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Supplementary Figure S1. Survival analysis in extreme quartiles of RAI2 expression in lung colon and ovarian cancer data sets.

Supplementary Figure S4. Data base analysis of correlation between RAI2 and ESR1 mRNA expression.

Supplementary Figure S3. qPCR verification of RAI2 expression and correlative analysis of RAI2 mRNA expression in primary breast tumors.

Supplementary Figure S6. Analysis of adherents junction formation following RAI2 depletion in MCF-7 and KPL-1.

Supplementary Figure S7. Gene expression profiling of MDA-MD-231 cells over expressing wild type and CtBP binding deficient RAI2 proteins.

Supplementary Figure S5. Quantification of CAMA-1 cells with mesenchymal transformed cellular morphology.

Supplementary Figure S2. Survival analysis in extreme quartiles of RERG and RLN2 mRNA expression in breast cancer data sets.

Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. Objective: To evaluate the long-term clinical effectiveness of a novel group-based outpatient physical therapy (PT) following total knee replacement (TKR). Methods: In this 2-center, unblinded, superiority, randomized controlled trial, 180 patients on a waiting list for primary TKR due to osteoarthritis were randomized to a 6 session group-based outpatient PT intervention and usual care (n = 89) or usual care alone (n = 91). The primary outcome was patient-reported functional ability measured by the Lower Extremity Functional Scale at 12 months postoperative. Secondary outcomes included knee symptoms, depression, anxiety, and satisfaction. Questionnaires were completed preoperatively and at 3, 6, and 12 months postoperatively. Results: The mean difference in function between groups was 4.47 (95% confidence interval [95% CI] 0.20, 8.75; P = 0.04) at 12 months postoperative, favoring the intervention. The mean difference in function between groups decreased over time, from 8.1 points at 3 months (95% CI 3.8, 12.4; P < 0.001) to 5.4 (95% CI 1.1, 9.8; P = 0.015) at 6 months postoperative. There were no clinically relevant differences in any secondary outcomes between groups, although patients in the intervention group were more likely to be satisfied with their PT. No serious adverse events related to the intervention were reported. Conclusion: Supplementing usual care with this group-based outpatient PT intervention led to improvements in function at 12 months after TKR, although the magnitude of the difference was below the minimum clinically important difference of 9 points. However, patient satisfaction was higher in the intervention group, and there was some evidence of clinically relevant improvements in function at 3 months.

Background: Prosthetic implants used in total hip replacements (THR) have a range of bearing surface combinations (metal-on-polyethylene, ceramic-on-polyethylene, ceramic-on-ceramic, and metal-on-metal), head sizes (small [

Objectives: To assess the feasibility of a multi-site randomised controlled trial to evaluate the effect of functional electrical stimulation on bradykinesia in people with Parkinson’s disease. Design: A two-arm assessor blinded randomised controlled trial with an 18 weeks intervention period and 4 weeks post-intervention follow-up. Setting: Two UK hospitals; a therapy outpatient department in a district general hospital and a specialist neuroscience centre. Participants: A total of 64 participants with idiopathic Parkinson’s disease and slow gait −1. Interventions: Functional electrical stimulation delivered to the common peroneal nerve while walking in addition to standard care compared with standard care alone. Main measures: Feasibility aims included the determination of sample size, recruitment and retention rates, acceptability of the protocol and confirmation of the primary outcome measure. The outcome measures were 10 m walking speed, Unified Parkinson’s Disease Rating Scale (UPDRS), Mini Balance Evaluation Systems Test, Parkinson’s Disease Questionnaire-39, EuroQol 5-dimension 5-level, New Freezing of Gait questionnaire, Falls Efficacy Score International and falls diary. Participants opinion on the study design and relevance of outcome measures were evaluated using an embedded qualitative study. Results: There was a mean difference between groups of 0.14 ms−1 (CI 0.03, 0.26) at week 18 in favour of the treatment group, which was maintained at week 22, 0.10 ms−1 (CI –0.05, 0.25). There was a mean difference in UPDRS motor examination score of –3.65 (CI –4.35, 0.54) at week 18 which was lost at week 22 –0.91 (CI –2.19, 2.26). Conclusion: The study design and intervention were feasible and supportive for a definitive trial. While both the study protocol and intervention were acceptable, recommendations for modifications are made.

Introduction/Background Ovarian cancer is the leading cause of death from gynaecological cancer, with more than 7000 new cases registered in the UK in 2014. Standard treatment includes surgical resection of all macroscopic tumour, followed by chemotherapy. Surgery can be extensive and associated with substantial blood loss which is conventionally replaced with a donor blood transfusion. While often necessary and lifesaving, the use of donor blood is associated with increased risks of complications and adverse surgical outcomes. Intraoperative cell salvage (ICS) is a blood conservation strategy in which red cells collected from blood lost during surgery are returned to the patient thus minimising the use of donor blood. The aim of this feasibility study was to assess whether ICS is a safe alternative to blood transfusion and if a larger, fully powered trial can successfully be planned and delivered. Methodology This is a randomised, controlled multi-centre feasibility trial conducted in four UK acute NHS hospitals over 12 months. Adult women requiring primary or interval surgery for suspected ovarian cancer were eligible for the trial if CT scan evidence supported FIGO stage III/IV ovarian or primary peritoneal cancer. Participants were randomised 1:1 ratio to receive either intra-operative cell salvage (ICS) reinfusion or donor blood transfusion intra-operatively,with stratification by study site. Results 173 women were approached, and 59 took part. In the ICS group, 16 (62%) of the 26 participants received ICS reinfusion. In the donor blood group, 14 of the 29 (48%) received donor blood. Twenty-two (40%) participants (9 ICS, 13 control) experienced infections, mainly wound, urinary tract or chest. Six participants died (2 ICS, 4 control) were all due to disease progression. Conclusion We have demonstrated that ICS is safe and acceptable alternative to blood transfusion in ovarian cancer surgery. Further larger randomised trial is needed to determine the long term outcomes. Disclosure Nothing to disclose.

