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Biomedical subjects

D A Carson

Publications and source records attributed to D A Carson.

At least 343 records · Page 19Linked to original sources
PubMed1980

Antibody to the rheumatoid arthritis nuclear antigen. Its relationship to in vivo Epstein-Barr virus infection.

Most patients with seropositive rheumatoid arthritis, and a variable but lesser percentage of normal subjects, have precipitating antibodies to a nuclear antigen, rheumatoid arthritis nuclear antigen, present in Epstein-Barr virus-infected human B lymphoblastoid cells. We have used a sensitive indirect immunofluorescence assay for antibody to rheumatoid arthritis nuclear antigen in a study of patients with infectious mononucleosis and healthy control subjects. Of 110 sera from normal, college-age cadets, 58 were from individuals without prior Epstein-Barr virus infection, as indicated by the lack of antibody to viral capsid antigen. All of these also lacked activity to rheumatoid arthritis nuclear antigen. 52 sera were positive for antibody to viral capsid antigen, and antibody to rheumatoid arthritis nuclear antigen was present in 26 (50%) of these. In 67 sequential sera from 11 college-age students with infectious mononucleosis who became positive for antibody to rheumatoid arthritis nuclear antigen, only 2 were positive during the 1 mo. Thereafter the incidence and titers increased progressively through the 1st yr after infection. This time-course resembled that for the development of antibody to Epstein-Barr nuclear antigen, another transformation antigen in Epstein-Barr virus-infected B lymphocytes. The development of positivity for both was much later than that of antibody to the structural viral capsid antigen, which in the current study was always positive by 1 wk. Thus, antibody to rheumatoid arthritis nuclear antigen is present in a large proportion of normal individuals and can now be clearly ascribed, from both in vivo and in vitro studies, to prior infection with Epstein-Barr virus.

Antibodies, Antinuclear↗
PubMed1980

Inheritance of immunoglobulin M rheumatoid-factor idiotypes.

The idiotypic determinants on IgM rheumatoid factor (RF) from a single family have been analyzed. Rabbit Fab'2 antiidiotypic antibody was prepared against purified IgM-RF from a patient with rheumatoid arthritis. As measured by radioimmunoassay, the antiidiotype reacted with at least 90% of the patient's RF, but not with non-RF immunoglobulins from the same serum, nor with 10 of 11 polyclonal and monoclonal RF from unrelated individuals. Cross-reacting idiotypes were detected on RF in four of the patients' first degree relatives, spanning three generations, without apparent relation of HLA type or clinical rheumatoid arthritis. These results suggest that IgM-RF associated idiotypes were inherited in this family.

Adult↗
PubMed1980

Abnormal regulation of methylthioadenosine and polyamine metabolism in methylthioadenosine phosphorylase-deficient human leukemic cell lines.

Approximately 30 to 40% of human leukemic cell lines are completely deficient in the purine catabolic enzyme 5'-methylthioadenosine phosphorylase. Using two 5'-methylthioadenosine phosphorylase-negative leukemias, we have for the first time been able to measure the synthesis and biological effects of 5'-methylthioadenosine (MTA) in intact mammalian tumor cells. Malignant cells lacking this enzyme, unlike enzyme-positive cells, excreted MTA into the culture medium at a rate of 0.58 to 0.70 nmol/hr/mg protein. The production of the nucleoside was inhibited effectively by nontoxic concentrations of methylglyoxal bis(guanylhydrazone), a putrescine-depending S-adenosylmethionine decarboxylase inhibitor, and also by spermidine and spermine but was enhanced by putrescine. In a reciprocal fashion, MTA at low concentrations progressively increased both the synthesis and concentration of putrescine but suppressed spermine production. The unique alterations in polyamine metabolism induced by elevated MTA levels could offer a selective growth advantage to the 5'-methylthioadenosine phosphorylase-deficient cells and thus may be related to the high frequency of this enzyme deficiency among human leukemic cell lines.

Adenosine↗
PubMed1980

Thymidine as a chemotherapeutic agent: pharmacologic, cytokinetic, and biochemical studies in a patient with T-cell acute lymphocytic leukemia.

