Background: Many patients with primary biliary cirrhosis (PBC) are asymptomatic at the time of diagnosis. However, because most studies of asymptomatic PBC have been small and from tertiary centres, asymptomatic PBC remains poorly characterised. Aims: To describe the features and progression of initially asymptomatic PBC patients. Methods: Follow up by interview and note review of a large geographically and temporally defined cohort of patients with PBC, collected by multiple methods. Results: Of a total of 770 patients, 469 (61%) were asymptomatic at diagnosis. These patients had biochemically and histologically less advanced disease than initially symptomatic patients. Median survival was similar in both groups (9.6 v 8.0 years, respectively) possibly due to excess of non-liver related deaths in asymptomatic patients (31% v 57% of deaths related to liver disease). Survival in initially asymptomatic patients was not affected by subsequent symptom development. By the end of follow up, 20% of initially asymptomatic patients had died of liver disease or required liver transplantation. The majority of initially asymptomatic patients developed symptoms of liver disease if they were followed up for long enough (Kaplan-Meier estimate of proportion developing symptoms: 50% after five years, 95% after 20 years). However, 45% of patients remained asymptomatic at the time of death. Conclusions: Although asymptomatic PBC is less severe at diagnosis than symptomatic disease, it is not associated with a better prognosis, possibly due to an increase in non-hepatic deaths. The reasons for this are unclear but may reflect confounding by other risk factors or surveillance bias. These findings have important implications for future treatment strategies.

Successful advances in the treatment of advanced malignant diseases rely on recruitment of patients into clinical trials of novel agents. However, there is a genuine concern for the welfare of individual patients. The aim of this study was to examine motives of patients entering early clinical trials of novel cancer therapies. Questionnaire survey with both open- and close-ended questions. The patients were surveyed after they had given informed consent and before or during the first cycle of treatment. In all, 38 phase I/II trial patients participated and completed the survey. Obtaining possible health benefit was listed by 89% as being a ‘very important' factor in their decision to participate, with only 17% giving reasons of helping future cancer patients and treatment. Other items cited as a ‘very important' motivating factor were ‘trust in the doctor' (66%), ‘being treated by the latest treatment available' (66%), ‘better standard of care and closer follow-up' (61%), and ‘closer monitoring of patients in trials' (58%). Only 47% patients indicated that someone had explained to them about any ‘reasonable' alternatives to the trial. In total, 71% strongly agreed that ‘surviving for as long time as possible was the most important thing (for them)'. Nearly all (97%) indicated that they knew the purpose of the trial and had enough time to consider participation in the trial (100%). In this survey, most patients entering phase I and II clinical trials felt they understood the purpose of the research and had given truly informed consent. Despite this, most patients participated in the hope of therapeutic benefit, although this is known to be a rare outcome in this patient subset. Trialists should be aware, and take account of the expectations that participants place in trial drugs.

No abstract

Background and aims-Twin and family studies suggest that there is a genetic component to primary biliary cirrhosis (PBC) but the genetic associations which have been described are weak with marked variations between centres. PBC is heterogeneous and genetic associations with disease progression may be obscured when the PBC population is analysed only as a whole and not subdivided. Methods-We have investigated two candidate gene loci in 164 well characterised patients, 88 (54%) of whom had advanced disease.Results-There was an increased frequency of the HLA DRB1*0801-DQA1*0401-DQB1*0402 haplotype in patients who had progressed to late stage disease (23% v 2% of controls; p=0000044; odds ratio (OR) 15.5, 95% confidence interval (CI) 3.52-68.4) but not in those with early stage disease (4% v 2%). Patients had a higher frequency of the IL-1B*1,1 genotype and lower frequencies of the IL-1B*1,2 and *2,2 genotypes (p=0.00078; OR 2.37, 95% CI 1.38-4.06), and higher frequency of the IL-1RN*1,1 genotype and lower frequency of the IL-1RN*1,2 genotype (p=0.0011; OR 2.28, 95% CI 1.34-3.89). The diVerence in the IL-1B*1,1 genotype distribution was most marked in patients with early stage disease (77% v 43% of controls; p=0.000003; OR 4.8, 95% CI 2.31-10) but the IL-1RN genotype distribution was similar in patients with early and late stage disease. Conclusions-These data indicate a complex relationship between immunoregulatory genes and PBC. While the IL-1 genes are markers of both disease susceptibility and progression, HLA genes appear to be principally associated with disease progression.

We retrospectively reviewed the provision and uptake of hospital services for 253 current and ex-intravenous drug users with hepatitis C virus (HCV). Overall, 237 attended at least one clinic (mean age 32 years, 70% male, 43% on maintenance methadone); 81% had evidence of active viral replication and 137 agreed to a liver biopsy to assess disease severity. Of these 137, 24% had mild chronic hepatitis with a low risk of progression to cirrhosis, but 9% had cirrhosis (mean age 40 years, mean time since initial intravenous drug use 15.8 years). Only 50 of the 100 patients in whom antiviral therapy was indicated, commenced treatment; 18 (36%) have had a sustained virological response. The natural history or response to treatment of chronic HCV in those who acquire it through intravenous drug use is not different to that previously reported for post-transfusion HCV. However, a substantial proportion default from follow-up or decline further intervention. As intravenous drug use is now the main risk factor for acquisition of HCV, these data have implications for future delivery of care aimed at limiting the morbidity of chronic HCV, and limiting the spread of hepatitis C virus infection amongst intravenous drug users.

Direct gene transfer methods in potato would facilitate the transfer of multiple genes and the manipulation of metabolic pathways in this species. In this study, up to 1.8 transformation events per shot (=0.5 per bombarded leaf) and 67.2 events per million protoplasts treated were obtained with particle bombardment and PEG-mediated direct DNA uptake, respectively. Limited disassociation of both HPT and GUS genes appeared to occur during the process of integration in only 19% of transformants. A large number of transformed potato plants with transgene expression at levels comparable to Agrobacterium-mediated transformation was obtained. High levels of GUS expression were only obtained in lines derived from PEG treatment. No correlation between the number of gene insertions and gene expression levels was found, suggesting that multiple insertions may have little or no effect on transgene expression.