A single WNT enhancer drives specification and regeneration of the Drosophila wing.

Wings have provided an evolutionary advantage to insects and have allowed them to diversify. Here, we have identified in Drosophila a highly robust regulatory mechanism that ensures the specification and growth of the wing not only during normal development but also under stress conditions. We present evidence that a single wing-specific enhancer in the wingless gene is used in two consecutive developmental stages to first drive wing specification and then contribute to mediating the remarkable regenerative capacity of the developing wing upon injury. We identify two evolutionary conserved cis-regulatory modules within this enhancer that are utilized in a redundant manner to mediate these two activities through the use of distinct molecular mechanisms. Whereas Hedgehog and EGFR signalling regulate Wingless expression in early primordia, thus inducing wing specification from body wall precursors, JNK activation in injured tissues induce Wingless expression to promote compensatory proliferation. These results point to evolutionarily linked conservation of wing specification and regeneration to ensure robust development of the wing, perhaps the most relevant evolutionary novelty in insects.

Patient-reported outcome measures for knowledge transfer and behaviour modification interventions in type 2 diabetes-the INDICA study: a multiarm cluster randomised controlled trial.

OBJECTIVE: This study assesses the effectiveness of different interventions of knowledge transfer and behaviour modification to improve type 2 diabetes mellitus patients' (T2DM) reported outcomes measures (PROMs) in the long-term. Design: open, community-based pragmatic, multicentre, controlled trial with random allocation by clusters to usual care (UC) or to one of the three interventions. PARTICIPANTS: A total of 2334 patients with uncomplicated T2DM and 211 healthcare professionals were included of 32 primary care centres. SETTING: Primary Care Centers in Canary Islands (Spain). INTERVENTION: The intervention for patients (PTI) included an educational group programme, logs and a web-based platform for monitoring and automated short message service (SMS). The intervention for professionals (PFI) included an educational programme, a decision support tool embedded into the electronic clinical record and periodic feedback about patients' results. A third group received both PTI and PFI (combined intervention, CBI). OUTCOME MEASURE: Cognitive-attitudinal, behavioural, affective and health-related quality of life (HQoL) variables. RESULTS: Compared with UC at 24 months, the PTI group significantly improved knowledge (p=0.005), self-empowerment (p=0.002), adherence to dietary recommendations (p<0.001) and distress (p=0.01). The PFI group improved at 24 months in distress (p=0.03) and at 12 months there were improvements in depression (p=0.003), anxiety (p=0.05), HQoL (p=0.005) and self-empowerment (p<0.001). The CBI group improved at 24 months in self-empowerment (p=0.008) and adherence to dietary recommendations (p=0.004) and at 12 months in knowledge (p=0.008), depression (p=0.006), anxiety (p=0.003), distress (p=0.01), HQoL (p<0.001) and neuropathic symptoms (p=0.02). Statistically significant improvements were also observed at 24 months in the proportion of patients who quit smoking for PTI and CBI (41.5% in PTI and 42.3% in CBI vs 21.2% in the UC group). CONCLUSIONS: Assessed interventions to improve PROMs in T2DM attain effectiveness for knowledge, self-empowerment, distress, diet adherence and tobacco cessation. PTI produced the most lasting benefits. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01657227 (6 August 2012) https://clinicaltrials.gov/ct2/show/NCT01657227.

Diminished S-adenosylmethionine biosynthesis and its metabolism in a model of hepatocellular carcinoma is recuperated by an adenosine derivative.

