New insights into the intracellular distribution pattern of cationic amphiphilic drugs

Cationic amphiphilic drugs (CADs) comprise a wide variety of different substance classes such as antidepressants, antipsychotics, and antiarrhythmics. It is well recognized that CADs accumulate in certain intracellular compartments leading to specific morphological changes of cells. So far, no adequate technique exists allowing for ultrastructural analysis of CAD in intact cells. Azidobupramine, a recently described multifunctional antidepressant analogue, allows for the first time to perform high-resolution studies of CADs on distribution pattern and morphological changes in intact cells. We showed here that the intracellular distribution pattern of azidobupramine strongly depends on drug concentration and exposure time. The mitochondrial compartment (mDsRed) and the late endolysosomal compartment (CD63-GFP) were the preferred localization sites at low to intermediate concentrations (i.e. 1 mu M, 5 mu M). In contrast, the autophagosomal compartment (LC3-GFP) can only be reached at high concentrations (10 mu M) and long exposure times (72 hrs). At the morphological level, LC3-clustering became only prominent at high concentrations (10 mu M), while changes in CD63 pattern already occurred at intermediate concentrations (5 mu M). To our knowledge, this is the first study that establishes a link between intracellular CAD distribution pattern and morphological changes. Therewith, our results allow for gaining deeper understanding of intracellular effects of CADs

Broader Autism Phenotype in Siblings of Children with ASD—A Review

Although less pronounced, social, cognitive, and personality characteristics associated with autism spectrum disorders (ASD) may be present in people who do not meet ASD diagnostic criteria, especially in first-degree relatives of individuals with ASD. Research on these characteristics, referred to as broader autism phenotype (BAP), provides valuable data on potential expressions of autism-specific deficits in the context of family relations. This paper offers a review of research on BAP in siblings of individuals with ASD, focusing on reports regarding social, communication, and cognitive deficits, published from 1993 to 2014. The studies are divided into two groups based on participants’ age: papers on preschool and older siblings of individuals with ASD; and publications on infants at risk for ASD. On the basis of this review, suggestions are offered for further research and its significance for our understanding of the genetic determinants of autism

Language abilities in preschool-aged siblings of children with autism spectrum disorders – preliminary report

Background The characteristics of autism spectrum disorders (ASD) observed among relatives of people affected with autism are referred to as broader autism phenotype (BAP). Among the components of BAP are language and communication skills. Research to date on these skills amongst the relatives of individuals with ASD is inconclusive. Furthermore, limited data are available about preschool-aged siblings of children with ASD. Participants and procedure Eighty-six children aged 4 years and 6 months – 6 years and 11 months took part in the study (32 girls and 54 boys). They were divided into four groups: siblings of children with autism (S/ASD), high-functioning children diagnosed with autism spectrum disorders (HF/ASD), siblings of children with Down syndrome (S/DS) and siblings of typically developing children (Controls, C). Communication and language skills were tested using the Vocabulary Test for Children (TSD). It was used to assess two kinds of verbal skills: receptive language (passive) and expressive language (active). Results No differences were observed in expressive lanquage or receptive language between siblings of children with ASD and siblings of children with DS as well as typically developing children. In terms of receptive language and general communication skills, siblings of children with ASD scored higher than high functioning children with ASD. High functioning children with ASD displayed difficulties with receptive language, expressive language, general language and communication skills. Conclusions The results suggest that siblings of children with ASD do not display deficits in communication and language skills. It is however important to note that due to a small sample size this study should be considered as preliminary

A longitudinal study of motivation and competence in children with Down syndrome: early childhood to early adolescence

Background Motivation has been identified as an area of difficulty for children with Down syndrome. Although individual differences in mastery motivation are presumed to have implications for subsequent competence, few longitudinal studies have addressed the stability of motivation and the predictive validity of early measures for later academic achievement, especially in atypical populations. Method The participants were 25 children with Down syndrome. Mastery motivation, operationalised as persistence, was measured in early childhood and adolescence using tasks and parent report. At the older age, preference for challenge, another aspect of mastery motivation, was also measured and the children completed assessments of academic competence. Results There were significant concurrent correlations among measures of persistence at both ages, and early task persistence was associated with later persistence. Persistence in early childhood was related to academic competence in adolescence, even when the effects of cognitive ability at the younger age were controlled. Conclusions For children with Down syndrome, persistence appears to be an individual characteristic that is relatively stable from early childhood to early adolescence. The finding that early mastery motivation is significant for later achievement has important implications for the focus of early interventions

New insights into the intracellular distribution pattern of cationic amphiphilic drugs

Cationic amphiphilic drugs (CADs) comprise a wide variety of different substance classes such as antidepressants, antipsychotics, and antiarrhythmics. It is well recognized that CADs accumulate in certain intracellular compartments leading to specific morphological changes of cells. So far, no adequate technique exists allowing for ultrastructural analysis of CAD in intact cells. Azidobupramine, a recently described multifunctional antidepressant analogue, allows for the first time to perform high-resolution studies of CADs on distribution pattern and morphological changes in intact cells. We showed here that the intracellular distribution pattern of azidobupramine strongly depends on drug concentration and exposure time. The mitochondrial compartment (mDsRed) and the late endolysosomal compartment (CD63-GFP) were the preferred localization sites at low to intermediate concentrations (i.e. 1 mu M, 5 mu M). In contrast, the autophagosomal compartment (LC3-GFP) can only be reached at high concentrations (10 mu M) and long exposure times (72 hrs). At the morphological level, LC3-clustering became only prominent at high concentrations (10 mu M), while changes in CD63 pattern already occurred at intermediate concentrations (5 mu M). To our knowledge, this is the first study that establishes a link between intracellular CAD distribution pattern and morphological changes. Therewith, our results allow for gaining deeper understanding of intracellular effects of CADs

A framework for examining leadership in extreme contexts

In this review, we develop a framework to guide future research and to examine the execution of leadership in extreme contexts. We start by defining and distinguishing extreme contexts from crisis and other contexts. A five component typology is developed comprised of magnitude of consequences, form of threat, probability of consequences, location in time and physical or psychological–social proximity. We discuss the unique influences these components have on leadership processes in extreme contexts examining the relevance of organization types such as critical action and high reliability organizations. Further, we present a set of factors that may attenuate or intensify the dimensions comprising an extreme context, thus influencing either a team or organization\u27s ability for adaptive leadership response. Ultimately this framework seeks to develop a richer understanding of extreme contexts to advance the future development of contextualized theories of leadership for extreme contexts