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Biomedical subjects

L R Ferguson

Publications and source records attributed to L R Ferguson.

At least 73 records · Page 4Linked to original sources
PubMed1994

DNA-directed aniline mustards with high selectivity for adenine or guanine bases: mutagenesis in a variety of Salmonella typhimurium strains differing in DNA-repair capability.

Two closely-related aniline monomustards (1 and 2), linked to a DNA-targeting acridine chromophore by a linker chain of different length, show high selectivity for alkylation of polymer DNA. The shorter-chain derivative (2) alkylates mainly at guanine N7 sites, while the longer-chain analogue (1) reacts almost exclusively at adenine N1. The biological effects of these compounds have been studied in standard Ames Salmonella typhimurium strains in order to determine the mutagenic consequences of such well-defined DNA lesions, and the effect of DNA-repair systems on them. Both compounds caused detectable mutations in strains TA1537, TA98 or TA100 and some related strains. Mutation rates were greatly enhanced in strains carrying either a uvrB deletion or the plasmid pKM101. Frameshift mutagenesis by both compounds was completely eliminated by recA deletion, in both the presence or absence of the plasmid. The adenine-selective compound (1) appeared more sensitive to the DNA-repair defects than the guanine-selective derivative (2). Additionally, only the adenine-selective compound (1) caused statistically significant levels of detectable mutation in the repair-proficient strains TA102, TA4001 or TA4006. The bacterial mutagenesis evidence suggests that a bulky, major groove-residing adenine lesion may be more readily recognised by DNA-repair systems, and more likely to lead to a wider range of mutagenic events, than a similar guanine lesion.

Adenine↗
PubMed1994

Alcohol-related expectations among Mexican-American women.

The article explores alcohol expectations among Mexican-American women utilizing the Alcohol Expectancy Questionnaire and a series of quantity/frequency alcohol use measures. The results indicate that Mexican-American women generally have similar expectations about the benefits of alcohol use as women in the larger population. Within the sample of Mexican-American women however, there were differences in alcohol expectations based on occupational status and acculturation level: those Mexican-American women who are more acculturated and hold higher professional status occupations have higher expectations of the benefits of alcohol use than less acculturated Mexican-American women in blue-collar or service occupations.

Acculturation↗
PubMed1994

Visualization and analysis of co-occurrence and cross-tabulation data in medical research.

Analyzing raw data can be prohibitively time consuming. A variety of graphical techniques have been developed to address this problem. Although graphical analysis can provide a simple yet comprehensive overview of a large dataset, often these techniques fail to capture the essence of data trends. In addition, the ability to easily query any component of the data subset frequently remains burdensome. In this paper, we present a general method to address these issues for cross-tabulation tables and provide examples of their use in medical research.

Computer Graphics↗
PubMed1994

The use of 32P-postlabelling to detect DNA adducts produced by experimental anticancer drugs: DNA-directed nitrogen mustards.

DNA alkylation by four acridine-linked 'DNA-targeted' aniline mustard derivatives has been studied by 32P-postlabelling. P1 nuclease digestion proved much more efficient than butanol extraction for enhancing the yield of adducted bases for these somewhat hydrophilic compounds. The yield of adducts was maximal after approximately 4 h digestion with micrococcal nuclease/spleen phosphodiesterase and remained relatively constant after that up to 24 h, suggesting that the adducts formed are stable under these conditions. There was some variation in the rates of phosphorylation of the adducts by T4 polynucleotide kinase, with optimal labelling generally occurring after 1 h. The (CH2)5O-linked half-mustard derivative 1 gave five nucleotide 3'-diphosphate adduct spots with calf thymus DNA. Two of these were identified as the adenine N1 and N3 adducts, corresponding to those previously identified as the main base adducts formed by 1 following acid digestion studies. The corresponding full mustard also gave five adduct spots. In contrast, the (CH2)3-linked half-mustard 3 gave only two adduct spots, the most intense of which was identified as a guanine adduct. The corresponding full mustard 4 gave three adduct spots, two of which were identified as guanine adducts. These results agree well with those obtained for the same compounds by the more tedious methods of acid digestion to base adducts, followed by isolation on HPLC, and show that the technique of 32P-labelling can be usefully applied to the study of alkylation of DNA by this class of 'targeted' mustards.

Aniline Mustard↗
PubMed1993

Dietary fibre: its composition and role in protection against colorectal cancer.