S-adenosylmethionine (SAM), biosynthesis from methionine and ATP, is markedly decreased in hepatocellularular carcinoma (HCC) for a diminution in ATP levels, and the down regulation of the liver specific MAT1a enzyme. Its metabolic activity is very important in the transmethylation reactions, the methionine cycle, the biosynthesis of glutathione (GSH) and the polyamine pathway, which are markedly affected in the HCC. The chemo-preventive effect of IFC305 in HCC induced by DEN, and the increase of ATP and SAM in CCl4-induced cirrhosis have been previously demonstrated. The aim of this work was to test whether this chemo-preventive effect is mediated by the induction of SAM biosynthesis and its metabolic flow. SAM hepatic levels and the methionine cycle were recovered with IFC305 treatment, restoring transmethylation and transsulfuration activities. IFC305 treatment, increased MAT1a levels and decrease MAT2a levels through modulation of their post-transcriptional regulation. This occurred through the binding of the AUF1 (binding factor 1 AU-rich sites) and HuR (human antigen R) ribonucleoproteins to Mat1a and Mat2a messenger RNAs, which maintained their nuclear localization. Finally, the compound inhibited the polyamine pathway favoring the recuperation of the normal methionine and one carbon cycle recuperating the metabolic flow of methionine, which probably facilitated its HCC chemo-preventive effect.

Different Pathological Complete Response Rates According to PAM50 Subtype in HER2+ Breast Cancer Patients Treated With Neoadjuvant Pertuzumab/Trastuzumab vs. Trastuzumab Plus Standard Chemotherapy: An Analysis of Real-World Data.

Background: Double blockade with pertuzumab and trastuzumab combined with chemotherapy is the standard neoadjuvant treatment for HER2-positive early breast cancer. Data derived from clinical trials indicates that the response rates differ among intrinsic subtypes of breast cancer. The aim of this study is to determine if these results are valid in real-world patients. Methods: A total of 259 patients treated in eight Spanish hospitals were included and divided into two cohorts: Cohort A (132 patients) received trastuzumab plus standard neoadjuvant chemotherapy (NAC), and Cohort B received pertuzumab and trastuzumab plus NAC (122 patients). Pathological complete response (pCR) was defined as the complete disappearance of invasive tumor cells. Assignment of the intrinsic subtype was realized using the research-based PAM50 signature. Results: There were more HER2-enriched tumors in Cohort A (70 vs. 56%) and more basal-like tumors in Cohort B (12 vs. 2%), with similar luminal cases in both cohorts (luminal A 12 vs. 14%; luminal B 14 vs. 18%). The overall pCR rate was 39% in Cohort A and 61% in Cohort B. Better pCR rates with pertuzumab plus trastuzumab than with trastuzumab alone were also observed in all intrinsic subtypes (luminal PAM50 41 vs. 11.4% and HER2-enriched subtype 73.5 vs. 50%) but not in basal-like tumors (53.3 vs. 50%). In multivariate analysis the only significant variables related to pCR in both luminal PAM50 and HER2-enriched subtypes were treatment with pertuzumab plus trastuzumab (Cohort B) and histological grade 3. Conclusions: With data obtained from patients treated in clinical practice, it has been possible to verify that the addition of pertuzumab to trastuzumab and neoadjuvant chemotherapy substantially increases the rate of pCR, especially in the HER2-enriched subtype but also in luminal subtypes, with no apparent benefit in basal-like tumors.

EQ-5D-5L utilities per health states in Spanish population with knee or hip osteoarthritis.

BACKGROUND: The objective of this study was to obtain utilities by means of EQ-5D-5L for different health states in patients with knee osteoarthritis (KOA) or hip osteoarthritis (HOA) in Spain, and to compare these values with those used in foreign studies with the aim of discussing their transferability for their use in economic evaluations conducted in Spain. METHODS: Primary study: Observational prospective study of KOA or HOA patients in Spain. Sociodemographic and clinical characteristics were collected to characterize the sample. Utilities were elicited using the EQ-5D-5L questionnaire. ANOVA and bivariable analyses were conducted to identify differences between health states. LITERATURE REVIEW: Using the bibliographic databases NSH EED and CEA Registry, we conducted searches of model-based cost utilities analyses of technologies in KOA or HOA patients. Health states and utilities were extracted and compared with values obtained from the Spanish sample. RESULTS: Three hundred ninety-seven subjects with KOA and 361 subjects with HOA were included, with average utilities of 0.544 and 0.520, respectively. In both samples, differences were found in utilities according to level of pain, stiffness and physical function (WOMAC) and severity of symptoms (Oxford scales), so that the worst the symptoms, the lower the utilities. The utilities after surgery were higher than before surgery. Due to limitations from our study related to sample size and observational design, it was not possible to estimate utilities for approximately half the health states included in the published models because they were directly related to specific technologies. For almost 100% of health states of the selected studies we obtained very different utilities from those reported in the literature. CONCLUSIONS: To our knowledge this is the first article with detailed utilities estimated using the EQ-5D-5L in Spain for KOA and HOA patients. In both populations, utilities are lower for worse health states in terms of level of pain, stiffness and physical function according to WOMAC, and according to the Oxford scales. Most utilities obtained from the Spanish sample are lower than those reported in the international literature. Further studies estimating utilities from local populations are required to avoid the use of foreign sources in economic evaluations.

Ask1 and Akt act synergistically to promote ROS-dependent regeneration in Drosophila.

How cells communicate to initiate a regenerative response after damage has captivated scientists during the last few decades. It is known that one of the main signals emanating from injured cells is the Reactive Oxygen Species (ROS), which propagate to the surrounding tissue to trigger the replacement of the missing cells. However, the link between ROS production and the activation of regenerative signaling pathways is not yet fully understood. We describe here the non-autonomous ROS sensing mechanism by which living cells launch their regenerative program. To this aim, we used Drosophila imaginal discs as a model system due to its well-characterized regenerative ability after injury or cell death. We genetically-induced cell death and found that the Apoptosis signal-regulating kinase 1 (Ask1) is essential for regenerative growth. Ask1 senses ROS both in dying and living cells, but its activation is selectively attenuated in living cells by Akt1, the core kinase component of the insulin/insulin-like growth factor pathway. Akt1 phosphorylates Ask1 in a secondary site outside the kinase domain, which attenuates its activity. This modulation of Ask1 activity results in moderate levels of JNK signaling in the living tissue, as well as in activation of p38 signaling, both pathways required to turn on the regenerative response. Our findings demonstrate a non-autonomous activation of a ROS sensing mechanism by Ask1 and Akt1 to replace the missing tissue after damage. Collectively, these results provide the basis for understanding the molecular mechanism of communication between dying and living cells that triggers regeneration.

Efficacy, Effectiveness, Safety, and Cost-effectiveness of Epidural Adhesiolysis for Treating Failed Back Surgery Syndrome. A Systematic Review.

BACKGROUND: Failed back surgery syndrome (FBSS) has a profound impact on patients' quality of life and represents a major clinical challenge and a significant economic burden for society. Adhesiolysis is used as a treatment to eliminate perineural/epidural adhesions in patients with chronic pain attributed to FBSS. OBJECTIVE: To evaluate the efficacy, effectiveness, safety, and cost-effectiveness of epidural adhesiolysis compared with other procedures for treating FBSS. METHOD: A systematic review was conducted. The electronic databases Medline/PreMedline, EMBASE, Cochrane Library Plus, Centre for Reviews and Dissemination databases, SCOPUS, Science Citation Index, and PEDRO were consulted through April 2017. Predefined criteria were used to determine inclusion of the studies and to assess their methodological quality. RESULTS: Ten reports were included. No randomized controlled trials (RCTs) on efficacy or cost-effectiveness were found. Three reports (corresponding to two RCTs, N = 212) suggested that adhesiolysis was effective, especially for pain and disability. However, both studies presented serious methodological flaws. In addition to RCTs, seven observational studies with high risk of bias reported data on effectiveness and safety. Fifty-eight adverse events were reported among 130 patients undergoing endoscopic adhesiolysis, and 19 among the 110 undergoing percutaneous adhesiolysis. CONCLUSIONS: The evidence on the efficacy and cost-effectiveness of adhesiolysis for treating FBSS is nonexistent, whereas evidence on its effectiveness and safety is insufficient. Incorporating data from observational studies did not improve the quality of the evidence on effectiveness.

