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Biomedical subjects

I H Fox

Publications and source records attributed to I H Fox.

At least 109 records · Page 6Linked to original sources
PubMed1979

Purine nucleoside phosphorylase deficiency: biochemical properties and heterogeneity in two families.

The biochemical features of two families with purine nucleoside phosphorylase deficiency are compared. Laboratory studies and an evaluation of kinetic and physical properties of erythrocyte purine nucleoside phosphorylase give evidence that a) the degree of abnormality in uric acid and nucleoside concentrations in plasma and urine reflect the severity of the enzymatic deficiency and b) structural alterations of the mutant enzymes result from structural gene mutations and demonstrate genetic heterogeneity in the disease purine nucleoside phosphorylase deficiency.

Child↗
PubMed1979

Human placental adenosine kinase: purification and characterization.

Human placental adenosine kinase has thus been purified 3600-fold and characterized with respect to molecular weight, substrate specificity, divalent cation requirements, pH optimum, isoelectric pH, and kinetic properties. These data contribute to the information currently available about the regulation of adenosine metabolism, information critical for an understanding of the biological properties of adenosine.

Adenosine Kinase↗
PubMed1979

Cellular immune deficiency with autoimmune hemolytic anemia in purine nucleoside phosphorylase deficiency.

Immunologic and metabolic abnormalities were studied in a five year old boy with 0.07 per cent of normal erythrocyte purine nucleoside phosphorylase activity. The clinical course is characterized by severe autoimmune hemolytic anemia, a transient neurologic disorder with tremor and ataxia, and minor infectious illnesses. There is severe lymphopenia with decreased absolute numbers of T and B lymphocytes. Mitogen-stimulated blastogenesis is reduced, but response to allogeneic lymphocytes is normal. A monoclonal IgG protein is present. There is hypouricemia, elevated plasma inosine level, hypouricosuria and an increase in the urinary concentration of inosine and guanosine. The pattern of heterozygote distribution in the patient's family is compatible with an autosomal recessive trait in which heterozygotes are identifiable. In addition, the unusual laboratory and clinical manifestations of this patient illustrate the heterogeneity of the clinical syndrome associated with purine nucleoside phosphorylase deficiency.

Anemia, Hemolytic, Autoimmune↗
PubMed1979

Biochemical basis for differential deoxyadenosine toxicity to T and B lymphoblasts: role for 5'-nucleotidase.

Deoxyadenosine metabolism was investigated in cultured human cells to elucidate the biochemical basis for the sensitivity of T lymphoblasts and the resistance of B lymphoblasts to deoxyadenosine toxicity. T lymphoblasts have a 20-to 45-fold greater capacity to synthesize deoxyadenosine nucleotides than B lymphoblasts at deoxyadenosine concentrations of 50--300 micron. During the synthesis of dATP, T lymphoblasts accumulate large quantities of dADP, whereas B lymphoblasts do not accumulate dADP. Enzymes affecting deoxyadenosine nucleotide synthesis were assayed in these cells. No substantial differences were evident in activities of deoxyadenosine kinase (ATP: deoxyadenosine 5'-phosphotransferase, EC 2.7.1.76) or deoxyadenylate kinase [ATP:(d)AMP phosphotransferase, EC 2.7.4.11]. The activity of 5'-nucleotidase (5'-ribonucleotide phosphohydrolase, EC 3.1.3.5) was increased 44-fold for AMP and 7-fold for dAMP in B lymphoblasts. A model for the regulation of deoxyadenosine nucleotide synthesis by 5'-nucleotidase activity is proposed on the basis of the observations.

Adenosine Deaminase↗
PubMed1979

Distribution of 5'-nucleotidase in human lymphoid tissues.

Low activity of 5'-nucleotidase (5'-ribonucleotide phosphohydrolase, EC 3.1.3.5) in T lymphoblasts may explain the marked sensitivity of this cell to deoxynucleotide accumulation when compared to B lymphoblasts. The relevance of such observations with cultured cells to the normal immune system requires the demonstration of similar differences in the 5'-nucleotidase activity of normal human lymphocyte subpopulations. Sheep erythrocyte (E) rosette-forming cells from normal thymus, tonsil, and peripheral mononuclear cells have 5'-nucleotidase activities of 1.7, 11.3, and 21.2 nmol/hr per 10(6) cells. Non-E-rosette forming cells from the peripheral blood or tonsil have 5'-nucleotidase activity comparable to the higher levels found in the peripheral E-RFC. Increased levels of 5'-nucleotidase activity may be a marker for post-thymic T lymphocytes. T lymphoblasts have 5'-nucleotidase activity similar to values demonstrated for E-RFC in thymus, whereas cultured B lymphoblasts have 5'-nucleotidase activity 15 times greater than that of T lymphoblasts. On the basis of these observations, the 5'-nucleotidase deficiency in congenital agammaglobulinemia has been reevaluated. In these patients the data indicate that peripheral E-rosette forming cells have the enzyme deficiency, demonstrating an abnormality of T lymphocytes in this disorder of immunoglobulin production.

Agammaglobulinemia↗
PubMed1979

Overproduction of uric acid in hypoxanthine-guanine phosphoribosyltransferase deficiency. Contribution by impaired purine salvage.

