Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis.

BACKGROUND: Inflammatory bowel diseases, encompassing Crohn's disease and ulcerative colitis, are characterised by persistent leucocyte tissue infiltration leading to perpetuation of an inappropriate inflammatory cascade. The neuronal guidance molecule netrin-1 has recently been implicated in the orchestration of leucocyte trafficking during acute inflammation. We therefore hypothesised that netrin-1 could modulate leucocyte infiltration and disease activity in a model of inflammatory bowel disease. DESIGN: DSS-colitis was performed in mice with partial genetic netrin-1 deficiency (Ntn-1(+/-) mice) or wild-type mice treated with exogenous netrin-1 via osmotic pump to examine the role of endogenous and therapeutically administered netrin-1. These studies were supported by in vitro models of transepithelial migration and intestinal epithelial barrier function. RESULTS: Consistent with our hypothesis, we observed induction of netrin-1 during intestinal inflammation in vitro or in mice exposed to experimental colitis. Moreover, mice with partial netrin-1 deficiency demonstrated an exacerbated course of DSS-colitis compared to littermate controls, with enhanced weight loss and colonic shortening. Conversely, mice treated with exogenous mouse netrin-1 experienced attenuated disease severity. Importantly, permeability studies and quantitative assessment of apoptosis reveal that netrin-1 signalling events do not alter mucosal permeability or intestinal epithelial cell apoptosis. In vivo studies of leucocyte transmigration demonstrate suppression of neutrophil trafficking as a key function mediated by endogenous or exogenously administered netrin-1. Finally, genetic studies implicate the A2B adenosine receptor in netrin-1-mediated protection during DSS-colitis. CONCLUSIONS: The present study identifies a previously unrecognised role for netrin-1 in attenuating experimental colitis through limitation of neutrophil trafficking.

A transgenic mouse model reveals fast nicotinic transmission in hippocampal pyramidal neurons.

The relative contribution to brain cholinergic signaling by synaptic- and diffusion-based mechanisms remains to be elucidated. In this study, we examined the prevalence of fast nicotinic signaling in the hippocampus. We describe a mouse model where cholinergic axons are labeled with the tauGFP fusion protein driven by the choline acetyltransferase promoter. The model provides for the visualization of individual cholinergic axons at greater resolution than other available models and techniques, even in thick, live, slices. Combining calcium imaging and electrophysiology, we demonstrate that local stimulation of visualized cholinergic fibers results in rapid excitatory postsynaptic currents mediated by the activation of α7-subunit-containing nicotinic acetylcholine receptors (α7-nAChRs) on CA3 pyramidal neurons. These responses were blocked by the α7-nAChR antagonist methyllycaconitine and potentiated by the receptor-specific allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxanol-3-yl)-urea (PNU-120596). Our results suggest, for the first time, that synaptic nAChRs can modulate pyramidal cell plasticity and development. Fast nicotinic transmission might play a greater role in cholinergic signaling than previously assumed. We provide a model for the examination of synaptic properties of basal forebrain cholinergic innervation in the brain.

Surgeon-estimated costs of common consumables in otolaryngology.

OBJECTIVES/HYPOTHESIS: The current fiscal climate demands increasing emphasis on curbing hospital expenses incurred from surgical procedures. Disposable instruments and consumables play a major role, but the end user (the surgeon) is often unaware of the cost of these materials. The objectives of our study were: 1) to assess knowledge of costs of disposable instruments and consumable products, and 2) to gauge interest in greater access to cost information and its potential to change practice. STUDY DESIGN: We used a cross-sectional survey study to meet our study's objectives. METHODS: A paper-based anonymous questionnaire was administered in the Department of Otolaryngology at McGill University and at Western University asking for estimations of costs of 23 commonly used products in the operating room. Our primary outcome measure was accuracy of cost estimations, which were considered accurate if within ± 50% of the true cost at the respective institution. RESULTS: The average accuracy was 29.9% (standard deviation = 16.7%). There was no significant difference between residents (32.5%, 95% confidence interval [CI]: 10.2%-54.7%) and staff (28.3%, 95% CI: 11.0%-45.6%). Less than 10% of participants were able to accurately estimate the costs of at least half of the disposable products. The majority of participants (82%) felt that greater information would change their use of consumables. CONCLUSIONS: Surgical residents and staff have a generally poor knowledge of the cost of common consumable products used in the operating room. There is potential for increased awareness of costs to change behavior. LEVEL OF EVIDENCE: NA.