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Biomedical subjects

D C Dale

Publications and source records attributed to D C Dale.

At least 73 records · Page 4Linked to original sources
PubMed1994

Effects of in vivo recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers.

Recombinant granulocyte colony stimulating factor (G-CSF) was administered daily for 14 days to healthy young (Y) (20 to 30 years) and elderly (O) (70 to 80 years) volunteers to evaluate the effects of age on the neutrophil (polymorphonuclear leukocytes, PMN) responses. Thirty-eight volunteers were randomized to receive 0 micrograms, 30 micrograms, or 300 micrograms per day. Baseline neutrophil counts (ANC), peak ANCs, and the rate of attaining the peak ANC were similar in both age groups at both doses. The peak ANC was increased 5-fold at 30 micrograms and 15-fold at 300 micrograms in both the young and elderly. Daily tests of PMN function, as measured by an automated chemiluminescence system, showed nearly identical responses to several agonists for both age groups. Marrow proliferative activity as reflected by the percentage of cells in the marrow neutrophil mitotic pool also increased similarly for both age groups at both doses. In contrast, there was an age-related change in blood colony formation as measured by the blood CFU-GM assay. Compared with controls at the 30 micrograms dose, mean colony formation was increased 2-fold in the young versus no change in the elderly and at the 300 micrograms dose 24-fold in the young versus 12-fold in the elderly. These studies indicate that neutrophil responses to rhG-CSF are equivalent in healthy young and elderly volunteers but the mobilization of progenitor cells, as measured by the CFU-GM assay appears to differ substantially.

Adult↗
PubMed1994

Autosomal dominant cyclic hematopoiesis: exclusion of linkage to the major hematopoietic regulatory gene cluster on chromosome 5.

Autosomal dominant cyclic hematopoiesis (ADCH), or cyclic neutropenia, is a genetic disorder characterized by cyclic oscillations of neutrophils and other blood cells. To determine if the gene for ADCH mapped within the major hematopoietic regulatory gene cluster at 5q23.3-q33.3, we tested five families with ADCH for genetic linkage between the disorder and loci on chromosome 5q. Two-point analyses gave significant evidence in favor of excluding linkage between ADCH and the hematopoietic genes granulocyte-macrophage colony-stimulating factor (CSF), interleukins 3, 4, 5, and 9, and the receptor of macrophage-CSF. Furthermore, the exclusion data provide evidence for rejecting the hypothesis that ADCH may be encoded by a new gene mapping within this cluster.

Chromosome Aberrations↗
PubMed1994

Gene transfer in baboons using prosthetic vascular grafts seeded with retrovirally transduced smooth muscle cells: a model for local and systemic gene therapy.

Prosthetic vascular grafts containing retrovirally transduced autologous vascular smooth muscle cells were studied as a model for introduction of human genes into baboons. Retroviral vectors encoding beta-galactosidase (beta-Gal) (LNPoZ) or human purine nucleoside phosphorylase (LPNSN-2), a control gene, were used for ex vivo transduction of autologous baboon smooth muscle cells obtained from vein biopsies. Transduced cells were placed into a collagen solution and seeded into the interstices of polytetrafluoroethylene vascular grafts. Endothelial cells were then seeded onto the luminal surface of the grafts to reduce thrombus formation. One LNPoZ-seeded graft and one LPNSN-2-seeded control graft were implanted bilaterally into the aorto-iliac circulation of each of 4 animals. All grafts remained patent until they were removed after 3-5 weeks and examined histochemically for vector-expressing cells. All histological cross-sections from the beta-Gal vector seeded grafts contained cells staining blue with the X-Gal chromogen. For the four grafts, the mean fraction of LNPoZ expressing cells was 10%, with a range of 2-20%, while no sections from the control grafts contained stainable cells. Smooth muscle cells expressing the reporter gene were localized within the graft wall but not in the newly forming intima or outer capsule of fibrous tissue. Implantation of transduced cells within this type of vascular graft may provide a useful approach for long-term local and systemic gene therapy.

Animals↗
PubMed1994

Potential role of colony-stimulating factors in the prevention and treatment of infectious diseases.

The colony-stimulating factors (CSFs) principally involved in the production of neutrophils and monocytes are granulocyte CSF, granulocyte-macrophage CSF, macrophage CSF, and interleukin 3 (sometimes called multi-CSF). The natural response to inflammation and infection in the immunocompetent host probably involves all of these CSFs. CSFs can be used as pharmacological agents to accelerate the production of neutrophils and monocytes/macrophages and to enhance mechanisms of host defense. Rapidly accumulating evidence appears to justify the use of CSFs for the prevention of fever and infections in several clinical settings, such as chemotherapy-associated neutropenia, bone marrow transplantation, and severe chronic neutropenia. Trials of CSF treatment of infections in settings not including neutropenia are under way.

Colony-Stimulating Factors↗
PubMed1994

Aging and marrow neutrophil reserves.

OBJECTIVES: Measurement of blood neutrophil (PMN) counts after the administration of hydrocortisone, granulocyte colony-stimulating factor (G-CSF) and epinephrine. DESIGN: Prospective study, with subjects serving as their own controls before and after administration of hydrocortisone, G-CSF, and epinephrine. SETTING: The G-CSF and hydrocortisone studies were conducted at the Clinical Research Center, University of Washington, and the epinephrine study was conducted at the Seattle VA Medical Center. PARTICIPANTS: Healthy volunteers of both sexes (ages 20 to 30 years and 70 to 80 years) were recruited from the community. The subjects had no acute or chronic medical problems and were on no prescription medications. MAIN OUTCOME MEASURES: Change in the blood PMN count after administration of hydrocortisone (25 and 200 mg intravenously), G-CSF (30 and 300 micrograms subcutaneously), or epinephrine (10, 25, and 50 ng/kg/min intravenously). RESULTS: Baseline PMN counts were similar for all comparison groups. The peak PMN response (maximum count-baseline count) to hydrocortisone was significantly less in the older subjects (P < 0.01) at both doses. The peak PMN responses were 4588 +/- 418/mm3 (25 mg) and 6906 +/- 1121/mm3 (200 mg) in the young and 1886 +/- 399/mm3 (25 mg) and 2387 +/- 372/mm3 (200 mg) in the elderly subjects. The peak PMN response following G-CSF was not different (P > 0.05) in the two groups at both the dosages: 6696 +/- 736/mm3 (30 micrograms) and 9801 +/- 893/mm3 (300 micrograms) in the young and 6340 +/- 833/mm3 (30 micrograms) and 9733 +/- 956/mm3 (300 micrograms) in the elderly. There was no age-related change in the response to epinephrine. CONCLUSIONS: Aging has no effect on baseline PMN counts, bone marrow PMN reserves as measured with G-CSF, and blood PMN pools as measured with epinephrine. However the ability to mobilize these PMNs from the marrow into blood, as measured by the hydrocortisone response, is significantly reduced in the elderly.

Adult↗
PubMed1993

Quality of life of patients with severe chronic neutropenia receiving long-term treatment with granulocyte colony-stimulating factor.

OBJECTIVE: To evaluate the impact of long-term granulocyte colony-stimulating factor (GCSF) treatment on quality of life of patients with congenital, cyclic, or idiopathic neutropenia. STUDY DESIGN, INTERVENTION, AND OUTCOME MEASURES: Twenty-one patients receiving daily subcutaneous GCSF responded to retrospective questions about disease-related symptoms and physical, psychological, and social functioning before and with GCSF therapy. RESULTS: Statistically significant improvement occurred in energy, emotional reactions, social isolation, functional ability, life satisfaction, decreased hospital admissions, and school attendance. CONCLUSION: GCSF greatly improves quality of life in patients with severe chronic neutropenia.

Adolescent↗
PubMed1993

A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia.

Patients with idiopathic, cyclic, and congenital neutropenia have recurrent severe bacterial infections. One hundred twenty-three patients with recurrent infections and severe chronic neutropenia (absolute neutrophil count < 0.5 x 10(9)/L) due to these diseases were enrolled in this multicenter phase III trial. They were randomized to either immediately beginning recombinant human granulocyte colony-stimulating factor (filgrastim) (3.45 to 11.50 micrograms/kg/d, subcutaneously) or entering a 4-month observation period followed by filgrastim administration. Blood neutrophil counts, bone marrow (BM) cell histology, and incidence and duration of infection-related events were monitored. Of the 123 patients enrolled, 120 received filgrastim. On therapy, 108 patients had a median absolute neutrophil count of > or = 1.5 x 10(9)/L. Examination of BM aspirates showed increased proportions of maturing neutrophils. Infection-related events were significantly decreased (P < .05) with approximately 50% reduction in the incidence and duration of infection-related events and almost 70% reduction in duration of antibiotic use. Asymptomatic splenic enlargement occurred frequently; adverse events frequently reported were bone pain, headache, and rash, which were generally mild and easily manageable. These data indicate that treatment of patients with severe chronic neutropenia with filgrastim results in a stimulation of BM production and maturation of neutrophils, an increase in circulating neutrophils, and a reduction in infection-related events.

Adult↗
PubMed1993

The effects of daily recombinant human granulocyte colony-stimulating factor administration on normal granulocyte donors undergoing leukapheresis.

The effects of daily administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to eight normal volunteers donating granulocytes for neutropenic relatives undergoing marrow transplantation were studied. Granulocyte donors consisted of seven marrow donors (5 syngeneic, 2 HLA identical) and one haploidentical son who had not donated marrow. All donors were administered daily rhG-CSF at a mean dose of 5 micrograms/kg/d (range 3.5 to 6.0) for a mean of 11.75 days (range 9 to 14 days), and granulocytes were collected a mean of 7.6 times (range 4 to 12). RhG-CSF was well tolerated and only minor side effects were observed. All donors became anemic from marrow donation and the removal of red blood cells during the collection procedures. Red blood cell transfusions were not given. All donors had a decrease in platelet counts and the magnitude of the decrement appeared to be greater than in historical donors. This was due in part to increased removal of platelets with the collection product, but a direct effect of rhG-CSF on platelet production cannot be excluded. The mean precollection granulocyte level was 29.6 x 10(9)/L (range 11.8 to 79.8), which was a 10-fold increase over baseline. The mean number of granulocytes collected was 41.6 x 10(9) (range 1.3 to 144.1), which was a six-fold increase over historical donors not receiving rhG-CSF. The mean granulocyte level 24 hours after transfusion into neutropenic recipients was 0.95 x 10(9)/L (median 0.57 and range .06 to 9.47). This study indicates that rhG-CSF is safe to administer to normal individuals, significantly improves the quantity of granulocytes collected, and results in significant circulating levels of granulocytes in neutropenic recipients. Further studies to evaluate rhG-CSF in normal granulocyte donors are warranted.

Adult↗
PubMed1993

Hematopoietic progenitors and aging: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3.

BACKGROUND: Changes either in the number or in the responsiveness of hematopoietic progenitors may be a major factor accounting for age-related changes in stimulus driven hematopoiesis. METHODS: To test these hypotheses, we compared the relative proportions and the responsiveness of CD34+ bone marrow cells from healthy young (20-30 yrs) and healthy elderly (70-80 yrs) volunteers to G-CSF, GM-CSF, and IL-3 in an in vitro marrow culture system. RESULTS: There was no age-related difference either in the proportion of CD34+ marrow cells or in the proportion of a more mature CD34+ subset, defined as CD34+, CD33+ cells. Maximal colony formation by CD34+ cells stimulated with a combination of G-CSF, GM-CSF, and IL-3 was similar in the two groups, but the dose-response studies with individual growth factors revealed a 2-fold decrease in sensitivity of the elderly subjects' cells to G-CSF (p < .01). CONCLUSIONS: Aging has little impact on the marrow content of early precursors of the neutrophil lineage. There is, however, a significant difference in the in vitro proliferative response of these cells to the lineage specific growth factor G-CSF. This alteration may account for the greater propensity in elderly populations for the development of neutropenia with severe infections and chemotherapy.

Adult↗
PubMed1992

Abnormal responsiveness of granulocyte-committed progenitor cells in cyclic neutropenia.

The mechanism(s) driving cyclic hematopoiesis in human cyclic neutropenia remains unknown. Clinical trials suggest that an abnormal responsiveness of bone marrow progenitor cells to hematopoietic growth factors might cause oscillatory blood counts. Studies were performed to determine whether an abnormal responsiveness to multiple growth factors exists in this disorder and whether the defect could be shown in highly enriched populations of marrow progenitor cells. Bone marrow mononuclear cells from patients with congenital cyclic neutropenia required higher concentrations of added granulocyte-colony-stimulating factor (G-CSF) to achieve half-maximal colony growth than cells from normal subjects (478 +/- 90 pmol/L v 53 +/- 12 pmol/L, P less than .01). Patients also differed in requirement for granulocyte-macrophage-CSF (P less than .05), but not for interleukin-3 (P greater than .30). CD34+ bone marrow cells from three patients also showed this difference in G-CSF responsiveness (P less than .05). These data suggest that the defect in congenital cyclic hematopoiesis lies in growth factor receptor binding or the postreceptor signal transduction system that drives granulocytopoiesis.

Bone Marrow↗
PubMed1992

Effect of endotoxin on serum granulocyte and granulocyte-macrophage colony-stimulating factor levels in dogs.

The biologic effects of endotoxin are attributed to the release of several cytokines, including interleukin-1, interleukin-6, tumor necrosis factor, and the colony-stimulating factors. To investigate the mechanism of endotoxin-induced neutrophilia in dogs, several cell lines known to proliferate selectively in response to recombinant human colony-stimulating factors were examined to determine their responses to recombinant canine granulocyte colony-stimulating factor (rcG-CSF) or recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF). The murine cell line NFS-60 was found to respond well to rcG-CSF and the human cell line TALL-101 to rcGM-CSF, and these responses were neutralized by antibodies to these recombinant proteins. These bioassays were then used to determine G-CSF and GM-CSF levels in dogs after intravenous endotoxin administration. G-CSF levels increased by 2 h, peaked at 4 h, and had not returned to normal by 24 h after endotoxin. In contrast, GM-CSF was not detectible before or after endotoxin administration.

Animals↗