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Biomedical subjects

D L Scott

Publications and source records attributed to D L Scott.

At least 217 records · Page 12Linked to original sources

Joint damage in rheumatoid arthritis: radiological assessments and the effects of anti-rheumatic drugs.

Joint damage is a major problem in the long-term course of rheumatoid arthritis. It is usually assessed radiologically. In this review the methods of measuring the radiological changes are outlined, and the effects of anti-rheumatic drugs on radiological progression summarised. Two methods of scoring radiographs have become standard techniques; these are the Sharp index and the Larsen index. They both concentrate on cartilage loss and erosive damage in the hands and wrists. Investigations of the effects of drugs upon the radiological progression of rheumatoid arthritis include: indirect studies evaluating the inter-relationships between clinical, laboratory and radiological variables; placebo-controlled studies of slow-acting drugs and similarly controlled studies without a placebo group; open studies evaluating the long-term effects of treatment of slow-acting drugs. Only slow-acting drugs such as gold have been persistently considered to have a possible effect on reducing radiological progression. Unfortunately the therapeutic studies use a wide range of different radiological assessment techniques, and the incomparability is therefore difficult. None of the studies give a good indication that there is a marked reduction in joint damage by slow-acting drugs. On balance studies do suggest minor effects on the process of progression. Instead of debating how strong the evidence of such minor effect really is, it is concluded that rheumatologists should look towards novel therapeutic approaches to induce a major reduction in the rate of damage.

Anti-Inflammatory Agents↗

Joint sepsis as a complication of sero-negative arthritis.

Septic arthritis is a recognised complication of rheumatoid arthritis but has not been well described in sero-negative spondarthritis. We report 3 patients with sero-negative inflammatory joint disease who developed joint sepsis early in the course of the disease. In none was there a recognisable source of infection. Two cases were complicated by osteomyelitis and in one the sepsis has been recurrent over thirty years.

Aged↗

Phosphoinositides in mitogenesis: neomycin inhibits thrombin-stimulated phosphoinositide turnover and initiation of cell proliferation.

Thrombin stimulates 32Pi incorporation into phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bis-phosphate (PIP2), and phosphatidylinositol (PI), and initiates DNA synthesis in hamster (NIL) fibroblasts at a half-maximal concentration of 125 ng/ml. Neomycin, which binds PIP2 and PIP, inhibits both thrombin-stimulated initiation of cell proliferation and 32P pI incorporation into at concentrations above 2 mM without affecting thrombin binding, thymidine uptake, or cellular protein synthesis. At lower concentrations, neomycin inhibits thrombin-stimulated release of inositol 1,4,5-trisphosphate (IP3), by selectively binding PIP2, but does not inhibit 32P incorporation into PI or initiation of DNA synthesis. Phosphoinositide recycling and diacylglycerol release therefore appear necessary for initiation of cell proliferation by thrombin. IP3-stimulated Ca++ mobilization may not be required for thrombin mitogenesis, however, since neomycin can block IP3 release without inhibiting initiation.

Animals↗

Amyloid 'degrading factor activity': a non-specific calcium-mediated effect.

The clarification of turbid AA-amyloid-fibril-containing agarose gels by serum has been ascribed to degradation of the fibrils and designated as 'amyloid degrading factor'. In the present study, sera of 32 healthy blood donors and 32 patients with rheumatoid arthritis all showed 'degrading factor activity' against both AA amyloid fibrils and a non-fibrillar reticulin preparation of normal liver in an agarose plate assay. AL amyloid fibrils were not affected. The 'degrading activity' of serum was correlated with the serum albumin concentration, and the effect was also given by purified human and bovine serum albumin, although it was not seen with other serum proteins. The 'degrading activity' of serum against AA amyloid and reticulin was significantly correlated: both substrates showed low levels in a chronic disease such as rheumatoid arthritis, and reticulin inhibited 'degrading activity' against AA amyloid and vice versa. These results suggest the same process involves both substrates. 'Degrading activity' was also given by EDTA and a specific calcium chelator, and was inhibited by calcium and magnesium. An enzyme inhibitor showed only partial inhibition of the 'degrading activity' of serum, purified albumin, and EDTA. These results suggest that serum 'degrading factor activity' is a non-specific calcium-mediated effect against AA amyloid and reticulin preparations dispersed in agarose. It may represent a change in the degree of aggregation of these proteins rather than being an effect of proteolytic degradation. This confirms the conclusions of other workers that amyloid 'degrading factor activity' is an phenomenon in vitro of doubtful pathophysiological significance.

Amyloid↗

Methods of X-ray assessment in rheumatoid arthritis: a re-evaluation.

We have re-examined the value of hand radiographs in the assessment of joint damage in rheumatoid arthritis in a series of related studies. Our objectives were: to assess the reproducibility of scoring hand radiographs and the relationships between different types of changes; to analyse the correlations between radiographic changes and hand function; and to assess the inter-relation between hand changes and overall joint damage. We confirmed the reproducibility of radiological assessments and showed that two observers can reproducibly score hand radiographs separately for joint space loss and erosions; both of these correlated with the Larsen score derived from standard radiographs. However, hand radiographic changes were not closely related to hand function; nor did they predict damage to large joints. Finally, examination of changes in 13 joint groups showed that there is a weak relationship between damage and disease duration, and the rate of damage is greatest in the initial years. We conclude that the status of hand radiography as a measure of overall outcome in rheumatoid arthritis remains an open question.

Arthritis, Rheumatoid↗

Serum amyloid A protein during the treatment of rheumatoid arthritis with second-line drugs.

Serum amyloid A protein (SAA), serum C-reactive protein (CRP) and the ESR were measured in 19 patients with rheumatoid arthritis before treatment and during therapy with gold, penicillamine or sulphasalazine for a mean period of 14.8 months (range 6-23 months). All three measurements decreased significantly; however, only 7% of SAA values fell to within the normal range (18-44 mg/l), compared to 38% measurements of serum CRP (less than 10 mg/l) and 32% of the ESR (less than 25 mm/h). In 8 (42%) of the 19 patients, SAA remained high (greater than 400 mg/l) for 3 months or more whilst serum CRP was depressed below 20 mg/l; this discrepancy was not related to particular drugs. We conclude that during treatment of rheumatoid arthritis with gold, penicillamine or sulphasalazine, SAA concentrations can be high when serum CRP and ESR are suppressed. SAA may be a more sensitive index of disease activity.

Adult↗

Anti-rheumatic drugs and joint damage in rheumatoid arthritis.

The effect of second-line anti-rheumatic drugs such as gold on the course and progression of joint damage has been the subject of considerable controversy. We have evaluated the effects of second-line anti-rheumatic drugs in three studies of 46-84 patients with rheumatoid arthritis given a second-line drug continuously for 12 months. Using two different methods of radiographic assessment we found that there was significant progression over the 12-month period when the mean changes in the groups of patients were examined, and there was similar indications of continuing disease activity shown by mean values of acute phase proteins and ESR which were above the normal range at both six and 12 months. But there were subgroups of patients who showed a reduction in ESR and joint tenderness with a related slowing of the rate of radiographic progression in the second six months of treatment. There was no direct relationship between changes in the ESR and radiographic progression in individual patients. Although anti-rheumatic drugs are not ideal and therapy does not cause remission in many patients, some patients respond well. Rheumatoid arthritis may represent a heterogeneous collection of patients who respond individually to different drugs.

Anti-Inflammatory Agents↗

Fibronectin in chronic inflammation: studies using the rat air pouch model of chronic allergic inflammation.

Fibronectin is a large glycoprotein of plasma, tissue fluids and tissues. The rat air pouch model of mesenchymal inflammation was used to examine changes in fibronectin levels during inflammation within a mesenchymal cavity. Rat plasma fibronectin levels showed a rapid and significant rise in relation to the induction of an air pouch. In contrast pouch fluid fibronectin levels were initially low and gradually increased with chronicity. They were unrelated to plasma levels. Pouch fluid fibronectin showed no relationship to cell content of the fluid, its volume, nor the weight of granulation tissue. Two-dimensional immuno-electrophoresis showed pouch fluid fibronectin was partially complexed but plasma fibronectin was not. These results show plasma and tissue fluid fibronectin have different patterns of response to inflammation. In rats plasma fibronectin is an acute-phase reactant, although this is not the case in humans.

Air↗

The significance of IgM antinuclear antinuclear antibody in rheumatoid arthritis and other connective tissue diseases.

An investigation of the incidence of IgG and IgM antinuclear antibodies (ANA) in patients with connective tissue diseases showed that IgM ANA predominated in rheumatoid arthritis, whilst in systemic lupus erythematosus IgG antibodies were more common. Patients with other connective tissue diseases less frequently had antinuclear antibodies and there was little difference in the incidence of IgG and IgM antibodies. Cross reacting rheumatoid factors contributed to the IgM antinuclear activity of rheumatoid sera. IgM ANA was not related to disease activity in patients with rheumatoid arthritis. Immunoglobulin class differences of ANA in rheumatoid arthritis and systemic lupus erythematosus may reflect the differing pathological processes of these two diseases and may be of value in their differential diagnosis.

Adult↗

Divergent effects of forskolin on 3',5' cyclic adenosine monophosphate production and parathyroid hormone secretion.

Forskolin, a diterpene which directly stimulates adenylate cyclase, markedly stimulated cAMP production in intact rat parathyroid glands and dispersed cells from hyperplastic and adenomatous human parathyroid tissues. Stimulation of cAMP production in human parathyroid adenomas occurred as early as 2 min and continued for at least 2 h; furthermore, a dose-response relationship was observed, with a maximal 80-fold cAMP response occurring at 100 microM forskolin. When PTH secretion by rat or human parathyroid tissues was studied at low (0.5 mM) and high (2.5 mM) extracellular Ca2+ in either the presence or absence of forskolin, no significant stimulation by forskolin was observed at 15 min, 1 h, and 2 h. When 10 human parathyroid specimens were studied with varying concentrations of forskolin at 1 mM Ca2+, 6 failed to show stimulation of PTH secretion and 4 showed modest but detectable increases in PTH that did not appear dose-related. We conclude that (1) at low and high Ca2+ levels, marked stimulation of cAMP production by forskolin can occur without a corresponding increase in PTH secretion; (2) inhibition of PTH secretion by high extracellular Ca2+ levels continues unchanged despite stimulation of cAMP production by forskolin; and (3) at intermediate Ca2+ levels (1.0 mM), PTH secretion is affected either minimally or not at all by forskolin in human hyperparathyroid tissue preparations. The marked stimulation of parathyroid adenylate cyclase by forskolin without concomitant increases in PTH secretion in the majority of tissues suggests that the level of cAMP production is not a primary or sufficient determinant of hormone secretion.

Adenoma↗

Septic arthritis and thigh abscess after dilatation and curettage.

A previously fit 57-year old housewife who developed a septic arthritis of the right knee and abscess in the right thigh after dilatation and curettage is described. This is the first report of joint and soft tissue complications occurring together after this procedure. Despite antibiotic therapy which eradicated the joint infection, the abscess required surgical intervention. This illustrates the potential morbidity of septic complications after a minor surgical procedure.

Abscess↗

Cause of death in rheumatoid arthritis.

A series of 489 consecutive patients with definite or classical rheumatoid arthritis was followed for a mean of 11.2 years. Cohort-analysis of the series showed a three-fold increase in mortality overall in comparison with age- and sex-specific rates in the general population. In patients first seen in hospital early in the course of the disease (less than 5 years from onset), the excess of deaths from circulatory, respiratory and musculoskeletal disorders was highly significant. Malignant disease and digestive system disorders accounted for a small excess of borderline significance. Patients who were referred later (greater than 5 years from onset) experienced, in addition, a highly significant excess of deaths from infections and disorders of the digestive and genito-urinary system but not from malignant neoplasms.

Adult↗

Reticulin and its related structural connective tissue proteins in the rheumatoid synovium.

Argyrophilic reticulin fibres are an important component of the rheumatoid synovium and their distribution and that of their individual protein constituents have been studied in synovial biopsies from a series of 29 cases of rheumatoid arthritis. In acutely inflamed synovia they are predominantly found underneath the hyperplastic synovial lining layer and related to the inflammatory cell infiltrate. With developing chronicity the reticulin network is gradually replaced by mature collagen. This histological pattern is mirrored by changes in the individual components of reticulin fibres-fibronectin, the non-collagenous reticulin component of Pras and Glynn (NCRC) and collagen type III.

Adult↗

Progression of radiological changes in rheumatoid arthritis.

A prospective study over one year of patients who had active rheumatoid arthritis discovered 64 who had received treatment for an adequate time with second-line drugs. In these patients there was evidence of continuing joint destruction as shown by radiological progression. During the year there were highly significant correlations between improvements in clinical and laboratory measurements, but neither group of tests was related to the degree of radiological change. However, in the second 6 months of treatment there was evidence that radiological progression was reduced. In a second prospective study of 88 patients with rheumatoid arthritis given prolonged, intensive therapy with second-line drugs and followed up for 10 years two-thirds showed radiological progression. However, the number of joints damaged per year fell significantly during the study period. There was a divergence between deterioration in radiological features and improvements in the ESR and functional capacity, though patients with a persistently low ESR had less radiological progression. These studies provide evidence that treatment may be associated with a reduced rate of radiological progression but suggest that changes in radiological progression and clinical and laboratory measurements may result from different mechanisms.

Adult↗