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Biomedical subjects

D G Nathan

Publications and source records attributed to D G Nathan.

At least 163 records · Page 9Linked to original sources
PubMed1979

The molecular basis of alpha-thalassemias: frequent occurrence of dysfunctional alpha loci among non-Asians with Hb H disease.

Study of Asians has previously indicated that deletion of alpha-globin structural genes is the predominant lesion in alpha-thalassemias and that Hb H disease occurs when three of four normal alpha loci per cell are deleted. To test the generality of this model, Hb H disease DNAs of both Asian and non-Asian origin were analyzed by restriction endonuclease mapping using the technique of Southern (1975). Whereas in normal DNA, alpha sequences are present in a single Eco Rl fragment of cellular DNA approximately 22.5 kb long, fragments of 22.5, 20 and 2.6 kb were found in various Hb H disease DNAs. The 20 kb Eco Rl fragment alone, in which a single alpha-globin structural locus resides, was found in Asian Hb H disease DNA. This finding is consistent with the deletion model of alpha-thalassemia. In contrast, seven of eight non-Asian Hb H disease DNAs displayed a more complex molecular composition. The fragment patterns observed were 22.5 kb alone, 22.5 plus 2.6 kb, 20 plus 2.6 kb and 20 kb alone. Non-Asian Hb H disease DNAs contained one, two or three alpha loci per cell in contrast to the one locus predicted by the simple deletion model of alpha-thalassemia. The data are best explained by the existence of defective alpha loci in certain individuals with alpha-thalassemia, particularly outside the Asian population. Restriction mapping of the 20 kb Eco Rl fragment found in Asian and some non-Asian Hb H disease DNAs demonstrated a striking similarity in the placement of restriction sites about the single alpha gene compared with sites about the two genes in the 22.5 kb Eco Rl fragment seen in normal DNA. These data are consistent with origin of the 20 kb fragment from the 22.5 kb normal Eco Rl fragment by either unequal crossing-over or a deletion event. The molecular heterogeneity and frequent occurrence of defective alpha loci in non-Asian Hb H disease DNAs described here may explain, in part, the clinical heterogeneity of alpha-thalassemias and the absence of the homozygous deletion state (hydrops fetalis) in non-Asians. Further study of cellular DNA fragments containing the defective alpha loci identified in this work may indicate the types of specific mutations responsible for abnormal globin gene expression and complement similar studies on abnormal beta genes in beta-thalassemias.

Asia↗
PubMed1979

Partial deletion of beta-globin gene DNA in certain patients with beta 0-thalassemia.

We have used restriction endonuclease mapping of cell DNA to investigate the structure of the beta-globin gene in beta-thalassemias. Among 17 individuals with beta +- and beta 0-thalassemia, we observed three patients of Indian origin with beta 0-thalassemia whose DNA revealed a consistent mapping abnormality. In one beta allele in each diploid cell, 0.6 kilobase of DNA was deleted from beta-specific Pst I and Bgl II restriction fragments. This deletion involved 3' beta-globin gene sequences and eliminated the EcoRI site normally present at codons 121/122, but it did not extend to the BamHI site at codons 98--100 on the 5' side of the 0.90-kilobase intervening sequence normally present in beta-globin genes. Partial beta-globin gene deletion appears, therefore, to be a primary molecular defect seen in certain patients with beta 0-thalassemia.

Base Sequence↗
PubMed1979

Successful bone marrow transplantation in sensitized recipients.

Fourteen patients with aplastic anemia and one with the Wiskott-Aldrich syndrome who were specifically sensitized against their donors were successfully engrafted with bone marrow from those donors. Sensitivity was detected in antibody-independent and antibody-dependent cell-mediated lysis assays. In order to erase this immunity to non-MHR familial transplantation antigens, multiagent immunosuppression with cyclophosphamide, procarbazine, and whole rabbit antithymocyte serum (ATS) was used. The data suggest that ATS was largely responsible for abrogation of this sensitivity and indicate that immunity does not represent a barrier to successful transplantation.

Anemia, Aplastic↗
PubMed1979

Improved prognosis for patients with mediastinal lymphoblastic lymphoma.

