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Biomedical subjects

N E Garrett

Publications and source records attributed to N E Garrett.

At least 19 recordsLinked to original sources
PubMed1995

Sensory denervation with capsaicin attenuates inflammation and nociception in arthritic rats.

The relatively few studies that have investigated the effects of the nervous system on chronic joint disease have reported conflicting results. We have reassessed the effects of capsaicin on experimental polyarthritis with particular reference to the relationship between changes in nociception and changes in process and outcome measures of disease activity. Capsaicin pretreatment significantly attenuated both joint swelling and disease outcome as determined by quantitative radiology and histology. There was a close correlation between process measures of inflammation and mechanical hyperalgesia in both the untreated and capsaicin treated arthritic groups. The results confirm a suppression of inflammation by capsaicin and imply that the nociceptive and pro-inflammatory (neurogenic inflammation) activities of capsaicin-sensitive fibres are closely linked such that stimuli which cause pain will also induce neurogenic inflammation and vice versa.

Animals↗
PubMed1995

Changes in preprotachykinin mRNA expression and substance P levels in dorsal root ganglia of monoarthritic rats: comparison with changes in synovial substance P levels.

We have measured changes in the expression of gamma-preprotachykinin mRNA and levels of the neuropeptide substance P in the lumbar 4 and 5 dorsal root ganglia at various time points following the induction of an antigenic monoarthritis in the rat knee. The results were compared with changes in substances P levels in the knee joint synovium during acute and chronic phases of the disease. On day 3 post-induction, there was a significant increase in the expression of gamma-preprotachykinin mRNA in the dorsal root ganglia. Concomitant with this increase in message was a rise in the levels of substance P in the dorsal root ganglia. On days 7, 10 and 21, mRNA expression had returned to control values whereas ganglion peptide levels were significantly below controls. In contrast there was little change in the total substance P levels in the synovium on days 1 and 3 despite the observed changes in the ganglia. By day 10, however, synovial levels had risen significantly above control values and remained elevated thereafter. Our results show a transitory increase in substance P synthesis after induction of an antigenic monoarthritis. This response is not mirrored in the periphery where there is no initial change in total substance P levels perhaps reflecting increased degradation be enzymes known to be present within inflamed tissue. Paradoxically synovial substance P levels are increased in the latter phases of the model which may serve to modify the inflammatory response.

Animals↗
PubMed1995

Streptozotocin-induced diabetes decreases substance P levels in experimental arthritis in the rat knee.

Diabetic patients with sensory neuropathy are predisposed to disorders of the musculoskeletal system. It has been postulated that altered neurogenic inflammation, involving the neuropeptide substance P, may play a part in this phenomenon. We investigated the effect of streptozotocin-induced (STZ) diabetes on the development of an antigenic (mBSA) monoarthritis in the rat with particular reference to changes in substance P levels in dorsal root ganglia (DRG) and knee joint synovium. We found that STZ-induced diabetes of 24 weeks duration reduced the substance P content of L4/L5 DRG and knee joint synovial tissue. Induction of mBSA arthritis in diabetic rats resulted in diminished increases in synovial substance P and knee joint swelling compared to non-diabetic arthritic controls. The results show that chronic STZ diabetes reduces neurogenic inflammatory responses in the rat knee which may render the joint more susceptible to arthritic attack.

Animals↗
PubMed1994

The role of bradykinin B1 receptors in the maintenance of intra-articular plasma extravasation in chronic antigen-induced arthritis.

