Smoking in vehicles is lower than mobile telephone use while driving, but is socially patterned.

Legislation is being considered which bans smoking in cars carrying children under the age of 16. This was an observational survey of smoking by drivers and passengers and mobile phone use by drivers in 2,230 cars over three time periods in two Dublin locations. The observed prevalence of mobile telephone use (2.56%) was higher than smoking (1.39%) (p < 0.01), but was low in both. There was no significant variation according to time of day. There was an inverse pattern according to car value for smoking drivers (p = 0.029). Eight adult passengers and just one child were observed as being exposed to a smoking adult driver. In conclusion, the public health importance of regulating passive smoke exposure is clear but the resources required to police such a ban in vehicles may be labour intensive for the yield in detection or prevention.

Socio-demographic and health-related predictors of uptake of first MMR immunisation in the Lifeways Cohort Study.

The aim of this study was to investigate the uptake of the first dose of measles, mumps and rubella (MMR) vaccine and factors associated with not receiving this vaccine. A cross-generation cohort study was conducted with prospective linkage to primary care and hospital health records in urban and rural settings in Ireland 2001-2004. Seven hundred and forty-nine singleton children were included, with an MMR uptake of 88.7% by the age of 5 years. These data confirm prospectively for the first time that in addition to factors associated with disadvantage, other health practices and beliefs, particularly mother's complementary and alternative medicine use, are associated with decreased MMR uptake (adjusted OR 2.65 (1.76-3.98)). This information suggests that parental attitudes and beliefs regarding vaccines must be considered when developing programmes to improve immunisation uptake.

Determinants of partial or no primary immunisations.

OBJECTIVE: To determine if different factors affect children having full, partial or no primary immunisations. METHODS: This was a crossgenerational cohort study with linkage to primary care and hospital records conducted in urban and rural settings in Ireland, recruiting in 2001-2003 with 5-year follow-up. A total of 749 children with immunisation information took part. RESULTS: The uptake of reported primary immunisations was 92.8% full, 4.9% partial and 2.3% no primary immunisations. Adjusted relative risk ratios for children receiving no primary immunisations were significant for: having a mother who had ever visited an alternative practitioner 3.69 (1.05 to 12.9), a mother with means tested full general medical services eligibility 8.11 (1.58 to 41.65), a mother who scored <50 for the World Health Organization Quality of Life (WHO-QOL) scale psychological domain 8.82 (1.79 to 43.6) or living in the west of Ireland (rural) 3.64 (1.0 to 13.2). Being born prematurely was associated with partial primary immunisation, adjusted OR 4.63 (1.24 to 17.3). CONCLUSIONS: Knowledge of these differences will help target campaigns to increase full uptake of primary immunisations.

Paradox of gastric cardia: it becomes more acidic following meals while the rest of stomach becomes less acidic.

INTRODUCTION: The proximal cardia region of the stomach has a high incidence of inflammation, metaplasia and neoplasia. It demonstrates less acid buffering following meals than the more distal stomach. Novel high definition pHmetry was employed to investigate acidity at the cardia under fasting conditions and in response to a meal. METHODS: 15 healthy subjects were studied. A custom-made 12-electrode pH catheter was clipped at the squamocolumnar junction with four electrodes recording proximal to and eight distal to the squamocolumnar junction. The most distal pH electrode was located at the catheter tip, and nine electrodes in the region of the squamocolumnar junction were 11 mm apart. RESULTS: The electrode situated in the cardia 5.5 mm distal to the squamocolumnar junction differed from all other intragastric electrodes during fasting in recording minimal acidity (pH <4 = 2.2%) while all other intragastric electrodes recorded high intragastric acidity (pH <4 =or>39%) (p<0.05). The cardia also differed from the rest of the stomach, showing a marked increase in acidity in response to the meal (from 2.2% fasting to 58.4% at 60-70 min after the meal; p<0.05) while the electrodes distal to the cardia all showed a marked decrease in acidity (p<0.05). These changes in acidity at the cardia following the meal caused the gastric acidity to extend 10 mm closer to the squamocolumnar junction. CONCLUSION: Whereas the rest of the stomach shows a marked fall in acidity on ingesting a meal, the cardia paradoxically increases in acidity to become the most acidic region throughout the postprandial period.

Severe reflux disease is associated with an enlarged unbuffered proximal gastric acid pocket.

