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Biomedical subjects

David L Scott

Publications and source records attributed to David L Scott.

At least 19 recordsLinked to original sources
PubMed2006

Is shared care with annual hospital review better value for money than predominantly hospital-based care in patients with established stable rheumatoid arthritis?

OBJECTIVE: To assess the cost effectiveness and cost effectiveness acceptability of symptom control delivered by shared care (SCSC) and aggressive treatment delivered in hospital (ATH) for established rheumatoid arthritis (RA). METHODS: Economic data were collected within the British Rheumatoid Outcome Study Group randomised controlled trial of SCSC and ATH. A broad perspective was used (UK National Health Service, social support services and patients). Cost per quality adjusted life year (QALY) gained, net benefit statistics and cost effectiveness acceptability curves were estimated. Costs and outcomes were discounted at 3.5%. Sensitivity analysis tested the robustness of the results to analytical assumptions. RESULTS: The mean (SD) cost per person was 4540 pounds (4700) in the SCSC group and 4440 pounds (4900) in the ATH group. The mean (SD) QALYs per person for 3 years were 1.67 (0.56) in the SCSC group and 1.60 (0.60) in the ATH group. If decision makers are prepared to pay > or = 2000 pounds to gain 1 QALY, SCSC is likely to be cost effective in 60-90% of cases. CONCLUSIONS: The primary economic analysis and sensitivity analyses indicate that SCSC is likely to be more cost effective than ATH in 60-90% of cases. This result seems to be robust to assumptions required by the analysis. This study is one of a limited number of randomised controlled trials to collect detailed resource use and health status data and estimate the costs and QALYs of treatment for established RA. This trial is one of the largest RA studies to use the EuroQol.

Adult↗
PubMed2006

Protein-lipid interactions: correlation of a predictive algorithm for lipid-binding sites with three-dimensional structural data.

BACKGROUND: Over the past decade our laboratory has focused on understanding how soluble cytoskeleton-associated proteins interact with membranes and other lipid aggregates. Many protein domains mediating specific cell membrane interactions appear by fluorescence microscopy and other precision techniques to be partially inserted into the lipid bilayer. It is unclear whether these protein-lipid-interactions are dependent on shared protein motifs or unique regional physiochemistry, or are due to more global characteristics of the protein. RESULTS: We have developed a novel computational program that predicts a protein's lipid-binding site(s) from primary sequence data. Hydrophobic labeling, Fourier transform infrared spectroscopy (FTIR), film balance, T-jump, CD spectroscopy and calorimetry experiments confirm that the interfaces predicted for several key cytoskeletal proteins (alpha-actinin, Arp2, CapZ, talin and vinculin) partially insert into lipid aggregates. The validity of these predictions is supported by an analysis of the available three-dimensional structural data. The lipid interfaces predicted by our algorithm generally contain energetically favorable secondary structures (e.g., an amphipathic alpha-helix flanked by a flexible hinge or loop region), are solvent-exposed in the intact protein, and possess favorable local or global electrostatic properties. CONCLUSION: At present, there are few reliable methods to determine the region of a protein that mediates biologically important interactions with lipids or lipid aggregates. Our matrix-based algorithm predicts lipid interaction sites that are consistent with the available biochemical and structural data. To determine whether these sites are indeed correctly identified, and whether use of the algorithm can be safely extended to other classes of proteins, will require further mapping of these sites, including genetic manipulation and/or targeted crystallography.

Algorithms↗
PubMed2006

Rheumatoid arthritis: acute presentations and urgent complications.

Rheumatoid arthritis is a common chronic disorder. Its many complications, comorbidities and adverse effects of treatment often involve general physicians. Particular risks are septic arthritis, systemic infections, upper gastrointestinal ulcers and systemic vasculitis. Delayed diagnosis will result in poor outcomes.

Acute Disease↗
PubMed2005

Huntingtin associates with acidic phospholipids at the plasma membrane.