BackgroundDisfigurement (visible difference) from wide-ranging congenital or acquired conditions, injuries, or treatments can negatively impact adolescents’ psychological well-being, education and health behaviours. Alongside medical interventions, appearance-specific cognitive behavioural and social skills training to manage stigma and appearance anxiety may improve psychosocial outcomes. YP Face IT (YPF), is a Web-based seven session self-help program plus booster quiz, utilising cognitive behavioural and social skills training for young people (YP) struggling with a visible difference. Co-designed by adolescents and psychologists, it includes interactive multimedia and automated reminders to complete sessions/homework. Adolescents access YPF via a health professional who determines its suitability and remotely monitors clients’ usage.ObjectiveTo establish the feasibility of evaluating YPF for 12-17 year olds self-reporting appearance-related distress and/or bullying associated with a visible difference.MethodsRandomized controlled trial with nested qualitative and economic study evaluating YPF compared with usual care (UC). Feasibility outcomes included: viability of recruiting via general practitioner (GP) practices (face to face and via patient databases) and charity advertisements; intervention acceptability and adherence; feasibility of study and data collection methods; and health professionals’ ability to monitor users’ online data for safeguarding issues. Primary psychosocial self-reported outcomes collected online at baseline, 13, 26, and 52 weeks were as follows: appearance satisfaction (Appearance Subscale from Mendleson et al’s (2001) Body Esteem Scale); social anxiety (La Greca’s (1999) Social Anxiety Scale for Adolescents). Secondary outcomes were; self-esteem; romantic concerns; perceived stigmatization; social skills and healthcare usage. Participants were randomised using remote Web-based allocation.ResultsThirteen charities advertised the study yielding 11 recruits, 13 primary care practices sent 687 invitations to patients on their databases with a known visible difference yielding 17 recruits (2.5% response rate), 4 recruits came from GP consultations. Recruitment was challenging, therefore four additional practices mass-mailed 3,306 generic invitations to all 12-17 year old patients yielding a further 15 participants (0.5% response rate). Forty-seven YP with a range of socioeconomic backgrounds and conditions were randomised (26% male, 91% white, mean age 14 years (SD 1.7)); 23 to YPF, 24 to UC). At 52 weeks, 16 (70%) in the intervention and 20 (83%) in UC groups completed assessments. There were no intervention-related adverse events; most found YPF acceptable with three withdrawing because they judged it was for higher-level concerns; 12 (52%) completed seven sessions. The study design was acceptable and feasible, with multiple recruitment strategies. Preliminary findings indicate no changes from baseline in outcome measures among the UC group and positive changes in appearance satisfaction and fear of negative evaluation among the YPF group when factoring in baseline scores and intervention adherence.ConclusionsYPF is novel, safe and potentially helpful. Its full psychosocial benefits should be evaluated in a large-scale RCT, which would be feasible with wide-ranging recruitment strategies.Trial RegistrationISRCTN registry ISRCTN40650639; http://www.isrctn.com/ISRCTN40650639

IntroductionKnee replacements are highly successful for many people, but if a knee replacement fails, revision surgery is generally required. Surgeons and patients may choose from a range of implant components and combinations that make up knee replacement constructs, all with potential implications for how long a knee replacement will last. To inform surgeon and patient decisions, a comprehensive synthesis of data from randomised controlled trials is needed to evaluate the effects of different knee replacement implants on overall construct survival. Due to limited follow-up in trials, joint registry analyses are also needed to assess the long-term survival of constructs. Finally, economic modelling can identify cost-effective knee replacement constructs for different patient groups.Methods and analysisIn this protocol, we describe systematic reviews and network meta-analyses to synthesise evidence on the effectiveness of knee replacement constructs used in total and unicompartmental knee replacement and analyses of two national joint registries to assess long-term outcomes. Knee replacement constructs are defined by bearing materials and mobility, constraint, fixation and patella resurfacing. For men and women in different age groups, we will compare the lifetime cost-effectiveness of knee replacement constructs.Ethics and disseminationSystematic reviews are secondary analyses of published data with no ethical approval required. We will design a common joint registry analysis plan and provide registry representatives with information for submission to research or ethics committees. The project has been assessed by the National Health Service (NHS) REC committee and does not require ethical review.Study findings will be disseminated to clinicians, researchers and administrators through open access articles, presentations and websites. Specific UK-based groups will be informed of results including National Institute for Health Research and National Institute for Health and Care Excellence, as well as international orthopaedic associations and charities. Effective dissemination to patients will be guided by our patient–public involvement group and include written lay summaries and infographics.PROSPERO registration numberCRD42019134059 and CRD42019138015.

RhoA regulates actin cytoskeleton but recent evidence suggest a role for this conserved Rho GTPase also in other cellular processes, including transcriptional control of cell proliferation and survival. Interestingy, loss of RhoA is synthetic lethal with oncogenic Myc, a master transcription factor that turns on anabolic metabolism to promote cell growth in many cancers. We show evidence indicating that the synthetic lethal interaction between RhoA loss and Myc arises from deficiency in glutamine utilization, resulting from impaired co-regulation of glutaminase expression and anaplerosis by Myc and RhoA – serum response factor (SRF) pathway. The results suggest metabolic coordination between Myc and RhoA/SRF in sustaining cancer cell viability and indicate RhoA/SRF as a potential vulnerability in cancer cells for therapeutic targeting.

Differentiated epithelial structure communicates with individual constituent epithelial cells to suppress their proliferation activity. However, the pathways linking epithelial structure to cessation of the cell proliferation machinery or to unscheduled proliferation in the context of tumorigenesis are not well defined. Here we demonstrate the strong impact of compromised epithelial integrity on normal and oncogenic Myc-driven proliferation in three-dimensional mammary epithelial organoid culture. Systematic silencing of 34 human homologs of Drosophila genes, with previously established functions in control of epithelial integrity, demonstrates a role for human genes of apico-basal polarity, Wnt and Hippo pathways and actin dynamics in regulation of the size, integrity and cell proliferation in organoids. Perturbation of these pathways leads to diverse functional interactions with Myc: manifested as a RhoA-dependent synthetic lethality and Par6-dependent effects on the cell cycle. Furthermore, we show a role for Par6G as a negative regulator of the phosphatidylinositol 3'-kinase/phosphoinositide-dependent protein kinase 1/Akt pathway and epithelial cell proliferation and evidence for frequent inactivation of Par6G gene in epithelial cancers. The findings demonstrate that determinants of epithelial structure regulate the cell proliferation activity via conserved and cancer-relevant regulatory circuitries, which are important for epithelial cell cycle restriction and may provide new targets for therapeutic intervention.

Regulatory pathways that drive early hematogenous dissemination of tumor cells are insufficiently defined. Here, we used the presence of disseminated tumor cells (DTC) in the bone marrow to define patients with early disseminated breast cancer and identified low retinoic acid–induced 2 (RAI2) expression to be significantly associated with DTC status. Low RAI2 expression was also shown to be an independent poor prognostic factor in 10 different cancer datasets. Depletion of RAI2 protein in luminal breast cancer cell lines resulted in dedifferentiation marked by downregulation of ERα, FOXA1, and GATA3, together with increased invasiveness and activation of AKT signaling. Functional analysis of the previously uncharacterized RAI2 protein revealed molecular interaction with CtBP transcriptional regulators and an overlapping function in controlling the expression of a number of key target genes involved in breast cancer. These results suggest that RAI2 is a new metastasis-associated protein that sustains differentiation of luminal breast epithelial cells. Significance: We identified downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERα-positive breast tumors. We specified the role of the RAI2 protein to function as a transcriptional regulator that controls the expression of several key regulators of breast epithelial integrity and cancer. Cancer Discov; 5(5); 506–19. ©2015 AACR. See related commentary by Esposito and Kang, p. 466 This article is highlighted in the In This Issue feature, p. 453

Intervenção social. - ISSN 0874-1611. - N. 49/50 (2017). - p. 67-83. Neste artigo pretende-se debater as virtualidades das histórias de vida, enquanto instrumento de pesquisa, tomando como exemplo uma investigação já concluída. Uma investigação cujo principal objetivo foi o de analisar um projeto de intervenção que se propôs inverter trajetórias de desinvestimento na qualificação escolar de jovens cuja socialização ocorreu em contextos fortemente restritivos de oportunidades. Partindo das reflexões produzidas na referida investigação, procurar-se-á discutir como se pode tirar partido das histórias de vida não só para aprofundar a compreensão dos processos sociais que empurram numerosos jovens para as margens da sociedade, mas também para neles desencadear a tomada de consciência de que podem distanciar-se, em alguma medida, dos seus habitus2 originais e, de certo modo, provocar a alteração do seu “destino” social.

