Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease.

We investigated the use of 'prophylactic' donor lymphocyte infusions (DLI) containing 1 x 107 CD3+ cells, given at 30, 60 and 90 days post-allogeneic blood and marrow transplantation (BMT), following conditioning with fludarabine 30 mg/m(2)/4 days and melphalan 70 mg/m(2)/2 days. GVHD prophylaxis consisted of cyclosporin A (CsA) 2 mg/kg daily with early tapering by day 60. Our goals were the rapid achievement of chimerism and disease control, providing an immunological platform for DLIs to treat refractory patients with hematological malignancies. Twelve heavily pre-treated patients with life expectancy less than 6 months were studied; none were in remission. Diagnoses were AML (n = 4), MDS (n = 1), ALL (n = 3), CML (n = 3) and multiple myeloma (n = 1). Response rate was 75%. Three patients are alive at a median of 450 days (range, 450-540). Two patients are in remission of CML in blast crisis and AML for more than 14 months. Median survival is 116 days (range, 25-648). Six patients received 12 DLIs; three patients developed acute GVHD after the first infusion and were excluded from further DLIs, but no GVHD occurred among patients receiving subsequent DLIs. One patient with CML in blast crisis went into CR after the first DLI. The overall incidence of acute GVHD was 70%. Primary causes of death were infections (n = 3), acute GVHD (n = 3), chronic GVHD (n = 1) and disease relapse (n = 2). We observed high response and chimerism rates at the expense of an excessive incidence of GVHD. DLI given at day +30 post BMT caused GVHD in 50% of the patients, and its role in this setting remains unclear.

The effect of full-time faculty hospitalists on the efficiency of care at a community teaching hospital.

BACKGROUND: Hospitalists are increasingly being used for inpatient care. OBJECTIVE: To investigate whether the use of hospitalists is beneficial. DESIGN: Retrospective cohort study. SETTING: Inpatient medical service of a 500-bed community teaching hospital. PARTICIPANTS: 1620 patients in the study group, seen during the hospitalist year; 1679 patients from the same outpatient practice as the study group, seen during the previous year (prehospitalist year); an unselected comparison group of 3413 patients seen during the prehospitalist year and 3223 patients seen during the hospitalist year; and a subset of the unselected comparison group, cared for by outpatient practices, who had a prehospitalist length of stay similar to that of the study group (743 patients in the prehospitalist year and 786 in the hospitalist year). INTERVENTIONS: Full-time faculty hospitalists cared for the study group, were in the hospital during normal working hours, and made decisions throughout the day. In the prehospitalist year and in the comparison groups, primary care physicians managed their own hospitalized patients. MEASUREMENTS: Length of stay; cost of care; costs of hematology and chemistry evaluation, pharmacy, and radiology; and readmissions were determined for the prehospitalist and hospitalist years. RESULTS: In the study group, median length of stay decreased from 6.01 to 5.01 days (P < 0.001). Median cost of care decreased from $4139 to $3552 (P < 0.001), and the 14-day readmission rate decreased from 9.9 to 4.64 readmissions per 100 admissions (P < 0.001). In the comparison groups, length of stay decreased but both cost of care and readmission rates increased. CONCLUSION: Hospitalists may improve the efficiency of inpatient care. Further study in various settings is needed to verify these findings.

Assessment of cocaethylene lethality in Long-Evans female and male rats.

Cocaethylene, the metabolite of cocaine produced only in the presence of alcohol, produces a number of pharmacological, physiological, and behavioral effects. It also has a range of toxicological consequences, the most severe being lethality. Given that the assessments of cocaethylene lethality have been limited to mice, the present study assessed the lethality of cocaethylene in rats. Further, because of within-species sex differences with its parent compound, cocaine, cocaethylene lethality was also examined in both females and males. Specifically, female and male rats were injected IP with 75, 87, 100, 115, and 133 mg/kg cocaethylene and observed over a 24-h period. Deaths were dose dependent and occurred within 30 min for both females and males. For females, the LD50 was 96 mg/kg; for males, the LD50 was 70 mg/kg. The percentage of rats displaying severe effects (i.e., seizure and death) increased with dose across all postinjection times. Further, these effects occurred earlier as dose increased. Differences in the LD50 for rats and mice, as well as the greater sensitivity to cocaethylene in male rats, are discussed.

