Individualized Drug Repositioning For Rheumatoid Arthritis Using Weighted Kolmogorov-Smirnov Algorithm.

BACKGROUND: Existing drugs are far from enough for investigators and patients to administrate the therapy of rheumatoid arthritis. Drug repositioning has drawn broad attention by reusing marketed drugs and clinical candidates for new uses. PURPOSE: This study attempted to predict candidate drugs for rheumatoid arthritis treatment by mining the similarities of pathway aberrance induced by disease and various drugs, on a personalized or customized basis. METHODS: We firstly measured the individualized pathway aberrance induced by rheumatoid arthritis based on the microarray data and various drugs from CMap database, respectively. Then, the similarities of pathway aberrances between RA and various drugs were calculated using a Kolmogorov-Smirnov weighted enrichment score algorithm. RESULTS: Using this method, we identified 4 crucial pathways involved in rheumatoid arthritis development and predicted 9 underlying candidate drugs for rheumatoid arthritis treatment. Some candidates with current indications to treat other diseases might be repurposed to treat rheumatoid arthritis and complement the drug group for rheumatoid arthritis. CONCLUSION: This study predicts candidate drugs for rheumatoid arthritis treatment through mining the similarities of pathway aberrance induced by disease and various drugs, on a personalized or customized basis. Our framework will provide novel insights in personalized drug discovery for rheumatoid arthritis and contribute to the future application of custom therapeutic decisions.

Bone Defects in Revision Total Knee Arthroplasty and Management.

This article reviews the recent updates in revision of total knee arthroplasty (RTKA). We reviewed the recent articles on RTKA in databases including PubMed, Google Scholar, and SCOPUS. Total knee arthroplasty (TKA) involves the replacement of all three compartments of the knee in surgery of the knee joint to restore capacity and function. TKA is one of the most common and reliable surgical treatment options for the treatment of knee diseases. However, some patients require revision of TKA (RTKA) after primary TKA for various reasons, including mechanical wear, implant loosening or breakage, malalignment, infection, instability, periprosthetic fracture, and persistent stiffness. Unfortunately, the overall outcome of RTKA is not as satisfactory as for primary TKA due to the uncertainty regarding the actual success rate and the risk factors for failure. Cementation, modular metal augmentation, bone grafting, autologous bone grafting, allogenic bone grafting, impactation bone grafting, structural bone allografting, metaphyseal fixation, using porous titanium coated press fit metaphyseal sleeves and porous tantalum structural cones, and megaprostheses or customized prostheses are the currently available management options for RTKA. However, most of the management systems possess specific complications. Novel approaches should be developed to improve functional capacity, implant survival rates, and quality of life in a cost-efficient manner.

Efficacy and safety of low-molecular-weight heparin after knee arthroscopy: A meta-analysis.

BACKGROUND: Venous thromboembolism (VTE) is considered a potentially serious complication of knee arthroscopy and leads to conditions such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Low-molecular-weight heparin (LMWH) is widely employed in knee arthroscopy to reduce perioperative thromboembolic complications. However, the efficacy and safety of LMWH in knee arthroscopy remains unclear. METHODS: Seven randomized controlled clinical trials on LMWH in knee arthroscopy were identified and included in this meta-analysis. The main outcomes of the effectiveness (prevention of DVT and PE) and complications (death, major bleeding, and minor bleeding) of LMWH in knee arthroscopic surgery were assessed using Review Manager 5.3 software. RESULTS: The meta-analysis indicated that LMWH prophylaxis comprised 79% of asymptomatic DVT. No association was found in symptomatic VTE (RR: 0.90; 95% confidence interval [CI]: 0.39-2.08; P = 0.80), symptomatic DVT (RR: 0.79; 95% CI: 0.28-2.23; P = 0.66), symptomatic PE (RR: 1.36; 95% CI: 0.37-4.97; P = 0.64) and major bleeding (RR: 0.70; 95% CI: 0.12-3.95; P = 0.68) risk during LMWH prophylaxis were identified. Death was not reported in these studies. Moreover, there was a lower incidence of minor bleeding (RR: 0.64; 95% CI: 0.49 to 0.83; P = 0.001) in the control group than in the LMWH group. CONCLUSION: Compared with the control group, the group treated with LMWH after knee arthroscopy was no association in reducing the symptomatic VTE rate, symptomatic DVT rate or symptomatic PE rate. The symptomatic VTE rate was 0.5% (11/2,166) in the LMWH group versus 0.6% (10/1,713) in the control group. Although the limitations of this meta-analysis cannot be ignored, the results of our study show that LMWH after knee arthroscopy is ineffective. We recommend that LMWH should not be routinely provided for knee arthroscopy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03164746.

Potential role of andrographolide in the proliferation of osteoblasts mediated by the ERK signaling pathway.

The aim of the present study was to explore the effects of andrographolide (AG) and the ERK signaling pathway on the proliferation of osteoblasts (OBs) in vitro. The calvarial OBs from Sprague Dawley (SD) rats were collected and treated at different concentrations of AG and U0126. The concentrations of AG were measured by colorimetry. Based on different treatment methods, the cells were separated into four groups: control group, U0126 group, AG group, and AG+U0126 group. The cells were cultured for 24h, 48h and 72h. An inverted phase contrast microscope was used to observe the morphologies of treated OBs. The MTT assay was performed to plot OB proliferation curves, and to measure the changes in alkaline phosphatase and hydroxyproline contents after U0126 treatments. The expressions of proliferating cell nuclear antigen (PCNA), Ki67, core binding factor alpha-1 (Cbfa1), type I collagen (Col I), osterix (OSX), p38, extracellular signal regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) were measured by fluorescent quantitative polymerase chain reaction (PCR) and Western blotting. In different cell groups, the in vitro proliferation rates of OBs reached the highest at an AG concentration of 20µmol/L, and the amounts of alkaline phosphatase, hydroxyproline, PCNA, Ki67, Cbfa1, Col I, OSX, and ERK were significantly higher than at other concentrations (all P<0.05). U0126 intervention significantly decreased the expressions of these factors (all P<0.05). At the meantime, p38 and JNK were not affected by AG and were only inhibited by U0126. In conclusion, ERK played an important role in mediating the functions of AG in the proliferation of OBs, indicating that the ERK signaling pathway may be the main pathway through which AG exerts its effects.

