PubMed Health⌕ Search

Biomedical subjects

D G Graham

Publications and source records attributed to D G Graham.

At least 91 records · Page 5Linked to original sources
PubMed1983

Immunodeficiency measles encephalitis.

The first case of measles encephalitis occurring in an adult with late onset primary hypogammaglobulinaemia is described. This diagnosis was confirmed by examination of the parietal cortex at autopsy with the electron microscope. As the fatal outcome of this case might have been prevented with immunoglobulin replacement therapy, we suggest that such therapy be commenced following the diagnosis even if the patient has only minor infective episodes.

Agammaglobulinemia↗
PubMed1982

Neurotoxicity of continuous (90 days) inhalation of technical grade methyl butyl ketone in hens.

Neurotoxicity was produced in 1-yr-old hens (five hens per treatment) by continual 90-d exposure in inhalation chambers to atmospheres containing 50, 100, 200, or 400 ppm technical grade methyl butyl ketone (MBK) containing 70% methyl n-butyl ketone (MnBK) and 30% methyl isobutyl ketone (MiBK). A 30-d observation period followed. Severity of clinical condition and progression or improvement of neurological deficit signs were dependent on the concentration of MBK and duration of exposure. Hens exposed to the two highest levels developed ataxia and paralysis; they died or were sacrificed before the designated exposure period ended. The intermediate level of MBK (100 ppm) caused severe ataxia; most treated hens showed no change in clinical condition during the observation period. Hens exposed to 50 ppm exhibited gross ataxia, with most demonstrating partial regression of neurological deficit after the exposure ceased. Hens exposed to the lowest tested level (10 ppm) remained normal. Only hens exposed to 400 or 200 ppm showed significant weight loss. Some hens from the 50-400 ppm treatment groups showed unequivocal histopathologic changes in the spinal cord and peripheral nerves. Severity of histopathologic changes depended on the level and duration of MBK exposure. These changes were characterized by excessive swelling, phagocytosis, degeneration, and demyelination of the axons.

Animals↗
PubMed1982

Coumaphos: delayed neurotoxic effect following dermal administration in hens.

This study reports the differential neurotoxic effects of coumaphos [O,O-diethyl O-(3-chloro-4-methyl-7-coumarinyl) phosphorothioate] when applied orally or dermally in the adult hen. Dermal administration of single (50-500 mg/kg) or daily (100 mg/kg) doses resulted in delayed neurotoxicity in hens, similar to that caused by other delayed neurotoxic organophosphorus compounds. Coumaphos caused loss of weight and produced ataxia, which progressed to paralysis and death. Degeneration of axons and myelin in the spinal cord was the most consistent histopathologic alteration and was identical to that reported for other delayed neurotoxic organophosphorus esters. Only one hen showed peripheral nerve degeneration. Oral administration of a single 100 mg/kg dose or daily doses of 10 mg coumaphos caused severe acute toxicity and killed all treated hens 1-8 d. These hens did not develop delayed neurotoxicity. Some hens given a single oral 50-mg/kg dose or daily 5-mg/kg doses of coumaphos recovered from the initial cholinergic effect and developed clinical signs of delayed neurotoxicity. These hens, however, improved with time and did not show unequivocal nervous-tissue damage at termination.

Administration, Oral↗
PubMed1980

The metabolic pathway catalyzed by the tyrosinase of Agaricus bisporus.

N-t-Butyloxycarbonyl-gamma-L-glutaminyl-2-bromo-4-hydroxybenzene alpha-benzyl ester was synthesized as a precursor to gamma-L-glutaminyl-4-hydroxy[2-3H]benzene. With this labeled compound and the previously synthesized gamma-L-glutaminyl-4-hydroxy[3,5-3H]benzene, the stoichiometry of ring substitution was determined for the tyrosinase-catalyzed metabolic pathway of Agaricus bisporus. In this pathway, gamma-L-glutaminyl-4-hydroxybenzene is hydroxylated to gamma-L-glutaminyl-3,4-dihydroxybenzene which is oxidized to gamma-L-glutaminyl-3,4-benzoquinone and a compound of previously unknown structure, "490." The results indicated that the "490" quinone was derived from gamma-L-glutaminyl-3,4-benzoquinone without further ring substitution. A base-catalyzed, nonenzymatic reaction of gamma-L-glutaminyl-3,4-benzoquinone was observed which yielded a compound with a 490 nm chromophore. gamma-Glutamyl transpeptidase cleavage of gamma-L-glutaminyl-3,4-dihydroxybenzene led to the release of 4-aminocatechol which air-oxidized to a compound with identical spectral properties to "490." The structure of "490" was thus determined to be 2-hydroxy-4-imino-2,5-cyclohexadiene-1-one(2-hydroxy-4-iminoquinone). The tyrosinase-catalyzed hydroxylation of gamma-L-glutaminyl-4-hydroxybenzene was found to be optimal at pH 8.0, while the enzymatic oxidation of gamma-L-glutaminyl-3,4-dihydroxybenzene was optimal at pH 6.0.

Agaricales↗
PubMed1980

Studies of the molecular pathogenesis of hexane neuropathy. I. evaluation of the inhibition of glyceraldehyde-3-phosphate dehydrogenase by 2,5-hexanedione.

Inhibition of the sulfhydryl enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by 2,5-hexanedione (2,5-HD) was found to be irreversible, proceeding via a reversible enzyme-inhibitor intermediate, while acetone was a weak reversible inhibitor. Comparison of 2,5-HD and acetone with p-chloromercuribenzoate (PCMB) and N-ethylmaleimide (NEM) demonstrated that the former are not significant sulfhydryl reagents, since they must be present at more than 10(4) times higher concentrations than PCMB or NEM to effect measurable inhibition of this enzyme. Thus it is unlikely that inhibition of GAPDH by 2,5-HD has any significance in the molecular pathogenesis of hexane neuropathy. The irreversibility of 2,5-HD inhibition, on the othe hand, suggests that 2,5-HD reacts with amino groups rather than sulfhydryl groups on proteins. This reaction is proposed as the molecular lesion in hexane neuropathy.

Acetone↗
PubMed1980

Melanocytotoxicity and the mechanism of activation of gamma-L-glutaminyl-4-hydroxybenzene.

gamma-L-Glutaminyl-4-hydroxybenzene is converted by the tyrosinase of the common mushroom, Agaricus bisporus, to the toxic, dormancy-inducing metabolite 2-hydroxy-4-imino-2,5-cyclohexadiene-1-one. Hydroxylation of gamma-L-glutaminyl-4-hydroxybenzene by mammalian tyrosinase was monitored by determining tritium water release from gamma-L-glutaminyl-[3,5-(3)H[4-hydroxybenzene and occurred at only 25% of the rate found with tyrosine. The dihydroxy product of the hydroxylation reaction, gamma-L-glutaminyl-3,4-dihydroxybenzene, was not oxidized by the mammalian enzyme. Therefore, oxidation of gamma-L-glutaminyl-4-hydroxybenzene to sulfhydryl-reactive quinones by mammalian tyrosinase is an unlikely explanation for the hair depigmentation and inhibition of melanocarcinoma growth observed following administration of this compound. Cleavage of gamma-L-glutaminyl-4-hydroxybenzene by gamma-glutamyl transpeptidase releasing p-aminophenol was demonstrated. p-Aminophenol was an active depigmenting and melanocytotoxic compound. N2-Methyl-gamma-L-glutaminyl-4-hydroxybenzene was synthesized, differing from gamma-L-glutaminyl-4-hydroxybenzene only by the presence of a methylated amide linkage. This chemical modification resulted in a compound resistant to cleavage by gamma-glutamyl transpeptidase and lacking in melanocytotoxic activity. gamma-Glutamyl transpeptidase cleavage is proposed as the route for transformation of gamma-L-glutaminyl-4-hydroxybenzene into an active inhibitor of melanocytes.

Aminophenols↗
PubMed1980

The role of gamma-glutamyl transpeptidase in the nephrotoxicity of an Agaricus bisporus metabolite.

The mushroom metabolite gamma-L-glutaminyl-3,4-dihydroxybenzene (GDHB) was found to have an LD50 of 100 to 200 mg/kg in neonatal C57Bl/6J mice. Adult mice given 200 mg/kg GDHB showed histopathologic evidence of proximal convoluted tubular injury as early as 2 hours after injection, which progressed by 24 hours to profound acute tubular necrosis. Focal acinar epithelial cell necrosis in the pancreas was also observed. The time course and location of the injury suggested that appearance of the ultimate toxic metabolite could be due to cleavage of GDHB by gamma-glutamyl transpeptidase (GGTP). The reaction in vitro of GDHB with crude porcine GGTP resulted in the release of 4-amino-catechol which air oxidized to 2-hydroxy--4-iminoquinone (HIQ), a known sulfhydryl reagent and cytotoxic compound. Synthesis of N2-methyl-gamma-glutaminyl-3,4-dihydroxybenzene (MeGDHB) provided a compound whose oxidized derivatives, when compared with those of GDHB, had similar half-wave potentials and visible absorption maxima. MeGDHB was resistant to cleavage by GGTP and was without apparent toxicitiy at 2-3 times the LD50 of GDHB. Therefore, cleavage by GGTP, an enzymatic transformation accessible to GDHB but unavailable to MeGDHB, is proposed as the mechanism of activation of the mushroom metabolite. The following pathogenic sequence is indicated: 1) release of 4-aminocatechol from GDHB by the action of GGTP and 2) irreversible injury resulting both from the generation of free radicals by the autoxidation of 4-aminocatechol and from the reaction of HIQ with cellular nucleophils, particularly sulfhydryl groups.

Agaricales↗
PubMed1979

Synthesis of gamma-L-glutaminyl-[3,5-3H]4-hydroxybenzene and the study of reactions catalyzed by the tyrosinase of Agaricus bisporus.

gamma-L-Glutaminyl-[3,5-3H]4-hydroxybenzene was synthesized in order to study the kinetics of its hydroxylation by tyrosinase purified from Agaricus bisporus and to explore its role in the induction of the dormant state in the spores of this species. It was found to be unique among the monophenolic substrates for tyrosinase in that the lag period for the hydroxylation reaction decreased with increasing substrate concentration. Unlike previously studied compounds, this phenol appeared to function as an electron donor, allowing it to act as its own co-substrate in the hydroxylation reaction. Its catechol product, gamma-L-glutaminyl-3,4-dihydroxybenzene, was found to be a superior co-substrate, yielding its electrons more readily (oxidation peak potential +0.18 V as compared with +0.65 V for the phenol). In situ periodate oxidation of gamma-L-glutaminyl-3,4-dihydroxybenzene to gamma-L-glutaminyl-3,4-benzoquinone confirmed the co-substrate role of the catechol in the hydroxylation reaction. The tyrosinase-mediated oxidation of gamma-L-glutaminyl-3,4-dihydroxybenzene to gamma-L-glutaminyl-3,4-benzoquinone occurred with an apparent Km = 1.54 mM and Vmax = 0.36 mmol/min/mg of enzyme. gamma-L-Glutaminyl-4-hydroxybenzene acted as an inhibitor of the oxidation reaction.

Agaricales↗