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Biomedical subjects

D L Scott

Publications and source records attributed to D L Scott.

At least 91 records · Page 5Linked to original sources
PubMed1997

Drug treatment of rheumatic diseases in the 1990s. Achievements and future developments.

There have been several advances in the therapy of arthritis. These are based on better understanding of the pathogenesis of rheumatic diseases, re-evaluation of previous therapeutic concepts such as combination therapy, and developments within biotechnology. There are 4 main areas of development, mainly involving the treatment of inflammatory synovitis. The first is with anti-inflammatory drugs, where there has been a focus on reducing gastrointestinal toxicity through the use of combination preparations such as diclofenac-misoprostol, and the introduction of drugs with more selectivity for cyclo-oxygenase-2 inhibition such as meloxicam. An additional approach has been the development of anti-inflammatory drugs such as tenidap which also control cytokine metabolism. The second area is slow-acting antirheumatic drugs with the introduction of cyclosporin as a single agent or in combination with methotrexate, the development of immunomodulating drugs such as leflunomide, and the demonstration that some antibiotics such as minocycline have slow-acting effects. The third area is the use of corticosteroids including the development of deflazacort as a bone sparing agent, the greater use of intramuscular depot steroids and the validation of low-dose oral corticosteroids in early rheumatoid arthritis. Finally, there have been advances in the biotechnology area with the demonstration that cytokine immunotherapy such as antibodies to tumour necrosis factor can rapidly improve the symptoms of rheumatoid arthritis, and that T cell immunotherapy with antibodies to the CD4 receptor may be effective in reducing synovitis. Many of these agents have not yet been introduced into clinical practice but they show the diversity of drug development and suggest the likelihood of major therapeutic benefits in the next few years.

Antirheumatic Agents↗
PubMed1997

Clinical significance of IgA rheumatoid factor subclasses in rheumatoid arthritis.

OBJECTIVE: IgA rheumatoid factor (RF) is associated with greater disease activity and radiological progression in rheumatoid arthritis (RA). We examined whether measuring IgA RF subclasses gives additional clinically relevant information. METHODS: Total IgA RF plus IgA1 RF and IgA2 RF subclasses were estimated by ELISA using rabbit IgG as antigen in 144 patients with established RA. Disease activity was assessed by Disease Activity Score and Health Assessment Questionnaire; the acute phase response was assessed by C-reactive protein levels and joint damage by the Larsen score. RESULTS: Fifty percent of patients had elevated total IgA RF, 60% elevated IgA1 RF, and 50% elevated IgA2 RF. There were significant correlations between total IgA RF and both IgA RF subclasses (p < 0.0001). Measures of disease activity, the acute phase response, and joint damage were all significantly higher (p < 0.001 in each case) in patients with elevated total IgA RF and both IgA RF subclasses compared with RF negative cases. Disease duration influenced the relationship of IgA RF subclasses to joint damage. The Larsen score was only significantly higher in late disease (duration 5 years or more) in both IgA1 RF and IgA2 RF positive patients. CONCLUSION: We found IgA RF positive patients have more aggressive RA than negative cases. Measuring IgA1 RF and IgA2 RF subclasses did not give more information about clinical status than measuring total IgA RF alone.

Aged↗
PubMed1996

Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation.

OBJECTIVE: There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) damage; it has been suggested that mucosal damage may be initiated by a "topical" action of NSAIDs involving mitochondrial injury. We evaluated the effect of a range of NSAIDs and related compounds on mitochondrial function and assessed the differences between them in relation to their physicochemical properties. METHODS: Stimulation of respiration, as an indicator of mitochondrial uncoupling, was measured in isolated coupled rat liver mitochondrial preparations, using an oxygen electrode. RESULTS: Conventional NSAIDs and acidic prodrugs all had stimulatory effects on mitochondrial respiration at micromolar concentrations (0.02-2.7 microM); higher concentrations were inhibitory. The uncoupling potency was inversely correlated with drug pKa (r = -0.87, P < 0.001; n = 12). Drugs known to have good GI tolerability, including modified flurbiprofen (dimero-flurbiprofen and nitrobutyl-flurbiprofen), nabumetone (a non-acidic prodrug), and non-acidic highly selective COX-2 inhibitors, did not cause uncoupling. CONCLUSION: The ability to uncouple mitochondrial oxidative phosphorylation is a common characteristic of antiinflammatory agents with an ionizable group. Modification or absence of an ionizable moiety reduces the effect on mitochondria and could lead to improved NSAID GI safety.

Animals↗
PubMed1996

Standardising joint assessment in rheumatoid arthritis.

Evaluating joint involvement in rheumatoid arthritis in a key clinical assessment. We investigated the extent of variation in measurement of joint swelling and tenderness and evaluated the impact of training to standardise methods. Eight observers (medical and nursing staff) examined eight rheumatoid patients for joint swelling and tenderness before and after training in clinical methods. The EULAR handbook for joint evaluation was used for training and assessments were based on the 28 joint count. There was extensive variability in both numbers of swollen and tender joints. Coefficients of variation for articular indices recorded by the 8 observers in individual patients were often high (up to a maximum of 204%), indicating considerable differences between observers. Training had an impact on the assessment of the numbers of swollen joints which increased by a mean of 32% (P < 0.05) and the number of tender joints which increased by 41% (p < 0.01). Training had only a limited impact on the variation among observers in determining the number of swollen and number of tender joints. After training, the mean coefficients of variation were still 59% for swollen joints and 65% for tender joints. These results highlight the extent of variation in clinical assessment of rheumatoid arthritis and show the advantages of training. It leads to increased sensitivity of measurement. Standardisation appears essential for clinical studies.

Analysis of Variance↗
PubMed1996

The clinical need for an acute rheumatology referral service.

Should rheumatologists provide an acute referral service for general practitioners (GPs) and other clinical units? Is it cost effective? We prospectively studied acute referrals to one unit over 10 months, recording their source, diagnosis, management and outcome. Current rheumatology patients and cases only needing telephone advice were excluded. There were 253 referrals: 82 from GPs, nine from Accident and Emergency, and 162 from other hospital units. Their diagnoses comprised connective tissue diseases (22), back pain (46), inflammatory arthritis (59), osteoarthritis (22), paediatric cases (11), soft tissue problems (41) and 52 other disorders. Thirty-two needed active treatment within 24 h (classified as emergencies); examples included cerebral lupus, vasculitic pulmonary haemorrhage, retroperitoneal lymphoma with sacral plexus compression, temporal arteritis with reduced visual acuity and acute monoarthritis. All needed immediate therapy; only one died. Most (176 cases) were less urgent and needed advice in 48 h. Examples included osteoporotic vertebral collapse and acute rheumatoid disease. Forty-five could have been seen routinely; examples included lateral epicondylitis and adhesive capsulitis. The service required 1 day per week of medical staff time at an average cost of 45 pounds per case. We concluded that an acute rheumatology service is needed; it can be provided within the working day and is cost effective.

Direct Service Costs↗
PubMed1996

Joint assessment in rheumatoid arthritis.

Determining the number of swollen joints and tender joints is a key component in the clinical assessment of rheumatoid arthritis (RA). There have been a series of investigations carried out in the last decade, which have defined the best ways to measure joint inflammation and have identified which joints should be evaluated. There is not complete agreement on the optimal joint count, but two approaches are widely used. These comprise counting either 66/68 or 28 joints. The main difference is that the 28-joint count excludes the joints in the feet. Both methods give similar information and are reproducible and valid. Tenderness and swelling should be measured separately. There are advantages and disadvantages associated with using the 28-joint count. It has the benefit of simplicity and takes less time, although some potentially relevant clinical information about the feet may be lost. There is general agreement that grading the severity of individual joint involvement is of limited advantage. Using weighted joint counts is also not widely accepted. Finally there is growing recognition of the need for training in the methods of assessing joints and the importance of international standardization. Joint counts are a component of the core clinical data set for RA and will continue to play a key role in the foreseeable future.

Arthritis, Rheumatoid↗
PubMed1996

Clinical and laboratory assessments in rheumatoid arthritis and osteoarthritis.

Clinical and laboratory assessments in rheumatoid arthritis and osteoarthritis precede imaging methods in both defining diagnosis and determining response to therapy. Some assessments are similar in both diseases, e.g. measuring joint pain, the number of involved joints and functional impairment. There are also areas of difference; for example, rheumatoid arthritis is a systemic disease with immune disturbance and positive tests for rheumatoid factor and elevated acute phase markers while osteoarthritis is a more local disease with little systemic upset. In both diseases pain and progressive joint damage result in increasing disability. There is agreement on a core data set in rheumatoid arthritis which comprises: swollen joint counts, tender joint counts, pain assessment, patient's global assessment, an acute phase marker such as the ESR and a self-administered functional questionnaire. There is less agreement on the core data set in osteoarthritis, though pain and functional impairment are both important. Combined or overall indices have been used in both rheumatoid arthritis (e.g. the disease activity score) and in osteoarthritis (e.g. the Lequesne functional index), but there is no general agreement on their value. In both diseases plain radiology is useful to define diagnostic groups and follow progression in long-term studies. Mortality is increased in rheumatoid arthritis and is useful for defining the long term effects of the disease; little is known about mortality in osteoarthritis. Standardizing clinical methods is important and much work is needed in this area.

Arthritis, Rheumatoid↗
PubMed1995

The 2.4 A crystal structure of cholera toxin B subunit pentamer: choleragenoid.

Cholera toxin, a heterohexameric AB5 enterotoxin released by Vibrio cholera, induces a profuse secretory diarrhea in susceptible hosts. Choleragenoid, the B subunit pentamer of cholera toxin, directs the enzymatic A subunit to its target by binding the GM1 gangliosides exposed on the luminal surface of intestinal epithelial cells. The crystal structure of choleragenoid has been independently solved and refined at 2.4 A resolution by combining single isomorphous replacement with non-crystallographic symmetry averaging. The structure of the B subunits, and their pentameric arrangement, closely resembles that reported for the intact holotoxin, choleragen, the heat-labile enterotoxin from Escherichia coli, and for a choleragenoid-GM1 pentasaccharide complex. In the absence of the A subunit the central cavity of the B pentamer is a highly solvated channel. The binding of choleragenoid to the A subunit or to its receptor pentasaccharide modestly affects the local stereochemistry without perceptibly altering the subunit interface.

Amino Acid Sequence↗
PubMed1995

The three-dimensional crystal structure of cholera toxin.

The clinical manifestations of cholera are largely attributable to the actions of a secreted hexameric AB5 enterotoxin (choleragen). We have independently solved and refined the three-dimensional structure of choleragen at 2.5 A resolution. The structure of the crystalline toxin closely resembles that described for the heat-labile enterotoxin from Escherichia coli (LT) with which it shares 80% sequence homology. In both cases, the wedge-shaped A subunit is loosely held high above the plane of the pentameric B subunits by the tethering A2 chain. The most striking difference between the two toxins occurs at the carboxyl terminus of the A2 chain. Whereas the last 14 residues of the A2 chain of LT threading through the central pore of the B5 assembly form an extended chain with a terminal loop, the A2 chain of choleragen remains a nearly continuous alpha-helix throughout its length. The four carboxyl-terminal residues of the A2 chain (KDEL sequence), disordered in the crystal structure of LT, are clearly visible in choleragen's electron-density map. In the accompanying article we describe the three-dimensional structure of the isolated B pentamer of cholera toxin (choleragenoid). Comparison of the crystalline coordinates of choleragen, choleragenoid, and LT provides a solid three-dimensional foundation for further experimental investigation. These structures, along with those of related toxins from Shigella dysenteria and Bordetella pertussis, offer a first step towards the rational design of new vaccines and anti-microbial agents.

