• Acute illness from Campylobacter jejuni may require high doses while infection occurs at low doses.

      Teunis, Peter F M; Bonačić Marinović, Axel; Tribble, David R; Porter, Chad K; Swart, Arno (2018-02-08)
      Data from a set of different studies on the infectivity and pathogenicity of Campylobacter jejuni were analyzed with a multilevel model, allowing for effects of host species (nonhuman primates and humans) and different strains of the pathogen. All challenge studies involved high doses of the pathogen, resulting in all exposed subjects to become infected. In only one study a dose response effect (increasing trend with dose) for infection was observed. High susceptibility to infection with C. jejuni was found in a joint analysis of outbreaks and challenge studies. For that reason four outbreaks, associated with raw milk consumption, were also included in the present study. The high doses used for inoculation did not cause all infected subjects to develop acute enteric symptoms. The observed outcomes are consistent with a dose response effect for acute symptoms among infected subjects: a conditional illness dose response relation. Nonhuman primates and human volunteers did not appear to have different susceptibilities for developing enteric symptoms, but exposure in outbreaks (raw milk) did lead to a higher probability of symptomatic campylobacteriosis.
    • Acute Otitis Media During Infancy: Parent-reported Incidence and Modifiable Risk Factors.

      Prins-van Ginkel, Annemarijn C; Bruijning-Verhagen, Patricia C J; Uiterwaal, Cuno S P M; van der Ent, Cornelis K; Smit, Henriette A; de Hoog, Marieke L A (2017-03)
      Age at exposure to acute otitis media (AOM) risk factors such as day care attendance, lack of breastfeeding and tobacco smoke is little studied but important for targeting AOM prevention strategies. Moreover, studies are typically restricted to clinically diagnosed AOM, while a significant subset can occur outside the health care system, depending on the country setting. This study aims to determine risk factor exposure and effect of its timing within the first year of life on parent-reported AOM symptom episodes.
    • Adaptation of Bordetella pertussis to the respiratory tract.

      van Beek, Lucille L F; de Gouw, Daan D; Eleveld, Marc M J; Bootsma, Hester H J; de Jonge, Marien M I; Mooi, Frits F R; Zomer, Aldert A; Diavatopoulos, Dimitri D A (2018-03-08)
      There is a lack of insight into the basic mechanisms by which Bordetella pertussis adapts to the local host environment during infection. We analysed B. pertussis gene expression in the upper and lower airways of mice and compared this to SO4-induced in vitro Bvg-regulated gene transcription. Approximately 30% of all genes were found to be differentially expressed between in vitro vs. in vivo conditions. This included several novel potential vaccine antigens that were exclusively expressed in vivo. Significant differences in expression profile and metabolic pathways were identified between the upper versus the lower airways, suggesting distinct antigenic profiles. We found high expression of several Bvg-repressed genes during infection and mouse vaccination experiments using purified protein fractions from both Bvg- and Bvg+ cultures demonstrated protection against intranasal B. pertussis challenge. This study provides novel insights into the in vivo adaptation of B. pertussis and may facilitate the improvement of pertussis vaccines.
    • Added Value of Serum Hormone Measurements in Risk Prediction Models for Breast Cancer for Women Not Using Exogenous Hormones: Results from the EPIC Cohort.

      Hüsing, Anika; Fortner, Renée T; Kühn, Tilman; Overvad, Kim; Tjønneland, Anne; Olsen, Anja; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Fournier, Agnes; Boeing, Heiner; et al. (2017-08-01)
      Purpose: Circulating hormone concentrations are associated with breast cancer risk, with well-established associations for postmenopausal women. Biomarkers may represent minimally invasive measures to improve risk prediction models.Experimental Design: We evaluated improvements in discrimination gained by adding serum biomarker concentrations to risk estimates derived from risk prediction models developed by Gail and colleagues and Pfeiffer and colleagues using a nested case-control study within the EPIC cohort, including 1,217 breast cancer cases and 1,976 matched controls. Participants were pre- or postmenopausal at blood collection. Circulating sex steroids, prolactin, insulin-like growth factor (IGF) I, IGF-binding protein 3, and sex hormone-binding globulin (SHBG) were evaluated using backward elimination separately in women pre- and postmenopausal at blood collection. Improvement in discrimination was evaluated as the change in concordance statistic (C-statistic) from a modified Gail or Pfeiffer risk score alone versus models, including the biomarkers and risk score. Internal validation with bootstrapping (1,000-fold) was used to adjust for overfitting.Results: Among women postmenopausal at blood collection, estradiol, testosterone, and SHBG were selected into the prediction models. For breast cancer overall, model discrimination after including biomarkers was 5.3 percentage points higher than the modified Gail model alone, and 3.4 percentage points higher than the Pfeiffer model alone, after accounting for overfitting. Discrimination was more markedly improved for estrogen receptor-positive disease (percentage point change in C-statistic: 7.2, Gail; 4.8, Pfeiffer). We observed no improvement in discrimination among women premenopausal at blood collection.Conclusions: Integration of hormone measurements in clinical risk prediction models may represent a strategy to improve breast cancer risk stratification. Clin Cancer Res; 23(15); 4181-9. ©2017 AACR.
    • Adherence to a food group-based dietary guideline and incidence of prediabetes and type 2 diabetes.

      den Braver, Nicolette R; Rutters, Femke; van der Spek, Andrea L J Kortlever; Ibi, Dorina; Looman, Moniek; Geelen, Anouk; Elders, Petra; van der Heijden, Amber A; Brug, Johannes; Lakerveld, Jeroen; et al. (2019-07-24)
      During a mean follow-up of 6.3 ± 0.7 years, 837 participants developed preT2D and 321 participants developed T2D. The highest adherence to the DHD15-index was significantly associated with lower T2D incidence [model 3, PRT3vsT1: 0.70 (0.53; 0.92), ptrend = 0.01]. The highest adherence to the DHD15-index pointed towards a lower incidence of preT2D [PRT3vsT1: 0.87 (0.74; 1.03), ptrend = 0.11]. Higher adherence to the DHD15-index was not associated with change in fasting plasma glucose levels [β10point: - 0.012 (- 0.034; 0.009)mmol/L].
    • Adherence to the WCRF/AICR Dietary Recommendations for Cancer Prevention and Risk of Cancer in Elderly from Europe and the United States: A Meta-Analysis within the CHANCES Project.

      Jankovic, Nicole; Geelen, Anouk; Winkels, Renate M; Mwungura, Blaise; Fedirko, Veronika; Jenab, Mazda; Illner, Anne K; Brenner, Hermann; Ordóñez-Mena, José M; Kiefte de Jong, Jessica C; et al. (2017)
      It is unknown whether dietary recommendations for cancer prevention are applicable to the elderly. We analyzed WCRF/AICR recommendations in cohorts of European and U.S. adults ages 60 years and above.
    • Adhering to a national surgical care bundle reduces the risk of surgical site infections.

      Koek, Mayke B G; Hopmans, Titia E M; Soetens, Loes C; Wille, Jan C; Geerlings, Suzanne E; Vos, Margreet C; van Benthem, Birgit H B; de Greeff, Sabine C (2017)
      In 2008, a bundle of care to prevent Surgical Site Infections (SSIs) was introduced in the Netherlands. The bundle consisted of four elements: antibiotic prophylaxis according to local guidelines, no hair removal, normothermia and 'hygiene discipline' in the operating room (i.e. number of door movements). Dutch hospitals were advised to implement the bundle and to measure the outcome. This study's goal was to assess how effective the bundle was in reducing SSI risk.
    • Adipokines and inflammation markers and risk of differentiated thyroid carcinoma: The EPIC study.

