Cyst initiation, cyst expansion and progression in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by large fluid-filled cysts and progressive deterioration of renal function necessitating renal replacement therapy. In this thesis different phases of ADPKD were studied. First, we studied the initiation of cyst formation. We showed that the proliferative status of the renal tissue is important for the rate at which cysts are formed after Pkd1 conditional deletion. In addition we concluded that improper positioning of centrosomes and altered canonical Wnt signaling are early events after Pkd1-gene disruption. Subsequently, we provided evidence for altered activation of the Hippo signaling pathway in cyst growth in ADPKD, suggesting that aberrant Hippo signaling is not an initiating event in cyst formation but accompanies progressive cystic growth. The Hippo-pathway provides a novel target for inhibiting cyst expansion PKD. Finally, we studied ADPKD disease progression and showed that cyst expansion is followed regression of cystic and renal volume accompanied by fibrosis and inflammation. Our data suggest suggests that renal volume may not be the best predictor of progression to renal failure and end stage renal disease. Cyst growth and ADPKD disease progression are complex processes regulated by many signaling networks. This not only provides many targets for therapeutic intervention but is also a difficulty at the same time. Aiming for a single therapeutic target will most likely be not successful, and therapeutic intervention in ADPKD requires a multi-target therapy.UBL - phd migration 201

In-lab three-dimensional printing:an inexpensive tool for experimentation and visualization for the field of organogenesis

The development of the microscope in 1590 by Zacharias Janssenby and Hans Lippershey gave the world a new way of visualizing details of morphogenesis and development. More recent improvements in this technology including confocal microscopy, scanning electron microscopy (SEM) and optical projection tomography (OPT) have enhanced the quality of the resultant image. These technologies also allow a representation to be made of a developing tissue’s three-dimensional (3-D) form. With all these techniques however, the image is delivered on a flat two-dimensional (2-D) screen. 3-D printing represents an exciting potential to reproduce the image not simply on a flat screen, but in a physical, palpable three-dimensional structure. Here we explore the scope that this holds for exploring and interacting with the structure of a developing organ in an entirely novel way. As well as being useful for visualization, 3-D printers are capable of rapidly and cost-effectively producing custom-made structures for use within the laboratory. We here describe the advantages of producing hardware for a tissue culture system using an inexpensive in-lab printer

Anxiety and attentional bias to threat in children at increased familial risk for Autism Spectrum Disorder

Anxiety and threat bias were examined in 6-8-year-old children at familial-risk for Autism Spectrum Disorder (ASD) and low-risk (LR, n = 37) controls. The high-risk (HR) group was divided into those who met diagnostic criteria for ASD (HR-ASD, n = 15) and those who did not (HR-non ASD, n = 24). The HR-ASD group had highest levels of parent-reported anxiety. The HR-non ASD group exhibited increased threat bias on a spatial-cueing task, while the HR-ASD group did not. Anxiety symptoms were associated with both threat bias and ASD severity. These findings suggest that the mechanisms underlying anxiety in HR siblings without ASD are similar to those in non-ASD populations. However, among children with ASD, hypersensitivity to threat may not underlie anxiety symptoms

Navigating the social world: The role of social competence, peer victimisation and friendship quality in the development of social anxiety in childhood

Social and communication (SC) difficulties predict increased social anxiety (SA) symptoms in childhood. Peer victimisation and friendship quality are commonly associated with both SC difficulties and SA. Based on this, we tested for a cascade effect of early SC difficulties, peer victimisation and friendship quality on SA in late childhood, using a population-based sample of 8028 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Parent-reported data were collected on SC difficulties at age 7 and SA at age 7, 10 and 13. Child-reported data on peer victimisation and friendship quality were collected at age 8. Our results revealed that SC difficulties predict increased negative friendship qualities and peer victimisation. Relational victimisation predicted increased SA symptoms at 13 years old. Neither overt nor relational victimisation mediated the developmental relationship between SC difficulties and SA. Furthermore, friendship quality did not moderate the developmental relationship between SC difficulties and SA. In addition, no sex differences were observed. The evidence demonstrates that peer victimisation and friendship quality do not explain why some children with SC difficulties go on to develop SA. Future research clarifying the complex etiological pathways contributing towards the development of SA in childhood and adolescence is warranted

Language and theory of mind in autism spectrum disorder : the relationship between complement syntax and false belief task performance.

This study aimed to test the hypothesis that children with autism spectrum disorder (ASD) use their knowledge of complement syntax as a means of “hacking out” solutions to false belief tasks, despite lacking a representational theory of mind (ToM). Participants completed a “memory for complements” task, a measure of receptive vocabulary, and traditional location change and unexpected contents false belief tasks. Consistent with predictions, the correlation between complement syntax score and location change task performance was significantly stronger within the ASD group than within the comparison group. However, contrary to predictions, complement syntax score was not significantly correlated with unexpected contents task performance within either group. Possible explanations for this pattern of results are considered

Impaired Competence for Pretense in Children with Autism: Exploring Potential Cognitive Predictors.

