Introduction

Periprosthetic osteolysis resulting in aseptic loosening is a leading cause for total hip arthroplasty (THA) failure. Individuals vary in their susceptibility to osteolysis, and it is thought that heritable factors contribute to this variation. We conducted two genome-wide association studies to identify genetic risk loci associated with osteolysis and genetic risk loci associated with time to prosthesis failure due to osteolysis.

Aims

The aim of this study was to screen the entire genome for genetic markers associated with risk for anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) injury.

This is the largest reported natural history study of frozen shoulder. 500 patients were identified from a specialist shoulder clinic register with a diagnosis of frozen shoulder based on Codman’s criteria. 273 patients with primary frozen shoulder replied to a detailed postal questionnaire regarding their condition. Mean follow up from symptom onset was 52 months (range 12–240months), with 89% of shoulders followed up for a minimum of 3 years. A positive family history was identified in 20% (n=45) of 1st degree relatives. The relative risk to siblings compared with a control population was 4:1. Patients with mild to moderate symptoms recovered more quickly than those with severe or unbearable symptoms. The mean age of onset was 53 years (range27–85yrs). The female to male ratio was 1.6:1. The condition was bilateral in 20%, with no incidence of ipsilateral recurrence. 22% of patients reported a history of minor trauma to the upper limb prior to the onset of symptoms. 16% were diabetic and 4% reported a history of Dupuytren’s contracture. Right and left arms were affected equally with no relationship to hand dominance. 61% reported slow, and 39% reported sudden onset of symptoms. Generally pain and stiffness improved with time but at 3 and 4 years after onset 13% and 9% respectively still had symptoms.

Frozen shoulder affects people mainly in their 6th decade. Genetic factors play an important role in the aetiology. The natural history is for improvement with time, with the less severe symptoms at onset improving most quickly. 9% of patients were still symptomatic at 4 year follow up.

Introduction

From the many human studies that attempt to identify genes for adolescent idiopathic scoliosis (AIS), the view emerging is that AIS is a complex genetic disorder with many predisposing genes exhibiting complex phenotypes through environmental interactions. Although advancements in genomic technology are transforming how we undertake genetic and genomic studies, only some success has been reached in deciphering complex diseases such as AIS. Moreover, the present challenge in AIS research is to understand the causative and correlative effects of discovered genetic perturbations. An important limitation to such investigations has been the absence of a method that can easily stratify patients with AIS.

To overcome these challenges, we have developed a functional test that allows us to stratify patients with AIS into three functional subgroups, representing specific endophenotypes. Interestingly, in families with multiple cases of AIS, a specific endophenotype is shared among the affected family members, indicating that such a transmission is inherited. Moreover, increased vulnerability to AIS could be attributable to sustained exposure to osteopontin (OPN), a multifunctional cytokine that appears to be at the origin of the Gi-coupled receptor signalling dysfunction discovered in AIS. We examined the molecular expression profiles of patients with AIS and their response to OPN.

Introduction: Spinal deformities and scoliosis in particular, represent the most prevalent type of orthopaedic deformities in children and adolescents. At present, the most significant problem for clinicians is that there is no proven method or test available to identify children or adolescents at risk of developing AIS or to identify which of the affected individuals are at risk of progression. As a consequence, the application of current treatments, such as bracing or surgical correction, has to be delayed until a significant deformity is detected or until a significant progression is clearly demonstrated, resulting in a delayed and less optimal treatment. Among patients with AIS needing treatment, 80% to 90% will be treated by brace and 10% will need surgery to correct the deformity by spinal instrumentation and fusion of the thoracic and/or lumbar spine. About 15000 such surgeries are done every year in North America, resulting in significant psychological and physical morbidity. Moreover, there is no pharmacotherapy available to either prevent or reduce spinal deformities due mainly to our limited knowledge of AIS aetiopathogenesis. We have recently reconciled the role of melatonin in AIS aetiopathogenesis by demonstrating a melatonin signalling dysfunction occurring in a cell autonomous manner in cells derived from AIS patients exhibiting severe scoliotic deformities. This defect could potentially explain the majority of abnormalities reported in AIS since melatonin receptors and signalling activities are normally found in all tissues and systems affected in AIS, thus offering a very innovative and unifying concept to explain the aetiology of AIS. Moreover, several lines of evidence suggested that inactivation of Gi proteins by an increased phosphorylation of serine residues could be at the source of this signalling defect in AIS. The goals of that study were to assess the possibility to establish a molecular classification of AIS patients and to demonstrate the feasibility to correct this melatonin signalling defect in cells of AIS patients using therapeutic compounds.

Methods: Primary cell cultures were prepared from musculoskeletal tissues of AIS patients (n=150) and age- and gender-matched controls (n=35) obtained intra-operatively. An informed consent was obtained for each subject as approved by our Institutional Ethical Committee. The osteoblasts, the bone-forming cells, were selected to assess whether or not an alteration of melatonin signalling pathway occurs in AIS and accordingly to identify which component of the melatonin transduction machinery could be involved. Co-immunoprecipitation experiments with membrane extracts were performed to identify interacting molecules with key components of melatonin signal transduction machinery. The functionality of melatonin signalling was assessed by investigating the ability of Gi proteins to inhibit stimulated adenyl cyclase activity in osteoblast cultures. Inhibition curves of cAMP production were generated by adding melatonin to the forskolin-containing samples in concentrations ranging from 10-11M to 10-5M in a final volume of 1 ml of _-MEM media containing 0.2% bovine serum albumin (BSA) alone or in presence of 2.5 _M of therapeutic compound A or therapeutic compound B (the nature of both compounds tested cannot be disclosed at this stage). The cAMP content was determined using an enzyme immunoassay kit (Amersham-Pharmacia Biosciences). All assays were performed in duplicate. A non-parametric test, the Wilcoxon matched pairs test was performed to verify the significance between 2 means. Significance was defined as P< 0.05.

Results: Osteoblasts from patients with AIS showed a lack or a markedly reduced inhibition of forskolin-stimulated adenyl cyclase activity by melatonin generating three distinct response-curves corresponding to three functional groups. In order to identify candidate genes involved in AIS aetiopathogenesis, we focused our attention on known kinases and phosphatases modulating Gi protein functions and characterised their interacting partners. Interestingly, PKC_ was initially targeted owing to its property to phosphorylate Gi proteins in vitro. Indeed, in normal osteoblast interactions occurring between MT2 melatonin receptor and RACK1 (a cytosolic protein that bind to and stabilises the actives form of PKC and permits its translocation to different sites within the cells) and PKC_ were detected although those interactions among different AIS patients were altered. Interestingly, treatment with compound A or B rescued melatonin signal defect in cells derived from 36% and 47% of AIS patients respectively. Overall, melatonin signal transduction was restored in cells of 64% of AIS patients (23/36) when treated by one of these therapeutic compounds.

Conclusions: The functional classification of AIS patients is correlated at the molecular level by distinct interactions between key molecules normally involved in melatonin signal transduction in spite that these patients exhibited the same curve type (right thoracic, Lenke type 1). Collectively, these data strongly argue that traditional curve pattern classification is not a relevant stratification of AIS patients to identify its genetic causes. Moreover, using that molecular system we have demonstrated also the possibility to identify therapeutic compounds to rescue the melatonin signalling defect observed in AIS without any prior knowledge of mutations in any defective genes causing AIS because we are measuring a function.

