Sequential organogenesis sets two parallel sensory lines in medaka.

Animal organs are typically formed during embryogenesis by following one specific developmental programme. Here, we report that neuromast organs are generated by two distinct and sequential programmes that result in parallel sensory lines in medaka embryos. A ventral posterior lateral line (pLL) is composed of neuromasts deposited by collectively migrating cells whereas a midline pLL is formed by individually migrating cells. Despite the variable number of neuromasts among embryos, the sequential programmes that we describe here fix an invariable ratio between ventral and midline neuromasts. Mechanistically, we show that the formation of both types of neuromasts depends on the chemokine receptor genes cxcr4b and cxcr7b, illustrating how common molecules can mediate different morphogenetic processes. Altogether, we reveal a self-organising feature of the lateral line system that ensures a proper distribution of sensory organs along the body axis.

S100A6 Regulates Endothelial Cell Cycle Progression by Attenuating Antiproliferative Signal Transducers and Activators of Transcription 1 Signaling.

OBJECTIVE: S100A6, a member of the S100 protein family, has been described as relevant for cell cycle entry and progression in endothelial cells. The molecular mechanism conferring S100A6's proliferative actions, however, remained elusive. APPROACH AND RESULTS: Originating from the clinically relevant observation of enhanced S100A6 protein expression in proliferating endothelial cells in remodeling coronary and carotid arteries, our study unveiled S100A6 as a suppressor of antiproliferative signal transducers and activators of transcription 1 signaling. Discovery of the molecular liaison was enabled by combining gene expression time series analysis with bioinformatic pathway modeling in S100A6-silenced human endothelial cells stimulated with vascular endothelial growth factor A. This unbiased approach led to successful identification and experimental validation of interferon-inducible transmembrane protein 1 and protein inhibitors of activated signal transducers and activators of transcription as key components of the link between S100A6 and signal transducers and activators of transcription 1. CONCLUSIONS: Given the important role of coordinated endothelial cell cycle activity for integrity and reconstitution of the inner lining of arterial blood vessels in health and disease, signal transducers and activators of transcription 1 suppression by S100A6 may represent a promising therapeutic target to facilitate reendothelialization in damaged vessels.

Neural stem cells induce the formation of their physical niche during organogenesis.

Most organs rely on stem cells to maintain homeostasis during post-embryonic life. Typically, stem cells of independent lineages work coordinately within mature organs to ensure proper ratios of cell types. Little is known, however, on how these different stem cells locate to forming organs during development. Here we show that neuromasts of the posterior lateral line in medaka are composed of two independent life-long lineages with different embryonic origins. Clonal analysis and 4D imaging revealed a hierarchical organisation with instructing and responding roles: an inner, neural lineage induces the formation of an outer, border cell lineage (nBC) from the skin epithelium. Our results demonstrate that the neural lineage is necessary and sufficient to generate nBCs highlighting self-organisation principles at the level of the entire embryo. We hypothesise that induction of surrounding tissues plays a major role during the establishment of vertebrate stem cell niches.

[Transcutaneous applications for vaccination and immunotherapy]. / Transkutane Applikationen bei Impfungen und Immuntherapien.

Although Edward Jenner applied the first vaccines by scratching cow pox material into the skin, the profound immunological properties of the skin have become evident through research and discoveries only in the last 20 years. The immunological cells in the epidermis and the dermis are suitable targets for transcutaneous vaccination and immunotherapy. However, as the skin represents a natural barrier for topically administered large molecules, novel methods to overcome this barrier function have been described. There are chemical, biochemical and physical methods, many of which are pain-free and therefore especially suitable for children. Also for adults non-invasive methods of vaccination and immunotherapy are attractive as self-administration is feasible. Future products are currently undergoing clinical tests which provide promising results.

Alors qu'Edward Jenner a utilisé la peau pour appliquer les premières vaccinations, la peau comme organe immunologique n'a été découverte et étudiée que dans les dernières 20 années. A cause d'une multitude de cellules immunologiques dans l'épiderme et le derme, la peau est appropriée pour la vaccination transcutanée et l'immunothérapie. Cependant, comme la peau est une barrière naturelle pour de grosses molécules, il y a des approches différentes pour surmonter cette barrière. On distingue entre les méthodes chimiques, biochimiques et physiques. Surtout pour les enfants, les traitements sans douleur seraient appropriés. Mais pour les adultes aussi, les méthodes de vaccination et d'immunothérapie non-invasives sont une alternative intéressante, puisqu'elles peuvent être administrées par les patients eux-mêmes. Des produits qui sont à l'essai actuellement dans des études de phase I­III fournissent des résultats prometteurs.

Minimal dose for severe poisoning and influencing factors in acute human clozapine intoxication: a 13-year retrospective study.

OBJECTIVES: Clozapine is an atypical antipsychotic drug used in the treatment of resistant schizophrenia. Intoxications with this drug are frequently observed. The aim of the present study was to identify a minimal dose and the dose bearing a 50% risk of developing moderate or severe intoxication symptoms. We also investigated the influence of age, sex, effect of decontamination measures, and pretreatment with clozapine on the severity of poisoning. METHODS: A retrospective case study of 73 acute clozapine monointoxications reported by physicians to the Swiss Toxicological Information Centre between 1995 and 2007. RESULTS: The most common symptoms were central nervous system depression (63.1%), tachycardia (39.7%), restlessness/agitation (16.4%), confusion/disorientation (15.1%), dysarthria (15.1%), arterial hypertension (10.9%), bradykinesia (9.6%), respiratory depression (9.6%), and QTc prolongation (8.2%). We found a significant correlation between ingested clozapine dose and severity of poisoning. The minimal dose for both moderate and severe intoxications was 0.1 g. The dose for a 50% risk of developing moderate or severe intoxications was 0.9 g in patients older than 50 years and 14.5 g in patients younger than 50 years. Patients older than 50 years had a significantly increased risk for a severe clinical course (odds ratio, 6.41; 95% confidence interval, 1.88-21.90). We found no significant correlation between pretreatment, sex or decontamination, and the severity of the intoxication. CONCLUSIONS: Moderate and severe clozapine intoxications can already occur after ingestion of doses in the low therapeutic range, especially in patients older than 50 years. Poisoned patients have to be monitored for central nervous system depression, tachycardia, blood pressure abnormalities, respiratory depression, and QTc prolongation.