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Biomedical subjects

D G Nathan

Publications and source records attributed to D G Nathan.

At least 19 recordsLinked to original sources
PubMed1993

Academic careers: choice and activity of graduates of a pediatric residency program 1974-1986.

In summary, our data suggest that the playing field for academic medicine is changing. It is more patient care oriented, more multifaceted and supported more by clinical dollars than in the past. Greater flexibility in what constitutes "academic success" is necessary to assure a supportive environment in which tomorrow's academic faculty can develop and flourish. To accomplish these goals promotion systems that reward not only research but also teaching and clinical care accomplishments will be necessary. Clinicians will need to be compared with clinicians, teachers with teachers, clinical investigators with clinical investigators and basic investigators with basic investigators. Sources of support will need to be more clearly targeted along activity lines with clinical dollars supporting the clinician, medical education dollars supporting the teacher-educators and federal and foundation dollars supporting research. In our department, time and effort for research (45%) approximates dollar support for this activity (44%), while clinical dollars (43%) fund to a greater degree time and effort committed to clinical care (34%), and administration and teaching dollars (13%) under fund time and effort committed to these activities (21%). This suggests the need to identify increased funding to support teaching and education. Promotion expectations for women will need to be more flexible and adjusted to family responsibilities and demands. Most of all, however, we academic faculty must support enthusiastically the importance and joy of our work. We must be encouraging to our colleagues and our students and continue to recognize that for all of the difficulties and challenges, academic life is a rewarding and fulfilling enterprise.

Academic Medical Centers↗
PubMed1992

Enhanced expression of interleukin-3 and granulocyte-macrophage colony-stimulating factor receptor subunits in murine hematopoietic cells stimulated with hematopoietic growth factors.

AIC2A and AIC2B are closely related genes encoding components of the receptors for murine interleukin-3 (IL-3) (AIC2A) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5 (AIC2B). We have studied the parallel regulation of expression of these genes in erythroid and myeloid progenitor cell lines. AIC2A and AIC2B transcription was transiently induced in these cells in response to a variety of hematopoietic growth factors, including erythropoietin (EPO), monocyte-CSF, IL-3, GM-CSF, and stem cell factor (SCF or kit ligand). Run-on assays established that the increase occurred mainly at the transcriptional level. Immunoprecipitation experiments confirmed that the increase in messenger RNA expression resulted in augmented synthesis of both AIC2A and AIC2B proteins, and binding studies further showed these proteins to be functional. We observed a fourfold increase in low-affinity IL-3 sites in an erythroid precursor cell line stimulated with EPO, and a threefold increase in GM-CSF high-affinity sites in a myeloid cell line stimulated with IL-3. In addition, we showed that the increase in the IL-3 receptor chain AIC2A in the erythroid precursor cell line correlated with the ability of IL-3 to exert a cooperative effect with EPO in the induction of beta-globin in these cells.

Base Sequence↗
PubMed1992

Careers chosen by graduates of a major pediatrics residency program, 1974-1986.

Knowing the career choices of a residency program's graduates helps those who direct the program improve their intern selection process, fashion a more appropriate curriculum, and assess the professional choices of their trainees. This report presents a summary of data the authors obtained in 1988 and 1989 on the career choices of 270 of the 276 graduates who had served at least two years in the pediatrics residency at The Boston Children's Hospital between 1974 and 1986. The study findings are compared with the findings of two other national surveys of career choices of pediatrics residents. The data indicate that 66% of the 270 graduates were in academic pediatrics careers, which is much higher than the 20-23% of those involved in such careers nationwide. The remaining graduates were either in pediatrics practice (31%) or in other professional activities (3%), such as working at the National Institutes of Health, in public health, and for industry. There was a steady increase in the percentage of women over the 12-year period covered by the study, from 30% to 39%. These and many more findings brought to light program deficiencies in a number of areas, which are now being remedied.

Boston↗
PubMed1992

The production of steel factor mRNA in Diamond-Blackfan anaemia long-term cultures and interactions of steel factor with erythropoietin and interleukin-3.

Diamond-Blackfan anaemia (DBA) is a congenital macrocytic anaemia. To investigate whether DBA is due to hyporesponsiveness to or hypoproduction of Steel factor (SF), we compared the in vitro responsiveness of the BFU-E contained in the Ficoll-Hypaque non-adherent cell fraction of six DBA marrows with that of four normal marrows and one transient erythroblastopenia of childhood (TEC) marrow. In addition, we studied the effect of soluble SF on long-term marrow cultures (LTMC) and analysed the stromal cells from these cultures for SF mRNA transcripts. All the patients showed an erythropoietin dose-related increase of small BFU-E. The number and size of BFU-E was increased with the addition to the epo of IL-3 or SF; IL-3+SF was not synergistic. The addition of soluble SF to LTMC of DBA patients was associated with a small but consistent increase in non-adherent cell production and an increase in the number of progenitors. Messenger RNA from immortalized stromal cell lines of three patients and from primary bone marrow stromal cells of one patient showed the presence of expected SF transcripts by PCR analysis. These results demonstrate that this group of DBA patients responds to SF and produces SF mRNA normally, indicating that SF itself is not involved in DBA pathophysiology. The effects observed suggest that, despite the lack of evidence for a causative role, SF may prove to be effective treatment for such patients.

Adult↗
PubMed1992

Hydroxyurea-induced HbF production in anemic primates: augmentation by erythropoietin, hematopoietic growth factors, and sodium butyrate.

Hydroxyurea, a cell-cycle-specific cytotoxic agent, has been shown to increase fetal hemoglobin (HbF) production. This property makes it an attractive drug for treatment of sickle cell disease and severe beta thalassemia. Its potential efficacy is limited because of a variable and often suboptimal response. Combinations of hydroxyurea and other drugs may induce more clinically significant increases in HbF. We have utilized chronically phlebotomized rhesus monkeys, treated with oral hydroxyurea, to investigate the capacity of several other agents to further augment HbF synthesis. Recombinant human erythropoietin, in super-pharmacologic doses, increased F-reticulocyte production when given on a weekly sequential schedule (3 of 7 days) with hydroxyurea (4 of 7 days), but it was less effective on an alternate day schedule when hydroxyurea was given daily. Neither recombinant human interleukin 3 (IL-3) nor recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), when infused individually, increased F-reticulocytes in animals receiving daily hydroxyurea. Sequential, overlapping infusions of IL-3 and GM-CSF produced a small but statistically significant increase in F-reticulocytes in one of two hydroxyurea-treated animals. Infusions of sodium butyrate produced a substantial augmentation in F-reticulocyte production in animals chronically treated with hydroxyurea. Thus, our studies have identified several agents that may prove useful in combination with hydroxyurea to achieve clinically beneficial levels of HbF.

Administration, Oral↗
PubMed1992

A service chief model for general pediatric inpatient care and residency training.

Pediatric training programs are faced with rapid, fundamental changes in hospital practice and an increasingly rigorous regulatory and fiscal environment. Traditional models for providing care and teaching students and house officers may not be sufficiently responsive to these challenges. In 1986, the Department of Medicine at Children's Hospital, Boston, reorganized the general inpatient program and implemented a "service chief" system adapted from British hospital "firms." Three age-based inpatient services (Thomas Morgan Rotch infant/toddler service, Kenneth Daniel Blackfan school-age service, and Charles Alderson Janeway adolescent/young adult service) were created, each headed by an experienced clinician and teacher (service chief). The service chiefs developed age-appropriate curricula, recruited a balanced faculty of generalists and specialists to serve as attending physicians and provide teaching in their areas of expertise, and established strong collaborative relationships with nurse managers on their respective wards. Implementation of the service chief system has been associated with development of faculty esprit de corps, standardized tracking of faculty performance, enhanced supervision and counseling of housestaff, and improved continuity of patient care. Relationships with referring physicians have improved dramatically, as measured by formal satisfaction surveys. Accountability and documentation have been emphasized, and departmental billings have increased sharply. Ongoing quality indicators have been developed, and collaborative patient care, teaching, and quality-improvement projects have been initiated with the nursing staff. Naming the services for distinguished past physicians-in-chief has provided a focus for fund-raising.(ABSTRACT TRUNCATED AT 250 WORDS)

Accreditation↗
PubMed1991

A functional isoform of the human granulocyte/macrophage colony-stimulating factor receptor has an unusual cytoplasmic domain.

The granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor (GMR) transduces a signal that results in the proliferation, differentiation, and functional activation of hematopoietic cells. This study sought to determine whether functional isoforms of the receptor exist that may be important in generating this diversity of cellular response. We have isolated a cDNA encoding an isoform of the low-affinity human GMR that is a product of alternative splicing of the GMR gene and results in a predicted 410-amino acid protein with a cytoplasmic domain that is rich in serine residues, a feature of regions critical in signal transduction for other receptors of the hematopoietin receptor superfamily. This receptor bound ligand and was functionally active when introduced into a murine factor-dependent cell line; mRNA transcripts representative of this isoform were coexpressed with those for a previously isolated 400-amino acid isoform of the GMR in normal hematopoietic and leukemic cells. In view of the recent isolation of a cDNA, designated GM-CSF R beta, that confers high-affinity binding of GM-CSF in cotransfection experiments with the low-affinity receptor, we suggest that the previously isolated low-affinity receptor be designated GM-CSF R alpha 1 and the one described in this report be designated GM-CSF R alpha 2.

Amino Acid Sequence↗
PubMed1990

Restoration of phagocyte function by interferon-gamma in X-linked chronic granulomatous disease occurs at the level of a progenitor cell.

Phagocytes from X-linked chronic granulomatous disease (X-CGD) patients are deficient in their ability to generate superoxide because of a defective gene that encodes a heavy chain of cytochrome b, a critical component in the superoxide-generating pathway. Previously we have shown that a single in vivo treatment of selected X-CGD patients with interferon-gamma (INF-gamma) resulted 14 days later in near-normal levels of superoxide generation by phagocytes. The effect persisted for 28 days. This prolonged effect suggested that the lymphokine affected progenitor cells. In this study, we examined progenitor-derived colonies from the peripheral blood from this unusual X-CGD kindred. Progenitor-derived colonies examined before treatment were unable to generate superoxide as visualized by lack of nitro blue tetrazolium (NBT) reduction compared with normal controls. By contrast, colonies derived 7 days after a single INF-gamma injection were able to generate superoxide as shown by increased NBT reduction. Colonies harvested 21 days after treatment contained only rare cells capable of NBT reduction. Our results indicate that INF-gamma can reprogram the myeloid progenitor cells to express a partially corrected phenotype. This corrected phenotype is later expressed in daughter cells.

Cell Differentiation↗
PubMed1990

The effect of desferrithiocin, an oral iron chelator, on T-cell function.

Desferrithiocin is a new, potent, orally available iron chelator. To determine whether this drug might be useful not only for iron-overload but also for immunosuppression, we studied the in vitro effects of desferrithiocin on T-lymphocyte function. Like deferoxamine, desferrithiocin inhibited, in a dose-dependent fashion, mitogen- and lectin-induced proliferation of both human and murine T cells. It was active at a concentration of 10 micrograms/mL. The inhibition of proliferation was reversed by ferrous chloride, but not by other metal salts, recombinant IL-2, or conditioned medium. Desferrithiocin also inhibited proliferation of constitutively dividing, and factor-independent EBV-transformed B cell and leukemic T-cell lines. Although desferrithiocin inhibited the induction of cytotoxic T lymphocyte (CTL) activity, it did not inhibit CTL- or natural killer-induced cytotoxicity. The agent did not inhibit the expression of activation antigens such as the IL-2 receptor on T cells, nor early measures of T-cell activation such as the influx of intracellular calcium. Thus, desferrithiocin, like deferoxamine, is a potent and reversible inhibitor of T-cell proliferation. This anti-proliferative effect inhibits T-cell function. Bioavailability after oral administration is a unique property of desferrithiocin, and would make it an attractive alternative to deferoxamine. Its immunomodulating properties may therefore be exploited in vivo to inhibit graft rejection or autoreactive T cells.

Antigens, Surface↗
PubMed1990

A phase I/II trial of recombinant granulocyte-macrophage colony-stimulating factor for children with aplastic anemia.

Nine pediatric patients (median age, 8 years; range, 0.7 to 19 years), eight with refractory aplastic anemia and one with newly diagnosed aplasia, were enrolled in a phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) administered via continuous intravenous infusion. Doses ranged from 8 to 32 micrograms/kg/d. Six of eight evaluable patients responded with a significant rise in neutrophil count (median fourfold increase; range, 2.5- to 31-fold) during the 28-day induction period. Five patients completed 2 further months of therapy (maintenance) with persistent or improved neutrophil responses. Three patients had bone marrow aspirates suggestive of increased erythropoiesis, although only one patient had improvement in peripheral hematocrit and platelet count. In the five patients completing maintenance, three experienced a rapid return to baseline counts after rhGM-CSF was discontinued, one maintained a neutrophil response for 2 months after drug discontinuation, and one has maintained a trilineage response for greater than 1 year off study. Drug therapy was well tolerated. Toxicity was minimal at doses from 8 to 16 micrograms/kg/d. Fever and rash were more commonly seen at 32 micrograms/kg/d. No patient developed an infection during the course of rhGM-CSF administration. These results demonstrate that rhGM-CSF increases peripheral neutrophil counts in children with refractory and newly diagnosed aplastic anemia and may be able to stimulate a multilineage response in a more limited number. Randomized, prospective trials are necessary to determine if rhGM-CSF administration will impact favorably on the morbidity and mortality of severe aplastic anemia.

Adolescent↗
PubMed1990

Positive and negative elements regulate human interleukin 3 expression.

The human interleukin 3 (IL-3) promoter is comprised of several cis-acting DNA sequences that modulate T-cell expression of IL-3. These are located within 315 nucleotides upstream of the mRNA start site. Transient expression of reporter genes linked to serially deleted sequences of the IL-3 promoter has allowed mapping of two activator sequences and an interposed repressor sequence. The proximal regulatory region is specific to IL-3 and prerequisite for efficient transcription. Its effect is enhanced by a second, more distal activating sequence consisting of an AP-1 binding site. Between the two activators lies a transcriptional silencer, which is a potent repressor in the absence of the AP-1 site. DNA-nuclear protein binding experiments demonstrate specific complex formation within each of these functional regions. Thus, both positive and negative regulatory elements appear to control expression of the human IL-3 gene in activated T cells.

Base Sequence↗
PubMed1990

Deficient T cell granulocyte-macrophage colony stimulating factor production in allogeneic bone marrow transplant recipients.

The proliferation and differentiation of donor hematopoietic progenitor cells in bone marrow transplantation (BMT) recipients is influenced by hematopoietic growth factors, which could derive from either T cells or adherent stromal bone marrow cells, or both. In this study of 20 BMT recipients, we asked whether T lymphocytes arising from donor bone marrow grafts were able to express normal levels of granulocyte-macrophage colony stimulating factor (GM-CSF) mRNA, and to secrete normal levels of soluble GM-CSF in response to the mitogen phytohemagglutinin. We have found that T cells obtained up to 18 months following BMT express little or no PHA-induced GM-CSF message. T cell GM-CSF secretion in response to PHA is also reduced or absent. This T cell GM-CSF defect was observed in all patients studied, whether or not donor bone marrows had undergone T cell depletion. This defect likely reflects a broader deficit in mitogen-induced lymphokine production. This defect likely contributes to BMT recipients' blunted responses to infections, and contributes to graft failure in T cell-depleted transplants.

Adolescent↗
PubMed1990

Oral iron chelators.

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Administration, Oral↗