To determine the effect of Dexamethasone on post-operative pain management in patients undergoing Total Knee Arthroplasty in terms of numerical pain rating scale and total opoid consumption. This Randomized Controlled Trail (RCT) was conducted for 02 years (7th September 2015 to 6th September 2017). All patients undergoing primary Unilateral Total Knee Replacement (TKR) for Osteoarthritis knee were included in the study. Patients with poor glycemic control (HbA1c > 7.6), Hepatic/Renal failure, corticosteroids/ Immunosuppression drug usage in the last 06 months, known psychiatric illnesses were excluded from the study. All patients were operated by consultant Orthopaedic surgeon under Spinal Anaesthesia and tourniquet control using medial para-patellar approach. Patients were randomly divided into 02 groups, A and B. 79 patients were placed in each group. Group A given 0.1mg/kg body weight Dexamethasone Intravenously 15 minutes prior to surgery and another dose 24 hours post-operatively while in group B (control group) no Dexamethasone given. Post-operative pain using the numerical pain rating scale (NRS) and total narcotics consumed converted to morphine dose equivalent noted immediately post-op, 12-, 24- and 48-hours post-operatively. Data analysis done using SPSS version 23. A total of 158 patients were included in the study. Of the total, 98 (62.02%) were females and 60 (37.98%) males. Average BMI of patients 26.94 ±3.14 kg/m2. Patients in group A required less post-operative analgesics (p < 0 .01) and had a better numerical pain rating scale score (p < 0 .01) as compared to group B. Pain scores at 24- and 48-hours post-op were significantly less for Dexamethasone group (p < 0 .01). Use of Dexamethasone per- and post-operatively reduces the pain and amount of analgesics used in patients undergoing TKA. For any reader queries, please contact . drjunaidrmc@gmail.com

To study in resolution of triggering 12 months after injection with either a soluble methylprednisolone acetate or dexamethasone for idiopathic trigger finger. Twenty-eight patients were enrolled in a prospective randomized controlled trial comparing methylprednisolone acetate and dexamethasone injection for idiopathic trigger finger. Twenty-seven patients completed the 6-week follow-up (11 methylprednisolone acetate arm, 16 dexamethasone arm) and thirteen patients completed the 3-month follow-up (4 methylprednisolone acetate arm, 9 dexamethasone arm). Outcome measures included resolution of triggering, recurrence rate of trigger finger, satisfaction on a visual analog scale, tender, snapping, locking, the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and tip to palm distance (mm.) at 2, 6, 12 and 24 weeks follow-up. Eight patients were repeated a second injection (3 methylprednisolone acetate arm, 5 dexamethasone arm) at 6-week follow-up. To preserve autonomy, patients were permitted operative treatment any time. The analysis was according to intention to treat principles. Six weeks after injection. Absence of triggering was documented in 6 of 11 patients in the methylprednisolone cohort and in 6 of 16 patients in the dexamethasone cohort. The rate 3-month after injection were 2 of 4 patients in the methylprednisolone cohort and in 8 of 9 patients in the dexamethasone cohort. There were no significant difference between recurrence rate of trigger finger, satisfaction on a visual analog scale, tender, snapping, locking, the Disabilities of the Arm, Shoulder and Hand (DASH) scores and tip to palm distance (mm.) at 2, 6, 12 and 24 weeks follow-up. Although there were no differences 3months after injection, our data suggest that in the dexamethasone cohort was better in resolution of triggering than the methylprednisolone cohort at 12-week follow-up

Introduction. Perioperative dexamethasone has been shown to effectively reduce post-operative nausea and vomiting and aide in analgesia after total joint arthroplasty (TJA), however systemic glucocorticoid therapy is carries the theoretical risk of increased susceptibility to prosthetic joint infection (PJI), increased white blood cell (WBC) counts, and increased blood glucose levels. The purpose of this study is to determine the effect of dexamethasone on PJI, WBC count, and blood glucose levels in diabetic and non-diabetic patients undergoing TJA. Methods. A retrospective chart review of all patients receiving primary total joint (hip or knee) arthroplasty between January 1, 2013 and December 31, 2015 (n = 1818) was conducted. The patients were divided into two main cohorts: those receiving dexamethasone (n = 1426) and those not receiving dexamethasone (n = 392); these groups were further subdivided into diabetic (n = 428 dexamethasone; n = 129 no dexamethasone) and non-diabetic patients (n = 998 dexamethasone, n = 263 no dexamethasone). The primary outcome was PJI; secondary measures included in (WBC) count, glucose levels, and days to infection. Statistics were carried out using chi-squared or ANOVA tests. Results. Of the 1818 joints, 1.05% (19) developed PJI; there was no significant difference between the dexamethasone and no dexamethasone groups (p = 0.1023): 12 (0.84%) in the dexamethasone group and 7 (1.79%) in the no-dexamethasone group. Additionally there was no significant effect on the increase in WBC count (p = 0.1784) or on the increase in blood glucose (p = 0.3120). Further subdividing the patients, there was a significantly higher rate of infection in those who received dexamethasone with diabetes (2.1%) compared to those without diabetes (0.30%) (p = 0.0016). Further, diabetics who received dexamethasone had a significantly greater elevation in blood glucose (p < 0.0001) compared to non-diabetics, but no significant change in WBC count (p = 0.6993). Conclusion. Perioperative intravenous dexamethasone had no statistically significant effect on the overall rate of prosthetic joint infections in primary total hip or knee arthroplasty; however diabetic patients had a significantly higher rate of infection compared to non-diabetics when given dexamethasone. WBC counts were not affected overall by administration of dexamethasone, or with stratification into diabetics and non-diabetics. Glucose levels were not effected by administration of dexamethasone

