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Biomedical subjects

D B McGregor

Publications and source records attributed to D B McGregor.

At least 19 recordsLinked to original sources
PubMed1995

Problem orientation is a new approach to surgical education.

BACKGROUND: There is increasing interest in educational methods that are loosely aggregated under the title of problem-based learning (PBL), but it remains unclear whether PBL is as successful as its conventional predecessor in transmitting factual information. MATERIALS AND METHODS: The authors designed and implemented a PBL curriculum for a third-year surgical clerkship, then prospectively compared that technique with the conventional format. Each student's subject-related knowledge was assessed with a specifically tailored 195-question written exam and correlated with National Board of Medical Examiners shelf exams. Student and faculty responses to the technique were also sought and tabulated. RESULTS: Student and faculty responses to PBL were uniformly positive. We were unable, however, to demonstrate effects on our evaluation instruments. Neither individual student performance nor grouped scores differed based on the mode of presentation. CONCLUSION: A PBL curriculum generates both student and faculty enthusiasm. Unfortunately, this does not translate into more efficient transmission of knowledge.

Clinical Clerkship↗
PubMed1994

A reexamination of the low prevalence of carcinogens in an early carcinogen screen.

In 1969 Innes et al. reported that 9% of 127 industrial chemicals and pesticides (including 7 positive controls) tested in a mouse bioassay were carcinogenic by oral administration. This is much lower than the prevalence of approximately 50% that has been found recently by the cancer bioassays conducted under the aegis of the U.S. National Toxicology Program (NTP) or reported in Carcinogen Potency Data Base compiled by Gold and collaborators. Using the CASE structure-activity relational expert system and the NTP cancer bioassay results as a learning set, we found that the predicted prevalence of carcinogens among the chemicals tested by Innes et al. is 62.7%. It is concluded that the bioassay protocol used by Innes et al. is less sensitive than the subsequently adopted bioassay procedures.

Animals↗
PubMed1993

The effect of simultaneous exposure to bromodeoxyuridine and methyl methanesulphonate on sister-chromatid exchange frequency in cultured human lymphocytes.

Assessment of genotoxicity in cultured cells or in experimental animals through the measurement of sister-chromatid exchanges (SCEs) commonly requires their simultaneous exposure to both the test agent and bromodeoxyuridine (BrdUrd). This dual exposure could lead to modified responses because of either synergistic or antagonistic interactions. Differences in protocol may also have their effect. There is, for example, time for DNA repair to take place in protocols in which there is separate exposure to the test agent and BrdUrd, such as human genetic monitoring studies. In this study, human lymphocyte cultures have been used to investigate the effect of the duration of simultaneous exposure to the mutagen methyl methanesulphonate (MMS) and to BrdUrd on SCE incidence. There was a direct relationship between SCE frequency and the time of simultaneous exposure to MMS and BrdUrd that was not dependent on either the total culture time or the total time of exposure to BrdUrd. This suggestion of an interaction between MMS and BrdUrd in inducing SCEs has important implications for the interpretation of SCE data in both experimental and human monitoring studies.

Analysis of Variance↗
PubMed1992

Effects of plate preparation on results in microbial mutation assays.

Glucose autoclaved in an alkaline phosphate solution (heated glucose+salts, HGS) results in the production of a moiety that is nonmutagenic but can interact with a series of 4-[2-(aryl)ethenyl]-2,6-dimethylphenols to result in an increase in bacterial revertants that is dependent on the amount of HGS in the minimal agar plates. The reaction between the HGS and the chemical to form a mutagen is independent of the presence of bacteria, does not result in a nutritive analog to enhance growth of the auxotrophic bacteria, and is effective only in Salmonella typhimurium and Escherichia coli strains that contain the plasmid pKM101. A sufficient amount of this glucose product may be formed in normal plate preparation to produce apparent mutagenic activity of these chemicals.

Escherichia coli↗
PubMed1992

The effects of positive expiratory pressure on peritoneovenous shunt flow.

