Notch-mediated induction of N-cadherin and α 9-integrin confers higher invasive phenotype on rhabdomyosarcoma cells

Altres ajuts: This work was supported by grants from Institut Català d'Oncologia (ICO), Instituto de Salud Carlos III (RD06/0020/1021 and PI11/00740), Fundació la Marató de TV3, Asociación Española Contra el Cáncer, Fundació SMALL and Fundació A. BOSCH.Rhabdomyosarcoma (RMS) is the commonest type of soft-tissue sarcoma in children. Patients with metastatic RMS continue to have very poor prognosis. Recently, several works have demonstrated a connection between Notch pathway activation and the regulation of cell motility and invasiveness. However, the molecular mechanisms of this possible relationship remain unclear. The Notch pathway was manipulated pharmacologically and genetically. The mRNA changes were analysed by quantitative PCR and protein variations by western blot and immunofluorescence. Finally, the capabilities of RMS cells to adhere, heal a wound and invade were assessed in the presence of neuronal cadherin (N-cadherin)- and α 9-integrin-blocking antibodies. Cells treated with γ -secretase inhibitor showed lower adhesion capability and downregulation of N-cadherin and α 9-integrin. Genetic manipulation of the Notch pathway led to concomitant variations in N-cadherin and α 9-integrin. Treatment with anti-N-cadherin-blocking antibody rendered marked inhibition of cell adhesion and motility, while anti- α 9-integrin-blocking antibody exerted a remarkable effect on cell adhesion and invasiveness. Neuronal cadherin and α 9-integrin are postulated as leading actors in the association between the Notch pathway and promotion of cell adhesion, motility and invasion, pointing to these proteins and the Notch pathway itself as interesting putative targets for new molecular therapies against metastases in RMS

Molecular and brain volume changes following aerobic exercise, cognitive and combined training in physically inactive healthy Late-Middle-Aged Adults: The Projecte Moviment Randomized Controlled Trial

Behavioral interventions have shown promising neuroprotective effects, but the cascade of molecular, brain and behavioral changes involved in these benefits remains poorly understood. Projecte Moviment is a 12-week (5 days per week—45 min per day) multi-domain, single-blind, proof-of-concept randomized controlled trial examining the cognitive effect and underlying mechanisms of an aerobic exercise (AE), computerized cognitive training (CCT) and a combined (COMB) groups compared to a waitlist control group. Adherence was > 80% for 82/109 participants recruited (62% female; age = 58.38 ± 5.47). In this study we report intervention-related changes in plasma biomarkers (BDNF, TNF-α, HGF, ICAM-1, SDF1-α) and structural-MRI (brain volume) and how they related to changes in physical activity and individual variables (age and sex) and their potential role as mediators in the cognitive changes. Our results show that although there were no significant changes in molecular biomarker concentrations in any intervention group, changes in ICAM-1 and SDF1-α were negatively associated with changes in physical activity outcomes in AE and COMB groups. Brain volume changes were found in the CCT showing a significant increase in precuneus volume. Sex moderated the brain volume change in the AE and COMB groups, suggesting that men may benefit more than women. Changes in molecular biomarkers and brain volumes did not significantly mediate the cognitive-related benefits found previously for any group. This study shows crucial initial molecular and brain volume changes related to lifestyle interventions at early stages and highlights the value of examining activity parameters, individual difference characteristics and using a multi-level analysis approach to address these questions

Effects and Mechanisms of Cognitive, Aerobic Exercise, and Combined Training on Cognition, Health, and Brain Outcomes in Physically Inactive Older Adults : The Projecte Moviment Protocol

Altres ajuts: It has also been rewarded with three pre-doctoral fellowships ( FPU014/01460, FI-2016, and FI-2018).Introduction: Age-related health, brain, and cognitive impairment is a great challenge in current society. Cognitive training, aerobic exercise and their combination have been shown to benefit health, brain, cognition and psychological status in healthy older adults. Inconsistent results across studies may be related to several variables. We need to better identify cognitive changes, individual variables that may predict the effect of these interventions, and changes in structural and functional brain outcomes as well as physiological molecular correlates that may be mediating these effects. Projecte Moviment is a multi-domain randomized trial examining the effect of these interventions applied 5 days per week for 3 months compared to a passive control group. The aim of this paper is to describe the sample, procedures and planned analyses. Methods: One hundred and forty healthy physically inactive older adults will be randomly assigned to computerized cognitive training (CCT), aerobic exercise (AE), combined training (COMB), or a control group. The intervention consists of a 3 month home-based program 5 days per week in sessions of 45 min. Data from cognitive, physical, and psychological tests, cardiovascular risk factors, structural and functional brain scans, and blood samples will be obtained before and after the intervention. Results: Effects of the interventions on cognitive outcomes will be described in intention-to-treat and per protocol analyses. We will also analyze potential genetic, demographic, brain, and physiological molecular correlates that may predict the effects of intervention, as well as the association between cognitive effects and changes in these variables using the per protocol sample. Discussion: Projecte Moviment is a multi-domain intervention trial based on prior evidence that aims to understand the effects of CCT, AE, and COMB on cognitive and psychological outcomes compared to a passive control group, and to determine related biological correlates and predictors of the intervention effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03123900

Adequacy and quality of abdominal echographies requested by primary care professionals

