Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in preterm infants and is characterized by translocation of LPS across the inflamed intestine. We hypothesized that the LPS receptor (TLR4) plays a critical role in NEC development, and we sought to determine the mechanisms involved. We now demonstrate that NEC in mice and humans is associated with increased expression of TLR4 in the intestinal mucosa and that physiological stressors associated with NEC development, namely, exposure to LPS and hypoxia, sensitize the murine intestinal epithelium to LPS through up-regulation of TLR4. In support of a critical role for TLR4 in NEC development, TLR4-mutant C3H/HeJ mice were protected from the development of NEC compared with wild-type C3H/HeOUJ littermates. TLR4 activation in vitro led to increased enterocyte apoptosis and reduced enterocyte migration and proliferation, suggesting a role for TLR4 in intestinal repair. In support of this possibility, increased NEC severity in C3H/HeOUJ mice resulted from increased enterocyte apoptosis and reduced enterocyte restitution and proliferation after mucosal injury compared with mutant mice. TLR4 signaling also led to increased serine phosphorylation of intestinal focal adhesion kinase (FAK). Remarkably, TLR4 coimmunoprecipitated with FAK, and small interfering RNA-mediated FAK inhibition restored enterocyte migration after TLR4 activation, demonstrating that the FAK-TLR4 association regulates intestinal healing. These findings demonstrate a critical role for TLR4 in the development of NEC through effects on enterocyte injury and repair, identify a novel TLR4-FAK association in regulating enterocyte migration, and suggest TLR4/FAK as a therapeutic target in this disease.

Purpose The objective of this study was to evaluate the histologic remodeling profile and biomechanical properties of the porcine abdominal wall after repair with HDMI-crosslinked (Permacol®) or non-crosslinked (Strattice®) porcine dermis in a porcine model of ventral hernia repair. Methods Bilateral incisional hernias were created in Yucatan minipigs and repaired after 21 days. The repair site, including mesh and abdominal wall, was harvested after 1, 6, and 12 months and subjected to histologic analysis and uniaxial testing. Native abdominal wall without mesh was also subjected to uniaxial tensile testing. Results Permacol® demonstrated significant improvement over time in every remodeling category except scaffold degradation, while remodeling characteristics of Strattice® remained relatively unchanged over time for every category except fibrous encapsulation and neovascularization. However, remodeling scores for Strattice® were already significantly higher after just 1 month compared to Permacol® in the categories of cellular infiltration, ECM deposition, and neovascularization, providing evidence of earlier remodeling of the non-crosslinked grafts compared to the crosslinked grafts. The tensile strength and stiffness of both crosslinked and non-crosslinked graft-tissue composites were greater than the tensile strength and stiffness of the native porcine abdominal wall in the very early post-operative period (1 month), but there was no difference in tensile strength or stiffness by the end of the study period (12 months). Conclusions HDMI collagen crosslinking of porcine dermis scaffolds reduces the early histologic remodeling profile but does not significantly impact the tensile strength or stiffness of the graft-tissue composites in a porcine model of ventral hernia repair.

We have quantitatively examined the ergonomics of TLS and RALS and shown that in a single surgeon, TLS procedures are associated with significantly elevated biceps, triceps, and deltoid activation bilaterally when compared to RALS procedures.

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Sidestep (Side) is a pivotal molecular player in embryonic motor axon pathfinding. But questions about its functional repertoire remain: (i) can Side permanently overturn targeting preferences? (ii) does it promote synaptogenesis, and (iii) can Side facilitate synaptic stabilization? To address these questions, Side was temporally and spatially misexpressed and the visible consequences for neuromuscular junction morphology were assessed. When Side was misexpressed either broadly or selectively in muscles during targeting in a wildtype background motor axon targeting preferences were permanently overturned. However the misexpression of Side in all muscles post-targeting neither changed synapse morphology, nor compensated for a lack of the synapse-stabilizing protein Fasciclin II (FasII). Rather Side appears to be dependent on FasII, instead of on intrinsic ability, for sustaining targeting changes. We propose that Side helps to bring motor axons to their correct muscle targets and promotes synaptogenesis, then FasII serves to stabilize the synaptic contacts.

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