Clinical and genetic risk factors for glucocorticoid-associated osteonecrosis of the femoral head: a prospective cohort study / 中华骨科杂志

Objective:To perform a prospective cohort study to identify individual susceptibility of glucocorticoid (GC) -associated osteonecrosis of the femoral head (GA-ONFH) and their clinical and genetic risk factors. Methods:The present prospective cohort study enrolled patients who received their first GC therapy between July 2015 and January 2018 at Zhongshan Hospital. All patients did not receive any GC treatment before enrollment. Further, they planned to start GC treatment with the dose (equivalent prednisone) of ≥30 mg/d, lasted ≥3 weeks, or pulse dose ≥200 mg/d, lasted ≥3 d. Blood samples were collected before GC treatment to evaluate bone metabolism and its released factors. Hip MRI was performed at the 1st, 3rd, 6th, 12th and 24th month to diagnose GA-ONFH. All patients were followed-up for ≥2 years. The endpoint was regarded as diagnosis of GA-ONFH or completion of 2 years follow-up. Lasso regression was performed to determine which clinical features were associated with GA-ONFH. A nested case-control sub-cohort (A, n=12) was established prospectively based on the main cohort by 1∶1 matching. Whole exome sequencing was performed to screen differential and functional candidate single nucleotide polymorphisms and insertion-deletions (SNP/InDels). Another sub-cohort (B, n=50) was constructed retrospectively in patients with GA-ONFH and non-ONFH patients received standard high dose GC treatment for more than two years. The candidate SNP/InDels were verified by Sanger sequencing based on the patients from sub-cohort B. Results:A total of 96 patients were enrolled of which 88 of them (32 males and 56 females, mean age 42.30 years) completed follow-up. Eight cases (9.1%) were diagnosed with GA-ONFH. The median time from the start of GC therapy to the diagnosis of ONFH was 53.00(34.00,13.50) days. The baseline characteristics, such as age, sex and body mass index, indicated no significant difference between the ONFH group and the non-ONFH group. The cumulative GC dose of the ONFH patients in the first month was higher than that of non-ONFH [32.74(29.55, 47.05) mg/kg vs. 24.00(21.10, 29.45) mg/kg, Z=-2.410, P=0.016]. However, there was no significant difference of patients who underwent pulse therapy (37.5% vs. 10.0%, adjusted χ 2=2.829, P=0.093). The ratio of serum apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) in patients with ONFH was higher than that in non-ONFH group before GC use [0.95(0.80, 1.50) vs. 0.70(0.60, 0.80), Z=-2.875, P=0.000]. Due to the multicollinearity, Lasso regression model was performed to reduce overfitting. All variables were included in the model. The results suggested that higher ApoB/ApoA1 ratio, lower serum β-c-terminal telopeptide (β-CTX) and higher cumulative GC dose in the first month were the top three risk factors of GA-ONFH. This model had an accuracy of 0.982 in internal validation. Seven differential candidate SNP/InDels were found by whole exome sequencing of sub-cohort A. We further verified these SNP/InDels in sub-cohort B. The patients with COLEC12 mutation (rs2305027, G1816A) were at risk of GA-ONFH ( OR=6.00, 95% CI: 1.17, 30.73). Conclusion:Higher first-month GC dose, lower serum β-CTX level before treatment, higher ApoB/ApoA1 ratio and COLEC12 mutation (rs2305027, G1816A) could increase the risk of GA-ONFH.

Strengthen the training of general practitioner to promote the construction of Healthy China / 中华全科医师杂志

Department of General Medicine in Zhongshan Hospital,Fudan University was founded in 1994,which was the only unit established in a tertiary hospital in the country at that time,engaged in clinical practice,teaching and research of general practice.Zhongshan Hospital won the second prize of National Teaching Achievement in 2014 forExploration and innovation of training system of general practitioners in China,which contributed to development of standardized training system of general practitioners suitable to China's national conditions.This article summarizes the experience in training general physician,development of disciplines and enhancing influence of Zhongshan Hospital over years,hopefully it will be of reference value for medical educators.

