Biomechanical behavior of mandibles reconstructed with fibular grafts at different vertical positions using finite element method.

BACKGROUND: For large mandibular defects, surgical reconstruction using microvascular fibular grafts has advantages over other alternatives in terms of blood supply and good quality of grafted bone. However, the fibular segment is usually lower in height than that of the original mandible, meaning that the vertical positioning of the fibular graft is variable, with different biomechanical consequences on the reconstructed mandible. OBJECTIVES: To use finite element method (FEM) to evaluate stress distribution and displacement of a reconstructed mandible versus an intact mandible under occlusal loads. METHODS: A three-dimensional intact edentulous mandibular bone (Model I) and a reconstructed mandible bone with fibular graft were created from CBCT images. Calculation models were generated with fibular bone graft extracted from the reconstructed mandible of identical length placed into a mimicked defect area on the right-hand side of the mandible at three different vertical positions: superior (Model II), intermediate (Model III), and inferior (Model IV). Forces were applied at lower left first molar region and lower left central incisor area. Von Mises stresses and mandibular displacement were calculated as outcome measurements during loadings. RESULTS: Maximum stress and strain within the reconstructed mandible were identified at the posterior border of the graft and the contralateral condyle. Maximum displacement occurred near the interface of fibular graft and anterior segment of the mandible. Stress distribution in the graft under functional loads is much higher than that in the residual mandibular segments from Models II to IV. The combined average maximum stress from anterior and posterior loads is 10.66 times higher in the mandible with inferiorly positioned graft (Model IV), 8.72 times for superior graft (Model II), and 3.68 times for intermediate graft (Model III) than that in the control group (Model I). The worst displacement result during functional loadings was in the group with fibular graft located at the inferior border of the mandible. CONCLUSIONS: The position of fibular graft placed in the surgical resection site has significant effects on the mechanical behavior of the reconstructed mandible. The fibular graft aligned with the inferior border of the mandible, the most common site designated location by clinicians, has the worst effects on the stress distribution and displacement to the mandibular under functional loads. The fibular graft placed at the intermediate location has the best biomechanics and provides favorable condition for subsequent prosthetic reconstruction.

T cell-intrinsic TLR2 stimulation promotes IL-10 expression and suppressive activity by CD45RbHi T cells.

While Toll-like receptors (TLRs) represent one of the best characterized innate immune pathways, evidence suggests that TLRs are not restricted to innate leukocytes and some epithelial cells, but are also expressed in T cells. Specifically, published evidence focusing on FoxP3+ regulatory T cells demonstrate that they express functional TLR2, which is already known among the TLR family for its association with immune suppression; however, little is known about the relationship between T cell-intrinsic TLR2 binding and cytokine production, T cell differentiation, or T cell receptor (TCR) stimulation. Here, we demonstrate that TCR and TLR2 co-stimulation provides a T cell-intrinsic signal which generates a dramatic, synergistic cytokine response dominated by IL-10. Importantly, the response was not seen in either CD4+CD25+ or CD4+FoxP3+ Tregs, yet resulted in the expansion of a suppressive CD4+CD25+CD62L-CD44+CD45Rbhi effector/memory T cell subset not typically associated with immune inhibition. This study reveals the striking ability of a prototypical innate immune receptor to trigger a potent and suppressive IL-10 response in effector/memory T cells, supporting the notion that TLR2 is a co-regulatory receptor on T cells.

Innate immune-directed NF-κB signaling requires site-specific NEMO ubiquitination.

While the I kappa kinase (IKK) scaffolding protein NF-κB essential modulator (NEMO) binds to polyubiquitin chains to transmit inflammatory signals, NEMO itself is also ubiquitinated in response to a variety of inflammatory agonists. Although there have been hints that polyubiquitination of NEMO is essential for avoiding inflammatory disorders, the in vivo physiologic role of NEMO ubiquitination is unknown. In this work, we knock in a NEMO allele in which two major inflammatory agonist-induced ubiquitination sites cannot be ubiquitinated. We show that mice with a nonubiquitinatable NEMO allele display embryonic lethality. Heterozygous females develop inflammatory skin lesions, decreased B cell numbers, and hypercellular spleens. Embryonic lethality can be complemented by mating onto a TNFR1(-/-) background, at the cost of severe steatohepatitis and early mortality, and we also show that NEMO ubiquitination is required for optimal innate immune signaling responses. These findings suggest that NEMO ubiquitination is crucial for NF-κB activity in response to innate immune agonists.

RIP2 activity in inflammatory disease and implications for novel therapeutics.

The role of NOD2 and RIP2 in inflammatory disease has been paradoxical. Whereas loss-of-function NOD2 polymorphisms cause CD, a granulomatous disease of the gastrointestinal tract, gain-of-function mutations cause EOS-a granulomatous disease primarily affecting the skin, joints, and eyes. Thus, gain-of-function mutations and loss-of-function polymorphisms cause granulomatous inflammatory disease, only in different anatomic locations. The situation is complicated further by the fact that WT NOD2 and WT RIP2 activity has been implicated in diseases such as asthma, inflammatory arthritis and MS. This article reviews the role that the NOD2:RIP2 complex plays in inflammatory disease, with an emphasis on the inhibition of this signaling pathway as a novel pharmaceutical target in inflammatory disease.

Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels.

Carvacrol, eugenol and thymol are major components of plants such as oregano, savory, clove and thyme. When applied to the tongue, these flavors elicit a warm sensation. They are also known to be skin sensitizers and allergens. The transient receptor potential channel (TRPV3) is a warm-sensitive Ca2+-permeable cation channel highly expressed in the skin, tongue and nose. Here we show that TRPV3 is strongly activated and sensitized by carvacrol, thymol and eugenol. Tongue and skin epithelial cells respond to carvacrol and eugenol with an increase in intracellular Ca2+ levels. We also show that this TRPV3 activity is strongly potentiated by phospholipase C-linked, G protein-coupled receptor stimulation. In addition, carvacrol activates and rapidly desensitizes TRPA1, which may explain the pungency of oregano. Our results support a role for temperature-sensitive TRP channels in chemesthesis in oral and nasal epithelium and suggest that TRPV3 may be a molecular target of plant-derived skin sensitizers.