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Deborah Ashby

Publications and source records attributed to Deborah Ashby.

25 records · Page 2Linked to original sources
PubMed2003

Thrombosis prevention trial: compliance with warfarin treatment and investigation of a retained effect.

BACKGROUND: The Thrombosis Prevention Trial was a primary prevention factorial trial that reported a reduction in the risk of coronary heart disease (CHD) with warfarin and/or aspirin. This article examines compliance (duration of treatment) with warfarin treatment and whether warfarin has a retained effect. METHODS: Risk of CHD while complying with warfarin treatment was compared with risk of CHD in all participants randomized to placebo. Simultaneously, risk of CHD in ex-warfarin users was compared with controls receiving placebo to determine the possibility of a retained effect. A second analysis, preserving the advantage of randomization, estimated the potential increase in the time to a CHD event in patients randomized to active treatment compared with patients randomized to placebo, if all patients in both active and placebo groups had fully complied with the trial treatment. RESULTS: Risk of all CHD while complying with warfarin treatment was associated with a hazard ratio (HR) of 0.75 (95% confidence interval [CI], 0.60-0.94), which was lower than the HR obtained by intention-to-treat analysis (0.79; 95% CI, 0.65-0.96). Regarding fatal cases of CHD, the HR was 0.49 (95% CI, 0.32-0.75) while compliant with warfarin treatment, which is also lower than the HR obtained by intention-to-treat analysis (0.61, 95% CI, 0.43-0.85). Ex-warfarin users had a retained risk reduction of 23% for all CHD (0.77; 95% CI, 0.58-1.02) and of 34% for fatal events (0.66; 95% CI, 0.41-1.04). Expected survival time to a CHD event if patients randomized to warfarin had fully complied with treatment was 1.39 times greater (95% CI, 1.12-1.69) than if patients randomized to placebo had fully complied with placebo, whereas for fatal CHD the relative increase in survival time was 2.04 times greater for the former (95% CI, 1.43-2.86). CONCLUSIONS: Full compliance with warfarin treatment may lower by 50% the risk of fatal CHD. There is also evidence of a retained effect. These results strengthen previous evidence of the potential benefits of low-intensity oral anticoagulation with warfarin.

Anticoagulants↗
PubMed2003

Smooth muscle cholinergic denervation hypersensitivity in diverticular disease.

BACKGROUND: Evidence from clinical and laboratory investigations into the causes of diverticular disease suggests that disturbances in cholinergic activity are important, the effector mechanisms of which have yet to be established. We aimed to investigate the role of smooth muscle and neural cholinergic activity in the pathogenesis of this disease. METHODS: Two investigators independently did a blinded immunohistochemical image analysis of localising antibodies to choline acetyltransferase, co-localised with protein gene product (PGP)--a marker of general neural tissue-and smooth muscle muscarinic M3 receptors, on three histological sections of sigmoid colons from ten patients with diverticular disease and ten controls, after resections for rectal tumours. We also did isotonic organ bath experiments to assess muscle strip sensitivities to exogenous acetylcholine. FINDINGS: In circular muscle, activity of choline acetyltransferase was lower in patients with diverticular disease than in controls: median percentage surface area of choline acetyltransferase over PGP was 17.5% (range 10.0-37.0) in patients with diverticular disease and 47.0% (29.0-54.0) in controls (p<0.0001). M3 receptors were upregulated in patients with diverticular disease compared with controls: the median surface area was 13.2% (6.0-23.3) in patients with diverticular disease and 2.5% (1.6-3.7) in controls (p<0.0001). The sensitivity to exogenous acetylcholine was increased in patients with diverticular disease (mean -log EC(50) 5.6 [SD 0.3]) compared with controls (4.9 [0.5]; difference 0.7 [95% CI 0.3-1.1], p=0.006). In longitudinal muscle, choline acetyltransferase activity was lower in patients with diverticular disease (median 19.5%, range 12.0-30.0) than in controls (47.0%, 35.0-60.0; p<0.0001), with upregulation of M3 receptors in diverticular disease (diverticular disease 7.8% [1.9-20.4], controls 1.7% [0.8-3.0]; p<0.0001). However, sensitivity to exogenous acetylcholine did not differ between the two groups (diverticular disease mean 5.6% [SD 0.3], controls 5.2% [0.4]; difference 0.4% [95% CI -0.02-0.7], p=0.06). INTERPRETATION: Our results suggest that cholinergic denervation hypersensitivity can affect smooth muscle. Upregulation of smooth muscle M3 receptors might account for specific clinical, physiological, and pharmacological abnormalities associated with diverticular disease.

Acetylcholine↗
PubMed2003

Using disease registries for pharmacoepidemiological research: a case study of data from a cystic fibrosis registry.

BACKGROUND: The Epidemiologic Registry of Cystic Fibrosis (ERCF) was a multicentre, longitudinal follow-up project of cystic fibrosis patients enrolled at some 200 centres in nine European countries between 1994 and 1999. PURPOSE: We aimed to assess and improve the quality of a subset of data from the ERCF relating to seven English centres (1184 patients), prior to using the data for a long-term cost-effectiveness analysis of dornase alfa (Pulmozyme). Specifically we wanted to assess the completeness and accuracy of the data and the comparability of cases across centres. METHODS: We used a subset of ERCF data relating to seven UK cystic fibrosis (CF) centres. Following initial data editing, key variable data from a sample of patients from five centres were subjected to a detailed verification of ERCF data against original data sources available in the centres. Disagreements between ERCF reports and original data sources were identified and corrected in the study dataset. In addition, centre staff were questioned about relevant clinical and recording practices. RESULTS: Thanks to detailed routine data checking procedures on key variables operated by the ERCF, the rates of disagreement between ERCF data and original data as identified in our verification process on the assessed variables are generally low (0.4-3.7%). Some outcome variables (deaths, hospitalisations) seem to be under-reported by some centres. Episodes of pulmonary exacerbation are difficult to identify and also to verify. Twenty-four patients were registered twice (consecutively in two different centres). There were some differences between centres in their interpretation of recording rules. CONCLUSIONS: Researchers seeking to use disease registry data should consider detailed data quality review processes. Apart from data accuracy, reliable definitions of both critical events as well as their timing are important. The degree of under-reporting, particularly of outcome variables, should be estimated. Information on local clinical and reporting practices is necessary to interpret multi-centre data. Data protection issues may limit the possibilities for detailed data quality assessments of secondary data, as does the accessibility of original data for verification purposes. Our experiences and recommendations may be valuable for those intending to use disease registry data as well as those devising and operating such registries.

Adult↗
PubMed2002

Respiratory syncytial virus bronchiolitis: disease severity, interleukin-8, and virus genotype.

In infants with respiratory syncytial virus (RSV) bronchiolitis, we investigated whether disease severity is associated with the genotype of the infecting virus, or with the infant's immunological response to the infection, as determined by measurement of interleukin-8 mRNA in the nasopharyngeal aspirate. This was a cross-sectional observational study, performed in the Accident and Emergency Department, wards, and Intensive Care Unit of a large pediatric hospital. Participants included 276 infants with respiratory syncytial virus infection. Outcome variables included: disease severity (infants requiring oxygen or ventilation were classified as having severe disease); RSV virus genotype (determined according to typing scheme based on the nucleoprotein and G glycoprotein genes); and amount of interleukin-8 mRNA in the nasopharyngeal aspirate, as measured by a semiquantitative polymerase chain reaction assay. This was corrected for the amount of cellular material in the sample by expressing it relative to mRNA for a constitutively expressed gene, HGPRT. We found a highly significant association between the ratio of interleukin-8 mRNA/HGPRT mRNA in the nasopharyngeal aspirate and the occurrence of severe disease. Odds ratio per unit increase of interleukin-8 mRNA/HGPRT mRNA was 1.15 (95% CI, 1.06, 1.24), P = 0.0004. There was no association between virus genotype and either disease severity or amount of interleukin-8 mRNA/HGPRT mRNA. In conclusion, there is a strong, dose-related association between interleukin-8 mRNA produced locally in the airways and disease severity, and a lack of association with virus genotype. This suggests that clinical manifestations of respiratory syncytial virus bronchiolitis are determined by local immunological responses to infection, rather than by characteristics of the infecting virus.

Bronchiolitis↗
PubMed2002

Cytokines in severe respiratory syncytial virus bronchiolitis.

Bronchiolitis caused by respiratory syncytial virus (RSV) infection is an important cause of severe lung disease in infants, and increasing evidence suggests that it is immunologically mediated. Experiments in mice suggest that this may be due to differential T-cell activation producing either type 1 or type 2 cytokines. We investigated this hypothesis in man by studying 24 infants ventilated with severe RSV bronchiolitis and by measuring messenger RNA (mRNA) for interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), by polymerase chain reaction, in nasopharyngeal aspirates (NPAs) and bronchoalveolar lavage (BAL) fluids. A semiquantitative assay was used to estimate concentrations of mRNA for these cytokines in comparison to mRNA of the constitutively expressed hypoxanthine guanine phosphoribosyl transferase gene. BAL from 18/24 infants showed polarization of cytokine production: 6 with only IFN-gamma mRNA, and 12 with only IL-4 mRNA. For the 6/24 infants in whom both IL-4 mRNA and IFN-gamma mRNA were detected in BAL fluid, each was present in low amounts, compared with those with mRNA for IL-4 or IFN-gamma alone. IL-4 and IFN-gamma mRNA were not detected in any of the NPAs.These findings provide the first direct evidence in infants that in RSV bronchiolitis there are divergent T-cell responses and suggest that more than one mechanism may be responsible for immune-mediated disease enhancement.

Bronchiolitis↗
PubMed2002

Diet and colorectal cancer: an investigation of the lectin/galactose hypothesis.

BACKGROUND & AIMS: Mucosal expression of terminal unsubstituted galactose is increased in colon cancer and precancer and allows interaction with mitogenic galactose-binding lectins of dietary or microbial origin. This study tests the hypothesis that galactose, which is variably plentiful in fruit and vegetable but not cereal fibers, might prevent cancer by binding and inhibiting such lectins. METHODS: Colorectal cancer cases (512) and controls (512) were matched for age, sex, primary care practitioner, and postal code. A 160-item food-frequency questionnaire was used to estimate their usual pre-illness (6 months previous) diet, aspirin intake, and exercise. RESULTS: Neither cereal fiber nor fruit and vegetable fiber were protective when assessed by univariate analysis, whereas dietary fiber galactose content showed a dose-related protective effect (odds ratio [OR] highest quartile/lowest quartile, 0.67; confidence interval [CI], 0.47-0.95) that remained protective when adjusted for energy, red meat, alcohol, calcium, protein and fat intake, regular aspirin usage, and exercise. Intake of nonlegume green vegetables, assessed because of the high lectin content of legumes, was also protective (OR, 0.54; CI, 0.35-0.81), but this was not independent of galactose. Protective effects of exercise and regular daily aspirin consumption and harmful effects of high energy consumption and high red meat intake were confirmed. CONCLUSIONS: The protective effect of fruit and vegetable fibers may be related to their galactose content. This provides further evidence that the association between diet and colon cancer is mediated via specific food components and may explain the discrepant results of studies addressing the protective effects of fiber.

Adult↗