Biochemical studies suggested that leukemia T-cells have low levels of TTP-catabolizing enzyme activity and are uniquely sensitive to thymidine (dThd). A child with T-cell acute lymphocytic leukemia (ALL), whose peripheral blood lymphoblasts manifested very low TTP catabolic capacity, was treated with 75 g dThd/m2/day by constant iv infusion for two courses of 5 and 8 days. The dThd caused an initial accumulation of peripheral blood blasts in S-phase at the expense of cells in G1, followed by a rapid reversal of this pattern consistent with a block in late G1 and/or early S. Concurrently, a prompt reduction of blasts was found in the peripheral blood. However, dThd treatment neither decreased the number of lymphoblasts in the cerebrospinal fluid (CSF) nor cleared the marrow. No major toxicity was observed, but the effect of dThd on normal marrow elements could not be evaluated in this patient. Blood concentrations of dThd were 1.4-3.0 mM, and concentrations of thymine were in the same range; beta half-life for dThd was 48 minutes. Steady-state CSF dThd was 9% of the simultaneous serum level. Clearance measurements demonstrated that catabolism of dThd was saturated and that renal clearance was a major determinant of total body clearance during high-dose dThd infusion. A good correlation was found between biochemical and cytokinetic parameters and response to dThd for the peripheral blood lymphoblasts. However, dThd did not produce a useful remission in this case of T-cell ALL.

Antineoplastic Agents↗
PubMed1979

Antibodies to Epstein-Barr virus-determined antigens in normal subjects and in patients with seropositive rheumatoid arthritis.

Prior studies have shown that patients with seropositive rheumatoid arthritis (RA) have an increased frequency of precipitating antibody against a nuclear antigen, the RA nuclear antigen, detected in human B lymphoblastoid cell lines infected by Epstein-Barr virus. The present investigations demonstrate that patients with seropositive RA also have specifically elevated titers of antibodies to another, better-characterized Epstein-Barr virus-associated B cell antigen, the Epstein-Barr nuclear antigen, which is detected by anti-complement immunofluorescence. Titers of these two antibodies were not affected by absorption of rheumatoid factor from serum. Furthermore, patients with RA did not have elevated titers of antibodies against the Epstein-Barr virus capsid antigen or to three other species of human herpesviruses: herpes simplex type 1, varicella-zoster virus, and cytomegalovirus. In both normal individuals and RA patients there was a significant association between the presence of antibodies to RA nuclear antigen and the titers of antibody to Epstein-Barr nuclear antigen. Thus, normal subjects with antibody to RA nuclear antigen had titers of antibody to Epstein-Barr nuclear antigen equivalent to those of patients with RA and significantly higher than normal subjects lacking antibody to RA nuclear antigen. One interpretation of these results is that patients with seropositive RA derive from a larger population with enhanced immune responsiveness to B lymphocyte nuclear antigens determined by the Epstein-Barr virus.

Antibodies, Antinuclear↗
PubMed1979

Biochemical basis for the enhanced toxicity of deoxyribonucleosides toward malignant human T cell lines.

Human malignant T cell lines have high levels of deoxyribonucleoside phosphorylating activity and low levels of deoxyribonucleotide dephosphorylating activity. When incubated with deoxyadenosine or thymidine, the malignant T cell lines rapidly accumulate toxic concentrations of dATP and dTTP, respectively. This unusual pattern of deoxyribonucleotide metabolism renders the malignant T cells especially vulnerable to the toxic effects of deoxyribonucleosides and related analogues.

B-Lymphocytes↗
PubMed1979

IgA rheumatoid factor in the sera and saliva of patients with rheumatoid arthritis and Sjögren's syndrome.

With a sensitive radioimmunoassay we have found elevated IgA rheumatoid factor (IgA-RF) levels in the sera of patients with rheumatoid arthritis, Sjögren's syndrome, and systemic lupus erythematosus. The IgA--RF showed a pattern of reaction with human IgG subclasses and animal gammaglobulins similar to that of IgM-RF from the same patients. Rheumatoid factors of both classes were shown to be present in saliva of patients with rheumatoid arthritis and Sjögren's syndrome.

Arthritis, Rheumatoid↗
PubMed1978

In vitro effects of Epstein-Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects.

