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Biomedical subjects

A M Denman

Publications and source records attributed to A M Denman.

At least 55 records · Page 3Linked to original sources
PubMed1986

Sister-chromatid exchange frequencies in lymphocytes of controls and patients with connective tissue diseases.

It has been considered by some workers that sister-chromatid exchange (SCE) frequencies are elevated in patients with scleroderma and systemic lupus erythematosus (SLE). However, these observations were based on limited numbers of patients. Other have postulated the presence of a defect in DNA repair in cells from patients with various connective tissue diseases, including scleroderma and SLE. We report our findings from a large survey of SCE frequencies in patients with connective tissue diseases. Their diagnoses are scleroderma, SLE, rheumatoid arthritis, juvenile chronic arthritis, Behcet's syndrome and polyarteritis nodosa. These patients had never received cytotoxic drugs. Healthy individuals, hospital patients with diagnoses other than connective tissue disease and relatives of patients with scleroderma have been used as controls. The results have been analysed by generalized linear modelling, and we have shown that patients with SLE and Behcet's syndrome and controls with viral infections have elevated SCE frequencies, both before and after adjustments have been made for the effect on SCEs of an individual's age, smoking habits, sex and race. The SCEs of patients with scleroderma and their relatives were normal. SCE frequencies increased with age by 4% per decade and the SCE frequencies of smokers were approximately 12% higher than those of nonsmokers of similar age. The sex of an individual did not significantly affect SCEs but individuals from the Middle East were found to have lower counts than those originating from other parts of the world.

Adolescent↗
PubMed1986

Thioguanine-resistant mutations induced by cytotoxic drugs in lymphocytes of patients with connective tissue diseases.

Cells with mutations at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus may be detected in vitro by their resistance to the toxic effects of thioguanine. We have assessed HPRT mutants in peripheral blood lymphocytes of patients with connective tissue diseases who have been treated for long periods with cytotoxic drugs. The results from patients treated with cyclophosphamide were abnormal suggesting the presence of drug-induced mutations. The results from patients treated with chlorambucil or azathioprine did not differ from controls--either these drugs have not induced mutations or, more likely, the technique is not sufficiently sensitive to detect them. These possibilities are discussed. Specific mutations induced by cytotoxic drugs in patients with connective tissue diseases have not been previously recorded.

Azathioprine↗
PubMed1986

Intensive immunosuppression in intractable rheumatoid arthritis.

Twelve patients with intractable rheumatoid arthritis were treated with antilymphocyte globulin (ALG), prednisolone and a cytotoxic agent, usually azathioprine, and were followed for 1 year. There was a significant (p less than 0.05) improvement in the mean score for early-morning stiffness, grip strength and the severity of nodules and vasculitis at 6 weeks and 3 months when compared to the initial visit. However, in most patients, this benefit was not sustained despite continued cytotoxic and steroid therapy. A rise in the haemoglobin and fall in ESR was maintained throughout the study period.

Antilymphocyte Serum↗
PubMed1986

2',5'-oligoadenylate synthetase induction in lymphocytes of patients with connective tissue diseases.

Spontaneous production of the interferon induced enzyme 2',5'-oligoadenylate synthetase (2',5'-A synthetase) was significantly greater in blood lymphocytes of patients with systemic lupus erythematosus (SLE), Behçet's syndrome, and rheumatoid arthritis than in control lymphocytes. Alpha interferon (IFN-alpha) induced comparable production of enzyme in normal, rheumatoid, and Behçet's lymphocytes, and reduced, but still appreciable amounts in SLE lymphocytes. Phytohaemagglutinin (PHA) did not induce enzyme. Thus spontaneous production of 2',5'-A synthetase is encountered in several connective tissue diseases and seems likely to be induced by in-vivo exposure to interferons.

2',5'-Oligoadenylate Synthetase↗
PubMed1986

Sister chromatid exchange frequencies in patients with scleroderma and their relatives.

Sister chromatid exchange (SCE) analysis is a sensitive measure of chromosome damage induced by many agents which damage DNA. These agents have been reported to be present in the serum of patients with scleroderma. Chromosome aberrations are thought to be more common in cells of these patients and their relatives than in cells of controls. We have observed that the SCE frequencies in blood lymphocytes of patients with scleroderma and their relatives do not differ from those of controls.

Adolescent↗
PubMed1986

Cyclophosphamide induces more chromosome damage than chlorambucil in patients with connective tissue diseases.

The potential for damaging chromosomes of the powerful and widely-used immunosuppressive agent cyclophosphamide has been tested by measuring sister chromatid exchanges in blood lymphocytes of patients with connective tissue diseases. This agent induces more chromosome damage than chlorambucil emphasising the need for sensitive means of predicting patients at particular risk of drug-induced malignant disease.

Chlorambucil↗
PubMed1985

Radiosensitivity of peripheral blood lymphocytes in autoimmune disease.

The proliferation of peripheral blood lymphocytes, cultured with Con A, can be inhibited by ionizing radiation. Lymphocytes from patients with conditions associated with autoimmunity, such as rheumatoid arthritis, systemic lupus erythematosus and polymyositis, are more radiosensitive than those from healthy volunteers or patients with conditions not associated with autoimmunity. The nuclear material isolated from the lymphocytes of patients with autoimmune diseases is, on average, lighter in density than the nuclear material from most healthy controls. This difference in density is not related to increased sensitivity to ionizing radiation but the degree of post-irradiation change in density (lightening) is proportional to the initial density, i.e. more dense nuclear material always shows a greater upward shift after radiation. The recovery of preirradiation density of nuclear material, 1 h after radiation exposure, taken as an indication of DNA repair, correlates with the radiosensitivity of lymphocyte proliferation (Con A response); failure to return to pre-irradiation density being associated with increased sensitivity of proliferative response. These results require extension but, taken with previously reported studies of the effects of DNA methylating agents, support the idea that DNA damage and its defective repair could be important in the aetio-pathogenesis of autoimmune disease.

