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Biomedical subjects

R Milne

Publications and source records attributed to R Milne.

At least 37 records · Page 2Linked to original sources
PubMed2001

Involving consumers in a needs-led research programme: a pilot project.

OBJECTIVES: To describe the methods used for involving consumers in a needs-led health research programme, and to discuss facilitators, barriers and goals. DESIGN: In a short action research pilot study, we involved consumers in all stages of the Health Technology Assessment (HTA) Programme: identifying and prioritizing research topics; commissioning and reporting research; and communicating openly about the programme. We drew on the experience of campaigning, self-help and patients' representative groups, national charities, health information services, consumer researchers and journalists for various tasks. We explored consumer literature as a potential source for research questions, and as a route for disseminating research findings. These innovations were complemented by training, one-to-one support and discussion. A reflective approach included interviews with consumers, co-ordinating staff, external observers and other programme contributors, document analysis and multidisciplinary discussion (including consumers) amongst programme contributors. RESULTS: When seeking research topics, face-to-face discussion with a consumer group was more productive than scanning consumer research reports or contacting consumer health information services. Consumers were willing and able to play active roles as panel members in refining and prioritizing topics, and in commenting on research plans and reports. Training programmes for consumer involvement in service planning were readily adapted for a research programme. Challenges to be overcome were cultural divides, language barriers and a need for skill development amongst consumers and others. Involving consumers highlighted a need for support and training for all contributors to the programme. CONCLUSIONS: Consumers made unique contributions to the HTA Programme. Their involvement exposed processes which needed further thought and development. Consumer involvement benefited from the National Co-ordinating Centre for Health Technology Assessment (NCCHTA) staff being comfortable with innovation, participative development and team learning. Neither recruitment nor research capacity were insurmountable challenges, but ongoing effort is required if consumer involvement is to be sustained.

Biomedical Technology↗
PubMed2001

In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis.

The in vitro pharmacodynamic properties of colistin and colistin methanesulfonate were investigated by studying the MICs, time-kill kinetics, and postantibiotic effect (PAE) against mucoid and nonmucoid strains of Pseudomonas aeruginosa isolated from patients with cystic fibrosis. Twenty-three clinical strains, including multiresistant strains, and one type strain were selected for MIC determination. Eleven strains were resistant; MICs for these strains were >128 mg/liter. For the susceptible strains, MICs of colistin ranged from 1 to 4 mg/liter, while the MICs of colistin methanesulfonate were significantly higher and ranged from 4 to 16 mg/liter. The time-kill kinetics were investigated with three strains at drug concentrations ranging from 0.5 to 64 times the MIC. Colistin showed extremely rapid killing, resulting in complete elimination at the highest concentrations within 5 min, while colistin methanesulfonate killed more slowly, requiring a concentration of 16 times the MIC to achieve complete killing within 24 h. Colistin exhibited a significant PAE of 2 to 3 h at 16 times the MIC against the three strains after 15 min of exposure. For colistin methanesulfonate, PAEs were shorter at the concentrations tested. Colistin methanesulfonate had lower overall bactericidal and postantibiotic activities than colistin, even when adjusted for differences in MICs. Our data suggest that doses of colistin methanesulfonate higher than the recommended 2 to 3 mg/kg of body weight every 12 h may be required for the effective treatment of P. aeruginosa infections in cystic fibrosis patients.

Anti-Bacterial Agents↗
PubMed2001

Systematic review of immunomodulatory drugs for the treatment of people with multiple sclerosis: Is there good quality evidence on effectiveness and cost?

