Atypical hypoadrenocorticism in a Birman cat.

A 1-year-old female spayed Birman cat was presented with a history of inappropriate urination and defecation, lethargy, anorexia, and weight loss. After intermittent responses to non-specific therapy she was diagnosed with atypical hypoadrenocorticism from the results of an adrenocorticotropic hormone stimulation test.

Direct gene therapy for bone regeneration: gene delivery, animal models, and outcome measures.

While various problems with bone healing remain, the greatest clinical change is the absence of an effective approach to manage large segmental defects in limbs and craniofacial bones caused by trauma or cancer. Thus, nontraditional forms of medicine, such as gene therapy, have been investigated as a potential solution. The use of osteogenic genes has shown great potential in bone regeneration and fracture healing. Several methods for gene delivery to the fracture site have been described. The majority of them include a cellular component as the carrying vector, an approach known as cell-mediated gene therapy. Yet, the complexity involved with cell isolation and culture emphasizes the advantages of direct gene delivery as an alternative strategy. Here we review the various approaches of direct gene delivery for bone repair, the choice of animal models, and the various outcome measures required to evaluate the efficiency and safety of each technique. Special emphasis is given to noninvasive, quantitative, in vivo monitoring of gene expression and biodistribution in live animals. Research efforts should aim at inducing a transient, localized osteogenic gene expression within a fracture site to generate an effective therapeutic approach that would eventually lead to clinical use.

Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT.

Aseptic loosening of total joint replacements is caused by wear debris-induced osteoclastic bone resorption, for which bisphosphonates (BPs) and RANK antagonists have been developed. Although BPs are effective in preventing metabolic bone loss, they are less effective for inflammatory bone loss. Because this difference has been attributed to the antiapoptotic inflammatory signals that protect osteoclasts from BP-induced apoptosis, but not RANK antagonists, we tested the hypothesis that osteoprotegerin (OPG) is more effective in preventing wear debris-induced osteolysis than zoledronic acid (ZA) or alendronate (Aln) in the murine calvaria model using in vivo micro-CT and traditional histology. Although micro-CT proved to be incompatible with titanium (Ti) particles, we were able to demonstrate a 3.2-fold increase in osteolytic volume over 10 days induced by polyethylene (PE) particles versus sham controls (0.49 +/- 0.23 mm(3) versus 0.15 +/- 0.067 mm(3); p < 0.01). Although OPG and high-dose ZA completely inhibited this PE-induced osteolysis (p < 0.001), pharmacological doses of ZA and Aln were less effective but still reached statistical significance (p < 0.05). Traditional histomorphometry of the sagital suture area of calvaria from both Ti and PE-treated mice confirmed the remarkable suppression of resorption by OPG (p < 0.001) versus the lack of effect by physiological BPs. The differences in drug effects on osteolysis were largely explained by the significant difference in osteoclast numbers observed between OPG versus BPs in both Ti- and PE-treated calvaria; and linear regression analyses that demonstrated a highly significant correlation between osteolysis volume and sagittal suture area versus osteoclast numbers (p < 0.001).

Micro-computed tomography prediction of biomechanical strength in murine structural bone grafts.

Correlating massive bone graft strength to parameters derived from non-invasive imaging is important for pre-clinical and clinical evaluation of therapeutic adjuvants designed to improve graft repair. Towards that end, univariate and multivariate regression between measures of graft and callus geometry from micro-CT imaging and torsional strength and rigidity were investigated in a mouse femoral graft model. Four millimeter mid-diaphyseal defects were grafted with live autografts or processed allografts and allowed to heal for 6, 9, 12, or 18 weeks. We observed that allograft remodeling and incorporation into the host remained severely impaired compared to autografts mainly due to the extent of callus formation around the graft, the rate and extent of the graft resorption, and the degree of union between the graft and host bone as judged by post-mechanical testing analysis of the mode of failure. The autografts displayed greater ultimate torque and torsional rigidity compared to the allografts over time. However the biomechanical properties of allografts were equivalent to autografts by 9 weeks but significantly decreased at 12 and 18 weeks. Multivariate regression analysis demonstrated significant statistical correlations between combinations of the micro-CT parameters (graft and callus volume and cross-sectional polar moment of inertia) with the measured ultimate torque and torsional rigidity (adjusted R(2)=44% and 50%, respectively). The statistical correlations approach used in this mouse study could be useful in guiding future development of non-invasive predictors of the biomechanical properties of allografts using clinical CT.