      Dossus, Laure; Franceschi, Silvia; Biessy, Carine; Navionis, Anne-Sophie; Travis, Ruth C; Weiderpass, Elisabete; Scalbert, Augustin; Romieu, Isabelle; Tjønneland, Anne; Olsen, Anja; et al. (2018-04-01)
      Other than the influence of ionizing radiation and benign thyroid disease, little is known about the risk factors for differentiated thyroid cancer (TC) which is an increasing common cancer worldwide. Consistent evidence shows that body mass is positively associated with TC risk. As excess weight is a state of chronic inflammation, we investigated the relationship between concentrations of leptin, adiponectin, C-reactive protein, interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α and the risk of TC. A case-control study was nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study and included 475 first primary incident TC cases (399 women and 76 men) and 1,016 matched cancer-free cohort participants. Biomarkers were measured in serum samples using validated and highly sensitive commercially available immunoassays. Odds ratios (ORs) of TC by levels of each biomarker were estimated using conditional logistic regression models, adjusting for BMI and alcohol consumption. Adiponectin was inversely associated with TC risk among women (ORT3vs.T1 = 0.69, 95% CI: 0.49-0.98, Ptrend = 0.04) but not among men (ORT3vs.T1 = 1.36, 95% CI: 0.67-2.76, Ptrend = 0.37). Increasing levels of IL-10 were positively associated with TC risk in both genders and significantly so in women (ORT3vs.T1 = 1.59, 95% CI: 1.13-2.25, Ptrend = 0.01) but not in men (ORT3vs.T1 = 1.78, 95% CI: 0.80-3.98, Ptrend = 0.17). Leptin, CRP, IL-6 and TNF-α were not associated with TC risk in either gender. These results indicate a positive association of TC risk with IL-10 and a negative association with adiponectin that is probably restricted to women. Inflammation may play a role in TC in combination with or independently of excess weight.
    • Adipose gene expression response of lean and obese mice to short-term dietary restriction.

      Schothorst, Evert M van; Keijer, Jaap; Pennings, Jeroen L A; Opperhuizen, Antoon; Brom, Charissa E van den; Kohl, Thomas; Franssen-van Hal, Nicole L W; Hoebee, Barbara (2006-06-01)
      Overweight and obesity lead to higher morbidity risks, which are alleviated even by mild weight loss. To gain insight in the molecular effects of weight loss in adipose tissue, we analyzed the effects of short-term dietary restriction (DR) on mice fed a low-fat diet (lean mice) or a high-fat diet (obese mice). Female C57Bl6/J mice on both diets were on DR until an average body weight loss of 20%, which was achieved in 8 to 12 days depending on body weight at the start of DR. Plasma free fatty acids and blood glucose levels decreased significantly on DR. In the (restricted) low-fat diet groups, gene expression analysis using adipose-enriched cDNA microarrays revealed only two transcripts to be significant differentially expressed by DR: up-regulation of malic enzyme (Mod1) and down-regulation of major urinary protein 1 (Mup1). Real-time polymerase chain reaction analysis confirmed these findings and showed, for the high-fat diet groups, an identical expression pattern for Mup1, whereas Mod1 showed an opposed gene expression pattern for the high-fat diet groups. In conclusion, initial weight loss induces transcriptional changes only in a very small number of adipose genes, which also depends on the (restricted) diet used.
    • ADMA, homocysteine and redox status improvement affected by 7-nitroindazole in spontaneously hypertensive rats

      Dovinová, Ima; Hrabárová, Eva; Jansen, Eugene; Kvandová, Miroslava; Majzúnová, Miroslava; Berenyiová, Andrea; Barančík, Miroslav (2018-10)
    • Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination.

      van Ravenhorst, Mariëtte B; van der Klis, Fiona R M; van Rooijen, Debbie M; Sanders, Elisabeth A M; Berbers, Guy A M (2017-08-24)
      Recently the incidence of meningococcal serogroup Y (MenY) and in particular serogroup W (MenW) invasive disease has risen in several European countries, including the Netherlands. Adolescents are a target group for primary prevention through vaccination to protect against disease and reduce carriage and induce herd protection in the population. The present study assessed MenA, MenW and MenY antibody levels in adolescents up to one year following primary vaccination with quadrivalent MenACWY-PS conjugated to tetanus toxoid (MenACWY-TT).
    • Advanced Toxicological Risk Assessment by Implementation of Ontologies Operationalized in Computational Models

      Staal, Yvonne C.M.; Pennings, Jeroen L.A.; Hessel, Ellen V.S.; Piersma, Aldert H.; Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.; Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.; Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.; Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. (2017-12)
    • Advancing food, nutrition, and health research in Europe by connecting and building research infrastructures in a DISH-RI: Results of the EuroDISH project

      Snoek, Harriëtte M.; Eijssen, Lars M.T.; Geurts, Marjolein; Vors, Cecile; Brown, Kerry A.; Bogaardt, Marc-Jeroen; Dhonukshe-Rutten, Rosalie A.M.; Evelo, Chris T.; Fezeu, Leopold K.; Finglas, Paul M.; et al. (2018-03)
    • Adverse effects of levamisole in cocaine users: a review and risk assessment.

      Brunt, Tibor Markus; van den Berg, Jorrit; Pennings, Ed; Venhuis, Bastiaan (2017-06)
      The immunomodulatory adjuvant and antihelminth levamisole is increasingly used as an adulterant in cocaine worldwide. An accumulating body of clinical and toxicological literature has appeared since 2010 describing neutropenia, agranulocytosis, leukoencephalopathy and vasculitis in cases associated with levamisole-adulterated cocaine. Mostly, neutropenia and agranulocytosis were reported, characterized by a decimation of neutrophils. A large proportion of cases also involved vasculopathy, characterized by pronounced black and purple skin purpura with cutaneous necrosis. Females are more susceptible for both agranulocytosis and vasculitis. Another complication reported with levamisole-adulterated cocaine is leukoencephalopathy, a disabling and potentially fatal neurological disorder caused by cerebral demyelination. In this review, all adverse effects associated with therapeutic levamisole and levamisole-adulterated cocaine are described. In addition, this review provides an update of the pharmacology of levamisole, its metabolism, including toxic metabolites and metabolites that are relevant for levamisole's addition to cocaine. Special emphasis is put on the immunopathology and the dose-effect relationship of chronic levamisole exposure. Finally, a risk assessment is provided based on the current level of levamisole adulteration in street cocaine, the dose range calculated per gram and the pattern of chronic exposure in heavy or dependent users.
    • An Adverse Outcome Pathway Analysis Employing DNA Methylation Effects in Arsenic-Exposed Zebrafish Embryos Supports a Role of Epigenetic Events in Arsenic-Induced Chronic Disease

      van der Ven, Leo T.M.; Jelinek, Jaroslav; Hodemaekers, Hennie M.; Zwart, Edwin P.; Ruiter, Sander; van den Brandhof, Evert-Jan; Issa, Jean-Pierre J.; Pennings, Jeroen L.A.; Luijten, Mirjam; Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.; et al. (2017-12)
    • An Adverse Outcome Pathway for Sensitization of the Respiratory Tract by Low-Molecular-Weight Chemicals: Building Evidence to Support the Utility of In Vitro and In Silico Methods in a Regulatory Context

      Sullivan, Kristie M.; Enoch, Steven J.; Ezendam, Janine; Sewald, Katherina; Roggen, Erwin L.; Cochrane, Stella; Physicians Committee for Responsible Medicine, Washington, District of Columbia.; School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, England.; National Institute for Public Health and the Environment (RIVM), Centre for Health Protection, Bilthoven, The Netherlands.; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.; et al. (2017-09-07)
    • Age-Dependent Pre-Vaccination Immunity Affects the Immunogenicity of Varicella Zoster Vaccination in Middle-aged Adults

      van der Heiden, Marieke; de Rond, Lia G. H.; van Zelm, Menno C.; Berbers, Guy A. M.; Boots, Annemieke M. H.; Buisman, Anne-Marie (2018-01-23)
    • Age-specific Incidence and Prevalence of Keratoconus: A Nationwide Registration Study.

