Biomedical subjects
M Doherty
Publications and source records attributed to M Doherty.
Plasminogen activators and their inhibitors in synovial fluids from normal, osteoarthritis, and rheumatoid arthritis knees.
OBJECTIVES: To establish baseline concentrations of plasminogen activators and their inhibitors in normal knee synovial fluids, and to compare them with well characterised osteoarthritis (OA) and rheumatoid arthritis (RA) knee fluids. METHODS: A total of 26 normal subjects, 71 patients with OA, and 17 patients with RA underwent knee aspiration. Patients with OA were subclassified according to presence of nodal generalised OA (NGOA) and synovial fluid calcium pyrophosphate crystals. Clinical assessment of inflammation (graded 0-6) was undertaken in OA and RA patients. Plasminogen activator (PA), plasminogen activator inhibitor (PAI), and urokinase-type PA receptor (uPAR) antigen concentrations were determined by enzyme linked immunosorbent assay. The species of PAs present were determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. RESULTS: Concentrations of all antigens (uPA, tissue-type PA (tPA), uPAR, and PAI-1), were significantly greater in RA than OA; those in OA were significantly greater than normal. The concentrations showed no direct association with clinically assessed inflammation of the knee. In normal fluids, no associations with age were observed. Antigen concentrations (uPA, tPA, and uPAR) in NGOA differed from those in other subclasses of OA, but the species of PA present did not appear to vary between disease groups. The predominant PA appeared to have identity with uPA. CONCLUSION: Because of the greater concentrations of these antigens in OA compared with normal fluids, OA cannot be used as a surrogate normal control in studies of the PA/PAI system. Alteration of the PA/PAI system was confirmed in RA and OA knee fluids, with greater changes evident in RA. The finding of different concentrations of PA antigens in NGOA compared with other OA fluids further supports a different pathogenic mechanism in this subset.
Association of two loci on chromosome 2q with nodal osteoarthritis.
OBJECTIVE: To search for genetic association between microsatellite marker loci and sibling pairs with nodal osteoarthritis (NOA). METHODS: Using the affected sibling pair method of analysis, genomic DNA from 66 sib pairs with NOA was analysed for association with highly polymorphic microsatellite marker loci. The microsatellite markers were amplified using polymerase chain reaction and typed on polyacrylamide gels. RESULTS: A significant association (p < 0.05) was identified between NOA and two loci on the short arm of chromosome 2 (2q 23-35). Candidate genes for osteoarthritis in this region include: fibronectin, a glycoprotein present in the extracellular matrix of normal cartilage; the alpha 2 chain of collagen type V, a major constituent of bone; and the interleukin-8 receptor, important in the regulation of neutrophil activation and chemotaxis. CONCLUSIONS: The chromosomal region 2q 23-35 requires further detailed study in NOA. Confirmation of these findings in large independent data sets and further analysis of candidate genes in this region will be important in unravelling the molecular basis for this common disease.
Association between synovial fluid levels of inorganic pyrophosphate and short term radiographic outcome of knee osteoarthritis.
