Billeknudsen2516

). No differences were found for the sagittal plane hip, knee, and ankle angles. CONCLUSION The ACLR limb experienced lower peak PFJ loads during running, explained by a small anterior shift in the foot-ground center of pressure during stance that offloaded the torque demand away from the ACLR knee. CLINICAL RELEVANCE Lower net PFJ loading during running in the ACLR limb more than 12 months after ACLR suggests that underloading might play a role in the onset of PFJ osteoarthritis after ACLR.Cyclic guanosine monophosphate (cGMP) signaling is an important regulator of newborn lung function and development. Although cGMP signaling is decreased in many models of newborn lung injury, the mechanisms are poorly understood. We determined how IL-1β regulates the expression of the α1-subunit of soluble guanylate cyclase (sGCα1), a prime effector of pulmonary cGMP signaling. Physiologic levels of IL-1β were discovered to rapidly decrease sGCα1 mRNA expression in a human fetal lung fibroblast cell line (IMR-90 cells) and protein levels in primary mouse pup lung fibroblasts. This sGCα1 expression inhibition appeared to be at a transcriptional level; IL-1β treatment did not alter sGCα1 mRNA stability although it reduced sGCα1 promoter activity. TGFβ-activated kinase 1 (TAK1) was determined to be required for IL-1β's regulation of sGCα1 expression; TAK1 knockdown protected sGCα1 mRNA expression in IL-1β-treated IMR-90 cells. Moreover, heterologously expressed TAK1 was sufficient to decrease sGCα1 mRNA levels in those cells. Nuclear factor-kappaB (NF-κB) signaling played a critical role in the IL-1β-TAK1-sGCα1 regulatory pathway; chromatin immunoprecipitation studies demonstrated enhanced activated NF-kB subunit (RelA) binding to the sGCα1 promoter after IL-1β treatment unless were treated with an IκB kinase2 inhibitor. Also, this NF-kB signaling inhibition protected sGCα1 expression in IL-1β-treated fibroblasts. Lastly, using transgenic mice in which active IL-1β was conditionally expressed in lung epithelial cells, we established that IL-1β expression is sufficient to stimulate TAK1 and decrease sGCα1 protein expression in the newborn lung. Together these results detail the role and mechanisms by which IL-1β inhibits cGMP signaling in the newborn lung.RATIONALE Structural changes to airway morphology such as increased bronchial wall thickness (BWT) and airway wall area are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis. OBJECTIVES Develop a µCT method for evaluating structural changes to the airways in ferrets, and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans. METHODS Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 months. µCT was conducted in vivo at 6 months; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWTLD ratio were conducted, and confirmed by a semi-automated algorithm. The square root of bronchial wall area (WA) vs. luminal perimeter was determined on an individual ferret basis. MEASUREMENTS AND MAIN RESULTS Smoke exposed ferrets reproducibly demonstrated 34% increased BWT (P less then 0.001); along with increased LD, and BWTLD ratio vs. air controls. Regression indicated the effect of smoking on BWT persisted despite controlling for covariates. Semi-automated measurements replicated findings. WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke exposed ferrets (P=0.015). Increased BWT and Pi4 developed steadily over time. CONCLUSIONS µCT-based airway measurements in ferrets are feasible and reproducible. Smoke exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. µCT can be used as a significant translational platform to measure dynamic airway morphological changes.SPOCK2 was previously associated with genetic susceptibility to bronchopulmonary dysplasia in a French population of very preterm neonates. Its expression increases during lung development and is increased after exposure of rat pups to hyperoxia as compared to controls bred in room air. To further investigate the role of SPOCK2 during lung development, we designed two mouse models, one that uses a specific anti-Spock2 antibody and one that reproduces the hyperoxia-induced Spock2 expression with a transgenic mouse model resulting in a conditional and lung-targeted over-expression of Spock2. When mice were bred under hyperoxic conditions, treatment with anti-Spock2 antibodies significantly improved alveolarization. Lung over-expression of Spock2 altered alveolar development in pups bred in room air and worsened hyperoxia-induced lesions. Neither treatment with anti-Spock2 antibody, nor over-expression of Spock2 were associated to abnormal activation of mmp2. These two models did not alter the expression of known players in alveolar development. This study brings strong arguments for the deleterious role of SPOCK2 on lung alveolar development especially after lung injury, suggesting its role in BPD susceptibility. These effects are not mediated by a deregulation in metalloproteases activity and in expression of factors essential to normal alveolarization. The balance between type 1 and 2 epithelial alveolar cells may be involved.OBJECTIVE. Cartilage loss on preoperative knee MRI is a predictor of poor outcomes after arthroscopic partial meniscectomy. The purpose of this study was to compare the ability to predict outcomes after arthroscopic partial meniscectomy with a clinically used modified Outerbridge system versus a semiquantitative MRI Osteoarthritis Knee Score system for grading cartilage loss. MATERIALS AND METHODS. Patients who underwent preoperative knee MRI within 6 months of arthroscopic partial meniscectomy and who had outcomes available from the time of surgery and 1 year later were eligible for inclusion. Cases were evaluated by two radiologists and one radiology fellow with the use of both grading systems. The accuracy of each system in discriminating between surgical success and failure was estimated using the ROC curve (AUC) with 95% CIs. Varoglutamstat A Wald test was used to assess noninferiority of the clinical grading system. Interreader agreement regarding the accuracy of the grading systems in predicting outcomes was also compared.