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Biomedical subjects

I D Mitchell

Publications and source records attributed to I D Mitchell.

At least 19 recordsLinked to original sources
PubMed2001

A prospective study to evaluate the role of complexed prostate specific antigen and free/total prostate specific antigen ratio for the diagnosis of prostate cancer.

PURPOSE: Patients are increasingly undergoing prostatic biopsy to identify localized prostate cancer. The decision to perform a biopsy is often made on the basis of total prostate specific antigen (PSA). However, this value lacks adequate specificity for this task. We evaluate the role that a number of these tests, including the Bayer complexed PSA (Bayer Diagnostics, Tarrytown, New York) and free/total PSA ratio, may have in our clinical practice. MATERIALS AND METHODS: A total of 160 consecutive patients attending a prostate assessment clinic were enrolled during an 18-month period in our study. All patients had a previously recorded total PSA (range 2.6 to 20.0 ng./ml.). Before transrectal ultrasound biopsy of the prostate gland, a blood sample was taken with patient consent. The findings on ultrasound were then recorded, including prostate volume. Serum samples were immediately sent for subsequent storage and analysis. RESULTS: Of the patients enrolled 109 had benign histology while 51 had prostatic carcinoma. The 2 patient groups were well matched for age. In our series patients with prostate cancer had significantly smaller prostates and higher mean total PSA. At a high sensitivity, such as 95%, it appeared that Bayer complexed PSA performed better than the other tests and ratios, with an estimated specificity of 24.8% compared with 17.4% for Bayer total PSA and 15.6% for Abbott free/total PSA (Abbott Laboratories, Abbott Park, Illinois). Receiver operator characteristics curves were drawn, and when the areas under them were calculated, we demonstrated that the area under the curve for Bayer complexed PSA (0.706) was between the values for total PSA (0.671) and free/total PSA ratio (0.731). However, the only statistically significant improvement in performance was in Bayer complexed PSA over the total PSA assays. CONCLUSIONS: Our study revealed that the overall diagnostic performance of Bayer complexed PSA appears to be better than the other PSA tests and ratios studied. The use of Bayer complexed PSA may lead to a reduction in the number of men undergoing unnecessary prostatic biopsy.

Aged↗
PubMed1999

Sustained-release alfuzosin and trial without catheter after acute urinary retention: a prospective, placebo-controlled.

OBJECTIVE: To establish whether the administration of sustained-release (SR) alfuzosin improves the outcome of a trial without catheter (TWOC) after an episode of acute urinary retention. PATIENTS AND METHODS: In a prospective, randomized, placebo-controlled trial, 81 patients with acute urinary retention related to benign prostatic obstruction received either SR alfuzosin (n=40), an alpha1-selective blocker, given at a dose of 5 mg twice daily, or placebo (n=41) for 48 h. The catheter was removed after 24 h of treatment. The main outcome measurement was success or failure of the TWOC. At the end of this double-blind phase the patients were followed up on an open basis. RESULTS: After removal of the catheter, 42% of patients voided successfully, 22 of 40 (55%) with SR alfuzosin and 12 of 41 (29%) with placebo (P=0.03). The mean age of patients voiding successfully, regardless of treatment group, was 68. 4 years, whilst the mean age of those who were not successful was 72. 9 years (P=0.015). In an intention-to-treat analysis of outcome adjusted for this age difference, the benefit in favour of those receiving SR alfuzosin was not significant, but at P=0.052 there was a strong suggestion of a positive treatment effect. The observed benefit remained significant in a per-protocol analysis adjusted for age. Taken together, these results indicate that treatment with SR alfuzosin was effective and that the observed benefit was not simply the effect of age difference between the groups. Of the 34 patients who voided successfully 23 (68%) required no further intervention within a mean follow-up of 7 months. CONCLUSIONS: Treatment with SR alfuzosin is effective in improving the success rate of a TWOC after an episode of acute urinary retention, although older patients are less likely to void successfully. By reducing the numbers of men sent home with urinary catheters, such treatment may result in a reduction in the associated perioperative morbidity in those undergoing prostatic surgery, and is clearly desirable for the patients' comfort and convenience.

Adrenergic alpha-Antagonists↗
PubMed1996

Comparative in-vivo genotoxicity of antiviral nucleoside analogues; penciclovir, acyclovir, ganciclovir and the xanthine analogue, caffeine, in the mouse bone marrow micronucleus assay.

Three purine nucleoside analogues, penciclovir (PCV), acyclovir (ACV) and ganciclovir (GCV), were assessed for in-vivo genotoxicity in the mouse bone marrow micronucleus assay, together with the xanthine (purine) analogue, caffeine (CAF). All these compounds exhibit anti-viral properties and the first three are marketed anti-viral drugs. All have been shown to be genotoxic in separate in-vitro and in-vivo studies. Because of their widespread use, we considered it important to directly compare their relative in-vivo genotoxic potencies as an aid to assessing their relative genotoxic risk to humans. Accordingly, two-dose (0 and 24 h)/single sample mouse micronucleus assays were performed on all four compounds. PCV and ACV appeared to give essentially arithmetic increases in induction of micronucleated polychromatic erythrocytes (MNPCE) with arithmetic increases in dose with apparent thresholds at approx. 1078 mumols/kg per day and 316 mumols/kg per day, respectively. The dose-response curve for GCV appeared more exponential, without a threshold, but with a no-effect dose of around 150 mumols/kg per day. With CAF, systemic toxicity allowed the assessment of only very weak effects, such that our estimate of a no-effect dose of 388 mumols/kg per day is subject to large errors. Taking into account magnitude of response, slope of dose-response curve and no-effect doses, the order of potency was GCV > ACV > (CAF?) > PCV. The relevance of these findings in terms of risk is uncertain.

Acyclovir↗
PubMed1996

A proposal for a two-dose/single-sample in vivo/in vitro rat hepatocyte unscheduled DNA synthesis assay.

We have developed a two dose/single-sample protocol for the in vivo/in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay. In order to enhance the effectiveness of grain detection by image analysis we found minor technical modifications to be beneficial. These included the use of 3% acetic acid in ethanol (or 4% aqueous paraformaldehyde) for hepatocyte fixation and 0.5% aqueous eosin for staining. Also, there was no correlation between cell viability (measured using the trypan blue method) and UDS response and, therefore, we do not reject animals from data analysis unless hepatocyte viability falls below 50%. Furthermore, we suggest that cell attachment is a more reliable indicator of toxicity than of cell viability. Therefore, our range-finding test has been modified to incorporate an extra animal per group so that hepatocyte cultures can be evaluated. Comparisons of a two-dose/single-sample protocol with the currently accepted single-dose/multiple-sample protocol demonstrated that the former was an acceptable alternative, in that responses with standard positive controls are very similar with both protocols. Furthermore, the two-dose protocol has clear advantages in that it uses fewer animals, resources and time and has better statistical discriminatory power. As a move away from the use of arbitrary values for determining the performance and outcome of assays, we use criteria based on confidence limits placed on historical data ranges. Where necessary, statistical analyses of concurrent data is performed using rank transformation followed by parametric analysis of the ranks; this combines the generality of a non-parametric methodology with the power and versatility of parametric analyses.

Animals↗
PubMed1995

Is polyploidy an important genotoxic lesion?

The importance of polyploidy as a genotoxic lesion is uncertain and there have been few publications and no reviews which have included data on spontaneous or induced polyploidy in routine genotoxicity screening. We have attempted to clarify some of the issues by reviewing the published literature and by reference to our historical data base for metaphase analysis of cultured human lymphocytes. In our studies on pharmaceutical compounds polyploidy was the lesion most often found, being induced by approximately 40% of the compounds tested. The mean spontaneous frequency was between 0.1 and 0.3%, and values for polyploidy induction were 5-fold to > 100-fold the spontaneous value. Spontaneous polyploids tended to be near-exact multiples of the haploid chromosome number whereas induced 'polyploids' were, in fact, very heteroploid with a wide range of chromosome numbers. Polyploidy induction often occurred at non-toxic concentrations, usually there were well defined no-effect (threshold) levels and it was unrelated to other genetic effects. Such observations would be expected for inducers of polyploidy because the target molecules are not DNA and for these non-DNA targets there is usually a degree of redundancy. Therefore, inducers of polyploidy are only likely to be a hazard for humans if they are positive at or below therapeutic concentrations. We conclude that polyploidy/near-polyploidy (shown as 'polyploidy' throughout) should be scored as accessory data which becomes important only when induction occurs at therapeutic levels.

Chromosome Aberrations↗
PubMed1991

Statistical issues arising from mouse micronucleus assay experiments of Ashby and co-workers.

