Objectives To explore the safety and efficacy of the enhanced recovery after surgery (ERAS) program for elderly total knee arthroplasty (TKA) patients. Methods A prospective controlled study was conducted for patients older than 65 years, who would undergo unilateral TKA with a minimum follow‐up of 2 years. Patients were divided into an ERAS group (n = 106) and a traditional group (n = 141) based on the patients’ willingness to participate in the ERAS program. Baseline parameters of American Society of Anesthesiologists classification and comorbidity were recorded. Complication, mortality, knee function assessment using knee society score and knee range of motion, and perioperative clinical outcomes were compared between the two groups. Results There were no significant differences between the two groups in terms of baseline parameters. Although no significant differences were found in postoperative nausea and vomiting, urinary tract infection, deep venous thrombosis, pulmonary embolism, wound delayed healing, superficial infection, and deep infection, there were significantly fewer total complications in the ERAS group (26/106 vs 52/141; P = 0.039). No significant difference was found in short‐term mortality (1/106 vs 3/141; P = 0.836) between the two groups. There were no significant differences in preoperative visual analogue scale (VAS), knee society score (KSS), and range of motion (ROM) between the two groups. Lower VAS scores were found in the ERAS group at time of postoperative day (POD) 1 (P = 0.012) and POD 5 (P = 0.020); no significant differences were observed at time of postoperative month (POM) 1 and final follow‐up. Higher KSS scores were found in the ERAS group at time of POD 1 (P = 0.013), and POD 5 (P = 0.011), no significant differences were observed at time of POM 1 and final follow‐up. Increased ROM degree was found in the ERAS group at time of POD 1 (P = 0.021); no significant differences were observed at time of POD 5, POM 1 and final follow‐up. Decreased intraoperative blood loss (P < 0.001), total blood loss (P < 0.001), transfusion rate (P = 0.004), and length of stay (P < 0.001) were found in the ERAS group; no significant differences were found in operative time and hospitalization costs between the two groups. Conclusion The ERAS program is safer and more efficacious in elderly TKA patients compared to the traditional pathway. It could effectively relieve perioperative pain and improve joint function, and reduce blood transfusion, length of stay, and total complications without increasing short‐term mortality.
Our previous studies discovered that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) and long-bone dysplasia in offspring rats, accompanied by maternal glucocorticoid over-exposure. This study is to explore whether intrauterine high glucocorticoid level can cause endochondral ossification retardation and clarify its molecular mechanism in PCE fetal rats. Pregnant Wistar rats were intragastrically administered 30 and 120 mg/kg day of caffeine during gestational days (GDs) 9–20, then collected fetal serum and femurs at GD20. In vitro, primary chondrocytes were treated with corticosterone (0–1250 nM), caffeine (0–100 μM), mitogen-inducible gene 6 (Mig-6) siRNA and epidermal growth factor receptor (EGFR) siRNA, respectively, or together. Results showed that the hypertrophic chondrocytes zone (HZ) of PCE fetal femur was widened. Meanwhile, the expression levels of chondrocytes terminal differentiation genes in the HZ were decreased, and the chondrocytes apoptosis rate in the HZ was decreased too. Furthermore, PCE upregulated Mig-6 and suppressed EGFR expression in the HZ. In vitro, a high-concentration corticosterone (1250 nM) upregulated Mig-6 expression, inhibit EGFR/c-Jun N-terminal kinase (JNK) signaling pathway and terminal differentiation genes expression in chondrocytes and reduced cell apoptosis, and these above alterations could be partly reversed step-by-step after Mig-6 and EGFR knockdown. However, caffeine concentration dependently increased chondrocyte apoptosis without significant changes in the expression of terminal differentiation genes. Collectively, PCE caused endochondral ossification retardation in the female fetal rats, and its main mechanism was associated with glucocorticoid (rather than caffeine)-mediated chondrocyte terminal differentiation suppression by the upregulation of Mig-6 and then inhibition of EGFR/JNK pathway-mediated chondrocyte apoptosis.
Prenatal dexamethasone exposure (PDE) induces developmental toxicities of multiple organs in offspring. Here, we verified the intergenerational effect of low peak bone mass induced by PDE and investigated its intrauterine programming mechanism. Pregnant rats were injected subcutaneously with 0.2 mg/kg/d dexamethasone from gestation day (GD) 9 to 20. Some pregnant rats were killed for the fetuses on GD20, and the rest went on to spontaneous labor to produce the first-generation (F1) offspring. The adult F1 male offspring were mated with normal females to produce the F2 offspring. In vivo, PDE leads to low peak bone mass in F1 male offspring rats at postnatal week (PW) 28. Furthermore, PDE reduced the bone mass in F1 male offspring from GD20 to PW12. Meanwhile, the osteogenic differentiation was suppressed and the local renin–angiotensin system (RAS) was activated continuously by PDE. Moreover, the histone 3 lysine 27 acetylation (H3K27ac) level in angiotensin-converting enzyme (ACE) promoter region was increased by PDE from GD20 to PW12. Likewise, PDE induced the low peak bone mass and the activated local RAS in F2 male offspring. Meaningfully, the H3K27ac level of ACE was increased by PDE in the F2 offspring. In vitro, dexamethasone inhibited bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation and promoted RAS activation. Furthermore, dexamethasone recruited CCAAT/enhancer-binding protein α and p300 into the BMSCs nucleus by activating glucocorticoid receptor, which cooperatively increased the H3K27ac level in the ACE promoter region. In conclusion, PDE induced the low peak bone mass and its intergenerational effect, which was mediated by sustained activation of RAS via increasing H3K27ac level of ACE.
BACKGROUND AND PURPOSEPrenatal exposure to dexamethasone slows down fetal linear growth and bone mineralization but the regulatory mechanism remains unknown. Here we assessed how dexamethasone regulates bone development in the fetus. EXPERIMENTAL APPROACHDexamethasone (1 mg·kg À1 ·day À1 ) was injected subcutaneously every morning in pregnant rats from gestational day (GD)9 to GD20. Fetal femurs and tibias were harvested at GD20 for histological and gene expression analysis. Femurs of 12-week-old female offspring were harvested for microCT (μCT) measurement. Primary chondrocytes were treated with dexamethasone (10, 50, 250 and 1000 nM). KEY RESULTSPrenatal dexamethasone exposure resulted in accumulation of hypertrophic chondrocytes and delayed formation of the primary ossification centre in fetal long bone. The retardation was accompanied by reduced maturation of hypertrophic chondrocytes, decreased osteoclast number and down-regulated expression of osteocalcin and bone sialoprotein in long bone. In addition, the mitogen-inducible gene-6 (Mig6) and osteoprotegerin (OPG) expression were stimulated, and the receptor activator of NF-κB ligand (RANKL) expression was repressed. Moreover, dexamethasone activated OPG and repressed RANKL expression in both primary chondrocytes and primary osteoblasts, and the knockdown of Mig6 abolished the effect of dexamethasone on OPG expression. Further, μCT measurement showed loss of bone mass in femur of 12-week-old offspring with prenatal dexamethasone exposure. CONCLUSIONS AND IMPLICATIONSPrenatal dexamethasone exposure delays endochondral ossification by suppressing chondrocyte maturation and osteoclast differentiation, which may be partly mediated by Mig6 activation in bone. Bone development retardation in the fetus may be associated with reduced bone mass in later life. Abbreviations
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