Prevention of Pregabalin-Related Side Effects Using Slow Dose Escalation Before Surgery: A Trial in Primary Total Joint Arthroplasty Within the Enhanced Recovery After Surgery Pathway.

BACKGROUND: The side effects of pregabalin likely occur after the first dose. We aimed to evaluate the effect of 75 milligrams (mg) of pregabalin prescribed as an initial dose with a slow dose escalation for primary total joint arthroplasty within the enhanced recovery after surgery pathway. METHODS: Participants were randomly assigned to two groups. Fifty-eight patients were enrolled, and twenty-nine were assigned to each group. Group 1 (G1) received pregabalin (37.5 mg) twice on the day before surgery, as well as pregabalin 75 mg two hours pre-operatively; Group 2 (G2) received none on the day before surgery and the same dose of pregabalin at two hours pre-operatively. The primary outcome was dizziness assessed by severity; secondary outcomes included nausea, vomiting, sedation, opioid consumption, independent transfer at six hours post-operatively, time to readiness for independent transfers, time to readiness for discharge, and pain. RESULTS: At two, four, and six hours post-operatively, the proportion of patients experiencing dizziness and nausea was significantly greater in G2 than in G1, and opioid consumption was significantly greater in G2 than in G1 (P = .012). The proportion of independent transfers at six hours post-operatively was significantly greater in G1 than in G2 (P = .010). The time to readiness for independent transfers was significantly shorter in G1 than in G2 (P = .016). CONCLUSION: Prescription of pregabalin 37.5 mg twice on the day before surgery was effective in reducing early postoperative dizziness and nausea after receiving pregabalin 75 mg two hours pre-operatively. It also promoted early independent transfers and reduced opioid consumption.

Fumonisin B1 exposure induces apoptosis of human kidney tubular epithelial cells through regulating PTEN/PI3K/AKT signaling pathway via disrupting lipid raft formation.

Fumonisin B1 (FB1) is a fungal metabolite that causes a variety of toxicological effects to human and animals. In this study, we aimed to investigate the effects of FB1 on kidney injury and clarify the possible mechanism. Human kidney tubular epithelial cells (HK-2) were treated with FB1 for different concentrations. The results demonstrated that FB1 could suppress the viability of HK-2 cells. FB1 could lead to the apoptosis of HK-2 cells in a dose-dependent manner. Furthermore, treatment of FB1 could induce the production of ROS and MDA. And the levels of SOD and GSH were decreased by FB1. The expression of Caspase-3 and Bax increased markedly and BCL2 expression was decreased by FB1 treatment. In addition, FB1 treatment could up-regulate PTEN expression and down-regulate PI3K and AKT expression. Also, FB1 could disrupt lipid raft by decreasing sphingomyelin level. In conclusion, FB1 exposure induces apoptosis of HK-2 cells through regulating PTEN/PI3K/AKT signaling pathway via disrupting lipid raft formation.

Ochratoxin A induces human kidney tubular epithelial cell apoptosis through regulating lipid raft/PTEN/AKT signaling pathway.

Ochratoxin A (OTA) is a fungal toxin that causes serious threat to human health. OTA could lead to the injury of various tissues, especially kidney injury. However, the toxic effects of OTA on human kidney tubular epithelial cell (HK-2) and the possible mechanism remains poorly understood. This study was to investigate the toxic effects of OTA on HK-2 and elucidate the molecular mechanism. HK-2 cells were treated OTA to evaluate the effect of OTA on cell viability and apoptosis. OTA inhibited the growth of HK-2 in a concentration-dependent manner. With the concentration increased, OTA significantly lead to the apoptosis of HK-2. OTA could increase the levels of reactive oxygen species (ROS) and Malondialdehyde (MDA). Superoxide dismutase (SOD) and glutathione (GSH) activities were decreased by OTA. Furthermore, OTA increased Caspase-3 and Bax expression and decreased BCL2 expression. Compared to the control group, the expression of PTEN was increased and the expression of PI3K and AKT were decreased in OTA treated groups. In addition, we found OTA could disrupt the formation of lipid raft by attenuating sphingomyelin and cholesterol levels. In conclusion, our results indicated that OTA induces apoptosis in HK-2 through regulating PTEN/AKT signaling pathway via disrupting lipid raft formation.

