in total hospital charges. The "dose" of the intervention was increased on medicine in the second year by combining the lecture and audit strategies. Again, total charges did not change significantly. While decreased use occurred for certain selected services, the impact was not great enough to affect total hospital charges significantly. We conclude that, in the absence of other cost containing incentives, physician education alone is not an effective hospital cost containment strategy.

What's so special about special care?

Special care units are the most advanced, intensive, technological, and costly of hospital services. They also have proliferated rapidly. Yet little is understood about the definition, prevalence, genesis, costs, or benefits of SCUs. This paper defines and examines the many forces that have promoted the growth of special care, including hospital cost containment policies, fee-for-service reimbursement, medical ethics, standards of care, and manpower, and the much less numerous forces that have inhibited its spread. It is concluded that a sound appreciation of the dynamics of SCUs will be crucial to guiding future policy decisions as the nation's population ages and as hospitals continue to improve their capability to care for critically ill patients.

The costs and risks of medical care: an annotated bibliography for clinicians and educators.

Understanding the costs and risks of medical care, as well as the benefits, is essential to good medical practice. The literature on this topic transcends disciplines, making it a challenge for clinicians and medical educators to compile information on costs and risks for use in patient care. This annotated bibliography presents summaries of pertinent references on (1) financial costs of care, (2) excessive use of medical services, (3) clinical risks of care, (4) decision analysis, (5) cost-benefit analyses, (6) factors affecting physician use of services and (7) strategies to improve physician ordering patterns.