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Biomedical subjects

G N Taylor

Publications and source records attributed to G N Taylor.

At least 55 records · Page 3Linked to original sources
PubMed1991

Plutonium- or americium-induced liver tumors and lesions in beagles.

Plutonium-239 or 241Am administered intravenously in the monomeric citrate form was initially deposited in beagle livers principally in the hepatocytes and to a much lesser extent in the sinusoidal macrophages and connective tissues. The initial distribution was quite uniform throughout the hepatic parenchyma; however, at later postinjection intervals, depending on the amount of injected activity, the liver burden became increasingly more focal due to: (1) a progressive shift of the radionuclide from the hepatic epithelium to the macrophages; (2) the movement of such macrophages toward the portal or central regions of the lobule; and (3) the displacement of the older more radioactive tissue by regenerating hepatocytes, which generally have a much lower radionuclide content. The hepatic lesions produced by Pu or Am included: (1) necrosis and degenerative changes that were clinically serious or fatal in some of the animals injected with approximately 107 kBq kg-1; (2) marked structural and circulatory changes resulting from necrosis and focal hepatocyte hyperplasia; (3) a significant incidence of both benign and malignant primary liver tumors. In both Pu- and Am-treated dogs, the most frequently appearing neoplasm was the bile duct adenoma, followed by the cholangiocarcinoma. The most obvious difference between Pu- and Am-induced liver neoplasia was the greater frequency of fibrosarcomas and mast cell sarcomas in the Am-treated groups. Hepatomas were of relatively low frequency in animals with Pu or Am burdens. Although the incidence of bone neoplasia was high among the dogs in these studies, the risk of liver tumors, especially in the Am-treated animals, exceeded that of the skeleton in some of the lower dosage levels where the survival times were long. A risk coefficient of approximately 1200 fatal liver malignancies (10(4) beagle Gy)-1, derived from the dosage groups with long survival times, was calculated for combined Pu and Am animals. The prominence of the liver syndromes in beagles with burdens of Pu or Am indicates that humans with body burdens of 239Pu, 241Am, or other actinide elements may be at risk from radiation effects in the liver, including neoplasia development.

Adenoma↗
PubMed1990

Kidney disease in beagles injected with polonium-210.

An unusually high incidence of kidney disease (tubular degeneration and necrosis with fibrous replacement) was observed among 24 beagles injected at about 5 years of age with 116 or 329 kBq 226Ra kg-1 but not among an additional 10 beagles given about 39 kBq 226Ra kg-1. This 226Ra solution also contained 210Pb, 210Bi, and 210Po. To determine whether the kidney disease was related to the radiation from 226Ra and its short-lived progeny or to the alpha radiation from 210Po, 2 beagles about 7 years of age were injected with 451 kBq 226Ra kg-1 of 210Po citrate. Measurements of polonium retention in the kidneys of 4 additional beagles given 210Bi citrate enabled us to model the retention of these emitters in the dog kidney and to estimate the kidney dose from the alpha radiation of 210Po following injection of either 226Ra + 210Bi + 210Po or 210Po only. Autoradiography revealed that almost equal concentrations of 210Po were in the tubular epithelium and/or its basement membrane and in the glomeruli, but very little of the 210Bi deposited in kidney tissue was present in the glomeruli. Radiation damage to the kidneys similar to that observed previously in beagles given 226Ra solutions that also contained 210Bi and 210Po was seen among the beagles given 210Po but not in the dogs given purified 226Ra. The analysis of these data indicated that the relatively high incidence of kidney disease among the mature beagles injected with 226Ra and its accompanying 210Bi and 210Po resulted from alpha irradiation of the kidneys by the substantial amount of 210Po that was in the injection solution.

Animals↗
PubMed1989

Fission fragment RBE for bone sarcoma induction.

Thirty beagles and 277 mice were injected with 249Cf, and 30 beagles and 274 mice were injected with 252Cf. The skeletal dose (in Gy) from 252Cf was about half from fission fragments and half from alpha particles, whereas 249Cf emits alpha particles in 100% of its transformations. Bone sarcomas (mostly osteosarcomas) were the main radiation-induced cancer. The relative biological effectiveness (RBE) of fission fragment dose relative to alpha-particle dose for bone sarcoma induction was calculated from the ratio of 249Cf/252Cf doses at equal times to bone sarcoma in (a) beagles and (b) mice, and (c) from the ratio 252Cf/249Cf risk coefficients in mice. The average RBE +/- standard deviation of the three evaluations was 0.1 +/- 0.1. The very low RBE for bone sarcomas is supported by the data of A. L. Batchelor, T. J. Jenner, and L. M. Cobb [Phys. Med. Biol. 28, 475-483 (1983)] for lung cancer induction in rats and by that of A. L. Brooks, J. A. Mewhinney, and R. O. McClellan [Health Phys. 22, 701-706 (1972)] for producing chromosome aberrations in the liver cells of Chinese hamsters. The low effectiveness of fission fragments relative to alpha particles, per gray of absorbed dose, is ascribed primarily to the much larger number of cells traversed by the alpha particles. Consideration might be given to decreasing the quality factor of fission fragments by an order of magnitude below that for alpha particles.

Alpha Particles↗
PubMed1988

Nicotine and cotinine effects on 3 alpha hydroxysteroid dehydrogenase in canine prostate.

We have recently observed that cigarette smoking affects plasma androgen concentrations. The effects of nicotine and cotinine, two products of cigarette smoking, on testosterone metabolism were determined. The activity of delta 4 steroid 5 alpha-reductase, which converts testosterone to 5 alpha-dihydrotestosterone (DHT) was measured in isolated dog prostate nuclei using testosterone (0-200 nM) as substrate and NADPH as cofactor. Activity of 3 alpha-hydroxysteroid dehydrogenase (HSD), which converts DHT to 3 alpha-androstanediol (3 alpha-diol) and is a reversible enzyme, was measured in isolated dog prostate microsomes with DHT (0-20 microM) as substrate and NADPH as cofactor. When microsomal fractions were incubated for 1 hour with and without nicotine (0-50 microM) and cotinine (0-100 microM), enzyme activity of HSD was significantly suppressed (p less than 0.001). The Vmax was not affected significantly (p greater than 0.60) and Km increased with increasing concentrations of nicotine and cotinine (p less than 0.05). Both nicotine and cotinine are competitive inhibitors of HSD in dog prostate microsomes with Ki's of 61 and 89 microM, respectively. The apparent 5 alpha-reductase activity was unaffected by nicotine and cotinine. The inhibitors produced a marked effect on activity of HSD when used in concentrations achieved in humans who smoke cigarettes. The results suggest that nicotine and cotinine are competitive inhibitors of the HSD, an important enzyme involved in the metabolism of DHT and produce an accumulation of DHT. These products of cigarette smoking could alter androgen action in tissue such as skin and prostate.

3-Hydroxysteroid Dehydrogenases↗
PubMed1988

The beagle: an appropriate experimental animal for extrapolating the organ distribution pattern of Th in humans.

The concentrations and the organ distribution patterns of 228Th, 230Th and 232Th in two 9-y-old dogs of our beagle colony were determined. The dogs were exposed only to background environmental levels of Th isotopes through ingestion (food and water) and inhalation as are humans. The organ distribution patterns of the isotopes in the beagles were compared to the organ distribution patterns in humans to determine if it is appropriate to extrapolate the beagle organ burden data to humans. Among soft tissues, only the lungs, lymph nodes, kidney and liver, and skeleton contained measurable amounts of Th isotopes. The organ distribution pattern of Th isotopes in humans and dog are similar, the majority of Th being in the skeleton of both species. The average skeletal concentrations of 228Th in dogs were 30 to 40 times higher than the average skeletal concentrations of the parent 232Th, whereas the concentration of 228Th in human skeleton was only four to five times higher than 232Th. This suggests that dogs have a higher intake of 228Ra through food than humans. There is a similar trend in the accumulations of 232Th, 230Th and 228Th in the lungs of dog and humans. The percentages of 232Th, 230Th and 228Th in human lungs are 26, 9.7 and 4.8, respectively, compared to 4.2, 2.6 and 0.48, respectively, in dog lungs. The larger percentages of Th isotopes in human lungs may be due simply to the longer life span of humans. If the burdens of Th isotopes in human lungs are normalized to an exposure time of 9.2 y (mean age of dogs at the time of sacrifice), the percent burden of 232Th, 230Th and 228Th in human lungs are estimated to be 3.6, 1.3 and 0.66, respectively. These results suggest that the beagle may be an appropriate experimental animal for extrapolating the organ distribution pattern of Th in humans.

Administration, Inhalation↗
PubMed1987

The beta 1----2-D-xylose and alpha 1----3-L-fucose substituted N-linked oligosaccharides from Erythrina cristagalli lectin. Isolation, characterisation and comparison with other legume lectins.

