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Murphy N.,Imperial College London | Norat T.,Imperial College London | Ferrari P.,International Agency for Research on Cancer IARC WHO | Jenab M.,International Agency for Research on Cancer IARC WHO | And 55 more authors.
PLoS ONE | Year: 2012

Background: Earlier analyses within the EPIC study showed that dietary fibre intake was inversely associated with colorectal cancer risk, but results from some large cohort studies do not support this finding. We explored whether the association remained after longer follow-up with a near threefold increase in colorectal cancer cases, and if the association varied by gender and tumour location. Methodology/Principal Findings: After a mean follow-up of 11.0 years, 4,517 incident cases of colorectal cancer were documented. Total, cereal, fruit, and vegetable fibre intakes were estimated from dietary questionnaires at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models stratified by age, sex, and centre, and adjusted for total energy intake, body mass index, physical activity, smoking, education, menopausal status, hormone replacement therapy, oral contraceptive use, and intakes of alcohol, folate, red and processed meats, and calcium. After multivariable adjustments, total dietary fibre was inversely associated with colorectal cancer (HR per 10 g/day increase in fibre 0.87, 95% CI: 0.79-0.96). Similar linear associations were observed for colon and rectal cancers. The association between total dietary fibre and risk of colorectal cancer risk did not differ by age, sex, or anthropometric, lifestyle, and dietary variables. Fibre from cereals and fibre from fruit and vegetables were similarly associated with colon cancer; but for rectal cancer, the inverse association was only evident for fibre from cereals. Conclusions/Significance: Our results strengthen the evidence for the role of high dietary fibre intake in colorectal cancer prevention. © 2012 Murphy et al.


Fredriksson L.,Leiden University | Wink S.,Leiden University | Herpers B.,Leiden University | Benedetti G.,Leiden University | And 8 more authors.
Toxicological Sciences | Year: 2014

Drug-induced liver injury (DILI) is an important clinical problem. Here, we used a genomics approach to in detail investigate the hypothesis that critical drug-induced toxicity pathways act in synergy with the pro-inflammatory cytokine tumor necrosis factor α (TNFα) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. Compounds displaying weak or no TNFα synergism, namely ketoconazole, nefazodone, and methotrexate, failed to synchronously induce both pathways. The ER stress induced was primarily related to protein kinase R-like ER kinase (PERK) and activating transcription factor 4 (ATF4) activation and subsequent expression of C/EBP homologous protein (CHOP), which was all independent of TNFα signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precisioncut human liver slices. Targeted RNA interference studies revealed that whereas ER stress signaling through inositol-requiring enzyme 1α (IRE1α) and activating transcription factor 6 (ATF6) acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNFα-induced apoptosis. Whereas inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNFα cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNFα-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing toward caspase-8-dependent TNFα- induced apoptosis. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


PubMed | Leiden University, University of Groningen and The National Institute for Public Health and the Environment RIVM
Type: Journal Article | Journal: Toxicological sciences : an official journal of the Society of Toxicology | Year: 2014

Drug-induced liver injury (DILI) is an important clinical problem. Here, we used a genomics approach to in detail investigate the hypothesis that critical drug-induced toxicity pathways act in synergy with the pro-inflammatory cytokine tumor necrosis factor (TNF) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of 80 DILI compounds in primary human hepatocytes. Compounds displaying weak or no TNF synergism, namely ketoconazole, nefazodone, and methotrexate, failed to synchronously induce both pathways. The ER stress induced was primarily related to protein kinase R-like ER kinase (PERK) and activating transcription factor 4 (ATF4) activation and subsequent expression of C/EBP homologous protein (CHOP), which was all independent of TNF signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision-cut human liver slices. Targeted RNA interference studies revealed that whereas ER stress signaling through inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. Whereas inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing toward caspase-8-dependent TNF-induced apoptosis.