Elevated MYC levels sensitize tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK dramatically synergizes with BCL-2/BCL-XL inhibitors to activate MYC-dependent apoptosis. We demonstrate the translational potential of an AMPK and BCL- 2/BCL-XL co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with either navitoclax or venetoclax efficiently inhibits tumor growth, confers survival benefits and induces tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re- growth with presentation of PD1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by tumor resection and adjuvant metformin+venetoclax+anti-PD1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance. Citation Format: Heidi M. Haikala, Johanna M. Anttila, Mariel Savelius, Elsa Marques, Tiina Raatikainen, Mette Ilander, Henna Hakanen, Johanna Mattson, Paivi Heikkila, Marjut Leidenius, Heikki Joensuu, Satu Mustjoki, Panu Kovanen, Martin Eilers, Joel D. Leverson, Juha T. Klefström. Pharmacological reactivation of MYC-dependent apoptosis cooperates with anti-PD1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-189.

For the last decade, stringent monitoring of waiting time performance targets provided English hospitals with incentives to reduce official waiting times for elective surgery. It is less clear whether the total amount of time patients waited in secondary care, from first referral to outpatient clinic until treatment, has also fallen. We used Hospital Episode Statistics inpatient data for patients undergoing total joint replacement during a period of active monitoring of targets (between 2006/7 and 2008/9) and linked it to outpatient data to reconstruct patients' pathway in the 3 years before surgery and provide alternative measurements of waiting times. Our findings suggest that although official waiting times decreased drastically in our study period, total waiting time in secondary care has not declined. Patients with shorter official waits spent a longer time in a ‘work-up’ period prior to inclusion in the official waiting list, and socio-economic inequities persisted in waiting times for joint replacement. We found no evidence that target policies achieved efficiency gains during our study period. Copyright © 2013 John Wiley & Sons, Ltd.

Objectives Economic evaluations alongside randomized controlled trials that collect data using patient-completed questionnaires are prone to missing data. Our objective was to determine whether giving patients a resource use log (RUL) at baseline would improve the odds of completing questions in a follow-up resource use questionnaire (RUQ) and to identify patients' views on RUL's usefulness and acceptability. Methods The RUL study was a randomized controlled trial and qualitative study nested within a larger randomized controlled trial (the Arthroplasty Pain Experience Study trial). Eighty-five patients were randomized at baseline to receive or not receive an RUL. At 3-month follow-up, all participants received a postal RUQ. We created dummy variables for 13 resource use categories indicating whether complete information had been given for each category. We compared the completion rates between arms by using descriptive statistics and logistic regression. We explored patients' experience of using the RUL by interviewing a different subsample of Arthroplasty Pain Experience Study patients (n = 24) at 2- to 4-week follow-up. Results At 3 months, 74 of the 85 (87% in each arm) patients returned the RUQ. Patients in the RUL arm were 3.5 times more likely to complete the National Health Service community-based services category ( P = 0.08). The RUL was positively received by patients and was generally seen as a useful memory aid. Conclusions The RUL is a useful and acceptable tool in reducing the amount of missing data for some types of resource use.

Methods 85 patients undergoing joint replacement were randomised to receive or not receive an RUL at hospital discharge. A postal RUQ was then administered to participants at 3-months after surgery. A blinded researcher extracted primary care resource use data in relation to the patient’s joint replacement from GP records from hospital discharge until completion of the 3-month RUQ. Data from both sources were coded into use of resource and number of contacts and two binary variables indicating perfect recall were calculated. For each resource use category, descriptive statistics were calculated by data source and trial arm, and adjusted odds ratios were estimated.

Amphetamines exert their persistent addictive effects by activating brain's reward pathways, perhaps through the release of dopamine in the nucleus accumbens (and/or in other places). On the other hand, there is a relationship between dopamine and all behavioural aspects that involve motor activity and it has been demonstrated that exercise leads to an increase in the synthesis and release of dopamine, stimulates neuroplasticity and promotes feelings of well-being. Moreover, exercise and drugs of abuse activate overlapping neural systems. Thus, our aim was to study the influence of chronic exercise in the mechanism of addiction using an amphetamine-induced conditioned-place-preference in rats.Adult male Sprague-Dawley rats were randomly separated in groups with and without chronic exercise. Chronic exercise consisted in a 8 week treadmill running program, with increasing intensity. The conditioned place preference test was performed in both groups using a procedure and apparatus previously established. A 2 mg.kg(-1) amphetamine or saline solution was administered intraperitonially according to the schedule of the conditioned place preference. Before conditioning none of the animals showed preference for a specific compartment of the apparatus. The used amphetamine dose in the conditioning phase was able to produce a marked preference towards the drug-associated compartment in the group without exercise. In the animals with exercise a significant preference by the compartment associated with saline was observed. These results lead us to conclude that a previous practice of regular physical activity may help preventing amphetamine addiction in the conditions used in this test.

IntroductionOvarian cancer is the leading cause of death from gynaecological cancer, with more than 7000 new cases registered in the UK in 2014. In patients suitable for surgery, the National Institute of Health and Care Excellence guidance for treatment recommends surgical resection of all macroscopic tumour, followed by chemotherapy. The surgical procedure can be extensive and associated with substantial blood loss which is conventionally replaced with a donor blood transfusion. While often necessary and lifesaving, the use of donor blood is associated with increased risks of complications and adverse surgical outcomes. Intraoperative cell salvage (ICS) is a blood conservation strategy in which red cells collected from blood lost during surgery are returned to the patient thus minimising the use of donor blood. This is the protocol for a feasibility randomised controlled trial with an embedded qualitative study and feasibility economic evaluation. If feasible, a later definitive trial will test the effectiveness and cost-effectiveness of ICS reinfusion versus donor blood transfusion in ovarian cancer surgery.Methods and analysisSixty adult women scheduled for primary or interval ovarian cancer surgery at participating UK National Health Service Trusts will be recruited and individually randomised in a 1:1 ratio to receive ICS reinfusion or donor blood (as required) during surgery. Participants will be followed up by telephone at 30 days postoperatively for adverse events monitoring and by postal questionnaire at 6 weeks and 3 monthly thereafter, to capture quality of life and resource use data. Qualitative interviews will capture participants’ and clinicians’ experiences of the study.Ethics and disseminationThis study has been granted ethical approval by the South West–Exeter Research Ethics Committee (ref: 16/SW/0256). Results will be disseminated via peer-reviewed publications and will inform the design of a larger trial.Trial registration numberISRCTN19517317.

