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Biomedical subjects

K Gray

Publications and source records attributed to K Gray.

At least 73 records · Page 4Linked to original sources
PubMed1993

Metabolic activation and deactivation of arylamine carcinogens by recombinant human NAT1 and polymorphic NAT2 acetyltransferases.

A genetic polymorphism at the NAT2 gene locus, encoding for polymorphic N-acetyltransferase (NAT2), segregates individuals into rapid, intermediate or slow acetylator phenotypes. Both rapid and slow acetylator phenotypes have been associated with increased incidence of cancer in certain target organs related to arylamine exposure, suggesting a role for acetylation in both the activation and deactivation of arylamine carcinogens. A second gene (NAT1) encodes for a different acetyltransferase isozyme (NAT1) that is not subject to the classical acetylation polymorphism. In order to assess the relative ability of NAT1 and NAT2 to activate and deactivate arylamine carcinogens, we tested the capacity of recombinant human NAT1 and NAT2, expressed in Escherichia coli XA90 strains DMG100 and DMG200 respectively, to catalyze the N-acetylation (deactivation) and O-acetylation (activation) of a variety of carbocyclic and heterocyclic arylamine carcinogens. Both NAT1 and NAT2 catalyzed the N-acetylation of each of the 17 arylamines tested. Rates of N-acetylation by NAT1 and NAT2 were considerably lower for heterocyclic arylamines such as 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), particularly those (e.g. IQ) with steric hindrance to the exocyclic amino group. For carbocyclic arylamines such as 4-aminobiphenyl and beta-naphthylamine, the apparent affinity was significantly (P < 0.05) higher for NAT2 than NAT1. NAT1/NAT2 activity ratios and clearance calculations suggest a significant role for the polymorphic NAT2 in the N-acetylation of carbocyclic arylamine carcinogens. Both NAT1 and NAT2 catalyzed acetyl coenzyme A-dependent O-acetylation of N-hydroxy-2-aminofluorene and N-hydroxy-4-aminobiphenyl to yield DNA adducts. NAT1 catalyzed paraoxon-resistant, intramolecular N,O-acetyltransferase-mediated activation of N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylaminobiphenyl at low rates; catalysis by NAT2 was not readily detectable in the presence of paraoxon. In summary these studies strongly suggest that the human acetylation polymorphism influences both the metabolic activation (O-acetylation) and deactivation (N-acetylation) of arylamine carcinogens via polymorphic expression of NAT2. These findings lend mechanistic support for human epidemiological studies suggesting associations between both rapid and slow acetylator phenotype and cancers related to arylamine exposure.

Acetylation↗
PubMed1992

Pharmacology of intrathecal VP-16-213 in dogs.

VP-16-213 is an anticancer drug that is active against a number of malignancies including small cell lung cancer, lymphoma, and leukemia which are often complicated by the development of leptomeningeal carcinomatosis. To investigate the potential usefulness of VP-16-213 for intrathecal administration, the pharmacology and toxicity of intrathecal VP-16-213 was determined. VP-16-213 at varying doses (0.01-1.0 mg.kg) was instilled intrathecally in dogs. Plasma, CSF, spinal cord, and brain tissue drug concentrations were determined by radiochemical and high performance liquid chromatography technique. Drug concentrations were strikingly higher in spinal cord tissue near the injection site compared to more distal cord sites. CSF concentration of VP-16-213 is 3-4 logs higher compared to concurrent plasma levels. Severe neurotoxicity occurred at the higher doses used. Due to limited diffusion and extremely low doses which could be used without life-threatening neurotoxicity, VP-16-213 does not appear to be a useful agent for intrathecal administration.

Animals↗
PubMed1992

Acetyltransferases and susceptibility to chemicals.