Lack of pretense in children with autism has been explained by a number of theoretical explanations, including impaired mentalising, impaired response inhibition, and weak central coherence. This study aimed to empirically test each of these theories. Children with autism (n=60) were significantly impaired relative to controls (n=65) when interpreting pretense, thereby supporting a competence deficit hypothesis. They also showed impaired mentalising and response inhibition, but superior local processing indicating weak central coherence. Regression analyses revealed that mentalising significantly and independently predicted pretense. The results are interpreted as supporting the impaired mentalising theory and evidence against competing theories invoking impaired response inhibition or a local processing bias. The results of this study have important implications for treatment and intervention

Disengagement of visual attention in infancy is associated with emerging autism in toddlerhood

Background: Early emerging characteristics of visual orienting have been associated with a wide range of typical and atypical developmental outcomes. In the current study, we examined the development of visual disengagement in infants at risk for autism. Methods: We measured the efficiency of disengaging from a central visual stimulus to orient to a peripheral one in a cohort of 104 infants with and without familial risk for autism by virtue of having an older sibling with autism. Results: At 7 months of age, disengagement was not robustly associated with later diagnostic outcomes. However, by 14 months, longer latencies to disengage in the subset of the risk group later diagnosed with autism was observed relative to other infants at risk and the low-risk control group. Moreover, between 7 months and 14 months, infants who were later diagnosed with autism at 36 months showed no consistent increases in the speed and flexibility of visual orienting. However, the latter developmental effect also characterized those infants who exhibited some form of developmental concerns (but not meeting criteria for autism) at 36 months. Conclusions: Infants who develop autism or other developmental concerns show atypicality in the development of visual attention skills from the first year of life

Spatial contrast sensitivity in adolescents with autism spectrum disorders

Adolescents with autism spectrum disorders (ASD) and typically developing (TD) controls underwent a rigorous psychophysical assessment that measured contrast sensitivity to seven spatial frequencies (0.5-20 cycles/degree). A contrast sensitivity function (CSF) was then fitted for each participant, from which four measures were obtained: visual acuity, peak spatial frequency, peak contrast sensitivity, and contrast sensitivity at a low spatial frequency. There were no group differences on any of the four CSF measures, indicating no differential spatial frequency processing in ASD. Although it has been suggested that detail-oriented visual perception in individuals with ASD may be a result of differential sensitivities to low versus high spatial frequencies, the current study finds no evidence to support this hypothesis

Enhanced visual search in infancy predicts emerging autism symptoms

In addition to core symptoms, i.e., social interaction and communication difficulties and restricted and repetitive behaviours, autism is also characterized by aspects of superior perception [1]. One well-replicated finding is that of superior performance in visual search tasks, in which participants have to indicate the presence of an odd-one-out element amongst a number of foils [2,3,4,5]. Whether these aspects of superior perception contribute to the emergence of core autism symptoms remains debated [6,4]. Perceptual and social interaction skills could reflect co-expressed but biologically independent pathologies, as suggested by a “fractionable” phenotype model of autism [7]. A developmental test of this hypothesis is now made possible by longitudinal cohorts of infants at high risk, such as of younger siblings of children with ASD. Around 20% of younger siblings are diagnosed with autism themselves [8], and up to another 30% manifest elevated levels of autism symptoms [9]. We used eye-tracking to measure spontaneous orienting to letter targets (O, S, V and +) presented amongst distractors (the letter X, Figure 1). At 9 and 15 months, emerging autism symptoms were assessed using the Autism Observation Scale for Infants (AOSI; 10) and at 2 years of age using the Autism Diagnostic Observation Schedule (ADOS; 11). Enhanced visual search performance at 9-month predicted a higher level of autism symptoms at 15 months and at 2 years. Infant perceptual atypicalities are thus intrinsically linked to the emerging autism phenotype

'Everyday memory' impairments in autism spectrum disorders

‘Everyday memory’ is conceptualised as memory within the context of day-to-day life and, despite its functional relevance, has been little studied in individuals with autism spectrum disorders (ASDs). In the first study of its kind, 94 adolescents with an ASD and 55 without an ASD completed measures of everyday memory from the Rivermead Behavioural Memory Test (RBMT) and a standard word recall task (Children’s Auditory Verbal Learning Test-2: CAVLT-2). The ASD group showed significant impairments on the RBMT, including in prospective memory, alongside impaired performance on the CAVLT-2. Social and communication ability was significantly associated with prospective remembering in an everyday memory context but not with the CAVLT-2. The complex nature of everyday memory and its relevance to ASD is discussed