Intergenerational transmission of child problem behavior

In the present thesis, the intergenerational transmission of child problem behavior will be investigated. In this introduction, we will explain why it is important to study transmission of problem behavior from parents to their offspring. In addition, we will describe the study design that is suitable for this type of research, and give a description of its methodological advantages and difficulties. We will summarize previous studies that have used this type of design, and made an important contribution to the research in intergenerational transmission of child problem behavior. Two factors that are thought to be important in the intergenerational transmission of problem behavior, parenting and parental psychopathology, will also be described. In addition, we will describe the possible relevance of developmental trajectories of problem behavior displayed by parents during their childhood, in predicting offspring problem behavior. Finally we will describe the aims, methods and structure of the present thesis

Towards sex-specific osteoarthritis risk models: evaluation of risk factors for knee osteoarthritis in males and females

Objectives The aim of this study was to identify sex-specific prevalence and strength of risk factors for the incidence of radiographic knee OA (incRKOA). Methods Our study population consisted of 10 958 Rotterdam Study participants free of knee OA in one or both knees at baseline. One thousand and sixty-four participants developed RKOA after a median follow-up time of 9.6 years. We estimated the association between each available risk factor and incRKOA using sex stratified multivariate regression models with generalized estimating equations. Subsequently, we statistically tested sex differences between risk estimates and calculated the population attributable fractions (PAFs) for modifiable risk factors. Results The prevalence of the investigated risk factors was, in general, higher in women compared with men, except that alcohol intake and smoking were higher in men and high BMI showed equal prevalence. We found significantly different risk estimates between men and women: high level of physical activity [relative risk (RR) 1.76 (95% CI: 1.29–2.40)] or a Kellgren and Lawrence score 1 at baseline [RR 5.48 (95% CI: 4.51–6.65)] was higher in men. Among borderline significantly different risk estimates was BMI ≥27, associated with higher risk for incRKOA in women [RR 2.00 (95% CI: 1.74–2.31)]. The PAF for higher BMI was 25.6% in women and 19.3% in men. Conclusion We found sex-specific differences in both presence and relative risk of several risk factors for incRKOA. Especially BMI, a modifiable risk factor, impacts women more strongly than men. These risk factors can be used in the development of personalized prevention strategies and in building sex-specific prediction tools to identify high risk profile patients

Rectification of thermal fluctuations in ideal gases

We calculate the systematic average speed of the adiabatic piston and a thermal Brownian motor, introduced in [Van den Broeck, Kawai and Meurs, \emph{Microscopic analysis of a thermal Brownian motor}, to appear in Phys. Rev. Lett.], by an expansion of the Boltzmann equation and compare with the exact numerical solution.Comment: 18 page

The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats

Background: Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie2 system, which regulates endothelial permeability, previously reduced hemorrhagic shock-induced vascular leakage. We hypothesized that as a consequence of vascular leakage, renal perfusion and function is impaired and that activating Tie2 restores renal perfusion and function. Methods: Rats underwent 1 h of hemorrhagic shock and were treated with either vasculotide or PBS as control, followed by fluid resuscitation for 4 h. Microcirculatory perfusion was measured in the renal cortex and cremaster muscle using contrast echography and intravital microscopy, respectively. Changes in the angiopoietin/Tie2 system and renal injury markers were measured in plasma and on protein and mRNA level in renal tissue. Renal edema formation was determined by wet/dry weight ratios and renal structure by histological analysis. Results: Hemorrhagic shock significantly decreased renal perfusion (240 +/- 138 to 51 +/- 40, p 0.9 at all time points) or reduce renal injury (NGAL p = 0.26, KIM-1 p = 0.78, creatinine p > 0.9, renal edema p = 0.08), but temporarily improved cremaster perfusion at 3 h following start of fluid resuscitation compared to untreated rats (resuscitation + 3 h: 11 +/- 3 vs 8 +/- 3 perfused vessels, p < 0.05). Conclusion: Hemorrhagic shock-induced renal impairment cannot be restored by standard fluid resuscitation, nor by activation of Tie2. Future treatment strategies should focus on reducing angiopoietin-2 levels or on activating Tie2 via an alternative strategy

Incidence, timing and outcome of AKI in critically ill patients varies with the definition used and the addition of urine output criteria

Background: Acute kidney injury (AKI) is a serious complication of critical illness with both attributed morbidity and mortality at short-term and long-term. The incidence of AKI reported in critically ill patients varies substantially with the population evaluated and the definitions used. We aimed to assess which of the AKI definitions (RIFLE, AKIN or KDIGO) with or without urine output criteria recognizes AKI most frequently and quickest. Additionally, we conducted a review on the comparison of incidence proportions of varying AKI definitions in populations of critically ill patients. Methods: We included all patients with index admissions to our intensive care unit (ICU) from January 1(st), 2014 until June 11th, 2014 to determine the incidence and onset of AKI by RIFLE, AKIN and KDIGO during the first 7 days of ICU admission. We conducted a sensitive search using PubMed evaluating the comparison of RIFLE, AKIN and KDIGO in critically ill patients Results: AKI incidence proportions were 15, 21 and 20% respectively using serum creatinine criteria of RIFLE, AKIN and KDIGO. Adding urine output criteria increased AKI incidence proportions to 35, 38 and 38% using RIFLE, AKIN and KDIGO definitions. Urine output criteria detected AKI in patients without AKI at ICU admission in a median of 13 h (IQR 7-22 h; using RIFLE definition) after admission compared to a median of 24 h using serum creatinine criteria (IQR24-48 h). In the literature a large heterogeneity exists in patients included, AKI definition used, reference or baseline serum creatinine used, and whether urine output in the staging of AKI is used. Conclusion: AKIN and KDIGO criteria detect more patients with AKI compared to RIFLE criteria. Addition of urine output criteria detect patients with AKI 11 h earlier than serum creatinine criteria and may double AKI incidences in critically ill patients. This could explain the large heterogeneity observed in literature

Insulin-like growth factor I gene promoter polymorphism, collagen type II alpha1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam Study

OBJECTIVE: To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene. METHODS: Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested. RESULTS: Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years. CONCLUSIONS: SUBJECTS: with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2x)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted

Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain

BACKGROUND AND OBJECTIVES: Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%–54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. METHODS: Northern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting >3 months and 242 929 controls were studied. Replication of three independent genome-wide significant single nucleotide polymorphisms was attempted in six independent European cohorts (n=43 080; cases=14 177). Genetic correlations with risk factors, tissue specificity and colocalisation were examined. RESULTS: Three genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes Ring Finger Protein 123 (RNF123), ATPase secretory pathway Ca (2+) transporting 1 (ATP2C1) and catechol-O-methyltransferase (COMT). The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227) and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth and years of schooling were identified. Tissue specificity and colocalisation analysis highlight the relevance of skeletal muscle in CWP. CONCLUSIONS: We report a novel association of RNF123 locus and a suggestive association of ATP2C1 locus with CWP. Both loci are consistent with a role of calcium regulation in CWP. The association with COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis