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J L O'Donnell

Publications and source records attributed to J L O'Donnell.

At least 19 recordsLinked to original sources
PubMed2006

Soluble human leukocyte antigen: a diagnostic indicator of rheumatoid arthritis?

Early stage rheumatoid arthritis (RA) is often difficult to diagnose because initial symptoms are non-specific. To aid diagnosis, suitable serological diagnostic markers are sought. Elevated levels of soluble MHC class II (soluble human leukocyte antigen; sHLA-DR) in human serum have been associated with rheumatoid and 'rheumatoid-like' autoimmune diseases. As a result, sHLA-DR has been suggested as a specific marker of RA. However, reported levels of sHLA-DR in sera of healthy donors vary significantly and the mechanism of release of HLA-DR into serum is poorly understood. Investigations into the diagnostic potential of this molecule necessitate the development of a sensitive and specific sHLA-DR assay. We have investigated multiple ELISA setups to develop such an assay and false positive signal has been carefully removed using a combination of isotype-matched controls and immuno-depletion. sHLA-DR levels in sera of RA patients were not significantly different from those in healthy donors which suggests sHLA-DR has limited utility in the diagnosis of RA. In RA patients, we detected high levels of sHLA-DR in aspirated synovial fluid (SF), but this did not correlate with sHLA-DR levels in serum.

Arthritis, Rheumatoid↗
PubMed2006

Levels of the soluble forms of CD80, CD86, and CD83 are elevated in the synovial fluid of rheumatoid arthritis patients.

The release of soluble forms of CD80 (sCD80), CD86 (sCD86), and CD83 (sCD83) provide a potentially powerful immunoregulatory mechanism. We therefore investigated the potential presence and relative levels of these molecules in the synovial fluid (SF) and serum of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum and SF levels were measured by enzyme-linked immunosorbent assay. Serum levels of sCD80, sCD86, and sCD83 in RA and OA patients were similar to those present in normal donor serum (NDS) and the SF of OA patients. In contrast, when compared with NDS and OA SF levels, almost all RA SF samples had elevated sCD83 levels (32/35, >0.63 ng/ml) and a substantial proportion had elevated sCD80 (13/29, >0.22 ng/ml) or sCD86 (16/33, >2.31 ng/ml) levels. Analysis of matched pairs of serum and SF from RA patients demonstrated that the SF/serum ratio for sCD80 (95% CI = 1.7-3), sCD86 (95% CI = 1.5-3.1), and sCD83 (95% CI = 3.6-7.8) levels was >1 in almost all patients. In conclusion, this study shows that the SF from almost all RA patients contain elevated levels of sCD83 and the majority of these samples also contain elevated levels of sCD80 and/or sCD86. These molecules may play a role in modulating immune responses within the rheumatoid joint.

Adolescent↗
PubMed2005

The epidemiology of Wegener's granulomatosis and microscopic polyangiitis in a Southern Hemisphere region.

OBJECTIVE: To determine the prevalence of Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) in the province of Canterbury, New Zealand. METHOD: Three hospital clinical databases and the immunology laboratory database were searched and case notes reviewed for patients fulfilling either the 1990 American College of Rheumatology (ACR) criteria for WG or a modification of those criteria that allowed for antineutrophil cytoplasmic antibody (ANCA) positivity in the absence of granulomatous vasculitis. MPA was defined by the Chapel Hill consensus definition; however, in the absence of histological evidence of pauci-immune glomerulonephritis, ANCA positivity in association with evidence of active glomerular disease was included as a criterion. The point prevalence at 31 December 2003 and the 5-yr period prevalence for the interval 1 January 1999 to 31 December 2003 were calculated. RESULTS: Seventy-three patients with WG and 28 patients with MPA fulfilled the inclusion criteria. A 5-yr period prevalence of 152 WG cases/million [95% confidence interval (CI) 117-186] and 58 MPA cases/million (95% CI 37-80) was calculated using 2001 census data as denominator. Nineteen patients with WG died and 10 patients with MPA died during the study period, resulting in a point prevalence for survivors at 31 December 2003 of 112 cases/million (95% CI 82-142) and 37 cases/million (95% CI 20-55), respectively. Using unmodified ACR criteria the 5-yr period and point prevalence for WG were 131/million (95% CI 99-163) and 93.5/million (95% CI 66-121), respectively. Apart from respiratory tract involvement, which formed part of the case definition of WG, organ involvement was similar in both diseases. CONCLUSION: The prevalence of WG and MPA in Canterbury is the highest reported to date. Restricting the case definition of WG to the ACR classification criteria we found a prevalence equivalent to that described in northern Norway. The clinical severity and serological characteristics were similar to descriptions in other WG and MPA patient cohorts. Studies of disease prevalence in other Southern Hemisphere centres will determine if the observed north-south negative disease gradient in the Northern Hemisphere is reciprocated.