Diagnostic Performance of Transvaginal Ultrasound for Detecting Cervical Invasion In Women With Endometrial Carcinoma: A Systematic Review and Meta-analysis.

OBJECTIVES: To evaluate the role of transvaginal ultrasound (TVUS) for diagnosing cervical invasion in the preoperative assessment of endometrial carcinoma. METHODS: A search for studies evaluating the role of TVUS for assessing cervical invasion in endometrial carcinoma from January 1990 to December 2016 was performed in the PubMed/MEDLINE, Web of Science, www.ClinicalTrials.gov, and www.who.int/trialsearchdatabases. The quality of the studies was evaluated by the Quality Assessment of Diagnostic Accuracy Studies 2. RESULTS: We identified 211 citations. Ultimately, 17 studies comprising 1751 women were included. The mean prevalence of cervical invasion was 16.3%. The risk of bias was high in 7 studies for the domains "patient selection" and "index test," whereas it was considered low for the "reference test" domain. Overall, the pooled estimated sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of TVUS for detecting cervical invasion were 63% (95% confidence interval [CI], 51%-74%), 91% (95% CI, 87%-94%), 10.2 (95% CI, 5.7-18.3), and 0.38 (95% CI, 0.28-0.53), respectively. Heterogeneity was high for both sensitivity and specificity. CONCLUSIONS: Transvaginal ultrasound has acceptable diagnostic performance for detecting cervical invasion in women with endometrial carcinoma.

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.

BACKGROUND: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. METHODS: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. FINDINGS: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10-4-0·0282; p=0·0067) and overall survival (0·080, 0·017-0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149-0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209-0·802; p=0·0063) and overall survival (0·409, 0·220-0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. INTERPRETATION: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies. FUNDING: "Obra Social" La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.

Heberprot-P's Effect on Gene Expression in Healing Diabetic Foot Ulcers.

NTRODUCTION Diabetic foot ulcers are a chronic complication in patients with diabetes mellitus. They appear as a result of the combination of diabetic polyneuropathy and angiopathy, and in many cases require amputation of the affected extremity. Clinical trials have demonstrated that repeated local infiltration with Heberprot-P can improve healing of chronic diabetic foot ulcers. Although there is evidence of its effects as a granulation stimulator and on cell migration and proliferation, genetic control mechanisms explaining its anti-inflammatory and oxidative stress reduction properties are not yet thoroughly understood. OBJECTIVE Analyze changes in expression of genes involved in healing after treatment of diabetic foot ulcers with Heberprot-P. METHODS Biopsies were collected from diabetic foot ulcers of 10 responding patients before and after 2 weeks' treatment with Heberprot-P (75-µg applied intralesionally 3 times per week). Total RNA was obtained and quantitative PCR used to determine expression of 26 genes related to inflammation, oxidative stress, cell proliferation, ngiogenesis and extracellular matrix formation. Genetic expression was quantified before and after treatment using REST 2009 v2.0.13. RESULTS After treatment, there was a statistically significant increase in expression of genes related to cell proliferation, angiogenesis and formation of extracellular matrix (PDGFB, CDK4, P21, TP53, ANGPT1, COL1A1, MMP2 and TIMP2). A significant decrease was observed in gene expression related to inflammatory processes and oxidative stress (NFKB1, TNFA and IL-1A). CONCLUSIONS Our findings suggest that Heberprot-P's healing action on diabetic foot ulcers is mediated through changes in genetic expression that reduce hypoxia, inflammation and oxidative stress, and at the same time increase cell proliferation, collagen synthesis and extracellular matrix remodeling. The kinetics of expression of two genes related to extracellular matrix formation needs further exploration. KEYWORDS Epidermal growth factor, EGF, diabetic foot ulcer, wound healing, quantitative real-time PCR, gene expression, Cuba.

