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Biomedical subjects

E A Martin

Publications and source records attributed to E A Martin.

At least 19 recordsLinked to original sources
PubMed1995

Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: promotion by phenobarbital.

Tamoxifen administered in the diet (420 ppm) to Wistar rats (TOX:P) for only 3 months caused cumulative hepatic DNA damage as assessed by 32P-postlabeling, consistent with the proposal that tamoxifen is a genotoxic carcinogen in this species. Promotion of tumor development with phenobarbital after discontinuation of dietary tamoxifen resulted in the formation of liver carcinomas after 9 months. At 12 and 20 months in this study, the majority of these rats had liver carcinomas. Rats treated with tamoxifen for 3 months but not promoted with phenobarbital also developed liver tumors over a longer period of time. These tumors were predominantly adenomas, with one carcinoma, and occurred at a lower incidence than the tumors produced by promotion with phenobarbital. Rats treated with phenobarbital alone did not develop tumors after 20 months. Tamoxifen-induced DNA adducts were relatively persistent, with only a 38% decrease 3 months after tamoxifen treatment had been discontinued. This demonstrates that, in a susceptible species (the rat), tamoxifen can cause initiation of liver cancer after only 3 months exposure. It is proposed that the persistence of such DNA adducts may account for the ability of phenobarbital to promote a high incidence of liver carcinoma, even after discontinuation of tamoxifen treatment. These data are relevant to the concern for women given prophylactic tamoxifen for long periods in that even if there is a relatively small amount of cumulative tamoxifen-induced liver DNA damage, liver tumors could be promoted by other agents, even after the cessation of tamoxifen treatment.

Animals↗
PubMed1995

Peroxidase activation of tamoxifen and toremifene resulting in DNA damage and covalently bound protein adducts.

When [14C]tamoxifen was incubated with horseradish peroxidase and H2O2, two major metabolites, separated and identified by HPLC, were N-desmethyltamoxifen and tamoxifen N-oxide. Toremifene incubated in a similar system yielded N-desmethyltoremifene and toremifene N-oxide. No 4-hydroxylated metabolites were detected with either drug. When calf thymus DNA was included in peroxidase incubation mixtures, DNA damage, as assessed by 32P-postlabelling, could also be detected. The extent of damage caused by tamoxifen and toremifene was similar. The major adducts formed following incubation of DNA with tamoxifen had similar Rf values to two of the 32P-postlabelled adducts seen following dosing of rats with tamoxifen. Peroxidase was able to activate both drugs to derivatives which covalently bound to bovine serum albumin. The pH optimum for covalent binding and N-demethylation was near to pH 6.0. Results from liquid chromatography-electrospray secondary ion mass spectrometry suggest that tamoxifen and toremifene are metabolized by peroxidase to putative reactive epoxide intermediates responsible for the genotoxic effects. It is proposed that peroxidase oxidizes tamoxifen to a carbon-centred free radical which reacts with oxygen to form peroxy radicals capable of inserting an oxygen atom into tamoxifen. Lactoperoxidase and prostaglandin synthase are also able to catalyse tamoxifen N-demethylation and binding to protein. These data show that peroxidase can activate both tamoxifen and toremifene to an intermediate(s) that can damage DNA and covalently react with protein. Since it is known that women treated with tamoxifen can develop endometrial tumours, it may be relevant to determine whether activation of tamoxifen by peroxidases may contribute to its carcinogenic action at extrahepatic sites.

Animals↗
PubMed1995

DNA damage as assessed by 32P-postlabelling in three rat strains exposed to dietary tamoxifen: the relationship between cell proliferation and liver tumour formation.

Tamoxifen was administered in the diet (420 p.p.m.) to female F344 (Fischer), Wistar (LAC-P) and LEW (Lewis) rats to determine for each strain the early morphological and biochemical changes associated with the subsequent development of liver cancer. Hepatic DNA damage, as determined by 32P-postlabelling, showed a cumulative increase with time from 500 adducts/10(8) nucleotides at 30 days to almost 3000 adducts/10(8) nucleotides after 180 days, with little difference between strains at this time point. A significant strain difference was found in the number of adducts present in the Fischer rats at 90 days, compared to the Wistar and Lewis strains. There was a marked strain differences in the time to development of liver tumours. After 6 months treatment, both Wistar and Lewis rats had tumours while none were seen in the Fischer animals. After 11 months, all of the Wistar and Lewis rats had developed liver carcinoma, while the Fischer rats developed liver carcinoma by 20 months. Depression in cell proliferation, relative to age-matched controls, was seen in the livers of Fischer rats after six months of exposure to tamoxifen, in contrast to an increase in the Wistar and Lewis rats. This observation is consistent with the promotion of foci to tumours and the subsequent progression of tumours to carcinomas in the latter two strains. These data may assist in establishing the possible risk factors, such as extent of DNA damage and increased liver cell proliferation, to women with long-term prophylactic exposure to tamoxifen.

Animals↗
PubMed1995

32P-postlabelled DNA adducts in liver obtained from women treated with tamoxifen.

32P-Postlabelling of DNA extracted from the livers obtained from seven women receiving tamoxifen (20 mg either once or twice daily) was compared with liver DNA from seven individuals not receiving this drug. In all but one of the treated women, tamoxifen and its N-desmethyltamoxifen metabolite could be detected in liver extracts by high performance liquid chromatography; none was detected in control samples. The total level of 32P-postlabelled DNA adducts extracted from the tamoxifen treated women ranged between 18-80 adducts/10(8) nucleotides. The pattern of 32P-postlabelled adducts was not the same as those seen in rats dosed with this drug. There was no significant difference in the level of DNA damage between the tamoxifen treated and control groups. Although only a small number of subjects has so far been examined it appears that women are less susceptible to liver DNA damage caused by tamoxifen than rats.

Adult↗
PubMed1992

Alfred Parsons on suspected perforated gastric ulcer. 1892.

Alfred Parsons (1864-1952) was noted for his vigour of mind and body and Spartan habits and his dramatic teaching. In 1891 while a junior doctor he cared for three fatal cases of acute perforation of a chronic ulcer of the stomach. In May 1892 he made a passionate plea for early diagnosis and surgery in this condition. The first successful operation was performed in the same month by Ludwig Heusner in Germany.

General Surgery↗
PubMed1992

The repair of large DNA adducts in mammalian cells.

This paper describes experiments involving the measurement of DNA damage and repair after treatment with 4-nitroquinoline 1-oxide (4NQO) or aflatoxin B1 (AFB1) epoxide in a number of mammalian cell cultures primarily associated with defects in the excision repair of UV-induced DNA damage. The results with transformed derivatives of XP cells belonging to different complementation groups showed that the extent of repair of 4NQO adducts at the N2 or C8 of guanosine did not correlate to the extent of repair reported by others after UV-irradiation. An examination of 4NQO repair in rodent UV-sensitive cell lines from different ERCC groups indicated that again there was little correlation between the extent of 4NQO and UV repair. However, regardless of complementation group those mutants that were defective in the repair of pyrimidine dimers and 6,4-photoproducts did exhibit a reduced ability to repair the 4NQO N2 guanosine adduct, whereas those mutants defective in pyrimidine dimer repair alone were able to repair this lesion as normal. In all of these cell lines there was a normal capacity to repair the 4NQO C8 guanosine adduct. Less extensive experiments involving AFB1 epoxide showed an XPC-transformed cell line was able to repair 40% of lesions after 6 h, whereas only 20% of repair is seen after UV. The rodent mutant V-C4 which belongs to the same ionising radiation group as irs2, was partially defective in repairing AFB1-induced damage. These experiments highlight the fact that although there are many commonalities between the repair of UV damages and lesions classed as large DNA adducts differences clearly exist, the most striking example here being the repair of the C8 guanosine 4NQO adduct which rarely correlates with a defect in UV repair.

4-Nitroquinoline-1-oxide↗
PubMed1992

Sensitivity and single-strand DNA break repair in Chinese hamster mutants exposed to the carcinogen aflatoxin B1 epoxide and its dichloride model.