1. The role of bradykinin B1 and B2 receptors in bradykinin- and des-Arg9-bradykinin-induced plasma extravasation in normal and inflamed rat knee joints was investigated by use of an antigen-induced model of chronic arthritis. A modification of an Evans blue extraction technique allowed the unstimulated (basal) plasma extravasation to be assessed in this model. The contributions of bradykinin B1 and B2 receptors towards basal synovial plasma extravasation were determined. 2. In normal knees, intra-articular injection of bradykinin (BK) induced plasma extravasation in a potent, dose-dependent manner with a threshold of 0.01 nmol and an ED50 of 0.1 nmol. In day 5 arthritic knees, basal plasma extravasation was substantially enhanced. Lower doses of BK had no demonstrable effect and increases above basal extravasation were first observed at 0.1 nmol. Thereafter the dose-response mirrored the response in normal knees and the maximal response was unaltered. 3. The B1 agonist, des-Arg9-BK, induced slight but significant plasma extravasation in normal knees but was less potent than bradykinin. This response was inhibited by the B1 receptor antagonist, des-Arg9, [Leu8]-BK. Lower doses of des-Arg9-BK bradykinin did not significantly increase basal extravasation in day 5 arthritic knees but, in contrast to BK, the maximal response was significantly enhanced. 4. The B2 antagonist, Hoe 140, inhibited BK-induced plasma extravasation in normal joints over a dose-range of 0.1-1.0 nmol but was relatively inactive in day 5 inflamed knees. The B1 receptor antagonist, des-Arg9, [Leu8]-BK, was relatively inactive in normal joints but showed increased potency against BK-induced plasma extravasation in day 5 arthritic joints.5. Hoe 140 and des-Arg9,[Leu8]-BK both inhibited basal extravasation in arthritic joints on days 1 and 5 post-challenge in a dose-dependent fashion. Whilst Hoe 140 was the more potent inhibitor on day 1, it was less potent than des-Arg9,[Leu8]-BK on day 5.6. Although the majority of responses to BK in normal tissue are mediated via B2 receptors, a small population of B1 receptors may exist in normal joint tissues. The data presented in this study suggest an evolving role for B1 receptors in the mediation of plasma extravasation in inflamed joint tissues. A role for BK antagonists in the treatment of arthritis is also suggested.

Animals↗
PubMed1994

Effect of three animal models of inflammation on nerve fibres in the synovium.

OBJECTIVES: Both sensory and sympathetic nerve fibres are depleted in the synovium in rheumatoid arthritis (RA). The hypothesis that the induction of an inflammatory response in the synovium is capable of causing depletion of nerve fibres was tested. METHODS: To investigate this phenomenon experimental arthritis in the rat was induced by three different methods and the synovium was examined for evidence of nerve depletion by immunocytochemistry. RESULTS: In a synovitis induced by latex spheres, a mainly macrophage foreign body type reaction, no nerve depletion was seen. In contrast both in an antigen-induced and a hydrogen peroxide-induced model of arthritis nerve fibre depletion was observed. This appeared to affect sensory and sympathetic nerve fibres equally. Nerve fibre depletion was only seen in areas of inflammatory cell infiltration indicating that a mixed lymphocyte and macrophage population of cells may be necessary for this effect. CONCLUSIONS: An inflammatory response, containing lymphocytes and macrophages, in the synovium is capable of the depletion of the finely myelinated and unmyelinated neuropeptide-containing nerves.

Animals↗
PubMed1991

The Genetic Activity Profile database.

A graphic approach termed a Genetic Activity Profile (GAP) has been developed to display a matrix of data on the genetic and related effects of selected chemical agents. The profiles provide a visual overview of the quantitative (doses) and qualitative (test results) data for each chemical. Either the lowest effective dose (LED) or highest ineffective dose (HID) is recorded for each agent and bioassay. Up to 200 different test systems are represented across the GAP. Bioassay systems are organized according to the phylogeny of the test organisms and the end points of genetic activity. The methodology for the production and evaluation of GAPs has been developed in collaboration with the International Agency for Research on Cancer. Data on individual chemicals have been compiled by IARC and by the U.S. Environmental Protection Agency. Data are available on 299 compounds selected from volumes 1-50 of the IARC Monographs and on 115 compounds identified as Superfund Priority Substances. Software to display the GAPs on an IBM-compatible personal computer is available from the authors. Structurally similar compounds frequently display qualitatively and quantitatively similar GAPs. By examining the patterns of GAPs of pairs and groups of chemicals, it is possible to make more informed decisions regarding the selection of test batteries to be used in evaluating chemical analogs. GAPs have provided useful data for the development of weight-of-evidence hazard ranking schemes. Also, some knowledge of the potential genetic activity of complex environmental mixtures may be gained from assessing the GAPs of component chemicals. The fundamental techniques and computer programs devised for the GAP database may be used to develop similar databases in other disciplines.

Animals↗
PubMed1986

Evaluation of the genetic activity profiles of 65 pesticides.

