A drunk and disorderly country: a nationwide cross-sectional survey of alcohol use and misuse in Great Britain.

OBJECTIVES: To explore current alcohol drinking patterns, behaviours and attitudes in Great Britain. DESIGN AND SETTING: Independent online cross-sectional survey. PATIENTS AND INTERVENTIONS: Survey of 2221 individuals from a representative panel. MAIN OUTCOME MEASURES AND RESULTS: Excessive alcohol consumption is a widespread problem across Great Britain. Binge-drinking is common among 18-24 year olds, with 19% reporting drinking 10+ drinks on the same drinking day. 'Pre-loading' with alcohol at home before going out was reported by 30% of 18-24-year-old drinkers, of whom 36% get drunk twice or more a month, with 27% having injured themselves while drunk. Among older drinkers, 25% regularly drink to excess, 8% drink seven or more drinks on a typical drinking day and 9% self-reported drink-driving. Male gender was an independent risk factor for heavy (>40 units/week) alcohol abuse (odds ratio 3.05 (95% CI 1.82 to 5.10)). Men (19%) were more likely than women (8%, p<0.001) to report binge-drinking, drink-driving (11% vs 3%, p<0.001), or to have missed work owing to alcohol consumption (12% vs 7%, p<0.001). Young drinkers said they were heavily influenced by overall alcohol price and drink promotions. Increasing average weekly alcohol consumption, age <55 years, male gender, never having been married and being in full-time employment were all independently associated with a history of alcohol-related self-harm. Alcohol abuse was not related to socioeconomic status. CONCLUSIONS: Alcohol abuse remains common across all socioeconomic strata and geographical areas of Great Britain. Minimum pricing strategies and interventions that target cheap on-trade alcohol products seem likely to bring major public health benefits.

TIPSS in the treatment of ectopic variceal bleeding.

BACKGROUND/AIMS: Bleeding from ectopic varices is a well recognized life-threatening complication of portal hypertension but the optimal treatment of this problem is yet to be established. METHODOLOGY: We retrospectively reviewed patients with ectopic variceal bleeding who underwent transjugular intrahepatic portosystemic shunting for recurrent bleeding not responding to conservative management. RESULTS: Over an eleven-year period we identified ten patients who underwent TIPSS for ectopic variceal hemorrhage. Six patients bled from rectal varices and four from stomal varices. TIPSS was successful in nine patients. The Childs-Pugh grade of the patients was A=3, B=3 and C=4. The follow-up period ranged from 7 days to 1380 days. Rebleeding occurred in three patients, two of whom died. The remaining patient had a blocked TIPSS and successfully underwent repeat stenting which re-established patency. Four patients (Childs B=2, Childs C=2) died within 60 days. All three patients with Childs A liver disease were alive at one year. CONCLUSIONS: TIPSS can be used effectively to treat ectopic variceal bleeding. Patients with Childs grade A liver disease appear to do well with TIPSS. Those with advanced liver disease (Childs B & C) have a uniformly poor outcome. In these patients ectopic variceal hemorrhage is likely to represent a terminal event.

Recent developments in the treatment of alcoholic hepatitis.

Alcoholic hepatitis is a form of acute injury to liver tissue that is also a precursor of cirrhosis, and carries significant morbidity and mortality. Severe alcoholic hepatitis in particular carries a high short-term mortality, and also places an enormous burden on stretched healthcare resources. Treatment of alcoholic hepatitis has been limited to supportive management and nutritional supplementation without clear improvements in outcome, and the timing and patient selection for hepatic transplantation is problematic. The use of corticosteroids has remained controversial for many years, but probably has a role in selected patients. Various other therapeutic strategies have been tested over the decades and none has shown any consistent benefit. Recently there have been major developments in our understanding of the mechanisms of alcoholic liver injury, including the role of cytokines and hepatocyte apoptosis. For the first time, there are exciting possibilities for specific therapies for this challenging and serious condition.

General practice nurses' knowledge of alcohol use and misuse: a questionnaire survey.

Nurses in general practice (termed practice nurses) are an under-utilized resource for the detection and management of patients with alcohol misuse. However, little is known about their knowledge and attitudes towards alcohol use and misuse. We therefore conducted a postal questionnaire survey of 132 practice nurses in Liverpool (UK). The results of our survey (response rate 77%) show that a knowledge and skills gap exists in the delivery of effective advice on alcohol-related issues. Indeed, our results suggest that only one in two women and one in three men are receiving correct advice on sensible limits of alcohol consumption, this despite the fact that alcohol histories are taken. Further training was requested by most nurses to develop their screening and health promotion roles, and to become involved in the management of patients with alcohol-related problems in primary care. We suggest practice nurses should be encouraged to become involved in screening for, and management of, alcohol-related problems. However, it is important to ensure that the nurses receive appropriate training and have adequate back-up facilities from doctors and other workers involved in the care of patients with alcohol-related problems.

