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Biomedical subjects

D G Nathan

Publications and source records attributed to D G Nathan.

At least 37 records · Page 2Linked to original sources
PubMed1994

Survival in medically treated patients with homozygous beta-thalassemia.

BACKGROUND: The prognosis of patients with homozygous beta-thalassemia (thalassemia major) has been improved by transfusion and iron-chelation therapy. We analyzed outcome and prognostic factors among patients receiving transfusions and chelation therapy who had reached the age at which iron-induced cardiac disease, the most common cause of death, usually occurs. METHODS: Using the duration of life without the need for either inotropic or antiarrhythmic drugs as a measure of survival without cardiac disease, we studied 97 patients born before 1976 who were treated with regular transfusions and chelation therapy. We used Cox proportional-hazards analysis to assess the effect of prognostic factors and life-table analysis to estimate freedom from cardiac disease over time. RESULTS: Of the 97 patients, 59 (61 percent) had no cardiac disease; 36 (37 percent) had cardiac disease, and 18 of them had died. Univariate analysis demonstrated that factors affecting cardiac disease-free survival were age at the start of chelation therapy (P < 0.001), the natural log of the serum ferritin concentration before chelation therapy began (P = 0.01), the mean ferritin concentration (P < 0.001), and the proportion of ferritin measurements exceeding 2500 ng per milliliter (P < 0.001). With stepwise Cox modeling, only the proportion of ferritin measurements exceeding 2500 ng per milliliter affected cardiac disease-free survival (P < 0.001). Patients in whom less than 33 percent of the serum ferritin values exceeded 2500 ng per milliliter had estimated rates of survival without cardiac disease of 100 percent after 10 years of chelation therapy and 91 percent after 15 years. CONCLUSIONS: The prognosis for survival without cardiac disease is excellent for patients with thalassemia major who receive regular transfusions and whose serum ferritin concentrations remain below 2500 ng per milliliter with chelation therapy.

Adult↗
PubMed1994

Studies of hybrid hematopoietic growth factor receptors.

To gain further insight into the mechanisms by which both granulocyte-macrophage-colony stimulating factor (GM-CSF) and erythropoietin receptors function, we have utilized a GM-CSF erythropoietin hybrid receptor with GM-CSF as the external domain and erythropoietin as the intracellular domain. Results show that the beta common GM-CSF receptor both enhances the affinity binding of GM-CSF to the receptor and plays an important role in signaling through the receptor. A truncated form of the beta common receptor actually acts as a dominant negative regulatory factor.

Animals↗
PubMed1994

Evaluation of granulocyte-macrophage colony-stimulating factor for treatment of pancytopenia in children with fanconi anemia.

Fanconi anemia is a congenital syndrome characterized by multiple specific physical anomalies, progressive marrow failure, and a predisposition to acute leukemia. We studied the toxicity and efficacy of daily subcutaneous administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with Fanconi anemia and pancytopenia. The toxicity of GM-CSF at the doses and schedule used was minimal. Six of seven patients entered had an increase in the neutrophil count of 7- to 25-fold, which was maintained during the course of study. Despite increases in the reticulocyte count, increases in hemoglobin concentration were rare. No improvement in platelet count was evident in any patient. No patient has evidence of leukemia after up to 19 months of continuous GM-CSF exposure, and all five surviving patients remain responsive to treatment. Although the optimal dose, schedule, and choice of cytokine for patients with marrow failure and Fanconi anemia are not established by this preliminary study, the data indicate that (1) GM-CSF may be able to palliate at least the neutropenia and potentially the neutropenic complications of the disease, (2) this effect can be sustained for more than 1 year, and (3) rapid evolution of acute leukemia is unlikely to be a frequent outcome of such treatment. The clinical impact of GM-CSF or other cytokines in patients with Fanconi anemia and pancytopenia remains to be established by further studies.

Adolescent↗
PubMed1993

Effects of interleukin-3 and granulocyte-macrophage colony-stimulating factor on thrombopoiesis in congenital amegakaryocytic thrombocytopenia.

