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Objective： This review aimed to provide a current recommendation to multidisciplinary physicians for early detection, diagnosis, and treatment of corticosteroid-induced osteonecrosis of the femoral head （ONFH） based on a comprehensive analysis of the clinical literature. Data Sources： For the purpose of collecting potentially eligible articles, we searched for articles in the PubMed, Cochrane Library, Embase, and CNKI databases up to February 2017, using the following key words： ＆quot;corticosteroid＆quot;, ＆quot;osteonecrosis of the femoral head＆quot;,＆quot;risk factors＆quot;, ＆quot;diagnosis＆quot;, ＆quot;prognosis＆quot;, and ＆quot;treatment＆quot;. Study Selection： Articles on relationships between corticosteroid and ONFH were selected for this review. Articles on the diagnosis, prognosis, and intervention of earlier-stage ONFH were also reviewed. Results： The incidence of corticosteroid-induced ONFH was associated with high doses of corticosteroids, and underlying diseases in certain predisposed individuals mainly occurred in the first 3 months of corticosteroid prescription. The enhanced awareness and minimized exposure to the established risk factors and earlier definitive diagnosis are essential for the success of joint preservation. When following up patients with ONFH, treatment should be started if necessary. Surgical treatment yielded better results than conservative therapy in earlier-stage ONFH. The ideal purpose of earlier intervention and treatment is permanent preservation of the femoral head without physical restrictions in daily living. Conclusions： Clinicians should enhance their precaution awareness of corticosteroid-induced ONFH. For high-risk patients, regular follow-up is very important in the 1st year after high-dose prescription of corticosteroids. Patients with suspected ONFH should be referred to orthopedists for diagnosis and treatment in its earlier stage to preserve the joint.

Objective: To propose a new definition of the pericollapse stage of osteonecrosis of the femoral head (ONFH) and review its significance in disease diagnosis and treatment selection. Data Sources: A search for eligible studies was conducted in three electronic databases including PubMed, Cochrane Library, and Embase up to August 10, 2018, using the following keywords: \"osteonecrosis\", \"prognosis\", and \"treatment\". Study Selection: Investigations appraising the clinical signs, symptoms, and imaging manifestations in different stages of ONFH were included. Articles evaluating the prognosis of various joint-preserving procedures were also reviewed. Results: The pericollapse stage refers to a continuous period in the development of ONFH from the occurrence of subchondral fracture to early collapse (<2 mm), possessing specific imaging features that mainly consist of bone marrow edema and joint effusion on magnetic resonance imaging (MRI), crescent signs on X-ray films, and clinical manifestations such as the sudden worsening of hip pain. Accumulating evidence has indicated that these findings may be secondary to the changes after subchondral fractures. Of note, computed tomography provides more information for identifying possible subchondral fractures than does MRI and serves as the most sensitive tool for grading the pericollapse lesion stage. The pericollapse stage may indicate a high possibility of progressive disease but also demonstrates satisfactory long- and medium-term outcomes for joint-preserving techniques. In fact, if the articular surface subsides more than 2 mm, total hip arthroplasty is preferable. Conclusions: The pericollapse stage with distinct clinical and imaging characteristics provides a last good opportunity for the use of joint-preserving techniques. It is necessary to separate the pericollapse stage as an independent state in evaluating the natural progression of ONFH and selecting an appropriate treatment regimen.

Diabetes mellitus (DM)-induced brain damage is characterized by cellular, molecular and functional changes. The mechanisms include oxidative stress, neuroinflammation, reduction of neurotrophic factors, insulin resistance, excessive amyloid beta (Aβ) deposition and Tau phosphorylation. Both antidiabetic and neuroprotective effects of the phytoestrogen genistein have been reported. However, the beneficial effect of genistein in brain of the ob/ob mouse model of severe obesity and diabetes remains to be determined. In this study, female ob/ob mice and lean control mice were fed with either a standard diet or a diet containing genistein (600mg/kg) for a period of 4 weeks. Body weight was monitored weekly. Blood was collected for the measurement of glucose, insulin and common cytokines. Mice brains were isolated for Western immunoblotting analyses. Treatment with genistein reduced weight gain of ob/ob mice and decreased hyperglycemia compared to ob/ob mice fed the standard diet. The main findings show that genistein treatment increased insulin sensitivity and the expression levels of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factors (BDNF). In these mice, genistein also reduced Aβ deposition and the level of hyper-phosphorylated Tau protein. The results of our study indicate the beneficial effects of genistein in the obese diabetic mouse brain, including improving brain insulin signaling, increasing neurotrophic support, and alleviating Alzheimer's disease-related pathology.