The burden of alcohol misuse on an inner-city general hospital.

Alcohol consumption in the UK has been increasing steadily. We prospectively studied the burden on hospital services caused by overt alcohol misuse, in an inner-city hospital in north-west England. All Accident & Emergency (A&E) patients were assessed to determine whether their hospital attendance was alcohol-related, and whether this resulted in admission and/or generated new out-patient appointments. Over 2 months, 1915 patients attended A&E with alcohol-related problems, accounting for 12% of attendances; 50% were aged 18-39 years, and acute alcohol intoxication was the commonest presenting complaint. Overall, 6.2% of all hospital admissions were due to alcohol-related problems. Over 2800 new out-patient visits were likely to have been generated over an 18-month period from initial attendance with an alcohol-related problem, mostly for orthopaedic clinics. The burden placed by overt alcohol-related problems on hospitals is enormous, both in terms of the emergency and out-patient services. The implementation of education, screening and intervention strategies in A&E departments, and employment of key trained personnel, should be considered, to optimize the clinical management of these patients.

Alcohol abuse and the burden on the NHS--time for action.

Alcohol misuse is a major drain on the resources of the NHS. Strategies that are adequately resourced are urgently needed to be able to cope with the burden of alcohol-related illness.

Effect of genotypes on the quantification of hepatitis C virus (HCV) RNA in clinical samples using the Amplicor HCV Monitor Test and the Quantiplex HCV RNA 2.0 assay (bDNA).

The Amplicor HCV Monitor test and the Quantiplex HCV RNA 2.0 (bDNA) assay are two commercially available assays for the quantification of hepatitis C virus (HCV) RNA in clinical samples. A direct comparison of the two assays was carried out using sera frozen previously from patients known to be chronically infected with HCV. Overall, 61 samples from 51 patients were tested simultaneously by the two methods: 67% (28/42) of the patients were infected by HCV genotype/serotype 1, 10% (4/42) with type 2, and 24% (10/42) with type 3. When the absolute value from each assay was examined, the Quantiplex assay gave a consistently higher reading and the mean logarithmic difference between the two assays was 1.4 (1.0 in type 1, 2.0 in type 2, and 2.2 in type 3). When analyzed according to genotype, strong correlation was observed between the two assays for type 1 (r = 0.83, 95% CI 0.63-0.93, P < 0.01), but not for nontype 1 samples. Despite the difference in absolute level reported by the two assays, there was a consistent trend of change in HCV RNA concentration by both assays in patients whose consecutive samples were analyzed and the differences between the two assays in consecutive samples were within 0.4 log of each other. The results suggested that with samples containing genotype 1, the Amplicor assay was more sensitive than the Quantiplex assay by about one log. However, the sensitivities of the two assays with nontype 1 samples were much closer probably due to the failure of the Amplicor assay to quantify nontype 1 genotypes effectively.

Abnormal duodenal bile composition in patients with acalculous chronic cholecystitis.

OBJECTIVE: Our goal was to characterize biliary lipid composition in patients with the syndrome of chronic biliary pain, absence of gallstones, and inflammation of the gallbladder mucosa (acalculous chronic cholecystitis). METHODS: Duodenal bile, obtained from 27 patients with a history of right upper quadrant pain and with negative imaging studies of the biliary tract, was analyzed enzymatically for bile acids, phospholipids, and cholesterol. Fifteen patients were found to have inflammation and/or fibrosis of the gallbladder at cholecystectomy. RESULTS: The 15 patients with abnormal gallbladder histology had more dilute duodenal bile, as indicated by a low bile acid concentration and a lower proportion of phospholipids (p < 0.01) when values were compared with those of duodenal bile samples from postmenopausal women without gallbladder disease or from radiolucent gallstone subjects participating in the National Cooperative Gallstone Study. Cholecystectomy relieved pain in 9 of 14 patients. CONCLUSIONS: Some patients with acalculous chronic cholecystitis have duodenal bile samples characterized by a decreased bile acid concentration and a decreased proportion of biliary phospholipids. The low biliary bile acid concentration may result from impaired gallbladder contraction and/or secretion by the biliary tract epithelium. The low proportion of phospholipid may result from posthepatic hydrolysis of luminal phosphatidylcholine followed by absorption of the hydrolysis products. The latter process could be caused by and/or contribute to mucosal inflammation and would also elevate the cholesterol saturation of bile, increasing the risk for cholesterol gallstone formation.

Hepatitis G virus RNA and its relation to hepatitis C infection in adult haemophilic patients.

The prevalence of hepatitis C virus (HCV) infection and hepatitis G virus (HGV) RNA were studied in 50 adult haemophilic patients who had received commercial clotting factors prior to 1980. HGV RNA was detectable in 6/ 50 patients (12%); 49/50 (98%) had antibody to HCV and 40/49 (82%) of these were viraemic with detectable HCV RNA; 5/6 patients with detectable HGV RNA had co-existing HCV infection and viraemia. The HGV PCR products from all six patients were directly sequenced and all were shown to be similar to that of HGV but more diverse from that of GB virus C. One patient who had persistent abnormal liver function tests had detectable HGV RNA but no evidence of hepatitis B or C. The presence of HGV RNA in the absence of hepatitis B and C infection indicates that this virus is capable of independent transmission. Independent response to interferon was demonstrated in one patient with co-infection who lost HGV but not HCV after interferon therapy.

Evaluation of two simplified methods for genotyping hepatitis C virus.

A number of different approaches have been used for genotyping hepatitis C virus (HCV). Two simplified methods were evaluated, both of which used polymerase chain reaction (PCR) to amplify products from the 5' non-coding region of HCV: non-isotopic restriction fragment length polymorphism (RFLP) analysis and type-specific PCR. Sixty-four viraemic patients suffering from chronic HCV infection were studied using these two techniques; 25/64 samples were further tested with a commercial serotyping ELISA based on synthetic NS4 antigen (Murex, U.K.). The results of the three typing methods were generally in agreement with each other. When only the predominant genotype identified by each method was analysed, the 3 methods had 100% agreement. RFLP did not detect any mixed infections and it was unsuccessful in 16/64 (25%) samples. Both type-specific PCR and serotyping ELISA detected mixed infections. However, serotyping ELISA did not give typeable results in 7/25 (28%) samples, whereas type-specific PCR gave typeable results in all 64 samples. Type-specific PCR detected more mixed infections than serotyping ELISA. Direct sequencing of four PCR products with indeterminate RFLP confirmed changes in restriction enzyme recognition sites. The sequences also confirmed the validity of the predominant genotype in cases of apparent mixed infections. It is possible that some of these cases were artefacts as a result of quasispecies.

Measurement of menadione-mediated DNA damage in human lymphocytes using the comet assay.

The model quinone compound menadione has been used to study the effects of oxidative stress in mammalian cells, and to investigate the mechanism of action of the quinone nucleus which is present in many anti-cancer drugs. We have used the alkaline single cell gel electrophoresis assay (comet assay) to investigate the effects of low doses of this compound on isolated human lymphocytes. We found that concentrations of menadione as low as 1 microM were sufficient to induce strand breaks in these cells. Pre-incubation with the NAD(P)H quinone oxidoreductase inhibitor dicoumarol, enhanced the production of menadione-induced strand breaks. In contrast, the metal ion chelator 1,10-phenanthroline inhibited formation of strand breaks, although prolonged incubation with 1,10-phenanthroline in combination with menadione resulted in an increase in a population of very severely damaged nuclei. A marked variation in the response of lymphocytes from different donors to menadione, and in different samples from the same donor was also observed.

Secondary bile acid induced DNA damage in HT29 cells: are free radicals involved?

Increased bile acid secretion, as a consequence of a high fat diet, results in the increased production of bile acids that may escape the enterohepatic circulation, and be subsequently metabolised by the colonic micro-flora to form the co-mutagenic and co-carcinogenic secondary bile acids. The potential of the secondary bile acids lithocholate (LOC) and deoxycholate (DOC), to induce DNA damage, in the colonocyte cell line HT29, at physiological concentrations both individually and in a 2:1 ratio was assessed. Results indicated significant levels of DNA damage induced by both bile acids, with LOC having the greater DNA damaging capacity. The potential role of vitamin A, and the antioxidant vitamin E, in reducing this damage was determined, over a range of vitamin concentrations. Both vitamins reduced the bile acid induced DNA damage. Vitamin A displayed a dose response relationship, whereas vitamin E reduced DNA damage close to negative control values at all concentrations above 50 microM. These results indicate a protective role for Vitamins A and E, against the DNA damaging capacity of LOC and DOC.

Quinone-induced DNA single strand breaks in a human colon carcinoma cell line.

It has been demonstrated that synthetic quinones, such as menadione, cause DNA damage in different cell systems, possibly being mediated by free radicals generated during redox cycling. It has been suggested that the damage caused could be related to tumor induction in different sites. To our knowledge it has not yet been demonstrated that the natural quinones, vitamin K1 and K2, exert the same activity. Using a colon carcinoma cell line, HT-29, we examined the extent of DNA damage induced by menadione, vitamin K1 and K2. Menadione caused significant DNA damage at low concentrations (25-200 microM) with a linear correlation of r = 0.95. In the presence of dicoumarol, a DT-diaphorase inhibitor, the damage was detected at concentrations five times lower indicating that free radicals generated during the redox cycling play a key role. Neither vitamin K1, incorporated in micelles, nor K2 caused detectable single strand breaks with respect to the controls either in the presence or in absence of dicoumarol. Our results demonstrate that, despite their redox cycling properties, the natural forms of vitamin K do not cause DNA damage in HT-29 cells as menadione does in the experimental conditions used.

Cost effectiveness of detecting Barrett's cancer.

BACKGROUND: Screening Barrett's oesophagus is controversial owing to a large variation in the reported incidence of neoplastic change and lack of evidence that screening improves tumour prognosis. AIMS: To determine the incidence of Barrett's cancer, its cost of detection, and stage of disease at time of diagnosis. PATIENTS AND METHODS: Data from our surveillance programme have been reviewed to assess the incidence of malignant change, tumour stage at diagnosis, and the cost per cancer detected. RESULTS: 166 patients had annual endoscopic surveillance. Six patients (five men) developed cancer-an incidence of one cancer per 59 male and 167 female patient-years of follow up. The screened group had a significantly earlier stage than a control group of unscreened cancers (p < 0.05). The cost of detecting one cancer was Pounds 14 868 for men and Pounds 42 084 for women. CONCLUSIONS: The cost of screening for Barrett's cancer is high but may be justified on the basis of the high incidence of detecting early stage disease.

Genetic polymorphism of cytochrome P4502E1 and risk of alcoholic liver disease in Caucasians.

Genetic factors may be of importance in determining inter-individual susceptibility to alcoholic liver disease (ALD). Among the candidate genes which have been considered to be important are those which code for enzymes involved in alcohol metabolism. Cytochrome P4502E1 (CYP2E1) metabolizes alcohol to acetaldehyde and the hydroxyethyl radical, and is also inducible by alcohol. A Rsa I restriction fragment length polymorphism (RFLP) in the 5'-flanking region of the CYP2E1 gene has been identified by other investigators, studies showing that the mutant allele (termed c2) shows greater transcriptional activity, higher protein levels and increased activity compared with the wild-type allele (c1). We have used PCR-RFLP analysis to determine whether the frequency of these alleles differed in 95 Caucasian patients with ALD compared with 205 control subjects (comprising 58 alcoholics with no liver disease, 47 patients with non-alcoholic liver disease and 100 healthy volunteers). In controls, the frequency (0.024) of the c2 allele was similar to that previously reported in other Caucasian populations. The c2 allele frequency in patients with ALD (0.1), however, was significantly (p = 0.0003; odds ratio (OR) 4.5, 95% CI 1.9-10.9) higher than in control subjects. The findings indicate that Caucasians carrying the Rsa I c2 allele of the CYP2E1 gene may be at higher risk of developing ALD if they abuse alcohol.

Liver biopsy in the diagnosis of malignancy.

In a National Audit of 1500 liver biopsies, 38% were for suspected malignancy. To measure their contribution to clinical decisions, the initial diagnoses, biopsy diagnoses, final diagnoses, and outcomes were coded by computer and compared. Most patients (92%) were investigated for advanced malignancy. The accuracy of clinical diagnosis was 78% against final diagnosis. Liver biopsy was seen as 'confirming' clinical diagnosis overall. This was achieved in 67% (75% with ultrasound guidance), and specificity was almost 100%. However, hepatocellular cancer was confirmed by biopsy in only 32% and haematological malignancy in 13% of suspected cases. Within 3 months, 44% of patients with histological malignancy had died. Histological tumour type was not used in 36% of final diagnoses. Of patients with a malignancy-negative liver biopsy--showing reactive hepatitis, normality, or cholangitis/cholestasis--25%, 47% and 60%, respectively, had final malignant diagnoses. In 6% of patients, biopsy showed chronic liver disease. Only 12% of deaths were autopsied. Liver biopsy contributes very high specificity to the diagnosis of malignancy, and detects non-malignant disease. Failure to use tumour type may result in sub-optimal therapy. Improving diagnostic practice requires more information on outcomes, including autopsies.