Role of circadian gene Clock during differentiation of mouse pluripotent stem cells

Biological rhythms controlled by the circadian clock are absent in embryonic stem cells (ESCs). However, they start to develop during the differentiation of pluripotent ESCs to downstream cells. Conversely, biological rhythms in adult somatic cells disappear when they are reprogrammed into induced pluripotent stem cells (iPSCs). These studies indicated that the development of biological rhythms in ESCs might be closely associated with the maintenance and differentiation of ESCs. The core circadian gene Clock is essential for regulation of biological rhythms. Its role in the development of biological rhythms of ESCs is totally unknown. Here, we used CRISPR/CAS9-mediated genetic editing techniques, to completely knock out the Clock expression in mouse ESCs. By AP, teratoma formation, quantitative real-time PCR and Immunofluorescent staining, we did not find any difference between Clock knockout mESCs and wild type mESCs in morphology and pluripotent capability under the pluripotent state. In brief, these data indicated Clock did not influence the maintaining of pluripotent state. However, they exhibited decreased proliferation and increased apoptosis. Furthermore, the biological rhythms failed to develop in Clock knockout mESCs after spontaneous differentiation, which indicated that there was no compensational factor in most peripheral tissues as described in mice models before (DeBruyne et al., 2007b). After spontaneous differentiation, loss of CLOCK protein due to Clock gene silencing induced spontaneous differentiation of mESCs, indicating an exit from the pluripotent state, or its differentiating ability. Our findings indicate that the core circadian gene Clock may be essential during normal mESCs differentiation by regulating mESCs proliferation, apoptosis and activity.

Multi-disciplinarily comprehensive therapy based on femoral head arthroplasty for old femoral neck fracture in the elderly / 中华创伤杂志

Objective To investigate the effect and safety of comprehensive therapy based on femoral head arthroplasty in treating old femoral neck fracture in the elderly complicated with other severe basic medical conditions.Methods Thirty-six elderly patients with old femoral neck fracture were treated with femoral head arthroplasty.Mean age of the patients was 78.2 years, and mean duration since injury was 13.7 months.All the patients had at least one severe basic medical problem.Perioperative complications were retrospectively analyzed, and function of hip joint was evaluated 6 months after operation.Results One patient died because of severe pulmonary infection, while 16 electrolyte imbalance, 7 hypotension, 4 arrhythmia, 2 acute heart failure and 1 acute kidney injury were cured in the rest 35 patients.Harris hip score of the 35 patients increased from (22.0 ± 6.8) points pre-operatively to (69.2 ± 10.8) points 6 months post-operatively (P ＜ 0.01).Conclusions Comprehensive therapy based on femoral head arthroplasty is effective for old femoral neck fracture in the elderly suffering severe underlying diseases.Early treatment, perfect pre-operative preparation, correct manipulation and appropriate perioperative management play important roles.

Modified free vascularized fibular grafting for the osteonecrosis of the femoral head / 中华显微外科杂志

Objective To evaluate the short term results of repairing osteonecrosis of the femoral head by modified free vascularized fibular grafting through Smith-Peterson approach without cutting the rectus femoris.Methods Between January,2009 and September,2012,14 osteonecrotic hips of 14 patients who underwent free vascularized fibular grafting were retrospectively studied including 10 male and 4 female.The follow up period was 24 months.The preoperative and postoperative symptoms relief,recovery of hip function (Harris score),radiographic assessment (X-ray).Results All patients got postoperative ipsilateral hip pain relief.Average Harris hip score improved significantly (68.47 ± 5.33,86.80 ± 4.72 points in preoperation and postoperation,respectively; paired t test,t =18.724,P ＜ 0.01).Postoperative X-ray results showed there were no progresses of osteonecrosis and no collapse in the operative side within 2 years follow-up.Conclusion The short term treatment results of femoral head avascular necrosis were satisfactory by using free vascularized fibular graft through Smith-Peterson approach without cutting off the rectus femoris and it may be a relatively practical option of surgical approach.

Investigation and reflections on the training for residents and specialists / 中华医学教育探索杂志

Talent training is the foundation for discipline construction and it is also the fundamental guarantee of hospital's sustainable development.The affiliated Zhongshan hospital of Fudan university launched investigations from the teaching management,teaching staff,resident and clinical skills to look for problems in clinical teaching and to propose improvement measures aiming at improving the clinical teaching and promoting hospital resident and specialists training.

The expression of type Ⅱ collagen in articular chondrocyte of osteoarthritis / 复旦学报（医学版）

Objective To investigate the expression of type Ⅱ collagen in the articular chondrocyte of osteoarthritis (OA) patients and normal human. Methods The samples of articular cartilage were obtained from the patients undergoing total joint replacement, including 8 primary OA patients, 8 secondary OA patients and 9 normal subjects. Type Ⅱ collagen expression in chondrocyte was detected by reverse transcriptase polymerase chain reaction (RT-PCR). Results The expressin of type Ⅱ collagen mRNA in normal OA group was higher than that in primary OA group and secondary OA group with a statistical difference (P=0.014), while there was no statistical difference between primary OA group and secondary OA group(P=0.716). Conclusions The reduction of type Ⅱ collagen expression leads to the change of collagen directly and possibly plays an important role in OA, which is the common pathway of the occurrence of both the primary and secondary OA.