Aim. Dexamethasone is often used as part of multimodal analgesia to prevent postoperative nausea and vomiting (PONV) and also to reduce postoperative pain. Because glucocorticoids have immunosuppressive and glucose-rising effects, the aim of current study was to examine if dexamethasone may be used safely in arthroplasty surgery. Methods. All consecutive total primary and revision hip and knee arthroplasties performed in the Hospital District of Helsinki and Uusimaa, Peijas Hospital were analyzed (n=18 872). Emergency operations, for example total hip arthroplasties for femur fractures, were also included. Prospective surveillance for postoperative infections was performed. All infections meeting the Musculoskeletal Infection Society definition for prosthetic joint infection (PJI) were included. Results. A total of 189 (1.0%) PJIs occurred: 0.8% after all primary arthroplasties and 1.9% after revision arthroplasties. The PJI rate after the emergency operations was 2.3 % (19/796). The PJI rate in the dexamethasone group was 1.0% (30/2 922) and in the non-dexamethasone group 1.0% (159/15 950), with no significant difference in the PJI incidence (P=0.849). The median time from the index operation to the infection was 16.0 (Q1–Q3 13.0–23.0) days. Total of 35 causative bacteria were cultured from the 30 PJI in dexamethasone group and 169 bacteria from the 159 PJI in non-dexamethasone group with no significant difference: Staphylococcus aureus (40.0% and 45.0%, respectively, P=1.000), Staphylococcus epidermidis (14.3% and 10.7%, P=0.375), other coagulase-negative staphylococci (11.4% and 11.8%, P=0.200), Streptococcus agalactiae (11.4% and 11.8%, P=0.695), Streptococcus betahemolyticus G (8.6% and 2.4%, P=0.081), other streptococci (0.0% and 4.1%, P=0.599), Enterococcus faecalis (2.9% and 5.3%, P=1.000), Enterobacter cloacae (2.9% and 3.6%, P=1.000), Pseudomonas aeruginosa (2.9% and 1.8%, P=0.502), and other bacteria (14.3% and 8.8%, P=0.544). Only one methicillin-resistant Staphylococcus aureus (MRSA) was detected in dexamethasone group. The proportion of polymicrobial PJIs was similar in both groups: 13.3% and 8.8%, respectively (p=0.495). Conclusions. In our study material, the use of 5–10mg dose of dexamethasone did not increase the incidence of postoperative PJI. The single 5–10 dose of dexamethasone may be safely used to prevent PONV and as part of multimodal analgesia on patients undergoing arthroplasty operation

Introduction: The response of osteoblasts to dexamethasone is dose-dependent. While low doses are used to stimulate osteoblasts to maintain their phenotype, high doses are cytotoxic. The purpose of this study was to test the hypothesis that mechanical stimulation alters the response of osteoblast-like cells to dexamethasone. Materials & Methods: MG-63 cells were propagated on 6-well Flexcell plates (flexible silicone membranes) under standard culture conditions. One half of the plates were subjected to biaxial strain at a frequency of 0.5 Hz through an imposed vacuum pressure of -7kPa (~1% stretch; 0.01 strain) for 42 hours using the Flexercell Apparatus. Replicate samples were maintained under static conditions. Simultaneously, the cells were exposed to either 0, .001, .01, or .1 nM of dexamethasone. The wells were then spiked with tritiated thymidine for 6 hours. The results were normalized to the control values. Triplicate wells were included for each experimental condition; and the experiment was repeated four times. Data were analyzed by JMP statistical package (SAS). Results: Increasing doses of dexamethasone resulted in decreasing cellular proliferation. For the unflexed cells, we noted the following reduction in proliferative capacity: 0.86% ± 0.09 (.001nM), 0.50% ± 0.07 (.01nM), and 0.39% ± 0.07 (.1nM). Similar results were observed for the cells exposed to cyclic loading: 0.89% ± 0.12 (.001nM), 0.52% ± 0.08 (.01nM), and 0.47% ± 0.07 (.1nM). Discussion: Our results confirmed the work of others that there is a decrease in the proliferation of osteoblasts (incubated under static conditions) when exposed to high levels of dexamethasone. Although cyclic loading had no effect on the proliferative response of osteoblasts to dexamethasone, it may still have had an effect on cellular metabolism or function, which remains to be evaluated