Dietary fibre has a complex and highly variable composition. Although some dietary fibres may protect against colorectal cancer, it is unlikely that all are equally protective. Dietary fibre is principally composed of plant cell walls, but it also includes components obtained from cell walls (e.g. cellulose, pectin, and lignin), and non-starch polysaccharides (NSPs) from other sources (e.g. seaweeds and micro-organisms). The AOAC and Englyst methods are commonly used to determine the total amount of dietary fibre in foods. Most of the cell walls in food plants are from parenchyma cells, which are extensively degraded by bacteria in the colon. Cell types with walls containing the hydrophobic polymers lignin, suberin, or cutin also occur in food plants in small numbers, but they may be important in preventing colorectal cancer. Lignin, and possibly the other polymers, protect these walls from degradation. Epidemiological, human intervention, and animal studies can be used to try to identify the most protective dietary fibres. Epidemiological studies are difficult to interpret because usually only the total amount of dietary fibre eaten is reported. Intervention studies indicate that wheat bran dietary fibre may be protective. The results of animal carcinogenesis studies are variable, but sources of insoluble dietary fibres, including wheat bran, appear more protective than soluble dietary fibres, and some dietary fibres appear to enhance carcinogenesis. Possible mechanisms for protection by dietary fibres can be divided into two groups: those where the dietary fibre is acting directly, and those which result from the dietary fibre being degraded by colonic bacterial enzymes and the products fermented. Possible direct mechanisms include the binding of carcinogens to undegradable dietary fibres, and the absorption of water by undegradable dietary fibre resulting in increased faecal bulk and shortened transit times. Possible indirect mechanisms include the lowering of the colon pH by the short-chain fatty acids produced by bacterial fermentation, and the specific effects of butyrate. There are also a number of possible mechanisms by which some dietary fibres may enhance carcinogenesis. Use of better defined dietary fibres will increase our understanding of the role of dietary fibres in modulating colorectal cancer.

Animals↗
PubMed1993

Diet and the prevention of colorectal cancer.

It is important for those working in the area of health-promotion that consensus be reached on the role of diet in colorectal cancer and its etiology. In developing health-promotion strategies, further research is needed into the beliefs, attitudes and behaviour of different groups. More qualitative data on the diet of different groups in the community is also needed. Further basic research on the role of diet in this cancer requires that biomarkers be related to human or animal dietary exposures. The development of new animal and human models may be appropriate.

Animals↗
PubMed1993

Multidrug resistance and mutagenesis.

Multidrug resistance, the phenomenon whereby the development of resistance to one drug is sometimes accompanied by the simultaneous development of resistance to a variety of other, often structurally unrelated, drugs, is frequently associated with the presence of an energy-dependent membrane-transport system which reduces the concentration of a drug or other chemical in the cytoplasm. The latter process (termed here MDR) occurs naturally in a number of normal mammalian tissues, including colon, jejunum, liver, kidney and bone marrow, as well as in other species including bacteria. The presence of MDR can reduce the mutagenic potential of a variety of compounds in mammalian and microbiological assays. MDR can be reversed by a diverse collection of compounds, many of which are hydrophobic cations with other physiological effects. An important consequence of these considerations is that MDR-reversing agents are potentially dangerous because, while having no intrinsic mutagenicity, they may significantly increase the mutagenicity of other compounds by poisoning protective MDR mechanisms in the body.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Induction of mitotic crossing-over by the topoisomerase II poison DACA (N-[2-dimethylamino)ethyl]acridine-4-carboxamide) in Saccharomyces cerevisiae.

The antitumor agent DACA (N-[2-dimethylamino)ethyl]acridine-4-carboxamide) a new DNA intercalating topoisomerase II poison, was distinguishable from clinical topoisomerase poisons (amsacrine, daunorubicin, doxorubicin and etoposide) in its induction of aberrant colonies in the yeast Saccharomyces cerevisiae D5. It was not only more recombinogenic, but was recombinogenic at non-toxic drug concentrations. DACA at 680 microM (2-h exposure time), induced 1.2% aberrant colonies of which 0.32% were mitotic crossing-over events. The presence of the rad52 mutation abolished mitotic crossing-over and greatly increased drug toxicity. The concentration for 50% inhibition of survival of the rad52 mutant was 100 microM, as compared with 4900 microM for the wild-type. Drug toxicity was marginally increased by the presence of rad3 and rad18 mutations. Rad3 mutations increased the incidence of crossing-over events but had little effect on other mutagenic or recombinogenic events. In contrast, the rad18 mutation increased the incidence of all types of aberrant colonies. The inclusion of hydroxyurea and caffeine, as non-specific repair inhibitors, caused weak and strong inhibition, respectively, of all types of aberrant colonies. Inclusion of the protein-synthesis inhibitor cycloheximide reduced mitotic cross-over but had little effect on the incidence of other aberrations. It is concluded that DACA induces lesions which are repaired by a recombinational repair pathway involving the RAD52 product, and that RAD3 and RAD18 products are each involved in the generation of recombinational events.

Acridines↗
PubMed1993

The size of cytokinesis-blocked micronuclei in human peripheral blood lymphocytes as a measure of aneuploidy induction by Set A compounds in the EEC trial.

We have investigated the potential value of estimating number and size of micronuclei in cytokinesis-blocked human peripheral blood lymphocytes as a measure of the aneuploidy-inducing ability of 5 chemicals in the EEC trial. Colchicine induced metaphase arrest, high numbers of cells with micronuclei and also of cells with completely fragmented nuclei. The majority of micronuclei were very significantly larger in relation to the main nucleus than a comparable set taken from untreated control cultures. In the same assay system, diazepam weakly increased the incidence of MN in a dose-related fashion. There was a slight increase in MN but only at toxic doses when cells were treated with econidazole, chloral hydrate or hydroquinone. For each of these 4 drugs, statistical treatment of the data confirmed a difference in size distribution of the MN as compared to those found in negative control cultures. Although this approach has potential, it may not be optimal to detect weak aneuploidy-inducing agents.

Aneuploidy↗
PubMed1993

The adsorption of a range of dietary carcinogens by alpha-cellulose, a model insoluble dietary fiber.

One of the ways dietary fibers may protect against colorectal cancer is by adsorbing carcinogens and carrying them out of the digestive tract, thus lessening interaction of the carcinogens with the colonic tissue. We investigated this mechanism of action by testing in vitro the abilities of a range of carcinogens, including known animal colon carcinogens, to adsorb to alpha-cellulose, which we have used as a model insoluble dietary fiber. The carcinogens were N-nitroso-N-methylurea (NMU), benzo[a]pyrene (B[a]P) and a number of heterocyclic aromatic amines which have been found in heated foods. It was found that the ability of a carcinogen to adsorb to alpha-cellulose is strongly related to the hydrophobicity of the carcinogen measured as the calculated logarithm of the partition coefficient between 1-octanol and water (C log P). The hydrophilic carcinogen, NMU, (C log P = -0.204), adsorbed only poorly, whereas the very hydrophobic carcinogen, B[a]P, (C log P = 6.124), adsorbed strongly. Carcinogens with intermediate hydrophobicities showed intermediate abilities to adsorb.

Adsorption↗
PubMed1993

Mouse micronucleus assays of sporidesmin, the toxin associated with facial eczema in ruminants.

Sporidesmin, a fungal toxin with widespread distribution within New Zealand, was previously shown to be a potent clastogen in Chinese hamster cells in vitro, but not in peripheral blood lymphocytes of sheep in vivo. In mice, massive oral doses led only to slight increases in micronucleus levels in the bone marrow, despite highly significant changes to other toxicological parameters. It would appear that the intact animal is protected in some fashion from the clastogenic effects of sporidesmin, although this substance must still be considered a potential human genotoxic agent.

Animal Diseases↗
PubMed1993

Blastomycosis of the skull base.

Blastomycosis is usually considered a pulmonary or cutaneous disease. A patient with blastomycosis of the infratemporal fossa temporal bone and sinuses without pulmonary disease is presented. Extensive skull base involvement required surgical debridement for relief of pain, and long-term systemic antifungal therapy. The literature is reviewed and discussed.

Journal Article↗
PubMed1993

The effects of soluble-fiber polysaccharides on the adsorption of a hydrophobic carcinogen to an insoluble dietary fiber.

Dietary fiber is believed to decrease the incidence of colorectal cancer, but not all types of fiber are equally protective. Dietary fibers may be divided broadly into insoluble and soluble fibers, and there is evidence from animal experiments that the latter not only fails to protect against colorectal cancer but may enhance its development. Adsorption of carcinogens to insoluble dietary fiber in the intestinal tract is one of the mechanisms by which dietary fiber is believed to protect against colorectal cancer. In previous in vitro experiments, we showed that the hydrophobic carcinogen 1,8-dinitropyrene (DNP) adsorbs to insoluble plant cell wall components (insoluble dietary fibers). Soluble polysaccharides (pectic polysaccharides) extracted from the walls of parenchyma cells of dicotyledonous plants were found to maintain DNP in aqueous solutions and decrease its adsorption to insoluble wall components. In the present study, we examined a commercial preparation of pectin and seven other soluble-fiber polysaccharides with diverse structures for their effects on the distribution of DNP. Many of these are used as emulsifiers and stabilizers in the food industry. They all maintained DNP in aqueous solution and decreased its adsorption to alpha-cellulose, which we used as an example of an insoluble dietary fiber. Gum arabic was the most effective and kappa-carrageenan the least. The capacity of the polysaccharides to act as emulsifiers and stabilizers may explain their effects on DNP distribution. The monosaccharide glucose and the disaccharide cellobiose had no effect on the distribution of DNP. These results indicate three possible mechanisms by which soluble-fiber polysaccharides may enhance the development of colorectal cancer. First, because they reduce the ability of insoluble dietary fibers to adsorb hydrophobic carcinogens, more carcinogens may enter the colon maintained in solution than adsorbed onto insoluble fibers. Second, if soluble-fiber polysaccharides are maintaining hydrophobic carcinogens in solution and these polysaccharides are degraded by bacterial enzymes in the colon, then the carcinogens may come out of solution and be deposited onto the mucosal surface of the colon. Third, soluble-fiber polysaccharides may cross the intestinal epithelium and carry with them carcinogens maintained in solution. These studies have important consequences for nutrition, because soluble-fiber polysaccharides represent a common component of foods.

