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Biomedical subjects

D G Nathan

Publications and source records attributed to D G Nathan.

At least 181 records · Page 10Linked to original sources
PubMed1978

Successful use of multiagent immunosuppression in the bone marrow transplantation of sensitized patients.

Of 23 patients with severe aplastic anemia, 17 were sensitized to histocompatibility antigens of HLA-A, -B, and -D loci-identical potential sibling donors as determined by cell-mediated lysis (CML) assays in vitro. Antibody-dependent sensitization was detected in 3 patients, antibody-independent cellular sensitization in 11, and both in 3. Fourteen sensitized patients were transplanted after initial multiagent immunosuppression consisting of rabbit anti-human thymocyte serum, procarbazine, and cyclophosphamide, eleven with a CML-positive donor and three with a CML-negative donor. Engraftment was achieved in each of 13 patients who were evaluable, and only 2 ultimately rejected their marrow grafts, 1 with subsequent return of his own marrow function. Five patients without evidence in vitro of sensitization were transplanted after immunosuppression with cyclophosphamide alone; none of these rejected their grafts. These studies show that sensitized bone marrow transplant recipients can be successfully transplanted after optimal donor selection and multiagent immunosuppression.

Adolescent↗
PubMed1978

Cation permeability alterations during sickling: relationship to cation composition and cellular hydration of irreversibly sickled cells.

Sickle erythrocytes (RBC) incubated under 100% nitrogen for 4 hr manifested marked Na gain with an equivalent K loss. There were no changes in cell total cation or water content under these conditions, and no irreversible sickle cells (ISC) were formed. In contrast, sickle RBC incubated for 24 hr under 100% nitrogen in a glucose-free Na medium containing calcium manifested marked ISC formation. ISC formed under these conditions also had elevated Na content, although K content was much more reduced, and consequently ISC were cation depleted and dehydrated. When sickle RBC were incubated 24 hr under 100% nitrogen in a glucose-free K medium containing calcium no ISC formed and there were no major changes in cation or water content. These studies indicate that the Na+K content and dehydration of ISC was not directly related to the increased cation permeability associated with sickling. Rather, the ISC changes appear to reflect the well-known Gardos effect (K and water loss occurring in ATP-depleted RBC incubated with calcium). In addition, these studies suggest that ISC formation per se is related to K and water loss, since no ISC were formed when ATP-depleted sickle RBC were deoxygenated in calcium-containing high-K media that prevented K loss and dehydration.

Adenosine Triphosphate↗
PubMed1977

Continuous subcutaneous administration of deferoxamine in patients with iron overload.

Since deferoxamine B, when administered as a single daily intramuscular injection of 0.75 g, is unable to promote sufficient urinary iron excretion to achieve net negative iron balance in siderosis, we evaluated its administration as a constant infusion over 24 hours. We compared intravenous and subcutaneous routes in 24 siderotic patients who had excreted 420 to 630 mg (mean, 480 mg) of iron per month on intramuscular therapy. With the intravenous route urinary iron excretions increased to 570 to 3690 mg (mean, 1595 mg) per month. Constant subcutaneous delivery was 90 per cent as effective as intravenous administration on a dose-for-dose basis. Noteworthy net cumulative urinary iron excretions (urinary iron excretions minus transfused iron), often in excess of 1 g per month, have been maintained in all patients. Constant subcutaneous deferoxamine administration may prove to be an effective and practical means of eliminating large quantities of iron in siderosis.

Administration, Oral↗
PubMed1977

Treatment of iron overload in adults with continuous parenteral desferrioxamine.

Adult patients with transfusional hemosiderosis were given ascorbic acid and treated with the iron chelator, desferrioxamine B. The drug was administered by continuous subcutaneous or intravenous infusions using a light weight portable constant infusion device. On this regimen, four of the five patients studied were able to excrete significant amounts of iron (greater than 35 mg/da) when receiving a daily desferrioxamine dose of 1.5 to 2.2 g. Continuous subcutaneous infusion was well tolerated and about 80 per cent as effective as intravenous therapy in chelating iron. The number of prior transfusions, the hepatic iron content and the serum ferritin levels appear to be useful in predicting which patients will respond to iron chelation therapy, especially if there is little bone marrow erythropoietic activity. One patient with ineffective erythropoiesis did not have significantly increased hepatic iron stores but responded to the administration of desferrioxamine. Continuous subcutaneously administered desferrioxamine may prove to be adaptable for long-term outpatient therapy, allowing patients with ongoing transfusion requirements to go into negative iron balance. Long-term studies will be needed to demonstrate reversal of endocrine, hepatic and cardiac dysfunction secondary to iron deposition in these patients.

Adult↗
PubMed1977

An unusual form of chronic neutropenia in a father and daughter with hypogammaglobulinaemia.

Chronic neutropenia, with an abundance of mature neutrophils in the bone marrow, was discovered in a father and daughter who also had common variable hypogammaglobulinaemia. Under the stress of infection or following the administration of typhoid vaccine, release of neutrophils from the marrow was enhanced sufficiently to abolish neutropenia temporarily. Although their morphology was abnormal, the function of neutrophils in vitro was normal. Thus, the increased susceptibility to infection that characterized these patients appeared to be due primarily to their defect in humoral immunity rather than their neutropenia.

Adult↗
PubMed1977

Bone marrow transplantation for an infant with neutrophil dysfunction.

A child with severe neutrophil dysfunction and intractable infections received bone marrow transplants from histocompatible siblings. After a first transplant preceded by cyclophosphamide (CY), antithymocyte serum (ATS) and procarbazine (PCB) preconditioning, there was no evidence for engraftment and autologous marrow function rapidly returned. Cell mediated lysis showed no evidence of patient sensitization against the marrow donor suggesting that graft rejection did not cause the transplant failure. A second transplant was performed utilizing another matched sibling donor. Total body irradiation was added to CY, ATS, and PCB for preconditioning after in vitro studies of the colony forming capacity (CFUc) of the patient's marrow cells showed normal sensitivity to radiation. Full engraftment ensued with correction of granulocyte function abnormalities. The patient eventually died of intractable pulmonary disease. Our experience with this child suggests that cyclophosphamide alone may be insufficient preparation for marrow transplantation in some patients with non-neoplastic hematologic disorders. Experimental and clinical data supporting this contention are reviewed.

Antilymphocyte Serum↗
PubMed1977

Use of homologous platelet survival in differential diagnoses of chronic thrombocytopenia in childhood.

Twenty-one children with chronic thrombocytopenia of obscure etiology, 19 of whom had normal numbers of bone marrow megakaryocytes, were evaluated in order to determine if factors extrinsic to the platelets themselves (presumably antibodies) caused the thrombocytopenia. The rapid destruction of platelets by such antibodies has been demonstrated to cause idiopathic thrombocytopenic purpura (ITP). History, physical examination, and routine laboratory studies were unable to provide an exact diagnosis in these patients. Measurement of platelet survival, using sodium chromate Cr 51 labeled homologous platelets obtained from unrelated donors, permitted a clear separation of these children into two groups. One group (11 patients) had a markedly shortened platelet life span, and was considered to have chronic ITP. The other group (10 patients) had a normal or only slightly reduced platelet life span. Thus, the destruction of platelets by extrinsic factors could be ruled out. Since the diagnosis of chronic ITP was excluded, splenectomy could be avoided in these patients since it is rarely useful in children with nonimmune forms of chronic thrombocytopenia. Homologous platelet survival measurement is a useful diagnostic tool in certain children with chronic thrombocytopenia.

Age Factors↗
PubMed1976

Prenatal diagnosis of hemoglobinopathies. A review of 15 cases.

We attempted prenatal diagnosis of hemoglobinopathies in 15 cases--11 for beta-thalassemia and four for sickle-cell disease. Fetoscopy was used in seven cases, and placental aspiration in eight. One premature labor, with fetal loss, followed placental aspiration. Globin synthesis was assessed by incubation of samples with 3H-leucine and chain separation on carboxymethylcellulose columns. Homozygous disease was predicted in two pregnancies, which were interrupted, and the diagnosis confirmed. In one case homozygosity was suspected. A repeat test was advised but not accepted. The fetus had thalassemia trait. One pregnancy was interrupted despite our prediction of thalassemia trait. Eight pregnancies went to term. Seven predictions that the infants would not have homozygous disease were confirmed. One prediction of sickle trait proved to be sickle-cell disease. Although prenatal diagnosis of hemoglobinopathies is feasible, the present frequency of fetal loss and diagnostic error indicates need for improvement.

Anemia, Sickle Cell↗
PubMed1976

The thalassemias.

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Age Factors↗
PubMed1976

Reassessment of the use of desferrioxamine B in iron overload.

Treatment of transfusion-induced iron overload by daily intramuscular injection of the chelator desferrioxamine has not produced impressive urinary iron excretion. We attempted to augment net iron excretion by altering both the route and quantity of chelator administered. Two ascorbic acid-replete patients excreted a mean of 14.5 mg of iron per 24 hours after a single intramuscular injection of 750 mg of desferrioxamine. Excretion increased to a mean of 44.9 mg when this dose was delivered by a continuous 24-hour intravenous infusion. When the intravenous dose of chelator was increased incrementally to as high as 16,000 mg per 24 hours, iron excretion increased up to 180 mg per day. At these high-dose levels, efficiency of binding of iron to chelator was compromised. Constant exposure of the labile iron pool to a chelating agent markedly enhances net iron excretion in splenectomized transfusion-dependent patients.

Adolescent↗
PubMed1976

Development of an effective treatment program for childhood acute lymphocytic leukemia: a preliminary report.

The development of an effective therapeutic regimen for acute lymphocytic leukemia (ALL) of childhood is described. By careful surveillance of toxicity and efficacy, positive modifications of treatment strategy were achieved without resorting to classically randomized trails. Teh resultant protocol utilizes vincristine-prednisone induction followed by asparaginase consolidation, intensive intermittent combination maintenance chemotherapy with adriamycin as a major component, and cranial radiotherapy plus intrathecal methotrexate for central nervous system prophylaxis. Preliminary analysis suggests that this regimen may result in prolonged continuous complete remission in at least 80% of children with ALL.

Adolescent↗