Adult↗
PubMed2005

Adult-onset inflammatory myopathy: North Canterbury experience 1989-2001.

AIM: To perform a clinical audit of all patients diagnosed with inflammatory myopathy in the North Canterbury region. METHODS: A retrospective case note audit of patients with a discharge diagnosis of inflammatory myopathy from June 1989 to June 2001 was performed. The audit was based at Christchurch Hospital, New Zealand, which services a population of 430,000. RESULTS: Of 77 case notes reviewed, 44 patients were identified who were considered to fulfil clinical criteria for inflammatory myopathy. There was a female preponderance (80% female, 20% male). Diagnostic categories in descending order of frequency included: dermatomyositis (41%), polymyositis (39%), inclusion body myositis (IBM) (14%) and overlap syndromes (6%). Malignancy-associated myositis occurred in 20% overall (dermatomyositis 11%, polymyositis 9%). Delays in diagnosis and late age at presentation (average 72 years) were seen in the IBM group. Proximal limb weakness was common, but not universal at presentation (80%). A muscle biopsy was performed in all patients and electromyography in 82%. All were treated with high dose prednisone (0.5-1 mg/kg) of whom 29% were maintained on prednisone alone. Immunosuppressives/immunomodulators used included: azathioprine (58%), methotrexate (31%), intravenous immunoglobulin (13%), chlorambucil (13%), and cyclophosphamide (9%). Thirteen patients (42%) required more than one agent, with three trialling five agents. There were 59 relapses in 20 patients (45%), with mean time to first relapse of 7.8 months. At audit completion, 33% had deceased with malignancy and respiratory failure the main causes. CONCLUSION: Inflammatory myopathy is a challenging condition in both diagnosis and management. Our audit has shown delays in the diagnosis of IBM, a relatively high incidence of malignancy and a notable risk of relapse and mortality.

Aged↗
PubMed2005

Prioritizing health-care funding.

In the face of limited resources, on what basis should we prioritize health-care funding? The most influential consideration should be the knowledge that an intervention does something beneficial for the person who receives it. Rather than using imposed knowledge or knowledge obtained by grace, modern medicine uses knowledge obtained by rational thought. Traditionally, two philosophical schools of rational thought support medical interventions: empiricism and rationalism. Empiricist knowledge underpins the treatment of risk, while rationalist knowledge underpins the treatment of disease. To introduce reasoned order into the rationing process we must understand the limitations inherent in the application of these two forms of knowledge. Why are screening programmes for breast and uterine cervical cancer supported while severe restrictions are placed on treatments for chronic arthritis? Can the benefits of cholesterol-lowering drugs be measured? Empiricism has achieved an unchallenged ascendancy in modern health-care delivery. Is this ascendancy justified? There is a need for reference criteria to compare the benefits of competing interventions across disciplines. As a starting point for debate we propose that interventions should be given a priority based on how closely they fulfil five criteria: knowledge of disease pathophysiology, measurability of short-term and long-term benefits, incidence of serious adverse effects and affordability. It is only by using and refining such funding criteria that better public understanding of the rationing process will be achieved and political interference minimized.

Adult↗
PubMed1999

Synovial fluid transforming growth factor beta inhibits dendritic cell-T lymphocyte interactions in patients with chronic arthritis.

