Objective To investigate the effects of locally and systemically administered alendronate on wear-debris induced osteolysis in vivo. Methods Endotnxin-free titanium particles were injected into rabbit femurs prior to insertion of a non-weight-bearing polymethylmethacrylate plug into the distal femur canal. Then the particles were repeatedly injected into the knee 2, 4 and 6 weeks after the implantation. Alendronate was incorporated into bone cement for local delivery at three different concentrations [0.1, 0.5, and 1.0 weight%(wt%)]. For systemic delivery, alendronate was subcutaneously injected ( 1.0 mg· kg-1·week-1).Results Eight weeks after operation, there was significant evidence of osteolysis surrounding the plug in the control group, while markedly-blocked osteolysis was noted in the local delivery group (0.5 wt% and 1.0 wt%), and the systemic delivery group. It was found that alendronate had improved peri-prosthetic bone mineral density in a dose-effect model. Notably, no significant difference was found between local delivery of 0.5 wt% alendronate and systemic delivery in bone mineral density and implant fixation. Conclusion Alendronate-loaded bone cement (0.5 wt% ) may be as effective as the systemic delivery in inhibiting titanium particle-induced osteolysis.

Objective To investigate the correlation between the prognosis and the early lactate clearance in patients with postcardiac surgery undergoing cardiopulmonary bypass.Methods The clinical data of 73 patients who underwent postcardiotomy undergoing cardiopulmonary bypass in SuBei Hospital of Jiangsu Provience,from March 2006 to February 2010,were prospectively collected and analyzed.The collection data including:( 1 ) Preoperative factors:including gender,age,diagnosis preoperative,NYHA grade,APACHE Ⅱ score and left ventricular end-diastolic diameter.(2) Operative factors:operation time,block aorta time.(3)Postoperation factors:hemorrhage volume,mechanical ventilation time,and factors of hemodynamics and oxygen metabolism at 6 hour postoperative:heart rate(HR),central venous pressure(CVP),pulmonary capilary wedged pressure( PCWP),cardiac output index( CI),arterial blood lactic acid,6 h lactate clearance,partial pressure of oxygen( PO2 ),mixed venous oxygen saturation ( SvO2 ),oxygen delivery index ( DO2I),oxygen consume index (VO2I),oxygen extraction ratio(O2ext).Patients were divided into survival group,control group,high level of lactate clearance group( lactate clearance rate ＞ 30％ ) and low level of lactate clearance group.Firstly,the data analyzed with process of single variable analysis and some parameters,which showed the significant difference,were sorted out from two groups.Then these parameters were put to the Logistic regression analysis.Consequently,the independent risk factors of death of postcardiac surgery could be found.Results The mortality in high lactate clearance group ( 4.55％ [ 2/44 ] ) was significantly less than the low lactate group (34.48％ [ 10/29] ) ( x2 =11.889,P ＜0.01 ).The single variable analysis had shown that there were significant difference on APACHE Ⅱ score ( [ 16.9 ± 2.9 ] vs [ 19.2 ± 2.6 ],t =2.537 ),left ventricular end-diastolic diameter( [ 53.9 ± 5.6 ] mm vs [ 63.8 ± 4.6 ] mm,t =5.847 ),block aorta time ( [ 101.2 ± 34.2 ] min vs [ 122.7 ±22.7 ] min,t =2.078 ),hemorrhage volume( [464.0 ± 158.8 ] ml vs [ 603.2 ± 159.5 ] ml,t =2.773 ),mechanical ventilation time( [ 22.6 ± 5.1 ] h vs [ 28.8 ± 5.2 ] h,t =3.857 ),arterial blood lactic acid ( [ 3.5 ±1.3 ] mmol/L vs [5.1 ± 1.5 ] mmol/L,t =3.912),lactate clearance ( [38.8 ± 17.4]％ vs [ 14.6 ±9.7]％,t =4.846),and SvO2( [69.1 ±4.2]％ vs [59.2 ±6.9]％,t =5.847) (P＜0.05 or P ＜0.001)between survival group and control group.Multiple regression analysis showed that lactate clearance and left ventricular enddiastolic diameter were the two independent risk factors of death,and the odds ratio(OR) were 7.773 (95％ CI 1.364-44.306,P ＜0.05) and 15.186(95％ CI 2.758-83.162,P ＜0.01).Conclusion Early lactate clearance rate can be used as an important indicator to evaluate the prognosis of patients with postcardiac surgery undergoing cardiopulmonary bypass.

Osteoarthritis (OA) is a prevalent joint disease with no effective treatment strategies. Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis. Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies, the epigenetic control of OA remains unclear. Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes, including cell differentiation, proliferation, autophagy, and apoptosis. However, the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown. In this work, we confirmed the upregulation of JMJD3 in aberrant force-induced cartilage injury in vitro and in vivo. Functionally, inhibition of JMJD3 by its inhibitor, GSK-J4, or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury. Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression. Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis, cartilage degeneration, extracellular matrix degradation, and inflammatory responses. In vivo, anterior cruciate ligament transection (ACLT) was performed to construct an OA model, and the therapeutic effect of GSK-J4 was validated. More importantly, we adopted a peptide-siRNA nanoplatform to deliver si-JMJD3 into articular cartilage, and the severity of joint degeneration was remarkably mitigated. Taken together, our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression. Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-siRNA nanocomplexes.
Cartilage, Articular/pathology* ; Chondrocytes/metabolism* ; Down-Regulation ; Epigenesis, Genetic ; Humans ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism* ; Osteoarthritis/pathology* ; RNA, Small Interfering/pharmacology*