Background: Osteoarthritis is a leading cause of disability in developed nations. In Australia it afflicts 16.5% of the adult population. Total joint arthroplasty is considered the treatment of choice for end stage osteoarthritis. The number of total joint arthroplasties undertaken in Australia has doubled over the last decade (more than 80,000 procedures in 2011). The incidence of pre-operative psychological distress in this group of patients is reported between 30% and 60% and pre-operative psychological distress is associated with poorer pain and functional outcomes after surgery. This study will use a mindfulness-based psychological intervention to enhance outcomes in people undergoing total joint arthroplasty and, in addition, will test hypotheses about coping with chronic illness in an aged population. This study is the first of its kind and will provide a greater understanding of the role of a mental health enhancement program on the physical recovery of total joint arthroplasty patients.Methods/Design: One hundred and fifty people with end-stage arthritis on the waiting list for total hip or knee arthroplasty will be recruited and randomly allocated to one of two groups using computer-generated block randomisation. A randomised controlled trial adhering to CONSORT guidelines will evaluate the efficacy of a mindfulness training program (weekly group-based classes in mindfulness practice, 2 1/2 hours, for 8 weeks plus a 7-hour Saturday session in Week 6) prior to total joint arthroplasty, compared to a "standard care" group who will undergo routine total joint arthroplasty. Primary outcomes will be evaluated by a blinded examiner at baseline, 3 and 12 months post-surgery, using a validated self-reported pain and physical function scale. Secondary outcomes will include i) a range of validated measures of psychological wellbeing and ii) health economic analysis. All analyses will be conducted on an intention to treat basis using linear regression models. Health economic modelling will be applied to estimate the potential cost-effectiveness of mindfulness training and total joint arthroplasty.

Superficial wound complications have been consistently implicated in the development of prosthetic joint infection. This cohort study aimed to determine perioperative risk factors associated with superficial wound complications. The study was performed over an 18-month period (January 2011 to June 2012) and included 964 patients undergoing prosthetic hip or knee replacement surgery. The factors associated with superficial wound complication differed according to arthroplasty site. In the combined cohort the following factors were associated with superficial wound complications: the use of 0.5% chlorhexidine in 70% alcohol for surgical skin preparation compared with 1% iodine in 70% alcohol (odds ratio (OR) 4.75; 95% confidence interval (CI) 1.42, 15.92; p=0.012); increasing age (OR, 1.13; 95% CI, 1.06,1.19; p0.18); increasing body mass index (BMI) (OR, 1.08; 95% CI, 1.05,1.12; p<0.001); rheumatoid arthritis (OR, 2.56; 95% CI, 1.17, 5.58; p0.018); and increasing blood transfusions (OR, 1.26; 95% CI, 1.06,1.49; p0.008). In the hip arthroplasty cohort, the use of 0.5% chlorhexidine in 70% alcohol for surgical skin preparation (OR, 13.35; 95% CI, 2.11, 84.29; p0.006), increasing BMI (OR, 1.13; 95% CI, 1.06, 1.19; p<0.001) and increasing blood transfusions (OR, 1.26; 95% CI, 1.06, 1.49; p0.008) were associated with superficial wound complications. In the knee arthroplasty cohort rheumatoid arthritis (OR, 2.75; 95% CI, 1.03, 7.33; p0.043) and increasing tourniquet time (OR, 1.01; 95% CI, 1.00, 1.02; p=0.029) were independent predictors of superficial wound complications. Further research is warranted to assess the impact of modification of these factors on the subsequent development of wound complications and prosthetic joint infection.

The recent discovery that normal and neoplastic epithelial cells re-enter the stem cell state raised the intriguing possibility that the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs) but from their proclivity to generate new CSCs from non-CSC populations. Here, we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC state. The observed cell plasticity is dependent on ZEB1, a key regulator of the epithelial-mesenchymal transition. We find that plastic non-CSCs maintain the ZEB1 promoter in a bivalent chromatin configuration, enabling them to respond readily to microenvironmental signals, such as TGF beta. In response, the ZEB1 promoter converts from a bivalent to active chromatin configuration, ZEB1 transcription increases, and non-CSCs subsequently enter the CSC state. Our findings support a dynamic model in which interconversions between low and high tumorigenic states occur frequently, thereby increasing tumorigenic and malignant potential.

BACKGROUND: Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor and from genetic and/or epigenetic differences amongst the cancer cells themselves. These factors conspire to create a disease with various phenotypes. There are 2 established models of cancer development and progression to metastatic disease. These are the clonal evolution and cancer stem cell models.CONTENT: The clonal evolution theory suggests that successive mutations accumulating in a given cell generate clonal outgrowths that thrive in response to microenvironmental selection pressures, dictating the phenotype of the tumor. The alternative cancer stem cell (CSC) model suggests that cancer cells with similar genetic backgrounds can be hierarchically organized according to their tumorigenic potential. Accordingly, CSCs reside at the apex of the hierarchy and are thought to possess the majority of a cancer's tumor-initiating and metastatic ability. A defining feature of this model is its apparent unidirectional nature, whereby CSCs undergo symmetric division to replenish the CSC pool and irreversible asymmetric division to generate daughter cells (non-CSCs) with low tumorigenic potential. However, evolving evidence supports a new model of tumorigenicity, in which considerable plasticity exists between the non-CSC and CSC compartments, such that non-CSCs can reacquire a CSC phenotype. These findings suggest that some tumors may adhere to a plastic CSC model, in which bidirectional conversions are common and essential components of tumorigenicity.SUMMARY: Accumulating evidence surrounding the plasticity of cancer cells, in particular, suggests that aggressive CSCs can be created de novo within a tumor. Given the current focus on therapeutic targeting of CSCs, we discuss the implications of non-CSC-to-CSC conversions on the development of future therapies.