OBJECTIVE: To examine whether rheumatoid synovial fluid (SF) inhibits dendritic cell (DC) expression of the CD80 and CD86 costimulator molecules and contributes to SF T lymphocyte hyporesponsiveness. METHODS: Cell-free rheumatoid SF was tested for its effect on DC-stimulated autologous/allogeneic mixed lymphocyte reactions and for its effect on DC surface antigen expression, as assessed by flow cytometry. Blocking monoclonal antibodies were used to identify the SF cytokines that inhibited DC-T lymphocyte interactions. RESULTS: Low concentrations of SF (2.5%) could inhibit DC-mediated autologous and allogeneic T lymphocyte proliferation. This inhibitory effect could be reversed by neutralizing transforming growth factor beta (TGFbeta) and interleukin-2 (IL-2), but not by IL-12, in the SF. Hyaluronic acid, IL-6, IL-10, and tumor necrosis factor alpha were not associated with SF inhibition. In vitro culture alone and crosslinking with the CD40 ligand up-regulated DC CD80/CD86 expression and costimulator function, and this was not affected by inclusion of SF. In the presence of SF, DC clustered with autologous T lymphocytes showed decreased CD80 and CD86 expression, and variable CD80/CD86 decreases were observed on DC clustered with allogeneic T lymphocytes. CONCLUSIONS: TGFbeta in SF appears to suppress T lymphocyte function, which may affect both signaling to DC and the induction of DC costimulator function.

Antibodies, Monoclonal↗
PubMed1997

Prolonged remission of longstanding systemic lupus erythematosus after autologous bone marrow transplant for non-Hodgkin's lymphoma.

We describe a patient with longstanding steroid-dependent systemic lupus erythematosus (SLE) in whom clinical and serological remission was achieved following high-dose therapy and autologous bone marrow rescue for high-grade non-Hodgkin's lymphoma. However, 3 years later, autoimmune disease re-presented in the form of immune thrombocytopenia (ITP), which had not previously been a feature of the SLE, necessitating reintroduction of steroid immunosuppression. Relapse of SLE is most likely, although de novo ITP post-BMT is also a possibility. The case suggests that severe long-standing autoimmune disease may be controlled by high-dose therapy and autologous stem cell reconstitution. However, further studies are required to determine the mechanism of re-emergence of autoimmunity and to evaluate optimal regimens and the potential value of such therapy in severe autoimmune diseases.

Anemia, Hemolytic, Autoimmune↗
PubMed1996

Prostaglandin E2 content in herniated lumbar disc disease.

STUDY DESIGN: A prospective series of biochemical assays for prostaglandin E2 content in symptomatic herniated lumbar disc specimens. OBJECTIVES: To help clarify the pathogenesis of lumbar radiculopathy. SUMMARY OF BACKGROUND DATA: Three recent studies have shown elevated levels of prostaglandin E2 in intervertebral disc herniations. None of these studies correlated symptoms with prostaglandin E2 levels. METHODS: Twenty-four disrupted disc samples were purified by a standard solid phase extraction method and analyzed for prostaglandin E2 with an enzyme-linked immunosorbent assay. Clinical and anatomic correlations were sought with analysis of variance and t test. RESULTS: Sequestered discs tended to be associated with a higher prostaglandin E2 content than extruded discs, which in turn, tended to be associated with higher prostaglandin E2 content than protruded ones. A positive straight leg raising test appeared to be associated with a higher prostaglandin E2 content than a negative test. CONCLUSIONS: Prostaglandin E2 appears to mediate some of the inflammatory effects of lumbar disc herniation. An intact anulus may provide some protection against this stimulus.

Dinoprostone↗
PubMed1996

Expression and function of CD80 and CD86 costimulator molecules on synovial dendritic cells in chronic arthritis.