Amegakaryocytic thrombocytopenia (AMT) is a rare and often fatal disorder of infancy and childhood presenting with isolated thrombocytopenia that progresses to marrow failure. The defect in thrombopoiesis is not well understood nor is the etiology of the progressive marrow failure. No standard modality of treatment exists. Here, we evaluated the capacity of marrow cells isolated from five patients with AMT and progressive marrow failure to generate megakaryocyte progenitor cells (CFU-MK). These in vitro studies demonstrated assayable numbers of CFU-MK from all patient bone marrows that responded in vitro to the addition of interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or the combination of both. These findings suggest that the defect in AMT might be partially correctable by the administration of these cytokines. A Phase I/II trial of in vivo administration of these same hematopoietins in the identical patients was conducted in which no significant toxicity was observed. IL-3 but not GM-CSF administration resulted in improved platelet counts in two patients and decreased bleeding and transfusion requirement in the remaining three. No clinical benefit was observed when GM-CSF was administered after IL-3 pretreatment. Prolonged IL-3 administration has resulted in platelet increases in an additional two patients. In vitro responsiveness of CFU-MK to either cytokine did not predict the degree of clinical response. Although the optimal dose and schedule of IL-3 either alone or in combination remains to be established, this study suggests that IL-3 may contribute to the treatment of patients with AMT.

Child, Preschool↗
PubMed1993

Interleukin-3 expression by activated T cells involves an inducible, T-cell-specific factor and an octamer binding protein.

Interleukin-3 (IL-3) is exclusively expressed by activated T and natural killer cells, a function that is tightly controlled both in a lineage-specific and in a stimulation-dependent manner. We have investigated the protein binding characteristics and functional importance of the ACT-1-activating region of the IL-3 promoter. This region binds an inducible, T-cell-specific factor over its 5' end, a site that is necessary for the expression of IL-3 in the absence of other upstream elements. Over its 3' end, it binds a factor that is ubiquitously and constitutively expressed. This factor is Oct-1 or an immunologically related octamer-binding protein, and it plays a role in coordinating the activity of several regulatory elements. These characteristics make the ACT-1 site analogous to the activating ARRE-1 site in the IL-2 promoter. Furthermore, and despite a lack of sequence homology, the promoters of IL-3 and IL-2 share an organizational pattern of regulatory elements that is likely to be important for the T-cell-specific expression of these genes.

Animals↗
PubMed1993

A low-affinity human granulocyte-macrophage colony-stimulating factor/murine erythropoietin hybrid receptor functions in murine cell lines.

To identify domains in hematopoietic growth factor receptors that are important for signal transduction, a hybrid receptor (GMER) was constructed by splicing the DNA of the entire extracellular and transmembrane domains of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha 2 subunit (GMR) to the cytoplasmic domain of the murine erythropoietin receptor (mEpoR). The hybrid receptor was introduced into the interleukin-3 factor-dependent murine hematopoietic cell line Ba/F3. Cells that expressed high receptor numbers were selected by cell sorting using phycoerythrin-labeled human GM-CSF. Immunoprecipitation of GMER from Ba/F3 cells showed a band with an Mr of 105,000 daltons. Human GM-CSF binding to Ba/F3 cells that expressed GMER showed a kd of 3.0 nmol/L and 475 binding sites/cell, while the same cells that expressed GMR had 300 sites/cell and a kd of 3.5 nmol/L. The proliferative response to GM-CSF of Ba/F3 cells that expressed GMER showed 1/2 maximal cell growth (as measured by 3H-thymidine incorporation) at a GM-CSF concentration of 2.5 x 10(-8) mol/L. When cultured in human GM-CSF, Ba/F3-GMER cells expressed cell surface glycophorin. Similar results were obtained with Ba/F3 cells transfected with the mEpoR and cultured in erythropoietin. Expression of GMR plus the human GM-CSF receptor beta chain in the same cell line also resulted in human GM-CSF stimulated proliferation; however, cell surface glycophorin was not detected. These data show that a low-affinity GM-CSF/Epo hybrid receptor can promote GM-CSF-dependent proliferation and can induce the expression of glycophorin, an erythroid-specific protein.

Animals↗
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↗