Adsorption↗
PubMed1993

Temporal meningiomas presenting as chronic otitis media.

Two cases of temporal bone meningiomas presenting as chronic drainage ears are presented. One case was indicated by computer tomographic scan at the time of initial surgery to be limited to the middle ear, but recurred 9 months later with extensive cerebellopontine angle extension and cranial nerve palsies. The tumor in the second case extended from the middle ear to the cavernous sinus, with extensive intradural involvement. Meningiomas involving the middle ear must be considered to have intracranial extension, and magnetic resonance is the imaging study of choice.

Diagnosis, Differential↗
PubMed1992

In vitro adsorption of a hydrophobic mutagen to gastrointestinal mucus glycoprotein (mucin) and dietary fibre.

The adsorption of mutagens by some dietary fibres has been suggested as one mechanism by which dietary fibres protect against colorectal cancer. It is thought that these dietary fibres carry the mutagen out of the digestive tract, decreasing the effective mutagen concentration to which epithelial cells are exposed. The ability of gastrointestinal mucin to alter the extent to which the hydrophobic mutagen 1,8-dinitropyrene (DNP) adsorbs in vitro onto the insoluble dietary fibre alpha-cellulose, was investigated. It was found that crude and purified human ileal mucins themselves adsorbed DNP and decreased the adsorption of DNP onto alpha-cellulose. Purified mucin which had been treated with trypsin also adsorbed DNP. These studies suggest that in the digestive tract there would be competition for the adsorption of DNP between mucin and insoluble dietary fibres, such as alpha-cellulose. This factor must be considered in predictions about the distribution of hydrophobic, mutagenic carcinogens in the digestive tract and their role in the etiology of colorectal cancer.

Adsorption↗
PubMed1992

Induction of the cytoplasmic 'petite' mutation by chemical and physical agents in Saccharomyces cerevisiae.

A range of physical and chemical agents induce the mitochondrial 'petite' mutation in the yeast Saccharomyces cerevisiae. DNA intercalating agents as well as chemicals which can interfere with DNA synthesis induce this mutation, but only in growing cells. Many chemical or physical agents that produce a DNA lesion which is not simply reversed can induce various levels of the petite mutation, and may be more effective in non-growing cells. A limited number of chemicals act like ethidium bromide, inducing a high frequency of petites which is partially reversible with increasing concentration or time. The ability of a specific compound to be transported into mitochondria or its affinity for AT base pairs in DNA may determine whether it acts primarily as a nuclear or mitochondrial mutagen. In mammalian cells, some neoplastic changes occur at the mitochondrial level. Analogies between yeast and mammalian mitochondria suggest that agents which increase petite mutagenesis in yeast may have some carcinogenic potential. Although some types of petite inducer may have potential as antitumour drugs, those which are very effective antimitochondrial agents appear to be too toxic for therapeutic use. A process comparable to early stages in petite mutagensis occurs in human degenerative diseases and it seems possible that a consequence of exposure to petite mutagens could be an increase in the rate of degenerative diseases or of the aging process.

Animals↗
PubMed1992

Modulation of mutagenic properties in a series of DNA-directed alkylating agents by variation of chain length and alkylator reactivity.

Four series of aniline mustards linked to a DNA-affinic acridine chromophore by alkyl chains of varying length (2-5 carbon atoms) have been studied for their mutagenic properties, as estimated in four strains of Salmonella typhimurium and in Saccharomyces cerevisiae strain D5. The four series have very different mustard reactivities, as determined by the aniline link group (-O-, -CH2-, -S- or -SO2-). Some of the derived compounds cause frameshift mutagenesis which can be detected in TA98 and also "petite" mutagenesis activity, neither of which occur to significant extents with the parent mustards or with 9-aminoacridine. None of the derived compounds are as effective as the parent mustards in mitotic crossing-over, nor do they show ability for frameshift mutagenesis in S. typhimurium TA1977 which is typical of acridines. Some of the compounds have comparable frameshift activity to compounds such as ICR-191, but appear to have a different base-pair preference. The results indicate clear structure-activity relationships for the spectrum of mutagenic activity, which relate to both chain length and alkylator reactivity, for these compounds.

Alkylating Agents↗