We have identified a domain in the N terminus of huntingtin that binds to membranes. A three-dimensional homology model of the structure of the binding domain predicts helical HEAT repeats, which emanate a positive electrostatic potential, consistent with a charge-based mechanism for membrane association. An amphipathic helix capable of inserting into pure lipid bilayers may serve to anchor huntingtin to the membrane. In cells, N-terminal huntingtin fragments targeted to regions of plasma membrane enriched in phosphatidylinositol 4,5-bisphosphate, receptor bound-transferrin, and endogenous huntingtin. N-terminal huntingtin fragments with an expanded polyglutamine tract aberrantly localized to intracellular regions instead of plasma membrane. Our data support a new model in which huntingtin directly binds membranes through electrostatic interactions with acidic phospholipids.

Amino Acid Sequence↗
PubMed2005

What are the consequences of early rheumatoid arthritis for the individual?

Rheumatoid arthritis (RA) has important impacts on health that can be related to the World Health Organization's new International Classification of Functioning, Disability and Health (ICF framework). The physical consequences of RA for the individual relate to body functions and structures in the ICF framework. The functional consequences of RA are related to activity in the ICF framework, and the impact of RA on society relates to participation in the ICF framework. Despite conventional treatment, early RA continues to result in significant physical consequences for most patients. From the patients' perspective, this primarily results from persistent pain, although symptoms such as fatigue and depression are also relevant. This is confirmed from the clinician's perspective by the infrequency of remission, persistence of disease activity and unrelenting radiographic progression in early RA. Patients with early RA often progress, within only a few years, to significant disability. This has mainly been shown in studies using the Health Assessment Questionnaire as the disability measure, although a small number of studies using generic health measures such as Short Form-36 have reached similar conclusions. RA patients and their friends and families incur the majority of costs associated with early RA. Many patients are not able to continue to work at the same level as they would have anticipated had they not developed RA. Later on, society bears an increased load, especially in patients with higher levels of disability; this results from major social care costs and interventions such as surgery. However, the evidence favouring expensive biological therapies, even in early RA, is likely to turn this analysis on its head in the near future.

Arthritis, Rheumatoid↗
PubMed2005

Physical function and health related quality of life: analysis of 2-year data from randomized, controlled studies of leflunomide, sulfasalazine, or methotrexate in patients with active rheumatoid arthritis.

OBJECTIVE: To determine whether improvements in physical function and health related quality of life (HRQOL) are sustained over 2 years of blinded treatment with leflunomide (LEF), methotrexate (MTX), or sulfasalazine (SSZ) in patients with active rheumatoid arthritis (RA). METHODS: Three phase III randomized, controlled trials compared LEF, MTX, and SSZ in patients with active RA. Improvements in physical function were assessed by Health Assessment Questionnaire Disability Index (HAQ-DI) and Modified Health Assessment Questionnaire (MHAQ); monthly MHAQ and mean HAQ scores were used to calculate American College of Rheumatology responses; HAQ-DI was assessed at baseline and 6-month intervals. In US301, the Medical Outcomes Study 36-Item Short-Form questionnaire (SF-36) assessed treatment-associated changes in HRQOL at baseline and 6-month intervals. RESULTS: Mean and median improvements in HAQ-DI after 12 and 24 months of active treatment in all phase III protocols significantly exceeded -0.22 or a minimum clinically important difference (MCID). These improvements closely reflected positive changes in SF-36 that met or exceeded MCID in all domains with LEF and MTX treatment. Problem Elicitation Technique Top 5 scores reflected improvements in performance of physical activities most important to patients. CONCLUSION: Improvements in physical function were sustained over 24 months of successful treatment with LEF, MTX, and SSZ, and reflected improvements in mental as well as physical domains of HRQOL.

Antirheumatic Agents↗
PubMed2005

The relationship between social deprivation, disease outcome measures, and response to treatment in patients with stable, long-standing rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) with lower socioeconomic status (SES) are known to have more severe disease, more comorbidity, and higher mortality. It is not known whether SES influences response to treatment in RA. We examined the relationship between area of residence (as a surrogate for SES) and baseline outcome measures and response to treatment, using data from the British Rheumatoid Outcome Study Group randomized controlled trial of aggressive versus symptomatic treatment of long-standing, stable RA. METHODS: A total of 466 patients from 5 centers were recruited to the trial. Baseline data included age, sex, smoking status, and comorbidity. Patients were assigned a Townsend score (a measure of social deprivation) according to their area of residence. Outcome measures including the Disease Activity Score (DAS28), Health Assessment Questionnaire, Medical Outcomes Study Short Form-36, and EuroQol (EQ5D) were recorded at the beginning and end of the 3 year trial. The baseline, 3 year values, and change data were examined by Townsend quintile adjusting for each treatment arm. RESULTS: Significant relationships between increasing social deprivation by area of residence and higher disease activity, higher pain, poorer physical function, poorer emotional aspects of mental health, and lower quality of life were found at baseline (adjusted for age, sex, disease duration, current smoking, treatment center, and treatment group). During the 3 year trial period, patients from the most deprived areas showed greater improvement, with statistically significant greater improvement on DAS28 (p = 0.041) and 28 tender joint count (p = 0.015). CONCLUSION: Area of residence is related to the severity of RA at recruitment and is a predictor of response in a clinical trial situation. The results suggest that measures of SES should be recorded for patients enrolled in clinical trials, longitudinal observational studies, and in the clinical setting.

Aged↗
PubMed2004

Rapid isolation of DNA from chocolate and date palm tree crops.

DNA isolation from plants is sometimes difficult due to the existence of high levels of endogenous phenolics, polysaccharides, or other substances that may interfere with DNA extraction. Theobroma cacao produces high levels of anthocyanins in young leaves. These plant polyphenols can interfere with DNA isolation. After examination of various procedures for DNA isolation, two commercial isolation procedures have proved to be repeatedly successful using these types of plants, the D(2) BioTechnologies DNA X-tract Plus kit and the Qiagen DNeasy Plant System DNA kit. These commercial kits were chosen for their speed and ease over the CTAB procedure, which is more labor intensive. All protocols assessed yielded DNA suitable for AFLP or SSR procedures. An additional factor in DNA extraction efficiency is the degree of cell breakage, which may be more difficult with the highly fibrous leaf tissue that is found in many monocots, including date palm. Two commercially produced pieces of equipment were tested and, for cacao, both resulted in template DNA yielding amplification product in AFLP or SSR fingerprinting. However, for the fibrous date palm leaf, the larger FastPrep homogenizer consistently yielded DNA that generated higher signals when amplified than did the smaller Disruptor Genie.

Arecaceae↗
PubMed2004

Use of imaging to assess patients with muscle disease.

PURPOSE OF REVIEW: A variety of imaging modalities can be used in muscle diseases. These range from plain x-rays to conventional magnetic resonance imaging (MRI) and phosphate magnetic resonance spectroscopy (MRS). This review places these imaging methods into their relevant clinical contexts on the basis of the best available research evidence. RECENT FINDINGS: Plain x-rays have limited roles in imaging patients with muscle disease. An exception is identifying calcinosis in patients with myositis; there is some evidence that effective early treatment may reduce its frequency and severity. Scintigraphy has been used in several centers but it appears to have limited value. Ultrasound, though successfully used in a number of units, is relatively little used, though the evidence suggests it would be sensible if this method were adopted more widely. MRI is currently the key imaging modality. It is useful in diagnosing pyomyositis, diabetic muscle infarction, and inflammatory myositis. Its main proven value is identifying the best sites for biopsy in early myositis, though it can help differentiate between different forms of muscle disease when there is diagnostic uncertainty. The area of most intense ongoing original research is MRS, which can show the bioenergetics of normal and abnormal muscles. Changes in the ratios of inorganic phosphate and phosphocreatine, particularly during exercise provide insights into the metabolic consequences of muscle diseases and may, in the future, suggest alternative therapeutic approaches. SUMMARY: Magnetic resonance imaging is a useful adjunct when diagnosing muscle diseases. It is particularly useful to identify suitable sites for muscle biopsy. Ultrasound may be equally helpful, though there is less supporting evidence from existing research. MRS is the area in which most current novel research is focused.

Humans↗
PubMed2004

Pursuit of optimal outcomes in rheumatoid arthritis.

