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Biomedical subjects

P J Maddison

Publications and source records attributed to P J Maddison.

At least 19 recordsLinked to original sources
PubMed2000

Mixed connective tissue disease: overlap syndromes.

Since the original description of mixed connective tissue disease (MCTD) as an apparently unique syndrome by Sharp and co-workers, the concept of MCTD has been highly controversial. In this chapter, a quarter of a decade later, we examine the evidence that MCTD is a distinctive entity rather than a haphazard association of clinical and serological features and that the presence of high titres of autoantibodies to UIRNP influences the expression of connective tissue disease in ways that are relevant to prognosis and treatment. Results of longterm clinical studies are presented, which show that the clinical phenotype of MCTD is robust and can be defined by classification criteria that show reasonable sensitivity and specificity. In addition, the chapter addresses the results of immunogenetic and serological studies that demonstrate that MCTD is quite distinctive from systemic lupus erythematosus and systemic sclerosis. Indeed, there is good evidence that the clinical and serological features of MCTD are not just a haphazard association but that these patients represent a distinctive subset of connective tissue disease in which the specific autoimmune response is relevant to clinical expression and to understanding the underlying pathogenesis.

Autoantibodies↗
PubMed2000

'Catastrophic' antiphospholipid syndrome.

When 'catastrophic' is applied as an adjective to the antiphospholipid syndrome, it implies a characteristic presentation due to predominantly small blood vessel thrombosis leading to rapidly progressive failure of multiple organs and a frequently fatal outcome. We present the case of a 48-year-old woman who presented with the 'catastrophic' antiphospholipid syndrome without previous history of coagulation disorder or connective tissue disease that illustrates the difficulties in diagnosing and managing this disorder. We also review the factors that have been reported to have a role in the development of this condition and show how this case throws light on its pathogenesis.

Anti-Inflammatory Agents↗
PubMed1999

Nature and nurture in systemic lupus erythematosus.

Nowhere across the spectrum of rheumatic and dermatological disease is the interaction of nature and nurture more relevant than in the connective tissue diseases such as SLE. While genetic and environmental factors are clearly involved in both the triggering of the disease and its expression, the interaction is complex with different combinations of factors contributing in different patients. For example, while genetic factors contribute substantially to susceptibility to lupus, this does not follow a simple Mendelian pattern of inheritance and mathematical models suggest that there may be varying contribution from at least four genes with differing inheritances. A variety of candidate genes and environmental factors have been highlighted in SLE but to dissect out the complexity of how these might interact requires the study of patient groups with a better defined clinical and serological phenotype. For example, studies of patients with subacute cutaneous lupus (SCLE) have shown associations with various genes in the MHC region (including HLA, complement and TNF) and suggest that the biological effect of inheriting an extended MHC region may be greater than its individual parts. One can now speculate on how interaction with an environmental factor such as UV light explains pathogenesis.

Adrenergic beta-Antagonists↗
PubMed1999

A disease severity scale for systemic sclerosis: development and testing.

OBJECTIVE: To develop and test a severity scale for individual organ involvements in systemic sclerosis (SSc, scleroderma). METHODS: An international study group completed the following tasks: (1) developed a glossary of terms including all pertinent variables for 9 potentially affected organ systems; (2) collected prospective data to determine the feasibility and practicality of each proposed variable; (3) revised the initial list of variables; (4) determined the association of each variable with mortality (a proxy for morbidity) using 579 patients in an existing comprehensive longitudinal scleroderma databank; (5) developed a severity grading scale for each organ system by discussion and consensus; and (6) externally validated the scale using an independent group of 680 patients from the same databank. RESULTS: Nine organ-specific severity scales were developed from 0 (no documented involvement) to 4 (endstage disease). The data required for scale completion are relatively easy and practical for all physicians to obtain. CONCLUSION: This preliminary severity scale will be useful for assessing disease severity status in individual patients both at one point in time and longitudinally. The severity scale will assist in the design and conduct of clinical trials and the comparison of study populations with one another. The scale will serve as a framework for developing a scleroderma disease activity index.

