Another "Blues" alert.
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Biomedical subjects
Publications and source records attributed to W F Tucker.
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Thirty-two drugs, including some in use for a variety of clinical disorders, were examined for their ability to inhibit calmodulin activity in vitro. From these, 10 drugs were selected for their inhibition of calmodulin activity and examined for their ability to inhibit proliferation of rapidly dividing human keratinocytes. A significant correlation between antiproliferative activity and calmodulin antagonist potency was found. Of these drugs there were several, including miconazole, dequalinium chloride, bromocriptine and tamoxifen, whose use is well established and well documented. The potential use of these drugs (and others identified in this way) as antipsoriatic agents is discussed.
28 patients with stable chronic psoriasis completed a trial in which they were randomly allocated to receive either 10 fish-oil capsules ('MaxEPA') or 10 placebo capsules (olive oil) daily. Patients were specifically instructed not to change their normal diet. After 8 weeks' treatment there was a significant lessening of itching, erythema, and scaling in the active treatment group, with a trend towards an overall decrease in body surface area affected. No change occurred in the placebo group.
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Epidermal calmodulin (CaM) has been reported to be elevated in psoriasis and to decrease following clearance of psoriasis with treatment. We set out to investigate whether any of the principle drugs used in the treatment of psoriasis had inherent CaM antagonist activity. Utilizing a CaM-activated phosphodiesterase we have demonstrated that even at very high concentrations, the systemic drugs etretinate, methotrexate, and 8-methoxypsoralen, and the topical agents hydrocortisone and crude coal tar showed minimal CaM inhibitory activity. Dithranol (anthralin), however, whether freshly prepared or oxidized, produced substantial inhibition of CaM activity and was demonstrated to be a potent competitive antagonist of CaM, suggesting another possible therapeutic mode of action of dithranol in psoriasis.
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Epidermal calmodulin levels were measured in lesional and non-lesional skin in 20 psoriatics before and after treatment by a variety of established topical and systemic regimes. Pretreatment, 10 out of 20 patients showed elevated calmodulin levels in lesional epidermis. Clearance of psoriatic plaques was accompanied by a significant overall reduction (p less than 0.05) in epidermal calmodulin, irrespective of the treatment regime used. For the non-lesional epidermis, only 5 out of 17 patients initially showed elevated calmodulin levels and there was no significant reduction in those levels following treatment.
Normal human peripheral blood mononuclear cells (PBMC) and leukaemic cell lines (three of human and one of gibbon origin) were found to contain similar levels of calmodulin (CaM) when expressed relative to the total cell protein. Two of the cell lines examined further were found to contain much higher amounts of CaM per cell (up to 5-fold) than PBMC but this was readily explained by their much greater cell size. Variations in CaM levels were noted during culture of both PBMC and leukaemic cells which were apparently independent of the percentage of cells undergoing active division in these cultures. These results do not support the contention that transformed cells contain a higher proportion of CaM than normal cells.
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The calmodulin content of epidermis was determined by assay of biologically active and radioimmunoassayable calmodulin in epidermal biopsy samples of 16 normal control subjects and 36 patients with psoriasis. Calmodulin levels in the involved epidermis of patients with psoriasis were significantly greater than in epidermis of control subjects, with both methods of calmodulin measurement. Levels of calmodulin in the uninvolved epidermis were also elevated but to a lesser degree, achieving statistical significance only when measured by radioimmunoassay. However, the degree of correlation between the two measurements of calmodulin was poor for the patient samples, suggesting that each may measure a different form of calmodulin. The specificity of the elevated calmodulin in psoriatic epidermis was investigated by measuring calmodulin in another unrelated tissue. Calmodulin activity in circulating peripheral blood lymphocytes of seven patients with psoriasis was similar to that found in the lymphocytes of ten normal volunteers. The relationship between calmodulin and the hyperproliferative state of the psoriatic epidermis was investigated. No significant increase in calmodulin activity was found after mitogen stimulation of lymphocyte proliferation or after Sellotape-stripping of the epidermis by a protocol which has been shown to cause hyperproliferation of the epidermis.
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The aim of this study was to determine whether levels of biologically active calmodulin are elevated in both lesional and uninvolved epidermis in psoriasis. Epidermal shave biopsies were obtained from normal controls and from both psoriatic plaques and nonlesional psoriatic skin. Following determination of the protein content, the calmodulin activity of the homogenized samples was then measured using a calmodulin-sensitive phosphodiesterase enzyme bioassay. In normal skin, calmodulin activity was 1.29 +/- 0.35 micrograms calmodulin mg-1 epidermal protein (mean +/- SEM, n = 12 volunteers) compared to 7.88 +/- 1.59 micrograms calmodulin mg-1 epidermal protein for plaque (n = 16 patients) and 10.19 +/- 2.35 micrograms calmodulin mg-1 epidermal protein for the uninvolved skin of 12 of these patients. The levels of biologically active calmodulin were therefore elevated in both plaque and uninvolved epidermis of patients with psoriasis compared to epidermis from normal volunteers. These results suggest that an abnormality in the regulation of calmodulin activity may be involved in the pathogenesis of psoriasis.
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Two elderly female patients are described with generalized histiocytosis X (Letterer-Siwe disease). In each case, a definitive diagnosis was not established until ultrastructural and immunoperoxidase investigations had been performed. The histopathological findings in skin biopsies from each patient were similar. Light microscopy demonstrated a bandlike epidermotrophic cellular infiltrate which included large atypical cells (histiocytosis X cells). Electron microscopy showed that these cells contained Birbeck granules. Monoclonal antibody studies demonstrated the presence of T6, T4 and HLA-DR surface antigens. Lysozyme and alpha-I-antitrypsin were absent from the cells. The associated cellular infiltrate included T4 and T8 positive lymphocytes. It is possible that more cases of generalized histiocytosis X in adults will be identified with the increasing use of specialized histopathological techniques and that the disease is more common than currently believed.
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