Barcelona, Spain
Barcelona, Spain

The Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition is a public research consortium which was founded on November 28, 2006 financed by the Instituto de Salud Carlos III and the Ministerio de Ciencia e Innovación .The CIBERObn gathers 25 investigation groups from different Spanish Hospitals, Universities and Research Centres. Its mission is to promote a better knowledge about the mechanisms contributing to obesity development in order to reduce its incidence and prevalence, as well as its complications, in addition to nutrition-related diseases.The CIBERObn is structured into 8 scientific programs intended to increase the collaboration between researchers, to strengthen synergies and to boost new research lines. Programs are as follows: Nutrition: effects of different types of diet and nutrients on human health. Adipobiology: identification of new signals released by the adipose tissue which are involved in the regulation of energy homeostasis. Obesity and Cancer: role of those proteins associated with cell cycle on metabolic control and obesity development. Obesity and Cardiovascular risk: hemodynamic, metabolic and inflammatory factors associated to cardiac and vascular diseases in obesity. Neurocognitive and Environmental Factors: environmental and emotional factors in nutrition and obesity disorders. Obesity in Childhood-Adolescence Period: biochemical, hormonal, metabolic, genetic, proteomic and body-composition study in children and adolescents. Biomarkers: new strategies, therapeutic and prevention technologies, biomarkers of obesity. Biological Models and Therapeutic Targets: development and validation of experimental models and therapeutic targets in case of obesity.Additionally, CIBERObn lays a particular emphasis on translational research, specially focusing on research transfer to clinical applications and practices. To this end, two cross-cutting programs have been created: Staff Training and Recruitment, which is intended to train our staff according to our research lines and priorities “Fat Bank” Structural Program: biobank infrastructure connecting the above mentioned programs in a cross way by contributing with common solutions.The Fat Bank is a strategic platform of the CIBERobn which offers the Scientific Community different kinds of biological material which are associated to thorough metabolic phenotyping. This information is entered by means of a tailor-made individualised software. This fat-bank- launched in 2009- currently contains 3000 samples of biologic material from more than 300 individuals. In 2009, 287 indexed articles were published. Their average impact factor is 4.05, which is very high for this subject area. Of them, 67 belong to the first decile and 105 more belong to the first quartile of the subject area of indexed journals. They accumulate a total impact factor of 1,165. Provisional data of 2010 show an increase of 10%, highly improving the international visibility of the consortium. Wikipedia.


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Bravo I.G.,Center for Public Health Research | Bravo I.G.,CIBER ISCIII | de Sanjose S.,CIBER ISCIII | de Sanjose S.,Catalan Institute of Nanoscience and Nanotechnology | Gottschling M.,Ludwig Maximilians University of Munich
Trends in Microbiology | Year: 2010

A significant fraction of human cancers is associated with infections by different papillomaviruses (PVs). In other vertebrates, the presence of specific PVs is also associated with different neoplasias. The popular view of PVs conceives them to be largely static and relies on generalized assumptions that have rarely been rigorously tested such as: virus-host codivergence, strict tissue tropism and host-specificity, their very low mutation rate and the absence of recombination. Here, we want to stress the need and the medical importance of understanding the evolutionary history and present-day dynamics of PVs. Understanding the way that PV genomes have evolved will clarify the link between a given genotype and the phenotypic and clinical outcome of the corresponding viral infection. © 2010 Elsevier Ltd.


Lopez-Campos J.L.,University of Seville | Lopez-Campos J.L.,CIBER ISCIII | Acuna C.C.,University of Seville | Acuna C.C.,CIBER ISCIII
Expert Review of Respiratory Medicine | Year: 2013

With the publication of the new guidelines (The Global Initiative for Chronic Obstructive Lung Disease 2011 and Guía Española de la COPD) on chronic obstructive pulmonary disease (COPD), the pharmacological treatment of this disease has changed substantially. In this article, the evidence supporting the use of pharmacological groups in COPD is summarized and the place of each of these drugs among the new therapeutic strategies is established. Although short-acting bronchodilators have been used as maintenance therapy for COPD for many years, few clinical trials are available on the efficacy and safety of these agents, whose role was defined at the very early stages of treatment. The introduction of long-acting bronchodilators, administered every 12 or 24h, led to an increase in therapeutic effects and an improvement in both treatment adherence and dosage; therefore, both guidelines consider these drugs as the standard therapy for all types of patients and clinical phenotypes. The combination of long-acting bronchodilators from different families has been established as a new therapeutic approach for patients with persistent symptoms despite an appropriate bronchodilator treatment. Anti-inflammatory therapy with inhaled corticosteroids has been discussed at length, and is considered in the current guidelines as the treatment of choice in patients with a high risk of exacerbations associated with an impaired lung function or previous exacerbations, or presenting with phenotypes that are susceptible to the effect of corticosteroids. Roflumilast is a novel drug with a clearly defined indication. Finally, further evidence about other therapies, such as antibiotics or mucolytics, is emerging that will help define their appropriate use in selected patients. At present, pharmacological management of COPD is being re-evaluated. As long as we are able to apply the new treatment approaches to the clinical reality of our patients we will achieve greater benefits in both the short and the long term with a reduction in potential complications. © 2013 Expert Reviews Ltd.


Corella D.,University of Valencia | Corella D.,CIBER ISCIII | Ordovas J.M.,IMDEA Madrid Institute for Advanced Studies | Ordovas J.M.,Tufts University
BioEssays | Year: 2014

Epidemiological evidence supports a health-promoting effect of the Mediterranean Diet (MedDiet), especially in the prevention of cardiovascular diseases. These cardiovascular benefits have been attributed to a number of components of the MedDiet such as monounsaturated fatty acids, antioxidant vitamins and phytochemicals. However, the underlying mechanisms remain unknown. Likewise, little is known about the genes that define inter-individual variation in response to the MedDiet, although the TCF7L2 gene is emerging as an illustrative candidate for determining relative risk of cardiovascular events in response to the MedDiet. Moreover, omics technologies are providing evidence supporting potential mechanisms, some of them implicating epigenetics (i.e. microRNAs, methylation), and certain data suggest that some traditional foods could contribute via microRNAs possibly acting as exogenous regulators of gene expression. Future research should aim at increasing and consolidating the nutrigenetic and nutrigenomic knowledge of the MedDiet in order to provide sound, personalized and optimized nutritional recommendations. © 2014 WILEY Periodicals, Inc.


De Carvalho Vidigal F.,Federal University of Viçosa | Bressan J.,Federal University of Viçosa | Babio N.,Rovira i Virgili University | Babio N.,CIBER ISCIII | And 2 more authors.
BMC Public Health | Year: 2013

Background: The metabolic syndrome (MS) is a complex of risk factors for cardiovascular disease. This syndrome increases the risk of diabetes, cardiovascular disease and all-cause mortality. It has been demonstrated that the prevalence of MS is increasing worldwide. Despite the importance of MS in the context of metabolic and cardiovascular disease, few studies have described the prevalence of MS and its determinants in Latin America. The present study aims to assess studies describing the prevalence of MS in Brazil in order to determine the global prevalence of the syndrome and its components. Methods. Systematic review. Searches were carried out in PubMed and Scielo from the earliest available online indexing year through May 2013. There were no restrictions on language. The search terms used to describe MS were taken from the PubMed (MeSH) dictionary: "metabolic syndrome x", "prevalence" and "Brazil". Studies were included if they were cross-sectional, described the prevalence of MS and were conducted in apparently healthy subjects, from the general population, 19-64 years old (adult and middle aged) of both genders. The titles and abstracts of all the articles identified were screened for eligibility. Results: Ten cross-sectional studies were selected. The weighted mean for general prevalence of MS in Brazil was 29.6% (range: 14.9%-65.3%). Half of the studies used the criteria for clinical diagnosis of MS proposed by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (2001). The highest prevalence of MS (65.3%) was found in a study conducted in an indigenous population, whereas the lowest prevalence of MS (14.9%) was reported in a rural area. The most frequent MS components were low HDL-cholesterol (59.3%) and hypertension (52.5%). Conclusions: Despite methodological differences among the studies selected, our findings suggested a high prevalence of MS in the Brazilian adult population. © 2013 de Carvalho Vidigal et al.; licensee BioMed Central Ltd.


Gonzalez-Dominguez R.,University of Huelva | Garcia-Barrera T.,University of Huelva | Vitorica J.,University of Seville | Vitorica J.,CIBER ISCIII | Gomez-Ariza J.L.,University of Huelva
Journal of Pharmaceutical and Biomedical Analysis | Year: 2015

The identification of pathological mechanisms underlying to Alzheimer's disease is of great importance for the discovery of potential markers for diagnosis and disease monitoring. In this study, we investigated regional metabolic alterations in brain from the APP/PS1 mice, a transgenic model that reproduces well some of the neuropathological and cognitive deficits observed in human Alzheimer's disease. For this purpose, hippocampus, cortex, cerebellum and olfactory bulbs were analyzed using a high-throughput metabolomic approach based on direct infusion mass spectrometry. Metabolic fingerprints showed significant differences between transgenic and wild-type mice in all brain tissues, being hippocampus and cortex the most affected regions. Alterations in numerous metabolites were detected including phospholipids, fatty acids, purine and pyrimidine metabolites, acylcarnitines, sterols and amino acids, among others. Furthermore, metabolic pathway analysis revealed important alterations in homeostasis of lipids, energy management, and metabolism of amino acids and nucleotides. Therefore, these findings demonstrate the potential of metabolomic screening and the use of transgenic models for understanding pathogenesis of Alzheimer's disease. © 2014 Elsevier B.V.All rights reserved.


Corella D.,University of Valencia | Corella D.,CIBER ISCIII | Ordovas J.M.,IMDEA Madrid Institute for Advanced Studies | Ordovas J.M.,Tufts University
Ageing Research Reviews | Year: 2015

In the study of longevity, increasing importance is being placed on the concept of healthy aging rather than considering the total number of years lived. Although the concept of healthy lifespan needs to be defined better, we know that cardiovascular diseases (CVDs) are the main age-related diseases. Thus, controlling risk factors will contribute to reducing their incidence, leading to healthy lifespan. CVDs are complex diseases influenced by numerous genetic and environmental factors. Numerous gene variants that are associated with a greater or lesser risk of the different types of CVD and of intermediate phenotypes (i.e., hypercholesterolemia, hypertension, diabetes) have been successfully identified. However, despite the close link between aging and CVD, studies analyzing the genes related to human longevity have not obtained consistent results and there has been little coincidence in the genes identified in both fields. The APOE gene stands out as an exception, given that it has been identified as being relevant in CVD and longevity. This review analyzes the genomic and epigenomic factors that may contribute to this, ranging from identifying longevity genes in model organisms to the importance of gene-diet interactions (outstanding among which is the case of the TCF7L2 gene). © 2014 Elsevier B.V.


Garcia-Ruiz P.J.,Fundacion Jimenez Diaz | Chaudhuri K.R.,King's College London | Martinez-Martin P.,Carlos III Institute of Health | Martinez-Martin P.,CIBER ISCIII
Journal of the Neurological Sciences | Year: 2014

Although Parkinson's disease (PD) has been classically defined as a motor disorder, a range of non-motor symptoms (NMS) including cognitive, mood, autonomic and sleep disturbances occur with the passage of time. Although it seems that the non-motor aspect of PD is a recent observation, classic authors (James Parkinson, Charcot, Gowers, Oppenheim and Wilson) had described many NMS including pain, fatigue, bladder dysfunction, cognitive decline and delusion. In this review we have collated the classic literature of NMS in PD. © 2014 Elsevier B.V.


Tena-Sempere M.,University of Cordoba, Spain | Tena-Sempere M.,CIBER ISCIII | Tena-Sempere M.,Hospital Universitario Reina Sofia
European Journal of Endocrinology | Year: 2012

Puberty is a fascinating developmental phase that involves the attainment of reproductive capacity and the completion of sexual and somatic maturation. As a life-changing event, puberty onset is precisely controlled by interconnected regulatory pathways that are sensitive to numerous endogenous signals and environmental cues. The mechanisms of normal puberty and its potential deviations have been thoroughly studied in humans and model species. Yet, characterization of the neurobiological basis of puberty is still incomplete. Progress on this front is not only relevant from a physiological perspective but would also help to unravel the underlying causes for the observed changes in the timing of puberty in humans, with a trend for earlier puberty onset, especially in girls. In this review, we will provide a synoptic overview of some recent developments in the field that have deepened our understanding of the neuroendocrine and molecular basis for the control of puberty onset. These include not only the demonstration of the involvement of the hypothalamic Kiss1 system in the control of puberty and its modulation by metabolic cues but also the identification of the roles of other neuropeptide pathways and molecular mediators in the regulation of puberty. In addition, the potential contribution of novel regulatory mechanisms, such as epigenetics, in the central control of puberty will be briefly discussed. Characterization of these novel players and regulatory mechanisms will improve our understanding of the basis of normal puberty and its eventual alterations in various pathological conditions. © 2012 European Society of Endocrinology.


Ferrandiz M.-J.,CIBER ISCIII | Schvartzman J.B.,CSIC - Biological Research Center | de la Campa A.G.,CIBER ISCIII
Nucleic Acids Research | Year: 2010

The transcriptional response of Streptococcus pneumoniae was examined after exposure to the GyrB-inhibitor novobiocin. Topoisomer distributions of an internal plasmid confirmed DNA relaxation and recovery of the native level of supercoiling at low novobiocin concentrations. This was due to the up-regulation of DNA gyrase and the downregulation of topoisomerases I and IV. In addition, >13% of the genome exhibited relaxation-dependent transcription. The majority of the responsive genes (>68%) fell into 15 physical clusters (14.6-85.6 kb) that underwent coordinated regulation, independently of operon organization. These genomic clusters correlated with AT content and codon composition, showing the chromosome to be organized into topology-reacting gene clusters that respond to DNA supercoiling. In particular, down-regulated clusters were flanked by 11-40 kb AT-rich zones that might have a putative structural function. This is the first case where genes responding to changes in the level of supercoiling in a coordinated manner were found organized as functional clusters. Such an organization revealed DNA supercoiling as a general feature that controls gene expression superimposed on other kinds of more specific regulatory mechanisms. © The Author(s) 2010. Published by Oxford University Press.


Gomez-Sintes R.,CIBER ISCIII | Lucas J.J.,CIBER ISCIII
Journal of Clinical Investigation | Year: 2010

Use of lithium, the mainstay for treatment of bipolar disorder, is limited by its frequent neurological side effects and its risk for overdose-induced toxicity. Recently, lithium has also been proposed as a treatment for Alzheimer disease and other neurodegenerative conditions, but clinical trials have been hampered by its prominent side effects in the elderly. The mechanisms underlying both the positive and negative effects of lithium are not fully known. Lithium inhibits glycogen synthase kinase-3 (GSK-3) in vivo, and we recently reported neuronal apoptosis and motor deficits in dominant-negative GSK-3-transgenic mice. We hypothesized that therapeutic levels of lithium could also induce neuronal loss through GSK-3 inhibition. Here we report induction of neuronal apoptosis in various brain regions and the presence of motor deficits in mice treated chronically with lithium. We found that GSK-3 inhibition increased translocation of nuclear factor of activated T cells c3/4 (NFATc3/4) transcription factors to the nucleus, leading to increased Fas ligand (FasL) levels and Fas activation. Lithium-induced apoptosis and motor deficits were absent when NFAT nuclear translocation was prevented by cyclosporin A administration and in Fas-deficient lpr mice. The results of these studies suggest a mechanism for lithium-induced neuronal and motor toxicity. These findings may enable the development of combined therapies that diminish the toxicities of lithium and possibly other GSK-3 inhibitors and extend their potential to the treatment of Alzheimer disease and other neurodegenerative conditions.


Peinado J.R.,University of Sfax | Pardo M.,Complejo Hospitalario Universitario Of Santiago Chus | Pardo M.,CIBER ISCIII | De la Rosa O.,Cellerix TM | And 2 more authors.
Proteomics | Year: 2012

The original concept of adipose tissue as an inert storage depot for the excess of energy has evolved over the last years and it is now considered as one of the most important organs regulating body homeostasis. This conceptual change has been supported by the demonstration that adipose tissue serves as a major endocrine organ, producing a wide variety of bioactive molecules, collectively termed adipokines, with endocrine, paracrine and autocrine activities. Adipose tissue is indeed a complex organ wherein mature adipocytes coexist with the various cell types comprising the stromal-vascular fraction (SVF), including preadipocytes, adipose-derived stem cells, perivascular cells, and blood cells. It is known that not only mature adipocytes but also the components of SVF produce adipokines. Furthermore, adipokine production, proliferative and metabolic activities and response to regulatory signals (i.e. insulin, catecholamines) differ between the different fat depots, which have been proposed to underlie their distinct association to specific diseases. Herein, we discuss the recent proteomic studies on adipose tissue focused on the analysis of the separate cellular components and their secretory products, with the aim of identifying the basic features and the contribution of each component to different adipose tissue-associated pathologies. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Leentjens A.F.,Maastricht University | Dujardin K.,Lille University Hospital Center | Marsh L.,Johns Hopkins University | Marsh L.,Baylor College of Medicine | And 3 more authors.
Movement Disorders | Year: 2011

Background: Anxiety is a prevalent and disabling condition in Parkinson's disease (PD). The lack of anxiety rating scales validated for this population hampers research into anxiety in PD. The aim of this study is to assess the clinimetric properties of the Hamilton anxiety rating scale (HARS), the Beck anxiety inventory (BAI), and the hospital anxiety and depression scale (HADS) in PD patients. Design: Three hundred forty-two PD patients underwent a standardized assessment including a structured interview for diagnostic and statistical manual diagnoses of anxiety disorders and completion of the HARS, BAI, and HADS. Inter-rater reliability of the HARS was assessed in 60 patients; test-retest reliability of the BAI and HADS in 213 and 217 patients, respectively. Results: Thirty-four percent of patients suffered from an anxiety disorder, whereas an additional 11.4% had clinically significant anxiety symptoms in the absence of a diagnosis of anxiety disorder. Acceptability, score distribution, and known groups validity over different levels of anxiety were adequate. Inter-rater reliability for the HARS and test-retest reliability for the BAI and HADS were good. The HARS, but not the BAI and HADS, had a satisfactory inter-item correlation, convergent validity and factorial structure. For all scales, the positive predictive value was poor, and the negative predictive value was moderate. Conclusions: Given the adequate known groups validity of all three rating scales, each of these scales is likely to be useful in clinical practice or research for evaluation of symptom severity. Limitations in the construct validity of the anxiety scales in this study raise questions regarding suitability for their use in PD. © 2011 Movement Disorder Society.


Badimon L.,Hospital Of La Santa Creu I Sant Pau | Badimon L.,CIBER ISCIII | Vilahur G.,Hospital Of La Santa Creu I Sant Pau | Vilahur G.,CIBER ISCIII | Padro T.,Hospital Of La Santa Creu I Sant Pau
Cardiovascular Therapeutics | Year: 2010

The high prevalence of obesity, atherosclerosis, and cardiovascular disease (CVD) is largely attributable to the contemporary lifestyle that is often sedentary and includes a diet high in saturated fats and sugars and low ingestion polyunsaturated fatty acids (PUFAs), fruit, vegetables, and fiber. Epidemiological studies have confirmed a strong association between fat intake, especially saturated- and transfatty acids, plasma cholesterol levels, and rate of coronary heart disease (CHD) mortality. In counterpart, beneficial cardiovascular effects have been reported in populations consuming the "healthy" Mediterranean-type diet. Indeed, many nutrients and phytochemicals in fruits, vegetables, and wine, including fiber, vitamins, minerals, antioxidants, have shown to be independently or jointly responsible for the apparent reduction in CVD risk. Therefore, in patients with overt CVD, efforts have focused on combining both drug treatments and nutrition interventions. Undoubtedly, the advances in the knowledge of both the disease processes and healthy dietary components have provided new avenues to develop pharmaceutical and/or dietary strategies to halt the development of vascular disease. In this regard, within the last years, pioneering nutritional strategies, such as nutraceuticals, have been developed aimed at reducing the main atherosclerotic risk factors and promoting cardiovascular health. Furthermore, a growing body of clinical evidence has demonstrated positive cardiovascular effects associated with dietary fibers, cholesterol-lowering natural agents, olive oil, ω-3 PUFAs, antioxidants, and polyphenols intake. Moreover, monounsaturated fatty acids intake has shown to modulate the expression of key atherosclerotic-related genes. Yet, in the case of antioxidants, some large clinical trials have failed to confirm such atheroprotective effects. Furthermore, there might be interactions between these natural food supplements and cardiovascular medications that cannot be overlooked. Hence, there is a need for a better understanding and more scientific evidence of the relative contribution of major nutraceutical constituents to the inhibition of the progression of atherosclerosis and its clinical consequences. © 2010 Blackwell Publishing Ltd.


