Src blockage by siRNA inhibits VEGF-induced vascular hyperpemeability and osteoclast activity – an in vitro mechanism study for preventing destructive repair of osteonecrosis

IntroductionDestructive repair is the pathological feature of ONFH characterized with the elevated vascular permeability and persistent bone resorption, which is associated with higher VEGF expression, activated c-Src, and vascular leakage. Activated c-Src also participates in mediating endothelial permeability and osteoclasts activity. However, the molecular mechanism of the VEGF and c-Src contributing to the destructive repair process remains unknown. The purpose of this study is to delineate the role of VEGF and c-Src in triggering destructive repair of osteonecrosis in vitro, as well as to elucidate if VEGF mediating vascular permeability and osteoclastic bone resorption are Src dependent.MethodsWe employed pharmacological VEGF to induce higher endothelial permeability and osteoclasts activity for simulating related pathological features of destructive repair in vitro. Src specific pp60^c-srcsiRNA was used for determining the contribution of VEGF and Src to destructive repair. The primary endothelial cells and osteoclasts were treated with 50 ng/ml VEGF and/or transfected with the pp60^c-srcsiRNA, while equivalent PBS and non-targeting siRNA were treated in the control groups.ResultsVEGF enhanced Src bioactivity through promoting dephosphorylation of Src at Y527 and phosphorylation of Src at Y416. Meanwhile, Src specific pp60^c-srcsiRNA significantly reduced Src expression in both cells. VEGF destroyed the junctional integrity of endothelial cells resulting in higher endothelial permeability. However, Src blockade significantly relieved VEGF induced actin stress and inhibited caveolae and VVOs formation, meanwhile further stabilized the complex β-catenin/VE-cadherin/Flk-1 through decreasing phosphorylation of VE-cadherin, ultimately decreasing VEGF-mediating higher vascular permeability. In addition, VEGF promoted osteoclasts formation and function without affecting the adhesion activity and cytoskeleton. We further found that Src blockade significantly impaired cytoskeleton resulting in a lower adhesion activity through down-regulation of phosphorylation of Src, Pyk2 and Cbl, and ultimately inhibited osteoclasts formation and function.ConclusionsThese findings provide a new insight into VEGF and c-Src mode of reaction in triggering destructive repair of osteonecrosis and further indicate that VEGF mediating vascular permeability and osteoclasts activity are Src-dependent. Blockade of Src may have great potential as an effective therapy targeting destructive repair in osteonecrosis.     

Regional differences in prolonged non-operative therapy utilization prior to primary ACDF surgery

There is a paucity of data characterizing regional variations in the utilization and costs of conservative management in patients suffering from cervical stenosis prior to anterior cervical discectomy and fusion (ACDF) surgery. An understating of these regional trends becomes critical as outcomes-based reimbursement strategies become standard. The objective of this investigation was to evaluate for regional differences in the utilization and overall costs of maximal non-operative therapy (MNT) prior to ACDF surgery. Medical records from patients with symptomatic cervical stenosis undergoing a ≤3-level index ACDF procedure between 2007 and 2016 were accessed from a large insurance database. Geographic regions (Midwest, Northeast, South, and West) reflected U.S. Census Bureau definitions. MNT utilization within 2-years prior to ACDF surgery was analyzed. An index ACDF surgery was performed in 15,825 patients. Patient regional breakdown was as follows: South (67.6% of patients), Midwest (21.8% of patients), West (8.9% of patients), Northeast (1.6% of patients). Regional variations were identified in the number of patients utilizing NSAIDs (p < 0.001), opioids (p < 0.001), muscle relaxants (p < 0.001), cervical epidural steroid injections (p = 0.001), physical therapy/occupational therapy treatments (p < 0.001), and chiropractor visits (p < 0.001). The West (64.5%) and South (63.5%) had the greatest proportion of patients utilizing narcotics. When normalized by the number of opioid using-patients however, the Northeast (691.4 pills/patient) and South (674.4 pills/patient) billed for the most opioid pills. The total direct cost associated with all MNT prior to index ACDF was $17,255,828. The Midwest ($1,277.72 per patient) and South ($1,047.86 per patient) had the greatest average dollars billed.     

A functional and bilateral ischiofemoral impingement with muscular hypertrophy in an 11-year-old dancer

Ischiofemoral impingement syndrome (IFIS) is an unusual cause of hip pain. Certain strenuous sports can cause this impingement, such as dancing. We report the case of an 11-year-old ballet dancer with bilateral IFIS secondary to overtraining and hypertrophy of the quadratus femoris. This syndrome is frequently evoked in the field of orthopedics following hip replacement. Bilateral IFIS is rare and should be sought in the context of an intense sport such as dance when any other cause has been eliminated.     

Chin-on-Chest in Neck of Femur Fracture (COCNOF) sign: A simple radiographic predictor of frailty and mortality in hip fracture patients

IntroductionFragility fractures are a significant public health challenge often occurring as a result of frailty. Identifying patients who have increased risk of adverse outcomes can aid treating teams in managing these patients appropriately. We hypothesise that the appearance of the patient's head overlapping the lung fields (named Chin on Chest in Neck of Femur sign (COCNOF)) in the admission chest radiograph was a predictor of increased mortality at 3, 6 and 12 months.MethodsAll consecutive patients admitted with hip fracture between 1^st January – 31st December 2019 were analysed. We collected patient characteristics, AMTS score, ASA grade, length of stay, place of discharge, Nottingham Hip Fracture Score, Rockwood Frailty score, Charlson Comorbidity Index and presence of COCNOF sign. The main outcome measures were mortality at 90 days, six months and 12 months following admission.Results469 patients with a mean age of 81.9 (SD 8.4) were included. 18% of patients were COCNOF positive. Univariate analysis showed positive COCNOF sign to be associated with higher mortality at 90 days (19.1 vs 10.8%; RR 1.95, 95%CI 1.05 – 3.63,p=0.03), six months (31.5% vs 14.2%; RR 2.77, 95%CI 1.62 – 4.72, p<0.001) and twelve months (41.6% vs 17.1%; RR 3.45, 95%CI 1.62-4.72, p<0.001). In the multivariate regression models the strongest predictors of mortality were age, gender and CCI it is therefore likely that the COCNOF sign is acting as a surrogate marker of these variables within the univariate models.ConclusionOur results suggest that COCNOF sign is a simple radiographic marker which can be used to identify patients with higher levels of frailty and increased risk of mortality following hip fracture.     

Curved versus straight-cut hinges for open-door laminoplasty: A finite element and biomechanical study

In this study, the stabilities of the hinge sides of plate-augmented open-door laminoplasties based on cutting in a curved or straight line were compared using a finite element (FE) model and an experimental assessment. Using FE models generated from CT scans of a human subject, straight and curved techniques for cutting the hinge side were evaluated. Compressive forces were applied to both simulated models, and the stress distributions on the respective hinge sites were evaluated by comparing the maximum von Mises stresses. Biomechanical testing procedures were then carried out on porcine cervical vertebrae, with straight- and curved-cut groups loaded to failure, and the corresponding reaction forces on the hinge sites were recorded using a loading cell. The FE analysis results revealed no significant differences between the straight- and curved-cut groups in terms of maximum stress forces on the superior, middle, or inferior portions of the hinge sites. In the experimental study, the curved-cut group withstood higher loads to failure at the hinge site than the straight-cut group. The ability of the curved-cut laminoplasty hinges to withstand higher compressive loading to failure than straight-cut hinges suggests the potential of the proposed technique to reduce the risk of hinge fracture and displacement.