Cirrhotic patients with peritoneovenous shunts may require mechanical ventilation. Despite the importance of flow to shunt patency and the relevance of intrathoracic pressure to that flow, the relationship between shunt flow and positive airway pressure has not been documented. To study the effects of positive expiratory pressure (PEEP) on shunt flow, models of ascites (n = 8) were created in adult male mongrel dogs. Each animal was anesthetized, intubated, and mechanically ventilated. Peritoneovenous shunts with in-line electromagnetic flow meters were surgically placed. Shunt flow, central venous pressure (CVP), and intraabdominal pressure (IAP) were monitored. Initial intraabdominal pressures were adjusted by infusion of warmed saline and positive expiratory airway pressures were added in increments. Changes in pressures (IAP, CVP) and shunt flow were tabulated and analyzed with linear and polynomial regression. Intraabdominal and central venous pressures increased linearly with PEEP at different rates such that IAP-CVP varied inversely with PEEP. Shunt flow varied inversely as a polynomial function of PEEP. Analyses of these relationships allowed creation of a nomogram which can be interpolated to indicate required intraabdominal pressure needed to maintain shunt flow throughout the clinically useful range of positive airway pressure.

Animals↗
PubMed1992

Chemicals classified by IARC: an investigation of some of their toxicological characteristics.

Chemicals classified by the IARC to its Groups 1, 2A, 2B and 3 were examined in an attempt to identify characteristics of their behaviour in experimental studies of carcinogenicity, genotoxicity and acute, mammalian toxicity that correlate with those categories. Only those agents for which carcinogenic potency information was available were studied. For both mice and rats, greater proportions of chemicals were potent carcinogens if they had been categorized in Group 1 (human carcinogens) than if they had been put into one of the other categories. Not surprisingly, there was a weak association between carcinogenic potency and acute toxicity. Mice were especially sensitive to tumour induction by halides, while the lower sensitivity of rats to any carcinogenic effect of halides could be due in part to the higher systemic toxicity of halides in this species: a reduced differential of toxic and carcinogenic doses decreases the dose window in which carcinogenic effects may be demonstrated. It was notable that the human carcinogens were active in those genotoxicity tests with higher specificity for identifying rodent carcinogens. Predictive assays for carcinogenicity considered to have high specificity were in vivo cytogenetic, hepatocyte unscheduled DNA synthesis and Salmonella (5 commonly used strains) and mammalian cell hprt locus mutation assays. None of the relationships was strong enough to form the basis of a simple categorization process, but they could serve to alert investigators to chemicals of special toxicological interest and importance.

Animals↗
PubMed1992

Chemicals classified by IARC: their potency in tests for carcinogenicity in rodents and their genotoxicity and acute toxicity.

Chemicals classified by the IARC to its groups 1, 2A, 2B and 3 were examined in an attempt to identify characteristics of their behaviour in experimental studies of carcinogenicity, genotoxicity and acute mammalian toxicity that correlate with those categories. Only those agents for which information on carcinogenic potency was available were studied. In both mice and rats, more chemicals were potent carcinogens if they had been categorized in Group 1 (human carcinogens) than if they had been put into one of the other categories. Not surprisingly, there was a weak association between carcinogenic potency and acute toxicity. Mice were especially sensitive to tumour induction by halides; the lower sensitivity of rats to any carcinogenic effect of halides could be due in part to their higher systemic toxicity in this species: a reduced differential of toxic and carcinogenic doses decreases the dose window in which carcinogenic effects may be demonstrated. It was notable that the human carcinogens were active in those genotoxicity tests with higher specificity for identifying rodent carcinogens. Predictive assays for carcinogenicity that were considered to be highly specific were tests for cytogenetic effects in vivo, unscheduled DNA synthesis in hepatocytes, mutation in any of the five commonly used strains of Salmonella typhimurium and mutation at the hprt locus in mammalian cells. None of the relationships was strong enough to form the basis of a simple categorization, but they could serve to alert investigators to chemicals of special toxicological interest and importance.

Animals↗
PubMed1991

Responses of the L5178Y mouse Lymphoma cell forward mutation assay. V: 27 coded chemicals.

Twenty-seven chemicals were tested for their mutagenic potential in the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay using procedures based upon those described by McGregor et al. (McGregor DB, Martin R, Cattanach P, Edwards I, McBride D, Caspary WJ (1987): Environ Mol Mutagen 9:143-160). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Statistically significant responses were obtained with acid orange 10, aniline, benzaldehyde, o-chloroaniline, chlorodibromomethane, cytembena, 1,2-dibromo-4-(1,2-dibromomethyl) cyclohexane, dieldrin, lithocholic acid, oxytetracycline, phenazopyridine HCl, 1-phenyl-3-methyl-5-pyrazolone, sodium diethyldithiocarbamate, solvent yellow 14, tetraethylthiuram disulfide (disulfiram), 2,4-toluene diisocyanate, and 2,6-toluene diisocyanate. Apart from phenazopyridine HCl, acid orange 10, and solvent yellow 14, rat liver S9 mix was not a requirement for the mutagenic activity of these compounds. Chemical not identified as mutagens were N-4-acetylaminofluorene, chlorpheniramine maleate, chloropropamide, 1,4-dioxane, endrin, ethylene glycol, iron dextran, methapyrilene, sodium(2-ethylhexyl)alcohol

Animals↗
PubMed1991

Endogenous xenobiotic enzyme levels in mammalian cells.

The response of mammalian cell lines to chemicals depends, in part, on the exogenous activation system used for the induction of a biological response. This could be attributed to differences in the expression of enzymes involved in xenobiotic metabolism. We have measured the activities of benzo[a]pyrene hydroxylase, dimethylaminoazobenzene N-demethylase, catalase, superoxide dismutase, peroxidase and glutathione-S-transferase in human lymphoblast TK6, mouse lymphoma L5178Y, Chinese hamster ovary (CHO) and lung (V79) and mouse C3H10T1/2 cell lines as well as in primary hepatocytes and S9 preparations of liver from male F344 rats. Nitroreductase was also measured in some of these preparations. Human lymphoblast TK6 and mouse C3H10T1/2 cells had the capacity to metabolize dimethylaminoazobenzene and the latter cell line also metabolized benzo[a]pyrene, indicating the presence of constitutive mono-oxygenase activity. Cytochrome P450 could not be detected spectrophotometrically in the cell lines. Western blot analysis indicated that P450 from the P450IIA family is expressed in C3H10T1/2 cells. Reactivity was also observed with an antibody to P450IA2; however, the identity of this protein remains uncertain. Superoxide dismutase, catalase and peroxidase, which protect cells against oxygen radical damage, were found in all the cell lines and in rat hepatocytes and S9. The human lymphoblast TK6 cell line, however, had the least of each of these three enzymes. Glutathione-S-transferase activity was detected at varying levels in all cell types. Nitroreductase activity was high in S9 and Chinese hamster ovary cells and lower in mouse lymphoma and Chinese hamster V79 cells.

Animals↗
PubMed1991

Pentagastrin stimulates potassium absorption from the rat colon.

Pentagastrin is trophic to the colon but the physiologic effects of pentagastrin are incompletely known. We compared in vivo potassium (K+) absorption from the colons of pentagastrin-treated (PG, n = 13), sham (S, n = 12), and control (C, n = 3) Sprague-Dawley rats during continuous intraluminal K+ perfusion. Preoperative intraperitoneal injections were administered to PG (pentagastrin 0.25 mg/kg in 2 mL 0.9% NaCl q 12 h x 48 h) and S (2 mL 0.9% NaCl q 12 h x 48 h). Under xylazine anesthesia, cannulae were placed in the cecum, rectum, and femoral artery of each rat. Intraluminal perfusion was performed for 2 h at 30 mL/min with 40 meq/L KCl in 0.9% NaCl (PG and S) or 0.9% NaCl (C). We monitored serum sodium (Na+) and K+ every 15 min, and the affluent and effluent Na+ and K+ every 30 min. At each interval past 60 min, we observed higher serum K+ in PG compared with S and C (P less than .002) and higher K+ in S compared with C (P less than .05). No changes in serum Na+ occurred. We conclude that pentagastrin stimulates potassium absorption from the colon.

Animals↗
PubMed1990

The effect of nifedipine on skin-flap survival.

Nifedipine, a calcium-channel blocker, is a peripheral vasodilator and has been shown to increase blood flow to skin. The hypothesis that nifedipine would thereby improve skin-flap viability was tested by comparing the extent of necrosis of long pedicle flaps in control and nifedipine-treated rats. Thirty male Sprague-Dawley rats were randomized to receive either 2.5 mg/kg nifedipine in chocolate PO t.i.d. or plain chocolate according to protocols. Serum nifedipine levels were determined by gas chromatography. Dorsal cephalad-based random vascular pedicle flaps (2 X 6 cm) were elevated, sutured to their beds, and photographed for computer-aided surface area determinations. The extent of distal flap necrosis was expressed as a percentage of the total flap area, and differences were studied by one-way analysis of variance. The differences between the mean percentages of necrosis at 1 and 2 weeks for the groups were not statistically significant. We conclude that nifedipine has no effect on the extent of necrosis of the random skin flap in the rat.