Humans↗
PubMed1999

Autoantibodies in SLE. Disease associations.

Antinuclear antibodies are an almost universal feature of SLE. Over the years they have been the subject of intensive study to understand the underlying pathogenesis of the disease. It is clear that ANA in the context of lupus are directed against highly selected targets and are not just the result of nonspecific polyclonal B cell activation. Frequently they react with components of nucleoprotein complexes involved in important cellular processes which are very specific targets for autoimmunity in this condition. The antibodies themselves belong primarily to the IgG1 and IgG3 subclasses of immunoglobulin, are high affinity, occur in large amounts, have important associations with particular HLA class II genes and show all the features of an antigen-driven, T cell-dependent immune response. Although at first glance there is a wide range of antibody specificities associated with SLE, in the individual patient the autoantibody profile is much more restricted. Methods to detect these antibodies have provided the clinician with valuable tools to assist both in diagnosis and assessment of lupus patients. It has been possible to recognise distinctive serological subsets within the spectrum of lupus which are associated with certain patterns of disease expression. This can be helpful in determining both disease classification and prognosis.

Antibodies, Antinuclear↗
PubMed1998

Cardiorespiratory responses to underwater treadmill walking in healthy females.

This study compared the cardiorespiratory responses of eight healthy women (mean age 30.25 years) to submaximal exercise on land (LTm) and water treadmills (WTm) in chest-deep water (Aquaciser). In addition, the effects of two different water temperatures were examined (28 and 36 degrees C). Each exercise test consisted of three consecutive 5-min bouts at 3.5, 4.5 and 5.5 km x h(-1). Oxygen consumption (VO2) and heart rate (HR), measured using open-circuit spirometry and telemetry, respectively, increased linearly with increasing speed both in water and on land. At 3.5 km x h(-1) VO2 was similar across procedures [chi = 0.6 (0.05) l x min(-1)]. At 4.5 and 5.5 km x h(-1) VO2 was significantly higher in water than on land, but there was no temperature effect (WTm: 0.9 and 1.4, respectively; LTm: 0.8 and 0.9 l x min(-1), respectively). HR was significantly higher in WTm at 36 degrees C compared to WTm at 28 degrees C at all speeds, and compared to LTm at 4.5 and 5.5 km x h(-1) (P < or = 0.003). The HR-VO2 relationship showed that at a VO2 of 0.9 l x min(-1) x HR was higher in water at 36 degrees C (115 beats x min[-1]) than either on land (100 beats min[-1]) or in water at 28 degrees C (99 beats x min[-1]). The Borg scale of perceived exertion showed that walking in water at 4.5 and 5.5 km x h(-1) was significantly harder than on land (WTm: 11.4 and 14, respectively; LTm: 9.9 and 11, respectively; P < or = 0.001). These cardiorespiratory changes occurred despite a slower cadence in water (the mean difference at all speeds was 27 steps/min). Thus, walking in chest-deep water yields higher energy costs than walking at similar speeds on land. This data has implications for therapists working in hydrotherapy pools.

Adult↗
PubMed1996

A randomized and controlled trial of hydrotherapy in rheumatoid arthritis.

OBJECTIVE: The aim of this study was to evaluate the therapeutic effects of hydrotherapy which combines elements of warm water immersion and exercise. It was predicted that hydrotherapy would result in a greater therapeutic benefit than either of these components separately. METHODS: One hundred thirty-nine patients with chronic rheumatoid arthritis were randomly assigned to hydrotherapy, seated immersion, land exercise, or progressive relaxation. Patients attended 30-minute sessions twice weekly for 4 weeks. Physical and psychological measures were completed before and after intervention, and at a 3-month followup. RESULTS: All patients improved physically and emotionally, as assessed by the Arthritis Impact Measurement Scales 2 questionnaire. Belief that pain was controlled by chance happenings decreased, signifying improvement. In addition, hydrotherapy patients showed significantly greater improvement in joint tenderness and in knee range of movement (women only). At followup, hydrotherapy patients maintained the improvement in emotional and psychological state. CONCLUSIONS: Although all patients experienced some benefit, hydrotherapy produced the greatest improvements. This study, therefore, provides some justification for the continued use of hydrotherapy.

Arthritis, Rheumatoid↗
PubMed1996

Differential expression of the costimulatory molecules B7.1 (CD80) and B7.2 (CD86) in rheumatoid synovial tissue.

CD4+ T-lymphocytes require two signals to become activated--antigen receptor (TcR) occupancy and an antigen-presenting cell (APC)-derived costimulus. The latter may be provided by B7.1 (CD80) or B7.2 (CD86) on APC interacting with CD28 on T-cells. We have studied the expression of these costimulatory molecules in rheumatoid and osteoarthritic synovial membrane. Very few B7.1-positive cells were seen in synovial tissue from either established or early rheumatoid disease, or in rheumatoid arthritis (RA) or osteoarthritis (OA) synovia at arthroplasty. In contrast, B7.2 was readily detected in rheumatoid synovia, predominantly in the lining layer, in a pattern of expression that corresponded to the presence of CD68-positive macrophages. Only occasional B7.2-positive cells were seen in OA synovia. The presence of B7.2 but the relative lack of expression of B7.1 may be partly responsible for the observations of 'frustrated' T-cell activation or T-cell hyporesponsiveness in the rheumatoid synovium.

Antigens, CD↗
PubMed1995

CAMPATH-1H, a humanized monoclonal antibody, in refractory rheumatoid arthritis. An intravenous dose-escalation study.

OBJECTIVE: To evaluate the biologic response, tolerability, and potential clinical effect of a humanized antilymphocyte monoclonal antibody, CAMPATH-1H, in patients with rheumatoid arthritis (RA). METHODS: Forty adult patients with active, refractory RA were treated with CAMPATH-1H, given intravenously, in a multicenter, open, single-dose-escalation study. Patients were assigned to dose groups of 1, 3, 10, 30, 60, and 100 mg CAMPATH-1H. RESULTS: There was a profound, immediate, and sustained reduction of the peripheral lymphocyte count; the most susceptible were the levels of CD4+ and CD8+ cells, which remained depressed during the study period. Sixty-three percent of patients developed antibodies to CAMPATH-1H. Side effects occurred frequently throughout the first 24 hours following infusion, and included fever, headache, nausea, vomiting, and hypotension. All of the immediate drug toxicities resolved within the initial 24-hour postdosing period. One patient developed a reactivation of Mycobacterium xenopi infection 10 weeks following infusion. Sixty-five percent of patients developed a clinical response; the mean duration of response was 2 weeks. CONCLUSION: CAMPATH-1H is a lymphocyte-depleting antibody that is biologically potent even after single-dose therapy. There was no correlation between biologic effect and clinical response. Sustained lymphocyte suppression was observed. Acute infusion toxicities were observed in most patients. The role of depleting monoclonal antibodies in the treatment of RA should be reevaluated.

Adult↗
PubMed1995

Air in the oesophagus: a sign of oesophageal involvement in systemic sclerosis.

An air oesophagogram, defined as a column of air involving the entire oesophagus, seen on a lateral chest X-ray was observed in 6 (20%) of 30 consecutive patients with systemic sclerosis (SSc) but in none of the controls. The presence of this sign was unrelated to the clinical subset of SSc and to age but was associated with the symptom of regurgitation.

Adult↗
PubMed1995

Anti-p57: a novel association with neonatal lupus.

IgG antibodies to a 57-kD protein (p57) present in various human and bovine extracts were detected by immunoblotting in the serum of the mother of a baby with congenital heart block, but not in the corresponding cord blood, suggesting specific antibody consumption in the baby. Since this indicates a possible functional role for these antibodies, the antigen target was characterized and the association of the antibodies to heart block was further studied. A human K562 lambda gt11 cDNA library was screened and two clones were identified whose products reacted with the prototype serum. Antibody affinity-purified by use of the cloned gene products reacted on immunoblot with the 57-kD band. Partial sequences of both inserts were identical, but differed from DNA encoding the Ro(SSA) and La(SSB) antigens. Antibodies to the p57 were detected in 10% of systemic lupus erythematosus (SLE) sera, almost exclusively in association with anti-Ro(SSA). Furthermore, they were present in 38% (8/21) mothers of babies with neonatal lupus expressing either cardiac or cutaneous manifestations. Antibodies to this 57-kD protein may be an additional risk factor for neonatal lupus in anti-Ro-positive women. Moreover, disappearance of antibody from cord blood suggests that they may have a role in disease manifestations.

Autoantibodies↗
PubMed1994

Abnormal hypothalamic-pituitary-adrenal axis function in rheumatoid arthritis. Effects of nonsteroidal antiinflammatory drugs and water immersion.

OBJECTIVE: To investigate the effects of nonsteroidal antiinflammatory drug (NSAID) therapy and water immersion on hypothalamic-pituitary-adrenal (HPA) axis function in rheumatoid arthritis (RA). METHODS: Plasma levels of adrenocorticotropic hormone (ACTH) and serum and urine levels of cortisol were compared in untreated RA patients, NSAID-treated RA patients, and healthy control subjects. RESULTS: ACTH levels were significantly higher in untreated RA patients (mean +/- SEM integrated area 11,377 +/- 5,246 hours ng/liter) than in NSAID-treated RA patients (2,285 +/- 388 hours ng/liter) or healthy controls (1,845 +/- 35.5 hours ng/liter) (P < 0.001). Serum and urine cortisol levels were not significantly different between groups. Two-hour head-out water immersion had no effect. CONCLUSION: Elevated ACTH levels without hypercortisolemia occur in untreated RA. NSAID therapy alters HPA axis response, but immersion has no effect.

Adrenocorticotropic Hormone↗
PubMed1994

Concentration of autoantibodies to native 60-kd Ro/SS-A and denatured 52-kd Ro/SS-A in eluates from the heart of a child who died with congenital complete heart block.

OBJECTIVE: To determine the serologic specificity of acid eluates from tissues of a child who died with congenital complete heart block (CCHB). METHODS: Tissues were extracted, acid eluted, and the IgG and antibody titers determined on the eluates by enzyme-linked immunosorbent assay. RESULTS: Antibodies to native 60-kd and denatured 52-kd Ro/SS-A were found to be enriched only in the heart eluate, and not in the eluates from brain, kidney, and skin. CONCLUSION: These findings indicate a major role for anti-native 60-kd Ro/SS-A in the immunopathogenesis of CCHB.

Adult↗
PubMed1994

The association of primary biliary cirrhosis and systemic sclerosis is not accounted for by cross reactivity between mitochondrial and centromere antigens.

A proportion of patients with primary biliary cirrhosis (PBC) develop the CREST variant of systemic sclerosis (SSc) and in these individuals antimitochondrial antibodies (AMA) and anticentromere antibodies (ACA) coexist. Immunological cross-reactivity between mitochondrial and centromere-associated antigens might account for the clinical and serological overlap between these conditions. Therefore, antibodies were affinity purified from the 70 kD polypeptide corresponding to the E2 component of the pyruvate dehydrogenase complex (PDHC) and from CENP-C, a 140 kD centromere-associated protein, to examine this possibility. Although the purified antibodies reacted with their corresponding antigens, no evidence of shared determinants between the 70 kD protein and CENP-C could be detected whether the antibodies were prepared from monospecific sera or from sera containing both AMA and ACA. Therefore, AMA and ACA present discrete autoantibody populations which may coexist in the same patient and may influence the clinical picture but have both structural and immunologically independent antigenic targets.

Aged↗