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Biomedical subjects

D L Scott

Publications and source records attributed to D L Scott.

At least 73 records · Page 4Linked to original sources
PubMed1998

Rheumatoid factor isotypes, disease activity and the outcome of rheumatoid arthritis: comparative effects of different antigens.

The value of rheumatoid factor (RF) isotypes for assessing rheumatoid arthritis (RA) remains debatable. We investigated whether using different antigens to measure RF alters the relationships between RF isotypes and clinical variables. The association between IgA and IgM RF, disease activity, and cumulative anatomical joint damage in RA was studied in 140 patients. The RF isotypes were measured using both rabbit IgG and horse IgG as antigens. Cumulative anatomical damage was assessed radiologically using Larsen's score and disease activity was determined by C-reactive protein (CRP), the health assessment questionnaire (HAQ), and a combined disease activity score (DAS). Patients positive for IgA RF and IgM RF against rabbit IgG had significantly higher disease activity and more radiological damage than negative patients. With horse IgG as antigen these differences were smaller or absent. Patients positive for only IgM RF had milder disease than patients positive for IgA RF with or without IgM RF. The clinical relationships of RF isotypes are related to the antigen used. Measuring IgA RF against rabbit IgG provides most information about disease activity, functional impairment and joint damage.

Adult↗
PubMed1998

Early referral and outcome in rheumatoid arthritis.

In a cross-sectional study of 200 outpatients with rheumatoid arthritis (RA) we tested the hypothesis that early specialist referral within one year of disease onset reduces subsequent functional disability. Early referral was defined as being seen in a specialist unit within one year of the onset of symptoms. Functional outcome was measured using the physical functional section of the full test (NHP) and (HAQ). Additional information was collected on other factors likely to influence disability including age, sex, pain scores, and rheumatoid factor positivity. The difference in average HAQ and NHP physical function scores between late and early referrals was 0.34 and 11.0 respectively (p< 0.01 in both cases) using unequal-variance t-test. After adjusting for the other risk factors, multiple regression analysis showed late referral patients had greater NHP physical function scores than early-referred patients by approximately 8 points and there was a similar trend with HAQ. We conclude that early referral for specialist advice is associated with improved health status, with reduced physical function scores on the NHP.

Aged↗
PubMed1998

Improvements in quadriceps sensorimotor function and disability of patients with knee osteoarthritis following a clinically practicable exercise regime.

OBJECTIVE: Quadriceps sensorimotor dysfunction may be important in the pathogenesis of knee osteoarthritis (OA) and a determinant of disability. Exercise regimes can increase quadriceps strength, but whether this improves proprioception and reduces disability is uncertain. Moreover, research regimes involve protracted treatment which is clinically impracticable. METHODS: We compared quadriceps sensorimotor function and disability in 60 patients with knee OA, before and after an exercise regime, with a control group (n = 37) who did not exercise. RESULTS: Exercise improved quadriceps strength (mean change, 95% CI; 73 N, 26-19 N), voluntary activation (14%, 5-20%), knee joint position sense (0.6 degrees, 0.1-1.8 degrees), and reduced the Lequesne Index (3.5, 0.5-4) and aggregate time of four activities of daily living (8.4 s, 0.2-16.7 s). At 6 month follow-up, these improvements were maintained. The parameters of the control group were unchanged. CONCLUSIONS: These results substantiate the association between quadriceps sensorimotor dysfunction and disability, emphasizing the importance of quadriceps exercise in the management of knee OA. The regimen is relatively brief and clinically practicable, but could be adapted to make it more cost effective.

Adult↗
PubMed1998

Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage by a non-prostaglandin (PG) dependent "topical" action and by inhibiting cyclooxygenase. AIMS: To discriminate between these two effects by studying some key pathophysiological steps in NSAID enteropathy following administration of (R)- and (S)-flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol. METHODS: The effects of dinitrophenol, racemic, (R)-, and (S)-flurbiprofen on mitochondria were assessed in vitro and on key pathophysiological features of small intestinal damage in vivo (ultrastructure by electron microscopy, mucosal prostanoid concentrations, intestinal permeability, inflammation, and ulcer count) in rats. RESULTS: All the drugs uncoupled mitochondrial oxidative phosphorylation in vitro, caused mitochondrial damage in vivo, and increased intestinal permeability. Dinitrophenol and (R)-flurbiprofen caused no significant decreases in mucosal prostanoid concentrations (apart from a decrease in thromboxane (TX) B2 concentrations following (R)-flurbiprofen) while racemic and (S)- flurbiprofen reduced mucosal prostanoids significantly (PGE, TXB2, and 6-keto-PGF1alpha concentrations by 73-95%). Intestinal inflammation was significantly greater following administration of (S)-flurbiprofen and racemate than with dinitrophenol and (R)-flurbiprofen. No small intestinal ulcers were found following dinitrophenol or (R)-flurbiprofen while both racemic and (S)-flurbiprofen caused numerous ulcers. CONCLUSIONS: Dinitrophenol and (R)-flurbiprofen show similarities in their actions to uncouple mitochondrial oxidative phosphorylation in vitro, alter mitochondrial morphology in vivo, increase intestinal permeability, and cause mild inflammation without ulcers. Concurrent severe decreases in mucosal prostanoids seem to be the driving force for the development of severe inflammation and ulcers.

Animals↗
PubMed1998

Choice of NSAID and management strategy in rheumatoid arthritis and osteoarthritis. The impact on costs and outcomes in the UK.

OBJECTIVE: Although nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective therapy for rheumatoid arthritis, they are associated with significant adverse effects, the management of which imposes additional costs on the healthcare system. Prescribing NSAIDs which have a lower risk of major adverse effects as the first-line NSAID for patients with rheumatoid arthritis and osteoarthritis may be expected to lead to an improvement in clinical outcomes and reduce overall treatment costs. This analysis examines data from a published randomised controlled trial of 5 NSAIDs to explore these hypotheses. DESIGN AND SETTING: Data from a clinical trial comparing 5 NSAIDs were combined with published cost data to construct 2 clinical decision models, reflecting alternative approaches to the management of major and minor adverse effects in the UK. INTERVENTIONS: The 5 NSAIDs evaluated in the analysis were nabumetone, diclofenac, ibuprofen, piroxicam and naproxen, although only the results for ibuprofen and nabumetone are reported. MAIN OUTCOME MEASURES AND RESULTS: The total cost of care per patient receiving nabumetone was estimated to be between 25 pounds sterling (Pound) and 41 Pounds more expensive than ibuprofen. In a hypothetical cohort of 100,000 patients, there were between 690 and 821 more major adverse effects using ibuprofen than nabumetone. The cost per life-year gained (LYG) from using nabumetone rather than ibuprofen ranged between 1880 Pounds and 2517 Pounds (1995 values), depending upon the management of adverse effects. CONCLUSIONS: These results indicate that: (i) prescribing the newer, currently more expensive, NSAIDs will not necessarily lead to cost savings; (ii) the management of adverse effects can have a significant impact on costs; and (iii) the additional cost may be justifiable in terms of the mortality and morbidity gains associated with the new lower-risk NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have reduced life expectancy; however, there are few data on the changing pattern of causes of death with longterm followup, or on the longterm effect of early presentation. The objectives of this study were (1) to examine the effect of early presentation on subsequent mortality; (2) to compare the causes of death early and late in the followup period; and (3) to compare survival of the cohort with that of the general population (adjusted for age and sex) over a followup period of up to 27 years. METHODS: A cohort of 448 patients with RA (inpatients and outpatients), assembled 1968-74, were followed to December 31, 1990. Death certificates were obtained for all who had died and coded using the International Classification of Diseases. Kaplan-Meier survival curves were constructed. RESULTS: By the end of the study, 266 patients (59%) had died. The standardized mortality ratio (SMR) was 2.7 (95% CI 2.4-3.1). Patients who presented early continued to do well. Most excess deaths were due to cardiovascular disease. SMR due to infection, renal failure, and non-Hodgkin's lymphoma rose with disease duration. CONCLUSION: Patients with RA should be referred early, and those with chronic disease should be closely monitored for evidence of infection and renal impairment.

Adult↗
PubMed1998

Angiotensin I converting enzyme gene polymorphisms in systemic lupus erythematosus: decreased prevalence of DD genotype in African American patients.

The presence of the D (deletion) allele at the angiotensin converting enzyme (ACE) gene has been associated with a) adverse vascular events contributing to early mortality and b) progressive deterioration of renal function in a variety of chronic glomerular diseases. We investigated the potential role of ACE polymorphisms in patients with systemic lupus erythematosus (SLE). Two hundred and sixteen (216) SLE patients (121 Caucasians; 78 African Americans; and 17 other) and 200 normal controls were studied; 134 patients had evidence of renal disease. ACE genotypes were determined by a polymerase chain reaction based assay. The frequency of genotype DD was increased in African American normal controls compared to Caucasians (55% vs. 37%, p = 0.017) and in African American normal controls vs. African American lupus patients (55% vs. 30%, p = 0.008). Trend analysis of the genotype distribution across the three African American groups (renal, non-renal, controls) revealed a trend of increased frequency of I and decreased frequency of D as likelihood of renal disease increases (p = 0.008). No association between any ACE genotype with parameters of renal disease and/or response to therapy was identified. African American patients with lupus have a lower frequency of DD genotype as compared to African American normal controls. Further studies will be necessary to address whether this is due to decreased survival of these patients, a protective effect of DD genotype from developing the disease or a chance sample effect.

Adult↗
PubMed1997

Detecting biomolecules in picoliter vials using aequorin bioluminescence.

The quantitative determination of proteins in picoliter-volume vials is described. The assay is based on the bioluminescence of the photoprotein aequorin along with photon-counting detection. Using this approach, avidin can be detected at femtomole levels by taking advantage of its inhibitory effect on the bioluminescence signal generated by biotinylated recombinant aequorin. The picoliter vials were fabricated on glass substrates using a laser ablation technique. Parameters that affect the reproducibility of the assay such as the fabrication and calibration of the pipets, the fabrication of the vials, and the composition of the assay solutions were studied.

Aequorin↗
PubMed1997

In vivo proton magnetic resonance spectroscopy in polymyositis and dermatomyositis: a preliminary study.

The aim of the study is to determine whether biochemical abnormalities, such as lipid, creatine and choline metabolites, are observed in the more distal muscles of polymyositis (PM) and dermatomyositis (DM) patients. 12 patients suffering from chronic active PM/DM and 9 controls underwent a combined proton magnetic resonance (MR) imaging and proton MR spectroscopy study of the calf muscle. From a combination of T1-weighted MR images and corresponding fat suppressed images, fat infiltration into the muscle of both PM and DM patients was consistently observed. Muscular atrophy with a variable distribution was also noted in all patients. The biochemical profile of the localised proton MR spectra of soleus muscle showed reduction of both 'choline' to lipid and 'creatine' to lipid ratios in chronic PM and DM patients when compared with controls.

Adipose Tissue↗
PubMed1997

Calibration of micropipets using the bioluminescent protein aequorin.

A new method for calibrating micropipets and determining accurate injection volumes using a pressure-based injector has been developed. This method employs the bioluminescent protein aequorin and can be used to determine injection volumes as small as 3 pL. The calibration plots are linear over at least 3 orders of magnitude. In contrast to conventional micropipet calibration methods that employ fluorescent molecules, the present method produces small background signals.

Aequorin↗
PubMed1997

Structural aspects of interfacial adsorption. A crystallographic and site-directed mutagenesis study of the phospholipase A2 from the venom of Agkistrodon piscivorus piscivorus.

Recent genetic and structural studies have shed considerable light on the mechanism by which secretory phospholipases A2 interact with substrate aggregates. Electrostatic forces play an essential role in optimizing interfacial catalysis. Efficient and productive adsorption of the Class I bovine pancreatic phospholipase A2 to anionic interfaces is dependent upon the presence of two nonconserved lysine residues at sequence positions 56 and 116, implying that critical components of the adsorption surface differ among enzyme species (Dua, R., Wu, S.-K., and Cho, W. (1995) J. Biol. Chem. 270, 263-268). In an effort to further characterize the protein residues involved in interfacial catalysis, we have determined the high resolution (1.7 A) x-ray structure of the Class II Asp-49 phospholipase A2 from the venom of Agkistrodon piscivorus piscivorus. Correlation of the three-dimensional coordinates with kinetic data derived from site-directed mutations near the amino terminus (E6R, K7E, K10E, K11E, and K16E) and the active site (K54E and K69Y) defines much of the interface topography. Lysine residues at sequence positions 7 and 10 mediate the adsorption of A. p. piscivorus phospholipase A2 to anionic interfaces but play little role in the enzyme's interaction with electrically neutral surfaces or in substrate binding. Compared to the native enzyme, the mutant proteins K7E and K10E demonstrate comparable (20-fold) decreases in affinity and catalysis on polymerized mixed liposomes of 1-hexadecanoyl-2-(1-pyrenedecanoyl)-sn-glycero-3-phosphocholine and 1,2-bis[12-(lipoyloxy)dodecanoyl]-sn-glycero-3-phosphoglycerol, while the double mutant, K7E/K10E, shows a more dramatic 500-fold decrease in catalysis and interfacial adsorption. The calculated contributions of Lys-7 and Lys-10 to the free energy of binding of A. p. piscivorus phospholipase A2 to anionic liposomes (-1.8 kcal/mol at 25 degrees C per lysine) are additive (i.e. -3.7 kcal/mol) and together represent nearly half of the total binding energy. Although both lysine side chains lie exposed at the edge of the proposed interfacial adsorption surface, they are geographically remote from the corresponding interfacial determinants for the bovine enzyme. Our results confirm that interfacial adsorption is largely driven by electrostatic forces and demonstrate that the arrangement of the critical charges (e.g. lysines) is species-specific. This variability in the topography of the adsorption surface suggests a corresponding flexibility in the orientation of the active enzyme at the substrate interface.

Adsorption↗
PubMed1997

Genetically engineered bacteria: electrochemical sensing systems for antimonite and arsenite.

A bacterial sensing system that responds selectively to antimonite and arsenite has been investigated. The bacteria used in these studies have been genetically engineered to produce the enzyme beta-galactosidase in response to these ions. This is accomplished by using a plasmid that incorporates the gene for beta-galactosidase (reporter gene) under the control of the promoter of the ars operon. This plasmid also encodes for the ArsR protein, a regulatory protein of the ars operon, which, in the absence of antimonite or arsenite, restricts the expression of beta-galactosidase. In the presence of antimonite or arsenite the ArsR protein is released from the operator/ promoter region of the ars operon and beta-galactosidase is expressed. The activity of this enzyme was monitored electrochemically using p-aminophenyl beta-D-galactopyranoside as the substrate. The bacterial sensing system responds selectively to arsenite and antimonite (and to a lesser extent arsenate) and shows no significant response to phosphate, sulfate, nitrate, and carbonate.

Antimony↗
PubMed1997

Clinical guidelines for management.

Guidelines provide explicit recommendations and seek to influence practice using a formal process to disseminate advice on most effective management in the light of scientific evidence. They provide a framework for the evaluation and treatment of common clinical problems, but are not intended to replace clinical judgement. There is considerable variation in rheumatology practice, fueled by uncertainty about the optimal measurement of disease outcome. Guidelines can help identify and eliminate ineffective or unnecessary care as they are systematically developed statements to assist practitioners and patients' decisions about appropriate health care. There are North American guidelines for the initial evaluation of adult patients with acute musculoskeletal symptoms, the management of rheumatoid arthritis and the management of osteoarthritis. These are discussed together with proposed guidelines for the management of early rheumatoid arthritis and areas of research into the value of guidelines. It is recommended that future work in this area should: (i) identify aspects of current guidelines which are directly related to outcome; (ii) educate clinicians in these aspects of care; (iii) ensure they are introduced into practice and the outcome of care subsequently improves; (iv) regularly update the guidelines to reflect current opinion. Present guidelines that give broadly similar recommendations from North American and UK perspectives. However, the available evidence all points to large variations between how clinicians practise and how they make their decisions and it may be unlikely that laying down exact recipes for practice will necessarily influence the clinician. Guidelines may appear relevant but they could prove to have very limited utility.

Arthritis, Rheumatoid↗
PubMed1997

The Nottingham Health Profile as a measure of disease activity and outcome in rheumatoid arthritis.

Clinical measurement in rheumatoid arthritis (RA) has focused on articular problems. Although measures like the Health Assessment Questionnaire (HAQ) are widely used to determine functional impairment, there is a need to determine the overall effect of RA on general health status. We evaluated the relationship of a generic health status measure-the Nottingham Health Profile (NHP)-to the clinical, laboratory and radiological changes in the EULAR core data set for RA. Two hundred consecutive out-patients with RA were recruited. Their mean age was 58.9 yr and mean disease duration 11.3 yr. Patients completed the NHP and the following assessments were made: the EULAR Core Data Set, the duration of morning stiffness, the Disease Activity Score (DAS), rheumatoid factor (RF) levels, and Larsen's score for X-rays of hands and wrists. RA patients had higher scores on the NHP than both a random population sample and a second sample of patients with a variety of common diseases. NHP scores were not related to age or disease duration in RA. There was little relationship between perceived distress and the Larsen score, RF, ESR and C-reactive protein levels. Moderate associations were seen between NHP scores and disease activity measures, including the number of tender and swollen joints, pain and the duration of early morning stiffness, and also with a disability measure-the HAQ. NHP scores were highly related to disease activity measured by DAS. High DAS scores were associated with high scores in the energy level, pain and sleep sections of the NHP. The NHP gives relevant information about RA patients. They have high scores for pain, physical mobility and energy level sections, and also have high distress for sleep and emotional reactions.

Adult↗
PubMed1997

Sensorimotor changes and functional performance in patients with knee osteoarthritis.

OBJECTIVE: Muscles are essential components of our sensorimotor system that help maintain balance and perform a smooth gait, but it is unclear whether arthritic damage adversely affects muscle sensorimotor function. Quadriceps sensorimotor function in patients with knee osteoarthritis (OA) was investigated, and whether these changes were associated with impairment of functional performance. METHODS: Quadriceps strength, voluntary activation, and proprioceptive acuity (joint position sense acuity) were assessed in 103 patients with knee OA and compared with 25 healthy control subjects. In addition, their postural stability, objective functional performance (the aggregate time for four activities of daily living), and disabilities (lequesne index) were also investigated. RESULTS: Compared with the control subjects, the patients with knee OA had weaker quadriceps (differences between group mean 100N, CI 136, 63N), poorer voluntary activation (20% CI 13, 25%) that was associated with quadriceps weakness, and impaired acuity of knee joint position sense (1.28 degrees, CI 0.84, 1.73 degrees). As a group the patients were more unstable (p = 0.0017), disabled (10, CI 7, 11), and had poorer functional performance (19.6 seconds, CI 14.3, 24.9 seconds). The most important predictors of disability were objective functional performance and quadriceps strength. CONCLUSIONS: In patients with knee OA, articular damage may reduce quadriceps motoneurone excitability, which decreases voluntary quadriceps activation thus contributing to quadriceps weakness, and diminishes proprioceptive acuity. The arthrogenic impairment in quadriceps sensorimotor function and decreased postural stability was associated with reduced functional performance of the patients.

Activities of Daily Living↗