      Godefrooij, Daniel A; de Wit, G Ardine; Uiterwaal, Cuno S; Imhof, Saskia M; Wisse, Robert P L (2017-03)
      To determine the age-specific incidence and prevalence of keratoconus in the modern era of diagnostics.
    • Aggregate consumer exposure to isothiazolinones via household care and personal care products: Probabilistic modelling and benzisothiazolinone risk assessment.

      Garcia-Hidalgo, Elena; Schneider, Dovilé; von Goetz, Natalie; Delmaar, Christiaan; Siegrist, Michael; Hungerbühler, Konrad (2018-09)
      Consumers regularly use household care and personal care products (HC&PCPs). Isothiazolinones are included in HC&PCPs as preservatives and are being held responsible for an epidemic rise in allergic contact dermatitis (ACD). The objective of this study was to assess the origin and extent of dermal exposure in order to evaluate the risk of ACD from isothiazolinones in HC&PCP. Individual-based aggregate dermal exposure to four isothiazolinones was estimated using the newly proposed Probabilistic Aggregated Consumer Exposure Model-Kinetic, Dermal (PACEM-KD) by combining the reported individual use patterns for HC&PCP in Switzerland (N = 669 (558 adults), ages 0-91) with isothiazolinone concentrations measured in products used by the individual person. PACEM-KD extends the original PACEM by considering exposure duration, product dilution and skin permeability. PACEM-KD-based higher-tier exposure on palms (99th percentile) was 15.4 ng/cm2, 1.3 ng/cm2, 0.9 ng/cm2, and 0.08 ng/cm2 for the isothiazolinones 1,2‑Benzisothiazol‑3‑(2H)‑one (BIT), 2‑Octyl‑3(2H)‑isothiazolinone (OIT), 2‑Methylisothiazolin‑3(2H)‑one (MI), and 5‑Chloro‑2‑methyl‑4‑isothiazolin‑3‑one (CMI), respectively. Major sources of exposure to BIT included all-purpose cleaners, dishwashing detergent, and kitchen cleaner, while exposure to OIT mainly stems from a fungicide. For MI, the main contributors were dishwashing detergent and all-purpose wet wipes, and for CMI all-purpose cleaner. A Quantitative Risk Assessment (QRA) for BIT using Sensitization Assessment Factors (SAFs) indicates that around 1% of the Swiss population is at risk to be sensitized by BIT in cosmetics and household chemicals. For isothiazolinones in general the presented higher-tier modelling approach suggests that household cleaners are currently more important sources of exposure than cosmetics.
    • Aggregation State of Metal-Based Nanomaterials at the Pulmonary Surfactant Film Determines Biophysical Inhibition.

      Yang, Yi; Xu, Lu; Dekkers, Susan; Zhang, Lijie Grace; Cassee, Flemming R; Zuo, Yi Y (2018-08-07)
      Metal-based nanomaterials (MNMs) represent a large category of the engineered nanomaterials, and have been extensively used to enhance the electrical, optical, and magnetic properties of nanoenabled consumer products. Inhaled MNMs can penetrate deeply into the peripheral lung at which they first interact with the pulmonary surfactant (PS) lining of alveoli. Here we studied the biophysical inhibitory potential of representative MNMs on a modified natural PS, Infasurf, using a novel in vitro experimental methodology called the constrained drop surfactometry (CDS). It was found that the biophysical inhibitory potential of six MNMs on Infasurf ranks in the order CeO