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Pregnancy complications such as preeclampsia cause increased fetal oxidative stress and fetal growth restriction, and associate with a higher incidence of adult metabolic syndrome. However, the pathophysiological contribution of oxidative stress per se is experimentally difficult to discern and has not been investigated. This study determined, if increased intrauterine oxidative stress (IUOx) affects adiposity, glucose and cholesterol metabolism in adult Ldlr−/−xSod2+/+ offspring from crossing male Ldlr−/−xSod2+/+ mice with Ldlr−/−xSod2 +/- dams (IUOx) or Ldlr−/−xSod2 +/- males with Ldlr−/−xSod2+/+ dams (control). At 12 weeks of age mice received Western diet for an additional 12 weeks. Adult male IUOx offspring displayed lower body weight and reduced adiposity associated with improved glucose tolerance compared to controls. Reduced weight gain in IUOx was conceivably due to increased energy dissipation in white adipose tissue conveyed by higher expression of Ucp1 and an accompanying decrease in DNA methylation in the Ucp1 enhancer region. Female offspring did not show comparable phenotypes. These results demonstrate that fetal oxidative stress protects against the obesogenic effects of Western diet in adulthood by programming energy dissipation in white adipose tissue at the level of Ucp1. Keywords: Fetal oxidative stress, Mitohormesis, Metabolic programming, Adiposity, Epigenetics, Methylation

Abstract Background Genetic and environmental factors play a role in the development of COPD. The epigenome, and more specifically DNA methylation, is recognized as important link between these factors. We postulate that DNA methylation is one of the routes by which cigarette smoke influences the development of COPD. In this study, we aim to identify CpG-sites that are associated with cigarette smoke exposure and lung function levels in whole blood and validate these CpG-sites in lung tissue. Methods The association between pack years and DNA methylation was studied genome-wide in 658 current smokers with >5 pack years using robust linear regression analysis. Using mediation analysis, we subsequently selected the CpG-sites that were also associated with lung function levels. Significant CpG-sites were validated in lung tissue with pyrosequencing and expression quantitative trait methylation (eQTM) analysis was performed to investigate the association between DNA methylation and gene expression. Results 15 CpG-sites were significantly associated with pack years and 10 of these were additionally associated with lung function levels. We validated 5 CpG-sites in lung tissue and found several associations between DNA methylation and gene expression. Conclusion This study is the first to validate a panel of CpG-sites that are associated with cigarette smoking and lung function levels in whole blood in the tissue of interest: lung tissue.

Abstract Background Publicly funded healthcare forms an intricate part of government spending in most Organisation for Economic Co-operation and Development (OECD) countries, because of its reliance on entitlements and dedicated revenue streams. The impact of budgetary rules and procedures on publicly funded health care might thus be different from other spending categories. In this study we focus on the potential of fiscal rules to contain these costs and their design features. Methods We assess the relationship between fiscal rules and the level of public health care expenditure of 32 (OECD) countries between 1985 and 2014. Our dataset consists of health care expenditure data of the OECD and data on fiscal rules of the International Monetary Fund (IMF) for that same period. Through a multivariate regression analysis, we estimate the association between fiscal rules and its subcategories and inflation adjusted public health care expenditure. We control for population, Gross Domestic Product (GDP), debt and whether countries received an IMF bailout for the specific period. In all our regressions we include country and year fixed effects. Results The presence of a fiscal rule on average is associated with a 3 % reduction of public health care expenditure. Supranational balanced budget rules are associated with some 8 % lower expenditure. Health service provision-oriented countries with more passive purchasing structures seem less capable of containing costs through fiscal rules. Fiscal rules demonstrate lagged effectiveness; the potential for expenditure reduction increases after one and two years of fiscal rule implementation. Finally, we find evidence that fiscal frameworks that incorporate multi-year expenditure ceilings show additional potential for cost control. Conclusions Our study shows that there seems a clear relationship between the potential of fiscal rules and budgeting health expenses. Using fiscal rules to contain the level of health care expenditure can thus be a necessary precondition for successful strategies for cost control.