OBJECTIVE: To test the hypothesis that high concentrations of extracellular inorganic pyrophosphate (PPi), which associate with increased cell synthesis and turnover in cartilage, may act as a marker for structural outcome in knee osteoarthritis (OA). METHOD: One hundred and thirty five consecutive patients referred to hospital with knee OA (59 men, 76 women; mean age 71 years, range 41-88) were followed prospectively for a median of 2.5 years (interquartile range 1.75-3.0). Synovial fluid (SF) aspirated at presentation (202 OA knees: 68 bilateral, 66 unilateral) was assessed for PPi content by radiometric assay. Knee radiographs at presentation and at final review were assessed for change in global (Kellgren) and individual features (narrowing, osteophyte, sclerosis, cyst, attrition) of OA. RESULTS: The median SF PPi level was 10.5 mumol (range 0.07-72.4). At baseline, high PPi was significantly associated with presence of calcium pyrophosphate crystals, chondrocalcinosis, and bone attrition. Radiographic change was observed in 164 knees. High PPi levels were negatively associated with change in Kellgren and Lawrence grade, further narrowing, and increase in osteophyte, but positively associated with development of attrition. In the 68 patients from whom bilateral data were obtained, there was correlation between right and left knees for PPi levels, all baseline radiographic scores, and changes in radiographic features. Multiple logistic regression analysis for PPi as a continuous variable (age, gender, and patient number included in model) showed a negative correlation with change in global Kellgren and Lawrence grade (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.95 to 0.99) and a positive correlation with attrition (OR 1.04, 95% CI 1.02 to 1.07). CONCLUSION: High SF levels of PPi are associated with favourable radiographic outcome in terms of progressive change in Kellgren grade. Such elevated PPi levels, however, may inhibit new bone formation and remodelling in knee OA.
Case records of Department of Medicine University of Mississippi Medical Center Diagnosis.
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Genetics of osteoarthritis (OA).
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New treatments in osteoarthritis (OA).
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ABC of rheumatology. Osteoarthritis.
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ABC of rheumatology. Fibromyalgia syndrome.
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Intra-articular hyaluronic acid compared to intra-articular triamcinolone hexacetonide in inflammatory knee osteoarthritis.
The aim of this study was to determine the comparative efficacy and safety of intra-articular (i/a) triamcinolone. hexacetonide (TH) and i/a hyaluronic acid (HA) in inflammatory knee osteoarthritis. A randomized double-blind comparative trail was carried out in a rheumatology outpatient department. There were 63 patients (24 male, 39 female, mean age 70.5 years) with bilateral symptomatic knee osteoarthritis with effusion. Each was given five HA injections at weekly intervals; or 20 mg TH followed by four placebo (saline) injections. Patients were examined weekly during the treatment period and then at monthly intervals for a further 6 months. Assessment included recording of: visual analog scores (VAS) for pain; duration of stiffness; range of movement; joint effusion; local heat; synovial thickening; joint-line and periarticular tenderness. The principal outcome measure was pain on a self-selected activity assessed by Vas. The two groups were comparable at entry and no significant differences between the groups developed at any time during the treatment period. However, there was a high drop-out rate and intention to treat analysis failed to demonstrate statistically significant differences between the groups. In patients remaining in the study, significantly less pain was experienced by the HA group during the 6 month follow-up period. Other parameters showed a similar trend in favor of experienced by the HA group during the 6 month follow-up period. Other parameters showed a similar trend in favor of HA. We could not, however, demonstrate significant differences between the placebo and active treatments. HA may therefore be a useful additional therapy for symptomatic knee osteoarthritis and may have a long duration of action.
Localisation of a gene for chondrocalcinosis to chromosome 5p.
Chondrocalcinosis is a common disorder which may associate with acute and chronic arthritis. A familial form, inherited as an autosomal dominant trait, has been mapped in a large family in which affected members also suffer recurrent fits in childhood. The gene which causes this disease shows linkage with several polymorphic markers on chromosome 5p with a maximum multipoint lod score of 4.6 between D5S810 and D5S416. Mapping a locus for chondrocalcinosis will allow the heterogeneity of the disorder to be assessed and may also be relevant to understanding the aetiology of osteoarthritis with which it commonly associates.
Arthropathy, leucopenia and recurrent infection associated with a TcR gamma delta population.