Gatta G.,Fondazione IRCSS Instituto Nazionale dei Tumori | Botta L.,Fondazione IRCSS Instituto Nazionale dei Tumori | Rossi S.,Instituto Superiore Of Sanita | Aareleid T.,National Institute for Health Development | And 19 more authors.
The Lancet Oncology | Year: 2014

Background: Survival and cure rates for childhood cancers in Europe have greatly improved over the past 40 years and are mostly good, although not in all European countries. The EUROCARE-5 survival study estimates survival of children diagnosed with cancer between 2000 and 2007, assesses whether survival differences among European countries have changed, and investigates changes from 1999 to 2007. Methods: We analysed survival data for 157499 children (age 0-14 years) diagnosed between Jan 1, 1978 and Dec 31, 2007. They came from 74 population-based cancer registries in 29 countries. We calculated observed, country-weighted 1-year, 3-year, and 5-year survival for major cancers and all cancers combined. For comparison between countries, we used the corrected group prognosis method to provide survival probabilities adjusted for multiple confounders (sex, age, period of diagnosis, and, for all cancers combined without CNS cancers, casemix). Age-adjusted survival differences by area and calendar period were calculated with period analysis and were given for all cancers combined and the major cancers. Findings: We analysed 59579 cases. For all cancers combined for children diagnosed in 2000-07, 1-year survival was 90·6% (95% CI 90·2-90·9), 3-year survival was 81·0 % (95% CI 80·5-81·4), and 5-year survival was 77·9% (95% CI 77·4-78·3). For all cancers combined, 5-year survival rose from 76·1% (74·4-77·7) for 1999-2001, to 79·1% (77·3-80·7) for 2005-07 (hazard ratio 0·973, 95% CI 0·965-0·982, p<0·0001). The greatest improvements were in eastern Europe, where 5-year survival rose from 65·2% (95% CI 63·1-67·3) in 1999-2001, to 70·2% (67·9-72·3) in 2005-07. Europe-wide average yearly change in mortality (hazard ratio) was 0·939 (95% CI 0·919-0·960) for acute lymphoid leukaemia, 0·959 (0·933-0·986) for acute myeloid leukaemia, and 0·940 (0·897-0·984) for non-Hodgkin lymphoma. Mortality for all of Europe did not change significantly for Hodgkin's lymphoma, Burkitt's lymphoma, CNS tumours, neuroblastoma, Wilms' tumour, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Disparities for 5-year survival persisted between countries and regions, ranging from 70% to 82% (for 2005-07). Interpretation: Several reasons might explain persisting inequalities. The lack of health-care resources is probably most important, especially in some eastern European countries with limited drug supply, lack of specialised centres with multidisciplinary teams, delayed diagnosis and treatment, poor management of treatment, and drug toxicity. In the short term, cross-border care and collaborative programmes could help to narrow the survival gaps in Europe. Funding: Italian Ministry of Health, European Commission, Compagnia di San Paolo Foundation. © 2014 Elsevier Ltd.


Llorens-Martin M.,CIBER ISCIII | Jurado-Arjona J.,CIBER ISCIII | Avila J.,CIBER ISCIII | Hernandez F.,CIBER ISCIII
Experimental Neurology | Year: 2015

Newborn neurons are continuously added to the hippocampal dentate gyrus (DG) throughout life. Mature and immature granule neurons are believed to send their axonal projections exclusively to the hippocampal CA3 field. However, recent data point to an alternative trisynaptic circuit, involving a direct axonal projection from mature granule neurons to the CA2 field. Whether this circuit takes place only in mature granule neurons or, on the contrary, whether immature granule neurons also contribute to this novel connection is unknown. We used various retroviral vectors to show that immature granule neurons send axonal processes to and establish synaptic contacts with CA2 pyramidal neurons and that axonal growth follows a similar time course to that described for CA3 innervation. In addition, we provide experimental evidence demonstrating that the pathway connecting newborn granule neurons and the CA2 field can be modulated by physiological and deleterious stimuli. © 2014 Elsevier Inc.


Lopez-Campos J.L.,University of Seville | Lopez-Campos J.L.,CIBER ISCIII | Ruiz-Ramos M.,Consejeria de Salud y Bienestar Social de Andalucia. Seville | Soriano J.B.,Fundacion Caubet Cimera
The Lancet Respiratory Medicine | Year: 2014

Background: Findings from studies done over the past 20 years suggest that mortality from chronic obstructive pulmonary disease (COPD) is decreasing worldwide, but little information is available for trends in Europe. We aimed to describe COPD mortality trends by sex and calendar year for the period of 1994 to 2010. Methods: We extracted data for COPD deaths between 1994 and 2010 in the 27 countries in the European Union (EU) from the statistical office of the EU (Eurostat), using the International Classification of Diseases 10 (ICD-10) codes J40-J44 and J47. We estimated age-standardised mortality rates (ASR), and analysed data using joinpoint regression, for women and men in the EU overall and by individual country for each year. We used the standard European population as the reference and present our findings as deaths per 100000 person-years. We compared findings for each country with the EU average by calculating standardised rate ratios (SRR) and 95% CIs. Findings: Between 1994 and 2010, there were 2348184 recorded COPD deaths in the EU. COPD mortality was higher in men than in women throughout the study period in all EU countries. In the EU overall, deaths per 100000 population decreased in men almost linearly from 90·07 in 1994 to 61·33 in 2010, and in women from 26·99 in 1994 to 25·15 in 2010, representing a narrowing in gender gap over the study period. Several countries had a higher SRR mortality than the EU average-eg, Ireland, Hungary, and Belgium for men and Denmark, the UK, and the Netherlands for women. Our joinpoint regression analysis identified no statistically significant changes in the trend for the whole EU, but several countries had changing trends over the study period. In men, we recorded a 2·56% constant and statistically significant decrease in ASRs in the EU. Five countries had an increase in ASR. Overall, in women, we recorded a 0·76% statistically significant decrease in ASRs. 14 countries had an increase in ASR. Interpretation: Our findings indicate a downward trend in COPD mortality in Europe between 1994 and 2010. The data also suggest a narrowing of the gap between COPD mortality in men and in women. The wide heterogeneity in mortality rates within European countries could serve as a reference to allow informed policy making. Funding: None. © 2014 Elsevier Ltd.


Borrell-Pages M.,Hospital Of La Santa Creu I Sant Pau | Romero J.C.,Hospital Of La Santa Creu I Sant Pau | Badimon L.,Hospital Of La Santa Creu I Sant Pau | Badimon L.,CIBER ISCIII | Badimon L.,Autonomous University of Barcelona
Journal of Cellular and Molecular Medicine | Year: 2014

Molecular changes involved in cell differentiation are only partially known. Circulating inflammatory cells need to differentiate to perform specialized functions in target tissues. Here, we hypothesized that low-density lipoprotein receptor-related protein 5 (LRP5) is involved, through its participation in the canonical Wnt/β-catenin signalling, in the differentiation process of monocytic cells. To this aim, we characterized differentiation mechanisms of HL60 cells and primary human monocytes. We show that silencing the LRP5 gene increased differentiation of HL60 cells and human monocytes, suggesting that LRP5 signalling abrogates differentiation. We demonstrate that the mechanisms behind this blockade include sequestration of β-catenin at the cellular membrane, inhibition of the Wnt signalling and increase of apoptosis. We further demonstrate the involvement of LRP5 and the Wnt/β-catenin signalling in the process because cellular differentiation can be rescued by the addition of downstream Wnt target genes to the monocytic cells. © 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.


Okoli C.,KTH Royal Institute of Technology | Sanchez-Dominguez M.,CIMAV | Sanchez-Dominguez M.,CIBER ISCIII | Boutonnet M.,KTH Royal Institute of Technology | And 4 more authors.
Langmuir | Year: 2012

Magnetic iron oxide nanoparticles (MION) for protein binding and separation were obtained from water-in-oil (w/o) and oil-in-water (o/w) microemulsions. Characterization of the prepared nanoparticles have been performed by TEM, XRD, SQUID magnetometry, and BET. Microemulsion-prepared magnetic iron oxide nanoparticles (ME-MION) with sizes ranging from 2 to 10 nm were obtained. Study on the magnetic properties at 300 K shows a large increase of the magnetization ∼35 emu/g for w/o-ME-MION with superparamagnetic behavior and nanoscale dimensions in comparison with o/w-ME-MION (10 emu/g) due to larger particle size and anisotropic property. Moringa oleifera coagulation protein (MOCP) bound w/o- and o/w-ME-MION showed an enhanced performance in terms of coagulation activity. A significant interaction between the magnetic nanoparticles and the protein can be described by changes in fluorescence emission spectra. Adsorbed protein from MOCP is still retaining its functionality even after binding to the nanoparticles, thus implying the extension of this technique for various applications. © 2012 American Chemical Society.


Gane E.J.,Auckland City Hospital | Deray G.,Pitie Salpetriere Hospital | Liaw Y.-F.,Chang Gung University | Lim S.G.,National University of Singapore | And 12 more authors.
Gastroenterology | Year: 2014

Background & Aims There is a close relationship between chronic hepatitis B virus infection and chronic renal disease. We analyzed changes in renal function using different markers of glomerular filtration rate (GFR) in multiple studies of telbivudine treatment of patients with chronic hepatitis B virus infection. Methods We used serum creatinine-based equations (ie, Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration) to estimate GFR (eGFR) in adults with chronic hepatitis B virus infection and compensated liver disease who participated in a phase III, randomized, double-blind study comparing the efficacy and safety of telbivudine (600 mg/d) and lamivudine (100 mg/d) for 2 years (the GLOBE study) and in long-term extension studies (4-6 years), as well as in patients with decompensated cirrhosis (2 years). Results eGFRs calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations were concordant, indicating improved renal function in telbivudine-treated patients during the 2-year GLOBE study (there was an 8.5% increase in mean eGFR, based on the Modification of Diet in Renal Disease equation). Improved renal function was maintained for 4-6 years. Increased eGFR with telbivudine treatment was also observed in patients at increased risk for renal impairment: patients with baseline eGFRs of 60-89 mL/min/1.73 m2 (+17.2%), older than 50 years (+11.4%), and with liver fibrosis/cirrhosis (+7.2% for patients with Ishak fibrosis score at 5-6). In decompensated patients with high renal risk, eGFR was also improved on telbivudine (+2.0%). Conclusions In global trials of patients with compensated and decompensated cirrhosis, long-term telbivudine therapy was associated with a sustained improvement of renal function - particularly among patients with increased risk of renal impairment. The mechanisms of this renal protective effect remain to be determined. © 2014 by the AGA Institute.


Ojosnegros S.,California Institute of Technology | Perales C.,CIBER ISCIII | Mas A.,University of Castilla - La Mancha | Domingo E.,CIBER ISCIII
Virus Research | Year: 2011

We review the origins of the quasispecies concept and its relevance for RNA virus evolution, viral pathogenesis and antiviral treatment strategies. We emphasize a critical point of quasispecies that refers to genome collectivities as the unit of selection, and establish parallels between RNA viruses and some cellular systems such as bacteria and tumor cells. We refer also to tantalizing new observations that suggest quasispecies behavior in prions, perhaps as a result of the same quantum-mechanical indeterminations that underlie protein conformation and error-prone replication in genetic systems. If substantiated, these observations with prions could lead to new research on the structure-function relationship of non-nucleic acid biological molecules. © 2011 Elsevier B.V.


Linda B.,Imperial College London | Hodgson S.,Northumbria University | Abellan J.J.,CIBER ISCIII | Jarup L.,Imperial College London
Environmental Health Perspectives | Year: 2010

Background: The initiation of environmental public health tracking systems in the United States and the United Kingdom provided an opportunity to advance techniques and tools available for spatial epidemiological analysis integrating both health and environmental data. Objective: The Rapid Inquiry Facility (RIF) allows users to calculate adjusted and unadjusted standardized rates and risks. The RIF is embedded in ArcGIS so that further geographical information system (GIS) spatial functionality can be exploited or results can be exported to statistical packages for further tailored analyses where required. The RIF also links directly to several statistical packages and displays the results in the GIS. Methods: The value of the RIF is illustrated here with two case studies: risk of leukemia in areas surrounding oil refineries in the State of Utah (USA) and an analysis of the geographical variation of risk of esophageal cancer in relation to zinc cadmium sulfide exposure in Norwich (United Kingdom). Results: The risk analysis study in Utah did not suggest any evidence of increased relative risk of leukemia, multiple myeloma, or Hodgkin's lymphoma in the populations around the five oil-refining facilities but did reveal an excess risk of non-Hodgkin's lymphoma that might warrant further investigation. The disease-mapping study in Norwich did not reveal any areas with higher relative risks of esophageal cancer common to both males and females, suggesting that a common geographically determined exposure was unlikely to be influencing cancer risk in the area. Conclusion: The RIF offers a tool that allows epidemiologists to quickly carry out ecological environmental epidemiological analysis such as risk assessment or disease mapping.


Kroep S.,Erasmus Medical Center | Lansdorp-Vogelaar I.,Erasmus Medical Center | Rubenstein J.H.,University of Michigan | Lemmens V.E.P.P.,Erasmus Medical Center | And 5 more authors.
American Journal of Gastroenterology | Year: 2014

OBJECTIVES: The incidence of esophageal adenocarcinoma (EAC) in the western world has been rapidly increasing. The trends in obesity and other lifestyle-associated factors have been hypothesized to be important drivers of this increase. We tested this hypothesis by comparing changes in these factors with changes in EAC incidence over time between three western countries. METHODS: Data on EAC incidence trends were abstracted from the SEER-9 registry (1975-2009) for the United States, from multiple cancer registries (1980-2004) in Spain, and from Eindhoven Cancer Registry in the Netherlands (1974-2010). In addition, we collected trend data on obesity, smoking, and alcohol consumption. The trend data were analyzed using log-linear regression. RESULTS: In 1980, the EAC incidence was similar among the three countries ((0.46-0.63) per 100,000). EAC incidence increased in all, with the largest increase observed in the Netherlands, followed by the United States and Spain (estimated annual percentage of change=9.7%, 7.4%, 4.3%, respectively). However, this pattern was not observed in lifestyle factors associated with EAC. With regards to obesity, the United States clearly has had the highest prevalence rates both in the past and in the present. For alcohol, the highest consumption rates are seen in Spain. Smoking showed a reverse trend compared with EAC among all three countries in the last 20 years. CONCLUSIONS: International trends in EAC incidence do not match corresponding trends in lifestyle-associated factors including obesity. Our findings suggest that factors other than obesity must be the important drivers for the increase in EAC incidence. © 2014 by the American College of Gastroenterology.


Diaz-Flores L.,University of La Laguna | Gutierrez R.,University of La Laguna | Garcia M.P.,Hospiten Hospitals | Saez F.J.,University of the Basque Country | And 4 more authors.
Histology and Histopathology | Year: 2014

We review the morphofunctional characteristics of CD34+ stromal fibroblastic/fibrocytic cells (CD34+ SFCs) and report our observations. We consider the following aspects of CD34+ SFCs: A) The confusing terms applied to this cell type, often combining the prefix CD34 with numerous names, including fibroblasts, fibrocytes, dendrocytes, keratocytes, telocytes and stromal, dendritic, adventitial, supraadventitial, perivascular, paravascular and delimiting cells; B) Changes in their immunophenotype, e.g., loss of CD34 expression and gain of other markers, such as those defining mesenchymal and derivate cells (myofibroblasts, osteoblasts, chondroblasts, adipocytes); C) Morphology (elongated or triangular cell body and thin, moniliform, bipolar or multipolar cytoplasmic processes), immunohistochemistry (co-expression of and changes in molecular expression) and structure (characteristics of nucleus and cytoplasmic organelles, and points of contact and junctions in quiescent and activated stages by light and electron microscopy); D) Location and distribution in the vessels (adventitia or external layer), in the tissues (connective, adipose, blood, muscle and nervous) and in the organs and systems (skin, oral cavity and oropharynx, respiratory, digestive, urinary, male, female, endocrine and lymphoid systems, serosal and synovial membranes, heart, eye and meninges); E) Origin from the mesoderm and cranial neural crest in the embryo, and from stem cells (themselves or other cells) and/or peripheral blood pluripotent stem cells (circulating progenitor cells) in post-natal life; F) Functions, such as synthesis of different molecules, progenitor of mesenchymal cells, immunomodulation, parenchymal regulation (growth, maturation and differentiation of adjacent cells), induction of angiogenesis, scaffolding support of other cells and phagocytic properties. Since CD34+ SFCs are the main reservoir of tissue mesenchymal cells (great mesenchymal potential, probably higher than that proposed for pericytes and other stromal cells), we dedicate a broad section to explain their in vivo behaviour during proliferation and differentiation in different physiologic and pathologic conditions, in addition to their characteristics in the human tissues of origin (adult stem cell niches); G) Involvement in pathological processes, e.g., repair (regeneration and repair through granulation tissue), fibrosis, tumour stroma formation and possible CD34+ SFC-derived tumours (e.g., solitary fibrous tumour, dermatofibrosarcoma protuberans, giant cell fibroblastoma, nuchal-type fibroma, mammary and extramammary myofibroblastoma, spindle and pleomorphic cell lipoma, and elastofibroma) and H) Clinical and therapeutic implications.


Fernandez A.M.,CIBER ISCIII | Jimenez S.,University of Seville | Mecha M.,Cajal Institute | Davila D.,CIBER ISCIII | And 3 more authors.
Molecular Psychiatry | Year: 2012

Whether insulin-like growth factor I (IGF-I) signaling in Alzheimer's disease (AD) is beneficial or detrimental remains controversial. We now show that a competitive regulation by IGF-I of the phosphatase calcineurin in reactive, but not in quiescent astrocytes drives Alzheimer's pathology. Calcineurin de-phosphorylates the transcription factor Foxo3 in response to tumor necrosis factor-α (TNFα), an inflammatory cytokine increased in AD, activating nuclear factor-κB (NFκB) inflammatory signaling in astrocytes. In turn, IGF-I inactivates and displaces Foxo3 from calcineurin in TNFα-stimulated astrocytes by recruiting the transcription factor peroxisome proliferator-activated receptor-γ, and NFB signaling is inhibited. This antagonistic mechanism reversibly drives the course of the disease in AD mice, even at advanced stages. As hallmarks of this calcineurin/Foxo3/NFκB pathway are present in human AD brains, treatment with IGF-I may be beneficial by antagonizing it. © 2012 Macmillan Publishers Limited All rights reserved.


Recent studies suggested that the post-natal mesothelium retain differentiative potential of the embryonic mesothelium, which generates fibroblasts and vascular smooth muscle cells (VSMCs), in developing coelomic organs via epithelial-to-mesenchymal transition (EMT). Whether adult mesothelial cells (MCs) are able to give rise to functional VSMCs in vitro and which are the factors and mechanisms directing this process remain largely unknown. Here, we isolated adipose tissue MCs (ATMCs) from adult mice, and demonstrated that ATMCs cultured in a serum-containing media supplemented with epidermal growth factor (EGF) efficiently increased both their proliferation and EMT above levels found in only serum-containing media cultures. EGF-induced ATMCs gained phosphorylation of the EGF receptor and activated simultaneously ILK/Erk1/2, PI3K/Akt and Smad2/3-dependent pathways. Sequential subculture onto collagen-I surface efficiently improved their vasculogenic EMT towards cells featuring VSMCs (α-SMA, calponin, caldesmon, SM22α, desmin, SM-MHC, smoothelin-B and PDGFR-β) that could actively contract in response to receptor and non-receptor-mediated vasoactive agonists. Overall, our results indentify EGF signalling as a robust vasculogenic inductive pathway for ATMCs, leading to their transdifferentiation into functional VSMC-like cells.


Van Den Berg M.E.L.,Carlos III Institute of Health | Castellote J.M.,Carlos III Institute of Health | Castellote J.M.,Complutense University of Madrid | De Pedro-Cuesta J.,Carlos III Institute of Health | And 2 more authors.
Journal of Neurotrauma | Year: 2010

Spinal cord injury (SCI) leading to neurological deficits produces long-term effects that persist over a lifetime. Survival analysis of patients with SCI, at individual and population level, is important for public health management and the assessment of treatment achievements. The current study evaluated survival following traumatic and non-traumatic SCI worldwide. A systematic review was conducted, and all included papers were assessed for quality using a purposely designed assessment form. Survival data were presented in Kaplan-Meier curves and compared using the log-rank test. Sixteen studies were included of which 11 concerned traumatic SCI, four non-traumatic SCI, and one both. Crude standard mortality rates (SMRs) revealed that overall mortality in SCI is up to three times higher than in the general population. Survival rates were statistically significantly lower in non-traumatic SCI than in traumatic SCI (log-rank p=0.000). Age at injury, neurological level, extent of lesion, and year of injury have been described as predictors of survival. Causes of death stem from secondary complications, with failure of the respiratory system being the leading cause. This is the first systematic literature review on survival analysis following SCI worldwide. An increase in survival over time was found. However, the SMRs of individuals with SCI still exceed those of an age-matched non-disabled population, mainly due to secondary complications. Lower survival rates were observed in non-traumatic SCI compared with traumatic SCI. Copyright 2010, Mary Ann Liebert, Inc.


Arnal C.,CIBER ISCIII | Osada J.,University of Zaragoza | Osada J.,CIBER ISCIII
Current Opinion in Lipidology | Year: 2011

Purpose of Review: To summarize currently available information about the mechanisms involved in liver fat accumulation. Recent Findings: The contribution of functional genomics approaches, such as those represented by high-throughput analysis and genetically modified mice, may envision a complex network involving fatty acid, triglyceride and phospholipid metabolisms and lipid droplet dynamics. Likewise, it may pose an exquisite regulation exerted through insulin, glucocorticoids, thyroid hormones, transcription factors and microRNAs, orchestrated with sexual differences and able to respond to environmental factors such as nutritional or viral influences among others. Summary: The information gathered will facilitate further research to complete gaps of interacting pieces among regulators and new contributing agents emerging from high-throughput analyses. With this new paradigm, new biomarkers able to discriminate the progression of hepatic steatosis into human steatohepatitis will eventually emerge, and hopefully new therapeutic approaches will be developed. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Vaquero J.,University of Salamanca | Briz O.,University of Salamanca | Briz O.,CIBER ISCIII | Herraez E.,University of Salamanca | And 4 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

The success of pharmacological treatments in primary liver cancers is limited by the marked efficacy of mechanisms of chemoresistance already present in hepatocytes. The role of the nuclear receptor FXR is unclear. Although, in non-treated liver tumors, its expression is reduced, the refractoriness to anticancer drugs is high. Moreover, the treatment with cisplatin up-regulates FXR. The aim of this study was to investigate whether FXR is involved in stimulating chemoprotection/chemoresistance in healthy and tumor liver cells. In human hepatocytes, the activation of FXR with the agonist GW4064 resulted in a significant protection against cisplatin-induced toxicity. In human hepatoma Alexander cells, with negligible endogenous expression of FXR, GW4064 also protected against cisplatin-induced toxicity, but only if they were previously transfected with FXR/RXR. Investigation of 109 genes potentially involved in chemoresistance revealed that only ABCB4, TCEA2, CCL14, CCL15 and KRT13 were up-regulated by FXR activation both in human hepatocytes and FXR/RXR-expressing hepatoma cells. In both models, cisplatin, even in the absence of FXR agonists, such as bile acids and GW4064, was able to up-regulate FXR targets genes, which was due to FXR-mediated trans-activation of response elements in the promoter region. FXR-dependent chemoprotection was also efficient against other DNA-damaging compounds, such as doxorubicin, mitomycin C and potassium dichromate, but not against non-genotoxic drugs, such as colchicine, paclitaxel, acetaminophen, artesunate and sorafenib. In conclusion, ligand-dependent and independent activation of FXR stimulates mechanisms able to enhance the chemoprotection of hepatocytes against genotoxic compounds and to reduce the response of liver tumor cells to certain pharmacological treatments. © 2013 Elsevier B.V.


Olivares M.,CSIC - Institute of Agricultural Chemistry and Food Technology | Neef A.,CSIC - Institute of Agricultural Chemistry and Food Technology | Castillejo G.,Hospital Universitario Sant Joan Of Reus | De Palma G.,CSIC - Institute of Agricultural Chemistry and Food Technology | And 10 more authors.
Gut | Year: 2015

Objective: Intestinal dysbiosis has been associated with coeliac disease (CD), but whether the alterations are cause or consequence of the disease is unknown. This study investigated whether the human leukocyte antigen (HLA)-DQ2 genotype is an independent factor influencing the early gut microbiota composition of healthy infants at family risk of CD. Design: As part of a larger prospective study, a subset (n=22) of exclusively breastfed and vaginally delivered infants with either high genetic risk (HLA-DQ2 carriers) or low genetic risk (non-HLA-DQ2/8 carriers) of developing CD were selected from a cohort of healthy infants with at least one first-degree relative with CD. Infant faecal microbiota was analysed by 16S rRNA gene pyrosequencing and real time quantitative PCR. Results: Infants with a high genetic risk had significantly higher proportions of Firmicutes and Proteobacteria and lower proportions of Actinobacteria compared with low-risk infants. At genus level, high-risk infants had significantly less Bifidobacterium and unclassified Bifidobacteriaceae proportions and more Corynebacterium, Gemella, Clostridium sensu stricto, unclassified Clostridiaceae, unclassified Enterobacteriaceae and Raoultella proportions. Quantitative real time PCR also revealed lower numbers of Bifidobacterium species in infants with high genetic risk than in those with low genetic risk. In high-risk infants negative correlations were identified between Bifidobacterium species and several genera of Proteobacteria (Escherichia/Shigella) and Firmicutes (Clostridium). Conclusions: The genotype of infants at family risk of developing CD, carrying the HLA-DQ2 haplotypes, influences the early gut microbiota composition. This finding suggests that a specific disease-biased host genotype may also select for the first gut colonisers and could contribute to determining disease risk.


Sanz-Herrera J.A.,University of Seville | Sanz-Herrera J.A.,CIBER ISCIII | Boccaccini A.R.,Imperial College London | Boccaccini A.R.,Friedrich - Alexander - University, Erlangen - Nuremberg
International Journal of Solids and Structures | Year: 2011

Bioactive glasses are a class of inorganic biomaterials widely used in bone tissue engineering and regenerative medicine. Once implanted in the human body, these biomaterials react with the body fluid resulting in the formation of a surface hydroxyapatite (HA) layer, which exhibits the ability to form a stable chemical bond with the adjacent living bone tissue. The experimental evaluation of the degradation of bioactive glasses in contact with body fluid requires long-term in vitro assays. In this work, a novel mathematical model is proposed to numerically analyze the dissolution and bioactivity of bioactive glasses in relevant conditions for their in vitro and in vivo applications. A detailed framework is described for the numerical implementation using the Voxel-FEM method, in order to account for the microstructural evolution as consequence of degradation and HA layer formation. Two examples of application are highlighted, showing the suitability and usefulness of the proposed model for the evaluation of bioactive glasses in tissue engineering applications. © 2010 Elsevier Ltd. All rights reserved.


