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A D Mitchell

Publications and source records attributed to A D Mitchell.

At least 55 records · Page 3Linked to original sources
PubMed1988

Evaluation of the L5178Y mouse lymphoma cell mutagenesis assay: methods used and chemicals evaluated.

A general protocol, modified from the one described by Clive and Spector (Mutat Res 31:17-29, 1975), was followed by two laboratories, Litton Bionetics, Inc., and SRI International, to evaluate 63 coded chemicals from 16 chemical classes for mutagenic activity at the thymidine kinase locus in L5178Y TK+/- 3.7.2C mouse lymphoma cells. The general protocol is discussed. Some procedural variations introduced by both laboratories are described and discussed in terms of their potential effect on the comparative results of the assay. Also included are the chemical structures, molecular weights, and functional classifications of the 63 chemicals. The assay appeared to tolerate the specific procedural variations in each laboratory without changing its reliability.

Animals↗
PubMed1988

Evaluation of the L5178Y mouse lymphoma cell mutagenesis assay: quality-control guidelines and response categories.

A data-based approach to formulating quality-control criteria for the mouse lymphoma cell forward mutation assay is described. Quality-control guidelines for solvent controls, positive controls, and compound-treated cultures were developed based on analysis of over 800 experiments. Frequency distributions of experimental parameters of control cultures, such as mutant frequencies, cloning efficiencies, and suspension growths, were examined. Cloning efficiency and relative total growth affected the variability only when the test chemical was highly toxic. This information was used to generate the quality-control criteria, which were applied to an experiment before it was evaluated for a response. The response categories for classifying the effect of test chemicals on the assay system are defined in terms of (1) the statistically significant differences in average mutant frequency between solvent control cultures and cultures exposed to a chemical and (2) the trend of the dose-related responses.

Animals↗
PubMed1988

Evaluation of the L5178Y mouse lymphoma cell mutagenesis assay: intralaboratory results for sixty-three coded chemicals tested at SRI International.

SRI used the L5178Y mouse lymphoma cell forward mutation assay to determine the mutagenic activity of 63 coded chemicals from 16 chemical classes. Replicate experiments were performed to assess the reproducibility of the assay within the laboratory. The evaluations (positive or negative) of the first two repeat experiments with the chemicals were the same for 116 (87%) of 134 tests. Evaluational differences between the first two experiments were fewer in the presence of induced S9 (6 tests) than in the absence of S9 (12 tests). The most commonly observed variability was the magnitude of positive mutagenic responses; this may be attributed to factors such as compound solubilities, S9 activation conditions, and differential recovery of mutant cells. Some consistency was observed in the responses of compounds of various chemical classes. Generally, antibiotics (ABO) and the azo dyes, azoxy and hydrazo compounds, diazoalkanes, nitriles and azides (AZO), were mutagenic with S9; alkyl, acyl, and aryl halides, halogenated ethers, and halohydrins (HAL) were more strongly mutagenic with than without S9; and monofunctional polycyclic aromatic hydrocarbons and fluorenones (PAH) were mutagenic only with S9. Amine-1-oxides (AMO), alkyl and aryl epoxides (EPO), and nitroalkanes, nitroaromatics, nitroquinolines, nitrofurans, and nitroimidazoles (NIT) were mutagenic with and without S9; amides, sulfonamides, aromatic amines, aliphatic amines, hydroxylamines, and benzidine and its derivatives (AMI) were mutagenic without S9; and methyl carbamate (the only monofunctional carbamate) and thioureas (CBM) induced a negative response under both conditions.

Animals↗
PubMed1988

Evaluation of the L5178Y mouse lymphoma cell mutagenesis assay: interlaboratory reproducibility and assessment.