BACKGROUND: An unbuffered pocket of highly acidic juice is observed at the gastric cardia after a meal in healthy subjects. AIMS: To compare the postprandial acid pocket in healthy subjects and patients with severe reflux disease and define its position relative to anatomical and manometric landmarks. METHODS: 12 healthy subjects and 16 patients with severe reflux disease were studied. While fasted, a station pull-through was performed using a combined dual pH and manometry catheter. Position was confirmed by radiological visualisation of endoscopically placed radio-opaque clips. The pull-through study was repeated 15 min after a standardised fatty meal. Barium meal examination was performed before and following the meal. RESULTS: A region of unbuffered acid (pH

Iron genes, iron load and risk of Alzheimer's disease.

BACKGROUND: Compound heterozygotes of the haemochromatosis gene (HFE) variants, H63D and C282Y, have raised transferrin saturation compared with that in the wild type. In the cohort of the Oxford Project To Investigate Memory and Ageing (OPTIMA), bicarriers of the HFE C282Y and the transferrin C2 gene variants are at five times greater risk of developing Alzheimer's disease; the addition of HFE H63D may raise the risk still further. OBJECTIVE: To investigate transferrin saturation by HFE and transferrin genotype among people without dementia-that is, controls and those with mild cognitive impairment (MCI)-and also among those with Alzheimer's disease. METHODS: Serum iron status and genotype were examined of 177 patients with Alzheimer's disease, 69 patients with MCI and 197 controls from the OPTIMA cohort. RESULTS: Although each of these variants alone had relatively little effect on iron status, the combination of either HFE C282Y and HFE H63D or of HFE C282Y and transferrin C2 markedly raised transferrin saturation in those without dementia, but had little effect in those with mature Alzheimer's disease. CONCLUSIONS: These combinations may raise the risk for Alzheimer's disease, owing to higher iron loads and therefore oxidative stress in the preclinical phase. If replicated, these findings will have implications for the prevention of Alzheimer's disease.

Atorvastatin associated liver disease.

Atorvastatin, a HMG-CoA reductase inhibitor, is widely used in the treatment of dyslipidaemia. A transient rise in serum transaminases occurs in up to 3% of patients using atorvastatin but this is usually self-limiting and inconsequential. Recent literature has indicated some potential for more serious but rare idiosyncratic reactions related to this drug. Seven patients with significant liver dysfunction from one centre during 2002-2005 are reported, with one death, that raises some concern over the safety of atorvastatin. A total of seven other patients are reported in the literature. The 14 patients were usually over 60 years, had a female:male ratio of 2:1 and showed a mixed cholestatic/hepatocellular reaction. The mean interval to onset of reaction was approximately 9 weeks and the liver often took several months to recover. Three deaths occurred. Adverse drug reaction reports from the UK Committee on Safety of Medicines reveal that four deaths due to hepatobiliary disease (0.5 deaths per annum) have been reported in association with atorvastatin treatment over 8 years. Simvastatin has had no hepatobiliary-related fatalities reported over 15 years. While acute hepatotoxicity with atorvastatin remains uncommon, any persistent abnormality in liver function should be treated with caution.

Recent advances in understanding haemochromatosis: a transition state.

Mutations in the hepcidin gene HAMP and the hemojuvelin gene HJV have recently been shown to result in juvenile haemochromatosis (JH). Hepcidin is an antimicrobial peptide that plays a key role in regulating intestinal iron absorption. Hepcidin levels are reduced in patients with haemochromatosis due to mutations in the HFE and HJV genes. Digenic inheritance of mutations in HFE and HAMP can result in either JH or hereditary haemochromatosis (HH) depending upon the severity of the mutation in HAMP. Here we review these findings and discuss how understanding the different types of haemochromatosis and our increasing knowledge of iron metabolism may help to elucidate the host's response to infection.

Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease.

BACKGROUND: There is evidence that iron may play a role in the pathology of Alzheimer's disease (AD). There may be genetic factors that contribute to iron deposition resulting in tissue damage thus exacerbating AD. METHODS: We have genotyped 269 healthy elderly controls, 191 cases with definite or probable AD, and 69 with mild cognitive impairment (MCI) from the OPTIMA cohort. RESULTS: We have examined the interaction between the C2 variant of the transferrin (TF) gene and the C282Y allele of the haemochromatosis (HFE) gene as risk factors for developing AD. Our results showed that each of the two variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. The interaction was significant by logistic regression (p = 0.014) and by synergy factor analysis (p = 0.015, synergy factor = 5.1). Further, carriers of these two alleles plus apolipoprotein E epsilon4 (APOE4) were at still higher risk of AD: of the 14 tri-carriers of the three variants, identified in this study, 12 had AD and two MCI. CONCLUSION: We suggest that the combination of TF C2 and HFE C282Y may lead to an excess of redox-active iron and the induction of oxidative stress in neurones, which is exacerbated in carriers of APOE4. Since 4% of Northern Europeans carry the two iron-related variants and since iron overload is a treatable condition, these results merit replication.