OBJECTIVE: To examine CD86 expression on dendritic cells isolated from the synovial fluid (SFDC) of patients with chronic arthritis, and to determine the importance of both CD80 and CD86 molecules in SFDC-T lymphocyte interactions. METHODS: CD86 messenger RNA (mRNA) and surface expression were analyzed in SFDC using reverse transcriptase-polymerase chain reaction and flow cytometry, respectively. The costimulator activity of the SFDC CD80 and CD86 molecules was determined by allogeneic mixed lymphocyte reaction (MLR). CD80 and CD86 induction on SFDC during in vitro culture was also examined. RESULTS: Fresh SFDC either lacked or showed very weak surface expression of CD86 molecules (as shown previously for CD80), yet contained CD86 mRNA. CD80 antibodies minimally inhibited an allogeneic MLR, whereas CD86 antibodies and CTLA-4 Ig showed significant inhibition. Both CD80 and CD86 molecules were inconsistently induced on SFDC following culture in either media, interferon-gamma, or granulocyte-macrophage colony-stimulating factor. CONCLUSION: SFDC may be defective antigen-presenting cells in vivo. The ability of CD80 and CD86 molecules to be induced and become functional on SFDC in vitro implies the presence of a negative regulatory compound(s) in the synovial environment.

Abatacept↗
PubMed1995

Dendritic cells in synovial fluid of chronic inflammatory arthritis lack CD80 surface expression.

Dendritic cells (DC) act as potent primary antigen-presenting cells in many immune responses and therefore may have a role in the initiation and perpetuation of the synovial inflammation in chronic inflammatory arthritis. To examine their function, it is important to isolate fresh DC from arthritic joints without aberrant activation. We have developed a technique using minimal cell manipulation to isolate DC from the synovial fluid of chronic arthritic patients. Using this method, DC were shown to be potent allostimulatory cells, with 63-90% of cells lacking lineage-specific markers (lin-), but positive for MHC class II molecules. Two morphologically distinct populations of these cells were identified in 10 out of 13 DC preparations. Both populations expressed CD40, intercellular adhesion molecule-1 (ICAM-1), ICAM-2, ICAM-3 and leucocyte function associated antigen-3 (LFA-3), but the predominant population, which was larger and more typical of cultured blood DC, had a higher density of these antigens compared with the minor population, which were smaller and morphologically similar to lymphocytes. Two new MoAbs which label activated human blood DC, HB15 (CD83) and CMRF-44, were tested. CD83 labelled very weakly or not at all, whereas CMRF-44 was positive on the larger cells only. Likewise, the costimulator molecule, B7/BB1 (CD80), was not detected on the surface of either synovial lin- cell population, reverse transcriptase polymerase chain reaction (RT-PCR) showed little or no CD80 mRNA, and no binding of the CTLA-4Ig fusion protein was found. These results suggest that synovial DC are not, despite the inflammatory environment, in a fully activated state.

Arthritis↗
PubMed1995

Monocyte-macrophage antigen expression on chondrocytes.

OBJECTIVE: To characterize chondrocytes in normal and arthritic joints and compare their phenotype to that of synovial macrophages present in rheumatoid joints. METHODS: Using an immunoperoxidase staining technique, we examined the presence and distribution of a number of leukocyte activation and differentiation antigens on samples of cartilage obtained from resected joints of normal controls and subjects with rheumatoid arthritis or osteoarthritis. RESULTS: Chondrocytes in each group were CD14+, CD68+, Thy-1+, CD11a+, CD18+, MAX.3-, and MAX.24-. Staining was variable for MAX.1 and CD45. HLA-DR and CD71 were expressed only on cells located in the superficial layer of rheumatoid cartilage. We found lower levels of expression of CD14 on chondrocytes in arthritic joints, whereas CD58 was expressed at higher levels. Surface expression of CD14 was confirmed on normal chondrocytes using flow cytometry and further supported by the detection of CD14 mRNA by polymerase chain reaction. CONCLUSION: Our findings demonstrate that chondrocytes express several antigens that are also found on monocytes and macrophages.

Arthritis, Rheumatoid↗
PubMed1994

No excuse.

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Dental Amalgam↗
PubMed1994

Adenocarcinoma of the colon and associated necrotizing vasculitis of mesenteric arteries.