Research project supported by La Fondation Yves Cotrel de l’Institut de France

Medical Genetics is a transversal discipline with the potential to impact on every specialty and subspecialty in medicine and the allied health sciences. The completion of the human genome project resulted in technical advancements in genomics, genomic testing and our understanding of genetic disorders in general. These advancements have greatly enhanced our understanding of the role of genetics in Orthopaedic practice, with respect to both monogenic and complex disorders. Tygerberg Hospital is currently the only state hospital in South Africa to support genetic testing in the form of gene panels as part of routine care. This is complemented by more comprehensive research testing in the form of exome and genome sequencing as part of the Undiagnosed Disease Programme. We audit the genetic and genomic testing done on patients referred from the Orthopaedic clinic over a period of 3 years (2020–2022) and review diagnostic rates and interesting results. The largest group of patients referred (n=50) had a clinical diagnosis of osteogenesis imperfecta (OI). A 100% diagnostic yield was achieved for these patients with the identification of recurring variants (FKBP10, COL1A2). Further families (n=20) with much rarer conditions are presented with important implications on the orthopaedic and medical management, prognosis, and genetic counselling for the families. We highlight the impact of genomic testing in the Orthopaedic clinic. Management changes and precision orthopaedic intervention were only possible due to a genetic diagnosis. We motivate for increased access to testing, especially for younger patients presenting with complex orthopaedic phenotypes

Primary bone tumors are rare, complex and highly heterogeneous. Its diagnostic and treatment are a challenge for the multidisciplinary team. Developments on tumor biomarkers, immunohistochemistry, histology, molecular, bioinformatics, and genetics are fundamental for an early diagnosis and identification of prognostic factors. The personalized medicine allows an effective patient tailored treatment. The bone biopsy is essential for diagnosis. Treatment may include systemic therapy and local therapy. Frequently, a limb salvage surgery includes wide resection and reconstruction with endoprosthesis, biological or composites. The risk for local recurrence and distant metastases depends on the primary tumor and treatment response. Cancer patients are living longer and bone metastases are increasing. Bone is the third most frequently location for distant lesions. Bone metastases are associated to pain, pathological fractures, functional impairment, and neurological deficits. It impacts survival and patient quality of life. The treatment of metastatic disease is a challenge due to its complexity and heterogeneity, vascularization, reduced size and limited access. It requires a multidisciplinary treatment and depending on different factors it is palliative or curative-like treatment. For multiple bone metastases it is important to relief pain and increases function in order to provide the best quality of life and expect to prolong survival. Advances in nanotechnology, bioinformatics, and genomics, will increase biomarkers for early detection, prognosis, and targeted treatment effectiveness. We are taking the leap forward in precision medicine and personalized care

Dupuytren's disease (DD) is a fibroproliferative soft tissue disease affecting the palmar fascia of the hand causing permanent and irreversible flexion contracture. Aberrant fibrosis is likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in soft tissue fibrosis in diseases such as DD is not well established. Therefore, we conducted a comprehensive multi-omic study investigating the epigenetic profiles that influence gene expression in DD pathology. Using control (patients undergoing carpal tunnel release) and diseased fibroblasts (patients undergoing Dupuytren's fasciectomy), we conducted ATAC-seq to assess differential chromatin accessibility between control and diseased fibroblasts. Additionally, ChIP-seq mapped common histone modifications (histone H4; H3K4me3, H3K9me3, H3K27me3, H4K16Ac, H4K20Me3) associated with fibrosis. Furthermore, we extracted RNA from control and DD tissue and performed bulk RNA-seq. ATAC-seq analysis identified 2470 accessible genomic loci significantly more accessible in diseased fibroblasts compared to control. Comparison between diseased and control cells identified numerous significantly different peaks in histone modifications (H4K20me3, H3K27me3, H3K9me3) associated with gene repression in control cells but not in diseased cells. Pathway analysis demonstrated a substantial overlap in genes being de-repressed across these histone modifications (Figure 1). Both, ATAC-seq and ChIP-seq analysis indicated pathways such as cell adhesion, differentiation, and extracellular matrix organisation were dysregulated as a result of epigenetic changes. Moreover, de novo motif enrichment analysis identified transcription factors that possibly contributed to the differential gene expression between control and diseased tissue, including HIC1, NFATC1 and TEAD2. RNA-seq analysis found that these transcription factors were upregulated in DD tissue compared to control tissue. The current epigenetic study provides insights into the aberrant fibrotic processes associated with soft tissue diseases such as DD and indicates that epigenetic-targeted therapies may be an interesting viable treatment option in future. For any figures or tables, please contact the authors directly

Aims. The processes linking long-term bisphosphonate treatment to atypical fracture remain elusive. To establish a means of exploring this link, we have examined how long-term bisphosphonate treatment with prior ovariectomy modifies femur fracture behaviour and tibia mass and shape in murine bones. Methods. Three groups (seven per group) of 12-week-old mice were: 1) ovariectomized and 20 weeks thereafter treated weekly for 24 weeks with 100 μm/kg subcutaneous ibandronate (OVX+IBN); 2) ovariectomized (OVX); or 3) sham-operated (SHAM). Quantitative fracture analysis generated biomechanical properties for the femoral neck. Tibiae were microCT scanned and trabecular (proximal metaphysis) and cortical parameters along almost its whole length measured. Results. Fracture analyses revealed that OVX+IBN significantly reduced yield displacement (vs SHAM/OVX) and resilience, and increased stiffness (vs SHAM). OVX+IBN elevated tibial trabecular parameters and also increased cortical cross-sectional area and second moment of area around minor axis, and diminished ellipticity proximally. Conclusion. These data indicate that combined ovariectomy and bisphosphonate generates cortical changes linked with greater bone brittleness and modified fracture characteristics, which may provide a basis in mice for interrogating the mechanisms and genetics of atypical fracture aetiology. Cite this article: Bone Joint Open 2020;1-9:512–519

Abstract. Objectives. Despite overwhelming need, with about 9 million osteoarthritis (OA) sufferers in UK alone, little progress has been made towards pathogenesis-based categorising of patients and subsequent intervention. Experimental studies relied heavily on animal models, which is inefficient and expensive, and has often produced drugs failing in phase I/II clinical trials due to off-target side effects or failure to predict human disease in animal models. This project aims to address this challenge by developing a scalable in vitro human organotypic tissue model. The model can be used to simulate OA processes and ultimately, exploited to seek biomarkers for early diagnosis or screen potential drugs for efficacy. Methods. We have previously shown that a stratified 3D-tissue akin of articular cartilage can be generated over a 35-day period using a tissue engineering approach with primary human chondrocyte progenitor cells. The engineered tissue mimics native cartilage both in structural organization and biochemical composition. Here, we explore the influence of the nature and homogeneity of initial cell population on cartilage development and maturation. Results. Cell commitment to chondrogenic lineage was found to be a pre-requisite for induction of appropriate appositional growth and stratification of cartilage. Fully differentiated chondrocytes failed to produce a zonated, cartilage-like matrix. Immortalized clonal cell lines were generated, and these were capable of reproducing an appropriate tissue architecture, showing that tissue formation depends on a single progenitor. Conclusion. These findings not only enable generation of human tissue at scale in a highly controlled way, but open up the possibility to consider developmental positional information or genetics within our model

The presentation of musculoskeletal disease differs in men and women, and recognition of the differences between men and women's burden of disease and response to treatment is critical to optimizing care. In this presentation, I will discuss the expanding evidence in the literature that examine the role of sex and gender in musculoskeletal disease, including how its examination increases the innovations and contributions, as well as expands the knowledge about musculoskeletal disease, conditions, and injury in a broad sense. We will discuss the role that structural anatomy differences, hormones, and genetics play in differential disease expression, to the historical biases in the subject populations of clinical and basic research projects. Participants will be provided with examples and opportunities to evaluate orthopaedic science through a sex and gender lens, and what impact this may play in setting the stage for both clinical practice and scientific investigation

Modifiable factors contributing to stiffness include alignment, implant size, implant position and rotation, and soft tissue tightness or laxity. Less modifiable factors include genetics as in predisposition to inflammation and fibrosis, aberrations in perception and experience of emotional pain, and preoperative range of motion. We reviewed 559 knees undergoing revision between 2007 and 2014, selecting out patients with a diagnosis of stiffness and greater than one-year follow-up. Stiffness was defined as greater than 15 degrees of flexion contracture or less than 75 degrees of flexion or less than 90 degrees of active motion and a chief complaint of limited motion and pain. Radiographic analysis used a set of matched controls with greater than 90 degrees and full extension prior to surgery and were further matched by age, gender, BMI. Flexion contracture changed from an average of 9.7 to an average of 2.3 degrees, flexion changed from an average of 81 to an average of 94 degrees, active motion changed from an average of 72 to an average of 92 degrees, pain scores improved from 44 to 72 points, and Knee Society function scores improved from an average of 49 to an average of 70 points. There were four failures for stiffness, two knees underwent additional manipulation, gaining an average of 10 degrees; and two knees were revised. Radiographic analysis demonstrated stiffness to be strongly correlated to anterior condylar offset ratio and to patellar displacement by multivariant regression analysis, suggesting that overstuffing the patellofemoral joint by anteriorization of the femoral component is associated with stiffness. Using modern revision techniques, revision for stiffness creates reliable improvements in pain, Knee Society clinical and functional scores, and motion

Aim. Toxin-antitoxin (TA) systems are small genetics elements found in the majority of bacteria which encode a toxin causing bacterial growth arrest and an antitoxin counteracting the toxic effect. In Salmonella and E. coli, TA systems were shown to be involved in the formation of persisters. Persisters are a bacterial subpopulation with low growth rate and high tolerance to antibiotics. They could be responsible for antibiotic treatment failure in chronic infections and relapses, notably in bone and joint infections (BJI) caused by Staphylococcus aureus. Currently, two type II TA system families were described in S. aureus, mazEF and axe/txe, but their physiological roles are not well described. In this work, we studied the importance of mazEF in the intracellular survival of S. aureus inside osteoblasts, one of the mechanisms considered in the chronicity of S. aureus BJI. Methods. Using an ex vivo model of intracellular infection of human osteoblast-like cells (MG-63), two strains of S. aureus HG003 wild type and its isogenic mutant HG003 ΔmazEF were compared in terms of : i) internalization and intracellular survival by lysostaphin protective assay and ii) cytotoxicity by quantifying LDH in the culture supernatant, 24h and 48h after infection. Results. The comparison of the two strains revealed that HG003 ΔmazEF had a lower capacity to be internalized by osteoblasts compared to the wild type (p=0.02). However, intracellular survival was greater for HG003 ΔmazEF compared to the wild type 24h and 48h post-infection (p=0.02 and 0.001 respectively). Concerning the bacteria-induced cell death, HG003 ΔmazEF appeared to be less cytotoxic than the wild type strain at 24h post infection (p=0.007) whereas no more differences could be observed after 48h. This delayed cytotoxicity with HG003 ΔmazEF was also observed after incubation of culture supernatants with osteoblasts during 8 hours, suggesting that the differences observed could be caused by a secreted molecule. Conclusions. Our results suggest that the mazEF system could be involved in S. aureus BJI physiopathology regulating cytotoxicity and persistence in osteoblasts. Our prospect is to identify the target of the mazF toxin which could be a therapeutic target

Background. The cartilaginous growth plate (GP) is a zonal structure, in which chondrocytes are organized into columns and drive the longitudinal elongation of the endochondral bones. In the proliferative zone (PZ), cells exhibit high mitotic activity, are flattened and oriented along the mediolateral (ML) axis of the GP. Mitotic figures in the elongated chondrocytes lie perpendicular to the proximo-distal (PD) direction of growth, while cell divisions occur parallel to the columns followed by a gliding movement of the daughter cells. The mechanisms responsible for the geometrical anisotropy and columnar arrangement of PZ chondrocytes are poorly understood. Here, we assessed the function of the adhesive receptor β1 integrins on spindle and division geometry in chondrocytes using mouse genetics. Methods. GP slices were prepared from wild type (wt) and β1fl/fl-Col2a1cre mice. Primary rib chondrocytes were cultured on substrate-coated glass slides and fluorescently stained with anti-alpha-tubulin and anti-pericentrin antibodies, with phalloidin and DAPI. Confocal stacks were built from images acquired by confocal microscopy. Cell and spindle orientation relative to the PD axis (in vivo) or to the substrate plane (SP) in vitro were determined by geometric functions. Shape indexes (SI) were calculated as the ratio of the length and height of the cell. Results. During GP morphogenesis, aggregating mesenchymal cells (E11) were polygonal (SI=1.43) and nonoriented. Upon chondrogenic differentiation at E12, wt GP chondrocytes showed moderate flattening (SI=1.93) and tend to align perpendicular to the PD axis. At E13, PZ chondrocytes further flattened (SI=3.41) and largely organized into lines along the ML axis. At E14, the first vertical stacks formed, which were gradually elongated along the PD axis at later stages and composed of extremely flat (SI=4.91), ML-oriented chondrocytes. Early spindles were randomly oriented at all stages, whereas late spindles were aligned along the long axis of the cell. In contrast, β1 integrin null PZ chondrocytes were rounded (SI=1.37), displayed random orientation of both early and late spindles, and failed to organize into columns. On collagen II, both wt and β1-null primary chondrocytes remained rounded and displayed random spindle orientation relative to the SP. On fibronectin (FN), wt chondrocytes were flattened (SI=3.26) and their spindle was aligned parallel to SP. Mutant cells lacking the major FN receptor α5β1 integrin did not spread, were rounded (SI=1.73) and aligned their spindle randomly. On vitronectin, both cell types spread and flattened well (SI=4.11 and SI=4.20) accompanied by parallel spindle orientation to the SP. Conclusion. We propose that β1 integrins provide adhesive cues for chondrocyte geometry and orientation, which in turn orients the mitotic spindle and determines the division axis; and for chondrocyte intercalation to shape the three-dimensional structure of the GP

Systemic concentrations of metal ions (cobalt and chromium) are persistently elevated in patients with metal-on-metal hip resurfacing (MOMHR) compared to conventional total hip arthroplasty (THA). Several studies by us and others have described the detrimental effects of metal exposure on survival and function of various cell types in-vitro, but the mechanisms for these effects remain unclear. Epigenetic modifications following chronic metal exposure is a possible mechanism that could mediate these effects. Here we test the methylation status in genomic DNA from MOMHR (“cases”) and THA (“controls”) patient-groups, and its correlation with circulating metal levels. The cohort consisted of 34 patients with a well-functioning MOMHR at a median follow-up of 9.75 years. These were individually matched for gender, age and time-since-surgery to a non-exposure group consisting of patients with THA. Genomic DNA was isolated from blood samples and cell composition estimated using the ‘estimateCellCounts’ function in ‘minfi R-package’. Methylation was assessed using the Illumina 450k BeadChip array analysing 426,225 probes. Logit model was fitted at each probe with case/control status as independent variable and covariates of gender, age, time-since-surgery, smoking, non-arthroplasty metal exposure, and cell composition. DNA methylation age was assessed using an online calculator (. https://dnamage.genetics.ucla.edu/. ) and comparisons made between cases and controls, and correlated with circulating metal levels. Cell distributions did not differ between the cases and controls (Wilcoxon test p<0.17) with no probe having an association at 5% FDR. Circulating metal levels and LVEDD also had no association with any probe at 5% FDR. There was no preferential age acceleration between cases and controls (Wilcox p<0.7), and it had no correlation with plasma-chromium or blood-cobalt levels (p<0.9). In summary, large methylation changes following MOMHR seem to be absent, compared to THA. Future research with larger samples will be needed to clarify the presence and extent of small methylation changes

Aims

Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease.

Purpose and Background. Low birth weight is related to decreased lumbar spine vertebral canal size and bone mineral content later in life, suggesting that antenatal factors affect spine development. The purpose of this study was to explore associations between antenatal factors and lumbar spine morphology in childhood. Methods. Antenatal data and supine MR images of the lumbar spine were available for 161 children. Shape modelling, using principle components analysis, was performed on mid-sagittal images to quantify different modes of variation in lumbar spine shape. Previously collected measures of spine canal dimensions were analysed. Results. Almost 75 % of all of the variation in lumbar spine shape was explained by just three modes. Modes 1 and 3 described the total amount and the distribution of curvature along the spine, respectively. Mode 2 (M2) captured variation in vertebral shape and size; increasing mode scores represented flatter vertebral bodies with increasing anterior-posterior dimensions. We saw no significant associations between mode scores and birth weight z-scores, placental weight, gestation length and no effect of maternal smoking (P>0.05). Controlling for gestation length revealed a positive correlation between birth weight and M2 (P=0.02). Males, longer babies and those from heavier mothers had higher M2 scores (P<0.05). This sex difference remained even when controlling for the other factors (P<0.001). Modes 1 and 2 correlated with spine canal dimensions (P<0.05). Conclusions. Our results suggest that antenatal factors have some effect on vertebral body morphology but not overall lumbar spinal shape. Perhaps environmental factors during growth and genetics play a larger role in determining the overall spine shape. This abstract has not been previously published in whole or substantial part nor has it been presented previously at a national meeting. Conflicts of interest: No conflicts of interest. Sources of funding: This work was supported by a studentship granted to the University and awarded to AVP

Scoliosis Clinic and the Department of Human Genetics, Hadassah University Hospital, Jerusalem Scoliosis appeared in fifteen members of a family in three generations. The eight members examined showed an idiopathic type of scoliosis. Father-to-son transmission occurred more than once. Although at first appearance transmission of the scoliosis is as an autosomal dominant trait, the concept of polygenic inheritance, as has been shown in previous population studies, could also explain the inheritance in this family

Networks of Excellence (NoE’s) are an instrument to overcome the fragmentation of the European research landscape with the objective to strengthen European excellence in a given area. Their purpose is to reach a durable restructuring/shaping and integration of efforts and institutions or parts of institutions in areas where this is necessary. The success of a NoE is not measured in terms of scientific results but by the extent to which the social fabric for researchers and research institutions in a given field has changed due to the project and the extent to which the existing capacities become more competitive as a result of this change. With that background a “European Network to promote research into uncommon cancers in adults and childrens: Pathology, Biology and Genetics of bone tumours” was initiated and founded by the European Commission in 2005 with the involvement of more than 20 institutions all over Europe. Osteosarcoma research represents an own research line within this network. Up to now a multitude of experience has accumulated over the years which will be presented. The obvious advantages of a close cooperation between the network partners are a major hallmark and success of the network and should further lead to an improved translation of the basic research results towards a clinical application

We have observed congenital hypophosphataemic rickets in two sons of a marriage between first cousins, their mother being clinically and biochemically normal. Both patients are now approaching middle age. In addition to severe childhood rickets and lifelong hypophosphataemia, their disease is characterised by gross osteosclerosis with extraskeletal ossification, clinically persistent osteomalacia in one and spinal cord compression in the other. The genetics of this disease can be satisfactorily explained only on the basis of autosomal recessive inheritance, a mode which has only once before been reported in the literature. The severity of certain features, which would be expected in a homozygous state, may help our understanding of the more usual X-linked form

The purpose of this study was to investigate the role that genetics play in the aetiology and symptomatology of full thickness tears of the rotator cuff. From a retrospective, cohort study of 205 patients diagnosed with full thickness rotator cuff tears, we determined, using ultrasound, the prevalence of full thickness tears in their 129 siblings. Using 150 spouses as controls, the relative risk of full thickness rotator cuff tear in siblings v controls was 2.42 (p< 0.0001, 95 % CI 1.77 to 3.31). The relative risk of symptomatic full thickness rotator cuff tear in siblings v controls was 4.65 (p< 0.0001, 95 % CI 2.42 to 8.63). The significantly increased risk for tears in siblings implies that genetic factors play a major role in the development of full thickness tears of the rotator cuff

Aims

Hip resurfacing remains a potentially valuable surgical procedure for appropriately-selected patients with optimised implant choices. However, concern regarding high early failure rates continues to undermine confidence in use. A large contributor to failure is adverse local tissue reactions around metal-on-metal (MoM) bearing surfaces. Such phenomena have been well-explored around MoM total hip arthroplasties, but comparable data in equivalent hip resurfacing procedures is lacking. In order to define genetic predisposition, we performed a case-control study investigating the role of human leucocyte antigen (HLA) genotype in the development of pseudotumours around MoM hip resurfacings.

While classically bone tumors were classified according to the differentiation and cellular morphology at the light microscopical level, it has become clear that over the past decade the array of knowledge which became available on the cytogenetic and molecular genetic level should influence tumor classification. This lead to an integrated approach in drafting the 2002 WHO nomenclature for bone tumors in which morphology was combined with the evolving genetic information. With regard to bone tumorigenesis distinct patterns can be recognized with regard to underlying genetics:. balanced translocations such as in Ewing sarcoma, or aneurysmal bone cysts. numerical chromosomal abnormalities like in adamantinoma. complex karyotypes with as yet no identified starting point from a genetic point of view such as in osteosarcomas or central chondrosarcomas. single gene events such as in fibrous dysplasia or osteochondroma. These different pathways in oncogenesis open an array of possibilities for studying the drivers in oncogenesis. Especially those pathways essential in keeping the proliferative state as opposed to the ones governing differentiation might proof to be potential targets for tailored drug treatment. Here high throughput screens focusing on kinase activity appear especially of interest. Within the EuroBoNeT consortium (. www.eurobonet.eu. ) several working groups act transnationally together in unraveling these events. Important key elements of study are the molecular-genetic networks involved in skeletogenesis as well, which amongst others are studied within the consortium using in vitro systems as well as in vivo models using xenografted mouse models, mesenchymal stem cell models and models exploring zebrafish development

Aims

This study aimed to evaluate the BioFire Joint Infection (JI) Panel in cases of hip and knee periprosthetic joint infection (PJI) where conventional microbiology is unclear, and to assess its role as a complementary intraoperative diagnostic tool.

This is a case series of 25 patients with Multiple Epiphyseal Dysplasia (MED), a genetically determined disorder characterised by abnormal ossification of multiple epiphyses. The Nottingham Skeletal Dysplasia Clinic has run since 1966. In 1994 it combined with the Clinical Genetics Service providing care to patients from throughout the region. We collected data on MED patients with follow up of 1 to 41 years (average 12 years) and described their presenting symptoms, genetic, clinical and radiographic features. We followed the natural history and vast array of treatments. From the genetic point of view, 90% of patients counselled had typical AD-MED and 10% syndromic MED. Seven families opted to have testing. There were MATN3 mutations in 10% of the cohort, with marked intra-familial variability of phenotype. The average age at presentation was thirteen, with 80% of patients presenting before their sixteenth birthday. A third was seen because of a known family history of MED. Newly diagnosed index patients tended to present later. The most commonly affected joint at presentation was the hip and the most common knee deformity genu valgum. Symptoms progressed with time and joints not clinically affected at presentation became symptomatic later. Sixty percent of patients had further joint involvement within 10 years of diagnosis. Treatment ranged from orthotics to arthroplasty. Half of patients required surgical intervention at least once. Six patients underwent hip arthroplasty at an average age of 37. MED is a rare diagnosis but has significant impact on the quality of life of those diagnosed, who require the support of a multidisciplinary team from an early age. This is not only to help manage symptoms and preserve function, but also to counsel on the progressive nature and the genetic aspects of the disorder

Aims

Pellino1 (Peli1) has been reported to regulate various inflammatory diseases. This study aims to explore the role of Peli1 in the occurrence and development of osteoarthritis (OA), so as to find new targets for the treatment of OA.

Aims

The purpose of this study was to evaluate the mid-term outcomes of autologous matrix-induced chondrogenesis (AMIC) for the treatment of larger cartilage lesions and deformity correction in hips suffering from symptomatic femoroacetabular impingement (FAI).

1. We have described here various forms of rickets and osteomalacia that we have studied ourselves and have come to recognise as comprising definite syndromes. We have included only diseases in which hereditary factors have been proved or might be suspected to play a part. 2. There are more of these syndromes than previously defined. 3. All these hereditary diseases can be treated, usually very satisfactorily, using the same general principles and with only very few simple medicines such as vitamin D and sodium bicarbonate. Careful control and long follow-up, however, may be required to achieve best results and to avoid accidents. 4. A study of the genetics of the diseases is a help in diagnosis and treatment. Broadly speaking the group of diseases which mimic vitamin D deficiency more or less closely tend to be inherited in dominant fashion. The groups with more severe degree of renal-tubule abnormality are inherited as recessives. 5. When more than one member of a family is affected it has been found that in each family each syndrome runs true to type

Aims

This study aimed, through bioinformatics analysis and in vitro experiment validation, to identify the key extracellular proteins of intervertebral disc degeneration (IDD).

Aims

Spinopelvic characteristics influence the hip’s biomechanical behaviour. However, to date there is little knowledge defining what ‘normal’ spinopelvic characteristics are. This study aims to determine how static spinopelvic characteristics change with age and ethnicity among asymptomatic, healthy individuals.

Multiple Hereditary Exostoses is a rare skeletal chondrodysplasia characterized by the presence of a variable number of osteochondromas, usually mostly affecting the long bones but possibly located anywhere. Appearance and growth of exostoses is parallel to the patient’s growth, essentially ending when skeletal maturity is reached. Its clinical expression is well known and may vary from asymptomatic to severe deformities and is rarely complicated by trasformation to secondary chondrosarcoma (0.5–2%). Research in the field of genetics has lead to identification of 2 responsible genes, EXT1 and EXT2, located respectively on chromosome 8 and 11, both coding for transmembrane glycoproteins involved in the synthesis of heparan-sulfate chains. A third rare abnormality (EXT3) has been located on chromosome 19 but the responsible gene has not been identified yet. Seems logical to investigate the genetic basis of the disease and the correlation with clinical aspects, either severity of the deformities and consequent functional impairment and potential for chondrosarcoma. At the authors’ Institution a total of 550 patients with Multiple Hereditary Exostoses are presently filed. Genetic screening by DHPLC (Denaturing High Performance Liquid Chromatography) and clinicoradiographic orthopedic evaluation has been carried out on 200 patients. So far, 45 mutations have been identified (35 in EXT1 and 10 in EXT2) in 167 patients, 20 of which presented with negative family history and are therefore considered “de-novo” mutations. Comparison of the clinical data and prospective long term follow-up will possibly clarify different prognosis and risk of secondary chondrosarcoma for different genotypes

It has been known for well over a century that the corresponding ossification centres of the hand tend to appear before those of the foot (Mall 1906), although even now the range of variability remains poorly defined. Presumably a similar asynchrony also obtains for chondrification, although precise timing is more difficult here than for ossification. Accordingly, it is tempting with respect to this syndrome to relate fusions restricted to the phalanges of the hand and to the tarsal bones to the action of a gene which during a very limited period of development exerts an effect on those small bones of the hand and foot which are in a very specific stage of development. But since there are other inherited abnormalities of the skeleton, such as brachydactyly, where homologous bones are involved, it is clear that at the descriptive level gene action can either appear to be "stage-specific" or "homologue-specific." There are also mutations affecting the axial skeleton such as the type of polydactyly of the foot described by Neel and Rusk (1963) which appear to be neither "stage" nor "homologue" specific, involving only the foot. Finally then, there are syndromes, such as Lawrence-Moon-Biedl-Bardot, in which involvement of the hands and feet (polydactyly) is associated with such other apparently completely unrelated defects as retinitis pigmentosa and hypogonadism. While it is tempting to try to construct theoretical patterns and systems of developmental processes on the basis of results such as these, it is clear that the ultimate understanding of how genes can appear to act in so many ways almost certainly depends on the identification of a genetically controlled, qualitative or quantitative biochemical lesion. With the current parallel developments in biochemical and developmental genetics, new insights into these enigmas will surely be forthcoming in the relatively near future

Aims: The aim of the study is to present patients, to who uncemented conic, polyethylene acetabular components of total hip endoprosthesis (EP) Endler model, were implanted. The study tries to establish whether the cause of aseptic loosening of polyethylene acetabular components is the particle disease itself, as a reaction on polyethylene, or the causes may be found in other factors as well. Materials and methods: In the period from 1985 to 1991, 100 patients (59 females and 41 males) were operated and 110 EP were implanted. The patients were followed from 10 to 16 years (median time – 12.47 years). In these study 72 patients with 80-implanted EP were evaluated (radiological, clinical and subjective evaluation). Results: In 42 (52.50%) implanted Endler acetabular components subjective, radiological and clinical findings were very good or excellent. In 38 (47.40%) implanted acetabular components reacetabuloplasty was performed due to aseptic loosening; in 22 of those components follow-up was 10 years and other 16 had follow-up of 11 to 16 years after the primary implantation. Conclusion: The results confirmed that aseptic loosening developed in one group of the patients (38 EP), but did not develop in the other group (42 EP) after long period. The comparison of postoperative biomechanic conditions which has not shown any statistically significant differences, led to conclusion that beside the main role of polyethylene and mechanic factors, immunological cell reaction and genetics can have an especially significant role. Necessities for new immunological studies in the application of total hip arthroplasty were stressed out by our results

Aims

The aim of this study is to define a core outcome set (COS) to allow consistency in outcome reporting amongst studies investigating the management of orthopaedic treatment in children with spinal dysraphism (SD).

Introduction: Diminished adult stature is a key feature of Hereditary Multiple Exostoses (HME). Current debate on the pathogenesis of skeletal abnormalities in HME centres on whether there are ‘field-change’ effects which might retard bone-growth, or whether exostoses themselves distort normal bone development locally. The latter theory allows for surgical excision of exostoses to improve prospects for local normal bone development whereas the former does not. No study has previously investigated patterns of height disturbance in HME. Such an analysis in a cohort of children and adults with HME may provide evidence for or against either pathogenesis theory, and throw light on the chance of success of lower limb surgery in improving final height. Methods: Between 1996 and 2000, 172 individuals from 78 families with HME had clinical measurement of standing height and leg length (anterior superior iliac spine to medial malleolus. 71 were skeletally immature (1st and 2nd decades). Surgical intervention in anatomical areas affecting stature (lower limb, pelvis and spine) were recorded. Centile heights were calculated from Tanner Whitehouse charts. Results: 25/172 (15%) exhibited severe short stature (< 3rd centile height). Overall, Statural retardation was not apparent up to age 10; thereafter progressive diminution in centile height was recorded (figure 1). Before age 10, 25/37 (68%) were over the 50th centile. Beyond this age, 98/35 (73%) were less than the 50th centile (X2=22.42, p< 0.001). 101 patients who had surgery did not achieve a greater stature than those who had not. In the normal population lower limb contribution to height increases with age, whereas in HME it remains static suggesting that the retardation of stature seen between ages 10 and 20 in HME is mainly due to lower limb, not spinal growth retardation. Leg length discrepancy of > 1% of centile height was seen in 35/167 (21%), encompassing all age groups without significant difference. Discussion: The pattern of height retardation observed in this study is consistent with a progressive linear disturbance which is not apparent in early childhood, but progresses significantly in the second decade. Overt spinal exostoses are rare; and the spine’s contribution to growth retardation in HME appears be far less than that due to the lower limb. Although the genetics of HME allow for a field-change effect as well as a local osteo-chondroma effect, these results reinforce the possibility that solutions to severe short stature in HME may be achieved through lower limb surgery

Aims

The effect of the gut microbiota (GM) and its metabolite on bone health is termed the gut-bone axis. Multiple studies have elucidated the mechanisms but findings vary greatly. A systematic review was performed to analyze current animal models and explore the effect of GM on bone.

Aims

Interleukin (IL)-1β is one of the major pathogenic regulators during the pathological development of intervertebral disc degeneration (IDD). However, effective treatment options for IDD are limited. Suramin is used to treat African sleeping sickness. This study aimed to investigate the pharmacological effects of suramin on mitigating IDD and to characterize the underlying mechanism.

Osteoporosis (OP) is a chronic metabolic bone disease characterized by the decrease of bone tissue per unit volume under the combined action of genetic and environmental factors, which leads to the decrease of bone strength, makes the bone brittle, and raises the possibility of bone fracture. However, the exact mechanism that determines the progression of OP remains to be underlined. There are hundreds of trillions of symbiotic bacteria living in the human gut, which have a mutually beneficial symbiotic relationship with the human body that helps to maintain human health. With the development of modern high-throughput sequencing (HTS) platforms, there has been growing evidence that the gut microbiome may play an important role in the programming of bone metabolism. In the present review, we discuss the potential mechanisms of the gut microbiome in the development of OP, such as alterations of bone metabolism, bone mineral absorption, and immune regulation. The potential of gut microbiome-targeted strategies in the prevention and treatment of OP was also evaluated.

Cite this article: Bone Joint Res 2020;9(8):524–530.

Aims

The aticularis genu (AG) is the least substantial and deepest muscle of the anterior compartment of the thigh and of uncertain significance. The aim of the study was to describe the anatomy of AG in cadaveric specimens, to characterize the relevance of AG in pathological distal femur specimens, and to correlate the anatomy and pathology with preoperative magnetic resonance imaging (MRI) of AG.

Introduction

The aim of this study is to report the 30 day COVID-19 related morbidity and mortality of patients assessed as SARS-CoV-2 negative who underwent emergency or urgent orthopaedic surgery in the NHS during the peak of the COVID-19 pandemic.

Aims

The purpose of this study was to use pharmacogenetics to determine the frequency of genetic variants in our total knee arthroplasty (TKA) patients that could affect postoperative pain medications. Pharmacogenetic testing evaluates patient DNA to determine if a drug is expected to have a normal clinical effect, heightened effect, or no effect at all on the patient. It also predicts whether patients are likely to experience side effects from medicine. We further sought to determine if changing the multimodal programme based on these results would improve pain control or reduce side effects.

Objectives

X-linked hypophosphataemic rickets (XLHR) is a disease of impaired bone mineralization characterized by hypophosphataemia caused by renal phosphate wasting. The main clinical manifestations of the disorder are O-shaped legs, X-shaped legs, delayed growth, and bone pain. XLHR is the most common inheritable form of rickets, with an incidence of 1/20 000 in humans. It accounts for approximately 80% of familial cases of hypophosphataemia and serves as the prototype of defective tubular phosphate (PO4³⁺) transport, due to extra renal defects resulting in unregulated FGF23 activity. XLHR is caused by loss-of-function mutations in the PHEX gene. The aim of this research was to identify the genetic defect responsible for familial hypophosphataemic rickets in a four-generation Chinese Han pedigree and to analyze the function of this mutation.

Objectives

The aim of this study was to review the impact of smoking tobacco on the musculoskeletal system, and on bone fractures in particular.

This systematic review examines the current literature regarding surgical techniques for restoring articular cartilage in the hip, from the older microfracture techniques involving perforation to the subchondral bone, to adaptations of this technique using nanofractures and scaffolds. This review discusses the autologous and allograft transfer systems and the autologous matrix-induced chondrogenesis (AMIC) technique, as well as a summary of the previously discussed techniques, which could become common practice for restoring articular cartilage, thus reducing the need for total hip arthroplasty. Using the British Medical Journal Grading of Recommendations, Assessment, Development and Evaluation (BMJ GRADE) system and Grade system. Comparison of the studies discussed shows that microfracture has the greatest quantity and quality of research, whereas the newer AMIC technique requires more research, but shows promise.

Cite this article: W. E. Hotham, A. Malviya. A systematic review of surgical methods to restore articular cartilage in the hip. Bone Joint Res 2018;7:336–342. DOI: 10.1302/2046-3758.75.BJR-2017-0331.

Aims

The aim of this study was to investigate the changes in femoral trochlear morphology following surgical correction of recurrent patellar dislocation associated with trochlear dysplasia in children.

Objectives

Advanced glycation end-products (AGEs) are a post-translational modification of collagen that form spontaneously in the skeletal matrix due to the presence of reducing sugars, such as glucose. The accumulation of AGEs leads to collagen cross-linking, which adversely affects bone quality and has been shown to play a major role in fracture risk. Thus, intervening in the formation and accumulation of AGEs may be a viable means of protecting bone quality.

Aim

Nail patella syndrome (NPS) is a skeletal dysplasia with patellofemoral dysfunction as a key symptom. We present the first in-depth radiological evaluation of the knee in a large series of NPS patients and describe the typical malformations.

This article provides an overview of the role of genomics in sarcomas and describes how new methods of analysis and comparative screening have provided the potential to progress understanding and treatment of sarcoma. This article reviews genomic techniques, the evolution of the use of genomics in cancer, the current state of genomic analysis, and also provides an overview of the medical, social and economic implications of recent genomic advances.

Objectives

Adipose-derived mesenchymal stem cells (ADMSCs) are a promising strategy for orthopaedic applications, particularly in bone repair. Ex vivo expansion of ADMSCs is required to obtain sufficient cell numbers. Xenogenic supplements should be avoided in order to minimise the risk of infections and immunological reactions. Human platelet lysate and human plasma may be an excellent material source for ADMSC expansion. In the present study, use of blood products after their recommended transfusion date to prepare human platelet lysate (HPL) and human plasma (Hplasma) was evaluated for in vitro culture expansion and osteogenesis of ADMSCs.

Aims

Recently, there has been considerable interest in quantifying the associations between bony abnormalities around and in the hip joint and osteoarthritis (OA). Our aim was to investigate the relationships between acetabular undercoverage, acetabular overcoverage, and femoroacetabular impingement (FAI) with OA of the hip, which currently remain controversial.

Objectives

All-suture anchors are increasingly used in rotator cuff repair procedures. Potential benefits include decreased bone damage. However, there is limited published evidence for the relative strength of fixation for all-suture anchors compared with traditional anchors.

In vivo animal experimentation has been one of the cornerstones of biological and biomedical research, particularly in the field of clinical medicine and pharmaceuticals. The conventional in vivo model system is invariably associated with high production costs and strict ethical considerations. These limitations led to the evolution of an ex vivo model system which partially or completely surmounted some of the constraints faced in an in vivo model system. The ex vivo rodent bone culture system has been used to elucidate the understanding of skeletal physiology and pathophysiology for more than 90 years. This review attempts to provide a brief summary of the historical evolution of the rodent bone culture system with emphasis on the strengths and limitations of the model. It encompasses the frequency of use of rats and mice for ex vivo bone studies, nutritional requirements in ex vivo bone growth and emerging developments and technologies. This compilation of information could assist researchers in the field of regenerative medicine and bone tissue engineering towards a better understanding of skeletal growth and development for application in general clinical medicine.

Cite this article: A. A. Abubakar, M. M. Noordin, T. I. Azmi, U. Kaka, M. Y. Loqman. The use of rats and mice as animal models in ex vivo bone growth and development studies. Bone Joint Res 2016;5:610–618. DOI: 10.1302/2046-3758.512.BJR-2016-0102.R2.

The October 2012 Research Roundup³⁶⁰ looks at: whether you can escape your genes; oral prophylaxis for DVT; non-responders and the internet; metal-on-metal, mice and damaged livers; sleeping on the job; cartilage contact stress in the normal human hip; and a perfect reason to subscribe to 360.

The aim of this study was to report the incidence of arthrofibrosis of the knee and identify risk factors for its development following a fracture of the tibial plateau. We carried out a retrospective review of 186 patients (114 male, 72 female) with a fracture of the tibial plateau who underwent open reduction and internal fixation. Their mean age was 46.4 years (19 to 83) and the mean follow-up was16.0 months (6 to 80).

A total of 27 patients (14.5%) developed arthrofibrosis requiring a further intervention. Using multivariate regression analysis, the use of a provisional external fixator (odds ratio (OR) 4.63, 95% confidence interval (CI) 1.26 to 17.7, p = 0.021) was significantly associated with the development of arthrofibrosis. Similarly, the use of a continuous passive movement (CPM) machine was associated with significantly less development of arthrofibrosis (OR = 0.32, 95% CI 0.11 to 0.83, p = 0.024). The effect of time in an external fixator was found to be significant, with each extra day of external fixation increasing the odds of requiring manipulation under anaesthesia (MUA) or quadricepsplasty by 10% (OR = 1.10, p = 0.030). High-energy fracture, surgical approach, infection and use of tobacco were not associated with the development of arthrofibrosis. Patients with a successful MUA had significantly less time to MUA (mean 2.9 months; sd 1.25) than those with an unsuccessful MUA (mean 4.86 months; sd 2.61, p = 0.014). For those with limited movement, therefore, performing an MUA within three months of the injury may result in a better range of movement.

Based our results, CPM following operative fixation for a fracture of the tibial plateau may reduce the risk of the development of arthrofibrosis, particularly in patients who also undergo prolonged provisional external fixation.

Cite this article: Bone Joint J 2015;97-B:109–14.

Invasive group A streptococcus (iGAS) is the most common cause of monomicrobial necrotising fasciitis. Necrotising infections of the extremities may present directly to orthopaedic surgeons or by reference from another admitting specialty. Recent epidemiological data from the Health Protection Agency suggest an increasing incidence of iGAS infection in England. Almost 40% of those affected had no predisposing illnesses or risk factors, and the proportion of children presenting with infections has risen. These observations have prompted the Chief Medical Officer for the Central Alerting System in England to write to general practitioners and hospitals, highlighting the need for clinical vigilance, early diagnosis and rapid initiation of treatment in suspected cases.

The purpose of this annotation is to summarise the recent epidemiological trends, describe the presenting features and outline the current investigations and treatment of this rare but life-threatening condition.

We evaluated the top 13 journals in trauma and orthopaedics by impact factor and looked at the longer-term effect regarding citations of their papers.

All 4951 papers published in these journals during 2007 and 2008 were reviewed and categorised by their type, subspecialty and super-specialty. All citations indexed through Google Scholar were reviewed to establish the rate of citation per paper at two, four and five years post-publication. The top five journals published a total of 1986 papers. Only three (0.15%) were on operative orthopaedic surgery and none were on trauma. Most (n = 1084, 54.5%) were about experimental basic science. Surgical papers had a lower rate of citation (2.18) at two years than basic science or clinical medical papers (4.68). However, by four years the rates were similar (26.57 for surgery, 30.35 for basic science/medical), which suggests that there is a considerable time lag before clinical surgical research has an impact.

We conclude that high impact journals do not address clinical research in surgery and when they do, there is a delay before such papers are cited. We suggest that a rate of citation at five years post-publication might be a more appropriate indicator of importance for papers in our specialty.

Cite this article: Bone Joint J 2014;96-B:414–19.

The February 2013 Children’s orthopaedics Roundup³⁶⁰ looks at: the human genome; new RNA; cells, matrix and gene enhancement; the histology of x-rays; THR and VTE in the Danish population; potential therapeutic targets for GCT; optimising vancomycin elution from cement; and how much sleep is enough.

The incidence of acute and chronic conditions of the tendo Achillis appear to be increasing. Causation is multifactorial but the role of inherited genetic elements and the influence of environmental factors altering gene expression are increasingly being recognised. Certain individuals’ tendons carry specific variations of genetic sequence that may make them more susceptible to injury. Alterations in the structure or relative amounts of the components of tendon and fine control of activity within the extracellular matrix affect the response of the tendon to loading with failure in certain cases.

This review summarises present knowledge of the influence of genetic patterns on the pathology of the tendo Achillis, with a focus on the possible biological mechanisms by which genetic factors are involved in the aetiology of tendon pathology. Finally, we assess potential future developments with both the opportunities and risks that they may carry.

Cite this article: Bone Joint J 2013;95-B:305–13.

The most frequent cause of failure after total hip replacement in all reported arthroplasty registries is peri-prosthetic osteolysis. Osteolysis is an active biological process initiated in response to wear debris. The eventual response to this process is the activation of macrophages and loss of bone.

Activation of macrophages initiates a complex biological cascade resulting in the final common pathway of an increase in osteolytic activity. The biological initiators, mechanisms for and regulation of this process are beginning to be understood. This article explores current concepts in the causes of, and underlying biological mechanism resulting in peri-prosthetic osteolysis, reviewing the current basic science and clinical literature surrounding the topic.

Giant cell tumours (GCT) of the synovium and tendon sheath can be classified into two forms: localised (giant cell tumour of the tendon sheath, or nodular tenosynovitis) and diffuse (diffuse-type giant cell tumour or pigmented villonodular synovitis). The former principally affects the small joints. It presents as a solitary slow-growing tumour with a characteristic appearance on MRI and is treated by surgical excision. There is a significant risk of multiple recurrences with aggressive diffuse disease. A multidisciplinary approach with dedicated MRI, histological assessment and planned surgery with either adjuvant radiotherapy or systemic targeted therapy is required to improve outcomes in recurrent and refractory diffuse-type GCT.

Although arthroscopic synovectomy through several portals has been advocated as an alternative to arthrotomy, there is a significant risk of inadequate excision and recurrence, particularly in the posterior compartment of the knee. For local disease partial arthroscopic synovectomy may be sufficient, at the risk of recurrence. For both local and diffuse intra-articular disease open surgery is advised for recurrent disease. Marginal excision with focal disease will suffice, not dissimilar to the treatment of GCT of tendon sheath. For recurrent and extra-articular soft-tissue disease adjuvant therapy, including intra-articular radioactive colloid or moderate-dose external beam radiotherapy, should be considered.

Given the growing prevalence of obesity around the world and its association with osteoarthritis of the knee, orthopaedic surgeons need to be familiar with the management of the obese patient with degenerative knee pain. The precise mechanism by which obesity leads to osteoarthritis remains unknown, but is likely to be due to a combination of mechanical, humoral and genetic factors.

Weight loss has clear medical benefits for the obese patient and seems to be a logical way of relieving joint pain associated with degenerative arthritis. There are a variety of ways in which this may be done including diet and exercise, and treatment with drugs and bariatric surgery. Whether substantial weight loss can delay or even reverse the symptoms associated with osteoarthritis remains to be seen.