OBJECTIVE: To review the clinical effectiveness and costs of a range of disease modifying drugs in multiple sclerosis. Drugs included are azathioprine, cladribine, cyclophosphamide, intravenous immunoglobulin, methotrexate, and mitoxantrone. METHODS: Electronic databases and bibliographies of related papers were searched for randomised controlled trials (RCTs) and systematic reviews, and experts and pharmaceutical companies were contacted for further information. Inclusion and quality criteria were assessed, data extraction undertaken by one reviewer and checked by a second reviewer, with discrepancies being resolved through discussion. Costs were obtained and cost-effectiveness papers sought. RESULTS: Seventeen studies met the inclusion criteria for the review. Evidence for the clinical effectiveness of the drugs showed some reductions in relapse rates and/or progression to disability for people with MS, although benefits may be lessened by wide ranging side effects. Annual drug costs/patient are estimated to range from 60 pounds to 10200 pounds. No cost effectiveness studies were found. CONCLUSION: Evidence for the effectiveness of these drugs in multiple sclerosis is problematic because there are few good quality trials for each drug. Trials often have methodological limitations and use different treatment regimes, patient groups, and outcome measures. Well conducted trials using outcome measures with clinical significance for groups of patients with different types of multiple sclerosis and long term follow up are needed if the evidence base of treatment for the disease is to be improved.

Adjuvants, Immunologic↗
PubMed2000

Apolipoprotein D.

Apolipoprotein D (apoD) is a 29-kDa glycoprotein that is primarily associated with high density lipoproteins in human plasma. It is an atypical apolipoprotein and, based on its primary structure, apoD is predicted to be a member of the lipocalin family. Lipocalins adopt a beta-barrel tertiary structure and transport small hydrophobic ligands. Although apoD can bind cholesterol, progesterone, pregnenolone, bilirubin and arachidonic acid, it is unclear if any, or all of these, represent its physiological ligands. The apoD gene is expressed in many tissues, with high levels of expression in spleen, testes and brain. ApoD is present at high concentrations in the cyst fluid of women with gross cystic disease of the breast, a condition associated with increased risk of breast cancer. It also accumulates at sites of regenerating peripheral nerves and in the cerebrospinal fluid of patients with neurodegenerative conditions, such as Alzheimer's disease. ApoD may, therefore, participate in maintenance and repair within the central and peripheral nervous systems. While its role in metabolism has yet to be defined, apoD is likely to be a multi-ligand, multi-functional transporter. It could transport a ligand from one cell to another within an organ, scavenge a ligand within an organ for transport to the blood or could transport a ligand from the circulation to specific cells within a tissue.

Animals↗
PubMed2000

Binding of an antibody mimetic of the human low density lipoprotein receptor to apolipoprotein E is governed through electrostatic forces. Studies using site-directed mutagenesis and molecular modeling.

Monoclonal antibody 2E8 is specific for an epitope that coincides with the binding site of the low density lipoprotein receptor (LDLR) on human apoE. Its reactivity with apoE variants resembles that of the LDLR: it binds well with apoE3 and poorly with apoE2. The heavy chain complementarity-determining region (CDRH) 2 of 2E8 shows homology to the ligand-binding domain of the LDLR. To define better the structural basis of the 2E8/apoE interaction and particularly the role of electrostatic interactions, we generated and characterized a panel of 2E8 variants. Replacement of acidic residues in the 2E8 CDRHs showed that Asp(52), Glu(53), and Asp(56) are essential for high-affinity binding. Although Asp(31) (CDRH1), Glu(58) (CDRH2), and Asp(97) (CDRH3) did not appear to be critical, the Asp(97) --> Ala variant acquired reactivity with apoE2. A Thr(57) --> Glu substitution increased affinity for both apoE3 and apoE2. The affinities of wild-type 2E8 and variants for apoE varied inversely with ionic strength, suggesting that electrostatic forces contribute to both antigen binding and isoform specificity. We propose a model of the 2E8.apoE immune complex that is based on the 2E8 and apoE crystal structures and that is consistent with the apoE-binding properties of wild-type 2E8 and its variants. Given the similarity between the LDLR and 2E8 in terms of specificity, the LDLR/ligand interaction may also have an important electrostatic component.