Vasculitis associated with malignancy is uncommon, with the most well-known association being that between hairy cell leukaemia and polyarteritis nodosa. The less common association of vasculitis and solid tumours usually involves a cutaneous leukocytoclastic vasculitis. We report a patient with Duke's C adenocarcinoma of the sigmoid colon with associated necrotizing vasculitis of the mesenteric arteries and postulate that local factors may predominate in its pathogenesis.

Adenocarcinoma↗
PubMed1994

Co-expression of the CD45RA and CD45RO antigens on T lymphocytes in chronic arthritis.

The site of T lymphocyte activation in chronic arthritis is unknown. Peripheral blood (PB) lymphocytes from chronic arthritis patients are in a 'naive' or non-activated state, as defined by expression of the CD45RA antigen and lack of HLA class II expression. In contrast, most synovial fluid (SF) T lymphocytes express a 'memory' or activated phenotype, as defined by the CD45RO antigen and high HLA class II expression. Following stimulation, naive cells lose CD45RA and gain CD45RO expression to become memory cells with a transitional stage of dual CD45RA, CD45RO antigen expression. To localize where this change in phenotype occurs we used dual colour immunofluorescence labelling to compare the percentage of dual CD45RA, CD45RO-positive T lymphocytes in PB and SF from chronic arthritic patients and from normal PB, assuming this population would be increased at the primary site of T lymphocyte activation. Expression of the intermediate and late activation marker, HLA-DR, was also analysed using dual colour immunofluorescence labelling. The percentage of dual positive T lymphocytes was similar between arthritic PB, SF, and normal PB, as was the density of both CD45RA and CD45RO antigens. Thus, CD45 isoform expression did not indicate where T lymphocytes were activated. However, we identified a previously unreported population of CD45RA+ CD45RO+ HLA-DR- T lymphocytes in arthritic and normal PB. In SF, this population was absent, but a substantial number of dual CD45RA, CD45RO-positive HLA-DR+ T lymphocytes were identified. This population would not be predicted by the current model of T lymphocyte activation. Division of T lymphocytes into functional groups on the basis of CD45 isoform expression is likely to be more complicated than previously thought. Based on our findings we propose an alternative model of T lymphocyte differentiation.

Arthritis↗
PubMed1993

Dual CD45RA, CD45RO positive T-lymphocytes within rheumatoid arthritic joints.

This report documents the presence of an expanded population of dual CD45RA, CD45RO positive T cells (up to 91% of T cells) in the rheumatoid joint. Cells from peripheral blood (PB) and synovial fluid (SF) were analysed by dual immunofluorescence labelling. Synovium from a separate patient population was analysed by single and dual immunoenzyme staining of serial sections. Dual CD45RA, CD45RO positive T cells were found in PB (up to 74%), SF (up to 91%) and synovium. This was associated with a lack of early activation antigens (4F2, interleukin-2 receptor, transferrin receptor) but increased HLA-Class II antigens (HLA-DR, -DP, -DQ) in SF compared with PB. This intermediate activation phenotype may support the hypothesis that T cell activation or reactivation occurs within the rheumatoid joint.

Adult↗
PubMed1993

Respiratory failure in Wegener's granulomatosis: response to pulse intravenous methylprednisolone and cyclophosphamide.

We describe a patient with respiratory failure due to Wegener's granulomatosis (WG) who obtained a dramatic and sustained response to pulse intravenous methylprednisolone and cyclophosphamide. Discussion includes a review of the literature with respect to the relative merits of daily oral cyclophosphamide versus pulse intravenous cyclophosphamide in WG and other vasculitides. While the combination of daily oral steroids and daily oral cyclophosphamide dramatically improves the outcome of WG, this therapy is not without serious side effects. Pulse therapy may be equally as effective and may lessen the frequency of serious side effects.

Administration, Oral↗
PubMed1992

Rheumatoid pleural effusion: response to intrapleural corticosteroid.

The management of a patient with a large symptomatic rheumatoid pleural effusion is described. Thoracentesis and bed rest gave only short term modest benefit. A more lasting and beneficial response was obtained with an intrapleural injection of (120 mg) depomethylprednisolone acetate. This treatment is a useful interim measure until disease suppressive therapy gives systemic control.

Aged↗