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Biomedical subjects

N L Edwards

Publications and source records attributed to N L Edwards.

At least 37 records · Page 2Linked to original sources
PubMed1986

Is running associated with degenerative joint disease?

Little information is available regarding the long-term effects, if any, of running on the musculoskeletal system. We therefore compared the prevalence of degenerative joint disease among 17 male runners (mean age, 56 years; height, 180 cm [5 ft 11 in]; and weight, 73.02 kg [161 lb] with 18 male nonrunners (mean age, 60 years; height, 178 cm [5 ft 10 in]; and weight, 78 kg [171 lb]). Running subjects (53% marathoners) ran a mean of 44.8 km (28 miles)/wk for 12 years. Pain and swelling of hips, knees, ankles, and feet and other musculoskeletal complaints among runners were comparable with those among nonrunners. Radiologic examinations (for osteophytes, cartilage thickness, and grade of degeneration) also were without notable differences among groups. We did not find an increased prevalence of osteoarthritis among the runners. Our observations suggest, within the limits of our study, that long-duration, high-mileage running need not be associated with premature degenerative joint disease in the lower extremities.

Aged↗
PubMed1986

Mechanism of activation of triciribine phosphate (TCN-P) as a prodrug form of TCN.

The tricyclic nucleotide triciribine phosphate (TCN-P) was synthesized as a water-soluble derivative of the tricyclic nucleoside TCN (L. B. Townsend et al, INSERM 81:37, 1978). Growth of L1210 cells in vitro was inhibited equally by TCN and TCN-P. A requirement for adenosine kinase activity for activation of both TCN and TCN-P was established by the observation that growth inhibition by either compound was decreased 200-fold by the adenosine kinase inhibitor 5-iodotubercidin and greater than 5000-fold in L1210/T, an adenosine kinase-deficient subline. The TCN/TCN-P resistance of L1210/T cells was correlated with lack of formation of intracellular TCN-P from either TCN or TCN-P. Thus, it appeared that TCN-P was hydrolyzed to TCN and then rephosphorylated intracellularly. Both the horse serum-containing culture medium and the intact cells possessed nucleotide phosphatase activity, which may contribute to the hydrolysis of TCN-P to TCN in the L1210 cell cultures. The requirement for hydrolysis of TCN-P to TCN for formation of intracellular TCN-P from exogenous TCN-P was also shown directly by the observation that human erythrocytes, which lack ectophosphatases, readily formed intracellular TCN-P from TCN but not from TCN-P when incubated in buffer.

Acenaphthenes↗
PubMed1985

Immunodeficiencies associated with errors in purine metabolism.

The genetic deficiencies of adenosine deaminase and purine nucleoside phosphorylase lead to blocks in the purine pathway. The intracellular accumulation of deoxynucleosides and deoxynucleotides is toxic to both dividing and nondividing lymphocytes via multiple mechanisms. T-lymphocytes are uniquely sensitive to purine-mediated cytotoxicity because of a functional imbalance of phosphorylating and dephosphorylating enzymatic activities. These inborn errors or purine metabolism are rare disorders. The study of these conditions, however, has uncovered unique enzymatic properties of lymphocytes and lymphocyte subclasses. A better understanding of the mechanisms of lymphocytotoxicity in these two purine enzyme defects may lead to better modes of therapeutic manipulation of the immune system.

Adenosine Deaminase↗
PubMed1985

Differential metabolism of deoxyribonucleosides by leukaemic T cells of immature and mature phenotype.