Establishing a Customized Guide Plate for Osteotomy in Total Knee Arthroplasty Using Lower-extremity X-ray and Knee Computed Tomography Images.

BACKGROUND: The conventional method cannot guarantee the precise osteotomies required for a perfect realignment and a better prognosis after total knee arthroplasty (TKA). This study investigated a customized guide plate for osteotomy placement in TKAs with the aid of the statistical shape model technique using weight-bearing lower-extremity X-rays and computed tomography (CT) images of the knee. METHODS: From October 2014 to June 2015, 42 patients who underwent a TKA in Guizhou Provincial People's Hospital were divided into a guide plate group (GPG, 21 cases) and a traditional surgery group (TSG, 21 cases) using a random number table method. In the GPG group, a guide plate was designed and printed using preoperative three-dimensional measurements to plan and digitally simulate the operation. TSG cases were treated with the conventional method. Outcomes were obtained from the postoperative image examination and short-term follow-up. RESULTS: Operative time was 49.0 ± 10.5 min for GPG, and 62.0 ± 9.7 min in TSG. The coronal femoral angle, coronal tibial angle, posterior tibial slope, and the angle between the posterior condylar osteotomy surface and the surgical transepicondylar axis were 89.2 ± 1.7°, 89.0 ± 1.1°, 6.6 ± 1.4°, and 0.9 ± 0.3° in GPG, and 86.7 ± 2.9°, 87.6 ± 2.1°, 8.9 ± 2.8°, and 1.7 ± 0.8° in TSG, respectively. The Hospital for Special Surgery scores 3 months after surgery were 83.7 ± 18.4 in GPG and 71.5 ± 15.2 in TSG. Statistically significant differences were found between GPG and TSG in all measurements. CONCLUSIONS: A customized guide plate to create an accurate osteotomy in TKAs may be created using lower-extremity X-ray and knee CT images. This allows for shorter operative times and better postoperative alignment than the traditional surgery. Application of the digital guide plate may also result in better short-term outcomes.

Cementless total hip arthroplasty with structural allograft for massive acetabular defect in hip revision.

OBJECTIVE: To study retrospectively 20 hip revison patients treated by cementless total hip arthroplasty with structural allograft. METHODS: Twenty patients suffering from aseptic loosening of an uncemented cup complicated by a large defect underwent cementless total hip arthroplasty with structural allograft and were followed up for at least 5 years. Clinical results were evaluated by Harris score and leg length measurements. Radiographic analysis included implants migration, graft absorbance, osteolysis and liner wear. RESULTS: No cup loosening or graft reabsorption was found at final follow-up. Clinical improvements in pain and functional status were demonstrated during the follow-up period. The mean Harris hip scores improved from 29 preoperatively (range 20-41) to 81 postoperatively (range 73-89). CONCLUSION: Our study shows that cementless total hip arthroplasty with allograft is a good way for massive defect in acetabular bone stock.

Osteogenic potential of the human bone morphogenetic protein 2 gene activated nanobone putty.

BACKGROUND: Nanobone putty is an injectable and bioresorbable bone substitute. The neutral-pH putty resembles hard bone tissue, does not contain polymers or plasticizers, and is self-setting and nearly isothermic, properties which are helpful for the adhesion, proliferation, and function of bone cells. The aim of this study was to investigate the osteogenic potential of human bone morphogenetic protein 2 (hBMP2) gene activated nanobone putty in inducing ectopic bone formation, and the effects of the hBMP2 gene activated nanobone putty on repairing bone defects. METHODS: Twenty four Kunming mice were randomly divided into two groups. The nanobone putty + hBMP2 plasmid was injected into the right thigh muscle pouches of the mice (experiment side). The nanobone putty + blank plasmid or nanobone putty was injected into the left thigh muscle pouches of the group 1 (control side 1) or group 2 (control side 2), respectively. The effects of ectopic bone formation were evaluated by radiography, histology, and molecular biology analysis at 2 and 4 weeks after operation. Bilateral 15 mm radial defects were made in forty-eight rabbits. These rabbits were randomly divided into three groups: Group A, nanobone putty + hBMP2 plasmid; Group B, putty + blank plasmid; Group C, nanobone putty only. Six rabbits with left radial defects served as blank controls. The effect of bone repairing was evaluated by radiography, histology, molecular biology, and biomechanical analysis at 4, 8, and 12 weeks after operation. RESULTS: The tissue from the experimental side of the mice expressed hBMP2. Obvious cartilage and island-distributed immature bone formation in implants of the experiment side were observed at 2 weeks after operation, and massive mature bone observed at 4 weeks. No bone formation was observed in the control side of the mice. The ALP activity in the experiment side of the mice was higher than that in the control side. The tissue of Group A rabbits expressed hBMP2 protein and higher ALP level. The new bone formation rate and antibending strength of group A was significantly higher than those of group B and C. The defects in blank control were not healed. CONCLUSIONS: The hBMP2 gene activated nanobone putty exhibited osteoinductive ability, and had a better bone defect repair capability than that of nanobone putty only.