Animals↗
PubMed1990

Studies on the activities of benzo[a]pyrene, benzidine and ethyl methanesulphonate in the L5178Y TK +/- mouse lymphoma mutagenicity assay using standardized and non-standardized protocols.

As part of the third UKEMS collaborative trial, ethylmethane sulphonate (EMS), benzo[a]pyrene (B[a]P) and benzidine (BZD) were assayed for mutagenicity using the L5178Y mouse lymphoma TK +/- forward mutation system. Exogenous metabolic activation was achieved with two different sources of rat liver S9 which were used under optimized conditions for B[a]P and BZD, the latter being tested also without S9. EMS was assayed in the absence of S9 only. Mutants were selected for trifluorothymidine (TFT) resistance after 48 and 72 h expression time. Mutant frequency (MF) data were subjected to ANOVA analysis and t-tests for differences between replicate cultures, linear trend and differences from solvent controls. Large TFT resistant colonies are believed to be due to induction of small amounts of genetic damage (point mutations, small deletions) at the tk locus, whilst small colonies are thought to be a result of larger effects. The relative proportions of the two colony types were determined in some experiments. All three compounds induced dose-related increases in MF under all conditions. B[a]P induced equal proportions of large and small colonies at all doses. EMS induced predominantly large colonies at all doses. The effect of BZD on colony size was variable. The source of S9 did not exert any consistent effect on toxicity, mutagenicity or mutant colony size. Maximum MF values occurred at 72 h for B[a]P and BZD but the results with EMS were variable. No consistent differences were apparent between estimates of toxicities made either by cloning immediately after treatment (day 0 cloning) or by estimating the relative total growth (RTG) at expression time.

Animals↗
PubMed1989

Pentagastrin stimulation of human colon carcinoma.

This study examines the trophic effects of pentagastrin administration on the growth of transplanted human colon carcinoma in mice. Three different human colon carcinomas were implanted into dorsal subcutaneous pouches of BALB-C athymic mice-tumor A, COLO 320 DM undifferentiated carcinoma; tumor B, WiDr epithelial carcinoma; and tumor C, mucus-producing signet-ring cell adenocarcinoma from a patient volunteer. Tumors grew for four to six weeks and then groups were randomly assigned to receive either saline injections or pentagastrin, 2.0 mg/kg three times a day for 14 days before harvest. Tumors were homogenized and analyzed for DNA, RNA, and protein contents. Each tumor type showed a different biochemical pattern of response to pentagastrin stimulation. The data confirm that pentagastrin is trophic to human colon carcinoma and suggest a possible clinical role for hormonal manipulation.

Adenocarcinoma↗
PubMed1989

Conditions affecting the mutagenicity of trichloroethylene in Salmonella.

Trichloroethylene (TCE) is a high production volume chemical frequently stabilized with oxiranes. These oxiranes may be responsible for the mutagenic activity of TCE in Salmonella, which has been occasionally, but not consistently, reported. High purity and oxirane-stabilized TCE samples were tested for their mutagenic potential in Salmonella typhimurium strains TA 1535, TA 98, and TA 100. Stabilized TCE was tested using a preincubation protocol up to a dose level of 10,000 micrograms per plate, but no mutagenic response was observed in either the presence or absence of a supplementary metabolic activation system (S9 mix) derived from Aroclor 1254-induced male rat liver. TCE without oxirane stabilizers also was nonmutagenic when tested in a vapor delivery system at nominal concentrations of up to 20% and using S9 mix derived from either rat or hamster. TCE containing 0.5-0.6% 1,2-epoxybutane did induce mutagenic responses from strains TA 1535 and TA 100 in the presence and absence of S9 mix. The lowest effective dose was about 0.63% in TA 1535 in the absence of S9 mix. Vapor-phase tests with 1,2-epoxybutane showed that an atmospheric concentration of 0.009% could induce 12-fold and 3-fold increases, respectively, in strains TA 1535 and TA 100. These increases would account for the mutagenic activity of the stabilized TCE sample. Epichlorohydrin (another commonly used stabilizer) induced similar increases in mutant numbers at an atmospheric concentration of 0.0009%. The absence of a significant response caused by unstabilized TCE in the presence of S9 mix is probably due to a lack of assay sensitivity, since chloral, a metabolite of TCE, is a mutagen in TA 100 [Haworth et al.: Environ Mutagen [Supplement 1] 5:3-142, 1983].