Theoretical research and clinical application of nerve tissue-engineering release-controlled system / 中国组织工程研究

Although autoallergic neural transplantation Is a gold standard to repair neurologic defect, nerve tissue engineering becomes an ideal replacement due to a limited collection of nerve. Nerve tissue-engineering release-controlled system promotes axonal regeneration via a scaffold to slowly release nerve growth factor and to create a suitable microenvironment for nerve growth. There are various materials and methods for creating nerve tissue-engineering release-controlled system; therefore, choosing a good material and a good method to control nerve growth factor and to cause excellent repairing effect are hot topics for researching nerve tissue-engineering release-controlled system. The aim of this review is to introduce the new methods and technologies applied in the delivery system of nerve growth factors in recent years. This review also attempts to classify the strategies of drug delivery of nerve growth factor in a new way.

Application of extended tibia tubercle osteotomy in revision of total knee arthroplasty / 中华创伤杂志

Objective To study the application of extended tibia tubercle osteotomy in revision of total knee arthroplasty. Methods Retrospective study was carried out in 12 cases that had received extended tibia tubercle osteotomy in Zhongshan Hospital from May 1998 to October 2002. Results After osteotomy, all knees were healed clinically and radiologically at 6th month postoperatively. Average range of joint motion increased from 79 degrees to 95 degrees. Average knee score improved from 60 to 85. Conclusion Extended tibia tubercle osteotomy can improve the exposure of operation and knee joint function.

Modulation of nitric oxide synthase isoenzymes in reperfused skeletal muscle / 中华创伤杂志(英文版)

OBJECTIVE: To investigate the modulation of nitric oxide synthase (NOS) isoenzymes in skeletal muscle during 3 h ischemia/reperfusion (I/R, 3 h ischemia followed by 3 h reperfusion). METHODS: The extensor digitorum longuses (EDLs) from 20 adult rats were divided into 4 groups: the normal, the sham operation, the ischemia (3 h), and the ischemia/reperfusion group. One normal EDL from each rat was used as the non-operated control, and the opposite ones are distributed into the 3 remaining groups. All the samples were studied with Western blotting technique and immunohistochemistry staining. RESULTS: Three sizes of protein bands verified with the proteins of relative molecule to be of 155000, 140000 and 135000, were detected in the EDL homogenate by Western blotting, which were comparable with the positive controls for nNOS, eNOS and iNOS, respectively. Immunostaining demonstrated that nNOS was present in the muscle fiber, with a similar location of the muscle stria, eNOS was found apparently in microvascular endothelia, but not found in muscle fibers, and iNOS was found in the leukocytes around the muscle fiber and some endothelia cells. Immunostaining paralleled the Western blotting results. CONCLUSIONS: It suggests that the constitutive nNOS and eNOS protein can be regulated by I/R, and I/R results in a down regulation of nNOS and up-regulation of eNOS and iNOS in reperfused skeletal muscle. The fact that nNOS is present around stria suggests that nNOS may have a close relationship with muscle function. The localization of eNOS in endothelial cell indicates its role in regulating blood supply of the muscle. Based on these findings, it is possible that NO produced by distinct NOS may play a different role in I/R injury.

Internal fixation of biocondylar tibia plateau fractures with antiglide plate: a review of 26 cases / 中华创伤杂志

Objective To evaluate the clinical results of a combination of lateral buttress plate and medical antiglide plate internal fixation for biocondylar tibia plateau fractures. Methods A total of 26 biocondylar tibia plateau fractures belonged to type Ⅴ and type Ⅵ according to Schatzker classification and treated with open reduction. Lateral buttress plate and medical antiglide plate were applied for limited internal fixation. The follow up continued till fracture healing to observe if there existed bone dislocation and determine the range of knee motion and Iowa knee score. Results No obvious shift of fragment was found in 26 cases with mean range of knee motion for 92? and mean Iowa knee score for 93 points. Conclusion Combination of lateral buttress plate and medical antiglide plate is a good method for internal fixation of biocondylar tibia plateau fractures,but the conclusion needs large number of clinical verifications.