Peripheral blood mononuclear cells from 10 patients with rheumatoid arthritis and 9 control subjects were cultured in vitro for 30 days with and without infection by Epstein-Barr virus. All cultures showed polyclonal stimulation of B cells as indicated by rising levels of IgM in the culture supernates, reaching maximal at 18-24 days, and with no quantitative or kinetic difference between the RA and control cells. IgM anti-IgG was also produced in both groups and maximally at 18-24 days, but in greater quantity by the RA lymphocytes. The anti-IgG made by the RA lymphocytes was more easily absorbed by solid phase IgG than was the anti-IgG made by the normal lymphocytes and thus was judged to be of higher affinity. RA lymphocytes uninfected with EBV had higher transformation scores than did the normal controls and developed spontaneously into permanent cell lines in six instances.

Antibodies, Anti-Idiotypic↗
PubMed1978

Deoxyribonucleoside toxicity in adenosine deaminase and purine nucleoside phosphorylase deficiency: implications for the development of new immunosuppressive agents.

The immunodeficient state associated with adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency may result from the selective phosphorylation by thymus-derived lymphocytes of the ADA substrate deoxyadenosine and the PNP substrate deoxyguanosine, leading to the intracellular trapping of toxic deoxyribonucleoside triphosphates. Agents such as deoxycytidine might be able to favourably modify the immunodeficient state by inhibiting deoxyribonucleoside phosphorylation. Deficiencies of other nucleotide catabolic enzymes, if selectively expressed by lymphocytes, might also lead to immunodeficiency via nucleoside trapping in lymphoid tissues. Purine deoxyribonucleoside analogues, either alone or in combination with ADA inhibitors, may have value as lymphospecific antimetabolites.

Adenosine Deaminase↗
PubMed1978

Light chain heterogeneity of 19S and 7S anti-gamma-globulins in rheumatoid arthritis and subacute bacterial endocarditis.

Both 19S and 7S anti-gamma-globulins in rheumatoid arthritis sera are enriched in kappa light chain bearing antibody molecules when compared to total 19S and 7S globulins from the same individuals. In patients with subacute bacterial endocarditis 19S anti-gamma-globulins are also, to a degree, enriched in kappa light chains, whereas the 7S anti-gamma-globulins have kappa to lambda light chain ratios indistinguishable from total 7S globulin.

Antibodies, Anti-Idiotypic↗
PubMed1978

Adenosine kinase initiates the major route of ribavirin activation in a cultured human cell line.

Inhibition of IMP dehydrogenase (EC 1.2.1.14) by ribavirin causes the normal human lymphoblast to excrete increased amounts of newly formed purine into the culture medium. In order for ribavirin to be active as an inhibitor of the dehydrogenase, this synthetic nucleoside must be phosphorylated. The effect of ribavirin on purine excretion has been determined with a normal lymphoblast line, and with lymphoblast lines deficient in hypoxanthine phosphoribosyltransferase (IMP:pyrophosphate phosphoribosyl-transferase, EC 2.4.2.8), in adenosine kinase (ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20), and in both hypoxanthine phosphoribosyltransferase and adenosine kinase. Resistance to the effect of ribavirin on purine excretion was associated only with those cell lines deficient in adenosine kinase activity. These cell lines have normal deoxyadenosine kinase (ATP:deoxyadenosine 5'-phosphotransferase, EC 2.7.1.76) activity. Therefore, the nucleoside kinase activity responsible for ribavirin phosphorylation is adenosine kinase.

Adenosine Kinase↗
PubMed1978

IgG rheumatoid factor in subacute bacterial endocarditis: relationship to IgM rheumatoid factor and circulating immune complexes.

With recently developed radioimmunoassays, we have been able to study the levels and properties of IgG rheumatoid factor (IgG RF) and IgM rheumatoid factor (IgM RF) in patients with subacute bacterial endocarditis (SBE), as well as the relationship of these autoantibodies to circulating immune complexes. We found significantly elevated amounts of IgG RF and IgM RF in SBE sera. The IgG RF chromatographed on Sepharose 6B as an intermediate complex, indistinguishable from the pattern seen in rheumatoid arthritis. RF levels peaked later in the course of SBE than did levels of circulating immune complexes. With antibiotic treatment RF levels declined, although not as fast nor as completely as circulating immune complexes. These results suggest that both IgG RF and IgM RF in SBE may be part of a polyvalent antibody response to elevated levels of circulating immune complexes which do not themselves contain RF.

Antigen-Antibody Complex↗