Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment

Current management strategies for patellofemoral pain: an online survey of 99 practising UK physiotherapists

Background: Patellofemoral pain (PFP) is considered one of the commonest forms of knee pain. This study aimed to identify how physiotherapists in the United Kingdom (UK) currently manage patellofemoral pain (PFP), particularly in relation to exercise prescription, and response to pain. Methods: An anonymous survey was designed with reference to previous surveys and recent systematic reviews. Practising UK physiotherapists who treat patients with PFP were invited to take part via an invitation email sent through professional networks, the ‘interactive Chartered Society of Physiotherapy (iCSP)’ message board, and social media (Twitter). Descriptive statistics were used to analyse the data. Results: A total of 99 surveys were completed. Responders reported a wide range of management strategies, including a broad selection of type and dose of exercise prescription. The five most common management strategies chosen were: closed chain strengthening exercises (98%); education and advice (96%); open chain strengthening exercises (76%); taping (70%) and stretches (65%). Physiotherapists with a special interest in treating PFP were statistically more likely to manage patients with orthotics (P=0.02) and bracing (P=0.01) compared to physiotherapists without a special interest. Approximately 55% would not prescribe an exercise if it was painful. Thirty-one percent of physiotherapists would advise patients not to continue with leisure and/or sporting activity if they experienced any pain. Conclusion: Current UK practice in the management strategies of PFP is variable. Further high quality research on which to inform physiotherapy practice is warranted for this troublesome musculoskeletal condition

Evolução na utilização e nos gastos de uma operadora de saúde

Brazil’s aging population and the rising number of people reliant upon the country’s supplementary healthcare system have elicited the concern of public and private managers regarding the increase in healthcare costs. In this paper, the costs per gender, per type of medical expenses and per age group of a major Brazilian self-managed healthcare provider between 2007 and 2013 were analyzed. This healthcare provider is of interest because, besides portraying a single condition of revenue growth restricted to the existing contributors, it also replicates the demographic profile expected for Brazil in 2050, when approximately one-third of its population will be over 60 years of age. The analyses confirm the current literature as they show an increase in healthcare plan usage by the elderly and the difference between admission rates by gender. They also reveal an increase in average length of stay in hospital and the increase in medical costs far above inflation, especially for materials and medicines. It is hoped that this study will help scholars and others interested in comparisons of medical expense trends, especially by age and sex, and that it encourages further collaboration on the sustainability of health insurance providers in Brazil

The Temporal Development of Fatty Infiltrates in the Neck Muscles Following Whiplash Injury: An Association with Pain and Posttraumatic Stress

Radiological findings associated with poor recovery following whiplash injury remain elusive. Muscle fatty infiltrates (MFI) in the cervical extensors on magnetic resonance imaging (MRI) in patients with chronic pain have been observed. Their association with specific aspects of pain and psychological factors have yet to be explored longitudinally.44 subjects with whiplash injury were enrolled at 4 weeks post-injury and classified at 6 months using scores on the Neck Disability Index as recovered, mild and moderate/severe. A measure for MFI and patient self-report of pain, loss of cervical range of movement and posttraumatic stress disorder (PTSD) were collected at 4 weeks, 3 months and 6 months post-injury. The effects of time and group and the interaction of time by group on MFI were determined. We assessed the mediating effect of posttraumatic stress and cervical range of movement on the longitudinal relationship between initial pain intensity and MFI. There was no difference in MFI across all groups at enrollment. MFI values increased in the moderate/severe group and were significantly higher in comparison to the recovered and mild groups at 3 and 6 months. No differences in MFI values were found between the mild and recovered groups. Initial severity of PTSD symptoms mediated the relationship between pain intensity and MFI at 6 months. Initial ROM loss did not.MFI in the cervical extensors occur soon following whiplash injury and suggest the possibility for the occurrence of a more severe injury with subsequent PTSD in patients with persistent symptoms

The relationship between hip abductor muscle strength and iliotibial band tightness in individuals with low back pain

<p>Abstract</p> <p>Background</p> <p>Shortening of the iliotibial band (ITB) has been considered to be associated with low back pain (LBP). It is theorized that ITB tightness in individuals with LBP is a compensatory mechanism following hip abductor muscle weakness. However, no study has clinically examined this theory. The purpose of this study was to investigate the muscle imbalance of hip abductor muscle weakness and ITB tightness in subjects with LBP.</p> <p>Methods</p> <p>A total of 300 subjects with and without LBP between the ages of 20 and 60 participated in this cross-sectional study. Subjects were categorized in three groups: LBP with ITB tightness (n = 100), LBP without ITB tightness (n = 100) and no LBP (n = 100). Hip abductor muscle strength was measured in all subjects.</p> <p>Results</p> <p>Analysis of Covariance (ANCOVA) with the body mass index (BMI) as the covariate revealed significant difference in hip abductor strength between three groups (P < 0.001). Post hoc analysis showed no significant difference in hip abductor muscle strength between the LBP subjects with and without ITB tightness (P = 0.59). However, subjects with no LBP had significantly stronger hip abductor muscle strength compared to subjects with LBP with ITB tightness (P < 0.001) and those with LBP without ITB tightness (P < 0.001).</p> <p>Conclusion</p> <p>The relationship between ITB tightness and hip abductor weakness in patients with LBP is not supported as assumed in theory. More clinical studies are needed to assess the theory of muscle imbalance of hip abductor weakness and ITB tightness in LBP.</p