Background: We sought to determine whether socio-economic status (SES) is an independent predictor of outcome following total knee (TKR) and hip (THR) replacement in Australians.Methods: In this prospective cohort study, we included patients undergoing TKR and THR in a public hospital in whom baseline and 12-month follow-up data were available. SES was determined using the Australian Bureau of Statistics'Index of Relative Advantage and Disadvantage' . Other independent variables included patients' demographics, comorbidities and procedure-related variables. Outcome measures were the International Knee Society Score and Harris Hip Score pain and function subscales, and the Short Form Health Survey (SF-12) physical and mental component scores.Results: Among 1,016 patients undergoing TKR and 835 patients undergoing THR, in multiple regression analysis, SES score was not independently associated with pain and functional outcomes. Female sex, older age, being a non-English speaker, higher body mass index and presence of comorbidities were associated with greater post-operative pain and poorer functional outcomes following arthroplasty. Better baseline function, physical and mental health, and lower baseline level of pain were associated with better outcomes at 12 months. In univariate analysis, for TKR, the improvement in SF-12 mental health score post arthroplasty was greater in patients of lower SES (3.8 +/- 12.9 versus 1.5 +/- 12.2, p = 0.008), with a statistically significant inverse association between SES score and post-operative SF-12 mental health score in linear regression analysis (coefficient-0.28, 95% CI: -0.52 to -0.04, p = 0.02).Conclusions: When adjustments are made for other covariates, SES is not an independent predictor of pain and functional outcome following large joint arthroplasty in Australian patients. However, relative to baseline, patients in lower socioeconomic groups are likely to have greater mental health benefits with TKR than more privileged patients. Large joint arthroplasty should be made accessible to patients of all SES.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is a process implicated in cancer metastasis that involves the conversion of epithelial cells to a more mesenchymal and invasive cell phenotype. In breast cancer cells EMT is associated with altered store-operated calcium influx and changes in calcium signalling mediated by activation of cell surface purinergic receptors. In this study, we investigated whether MDA-MB-468 breast cancer cells induced to undergo EMT exhibit changes in mRNA levels of calcium channels, pumps and exchangers located on intracellular calcium storing organelles, including the Golgi, mitochondria and endoplasmic reticulum (ER). METHODS: Epidermal growth factor (EGF) was used to induce EMT in MDA-MB-468 breast cancer cells. Serum-deprived cells were treated with EGF (50 ng/mL) for 12 h and gene expression was assessed using quantitative RT-PCR. RESULTS AND CONCLUSIONS: These data reveal no significant alterations in mRNA levels of the Golgi calcium pump secretory pathway calcium ATPases (SPCA1 and SPCA2), or the mitochondrial calcium uniporter (MCU) or Na+/Ca2+ exchanger (NCLX). However, EGF-induced EMT was associated with significant alterations in mRNA levels of specific ER calcium channels and pumps, including (sarco)-endoplasmic reticulum calcium ATPases (SERCAs), and inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RYR) calcium channel isoforms. The most prominent change in gene expression between the epithelial and mesenchymal-like states was RYR2, which was enriched 45-fold in EGF-treated MDA-MB-468 cells. These findings indicate that EGF-induced EMT in breast cancer cells may be associated with major alterations in ER calcium homeostasis.

Osteoarthritis (OA) is one of the 10 most disabling diseases in developed countries and worldwide estimates are that 10% of men and 18% of women aged over 60 years have symptomatic OA, including moderate and severe forms. Total joint replacement (TJR) is considered the most effective treatment for end-stage OA in those who have exhausted available conservative interventions. The demand for TJR is continually rising due to the ageing population; in the United States, more than 1 million TJRs were performed in 2010 and the number of procedures is projected to exceed 4 million in the US by 2030. It has been estimated that of all hip and knee replacements performed, approximately one quarter of the patients may be considered inappropriate candidates. Predicting who will benefit from TJR and who will not would seem critical in terms of containing the current and projected expenditure as well as improving satisfaction in TJR recipients. Few formal predictive tools are available to aid referring clinicians to determine those likely to be good or poor responders to surgery and current available tools tend to focus on disease severity alone with little consideration of risk factors that may predict a poor outcome or impede an effective response to surgery. This review examines the tools available to assist with assessing appropriateness for TJR; investigates the modifiable risk factors associated with poor outcome; and identifies areas for future research in selecting those appropriate for joint replacement.

OBJECTIVE: To compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon-beta (IFNβ) after an on-treatment relapse on IFNβ or GA using propensity score matched real-world datasets. METHODS: Patients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFNβ or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFNβ/GA treatment ≤6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFNβ only [n = 578/group], GA only [n = 165/group], or both IFNβ and GA [n = 176/group]). RESULTS: Compared to switching between IFNβ and GA, switching to natalizumab reduced annualized relapse rate in year one by 65-75%, the risk of first relapse by 53-82% (mean follow-up 1.7-2.2 years) and treatment discontinuation events by 48-65% (all P ≤ 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS-years (P < 0.0001) over the first 24 months post switch. INTERPRETATION: Using large, real-world, propensity-matched datasets we demonstrate that after a relapse on IFNβ or GA, switching to natalizumab (rather than between IFNβ and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity.