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The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule fibrosis in mice.

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It has been established that mechanical stimulation benefits tendon-bone (T-B) healing, and macrophage phenotype can be regulated by mechanical cues; moreover, the interaction between macrophages and mesenchymal stem cells (MSCs) plays a fundamental role in tissue repair. This study aimed to investigate the role of macrophage-mediated MSC chondrogenesis in load-induced T-B healing in depth.

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CRP is an acute-phase protein that is used as a biomarker to follow severity and progression in infectious and inflammatory diseases. Its pathophysiological mechanisms of action are still poorly defined. CRP in its pentameric form exhibits weak anti-inflammatory activity. The monomeric isoform (mCRP) exerts potent proinflammatory properties in chondrocytes, endothelial cells, and leucocytes. No data exist regarding mCRP effects in human intervertebral disc (IVD) cells. This work aimed to verify the pathophysiological relevance of mCRP in the aetiology and/or progression of IVD degeneration.

Abstract. Objectives. The term heterotopic ossification (HO) describes lamellar bone formation within soft tissues following injury. A genome-wide scan of patients after hip arthroplasty has identified that variation within the lncRNA CASC20 is associated with HO susceptibility. Previous findings in our lab have demonstrated upregulation of CASC20 during BMP2-induced osteodifferentiation of adipose-derived stem cells (hMAD) alongside osteodifferentiation markers, RUNX2 and OSX. We hypothesize that CASC20 is a novel regulator of bone formation and aim to investigate CASC20 function in bone formation. Methods. 1) We used miRanda prediction algorithm and the ENCORI database to respectively predict which miRNAs CASC20 interacts with and to select for experimentally validated miRNAs. 2) We characterized the expression and functional role of CASC20-interacting miRNAs by respectively analyzing publicly available datasets (GSE107279 and pubmed.ncbi.nlm.nih.gov/26175215/) and by using Gene Ontology (GO) analysis. 3) We overexpressed CASC20 in hMAD using a lentiviral system and tested the effect of CASC20 overexpression in osteodifferentiation and expression of putative CASC20-interacting miRNAs. Results. 1) We identified 64 experimentally validated miRNAs that are predicted to interact with CASC20. 2) GO analysis revealed that the most frequently targeted molecular functions included SMADs, MAPKK and other kinase activities known to play a central role in osteo and chondrogenesis. We found 10 miRNAs including hsa-miR-485-3p that demonstrated down-regulation in both osteo- and chondrogenesis. 3) We found that CASC20-overexpression augmented the osteodifferentiation of hMAD measured in mineralization using Alizarin Red S. CASC20 overexpression increased the expression of osteogenic marker ALP and decreased the expression of hsa-miR-485-3p. Conclusion. Here we show how CASC20 may regulate bone formation by acting as a competitive endogenous RNA (ceRNA). We are currently using CASC20 overexpression model in osteo- and chondrogenesis, and testing CASC20-miRNA interaction to establish the underlying mechanism for the observed associations

Introduction. Missile injuries are very serious injuries particularly in the cervical region. They are classified into high and low missile injuries when it involves the cervical spine. In modern guerrilla warfare, one must be aware of ballistic pathology with bullets as well as from explosives. In particular, improvised explosive devices commonly known as IED's play a new and important pathophysiology whether they are suicided vests or roadside bombs. They usually produce severe or lethal injuries and serious neurovascular deficit is frequent. We present the details of 40 patients with local experience on how to handle serious penetrating cervical missile injuries. Methods. All cases were collected from the record of Basrah University Hospital, Iraq. Healthy military gentlemen with ages ranging between 20–35 years were included. Results. 11 patients had bullet injuries and 29patients had fragments of shell injuries. The sites of injuries were 9: C2–C3, 12: C5–C6, 12: C4–C5 and 7: C7-T1. Bullet entrance was anterior in 23 patients, posterior in 7 patients and lateral in 10 patients. The cervical vertebrae were injured in 37 patients at body or lamina level while in 3 patients it was only neural tissue injuries. Missiles were retained in 13 patients. All injuries showed some degree of neurological deficit with quadriplegia in 26 patients. 9 patients presented with very serious injuries. No relation was found between the size of the missile and the extent of damage. Outcome of treatment in all patients was poor. Conclusion. Gunshot wounds only account for approximately one third of penetrating missile injuries in patients who survive and are well enough to receive medical treatment. 62% of patients' cohort were from explosive devices, consistent with data from 2010, where 58% of fatalities were from IED's occurring in foreign soldiers in Afghanistan. We discuss the importance of general supportive measures, generous wound excision, removal of the retained missiles and heavy cover of antibiotics

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To identify the prevalence of neuropathic pain after lower limb fracture surgery, assess associations with pain severity, quality of life and disability, and determine baseline predictors of chronic neuropathic pain at three and at six months post-injury.

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Despite recent advances in arthroscopic rotator cuff repair, re-tear rates remain high. New methods to improve healing rates following rotator cuff repair must be sought. Our primary objective was to determine if adjunctive bone marrow stimulation with channelling five to seven days prior to arthroscopic cuff repair would lead to higher Western Ontario Rotator Cuff (WORC) scores at 24 months postoperatively compared with no channelling.

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Femoroacetabular impingement (FAI) is a potential cause of hip osteoarthritis (OA). The purpose of this study was to investigate the expression profile of matrix metalloproteinases (MMPs) in the labral tissue with FAI pathology.

Stem cells are defined by their potential for self-renewal and the ability to differentiate into numerous cell types, including cartilage and bone cells. Although basic laboratory studies demonstrate that cell therapies have strong potential for improvement in tissue healing and regeneration, there is little evidence in the scientific literature for many of the available cell formulations that are currently offered to patients. Numerous commercial entities and ‘regenerative medicine centres’ have aggressively marketed unproven cell therapies for a wide range of medical conditions, leading to sometimes indiscriminate use of these treatments, which has added to the confusion and unpredictable outcomes. The significant variability and heterogeneity in cell formulations between different individuals makes it difficult to draw conclusions about efficacy. The ‘minimally manipulated’ preparations derived from bone marrow and adipose tissue that are currently used differ substantially from cells that are processed and prepared under defined laboratory protocols. The term ‘stem cells’ should be reserved for laboratory-purified, culture-expanded cells. The number of cells in uncultured preparations that meet these defined criteria is estimated to be approximately one in 10 000 to 20 000 (0.005% to 0.01%) in native bone marrow and 1 in 2000 in adipose tissue. It is clear that more refined definitions of stem cells are required, as the lumping together of widely diverse progenitor cell types under the umbrella term ‘mesenchymal stem cells’ has created confusion among scientists, clinicians, regulators, and our patients. Validated methods need to be developed to measure and characterize the ‘critical quality attributes’ and biological activity of a specific cell formulation. It is certain that ‘one size does not fit all’ – different cell formulations, dosing schedules, and culturing parameters will likely be required based on the tissue being treated and the desired biological target. As an alternative to the use of exogenous cells, in the future we may be able to stimulate the intrinsic vascular stem cell niche that is known to exist in many tissues. The tremendous potential of cell therapy will only be realized with further basic, translational, and clinical research.

Cite this article: Bone Joint J 2019;101-B:361–364.

INTRODUCTION. Interest in tissue-preserving or minimally invasive total hip arthroplasty (THA) is increasing with focus toward decreased hospital stay, enhanced rehabilitation, and quicker recovery for patients. Two tissue-preserving techniques, the anterior and superior approaches to THA, have excellent clinical results, but little is known about their relative impact on soft tissue. The purpose of this study was to evaluate the type and extent of tissue damage after THA with each approach, focusing on abductors, short external rotators, and the hip capsule. METHODS. Total hip arthroplasty was performed on bilateral hips of eleven fresh-frozen cadavers (22 hips). They were randomized to anterior THA performed on one side and superior THA performed on the other, in the senior authors' standard technique. Two independent examiners graded the location and extent of tissue injury by performing postsurgical dissections. Muscle bellies, tendons, and capsular attachments were graded as intact, split, damaged (insignificant, minimal, moderate, or extensive damage), or detached based on direct visual inspection of each structure. Tissue injury was analyzed with either a chi-squared (≥5 qualifying structures) or Fisher's exact test (<5 qualifying structures). P values <0.05 were significant. RESULTS. The abductor muscles or tendons were intact or insignificantly damaged in 63.6% of anterior approach specimens compared with 84.1% of the superior specimens (p= 0.03). Specifically, the gluteus minimus tendon had moderate or extensive damage in 63.6% of anterior specimens compared with none of the superior specimens (p <0.01). Short external rotators (SERs) group, defined as both the muscle and tendon of the piriformis, conjoint, obturator externus, and quadratus, were intact or insignificantly damaged in 63.6% of anterior approach specimens compared with 80.5% of the SER group of superior specimens (p = 0.02). The femoral attachments of the anterior, posterior, and superior capsules were extensively damaged or detached in 90.9%, 81.8%, and 100% of anterior approach specimens respectively compared with 0%, 9.1% and 9.1% of superior approach specimens respectively (all p <0.01). CONCLUSION. In a cadaveric study examining superior and anterior approaches to THA, the superior approach demonstrated significantly less soft-tissue destruction than the anterior approach, specifically to the gluteus minimus tendon, short external rotators, and the hip capsule

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Emerging evidence indicates that tendon disease is an active process with inflammation that is critical to disease onset and progression. However, the key cytokines responsible for driving and sustaining inflammation have not been identified.

Objectives

Cellular movement and relocalisation are important for many physiologic properties. Local mesenchymal stem cells (MSCs) from injured tissues and circulating MSCs aid in fracture healing. Cytokines and chemokines such as Stromal cell-derived factor 1(SDF-1) and its receptor chemokine receptor type 4 (CXCR4) play important roles in maintaining mobilisation, trafficking and homing of stem cells from bone marrow to the site of injury. We investigated the differences in migration of MSCs from the femurs of young, adult and ovariectomised (OVX) rats and the effect of CXCR4 over-expression on their migration.

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After an injury, the biological reattachment of tendon to bone is a challenge because healing takes place between a soft (tendon) and a hard (bone) tissue. Even after healing, the transition zone in the enthesis is not completely regenerated, making it susceptible to re-injury. In this study, we aimed to regenerate Achilles tendon entheses (ATEs) in wounded rats using a combination of kartogenin (KGN) and platelet-rich plasma (PRP).

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The aims of this study were to increase the diagnostic accuracy of the analysis of synovial fluid in the differentiation of prosthetic joint infection (PJI) by the addition of inexpensive biomarkers such as the levels of C-reactive protein (CRP), adenosine deaminase (ADA), alpha-2-macrogloblulin (α2M) and procalcitonin.

Objectives. Rotator cuff tears are among the most frequent upper extremity injuries. Current treatment strategies do not address the poor quality of the muscle and tendon following chronic rotator cuff tears. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that activates many genes that are important in skeletal muscle regeneration. HIF-1α is inhibited under normal physiological conditions by the HIF prolyl 4-hydroxylases (PHDs). In this study, we used a pharmacological PHD inhibitor, GSK1120360A, to enhance the activity of HIF-1α following the repair of a chronic cuff tear, and measured muscle fibre contractility, fibrosis, gene expression, and enthesis mechanics. Methods. Chronic supraspinatus tears were induced in adult rats, and repaired 28 days later. Rats received 0 mg/kg, 3 mg/kg, or 10 mg/kg GSK1120360A daily. Collagen content, contractility, fibre type distribution and size, the expression of genes involved in fibrosis, lipid accumulation, atrophy and inflammation, and the mechanical properties of the enthesis were then assessed two weeks following surgical repair. Results. At two weeks following repair, treatment groups showed increased muscle mass but there was a 15% decrease in force production in the 10 mg/kg group from controls, and no difference between the 0 mg/kg and the 3 mg/kg groups. There was a decrease in the expression of several gene transcripts related to matrix accumulation and fibrosis, and a 50% decrease in collagen content in both treated groups compared with controls. Additionally, the expression of inflammatory genes was reduced in the treated groups compared with controls. Finally, PHD inhibition improved the maximum stress and displacement to failure in repaired tendons. Conclusions. GSK1120360A resulted in improved enthesis mechanics with variable effects on muscle function. PHD inhibition may be beneficial for connective tissue injuries in which muscle atrophy has not occurred. Cite this article: J. P. Gumucio, M. D. Flood, A. Bedi, H. F. Kramer, A. J. Russell, C. L. Mendias. Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear. Bone Joint Res 2017;6:57–65. DOI: 10.1302/2046-3758.61.BJR-2016-0232.R1

Spinal cord injury (SCI) is a devastating disorder for which the identification of exacerbating factors is urgently needed. Although age, blood pressure and infection are each considered to be prognostic factors in patients with SCI, exacerbating factors that are amenable to treatment remain to be elucidated. Microglial cells, the resident immune cell in the CNS, form the first line of defense after being stimulated by exposure to invading pathogens or tissue injury. Immediately after SCI, activated microglia enhance and propagate the subsequent inflammatory response by expressing cytokines, such as TNF-α, IL-6 and IL-1β. Recently, we demonstrated that the activation of microglia is associated with the neuropathological outcomes of SCI. Although the precise mechanisms of microglial activation remain elusive, several basic research studies have reported that hyperglycemia is involved in the activation of resident monocytic cells, including microglia. Because microglial activation is associated with secondary injury after SCI, we hypothesized that hyperglycemia may also influence the pathophysiology of SCI by altering microglial responses. The mice were anesthetized with pentobarbital (75 mg/kg i.p.) and were subjected to a contusion injury (70 kdyn) at the 10th thoracic level using an Infinite Horizons Impactor (Precision Systems Instrumentation). For flow cytometry, the samples were stained with the antibodiesand analyzed using a FACS Aria II flow cytometer and the FACSDiva software program (BD Biosciences). We retrospectively identified 528 SCI patients admitted to the Department of Orthopaedic Surgery at the Spinal Injuries Center (Fukuoka, Japan) between June 2005 and May 2011. The patients' data were obtained from their charts. We demonstrate that transient hyperglycemia during acute SCI is a detrimental factor that impairs functional improvement in mice and human patients after acute SCI. Under hyperglycemic conditions, both in vivo and in vitro, inflammation was enhanced through promotion of the nuclear translocation of the nuclear factor kB (NF-kB) transcription factor in microglial cells. During acute SCI, hyperglycemic mice exhibited progressive neural damage, with more severe motor deficits than those observed in normoglycemic mice. Consistent with the animal study findings, a Pearson χ2 analysis of data for 528 patients with SCI indicated that hyperglycemia on admission (glucose concentration ≥126 mg/dl) was a significant risk predictor of poor functional outcome. Moreover, a multiple linear regression analysis showed hyperglycemia at admission to be a powerful independent risk factor for a poor motor outcome, even after excluding patients with diabetes mellitus with chronic hyperglycemia (regression coefficient, −1.37; 95% confidence interval, −2.65 to −0.10; P < 0.05). Manipulating blood glucose during acute SCI in hyperglycemic mice rescued the exacerbation of pathophysiology and improved motor functional outcomes. Our findings suggest that hyperglycemia during acute SCI may be a useful prognostic factor with a negative impact on motor function, highlighting the importance of achieving tight glycemic control after central nervous system injury

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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.

Background. Some reports have suggested that debris generated from the head neck taper junction is more destructive than equivalent doses from metal bearing surfaces. Methods. Part 1. We examined the relationship between the source (taper/bearing) and volume of metal debris on Cr and Co concentrations in corresponding blood and hip synovial fluid samples and the observed agglomerated particle sizes in excised tissues using regression analysis of prospectively collected data at a single revision unit. Part 2. We investigated variables most strongly associated with macroscopic soft tissue injury as documented at revision surgery using ordinal logistic regression. Independent variables included source and volume of CoCr exposure, Cr and Co joint fluid concentrations, joint fluid grade, ALVAL (Aseptic Lymphocytic Vasculitis Associated Lesion) grade, presence of vascular hyalinisation, agglomerated particle size, implant type, patient sex and age. Results. A total of 199 explanted MoM hips were analysed. Multiple regression statistical modelling suggested that a greater source contribution of metal debris from the taper junction was associated with smaller aggregated particle sizes in the local tissues and a relative reduction of Cr ion concentrations in the corresponding synovial fluid and blood samples. There was an association between increasing Co concentrations in the joint fluid and an increasing ALVAL score (p<0.001). In contrast, higher Cr concentrations were inversely related to ALVAL (p<0.001). The ALVAL response was itself strongly associated with larger fluid collections (p<0.001). Vascular hyalinisation and larger fluid collections were significantly associated with macroscopic tissue injury (coefficient 2.22, p<0.001 for fluid grade and 4.35, p<0.001 for hyalinisation). Discussion. Metal debris generated from taper junctions appears to be associated with a different biochemical environment than debris generated from bearing surfaces. We believe that this finding may provide some explanation as to the poor performance of MoM THRs compared to the equivalent resurfacing devices and the confusion surrounding the significance of blood metal testing. Conclusion. Chromium does seem to inhibit the development of ALVAL

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Total joint arthroplasty (TJA) is commonly performed in elderly patients. Frailty, an aggregate expression of vulnerability, becomes increasingly common with advanced age, and independently predicts adverse outcomes and the use of resources after a variety of non-cardiac surgical procedures. Our aim was to assess the impact of frailty on outcomes after TJA.