Expression and Prognostic Value of Oestrogen Receptor Beta in Colorectal Cancer.

Differences between men and women in the incidence and biological mechanisms of colorectal cancer (CRC) suggest that estrogens may play a role in the pathogenesis of this disease. The identification of the human estrogen receptor beta (ERß) and its expression in the intestinal mucosa led to further studies that revealed that estrogens have a protective function against CRC mediated by the activation of ERß. However, ERß expression and its role in CRC is controversial. The purpose of this study was to determine the distribution and prognostic value of ERß expression in the intestinal mucosa of patients diagnosed and surgically treated for CRC, and its association with other known prognostic factors. A total of 109 paraffin-embedded samples of the wild-type ERß isoform were analyzed by immunohistochemical nuclear staining in patients with colorectal adenocarcinoma. Clinical/pathological and survival data were collected. Immunohistochemical quantification was performed using the category scoring system, which has been validated for assessing estrogen receptor alfa. The wild-type ERß isoform -also called ERß1- was positive in 101 patients (92.7%) and negative in nine patients (7.3%). Univariate analysis revealed that the absence of expression of the ERß1 gene was correlated with mucinous adenocarcinoma (p < 0.05). Also, a non-significant tendency was observed for ERß expression to be down-regulated in advanced tumors. With a median follow-up of 47 months, the overall survival and progression-free survival were not found to be associated with ERß1 expression (p = 0.2). Although the wild-type ERß isoform was expressed in most study patients with colorectal cancer, it does not seem to have any prognostic value for the course of the disease. Further studies should be conducted to investigate whether the down-regulation of ERß expression has any biological function in mucinous colorectal cancer.

A Drosophila model of myeloproliferative neoplasm reveals a feed-forward loop in the JAK pathway mediated by p38 MAPK signalling.

Myeloproliferative neoplasms (MPNs) of the Philadelphia-negative class comprise polycythaemia vera, essential thrombocythaemia and primary myelofibrosis (PMF). They are associated with aberrant numbers of myeloid lineage cells in the blood, and in the case of overt PMF, with development of myelofibrosis in the bone marrow and failure to produce normal blood cells. These diseases are usually caused by gain-of-function mutations in the kinase JAK2. Here, we use Drosophila to investigate the consequences of activation of the JAK2 orthologue in haematopoiesis. We have identified maturing haemocytes in the lymph gland, the major haematopoietic organ in the fly, as the cell population susceptible to induce hypertrophy upon targeted overexpression of JAK. We show that JAK activates a feed-forward loop, including the cytokine-like ligand Upd3 and its receptor, Domeless, which are required to induce lymph gland hypertrophy. Moreover, we present evidence that p38 MAPK signalling plays a key role in this process by inducing expression of the ligand Upd3. Interestingly, we also show that forced activation of the p38 MAPK pathway in maturing haemocytes suffices to generate hypertrophic organs and the appearance of melanotic tumours. Our results illustrate a novel pro-tumourigenic crosstalk between the p38 MAPK pathway and JAK signalling in a Drosophila model of MPNs. Based on the shared molecular mechanisms underlying MPNs in flies and humans, the interplay between Drosophila JAK and p38 signalling pathways unravelled in this work might have translational relevance for human MPNs.

Gene Dosage Imbalance Contributes to Chromosomal Instability-Induced Tumorigenesis.

Chromosomal instability (CIN) is thought to be a source of mutability in cancer. However, CIN often results in aneuploidy, which compromises cell fitness. Here, we used the dosage compensation mechanism (DCM) of Drosophila to demonstrate that chromosome-wide gene dosage imbalance contributes to the deleterious effects of CIN-induced aneuploidy and its pro-tumorigenic action. We present evidence that resetting of the DCM counterbalances the damaging effects caused by CIN-induced changes in X chromosome number. Importantly, interfering with the DCM suffices to mimic the cellular effects of aneuploidy in terms of reactive oxygen species (ROS) production, JNK-dependent cell death, and tumorigenesis upon apoptosis inhibition. We unveil a role of ROS in JNK activation and a variety of cellular and tissue-wide mechanisms that buffer the deleterious effects of CIN, including DNA-damage repair, activation of the p38 pathway, and cytokine induction to promote compensatory proliferation. Our data reveal the existence of robust compensatory mechanisms that counteract CIN-induced cell death and tumorigenesis.

Economic evaluation of Chagas disease screening in Spain.

Although Spain is the European country with the highest Chagas disease burden, the country does not have a national control program of the disease. The purpose of this study is to evaluate the efficiency of several strategies for Chagas disease screening among Latin American residents living in Spain. The following screening strategies were evaluated: (1) non-screening; (2) screening of the Latin American pregnant women and their newborns; (3) screening also the relatives of the positive pregnant women; (4) screening also the relatives of the negative pregnant women. A cost-utility analysis was carried out to compare the four strategies from two perspectives, the societal and the Spanish National Health System (SNHS). A decision tree representing the clinical evolution of Chagas disease throughout patient's life was built. The strategies were compared through the incremental cost-utility ratio, using euros as cost measurement and quality-adjusted life years as utility measurement. A sensitivity analysis was performed to test the model parameters and their influence on the results. We found the "Non-screening" as the most expensive and less effective of the evaluated strategies, from both the societal and the SNHS perspectives. Among the screening evaluated strategies the most efficient was, from both perspectives, to extent the antenatal screening of the Latin American pregnant women and their newborns up to the relatives of the positive women. Several parameters influenced significantly on the sensitivity analyses, particularly the chronic treatment efficacy or the prevalence of Chagas disease. In conclusion, for the general Latin American immigrants living in Spain the most efficient would be to screen the Latin American mothers, their newborns and the close relatives of the mothers with a positive serology. However for higher prevalence immigrant population the most efficient intervention would be to extend the program to the close relatives of the negative mothers.

Intracameral cefuroxime and moxifloxacin used as endophthalmitis prophylaxis after cataract surgery: systematic review of effectiveness and cost-effectiveness.

Postoperative endophthalmitis is one of the most serious potential complications of ocular lens surgery. Its incidence can be reduced by means of antibiotic prophylaxis. Although the prophylactic use of intracameral cefuroxime has been extended, other drugs, such as moxifloxacin, have arisen as alternatives. We performed a systematic literature review on the effectiveness and efficiency of intracameral cefuroxime and moxifloxacin for the prophylaxis of postoperative endophthalmitis after cataract surgery. Several bibliographic databases were searched up to October 2010 and were updated up to January 2013. Outcomes were the onset of endophthalmitis after surgery and the cost-effectiveness ratio of using both antibiotic prophylaxis alternatives. The following were included: a clinical trial reported in two papers, six observational studies, and an economic evaluation. All studies assessed cefuroxime compared with another antibiotic prophylaxis or no prophylaxis. The only randomized controlled trial performed by the European Society of Cataract and Refractive Surgery found that intracameral cefuroxime is significantly more effective than not using prophylaxis or the use of a topical antibiotic. The observational studies support these results. The economic evaluation compared different prophylaxis regimens and concluded that intracameral cefuroxime showed the best cost-effectiveness ratio. Both the observational studies and the economic evaluation have methodological limits that reduce their validity. This review confirmed that cefuroxime can prevent endophthalmitis after cataract surgery. Further randomized controlled trials, with large sample sizes, are required to compare different antibiotic prophylaxis regimens.

Mei-P26 mediates tissue-specific responses to the Brat tumor suppressor and the dMyc proto-oncogene in Drosophila.

