Hypoxia Inducible Factor: a breath of fresh air in lung development

Chapter 1 is a general introduction to normal and abnormal lung development. It outlines the current state of knowledge of the molecular basis of normal fetal lung development and then discusses the importance of these molecules in aberrant human lung development. It highlights the most important growth and transcription factors in each phase of lung development and describes where neonatal disease may arise and deals with the possible culprits. In chapter 2 an outline of the thesis is given. The role of HIF during basic murine lung development and the impact of the HIF pathway in the etiology of clinical diseases such as PPHN and ACD are important for understanding the effect HIF has on angiogenesis and pulmonary development. With these new insights innovative treatment strategies may be contemplated. Vessel formation in the lung is crucial for normal lung branching in the early embryonic phase as well as in the alveolar phase of lung development. In chapter 3 we demonstrate that in early fetal lung development over-expression of oxygen insensitive HIF-1a (HIF-1a .ODD) in mice leads to increased vascularization. This increase in vasculature seen in transgenic mice did not have an impact on branching. Low oxygen stimulated vessel growth in control and transgenic lungs as shown before. Pulmonary morphometric analyses of postnatal mice at various stages in alveolar development (postnatal days 2, 8, 14, 21) show an advancement of alveolarization in the HIF-1a .ODD lungs. Moreover, small vessel density was increased in HIF-1a .ODD lungs at E18.5 and postnatal days 2, 8 and 14. The HIF- 1a .ODD lungs had significantly higher VEGF mRNA expression than C57 control lungs on postnatal days 2, 8, and 14. The continuous activation of the HIF pathway and subsequent up-regulation of VEGF may account for this enhanced vascularization and subsequent alveolar formation

Substance use disorders in adolescents with attention deficit hyperactivity disorder: a 4-year follow-up study

Aim To examine the relationship between a childhood diagnosis of attention deficit hyperactivity disorder (ADHD) with or without oppositional defiant disorder (ODD)/conduct disorder (CD) and the development of later alcohol/drug use disorder [psychoactive substance use disorder (PSUD)] and nicotine dependence in a large European sample of ADHD probands, their siblings and healthy control subjects. Participants design and settingSubjects (n=1017) were participants in the Belgian, Dutch and German part of the International Multicenter ADHD Genetics (IMAGE) study. IMAGE families were identified through ADHD probands aged 5-17 years attending out-patient clinics, and control subjects from the same geographic areas. After a follow-up period (mean: 4.4 years) this subsample was re-assessed at a mean age of 16.4 years. Measurements PSUD and nicotine dependence were assessed using the Diagnostic Interview Schedule for Children, Alcohol Use Disorders Identification Test, Drug Abuse Screening Test and Fagerstrom test for Nicotine Dependence. Findings The ADHD sample was at higher risk of developing PSUD [hazard ratio (HR)=1.77, 95% confidence interval (CI)=1.05-3.00] and nicotine dependence (HR=8.61, 95% CI=2.44-30.34) than healthy controls. The rates of these disorders were highest for ADHD youth who also had CD, but could not be accounted for by this comorbidity. We did not find an increased risk of developing PSUD (HR=1.18, 95% CI=0.62-2.27) or nicotine dependence (HR=1.89, 95% CI=0.46-7.77) among unaffected siblings of ADHD youth. Conclusions A childhood diagnosis of attention deficit hyperactivity disorder is a risk factor for psychoactive substance use disorder and nicotine dependence in adolescence and comorbid conduct disorder, but not oppositional defiant disorder, further increases the risk of developing psychoactive substance use disorder and nicotine dependence

Prepotent response inhibition in autism: Not an inhibitory deficit?:Special Issue “Neurodevelopmental Neurodiversity”: Research Report

Research outcomes on prepotent response inhibition in neurodevelopmental conditions during adulthood seem inconsistent, especially in autism. To gain further insight in these inconsistencies, the current study investigates inhibitory performance, as well as task strategies such as adaptive behavior during inhibitory tasks in autistic adults. As Attention-Deficit/Hyperactivity Disorder (ADHD) is often co-occurring in autism and associated with differences in both inhibition and adaptation, the role of ADHD symptoms is explored. Additionally, prior research is extended to middle- and late-adulthood, and the role of cognitive aging is assessed. Hundred-and-five autistic adults and 139 non-autistic adults (age: 20-80 yrs) were compared on a Go-NoGo task. No significant group differences in inhibitory difficulties (commission errors) or adaptation (post error slowing) were observed, and both did not relate significantly to ADHD symptoms. However, when controlling for reaction time autistic individuals made significantly more inhibitory errors than non-autistic individuals, yet the effect size was modest (Cohen's d = .27). Exploratory analyses showed that adaption significantly related to inhibition in non-autistic individuals only, possibly hinting at altered adaptive behavior during inhibitory tasks in autistic adults. ADHD symptoms related to response variability in the autism group only. Furthermore, task strategy changed with older age in both groups, with slower and more cautious responses at older age. Taken together, although minor differences may exist, autistic and non-autistic people show largely similar patterns of inhibitory behavior throughout adulthood. Differences in task timing and strategy seem relevant for future longitudinal studies on cognitive aging across neurodevelopmental conditions.</p