Biomedical subjects
Publications and source records attributed to M Doherty.
We describe a patient with eosinophilic fasciitis in whom there was a late onset of inflammatory polyarthritis. Response of the arthritis to sulfasalazine was demonstrated, both initially and after a flare of synovitis which followed dose reduction. Sulfasalazine may be of benefit in this rare condition.
3 experiments were carried out to examine children's understanding of the role of covariation evidence in hypothesis formation. Previous research suggested that it is not until 8 to 11 years of age that children begin to understand how a given pattern of covariation supports a particular hypothesis about which factor is causally responsible for an observed effect. Experiments 1 to 3 employed a different (fake evidence) technique than previous research and showed that by 6 years of age most children understand how evidence would lead a story character to form a different hypothesis than the subject's own. Experiment 3 showed that most 6- and young 7-year-olds understand how a character's future actions (e.g., choice of an object) and predictions of future outcomes depend on the hypothesis he or she holds.
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High-performance liquid chromatographic assay procedures have been developed for naproxen, ibuprofen and diclofenac in human plasma and synovial fluid samples. A single liquid-liquid extraction procedure was used to isolate each compound from acidified biological matrix prior to the quantitative analysis. A Spherisorb ODS column (12.5 cm x 4.6 mm I.D.) was used for all the chromatography. Naproxen was eluted with a mobile phase of methanol-Sörensen's buffer at pH 7 (37:63, v/v). Ibuprofen and diclofenac were eluted using mobile phases of methanol-water at pH 3.3 (65:35, v/v and 63:37, v/v, respectively). Diphenylacetic acid was used as the internal standard for the assay of naproxen and flurbiprofen was used in the analysis of ibuprofen and diclofenac. Inter- and intra-day coefficients of variation were less than 7%. The assays were used in clinical studies of the three drugs in osteo- and rheumatoid arthritis patients.
Therapy with high-dose carboplatin plus etoposide-based chemotherapy plus autologous bone marrow rescue (AUBMR) was administered to 29 patients with advanced germ cell tumors (GCT) refractory to cisplatin-based chemotherapy. Two groups of patients with refractory disease were treated. Sixteen patients had been identified as "poor risk" at diagnosis and had an inappropriately slow decline of serum tumor markers after two cycles of induction cisplatin-based therapy (Group A). In addition, 13 patients were treated who had never had a complete response (CR) or had relapses after ifosfamide-based salvage chemotherapy (Group B). Patients in Group A were treated with high-dose carboplatin etoposide, and patients in Group B received high-dose carboplatin, etoposide, and cyclophosphamide. Fifteen of 29 (52%) patients had a CR (9, Group A; 6, Group B). The patients in Group A had fewer hematologic toxic effects, and the median number of days from day 0 to a granulocyte count greater than 0.5/microliters was 16 and to a platelet count of more than 50/microliters was 15, compared with 22 days and 23 days in Group B, respectively. There were fewer episodes of culture-positive sepsis in Group A (12%) compared with Group B (26%), and the only treatment-related death occurred in Group B. Therapy with high-dose carboplatin plus etoposide-based chemotherapy plus AUBMR is effective for patients with GCT refractory to regimens of cisplatin with or without ifosfamide. Early use of high-dose chemotherapy reduces hematologic toxic effects and allows patients to start treatment in a more predictable fashion after cytoreduction, rather than when the disease is progressing rapidly.
