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Biomedical subjects

E M Flanagan

Publications and source records attributed to E M Flanagan.

12 recordsLinked to original sources
PubMed1996

Effects of 540C91 [(E)-3-[2-(4'-pyridyl)-vinyl]-1H-indole], an inhibitor of hepatic tryptophan dioxygenase, on brain quinolinic acid in mice.

Studies were undertaken to assess the role of the liver in the formation of the neurotoxin quinolinic acid in the brain. A selective and potent inhibitor of hepatic tryptophan 2,3-dioxygenase, 540C91 [(E)-3-[2-(4'-pyridyl)-vinyl]-1H-indole], largely prevented the elevation in mouse brain quinolinic acid resulting from parenteral injection of tryptophan (TRP). In contrast, 540C91 did not affect basal levels of the neurotoxin. Following induction of indoleamine dioxygenase with bacterial lipopolysaccharide, 540C91 was less effective in preventing the TRP-induced elevations in quinolinic acid. The data suggest that kynurenines, formed from tryptophan, by the liver and other extrahepatic organs can give rise to brain quinolinic acid.

Animals↗
PubMed1996

The neurotoxin quinolinic acid is increased in spinal cords of mice with herpes simplex virus encephalitis.

Following retroperitoneal, intradermal inoculation of mice with HSV-1, signs of encephalomyelitis (hind-limb paralysis, flaccid tail and loss of bladder control) appeared 6-7 days later. Levels of quinolinic acid (QUIN; determined by gas chromatography with mass-spectrometry), rose approximately 40-fold in mice with encephalomyelitis, primarily in the spinal cord. Live virus could also be grown from homogenates of the affected spinal cords. Time-course studies, demonstrated that the increase in QUIN coincided with the appearance of encephalomyelitis. Large increases in indoleamine dioxygenase activity were observed in spinal cords from the affected mice, suggesting that the QUIN was synthesized within the spinal cord. It is, therefore, possible that QUIN may contribute to the pathology of HSV-1 encephalomyelitis.

3-Hydroxyanthranilate 3,4-Dioxygenase↗
PubMed1996

The regulation of quinolinic acid in human immunodeficiency virus-infected monocytes.

Quinolinic acid (Quin) is thought to underlie cognitive and motor dysfunctions for a variety of neurological disorders. Specifically, in human immunodeficiency virus (HIV)-associated dementia, Quin levels correlate with the degree of neurological dysfunction observed in affected individuals. Since recent data from our laboratories suggest that both HIV-1 infection and activation of brain macrophages are required for the development of neurotoxicity we examined Quin production during virus infection and immune activation. HIV-1 infection of monocytes induced low levels of Quin while lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) activation of the virus-infected cells elicited 10-fold higher levels. The combined effects of LPS and IFN-gamma for Quin production in HIV-infected monocytes was identical to each factor added alone. Little or no Quin was detected in unstimulated uninfected monocytes. LPS or IFN-gamma activation of uninfected monocytes produced substantially higher levels of Quin than found in similarly stimulated HIV-1-infected monocytes. These results were at variance to the production of tumor necrosis factor-alpha (TNF-alpha). Here, a 2-to 5-fold increase in TNF-alpha levels were observed in culture fluids of LPS-activated HIV-infected cells when compared to similarly stimulated uninfected monocytes. The effect of LPS-induced Quin production by HIV-infected monocytes was not altered by primary human astrocytes. These data suggest that Quin levels seen in HIV dementia are a reflection of macrophage/ microglial activation seen during advanced clinical disease. These findings could help explain, in part, why few HIV-1-infected brain macrophages can give rise to significant neurological impairments.

AIDS Dementia Complex↗
PubMed1995

Neurotoxin quinolinic acid is selectively elevated in spinal cords of rats with experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) is an autoimmune, animal model of multiple sclerosis (MS) in which demyelination and paralysis are evident. Quinolinic acid (QUIN) is a neurotoxin and endogenous N-methyl-D-aspartate receptor agonist formed from tryptophan. The role of neurotoxins in general and QUIN in particular in EAE or MS is unknown. Lewis rats inoculated with myelin basic protein developed signs of EAE by day 12, were killed, and their tissues assayed for QUIN by gas chromatography with mass spectrometry. QUIN levels were significantly elevated in the more caudal regions of the spinal cords of animals with EAE. Brain, serum, and liver levels of QUIN were not altered. In a similar manner, QUIN in mylin basic protein-injected, asymptomatic animals was not different from control animals. The time course for QUIN was similar to the neurological signs of the disorder; however, the initial elevation in QUIN occurred before the appearance of behavioral signs. Last, treatment with the glucocorticoid dexamethasone prevented both the signs of EAE and the elevation in spinal cord QUIN. It is not known whether QUIN contributes to the paralysis in EAE. However, if QUIN is pathogenic in EAE this finding could have therapeutic implications for MS.

Animals↗
PubMed1994

Elevation of the neurotoxin quinolinic acid occurs following spinal cord trauma.

Excitatory amino acid neurotoxicity and the inflammatory response are suspected as mediators of some of the pathological sequelae occurring as a result of spinal cord injury. Here we report temporal and regional increases of the NMDA receptor agonist, quinolinic acid (QUIN), in an experimental model of spinal contusion injury. These changes occurred at a time when the blood-brain barrier is known to be dysfunctional and the activation state and density of microglia and macrophages are increased. Thus, alterations in tissue QUIN levels may occur as a result of secondary activation of CNS inflammatory cells or from peripherally derived sources across a damaged blood-brain barrier.

Animals↗
PubMed1992

A radiometric assay for kynurenine 3-hydroxylase based on the release of 3H2O during hydroxylation of L-[3,5-3H]kynurenine.

A rapid and sensitive assay for kynurenine 3-hydroxylase (KH) has been developed. This radiometric assay is based on the enzymatic synthesis of tritiated water from L-[3,5-3H]kynurenine during the hydroxylation reaction. Radiolabeled water is quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. The assay is suitable for detecting 0.1 pmol enzyme activity per minute per milligram protein in tissues displaying low levels of the enzyme. The amount of water produced in the reaction, as calculated from the tritium released, was stoichiometric with the 3-hydroxykynurenine product detected by HPLC. Rat liver KH was characterized by cofactor specificity and kinetic parameters. NADPH was preferred over NADH as coreductant in the reaction. Tetrahydrobiopterin was not a cofactor. The tissue distribution of KH activity in the rat suggested that the majority of active enzyme is located in liver and kidney. Detectable amounts were found in several other tissues, including brain which had low but significant levels of activity in every region assayed.

Animals↗
PubMed1990

Stark reality.

On Feb. 9, 1989, amid considerable attention in the healthcare industry, Rep. Fortney H. ("Pete") Stark, D-CA, introduced in Congress the Ethics in Patient Referrals Act (H.R. 939). At the time, the so-called Stark bill would have effectively prohibited physicians from referring Medicare patients to any healthcare entity in which they had a financial interest, including hospitals, hospital departments, and physician-hospital joint ventures. The bill that emerged and was signed into law months later is but a shadow of its former self: The prohibition against physician referrals is directed only at certain clinical laboratories and certain relationships between physicians and the laboratories. Hospitals and physicians may be overly optimistic about the results of this most recent incursion into physician ownership. This was not the first government intrusion into physicians' financial affairs, and it is not likely to be the last. Congress will no doubt continue to focus attention on physicians and hospitals that seek revenues through joint investments in healthcare providers. In fact, Congress has already put referring physicians on notice, saying that if the Government Accounting Office finds evidence of inappropriate referrals, or increased Medicare costs, "it would be the intent of the relevant Committees to consider legislation banning referrals at the earliest possible date."

Crime↗