Babisch W.,Federal Environment Agency | Pershagen G.,Karolinska Institutet | Selander J.,Karolinska Institutet | Houthuijs D.,The National Institute for Public Health and the Environment RIVM | And 9 more authors.
Science of the Total Environment | Year: 2013

Objectives: The effect modifying impact of annoyance due to aircraft noise and road traffic noise on the relationships between the aircraft noise level and road traffic noise level on the prevalence of hypertension was investigated in 4861 subjects of the HYENA study (HYpertension and Exposure to Noise near Airports). Methods: Different models were investigated either including the noise level and noise annoyance variables separately, or simultaneously, or together with an interaction term referring to the same noise source for the noise level and the noise annoyance. Results: Significant effect modification was found with respect to the association between aircraft noise and hypertension. The association was stronger in more annoyed subjects. No clear interaction was found with respect to road traffic noise. The comparison of the magnitude of the main effects (per standard deviation or inter-quartile range) of noise level and noise annoyance variables revealed stronger associations with hypertension for the noise levels. Conclusion: There is some indication that the noise level has a stronger predictive meaning for the relationship between noise exposure and hypertension than the reported noise annoyance (main effects). The results from the Hyena study support the hypothesis that noise annoyance acts as an effect modifier of the relationship between the noise level and hypertension. © 2013 Elsevier B.V.


Bayer C.,Robert Koch Institute | Bayer C.,Centers for Disease Control and Prevention | Bernard H.,Robert Koch Institute | Prager R.,Robert Koch Institute | And 9 more authors.
Eurosurveillance | Year: 2014

The largest Salmonella enterica serovar Newport outbreak (n=106) ever reported in Germany occurred in October and November 2011. Twenty associated cases were reported in the Netherlands. The outbreak investigation included an analytical epidemiological study, molecular typing of human and food isolates and food traceback investigations. Unspecified Salmonella had been detected in samples of mung bean sprouts at a sprout producer (producer A) in the Netherlands and mung bean sprouts contaminated with S. Newport had been found during routine sampling at a sprout distributor in Germany. Therefore, we tested the hypothesis of sprouts being the infection vehicle. In a case-control study, we compared 50 notified adult S. Newport cases with 45 Salmonella enterica serovar Enteritidis cases regarding their food consumption in the three days before illness. In multivariable logistic regression analysis, only sprout consumption was significantly associated with S. Newport infection (odds ratio: 18.4; 95% confidence interval: 2.2-150.2). Molecular typing patterns of human isolates were indistinguishable from a mung bean sprouts isolate. Traceback of sprouts led to distributors and producer A in the Netherlands. Since sprouts are frequently contaminated with microorganisms, consumers need to be aware that consumption of raw or insufficiently cooked sprouts may pose a health risk.


PubMed | University of Amsterdam, The National Institute for Public Health and the Environment RIVM and Radboud University Nijmegen
Type: | Journal: The Journal of antimicrobial chemotherapy | Year: 2016

To define appropriate antibiotic use in hospitalized adults treated for a bacterial infection, we previously developed and validated a set of six generic quality indicators (QIs) covering all steps in the process of antibiotic use. We assessed the association between appropriate antibiotic use, defined by these QIs, and length of hospital stay (LOS).An observational multicentre study in 22 hospitals in the Netherlands included 1890 adult, non-ICU patients using antibiotics for a suspected bacterial infection. Performance scores were calculated for all QIs separately (appropriate or not), and a sum score described performance on the total set of QIs. We divided the sum scores into two groups: low (0%-49%) versus high (50%-100%). Multilevel analyses, correcting for confounders, were used to correlate QI performance (single and combined) with (log-transformed) LOS and in-hospital mortality.The only single QI associated with shorter LOS was appropriate intravenous-oral switch (geometric means 6.5 versus 11.2days; P<0.001). A high sum score was associated with a shorter LOS in the total group (10.1 versus 11.2days; P=0.002) and in the subgroup of community-acquired infections (9.7 versus 10.9 days; P=0.007), but not in the subgroup of hospital-acquired infections. We found no association between performance on QIs and in-hospital mortality or readmission rate.Appropriate antibiotic use, defined by validated process QIs, in hospitalized adult patients with a suspected bacterial infection appears to be associated with a shorter LOS and therefore positively contributes to patient outcome and healthcare costs.

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