Deciphering the genetic relationships between major depressive disorder (MDD) and osteoarthritis (OA) may facilitate an understanding of their biological mechanisms, as well as inform more effective treatment regimens. We aim to investigate the mechanisms underlying relationships between MDD and OA in the context of common genetic variations. Linkage disequilibrium score regression was used to test the genetic correlation between MDD and OA. Polygenic analysis was performed to estimate shared genetic variations between the two diseases. Two-sample bidirectional Mendelian randomization analysis was used to investigate causal relationships between MDD and OA. Genomic loci shared between MDD and OA were identified using cross-trait meta-analysis. Fine-mapping of transcriptome-wide associations was used to prioritize putatively causal genes for the two diseases.Aims
Methods
Osteosarcoma (OSA) is a rare, but disproportionately lethal cancer that predominantly affects children. Sadly, discovery of new therapies for OSA has largely been unsuccessful in the past 30 years; there is an urgent need to identify new treatments for OSA. Pet dogs with naturally-occurring OSA represent a unique comparative “model” to discover new treatments for OSA. Unlike humans, in which fewer than 1,000 cases of OSA occur each year, there are nearly 50,000 new cases each year of OSA in dogs. In addition, dogs have an intact immune system, a shared environment with humans, and more rapid progression of disease. Together these factors make dogs an important comparative model for new therapies for OSA. The purpose of this study was: 1) to validate this mouse-dog-human pipeline for drug discovery and 2) to validate CRM1 as a novel target for ostesoarcoma treatment. We developed patient-derived cell lines and xenografts of OSA from both dogs and humans and applied these models to identify new therapies for OSA using high-throughput drug screens in vitro followed by in vivo validation. Whole exome sequencing was performed on the patient-derived models and original tumors to identify potential driver mutations. A high-throughput screen in both dog and human OSA identified CRM1 inhibitors as effective at killing dog and human OSA patient-derived cell lines in vitro. In vivo, CRM1 inhibition led to significant tumor growth inhibition in patient-derived xenografts from dogs and humans. Western blotting demonstrated increased levels of CRM1 protein expression across nine different dog and human OSA cell lines compared to non-transformed human osteoblasts. CRM1 upregulation in OSA cells was further verified by immunofluorescence staining. Increased CRM1 expression was prognostic for poorer metastasis-free survival and poorer overall survival. Our cross-species personalized medicine pipeline identified CRM1 as a potential therapeutic target to treat OSA in both dogs and humans. Future studies are focused on testing CRM1 inhibitors in canine clinical trials.
Osteoarthritis commonly affects the first metatarsophalangeal joint. Stress across this joint has been postulated to increase the incidence of osteoarthritis. Certain foot structures have been associated with a higher incidence of osteoarthritis of the big toe. Utilizing finite elemental analysis, bone stress across the first metatarsophalangeal joint was calculated during mid stance phase of gait and compared in different foot structures. A geometrically accurate three dimensional model of the first metatarsophalangeal joint was created utilising a high resolution 7 tesla MRI and Mimics v14 imaging software. Planus, rectus and cavus feet were simulated by varying the metatarsophalangeal declination angle to 10.1, 20.2 and 30.7 degrees, respectively. A non-manfold computer aided design technique in Mimics v14.2 and finite element method in ANSYS v12 FE were utilised to create the boundary conditions, representing the double support stance phase of gait. Using information from 61 asymptomatic patients with different foot types walking over a Novel emed-x plantar pressure measuring system, plantar loading conditions were applied. Finite elemental analysis was used to predict stress in the first metatarsophalangeal joint in the different foot types.Introduction
Method
Giant cell tumours of tendon sheaths have been given multiple denominations due to the uncertain pathologic nature of this lesion. Various contributory factors have been accounted for a wide variation in their recurrence rates. Owing to their high recurrence rates ranging from 9% to 44%, these tumours continue to present with treatment dilemma. There is a lack of consensus regarding how to best manage the balance between extensive dissection and preservation of normal tissues for normal function and recovery versus the risk of recurrence. The authors studied 46 patients with histopathologically confirmed Giant cell tumours over a period of 9 years between 1997 and 2006. The average follow-up in this case series was 35 months. This study aims to analyse the distribution of giant cell tumours of tendon sheaths in hand and our experience with their resection in a District General Hospital with possible predictors associated with recurrence. The referral letters, radiographs, operative and histology records were reviewed. The data was carefully analysed including patients' age and sex at the time of presentation and surgery, presenting symptoms, any associated trauma and the anatomical location of the tumour. A telephonic questionnaire was conducted and the patients with any complications or recurrence were reviewed. Our recurrence rate of 8.6% (4 patients) is lower than previously reported in the literature when the patients did not receive post-operative radiotherapy. Recurrence was seen to be statistically higher in cases where the tumours were excised piecemeal as opposed to removed in one piece and in patients with osseous erosions which were confirmed radiologically and intra-operatively. No atypical mitosis was reported on histology. None of our patients received radiotherapy post-operatively. Other factors including age, size, degenerative joint disease and location within the digit were not confirmed as risk factors in our study. We recommend meticulous surgical technique by an experienced hand surgeon and warning patients of the risk of recurrence if any risk factors were identified.
Fat embolism occurs following fractures of a long bone or arthroplasty. We investigated whether paradoxical embolisation through a venous-to-arterial circulation shunt (v-a) could lead to cerebral embolisation during elective hip or knee arthroplasty. Transcranial Doppler ultrasound (TCD), following the intravenous injection of microbubble contrast, identified the presence of a shunt in 41 patients undergoing hip (n=20) or knee (n=21) arthroplasty. Intra-operative cerebral embolism was detected during continuous TCD monitoring. Of the 41 patients, 34 had a v-a shunt of whom 18 had an embolism and embolism only occurred in patients with a shunt (p = 0.012). Spontaneous and larger shunts were associated with a greater number of emboli (rs = 0.67 and rs = 0.71 respectively, p <
0.01). Observations in two patients with large spontaneous shunts revealed 368 and 203 emboli and unexplained post-operative confusion and pancreatitis. Paradoxical cerebral embolisation only occurred in patients with a shunt and may explain both postoperative confusion and fat embolism syndrome following surgery.
Tibialis posterior tendon (TPT) dysfunction is a disorder of unknown aetiology. Trauma, inflammatory processes, anatomical abnormalities and iatrogenic factors have all been implicated as causative mechanisms. The condition presents with pain and swelling around the medial malleolus. The pain is characteristically worse on exercise and relieved by elevation. The disorder has been classified by Johnson and Strom (1989); stage I is characterized by pain around the medial malleolus and mild weakness of single heel raising. Without treatment the condition may progress to a fixed valgus deformity along with pes planus.
To assess the outcome of surgical decompression of stage I TPT dysfunction.
Ten cases were identified, operated on by a single surgeon over a three-year period. The patients were assessed in a dedicated clinic by administration of a questionnaire and by clinical examination.
Nine patients with an average age of 30 years (13–51) agreed to participate in the study. Six of the nine patients recalled a sporting injury to the ankle prior to onset of symptoms. Eight of these of patients underwent a course of physiotherapy prior to surgery. After decompression all patients reported reduction of pain as measured using a visual analogue scale, with five patients reporting complete resolution of pain. Patients experienced relief of pain on average four weeks (1.5–6) after surgery. All patients were able to return to work and normal leisure activities after appropriate rehabilitation.
Decompression of the tibialis posterior tendon in stage I dysfunction leads to pain relief and enables an early return to normal activities. Therefore surgical decompression of the tibialis posterior tendon may be considered in cases of stage I dysfunction which are refractory to conservative measures, particularly in young and active patients.
