Smoking and the risk of gastric cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC)

Smoking has recently been recognised as causally associated with the development of gastric cancer (GC). However, evidence on the effect by sex, duration and intensity of smoking, anatomic subsite and cessation of smoking is limited. Our objective was to assess the relation between tobacco use and GC incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC). We studied data from 521,468 individuals recruited from 10 European countries taking part in the EPIC study. Participants completed lifestyle questionnaires that included questions on lifetime consumption of tobacco and diet in 1991-1998. Participants were followed until September 2002, and during that period 305 cases of stomach cancer were identified. After exclusions, 274 were eligible for the analysis, using the Cox proportional hazard model. After adjustment for educational level, consumption of fresh fruit, vegetables and preserved meat, alcohol intake and body mass index (BMI), there was a significant association between cigarette smoking and gastric cancer risk: the hazard ratio (HR) for ever smokers was 1.45 (95% confidence interval [CI] = 1.08-1.94). The HR of current cigarette smoking was 1.73 (95% CI = 1.06-2.83) in males and 1.87 (95% CI = 1.12-3.12) in females. Hazard ratios increased with intensity and duration of cigarette smoked. A significant decrease of risk was observed after 10 years of quitting smoking. A preliminary analysis of 121 cases with identified anatomic site showed that current cigarette smokers had a higher HR of GC in the cardia (HR = 4.10) than in the distal part of the stomach (HR = 1.94). In this cohort, 17.6 % (95% CI = 10.5-29.5 %) of GC cases may be attributable to smoking. Findings from this large study support the causal relation between smoking and gastric cancer in this European population. Stomach cancer should be added to the burden of diseases caused by smoking.     

Nitric oxide potentiates response of trigeminal neurones to dural or facial stimulation in the rat

Infusing glyceryl trinitrate as a donor molecule, we have used electrophysiological and c-fos immunostaining techniques to study the effects of nitric oxide on neurones in the nucleus trigeminalis caudalis. Following infusion of glyceryl trinitrate, responses of neurones to electrical stimulation of periorbital cutaneous afferents were potentiated and threshold for activation of neurones by stimulation of dural afferents was reduced. Expression of c-fos was unchanged by glyceryl trinitrate compared to saline controls. Intradermal injection of capsaicin in the periorbital area increased c-fos expression in nucleus trigeminalis caudalis; this was significantly potentiated by glyceryl trinitrate. These results suggest that, in the anaesthetized rat, glyceryl trinitrate alone may not acutely activate the trigeminovascular system to a significant degree at doses that cause headache and later trigger migraine headache in migraineurs. Nevertheless, it is susceptible to exogenous nitric oxide in that activation of trigeminal neurones through cutaneous or dural pathways is potentiated. This may in some measure underlie the pathogenesis of migraine headache.     

Dietary assessment in Whitehall II: comparison of 7 d diet diary and food-frequency questionnaire and validity against biomarkers