The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading.

BACKGROUND: Patients with hereditary haemochromatosis (HH) are usually homozygous for the C282Y mutation in the HFE gene. They have variable expression of iron overload and present with a variety of complications, including liver disease, diabetes, arthropathy, fatigue, and cardiomyopathy. The mitochondrial 16189 variant is associated with diabetes, dilated cardiomyopathy, and low body fat at birth, and might contribute to genetic predisposition in further multifactorial disorders. The objective of this study was to determine the frequency of the 16189 variant in a range of patients with haemochromatosis, who had mutations in the HFE gene. METHODS: Blood DNA was analysed for the presence of the 16189 variant in British, French, and Australian C282Y homozygotes and controls, with known iron status, and in birth cohorts. RESULTS: The frequency of the mitochondrial 16189 variant was found to be elevated in individuals with haemochromatosis who were homozygous for the C282Y allele, compared with population controls and with C282Y homozygotes who were asymptomatic (42/292 (14.4%); 102/1186 (8.6%) (p = 0.003); and 2/64 (3.1%) (p = 0.023), respectively). CONCLUSIONS: Iron loading in C282Y homozygotes with HH was exacerbated by the presence of the mitochondrial 16189 variant.

A targeted approach significantly increases the identification rate of patients with undiagnosed haemochromatosis.

OBJECTIVE: To determine the optimal means of identifying patients with undiagnosed haemochromatosis. DESIGN: Case-control study where cases are defined by the presence of specific clinical diagnoses or symptoms. SETTING: Primary care patients were recruited from three Oxfordshire practices and secondary care patients were recruited from those patients attending specialist clinics in Amiens University Hospital. SUBJECTS: A total of 569 patients recruited via hospital clinics and 60 primary care patients (recruited from 4022 consultations) presenting with the following haemochromatosis associated conditions, diabetes, arthralgia/chronic fatigue, osteoporosis or arthropathy were studied. The control group, a total of 991 healthy volunteers, were recruited through a Health Appraisal Centre. Patients and controls were included in the study if they or their family members had not previously been diagnosed with hereditary haemochromatosis. MAIN OUTCOME MEASURES: Serum ferritin concentration, transferrin saturation (Tsat) and presence of HFE mutations, C282Y and H63D. The check-up in controls consisted of a questionnaire, clinical examination, biochemical tests and screening for the presence of the C282Y and H63D mutations. RESULTS: Patient groups presenting with unstable diabetes or chronic fatigue and arthralgia together with a raised serum ferritin concentration showed an enrichment in the haemochromatosis-associated genotype HH/YY, odds ratio (OR) = 40.1, confidence interval (CI) = 8.0-202.1 and OR = 103, CI = 22.9-469.7, respectively. CONCLUSION: Patients presenting to hospital clinics with haemochromatosis associated conditions should be screened biochemically for iron overload. Only those with a serum ferritin >300 microg L-1 or Tsat >40% should subsequently go on to be genotyped for HFE mutations. The patients at greatest risk of having undiagnosed haemochromatosis are those presenting with unstable diabetes, or fatigue and/or arthralgia in the absence of any other explanation.

Detection of C282Y and H63D in the HFE gene.

The gene for hemochromatosis was identified in 1996 and two mutations were found. Homozygosity for one of these, C282Y, is associated with hemochromatosis in a high percentage of patients. Genetic analysis of patient DNA is, therefore, a very useful tool to aid and confirm diagnosis and to screen asymptomatic relatives of patients to identify those at risk of developing this common, easily treated disease.

Uncommon mutations and polymorphisms in the hemochromatosis gene.