Effect of Patellar Denervation on Anterior Knee Pain and Knee Function in Total Knee Arthroplasty without Patellar Resurfacing: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The aim of the present study was to evaluate the effect of patellar denervation (PD) in preventing anterior knee pain (AKP) and improving knee function after total knee arthroplasty (TKA) without patellar resurfacing, and to help surgeons decide whether or not to use PD in TKA. METHODS: The electronic databases of Pubmed, Embase, Cochrane, Web of Science, and Scopus were searched for all randomized controlled trials (RCT) comparing the outcomes of PD and no patellar denervation (NPD) in TKA without patellar resurfacing. Primary outcomes were incidence of AKP, visual analogue scale for pain (VAS), and patellar score (PS). Secondary outcomes were Knee Society Score (KSS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Oxford Knee Score (OKS), knee range of motion (ROM), and complications. RESULTS: A total of nine RCT met the inclusion criteria. On meta-analysis, PD significantly reduced the incidence of AKP (odds ratio 0.49; 95% confidence interval [CI] 0.26 to 0.92), reduced the VAS (weighted mean difference [WMD] -0.57; 95% CI -1.02 to -0.11), and improved the WOMAC (WMD -4.63; 95% CI -6.49 to -2.77) and the ROM (WMD 9.60; 95% CI 0.39 to 18.81) during the follow-up within 12 months. In addition, PD improved the PS (WMD 1.01; 95% CI 0.65 to 1.38), KSS (WMD 1.12; 95% CI 0.10 to 2.14), and the WOMAC (WMD -1.41; 95% CI -2.74 to -0.08) during the follow-up after 12 months. CONCLUSION: Patellar denervation could significantly reduce the VAS and the incidence of AKP in the early stages after TKA as well as improve the clinical outcomes in terms of the PS, the WOMAC, the KSS, and the ROM. This study demonstrates that PD is a safe and recommendable technique that could be routinely performed in TKA.

Mangiferin Alleviates Renal Interstitial Fibrosis in Streptozotocin-Induced Diabetic Mice through Regulating the PTEN/PI3K/Akt Signaling Pathway.

Renal interstitial fibrosis is considered to be the typical manifestation of diabetic nephropathy (DN). Mangiferin has shown positive effect on the prevention or treatment of diabetes and its complications. The aim of this study was to explore the inhibitive effect and mechanism of mangiferin on renal interstitial fibrosis in diabetic mice. Streptozotocin- (STZ-) induced diabetic mice were treated with mangiferin (15, 30, and 60 mg/kg/d) for 4 weeks. The morphology of kidneys was observed by Masson's trichrome staining, and the biochemical parameters (fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), blood urea nitrogen (BUN), serum creatinine (SCr), and urine protein) were determined by kits. In addition, the levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin- (IL-) 6, and IL-1ß), antioxidant enzymes (SOD, CAT, and GSH-Px), MDA, and ROS were assessed. Furthermore, the expressions of fibronectin (FN), collagen I (Col I), and α-SMA were measured by immunohistochemistry. Regulations of TGF-ß1 and the PTEN/PI3K/Akt pathway were detected by Western blotting. Treatment with mangiferin significantly ameliorated renal dysfunction in diabetic mice, as evidenced by the increase in body weight and decreases in FBG, TG, TC, BUN, SCr, urine protein, and the kidney to body weight ratio (KW/BW). Furthermore, mangiferin treatment prevented renal interstitial fibrosis evidenced by decreases in the positive expression of FN, Col I, and α-SMA, in comparison with morphological changes in the renal tissue. Meanwhile, mangiferin increased antioxidant enzymes, reduced the TNF-α, IL-6, and IL-1ß, as well as MDA and ROS. Additionally, mangiferin administration also downregulated TGF-ß1, upregulated PTEN, and decreased the phosphorylation of both PI3K and Akt. These findings demonstrate that mangiferin may reduce inflammation and oxidative stress in DN, thereby inhibiting the renal interstitial fibrosis by reducing the TGF-ß1-mediated elevation of Col I, FN, and α-SMA through the PTEN/PI3K/Akt pathway.