Background： The lateral pillar of the femoral head is an important site for disease development such as osteonecrosis of the femoral head. The femoral head consists of medial, central, and lateral pillars. This study aimed to determine the biomechanical effects of early osteonecrosis in pillars of the femoral head via a finite element （FE） analysis. Methods： A three-dimensional FE model of the intact hip joint was constructed from the image data of a healthy control. Further, a set of six early osteonecrosis models was developed based on the three-pillar classification. The von Mises stress and surface displacements were calculated for all models. Results： The peak values of von Mises stress in the cortical and cancellous bones of normal model were 6.41 MPa and 0.49 MPa, respectively. In models with necrotic lesions in the cortical and cancellous bones, the von Mises stress and displacement of lateral pillar showed significant variability： the stress of cortical bone decreased from 6.41 MPa to 1.51 MPa （76.0% reduction）, while cancellous bone showed an increase from 0.49 MPa to 1.28 MPa （159.0% increase）; surface displacements of cortical and cancellous bones increased from 52.4 μm and 52.1 μm to 67.9 μm （29.5%） and 61.9 μm （18.8%）, respectively. In addition, osteonecrosis affected not only pillars but also adjacent structures in terms of the von Mises stress and surface displacement levels. Conclusions： This study suggested that the early-stage necrosis in the femoral head could increase the risk of collapse, especially in lateral pillar. On the other hand, the cortical part of lateral pillar was found to be the main biomechanical support of femoral head.

Background: Systemic administration of bisphosphonates has shown promising results in the treatment of osteonecrosis of the femoral head (ONFH). However, few studies have evaluated the efficacy of local zoledronate (ZOL) administration in the treatment of ONFH. The purpose of this study was to investigate whether local administration of bisphosphonate-soaked hydroxyapatite (HA) could improve bone healing in an experimental rabbit model of ONFH. Methods: This experimental study was conducted between October 2014 and June 2015. Forty-five rabbits underwent simulated ONFH surgery. Immediately following surgery, they were divided into three groups: model (untreated, n = 15), HA (treated with HA alone, n = 15), and HA + ZOL (treated with HA soaked in a low-dose ZOL solution, n = 15). Histological, immunohistochemical, and quantitative analyses were performed to evaluate bone formation and resorption 2, 4, and 8 weeks after surgery. Results: Gross bone matrix and hematopoietic tissue formation were observed in the HA + ZOL group 4 weeks after surgery. The immunohistochemical staining intensities for 5-bromodeoxyuridine, runt-related transcription factor 2, osteocalcin, osteopontin, and osteoprotegerin were significantly higher in the HA + ZOL group than that in the model (P < 0.001, P< 0.001, P< 0.001, P< 0.001, and P = 0.018, respectively) and HA groups (P = 0.003, P = 0.049, P< 0.001, P = 0.020, and P = 0.019, respectively), whereas receptor activator of the nuclear factor-κB ligand staining intensity was significantly lower in the HA + ZOL group than that in the model and HA groups (P = 0.029 and P = 0.015, respectively) 4 weeks after surgery. No significant differences in bone formation or bone resorption marker expression were found between the three groups 2 or 8 weeks after surgery (P > 0.05). Conclusions: Local administration of HA soaked in a low-dose ZOL solution increased new bone formation while inhibiting bone resorption in an animal model of ONFH, which might provide new evidence for joint-preserving surgery in the treatment of ONFH.