Background and purpose: Diffusion weighted (DW) MRI may facilitate target volume delineation for head-and-neck (HN) radiation treatment planning. In this study we assessed the use of a dedicated, geometrically accurate, DW-MRI sequence for target volume delineation. The delineations were compared with semi-automatic segmentations on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images and evaluated for interobserver variation. Methods and materials: Fifteen HN cancer patients underwent both DW-MRI and FDG-PET for RT treatment planning. Target delineation on DW-MRI was performed by three observers, while for PET a semi-automatic segmentation was performed using a Gaussian mixture model. For interobserver variation and intermodality variation, volumes, overlap metrics and Hausdorff distances were calculated from the delineations. Results: The median volumes delineated by the three observers on DW-MRI were 10.8, 10.5 and 9.0 cm3 respectively, and was larger than the median PET volume (8.0 cm3). The median conformity index of DW-MRI for interobserver variation was 0.73 (range 0.38–0.80). Compared to PET, the delineations on DW-MRI by the three observers showed a median dice similarity coefficient of 0.71, 0.69 and 0.72 respectively. The mean Hausdorff distance was small with median (range) distances between PET and DW-MRI of 2.3 (1.5–6.8), 2.5 (1.6–6.9) and 2.0 (1.35–7.6) mm respectively. Over all patients, the median 95th percentile distances were 6.0 (3.0–13.4), 6.6 (4.0–24.0) and 5.3 (3.4–26.0) mm. Conclusion: Using a dedicated DW-MRI sequence, target volumes could be defined with good interobserver agreement and a good overlap with PET. Target volume delineation using DW-MRI is promising in head-and-neck radiotherapy, combined with other modalities, it can lead to more precise target volume delineation. Keywords: Radiotherapy, Head and neck, Target volume delineation, Diffusion MRI, PET

The impact of prenatal smoke exposure (PSE) on DNA methylation has been demonstrated in blood samples from children of smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. As the identified differentially methylated genes can be associated with developmental processes, and insulin-like growth factors (IGFs) play a critical role in prenatal tissue growth, we hypothesized that PSE induces fetal programming of Igf1r and Igf1. Using a mouse model of smoking during pregnancy, we show that PSE alters promoter methylation of Igf1r and Igf1 and deregulates their gene expression in lung and liver of fetal (E17.5) and neonatal (D3) mouse offspring. By further comparing female versus male, lung versus liver, or fetal versus neonatal time point, our results demonstrate that CpG site-specific aberrant methylation patterns sex-dependently vary per organ and time point. Moreover, PSE reduces gene expression of Igf1r and Igf1, dependent on organ, sex, and offspring's age. Our results indicate that PSE may be a source of organ-specific rather than general systemic fetal programming. This is exemplified here by gene promoter methylation and mRNA levels of Igf1r and Igf1, together with a sex- and organ-specific naturally established correlation of both parameters that is affected by prenatal smoke exposure. Moreover, the comparison of fetuses with neonates suggests a CpG site-dependent reversibility/persistence of PSE-induced differential methylation patterns.

Abstract Background Previous research has provided evidence for the link between psychological processes and psychophysiological health outcomes. Psychological interventions, such as face-to-face or online cognitive behavioral therapy (CBT) and serious games aimed at improving health, have shown promising results in promoting health outcomes. Few studies so far, however, have examined whether Internet-based CBT combined with serious gaming elements is effective in modulating health outcomes. Moreover, studies often did not incorporate psychophysiological or immunological challenges in order to gain insight into physiological responses to real-life challenges after psychological interventions. The overall aim of this study is to investigate the effects of a psychological intervention on self-reported and physiological health outcomes in response to immune and psychophysiological challenges. Methods/design In a randomized controlled trial, 60 healthy men are randomly assigned to either an experimental condition, receiving guided Internet-based (e-health) CBT combined with health-related serious gaming elements for 6 weeks, or a control condition receiving no intervention. After the psychological intervention, self-reported vitality is measured, and participants are given an immunological challenge in the form of a Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccination. One day after the vaccination, participants are asked to perform several psychophysiological tasks in order to explore the effects of the psychological intervention on participants’ stress response following the immune challenge. To assess the delayed effects of vaccination on self-reported and physiological health outcomes, a follow-up visit is planned 4 weeks later. Total study duration is approximately 14 weeks. The primary outcome measure is self-reported vitality measured directly after the intervention. Secondary outcome measures include inflammatory and endocrine markers, as well as psychophysiological measures of heart rate and skin conductance in response to the psychophysiological tasks after the BCG vaccination. Discussion The innovative design features of this study – e.g., combining guided e-health CBT with health-related serious gaming elements and incorporating immunological and psychophysiological challenges – will provide valuable information on the effects of a psychological intervention on both self-reported and physiological health outcomes. This study will offer further insights into the mechanisms underlying the link between psychological factors and health outcomes and is anticipated to contribute to the optimization of health care strategies. Trial registration Nederlands Trial Register, NTR5610 . Registered on 4 January 2016.

The anti-angiogenic soluble fms-like tyrosine kinase 1 (sFLT1) is one of the candidates in the progression of preeclampsia, often associated with fetal growth restriction (FGR). Therapeutic agents against preeclampsia with/without FGR, as well as adequate transgenic sFLT1 mouse models for testing such agents, are still missing. Much is known about sFLT1–mediated endothelial dysfunction in several tissues; however, the influence of sFLT1 on placental and fetal development is currently unknown. We hypothesize that sFLT1 is involved in the progression of FGR by influencing placental differentiation and vascularization and is a prime candidate for interventional strategies. Therefore, we generated transgenic inducible human sFLT1/reverse tetracycline-controlled transactivator (hsFLT1/rtTA) mice, in which hsFLT1 is ubiquitously overexpressed during pregnancy in dams and according to the genetics in hsFLT1/rtTA homozygous and heterozygous fetuses. Induction of hsFLT1 led to elevated hsFLT1 levels in the serum of dams and on mRNA level in all placentas and hetero-/homozygous fetuses, resulting in FGR in all fetuses at term. The strongest effects in respect to FGR were observed in the hsFLT1/rtTA homozygous fetuses, which exhibited the highest hsFLT1 levels. Only fetal hsFLT1 expression led to impaired placental morphology characterized by reduced placental efficiency, enlarged maternal sinusoids, reduced fetal capillaries, and impaired labyrinthine differentiation, associated with increased apoptosis. Besides impaired placental vascularization, the expression of several transporter systems, such as glucose transporter 1 and 3 (Glut-1; Glut-3); amino acid transporters, solute carrier family 38, member one and two (Slc38a1; Slc38a2); and most severely the fatty acid translocase Cd36 and fatty acid binding protein 3 (Fabp3) was reduced upon hsFLT1 expression, associated with an accumulation of phospholipids in the maternal serum. Moreover, the Vegf pathway showed alterations, resulting in reduced Vegf, Vegfb, and Plgf protein levels and increased Bad and Caspase 9 mRNA levels. We suggest that hsFLT1 exerts an inhibitory influence on placental vascularization by reducing Vegf signaling, which leads to apoptosis in fetal vessels, impairing placental differentiation, and the nutrient exchange function of the labyrinth. These effects were more pronounced when both the dam and the fetus expressed hsFLT1 and ultimately result in FGR and resemble the preeclamptic phenotype in humans.

Short stress management interventions such as relaxation therapy have demonstrated preliminary effectiveness in reducing stress-related problems. A promising tool to strengthen the effectiveness of relaxation-based interventions is the use of verbal suggestions, as previous research provided evidence that verbal suggestions can induce positive outcome expectancies, facilitate adaptive responses to stress and improve health outcomes. The present experimental proof-of-concept study aimed to investigate the effects of a brief relaxation intervention and specifically the role of verbal suggestions on stress-related outcomes assessed by self-report questionnaires and psychophysiological data. 120 participants (mean age = 22.1 years) were randomized to one of four intervention conditions: a brief relaxation intervention plus verbal suggestions condition, a brief relaxation intervention only condition, a verbal suggestions only condition, and a control condition. Afterwards, participants were subjected to a psychosocial stress challenge to assess reactivity to a stressful event. Immediately after both relaxation interventions (with and without verbal suggestions), lower self-reported state anxiety was found compared to the control condition, but no differences were observed in response to the stressor. The verbal suggestions only condition did not impact state anxiety. No significant effects were found for verbal suggestion interventions on cortisol, alpha amylase, heart rate and skin conductance. This is the first study investigating the role of verbal suggestions in the effectiveness of a brief relaxation intervention. Although this experimental proof-of-concept study provides support for the effectiveness of a brief relaxation intervention in lowering state anxiety directly after the intervention, the effects did not impact the response to a subsequent stressor and we did not observe any evidence for the add-on effectiveness of verbal suggestions. The effectiveness of brief relaxation interventions on stress responses should be investigated further in future research by incorporating interventions that are tailored to the specific stress challenge and various types of verbal suggestions.

BACKGROUND:Fatigue is a disabling problem in patients with visual impairment, but its etiology is still poorly understood. Our objective was to identify the determinants of fatigue in adults with visual impairment compared to adults with normal sight. METHODS:Cross-sectional data on fatigue and sociodemographic, psychological and health-related factors was obtained with validated questionnaires. Structural equational modeling using hypothesized relationships and explorative analyses were used to identify (in)direct pathways contributing to fatigue in 247 adults with visual impairment. The model was then tested in a reference group of 151 adults with normal sight. RESULTS:The final model explained 64% of fatigue variance in participants with visual impairment and revealed the following factors to be directly associated with fatigue: depressive symptoms (β = 0.723, p

BackgroundIn Fetal Growth Restriction 'fetal programming' may take place via DNA methylation, which has implications for short-term and long-term health outcomes. Small-for-gestational age fetuses are considered fetal growth restricted, characterized by brain-sparing when fetal Doppler hemodynamics are abnormal, expressed as a cerebroplacental ratio (CPR) MethodsWe compared DNA methylation of six genes in 41 small-for-gestational age placentas with a normal or abnormal CPR. We selected EPO, HIF1A, VEGFA, LEP, PHLDA2, and DHCR24 for their role in angiogenesis, immunomodulation, and placental and fetal growth. DNA methylation was analyzed by pyrosequencing.ResultsGrowth restricted fetuses with an abnormal CPR showed hypermethylation of the VEGFA gene at one CpG (VEGFA-309, p = .001) and an overall hypomethylation of the LEP gene, being significant at two CpGs (LEP-123, p = .049; LEP-51, p = .020). No differences in methylation were observed for the other genes.ConclusionsVEGFA and LEP genes are differentially methylated in placentas of small-for-gestational age fetuses with brain-sparing. Hypermethylation of VEGFA-309 in abnormal CPR-placentas could indicate successful compensatory mechanisms. Methylation of LEP-51 is known to suppress LEP expression. Hypomethylation in small-for-gestational age placentas with abnormal CPR may result in hyperleptinemia and predispose to leptin-resistance later in life.

Realistic microscopic traffic simulation is essential for prospective evaluation of the potential impacts of new traffic control strategies. Freeway corridors with interacting bottlenecks and dedicated lanes generate complex traffic flow phenomena and congestion patterns, which are difficult to reproduce with existing microscopic simulation models. This paper discusses two alternative driving behavior models that are capable of modeling freeways with multiple bottlenecks and dedicated lanes over an extended period with varying demand levels. The models have been calibrated using archived data from a complicated 13-mile long section of the northbound SR99 freeway near Sacramento, California, for an 8-hour time period in which the traffic fluctuated from free-flow to congested conditions. The corridor includes multiple bottlenecks, multiple entry and exit ramps, and an HOV lane. Calibration results show extremely good agreement between field data and model predictions. The models have been cross-validated and produced similar macroscopic traffic performance. The main behavior that should be captured for successful modeling of such a complex corridor includes the anticipative and cooperative driver behavior near merges, lane preference in presence of dedicated lanes, and variations in desired headway along the corridor.