Amino Acid Sequence↗
PubMed1995

Clinical implications of patients' knowledge.

We evaluated the effectiveness of current strategies for educating patients in routine clinical practice in three related studies. (1) A study of overall knowledge in 100 patients with rheumatoid arthritis (RA) and osteoarthritis (OA) showed knowledge of diagnosis and treatment effects were high (86% and 83% respectively) but only a minority (37%) were well informed about side effects. (2) Patients' detailed knowledge of drug therapy was assessed in 50 RA and OA patients. Between 56%-92% knew why drugs were given, their use and their likely effects. But many patients were unaware of the main adverse reactions and also how to avoid or limit them. (3) The relationship of patient education to overall disease management was evaluated in 89 RA patients with 5-10 years disease duration using validate guidelines for specialist care. Those patients who had been give inadequate education about drug therapy had a reduced level of overall care. Although education is considered important by patients, it is often inadequate, and this is associated with a less effective overall treatment.

Aged↗
PubMed1995

Are slow-acting anti-rheumatic drugs monitored too often? An audit of current clinical practice.

Rheumatologists usually recommend monthly blood monitoring when patients with rheumatoid arthritis (RA) are treated with slow-acting anti-rheumatic drugs (SAARDs). Is monthly monitoring needed or could its frequency be reduced? We audited the opinions of UK rheumatologists and reviewed clinical experience at three centres. To ascertain the interval at which patients are monitored and the determinants of monitoring policy we sent a questionnaire to 193 consultant rheumatologists; 143 (74%) replied. The majority use monthly monitoring for most SAARDs except sulphasalazine, chloroquine and hydroxychloroquine. There is extensive variation, which is not related to the type of rheumatology unit or whether a shared scheme with general practitioners is used. Reviewing experience in 390 patients treated with SAARDs at three adjacent rheumatology units in London showed that haematological adverse reactions were infrequent. During 1560 patient-years of treatment involving 18,720 monthly monitoring visits there were 13 haematological adverse reactions (11 thrombocytopenias and two leucopenias). Five thrombocytopenias developed after 6 months of treatment; five occurred gradually over 5 months or more and one borderline low platelet count was seen once. The two leucopenias were borderline low white cell counts occurring gradually over 3-6 months. Such frequent monitoring is expensive. The total cost of monitoring 390 patients for 1560 patient-years was 420,000 pounds. The cost of detecting each adverse reaction was 32,000 pounds. Three-monthly monitoring when therapy is established after an initial stabilizing period would have identified seven out of eight late adverse reactions. Monitoring policies are mainly based on clinical consensus with few prospective studies of their value; they need re-evaluation.

Antirheumatic Agents↗
PubMed1995

Prognostic markers in rheumatoid arthritis and classification of antirheumatic therapies.

Rheumatoid arthritis is characterised by a generally poor outcome and high morbidity, and has a variable course. Identifying those patients most likely to have a poor prognosis is of key clinical significance. Disease outcome can be predicted from a variety of prognostic markers. Some of these are simple demographic features of the patients, and include age, disease duration, and gender. Others are more specific features of rheumatoid arthritis, including the presence of early erosive changes on plain radiographs, high rheumatoid factor titres, high levels of C-reactive protein, and high scores for disease activity. Although no single marker has adequate specificity or sensitivity to form the basis of clinical decisions, the presence of several is predictive of more severe disease. Thus, patients with early erosive damage who are seropositive for rheumatoid factor and have high levels of C-reactive protein are more likely to have a poor outcome. New markers and imaging techniques are likely to become the prognostic tools for the future. These include genetic markers, and a combination of magnetic resonance imaging and dual energy x-ray absorption scans for localised osteoporosis.

Antirheumatic Agents↗
PubMed1995

Identification of the central regulatory segment of plasmid R6K complexed with the membranes of Escherichia coli.

Understanding the mechanisms which control replication of chromosomes with multiple origins of replication have been the subject of many investigations. The plasmid, R6K, has three origins of replication, alpha, beta, and gamma. In vivo, alpha and beta are utilized with equal frequencies while the gamma origin is rarely used in the parental plasmid, or remains silent in several miniplasmids. Hence, in the present study, the multiple origin plasmid, R6K, was utilized as a model system to investigate DNA replication. A 1.6 kb PCR (polymerase chain reaction) amplified region of R6K containing the central regulatory segment (CRS) was examined to determine if membrane complexing is required for maintenance. Crude membrane extracts from exponentially growing cultures were prepared and sedimented through 30-50% (w/v) linear sucrose gradients. Fractions collected were probed using quantitative PCR which revealed two fractions containing CRS DNA. These complexes were localized in a region between the inner and outer membranes of Escherichia coli.

Base Sequence↗
PubMed1994

Mouse fibroblasts defective in thrombin mitogenesis possess functional proteolytically activated receptor for thrombin: requirement for a second signaling pathway.

Thrombin mitogenesis in fibroblasts requires two distinguishable subsets of signals; one generated by proteolytic cleavage, the other by high-affinity cell surface binding. Characterizing two closely related mouse embryo (ME) cell lines with high numbers of thrombin binding sites, we found that one line, B11-A, responds mitogenically to thrombin, epidermal growth factor (EGF), and serum, whereas the B11-B cell line is responsive to EGF and serum, but not to thrombin. The B11-B defect responsible for loss of thrombin responsiveness is not due to differences in the number of high-affinity binding sites, the affinity of thrombin binding to these sites, or to differences in cell surface expression of proteolytically activated receptors for thrombin (PART). The defect is also not associated with an inability of thrombin to activate PART since thrombin stimulates the cleavage-dependent induction of the proto-oncogene c-fos in both B11-A and B11-B cells. Various combinations of thrombin, synthetic thrombin receptor peptide, TRP-14 (SFFLRNPGENTFEL), platelet-derived growth factor (PDGF), and phorbol 12-myristate 13-acetate (PMA) were used to better define the defect in thrombin-mediated mitogenesis in B11-B cells. Direct activation of protein kinase C with PMA in combination with thrombin did not overcome B11-B nonresponsiveness. However, mitogenic responsiveness was regained in B11-B cells by simultaneous addition of PDGF and either thrombin or TRP-14. Therefore, the B11-B defect may involve a set of signals initiated by nonproteolytic thrombin interactions distinct from those initiated by PART, but related to the downstream signals initiated by the tyrosine kinase-associated growth factors, EGF and PDGF.

Amino Acid Sequence↗
PubMed1994

The electrostatic basis for the interfacial binding of secretory phospholipases A2.

Biochemical and structural data suggest that electrostatic forces play a critical role in the binding of secretory phospholipases A2 to substrate aggregates (micelles, vesicles, monolayers, and membranes). This initial binding (adsorption) of the enzyme to the interface is kinetically distinct from the subsequent binding of substrate to the buried active site. Thus, in the absence of specific active-site interactions, electrostatic forces operating at the molecular surface may orient and hold the enzyme at the interface. We have calculated the electrostatic potentials for 10 species of secretory phospholipases A2 whose atomic coordinates have been determined by x-ray crystallography. Most of these enzymes show a marked electrostatic sidedness that is accentuated to a variable degree by the presence of the essential cofactor calcium ion. This asymmetry suggests a discrete interfacial binding region on the protein's surface, the location of which is in general agreement with proposals derived from the results of chemical modification, mutational, and crystallographic experiments.

Amino Acid Sequence↗