GAD(65) and GAD(67) isoforms of the glutamic acid decarboxylase gene originated before the divergence of cartilaginous fishes.
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Biomedical subjects
L MacEachern
Publications and source records attributed to L MacEachern.
Talc: occurrence, characterization, and consumer applications.
Talc is a mineral compound with unique attributes and significant commercial importance. As used in consumer products, talc has a long and proven history of safe use. Direct consumer applications include body powders, other cosmetic formulations, pharmaceutical tableting, and some confectionery food products. Production, characterization, and consumer applications of FDA-regulated talc products, particularly cosmetics, are described. The implementation of stringent safety and quality control measures designed to ensure the absence of asbestos fibers from consumer talc products is discussed. Consumer exposure to talc-containing products is at least 350 times lower than permissible industrial exposure.
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Enhanced production of nitric oxide by bone marrow cells and increased sensitivity to macrophage colony-stimulating factor (CSF) and granulocyte-macrophage CSF after benzene treatment of mice.
Nitric oxide is a short-lived reactive mediator that inhibits bone marrow (BM) cell proliferation induced by granulocyte-macrophage colony-stimulating factor (GM-CSF). The present studies show that nitric oxide also inhibits macrophage colony-stimulating factor (M-CSF)-induced growth of mouse BM cells, an effect that was dependent on the presence of an inflammatory mediator and blocked by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMA). Treatment of mice with the hematotoxicant benzene (800 mg/kg, intraperitoneally, two times per day, for 2 days) resulted in a significant increase in nitric oxide production by BM cells stimulated with lipopolysaccharide (LPS) and interferon gamma alone or in combination with M-CSF or GM-CSF. Cells from benzene-treated mice also displayed increased sensitivity to the growth-promoting effects of M-CSF and GM-CSF. These results suggest that benzene treatment of mice primes BM cells to inducers of nitric oxide. Northern blot analysis showed that this was, at least in part, caused by increased expression of mRNA for inducible nitric oxide synthase (iNOS). Surprisingly, treatment of mice with L-NMA was found to cause a depression in BM cell proliferation and to potentiate benzene-induced decreases in BM cellularity and increases in nitric oxide production. L-NMA administration also augmented nitric oxide production by BM cells. These data indicate that L-NMA is hematotoxic and suggest that it may have actions distinct from inhibition of nitric oxide synthase in the BM.
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Increased production of tumor necrosis factor-alpha by bone marrow leukocytes following benzene treatment of mice.
Hematopoiesis is regulated by cytokines released from bone marrow stromal cells and mature leukocytes. Recent studies have identified these cells as targets for benzene-induced hematotoxicity. In the present studies we analyzed the effects of benzene treatment of mice on the production of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) by bone marrow leukocytes. Bone marrow cells isolated from control or benzene-treated mice (660 mg/kg, once/day, 3 days) were purified on lymphocyte separation medium. Cells were then cultured in the presence of varying concentrations of lipopolysaccharide (0.1-10 micrograms/ml) for 0.5-48 hr. IL-1, IL-6, and TNF-alpha activity in culture supernatants was then quantified. We found a significant (p less than or equal to 0.02) increase in TNF-alpha production by bone marrow leukocytes from benzene-treated mice when compared to cells from control animals. Furthermore, this increase was dependent on the macrophage-specific growth factor, colony stimulating factor-1. Benzene treatment was also found to induce a small but significant (p less than or equal to 0.02) increase in the production of IL-1 by bone marrow leukocytes. This increase was rapid and transient, occurring in supernatants collected 2 hr after inoculation of bone marrow cells into culture. In contrast, benzene treatment had no effect on the production of IL-6 by bone marrow leukocytes. These results demonstrate that benzene treatment of mice stimulates mature bone marrow leukocytes to produce elevated levels of growth regulatory cytokines.
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Alterations in the morphology and functional activity of bone marrow phagocytes following benzene treatment of mice.
Benzene is a well-established hematotoxin that affects developing leukocytes and erythrocytes as well as bone marrow stromal cells. In the present studies we analyzed the effects of benzene on the morphology and functional activity of bone marrow phagocytes. Male Balb/c mice were treated with benzene (660 mg/kg) once per day for 3 days. Bone marrow cells were then isolated and fractionated by density gradient centrifugation. Using highly sensitive techniques in flow cytometry/cell sorting, we found that we could separate three distinct populations of bone marrow cells that differed with respect to size and density. Monoclonal antibody binding and cell sorting revealed a large, dense population that consisted predominantly of granulocytes, a smaller, less dense population of lymphocytes, and a population of intermediate size and density consisting of mononuclear phagocytes and precursor cells. Differential staining of sorted mononuclear phagocytes revealed that benzene treatment of mice caused a marked increase in the number of mature, morphologically activated macrophages in the bone marrow. Benzene treatment of mice also resulted in enhanced chemotaxis and production of hydrogen peroxide by bone marrow granulocytes and mononuclear phagocytes. In contrast, treatment of mice with the combination of hydroquinone and phenol (50 mg/kg each, 1 x/day, 3 days), two metabolites of benzene, resulted in a significant (p < or = 0.02) depression of granulocyte chemotaxis and had no effect on hydrogen peroxide production by bone marrow phagocytes compared to cells from control animals. Taken together these results demonstrate that benzene causes increased differentiation and/or activation of phagocytes in the bone marrow.
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Activation of bone marrow phagocytes following benzene treatment of mice.
Techniques in flow cytometry/cell sorting were used to characterize the effects of benzene and its metabolites on subpopulations of bone marrow cells. Treatment of male Balb/c mice with benzene (880 mg/kg) or a combination of its metabolites, hydroquinone and phenol (50 mg/kg), resulted in a 30 to 40% decrease in bone marrow cellularity. Flow cytometric analysis revealed two subpopulations of bone marrow cells that could be distinguished by their size and density or granularity. The larger, more dense subpopulation was found to consist predominantly of macrophages and granulocytes as determined by monoclonal antibody binding and by cell sorting. Benzene treatment had no selective cytotoxic effects on subpopulations of bone marrow cells. To determine if benzene treatment activated bone marrow phagocytes, we quantified production of hydrogen peroxide by these cells using the fluorescent indicator dye, 2',7'-dichlorofluorescein diacetate. We found that macrophages and granulocytes from bone marrow of treated mice produced 50% more hydrogen peroxide in response to the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate than did cells from control animals. It is hypothesized that phagocyte activation and production of cytotoxic reactive oxygen intermediates may contribute to hematotoxicity induced by benzene.
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