Biomedical subjects
Publications and source records attributed to R Cox.
A patient with epispadias had a ureterosigmoidostomy. This was converted to an ileal conduit 3.5 years later. 24 years after this, he developed an adenocarcinoma at the site of the ureteric stump. Abnormal mucin staining was found in the resected colon. This stain is not predictive of malignant change, and therefore regular colonoscopy is required for these patients.
A total of 45 patients with the painful heel syndrome without evidence of an associated inflammatory arthritis, seven of whom had pain in both heels, were studied using technetium-99 isotope bone scans and lateral and 45 degrees medial oblique radiographs of both feet. Of the 52 painful heels 31 (59.6%) showed increased uptake of tracer at the calcaneum. Patients with scans showing increased uptake tended to have more severe heel pain and responded more frequently to a local hydrocortisone injection. On plain x-ray, 39 of 52 painful heels (75%) and 24 of the 38 opposite nonpainful heels (63%) showed plantar spurs, compared with five of 63 (7.9%) heels in 59 age- and sex-matched controls. No evidence of stress fractures was seen.
We have utilized DNA transfer and recombinant DNA techniques to probe DNA double-strand break repair in the human ionizing radiation-sensitive genetic syndrome ataxia-telangiectasia (A-T). Using restriction enzyme-generated double-strand breaks in the coding sequence of a selectable gene we have detected a significantly greater frequency of mis-repair of such breaks in a permanent A-T cell line compared with cell lines of normal radiosensitivity. This mis-repair in A-T can plausibly explain many of the clinical features of the disease but was insufficiently detailed to address the broad problem of DNA repair mechanisms relevant to ionizing radiation-induced damage. To extend these observations of DNA double-strand break mis-repair we have now applied this type of repair assay to novel, de novo induced mammalian X-ray-sensitive cell lines and to appropriate Escherichia coli mutants. In both cellular systems we have now found some equivalence to the A-T repair defect. In particular, studies on one E. coli mutant have provided evidence suggesting an involvement of a topoisomerase activity in DNA double-strand break mis-repair, which may be relevant to the biochemical defect in A-T.
Measurements of erythropoietin (Ep) levels in patients with the anaemia of chronic disorders due to malignant disease have given variable results. This variation may be due to the wide range of malignancies studied and the assay method (whole animal) used. In this study Ep levels were measured, using the foetal mouse liver assay, in 39 patients with lung cancer and 19 controls. Twelve patients had reduced haemoglobin levels (Hb less than 11.5 g/dl for males and 11 g/dl for females) and the features of the anaemia of chronic disorders. Their mean Ep level was 0.21 iu/ml. This was significantly lower than for the normal controls, whose mean value was 0.31 iu/ml (P less than 0.02). This data supports the concept that lack of an appropriate Ep response to anaemia is one factor in the genesis of anaemia in malignancy.
Serum ferritin levels were measured before treatment, using an immunoradiometric method, in 39 patients with small cell lung cancer. In 11 patients serial estimations were also made. The median serum ferritin level for male patients was 660 micrograms/l (range 13-1329) and for females 306 (range 134-5300), the normal range being 32-501. This increase is significant (P less than 0.001). Serum ferritin levels were not related to metastatic, haematological or iron status. Serial ferritin levels did not reflect the clinical course of the disease. Patients with a pre-treatment serum ferritin of less than 600 micrograms/l had a significant prolongation of median survival compared to those with an initial serum ferritin of greater than 600 micrograms/l (P less than 0.02). Serum ferritin levels are not of value in staging small cell lung cancer nor in monitoring its progress. However, the initial serum ferritin is of prognostic significance.
Sodium selenite is a good inducer of hemoglobin production in Friend erythroleukemic cells (FELC). At a concentration of 20 microM 70-80% of the cells produce hemoglobin and the DNA is hypomethylated. What is the mechanism for sodium selenite alteration of the DNA methylation pattern? Experiments with methionine adenosyltransferase (the enzyme that synthesizes adenosylmethionine) showed little effect of selenite on the activity of this enzyme in vitro or in vivo. Therefore, FELC are able to synthesize S-adenosylmethionine in the presence of sodium selenite. When sodium selenite was added to an in vitro assay for DNA methylase, the enzyme was non-competitively inhibited by 80% at 20 microM selenite with a Ki of 6 microM. DNA methylase isolated from control and selenite-treated FELC was purified through a DEAE-Sephacel column and no difference in activity was found. In the presence of selenite, DNA methylase is very sensitive to selenite inhibition, but removal of the selenite restores activity. However, DNA synthesized by FELC grown in the presence of selenite (no DNA methylase activity) was found to be hypomethylated. These results suggest that DNA methylase activity is inhibited in FELC grown in the presence of sodium selenite.