Methamphetamine (METH) is a powerful psychostimulant whose noxious effects depend largely on the pattern of abuse. METH-induced glutamate release may overactivate N-methyl-d-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (NMDAR and AMPAR, respectively) causing excitotoxicity. In the brain, these receptors are also known for their essential role in mediating memory consolidation. Therefore, we assessed glial fibrillary acidic protein (GFAP) expression as a marker for astrogliosis and neurodegeneration by using Fluoro-Jade C (F-J C) staining. Moreover, we investigated the effect of two METH regimens on NMDAR NR1 and NR2A and on AMPAR GluR2 subunit expression in the rat striatum and frontal cortex 24 h after drug treatment. Adult Sprague-Dawley rats were injected subcutaneously (s.c.) on six consecutive days with saline (control and acute groups) or with an increasing dose of METH (10, 15, 15, 20, 20, 25 mg/kg/day; ED group). On the seventh day, both METH groups were given a "bolus" of 30 mg/kg METH, whereas controls received saline. We evaluated the expression levels of GFAP by both Western blot and immunohistochemical assays and concluded that there was no difference from control levels. In addition, neither drug regimen resulted in neurodegeneration within 24 h of last METH administration. In the frontal cortex of the acute group, NR1 expression level was decreased, and both NR2A and GluR2 were increased. Also, in the striatum of the acute group, the expression level of GluR2 was significantly increased, and both GluR2 and NR2A levels were augmented in the striatum of the ED group. Taken together, these results suggest a protective mechanism by decreasing permeability and/or functionality of AMPAR and NMDAR to counteract METH-induced glutamate overflow in the brain. Moreover, these results may explain, in part, the mnemonic deficits and psychotic behavior associated with METH abuse.

The glutamate-glutamine cycle between neurons and glia is tightly related to excitatory glutamatergic and inhibitory GABAergic regulation in brain. The role of this neuron-astrocyte cross-talk on the neurotoxicity induced by amphetamines is not understood. Also, the impact of neurotoxic doses of amphetamines on the balance between glutamatergic and GABAergic circuits is largely unknown. The aim of this work was to assess the acute effect of a neurotoxic regimen of amphetamine (AMPH) on glutamine (GLN, an astrocytic marker) levels and on glutamine/glutamate (an index for glutamate-glutamine cycle) and GABA/glutamate ratios in rat brain. Sprague-Dawley rats were sacrificed 4 and 24 h after a single-dose regimen of AMPH (30 mg/kg, i.p.), and the caudate-putamen (CPu), frontal cortex (FC), and hippocampus (Hp) were dissected for analysis of glutamate (GLU), gamma-aminobutyric acid (GABA), and GLN. The total content of these amino acids was measured using a microbore HPLC electrochemical detector. Although AMPH did not change GLU levels, it increased both GLN content and GLN/GLU ratio (160-469%) at 4 h, but not at 24 h, in all regions after injection. Striatal GABA levels and GABA/GLU ratio were increased (46 and 100%, respectively) at 24 h. In hippocampus the GABA/GLU increase (60%) occurred as early as 4 h after treatment. To the contrary, AMPH exerted no effect in GABA/GLU balance in frontal cortex. These data strongly suggest that this neurotoxic AMPH regimen provoked an early increase in the glutamate-glutamine cycle between neurons and glia. This increase may ultimately lead to an upregulation of the inhibitory system as a compensatory response.

The aim of this study was to verify the effect of chronic exercise on the striatal dopamine (DA) outflow induced by low and high single doses of amphetamine (AMPH), and verify the existence of an exercise protective role on neurodegeneration. Adult male Sprague-Dawley rats were randomly separated into six groups: chronic exercise, saline; chronic exercise, 5 mg kg(-1) AMPH; chronic exercise, 30 mg kg(-1) AMPH; without exercise, saline; without exercise, 5 mg kg(-1) AMPH; without exercise, 30 mg kg(-1) AMPH. Chronic exercise consisted of an 8-week running program on a treadmill, with increasing intensity. Animals were anesthetized, placed into a stereotaxic frame and an intracerebral guide cannula implanted into the caudate-putamen. When indicated, microdialysis was performed. Dialysate samples were collected during 30-min intervals for 6 h, before and after the intraperitonial administration of AMPH or saline solution. HPLC with electrochemical detection was used to quantify DA. Chronic exercise did not significantly change the extracellular DA basal values. Regarding the maximal DA levels in the dialysates, in the rats treated with 5 mg kg(-1) AMPH, there was no significant difference between groups with and without chronic exercise; on the contrary, in animals treated with 30 mg kg(-1) AMPH, the DA release was lower in the group with chronic exercise. Moreover, the maintenance of higher levels of DA along time in the training group suggests a diminished reuptake of DA. By using the Fluoro-Jade C staining technique, we did not find neuronal death in any of the groups. In conclusion, these results suggest that chronic exercise leads to a diminished release and reuptake of DA after administration of a high dose of AMPH, whereas neither chronic exercise nor AMPH seems to induce neurodegeneration.

Methamphetamine (METH) is a powerful psychostimulant that increases glutamate (Glu) levels in the mammalian brain and it is currently known that hippocampi are particularly susceptible to METH. Moreover, it is well established that the overactivation of N-methyl-d-aspartate (NMDA) and AMPA ionotropic Glu receptors causes excitotoxicity. In the present study, we investigated the effect of acute (30 mg/kg) versus escalating dose (ED) administration of METH on NMDA receptor 1, NMDA receptor 2 and glutamate receptor 2 (GluR2) subunit expression in the hippocampus and on memory. Adult Sprague-Dawley rats were injected s.c. during six consecutive days with saline (control and acute groups) or with a growing dose of METH (10, 15, 15, 20, 20, 25 mg/kg/day; ED group). On the 7th day, both METH groups were injected with a 'bolus' of 30 mg/kg METH whereas controls received saline. Western blot analysis showed an increase of GluR2 and NR2A expression levels and no alterations on NR1 subunit in the acute group. On the other hand, in the ED group, GluR2 and NR2A expression levels were unaltered and there was a decrease on NR1 levels. Moreover, we did not observe neurodegeneration with both administration paradigms, as assessed by Fluoro-Jade C staining, but we did observe a strong astrogliosis in the acute administration group by using both immunohistochemistry and Western blot analysis. The impact of METH on working memory was evaluated using the Y maze test and revealed significant mnemonic deficit in the rats acutely treated with the drug. Overall, our results suggest a protection mechanism under conditions of METH administration by decreasing permeability and/or functionality of NMDA and AMPA receptors, which has implications on memory. So, the participation of the glutamatergic system should be considered as an important pharmacological target to design new strategies to prevent or diminish the harmful effect of drug consumption.

BACKGROUND: Prosthetic hip implants have many combinations of bearing surface materials, sizes, and fixation techniques, which can determine the quality of life of patients after primary total hip replacement (THR) and the likelihood of needing revision surgery. When an implant fails, patients require revision THR, which is distressing to the patient and expensive for the health care payer. Primary THR is one of the most common elective procedures performed worldwide, with over 300,000 performed annually in the USA and over 80,000 in England and Wales. It is important to review all available randomised controlled trial (RCT) evidence to determine which implant bearing surface materials, size, and fixation technique are most effective for patients.METHODS/DESIGN: This is a protocol for a systematic review and meta-analysis of RCTs comparing outcomes of hip implant bearing surfaces, size, and fixation techniques used in THR. Implant combinations compared in the literature include four bearing surface combinations (metal-on-polyethylene, metal-on-metal, ceramic-on-polyethylene, and ceramic-on-ceramic); two femoral head sizes (large vs small heads); and four fixation techniques (uncemented, cemented, hybrid, and reverse hybrids). The primary outcome will be revision surgery. We will also collect data on patient characteristics, mortality, quality of life, and other outcomes. In network meta-analysis, we will estimate the relative effectiveness of every implant bearing surface, head size (large vs small), and fixation permutation, using evidence where implants have been compared directly in an RCT and indirectly through common comparators in different RCTs.DISCUSSION: There has been much debate about materials used for prosthetic implants in THR. Different combinations of prosthetic materials, sizes, and fixation, can vary widely in cost and fail at different rates for different patient groups. Given the number of THRs performed yearly, and the increasing use of expensive implants, it is important to review evidence to inform surgeons, patients, and health care providers of optimal implant bearing combinations for given patient characteristics. This review will inform a cost-effectiveness model that will include evidence from other sources, to determine the most effective and cost-effective implant bearing combination for patients.SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019435.

Background Problem alcohol drinking in homeless and vulnerably housed people can lead to malnutrition, which is associated with complications such as alcohol-related brain damage. Homeless alcohol drinkers are likely to have worse health outcomes and different nutritional needs compared with housed alcohol-drinking persons. It is not clear whether interventions to improve nutritional status in this population have been effective. The purpose of this review is to assess the effectiveness and cost-effectiveness of interventions for preventing or correcting micronutrient deficiencies and other forms of malnutrition and related comorbidities in this population. Methods/design A systematic search for studies of a nutrition-based intervention applied in the homeless or vulnerably housed population with problem drinking will be conducted. The following electronic databases will be systematically searched for relevant studies: MEDLINE, EMBASE, Web of Science, PsycINFO, CAB abstracts, CINAHL, Cochrane Public Health Group Register and Cochrane Drugs and Alcohol Group Register. Screening of identified abstracts for relevance and assessment of papers for inclusion will be done in duplicate. One reviewer will extract data from the studies and assess quality, and this will be checked by another reviewer. Discrepancies will be resolved by consensus. The primary outcomes are (mal)nutrition status or micronutrient deficiencies or change in (mal)nutrition status or micronutrient deficiencies, measures of liver damage and cognitive function. Secondary outcomes include comorbidities, quality of life and functional scales, resources used to deliver treatment, uptake/acceptability of the intervention and engagement with treatment services. Results will be analysed descriptively, and, if appropriate, meta-analyses will be performed. Discussion The results of this review should help to inform the development of effective interventions that can be implemented in the community to improve the health of homeless people who are problem drinkers. Systematic review registration PROSPERO CRD42015024247 Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0114-3) contains supplementary material, which is available to authorized users.

The regulatory networks of cell polarization and polarity effector proteins have been subjects of feverish interest in the field of cell and developmental biology but many advances in the polarity research may have flown unnoticed past the radar of mainstream cancer biologist. However, recent findings suggesting important cell cycle gatekeeping functions for polarity proteins may change that. For example, PAR6 proteins interact with classical cancer driver signaling pathways, including MAPK and PI3K and moreover, PAR6 (PARD6) genes are frequently altered in various cancers. Mammalian genomes harbor three different PARD6 genes. Recent studies in breast cancer have suggested that different PARD6 genes are not only important players but may play even opposite roles during tumorigenesis. Par-6 is one of the partitioning-defective (par) genes identified by Kemphues et al in a landmark genetic screen, which discovered genes important for the first, asymmetric embryonic cell division in C.elegans [1]. In the invertebrate oocytes, most Par proteins are segregated to two opposite poles of the cells - the anterior cell cortex is occupied by Par-3 and Par-6, which interact with each other via PSD95/Dlg/ZO1 (PDZ) domains. In epithelial cells of diverse species, including humans, the PAR3/PAR6 defines the apical region and co-localizes with tight junctions. A current view is that PAR6 is a multimodular scaffold protein, which together with PAR3 forms a loose or non-constitutive complex with atypical protein kinase C (aPKC) and CDC42. This PAR3-PAR6-aPKC/CDC42 or ‘PAR complex’ has a principal role in most if not all process where cellular asymmetry is important, for example asymmetric cell division, apico-basal and anterio-posterior polarity, axon specification and directional migration [2, 3]. The evolution's kitchen has added an extra degree of complexity to the polarizing systems in large and long-lived animals by multiplying the single Par-6 gene in invertebrates to three separate PARD6 genes in mammals: PARD6A, PARD6B and PARD6G. In humans and mice, all PARD6 genes reside in different chromosomes yet they are very similar, with > 70% sequence similarity. Nevertheless, many PAR6 studies do not clearly indicate which of the three proteins was studied and not surprisingly, the picture of individualistic functions of PAR6 proteins has remained incomplete. Recent findings in breast cancer research have suggested intriguing differences between the PARD6 genes. PARD6B locus resides in a chromosomal region that is frequently amplified and overexpressed in breast cancer [4]. In cell culture, PAR6A-aPKC activity is important for HER2/ErbB2-dependent disruption of organized epithelial structure [5]. Moreover, elevated PARD6A or PARD6B expression signals together with aPKC (PKCɩ) and CDC42 to stimulate MAPK signaling and cell proliferation, without affecting the apico-basal polarity [4]. Thus, the genetic and functional evidence suggest a gain-of function i.e. oncogenic mode of activity for PARD6B in breast cancer. Contrary to the earlier findings, our shRNA screen identified both PAR6B and PAR6G as critical suppressors of cell proliferation [6]. The study was designed to identify genes important for epithelial cell cycle restriction in three-dimensional mammary epithelial organoid culture. MCF10A cells undergo morphogenesis to form quiescent acinar structures in basement membrane gels. The neighborhood suppression of proliferation is tight in matured structures, able to resist even the cell autonomous proliferation signals from oncogenic Myc. The tumor suppressor gene LKB1 has been earlier identified as a key proliferation gatekeeper in mature MCF10A organoids [7]. LKB1 is a human homolog of par-4 (one of the Kemphues genes) and therefore, it was thrilling to discover similar cell cycle gatekeeping functions in other PARD genes [6]. Loss of PAR6G could alone prevent the epithelial cell cycle restriction, whereas loss of PAR6B needed cooperation with oncogenic Myc to trigger the cell cycle re-entry in quiescent MCF10A structures. Loss of PAR6B or PAR6G diminished the phosphorylation of PKCz, which indicates decreased PAR complex activity and the gene deficiencies enabled growth factor-independent cell cycle progression in monolayer culture. The PAR6B or PAR6G-deficiency induced cell cycle deregulation associated with strong AKT phosphorylation on T308, which residue is used for AKT phosphoactivation by PI3K/PDK1 pathway. Therefore, PAR6 activity appears to be important for repressive regulation of PI3K/PDK1/AKT-dependent proliferation signaling [6]. Should we interpret these findings so that any shift in PAR6 activity, up or down, predisposes to uncontrolled cell proliferation and tumorigenesis? The question was addressed by investigating cancer genomes for the type of mutations affecting different PARD6 genes. Consistent with the suggested oncogenic role of PAR6B, chromosomal gains, amplifications and overexpression dominated the landscape of PARD6B mutations. The surprising finding was that PARD6G landscape was etched with typical loss of function mutations: chromosomal losses, deletions and loss of heterozygosity. Thus, PARD6B and PARD6G genes display essentially opposite mutational landscape in tumors. We posit that while a change in any individual PAR6 protein has the capacity to bring PAR6 activity up- or downwards in the cells to instigate specific cell proliferation pathways, for some reason the tumorigenic processes seem to favor gains for PARD6B and losses for PARD6G (Fig.​(Fig.1).1). The differences could arise from cell type-specific expression, subcellular compartmentalization of the protein or even from different context-dependent functions of PAR6 proteins in tissues, which will eventually determine in which way an expression-altered PAR6 protein best serves the process of tumorigenesis. Future studies will be needed to better clarify the roles of individual PAR6 genes in tumor development – which surely will be an exciting research area offering perspectives to evolutionary biology and oncology alike. Figure 1 PAR6 proteins play opposite roles in tumorigenesis

