SHORT syndrome due to a novel de novo mutation in PRKCE (Protein Kinase Cɛ) impairing TORC2-dependent AKT activation.

SHORT syndrome is a rare, recognizable syndrome resulting from heterozygous mutations in PIK3R1 encoding a regulatory subunit of phosphoinositide-3-kinase (PI3K). The condition is characterized by short stature, intrauterine growth restriction, lipoatrophy and a facial gestalt involving a triangular face, deep set eyes, low hanging columella and small chin. PIK3R1 mutations in SHORT syndrome result in reduced signaling through the PI3K-AKT-mTOR pathway. We performed whole exome sequencing for an individual with clinical features of SHORT syndrome but negative for PIK3R1 mutation and her parents. A rare de novo variant in PRKCE was identified. The gene encodes PKCε and, as such, the AKT-mTOR pathway function was assessed using phospho-specific antibodies with patient lymphoblasts and following ectopic expression of the mutant in HEK293 cells. Kinase analysis showed that the variant resulted in a partial loss-of-function. Whilst interaction with PDK1 and the mTORC2 complex component SIN1 was preserved in the mutant PKCε, it bound to SIN1 with a higher affinity than wild-type PKCε and the dynamics of mTORC2-dependent priming of mutant PKCε was altered. Further, mutant PKCε caused impaired mTORC2-dependent pAKT-S473 following rapamycin treatment. Reduced pFOXO1-S256 and pS6-S240/244 levels were also observed in the patient LCLs. To date, mutations in PIK3R1 causing impaired PI3K-dependent AKT activation are the only known cause of SHORT syndrome. We identify a SHORT syndrome child with a novel partial loss-of-function defect in PKCε. This variant causes impaired AKT activation via compromised mTORC2 complex function

Aerobic exercise in adolescents with obesity: preliminary evaluation of a modular training program and the modified shuttle test

BACKGROUND: Increasing activity levels in adolescents with obesity requires the development of exercise programs that are both attractive to adolescents and easily reproducible. The aim of this study was to develop a modular aerobic training program for adolescents with severe obesity, with a focus on variety, individual targets and acquiring physical skills. We report here the effects on aerobic fitness from a pilot study. Furthermore, we examined the feasibility of the modified shuttle test (MST) as an outcome parameter for aerobic fitness in adolescents with severe obesity. METHODS: Fifteen adolescents from an inpatient body weight management program participated in the aerobic training study (age 14.7 ± 2.1 yrs, body mass index 37.4 ± 3.5). The subjects trained three days per week for 12 weeks, with each session lasting 30–60 minutes. The modular training program consisted of indoor, outdoor and swimming activities. Feasibility of the MST was studied by assessing construct validity, test-retest reliability and sensitivity to change. RESULTS: Comparing pretraining and end of training period showed large clinically relevant and significant improvements for all aerobic indices: e.g. VO(2 peak )17.5%, effect size (ES) 2.4; W(max )8%, ES 0.8. In addition, a significant improvement was found for the efficiency of the cardiovascular system as assessed by the oxygen pulse (15.8%, ES 1.6). Construct validity, test-retest reliability and sensitivity to change of the MST were very good. MST was significantly correlated with VO(2 peak )(r = 0.79) and W(max )(r = 0.84) but not with anthropometric measures. The MST walking distance improved significantly by 32.5%, ES 2.5. The attendance rate at the exercise sessions was excellent. CONCLUSION: This modular, varied aerobic training program has clinically relevant effects on aerobic performance in adolescents with severe obesity. The added value of our aerobic training program for body weight management programs for adolescents with severe obesity should be studied with a randomized trial. This study further demonstrated that the MST is a reliable, sensitive and easy to administer outcome measure for aerobic fitness in adolescent body weight management trials

"Wiederholung ist Erinnerung nach vorne" - zum philosophischen Konzept der Wiederholung in der Lyrik Paul Celans

Diese Arbeit stellt den Versuch dar, das Konzept der Wiederholung Kierkegaards – Wiederholung sei Erinnerung nach vorne – auf die Lyrik Paul Celans anzuwenden. Damit werden einerseits die verschiedenen Ebenen der Wiederholung in dessen Gedichten aufgeschlüsselt, andererseits wird so eine Möglichkeit geboten, seine Gedichte zu verstehen, etwa durch grundlegende Begriffe wie Sprache und Erinnerung. Der Rahmen der Wiederholung steht am Ende dafür, dass wir, vor allem im Hinblick auf Celans Hintergrund, wohl nie vollständig verstehen werden – gerade deshalb (uns) aber umso dringender wieder und wieder erinnern müssen. Mit Philosophen wie Jacques Derrida und Martin Heidegger geht die vorliegende Arbeit dabei einerseits von vom Dichter selbst gelesener Philosophie aus, andererseits von einer von ihm inspirierten. Über die Frage, wie angemessenes Erinnern aussieht, bis hin zu jener, ob Schreiben nach Auschwitz überhaupt möglich ist, will diese Arbeit zugleich auch einen Bogen über Celans frühe Dichtung spannen und verknüpft sie damit auf mehrere Weisen mit der Philosophie

Uncertainty propagation and sensitivity analysis in composite manufacturing cost estimation: ALPHA-framework and cost tool development

The presented ALPHA cost tool is a novel highly flexible bottom-up parametric hybrid cost estimation framework. It combines the benefits of both methods with the aim of providing cost information during all product development phases. The software offers full transparency to the user and advanced two-level uncertainty management to not only understand any project’s cost structure but also aid to identify its cost driving parameters. The implementation of sensitivity analysis makes the intrinsic uncertainty inevitable embedded in cost estimation become graspable. Gaussian error propagation offers direct feedback without extra calculation time while classic Monte Carlo Simulation gives detailed insight through post estimation analysis. From the vast number of commercially available or self-developed cost tools many probably already incorporate uncertainty measures similar to those proposed here. But this article shows both the potential of the additionally obtainable information from uncertainty propagation and demonstrates a way of integrating these risk considerations into a self-developed cost tool

Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome

Reports of SHORT syndrome have, to date, focused on the clinical features which lie at the core of the diagnosis but there has been little by way of report of long-term outcome, either in terms of medical complications or of intellectual development. We now report two children in whom nephrocalcinosis has developed and a third, adult, with similar findings. It may be that clinicians should be looking among cases of unexplained hypercalcaemia for an alternative phenotypic presentation of this short stature syndrom