Objectives. To assess the structure and extracellular matrix molecule expression of osteogenic cell sheets created via culture in medium with both dexamethasone (Dex) and ascorbic acid phosphate (AscP) compared either Dex or AscP alone. Methods. Osteogenic cell sheets were prepared by culturing rat bone marrow stromal cells in a minimal essential medium (MEM), MEM with AscP, MEM with Dex, and MEM with Dex and AscP (Dex/AscP). The cell number and messenger (m)RNA expression were assessed in vitro, and the appearance of the cell sheets was observed after mechanical retrieval using a scraper. β-tricalcium phosphate (β-TCP) was then wrapped with the cell sheets from the four different groups and subcutaneously implanted into rats. Results. After mechanical retrieval, the osteogenic cell sheets from the MEM, MEM with AscP, and MEM with Dex groups appeared to be fragmented or incomplete structures. The cell sheets cultured with Dex/AscP remained intact after mechanical retrieval, without any identifiable tears. Culture with Dex/AscP increased the mRNA and protein expression of extracellular matrix proteins and cell number compared with those of the other three groups. More bridging bone formation was observed after transplantation of the β-TCP scaffold wrapped with cell sheets cultured with Dex/AscP, than in the other groups. Conclusions. These results suggest that culture with Dex/AscP improves the mechanical integrity of the osteogenic cell sheets, allowing retrieval of the confluent cells in a single cell sheet structure. This method may be beneficial when applied in cases of difficult tissue reconstruction, such as nonunion, bone defects, and osteonecrosis. Cite this article: M. Akahane, T. Shimizu, T. Kira, T. Onishi, Y. Uchihara, T. Imamura, Y. Tanaka. Culturing bone marrow cells with dexamethasone and ascorbic acid improves osteogenic cell sheet structure. Bone Joint Res 2016;5:569–576. DOI: 10.1302/2046-3758.511.BJR-2016-0013.R1

Single shot interscalene blocks are an effective analgesic for arthroscopic shoulder surgery. However, patients receiving these blocks are often found to be in significant pain when the block wears off, usually in the late evening or early hours of the morning. Overnight admission is currently routine in our unit, to ensure adequate analgesia can be administered during this period. Recent studies have suggested that adding dexamethasone to the local anaesthetic agent can prolong the duration of the block. We carried out a prospective study to assess whether addition of dexamethasone to brachial plexus blocks could reduce patient's post-operative analgesic demands and allow safe discharge on the same day after surgery. Twenty-six patients undergoing arthroscopic shoulder surgery during a morning theatre list, had ultrasound guided brachial plexus blocks using a mixture of 0.25% bupivacaine 20–30ml with 2–3mg of dexamethasone. All were admitted to the ward afterwards for analgesia and physiotherapy. Pain numerical rating scores (0–10) were recorded at rest in recovery one hour postoperatively by the attending anaesthetist and on active movement of the shoulder joint 24 hours after surgery by the attending physiotherapist. A standardised analgesia regime was prescribed with regular and as required medication, including as required strong opiates. Mean pain scores in recovery were 0.31 and on the morning after surgery were 2.38. Sixteen out of 26 required no further analgesia, with only 3 out of the 10 who did requiring opiates. The use of dexamethasone provides adequate analgesia for a prolonged period for most patients after brachial plexus block for shoulder surgery and does not result in a significant analgesic requirement when the block wears off. This may provide support for avoiding overnight admission in selected patients after arthroscopic shoulder surgery