Arylamine chemicals inflict a number of toxicities including cancer. Metabolic activation (i.e., oxidation) is required in order to elicit the toxic actions. Acetylation is an important step in the metabolic activation and deactivation of arylamines. N-acetylation forms the amide derivative which is often nontoxic. However, O-acetylation of the N-hydroxyarylamine (following oxidation) yields an acetoxy arylamine derivative which breaks down spontaneously to a highly reactive arylnitrenium ion, the ultimate metabolite responsible for mutagenic and carcinogenic lesions. Human capacity to acetylate arylamine chemicals is subject to a genetic polymorphism. Individuals segregate into rapid, intermediate, or slow acetylator phenotypes by Mendelian inheritance regulated by a single gene encoding for a polymorphic acetyltransferase isozyme (NAT2). Individuals homozygous for mutant alleles are deficient in the polymorphic acetyltransferase and are slow acetylators. A second acetyltransferase isozyme (NAT1) is monomorphic and is not regulated by the acetylator genotype. Several human epidemiological studies suggest an association between slow acetylator phenotype and urinary bladder cancer. In contrast, a few studies suggest a relationship between rapid acetylator phenotype and colorectal cancer. The basis for this paradox may relate to the relative importance of N- versus O-acetylation in the etiology of these cancers. Conclusions drawn from human epidemiological data are often compromised by uncontrolled environmental and other genetic factors. Our laboratory recently completed construction of homozygous rapid, heterozygous intermediate, and homozygous slow acetylator congenic Syrian hamsters to be homologous in greater than 99.975% of their genomes. The availability of these acetylator congenic lines should eliminate genetic variability in virtually all aspects of arylamine carcinogenesis except at the acetylator gene locus. Ongoing studies in these congenic hamster lines should provide unequivocal information regarding the role of genetic acetylator phenotype in susceptibility to arylamine-related cancers.

Acetylation↗
PubMed1991

Dichloroacetate reduces sympathetic nerve responses to static exercise.

Lactic acid is thought to be a stimulant of muscle metaboreceptors. The goal of the present study was to determine if inhibition of lactic acid production by dichloroacetate (DCA) would attenuate muscle sympathetic nerve activity (MSNA) during static forearm exercise. DCA increases pyruvate dehydrogenase levels. Thus, for a given amount of pyruvate produced, less lactic acid is formed. Seven subjects performed static forearm exercise at 20% maximal voluntary contraction until fatigue followed by posthandgrip circulatory arrest (PHG-CA) (trial.1). Subjects then received DCA (35 mg/kg) and repeated the exercise protocol (trial 2). We observed an attenuated rise in forearm venous lactate and MSNA. The trial 2 MSNA value during PHG-CA was 51 +/- 11% less than the value during trial 1 (P less than 0.01). In seven control subjects, two bouts of static forearm exercise were performed with an intervening saline infusion. This intervention had no effect on lactate or MSNA responses to exercise. We conclude that DCA attenuates lactate responses to static exercise, and this is associated with a blunted MSNA response.

Adult↗
PubMed1990

In vivo versus simulation training: an interactional analysis of range and type of training exemplars.

We analyzed the role of the range of variation in training exemplars as a contextual variable influencing the effects of in vivo versus simulation training in producing generalized responding. Four mentally retarded adults received single case instruction, followed by general case instruction, on washing machine and dryer use; one task was taught using actual appliances (in vivo) and the other using simulation. In vivo and simulation training were counterbalanced across the two tasks for the 2 subject pairs, using a within-subjects Latin square design. With both paradigms, more errors were made after single case than after general case instruction during probe sessions with untrained washing machines and dryers. These results suggest that generalization errors were affected by the range of training exemplars and not by the use of simulated versus natural training stimuli. Although both general case simulation and general case in vivo training facilitated generalized performance of laundry skills, an analysis of training time and costs indicated that the former approach was more efficient. The study illustrates a methodology for studying complex interactions and guiding decisions on the optimal use of instructional alternatives.

Activities of Daily Living↗
PubMed1988

Chemoprevention of N-nitrosomethylbenzylamine-induced esophageal cancer in rats by the naturally occurring thioether, diallyl sulfide.

Diallyl sulfide (DAS) is a principal thioether of garlic (Allium sativum) accounting, in part, for the flavor and fragrance of this herb. Previous studies have shown that DAS is a potent inhibitor of experimentally induced colon cancer in mice. Metabolic studies of other garlic-derived substances suggested that DAS could prevent tumorigenicity of other hepatic activated carcinogens. The present study was designed to determine whether DAS could inhibit the DNA-damaging and tumorigenic effects of N-nitrosomethylbenzylamine in rat esophagus. A dose of 200 mg/kg of DAS given p.o. 3 h prior to N-nitrosomethylbenzylamine administration was found to inhibit the carcinogen-induced nuclear toxicity by 64% to 56% at the two doses (3 and 5 mg/kg) of NMBA tested. These results suggested that the compound was potentially anticarcinogenic. In the carcinogenicity experiment it was found that DAS totally inhibited tumor formation in rats treated with a carcinogenic dose of NMBA (100% inhibition of papilloma and squamous cell carcinoma incidence, P less than 0.0001). Additionally DAS was found to substantially reduce hepatic microsomal metabolism of the carcinogen. These data demonstrate that DAS is unique in its anticarcinogenic activity. It strongly suppresses the tumorigenic effects of potent, metabolically activated monoalkylating carcinogens in the gastrointestinal tract.