A review of 125 ureteroscopies in 111 patients is reported. Eight per cent suffered major complications of perforation or stricture formation and 3% required ureteric reimplantation. Clinical follow-up and imaging studies performed more than a year after ureteroscopy produced no evidence that late complications arise.
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The results of inserting 55 Kaufman prostheses into 45 patients with post-prostatectomy incontinence have been reviewed. Twenty-seven patients (60%) were continent and 3 were greatly improved. Ten patients were dry after their first prosthesis, 11 required 'topping up' of the device, and 5 were after the first prosthesis had been replaced. Results improved in the later part of the series. The Kaufman prosthesis is a valuable device in the treatment of post-prostatectomy incontinence.
DNA in mammalian cells is enzymatically methylated at the 5-position of cytosine via S-adenosylmethionine and DNA methyltransferase. Several chemical carcinogens have been shown to inhibit this reaction, altering DNA methylation. We have been studying the mechanism by which carcinogens alter the methylation of DNA in order to better understand the cellular regulation of DNA methylase activity and to understand the role, if any, of DNA methylation in the carcinogenic process. We have utilized an in vitro assay for DNA methylase isolated from purified rat-liver nuclei. Ethionine, a liver carcinogen, given to rats 17 hr after partial hepatectomy inhibited the incorporation of [methyl-3H]-methionine into 5-methylcytosine residues of DNA. DNA isolated from these ethionine-treated rats was able to accept methyl groups from S-adenosylmethionine 8 times more than control DNA. It was further demonstrated that S-adenosylethionine competitively inhibited the DNA methylase resulting in hypomethylated DNA. N-Methyl-N-nitro-N-nitrosoguanidine reacted with the DNA methylase at the sulfhydryl sites inactivating the enzyme. Methylnitrosourea did not react directly with the methylase enzyme, but when reacted with DNA, the DNA methylase activity was inhibited by the carcinogen alkylated DNA. Sodium selenite also inhibited the enzyme non-competitively with a Ki of 6.7 microM. 5-Azacytidine prevented the 2 to 3 fold increase in DNA methylase seen 2 days following partial hepatectomy. All of these data with various carcinogens, altering DNA methylation by different mechanisms, support the hypothesis that DNA methylation plays a role in the initiation of carcinogenesis.
The psychosocial problems that develop in long-term survivors of Hodgkin's disease were examined in a cross-sectional survey of 403 patients. The average age at treatment was 27 years and at interview was 36 years. The median time since treatment was 9 years. Sixty percent of the patients were treated for stage I or II disease and 40% for stage III or IV. Eighty-two percent of the patients had never relapsed, and 98% were free of disease at the time of interview. The study investigated the type and frequency of problems by means of a self-administered questionnaire using standard survey items to assess disruption in three areas of life: sense of well-being, family relationships, and employment. Results indicate that energy had not returned to patients' satisfaction in 37% of the cases. This was influenced by age, time since therapy, stage of disease, and type of treatment. Patients with self-reported energy loss were more likely to be depressed. Moderately high divorce rates (32%), problems with infertility (18%), and less interest in sexual activity (20%) were reported. Employment patterns favored men returning to work, and number of hours worked was highly correlated with less depression, younger age, and return of energy. Difficulties at work were reported by 42% of the cases. The interaction of treatment, biologic, psychosocial, and functional variables is described.
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The ability of three normal and one radiosensitive Ataxia-telangiectasia (A-T) human cell lines to rejoin restriction endonuclease-induced double-stranded (ds) DNA scissions was investigated using gene-transfer techniques with recombinant plasmid as target DNA. The results of cellular experiments using gene transfer frequencies as a measure of DNA rejoining strongly suggested that the A-T cell line had a greatly elevated frequency of misrepair of double-stranded DNA scissions. Southern blot analysis of DNA from plasmid-transformed cells confirmed this and further suggested that the misrepair in the A-T cell line took the form of large deletions and/or rearrangements at or around the scission. We postulate a disequilibrium in A-T between rejoining and exonuclease digestion of DNA termini as a possible basis for the misrepair and discuss this mechanism in relation to the major clinical features of the disease.
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DNA methylase from rat liver was partially purified through a DEAE sephacel column and characterized in an in vitro assay with respect to time, protein, DNA and S-adenosylmethionine curves. The Km for S-adenosylmethionine was 2.5 microM. Sodium selenium inhibited the methylation of DNA in a dose dependent fashion when added to the assay. It was also demonstrated that selenite non-competitively inhibits rat-liver DNA methylase with a Ki of 6.7 microM. Dithiothreitol had no effect on selenite inhibition and increasing amounts of DNA did not alter the inhibition. However, increasing amounts of protein overcame the inhibition, suggesting that selenite is reacting with the DNA methylase protein. DNA methylase isolated from selenite treated animals had only 43% of the activity as enzyme from control rats. It appears that selenite is a good inhibitor of DNA methylase.
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