OBJECTIVE: Recently, 2 classes of cytokine inhibitors have been defined at the molecular level. The largest group comprises the extracellular domains of cell surface cytokine receptors, and includes both tumor necrosis factor receptors (TNF-R). The present study was conducted to investigate the role of TNF inhibitors in arthritis. METHODS: We measured p55 and p75 soluble TNF-R (sTNF-R) in serum and synovial fluid (SF) samples from patients with rheumatic diseases and compared their levels with levels of soluble interleukin-2 receptors (sIL-2R). Sensitive enzyme-linked immunosorbent assays (ELISA), specific for p55 and p75 sTNF-R and for sIL-2R, were used. RESULTS: Serum levels of p75 sTNF-R were 3-4-fold higher than levels of p55 sTNF-R, and both were significantly elevated in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) compared with healthy controls. RA SF levels of sTNF-R were 4-5-fold higher than levels in serum, suggesting local production in the joint, and were significantly higher than levels in the SF of patients with seronegative arthropathy or OA. Furthermore, levels of p55 and p75 sTNF-R, but not sIL-2R or TNF alpha measured by ELISA, were increased in the SF of patients with clinically active RA. The soluble TNF-R in RA and OA SF were functional since they inhibited TNF activity in a cytotoxicity assay in proportion to the levels of inhibitor present. Evaluation of serially obtained serum samples suggested that sTNF-R may be a useful parameter for monitoring RA disease activity. CONCLUSION: Biologically active soluble TNF-R are up-regulated in patients with rheumatic disease and are produced locally in the joints. Measurement of serum levels of TNF-R may be useful for monitoring of disease, and determination of SF levels could be of diagnostic value.
Although many metabolic and endocrine diseases have been reported to predispose to calcium pyrophosphate dihydrate crystal deposition, the validity of many of these associations remains unclear. A critical review of the literature relating to these associations, with illustrative cases and data derived from the authors' own experience, is presented. It is concluded that there is good evidence to associate hypophosphatasia, hypomagnesemia, and hyperparathyroidism with chondrocalcinosis and acute attacks of "pseudogout." Meta-analysis also suggests a small but significant association between hypothyroidism and chondrocalcinosis. Hemochromatosis stands alone in clearly associating not only with chondrocalcinosis but also with structural change and chronic arthropathy. The biochemical mechanisms that may produce these various associations are discussed. Recommendations are made concerning appropriate screening for metabolic and endocrine disease in patients with chondrocalcinosis.
There is a strong feeling that despite the increasing awareness of their adverse effects, non-steroidal anti-inflammatory drugs (NSAIDs) are not always used appropriately. To examine this problem amongst elderly patients who may be at particular risk, 500 acute admissions to Health Care of the Elderly wards were studied prospectively. Sixty-five patients were currently receiving NSAIDs; 56 had medical conditions possibly caused by, or aggravated by NSAIDs. Indications for NSAIDs were often no longer apparent, and these drugs were successfully discontinued in 56; in 22 no alternative therapy was required. Importantly, following discharge the majority of patients remained off NSAIDs. These data support the need for continual review of NSAID requirements and regular monitoring for adverse effects, particularly in this high risk group.
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Symptomatic locomotor abnormalities are common in medical in-patients, form a significant part of a general practitioner's workload, and are the single most important factor influencing disability in later life. That any qualifying doctor should have basic competencies with respect to the locomotor system thus seems appropriate. A survey of medical schools undertaken jointly by the Arthritis and Rheumatism Council (ARC) and British Society for Rheumatology (BSR) in 1990, however, suggests that the locomotor system still has a relatively low priority in undergraduate medical training. In 1990 therefore, the Education Committees of ARC and BSR established a joint working party to define guidelines on an undergraduate curriculum for rheumatology. These guidelines were discussed and developed at a Workshop in Oxford, and circulated to the Deans and Chairmen of Curriculum Committees at all UK Medical Schools in October 1991. It is hoped these guidelines will encourage inclusion of basic rheumatological competencies within the 'core' curriculum for all medical undergraduates.
Tophaceous deposition of calcium pyrophosphate dihydrate (CPPD) crystals is considered unusual as is deposition within tendon sheaths. Associated tendon rupture is described but is rare. We report a lady with tophaceous CPPD deposition at the wrist, a previously unreported site. Contrary to previous cases, this occurred in the setting of symptomatic, polyarticular, pyrophosphate arthropathy. An additional point of interest was development of associated extensor tendon rupture with features favouring a non-inflammatory mechanism of tendon damage.