BackgroundSince self-limited repair ability of the necrotic lesion may be a cause for failure of the technique, the possibility has been raised that bone marrow mononuclear cells (BMMCs) containing BMSCs implanted into a necrotic lesion of the femoral head with core decompression (CD) may be of benefit in the treatment of this condition. For this reason, we studied the implantation of the concentrated autologous bone marrow containing mononuclear cells in necrotic lesion of the femoral head to determine the effect of the method.MethodsThe study included 45 patients (59 hips, 9 females, 36 males; mean age 37.5 years, range 16–56 years) with stages I–IIIA nontraumatic avascular necrosis of the femoral head according to the system of the Association Research Circulation Osseous. Concentrated bone marrow (30–50 ml) containing mononuclear cells has been gained from autologous bone marrow (100–180 ml) obtained from the iliac crest of patient with the cell processor system. Concentrated bone marrow was injected through a CD channel into the femoral head. The outcome was determined by the changes in the Harris hip score, by progression in radiographic stages, and by the need for hip replacement. The mean follow-up was 27.6 months (range 12–40 months).ResultsPre- and post-operative evaluations showed that the mean Harris hip score increased from 71 to 83. Clinically, the overall success is 79.7%, and hip replacement was done in 7 of the 59 hips (11.9%). Radiologically, 14 of the 59 hips exhibited femoral head collapse or narrowing of the coxofemoral joint space, and the overall failure rate is 23.7%. The number of BMMCs increased from 12.2 ± 3.2 × 106/ml to 35.2 ± 12 × 106/ml between pre-concentration and post-concentration.ConclusionThe concentrated autologous bone marrow containing mononuclear cells implantation relieves hip pain, prevents the progression of osteonecrosis. Therefore, it may be the treatment of choice particularly in stages I–II nontraumatic osteonecrosis of the femoral head.

Objective This study aimed to analyze the clinical factors related to the failure of autologous bone marrow mononuclear cells grafting (BMMCG) following core decompression (CD) in early stage osteonecrosis of the femoral head (ONFH). Methods In total, 148 patients (192 hips) underwent CD with autologous BMMCG for treatment of non-traumatic ONFH. The patients were classified by their ARCO staging and China-Japan Friendship Hospital (CJFH) typing system. All patients were clinically and radiographically followed up every three months during the first year and every six months in the following years. The clinical evaluation was conducted by pre- and post-operative Harris hip scores (HHS), while serial anteroposterior (AP) and frog lateral radiographs were used for post-operative radiographic evaluation. Results There were 56 hips as clinical failure cases, and 50 hips (89.29%) of failure cases developed between three and ten months after operation. Based on CJFH classification system, type L2 showed more failure rate with 60.0% (9 of15). The Cox risk model showed that disease type was an independent risk factor for post-operative clinical failure ( P  = 0.042). Multivariate analysis of the Cox proportional-hazards model showed that type L1 had a hazard ratio (HR) of 0.286 (95% CI 0.100–0.816), type L3 with HR of 0.245 (95% CI 0.079–0.759), respectively. Conclusion Disease type is an important risk factor for autologous BMMCG combined with CD, and the degree of lateral pillar necrosis is a significant reference index for prognosis evaluation in early stage of ONFH.

The abnormal initiation of autophagy flux in neurons after ischemic stroke caused dysfunction of autophagy-lysosome, which not only led to autophagy flux blockage, but also resulted in autophagic death of neurons. However, the pathological mechanism of neuronal autophagy-lysosome dysfunction did not form a unified viewpoint until now. In this review, taking the autophagy lysosomal dysfunction of neurons as a starting point, we summarized the molecular mechanisms that led to neuronal autophagy lysosomal dysfunction after ischemic stroke, which would provide theoretical basis for the clinical treatment of ischemic stroke. Graphical Abstract

Intravascular-thrombosis and extravascular-lipid-deposit are the two key pathogenic events considered to interrupt intraosseous blood supply during development of steroid-associated osteonecrosis (ON). However, there are no clinically employed agents capable of simultaneously targeting these two key pathogenic events. The present experimental study demonstrated that constitutional flavonoid glycosides derived from herb Epimedium (EF, composed of seven flavonoid compounds with common stem nuclear) exerted dose-dependent effect on inhibition of both thrombosis and lipid-deposition and accordingly reducing incidence of steroid-associated ON in rabbits, which was not via direct action by themselves rather by their common metabolite on potential cellular targets involved in the two pathogenic pathways. The underlying mechanism could be explained by counteracting endothelium injury and excessive adipogenesis. These findings encourage designing clinical trials to investigate potential of EF in prevention of steroid-associated ON.