Biomedical subjects
Publications and source records attributed to P Emery.
Mammary gigantism is a rare complication of D-penicillamine treatment. We report a further case with pathological and endocrine details together with a review of the seven cases previously reported and possible mechanisms.
The presence of anergy and its relationship to malnutrition was investigated in patients with rheumatoid arthritis (RA) and in controls. A generalised reduction in delayed cutaneous hypersensitivity to 7 recall antigens were found in 104 RA patients compared with 67 controls. No measured of the disease was capable of predicting cutaneous anergy, which was present in 36% of patients but none of the controls. A detailed dietary assessment in 30 RA patients and 30 controls revealed little evidence of clinically important malnutrition. It is therefore concluded that the cutaneous anergy of rheumatoid arthritis is not a consequence of nutritional factors.
Sulphoxidation of carbocysteine, a drug structurally similar to D-penicillamine, displays a skewed distribution within a population. In 66 patients with rheumatoid arthritis (RA) a significant association between impaired sulphoxidation and toxicity (p less than 0.001) was found; HLA-DR3, although associated with toxicity (p less than 0.05), appeared to be an independent risk factor of most importance in the group with extensive sulphoxidation. The relative risk of toxicity in a patient possessing either DR3 or impaired sulphoxidation was 25. The prevalence of poor sulphoxidizers within this group of RA patients was increased compared to that in a previous population study and requires further investigation. Our findings explain a number of the toxic phenomena associated with D-penicillamine administration in RA.
The depressed cell-mediated immunity in rheumatoid arthritis was investigated in vivo by cutaneous hypersensitivity responses to seven antigens including tuberculin PPD, and in vitro by lymphocyte transformation to the latter antigen. In vivo 40% of rheumatoid patients were anergic compared to 2% of controls (P less than 0.001) with an associated reduction in sum score (5.9 +/- 6.5 vs 15.3 +/- 8.7, P less than 0.001). In vitro lymphocyte proliferation to PPD was also significantly depressed (P less than 0.001) and could not be reversed by indomethacin. A significant correlation between the in vivo sum scored (induration in mm) and in vitro thymidine incorporation (d/min) (r = 0.59, P less than 0.001) was found. In an attempt to overcome the depressed in vitro response the addition of a crude supernatant from a mixed lymphocyte reaction was found to return the PPD stimulated lymphocyte proliferation to the normal range. This effect was mimicked by purified IL-2 but not purified IL-1. The implications of this finding are are discussed.
To define the appropriate regime for the transition from intravenous lignocaine to oral tocainide after uncomplicated acute myocardial infarction, 43 patients received lignocaine to steady state. Each patient then received a tocainide dosage schedule. Plasma concentration of lignocaine and tocainide was measured frequently until the third peak plasma tocainide level. Tocainide 400 mg 8 hourly starting 4 h before cessation of lignocaine and tocainide 400 mg 4 hourly starting at the end of the infusion produced therapeutic plasma tocainide concentration (3.5-9 mg/l) only after the second dose. Tocainide 600 mg 12 hourly starting 6 h before cessation of lignocaine and tocainide 600 mg 6 hourly starting at the end of the infusion quickly achieved therapeutic plasma tocainide concentration which declined to give subtherapeutic first dose troughs of 2.42 mg/l (+/- 0.28 SEM) and 2.79 mg/l (+/- 0.27 SEM) respectively. Consistently therapeutic plasma tocainide concentrations were achieved by both of these regimens after the second dose. The short plasma half-life of lignocaine which for these regimes was 3.71 h (+/- 0.25 SEM), resulted in subtherapeutic lignocaine concentrations before consistently therapeutic plasma tocainide concentrations had been achieved. On the basis of these results, the 600 mg 6 hourly tocainide dosage schedule was studied with cessation of lignocaine infusion either two or six h after the first tocainide dose. With the former regime only three of 5 patients had therapeutic lignocaine at the subtherapeutic tocainide trough.(ABSTRACT TRUNCATED AT 250 WORDS)
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BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX), which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostaglandins. Gastrointestinal injury is a common outcome. We compared the efficacy, safety, and tolerability of long-term therapy with celecoxib, a COX-1 sparing inhibitor of COX-2, with diclofenac, a non-specific COX inhibitor. METHODS: 655 patients with adult-onset rheumatoid arthritis of at least 6 months' duration were randomly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks. Anti-inflammatory and analgesic activity and tolerability were assessed at baseline, every 4 weeks, and at week 24. We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available. Analysis was by intention-to-treat. FINDINGS: 430 patients underwent endoscopy (celecoxib n=212, diclofenac n=218). The two drugs were similar in management of rheumatoid arthritis pain and inflammation. Gastroduodenal ulcers were detected endoscopically in 33 (15%) patients treated with diclofenac and in eight (4%) in the celecoxib group (p<0.001). The rate of withdrawal for any gastrointestinal-related adverse event, most commonly abdominal pain, diarrhoea, and dyspepsia, was nearly three times higher in the diclofenac-treated group than in the celecoxib group (16 vs 6%; p<0.001). INTERPRETATION: Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac, with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events, and tolerability was better.