The effects of cocaine preexposure on the acquisition of cocaine-induced taste aversions.

In separate experiments, rats received either five intraperitoneal or five subcutaneous injections of cocaine (once daily or spaced every fourth day) prior to receiving repeated saccharin-cocaine pairings (during taste aversion conditioning). Both spaced and massed subcutaneous cocaine preexposure attenuated the subsequent acquisition of taste aversions induced by cocaine. Specifically, aversions in the preexposed subjects were acquired at a slower rate and/or to a lesser degree than those acquired by subjects preexposed to the cocaine vehicle and injected with cocaine during conditioning. Spaced and massed intraperitoneal cocaine preexposure had only a weak or no effect, respectively, on the subsequent acquisition of cocaine-induced taste aversions. Specifically, subjects receiving spaced intraperitoneal injections of cocaine during preexposure differed from nonpreexposed subjects on only a single conditioning trial, and subjects receiving massed intraperitoneal injections of cocaine during preexposure displayed aversions comparable to those of nonpreexposed subjects. Although the effects of subcutaneous cocaine preexposure were similar to those reported with other drugs within the aversion design, it is clear that the preexposure effect with cocaine is dependent upon the specific parameters of preexposure. Several possibilities for these differential effects of cocaine preexposure were discussed, including the influence of changing the route of administration from preexposure to conditioning (i.e., from i.p. to s.c.) and the differential masking of the aversive effects of cocaine during conditioning by differential sensitization to cocaine's reinforcing properties following s.c. and i.p. preexposure. Although the present series of experiments did not directly address the mechanism(s) underlying the attenuating effects of cocaine preexposure on aversion learning, several possibilities were noted, including adaptation or tolerance to the aversive effects of cocaine and sensitization to its rewarding effects.

Interleukin-1beta-stimulated invasion of articular cartilage by rheumatoid synovial fibroblasts is inhibited by antibodies to specific integrin receptors and by collagenase inhibitors.

OBJECTIVE: To study the role of integrin receptors in the invasion of cartilage by rheumatoid synovial fibroblasts (RSF). METHODS: RSF were cocultured with cartilage slices alone or in the presence of various potential activators or inhibitors. The penetration of the cartilage surface by RSF was determined by live-cell imaging of fluorescent-labeled cells. RESULTS: Interleukin-1beta (IL-1beta) and IL-8 stimulated the RSF invasion of cartilage. Invasion was specific for RSF and required a concentration gradient of IL-1beta. The IL-1beta-activated invasion of cartilage was inhibited by anti-IL-1 antibodies, IL-1 receptor antagonist, and collagenase inhibitors. RSF invasion was also inhibited by antibodies to alpha4, alpha5, alphaV, and beta1 integrins. CONCLUSION: In this study, an IL-1beta concentration gradient was required for RSF invasion into cartilage, raising the possibility that in vivo invasion may be induced by IL-1beta released by chondrocytes. The IL-1beta activation of RSF assayed in vitro may contribute to the RSF invasion of cartilage in vivo. Cartilage invasion requires the availability of beta1 and alpha4, alpha5, and alphaV integrins and the presence of collagenase activity.

Deficit of T-cell recovery after allogeneic bone marrow transplantation in chronic myeloid leukemia patients.

The immunological reconstitution that follows bone marrow transplantation (BMT) was studied in 40 leukaemia patients: 19 with chronic myeloid leukaemia (CML), 12 with acute myeloid leukaemia (AML) and the remaining 9 with acute lymphoblastic leukaemia (ALL). The recovery of the CML group was slower than that of the ALL and AML groups. This difference was produced by the T cell compartment, as NK cell activity and B cell numbers did not differ significantly. Factors such as conditioning treatment and graft versus host disease (GVHD) prophylaxis were analysed. Our experience suggests that all leukaemia patients should not be considered as one group when analysing their immunological reconstitution, as factors related to the original disease may affect their outcome.

Fibronectin induces protease dependent focal matrix depletion and cell overlap in cultured rheumatoid synoviocytes.

OBJECTIVE: To characterize the effect of added fibronectin (Fn) on human rheumatoid synoviocytes (RAS). METHODS: Early passage cultured RAS were studied by fluorescent imaging microscopy with multiple parameter overlaying and confocal laser scanning microscopy. RESULTS: Added Fn induced a localized decrease in matrix Fn at sites of cell overlap. Similar matrix depletion could be induced by collagen VI, cell binding (120 k) and heparin binding (60 k) fragments of Fn, but not by gelatin binding fragment (45 k). CONCLUSION: The decrease in matrix Fn was associated with the induction of a transformation-like phenotype of overlapping cell growth. Both phenomena were inhibited by serine protease inhibitors.

Total quality management of a medical residency.

Although many hospitals have begun the long and difficult process of adapting to the concepts of total quality management, few have reported efforts to apply total quality management to a medical residency. We report here the initial results of the Western Pennsylvania Hospital's efforts, as part of the hospital's conversion of its management structure to total quality management.

Immunological recovery after bone marrow transplantation for severe aplastic anaemia: a Brazilian experience.

Twenty-nine patients with severe aplastic anaemia (SAA) were submitted to bone marrow transplantation (BMT) and their immunological recovery analysed. Total lymphocyte counts, estimation of B lymphocytes, T lymphocytes and their subsets, natural-killer (NK) activity were performed. Cells with the CD8+ phenotype and NK activity were the first signs of immunological recovery, whereas the CD4+ subset recovered later in patients who suffered from acute graft versus host disease (GvHD) and infections. Acute and chronic GvHD, cirrhosis, rejection and HIV viral infection contributed to the persistence of the profound immunodeficiency status observed after BMT. Our results did not differ greatly from the others and confirmed that BMT may be performed in underdeveloped countries despite the difficulties it might pose.

Improved in vitro models for assay of rheumatoid synoviocyte chemotaxis.

OBJECTIVES: (1) To define the optimal conditions for transwell assay of synoviocyte chemotaxis. (2) To develop a live cell imaging chemotaxis assay for synoviocytes. (3) To characterize the chemotaxis of rheumatoid synoviocytes (RAS). RESULTS: Optimal conditions for transwell assay of synoviocyte chemotaxis were 8 microns pore size filters coated with collagen I (C1), assayed for 24 hours. Without the C1 coating 2.9 x 10(3) RAS migrated to the lower chamber. This increased to 4.7 x 10(3) when 20 micrograms/ml fibronectin (Fn) was added. With the C1 coating 4.3 x 10(3) cells migrated through the filter without chemotactic stimulation compared to 12.8 x 10(3) with interleukin 1 beta (IL-1 beta) 5 ng/ml, 12.2 x 10(3) with granulocyte-macrophage colony stimulating factor (GM-CSF) 25 ng/ml, 11.7 x 10(3) with Fn 20 micrograms/ml, and 9.0 x 10(3) with transforming growth factor-beta 1 (TGF-beta 1) 20 ng/ml (all p < 0.01). In the imaging assay, 50.7% of the RAS migrated toward the C1 coating without bound chemoattract. The percentage of cells migrating toward each chemoattractant at its optimal concentration was 64.3% for IL-1 beta, 60.8% for IL-8, 64.7% for GM-CSF, 61.0% for Fn, 58.9% for IL-6, and 69.1% for TGF-beta 1 (all p < 0.01). All of these chemoattractants increased directed migration without changing the random migration. Indomethacin (100 ng/ml) and Dexamethasone (10 ng/ml) inhibited Fn-induced chemotaxis. CONCLUSION: We report two in vitro assays for synoviocyte chemotaxis adapted and optimized for the study of synoviocytes. The live cell imaging assay had the advantage that it could separate directed and random migration.

An analysis of the cost and revenue of an expanded medical residency.

OBJECTIVE: To analyze the additive costs and revenues resulting from expansion of a medical residency and associated subspecialty programs. METHODS: Direct and indirect costs of the residency program were analyzed as was reimbursement for the costs of the residency. To determine whether expansion of the residency affected cost of care, the authors compared the costs of care on the teaching service and nonteaching services. RESULTS: The number of residents increased from 18 medical resident and subspecialty fellows in the 1988 academic year to 36 medical residents and 12 subspecialty fellows in the 1991 academic year. Total measured costs increased by $2,036,570 to $3,911,196. Reimbursement increased to $5,319,117, of which $2,290,221 was attributed to the increase in the number of residents. Net income from the residency after subtracting costs increased by $815,714 to a total of $1,407,971, excluding any higher costs at the authors' hospital that were an indirect result of the teaching program. Costs for the same diagnosis-related groups (DRGs) were not significantly different on the teaching and nonteaching services. CONCLUSIONS: Expanding the medical residency increased the net income available to offset the higher costs per DRG at the hospital. These costs did not increase in proportion to the increase in resident numbers. Increased revenue came primarily from Medicare indirect cost reimbursement. A reduction in this rate from 7.7% to less than 4.1% would have resulted in a net loss for medical education costs. Present reimbursement policy is not aligned with actual costs or public policy goals. This may have undesired effects both now and in the future.

Late marrow allograft rejection following alpha-interferon therapy for hepatitis in a patient with paroxysmal nocturnal hemoglobinuria.

We describe a case of allograft rejection that occurred 23 months after successful bone marrow transplantation for severe aplastic anemia in a patient with paroxysmal nocturnal hemoglobinuria. The allograft rejection appears to have been induced by recombinant alpha-interferon (rINF-alpha) treatment for non-A, non-B hepatitis that developed 11 months after transplantation. During the 9 months of active hepatitis, the donor graft functioned normally; however, 3 months after rINF-alpha therapy was started, pancytopenia and a chimeric hematopoietic state developed. rINF-alpha was discontinued, cyclosporin A was reintroduced, and autologous bone marrow recovery followed. rINF-alpha treatment may be detrimental to some recipients of allogeneic bone marrow transplants.

Successful treatment of T-gamma lymphoproliferative disease with human-recombinant granulocyte colony stimulating factor.

A trial of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was attempted in a male with agranulocytosis, infection, and T-gamma lymphoproliferative disease (T-gamma-LPD). During five days of rhG-CSF (960 micrograms/day), the absolute neutrophil count (ANC) increased from 0.0 to 4.5 K/microliters. There were no changes in eosinophil or lymphocyte counts. In addition, there was no toxicity. Bone marrow cytotoxic/suppressor cells (CD57+/CD8+) were elevated (21.9%) before and decreased to 10.6% (normal less than 12%) following rhG-CSF. By contrast, there was no change in activated T cells (CD3+DR+) or T cell gene rearrangements. These findings suggest rhG-CSF can improve granulopoiesis in T-gamma-LPD, possibly by altering T-cell mediated marrow suppression.

Study of lymphocyte populations and natural killer activity in severe aplastic anaemia.

Thirty-one patients (pts) with aplastic anaemia (AA) were studied whose probable etiology were: idiopathic (16 pts), nocturnal aroxysmal haemoglobinuria (NPH) (2 pts), benzene (4 pts), agrotoxics (5 pts), pharmaceutical drugs (2 pts) and insecticides (2 pts). A decrease in total lymphocyte counts was seen in 10 pts belonging mainly to the NPH and pharmaceutical drug groups, whereas, in the benzene group the opposite was found. B cell levels were low in 9 out of 20 pts. T cell levels varied, the majority of patients had normal levels, 13 presented low levels and 4 had increased numbers. CD4 levels were low in 14 pts and T cell numbers were compensated in some by an increase in CD8 cells. Our results show that there is a great heterogeneity among the patients and there might be differences in the immunological profile of aplastic anaemia depending on the causative agent of the disease.

Control of crystal-induced arthropathies.

Present approaches to the treatment to crystal-induced arthropathies and indications for their use are reviewed. Successes and limitations of such therapy are discussed and potential new approaches to treatment are discussed. Treatment of gout hyperuricemia is generally effective if appropriately applied and is likely to be improved principally by better application of presently available drugs. New approaches to treatment may improve care for those patients in whom present approaches to management remain unsatisfactory.