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Background Clinical trials remain key to the development of evidence‐based medical practice. However, they are becoming increasingly complex, mainly in a multinational setting. To address these challenges, the European Union (EU) adopted the Clinical Trial Regulation EU No. 536/2014 (CTR). Once in force, the CTR will lead to more consistent rules and simplification of procedures for conducting clinical trials throughout the EU. Existing harmonization initiatives and “research infrastructures” for clinical trials may facilitate this process. This publication offers a snapshot of the current level of harmonization activities in academic clinical research in Europe. Methods A survey was performed among the member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardized questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the harmonization of academic clinical research processes at national level, to facilitate the exchange of expertise and experience among countries, and to identify new fields of action. Results Most scientific partners already have in place various working groups and harmonization activities at national level. Furthermore, they are involved in and open to sharing their know‐how and documents. Since harmonization was mainly a bottom‐up approach up until now, the extent and topics dealt with are diverse and there is only little cross‐networking and cross‐country exchange so far. Conclusions Currently, the ECRIN member countries offer a very solid base and collaborative spirit for further aligning processes and exchanging best practices for clinical research in Europe. They can support a smooth implementation of the EU CTR and may act as single contact with consolidated expertise in a country.

The increasing knowledge of the mechanisms involved in metabolism is shifting the paradigms by which the pathophysiology of many pulmonary diseases is understood. Metabolic dysfunction is recognized in obesity-associated asthma, but other metabolic conditions have been shown to be independently related to asthma. Novel insights have also recently been brought by metabolomics in this filed. The purpose of this review is to discuss current perspectives regarding metabolic dysfunction in asthma, from obesity-related asthma to other metabolic conditions and the role of current pharmacological therapeutic strategies and lifestyle interventions. Obesity is a well-recognized risk factor for asthma across the lifespan, which is generally associated with poorer response to current available treatments, rendering a more severe, refractory disease status. Besides the epidemiological and clinical link, untargeted metabolomics studies have recently supported the obesity-associated asthma phenotype at the molecular level. Not only obesity-related, but also other aspects of metabolic dysregulation can be independently linked to asthma. These include hyperinsulinemia, dyslipidemia and hypertension, which need to be taken into account, even in the non-obese patient. Untargeted metabolomics studies have further highlighted several other metabolic pathways that can be altered in asthma, namely regarding oxidative stress and systemic inflammation, and also suggesting the importance of microbiota in asthma pathogenesis. Considering the reduced response to corticosteroids, other pharmacologic treatments have been shown to be effective regardless of body mass index. Non-pharmacologic treatments (namely weight reduction and dietary changes) may bring substantial benefit to the asthmatic patient. Taken together, this evidence points towards the need to improve our knowledge in this filed and, in particular, to address the influence of environmental factors in metabolic dysfunction and asthma development. Personalized medicine is definitely needed to optimize treatment, including a holistic view of the asthmatic patient in order to set accurate pharmacologic therapy together with dietary, physical exercise and lifestyle interventions. publishersversion published

iNOVA4Health–UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement is acknowledged (Ref: 201601-02-021). Authors supported by Fundação para a Ciência e a Tecnologia (FCT–Portugal): for V.S.; PD/BD/105892/2014 for C.G.-D.;RNEM-LISBOA-01-0145-FEDER-022125022125 for J.M.; SFRH/BD/130911/2017 for M.J.C.; D/BD/114257/2016 for N.R.C.; Programa Operacional Potencial Humano and the European Social Fund (IF/01091/2013) for A.M.M.A. The mercapturate pathway is a unique metabolic circuitry that detoxifies electrophiles upon adducts formation with glutathione. Since its discovery over a century ago, most of the knowledge on the mercapturate pathway has been provided from biomonitoring studies on environmental exposure to toxicants. However, the mercapturate pathway-related metabolites that is formed in humans—the mercapturomic profile—in health and disease is yet to be established. In this paper, we put forward the hypothesis that these metabolites are key pathophysiologic factors behind the onset and development of non-communicable chronic inflammatory diseases. This review goes from the evidence in the formation of endogenous metabolites undergoing the mercapturate pathway to the methodologies for their assessment and their association with cancer and respiratory, neurologic and cardiometabolic diseases. publishersversion published

