Myelostimulatory activity of recombinant human interleukin-2 in mice

In a series of studies designed to extend our understanding of interleukin-2 (IL-2) and to study the effect of biologic response modifiers on bone marrow, we observed that administering recombinant human (rH) IL-2 to normal mice resulted in an increase in the frequency of colony-forming units-culture (CFU-C) in bone marrow. In addition, rH IL-2 was able to accelerate host recovery from cyclophosphamide (CTX)- or radiation-induced bone marrow depression and peripheral blood leukopenia. Not only can rH IL-2 accelerate, in a dose-dependent manner, the return of bone marrow, peripheral blood cellularity, and CFU-C frequency to normal levels following cytoreduction by CTX or irradiation, but it also significantly increases CFU-C frequency to greater than normal levels. Furthermore, rH IL-2 can significantly prolong survival of animals receiving a lethal dose of irradiation or CTX. Thus, multiple mechanisms are responsible for the synergistic therapeutic activity associated with rH IL-2 and CTX. rH IL-2 does not act only as an immunomodulatory agent in the presence or absence of suppressor T cells, but also accelerates host recovery from cytoreductive agents, resulting in decreased leukopenia and perhaps resistances to secondary infection. Thus, rH IL-2 plus chemotherapy may increase therapeutic activity against neoplastic disease, not only by adding immune stimulation to the direct antitumor effect of the drug but also by allowing delivery of higher, more effective doses of chemotherapy.     

Ectopic expression of rhombotin-2 causes selective expansion of CD4-CD8- lymphocytes in the thymus and T-cell tumors in transgenic mice

Although the proto-oncogene rhombotin-2 (RBTN-2) is widely expressed in most tissues, it is not expressed in T cells. We investigated the potential for overexpression of RBTN-2 to cause tumors in T cells and other tissues by constructing transgenic mice that expressed RBTN-2 under control of the metallothionein-1 promoter. Despite overexpression of RBTN-2 in all tissues, transgenic mice developed T-cell tumors only, thus indicating that tumorigenesis caused by RBTN-2 is T-cell-specific. Thymic tumors were found between 37 and 71 weeks and were invariably associated with metastasis to nonlymphoid organs. Thymuses from apparently healthy transgenic mice were also examined. In some mice there was an 10-fold increase in the CD4-CD8- thymocyte subset, yet the total number of thymocytes was the same as that in wild-type mice. Thymic homeostasis was maintained by a compensatory reduction in the CD4+CD8+ subset. The expansion of CD4-CD8- thymocytes was associated with increased expression of RBTN-2 and with increased cell proliferation. No differences were found in the proportion of thymocytes undergoing apoptosis in transgenic mice. Furthermore, RBTN-2- induced expansion of CD4-CD8- cells did not block differentiation of these cells. Thymuses with 30% CD4-CD8- cells were essentially monoclonal, indicating that all thymic immunophenotypes were derived from a single clone. Overall, our data are consistent with the following scenario: (1) RBTN-2 expression in T cells causes selective and polyclonal proliferation of CD4-CD8- thymocytes accompanied by a compensatory decrease in other thymocyte subsets; (2) a clone with growth advantage and differentiation potential is selected and populates the thymus; and (3) this clone eventually breaches homeostasis of the thymus, accompanied or followed by metastasis to other organs.     

Iatrogenic complications in high-risk, elderly patients.

BACKGROUND--This study explores the quality improvement potential of reviewing care for long-stay, elderly medicine service patients hospitalized for congestive heart failure, acute myocardial infarction, or pneumonia at a large Midwestern teaching hospital. METHODS--Medical records were reviewed for 120 patients aged 65 years or older who were discharged between January 1987 and June 1989, with hospital stays of 15 days or longer. Patients' severity of illness on admission was rated using the Medicare Mortality Predictor System; process quality of care was rated using a structured implicit review form for judging several dimensions of clinical assessment and decision making. Serious complications were coded by etiology and type and judged as possibly or probably preventable. Logistic regression was used to identify risk factors for iatrogenic events; multiple regression was used to assess potential outcome bias in ratings of overall quality of care. RESULTS--Of 120 medical records reviewed, 70 (58.3%) suffered at least one iatrogenic complication. Forty-three patients (35.8%) suffered an iatrogenic complication rated as potentially preventable. Significant predictors of all iatrogenic complications were quality ratings of initial physician assessment, patients' inability to walk unassisted, and low Glasgow Coma Score. For potentially preventable complications, quality ratings for physician documentation of functional status were also significant. Ratings for overall quality of care were not significantly influenced by the mere presence of death or complications. CONCLUSIONS--Iatrogenic complications are likely to be an extremely common experience for elderly medicine service patients with long lengths of stay. A significant portion of these complications may be potentially preventable with closer attention to initial assessment and documentation of patients' functional status.     

Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand

We have further characterized the biological activities, mechanism of action, and target cell populations of recombinant human and murine thrombopoietin (rhTPO and rmTPO) in in vitro human and murine model systems. Alone, hTPO or mTPO stimulated the maturation of immature murine megakaryoblasts as measured in a single cell assay. The combination of hTPO or mTPO and interleukin-6 (IL-6) resulted in a further increase in megakaryocyte differentiation in this system. Murine TPO stimulated mouse megakaryocyte progenitor development. Human megakaryocyte progenitor development was potentiated by hTPO alone and further augmented in the presence of the early-acting cytokines (IL-3) or kit ligand/stem cell factor (KL/SCF). To further define the mechanism of action of TPO, neutralization studies were performed with antisera to IL-3, granulocyte-macrophage colony-stimulating factor (GM- CSF), IL-1 beta, and IL-11. No diminution in TPO activity was observed in the presence of these antisera. Moreover, because adhesive interactions are known to modulate hematopoiesis, we studied whether hTPO might alter such interactions between human bone marrow (BM) megakaryocytes and human BM stromal fibroblasts. No changes were observed in either megakaryocyte expression of the surface molecules lymphocyte function-associated antigen-1, very late activation antigen- 4, or intercellular adhesion molecule-1 or the adhesion of megakaryocytes to stromal fibroblasts after treatment with the growth factor. Furthermore, no induction of secretion of the cytokines IL-1 alpha, IL-1 beta, GM-CSF, IL-6, granulocyte-CSF, tumor necrosis factor- alpha, transforming growth factor-beta 1, or transforming growth factor- beta 2 by primary human BM megakaryocytes was noted after treatment of the cells with hTPO. To address whether TPO affects very primitive hematopoietic progenitors, we studied the residual cells from the BMs of mice treated with high doses of 5-fluorouracil. Although no effect of mTPO alone was noted on the viability or replication of such primitive murine progenitor populations, the triple combination of IL-3 + KL/SCF + TPO stimulated growth of megakaryocyte progenitors. These results indicate that TPO is a highly lineage-specific growth factor whose primary biological effects are likely to be direct modulation of the growth and maturation of committed megakaryocyte precursors and immature megakaryoblasts.     

Do the benefits of breastfeeding outweigh the risk of postnatal transmission of HIV via breastmilk?

Conflicting recommendations have been offered about whether HIV+ mothers should breastfeed. Since there is a strong precedent for US infant feeding practices to be imitated in developing countries, a model was constructed to estimate infant mortality if the CDC admonition for HIV+ mothers not to breastfeed were upheld in less developed settings. Estimates are given for infant mortality in the presence and absence of breastfeeding across several baseline levels of infant mortality and across several theoretical rates of transmission through breastfeeding. The infant mortality associated with HIV infection acquired through breastfeeding is estimated to be lower than the mortality associated with the diseases of infancy that would result if breastmilk were withheld. The difference in these estimates is greater in areas with high baseline levels of infant mortality.     

Phase I trial of interleukin-2 after unmodified HLA-matched sibling bone marrow transplantation for children with acute leukemia

Allogeneic bone marrow transplantation (BMT) for advanced acute leukemia is associated with a high risk of relapse. It is postulated that interleukin-2 (IL-2) administered after BMT might induce or amplify a graft-versus-leukemia effect and thereby reduce the relapse rate. To identify an IL-2 regimen for testing this hypothesis, a phase I trial of IL-2 (Roche) was performed in children in complete remission (CR) without active graft-versus-host disease (GVHD) off immunosuppressive agents after unmodified allogeneic matched-sibling BMT for acute leukemia beyond first remission. Beginning a median of 68 days after BMT, 17 patients received escalating doses of induction IL-2 (0.9, 3.0, or 6.0 x 10(6) IU/m2/d representing levels I, II, and III) for 5 days by continuous intravenous infusion (CIV). After 6 days of rest, they received maintenance IL-2 (0.9 x 10(6) IU/m2/d) for 10 days by CIV infusion. Levels I and II were well-tolerated, but, of 6 patients at level III, 1 developed pulmonary infiltrates, 1 developed hypotension (both resolved), and 1 died of bacterial sepsis and acute respiratory distress syndrome. Grade II acute GVHD developed in 1 patient at level I and 1 at level III. The maximum tolerated dose of induction IL-2 was level II. IL-2 induced lymphocytosis, with an increase in CD56+ and CD8+ cells. Ten patients remain in CR at 5+ to 67+ months. Thus, a regimen of IL-2 has been identified that did not induce a high incidence of acute GVHD when administered to children after unmodified allogeneic BMT. Its clinical activity will be assessed in a phase II trial.     

An Extension and Moderational Analysis of the Family Stress Model Focusing on African American Adolescents

This study focuses on 422 African American families with two caregivers as children transition into adolescence. The family stress model was tested longitudinally using structural equation modeling. Results showed that economic stress was associated with economic pressure and depressive symptoms among caregivers, which in turn was related to caregiver conflict. Higher levels of conflict had a negative influence on parenting quality at Wave 2, and this was linked to adolescent functioning. The depressive symptomology of secondary caregivers (SCs) exerted a greater indirect effect in the models than that of primary caregivers (PCs) and had a direct relationship to adolescent's positive adjustment. Moderational effects of caregiver conflict on the link between economic pressure/adolescent outcomes and economic pressure/hostile parenting were also tested. The case for the importance of including PCs and SCs of children and adolescents in future research focusing on African American families facing economic hardship is made.     

Application of the IML Resistograph to the infield assessment of basic density in plantation eucalypts

Average bark-to-bark resistance of the IML Resistograph PD400 (hereafter referred to as ‘Resi’) was found to provide strong linear correlations with the basic density of 12-mm-diameter increment cores taken from standing plantation eucalypt trees. Relationships between Resi values and approximately 2 000 cores (predominantly Eucalyptus globulus but some E. nitens) were examined across seven studies (representing samples from nine distinct sites) in Tasmania, Victoria and Western Australia. Custom-written software was developed to process the Resi traces to automatically perform a linear baseline correction of the trace, and extract:

• over-bark and under-bark diameter

• bark thickness

• average resistance of the bark-to-bark (under-bark) trace

• average resistance of the outer 50 mm on the entry and exit side of the traces.

Baseline correction was needed to counter the variable effects among trees of needle drag across the diameter, largely a function of tree diameter and wood density.

Individual traces were collected in less than 20 s tree^?1. The sampling conditions of 150 cm min^?1 speed of forward movement (feed speed) and 3 500 revolutions per minute (rpm) were identified as optimal for the plantation eucalypts studied. The relationship between different feed speeds and rpm were linear and coefficients determined to allow average Resi resistance to be converted to a common set of sampling conditions. A simple linear regression was identified in each study to define a slope and intercept to convert the Resi values to basic density and determine the variance between them. Resi traces from different studies were not always collected using the same instrument and this is believed to explain most of the between-study variance in slope and intercept.

Trace processing software was built into a web-based package that is available to make trace processing easy, with defined variables downloadable for use in routine plantation assessment. Users can change the default slope and intercept values to suit their individual instruments or species as required. Further work is required to fully define the effects of instrument, site and species on these relationships.

The IML Resistograph PD400 was found to be an accurate and quick (40–70 trees hour^?1 person^?1) infield tool for estimating diameter and wood density in standing trees. When combined with automated, web-based processing software the methodology is among the lowest cost options conceivable for wood density assessment of plantation eucalypts.     

A Systematic Review of Palliative Care Intervention Outcomes and Outcome Measures in Low-Resource Countries

Context

To meet the growing need for palliative care in low-resource countries, palliative care programs should be evidence based and contextually appropriate. This study was conducted to synthesize the current evidence to guide future programmatic and research efforts.