Non-invasive characterization of fracture callus structure and composition may facilitate development of surrogate measures of the regain of mechanical function. As such, quantitative computed tomography- (CT-) based analyses of fracture calluses could enable more reliable clinical assessments of bone healing. Although previous studies have used CT to quantify and predict fracture healing, it is unclear which of the many CT-derived metrics of callus structure and composition are the most predictive of callus mechanical properties. The goal of this study was to identify the changes in fracture callus structure and composition that occur over time and that are most closely related to the regain of mechanical function. Micro-computed tomography (μCT) imaging and torsion testing were performed on murine fracture calluses (n=188) at multiple post-fracture timepoints and under different experimental conditions that alter fracture healing. Total callus volume (TV), mineralized callus volume (BV), callus mineralized volume fraction (BV/TV), bone mineral content (BMC), tissue mineral density (TMD), standard deviation of mineral density (σTMD), effective polar moment of inertia (Jeff), torsional strength, and torsional rigidity were quantified. Multivariate statistical analyses, including multivariate analysis of variance, principal components analysis, and stepwise regression were used to identify differences in callus structure and composition among experimental groups and to determine which of the μCT outcome measures were the strongest predictors of mechanical properties. Although calluses varied greatly in the absolute and relative amounts of mineralized tissue (BV, BMC, and BV/TV), differences among timepoints were most strongly associated with changes in tissue mineral density. Torsional strength and rigidity were dependent on mineral density as well as the amount of mineralized tissue: TMD, BV, and σTMD explained 62% of the variation in torsional strength (p<0.001); and TMD, BMC, BV/TV, and σTMD explained 70% of the variation in torsional rigidity (p<0.001). These results indicate that fracture callus mechanical properties can be predicted by several μCT-derived measures of callus structure and composition. These findings form the basis for developing non-invasive assessments of fracture healing and for identifying biological and biomechanical mechanisms that lead to impaired or enhanced healing.

Eosinophils are important in the pathogenesis of many diseases, including asthma, eosinophilic esophagitis, and eczema. While IL-5 is crucial for supporting mature eosinophils, the signals that support earlier eosinophil lineage events are less defined. The IL-33 receptor, ST2, is expressed on several inflammatory cells, including eosinophils, and is best characterized for its role during the initiation of allergic responses in peripheral tissues. Recently, ST2 expression was described on hematopoietic progenitor subsets, where its function remains controversial. Our findings demonstrate that IL-33 is required for basal eosinophil homeostasis, since both IL-33– and ST2-deficient mice exhibited diminished peripheral blood eosinophil numbers at baseline. Exogenous IL-33 administration increased mature eosinophils in both the bone marrow and periphery in WT and IL-33–deficient, but not ST2-deficient, mice. Systemic IL-5 was also increased under this treatment, and blocking IL-5 with a neutralizing antibody ablated of the IL-33-induced mature eosinophil expansion. The homeostatic hypereosinophilia seen in IL-5–transgenic mice was significantly lower with ST2 deficiency despite similar elevations in systemic IL-5. Finally, in vitro treatment of bone marrow cells with IL-33, but not IL-5, led to specific early expansion of IL-5Rα–expressing precursor cells. In summary, our findings establish a basal defect in eosinophilopoiesis in IL-33– and ST2-deficient mice and a mechanism whereby IL-33 supports mature eosinophils by driving both systemic IL-5 production and the expansion of IL-5Rα–expressing precursor cells.

Food allergies represent an increasingly prevalent human health problem and therapeutic options remain limited, with avoidance being mainstay despite its adverse effects on quality of life. A better understanding of the key immunological mechanisms involved in such responses will likely be vital for development of new therapies. This review outlines the current understanding of how the immune system is thought to contribute to prevention or development of food allergies. Drawing from animal studies as well as clinical data when available, the importance of oral tolerance in sustaining immunological non-responsiveness to food antigens, our current understanding of why oral tolerance may fail and sensitization may occur, as well as the knowledge of pathways that may lead to anaphylaxis and food allergy–associated responses are addressed.

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Defining how mechanical cues regulate tissue differentiation during skeletal healing can benefit treatment of orthopaedic injuries and may also provide insight into the influence of the mechanical environment on skeletal development. Different global (i.e., organ-level) mechanical loads applied to bone fractures or osteotomies are known to result in different healing outcomes. However, the local stimuli that promote formation of different skeletal tissues have yet to be established. Finite element analyses can estimate local stresses and strains but require many assumptions regarding tissue material properties and boundary conditions. This study used an experimental approach to investigate relationships between the strains experienced by tissues in a mechanically stimulated osteotomy gap and the patterns of tissue differentiation that occur during healing. Strains induced by the applied, global mechanical loads were quantified on the mid-sagittal plane of the callus using digital image correlation. Strain fields were then compared to the distribution of tissue phenotypes, as quantified by histomorphometry, using logistic regression. Significant and consistent associations were found between the strains experienced by a region of the callus and the tissue type present in that region. Specifically, the probability of encountering cartilage increased, and that of encountering woven bone decreased, with increasing octahedral shear strain and, to a lesser extent, maximum principal strain. Volumetric strain was the least consistent predictor of tissue type, although towards the end of the four-week stimulation timecourse, cartilage was associated with increasingly negative volumetric strains. These results indicate that shear strain may be an important regulator of tissue fate during skeletal healing.