Surgery for osteoarthritis in the obese patient can be technically more challenging and carries a risk of additional complications. Substantial weight loss before undertaking total knee replacement is advisable. More prospective studies that evaluate the effect of significant weight loss on the evolution of symptomatic osteoarthritis of the knee are needed so that orthopaedic surgeons can treat this patient group appropriately.

The aim of this study was to investigate genetic influences on the development and progression of tears of the rotator cuff. From a group of siblings of patients with a tear of the rotator cuff and of controls studied five years earlier, we determined the prevalence of tears of the rotator cuff with and without associated symptoms using ultrasound and the Oxford Shoulder Score.

In the five years since the previous assessment, three of 62 (4.8%) of the sibling group and one of the 68 (1.5%) controls had undergone shoulder surgery. These subjects were excluded from the follow-up.

Full-thickness tears were found in 39 of 62 (62.9%) siblings and in 15 of 68 (22.1%) controls (p = 0.0001). The relative risk of full-thickness tears in siblings as opposed to controls was 2.85 (95% confidence interval (CI) 1.75 to 4.64), compared to 2.42 (95% CI 1.77 to 3.31) five years earlier. Full-thickness tears associated with pain were found in 30 of 39 (76.9%) tears in the siblings and in eight of 15 (53.3%) tears in the controls (p = 0.045). The relative risk of pain associated with a full-thickness tear in the siblings as opposed to the controls was 1.44 (95% CI 2.04 to 8.28) (p = 0.045).

In the siblings group ten of 62 (16.1%) had progressed in terms of tear size or development compared to one of 68 (1.5%) in the control group which had increased in size.

Full-thickness rotator cuff tears in siblings are significantly more likely to progress over a period of five years than in a control population. This implies that genetic factors have a role, not only in the development but also in the progression of full-thickness tears of the rotator cuff.

The management of osteoarthritis of the knee associated with patellar instability secondary to external tibial torsion > 45° is challenging. Patellofemoral biomechanics in these patients cannot be achieved by intra-articular correction using standard techniques of total knee replacement.

We reviewed seven patients (eight knees) with recurrent patellar dislocation and one with bilateral irreducible lateral dislocation who had undergone simultaneous total knee replacement and internal tibial derotational osteotomy. All had osteoarthritis and severe external tibial torsion. The mean follow-up was for 47.2 months (24 to 120).

The mean objective and functional Knee Society scores improved significantly (p = 0.0001) from 29.7 and 41.5 pre-operatively to 71.4 and 73.5 post-operatively, respectively. In all patients the osteotomies healed and patellar stability was restored.

Excessive external tibial torsion should be identified and corrected in patients with osteoarthritis and patellar instability. Simultaneous internal rotation osteotomy of the tibia and total knee replacement is a technically demanding but effective treatment for such patients.

When using a staged approach to eradicate chronic infection after total hip replacement, systemic delivery of antibiotics after the first stage is often employed for an extended period of typically six weeks together with the use of an in situ antibiotic-eluting polymethylmethacrylate interval spacer. We report our multi-surgeon experience of 43 consecutive patients (44 hips) who received systemic vancomycin for two weeks in combination with a vancomycin- and gentamicin-eluting spacer system in the course of a two-stage revision procedure for deep infection with a median follow-up of 49 months (25 to 83).

The antibiotic-eluting articulating spacers fractured in six hips (13.9%) and dislocated in five patients (11.6%). Successful elimination of the infecting organisms occurred in 38 (92.7%) of 41 hips with three patients developing superinfection with a new organism.

We conclude that prolonged systemic antibiotic therapy may not be essential in the two-stage treatment of a total hip replacement for Gram-positive infection, provided that a high concentration of antibiotics is delivered locally using an antibiotic-eluting system.

Deep-seated lipomas are often atypical histologically and are considered by some to have a high risk of recurrence after excision. We reviewed 215 deep-seated lipomas of the extremities and trunk wall with reference to histology, cytogenetics, clinical features and local recurrence. We classified tumours with atypical features and/or ring chromosomes as atypical lipomas. These were more common in men, larger than ordinary lipomas and more often located in the upper leg. The annual incidence was estimated as ten per million inhabitants and the ratio of atypical to ordinary lipomas was 1:3. In total, six tumours (3%), recurred locally after a median of eight years (1 to 16); of these, four were classified as atypical.

The low recurrence rate of deep-seated lipomas of the extremity or trunk wall, irrespective of histological subtype, implies that if surgery is indicated, the tumour may be shelled out, that atypical lipomas in these locations do not deserve the designation well-differentiated liposarcoma, and that routine review after surgery is not required.

Technological advances and shorter rescue times have allowed early and effective resuscitation after trauma and brought attention to the host response to injury. Trauma patients are at risk of progressive organ dysfunction from what appears to be an uncontrolled immune response. The availability of improved techniques of molecular diagnosis has allowed investigation of the role of genetic variations in the inflammatory response to post-traumatic complications and particularly to sepsis.

This review examines the current evidence for the genetic predisposition to adverse outcome after trauma. While there is evidence supporting the involvement of different polymorphic variants of genes in determining the post-traumatic course and the development of complications, larger-scale studies are needed to improve the understanding of how genetic variability influences the responses to post-traumatic complications and pharmacotherapy.

The scoliosis observed in chickens after pinealectomy resembles that seen in humans with an adolescent idiopathic scoliosis, suggesting that melatonin deficiency may be responsible. However, to date there have been no studies of pineal gland glucose metabolism in patients with adolescent idiopathic scoliosis that might support this hypothesis.

We examined the excretion of urinary 6-sulfatoxyl-melatonin as well as the glucose metabolism of the pineal gland in 14 patients with an adolescent idiopathic scoliosis and compared them with those of 13 gender-matched healthy controls using F-18 fluorodeoxyglucose brain positron emission tomography. There was no significant difference in the level of urinary 6-sulfatoxyl-melatonin or pineal gland metabolism between the study and the control group. We conclude that permanent melatonin deficiency is not a causative factor in the aetiology of adolescent idiopathic scoliosis.

We stably transfected early passage chondrocytes with an anti-apoptotic Bcl-2 gene in vitro using a retrovirus vector. Samples of articular cartilage were obtained from 11 patients with a mean age of 69 years (61 to 75) who were undergoing total knee replacement for osteoarthritis. The Bcl-2-gene-transfected chondrocytes were compared with non-transfected and lac-Z-gene-transfected chondrocytes, both of which were used as controls. All three groups of cultured chondrocytes were incubated with nitric oxide (NO) for ten days. Using the Trypan Blue exclusion assay, an enzyme-linked immunosorbent assay and flow cytometric analysis, we found that the number of apoptotic chondrocytes was significantly higher in the non-transfected and lac-Z-transfected groups than in the Bcl-2-transfected group (p < 0.05). The Bcl-2-transfected chondrocytes were protected from NO-induced impairment of proteoglycan synthesis.

We conclude that NO-induced chondrocyte death involves a mechanism which appears to be subject to regulation by an anti-apoptotic Bcl-2 gene. Therefore, Bcl-2 gene therapy may prove to be of therapeutic value in protecting human articular chondrocytes.

Treatment strategies for osteoarthritis most commonly involve the removal or replacement of damaged joint tissue. Relatively few treatments attempt to arrest, slow down or reverse the disease process. Such options include peri-articular osteotomy around the hip or knee, and treatment of femoro-acetabular impingement, where early intervention may potentially alter the natural history of the disease. A relatively small proportion of patients with osteoarthritis have a clear predisposing factor that is both suitable for modification and who present early enough for intervention to be deemed worthwhile. This paper reviews recent advances in our understanding of the pathology, imaging and progression of early osteoarthritis.