Fine-Scale Variation and Genetic Determinants of Alternative Splicing across Individuals

Recently, thanks to the increasing throughput of new technologies, we have begun to explore the full extent of alternative pre–mRNA splicing (AS) in the human transcriptome. This is unveiling a vast layer of complexity in isoform-level expression differences between individuals. We used previously published splicing sensitive microarray data from lymphoblastoid cell lines to conduct an in-depth analysis on splicing efficiency of known and predicted exons. By combining publicly available AS annotation with a novel algorithm designed to search for AS, we show that many real AS events can be detected within the usually unexploited, speculative majority of the array and at significance levels much below standard multiple-testing thresholds, demonstrating that the extent of cis-regulated differential splicing between individuals is potentially far greater than previously reported. Specifically, many genes show subtle but significant genetically controlled differences in splice-site usage. PCR validation shows that 42 out of 58 (72%) candidate gene regions undergo detectable AS, amounting to the largest scale validation of isoform eQTLs to date. Targeted sequencing revealed a likely causative SNP in most validated cases. In all 17 incidences where a SNP affected a splice-site region, in silico splice-site strength modeling correctly predicted the direction of the micro-array and PCR results. In 13 other cases, we identified likely causative SNPs disrupting predicted splicing enhancers. Using Fst and REHH analysis, we uncovered significant evidence that 2 putative causative SNPs have undergone recent positive selection. We verified the effect of five SNPs using in vivo minigene assays. This study shows that splicing differences between individuals, including quantitative differences in isoform ratios, are frequent in human populations and that causative SNPs can be identified using in silico predictions. Several cases affected disease-relevant genes and it is likely some of these differences are involved in phenotypic diversity and susceptibility to complex diseases

Patellofemoral pain syndrome (PFPS): a systematic review of anatomy and potential risk factors

Patellofemoral Pain Syndrome (PFPS), a common cause of anterior knee pain, is successfully treated in over 2/3 of patients through rehabilitation protocols designed to reduce pain and return function to the individual. Applying preventive medicine strategies, the majority of cases of PFPS may be avoided if a pre-diagnosis can be made by clinician or certified athletic trainer testing the current researched potential risk factors during a Preparticipation Screening Evaluation (PPSE). We provide a detailed and comprehensive review of the soft tissue, arterial system, and innervation to the patellofemoral joint in order to supply the clinician with the knowledge required to assess the anatomy and make recommendations to patients identified as potentially at risk. The purpose of this article is to review knee anatomy and the literature regarding potential risk factors associated with patellofemoral pain syndrome and prehabilitation strategies. A comprehensive review of knee anatomy will present the relationships of arterial collateralization, innervations, and soft tissue alignment to the possible multifactoral mechanism involved in PFPS, while attempting to advocate future use of different treatments aimed at non-soft tissue causes of PFPS

Impact of dietary organic acids and botanicals on intestinal integrity and inflammation in weaned pigs

BACKGROUND: Organic acids, such as citric and sorbic acid, and pure plant-derived constituents, like monoterpens and aldehydes, have a long history of use in pig feeding as alternatives to antibiotic growth promoters. However, their effects on the intestinal barrier function and inflammation have never been investigated. Therefore, aim of this study was to assess the impact of a microencapsulated mixture of citric acid and sorbic acid (OA) and pure botanicals, namely thymol and vanillin, (PB) on the intestinal integrity and functionality of weaned pigs and in vitro on Caco-2 cells. In the first study 20 piglets were divided in 2 groups and received either a basal diet or the basal diet supplemented with OA + PB (5 g/kg) for 2 weeks post-weaning at the end of which ileum and jejunum samples were collected for Ussing chambers analysis of trans-epithelial electrical resistance (TER), intermittent short-circuit current (I(SC)), and dextran flux. Scrapings of ileum mucosa were also collected for cytokine analysis (n = 6). In the second study we measured the effect of these compounds directly on TER and permeability of Caco-2 monolayers treated with either 0.2 or 1 g/l of OA + PB. RESULTS: Pigs fed with OA + PB tended to have reduced I(SC) in the ileum (P = 0.07) and the ileal gene expression of IL-12, TGF-β, and IL-6 was down regulated. In the in vitro study on Caco-2 cells, TER was increased by the supplementation of 0.2 g/l at 4, 6, and 14 days of the experiment, whereas 1 g/l increased TER at 10 and 12 days of treatment (P < 0.05). Dextran flux was not significantly affected though a decrease was observed at 7 and 14 days (P = 0.10 and P = 0.09, respectively). CONCLUSIONS: Overall, considering the results from both experiments, OA + PB improved the maturation of the intestinal mucosa by modulating the local and systemic inflammatory pressure ultimately resulting in a less permeable intestine, and eventually improving the growth of piglets prematurely weaned