Introduction and Aims: This randomised, double-blind, placebo-controlled study evaluated the safety and effectiveness of dermal iontophoretic administration of Dexamethasone Sodium Phosphate 0.4% Injection, USP versus placebo in patients with medial and lateral elbow epicondylitis. Method: 199 patients with elbow epicondylitis received 40 mA-min of either active or placebo treatment on six occasions. Treatments were spaced one to three days apart and were completed within 15 days. Efficacy variables included patient and investigator global evaluation of improvement, patient and investigator pain evaluation, patient evaluation of symptoms, investigator disease severity assessment and investigator evaluation of tenderness. Baseline scores were compared with scores two days and one month after the sixth treatment. Results: Dexamethasone produced a 23 mm improvement in patient visual analog scale ratings compared with 14 mm for placebo (p=0.012) at two days and 24 mm compared with 19 mm (p=0.249) at one month. More dexamethasone patients than placebo patients had a score of moderate or better on the investigator global improvement score (52% vs 33%, p=0.013) at two days. This was not significant at one month (54% vs 49%, p=0.650). Investigator pain scores and tenderness scores favoured dexamethasone over placebo (p=0.019 and p< 0.001, respectively) at two days. Patients completing six treatments in ≤10 days appeared to show better efficacy than patients completing treatments over a longer period of time. Conclusion: Iontophoresis treatment was well tolerated by the majority of the patients and was effective in reducing symptoms of epicondylitis at short-term follow-up

Controlling postoperative pain and nausea after total joint arthroplasty remains an important challenge. We conducted a prospective, randomized controlled trial with 120 patients to determine if the addition of perioperative dexamethasone to a multimodal regimen improves antiemetic and analgesic control, enhances mobility, and shortens hospital length of stay after total hip and knee arthroplasty. Patients administered 10 mg of intravenous dexamethasone intraoperatively consumed less daily rescue anti-emetic and analgesic medication, reported superior VAS nausea and pain scores, ambulated further distances, and had a significantly shorter length of stay compared to the control group (p < 0.05). A second, 24-hour postoperative dose of 10 mg intravenous dexamethasone provided significant additional pain and nausea control and further reduced length of stay (p < 0.05). No adverse events were detected with the administration of the intraoperative and/or postoperative dexamethasone

Introduction: Our previous study found that glucocorticoids shifted the properties of osteogenesis to adipogenesis in murine marrow stem cells. These effects may be one of the important mechanisms in the pathogenesis of osteonecrosis. Statins prevented these steroid effects. In this study, we investigated the effects of dexamethasone and lovastatin on the expressions of bone morphogenetic protein-2 (BMP2) in the bone marrow stroma cells cultured from osteonecrotic patients. Materials and Methods: Bone marrow fluid aspiration from iliac crest was performed in osteonecrosis (ON) and non-ON patients after surgical treatment for their hip disorder. The mean age of the patients was 59 years in the ON group and 63 years in the non-ON group. Nucleated stroma cells were isolated from bone marrow fluid by percol separation. The third passage cultures were used for experiments. Drug treatments for cultures included dexamethasone (10. −7. M), lovastatin (10. −6. M), and dexamethasone plus lovastatin for 4 days. BMP-2 mRNA expression was evaluated by RT-PCR. Different responses to drugs between the ON group and the non-ON group were compared. Results: Bone marrow stroma cells of ON patients were found to be more susceptible to the suppressive effect of dexamethasone on BMP2 expression. Discussion: Lovastatin stimulated the osteogenesis and reversed the steroid suppressive effect in bone marrow stroma cells in non-ON cases. However, this reverse effect was found to be mild in ON cases

The effects of dexamethasone (dex), during in vitro human osteogenesis, are contrasting. Indeed, dex downregulates SOX9 during osteogenic differentiation of human bone marrow mesenchymal stromal cells (HBMSCs). However, dex also promotes PPARG expression, resulting in the formation of adipocyte-like cells within the osteogenic monolayers. The regulation of both SOX9 and PPARG seems to be downstream the transactivation activity of the glucocorticoid receptor (GR), thus the effect of dex on SOX9 downregulation is indirect. This study aims at determining whether PPAR-γ regulates SOX9 expression levels, as suggested by several studies. HBMSCs were isolated from bone marrow of patients with written informed consent. HBMSCs were cultured in different osteogenic induction media containing 10 or 100 nM dex. Undifferentiated cells were used as controls. Cells were treated either with a pharmacological PPAR-γ inhibitor T0070907 (donors n=4) or with a PPARG-targeting siRNA (donors n=2). Differentiation markers or PPAR-γ target genes were analysed by RT-qPCR. Mineral deposition was assessed by ARS staining. Two-way ANOVA followed by a Tukey's multiple comparison test compared the effects of treatments. At day 7, T0070907 downregulated ADIPOQ and upregulated CXCL8, respectively targets of PPAR-γ-mediated transactivation and transrepression. RUNX2 and SOX9 were also significantly downregulated in absence of dex. PPARG was successfully downregulated by siRNA. ADIPOQ expression was also inhibited, while CXCL8 did not show any significant difference between siRNA treatment groups. RUNX2 was downregulated by the PPARG-siRNA treatment in presence of 100 nM dexamethasone, while SOX9 levels were not affected. ARS showed no change in the mineralization levels when PPARG expression or activity was inhibited. Understanding how dex regulates HBMSC differentiation is of pivotal importance to refine current in vitro models. These results suggest that PPARG does not mediate SOX9 downregulation. Unexpectedly, RUNX2 expression was also unaltered or even downregulated after PPAR-γ inhibition. Acknowledgements: AO Foundation, AO Research Institute (CH) and PRIN 2017 MUR (IT) for financial support

Objectives. Healing in cancellous metaphyseal bone might be different from midshaft fracture healing due to different access to mesenchymal stem cells, and because metaphyseal bone often heals without a cartilaginous phase. Inflammation plays an important role in the healing of a shaft fracture, but if metaphyseal injury is different, it is important to clarify if the role of inflammation is also different. The biology of fracture healing is also influenced by the degree of mechanical stability. It is unclear if inflammation interacts with stability-related factors. Methods. We investigated the role of inflammation in three different models: a metaphyseal screw pull-out, a shaft fracture with unstable nailing (IM-nail) and a stable external fixation (ExFix) model. For each, half of the animals received dexamethasone to reduce inflammation, and half received control injections. Mechanical and morphometric evaluation was used. Results. As expected, dexamethasone had a strong inhibitory effect on the healing of unstable, but also stable, shaft fractures. In contrast, dexamethasone tended to increase the mechanical strength of metaphyseal bone regenerated under stable conditions. Conclusions. It seems that dexamethasone has different effects on metaphyseal and diaphyseal bone healing. This could be explained by the different role of inflammation at different sites of injury. Cite this article: Bone Joint Res 2015;4:170–175

Objectives. The aims of this study were to determine whether the administration of anti-inflammatory and antifibrotic agents affect the proliferation, viability, and expression of markers involved in the fibrotic development of the fibroblasts obtained from arthrofibrotic tissue in vitro, and to evaluate the effect of the agents on arthrofibrosis prevention in vivo. Methods. Dexamethasone, diclofenac, and decorin, in different concentrations, were employed to treat fibroblasts from arthrofibrotic tissue (AFib). Cell proliferation was measured by DNA quantitation, and viability was analyzed by Live/Dead staining. The levels of procollagen type I N-terminal propeptide (PINP) and procollagen type III N-terminal propeptide (PIIINP) were evaluated with enzyme-linked immunosorbent assay (ELISA) kits. In addition, the expressions of fibrotic markers were detected by real-time polymerase chain reaction (PCR). Fibroblasts isolated from healthy tissue (Fib) served as control. Further, a rabbit model of joint contracture was used to evaluate the antifibrotic effect of the three different agents. Results. Dexamethasone maintained the viability and promoted the proliferation of AFib. Diclofenac decreased the viability and inhibited the cell proliferation during the first week of cultivation. However, decorin inhibited AFib proliferation and downregulated the expressions of fibrotic markers. Additionally, decorin could improve the flexion contracture angle and inhibit the deposition of interstitial matrix components in the rabbit joint model. Conclusion. Decorin decreased the expression of myofibroblast markers in AFib, inhibited the proliferation of AFib, and prevented the initial procedure of arthrofibrosis in vivo, suggesting that decorin could be a promising treatment to inhibit the development of arthrofibrosis. Cite this article: X. Tang, S. Teng, M. Petri, C. Krettek, C. Liu, M. Jagodzinski. The effect of anti-inflammatory and antifibrotic agents on fibroblasts obtained from arthrofibrotic tissue: An in vitro and in vivo study. Bone Joint Res 2018;7:213–222. DOI: 10.1302/2046-3758.73.BJR-2017-0219.R2