The carbohydrate moieties of Erythrina cristagalli lectin were released as oligosaccharides by hydrazinolysis, followed by N-acetylation and reduction with NaB3H4. Fractionation of the tritium-labelled oligosaccharide mixture by Bio-Gel P-4 column chromatography and high-voltage borate electrophoresis revealed that it is composed of five neutral oligosaccharides. Structural studies by sequential exoglycosidase digestion in combination with methylation analysis and two-dimensional 1H-NMR showed that the major component was the fucose-containing heptasaccharide Man alpha 3(Man alpha 6)(Xyl beta 2)Man beta 4GlcNAc beta 4(Fuc alpha 3)GlcNAcol. This is the first report of such a structure in plant lectins. Small amounts of the corresponding afucosyl hexasaccharide were also identified, as well as three other minor components. The structure of the heptasaccharide shows the twin characteristics of a newly established family of N-linked glycans, found to date only in plants. The characteristics are substitution of the common pentasaccharide core [Man alpha 3(Man alpha 6)Man beta 4GlcNAc beta 4GlcNAc] by a D-xylose residue linked beta 1----2 to the beta-mannosyl residue and an L-fucose residue linked alpha 1----3 to the reducing terminal N-acetylglucosamine residue. The oligosaccharide heterogeneity pattern for Erythrina cristagalli lectin was also found for the lectins from four other Erythrina species and the lectins of two other legumes, Sophora japonica and Lonchocarpus capassa.

Carbohydrate Conformation↗
PubMed1987

Cancer incidence and lifespan vs. alpha-particle dose in beagles.

Young adult beagles were injected with graded activities of 239Pu, 241Am, 228Th, 228Ra or 226Ra and observed throughout their lifespans. The vast majority of the dose was from alpha particles. The lifetime incidence of bone sarcoma increased with average skeletal dose, more or less linearly up to high incidence for 239Pu, 241Am, 228Th and 226Ra, but sigmoid fashion for 228Ra. Based on average skeletal dose, the toxicity of the emitters relative to 226Ra = 1.0 was 239Pu = 16.6 +/- 4.5, 241Am = 5.4 +/- 1.6, 228Th = 8.5 +/- 2.3 and 228Ra = 2.0 +/- 0.5. At the lowest doses, the average lifespans were 97% +/- 3% of that in the controls. If beneficial effects occurred, they may have been overwhelmed by the destructiveness of the densely ionizing alpha particles. A cell nucleus 5 micron in diameter receives a mean dose of about 1 Gy (100 rad) when traversed by a single alpha particle. We found no evidence that alpha-particle doses suppressed cancer or lengthened lifespan in beagles.

Alpha Particles↗
PubMed1986

Reducing the cancer risk of 239Pu by chelation therapy.

Groups of adult female C57BL/Do mice were injected intraperitoneally with graded activities of monomeric 239Pu(IV) citrate at 10 weeks of age. Beginning 3 days after plutonium injection, some mice received repeated subcutaneous injections of Zn Na3 diethylenetriaminepentaacetate (Zn-DTPA). Each injection was 37 mumol Zn-DTPA/kg body weight. To evaluate protection from bone sarcoma, brief, intermediate, or protracted chelation therapies were administered to groups of mice. The brief chelation therapy covered a 2-week period, the intermediate therapy 2 months, and the protracted therapy 1 year. The mice were followed throughout life and examined for bone sarcoma. Both skeletal dose and bone sarcoma risk were reduced by chelation. The bone sarcoma incidences in the mice given chelation treatments generally fell below the dose-response curve for the mice not given DTPA, indicating that the cancer risk was reduced more than that corresponding to the decreased skeletal dose. This results suggests that Zn-DTPA preferentially removed Pu from the most carcinogenic locations in the skeleton, such as on bone surfaces near living cells.

Animals↗
PubMed1985

Analogues of aminoglutethimide: selective inhibition of aromatase.

In exploring further the structural features that influence the relative efficacy of analogues of aminoglutethimide [1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] as inhibitors of the cholesterol side-chain cleavage enzyme system desmolase and the estrogen forming system aromatase, analogues have been synthesized in which the aminophenyl substituent is replaced by pyridyl or substituted pyridyl. The 4-pyridyl analogue 5 [3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione] is a strong competitive inhibitor of aromatase (Ki = 1.1 microM; value for 1, 0.60 microM), which exhibits a type II difference spectrum (Ks = 0.28 microM; value for 1, 0.13 microM) but is noninhibitory toward desmolase. The 2- and 3-pyridyl analogues (3 and 4) inhibit neither enzyme system. 1-Amino-3-ethyl-3-phenylpiperidine-2,6-dione (2) is a strong and selective inhibitor of desmolase but the 4-pyridyl analogue 10 [1-amino-3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione] is a weak inhibitor of desmolase and aromatase. Analogues of 5 having a less basic aromatic substituent, namely, the N-oxide 11 and the 2,3,5,6-tetrafluoro derivative 13, were also prepared. The latter is a weak inhibitor of aromatase and the former inhibits neither enzyme system.

Aminoglutethimide↗