Peripheral contribution of NGF and ASIC 1a to colonic hypersensitivity in a rat model of irritable bowel syndrome

Abstract Background Irritable bowel syndrome ( IBS ) is a functional gastrointestinal disorder associated with idiopathic colonic hypersensitivity ( CHS ). However, recent studies suggest that low‐grade inflammation could underlie CHS in IBS . The pro‐inflammatory mediator nerve growth factor ( NGF ) plays a key role in the sensitization of peripheral pain pathways and several studies have reported its contribution to visceral pain development. NGF modulates the expression of Acid‐Sensing Ion Channels ( ASIC s), which are proton sensors involved in sensory neurons sensitization. This study examined the peripheral contribution of NGF and ASIC s to IBS ‐like CHS induced by butyrate enemas in the rat colon. Methods Colorectal distension and immunohistochemical staining of sensory neurons were used to evaluate NGF and ASIC s contribution to the development of butyrate‐induced CHS . Key Results Systemic injection of anti‐ NGF antibodies or the ASIC s inhibitor amiloride prevented the development of butyrate‐induced CHS . A significant increase in NGF and ASIC 1a protein expression levels was observed in sensory neurons of rats displaying butyrate‐induced CHS . This increase was specific of small‐ and medium‐diameter L1 + S1 sensory neurons, where ASIC 1a was co‐expressed with NGF or trkA in CGRP ‐immunoreactive somas. ASIC 1a was also overexpressed in retrogradely labeled colon sensory neurons. Interestingly, anti‐ NGF antibody administration prevented ASIC 1a overexpression in sensory neurons of butyrate‐treated rats. Conclusions & Inferences Our data suggest that peripheral NGF and ASIC 1a concomitantly contribute to the development of butyrate‐induced CHS NGF ‐ ASIC 1a interplay may have a pivotal role in the sensitization of colonic sensory neurons and as such, could be considered as a potential new therapeutic target for IBS treatment

Colonic overexpression of the T‐type calcium channel Ca v 3.2 in a mouse model of visceral hypersensitivity and in irritable bowel syndrome patients

Abstract Background Among the different mechanisms involved in irritable bowel syndrome ( IBS ) physiopathology, visceral hypersensitivity seems to play a key role. It involves sensitization of the colonic primary afferent fibers, especially through an overexpression of ion channels. The aims of this translational study were to investigate the colonic expression of Ca v 3.2 calcium channels and their involvement in an animal model of colonic hypersensitivity, and to assess their expression in the colonic mucosa of symptomatic IBS patients. Methods This bench‐to‐bed study combined a preclinical experimental study on mice and a case–control clinical study. Preclinical studies were performed on wild‐type and Ca v 3.2‐ KO mice. Colonic sensitivity and Ca v 3.2 expression were studied after a low‐dose treatment of dextran sodium sulfate ( DSS 0.5%). Regarding the clinical study, colonic biopsies were performed in 14 IBS patients and 16 controls during a colonoscopy to analyze the mucosal Ca v 3.2 expression. Key results Wild‐type, but not Ca v 3.2‐ KO , mice developed visceral hypersensitivity without colonic inflammation, after 0.5% DSS treatment. A significant increase of Ca v 3.2 mRNA ( p = 0.04) was found in the colon of low‐dose DSS ‐treated wild‐type ( WT ) mice compared to their controls. In human colonic biopsies, the Ca v 3.2 mRNA level was significantly higher in the IBS group compared to the control group ( p = 0.01). The immunofluorescence staining revealed their protein expression in colonic mucosa, particularly in nerve fibers. Conclusions & inferences This translational study supports the involvement of the calcium channels Ca v 3.2 in abdominal pain, as observed in IBS patients. It opens new therapeutic perspectives based on molecules specifically blocking these channels

A large abelisauroid theropod dinosaur from the Early Cretaceous of Libya

Despite increasingly intensive paleontological sampling, Cretaceous terrestrial vertebrates from continental Africa remain relatively poorly known, frustrating efforts to characterize paleoecosystems in the region, as well as the paleobiogeography of the southern continents during this interval. Here we describe the partial skeleton of a large-bodied theropod dinosaur from the Early Cretaceous (early Aptian, ∼125-120 Ma) of Libya. The specimen consists of associated elements (two incomplete dorsal vertebrae, a proximal caudal centrum, a partial proximal caudal neural arch, the distal right femur, and the mostly complete right tibia) and is referable to the widespread ceratosaurian clade Abelisauroidea. The discovery adds to the growing record of abelisauroids from mainland Africa, and firmly establishes the presence of the clade on the continent prior to its final separation from South America. Indeed, the age of the Libyan theropod predates or is penecontemporaneous with the accepted timing of fragmentation of most major Gondwanan landmasses, supporting the hypothesis that abelisauroids could have dispersed throughout the southern continents before land connections between these areas were severed. Moreover, the considerable size of the Libyan form challenges assertions that abelisauroids were ecologically subordinate to basal tetanuran theropods in Early and middle Cretaceous paleoenvironments of Gondwana. © 2010 The Paleontological Society

High Diversity in Cretaceous Ichthyosaurs from Europe Prior to Their Extinction

Background: Ichthyosaurs are reptiles that inhabited the marine realm during most of the Mesozoic. Their Cretaceous representatives have traditionally been considered as the last survivors of a group declining since the Jurassic. Recently, however, an unexpected diversity has been described in Upper Jurassic–Lower Cretaceous deposits, but is widely spread across time and space, giving small clues on the adaptive potential and ecosystem control of the last ichthyosaurs. The famous but little studied English Gault Formation and ‘greensands’ deposits (the Upper Greensand Formation and the Cambridge Greensand Member of the Lower Chalk Formation) offer an unprecedented opportunity to investigate this topic, containing thousands of ichthyosaur remains spanning the Early–Late Cretaceous boundary. Methodology/Principal findings: To assess the diversity of the ichthyosaur assemblage from these sedimentary bodies, we recognized morphotypes within each type of bones. We grouped these morphotypes together, when possible, by using articulated specimens from the same formations and from new localities in the Vocontian Basin (France); a revised taxonomic scheme is proposed. We recognize the following taxa in the ‘greensands’: the platypterygiines ‘Platypterygius’ sp. and Sisteronia seeleyi gen. et sp. nov., indeterminate ophthalmosaurines and the rare incertae sedis Cetarthrosaurus walkeri. The taxonomic diversity of late Albian ichthyosaurs now matches that of older, well-known intervals such as the Toarcian or the Tithonian. Contrasting tooth shapes and wear patterns suggest that these ichthyosaurs colonized three distinct feeding guilds, despite the presence of numerous plesiosaur taxa. Conclusion/Significance: Western Europe was a diversity hot-spot for ichthyosaurs a few million years prior to their final extinction. By contrast, the low diversity in Australia and U.S.A. suggests strong geographical disparities in the diversity pattern of Albian–early Cenomanian ichthyosaurs. This provides a whole new context to investigate the extinction of these successful marine reptiles, at the end of the Cenomanian