Allyl Compounds↗
PubMed1988

Bacterial challenge study of a porous carbon percutaneous implant.

Numerous percutaneous devices for power transmission and control to electrically powered, intracorporeal blood pumps have been used for periods ranging from 12 months to 4 yrs; however, consistent and reliable performance has not been achieved, due most frequently to the development of infection and sinus tracts at the percutaneous lead exit site. The present study showed that percutaneous devices fabricated from porous vitreous carbon can function satisfactorily in vivo over extended periods. The implant sites successfully resisted infection by normal flora bacteria for as long as 48 months, although superficial surface colonization and infection did occur after deliberate application of pathogens.

Animals↗
PubMed1988

Comparison of proteins in lacrimal gland fluid secreted in response to different stimuli.

To determine if different stimuli cause secretion of different proteins in lacrimal gland fluid (LGF), rabbits were anesthetized and LGF collected under baseline conditions (with the local anesthetic proparacaine), with ocular reflexes present, and in response to arterial injection of the cholinergic agonist acetylcholine (ACh) or the peptide vasoactive intestinal peptide (VIP). Proteins in LGF were separated by nondenatured gradient polyacrylamide gel electrophoresis. Except for minor differences, the number, the approximate molecular weights, and the amounts were the same in LGF secreted in response to four different stimuli. We concluded that the different stimuli caused protein release either from the same secretory cells or from different populations of secretory cells with the same secretory proteins.

Acetylcholine↗
PubMed1981

Memory development: an approach to the mentally impaired elderly in the long-term care setting.

Based upon a review of the literature on memory and cognitive impairments a number of procedures were implemented to improve memory function among nursing home residents. This paper describes the conceptual basis for the program called Memory Development (MD), and delineates procedures and techniques involving the use of cues, practice, and motivation. MD is compared to the traditional Reality Orientation (RO) approach.

Aged↗
PubMed1978

Demonstration of Fc receptors on the surface of B lymphocytes.

Human blood lymphocytes were tested by an immunofluorescence technique for surface immunoglobulin and by a rosette test with IgG-sensitised red cells for Fc receptors. From combined tests and experiments involving fractionation of lymphocyte populations it is concluded that Fc receptors are demonstrable on most B lymphocytes by the rosette test, but only if the red cells are optimally sensitised. These observations are advanced as an explanation of the discrepant results of surface marker tests on B cells.

Animals↗
PubMed1977

Glossopharyngeal neuralgia with syncope.

Thirty-two cases of glossopharyngeal neuralgia complicated by syncope, cardiac arrhythmias or convulsions, singly or together, have been reported in the world literature. A further case is described and the clinical features of these thirty-three are reviewed. It is recommended that treatment should be undertaken as a matter of urgency. In the first place, Carbamezapine, with often the addition of Atropine, may prove effective. However, surgical intervention appears to give a better chance of permanent relief. Four alternative methods of surgery are discussed and the cervical or the intracranial approach recommended. Surgery should not be delayed in patients who fail to respond to medical treatment or in whom recurrence of symptoms occurs.

Adult↗
PubMed1977

Increase in peripheral blood 'null' cells in extrinsic bronchial asthma.

Lymphocyte subpopulations were measured in the peripheral blood of fifteen patients with extrinsic bronchial asthma and twenty-seven normal control subjects. No significant differences in the absolute numbers of relative proportions of T, B or K lymphocytes were found. Antibody-dependent lymphocyte-mediated cytotoxicity (K-cell activity) was also found to be normal. The proportion and absolute number of 'null' cells were significantly increased in the asthmatic group: this population did not correlate with serum IgE levels, the eosinophil count or the duration of disease. The significance of these results in relation to suppressor T-cell control of IgE formation is discussed.

Adolescent↗
PubMed1976

Human lymphocyte sub-populations and K cells.

Peripheral blood lymphocytes from 19 normal subjects were examined for surface Ig (SIg) and capacity to form rosettes with normal and neuraminidase-treated sheep erythrocytes and with chicken erythrocytes sensitised with IgG antibody. Information on the relationship between the presence of SIg and capacity to form rosettes was obtained by combined tests and depletion experiments. By these means, a population of lymphocytes with Fc receptors, but lacking SIg (mean 14.6%) was defined and shown to correlate closely with cytotoxic activity for antibody-sensitised target cells. Indirect evidence was also obtained that these lymphocytes, which are regarded as the major population of antibody-dependent cytotoxic cells, are capable of forming rosettes with normal and neuraminidase-treated sheep erythrocytes. The nature of these cells is briefly discussed.

Animals↗