The aim of the present cross-sectional study was to examine the agreement and disagreement between a 7 d diet diary (7DD) and a self-administered machine-readable food-frequency questionnaire (FFQ) asking about diet in the previous year, and to validate both methods with biomarkers of nutrient intake. The subjects were an age- and employment-grade-stratified random subsample of London-based civil servants (457 men and 403 women), aged 39-61 years, who completed both a 7DD and a FFQ at phase 3 follow-up (1991-1993) of the Whitehall II study. Mean daily intakes of dietary energy, total fat, saturated, monounsaturated and polyunsaturated fatty acids, linoleic acid, total carbohydrate excluding fibre, sugars, starch, dietary fibre, protein, vitamin C, vitamin E (as alpha-tocopherol equivalents), folate, carotenes (as total beta-carotene activity), Fe, Ca, Mg, K and alcohol were measured. Serum cholesteryl ester fatty acids (CEFA), plasma alpha-tocopherol and beta-carotene were also measured as biomarkers. Estimates of mean energy intake from the two methods were similar in men, and some 10 % higher according to the FFQ in women. Compared with the 7DD, the FFQ tended to overestimate plant-derived micronutrient intakes (carotenes from FFQ v. 7DD men 2713 (SD 1455) v. 2180 (SD 1188) microg/d, women 3100 (SD 1656) v. 2221 (SD 1180) microg/d, both differences P<0.0001) and to underestimate fat intake. Against plasma beta-carotene/cholesterol, carotene intake was as well estimated by the FFQ as the 7DD (Spearman rank correlations, men 0.32 v. 0.30, women 0.27 v. 0.22, all P< or =0.0001, energy-adjusted data). Ranking of participants by other nutrient intakes tended to be of the same order according to the two dietary methods, e.g. rank correlations for CEFA linoleic acid against FFQ and 7DD estimates respectively, men 0.38 v. 0.41, women 0.53 v. 0.62, all P< or =0.0001, energy-adjusted % fat). For alpha-tocopherol there were no correlations between plasma level and estimated intakes by either dietary method. Quartile agreement for energy-adjusted nutrient intakes between the two self-report methods was in the range 37-50 % for men and 32-44 % for women, and for alcohol, 57 % in both sexes. Disagreement (misclassification into extreme quartiles of intake) was in the range 0-6 % for both sexes. The dietary methods yielded similar prevalences (about 34 %) of low energy reporters. The two methods show satisfactory agreement, together with an expected level of systematic differences, in their estimates of nutrient intake. Against the available biomarkers, the machine-readable FFQ performed well in comparison with the manually coded 7DD in this study population. For both methods, regression-based adjustment of nutrient intake to mean dietary energy intake by gender appears on balance to be the optimal approach to data presentation and analysis, in view of the complex problem of low energy reporting.     

Dose-dependent effect of dietary meat on endogenous colonic N-nitrosation

Human male volunteers were studied in a metabolic facility whilst they were fed randomized controlled diets. In eight volunteers there was a significant increase in faecal apparent total N:-nitroso compounds (ATNC) and nitrite excretion (P < 0.0001 and P = 0.046, respectively) when randomized doses of meat were increased from 0 to 60, 240 and 420 g/day over 10 day periods. Mean (+/- SE) faecal ATNC levels were 54 +/- 7 microg/day when the diets contained no meat, 52 +/- 11 microg/day when the diets contained 60 g meat/day, 159 +/- 33 microg/day with 240 g meat and 199 +/- 36 microg/day with 420 g meat. Higher concentrations of NOC were associated with longer times of transit in the gut (r = 0.55, P = 0.001) and low faecal weight (r = -0.51, P = 0.004). There was no significant decline in levels in individuals fed 420 g meat for 40 days. The exposures found on the higher meat diets were comparable with other sources of N:-nitroso compounds (NOC), such as tobacco smoke. Many NOC are known large bowel initiators and promotors in colon cancer, inducing G-->A transitions in codons 12 and 13 of K-ras. Endogenous NOC formation, combined with prolonged transit times in the gut, may explain the epidemiological associations between high meat/low fibre diets and colorectal cancer risk.     

Epidemiological assessment of diet: a comparison of a 7-day diary with a food frequency questionnaire using urinary markers of nitrogen, potassium and sodium

BACKGROUND: Validation studies of dietary instruments developed for epidemiological studies have typically used some form of diet record as the standard for comparison. Recent work suggests that comparison with diet record may overestimate the ability of the epidemiological instrument to measure habitual dietary intake, due to lack of independence of the measurement errors. The degree of regression dilution in estimating diet-disease association may therefore have been correspondingly underestimated. Use of biochemical measures of intake may mitigate the problem. In this paper, we report on the use of urinary measures of intakes of nitrogen, potassium and sodium to compare the performance of a semi-quantitative food frequency questionnaire (FFQ) and a 7-day diet diary (7DD) to estimate average intake of these nutrients over one year. METHODS: In all, 179 individuals were asked to complete an FFQ and a 7DD on two occasions separated by approximately 12 months. The individuals were also asked to provide 24-hour urine samples on six occasions over a 6-9-month period, covering the time at which the record FFQ and 7DD were completed. The urine was assayed for nitrogen, potassium and sodium. The protocol was completed by 123 individuals. The data from these individuals were analysed to estimate the covariance structure of the measurement errors of the FFQ, the 7DD and a single 24-hour urine measurement, and to estimate the degree of regression dilution associated with the FFQ and 7DD. RESULTS: The results demonstrated that: (1) the error variances for each of the three nutrients was more than twice as great with the FFQ than the 7DD; (2) there was substantial correlation (0.46-0.58) between the error of both the FFQ and the 7DD completed on different occasions; (3) there was moderate correlation (0.24- 0.29) between the error in the FFQ and the error in the 7DD for each nutrient; (4) the correlation between errors in different nutrients was higher for the FFQ (0.77-0.80) than for the 7DD (0.52-0.70). CONCLUSIONS: The regression dilution with the FFQ is considerably greater than with the 7DD and also, for the nutrients considered, greater than would be inferred if validation studies were based solely on record or diary type instruments.     