The aim of this review is to describe methods of quantifying disease activity and symptomatology and discuss treatment goals for rheumatoid arthritis (RA). The benefits and limitations of existing therapeutic approaches, the importance of early therapy in preventing disease progression and the place of biologicals in early therapy will be discussed. Disease activity and symptomatology in RA are often measured using a set of core endpoints that incorporate pain, patient global assessment, physical disability, swollen joints, tender joints, acute phase reactants, physician global assessment and radiographic imaging of joints. Imaging of joints is the only means by which to measure the effects of disease-modifying antirheumatic drugs (DMARDs) on the irreversible joint damage that occurs during RA. There is increasing evidence that this damage and its functional consequences occur early in the onset of disease. The consensus is that patients with RA should be treated with DMARDs earlier rather than later in the disease process. Remission, or a state of sustained response or low disease activity that is not damaging or disabling, is the ideal goal of therapy for RA, but formal criteria defining a state of remission need to be revised and, ideally, updated to include a radiographic component. Currently available DMARDs are limited in their ability to achieve early, sustained response or remission, by delayed onset of action, cumulative toxicity and lack of long-term therapeutic response. It is hoped that the emergence of novel DMARDs--targeted biological agents, such as anti-tumour necrosis factor-alpha (anti-TNF-alpha)--will help to counteract such limitations and will allow early DMARD use to be adopted as standard practice in place of their use as a last resort therapy after failure of other treatment. One such biological agent, etanercept, has been shown to reduce radiographic disease progression and induce overall clinical response during the early stages of RA. It is significantly more effective and fast-acting than methotrexate, one of the most effective, commonly used DMARDs.

Antirheumatic Agents↗
PubMed2004

Radiological progression in established rheumatoid arthritis.

Radiographic progression in established rheumatoid arthritis (RA) gives an objective measure of anatomical damage that defines the course of the disease and the longterm effects of treatment. This review defines the rate of joint damage, progression in individual joints, and predictive factors. Six longitudinal prospective studies of 103-378 RA patients followed for up to 20 years show that initially patients had less than 3% maximum possible damage, this rose to 11% maximal damage by 5 years and over 40% by 20 years. The rate of progression changed from an initial rate of 1.6% maximal progression annually to a later rate of 2.0% annually. Between 1977 and 1998 5 prospective studies of 40-147 hospital-based RA cases seen within 12 months of developing RA showed 60-73% of cases developed one or more erosions in the hands and wrists. However a community-based cohort of early RA patients reported, more recently showed 41% of 335 cases developed erosions. There are marked differences between joints. The wrists show most damage and in one series of 103 cases, by 20 years 18% of wrists were completely destroyed and only 25% were nonerosive. The same series showed ankle joints are rarely involved; at 20 years only 7 patients had major abnormalities with minor changes in 17 cases. Rheumatoid factor (RF) positivity is the dominant predictor of erosive damage. In one survey of 439 cases who presented with inflammatory polyarthritis, patients with an initial high RF had over twice the radiographic progression of seronegative cases. A further 8 studies, which enrolled 1395 patients, all show a strong link between radiolographic damage and RF status. The other key clinical predictor is disease activity indicated by surrogate measures such as the C-reactive protein (CRP) level. Suppressing disease activity judged by CRP levels not only decreases the progression of joint damage, but also may reduce new joint involvement to a greater extent than progression in already damaged joints. New potential markers of damage such as anticyclic citrullinated peptide ELISA tests may further improve the identification of those RA patients most at risk of erosive damage and, by implication, most in need of suppressive therapy.

Arthritis, Rheumatoid↗
PubMed2004

Donation after cardiac death: the University of Wisconsin experience.