Experimental evidence has indicated that T lymphoblasts are more sensitive to deoxynucleoside toxicity than are B lymphoblasts. These data have led to the use of purine enzyme inhibitors as selective chemotherapeutic drugs in the treatment of T cell malignancies ranging from T cell acute lymphoblastic leukaemia to cutaneous T cell lymphomas. We have compared the toxicities of 2'-deoxyadenosine, 2'-deoxyguanosine, and thymidine for T cell lines derived from patients with T cell acute lymphoblastic leukaemia with those for mature T cell lines derived from patients with cutaneous T cell leukaemia/lymphoma. We have found that both deoxynucleosides are far less toxic to the mature T cell lies than to T lymphoblasts and that the mature cells accumulate much lower amounts of dATP and dGTP when exposed to deoxyadenosine and deoxyguanosine, respectively. Similar studies performed on peripheral blood cells from patients with T cell leukaemias of mature phenotype and on peripheral blood T cells demonstrate similar low amounts of deoxynucleotide accumulation. Measurements of the activities of several purine metabolizing enzymes that participate in deoxynucleoside phosphorylation or degradation do not reveal differences which would explain the toxicity of deoxynucleosides for immature, as compared to mature, T cells. We conclude that deoxynucleoside metabolism in leukaemic T cells varies with their degree of differentiation. These observations may be relevant to the design of chemotherapeutic regimes for T cell malignancies.

Adult↗
PubMed1985

Lesch-Nyhan syndrome: CSF neurotransmitter abnormalities.

Serial determinations of spinal fluid homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were made in four patients with the Lesch-Nyhan syndrome over a 5-year period. Control spinal fluids for age-matched comparison were obtained from 194 neurologic and nonneurologic pediatric patients. A rapid decline in control spinal fluid HVA and 5-HIAA occurs over the first 3 years of life (50 and 60%, respectively), and a more gradual decline persists throughout adolescence. The Lesch-Nyhan subjects have similar age-related changes in their spinal fluid neurotransmitter levels. Sequential 5-HIAA determinations from the four Lesch-Nyhan boys fall within the control range. The Lesch-Nyhan HVA levels are lower than the mean value for the age-matched control group in 18 of 19 samples. Ten of 19 determinations fell below the control range. Our findings provide evidence for altered CNS dopamine metabolism in the Lesch-Nyhan syndrome.

Adolescent↗
PubMed1984

Disorders associated with purine and pyrimidine metabolism.

There has been an explosion of knowledge in disorders of purine and pyrimidine metabolism during the last 20 years. During this time, more than 10 diseases have been discovered and their metabolic bases studied. Hyperuricemia and gout remain the most common clinical disorder. Rarely these disorders are explainable by an inherited enzyme abnormally, such as hypoxanthine-guanine phosphoribosyltransferase deficiency, phosphoribosyl-pyrophosphate synthetase deficiency, or glucose-6-phosphatase deficiency. The description of immunodeficiency syndromes in association with purine enzyme deficiency has led to a novel area of investigation encompassing the biochemical basis for immune function. Although less information is available concerning the other diseases associated with renal calculi, myopathy, anemia, and central nervous system dysfunction, further research will elucidate important metabolic relationships. These will no doubt expand our understanding of the pathogenesis of these disorders and provide innovative therapeutic approaches.

5'-Nucleotidase↗
PubMed1984

Purine metabolizing enzymes as predictors of lymphoblast sensitivity to deoxyadenosine.

The toxicity of low concentrations of 2'-deoxyadenosine for T-lymphoblasts and certain null lymphoblasts has been attributed to the decreased degradation of the deoxynucleotides formed from deoxyadenosine in these cells. Low activities of the ectoenzymes ecto-5'-nucleotidase and ecto-ATPase have each been associated with deoxyadenosine sensitivity and dATP accumulation in human T-lymphoblasts. We studied a B-lymphoblast cell line, NC-37, which lacks detectable ecto-5'-nucleotidase and ecto-ATPase activities, but which is otherwise easily distinguishable from T-lymphoblasts by its low adenosine deaminase activity and its pattern of reactivity with monoclonal antibodies to cell surface antigens (Bl and IgM positive). The NC-37 B cells were completely analogous to other B-lymphoblast lines with high ectonucleotidase activities in their relative resistance to deoxyadenosine toxicity and low rates of dATP accumulation. This resistance could not be accounted for by lower rates of deoxyadenosine phosphorylating activity. Cytoplasmic nucleotidase activity in crude extracts from the NC-37 line was similar to that in other B-lymphoblasts with regard to both substrate specificity and optimal pH. We conclude that low ectonucleotidase activities are not etiologically associated with the accumulation of deoxynucleotides by human lymphoblasts, although they may serve as markers of deoxyadenosine sensitivity in certain malignant lymphoid cells.