Aflatoxin B1 (AFB1) is a potent carcinogen and mutagen. It requires metabolic activation to be converted to the DNA-binding product aflatoxin B1 epoxide (AFB1-epoxide). A model of this epoxide is aflatoxin B1 dichloride (AFB1Cl2). Both react at the N7 position of guanine to form large adducts. The major adduct formed can either be rapidly removed to leave an apurinic site or can undergo ring opening of the imidazole ring to form a chemically stable adduct. A number of Chinese hamster DNA repair-deficient mutants have been screened for their sensitivity to AFB1-epoxide and AFB1Cl2. Some of the mutants screened belong to different UV complementation groups. Human genes involved in nucleotide excision-repair correct deficiencies found in these complementation groups. The mutants which were found to be most sensitive to AFB1 (V-C4 and V-H1) were further investigated. Alkaline elution was used to measure AFB1-induced DNA single-strand break repair in the mutants. V-H1 repaired completely in 24 h whereas V-C4 displayed only partial repair.

Aflatoxin B1↗
PubMed1992

Bilateral paramedian thalamic infarction: a distinct but poorly recognized stroke syndrome.

Six patients with bilateral paramedian thalamic infarction were seen in a general hospital over a 4 year period. This distinct stroke syndrome was recognized by the features of disturbed vigilance, often episodic, with vertical gaze disorder. Other signs included an amnesic syndrome, convergence difficulty, third nerve palsies, eyelid retraction, dysarthria, ataxia and involuntary limb movements. Diagnosis was confirmed by CT brain scan or magnetic resonance imaging. A variety of risk factors for stroke were present. All patients improved but two had significant residual disabilities.

Adult↗
PubMed1986

Peripheral blood T lymphocyte changes in multiple sclerosis: a marker of disease progression rather than of relapse?

A serial study of peripheral blood T lymphocytes in 27 patients with clinically definite multiple sclerosis and 11 healthy controls was carried out over a 12 month period. This showed that contrary to many previous reports, relapses were not consistently associated with reduced numbers of peripheral blood suppressor T lymphocytes or any other T cells. Persistently low T cells numbers, including both the helper and suppressor T cell subsets, were, however, associated with disease activity as measured by the development of increased disability during the course of the study. This was true both for the patients with relapsing/remitting disease and those with progressive disease. The importance of carrying out a serial study was emphasised by the consistent and significant differences that were detected between individuals in both the control and the patient groups. A serial study is the most reliable means by which clinical events can clearly be correlated with laboratory estimations. The association in this study between the development of increased disability and persistently low levels of peripheral blood T lymphocytes suggest that both may be related to the underlying disease process in multiple sclerosis.

Adult↗
PubMed1986

A clinical and laboratory study of benign multiple sclerosis.

In a hospital-based study of 400 patients with multiple sclerosis (MS), 42 per cent of patients who had had MS for 10 years or more had benign disease. Early age of onset and a long first remission were significantly associated with a good prognosis. There was a suggestion that initial presentation with paraesthesiae and possibly optic neuritis were associated with a benign prognosis, but the only significant finding was the association between limb weakness and a poor outcome (p less than 0.05). Fewer patients with benign disease had a progressive element to their disease than those in the more disabled group (p less than 0.001). The only laboratory test which was associated with a benign prognosis was the absence of CSF myelin basic protein in remission. Abnormalities of visual evoked response, CSF IgG and peripheral blood T lymphocytes appeared to have no value in assessing prognosis in the patients studied.

Adult↗
PubMed1986

An investigation regarding the use of a dynamic seat-pan display for training and as a device for communicating roll-axis motion information.

This paper describes a research program conducted to determine the feasibility of providing useful angular onset-motion information via a broad-area tactual seat-pan display. The experiment was designed to evaluate the utility of the display as a training device as well as its efficacy for imparting motion information. The results indicate that, with proper attention given the drive law, the tactual display can elicit both performance and control behavior indistinguishable from that observed in a whole-body motion environment. Unfortunately, the training transfer results were not as encouraging. These results indicated that the seat-pan display as used in this study was not adequate for training naive subjects to properly interpret and use the motion information available in a whole-body motion environment.