We have previously reported the qualitative results of a major study on 65 pesticides (Waters et al., 1982). Dose information from this investigation (either lowest effective or highest ineffective dose tested) has now been incorporated into a computerized data management system. This report focuses on the qualitative profiles of genetic activity produced by these pesticides and our efforts to classify them according to their genotoxic effects and chemical structures. Three main categories may be distinguished based on the qualitative results: Category 1 pesticides were active in most of the in vitro and in vivo assays employed. These 9 compounds include the structurally similar organophosphate insecticides, acephate, demeton, monocrotophos and trichlorfon; the phthalimide fungicide analogues, captan and folpet; and the thiocarbamate herbicide analogues, diallate, sulfallate and triallate. The 26 Category 2 compounds demonstrated fewer positive results and may be subdivided into two parts, one of which contains 12 halogenated aromatic or heterocyclic ring compounds, including the phenoxy herbicides, 2,4-D, 2,4-DB and 2,4,5-T. The remaining part of Category 2 (14 compounds) consists of structurally similar organophosphate insecticides, azinphos-methyl, crotoxyphos, disulfoton, methyl parathion; three similar ethylenebisdithiocarbamate fungicides, maneb, mancozeb, and zineb; three similar pyrethroid insecticides, allethrin, chrysanthemic acid, and ethyl chrysanthemate; and four structurally diverse compounds, cacodylic acid, dinoseb, sec.-butylamine and benomyl. The third category of 30 pesticides gave negative results in all tests and represents structurally diverse compounds. Using the computerized profile matching methodology, from 2080 possible pairwise chemical combinations of the 65 pesticides, 20 statistically significant pairs were selected, 6 groups of pesticides were identified which were substantially similar to groups of pesticides we had formed previously (Waters et al., 1982) based on genetic activity and chemical structure. The matches showed excellent qualitative and, in most cases, excellent quantitative agreement. Hence it appears that specific patterns of test results present in the genetic activity profiles are related directly to chemical structure. Conversely, the data suggests that certain groups of compounds may be recognized by a well defined series of concordant tests results. As additional data is added, comparison of test results for new chemicals with existing data for known genotoxicants should aid in the evaluation of potential genetic health hazards.

Animals↗
PubMed1984

Using the desk top computer in cellular toxicity and mutagenesis.

A series of programs applicable to in vitro test symptoms in environmental toxicology are described for the Tektronix 4050 series graphic system computer. The file structure, experimental design and identification, the program library, data entry program, and programs to compile data from separate experiments are presented. Experimental design information and test data are stored on magnetic tape. The programs are designed to compute cell number and viability, adenosine triphosphate level, and protein and DNA synthetic activity from raw data obtained from cellular toxicity experiments; and cloning efficiency, mutation yield, mutation frequency, and other parameters for mutagenicity. A set of subprograms can be used for statistical analysis of the data and for construction of frequency distributions. The applicability of the programs is illustrated by data obtained from exposure of Chinese hamster ovary cells to cadmium chloride or N-methyl-N'-nitro-N-nitroso-guanidine.

Animals↗
PubMed1983

Cellular toxicity in Chinese hamster ovary cell cultures. I. Analysis of cytotoxicity endpoints for twenty-nine priority pollutants.

Chinese hamster ovary cells were exposed to 29 toxic chemical substances which were representative of several classes of compounds listed by the Natural Resources Defense Council Consent Decree as priority toxic pollutants. After cell cultures were exposed to the test substance, cell samples were assayed for protein and DNA synthesis, ATP, cell number, and viability. A filter-disk technique employing a batch-washing procedure was used for the determination of protein and DNA synthesis. Dose-response data were obtained for 15 of the more toxic agents including chlorinated aromatics, metallic compounds, phenols, and polychlorinated biphenyls. Estimates of the sample concentrations necessary to produce a 50% reduction in response were used to compare cytotoxicity endpoints. ATP and protein synthesis were approximately equally effective as indicators of cellular toxicity. Cadmium chloride, nickel nitrate, arsenic trioxide, and potassium chromate produced a more pronounced effect on DNA synthesis than on ATP or protein synthesis. The dose-response relationship for protein and DNA synthesis was a smooth, continuous function for responses as low as 1 to 2% of the control. On a log-log scale, the dose-response relation yielded a unique pattern for several chemical classes. A ranking of the compounds based on their inhibition of DNA synthesis was compared to a ranking obtained from the literature for whole-animal toxicity. With the exception of the polychlorinated biphenyls, the in vitro results correlated well with animal test data.

Adenosine Triphosphate↗
PubMed1983

Cellular toxicity in Chinese hamster ovary cell cultures. II. A statistical appraisal of sensitivity with the rabbit alveolar macrophage, Syrian hamster embryo, BALB 3T3 mouse, and human neonatal fibroblast cell systems.

Chinese hamster ovary, rabbit alveolar macrophage, Syrian hamster embryo, BALB 3T3 mouse, and human neonatal fibroblast cells were employed in a statistical evaluation of the relative sensitivity of the cells to toxic substances. The cells were exposed to 1,2,4-trichlorobenzene, 2,4-dimethylphenol, Aroclor 1248, cadmium chloride, lead sulfate, nickel nitrate, lead oxide-coated fly ash, and a fine particulate from coal combustion. A filter-disk technique was used to measure the inhibition of protein and DNA synthesis. A quantitative ranking of cell-system sensitivity was determined from comparisons of statistically significant differences (P less than or equal to 0.01) in protein and DNA synthesis expressed as a percentage of control. An overall ranking of sensitivity showed that rabbit alveolar macrophages, Syrian hamster embryo cells, and Chinese hamster ovary cells were more sensitive than another of the five cell systems in 75, 68, and 62% of the experiments, respectively. The corresponding values for BALB 3T3 mouse and human neonatal fibroblast cells were 38 and 28%, respectively, under our experimental conditions. Detailed data on the control cell cultures are also presented.

Animals↗
PubMed1976

Rapid breakdown of diphosphoinositide and triphosphoinositide in erythrocyte membranes.

Incubation of rabbit erythrocytes with 32Pi resulted in labeling of membrane diphosphoinositide, triphosphoinositide, and phosphatidic acid. Hypotonic lysis at 37 degress C resulted in an extremely rapid breakdown of the labeled polyphosphoinositides. This breakdown could be retarded by lysis in the presence of EDTA and by lowering the temperature to 0 degrees thus allowing preparation of membranes with minimum breakdown of the labeled lipids. Rapid breakdown of di- and triphosphoinositide in isolated membranes could be initiated by Ca++ or to a lesser extent by Mg++ and prevented by detergents and by heating to 75 degrees C. Assay of radiolabeled lipid was carried out by a method which bypassed prior lipid extraction and which enabled sequential sampling of reactions at 10-second intervals. This method was more convenient than standard procedures and gave yields of di- and triphosphoinositide equivalent to that obtained by the method of Folch.

Animals↗
PubMed1975

Interaction of adenine nucleotides with multiple binding sites on beef heart mitochondrial adenosine triphosphatase.

Beef heart mitochondrial ATPase (F1) contained 2 mol of ADP and 1 mol of ATP/mol of enzyme, which resisted removal by Sephadex chromatography with dilute buffers or repeated precipitation with ammonium sulfate. The native enzyme also contained two apparently equivalent binding sites, which participated in readily reversible binding of adenyl-5'-ylimidodiphosphate (AMP-P(NH)P), with a Kd of 1.3 mum. The failure of AMP-P(NH)P to compete effectively with ADP for binding sites on F1 may be related to the failure of the analog to inhibit oxidative phosphorylation. Virtually complete removal of all adenine nucleotides from F1 occurred when the enzyme was chromatographed on columns of Sephadex equilibrated with 50% glycerol. No loss in ATPase activity was observed following removal of nucleotides from the enzyme, which was then capable of binding more than 4 mol of ADP and almost 5 mol of AMP-P(NH)P/mol of protein. Subsequent chromatography on columns of Sephadex equilibrated with dilute buffers containing Mg2+ removed only 1.5 mol of ADP and no AMP-P(NH)P from the enzyme. Reconstitution of F1 with ADP or with almost 5 mol of AMP-P(NH)P resulted in preparations that exhibited an undiminished capacity to restore oxidative phosphorylation in F1-deficient submitochondrial particles.

Adenine Nucleotides↗
PubMed1975

Physical and enzymatic properties of nucleotide-depleted beef heart mitochondrial adenosine triphosphatase.

Tightly bound adenine nucleotides are removed from multiple binding sites on beef heart mitochondrial ATPase (F1) by chromatography on columns of Sephadex equilibrated with 50% glycerol. Release of nucleotides from the enzyme is associated with large decreases in sedimentation velocity (from 11.9 S to 8.4 S) which may be observed in concentrated solutions of polyols. Polyol-induced conformational changes are reversed when the enzyme is returned to dilute buffers. The nucleotide-depleted enzyme restores oxidative phosphorylation in F1-deficient submitochondrial particles. Reconstitution of nucleotide-depleted F1 with the ATP analog (adenylyl-imidodiphosphate (AMP-PNP), almost 5 moles of AMP-PNP per mole of enzyme, results in preparations with substantially inhibited ATPase activity which nevertheless restores oxidative phosphorylation and the 32Pi-ATP exchange reaction in F1-deficient submitochondrial particles. Incubation of the analog-labeled enzyme with ATP and Mg++ results in partial displacement of the analog and a time-dependent recovery of ATPase activity.

Adenine Nucleotides↗