5'-Nucleotidase↗
PubMed1983

Deoxyribonucleoside triphosphate accumulation by leukemic cells.

The toxicity of the deoxyribonucleosides, 2'-deoxyadenosine, 2'-deoxyguanosine, and thymidine, for human T lymphoblasts is mediated by the accumulation of the corresponding deoxyribonucleoside triphosphate (dATP, dGTP, or dTTP, respectively). We have examined whether leukemic cells of non-T-cell origin are capable of accumulating deoxyribonucleotides in culture and whether this capability correlates with the activities of purine metabolizing enzymes in these cells. We have found that non-T, non-B acute lymphoblastic leukemia cells with low ecto-5'-nucleotidase and high adenosine deaminase activities increase their dATP pools by greater than tenfold when exposed to deoxyadenosine and an inhibitor of adenosine deaminase in culture. Cells from 2 of 9 patients with chronic lymphocytic leukemia and 4 of 11 patients with acute nonlymphoblastic leukemia achieved similar elevations in dATP, but there was no relationship between dATP accumulation and adenosine deaminase, purine nucleoside phosphorylase, or ecto-5'-nucleotidase activities. Treatment of four individuals with acute lymphoblastic leukemia with the adenosine deaminase inhibitor, 2'-deoxycoformycin, resulted in elevations in plasma deoxyadenosine concentrations and in increments in lymphoblast dATP levels that were similar to those measured in lymphoblasts cultured with deoxyadenosine and deoxycoformycin prior to treatment. In vitro incubations of leukemic cells with deoxyribonucleosides may provide a rational basis for the use of these compounds as chemotherapeutic agents.

Adenosine Deaminase↗
PubMed1982

Regulation of purine metabolism by plasma membrane and cytoplasmic 5'-nucleotidases.

The contribution of plasma membrane 5'-nucleotidase (E.C. 3.1.3.5) to intracellular purine degradation and release was evaluated in cultured human lymphoblasts. B-lymphoblasts and T-lymphoblasts are characterized by high and low levels of plasma membrane 5'-nucleotidase activity, respectively. After radiolabeling of the cellular adenine nucleotide pools with [8-14C]adenine, deoxyglucose-induced purine nucleotide degradation resulted in a 2-2.5 times greater release of cellular radioactivity from the B-lymphoblasts than from the T-lymphoblasts. Specific inhibition of plasma membrane 5'-nucleotidase with 50 microM alpha, beta-methylene adenosine diphosphate (AMPCP) did not decrease purine release during deoxyglucose-induced nucleotide degradation. Similarly, the inhibition of B-lymphoblast membrane 5-nucleotidase did not alter the incorporation of [8-14C]adenine into the nucleotide pool. Therefore, to explain the relatively high release of purine nucleotide degradation products in B-lymphoblasts when compared with T-lymphoblasts, cytoplasmic 5'-nucleotidase activity was investigated in these cell lines. B-lymphoblasts have seven times more cytoplasmic 5'-nucleotidase activity for dAMP and two to three times more activity for other purine nucleoside 5'-monophosphates than do T-lymphoblasts at pH 7.4. Membrane and cytoplasmic nucleotidase activities are produced by different enzymes that can be distinguished by differences in pH optima, Michaelis constants for purine substrates, divalent cation requirements, and susceptibilities to AMPCP inhibition. The data suggest that plasma membrane 5'-nucleotidase hydrolyzes extracellular nucleoside 5'-monophosphates only. Cytoplasmic 5'-nucleotidase most likely regulates the degradation of intracellular nucleoside 5'-monophosphates and may be responsible for the increased purine release observed in B-lymphoblasts.