OBJECTIVE: To determine whether HLA type is associated with career progress in rheumatology. DESIGN: Comparison of HLA type after HLA analysis of samples of venous blood. SETTING: Department of Rheumatology Research, University of Birmingham. SUBJECTS: All (37) staff in the department. RESULTS: All the senior academics and most staff with a PhD expressed HLA-DR4. The prevalence of expression in each of these groups was significantly greater than that found in the controls. None of the junior doctors or secretaries expressed DR4. CONCLUSION: The junior doctors in the department have poor career prospects as HLA-DR4 seems to be associated with academic achievement.
Inflammation is the body's response to tissue damage. The signs of inflammation are pain, swelling and edema. One of the major chemical mediators involved in the inflammatory response is the group of prostaglandins (PGs) synthesized by the enzyme cyclooxygenase (COX). There are two isoforms of COX, the constitutive enzyme COX-1, which is responsible for the production of PGs with general housekeeping functions such as maintenance of renal perfusion and a protective effect on the gastric mucosa against ulceration; and the inducible enzyme COX-2, which is responsible for the production of proinflammatory PGs. Non-steroidal antiinflammatory drugs (NSAIDs), by inhibiting the COX enzyme, are able to reduce the pain and swelling associated with inflammation. In theory, new molecules that preferentially inhibit the inducible enzyme alone would not affect the housekeeping function of COX-1 but would retain the antiinflammatory action. Currently, there are a number of molecules available which claim to have some selectivity for the COX-2 enzyme. These have been labeled COX-2 preferential drugs. Highly selective COX-2 enzyme inhibitors are being assessed in phase II and phase III clinical studies. What are the issues these drugs will create and will they be successful? The first question is whether they are truly COX-2-selective. The balance of evidence suggests that they are. There is less gastric ulceration by the preferential drugs and there is very little evidence of gastric damage with the COX-2-selective drugs. All these drugs seem to maintain renal perfusion better than other NSAIDs and platelet aggregation is not affected. The second question is whether these drugs are as effective as conventional NSAIDs. From the preliminary data available it appears that the inhibition of COX-2 is effective in reducing inflammation. There are some doubts from studies in animal models as to whether some inhibition of COX-1 is also required, but this has not yet been shown in humans. There are concerns regarding the cerebral function of COX-2 and the expression of COX-2 in the kidney and gut. Thirdly, will new benefits arise from the use of these drugs? It seems likely that selective COX-2 inhibition will have the same beneficial effects on Alzheimer's disease and colonic cancer as nonselective drugs. In fact, these may even become new indications. What are the likely hazards? There will probably be individual problems with particular drugs but these cannot be predicted. The crucial issue is that patients who benefit most from NSAIDs are those who will be most likely to have side effects from the nonselective COX-1 and COX-2 inhibitors. Therefore, once there is good evidence of their efficacy and safety they will become widely used drugs.
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Conventional radiology (CR) is a major tool for the diagnosis and assessment of early arthritis. However, CR does not image the primary pathology of rheumatoid arthritis (RA), i.e. the synovium, and is insensitive for radiological erosions. New techniques, particularly magnetic resonance imaging (MRI) and ultrasonography (US) have shown their potential to improve on the sensitivity of CR. This article reviews the current status of this approach in early disease.
Biologic blockade of tumour necrosis factor alpha is an exciting new development in the treatment of the spondyloarthropathies (SpA). Recent reports suggest that both infliximab and etanercept are potent suppressors of inflammation in SpA and this has been confirmed by studies showing suppression of inflammatory indices as well as complete regression or improvement in the inflammatory lesions as shown by magnetic resonance imaging (MRI). Whilst limited follow up data have been reported in the case of infliximab there are no data on how patients on etanercept fare after a years' treatment.
Advances in ultrasound (US) and magnetic resonance imaging (MRI) techniques have provided new methods for evaluating early rheumatoid arthritis (RA). Their diagnostic properties in terms of detecting primary pathology of RA (i.e., erosions, bone changes, synovitis, tenosynovitis, and effusion) are reviewed. High-resolution US plays a significant role in therapeutic and diagnostic procedures. MRI also assists in the understanding of RA pathogenesis and joint mechanics.
Therapeutic strategies for the treatment of rheumatoid arthritis (RA) have changed significantly in the last decade. The emphasis is now on early intervention with the aim of preventing disability and irreversible damage. Advocates of early intervention would suggest an alteration in the disease process, not just debulking of inflammatory disease. The data would at least support attenuation of the disease process with aggressive early therapy. Further research is required to elucidate the scientific mechanisms involved and their impact on the pathological progress of RA.