Sexually transmitted infections in Estonia

Estonia, one of the Baltic countries, regained its independence in 1991, after the collapse of the USSR. This process led to great changes in every sphere of life--in politics, in the economy and in medicine. The service providing care for sexually transmitted infections (STIs) was involved in the process of these changes, too. However, freedom was followed not only by great happiness, but also by social destabilization and transformation of the old moral norms, the most evident features of which were the dramatic rise in crime, a sexual revolution and public prostitution. These 2 great simultaneous transformations in the STI care system and public mores led to the rapid increase of STIs in Estonia in the first half of the 1990s. Now some stabilization, and even a fall in incidence has occurred.     

Mammographic patterns as a predictive biomarker of breast cancer risk: effect of tamoxifen.

Mammographic breast density has been shown to be associated with up to a 4- to 6-fold increase in risk of breast cancer, whereas tamoxifen therapy increases disease-free survival and reduces mortality. We have therefore investigated whether these effects are related. To determine the effects of tamoxifen on mammographic density, mammograms from 94 women who had received tamoxifen for breast cancer and 188 women (without breast cancer) who had not received tamoxifen were visually classified according to the criteria of Wolfe. Two controls were age-matched to each case. All of the women were postmenopausal (ages, 50-64 years), neither group was taking hormone replacement therapy, and none of the cases had received chemotherapy. There were significant differences in breast density between cases and controls at the initial mammogram (P = 0.0001) but no significant differences at the follow-up mammogram (P = 0.51). A significant change to a more lucent pattern had occurred among the case group (P = 0.0001). The odds ratio for cancer that was associated with the more dense (P2 and DY) patterns with respect to the more lucent (N1 and P1) patterns was 3.6 (95% confidence interval, 2.11-6.18) at the initial mammogram. This was significantly reduced to 1.5 (95% confidence interval, 1.32-1.70) after treatment with tamoxifen (P = 0.019; chi2 = 5.52). The substantial reduction in breast density with tamoxifen provides evidence that tamoxifen has the capacity to favorably alter postmenopausal breast density toward a more lucent pattern, which is associated with reduced risk of breast cancer. Mammographic pattern is, thus, a potential biomarker of breast cancer risk.     

Scorpion Toxins Specific for Potassium (K+) Channels: A Historical Overview of Peptide Bioengineering

Scorpion toxins have been central to the investigation and understanding of the physiological role of potassium (K⁺) channels and their expansive function in membrane biophysics. As highly specific probes, toxins have revealed a great deal about channel structure and the correlation between mutations, altered regulation and a number of human pathologies. Radio- and fluorescently-labeled toxin isoforms have contributed to localization studies of channel subtypes in expressing cells, and have been further used in competitive displacement assays for the identification of additional novel ligands for use in research and medicine. Chimeric toxins have been designed from multiple peptide scaffolds to probe channel isoform specificity, while advanced epitope chimerization has aided in the development of novel molecular therapeutics. Peptide backbone cyclization has been utilized to enhance therapeutic efficiency by augmenting serum stability and toxin half-life in vivo as a number of K⁺-channel isoforms have been identified with essential roles in disease states ranging from HIV, T-cell mediated autoimmune disease and hypertension to various cardiac arrhythmias and Malaria. Bioengineered scorpion toxins have been monumental to the evolution of channel science, and are now serving as templates for the development of invaluable experimental molecular therapeutics.