TRIM-NHL proteins are a family of translational regulators that control cell growth, proliferation, and differentiation during development. Drosophila Brat and Mei-P26 TRIM-NHL proteins serve as tumor suppressors in stem cell lineages and have been proposed to exert this action, in part, via the repression of the protooncogene dMyc. Here we analyze the role of Brat, Mei-P26, and dMyc in regulating growth in Drosophila imaginal discs. As in stem cell lineages, Brat and Mei-P26 repress dMyc in epithelial cells by acting at the post-transcriptional and protein level, respectively. Analysis of cell and organ size unravel that Mei-P26 mediates tissue-specific responses to Brat and dMyc activities. Loss-of-function of brat and overexpression of dMyc induce overgrowth in stem cell lineages and eventually can participate in tumor formation. In contrast, an increase in Mei-P26 levels inhibits growth of epithelial cells in these two conditions. Upon depletion of Brat, Mei-P26 up-regulation prevents an increase in dMyc protein levels and leads to tissue undergrowth. This mechanism appears to be tissue-specific since Mei-P26 is not upregulated in brain tumors resulting from brat loss-of-function. Driving Mei-P26 expression in these tumors -mimicking the situation in epithelial cells- is sufficient to prevent dMyc accumulation, thus rescuing the overgrowth. Finally, we show that Mei-P26 upregulation mediates dMyc-induced apoptosis and limits dMyc growth potential in epithelial cells. These findings shed light on the tumor suppressor roles of TRIM-NHL proteins and underscore a new mechanism that maintains tissue homeostasis upon dMyc deregulation.

A prospective study of the association of patient expectations with changes in health-related quality of life outcomes, following total joint replacement.

BACKGROUND: Patient expectations regarding surgery may be related to outcomes in total joint replacement (TJR). The aim of this study was to determine the association of patient expectations with health related quality of life (HRQoL) outcomes measured by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Short Form 12 (SF-12) and satisfaction with current symptoms measured on a 4-point Likert scale, one year after surgery, adjusting for Body Mass Index (BMI), age, gender, joint, education, previous intervention and baseline scores. METHODS: Consecutive patients preparing for TJR of the knee or hip due to primary osteoarthritis (OA) in 15 hospitals in Spain were recruited for the study. Patients completed questionnaires before surgery and 12 months afterwards: five questions about expectations before surgery; an item to measure satisfaction; two HRQoL instruments-WOMAC and SF-12; as well as questions about sociodemographic information. To determine the association of patient expectations at baseline, with changes in HRQoL 12 months after surgery and with satisfaction, general linear models and logistic regression analysis were performed. RESULTS: A total of 892 patients took part in the study. Patients who had higher pain relief or ability to walk expectations improved more in HRQoL at 12 months. Moreover, patients with high daily activity expectations were more satisfied. CONCLUSIONS: Patients with higher baseline expectations for TJR, improved more in HRQoL at one year and had more likelihood to be satisfied than patients with lower expectations, adjusted for BMI, age, gender, joint, education, previous intervention and HRQoL baseline scores.

Regulation of atrophin by both strands of the mir-8 precursor.

In Drosophila melanogaster, miR-8-3p regulates mRNA levels of atrophin, a factor involved in neuromotor coordination, and we found that Blattella germanica with suppressed atrophin showed motor problems. Bionformatic predictions and luciferase-reporter tests indicated that B. germanica atrophin mRNA contains target sites for miR-8-3p and miR-8-5p. Suppression of miR-8-3p or miR-8-5p appeared to increase atrophin mRNA. The effects of suppression of Argonaute (AGO) 1 or AGO2 expression on miR-8-3p and miR-8-5p suggested that miR-8-3-p might predominantly bind to AGO1, whereas miR-8-5p might bind to a moderate extent to both AGO1 and AGO2 in the respective RNA-induced silencing complexes (RISCs). We propose that the interplay of miR-8-3p, miR-8-5p, AGO1 and AGO2, maintain the appropriate levels of atrophin mRNA. This would be the first example of two strands of the same miRNA precursor regulating a single transcript.