Christopher P. Wild

Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study

Correction to Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study, dx.doi.org/10.1136/bmj.a2332 available on the LRA at http://hdl.handle.net/2381/16058

A systematic review and meta-analysis of the risk of increasing adiposity on Barrett's esophagus.

OBJECTIVES:Esophageal adenocarcinoma and its precursor lesion, Barretts esophagus, are increasing in incidence in western populations. Gastroesophageal reflux disease (GERD) and high body mass index (BMI) are known risk factors, but it is unclear whether BMI mediates its risk on Barretts esophagus independently. This systematic review and meta-analysis investigated whether increasing BMI is associated with Barretts esophagus as compared to general population and GERD controls.METHODS:Search strategies were conducted in MEDLINE (U.S. National Library of Medicine, Bethesda, MD) (1966–2005) and EMBASE (Reed Elsevier PLC, Amsterdam, The Netherlands) (1980–2005). Studies to be included were required to present “current” BMI data for consecutively recruited Barretts esophagus patients and appropriate comparison arms with a minimum number of 30 subjects in each.RESULTS:The literature search produced 5,501 hits from which 295 papers were extracted. Only 10 studies met the criteria for inclusion. The Statistics/Data Analysis (STATA) program was used to conduct random effects meta-analyses. Nine studies comparing the BMI of the Barretts esophagus and GERD groups produced a pooled odds ratio (OR) of 0.99 per kg/m2 (95% confidence interval [CI] 0.97–1.01, I2 = 52%), while the pooled estimate of three studies comparing Barretts esophagus with general population controls was 1.02 per kg/m2 (95% CI 1.01–1.04, I2 = 0%).CONCLUSIONS:Increasing adiposity is only an indirect risk factor of Barretts esophagus through the precursor lesion of GERD. Hence, BMI status has no predictive value with respect to GERD patients and their risk of progression to Barretts esophagus.

Association between Tortilla Consumption and Human Urinary Fumonisin B1 Levels in a Mexican Population

Fumonisins are mycotoxins produced by Fusarium spp. and commonly contaminate maize and maize products worldwide. Fumonisins are rodent carcinogens and have been associated with human esophageal cancer. However, the lack of a valid exposure biomarker has hindered both the assessment of human exposure and the evaluation of disease risk. A sensitive liquid chromatography-mass spectrometry method to measure urinary fumonisin B1 (FB1) following extraction on Oasis MAX cartridges was established and applied to urine samples from women in a cohort recruited in Morelos County, Mexico. Urinary FB1 was compared with dietary information on tortilla consumption. FB1 recovery in spiked samples averaged 94% as judged by deuterium-labeled FB1 internal standard. Urinary FB1 was determined in 75 samples from women selected based on low, medium, or high consumption of maize-based tortillas. The geometric mean (95% confidence interval) of urinary FB1 was 35.0 (18.8-65.2), 63.1 (36.8-108.2), and 147.4 (87.6-248.0) pg/mL and the frequency of samples above the detection limit (set at 20 pg FB1/mL urine) was 45%, 80%, and 96% for the low, medium, and high groups, respectively. Women with high intake had a 3-fold higher average FB1 levels compared with the “low intake” group (F = 7.3; P = 0.0015). Urinary FB1 was correlated with maize intake (Ptrend = 0.001); the correlation remained significant after adjusting for age, education, and place of residence. This study suggests that measurement of urinary FB1 is sufficiently sensitive for fumonisin exposure assessment in human populations and could be a valuable tool in investigating the associated health effects of exposure. (Cancer Epidemiol Biomarkers Prev 2008;17(3):688–94)

Dietary wheat reduction decreases the level of urinary deoxynivalenol in UK adults

In animals deoxynivalenol (DON) causes vomiting, feed refusal, growth retardation, and affects the immune system. DON is a common contaminant of wheat, however, validated biomarker data to assess exposure at the individual level and therefore any associated health effects are lacking. The development of a highly robust assay for urinary DON involving immunoaffinity (IAC) clean-up and liquid chromatography (LC)-mass spectrometric (MS) detection has allowed the assessment of (1) DON exposure within UK individuals and (2) a wheat intake intervention on urinary DON levels. Twenty-five volunteers from the United Kingdom (aged 21–59 years) completed semi-weighed food diaries on days 1 and 2 (normal diet), and a morning urine sample was provided on day 3. On days 3–6 (intervention), individuals restricted major sources of wheat intake following dietary guidance. Diaries were completed on days 5 and 6, and a further morning urine was provided on day 7. Urinary DON was measured following IAC clean-up and analysis by LC–MS. Wheat-based food intake (mean 322 g/day, range: 131–542 g/day), was significantly (P<0.001) reduced during the intervention to 26 g/day (range: 0–159 g/day) indicating good compliance. DON was detected in all 25 urine samples taken on day 3 (geometric mean 7.2 ng DON/mg creatinine (95% confidence interval (CI) 4.9–10.5 ng/mg), but following the intervention there was a significant 11-fold reduction (P<0.001) to 0.6 ng per mg (95% CI 0.4–0.9 ng/mg). These data are unique in demonstrating human exposure to DON in the United Kingdom using a urinary biomarker. Furthermore, the study demonstrates that exposure can be markedly reduced by avoiding wheat in the diet. On the basis of urinary biomarker levels some individuals are predicted to exceed current recommended daily intakes of DON, and thus the health consequences of these exposures merit further investigation.

Deoxynivalenol: rationale for development and application of a urinary biomarker.

Mycotoxins are common dietary contaminants in most regions of the world. The frequency of exposure to the various families of mycotoxins is often dependent on geographic location, national wealth and related agricultural and regulatory infrastructure, combined with diversity of diet and degree of food sufficiency. Deoxynivalenol (DON) is a Fusarium mycotoxin that frequently contaminates wheat, corn and barley in temperate regions. A number of acute poisoning incidences have been linked to DON-contaminated foods and chronic exposure to lower levels of DON has been predicted in many regions. DON is a potent animal toxin and exposure in humans may cause gastroenteritis, growth faltering and immune toxicity. An ability to conduct accurate exposure assessment at the individual level is required to fully understand the potential health consequences for humans. To date, such exposure biomarkers have been lacking for many important mycotoxins, including DON. To better assess exposure to DON at the individual level, we have developed a robust urinary assay, incorporating immunoaffinity column (IAC) enrichment and LC–MS detection. Further refinement of this urinary assay, by inclusion of 13C-DON as an internal standard, was then undertaken and tested within the UK. DON was frequently observed in urine and was significantly associated with cereal intake. A dietary intervention study demonstrated that avoiding wheat in the diet markedly reduced urinary levels of DON. This biomarker requires further validation but our initial data suggest it may provide a useful tool in epidemiological investigations of the potential health consequences of this common environmental toxin.

Proteomic Screening of a Cell Line Model of Esophageal Carcinogenesis Identifies Cathepsin D and Aldo-Keto Reductase 1C2 and 1B10 Dysregulation in Barrett’s Esophagus and Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EA) incidence is increasing rapidly and is associated with a poor prognosis. Identifying biomarkers of disease development and progression would be invaluable tools to inform clinical practice. Two-dimensional polyacrylamide gel electrophoresis was used to screen 10 esophageal cell lines representing distinct stages in the development of esophageal cancer. Thirty-three proteins were identified by MALDI-TOF-MS which demonstrated differences in expression across the cell lines. Western blotting and qRT-PCR confirmed increased cathepsin D and aldo-keto reductases 1C2 and 1B10 expression in metaplastic and dysplastic cell lines. Expression of these proteins was further assessed in esophageal epithelium from patients with nonerosive (NERD) and erosive gastro-esophageal reflux disease, Barretts esophagus (BE) and EA. When compared with normal epithelium of NERD patients, (i) cathepsin D mRNA levels demonstrated a stepwise increase in expression (p<0.05) in erosive, metaplastic and EA tissue; (ii) AKR1B10 expression increased (p<0.05) 3- and 9-fold in erosive and Barretts epithelium, respectively; and (iii) AKR1C2 levels increased (p<0.05) in erosive and Barretts epithelium, but were reduced (p<0.05) in EA. These proteins may contribute to disease development via effects on apoptosis, transport of bile acids and retinoid metabolism and should be considered as candidates for further mechanistic and clinical investigations.