5'-Nucleotidase↗
PubMed1981

Increased adenine nucleotide turnover in duchenne muscular dystrophy.

To investigate a possible disorder of adenine nucleotide turnover in Duchenne muscular dystrophy, we evaluated 15 patients with mild Duchenne muscular dystrophy, eight patients with severe muscular dystrophy, seven patients with other neuromuscular disorders, and eight patients with hypogammaglobulinemia but no muscle disease. The serum urate concentration was similar in all four groups. Base line urinary purine excretion was elevated in all patients with neuromuscular disease with values of 1.72 +/- 0.15, 2.37 +/- 0.22, 2.49 +/- 0.35, and 2.60 +/- 0.48 mumoles/100 ml glomerular filtration for control subjects, mild Duchenne muscular dystrophy, severe disease, and other neuromuscular diseases, respectively. Adenine nucleotide pool turnover was measured by labeling with [8-14C]adenine and then 5 days later administering intravenous fructose. Five-day cumulative mean radioactivity excretion was elevated in mild and severe Duchenne muscular dystrophy with excretion values of 11.4 +/- 0.7 and 11.5 +/- 1.1% of administered radioactivity, respectively, as compared to 9.0 +/- 0.9% of administered radioactivity for control subjects. After intravenous fructose infusion, patients with Duchenne muscular dystrophy had a less than normal rise in serum urate concentration, a normal increase of urinary urinary purine excretion, and a greater than normal elevation of urinary radioactivity excretion and urinary purine specific activity. Patients with other neuromuscular diseases had virtually no rise in plasma urate concentration, less than normal increase in urinary total purine excretion, and a greater than normal increase of urinary radioactivity excretion and urinary specific activity. These observations suggest that there is an increased rate of adenine nucleotide turnover in Duchenne muscular dystrophy. In patients with other neuromuscular disease an increased rate of adenine nucleotide turnover resembled the abnormality expected from a diminished adenine nucleotide pool.

Adenine Nucleotides↗
PubMed1981

Enhanced purine salvage during allopurinol therapy: an important pharmacologic property in humans.

The contribution of enhanced purine salvage to the decreased total purine excretion associated with allopurinol therapy was measured by the intravenous administration of tracer doses of [8-(14)C] adenine to four patients with gout and normal purine salvage enzyme activity and four patients with the Lesch-Nyhan syndrome and absent purine salvage activity. The mean cumulative excretion of radioactivity 5 days after the adenine administration to patients not receiving and receiving (off and on) allopurinol therapy was 6.1% and 3.6% of infused radioactivity for gouty subjects and 15.9% and 20.8% for the Lesch-Nyhan patients. Urate pool size and urate turnover, as measured by pool labeling with [2-(14)C]uric acid, were substantially decreased in both groups of patients during allopurinol therapy. The intestinal loss of uric acid was estimated from these pool measurements on and off allopurinol. With a correction for this extrarenal purine loss, the mean cumulative excretions of radioactivity 5 days after adenine administration to patients off and on allopurinol therapy were 11.9% and 4.8% for the gouty subjects and 31.7% and 24.5% for the Lesch-Nyhan patients. In vitro studies demonstrated no alteration of the synthesis or degradation of adenine nucleotides by allopurinol in cultured human diploid fibroblasts. These observations suggest that enhanced purine salvage is an important component leading to decreased purine excretion during allopurinol therapy.

Adenine Nucleotides↗
PubMed1980

Hypoxanthine salvage in man: its importance in urate overproduction in the Lesch-Nyhan syndrome.

1. A daily urinary excretion of 0.8 percent of the administered radioactivity results from the turnover of the labeled adenine nucleotide pool. 2. A 4-fold increase of urinary radioactivity excretion occurs in patients with the Lesch-Nyhan syndrome and support the role of impaired hypoxanthine salvage in the purine overexcretion associated with HGPRT deficiency. 3. Our data do not support the possibility that the increased radioactivity excretion in the HGPRT deficient subjects results from an elevated rate of adenine nucleotide degradation.

Adenine↗