Antibodies, Monoclonal↗
PubMed2000

Immunological analysis of the tegument phosphoprotein ppUL83 of human cytomegalovirus.

Immunological properties of the tegument phosphoprotein, ppUL83, of human cytomegalovirus (HCMV), expressed using a replication deficient recombinant adenovirus vector (RAd83) are described. The initial characterisation of this protein was carried out by immunofluorescence (IF), immunoprecipitation (RIP) and immunoblotting using nine mouse monoclonal antibodies (Mabs) directed against five linear and four conformational epitopes of ppUL83. The reactivity of the recombinant protein with the Mabs was similar to that observed with native ppUL83, although, the kinetics of its expression was in agreement with expression derived from the HCMV major immediate early promoter (MIEP). The recombinant antigen was used successfully in an Enzyme Immunoassay (EIA) for the detection of IgG class antibodies in 171 sequential sera taken from 21 heart transplant recipients. Comparison of HCMV-infected and RAd83-infected cell extracts in this experiment showed that recombinant antigen could substitute whole virus extracts as a single well-characterised protein in EIA. Serum IgG avidity measurements, using the recombinant ppUL83, differentiated between primary and past HCMV infections in the population studied.

Adenoviruses, Human↗
PubMed2000

Eye movement desensitization and reprocessing in the treatment of post-traumatic stress disorder: a review of an emerging therapy.

BACKGROUND: Eye Movement Desensitization and Reprocessing (EMDR) is a relatively new form of psychotherapy for post-traumatic stress disorder. We critically reviewed randomized controlled trials of EMDR. METHODS: A wide range of electronic databases and reference lists of articles obtained were searched and relevant experts were consulted. Studies were critically appraised according to established criteria. RESULTS: We found 16 published randomized controlled trials (RCTs) comparing EMDR with alternative psychotherapy treatments, variants of EMDR and with delayed treatment groups. Studies were generally small (mean number of patients = 35) and of variable methodological quality, with only five reporting blinding of outcome assessors to treatment allocation, and in some cases with high loss to follow-up. In most cases EMDR was shown to be effective at reducing symptoms up to 3 months after treatment. In one case benefit was maintained up to 9 months and in another (uncontrolled) follow-up treatment effect was present at 15 months. Two studies suggest that EMDR is as effective as exposure therapies, three claim greater effectiveness in comparison to relaxation training, and three claim superiority over delayed treatment groups. Of the studies examining specific treatment components, two found that treatment with eyes moving was more effective than eyes fixed, while three studies found the two procedures to be of equal effectiveness. CONCLUSION: The evidence in support of EMDR is of limited quality but results are encouraging for this inexpensive, simple therapy. Further research is warranted in larger samples with longer periods of follow-up.

Desensitization, Psychologic↗
PubMed2000

What are the relative merits of the sources used to identify potential research priorities for the NHS HTA programme?

The NHS Health Technology Assessment (HTA) Programme runs an annual process of identifying suggestions for health technology assessment. The objective of this paper is to describe and evaluate the relative importance of the different sources used by the program in 1998 to identify potential priorities. There were four different sources: a) a widespread consultation of healthcare commissioners, providers and consumers; b) research recommendations from systematic reviews; c) reconsidering previous research priorities which had not been taken forward for funding; and d) horizon scanning. Collectively, the four sources generated just over 1,100 HTA suggestions. By far the largest source of suggestions and priorities was the widespread consultation. However, the success rate of this source, in terms of being commissioned, was low. Research recommendations from systematic reviews provided the second largest source of priorities and the best success rate of all sources. Value was found from different sources for different healthcare areas.

Health Priorities↗
PubMed2000

Leflunomide and rheumatoid arthritis: a systematic review of effectiveness, safety and cost implications.

OBJECTIVE: To assess the effectiveness, safety and cost implications of leflunomide treatment for rheumatoid arthritis. DESIGN: Systematic review. SETTING: Four trials retrieved from Medline, Embase, the Cochrane Library, Econlit, HMIC (Dhdata), HMIC (Helmis), HMIC (King's Fund Database) and Best Evidence3. MAIN OUTCOME MEASURES: Efficacy measures (including tender joint counts, swollen joint counts, assessment of functioning, Health Assessment Questionnaire, Modified Health Assessment Questionnaire, pain (visual analogue scale), Erythrocyte Sedimentation Rate, C-reactive Protein), radiological progression and treatment adverse events. RESULTS: Leflunomide therapy was demonstrated to be significantly superior to placebo in relation to the efficacy outcome measures and it slowed the radiological progression of patients' disease in three studies. Treatment success and duration of sustained response were also significantly superior than on placebo, as were quality of life measures. Leflunomide treatment was comparable to sulphasalazine and methotrexate with respect to efficacy, radiological progression and quality of life measures. The most common adverse effects leading to withdrawal from leflunomide treatment were gastrointestinal symptoms (diarrhoea and nausea), allergic reactions (rash and pruritus), alopecia, dyspepsia, hypertension and elevated transaminase levels. Weight loss and dizziness have also been reported for leflunomide therapy. Leflunomide is more expensive than most DMARDs, costing about pound400 a year more than sulphasalazine. CONCLUSION: Despite the small number of published articles relating to leflunomide treatment, the evidence suggests that leflunomide is similar in efficacy to both sulphasalazine and methotrexate, although with a differential pattern of side-effects. There is a need for further research to assess the long-term outcomes of leflunomide treatment.

Aged↗
PubMed2000

Orlistat for the treatment of obesity: rapid review and cost-effectiveness model.

The aim of this study is to clarify the potential benefits, disbenefits and costs of Orlistat for the treatment of obesity. The method was a search for relevant systematic reviews and randomized controlled trials, in Medline, Pre-Medline, Embase and the Cochrane Library, using Orlistat and its synonyms. Identified trials were appraised using a standard appraisal checklist and trial data were extracted for use in cost-effectiveness modelling. Three large multicentre, randomized placebo controlled trials were included in the rapid review. On average, Orlistat results in obese people losing an additional 3-4% of their initial body weight over diet alone during a 2 year period. There was no strong evidence that this short-term weight loss would have a longer-term impact on morbidity and mortality. The cost utility of Orlistat treatment was estimated at around 46,000 Pounds per Quality Adjusted Life Year gained (extreme values sensitivity analysis 14,000 Pounds to 132,000 Pounds). This rapid review raises some important questions about the potential value of Orlistat in the treatment of obesity. Further research is needed, not only to clarify the longer-term impact of Orlistat treatment, but also to uncover the longer-term impact on mortality and morbidity from short-term weight loss.

Anti-Obesity Agents↗
PubMed2000

Implantable cardioverter defibrillators: arrhythmias. A rapid and systematic review.

