Can the reinnervation of a skeletaJ muscle by centripete vagal fibres be used as study method for vagal receptors

A la suite d’une suture croisée entre l’extrémité périphérique du nerf vague sectionné au-dessus du ganglion plexiforme et celle du nerf spinal accessoire, nous avons fait réinnerver le muscle mastoïdo-huméral par des axones vagaux centripètes. Sous anesthésie générale, la stimulation du nerf vague anastomosé évoque des potentiels dans le muscle. Chez le mouton éveillé, on recueille l’activité d’unités motrices réinnervées en association avec la respiration, la déglutition et la motricité gastrique. Les unités œsophagiennes, actives pendant le péristaltisme œsophagien, sont stimulées par l’étirement de la muqueuse de l’œsophage ; elles traduisent l’activité de récepteurs œsophagiens muqueux mis en jeu lors du transit du bol. Par contre, les unités gastriques ne répondent pas à des stimulations périphériques de la paroi du réticulo-rumen et continuent à décharger, en l’absence de toute motricité. Il est suggéré qu elles traduisent l’activité de fibres vagales centripètes, collatérales de neurones post-ganglionnaires, véhiculant une copie du message du moteur gastrique. Ce type de suture conduit donc à la réinnervation du muscle par des fibres vagales centri pètes cholinergiques dont une partie seulement sont des axones sensitifs. Cet artifice expérimental est d’intérêt limité pour l’étude des interocepteurs du territoire vagal chez l’animal éveillé.Fibres of the stemo-cleido-mastoid muscle (so called mastoïdo-humeral in sheep) normally innervated by effects of the accessory nerve have been reinnervated by centripetal fibres of the vagus nerve after supranodose vagal-accessory nerve anastomoses. Evidence that there was reinnervation of the muscle by centripetal vagal fibres was provided from the observa tions that 1) electrical stimulations of the anastomosed cervical vagus nerve elicited potentials in the reinnervated muscle, 2) discharges recorded as bursts of electromyographic potentials occurred during spantaneous movements of larynx, respiratory tract, oesophagus and stomach, 3) electrically evoked potentials and spontaneous discharges were abolished by local anaesthesia of the anastomosed vagus nerve. The fibres contributing to the reinnervation were confirmed to be cholinergic as transmission was blocked by gallamine. As activity in respiratory, laryngeal and oesophageal units was regu larly elicited by mechanical stimulations of larynx, respiratory tract and oesophagus, it may be asserted that muscle was reinnervated by afférents of the vagus coming from these structures. On the contrary, gastric units recorded with phasic discharge patterns bearing a fixed temporal relationships to forestomach movements generally failed to be activated by mechanical stimulations of the gastric walls. It is suggested that their activity came from collateral branches of the contra lateral vagal motor pathway arising from the myenteric plexus and ascen ding in the ipsilateral vagus. The small extent of reinnervation and the fact that all the reinnervating centripetal vagal fibres are not sensory limit further exploitation of such a crossed nerve anastomoses for studying vagal afferent impulse traffic in conscious animals

Evidence of the inhibitory effects of the vagal imput upon the gastric motility in conscious sheep

Chez le mouton éveillé, la suppression chirurgicale des afférences vagales entraîne une augmentation de 17 à 46 % de la fréquence des cycles primaires gastriques. La réduction marquée des afférences gastriques, obtenue en sup primant la motricité du réticulo-rumen, provoque une augmentation de la fré quence de l’activité cyclique des neurones préganglionnaires vagaux innervant les préestomacs et une augmentation de la durée de leur décharge. Ces résultats sont en faveur de l’existence d’un effet inhibiteur permanent des afférences vagales sur les centres gastriques.In conscious sheep, surgical vagal deafferentation led the frequency of primary gastric cycles to be increased in the range between 17 and 46 %. The effects of a marked reduction of the gastric vagal input due to inhibition of gastric motility upon gastric vagal efferent neurones can ben evaluated by i) a shortening of the interval between onsets of two successive bursts, ii) an increase in the duration of their discharges. Interest in the common result of both experiments suggests that under physiological circonstances the result ing afferent drive from gastric comportments is inhibitory in the « gastric centres » and consequently on reticulo-rumen motility

Low-dose mycophenolate mofetil improves survival in a murine model of Staphylococcus aureus sepsis by increasing bacterial clearance and phagocyte function.

Regulators of TLRs signaling pathways play an important role in the control of the pro-inflammatory response that contributes to sepsis-induced tissue injury. Mycophenolate mofetil, an immunosuppressive drug inhibiting lymphocyte proliferation, has been reported to be a regulator of TLRs signaling pathways. Whether MMF used at infra-immunosuppressive doses has an impact on survival and on innate immune response in sepsis is unknown. C57BL/6J mice were infected intraperitoneally with 10 <sup>8</sup> CFU Staphylococcus aureus, and treated or not with low-dose of MMF (20mg/kg/day during 4 days). Survival rate and bacterial clearance were compared. Cytokine levels, quantitative and qualitative cellular responses were assessed. S. aureus - infected mice treated with MMF exhibited improved survival compared to non-treated ones (48% vs 10%, p<0.001). With the dose used for all experiments, MMF did not show any effect on lymphocyte proliferation. MMF treatment also improved local and systemic bacterial clearance, improved phagocytosis activity of peritoneal macrophages resulting in decreased inflammatory cytokines secretion. MMF-treated mice showed enhanced activation of NF-κB seemed with a suspected TLR4-dependent mechanism. These results suggest that infra-immunosuppressive doses of MMF improve host defense during S. aureus sepsis and protects infected mice from fatal outcome by regulating innate immune responses. The signaling pathways involved could be TLR4-dependent. This work brings new perspectives in pathogenesis and therapeutic approaches of severe infections

Opposing effects of high- and low-molecular weight hyaluronan on CXCL12-induced CXCR4 signaling depend on CD44

The tumor microenvironment makes a decisive contribution to the development and dissemination of cancer, for example, through extracellular matrix components such as hyaluronan (HA), and through chemokines that regulate tumor cell behavior and angiogenesis. Here we report a molecular link between HA, its receptor CD44 and the chemokine CXCL12 in the regulation of cell motility and angiogenesis. High-molecular-weight HA (hHA) was found to augment CXCL12-induced CXCR4 signaling in both HepG2iso cells and primary human umbilical vein endothelial cells, as evidenced by enhanced ERK phosphorylation and increased cell motility. The augmentation of CXCR4 signaling translated into increased vessel sprouting and angiogenesis in a variety of assays. Small HA oligosaccharides (sHA) efficiently inhibited these effects. Both siRNA-mediated reduction of CD44 expression and antibodies that block the interaction of CD44 with HA provided evidence that CXCL12-induced CXCR4 signaling depends on the binding of hHA to CD44. Consistently, CD44 and CXCR4 were found to physically interact in the presence of CXCL12, an interaction that could be inhibited by sHA. These findings provide novel insights into how microenvironmental components interact with cell surface receptors in multi-component complexes to regulate key aspects of tumor growth and progression

Scroll waves in isotropic excitable media : linear instabilities, bifurcations and restabilized states

Scroll waves are three-dimensional analogs of spiral waves. The linear stability spectrum of untwisted and twisted scroll waves is computed for a two-variable reaction-diffusion model of an excitable medium. Different bands of modes are seen to be unstable in different regions of parameter space. The corresponding bifurcations and bifurcated states are characterized by performing direct numerical simulations. In addition, computations of the adjoint linear stability operator eigenmodes are also performed and serve to obtain a number of matrix elements characterizing the long-wavelength deformations of scroll waves.Comment: 30 pages 16 figures, submitted to Phys. Rev.