The L5178Y mouse lymphoma cell mutagenesis assay is used to detect the mutagenic activity of chemicals in a mammalian cell system. To evaluate this assay we compared the results of assays performed independently on 63 chemicals by laboratories at SRI International and Litton Bionetics, Inc. The two laboratories used similar protocols. The solvent and positive control mutant frequencies and cloning efficiencies obtained by the two laboratories were similar, which justified the use of the same quality-control criteria and analytical procedures for analyzing the results from both laboratories. The rate of concordance between the two laboratories was 92% for tests in the absence of S9 activation and 95% for tests in its presence. The results of the assays agreed for 57 of the 63 chemicals; three chemicals could not be compared because there were questionable calls in at least one of the laboratories; the results disagreed for the three remaining chemicals. The concordance rate for these overall assay evaluations was 95%. The interlaboratory concordance rates were similar to concordance rates for replicate experiments within the laboratories (96% at LBI, 94% at SRI). The mouse lymphoma cell mutagenicity results are concordant with the rodent chronic assay results in 78% of 50 chemicals and with the Salmonella assay results in 79% of 56 chemicals. Fifteen carcinogens were examined for genotoxic effects in mouse lymphoma, Salmonella, Chinese hamster ovary (CHO) chromosomal aberration, and CHO sister chromatid exchange assay. Eight of these were positive in all four assays. Of the seven noncarcinogens that were tested in these four assays, none was negative in all four. The main conclusion to be drawn from this study is that the mouse lymphoma cell forward mutation assay, as performed and evaluated in this study, detects chemical mutagenicity in a manner that is highly consistent with other genetic endpoints as well as rodent carcinogenicity studies. Thus the assay quality control and response criteria established in this study led not only to a high degree of reproducibility but also to an apparently reliable detection of mutagenic activity.

Animals↗
PubMed1988

The mutagenic activity of selected compounds at the TK locus: rodent vs. human cells.

The mutagenic (TFT resistance) and toxic responses of mouse lymphoma (MOLY) L5178Y cells and human lymphoblast (HULY) TK6 cells were compared for 13 chemicals. The mutagenic activities of 8 of the 13 chemicals (62%) examined in the HULY and MOLY assays are in agreement - the results being judged positive in both assays. However, a dramatic difference is observed when the two conditions of metabolic activation are considered separately; the overall concordance of 8/13 has been achieved by combining a 13/13 (100%) agreement in the absence of S9 with a 1/6 (17%) agreement in the presence of S9. In the absence of S9, the concentration ranges, lowest significant doses, and shapes of the concentration-response curves for both toxicity and mutagenicity were similar in spite of the differences in exposure times (4 h for MOLY, 20 for HULY) and expression times (2 days for MOLY, 3 days for HULY). The general agreement observed in the absence of S9 contrasted with the differences manifested in its presence. 6 compounds which were negative in the absence of S9 were tested in both the MOLY and HULY assays in the presence of S9. Of the 6 chemicals, only 1 was positive in both MOLY and HULY under the latter condition; 4 others were positive in MOLY and negative in HULY whereas 1 was positive in HULY and negative in MOLY.

Animals↗
PubMed1988

Chicken hepatic metabolism in vitro. Protein and energy relations in the broiler chicken--VI. Effect of dietary protein and energy restrictions on in vitro carbohydrate and lipid metabolism and metabolic hormone profiles.

1. Ross male broiler chicks growing from 14 to 28 days of age were fed 14 and 20% protein diets (4 kcal day-1/body wt0.66) or 20 and 28% protein diets (2.8 kcal day-1/body wt0.66) in a 2 x 2 factorial arrangement to determine the effects of protein and energy intakes on in vitro lipogenesis (IVL) and net glucose production (NGP). Plasma concentrations of insulin, glucagon, thyroid hormones (T3 and T4) and somatomedin-C (Sm-C) were estimated by radioimmunoassay. 2. There was a significant (P less than 0.05) decrease in IVL in the chicks given the higher daily protein intake. 3. The higher protein intake increased (P less than 0.05) NGP while the lower energy intake decreased (P less than 0.05) NGP. 4. Insulin, both thyroid hormones and Sm-C were affected by dietary energy and protein intakes.

Animals↗
PubMed1988

Survey of the long term incidence of osteonecrosis of the hip and adverse medical events in rheumatoid arthritis after high dose intravenous methylprednisolone.

A prospective, randomised, double blind, matched cohort survey using retrospective data was undertaken to assess the long term incidence of osteonecrosis of the hip and adverse medical effects occurring after intravenous pulsed methylprednisolone used in the treatment of rheumatoid arthritis over the period 1977-86. One hundred and forty three patients were matched for age, sex, duration and severity of the disease, erosive and serological status. Information was obtained by direct questioning and from hip x rays, the latter being read independently by two 'blind' radiologists. Two definite cases of osteonecrosis were identified, one in both the treated and control groups and three possible cases (radiological disagreement) in the treated group. Adverse medical events, when analysed by systems, were similar in both groups. This study did not provide evidence of increased osteonecrosis of the hip or adverse medical events in the treated group compared with the control group.

Adult↗
PubMed1988

Interrelationships between energy intake and endogenous porcine growth hormone administration on the performance, body composition and protein and energy metabolism of growing pigs weighing 25 to 55 kilograms live weight.

Thirty-six barrows were used in a 2 X 3 factorial experiment to investigate the effects of porcine growth hormone (pGH) administration (USDA-pGH-B1; 0 and 100 micrograms.kg body weight-1.d-1) and three levels of feeding of a single diet (EI; ad libitum, 1.64 and 1.38 kg/d) on the performance, body composition and rates of protein and fat deposition of pigs growing over the live weight phase 25 to 55 kg. Raising EI resulted in linear increases in growth rate and in protein and fat accretion but had no effect on the feed to gain ratio (F/G). Carcass fat content and carcass fat measurements also increased with EI, whereas carcass protein and water decreased (P less than .01). Growth hormone administration resulted in improvements in growth rate (16 to 26%), F/G (23%), protein deposition (34 to 50%) and increases in carcass protein and water at each level of feeding, but reduced ad libitum feed intake (P less than .01), carcass fat content (P less than .01) and carcass fat measurements (P less than .01). Estimated maintenance energy expenditure was increased by pGH administration (2.02 vs 1.72 Mcal digestible energy/d). Results indicate that the effects of pGH on growth performance and energy and protein metabolism were largely independent of, and additive to, the effects of energy intake.

Animals↗
PubMed1987

Comparison of urea space, deuterium oxide space and body composition in growing pigs.

Urea and deuterium oxide (D2O) space were compared by simultaneous infusion into pigs weighing approximately 55 or 90 kg. Urea was cleared from the plasma pool more rapidly than D2O and appeared to equilibrate at a relative concentration which was lower than that of D2O. Consequently, urea and D2O space values were closest when extrapolated to zero time values. Correlations between urea space and D2O space were highest at 15 minutes post infusion (R2 = .75) or between urea space at 15 minutes and D2O at equilibrium (R2 = .86). Results of urea and D2O space measurements were compared with water, lipid and protein content of the carcass. Urea space at 15 minutes and D2O space at 35 minutes most closely approximated total body water while D2O space at 15 minutes was nearly equivalent to empty body water. Overall, D2O space at equilibrium had the highest correlations with carcass values of water, lipid and protein and appears to be preferable to urea space for estimating carcass composition in pigs.

Animals↗
PubMed1986

Chromosome analysis of trifluorothymidine-resistant L5178Y mouse lymphoma cell colonies.

Cells from small (sigma) and large (lambda) trifluorothymidine-resistant (TFTr) colonies induced by chemical mutagen treatment of TK+/-L5178Y mouse lymphoma cells were examined for chromosomal abnormalities. Analysis of G-banded metaphase chromosomes from 34 sigma-TFTr colonies revealed that cells from 20 (59%) possessed one or more chromosomal abnormalities. The most frequent (16/20 colonies) abnormality observed in cells from sigma-TFTr colonies involved the addition of extra chromatin to the distal region of one chromosome number 11. In 13 of these 16 colonies, the origin of the chromatin translocated to chromosome number 11 could not be identified; the chromatin was not missing elsewhere in the genome. The remaining three sigma-TFTr colonies with an abnormal chromosome number 11 had apparently whole chromosomes translocated, in tandem, to the distal region of chromosome number 11. Chromosomal abnormalities observed in cells from sigma-TFTr colonies with normal number 11 chromosomes included 2N/4N and 2N/4N/8N mosaicism (two colonies), a Robertsonian translocation involving chromosome 10 and a marker chromosome (one colony), and trisomy 7 (one colony). In most (14/16) sigma-TFTr colonies with structural damage to chromosome number 11, the cells within a colony were heterogeneous in that some possessed chromosomal damage whereas others were apparently normal. Analysis of chromosomes in cells from eight lambda-TFTr colonies revealed one colony in which all cells had a Robertsonian translocation involving chromosomes 1 and 16 plus other structural abnormalities. The chromosomes of cells from the remaining lambda-TFTr colonies were apparently normal.

Animals↗
PubMed1986

Stable dicentric chromosomes induced by chemical mutagens in L5178Y mouse lymphoma cells.

Stable, tandem dicentric chromosomes were discovered in two mutant cell colonies resulting from exposure of L5178Y mouse lymphoma cells to chemical mutagens. These unusual dicentrics were present in all metaphase cells examined from these colonies, even after approximately 65 cell generations in culture. Observation of cells in metaphase and anaphase suggests that the interstitial centromere in these dicentrics is non-functional, and that the terminal centromere is solely responsible for their orderly anaphase segregation.

Acrolein↗
PubMed1986

Energy and protein relations in the broiler chicken. 4. Role of sex, line and substrate on in vitro lipogenesis.

Experiments were conducted with dwarf (dw) and normal lines of chickens to determine the effect of sex, diet and line on lipogenesis in the 28-day-old chick. The chicks were fed diets containing 12, 18, 23 and 30% protein. In the first experiment, in vitro lipogenesis (incorporation of [2-14C] sodium acetate into hepatic fatty acids) as well as growth from 7 to 28 days of age were determined in males and females of both lines. In the second experiment, only males and females of the dwarf line were fed to determine the relative contribution of acetate and pyruvate to in vitro lipogenesis (incorporation of either [2-14C] sodium acetate or [2-14C] pyruvate into hepatic fatty acids). Chicks of the dwarf line were smaller (P less than .01) than were those of the normal line. Females of both lines were smaller (P less than .01) than males. In vitro lipogenesis was lower (P less than .01) in the dwarf line; however, the rate for both sexes within a given line was equal. An increase in the dietary protein decreased (P less than .05) in vitro lipogenesis in both lines. The use of pyruvate as an in vitro precursor indicated that the regulation of lipid and carbohydrate metabolism may be an integrated process involving pyruvate carboxylation and subsequent flux of pyruvate carbon into either glucose or fatty acids. Based on the data presented, there is no evidence to assume, that the dwarf gene per se influences lipogenesis.

Acetates↗
PubMed1985

Evaluation of the genotoxic potential of certain pesticides used in Pakistan.

The mutagenicity of fifteen insecticides, five fungicides, four herbicides, and an acaricide commonly used in Pakistan was evaluated by employing thirteen short-term bioassays. The genetic endpoints used included point or gene mutation, primary DNA damage, and chromosomal effects. Initially, all pesticides were tested in a "core" battery of four in vitro bioassays. A carefully selected group among these chemicals was retested in higher level test systems to confirm the results obtained in the initial phase. Of the pesticides tested, only a small portion consistently displayed mutagenicity across test systems. The Saccharomyces cerevisiae bioassays detected mutagenicity for the largest number of pesticides. The Salmonellaces typhimurium strain, TA100, was able to detect genetic activity in all of the pesticides that produced positive results in this bioassay. The cytogenetic effects observed from the Vicia faba root assay were consistent with those obtained in mammalian cells in culture. All pesticides which displayed mutagenicity were not carcinogenic in animal bioassays but, in general, mutagenicity in a battery of short-term bioassays was a reliable indicator of the carcinogenic potential in animals. A simple test battery is proposed for evaluating the genetic potential of agricultural pesticides.

Animals↗
PubMed1984

Evaluation of diallate and triallate herbicides for genotoxic effects in a battery of in vitro and short-term in vivo tests.

Commercial-grade preparations of two thiocarbamate herbicides, diallate and triallate, were evaluated for their mutagenic potential in a battery of short-term bioassays. All in vitro bioassays were performed with and without mammalian metabolic activation, and all such tests were repeated after an interval of at least 1 week. Diallate and triallate were tested in the Salmonella/microsome assay over dose ranges of 0.59 to 118.0 micrograms/plate and 6.37 to 1273 micrograms/plate, respectively. Both diallate and triallate gave positive results in S. typhimurium strains TA1535, TA98, and TA100 only in the presence of a rat-liver metabolic activation system. In Saccharomyces cerevisiae strain D7, diallate was tested at concentrations from 1.18 to 29.50 micrograms/ml, and triallate was tested at 0.955 to 9.548 micrograms/ml. Both diallate and triallate gave negative results for mitotic gene conversion, mitotic crossing-over, and reverse mutation. In the mouse lymphoma L5178Y TK+/- assay, diallate was tested at concentrations ranging from 1 to 72 micrograms/ml, and triallate was tested at 0.5 to 60 micrograms/ml. Both herbicides produced mutagenic responses in the mouse lymphoma assay in the presence of metabolic activation. In the Drosophila sex-linked recessive lethal test, flies were exposed to 0.0004% diallate and 0.001% triallate. In this assay, diallate was considered mutagenic, whereas triallate did not produce a detectable mutagenic response.

Animals↗
PubMed1984

Comparison of nifedipine (retard formulation) and mefruside in the treatment of mild to moderate hypertension--a prospective randomized double-blind crossover study in general practice.

Twenty-two patients under general practice care, suffering mild to moderate hypertension and receiving no active treatment had three baseline blood pressure measurements taken during a single blind 4-week placebo run-in period. One patient was secondarily excluded at this stage because of a placebo response and one patient dropped out for personal reasons. The remaining 20 patients were randomized to receive either nifedipine 20 mg twice a day or mefruside 25 mg once a day in a classical two-period crossover design with 8-week treatment periods separated by a 4-week single-blind placebo washout. During 8 weeks nifedipine therapy the mean supine blood pressure was reduced from 173 (s.d. = 15.4)/107(s.d. = 6.4) mmHg to 150(s.d. = 16.7)/93(s.d. = 10.8) mmHg whereas the corresponding reduction for mefruside was from 174(s.d. = 15.9)/107(s.d. = 9.4) mmHg to 153(s.d. = 19.1)/94(s.d. = 9.7) mmHg. Neither drug affected postural changes in blood pressure. Standing blood pressure measurements under 8 weeks nifedipine therapy fell from 172(s.d. = 12.3)/103(s.d. = 5.6) mmHg to 150(s.d. = 17.9)/94(s.d. = 10.0) mmHg with corresponding changes for mefruside being 174(s.d. = 14.7)/106(s.d. = 9.0) mmHg to 150(s.d. = 20.2)/95(s.d. = 9.4) mmHg. Since blood pressures returned to within 4% of baseline values by the end of the placebo washout period it can be inferred that each therapy was a significant (P less than 0.05 for all blood pressure variables) antihypertensive treatment in its own right.

Clinical Trials as Topic↗
PubMed1983

Baseline epidemiological studies for a hepatitis B vaccine trial in Kangwane.

Hepatitis B markers were determined by radioimmunoassay of serum samples from 1 495 Black subjects representative of the resident population of Kangwane, a rural area with a high incidence of chronic liver disease and hepatocellular carcinoma. Pregnant women formed an important part of the study group, since it was intended to assess the frequency of perinatal transmission and the passive immunity of their infants, two factors which would markedly influence an infant immunization programme. A high overall marker positivity rate was found, indicating that hepatitis B is endemic. The hepatitis B surface antigen (HBsAg) carrier rate was 14,6% in adult males and 4,6% in adult females, while 82.6% of adult males and 69,4% of adult females were positive for at least one marker, indicating that infection had been present at some stage. Of infants under 1 year of age 34,5% were positive for antibodies to HBsAg (anti-HBs), compared with 9,3% at 13-24 months, which indicates that transplacental transfer of anti-HBs is frequent. Other markers were acquired even in the 1st year of life, with the sharpest increase at 3-11 years. Perinatal transmission was not common, however, and horizontal transmission during early childhood seemed to play an important role. It was concluded that the risk and frequency of infection justified a vaccine trial in this population and that the target group for vaccination should be infants under 1 year of age.

Adolescent↗