PROPOSED SERVICE: The service proposed is the use of implantable cardioverter defibrillators (ICDs) in the management of risk factors leading to sudden cardiac death (SCD). ICDs are similar in size to a pacemaker and are intended to prevent death due to life-threatening ventricular tachyarrhythmias. EPIDEMIOLOGY AND BACKGROUND: SCD occurs in approximately 100,000 people annually in the UK and is usually due to ventricular tachyarrhythmia. Increasing numbers of people are surviving a first episode of ventricular tachyarrhythmia and are at high risk of further episodes. Standard treatments for those at high risk have been anti-arrhythmic drugs, catheter ablation or surgery and, increasingly, vasodilating beta-blockers. METHODS: Electronic databases were searched for the period 1980-99. In addition, bibliographies of related papers were assessed for relevant studies, and experts were contacted to identify additional published and unpublished references. Studies were included if they were systematic reviews, meta-analyses or randomised controlled trials (RCTs) comparing ICDs with conventional therapy in people at high risk of SCD. NUMBER AND QUALITY OF STUDIES AND DIRECTION OF EVIDENCE: Seven RCTs on effectiveness the majority of which were of good quality, eight cost-effectiveness analyses most of which were older studies and based on non-UK data, and two good-quality literature reviews one of which was a critical appraisal of the literature of effectiveness and cost-effectiveness of ICD therapy, and the other a review of the cost-effectiveness of ICD therapy. These showed changes in absolute risk of total mortality ranging from an increase of 1.7% to a reduction of 22.8% (relative risk reductions of -7% to +54%). SUMMARY OF BENEFITS: Estimated benefits from RCT data are 0.23-0.8 additional years of life with ICD therapy compared with anti-arrhythmic drug therapy. COSTS: Unit cost of ICDs (based on 1999/2000 prices), ranges from pound 12,500 to pound 22,000. Total discounted costs for 3 years range from pound 20,000 to pound 29,000. COST-EFFECTIVENESS: Cost-effectiveness estimates in the literature identified range from $11,000 to $146,000 per life-year saved. Using UK cost data from three hospitals and trial survival data from one RCT, the estimate of cost-effectiveness from this review ranges between pound 20,250 and pound 87,000 per life-year saved. COST-UTILITY: Cost per quality-adjusted life-year is estimated by the authors of this review at pound 21,300 to pound 108,800 (using survival data from one trial and quality-of-life indices derived from clinical opinion). These figures remain speculative until quality-of-life data from ongoing trials are available to inform future UK cost-effectiveness/utility analyses. IMPLICATIONS: If implemented for indications supported by evidence from RCTs, ICDs may cost the NHS in excess of pound 24 million per annum. FUTURE RESEARCH: Future research should include the use of British Pacing and Electrophysiological Group registries to assess the use of different types of ICD and current service provision.

Anti-Arrhythmia Agents↗
PubMed1999

Modulation of apolipoprotein D and apolipoprotein E expression in rat hippocampus after entorhinal cortex lesion.

Apolipoprotein (apo) D is a member of the lipocalin family of proteins. Although its physiological function is unknown, apoD is thought to transport one or more small hydrophobic ligands. A second apolipoprotein, apoE is known to play an important role in lipid transport, and apoE genetic polymorphism has been shown to be associated with susceptibility to Alzheimer's disease. Both apoD and apoE are expressed in the central nervous system (CNS) and both proteins accumulate at sites of peripheral nerve injury due to increased local synthesis. The two proteins may have overlapping or complementary functions within nervous tissue. In order to define the role of apoD within the CNS, we have studied the regional distribution of apoD and apoE mRNA and protein within the normal rat brain and the changes in apoD and apoE expression in the hippocampus of rats after entorhinal cortex lesion (EC lesion). Within the brains of normal rats, apoD expression in the hippocampus was as high as 180-fold that of the liver. ApoD mRNA levels in other areas of the rat brain ranged from 40 to 120 times the hepatic levels. The distribution of apoE gene expression within the brain was similar to that of apoD, but was much lower than hepatic apoE expression. When rats were subjected to EC lesion, the apoD message increased by 54% at 4 days post lesion (DPL) in the ipsilateral region of hippocampus while apoE mRNA levels (ipsilateral and contralateral) decreased by 43%. At 6 to 8 DPL apoD mRNA in the ipsilateral hippocampus remained elevated (42% above controls) whereas the apoE mRNA levels increased to about 15% above those of controls. At 14 and 31 DPL, both apoD and apoE expression was similar to controls. The increase in immunoreactive apoD in hippocampal extracts was more dramatic. At 1 DPL, immunoreactive apoD levels were already 16-fold higher than those in extracts of non-lesioned animals and, at 31 DPL, levels were still 8-fold higher than those of control animals. Finally, we have demonstrated that the levels of apoD in the brains of apoE-deficient mice are 50-fold those of wildtype control mice. ApoD clearly has an important function within the CNS in both normal and pathological situations.

Animals↗