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism. Iron absorption from the gut is inappropriately high, resulting in increasing iron overload. The hemochromatosis gene (HFE) was identified in 1996 by extensive positional cloning by many groups over a period of about 20 years. Two missense mutations were identified. Homozygosity for one of these, a substitution of a tyrosine for a conserved cysteine (C282Y), has now clearly been shown to be associated with HH in 60-100% of patients. The role of the second mutation, the substitution of an aspartic acid for a histidine (H63D), is not so clear but compound heterozygotes for both these mutations have a significant risk of developing HH. Here we review other putative mutations in the HFE gene and document a number of diallelic polymorphisms in HFE introns.

Geography of HFE C282Y and H63D mutations.

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder causing inappropriate dietary iron absorption that affects North Europeans. HH is associated with the C282Y mutation of the HFE gene, and the H63D mutation to a lesser degree. Both mutations are abundant in Europe, with H63D also appearing in North Africa, the Middle East, and Asia. Emigration from Europe over the past 500 years has introduced C282Y and H63D to America, Australia, New Zealand, and South Africa in an essentially predictable fashion. The distinctive characteristics of the population genetics of HH are the confined racial distribution and high frequency in North European peoples. C282Y frequencies in North Europeans are typically between 5% and 10%, with homozygotes accounting for between 1/100 and 1/400 of these populations. The scarcity of the C282Y mutation in other populations accounts for the lack of HH in non-Europeans.

Sources of information for acute poisoning in accident and emergency departments in Dublin, Ireland.

BACKGROUND: Access by accident and emergency staff to up-to-date information on poisoning is essential for optimal management of acute poisoning. Apart from the National Poisons Information Centre, other information sources can be used. The objectives of the study were to identify sources of information on acute poisoning in accidents and emergencies and satisfaction with their use. METHODS: In a cross-sectional survey of medical staff of accidents and emergencies in Dublin in 1997, data were collected by interviewer-administered questionnaire. RESULTS: All 11 accidents and emergencies participated, with a staff response rate of 95%. One hundred and twenty-eight respondents were included. Ninety-seven percent had managed cases of poisoning (median 3 per week). The National Poisons Information Centre had been used by 93% of respondents, textbooks by 80%, paper database by 63%, and disc database (CD-ROM) by 10%. Of those managing cases, the National Poisons Information Centre would always be contacted by 23% and by 53% in most cases. The National Poisons Information Centre and CD-ROMs were rated the most useful sources of information. Information provided by the National Poisons Information Centre was considered sufficient by 98% of respondents. Thirty-three percent considered that advice should always be confirmed by fax. Limitations with the National Poisons Information Centre were described by 55% (e.g., manual transcription), with textbooks (e.g., limited content) by 83%, with paper databases (e.g., incompleteness) by 85%, and with CD-ROMs (e.g., time-consuming) by 54%. CONCLUSION: For the optimal management of acute poisoning, direct access to computerized information databases in accidents and emergencies combined with telephone access to the National Poisons Information Centre is required, with information available in hard copy.

The haemochromatosis gene: a global perspective and implications for the Asia-Pacific region.

Mutations in the haemochromatosis (HFE) gene cause most of the cases of hereditary haemochromatosis among people of Northern European ancestry while remaining a rare cause of iron overload among indigenous persons of the Asia-Pacific region. Advances in understanding of the role of the HFE protein product and other recently cloned iron transporters signify an exciting period, as previously unknown components of the iron metabolism pathway are revealed one by one. Epidemiological studies have shown that this gene is more widespread than its phenotypic expression would suggest and that the heterozygous state may be implicated in the expression of other diseases of the liver such as porphyria cutanea tarda, hepatitis C virus infection and non-alcoholic steatohepatitis. The diagnosis, management and ethical implications for clinical practice in the aftermath of this discovery are discussed.

A retrospective anonymous pilot study in screening newborns for HFE mutations in Scandinavian populations.

We have retrospectively analyzed 837 random anonymized dried blood spot (DBS) samples from neonatal screening programs in Scandinavia for mutations in HFE, the candidate gene for hemochromatosis. We have found C282Y allele frequencies of 2.3% (+2.0%) (-1.3%) in Greenland, 4.5%+/-1.9% in Iceland, 5.1%+/-2.3% in the Faeroe Islands, and 8.2%+/-2.7% in Denmark. The high prevalence of HFE mutations in Denmark suggests that population screening for the C282Y mutation could be highly advantageous in terms of preventive health care. Long-term follow-up evaluation of C282Y homozygotes and H63D/C282Y compound heterozygotes will give an indication of the penetrance of the mutations.

Multicentric origin of hemochromatosis gene (HFE) mutations.

Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends