Piet A. van den Brandt

Factors influencing the composition of the intestinal microbiota in early infancy.

OBJECTIVE. The aim of this study was to examine the contribution of a broad range of external influences to the gut microbiotic composition in early infancy. METHODS. Fecal samples from 1032 infants at 1 month of age, who were recruited from the KOALA Birth Cohort Study in the Netherlands, were subjected to quantitative real-time polymerase chain reaction assays for the enumeration of bifidobacteria, Escherichia coli, Clostridium difficile, Bacteroides fragilis group, lactobacilli, and total bacterial counts. Information on potential determinants of the gut microbiotic composition was collected with repeated questionnaires. The associations between these factors and the selected gut bacteria were analyzed with univariate and multivariate analyses. RESULTS. Infants born through cesarean section had lower numbers of bifidobacteria and Bacteroides, whereas they were more often colonized with C difficile, compared with vaginally born infants. Exclusively formula-fed infants were more often colonized with E coli, C difficile, Bacteroides, and lactobacilli, compared with breastfed infants. Hospitalization and prematurity were associated with higher prevalence and counts of C difficile. Antibiotic use by the infant was associated with decreased numbers of bifidobacteria and Bacteroides. Infants with older siblings had slightly higher numbers of bifidobacteria, compared with infants without siblings. CONCLUSIONS. The most important determinants of the gut microbiotic composition in infants were the mode of delivery, type of infant feeding, gestational age, infant hospitalization, and antibiotic use by the infant. Term infants who were born vaginally at home and were breastfed exclusively seemed to have the most “beneficial” gut microbiota (highest numbers of bifidobacteria and lowest numbers of C difficile and E coli).

Association between mortality and indicators of traffic-related air pollution in the Netherlands: a cohort study

BACKGROUND Long-term exposure to particulate matter air pollution has been associated with increased cardiopulmonary mortality in the USA. We aimed to assess the relation between traffic-related air pollution and mortality in participants of the Netherlands Cohort study on Diet and Cancer (NLCS), an ongoing study. METHODS We investigated a random sample of 5000 people from the full cohort of the NLCS study (age 55-69 years) from 1986 to 1994. Long-term exposure to traffic-related air pollutants (black smoke and nitrogen dioxide) was estimated for the 1986 home address. Exposure was characterised with the measured regional and urban background concentration and an indicator variable for living near major roads. The association between exposure to air pollution and (cause specific) mortality was assessed with Coxs proportional hazards models, with adjustment for potential confounders. FINDINGS 489 (11%) of 4492 people with data died during the follow-up period. Cardiopulmonary mortality was associated with living near a major road (relative risk 1.95, 95% CI 1.09-3.52) and, less consistently, with the estimated ambient background concentration (1.34, 0.68-2.64). The relative risk for living near a major road was 1.41 (0.94-2.12) for total deaths. Non-cardiopulmonary, non-lung cancer deaths were unrelated to air pollution (1.03, 0.54-1.96 for living near a major road). INTERPRETATION Long-term exposure to traffic-related air pollution may shorten life expectancy.

Dietary heme iron and the risk of colorectal cancer with specific mutations in KRAS and APC

Red meat intake has been linked to increased colorectal cancer (CRC) risk. Although the underlying mechanisms remain unclear, experimental studies suggest a role for dietary heme iron. Because heme iron was shown to promote specific mutations, it would be insightful to link heme iron data to CRC with mutations in key genes in an observational, population-based study. We investigated the association between dietary heme iron intake and risk of CRC with mutations in APC (adenomatous polyposis coli) and KRAS (Kirsten ras) and P53 overexpression in the Netherlands Cohort Study. After 7.3 years of follow-up, excluding the first 2.3 years due to incomplete coverage of the pathology registry and to avoid preclinical disease, adjusted hazard ratios (including adjustment for total meat) and 95% confidence intervals were calculated, using 4026 subcohort members (aged 55-69 years at baseline), 435 colon and 140 rectal cancer patients. When comparing the highest with the lowest tertile of intake, heme iron intake was associated with an increased risk of CRC harboring activating mutations in KRAS (hazard ratio = 1.71, 95% confidence interval: 1.15-2.57; P for trend = 0.03) and CRC without truncating mutations in APC (hazard ratio = 1.79, 95% confidence interval: 1.23-2.60; P for trend = 0.003). We observed a positive association between heme iron intake and the risk of CRC with activating G>A mutations in KRAS (P for trend = 0.01) and overall G>A mutations in APC (P for trend = 0.005). No associations were found with CRC harboring G>T mutations in KRAS/APC. Heme iron intake was positively associated with the risk of P53 overexpressed tumors but not with tumors without P53 overexpression (Pheterogeneity = 0.12). Heme iron intake was associated with an increased risk of colorectal tumors harboring G>A transitions in KRAS and APC and overexpression of P53. These novel findings suggest that alkylating rather than oxidative DNA-damaging mechanisms are involved in heme-induced colorectal carcinogenesis.

Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study.

Background and aims: Perturbations in intestinal microbiota composition due to lifestyle changes may be involved in the development of atopic diseases. We examined gut microbiota composition in early infancy and the subsequent development of atopic manifestations and sensitisation. Methods: The faeces of 957 infants aged 1 month and participating in the KOALA Birth Cohort Study were analysed using quantitative real-time PCR. Information on atopic symptoms (eczema, wheeze) and potential confounders was acquired through repeated questionnaires. Total and specific IgE were measured in venous blood samples collected during home visits when the infant was 2 years old. During these home visits a clinical diagnosis of atopic dermatitis was made according to the UK-Working Party criteria. Results: The presence of Escherichia coli was associated with a higher risk of developing eczema (ORadj = 1.87; 95% CI 1.15 to 3.04), this risk being increased with increasing numbers of E coli (pfor trend = 0.016). Infants colonised with Clostridium difficile were at higher risk of developing eczema (ORadj = 1.40; 95% CI 1.02 to 1.91), recurrent wheeze (ORadj = 1.75; 95% CI 1.09 to 2.80) and allergic sensitisation (ORadj = 1.54; 95% CI 1.02 to 2.31). Furthermore, the presence of C difficile was also associated with a higher risk of a diagnosis of atopic dermatitis during the home visit (ORadj = 1.73; 95% CI 1.08 to 2.78). Conclusion: This study demonstrates that differences in gut microbiota composition precede the development of atopy. Since E coli was only associated with eczema and C difficile was associated with all atopic outcomes, the underlying mechanisms explaining these association may be different.

Long-term effects of traffic-related air pollution on mortality in a Dutch cohort (NLCS-AIR study)

Background Several studies have found an effect on mortality of between-city contrasts in long-term exposure to air pollution. The effect of within-city contrasts is still poorly understood. Objectives We studied the association between long-term exposure to traffic-related air pollution and mortality in a Dutch cohort. Methods We used data from an ongoing cohort study on diet and cancer with 120,852 subjects who were followed from 1987 to 1996. Exposure to black smoke (BS), nitrogen dioxide, sulfur dioxide, and particulate matter ≤mu;M2.5), as well as various exposure variables related to traffic, were estimated at the home address. We conducted Cox analyses in the full cohort adjusting for age, sex, smoking, and area-level socioeconomic status. Results Traffic intensity on the nearest road was independently associated with mortality. Relative risks (95% confidence intervals) for a 10-μg/m3 increase in BS concentrations (difference between 5th and 95th percentile) were 1.05 (1.00–1.11) for natural cause, 1.04 (0.95–1.13) for cardiovascular, 1.22 (0.99–1.50) for respiratory, 1.03 (0.88–1.20) for lung cancer, and 1.04 (0.97–1.12) for mortality other than cardiovascular, respiratory, or lung cancer. Results were similar for NO2 and PM2.5, but no associations were found for SO2. Conclusions Traffic-related air pollution and several traffic exposure variables were associated with mortality in the full cohort. Relative risks were generally small. Associations between natural-cause and respiratory mortality were statistically significant for NO2 and BS. These results add to the evidence that long-term exposure to ambient air pollution is associated with increased mortality.

