Prior studies have established the requirement for enzymatic hydrolysis of glucosylceramides to ceramide for epidermal barrier homeostasis. In this study, we asked whether sphingomyelin-derived ceramide, resulting from acid-sphingomyelinase activity, is also required for normal barrier function. We showed first, that a subset of Niemann-Pick patients with severe acid-sphingomyelinase deficiency (i.e., <2% residual activity) demonstrate abnormal permeability barrier homeostasis, i.e., delayed recovery kinetics following acute barrier disruption by cellophane tape-stripping. To obtain further mechanistic insights into the potential requirement for sphingomyelin-to-ceramide processing for the barrier, we next studied the role of acid-sphingomyelinase in hairless mouse skin. Murine epidermis contains abundant acid-sphingomyelinase activity (optimal pH 5.1-5.6). Two hours following acute barrier disruption by tape-stripping, acid-sphingomyelinase activity increases 1. 44-fold (p<0.008 versus vehicle-treated controls), an increase that is blocked by a single topical application of the acid-sphingomyelinase inhibitor, palmitoyldihydrosphingosine. Furthermore, both palmitoyldihydrosphingosine and desipramine, a chemically and mechanically unrelated acid-sphingomyelinase inhibitor, significantly delay barrier recovery both 2 and 4 h after acute barrier abrogation. Inhibitor application also causes both an increase in sphingomyelin content, and a reduction of normal extracellular lamellar membrane structures, in the stratum corneum. Both of the inhibitor-induced delays in barrier recovery can be overridden by co-applications of topical ceramide, demonstrating that an alteration of the ceramide-sphingomyelin ratio, rather than sphingomyelin accumulation, is likely responsible for the barrier abnormalities that occur with acid-sphingomyelinase deficiency. These studies demonstrate an important role for enzymatic processing of sphingomyelin-to-ceramide by acid-sphingomyelinase as a mechanism for generating a portion of the stratum corneum ceramides for permeability barrier homeostasis in mammalian skin.

SUMMARY Healthy infants' sucking, swallowing and breathing movements were observed ultrasonographically during breast‐ and bottle‐feeding between two and five days after birth. Sucks were found to occur either on their own or in combination with a swallow. Swallows did not occur on their own. Younger babies' swallowing invariably was associated with a pause in breathing. Older babies generally showed better co‐ordination of sucking, swallowing and breathing than younger ones, whether breast‐ or bottle‐feeding. RÉSUMÉ Etudes à l'ultrason de l'organisation de la succion et de la déglutition chez le nouveau‐né La succion, la déglutition et les mouvements respiratoires de nouveau‐nés en bonne santé ont étéétudiés par enregistrement ultrasonores durant l'alimentation au sein ou au biberon, entre deux et cinq jours aprts la naissance. La succion a été trouvée isolte ou en combinaison avec un mouvement de déglutition. La déglutition ne survient pas isolément. La déglutition des plus jeunes nouveau‐nés est associée invariablement à une pause respiratoire. Les bébés plus âgés ont montré généralement une meilleure coordination entre succion, déglutition et respiration que chez les plus jeunes, qu'il s'agisse d'alimentation au sein ou au biberon. ZUSAMMENFASSUNG Sonographische Untersuchungen des Saugens und Schluckens bei Neugeborenen Vom zweiten bis fünften Tag nach der Geburt wurden bei gesunden Neugeborenen die Saug‐, Schluck‐ und Atembewegungen beim Stillen und beim Flaschetrinken sonographisch registriert. Das Saugen konnte allein oder in Verbindung mit dem Schlucken auftreten. Das Schlucken wurde nicht allein registriert. Bei jüngeren Babies war das Schlucken immer mit einer Atempause verbunden. Bei älteren Babies war die Koordination zwischen Saugen, Schlucken und Atmen besser als bei den jungeren, unabhängig ob sie gestillt oder mit der Flasche gefüttert wurden. RESUMEN Estudio ultrasonográfico de la organización de la succión y deglución en los recién nacidos Se observaron los movimientos de succión, deglución y respiración en lactantes sanos utilizando ultrasonografia durante la alimentación al pecho y al tomar el biberón, dos y cinco dias después del nacimiento. Se observó que el chupeteo tenía lugar aisladamente o en combinación con la deglución. La deglución no tenía lugar aisladamente. La deglución de los niños más pequeños se asociaba invariablemente a una pausa en la respiración. Los niños mayores, en general mostraban una mejor coordinación en la succión, deglución y respiración que los niños más jóvenes tanto si tomaban el pecho como el biberón.

The IL-1R family member IL-33R mediates Fcε-receptor-I (FcεRI)-independent activation of mast cells leading to NF-κB activation and consequently the production of cytokines. IL-33 also induces the activation of MAPKs, such as p38. We aimed to define the relevance of the p38-targets, the MAPK-activated protein kinases 2 and 3 (MK2 and MK3) in IL-33-induced signaling and the resulting mast cell effector functions in vitro and in vivo. We demonstrate that the IL-33-induced IL-6 and IL-13 production strongly depends on the MK2/3-mediated activation of ERK1/2 and PI3K signaling. Furthermore, in the presence of the stem cell factors, IL-33 did induce an MK2/3-, ERK1/2- and PI3K-dependent production of TNF-α. In vivo, the loss of MK2/3 in mast cells decreased the IL-33-induced leukocyte recruitment and the resulting skin inflammation. Therefore, the MK2/3-dependent signaling in mast cells is essential to mediate IL-33-induced inflammatory responses. Thus, MK2/3 are potential therapeutic targets for suppression of IL-33-induced inflammation skin diseases such as psoriasis.

Normolipemic and genetically hypercholesterolemic pigs of defined lipoprotein genotype were fed a standard diet supplemented with 50 micrograms/g tocotrienol-rich fraction (TRF) isolated from palm oil. Hypercholesterolemic pigs fed the TRF supplement showed a 44% decrease in total serum cholesterol, a 60% decrease in low-density-lipoprotein (LDL)-cholesterol, and significant decreases in levels of apolipoprotein B (26%), thromboxane-B2 (41%), and platelet factor 4 (PF4; 29%). The declines in thromboxane B2 and PF4 suggest that TRF has a marked protective effect on the endothelium and platelet aggregation. The effect of the lipid-lowering diet persisted only in the hypercholesterolemic swine after 8 wk feeding of the control diet. These results support observations from previous studies on lowering plasma cholesterol in animals by tocotrienols, which are naturally occurring compounds in grain and palm oils and may have some effect on lowering plasma cholesterol in humans.