Cyclooxygenase-2 and Inducible Nitric Oxide Synthase Gene Polymorphisms and Risk of Reflux Esophagitis, Barrett's Esophagus, and Esophageal Adenocarcinoma

The incidence of esophageal adenocarcinoma has increased in recent years, and Barretts esophagus is a recognized risk factor. Gastroesophageal reflux of acid and/or bile is linked to these conditions and to reflux esophagitis. Inflammatory disorders can lead to carcinogenesis through activation of “prosurvival genes,” including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Increased expression of these enzymes has been found in esophageal adenocarcinoma, Barretts esophagus, and reflux esophagitis. Polymorphic variants in COX-2 and iNOS genes may be modifiers of risk of these conditions. In a population-based case-control study, we examined associations of the COX-2 8473 T>C and iNOS Ser608 Leu (C>T) polymorphisms with risk of esophageal adenocarcinoma, Barretts esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barretts esophagus (n = 212), and reflux esophagitis (n = 230) and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. The presence of at least one COX-2 8473 C allele was associated with a significantly increased risk of esophageal adenocarcinoma (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.40). There was no significant association between this polymorphism and risk of Barretts esophagus or reflux esophagitis or between the iNOS Ser608 Leu polymorphism and risk of these esophageal conditions. Our study suggests that the COX-2 8473 C allele is a potential genetic marker for susceptibility to esophageal adenocarcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(3):727–31)

Assessing caffeine exposure in pregnant women

Studies on the effects of caffeine on health, while numerous, have produced inconsistent results. One of the most uncertain and controversial effects is on pregnancy outcome. Studies have produced conflicting results due to a number of methodological variations. The major challenge is the accurate assessment of caffeine intake. The aim of the present study was to explore different methods of assessing caffeine exposure in pregnant women. Twenty-four healthy pregnant women from the UK city of Leeds completed both a detailed questionnaire, the caffeine assessment tool (CAT) designed specifically to assess caffeine intake and a prospective 3 d food and drink diary. The women also provided nine saliva samples over two consecutive days for estimation of caffeine and a metabolite (paraxanthine). Caffeine intakes from the CAT and diary showed adequate agreement (intra-class correlation coefficient of 0.5). For saliva caffeine and paraxanthine measures, the between-sample variation (within the same woman) was greater than between-woman and between-day variation. However, there was still adequate agreement between these measures and the CAT. The CAT is a valuable tool that is now being used in a large prospective study investigating caffeines role in pregnancy outcome.

No association between hOGG1, XRCC1, and XPD polymorphisms and risk of reflux esophagitis, Barrett's Esophagus, or esophageal adenocarcinoma: Results from the factors influencing the Barrett's adenocarcinoma relationship case-control study

Reflux of gastric contents can lead to development of reflux esophagitis and Barretts esophagus. Barretts esophagus is a risk factor for esophageal adenocarcinoma. Damage to DNA may lead to carcinogenesis but is repaired through activation of pathways involving polymorphic enzymes, including human 8-oxoguanine glycosylase 1 (hOGG1), X-ray repair cross-complementing 1 (XRCC1), and xeroderma pigmentosum group D (XPD). Of the single nucleotide polymorphisms identified in these genes, hOGG1 Ser326Cys, XRCC1 Arg399Gln, and XPD Lys751Gln are particularly common in Caucasians and have been associated with lower DNA repair capacity. Small studies have reported associations with XPD Lys751Gln and esophageal adenocarcinoma. XRCC1 Arg399Gln has been linked to Barretts esophagus and reflux esophagitis. In a population-based case-control study, we examined associations of the hOGG1 Ser326Cys, XRCC1 Arg399Gln, and XPD Lys751Gln polymorphisms with risk of esophageal adenocarcinoma, Barretts esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barretts esophagus (n = 212), reflux esophagitis (n = 230), and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. There were no statistically significant associations between these polymorphisms and risk of esophageal adenocarcinoma, Barretts esophagus, or reflux esophagitis. (Cancer Epidemiol Biomarkers Prev 2008;17(3):736–9)

Sodium deoxycholate causes nitric oxide mediated DNA damage in oesophageal cells.

Patients with chronic gastro-oesophageal reflux disease experience the reflux of acid and bile into the distal oesophagus. The secondary bile salt sodium deoxycholate (NDC) is implicated in the induction of mucosal injury during reflux episodes. This study hypothesized that NDC damages DNA in oesophageal cells by an oxidative mechanism. In the oesophageal cell line HET1-A, increased production of nitric oxide (NO) was measured in NDC-treated cells. Protection from DNA strand breaks induced by NDC (10 µm) was observed in cells coincubated with the nitric oxide scavenger C-PTIO (p<0.012) or pre-incubated with the NO synthase inhibitor L-NAME (p<0.009) or the NFκB inhibitor, TPCK (p<0.036). Collectively these data implicate the involvement of NFκB and nitric oxide synthase in the DNA damage induced by NDC in oesophageal cells. In conclusion, NDC-driven NO production may play an important role in inducing DNA damage during episodes of gastro-oesophageal reflux and thereby contribute to reflux-related carcinogenesis.