Data from a series of mouse micronucleus assays have been reanalysed to illustrate various statistical issues raised by Ashby and co-workers during the development of the assay. Most of the statistical points discussed in these earlier papers can be explained by the stochastic nature of the data. Reanalysis shows that the type of data collected in mammalian micronucleus assays is amenable to analysis by standard biometric methods. It is concluded that statistical analysis has an important role in the exploration and interpretation of data from the micronucleus assay.

Analysis of Variance↗
PubMed1991

Noscapine-induced polyploidy in vitro.

The conditions under which noscapine causes high levels of polyploidy in vitro in human lymphocytes were investigated to try to determine its mode of action and to assess whether it was likely to be a genotoxic hazard when used as an antitussive agent. Irrespective of duration of treatment or type of medium, there seemed to be a threshold for polyploidy induction between 15.0 and 30.0 micrograms/ml and a maximum between 100.0 and 150.0 micrograms/ml noscapine. High levels (10.0-20.0%) of noscapine-induced polyploidy were never found with 4 h treatments or with RPMI 1640 medium plus 15% (v/v) foetal calf serum; the use of Iscove's modified Dulbecco's medium and 24 h treatments were needed. The reasons for these observations seemed to be the faster cell division and greater sensitivity of cells grown in Iscove's medium. There was conflicting evidence about the mechanism of polyploidy induction by noscapine; either spindle damage or cell fusion remain as possibilities. The need for prolonged exposure and the precise nutritional requirements suggest that a short exposure, albeit at high concentration, in the upper gastro-intestinal tract is unlikely to be a hazard for humans. Furthermore, evidence of a threshold at approximately 20 micrograms/ml plus the virtual elimination of noscapine-induced polyploidy by microsomal metabolism (S9 mix) together with published metabolic data imply that the low-level systemic exposure after absorption may well not be hazardous. We conclude that the use of noscapine in cough mixtures does not pose a significant potential hazard for humans.

Bromodeoxyuridine↗
PubMed1990

The use of historical data for identifying biologically unimportant but statistically significant results in genotoxicity assays.

The definition of a negative result is a problem in genetic toxicology. Here we suggest that a result may be considered biologically unimportant (negative) if it falls within the limits of variation usually found in the negative controls of the particular test. To determine 'usual' variation, we have set 95% confidence limits on three indices of variation, calculated from historical values for duplicate negative control data from several genotoxicity tests. These tests showed four characteristic types of response and the appropriate index of variability was determined for each. Where there was little test-to-test variation in true mean (micronucleus test and metaphase analysis), confidence limits set on the overall distribution of negative controls were the best index of variability. In other assays (Ames, yeast and mouse lymphoma), there was considerable test-to-test variation so that differences between, or ratios of, the members of control duplicates were the preferred measure of variability. This approach can define what is biologically unimportant in terms of the test system. However, no inference can be drawn as to potential importance. Thus the main use is the removal of the positive 'label' from statistically significant results which fall within the usual range of spontaneous variation for the assay under consideration.

Animals↗
PubMed1989

Optimization of metabolic activation for four mutagens in a bacterial, fungal and two mammalian cell mutagenesis assays.

The optimum concentrations of Aroclor-induced rat liver S9 microsomal fraction for the mutagenic activity of the four standard mutagens 2-aminofluorene (2-AF), acriflavine (ACR), benzo[a]pyrene (BP) and cyclophosphamide (CP) were determined in four mutation assays. The four assays were the Ames test using Salmonella typhimurium strain TA100, cycloheximide resistance in the yeast Saccharomyces cerevisiae, the mouse lymphoma TK assay and the human peripheral lymphocyte cytogenetic assay. BP was the only mutagen to be most active at comparable S9 concentrations, of approximately 1%, for all four assays. The optimum S9 concentrations for each of the remaining three mutagens varied substantially between the four assays. ACR was a potent direct-acting mutagen in both mammalian cell assays. The mouse lymphoma TK assay results showed similar optimal values of 1.5% S9 or below for each of the four test agents. The assay with the largest variation of optimal S9 values for the four mutagens was the Ames test in strain TA100, although it also had the widest peaks of activity over the range of S9 concentrations tested. It is likely that the diversity of findings is due to a variety of metabolites affecting the different genetic endpoints that are measured in these assays. Thus from these results it is not possible for bacterial optimization data to be related to other routine in vitro systems. The use of more than one concentration of S9 would contribute useful information.

Animals↗
PubMed1987

The interaction of statistical significance, biology of dose-response and test design in the assessment of genotoxicity data.

The most useful function of statistical significance in genetic toxicology is to separate weakly positive from negative data. To achieve this objective, the experimental system, design and analysis must be considered as a whole and not as separate entities. Assumptions underlying statistical methods should be checked for applicability to the biology of the test. The number and arrangement of samples and dose levels must be organized to suit the selected statistical method. The number of observations in the test and in each sample will depend on the smallest increase of biological importance which should be detected as significant (at a selected value for alpha error) and the maximum acceptable chance of failing to detect this increase as significant (beta error). Generally, a few dose levels and a high degree of replication are desirable with a repeat test if practical. In the analyses of data it is particularly important to adapt the statistics if there are multiple comparisons. Even after correct determination of significance, interpretation can be difficult because of possible experimental artefacts and chance errors plus the impossibility of proving a negative result.

Data Interpretation, Statistical↗
PubMed1985

An assessment of the importance of error-prone repair and point mutations to forward mutation to L-azetidine-2-carboxylic acid resistance in Escherichia coli.

By comparison of E. coli WP2 with CM891 (uvrA- pKM101) we found that pKM101 plasmid and uvrA- mutation considerably enhanced both spontaneous and chemically-induced reversion at the trp locus. However, little or no increase was observed for forward mutation at the A2C locus. Furthermore, mutation frequency decline was considerably greater for trp reversion than for mutation to A2Cr. Thus neither error-prone repair nor point mutation seemed likely to be the major mechanism for forward mutation at the A2C locus. Results for spontaneous mutation of recA-, polA- and gyrA- strains showed that polA- and gyrA- gave good increases in forward mutation but not in reversion. It was inferred that deletion, transposition and/or larger chromosomal effects rather than point mutation were mainly responsible for most forward mutation.

Azetidinecarboxylic Acid↗
PubMed1984

The effect of pretreatment of Escherichia coli CM891 with ethylenediaminetetraacetate on sensitivity to a variety of standard mutagens.

The effect of EDTA pretreatment on the sensitivity of E. coli CM891 to 10 standard mutagens was assayed for cytotoxicity, trp- reversion and mutation to A2Cr . There was no obvious correlation of effect with molecular weight but good correlation with water solubility. EDTA pretreatment did not improve the sensitivity of E. coli to agents which were very soluble in water viz. MMS, CP, ACR, DR and GM. However, with very water-insoluble agents, EDTA pretreatment usually gave a significant, 2-5-fold increase in mutation, viz. with 2NF , BP and CAP (trp locus) but not with 9AA . 2AP , which was moderately soluble in distilled water, only showed a small significant increase at the A2C locus after EDTA pretreatment. Increases in mutation were not always paralleled by increases in cytotoxicity.

Cell Survival↗
PubMed1981

Somatic eye mutation in Drosophila melanogaster as a short-term test for mutagens and carcinogens.

Six mutagenic and/or carcinogenic agents were tested for their ability to cause somatic eye mutation (red sectors on a yellow eye) in Drosophila melanogaster. Results were analysed by the chi-squared method and by the Kolmogorov-Smirnov two-sample (non-parametric) test. Methyl methanesulphonate, cyclophosphamide, acriflavine and procarbazine were active, whereas acetamide and tetracycline failed to elicit a significant response. Thus, relative to other mutagenicity assays, this somatic system seemed to possess no special ability to correctly identify carcinogens because both acriflavine and acetamide were misidentified on a carcinogenicity basis. However, it could be a suitable alternative to the recessive lethal test for mutation, because of its technical simplicity and rapidity, subject to an increase in the size of the data base.

Acetamides↗
PubMed1980

Forward mutation in Escherichia coli and gene conversion in Saccharomyces cerevisiae compared quantitatively with reversion in Salmonella typhimurium.

Forward mutation to c'azetidine carboxylic acid resistance in Escherichia coli WP2 and gene conversion at the tryptophan locus in Saccharomyces cerevisiae D4 were compared with reversion in strains TA98, TA100 and TA1537 of S. typhimurium for sensitivity and range of agents detected. Eight mutagens of known and differing modes of action were used in assays in liquid culture. It was concluded that neither non-specific system could replace all the Salmonella strains in a programme of mutagenicity assays in liquid culture; however, E. coli caca(r) could adequately replace strains TA100 and TA1537, provided that TA98 was retained to detect certain types of frame-shift mutation. Also gene conversion would prove useful in the assay of antibacterial agents.

Biological Assay↗