Patients with diffuse lymphoblastic lymphoma (which includes convoluted lymphocytic lymphoma) with mediastinal involvement have predictable progression of disease to a leukemic phase that is cytologically indistinguishable from acute lymphoblastic leukemia (ALL). Therefore we treated 12 patients with diffuse lymphoblastic lymphoma involving the mediastinum with therapy that is effective in ALL. Treatment consisted of intermittent combination chemotherapy with adriamycin and preventive central nervous system therapy (craniocervical irradiation and intrathecal methotrexate). Mediastinal irradiation was given either for initial respiratory distress or to patients who had incomplete regression of disease following induction chemotherapy. Eleven patients achieve complete remission. With a median follow-up of 41 mo, and using life table analysis, 86% of these patients have remained in continuous complete remission. The results of this study demonstrate the efficacy of treating diffuse lymphoblastic lymphoma with mediastinal presentation as a disseminated lymphoid malignancy.

Adolescent↗
PubMed1978

Application of endonuclease mapping to the analysis and prenatal diagnosis of thalassemias caused by globin-gene deletion.

We applied a recently developed and more direct technic to diagnose thalassemia syndromes associated with deletion of particular globin structural genes and to assess a fetus at risk for one of those conditions, deltabeta-thalassemia. The method allows assessment of the globin genes present in total cellular DNA and is applicable to amniotic-fluid cell DNA. Cellular DNA fragments produced by cleavage using two specific restriction endonucleases are separated on the basis of size by agarose-gel electrophoresis, and the distribution of specific sequences among the DNA fragments determined by molecular hybridization. We observed the total deletion of alpha-globin genes in homozygous alpha-thalassemia (hydrops fetalis with hemoglobin Bart's) and the deletion of particular beta and beta-like sequences in cases homozygous for hereditary persistence of fetal hemoglobin and deltabeta-thalassemia. Analysis of amniotic-fluid cell DNA from a fetus at risk for deltabeta-thalassemia demonstrated the feasibility of these improved methods for antenatal diagnosis. The molecular studies confirmed the diagnosis predicted by analysis of fetal blood and established at birth.

Adult↗
PubMed1978

Normal erythropoietic helper T cells in congenital hypoplastic (Diamond-Blackfan) anemia.

To examine the erythropoietic function of T and null cells in congenital hypoplastic (Diamond-Blackfan) anemia, we fractionated the peripheral blood of three normal subjects and three affected patients into subclasses of null, T and B cells. Mixtures of these cells were co-cultured in plasma clots in the presence of erythropoietin. Erythroid colonies grew in cultures of normal null cells if either normal or patient T cells were co-cultured with them. Null cells of patients with hypoplastic anemia did not produce erythroid colonies under any culture conditions. We conclude that in this disorder, T cells function normally as helper cells in erythropoiesis and do not suppress colony formation, whereas the erythroid progenitor cells in the peripheral blood null-cell fractions are deficient in either number of function.

Adolescent↗
PubMed1978

Complete correction of the Wiskott-Aldrich syndrome by allogeneic bone-marrow transplantation.

Two patients with the Wiskott-Aldrich syndrome had complete donor lymphoid and hematopoietic engraftment after successful allogeneic bone-marrow transplantation. One patient had had only a temporary donor T-lymphocyte graft after a previous transplantation, for which he had been prepared with cytarabine and cyclophosphamide; the patient's own T lymphocytes returned six months later. A repeat transplant, for which the patient was prepared with anti-human thymocyte serum, total-body irradiation and procarbazine, resulted in complete donor engraftment. The second patient underwent a successful transplantation after similar preparation, except that procarbazine was omitted. At 11 and five months after transplantation both had normal hematopoiesis and no evidence of graft-versus-host disease. This treatment of the Wiskott-Aldrich syndrome may be a model for the correction of other genetically determined immune and hematologic bone-marrow disorders.

Antilymphocyte Serum↗
PubMed1978

Antenatal diagnosis of thalassaemia major.

Haemoglobin synthesis was studied in fetal blood samples obtained at 17 to 20 weeks' gestation in 22 women at risk of carrying a fetus with homozygous beta-thalassaemia. A presumptive diagnosis of homozygous beta-thalassaemia was made in four cases, and the pregnancy was terminated. An inconclusive answer was obtained in one case, and the patient also chose to have her pregnancy terminated. Two fetuses were lost as a result of the procedure. Of the remaining 15 pregnancies, 13 proceeded to term and two to 36 weeks; in each case a normal infant or one heterozygous for beta-thalassaemia was delivered. Current efforts should be directed towards improving the blood sampling technology so that fetal blood sampling can be used widely in those countries where thalassaemia is a major problem.

Abortion, Eugenic↗
PubMed1978

Human erythroid burst-forming unit: T-cell requirement for proliferation in vitro.

Human mononuclear leukocytes were fractionated into populations of null, T and B cells by immunoabsorbent column chromatography followed by E-rosette formation and purification of T cells by differential centrifugation and osmotic lysis. The unfractionated and fractionated cell populations were first separately cultured for 14 days in plasma clots in the presence of two international units erythropoietin. Typical erythroid burst-forming unit (BFU-E)-derived colonies grew in the unfractionated cell cultures but not from T- or B-cell cultures. BFU-E colonies grew in null cell cultures but most of the colonies were small and variably hemoglobinized with less than three subcolonies. When intact T cells were added to null cells and cocultured, many typical large BFU-E colonies with more than 10 well homogenized subcolonies appeared. Increasing numbers of large BFU-E colonies in null cell cultures were induced by stepwise addition of T cells but not by the addition of B cells. A conditioned medium in which T cells had been induced to divide by tetanus toxoid substituted for intact T cells in this T-cell-dependent BFU-E colony formation observed in null cells. These findings demonstrate that the BFU-E, a committeded erythroid stem cell, resides in the null cell fraction of peripheral blood, but its proliferative capacity and differentiation in vitro requires a soluble product of T cells. Such experiments now permit a new approach to the assessment of various disorders of erythropoiesis. Erythroid hypoplasia in a particular case may be due to dysfunction of the committed precursor cell or to a failure of a helper effect induced by T cells.

B-Lymphocytes↗
PubMed1978

Energy reserve and cation composition of irreversibly sickled cells in vivo.

Cation composition, cellular hydration, and adenosinetriphosphate (ATP) content were measured in irreversible sickle cells (ISC's) separated from the blood of patients with sickle cell anaemia. Total monovalent cation (Na+ + K+) content was markedly reduced in ISC's and this largely was due to cell K+ depletion. Corresponding to the reduced cation content, cells were dehydrated as indicated by a reduced mean cell volume. ISC's also appeared to be grossly depleted of ATP. These biochemical characteristics allow us to expand the definition of ISC's beyond morphologic characteristics. In addition, these chemical alterations provide a means for elucidating the mechanism of ISC production in vitro.

Adenosine Triphosphate↗
PubMed1978

Erythroid precursors in congenital hypoplastic (Diamond-Blackfan) anemia.

To explore the etiology of congenital hypoplastic anemia (CHA) or the Diamond-Blackfan anemia, erythropoietin responsive committed erythroid precursors were enumerated by the plasma clot method. These included blood and marrow erythroid burst-forming units (BFU-E) and marrow erythroid colony-forming units (CFU-E). The peripheral blood nucleated cells of 11 patients and the marrow cells of seven of these patients were examined. Studies were repeated in several patients during relapse and after induction of remission. BFU-E were undetectable in the marrow and blood of all but one relapsed patient, and the numbers of marrow CFU-E were depressed in all relapsed patients. Blood BFU-E remained low in all of the patients in remission. No evidence was obtained for suppression of normal CFU-E or BFU-E by CHA lymphocytes. Erythropoietin dose-response curves performed in two patients revealed a 10-fold increase in erythropoietin requirement for marrow CFU-E colony growth. This marked unresponsiveness to erythropoietin was strikingly improved by steroid therapy in one patient. We suggest that CHA is the result of a qualitative and/or quantitative deficiency of BFU-E. If BFU-E are produced, they must be relatively unresponsive to erythropoietin. The abnormal BFU-E give rise to erythropoietin unresponsive CFU-E and, thence, to proerythroblasts that are, in turn, trapped in that early stage of development because of their poor erythropoietic response. Hence, red cell production is deficient. Steroids appear to improve the erythropoietin response of CHA erythroid precursors.

Adolescent↗
PubMed1978

Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukemia: clinical results.

One hundred thirty-seven children with previously untreated acute lymphoblastic leukemia were entered into a new program that included intermittent combination chemotherapy featuring Adriamycin. Remission induction was initially randomized to vincristine and prednisone with or without an anthracycline. All children received asparaginase consolidation and central nervous system prophylaxis with cranial irradiation and intrathecal methotrexate. There were no primary failures of CNS prophylaxis. Complications were primarily infectious. Clinical evidence of cardiotoxicity and leukoencephalopathy were not observed. The time to enter complete remission and the presence of an anterior mediastinal mass at diagnosis were found to be statistically significant adverse prognostic factors, whereas presenting age and white blood count were not. With a median follow-up of 26 mo, and using life plot analysis, 65% of the children have remianed in continuous complete remission.

Adolescent↗