A novel injectable hydrogel based on DNA and silicate nanodisks was fabricated and optimized to obtain a suitable drug delivery platform for biomedical applications. Precisely, the hydrogel was designed by combining two different type of networks: a first network (type A) made of interconnections between neighboring DNA strands and a second one (type B) consisting of electrostatic interactions between the silicate nanodisks and the DNA backbone. The silicate nanodisks were introduced to increase the viscosity of the DNA physical hydrogel and improve their shear-thinning properties. Additionally, the silicate nanodisks were selected to modulate the release capability of the designed network. DNA 4% solutions were heated at 90°C for 45 seconds and cooled down at 37°C degree for two hours. In the second step, the silicate nanodisks suspension in water at different concentrations (0.1 up to 0.5%) were then mixed with the pre-gel DNA hydrogels to obtain the nanocomposite hydrogels. Rheological studies were carried out to investigate the shear thinning properties of the hydrogels. Additionally, the hydrogels were characterized by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron microscopy. The hydrogels were loaded with the osteoinductive drug dexamethasone and its release was tested in vitro in phosphate buffer pH 7.4. The drug activity upon release was tested evaluating the osteogenic differentiation of human adipose derived stem cells (hASCs) in vitro through analysis of main osteogenic markers and quantification of alkaline phosphatase activity and calcium deposition. Finally, the hydrogels were tested in vivo and injected into cranial defects in rats to assess their biocompatibility and bone regeneration potential. The inclusion of the silicate nanodisks increased the viscosity of the hydrogels and the best results were obtained with the highest concentration of the nanoclay (0.5%). The hydrogels possessed shear-thinning properties as demonstrated by cyclic strain sweep tests and were able to recover their original storage modulus G' upon removal of strain. Such improvement in the injectable properties of the formulated hydrogels was mainly attributed to the formation of electrostatic interactions between the silicate nanodisks and the phosphate groups of the DNA backbone as confirmed by XPS analysis of the O, N, and P spectra. Additionally, laponite was able to sustain the release of the osteoinductive drug dexamethasone which was instead completely released from the DNA-based hydrogels after a week. The drug after being released was still active and promoted the osteogenic differentiation of hASCs as confirmed by ALP expression and expression of main osteogenic markers including ALP and COLA1. Finally, the gels proved to be biocompatible in vivo when injected into cranial defects and promoted bone formation at the periphery of the defect after a month post-treatment. A novel injectable shear-thinning DNA-based hydrogel was characterized and tested for its drug delivery properties. The hydrogel can promote the sustain release of a small molecule like dexamethasone and be biocompatible in vitro and in vivo. Due to these promising findings, the designed system could find also applicability for the delivery of growth factors or other therapeutic molecules

Chronic glucocorticoid use causes osteogenesis loss, accelerating the progression of osteoporosis. Histone methylation is shown to epigenetically increase repressive transcription, altering lineage programming of mesenchymal stem cells (MSC). This study is undertaken to characterize the action of histone demethylase UTX to osteogenic lineage specification of bone-marrow MSC and bone integrity upon glucocorticoid treatment. Bone-marrow MSC were incubated in osteogenic medium containing supraphysiological dexamethasone. Osteogenic gene expression and mineralized nodule formation were probed using RT-PCR and von Kossa staining. The enrichment of trimethylated lysine 27 at histone 3 (H3K27me3) in Dkk1 promoter was quantified using chromatin immunoprecipitation-PCR. Bone mass and trabecular morphometry in methylprednisolone-treated skeletons were quantified using microCT analysis. Supraphysiological dexamethasone decreased osteogenic genes Runx2 and osteocalcin expression and mineralized matrix production along with reduced UTX expression in MSC. Forced UTX expression attenuated the glucocorticoid-mediated loss of osteogenic differentiation, whereas UTX knockdown provoked osteogenesis loss and cytoplasmic oil overproduction. UTX demethylated H3K27 and reduced the glucocorticoid-mediated the H3K27 enrichment in Dkk1 promoter, reversing beta-catenin signal, but downregulating Dkk1 production by MSC. In vivo, treatment with UTX inhibitor GSK-J4 significantly suppressed bone mineral density, trabecular volume, and thickness along with porous trabecular, fatty marrow and disturbed beta-catenin/Dkk1 histopathology comparable with glucocorticoid-induced osteoporosis condition. This study offers a productive insight into how UTX protects MSC from methylated histone-mediated osteogenesis repression in the development of glucocorticoid-induced osteoporosis

Objective. Excessive mechanical stress on synovial joints causes osteoarthritis (OA) and results in the production of prostaglandin E2 (PGE2), a key molecule in arthritis, by synovial fibroblasts. However, the relationship between arthritis-related molecules and mechanical stress is still unclear. The purpose of this study was to examine the synovial fibroblast response to cyclic mechanical stress using an in vitro osteoarthritis model. Method. Human synovial fibroblasts were cultured on collagen scaffolds to produce three-dimensional constructs. A cyclic compressive loading of 40 kPa at 0.5 Hz was applied to the constructs, with or without the administration of a cyclooxygenase-2 (COX-2) selective inhibitor or dexamethasone, and then the concentrations of PGE2, interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), IL-6, IL-8 and COX-2 were measured. Results. The concentrations of PGE2, IL-6 and IL-8 in the loaded samples were significantly higher than those of unloaded samples; however, the concentrations of IL-1β and TNF-α were the same as the unloaded samples. After the administration of a COX-2 selective inhibitor, the increased concentration of PGE2 by cyclic compressive loading was impeded, but the concentrations of IL-6 and IL-8 remained high. With dexamethasone, upregulation of PGE2, IL-6 and IL-8 was suppressed. Conclusion. These results could be useful in revealing the molecular mechanism of mechanical stress in vivo for a better understanding of the pathology and therapy of OA. Cite this article: Bone Joint Res 2014;3:280–8