The Impact of Characteristics of Cigarette Smoking on Urinary Tract Cancer Risk A Meta-Analysis of Epidemiologic Studies

Although narrative reviews have concluded that there is strong support for an association between cigarette smoking and urinary tract cancer, the association has never been quantified systematically in reviews. The purpose of this systematic review was to summarize and quantify the impact of different smoking characteristics (status, amount, duration, cessation, and age at first exposure) both unadjusted and adjusted for age and gender.

Nitrate, nitrite and N-nitroso compounds

A risk assessment has been made on nitrate, nitrite and N-nitroso compounds encountered in the human diet. Vegetables constitute a major source of nitrate providing over 85% of the average daily human dietary intake. Nitrite and N-nitroso compounds present in the diet contribute relatively small amounts to the body burden and the major source of these biologically reactive compounds is derived from the bacterial and mammalian metabolism of ingested nitrate. Additionally, endogenous synthesis provides an important source contributing to the body burden of nitrate. Data from animal toxicological studies, human effects and epidemiological surveys have been reviewed and evaluated. It is concluded that there is no firm scientific evidence at present to recommend drastic reductions beyond the average levels of nitrate encountered in vegetables grown in keeping with good agricultural practice. Recommendations have also been made for further animal and human studies to be carried out to elucidate the potential risks to man from ingested nitrate.

Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy.

BACKGROUND Both gastrointestinal microbiota composition and cesarean section have been linked to atopic manifestations. However, results are inconsistent, and the hypothesized intermediate role of the microbiota in the association between birth mode and atopic manifestations has not been studied yet. OBJECTIVES We sought to investigate the relationship between microbiota composition, mode and place of delivery, and atopic manifestations. METHODS The Child, Parent and Health: Lifestyle and Genetic Constitution Birth Cohort Study included data on birth characteristics, lifestyle factors, and atopic manifestations collected through repeated questionnaires from birth until age 7 years. Fecal samples were collected at age 1 month (n = 1176) to determine microbiota composition, and blood samples were collected at ages 1 (n = 921), 2 (n = 822), and 6 to 7 (n = 384) years to determine specific IgE levels. RESULTS Colonization by Clostridium difficile at age 1 month was associated with wheeze and eczema throughout the first 6 to 7 years of life and with asthma at age 6 to 7 years. Vaginal home delivery compared with vaginal hospital delivery was associated with a decreased risk of eczema, sensitization to food allergens, and asthma. After stratification for parental history of atopy, the decreased risk of sensitization to food allergens (adjusted odds ratio, 0.52; 95% CI, 0.35-0.77) and asthma (adjusted odds ratio, 0.47; 95% CI, 0.29-0.77) among vaginally home-born infants was only found for children with atopic parents. Mediation analysis showed that the effects of mode and place of delivery on atopic outcomes were mediated by C difficile colonization. CONCLUSION Mode and place of delivery affect the gastrointestinal microbiota composition, which subsequently influences the risk of atopic manifestations.

Type I and II Endometrial Cancers: Have They Different Risk Factors?

PURPOSE Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. PATIENTS AND METHODS Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. RESULTS Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. CONCLUSION The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.

Fatigue and psychological distress in the working population: Psychometrics, prevalence, and correlates

OBJECTIVE The purposes of this study were: (1) to explore the relationship between fatigue and psychological distress in the working population; (2) to examine associations with demographic and health factors; and (3) to determine the prevalence of fatigue and psychological distress. METHODS Data were taken from 12,095 employees. Fatigue was measured with the Checklist Individual Strength, and the General Health Questionnaire (GHQ) was used to measure psychological distress. RESULTS Fatigue was fairly well associated with psychological distress. A separation between fatigue items and GHQ items was shown. No clear, distinct pattern of associations was found for fatigue vs. psychological distress with respect to demographic factors. The prevalence was 22% for fatigue and 23% for psychological distress. Of the employees reporting fatigue, 43% had fatigue only, whereas 57% had fatigue and psychological distress. CONCLUSIONS The results indicate that fatigue and psychological distress are common in the working population. Although closely associated, there is some evidence suggesting that fatigue and psychological distress are different conditions, which can be measured independently.