Background The Arthroplasty Pain Experience (APEX) studies are two randomised controlled trials in primary total hip (THR) and total knee replacement (TKR) at a large UK orthopaedics centre. APEX investigated the effect of local anaesthetic wound infiltration (LAI), administered before wound closure, in addition to standard analgesia, on pain severity at 12 months. This article reports results of the within-trial economic evaluations. Methods Cost-effectiveness was assessed from the health and social care payer perspective in relation to quality adjusted life years (QALYs) and the primary clinical outcome, the WOMAC Pain score at 12-months follow-up. Resource use was collected from hospital records and patient-completed postal questionnaires, and valued using unit cost estimates from local NHS Trust finance department and national tariffs. Missing data were addressed using multiple imputation chained equations. Costs and outcomes were compared per trial arm and plotted in cost-effectiveness planes. If no arm was dominant (i.e., more effective and less expensive than the other), incremental cost-effectiveness ratios were estimated. The economic results were bootstrapped incremental net monetary benefit statistics (INMB) and cost-effectiveness acceptability curves. One-way deterministic sensitivity analyses explored any methodological uncertainty. Results In both the THR and TKR trials, LAI was the dominant treatment: cost-saving and more effective than standard care, in relation to QALYs and WOMAC Pain. Using the £20,000 per QALY threshold, in THR, the INMB was £1,125 (95 % BCI, £183 to £2,067) and the probability of being cost-effective was over 98 %. In TKR, the INMB was £264 (95 % BCI, −£710 to £1,238), but there was only 62 % probability of being cost-effective. When considering an NHS perspective only, LAI was no longer dominant in THR, but still highly cost-effective, with an INMB of £961 (95 % BCI, £50 to £1,873). Conclusions Administering LAI is a cost-effective treatment option in THR and TKR surgeries. The evidence, because of larger QALY gain, is stronger for THR. In TKR, there is more uncertainty around the economic result, and smaller QALY gains. Results, however, point to LAI being cheaper than standard analgesia, which includes a femoral nerve block. Trial registration ISRCTN96095682, 29/04/2010. Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0389-1) contains supplementary material, which is available to authorized users.

Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination.

Objective To compare the survival of different implant combinations for primary total hip replacement (THR). Design Systematic review and network meta-analysis. Data sources Medline, Embase, The Cochrane Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and the EU Clinical Trials Register. Review methods Published randomised controlled trials comparing different implant combinations. Implant combinations were defined by bearing surface materials (metal-on-polyethylene, ceramic-on-polyethylene, ceramic-on-ceramic, or metal-on-metal), head size (large ≥36 mm or small

ObjectivesTo evaluate the impact of an expansion of liaison psychiatry services (LPS) on patient management, outcomes and treatment costs for emergency department (ED) attendances for self-harm.DesignRetrospective before and after cohort study using routinely collected Self-Harm Surveillance Register data.SettingA large hospital in South West England.SubjectsPatients attending the ED for self-harm.InterventionsExtension of the LPS’ working hours from 9:00 to 17:00, Monday to Friday to 8:00 to 22:00, 7 days a week, following a £250 000 annual investmentMain outcome measuresNumber and characteristics of ED attendances for self-harm. The before and after cohorts were compared in terms of key process measures, including proportion of patients receiving a psychosocial assessment, average length of hospital stay, waiting times for assessment, proportion of patients who self-discharged without an assessment, levels of repeat self-harm attendances and mean cost per patient attendance.Results298 patients attended ED for self-harm on 373 occasions between January and March 2014, and 318 patients attended on 381 occasions between January and March 2015. The proportion of ED attendances where patients received a psychosocial assessment increased from 57% to 68% (p=0.003), median waiting time decreased by 3 hours and 14 min (p=0.017), and the proportion of episodes where patients self-discharged without a psychosocial assessment decreased from 20% to 13% (p=0.022). The mean cost per patient attendance was marginally lower after the intervention (−£84; 95% CI −£254 to £77).ConclusionsThe extended LPS seems to have had a favourable effect on the management and outcomes of self-harm patients. The cost of extending the LPS’ working hours might be partially offset by more efficient assessment and discharge. The impact of the extended LPS on the care of hospitalised patients with mental health problems other than self-harm requires further evaluation.

s / Osteoarthritis and Cartilage 22 (2014) S7–S56 S9 cartilage and open a new window of opportunity to modulate the Wnt pathway for the treatment of acute and chronic cartilage injury. 5 THE EFFECT OF LOCAL ANAESTHETIC WOUND INFILTRATION ON CHRONIC PAIN AFTER TOTAL HIP REPLACEMENT: A RANDOMISED CONTROLLED TRIAL V. Wylde y, E. Lenguerrand y, R. Gooberman-Hill y, A. Beswick y, E. Marques y, S. Noble y, J. Horwood y, M. Pyke z, P. Dieppe x, A. Blom y. yUniv. of Bristol, Bristol, United Kingdom; zNorth Bristol NHS Trust, Bristol, United Kingdom; xUniv. of Exeter, Exeter, United Kingdom Purpose: Most patients who have hip replacement do so to relieve pain and stiffness associated with osteoarthritis. However, around 10% of patients who have total hip replacement report chronic pain related to their operated joint 3 months after surgery. It is important to identify ways to reduce the chance that patients will have this type of ongoing pain. A known risk factor for chronic post-surgical pain is the severity of acute post-operative pain. There is evidence that local anaesthetic wound infiltration reduces acute post-operative pain; however, it is uncertain whether it is also effective at reducing chronic pain in the long-term. The aim of this randomised controlled trial (RCT) was to determine if local anaesthetic wound infiltration could significantly reduce the severity of joint pain at 12-months after total hip replacement. Methods: This study was a double-blind randomised controlled trial of patients undergoing primary total hip replacement for osteoarthritis at a high volume elective orthopaedic centre in the UK. Patients were randomised to receive additional intra-operative local anaesthetic wound infiltration or the standard anaesthesia regimen alone. The usual anaesthesia regimen consisted of spinal or general anaesthetic, depending on patient clinical factors. Patients in the intervention group received an added injection of 60 mls of 0.25% bupivacaine with 1 in 200,000 adrenaline at the wound site before surgical closure. Postoperative pain management was the same for the intervention and usual care group, and included a patient-controlled analgesia device. Randomisation was minimised by baseline hip pain severity and surgical approach. The primary outcome was pain at 12-months postoperative measured by the WOMAC Pain scale. Secondary outcomes included the WOMAC Function and Stiffness scales, the Intermittent and Constant Osteoarthritis Pain (ICOAP) measure and the PainDETECT (a measure of neuropathic pain), collected by postal questionnaires administered at 3-months, 6-months and 12-months after surgery. Measurements of daily acute post-operative pain severity were collected on post-operative days 1-3 using a visual analogue scale. Complications and adverse events were collected from patients’ self-report at 3-months and 12-months and a review of medical records. WOMAC Pain scores at 12-months post-operative were categorised into “No pain”; “Mild”; “Moderate” and “Severe” and analyzed using generalized ordered logit models in an intent-to-treat approach. Results are presented as odds ratios and 95% confidence intervals (CIs). Secondary outcomes were analysed using generalised linear models and generalized linear mixed models. Results: 639 eligible patients were approached to take part in this study and 322 consented to participate (50% recruitment rate). Prior to surgery, 163 patients were randomised to the intervention group and 159 to the standard care group. Patients receiving additional local anaesthetic wound infiltration were less likely to report severe pain at 12months post-operative compared with patients receiving the usual anaesthetic regimen alone (OR1⁄40.13; 95% CIs1⁄40.03, 0.62; p1⁄40.011). At 12-months post-operative, patients in the intervention group were also less likely to report neuropathic pain on the PainDETECT questionnaire (OR1⁄40.22; 95% CIs1⁄40.05, 0.97; p1⁄40.046). No differences were observed for outcomes assessed through ICOAP, WOMAC function or WOMAC stiffness questionnaires. During their inpatient stay, patients of both groups reported comparable levels of daily pain, with the exception of pain on the second post-operative night (Coef.1⁄4 -0.83; 95% CIs -1.41, -0.26; p1⁄40.005). Complications and adverse events were similar between the intervention and standard care groups. Conclusions: This is the first RCT to assess the longer-term effects of a local anaesthetic wound infiltration on pain severity after hip replacement. We found that local anaesthetic wound infiltration administered before wound closure is effective in reducing the number of patients experiencing severe pain at 12-months after hip replacement. There was also some evidence of reductions in neuropathic pain at 12-months post-operative and pain on the second post-operative night for patients in the intervention group compared with the usual care group. We recommend the addition of local anaesthetic wound infiltration to the usual anaesthesia regimen during primary total hip replacement surgery to reduce the risk of severe chronic pain after surgery. 6 EFFECTIVENESS OF EXERCISE THERAPY ADDED TO GENERAL PRACTITIONERS’ CARE VERSUS GENERAL PRACTITIONERS’ CARE ALONE IN PATIENTS WITH HIP OSTEOARTHRITIS C. Teirlinck y, P. Luijsterburg y, J. Dekker z, A. Bohnen y, P. van Es y, J. Verhaar y, M. Koopmanschap x, B. Koes y, S. Bierma-Zeinstra y. y Erasmus MC, Erasmus Univ. Med. Ctr., Rotterdam, Netherlands; zVU Med. Ctr./EMGO Inst., Amsterdam, Netherlands; x Erasmus Univ. Rotterdam, Rotterdam, Netherlands Purpose: The main goal of this comparative study was to investigate whether exercise therapy added to general practitioners’ care is effective compared to general practitioners’ care only in patients with a new episode of hip OA in general practice, over a period of 12 months. Methods: Study design used was a randomized controlled trial with a parallel group design. Patients could participate the trial if they were 45 years or older, comply with the clinical American College of Rheumatology criteria for hip OA, and visited their general practitioner for a new episode of complaints due to hip osteoarthritis. Patients were excluded if they: 1) were already treated with exercise therapy in the present episode of hip OA, 2) had a hip pain score of

Background Surgical pain is managed with multi-modal anaesthesia in total hip replacement (THR) and total knee replacement (TKR). It is unclear whether including local anaesthetic infiltration before wound closure provides additional pain control. Methods We performed a systematic review of randomised controlled trials of local anaesthetic infiltration in patients receiving THR or TKR. We searched MEDLINE, Embase and Cochrane CENTRAL to December 2012. Two reviewers screened abstracts, extracted data, and contacted authors for unpublished outcomes and data. Outcomes collected were post-operative pain at rest and during activity after 24 and 48 hours, opioid requirement, mobilisation, hospital stay and complications. When feasible, we estimated pooled treatment effects using random effects meta-analyses. Results In 13 studies including 909 patients undergoing THR, patients receiving local anaesthetic infiltration experienced a greater reduction in pain at 24 hours at rest by standardised mean difference (SMD) -0.61 (95% CI -1.05, -0.16; p = 0.008) and by SMD -0.43 (95% CI -0.78 -0.09; p = 0.014) at 48 hours during activity. In TKR, diverse multi-modal regimens were reported. In 23 studies including 1439 patients undergoing TKR, local anaesthetic infiltration reduced pain on average by SMD -0.40 (95% CI -0.58, -0.22; p

For the last decade, stringent monitoring of waiting time performance targets provided English hospitals with incentives to reduce official waiting times for elective surgery. It is less clear whether the total amount of time patients waited in secondary care, from first referral to outpatient clinic until treatment, has also fallen. We used Hospital Episode Statistics inpatient data for patients undergoing total joint replacement during a period of active monitoring of targets (between 2006/7 and 2008/9) and linked it to outpatient data to reconstruct patients' pathway in the 3 years before surgery and provide alternative measurements of waiting times. Our findings suggest that although official waiting times decreased drastically in our study period, total waiting time in secondary care has not declined. Patients with shorter official waits spent a longer time in a 'work-up' period prior to inclusion in the official waiting list, and socio-economic inequities persisted in waiting times for joint replacement. We found no evidence that target policies achieved efficiency gains during our study period.

Epithelial architecture is formed in tissues and organs when groups of epithelial cells are organized into polarized structures. The epithelial function and integrity as well as signaling across the epithelial layer is orchestrated by apical junctional complexes (AJCs), which are landmarks for PAR/CRUMBS and lateral SCRIB polarity modules and by dynamic interactions of the cells with underlying basement membrane (BM). These highly organized epithelial architectures are demolished in cancer. In all advanced epithelial cancers, malignant cells have lost polarity and connections to the basement membrane and they have become proliferative, motile, and invasive. Clearly, loss of epithelial integrity associates with tumor progression but does it contribute to tumor development? Evidence from studies in Drosophila and recently also in vertebrate models have suggested that even the oncogene-driven enforced cell proliferation can be conditional, dependant on the influence of cell-cell or cell-microenvironment contacts. Therefore, loss of epithelial integrity may not only be an obligate consequence of unscheduled proliferation of malignant cells but instead, malignant epithelial cells may need to acquire capacity to break free from the constraints of integrity to freely and autonomously proliferate. We discuss how epithelial polarity complexes form and regulate epithelial integrity, highlighting the roles of enzymes Rho GTPases, aPKCs, PI3K, and type II transmembrane serine proteases (TTSPs). We also discuss relevance of these pathways to cancer in light of genetic alterations found in human cancers and review molecular pathways and potential pharmacological strategies to revert or selectively eradicate disorganized tumor epithelium.

Epithelial architecture is formed in tissues and organs when groups of epithelial cells are organized into polarized structures. The epithelial function and integrity as well as signaling across the epithelial layer is orchestrated by apical junctional complexes (AJCs), which are landmarks for PAR/CRUMBS and lateral SCRIB polarity modules and by dynamic interactions of the cells with underlying basement membrane (BM). These highly organized epithelial architectures are demolished in cancer. In all advanced epithelial cancers, malignant cells have lost polarity and connections to the basement membrane and they have become proliferative, motile, and invasive. Clearly, loss of epithelial integrity associates with tumor progression but does it contribute to tumor development? Evidence from studies in Drosophila and recently also in vertebrate models have suggested that even the oncogene-driven enforced cell proliferation can be conditional, dependant on the influence of cell-cell or cell-microenvironment contacts. Therefore, loss of epithelial integrity may not only be an obligate consequence of unscheduled proliferation of malignant cells but instead, malignant epithelial cells may need to acquire capacity to break free from the constraints of integrity to freely and autonomously proliferate. We discuss how epithelial polarity complexes form and regulate epithelial integrity, highlighting the roles of enzymes Rho GTPases, aPKCs, PI3K, and type II transmembrane serine proteases (TTSPs). We also discuss relevance of these pathways to cancer in light of genetic alterations found in human cancers and review molecular pathways and potential pharmacological strategies to revert or selectively eradicate disorganized tumor epithelium.

By the PRMS protocol, there is an indication for brace treatment. Conclusion Clinical evidence supports the application of more variables in the treatment decision of whether to recommend brace wearing. Cobb angle, Risser sign and chronological age may not be enough. It is important to obtain other data from the observation of the patient, including a hand-wrist X-ray according to Greulich and Pyle Atlas.

In der postoperativen Phase nach Huft- oder Kniegelenkersatz geben etwa die Halfte der Patienten moderate bis starke Schmerzen an. Aber auch in der Langzeitbeobachtung nach 3 Monaten bzw. Jahre nach dem Eingriff sind noch sehr viele Betroffene nicht schmerzfrei. Studien belegen den Nutzen der intraoperativen lokalen Wundinfiltrationsanasthesie als effektives Schmerzmanagement in der postoperativen Phase bis 48 Stunden. Im Rahmen der APEX-Studien („The Arthroplasty Pain Experience“) wurde gepruft, ob die zusatzliche Methode auch die Langzeitprognose in Bezug auf Schmerzen verbessert.

Oncogenic transcription factor Myc deregulates the cell cycle and simultaneously reprograms cellular metabolism to meet the biosynthetic and bioenergetic needs of proliferation. Myc also sensitizes cells to mitochondria-dependent apoptosis. Although metabolic reprogramming has been circumstantially connected to vulnerability to apoptosis, the connecting molecular pathways have remained poorly defined. Our recent studies revealed that Myc-dependent ATP depletion activates the energy sensor AMP-activated protein kinase (AMPK), which induces stabilizing phosphorylation of p53 at Ser15. AMPK-stabilized tumor suppressor protein p53 then accumulates in the mitochondria and interacts with the protein complex comprised of Bak and Bcl-xL, to sensitize cells to apoptosis. These results reveal an unexpected pro-apoptotic function of AMPK in context of Myc transformed cells. We have explored possibilities to therapeutically exploit the Myc-AMPK facilitated apoptosis pathway. We show that a BH3-mimetic small molecule ABT-737, which neutralizes Bcl-2 and Bcl-xL, sensitizes to Myc-dependent apoptosis ex vivo and in vivo WAP-Myc tumours. ABT-737 also reduced WAP-Myc driven primary tumor growth and lung metastases in transgenic and syngrafted mice. Nevertheless, ABT-737 only delayed but did not prevent the formation of Wap-Myc tumors. In a drug combination screen designed to identify small molecules that potentiate the efficacy of ABT-737, we found several compounds influencing the status of AMPK activity. The synergistic apoptotic action between ABT-737 and AMPK modulating agents has been validated in explant 3D cultures from patient derived Myc positive breast cancers. The mechanisms behind the proapoptotic AMPK function will be discussed. Our results provide evidence that AMPK has a context-dependent pro-apoptotic function that can be therapeutically exploited as a tumour cell-specific vulnerability. Citation Format: Heidi M. Haikala, Elsa Marques, Vilja Eskelinen, Anni Viheriäranta-Nieminen, Sirkku Saarikoski, Liina Nevalaita, Panu Kovanen, Päivi Heikkilä, Marjut Leidenius, Daniel Laajala, Tero Aittokallio, Pauliina Munne, Juha Klefström. Pro-apoptotic functions of AMPK revealed by Myc. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B32.

Introduction - Currently identification, and therefore, management of patients at risk of osteoporotic fracture in the UK is suboptimal. As the majority of patients who fracture have fallen, it follows that people who fall can usefully be targeted in any programme that aims to reduce osteoporotic fracture. Targeting vulnerable patients who are likely to benefit from intervention may help shift the management of fracture prevention into primary care, away from emergency departments. Paramedics who attend to patients who have fallen may be well placed to assess future fracture risk, using the Fracture Risk Assessment Tool (FRAX) and communicate that information directly to general practitioners (GPs).Methods and analysis - This feasibility study takes the form of a pragmatic, randomised controlled trial aimed at exploring and refining issues of study design, recruitment, retention, sample size and acceptability preceding a large-scale study with fracture as the end point. Patients (aged >50) who fall, call an ambulance, are attended by a study paramedic and give verbal consent will be asked FRAX and fall questions. Patients who subsequently formally consent to participation will be randomised to control (usual care) or intervention groups. Intervention will constitute transmission of calculated future fracture risk to the patients’ GP with suitable, evidence-based recommendations for investigation or treatment. 3 months after the index fall, data (proportion of patients in each group undergoing investigation or starting new treatment, quality of life and health economic) will be collected and analysed using descriptive statistics. A nested qualitative study will explore issues of acceptability and study design with patients, paramedics and GPs.Ethics and dissemination - This protocol was approved by NRES Committee South Central Oxford C in October 2012. Research Ethics Committee ref.12/SC/0604. The study findings will be disseminated through peer-reviewed journals, conference presentations and local public events. A publication plan and authorship criteria have been preagreed.Trial registration number - ISRCTN: 36245726

Background. Opiate substitution treatment (OST) reduces the harm of injecting and opiate dependence. The SCID trial tested whether offering people who inject heroin attending a low threshold agency immediate access to OST via specialist primary care increased the number in OST at 3 months, compared to offering advice and case management. Methods. Un-blinded randomised control trial with a qualitative study was conducted at Bristol Drugs Project needle exchange. A total 311/1371 individuals were eligible and 100 consented. Twenty were interviewed. Findings. Follow-up was 86%. At 3 months 51% & 47% of the intervention and control group were in OST. Opiate use reduced by 79% and 72% respectively. Physical and mental health improved but there was insufficient evidence of differences between groups. Motivation to participate concerned the need to secure treatment. Securing OST included improvements in health, self-care, harm reduction and crime. Conclusions. Trial conduct was successful but there was insufficient evidence of an effect compared to case management. Participating in the trial enabled intervention participants to obtain treatment for their drug use. Completing baseline questionnaires seemed to be a motivating factor for the control to seek OST from their GP. Further development and evaluation of case management approaches is warranted.