The frequencies of autoantibodies, including class specific rheumatoid factors, Gm allotypes, and levels of immunoglobulins were determined in 86 patients with nodal generalized osteoarthritis (NGOA), 79 patients with non-nodal large joint osteoarthritis (LJOA), and 90 non-osteoarthritic controls. NGOA patients had a higher frequency of IgG rheumatoid factor (P less than 0.0001) compared to LJOA and normal subjects. Both osteoarthritic groups had lower mean levels of IgA than normals (P less than 0.05), and NGOA patients had a higher frequency of subnormal IgA levels than normals. No differences in other rheumatoid factors nor in frequencies of Gm allotypes were seen. These data support characterization of NGOA as a distinct subset of osteoarthritis, and suggest involvement of immune processes in its pathogenesis.
1. The treatment of osteoarthritis is currently purely symptomatic. To enable rational therapy, careful clinical assessment is necessary to identify the origin of symptoms. Often, effective therapy can result from a biomechanical approach such as surgery, orthotics, physiotherapy and dieting. If drugs are required, there is little evidence that the current over-reliance on non-steroidal anti-inflammatory drugs (NSAIDs) is justified. Full dose regular paracetamol should be the first line of analgesic therapy. In the majority of patients, simple analgesics are probably as effective as NSAIDs. If NSAIDs are used it is necessary to review regularly their use and to be aware of potential toxicity. 2. Many alternative strategies of pain management such as topical preparations, intra-articular steroid injections, acupuncture, radiosynovectomy, transcutaneous nerve stimulation and anti-depressants, may be effective but their precise place in the armamentarium is not yet fully established. 3. The realisation that osteoarthritis is not a passive 'wear and tear' phenomenon but an active process that may be potentially modified, has led to interest in 'chondroprotective' agents, which may beneficially affect the osteoarthritic process. To date there are no convincing data available that such agents are, in fact, chondroprotective in humans.
A number of patterns of osteoarthritis of the hip are described, though studies are conflicting with respect to the frequency of such patterns and their associations. Two hundred and eleven patients (133 women, 78 men; mean age 66 years, range 29-86) referred to hospital with osteoarthritis of the hip were studied. Involvement was unilateral in 108 (51%) and bilateral in 89 (42%); 14 (7%) had undergone arthroplasty and were presenting with osteoarthritis hips). Sixty one per cent of hips had severe, 28% moderate, and 11% mild changes (Kellgren grade). Superior pole migration occurred in 82% (46% superolateral, 25% intermediate, 11% superomedial), medial/axial migration occurred in only 8%, and in 10% the pattern was indeterminate. In bilateral osteoarthritis of the hip the pattern was generally symmetrical. Superomedial and medial/axial patterns were proportionately more common in women, whereas superlateral osteoarthritis predominated in men. No association was found between multiple clinical nodes, radiographic polyarticular interphalangeal or first carpometacarpal osteoarthritis and any migration pattern. Any interphalangeal osteoarthritis was negatively associated with medial migration. Only 40% of hips could be categorised as hypertrophic or atrophic; chondrocalcinosis at any site was associated with atrophic osteoarthritis; no associations were seen with Forestier's disease. This large survey confirms the association between chondrocalcinosis and atrophic osteoarthritis of the hip. Importantly it suggests that gender, rather than associated osteoarthritis at other sites, is a major determinant of the pattern of osteoarthritis of the hip.
The locomotor system is complex and difficult to examine. A selective clinical process to detect important locomotor abnormalities and functional disability could prove valuable. A screen based on a tested 'minimal' history and examination system is described, together with a simple method of recording. The screen is fast and easy to perform. As well as providing a useful introduction to examination of the locomotor system, the screen includes objective observation of functional movements relevant to activities of daily living. Its inclusion in the undergraduate clerking repertoire could improve junior doctors' awareness and recognition of rheumatic disease and general disability. It could also provide a valuable screening test for use in general practice.
A system for assessing symptoms (pain, stiffness, gelling) and signs (local temperature, effusion, tenderness, synovial swelling, popliteal cyst, crepitus) of osteoarthritis of the knee has been developed. The system has been assessed for intra- and interobserver variation using normal and osteoarthritic knees. Intraobserver variability is low for all indices but interobserver variability is high for physical signs. It is suggested that the components within this system, when applied by a single observer, may provide a reasonable framework for clinical assessment of osteoarthritis of the knee.
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