[Long-term outcomes of Chiari osteotomy for Legg-Calvé-Perthes disease in children].

OBJECTIVE: To explore long-term outcomes of Chiari osteotomy for Legg-Calvé-Perthes disease in children with type Catterall III or IV, and to analyze clinical effect of osteotomy angle on clinical and radiographic results. METHODS: From March 2005 to July 2013, 26 children with Legg-Calvé-Perthes disease with type Catterall III or IV were treated by Chiari osteotomy, including 17 males and 9 females, aged from 4 to 13 years old with an average of (8.9±2.6) years old. Children were divided into low osteotomy angle group and high osteotomy angle group. according to osteotomy angle. There were 10 children in low osteotomy angle group with an osteotomy angle of 10 degrees, including 8 boys and 2 girls, aged from 4 to 13 years old with an average of (9.2±3.3) years old; while there were 16 children in high osteotomy angle group with an osteotomy angle of 15 degress, including 9 boys and 7 girls, aged from 6 to 12 years old with an average of (8.8±2.1) years old. HHS score before operation and at the latest follow-up were recorded to observe clinical results. CE angle of hip joint, acetabular index, Sharp angle, Shenton's line continuity, femoral head coverage, acetabular depth ratio were recorded to compare radiographic results. Stulberg classification was analyzed to compare reshaping ability of femoral head. RESULTS: Twenty-six children were followed up for 4.5 to 12.0 years with an average of (7.9±1.8) years. All incisions were healed at stage I for 10 to 14 days, with an average of(12.3±1.1) days. No inflammation, skin necrosis and injury of vessel and nerve occurred. All osteotomies achieved bone union for 8 to 13 weeks, with an average of(9.8±1.4) weeks. HHS score increased from 75.8±6.5 before operation to 93.5±2.5 at the latest follow-up in low osteotomy angle group(P<0.05), and form 77.6±6.2 to 97.8±1.6 in high osteotomy angle group (P<0.05). HHS score of high osteotomy angle group at the latest follow-up was higher than that of low osteotomy angle group (P<0.05). The acetabular index decreased from (10.1±2.5)° before operation to (4.5±1.3)° at the latest follow-up in low osteotomy angle group (P<0.05), and from (10.7±3.3)° before operation to (2.0±1.1)° in high osteotomy angle group (P<0.05). The acetabular index of high osteotomy angle group at the latest followup was better than low osteotomy angle group(P<0.05). There was no significant difference in CE angle, Sharp angle, Shenton's continuity, femoral head coverage, acetabular depth ratio between two groups. According to Stulberg classification, the femoral head reshaping ability in high osteotomy angle group was better than that of low osteotomy angle group(P<0.05). CONCLUSIONS: Chiari osteotomy with 15° for Legg-Calvé-Perthes disease in children with type Catterall III or IV could effectively decrease index of acetabulum, and helpful for femoral head reshaping ability, then in further improve clinical effects.

Long-term outcomes of Wagner self-locking stem with bone allograft for Paprosky type II and III bone defects in revision total hip arthroplasty: A mean 15.7-year follow-up.

PURPOSE: Massive bone defects represent a challenge in revision total hip arthroplasty (THA). Wagner self-locking (SL) stem is a favorable option for this technique; however, its long-term outcomes with bone allograft have rarely been reported. The purpose of this study was to investigate the long-term outcomes of this stem with bone allograft for Paprosky type II and III bone defects in revision THA. METHODS: A total of 38 patients (40 hips) who underwent revision THA with the Wagner SL stem were retrospectively reviewed. Bone allograft was placed in every patient. Clinical outcomes were determined using the Japanese Orthopedic Association's hip scoring system (JOA hip score). Stem subsidence, stem fixation, and remodeling of the grafted bone were assessed radiographically. The survival rate of the stem was assessed by Kaplan-Meier survival analysis. RESULTS: The mean JOA hip score at the latest follow-up was 75.3 points. Stem subsidence of ≥10 mm was observed in four hips (10.0%). Moreover, 67.5% (27/40) of hips were stable, and 27.5% (11/40) had fibrous fixation. Bone restoration was observed in 25 hips (62.5%). At a mean follow-up of 15.7 years, the cumulative stem survival rates were 96.6%and 91.7% with "stem re-revision for loosening" and "stem re-revision for any reason" as the end points, respectively. CONCLUSION: The Wagner SL stem with bone allograft for proximal femoral bone defects in revision THA is a clinically beneficial procedure.