OBJECTIVES: The objective of this analysis was to compare the results of transplantation of livers, pancreases, kidneys, and lungs from donation after cardiac death (DCD) donors to organs transplanted from donation after brain death (DBD) donors. METHODS: From January 1984 through July 2000, outcomes of 382 DCD kidneys were compared to 1,089 kidneys (SPK) transplants and 36 liver transplants from DCD donors were compared to 455 SPK and 510 liver transplants from DBD donors. Likewise, 31 simultaneous pancreas-kidneys transplants from DBD donors. RESULTS: The rate of delayed graft function (DGF) was higher in kidneys transplanted from DCD donors (27.5% versus 21.3%, p=0.01). Likewise, discharge creatinines were higher in recipients of DCD kidneys (1.9 mg/dL versus 1.7 mg/dL, p=0.001). There was no difference in 10-year graft survival between DCD and DBD recipients (45.0% versus 48.0%, p=0.054). No difference in 5-year pancreatic and renal allograft survival was seen after SPK from DCD or DBD donors. After liver transplantation, biliary strictures were higher in recipients of DCD livers (13.9% versus 8.0%, p=0.03). Likewise, 3-year patient and graft survivals were lower for recipients of DCD livers (65.8% versus 84.9%, p=0.01; and 58.6% versus 76.9%, p=0.006). CONCLUSIONS: This large experience with transplantation from DCD donors demonstrates that similar patient and graft survivals can be expected when compared to recipients of organs from DBD donors.

Brain Death↗
PubMed2003

Evidence for early disease-modifying drugs in rheumatoid arthritis.

Some research evidence supports early aggressive treatment of rheumatoid arthritis (RA) using combination therapy with two or more disease modifying anti-rheumatic drugs (DMARDs) plus steroids, or even DMARDs plus an anti-TNF. By contrast, conservatively delayed DMARD monotherapy, given after non-steroidal anti-inflammatory drugs have failed, has been criticised. However, recent long-term studies highlight the complexities in evaluating whether to abandon pyramidal treatment in favour of early DMARDs. Although patients given early DMARD therapy show short-term benefits, longer-term results show no prolonged clinical advantages from early DMARDs. By 5 years patients receiving early DMARDs had similar disease activity and comparable health assessment questionnaire scores to patients who received DMARDs later in their disease course. X-ray progression was persistent and virtually identical in both groups. These negative findings do not invalidate the case for early DMARD therapy, as it is gives sustained reductions in disease activity in the early years of treatment without excessive risks from adverse effects. However, early DMARDs alone do not adequately control RA in the longer term. This may require starting with very aggressive therapy or treating patients more aggressively after early DMARD therapy has been initiated.

Editorial↗
PubMed2003

Crystallization and preliminary X-ray analysis of Der f 2, a potent allergen derived from the house dust mite (Dermatophagoides farinae).

Although a number of allergens have been identified and isolated, the underlying molecular basis for the potent immune response is poorly understood. House dust mites (Dermatophagoides sp.) are ubiquitous contributors to atopy in developed countries. The rhinitis, dermatitis and asthma associated with allergic reactions to these arthropods are frequently caused by relatively small (125-129 amino acids) mite proteins of unknown biological function. Der f 2, a major allergen from the mite D. farinae, has been recombinantly expressed, characterized and crystallized. The crystals belong to the tetragonal space group I4(1)22, with unit-cell parameters a = b = 95.2, c = 103.3 A. An essentially complete (97.2%) data set has been collected to 2.4 A at a synchrotron source. Attempts to solve the crystal structure of Der f 2 by molecular replacement using the NMR coordinates for either Der f 2 or Der p 2 (the homologous protein from D. pteronyssinus) failed, but preliminary searches using the crystalline Der p 2 atomic coordinates appear to be promising.

Allergens↗
PubMed2003

Crystallization and preliminary X-ray analysis of recombinant human acid beta-glucocerebrosidase, a treatment for Gaucher's disease.

Acid beta-glucocerebrosidase (N-acylsphingosyl-1-O-beta-D-glucoside:glucohydrolase) is a lysosomal glycoprotein that catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide. Inadequate levels of this enzyme underly the pathophysiology of Gaucher's disease. Cerezyme (Genzyme Corporation, Cambridge, MA, USA) is a partially deglycosylated form of recombinant human acid beta-glucocerebrosidase that is used in the treatment of Gaucher patients. Although acid beta-glucocerebrosidase belongs to a large family of glycosidases, relatively little is known regarding its structural biology. Here, the crystallization and the initial diffraction analysis of Cerezyme are reported. The crystals are C-centered orthorhombic, with unit-cell parameters a = 285.0, b = 110.2, c = 91.7 A. A 99.9% complete data set has been collected to 2.75 A with an R(sym) of 8.8%.

Crystallization↗