Animals↗
PubMed1989

TFT and 6TG resistance of mouse lymphoma cells to analogs of azacytidine.

5-Azacytidine (5-aza-CR) and six of its analogs were examined for their ability to induce trifluorothymidine (TFT) and/or 6-thioguanine (6TG) resistance in L5178Y mouse lymphoma cells. These analogs were 5-aza-2'-deoxycytidine (5-aza-CdR), 5-fluoro-2'-deoxycytidine (5-FCdR), 5,6-dihydro-5-azacytidine (dH-aza-CR), 6-azacytidine (6-aza-CR), cytidine (CR) and 1-b-D-arabinofuranosylcytosine (ara-C). 5-Aza-CR and 6-aza-CR were examined for their ability to induce 6TG-resistant colonies and results demonstrated no effect. At least a 5-fold increase in TFT resistance was observed for 5-aza-CR, 5-aza-CdR, 5-FCdR, dH-aza-CR and ara-C. The concentration at which these compounds induced TFT resistance correlated well with the potential of the nucleoside analogs to induce differentiation in C3H10T1/2 cells as determined by Constantinides et al. (Nature, 267, 364-366, 1977). In L5178Y mouse lymphoma (MOLY) cells, 5-aza-CR induced TFT resistance and produced both small and large colonies. Previous studies using mammalian cells showed the absence of mutagenic activity with 5-aza-CR and some of its analogs at the ATPase and hgprt loci. However, the different spectrum of DNA lesions detected at the tk locus may be responsible for the response of MOLY cells to 5-aza-CR.

Animals↗
PubMed1988

Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay. II: 18 coded chemicals.

Eighteen chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay by the use of procedures based upon those described by Clive and Spector [Mutat Res 44:269-278, 1975] and Clive et al [Mutat Res 59:61-108, 1979]. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Significant responses were obtained with benzofuran, benzyl chloride, bromodichloromethane, butylated hydroxytoluene, chlorendic acid, o-chlorobenzalmalonitrile, 1,2,3,4-diepoxybutane, dimethyl formamide, dimethyl hydrogen phosphite, furfural, glutaraldehyde, hydroquinone, 8-hydroxyquinoline, and resorcinol. Apart from bromodichloromethane, butylated hydroxytoluene and dimethyl hydrogen phosphite, rat liver S9 mix was not a requirement for the activity of any of these compounds. Chemicals not identified as mutagens were water, tert-butyl alcohol, pyridine, and witch hazel.

Animals↗
PubMed1988

Reactivity of catecholamines and related substances in the mouse lymphoma L5178Y cell assay for mutagens.

Using the L5178Y mouse lymphoma cell thymidine kinase locus and the Salmonella his locus assays, the mutagenic potentials of several catecholamines and related compounds were examined. No supplementary metabolic activation systems were used. In the mouse lymphoma assay, the dihydroxybenzenes catechol and hydroquinone had similar and appreciable mutagenic potentials, whereas resorcinol was less active. Derivatives of catechol, such as dopamine and epinephrine, were mutagenic, whereas the related monohydroxylated compounds tyramine and synephrine were inactive. The primary amine, arterenol, and the corresponding secondary amine, epinephrine, induced similar mutagenic responses. Carboxylation of the side chain of dopamine, giving L-dopa, reduced the maximum mutagenic response. The introduction of charged groups directly on to the aromatic ring also reduced mutagenic activity, while an intervening methylene reversed this effect. Thus, 3,4-dihydroxyhydrocinnamic acid was more active than 3,4-dihydroxybenzoic acid. The compound active at the lowest doses was 4-tert-butyl catechol. The activities of these compounds are highly dependent upon substituent groups. Experiments with superoxide dismutase gave circumstantial evidence for some of the mutagenic activity being due to superoxide anion. Active oxygen species might be responsible for some of the observed effects, but this cannot be concluded from the superoxide dismutase experiments. Mutagenic responses in Salmonella were very low but were significant for L-dopa in three strains and for epinephrine and arterenol in one strain. Limited DNA association studies of 14C-dopamine suggest interactions in L5178Y and Salmonella cells and in mouse liver. The mutagenicity of dopamine in L5178Y is reduced by high serum concentrations during the exposure period, while the apparent association with DNA is unaffected.

Animals↗