The effect of PLGA-based hydrogel scaffold for improving the drug maximum-tolerated dose for in situ osteosarcoma treatment.

Although hydrogel-based therapeutic agents have shown great potential for localized cancer treatments, the maximum tolerated dose (MTD) of these methods remains uncertain. To confirm this, doxorubicin (DOX) loaded PLGA-PEG-PLGA hydrogel was employed to investigate the MTD of DOX for localized osteosarcoma treatment. This hydrogel showed good injectable and biodegradable properties in vivo. And the drug remaining time was also obviously prolonged in the tumor site. Different doses of DOX (5.0, 15, 30 mg/kg) with/without hydrogel were adopted to the treatment of tumor-bearing mice. Despite both localized administrations of 5.0 mg/kg DOX showing no obvious systemic toxicity, this dose failed to control the persistent growth of tumors or prolong the survival time in comparison with the control groups. Localized administration of 30 mg/kg DOX showed a high efficacy for suppressing tumor growth, but exhibited obvious body weight losing at the same time. Correspondingly, the DOX-loaded hydrogel with the dose of 15 mg/kg achieved significantly improved anti-tumor efficacy and prolonged mean survival time compared with both the free DOX (15 mg/kg) and other control groups. Furthermore, during the whole therapeutic process, the mice showed no obvious body weight loss, major organs damage or death in this group. The MTD of DOX-loaded agent based on the PLGA-PEG-PLGA hydrogel gave a 2-fold increase compared to the MTD of free DOX (7.5 mg/kg, intravenous injection) for the mouse without significant systemic toxicity.

Intracapsular cuneiform osteotomy compared with in-situ pinning for the management of slipped capital femoral epiphysis.

Intracapsular cuneiform osteotomy was initially introduced to restore the morphology of the proximal femur after slipped capital femoral epiphysis (SCFE). However, whether this procedure results in a higher risk of avascular necrosis (AVN) or lower incidence of cam deformity than in-situ pinning is unclear. The aim of this study was to compare the outcomes of intracapsular cuneiform osteotomy and in-situ pinning to treat SCFE in children. Twenty-three children who suffered from SCFE underwent either intracapsular cuneiform osteotomy (eight patients, eight hips) or in-situ pinning (15 patients, 18 hips) between 2006 and 2014. No patient was lost to follow-up at a mean of 4.5 years. In the osteotomy group, the Japanese Orthopedic Association's hip score system score increased from 50.5 (20-89) to 98.9 (95-100) and from 65.9 (48-90) to 99.0 (44-100) in the in-situ pinning group. On the basis of the slip angle, α angle, and epiphyseal-metaphyseal offset, intracapsular cuneiform osteotomy showed a significantly better result in restoring the morphology of the proximal femur than in-situ pinning (P<0.001). The incidences of AVN, chondrolysis, and lower limb discrepancy were similar between the two groups. On the basis of clinical outcomes, both intracapsular cuneiform osteotomy and in-situ pinning had acceptable abilities to treat SCFE. The incidence of AVN was not related to which technique was used. Osteotomy significantly restored the morphology of the proximal femur.

Long-term clinical and radiographic results of the cementless Spotorno stem in Japanese patients: A more than 15-year follow-up.