Introduction. Day Case Surgery (defined as same day discharge) is a priority within the National Health Service and has been shown to provide beneficial outcomes for patients and hospitals. We report our experience developing a Day Case Programme for Total Ankle Replacement (TAR). Methods. Prior to the introduction of a Day Case Programme, average length of stay following TAR in our unit was 3.5 days. Stakeholders were consulted about ways in which same day discharge could be facilitated. Patients' post-operative pain charts were reviewed prior to the introduction of this programme. Inclusion criteria included non-complex surgery (anticipated tourniquet < 2hrs), friend or relative support and pre-operative walking-aid assessment. An enhanced recovery protocol included long-acting popliteal block and dexamethasone. Patients were discharged with opiate analgesia and written pain instructions. Patients were asked to complete a pain and satisfaction questionnaire. Patient Reported Outcome Measures (PROMs) were recorded. Results. From September 2017 to April 2019 21 of 70 patients underwent TAR as a Day Case. Mean age was 67 years (43-85 years). Complications included two delayed wound healings and one representation on day three with urinary retention. No patients reported post-operative nausea or vomiting, 60% did not use Oramorph at home. Average Visual Analogue Score for pain was 23/100 on day one and 21/100 day three post-operatively. There was no significant difference in pre-operative or overall change in MOXFQ, VAS or EQ5D PROMS. Conclusions. Early results suggest that Day Case Total Ankle Replacements are safe. Appropriate patient selection is necessary. Day Case Surgery relies on support and communication between multiple teams to organise and run effectively

Perioperative glucocorticoids have been used as a successful non-opioid analgesic adjunct for various orthopaedic procedures. Here we describe an ongoing randomized control trial assessing the efficacy of a post-operative methylprednisolone taper course on immediate post-operative pain and function following surgical distal radius fixation. We hypothesize that a post-operative methylprednisolone taper course following distal radius fracture fixation will lead to improved patient pain and function. This study is a randomized control trial (NCT03661645) of a group of patients treated surgically for distal radius fractures. Patients were randomly assigned at the time of surgery to receive intraoperative dexamethasone only or intraoperative dexamethasone followed by a 6-day oral methylprednisolone (Medrol) taper course. All patients received the same standardized perioperative pain management protocol. A pain journal was used to record visual analog pain scores (VAS-pain), VAS-nausea, and number of opioid tablets consumed during the first 7 post-operative days (POD). Patients were seen at 2-weeks, 6-weeks, and 12-weeks post-operatively for clinical evaluation and collection of patient reported outcomes (Disabilities of the Arm, Shoulder and Hand Score [qDASH]). Differences in categorical variables were assessed with χ2 or Fischer's exact tests. T-tests or Mann-Whitney-U tests were used to compare continuous data. Forty-three patients were enrolled from October 2018 to October 2019. 20 patients have been assigned to the control group and 23 patients have been assigned to the treatment group. There were no differences in age (p=0.7259), Body Mass Index (p=0.361), race (p=0.5605), smoking status (p=0.0844), or pre-operative narcotic use (p=0.2276) between cohorts. 83.7% (n=36) of patients were female and the median age was 56.9 years. No differences were seen in pre-operative qDASH (p=0.2359) or pre-operative PRWE (p=0.2329) between groups. In the 7 days following surgery, patients in the control group took an average of 16.3 (±12.02) opioid tablets, while those in the treatment group took an average of 8.71 (±7.61) tablets (p=0.0270). We see that significant difference in Opioid consumption is formed at postoperative day two between the two groups with patients in the control group taking. Patient pain scores decreased uniformly in both groups to post-operative day 7. Patient pain was not statistically from POD0 to POD2 (p=0.0662 to 0.2923). However, from POD4 to POD7 patients receiving the methylprednisolone taper course reported decreased pain (p=0.0021 to 0.0497). There was no difference in qDASH score improvement at 6 or 12 weeks. Additionally, no differences were seen for wrist motion improvement at 6 or 12 weeks. A methylprednisolone taper course shows promise in reducing acute pain in the immediate post-operative period following distal radius fixation. Furthermore, although no statistically significant reductions in post-operative opioid utilization were noted, current trends may become statistically significant as the study continues. No improvements were seen in wrist motion or qDASH and continued enrollment of patients in this clinical trial will further elucidate the role of methylprednisolone for these outcomes

Chronic postoperative pain (CPP) can occur in elective mid/hindfoot and ankle surgery patients. Multimodal pain management has been reported to reduce postoperative pain and opioid use, which may prevent the development of CPP. However, few studies have examined the impact of multimodal pain management strategies on CPP following complex elective mid/hindfoot and ankle surgery. The purpose of this study was to 1) evaluate current pain management strategies and 2) determine current definitions, incidence, and prevalence of CPP after elective mid/hindfoot and ankle surgery. Three databases (MEDLINE, Embase and Cochrane Library) were manually and electronically searched for English language studies published between 1990 and July 2017. For the first aim, we included comparative studies of adults undergoing elective mid/hindfoot and ankle surgery that investigated pre-, peri- or postoperative pain management. For the second aim, we included observational studies examining CPP definition, incidence, and prevalence. Two reviewers independently screened titles and abstracts, followed by full texts. Conflicts were resolved through discussion with a third reviewer. Reviewers also independently assessed the quality of studies meeting inclusion criteria using the Joanna Briggs Institute Critical Appraisal Checklist. For the first aim, 1159 studies were identified by the primary search, and seven high quality randomized controlled trials were included. Ankle arthroplasty or fusion and calcaneal osteotomy were the most common procedures performed. The heterogeneity of study interventions, though all regional anesthesia techniques, precluded meta-analysis. Most investigated continuous popliteal, sciatic and/or femoral nerve blockade. Participants were typically followed up to 48 hours postoperatively to examine postoperative pain levels and morphine consumption in hospital. Interventions effective at reducing postoperative pain and/or morphine consumption included inserting popliteal catheters using ultrasound instead of nerve stimulation guidance, perineural dexamethasone, and adding continuous femoral blockade to continuous popliteal blockade. Using more than one analgesic was generally more effective than using a single agent. Only two studies examined longer term pain management. One found no difference in pain levels and opioid consumption at two weeks with perineural or systemic dexamethasone use. The other found that pain with activity was significantly reduced at six months postoperatively with the addition of a femoral catheter infusion to a popliteal catheter infusion. For the second aim, only two studies of the 747 identified were selected. One prospective observational study defined CPP as moderate-to-severe pain at one year after foot and ankle surgery, and reported 21% and 43% of patients as meeting their definition at rest and with activity, respectively. The other study was a systematic review that reported 23–60% of patients experienced residual pain after total ankle arthroplasty. There is no standardized definition of CPP in this population, and incidence and prevalence are rarely reported and vary largely based on definition. Although regional anesthesia may be effective at reducing in-hospital pain and opioid consumption, evidence is very limited regarding longer-term pain management and associated outcomes following elective mid/hindfoot and ankle surgery

Osteoporosis is a common skeletal disorder characterised by a reduced bone mass and a progressive microarchitectural deterioration in bone tissue leading to bone fragility and susceptibility to fracture. The Wnt/β-catenin pathway is a major signaling cascade in bone biology, playing a key role in regulating bone development and remodeling, with aberrations in signalling resulting in disturbances in bone mass. Our objectives were to assess the gene expression profile of primary human osteoblasts (HOBs) exposed to dexamethasone with a view to identifying key genes driving bone mass regulation and to assess the effects of the Wnt antagonist Dickkopf-1 (Dkk1) on the bone profile of primary human osteoblasts exposed in vitro to dexamethasone. HOBs were cultured in vitro and exposed to 10–8M dexamethasone over a time course of 4hr, 12hr and 24hr. RNA isolation, cDNA synthesis, in vitro transcription and microarray analysis were performed. Microarray data was validated by quantitative real time RT-PCR. Dkk1 expression was silenced using small interfering RNA (siRNA). Quantitative RT-PCR was performed to confirm gene knockdown. Control and Dex-treated HOBs were compared with respect to bone turnover. Markers of bone turnover analyzed included alkaline phosphatase activity, calcium deposition, osteocalcin expression, along with cell proliferation and cellular apoptosis. Global changes in HOB gene expression were elicited by dexamethasone. Development associated gene pathways were co-ordinately dysregulated with the expression profile of key genes of the Wnt Pathway significantly altered. Dkk1 expression in HOBs was increased in response to dexamethasone exposure with an associated reduction in alkaline phosphatase activity, calcium deposition and osteocalcin expression. Silencing of Dkk1 expression, as confirmed by quantitative RT-PCR, was associated with an increase in alkaline phosphatase activity and calcium deposition, along with increased cell proliferation and reduced cellular apoptosis. Dkk1 is an antagonist of Wnt/β-catenin signalling and plays a key role in regulating bone development and remodeling. Silencing the expression of Dkk1 in primary human osteoblasts has been shown to rescue the effects of dexamethasone-induced bone loss in vitro. The pharmacological targeting of the Wnt/β-catenin signaling pathway offers an exciting opportunity for the development of novel anabolic bone agents to treat osteoporosis and disorders of bone mass