The contribution of reduced purine salvage to the hyperuricemia associated with hypoxanthine-guanine phosphoribosyltransferase deficiency was measured by the intravenous administration of tracer doses of [8-(14)C]adenine to nine patients with normal enzyme activity, three patients with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, and six patients with the Lesch-Nyhan syndrome. The mean cumulative excretion of radioactivity 7 d after the adenine administration is 5.6+/-2.4, 12.9+/-0.9, and 22.3+/-4.7% of infused radioactivity for control subjects, partial hypoxanthine-guanine phosphoribosyltransferase-deficient subjects, and Lesch-Nyhan patients, respectively. To assess relative rates of nucleotide degradation in control and hypoxanthine-guanine phosphoribosyltransferase-deficient patients two separate studies were employed. With [8-(14)C]inosine administration, three control subjects excreted 3.7-8.5% and two enzyme-deficient patients excreted 26.5-48.0% of the injected radioactivity in 18 h. The capacity of the nucleotide catabolic pathway to accelerate in response to d-fructose was evaluated in control and enzyme-deficient patients. The normal metabolic response to intravenous fructose is a 7.5+/-4.2-mmol/g creatinine increase in total urinary purines during the 3-h after the infusion. The partial hypoxanthine-guanine phosphoribosyltransferase-deficient subjects and Lesch-Nyhan patients show increases of 18.6+/-10.8 and 17.3+/-11.8 mmol/g creatinine, respectively. Of the observed rise in purine exretion in control subjects, 40% occurs from inosine excretion and 32% occurs from oxypurine excretion. The rise in total purine excretion with Lesch-Nyhan syndrome is almost entirely accounted for by an elevated uric acid excretion. Increases in urine radioactivity after fructose infusion are distributed in those purines that are excreted in elevated quantities.The observations suggest that purine salvage is a major contributor to increased purine excretion and that the purine catabolic pathway responds differently to an increased substrate load in hypoxanthine-guanine phosphoribosyltransferase deficiency. The purine salvage pathway is normally an important mechanism for the reutilization of hypoxanthine in man.

Adenine↗
PubMed1979

Deoxyadenosine inhibits DNA synthesis in cultured human fibroblasts.

The rate of DNA synthesis in cultured diploid fibroblasts, nonmalignant human cells, is decreased by 50 microM 2'-deoxyadenosine when adenosine deaminase is inhibited and 2'-deoxyadenosine is phosphorylated to dATP. No inhibiton of DNA synthesis occurs with 100 microM adenosine under identical conditions or with 50 microM deoxyadenosine when adenosine deaminase is not blocked. Inhibition of DNA synthesis may be an important link between adenosine deaminase deficiency and severe combined immunodeficiency if the tissue culture model is relevant to lymphocyte function in man.

Adenine↗
PubMed1978

Lymphocyte ecto-5'-nucleotidase deficiency in agammaglobulinemia.

Fresh peripheral blood lymphocytes from eight patients with congenital agammaglobulinemia demonstrate reduced ecto-5'-nucleotidase activity when compared to the mean activity of normal subjects and patients with other forms of immunoglobulin deficiency. A specific defect of ecto-5'-nucleotidase is further suggested by normal values for lymphocyte ecto-adenosinetriphosphatase and ecto-nonspecific phosphatase. The data provide evidence for an enzyme deficiency in this X-linked, B lymphocyte deficiency syndrome.

Agammaglobulinemia↗
PubMed1978

Partial purine nucleoside phosphorylase deficiency. Studies of lymphocyte function.

Immune function in two brothers with a deficiency of purine nucleoside phosphorylase was evaluated in vivo and in vitro. Both patients had a history of recurrent infections and profound lymphopenia. Studies of cell-mediated immunity revealed an absence of delayed cutaneous reactivity to a number of antigens, including dinitrochlorobenzene, and significantly reduced lymphocyte proliferative responses to nonspecific mitogens, specific antigen, and allogeneic cells. E-rosetting cells were present but reduced in number (20.0% and 31.5%). Serum immunoglobulin levels, percentages of circulating immunoglobulin-and C3-receptor-bearing B cells, as well as the ability to produce antibody in response to specific antigen in vivo were normal. Moreover, studies of the in vitro induction of specific IgM antibody delineated the presence of T-helper and T-regulator cells. The normal induction of bone marrow precursor T-cell maturation by human thymic epithelium-conditioned medium or thymosin suggested that the initial stages of T-cell generation were intact in these patients. Attempts to reconstitute the in vitro proliferative response with a variety of reagents, including purine nucleoside phosphorylase itself, were unsuccessful. Selective impairment of certain aspects of T-cell function in these patients and a less severe clinical picture than previously described may be explained by the presence of a partial deficiency of nucleoside phosphorylase activity and incomplete block of purine catabolism.

Antibody Formation↗
PubMed1978

Purine metabolism in Friedreich's ataxia.

In a detailed investigation of nucleotide synthesis, interconversion and degradation, no difference was found between subjects with Friedreich's Ataxia and normal controls. It appears improbable that this disorder is related to a primary defect in purine metabolism.

Adolescent↗