PURPOSE: Although previous studies have reported encouraging results of cementless Spotorno (CLS) stem, studies with more than 15 years of follow-up are rare. The objective of this study is to investigate the long-term results of CLS stem and the factors potentially influencing the outcomes. METHODS: The clinical and radiographic data of 79 hips (64 patients) were reviewed. Clinical outcome was determined using the Japanese Orthopedic Association's hip scoring system (JOA hip score). Survival rate was assessed by Kaplan-Meier survival analysis. The main end point for survival analysis was revision of stem. The correlations between patient demographics, radiographic factors, and stem survival rates were analyzed. RESULTS: At a mean follow-up period of 20.1 years, the mean JOA hip score at final follow-up was 84.7 points. Stem survival rate for all revisions was 97.5% at 20 years, and stem survival for aseptic loosening was 98.9%. Varus alignment had a significant negative influence on the survival of the femoral stem. CONCLUSION: This study demonstrates acceptable long-term clinical and radiographic results of the CLS stem in Japanese patients. Caution should be exercised to avoid varus stem alignment.

Biomechanical comparison of xenogeneic bone material treated with different methods.

Bone xenografting is considered one of the most effective ways to address the shortage of bone autografts and allografts. Various methods have been employed to minimize the immune rejection issues associated with bone xenografts. However, the side effects of such methods on bone biomechanical properties remain unclear. As such, the objective of this study was to compare the influence of different treatments on the biomechanical properties of porcine bones. Fresh pig ribs were cut into 1.5 × 0.5 × 0.4 cm specimens, which were randomly divided into four groups and subjected to different modification regimes: group A by degreasing and partial deproteinization, group B by cryopreservation, group C by cryopreservation and enzyme digestion, and group D was a control group using fresh bone. Biomechanical tests and α-Gal antigen detection were performed for all groups. In the axial compression test, the values for maximum load were as follows: group D > group C > group B > group A. The maximum load in group A was significantly less than in the other groups (P < .05). There were no differences between groups D, C, and B in terms of the maximum stress and elastic modulus (P > .05). The maximum stress and elastic modulus values recorded for group A were significantly less than for the other groups (P < .05). There were no significant differences in the maximum load or elastic modulus among groups B, C, and D, in the three-point bending test (P > .05). However, the maximum load and elastic modulus values recorded for group A were significantly lower than the other groups (P < .05). In groups A and C, no α-Gal antigen-positive expression was detected. In group B, there was low level α-Gal antigen-positive expression, while a high level of α-Gal antigen-positive expression was observed in fresh bone samples. The results indicated that xenogeneic bone subjected to degreasing and partial deproteinization had the worst biomechanical properties. Cryopreservation and cryopreservation with enzyme digestion had little effect on the bone biomechanical properties, although enzyme digestion resulted in the complete elimination of the α-Gal antigen. Cryopreservation with enzyme digestion treatment presented the best results in terms of removing the immune-response triggering α-Gal antigen, while preserving the good biomechanical properties of bone xenografts.

Localized Co-delivery of Doxorubicin, Cisplatin, and Methotrexate by Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment.

Localized cancer treatments with combination drugs have recently emerged as crucial approaches for effective inhibition of tumor growth and reoccurrence. In this study, we present a new strategy for the osteosarcoma treatment by localized co-delivery of multiple drugs, including doxorubicin (DOX), cisplatin (CDDP) and methotraxate (MTX), using thermosensitive PLGA-PEG-PLGA hydrogels. The release profiles of the drugs from the hydrogels were investigated in vitro. It was found that the multidrug coloaded hydrogels exhibited synergistic effects on cytotoxicity against osteosarcoma Saos-2 and MG-63 cells in vitro. After a single peritumoral injection of the drug-loaded hydrogels into nude mice bearing human osteosarcoma Saos-2 xenografts, the hydrogels coloaded with DOX, CDDP, and MTX displayed the highest tumor suppression efficacy in vivo for up to 16 days, as well as led to enhanced tumor apoptosis and increased regulation of the expressions of apoptosis-related genes. Moreover, the monitoring on the mice body change and the ex vivo histological analysis of the key organs indicated that the localized treatments caused less systemic toxicity and no obvious damage to the normal organs. Therefore, the approach of localized co-delivery of DOX, CDDP, and MTX by the thermosensitive hydrogels may be a promising approach for enhanced osteosarcoma treatment.