Anergic CD8+ T cells can persist and function in vivo.

Using a mouse model system, we demonstrate that anergic CD8+ T cells can persist and retain some functional capabilities in vivo, even after the induction of tolerance. In TCR Vbeta5 transgenic mice, mature CD8+Vbeta5+ T cells transit through a CD8lowVbeta5low deletional intermediate during tolerance induction. CD8low cells are characterized by an activated phenotype, are functionally compromised in vitro, and are slated for deletion in vivo. We now demonstrate that CD8low cells derive from a proliferative compartment, but do not divide in vivo. CD8low cells persist in vivo with a t1/2 of 3-5 days, in contrast to their in vitro t1/2 of 0.5-1 day. During this unexpectedly long in vivo life span, CD8low cells are capable of producing IFN-gamma in vivo despite their inability to proliferate or to kill target cells in vitro. CD8low cells also accumulate at sites of inflammation, where they produce IFN-gamma. Therefore, rather than withdrawing from the pool of functional CD8+ T cells, anergic CD8low cells retain a potential regulatory role despite losing their capacity to proliferate. The ability of anergic cells to persist and function in vivo adds another level of complexity to the process of tolerance induction in the lymphoid periphery.

Chronic modulation of the TCR repertoire in the lymphoid periphery.

Using TCR V beta 5 transgenic mice as a model system, we demonstrate that the induction of peripheral tolerance can mold the TCR repertoire throughout adult life. In these mice, three distinct populations of peripheral T cells are affected by chronic selective events in the lymphoid periphery. First, CD4+V beta 5+ T cells are deleted in the lymphoid periphery by superantigens encoded by mouse mammary tumor viruses-8 and -9 in an MHC class II-dependent manner. Second, mature CD8+V beta 5+ T cells transit through a CD8lowV beta 5low deletional intermediate during tolerance induction by a process that depends upon neither mouse mammary tumor virus-encoded superantigens nor MHC class II expression. Third, a population of CD4-CD8-V beta 5+ T cells arises in the lymphoid periphery in an age-dependent manner. We analyzed the TCR V alpha repertoire of each of these cellular compartments in both V beta 5 transgenic and nontransgenic C57BL/6 mice as a function of age. This analysis revealed age-related changes in the expression of V alpha families among different cellular compartments, highlighting the dynamic state of the peripheral immune repertoire. Our work indicates that the chronic processes maintaining peripheral T cell tolerance can dramatically shape the available TCR repertoire.

Loss of cell cycle controls in apoptotic lymphoblasts of the bursa of Fabricius.

Lymphoblasts of the normal embryonic follicles of the chicken bursa of Fabricius undergo rapid apoptosis when exposed to gamma-radiation or when cell-cell contacts are disrupted by mechanical dispersion in short term culture. We have observed previously that overexpression of v-myc sensitizes preneoplastic bursal lymphoblasts to induction of cell death, whereas resistance to induced cell death is acquired during progression to neoplasia. In this study we observed extensive DNA degradation in the large majority of the lymphoblast population within the first hour after dispersion-induced apoptosis. Paradoxically these cells continued to progress into S-phase with the bulk of DNA cleavage and death occurring in S-phase cells (i.e., in cells with more than 2C and less than 4C DNA content). We confirmed the S phase status of apoptotic cells by determining that detection of nuclear cyclin A in individual cells also corresponded with detection of DNA breakage. Levels of cyclin E, cyclin E-dependent H1 histone kinase, and p53 proteins were maintained during dispersion-induced DNA cleavage. gamma-radiation failed either to inhibit cell cycle progression or to raise p53 levels in dispersed bursal lymphoblasts. In intact bursal follicles low doses of gamma-radiation induced p53 whereas higher, apoptosis-inducing doses failed to induce p53 or prevent G1 to S-phase progression. These results suggest that normal DNA damage-induced cell cycle checkpoint controls are lost or overridden when apoptosis is induced in bursal lymphoblasts.

Half a loaf is better than waiting for the bread truck. A computerized mini-medical record for outpatient care.

We describe a locally developed system for partial computer storage of medical data, called the mini-medical record system. The system produces a typed face sheet prior to each patient visit. The face sheet, which also serves as a progress note, contains patient demographic data, medical problem lists, previous vital signs, allergies, medication profile, and health maintenance reminders. Between regularly scheduled visits, all computerized data are available by computer printout for unscheduled visits to walk-in clinics and the emergency department. Structured reports are generated by the system that describes each resident and faculty members' practice. Quality assurance reports are also available. Since the system draws from several already existing databases, new data entry requirements are modest and cost to the institution is low. Partially computerized systems can be developed inexpensively and are well received in multispecialty practices, where interphysician communication is vital.

Cost accounting, management control, and planning in health care.

Advantages and pharmacy applications of computerized hospital management-control and planning systems are described. Hospitals must define their product lines; patient cases, not tests or procedures, are the end product. Management involves operational control, management control, and strategic planning. Operational control deals with day-to-day management on the task level. Management control involves ensuring that managers use resources effectively and efficiently to accomplish the organization's objectives. Management control includes both control of unit costs of intermediate products, which are procedures and services used to treat patients and are managed by hospital department heads, and control of intermediate product use per case (managed by the clinician). Information from the operation and management levels feeds into the strategic plan; conversely, the management level controls the plan and the operational level carries it out. In the system developed at New England Medical Center, Boston, Massachusetts, the intermediate product-management system enables managers to identify intermediate products, develop standard costs, simulate changes in departmental costs, and perform variance analysis. The end-product management system creates a patient-level data-base, identifies end products (patient-care groupings), develops standard resource protocols, models alternative assumptions, performs variance analysis, and provides concurrent reporting. Examples are given of pharmacy managers' use of such systems to answer questions in the areas of product costing, product pricing, variance analysis, productivity monitoring, flexible budgeting, modeling and planning, and comparative analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuity of care after July: what happens to the resident's patients?

When internal medicine residents leave teaching programs, continuity of care for outpatients is affected. The authors had departing residents send their patients computer-generated letters identifying another physician to provide continuing care. The letters were randomly withheld from 20% of the patients (NL), and they were compared with patients who received letters (RL). A telephone survey was administered and visits and no-show rates were determined. The RL patients more often knew of the change in provider (84% vs 54%, p less than 0.01) and identified the resident as the source of the information (77% vs 43%, p less than 0.01) than NL patients. There were no significant differences between RL and NL patients in mean numbers of appointments (1.0 vs 0.8) or no-show rates (24% vs 21%) following housestaff turnover. Both groups wanted to be told by the physician about future changes and were willing to be informed by letter. A computer-generated letter appears to be an effective way of notifying patients about transfer of care during the annual housestaff turnover in teaching programs.