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)., The carotid bodies (CB) are peripheral chemoreceptors that sense changes in arterial blood O2, CO2 and pH levels. Hypoxia, hypercapnia and acidosis activate the CB, which respond by increasing the action potential frequency in their sensory nerve, the carotid sinus nerve (CSN). CSN activity is integrated in the brain stem to induce a panoply of cardiorespiratory reflexes aimed, primarily, to normalize the altered blood gases, via hyperventilation, and to regulate blood pressure and cardiac performance, via sympathetic nervous system (SNS) activation. Besides its role in the cardiorespiratory control the CB has been proposed as a metabolic sensor implicated in the control of energy homeostasis and, more recently, in the regulation of whole body insulin sensitivity. Hypercaloric diets cause CB overactivation in rats, which seems to be at the origin of the development of insulin resistance and hypertension, core features of metabolic syndrome and type 2 diabetes. Consistent with this notion, CB sensory denervation prevents metabolic and hemodynamic alterations in hypercaloric feed animal. Obstructive sleep apnoea (OSA) is another chronic disorder characterized by increased CB activity and intimately related with several metabolic and cardiovascular abnormalities. In this manuscript we review in a concise manner the putative pathways linking CB chemoreceptors deregulation with the pathogenesis of insulin resistance and arterial hypertension. Also, the link between chronic intermittent hypoxia (CIH) and insulin resistance is discussed. Then, a final section is devoted to debate strategies to reduce CB activity and its use for prevention and therapeutics of metabolic diseases with an emphasis on new exciting research in the modulation of bioelectronic signals, likely to be central in the future., This work was supported by the Portuguese Foundation for Science and Technology [Grants EXPL/NEU-SCC/2183/2013] and by the L’Oreal/FCT/UNESCO Medals of Honorf or Women in Science 2009 (to Sílvia V. Conde) and by Spanish Ministry of Economy and Competitiveness [Grant BFU2012-37459 to Constancio Gonzalez] and by Spanish Ministry of Health-Institute Carlos III [CIBERES to Constancio Gonzalez].

Resumen del póster presentado al Joint FEPS & XXXVI Spanish Physiological Society Congress (Sociedad Española de Ciencias Fisiológicas) celebrado en Santiago de Compostela (España) del 8 al 11 de septiembre de 2012., [Objectives]: Carotid body (CB) chemoreceptor cells are PO2, PCO2/pH sensors-efectors which upon a decrease in PO2 or a PCO2/[H+] increase, release neurotransmitters that regulate the firing rate in the sensory fibres of the carotid sinus nerve (CSN). CSN terminate in the brainstem, where the information it coveys is integrated to generate compensatory ventilatory responses aimed to normalize blood gases. The chemoreceptor cells possess a wide array of neurotransmitters, whose relative significance in the genesis of conducted activity in the CSN is unknown. Present study, carried out in young adult rats, aimed to define the significance of adenosine and ATP to generate conducted action potentials in the CSN at different intensities of hypoxia. [Materials]: To ascertain their significance we have measured: a) adenosine and ATP receptors in the somas of the CSN sensory neurons; b) metabolic profile of adenosine and ATP in chemoreceptor cells and their rate of release at several PO2 levels, c) effect of selective adenosine and ATP antagonists on the firing frequencies recorded in the CSN; d) effect of adenosine and ATP antagonists on ventilation at different ischemic hypoxic intensities; e) some additional data on aged animals and in animals exposed to chronic sustained hypoxia (CSH) would also be presented. [Results]: Findings indicate that adenosine and ATP are the main players of the hypoxic chemotransmission in the CB sensory synapse. Adenosine is more relevant during mild hypoxia while ATP is prime during intense hypoxia. This relative contribution is maintained in aging, although overall CB drive lessens. In CSH the role of adenosine in fixing CSN responses and ventilation to acute hypoxic tests seems maintained, but ATP function seems to decrease. [Conclusions]: In the presentation of our data we shall also provide some information on the functional significance of adenosine and ATP on the central control of breathing., Grants: PTDC/SAU-ORG/111417/2009, PT2009-0172, JCyL2011 and CIBERES.