Hearing loss in HDR syndrome: a study of mice and men

Naar schatting kunnen wereldwijd meer dan 70.000.000 mensen door een auditieve handicap niet participeren in normale mondelinge communicatie. De laatste decennia is er in de westerse wereld, door afname van exogene factoren, een relatieve toename van het percentage ziektegevallen met een genetische oorzaak opgetreden. Het HDR syndroom is een autosomaal dominant overervende aandoening veroorzaakt door haplo-insufficiëntie van de transcriptiefactor GATA3, die wordt gekenmerkt door hypoparathyreoïdie, perceptieslechthorendheid en nierdysplasie. In dit proefschrift beschrijven wij de precieze aard en de pathofysiologie van slechthorendheid binnen het HDR syndroom aan de hand van onderzoek aan patiënten en een muismodel. Een frequent gebruikte methode om het gehoor van proefdieren te onderzoeken is hersenstamaudiometrie (brainstem evoked response audiometry - BERA). Daar in het verleden al werd aangetoond dat het gebruik van anesthesie in proefdieren een toename gaf van BERA- latentietijden ontwikkelden wij een techniek, die het mogelijk maakt longitudinaal BERA’s te meten in wakkere muizen. We laten zien dat narcose met de in proefdieren vaak gebruikte middelen ketamine en xylazine, een significante BERA-drempel verhoging teweegbrengt, evenals een significante toename van BERA-piek latentietijden en het I-III interpiek interval Om de aard van het gehoorsverlies binnen het HDR syndroom te determineren, vergeleken wij audiometrische en histologische data van heterozygote Gata3 knock-out muizen met die van gezonde controle muizen. BERA-drempels van heterozygote Gata3 knock-out muizen in de leeftijd van 1 tot en met 19 maanden zijn bij alle onderzochte frequenties significant (ongeveer 30 dB) hoger dan die van gezonde controle muizen. Tussen de genotypen bestaan geen significante verschillen in piek- en interpiek latentietijden. De hierboven beschreven bevindingen tonen aan dat het gehoorsverlies in de mutante muizen wordt veroorzaakt door een perifere, en specifieker een cochleaire afwijking. De snelle achteruitgang de van buitenste haarcelfunctie in de knock-outs gedurende de eerste zeven levensmaanden, zoals wij aantoonden met behulp van otoacoustische emissies, levert hiervoor nog verder bewijs. Heterozygote Gata3 knock-out muizen vertonen een met de leeftijd progressief cochleair celverlies. Het eerste teken van de door GATA3 haplo-insufficiëntie veroorzaakte degeneratie zijn onregelmatig gevormde vacuoles in alle rijen buitenste haarcellen, die op zowel licht- als electronenmicroscopisch niveau te zien zijn. De degeneratie treedt al op vanaf de eerste levensmaand en betreft in eerste instantie alleen de apicale buitenste haarcellen, maar later alle haarcellen, steuncellen en zenuwvezels in de cochlea. Tenslotte beschrijven we het gehoor van twee menselijke HDR patiënten. Beide patiënten waren aangedaan door een matig tot ernstig, vermoedelijk leeftijdsafhankelijk gehoorsverlies, dat het meest uitgesproken is in de hoge tonen. De BERA interpiek latenties zijn niet afwijkend, maar otoacoutische emissies zijn niet opwekbaar en beide patiënten scoren slecht bij de spraakverstaan in ruis. Wij concluderen dat GATA3 haplo-insufficiëntie zowel in muizen, als in mensen een perifeer, cochleair gehoorsverlies veroorzaakt. Het gehoorsverlies bij HDR syndroom wordt vooral veroorzaakt door verminderd functioneren en degenereren van buitenste haarcellen, maar binnenste haarcellen spelen mogelijk ook een rol

The ENDORSE study: Research into environmental determinants of obesity related behaviors in Rotterdam schoolchildren

Background: Children and adolescents are important target groups for prevention of overweight and obesity as overweight is often developed early in life and tracks into adulthood. Research into behaviors related to overweight (energy balance-related behaviors) and the personal and environmental determinants of these behaviors is fundamental to inform prevention interventions. In the Netherlands and in other countries systematic research into environmental determinants of energy balance related behaviors in younger adolescents is largely lacking. This protocol paper describes the design, the components and the methods of the ENDORSE study (Environmental Determinants of Obesity in Rotterdam SchoolchildrEn), that aims to identify important individual and environmental determinants of behaviors related to overweight and obesity and the interactions between these determinants among adolescents. Methods: The ENDORSE study is a longitudinal study with a two-year follow-up of a cohort of adolescents aged 12–15 years. Data will be collected at baseline (2005/2006) and at two years follow-up (2007/2008). Outcome measures are body mass index (BMI), waist circumference, time spent in physical activity and sedentary behaviors, and soft drink, snack and breakfast consumption. The ENDORSE study consists of two phases, first employing qualitative research methods to inform the development of a theoretical framework to examine important energy balance related behaviors and their determinants, and to inform questionnaire development. Subsequently, the hypothetical relationships between behavioral determinants, energy balance related behaviors and BMI will be tested in a quantitative study combining school-based surveys and measurements of anthropometrical characteristics at baseline and two-year follow-up. Discussion: The ENDORSE project is a comprehensive longitudinal study that enables investigation of specific environmental and individual determinants of overweight and obesity among younger adolescents. The project will result in specific recommendations for obesity prevention interventions among younger adolescents

Self-report in Youth Health Monitoring: evidence from the Rotterdam Youth Monitor

Under Dutch law, preventive youth healthcare organisations have a duty to ensure the early identification of children with health or developmental problems. Similarly, municipalities have a duty to monitor young people’s health at least every four years. For problem identification and monitoring, both individual and collective, these organisations often use self-report questionnaires. The overall aim of this thesis is to study various methodological and validity issues related to the use of self-report questionnaires among young people in a preventive youth healthcare setting. Seven specific research questions are derived from the Rotterdam Youth Monitor (RYM), a longitudinal youth health surveillance system integrated into preventive youth healthcare in the greater Rotterdam area

Wilders de 'gedoger': andere rol, andere stijl?

Veranderde de stijl van Wilders in de jaren dat hij als 'gedoger' in de Tweede Kamer zat?Language Use in Past and Presen

Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain.

Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI

Associations between parent-adolescent attachment relationship quality, negative life events and mental health

Purpose: The aim of this study was to examine the association of negative life events and parent-adolescent attachment relationship quality with mental health problems and to explore an interaction between the parent-adolescent attachment relationship and one or multiple negative life events on the mental health of adolescents. Methods: A two-year longitudinal study was conducted among first-year secondary school students (N = 3181). The occurrence of life events and the quality of parent-adolescent attachment were assessed at baseline and mental health status at two-year follow-up by means of self-report questionnaires. Binary logistic regression analyses were conducted to assess associations between life events, parent-adolescent attachment and mental health problems. Relative Excess Risk due to Interaction techniques were used to determine the interaction effects on the additive scale. Results: Life events were related to mental health status, as was parent-adolescent attachment. The combined effect of an unfavourable parent-adolescent attachment with life events on mental health was larger than the sum of the two individual effects. Among adolescents with one life event or multiple life events, an unfavourable parent-adolescent attachment increased the risk of mental health problems at follow-up compared to the group without life events. Conclusion: Results supported an interaction effect between parent-adolescent attachment and negative life events on mental health. Especially adolescents with one or multiple life events and an unfavourable parent-adolescent attachment seems to be a vulnerable group for mental health problems. Implications for further research are discussed