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Biomedical subjects

A S Wright

Publications and source records attributed to A S Wright.

At least 19 recordsLinked to original sources
PubMed1997

Computer-assisted psychotherapy.

The rationale for using computers in psychotherapy includes the possibility that therapeutic software could improve the efficiency of treatment and provide access for greater numbers of patients. Computers have not been able to reliably duplicate the type of dialogue typically used in clinician-administered therapy. However, computers have significant strengths that can be used to advantage in designing treatment programs. Software developed for computer-assisted therapy generally has been well accepted by patients. Outcome studies have usually demonstrated treatment effectiveness for this form of therapy. Future development of computer tools may be influenced by changes in health care financing and rapid growth of new technologies. An integrated care delivery model incorporating the unique attributes of both clinicians and computers should be adopted for computer-assisted therapy.

Forecasting↗
PubMed1996

Relative potency of testosterone and dihydrotestosterone in preventing atrophy and apoptosis in the prostate of the castrated rat.

Although dihydrotestosterone (DHT) is the principal androgen in the prostate, testosterone can also act as an androgen in this tissue. To determine the relative potencies of testosterone and DHT in preventing prostate regression, castrated rats were implanted for 4 d with varying doses of testosterone in the presence or absence of the 5alpha-reductase inhibitor finasteride. In the absence of finasteride, testosterone in the prostate is converted to DHT, creating an intraprostatic DHT dose response. In the presence of finasteride, this conversion is blocked, and an intraprostatic testosterone dose response is achieved. DHT was 2.4 times more potent than testosterone at maintaining normal prostate weight and duct lumen mass, a measure of epithelial cell function. The two androgens were equipotent at preventing DNA fragementation and expression of testosterone-repressed prostate message, two measures of apoptosis (cell death). The intraprostatic testosterone concentration that results from finasteride treatment in rats is sufficient to inhibit apoptosis but will not maintain normal epithelial cell activity. In conclusion, whereas DHT is more potent than testosterone at stimulating prostate epithelial cell function as measured by ductal mass, the two androgens are equipotent at preventing prostate cell death after castration. These results explain why finasteride causes prostate involution in the rat with minimal evidence of prostate cell death.

Animals↗
PubMed1995

The gp15/400 polyprotein antigen of Brugia malayi binds fatty acids and retinoids.

Gp15/400 is a surface-proximal antigen of the filarial nematode Brugia malayi, produced as a large polyprotein precursor comprising an array of polypeptide units of approx. 14.5 kDa. Here we describe a biochemical function for gp15/400. A single 14.5-kDa unit of gp15/400 has been expressed in Escherichia coli, and found to dimerise spontaneously. This protein (designated P-RUNG) has high-affinity fatty acid and retinoid binding activity, suggesting that the parent polypeptide itself has these properties. Fluorescent fatty acid probes show significant enhancement of fluorescence intensity and shifts in emission wavelength in the presence of P-RUNG, which can be reversed by competing non-fluorescent fatty acids (oleic, palmitic, steric, arachidonic), retinoids (retinol and retinoic acid) and oleoyl Coenzyme A, but not by tryptophan, cholesterol, caproic acid, squalene, tocopherol, tocopherol acetate, succinyl CoA, 2-methylbutyric acid and 2-methylvaleric acid. Changes in intrinsic fluorescence of retinol or retinoic acid confirmed the retinoid binding function. The results of fluorescence titration experiments are consistent with stoichiometric binding to a single protein site per monomer unit with affinities (Kd) in the range 2 x 10(-6) M (for the fluorescent probe 11-((5-dansyl)amino)undecanoic acid) and 2 x 10(-7) M (for oleic acid). The extreme blue shift of the fluorescent fatty acid-protein complex suggests an unusually low polarity for the protein binding site. The intrinsic fluorescence of the single tryptophan residue of P-RUNG indicates that it also is deeply buried in a non-polar environment, but is probably not involved in ligand binding. Gp15/400, therefore, represents a new class of lipid binding protein which is possibly restricted to nematodes.

Animals↗
PubMed1995

Evaluation of modified bacterial mutagenicity assays for the genotoxicity testing of mineral oils.

A modified bacterial mutagenicity assay based on the Ames Salmonella/mammalian microsome test has been developed for application in the genotoxicity testing of mineral oils. The assay uses washed microsomes from rat liver in place of S9 fraction in order to increase the sensitivity of detection of genotoxicity. The modified assay was used to test a series of oils for which skin carcinogenicity bioassay data in mice were available. Oils were tested as emulsions in water using Tween 80 as a dispersant. A mutagenicity index for each oil was obtained using non-linear regression analysis of data from the dose-response curve. The results showed an empirical correlation between increasing mutagenicity index, carcinogenicity and the polycyclic aromatic hydrocarbon content of the oils. The washed-microsome assay was also compared with modified Ames assays developed by Blackburn et al. (Cell Biol. Toxicol., 1, 40, 1984; Cell Biol. Toxicol., 2, 63, 1986) which employed increased levels of S9 (rat and hamster liver) to test dimethyl sulphoxide extracts of oils. The washed-microsome assay can be used for the testing of whole oils rather than extracts which are necessary for the modified Ames assay. It is recognised that the determinants of carcinogenic activity in vivo include promoting activity which such assays are unable to detect. Nevertheless, such modified bacterial assays may be a useful prescreen since genotoxicity is recognised as a key initial step in carcinogenesis.

Animals↗
PubMed1995

Evidence for atrophy and apoptosis in the ventral prostate of rats given the 5 alpha-reductase inhibitor finasteride.

Castration causes cell loss in the rat ventral prostate through a process called apoptosis. Although 5 alpha-reductase inhibition also causes prostate cell loss, the mechanisms involved have been debated. To investigate this question further, we have evaluated the histological responses of the rat ventral prostate to both castration and 5 alpha-reductase inhibition. Rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride. After 4, 9, 14, and 21 days the prostates were excised, the androgen and DNA content determined, and the tissue was subjected to histological and histomorphometric analysis. Finasteride and castration decreased prostate weight at day 21 by 65% and 93%, respectively. Castration decreased DNA content (micrograms per prostate) by a maximum of 88% at 14 days. Finasteride had no significant effect on DNA content after 4 days and decreased DNA content by a maximum of 52% at 14 days. When castrate prostate sections were stained for tissue transglutaminase, a marker of apoptotic cell death, a maximum of 23% of epithelial cells were stained by day 14 with a return to control levels by day 21. Finasteride caused a less intense increase in staining in which 16% of epithelial cells stained for tissue transglutaminase on day 9 with a return to baseline by day 14. When prostate sections were stained for DNA breaks, another marker of cell death, castration, caused a peak of staining on day 4 with 6% of epithelial cells staining and a return to near control levels by day 21. Finasteride-induced staining was less intense with peak staining at day 4 (0.7% of epithelial cells) and a return to control values by day 9. Morphometrics were used to assess the effect of castration and finasteride on prostate duct size and epithelial cell mass. After 4 days of finasteride treatment, the mean ductal mass decreased by 47%, with no significant change thereafter. The mean epithelial cell mass decreased by 15% on day 4 and 60% on day 9, with no further decrease thereafter. Castration caused a more rapid and greater decrease in both morphometric parameters with a 95% reduction in the mass of prostate ducts and a 93% decrease in epithelial cell mass by day 9. We conclude that castration induces a more profound involution of the rat ventral prostate than does 5 alpha-reductase inhibition. Cell loss occurs in both groups, but the degree of cell loss is less with finasteride.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Molecular dosimetry of DNA adducts in rainbow trout (Oncorhynchus mykiss) exposed to benzo(a)pyrene by different routes.

Farm raised rainbow trout (Oncorhynchus mykiss) were exposed by various routes to benzo(a)pyrene (BP) as a representative carcinogenic polycyclic aromatic hydrocarbon (PAH). Following exposure of fish to the chemical by intraperitoneal (i.p.) injection, 32P-postlabelling studies indicated that non-feral trout were relatively resistant to the formation of BP-DNA adducts in liver. No adducts were detected in fish exposed to single doses (20 mg/kg) of BP. Multiple exposures (e.g. 2 x 25 mg/kg) were necessary in order for adducts to be detected, indicating that induction of the metabolising enzymes required for the bioactivation of BP is necessary. These studies provided reference information on DNA adducts for comparison with data from subsequent experiments at environmentally realistic low level exposures. Two types of low level aquatic exposure were carried out. The first procedure exposed fish for 30 days to a nominally constant low level (1.2 and 0.4 micrograms/l) of a homogeneous dispersion of BP in water, to simulate low level aquatic environmental exposures. Following 32P-postlabelling analysis of the liver DNA of exposed fish, BP-DNA adducts were not detected. In the second procedure, fish were exposed to a constant low level of BP (ca. 0.5 micrograms/l) for 15 days then to a pulse (60 micrograms/l) which was allowed to naturally decline (to ca. 2 micrograms/l) during a further 15 days. Following this exposure, significant levels of BP-DNA adducts were detected in livers of trout. The effect of dietary exposures was investigated by feeding trout a diet containing either 58 micrograms or 288 micrograms BP per day for 6 days, equivalent to total doses of 43 mg/kg and 216 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Class-specific immunoadsorption purification for polycyclic aromatic hydrocarbon-DNA adducts.

An immunoenrichment procedure has been developed for applications in the detection and identification of a broad range of polycyclic aromatic hydrocarbon (PAH)-DNA adducts at very low abundance. The procedures are based on a monoclonal antibody raised to r-7,trans-8,trans-9-trihydroxy-cis-10-(N2-deoxyguanosyl-5'-phospha te)- 7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE-N2-dG) which has been tested for cross-reactivity towards DNA and proteins (bovine serum albumin, chicken gamma globulin and human globin) covalently modified with a range of PAH diol-epoxides. The antibody recognised DNA adducted with the diol-epoxides of benzo[a]pyrene, benz[a]anthracene, chrysene, dibenz[a,h]anthracene or picene. The antibody also cross-reacted with the 7,8,9,10-tetraol derived from benzo[a]pyrene and the 1,2,3,4-tetraols of benz[a]anthracene and chrysene. The degree of cross-reactivity was greatest for PAH adducts with structural features similar to anti-BPDE-N2-dG proximate to the base attachment. The antibody also recognised a range of PAHs adducted to human globin; these included adducts of benzo[a]pyrene, benz[a]anthracene and chrysene diol-epoxides. This wide range of recognition provides good evidence for the class-specific recognition of PAH adducts by the antibody. When immobilized on Sepharose 4B and used in the immunoadsorption purification of adducted nucleotides, the antibody selectively enriched adducts of benzo[a]pyrene, benz[a]anthracene and chrysene from normal nucleotides. Quantitative measurements with [14C]benzo[a]pyrene-DNA adducts showed that the immobilized antibody was able to enrich benzo[a]pyrene adducts from a DNA hydrolysate containing adducts at a level of 1 adduct/10(10) normal nucleotides. In addition, this immunoadsorption technique was effective in enriching a mixture of DNA adducts formed in the skin of CF1 mice treated cutaneously with a mixture of [3H]benzo[a]pyrene and [3H]chrysene. Class-specific immunoenrichment procedures for DNA adducts are important in assisting the identification of genotoxic components in complex mixtures. The performance characteristics of this immobilized antibody suggest that it may be suitable for application in the detection, identification and monitoring of human exposures to low levels of PAHs.

Animals↗
PubMed1993

Androgen metabolism in men receiving finasteride before prostatectomy.

Oral administration of finasteride, a 5 alpha-reductase inhibitor, affects intraprostatic androgens by suppressing dihydrotestosterone and increasing testosterone. This study was designed to determine the correlation of these effects of finasteride with changes in serum dihydrotestosterone, testosterone and androstanediol glucuronide. In a double blind, placebo-controlled study, 27 men with symptomatic benign prostatic hyperplasia were treated with placebo or 1 or 5 mg. per day finasteride for 6 to 8 weeks before transurethral resection of the prostate. There was no significant change in serum testosterone in any group, or in serum dihydrotestosterone or androstanediol glucuronide in the placebo group. There was a decrease in serum dihydrotestosterone by 66 +/- 4% and 70 +/- 8% (p = 0.32), and of serum androstanediol glucuronide by 78 +/- 3% and 86 +/- 3% (p = 0.012) in the 1 and 5 mg. finasteride groups, respectively. Intraprostatic dihydrotestosterone in the placebo group decreased from 18.6 +/- 1.4 nmol./kg. to 3.8 +/- 1.0 nmol./kg. and 1.7 +/- 0.7 nmol./kg. with 1 mg. and 5 mg. finasteride, respectively (p = 0.049 between 1 mg. and 5 mg. finasteride). Intraprostatic testosterone in the placebo group increased from 1.1 +/- 0.2 nmol./kg. to 7.6 +/- 1.0 nmol./kg. and 8.3 +/- 0.7 nmol./kg. with 1 mg. and 5 mg. finasteride, respectively (no significant difference between 1 mg. and 5 mg. finasteride). Serum and intraprostatic dihydrotestosterone correlated (p = 0.002). There was no correlation between intraprostatic dihydrotestosterone and serum androstanediol glucuronide. We conclude that 5 mg. of finasteride cause greater inhibition of intraprostatic 5 alpha-reductase than 1 mg. and that serum dihydrotestosterone is a better marker of intraprostatic dihydrotestosterone than androstanediol glucuronide.

Androstane-3,17-diol↗
PubMed1990

Mutations in the Ha-ras proto-oncogene in spontaneous and chemically induced liver tumours of the CF1 mouse.

Mutations in codon 61 of the Ha-ras proto-oncogene have been shown to occur with a high frequency in both spontaneous and carcinogen-induced liver tumours of the B6C3F1 mouse. In the present study we analysed the frequency and pattern of Ha-ras mutations in liver tumours in a different strain of mice, namely the CF1 mouse. These liver tumours occurred spontaneously or after administration of either aflatoxin B1, phenobarbital or dieldrin. Mutation analysis was performed by in vitro amplification of DNA using the polymerase chain reaction combined with selective oligonucleotide hybridization. Our results demonstrate the presence of mutations in the Ha-ras gene in liver tumours of the CF1 strain. In total, 6 out of 35 liver tumours of male CF1 mice, two of them occurring after treatment with the tumour promoter phenobarbital solely, contained mutations at either the first or second base of codon 61 of the Ha-ras gene. The types of mutations found in liver tumours of the CF1 mouse were very similar to those described in the B6C3F1 mouse, indicating that mutations in the Ha-ras proto-oncogene may represent a critical event in mouse hepatocarcinogenesis.

Aflatoxin B1↗
PubMed1988

Prospective detection and assessment of genotoxic hazards: a critical appreciation of the contribution of L. Ehrenberg.

Advances in our understanding of the mechanisms of chemical carcinogenesis are now being applied to improve the quality of prospective risk assessment. The contribution of Ehrenberg and his colleagues (at the University of Stockholm) probably represents the most comprehensive application of mechanistic knowledge to this field during the past 20 years. The strategic approach developed by the Swedish group was based on the identification of differences between man and experimental risk models in factors that determine the relationships between exposure and biological response and the development of methods to compensate for these differences. Many of the critical stages in chemical carcinogenesis and the cellular determinants of these stages have now been identified. As a first step in seeking to improve risk assessment, Ehrenberg introduced the target dose concept, in which the doses of carcinogens penetrating to the cellular target (DNA) are determined. This approach provides an improved basis for determining exposures to carcinogenic agents and also for compensating for species differences in factors such as metabolism that determine the relationships between exposure dose and the dose at the critical target. The target dose concept is now widely accepted and has led to the development of new biomedical monitoring techniques, based, for example, on the measurement of haemoglobin adducts, which are now being applied to detect and identify genotoxic hazards. The introduction of the target dose concept has led to significant improvements in the quality of prospective risk assessment. Further improvements necessitate procedures to compensate for differences between man and prospective risk models in factors that determine subsequent stages of the carcinogenic process. Ehrenberg has proposed that the rad-equivalence approach may be of value in this respect. Its application has accurately predicted the incidence of leukaemias in occupational cohorts which had exposures to ethylene oxide in common. The possible general applicability of this approach is discussed.

Carcinogenicity Tests↗
PubMed1988

An immunoassay for monitoring human exposure to ethylene oxide.

A novel immunochemical approach has been developed to monitor human exposures to ethylene oxide (EO). The method exploits the interaction of EO with the amino function of the N-terminal valine residue of the alpha-chain of human haemoglobin (Hb). Antibodies were raised against the adducted valine in the form of the N-terminal tryptic heptapeptide and have been used to develop a sensitive radioimmunoassay (RIA) for the adducted heptapeptide. This method has been fully validated against a gas chromatography-mass spectrometry (GC-MS) method and has been applied to the monitoring of EO exposure in a group of sterilization workers.

Environmental Monitoring↗
PubMed1988

Human organ culture techniques for the detection and evaluation of genotoxic agents.

In order to obtain information on the genotoxic metabolism of carcinogens in human skin in vivo, model in-vitro systems have been developed to mimic in-vivo metabolism qualitatively. Direct labelling (3H and 14C) and 32P-postlabelling analyses of benzo[alpha]pyrene (BP)-DNA adducts in human skin explants, CD1 mouse explants and CD1 mouse skin in vivo have thus allowed comparisons of the genotoxic metabolism of BP in mouse and human skin.

Animals↗