Aerospace Medicine↗
PubMed1985

CSF myelin basic protein in multiple sclerosis.

Cerebrospinal fluid (CSF) from 221 patients with multiple sclerosis (MS) and 85 patients with other neurological disorders (OND) was examined using a competitive radioimmunoassay for myelin basic protein (MBP) immunoreactivity. MBP was found in 46 of 55 MS patients (84%) examined within six weeks of relapse but in only 11 of 85 patients (13%) with OND. There was a significant correlation between the concentration of MBP in the CSF and relapse severity in patients seen within four weeks of the onset of symptoms (p less than 0.01). Of 44 patients in remission, MBP was detected in 12, and these patients had a significantly higher tendency to subsequent relapse (p less than 0.05). In 72 patients with progressive disease the presence of MBP in the CSF reflected the confidence of clinical diagnosis. The results of this study suggest that measurement of MBP in the CSF gives an objective method of monitoring disease activity in patient with MS.

Acute Disease↗
PubMed1985

Suppressor T cell changes in active multiple sclerosis: analysis with three different monoclonal antibodies.

This study demonstrates a significant reduction in the number of both total T cells and suppressor T cells identified by monoclonal antibodies in multiple sclerosis patients in acute relapse but not in those in remission. The reduction in the number of suppressor T cells was shown by all three monoclonal antibodies used but was most clearly demonstrated using Leu 2a rather than either OKT 8 or OKT 5. These findings suggest that the choice of monoclonal antibody used in a study of suppressor T cell numbers will influence the results and may help explain the lack of agreement in previous studies.

Antibodies, Monoclonal↗
PubMed1985

Suspected and clinically definite multiple sclerosis: the relationship between CSF immunoglobulins and clinical course.

CSF immunoglobulins were examined in 103 patients with clinically definite multiple sclerosis, 106 patients with either suspected or progressive possible multiple sclerosis and 72 patients with other neurological diseases. Raised CSF IgG index and oligoclonal banding were found in 71% and 75% of clinically definite multiple sclerosis patients respectively and both tests were abnormal in 11% of patients with other neurological diseases. The CSF IgG index and the presence of oligoclonal IgG did not relate to the severity or duration of established disease in these patients. In patients with suspected and progressive possible multiple sclerosis, both a raised IgG index and the presence of oligoclonal banding were found significantly more frequently than in the OND group. Abnormalities of these parameters were significantly correlated with the presence of an abnormal evoked response in these patients (chi 2 = 10.16 p less than 0.01). When 47 patients with suspected multiple sclerosis were studied prospectively the presence of oligoclonal banding at presentation was associated with development of further disease activity.

Brain Stem↗
PubMed1984

Clinical correlates of abnormal brain-stem auditory evoked responses in multiple sclerosis.

Brain-stem auditory evoked responses (BAERs) were examined in 178 patients with multiple sclerosis (MS) and compared to the frequency of abnormalities in visually evoked responses (VERs) and in CSF electrophoresis. In clinically definite MS, BAERs were abnormal in 61% and a significant relationship was noted between disability due to MS and the frequency and severity of BAER abnormalities. In suspected MS, BAERs showed evidence of a second lesion in 14% whereas VERs indicated a second lesion in 24%. Abnormal BAERs in patients with suspected MS with brain-stem signs were significantly associated with the presence of truncal and limb ataxia. In progressive possible MS, abnormal BAERs were found in 49% but indicated a second lesion in 35% of patients and were significantly related to the duration of illness. In progressive possible MS, abnormal VERs but not abnormal BAERs, were significantly associated with the presence of CSF oligoclonal IgG banding. Normal BAERs in association with clinical brain-stem abnormalities were found in 24% of patients with clinically definite MS, 50% with suspected MS and 33% with progressive possible MS.

Brain Stem↗