<p>Abstract</p> <p>Background</p> <p>The value of abdominal echography in primary care is great because it is innocuous, inexpensive, easy to perform and provides a great deal of information making this the first examination to be requested in cases of probable abdominal disease. <b>However, too many abdominal echographies are probably requested overcrowding the Departments of Radiodiagnosis with not always justified petitions or with repetition of tests based on little clinical criteria</b>.</p> <p>Methods/Design</p> <p><b>The aim of the study is </b>to evaluate the adequacy and quality of abdominal echographies requested by primary care physicians in the Maresme County (North of Barcelona), develop guidelines for indicating echographies and reevaluate this adequacy after implementing these guidelines.</p> <p>We will perform a two-phase study: the first descriptive, and retrospective evaluating the adequacy and quality of petitions for abdominal echographies, and in the second phase we will evaluate the impact of recommendations for indicating abdominal echographies for PC physicians on the adequacy and quality of echography petitions thereafter.</p> <p><b>This study will be carried out in 10 primary care centres </b>in the Maresme (Barcelona).</p> <p>1067 abdominal echographies requested by primary care physicians from the above mentioned centres from January 2007 to April 2010 and referred to the Department of Radiology and the same number of applications after the intervention.</p> <p>All the petitions for abdominal echographies requested will be analysed and the clinical histories will be obtained to determine demographic variables, the reason for the visit and for the echography petition and diagnostic orientation, clinical and echographic data, evaluation of the echographies according to the quality and variables characterising the professionals requesting the echographies including: age, sex, laboral situation, length of time in work post, formation, etc.</p> <p>To achieve a consensus of the adequacy of abdominal echography, a work group including gastroenterologists, radiologists and general practitioners will be created following the nominal group. This will allow the design of guidelines for the indication of abdominal echography and posterior evaluation of their impact among physicians by diffusion and posterior reevaluation of the adequacy of the petitions.</p

Female Genital Mutilation: perceptions of healthcare professionals and the perspective of the migrant families

<p>Abstract</p> <p>Background</p> <p>Female Genital Mutilation (FGM) is a traditional practice which is harmful to health and is profoundly rooted in many Sub-Saharan African countries. It is estimated that between 100 and 140 million women around the world have been victims of some form of FGM and that each year 3 million girls are at risk of being submitted to these practices. As a consequence of the migratory phenomena, the problems associated with FGM have extended to the Western countries receiving the immigrants. The practice of FGM has repercussions on the physical, psychic, sexual and reproductive health of women, severely deteriorating their current and future quality of life. Primary healthcare professionals are in a privileged position to detect and prevent these situations of risk which will be increasingly more present in Spain.</p> <p>Methods/Design</p> <p>The objective of the study is to describe the knowledge, attitudes and practices of the primary healthcare professionals, working in 25 health care centres in Barcelona and Girona regions, regarding FGM, as well as to investigate the perception of this subject among the migrant communities from countries with strong roots in these practices. A transversal descriptive study will be performed with a questionnaire to primary healthcare professionals and migrant healthcare users.</p> <p>Using a questionnaire specifically designed for this study, we will evaluate the knowledge, attitudes and skills of the healthcare professionals to approach this problem. In a sub-study, performed with a similar methodology but with the participation of cultural mediators, the perceptions of the migrant families in relation to their position and expectancies in view of the result of preventive interventions will be determined.</p> <p>Variables related to the socio-demographic aspects, knowledge of FGM (types, cultural origin, geographic distribution and ethnicity), evaluation of attitudes and beliefs towards FGM and previous contact or experience with cases or risk situations will be obtained.</p> <p>Discussion</p> <p>Knowledge of these harmful practices and a preventive approach from a transcultural perspective may represent a positive intervention model for integrative care of immigrants, respecting their values and culture while also being effective in eliminating the physical and psychic consequences of FGM.</p

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure

Intraventricular conduction defects (IVCDs) can impair prognosis of heart failure (HF), but their specific impact is not well established. This study aimed to analyse the clinical profile and outcomes of HF patients with LBBB, right bundle branch block (RBBB), left anterior fascicular block (LAFB), and no IVCDs. Clinical variables and outcomes after a median follow-up of 21 months were analysed in 1762 patients with chronic HF and LBBB (n = 532), RBBB (n = 134), LAFB (n = 154), and no IVCDs (n = 942). LBBB was associated with more marked LV dilation, depressed LVEF, and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics, and patients with no IVCDs were more often women with less enlarged left ventricles and less depressed LVEF. Death occurred in 332 patients (interannual mortality = 10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden death in 59). An adjusted Cox model showed higher risk of cardiac death and pump failure death in the LBBB and RBBB than in the LAFB and the no IVCD groups. LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCDs. Further research in HF patients with RBBB is warranted

Use of Human Central Nervous System Cell Cultures in Neurotoxicity Testing

The nervous system is highly sensitive to toxic damage. Many environmental contaminants can produce acute or chronic neurological effects, and contribute to neural damage and cell death in neurodegenerative diseases. The utilization of primary cultures of neurons and glial cells is an essential step in investigating the specificity of the effects and mechanisms of action of the test chemical. If we take into account interspecies differences, cultures of human central nervous system (CNS) cells would be the best-suited test models for in vitro neurotoxicity testing. For practical and ethical reasons, human neuronal and glial cultures cannot be used for routine neurotoxicity testing, but they may be very useful for validating results from murine cultures and to address specific toxicity questions. For instance, we are investigating the action of agents producing oxygen radical damage in CNS cells. Oxidative stress is known to trigger apoptotic death of neurons and lead to neurodegeneration. A useful model in which to study these processes could be neuronal cultures obtained from CNS tissue with trisomy 21, since these cells suffer oxidative stress and apoptotic cell death in vitro. Besides primary cultures, human-derived clonal cell lines such as neuroblastoma SH-SY5Y can offer a first-step approach in neurotoxicity testing.This work was supported by the Spanish Fondo de Investigaciones Sanitarias (grant FIS97/0656) and grants from the Medical Research Council of Canada. C. Sanfeliu received a mobility grant from the Spanish Ministerio de Educación y Ciencia. Assistance with photographic material by E. Bustamante is gratefully acknowledged