This report documents the presence of clonal gamma delta T-cell receptor (TcR) population in the blood of a patient who presented with an arthropathy of undetermined cause, leucopenia and splenomegaly. There was no evidence for lymphoid malignancy clinically or at post-mortem. The phenotype and genotype of the clonal T-cell population were not associated with the predominant TcR delta rearrangement found in peripheral blood gamma delta cells, but were similar to those found in gamma delta TcR cells infiltrating rheumatoid synovium. The data indicate the presence of a monoclonal population of gamma delta cells TcR cells which in the face of continued immunosuppression behaved benignly. The case may represent a cytomorphologically atypical example of the large granular lymphocytes, neutropenia and arthropathy syndrome/lymphoproliferative disease of granular lymphocytes and, although the patient's clinical features were not 'classical', rheumatoid arthritis (RA) may have been the underlying primary disorder.
Factors affecting radiographic progression of knee osteoarthritis.
OBJECTIVES: To evaluate the prognostic significance of patient characteristics and radiographic features at the knee for outcome of knee osteoarthritis. METHODS: This was a prospective observational study of 350 osteoarthritic knees. Clinical and radiographic data were obtained on 188 hospital referred patients (mean age 70, range 34-91 years). RESULTS: Median duration of follow up was two years (range 1-5 years). The majority of patients (48%) reported deterioration, but 23% experienced improvement in symptoms during the study period. Reported exercise tolerance remained unchanged in the majority (62%) and deteriorated in 35%. Change in at least one individual radiographic feature of osteoarthritis was seen in 252 (72%) knees: increase in joint space narrowing occurred in 52%, osteophyte in 32%, cysts in 19%, sclerosis in 14%, and attrition in 30%. Increase in Kellgren grade occurred in 137 (39%) knees. Knee effusion, osteoarthritis at multiple joint sites, and nodal change associated with change in Kellgren grade (odds ratios 1.03, 2.39, and 1.80; 95% confidence intervals (CI) 1.01 to 1.05, 1.16 to 4.93, and 1.02 to 3.17, respectively); warmth at the knee associated with change in any radiographic feature (odds ratio 2.22; 95% CI 1.19 to 4.14). Development of, or increase in, attrition and joint space narrowing associated with worsening symptoms and function and occurred with increased frequency in knees with effusions, clinical warmth and calcium pyrophosphate crystals in synovial fluid (p < 0.05). CONCLUSIONS: A high rate of change, radiographic more than clinical, was seen in osteoarthritic knees during this study. Poor clinical and radiographic outcome associated with calcium pyrophosphate crystal deposition and clinical inflammation as reflected by knee effusion and warmth.
Distribution of cases of systemic lupus erythematosus at time of first symptom in an urban area.
OBJECTIVES: To determine the geographical distribution of cases of systemic lupus erythematosus (SLE) in a defined geographical area in the East Midlands, UK, and, in particular, to search for spatial variation in cases that may implicate the role of environmental factors in SLE aetiology. METHODS: Six methods of case ascertainment were used. The postcode of the patient's domicile at time of first definite symptom of SLE was used for analysis which included case mapping, probability mapping by electoral ward, and variogram analysis. RESULTS: The study area population of 613,700 contained 200 SLE patients, 188 of whom experienced their first symptom whilst residing in the area. Case mapping revealed 12 SLE patients residing within an area of one square mile, including four men and six patients with RNP antibodies. The use of probability mapping showed five wards in close proximity to each other to have a greater number of SLE cases than would be expected by chance (p < 0.1). The 'cluster' of patients seen on the case map fell into two wards which showed a significant excess of cases only when combined (p = 0.006). The variogram of the incidence rates for each ward did not confirm any structure or pattern to the distribution of cases for the whole area. CONCLUSIONS: Some areas have a greater than expected prevalence of SLE. The normal result from variogram analysis suggests that the cause(s) for these excess number of cases does not have an effect across the whole study area.
Missed opportunity following diagnosis of gout.
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Indomethacin hastens large joint osteoarthritis in humans--how strong is the evidence?
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Calcium pyrophosphate in joint disease.
Shedding of crystals from cartilage into a joint space can cause pseudogout, the most common acute monarthritis in the elderly. The calcification may also be associated with structural change identical to osteoarthritis. Treatment seeks to reduce symptoms and improve function.
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