There is initial support for the effectiveness of approach-avoidance trainings in altering food-related health behaviors. Furthermore, outcome expectancies induced by verbal suggestions might optimize the effectiveness of these interventions, as shown in placebo research. The present study investigated the effectiveness of a gamified approach-avoidance training on food-related outcomes and whether verbal suggestions could strengthen those effects. A total of 120 participants were randomly assigned to 1 of 4 conditions: serious gaming only, verbal suggestions only, serious gaming combined with verbal suggestions, or a gaming control condition. Virtual food preference and food choice were assessed with a food choice task, with pairs differing in healthiness or in healthiness and attractiveness. Implicit food preference was assessed with an Implicit Association Test and food intake with a bogus taste test. Participants in both serious gaming conditions made healthier food choices for pairs differing in healthiness and attractiveness and had healthier implicit food preferences compared to gaming control. No effects were found on food intake. These findings provide the first preliminary support for the effects of a gamified approach-avoidance training on virtual food choice and implicit food preference. Future studies should further elucidate these effects, also in other health domains such as physical activity.

With low-level vehicle automation already available, there is a necessity to estimate its effects on traffic flow, especially if these could be negative. A long gradual transition will occur from manual driving to automated driving, in which many yet unknown traffic flow dynamics will be present. These effects have the potential to increasingly aid or cripple current road networks. In this contribution, we investigate these effects using an empirically calibrated and validated simulation experiment, backed up with findings from literature. We found that low-level automated vehicles in mixed traffic will initially have a small negative effect on traffic flow and road capacities. The experiment further showed that any improvement in traffic flow will only be seen at penetration rates above 70%. Also, the capacity drop appeared to be slightly higher with the presence of low-level automated vehicles. The experiment further investigated the effect of bottleneck severity and truck shares on traffic flow. Improvements to current traffic models are recommended and should include a greater detail and understanding of driver-vehicle interaction, both in conventional and in mixed traffic flow. Further research into behavioural shifts in driving is also recommended due to limited data and knowledge of these dynamics.

Hodgkin lymphoma (HL) is derived from preapoptotic germinal center B cells, although a general loss of B cell phenotype is noted. Using quantitative reverse transcription-polymerase chain reaction and miRNA microarray, we determined the microRNA (miRNA) profile of HL and compared this with the profile of a panel of B-cell non-Hodgkin lymphomas. The two methods showed a strong correlation for the detection of miRNA expression levels. The HL-specific miRNA included miR-17-92 cluster members, miR-16, miR-21, miR-24, and miR-155. Using a large panel of cell lines, we found differential expression between HL and other B-cell lymphoma-derived cell lines for 27 miRNA. A significant down-regulation in HL compared to non-Hodgkin lymphoma was observed only for miR-150. Next, we performed target gene validation of predicted target genes for miR-155, which is highly expressed in HL and is differentially expressed between HL and Burkitt lymphoma. Using luciferase reporter assays, we validated 11 predicted miR-155 target genes in three different HL cell lines. We demonstrated that AGTR1, FGF7, ZNF537, ZIC3, and IKBKE are true miR-155 target genes in HL.

Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellular interactions within the bone microenvironment limit current treatment options thus prostate to bone metastases remains incurable. This study uses voxel-based analysis of diffusion-weighted MRI and CT scans to simultaneously evaluate temporal changes in normal bone homeostasis along with prostate bone metatastsis to deliver an improved understanding of the spatiotemporal local microenvironment. Dynamic tumor-stromal interactions were assessed during treatment in mouse models along with a pilot prospective clinical trial with metastatic hormone sensitive and castration resistant prostate cancer patients with bone metastases. Longitudinal changes in tumor and bone imaging metrics during delivery of therapy were quantified. Studies revealed that voxel-based parametric response maps (PRM) of DW-MRI and CT scans could be used to quantify and spatially visualize dynamic changes during prostate tumor growth and in response to treatment thereby distinguishing patients with stable disease from those with progressive disease (p