Adult↗
PubMed1985

Chlorambucil induced chromosome damage in juvenile chronic arthritis.

Sister chromatid exchanges, a sensitive measure of chromosome damage, were counted in peripheral blood lymphocytes from 23 patients with juvenile chronic arthritis receiving long term, low dose chlorambucil treatment. Thirty five patients with juvenile chronic arthritis who had not been treated with cytotoxic drugs served as controls. All of the treated patients have cells with abnormal sister chromatid exchange frequencies. Damage is related to the daily dose and may, in part, be determined by the duration of treatment. Sister chromatid exchanges from nine patients who had received chlorambucil at some time in the past remained high for at least five months after stopping the drug. Long term follow up will determine whether sister chromatid exchange analysis can help predict those most at risk of drug induced malignancies.

Adolescent↗
PubMed1985

Immunoregulatory effects of alpha-interferon. Effects on in-vitro antibody synthesis by lymphocytes from patients with rheumatoid arthritis.

The immunosuppressive effects of alpha-interferon (IFN) on the in-vitro synthesis of specific anti-influenza virus antibody by lymphocytes from 20 healthy donors were compared with those from 12 patients with rheumatoid arthritis. No differences were observed between the two groups. IFN suppressed the induction of in-vitro antibody synthesis by lymphocytes from rheumatoid donors but did not affect antibody synthesis once this had been initiated. Furthermore, the IFN-mediated suppression of antibody synthesised by rheumatoid lymphocytes could also be reversed by B cell helper supernatant. These findings make it unlikely that alpha-IFN affects established B cell responses characteristic of the rheumatic diseases.

Antibody Formation↗
PubMed1985

Immunoregulatory effects of interferon-alpha. I. Interferon-alpha inhibits in vitro antibody synthesis by normal human lymphocytes.

The effects of human interferon-alpha (IFN-alpha) on in vitro synthesis of specific anti-influenza virus antibody were measured in cultures of peripheral blood lymphocytes from normal donors. IFN-alpha suppressed antibody synthesis in a time and dose related manner. This suppression was also produced by monoclonal antibody purified IFN-alpha and was blocked by anti-IFN-alpha antibody. However antibody induced by a combination of antigen and 'B cell helper supernatant' was not suppressed indicating that IFN-alpha inhibits the initial events in antibody synthesis but does not affect cells committed to antibody production.

Adult↗
PubMed1985

The rheumatoid synovial membrane participates in systemic anti-viral immune responses.

Sixteen patients with rheumatoid arthritis were systemically immunized with influenza virus vaccine and in vitro anti-influenza antibody responses by blood lymphocytes and lymphocytes isolated from synovectomy specimens were measured after in vitro challenge with this influenza antigen. Synovial lymphocytes from eight of these patients produced anti-viral antibody, thereby indicating that infiltrating lymphocytes participate in a systemic anti-viral immune response.

Adult↗
PubMed1984

Chlorambucil-induced chromosome damage to human lymphocytes is dose-dependent and cumulative.

Sister chromatid exchanges (SCEs), a sensitive measure of chromosome damage, were counted in peripheral-blood lymphocytes from 10 patients with Behcet's syndrome receiving chlorambucil. All patients had abnormal counts. Damage was related to both daily dose and duration of therapy and was occurring at a greater rate than its repair. The patient who had been treated the longest and had received the highest total dose also had the highest SCE count. He died from acute leukaemia. SCE analysis may provide a method for detecting patients at risk from oncogenic effects of cytotoxic drugs.

Adult↗
PubMed1984

Malignancies induced by chlorambucil.

There is a high incidence of acute myeloid leukaemia in patients who have been treated with chlorambucil. This appears at least in part to be directly due to the drug itself and cannot be attributed to the disease processes for which the drug is given. Patients with connective tissue diseases may be more sensitive to this leukaemogenic effect of chlorambucil than patients with other non-malignant conditions.

Adolescent↗
PubMed1984

Infection and interferon production in systemic juvenile chronic arthritis: a prospective study.

Twenty-four episodes of disease exacerbation in 19 children suffering from systemic juvenile chronic arthritis were studied. Sixteen of these were preceded by an infection (chi 2 = 20.14, p less than 0.001), mostly of the upper respiratory tract. In the 10 cases seen during an infection causative agents were identified in 5 (herpes simplex, rhinovirus, and on 3 occasions streptococcus). The total number of infections was not increased when compared with infection rates predicted by several reported studies. In the absence of clinical infection, specific antibody titres to a panel of microbial antigens were similar to those of a control group but with a trend toward higher titres in patients with hypergammaglobulinaemia. Interferon (IFN) responses were not defective, though sequential in-vitro IFN production from peripheral blood mononuclear cells (PBM) fluctuated considerably in the same patients, occasionally being absent with no obvious clinical correlate. IFN-alpha was induced by stimulation with Newcastle disease virus (NDV), and the mean responses of the patients were significantly greater than those of controls. IFN-gamma production on phytohaemagglutinin (PHA) stimulation was similar in patients and control groups. IFN was not detected in any of the sera from patients or controls.

Adolescent↗