Kurtis M.M.,Hospital Ruber International | Rodriguez-Blazquez C.,CIBER ISCIII | Martinez-Martin P.,CIBER ISCIII | Martinez-Martin P.,Carlos III Institute of Health
Parkinsonism and Related Disorders | Year: 2013

Background: The association between sleep disorders and other non-motor symptoms (NMS) in Parkinson's disease (PD) has been scarcely investigated. Objective: To describe the prevalence of insomnia and hypersomnia in PD and analyze their relationship with other NMS. Methods: Cross-sectional, multicenter study including 388 PD patients evaluated with Hoehn and Yahr, Clinical Impression of Severity Index for PD, Scales for Outcomes in Parkinson's Disease (SCOPA)-Sleep(S), SCOPA-Cognition, SCOPA-Psychiatric Complications, SCOPA-Autonomic, Hospital Anxiety and Depression Scale, and fatigue and pain visual analogue scales. Spearman correlation coefficients, Mann-Whitney test and multiple linear regression analysis were applied. Results: Mean age (54% male) was 65.9±11.2 years old, with disease duration of 8.1±6.0 years and median HY=2 (range: 1-5). Mean SCOPA-S nocturnal sleep (NS) was 5.4±4.0 (range: 0-15), daytime sleepiness (DS) was 3.76±3.04 (range: 0-15). Most of the sample declared nocturnal or daytime sleep problems (87.4%). Weak-to-moderate correlations were found between sleep disturbances and other NMS (range: 0.14-0.37). SCOPA-S subscales showed higher scores with the presence of most other NMS such as psychiatric complications and autonomic dysfunctions (p<0.05). Regression models showed that fatigue, depression, urinary, cardiovascular, and thermoregulatory dysfunctions were significant determinants of SCOPA-NS score (variance: 23%); cognitive impairment, urinary, cardiovascular, and pupillomotor disorders influenced SCOPA-DS score (variance: 14%). Conclusions: Insomnia and daytime sleepiness are extremely prevalent in PD. Depression, fatigue, cognitive impairment, cardiovascular, urinary and thermoregulatory dysfunctions may contribute to insomnia/hypersomnia. This is the first clinical study to relate cardiovascular and thermoregulatory dysfunctions with sleep in PD. © 2013 Elsevier Ltd.


Povoa P.,Sao Francisco Xavier Hospital | Nseir S.,Lille University Hospital Center | Salluh J.,Institute for Research and Education Postgraduate Program | Curcio D.,Hospital Municipal Of Chivilcoy | Martin-Loeches I.,CIBER ISCIII
Critical Care | Year: 2014

Introduction: Several aspects of ventilator-associated tracheobronchitis (VAT)-including diagnostic criteria, overlap with ventilator-associated pneumonia (VAP), and appropriate treatment regimens-remain poorly defined. The objectives of this study were to survey reported practices in the clinical and microbiological diagnosis of VAT and to evaluate perceptions of the impact of VAT on patient outcomes. Methods: We developed a questionnaire consisting of (a) characteristics of the respondent, the ICU, and hospital; (b) current clinical and microbiological diagnostic approach; (c) empirical antibiotic therapy; and (d) the perception of physicians regarding the clinical impact of VAT and its implications. Results: A total of 288 ICUs from 16 different countries answered the survey: 147 (51%) from the Latin American (LA) group and 141 (49%) from Spain, Portugal, and France (SPF group). The majority of respondents (n = 228; 79.2%) reported making the diagnosis of VAT based on clinical and microbiological criteria, and 40 (13.9%) by clinical criteria alone. Approximately half (50.3%) of the respondents agreed that patients should receive antibiotics for the treatment of VAT. Out of all respondents, 269 (93.4%) assume that a VAT episode increases ICU length of stay, and this perception is greater in the LA group (97.3%) than in the SPF group (89.4%, P <0.05). Half of the physicians considered that VAT increases the risk of mortality, and this perception is again greater in the LA group (58.5% versus 41.1%, P <0.05). Conclusions: Given the possible high incidence of VAT and the perception of its importance as a risk factor for VAP and mortality, a large multicenter international prospective study would be helpful to validate a consensual definition of VAT, determine its incidence, and delineate its impact on subsequent VAP occurrence. © 2014 Rodríguez et al.; licensee BioMed Central Ltd.


Macias D.,University of Seville | Macias D.,CIBER ISCIII | Fernandez-Aguera M.C.,University of Seville | Fernandez-Aguera M.C.,CIBER ISCIII | And 4 more authors.
EMBO Molecular Medicine | Year: 2014

Mutations of the von Hippel-Lindau (VHL) gene are associated with pheochromocytomas and paragangliomas, but the role of VHL in sympathoadrenal homeostasis is unknown. We generated mice lacking Vhl in catecholaminergic cells. They exhibited atrophy of the carotid body (CB), adrenal medulla, and sympathetic ganglia. Vhl-null animals had an increased number of adult CB stem cells, although the survival of newly generated neuron-like glomus cells was severely compromised. The effects of Vhl deficiency were neither prevented by pharmacological inhibition of prolyl ydroxylases or selective genetic down-regulation of prolyl hydroxylase-3, nor phenocopied by hypoxia inducible factor overexpression. Vhldeficient animals appeared normal in normoxia but survived for only a few days in hypoxia, presenting with pronounced erythrocytosis, pulmonary edema, and right cardiac hypertrophy. Therefore, in the normal sympathoadrenal setting, Vhl deletion does not give rise to tumors but impairs development and plasticity of the peripheral O2-sensing system required for survival in hypoxic conditions. © 2014 The Authors.


Reed C.,Eli Lilly and Company | Goetz I.,Eli Lilly and Company | Vieta E.,University of Barcelona | Haro J.M.,CIBER ISCIII
European Psychiatry | Year: 2010

Objectives: To explore factors associated with work impairment at 2 years following an acute episode. Methods: European Mania in Bipolar disorder Longitudinal Evaluation of Medication (EMBLEM) is a prospective, observational study on the outcomes of patients with a manic/mixed episode. Work impairment was measured using a Longitudinal Interval Follow-up Evaluation (slice of LIFE) item and patients were categorised with either low or high work impairment at each observation. Baseline factors associated with work impairment at 2 years were assessed using multivariate modelling. Results: At baseline (n=2289), 69% of patients had high work impairment. At 2 years (n=1393), high impairment reduced to 41%. Modelling identified rapid cycling as the strongest disease-related factor associated with high work impairment at 2 years, although high work impairment at baseline had the strongest association overall. Lower levels of education, recent admissions, CGI-BP overall severity in the 12 months prior to baseline and CGI-BP mania at baseline all predicted higher work impairment. Living together in a relationship and independent housing were both significantly associated with having low work impairment at 2 years. Conclusions: Work impairment in bipolar disorder is maintained over long periods, and is strongly associated with relationship status, living conditions and various disease-related factors. © 2010 Elsevier Masson SAS.


Miravitlles M.,Hospital Universitari Vall dHebron | Miravitlles M.,CIBER ISCIII | Soriano J.B.,Fundacion Caubet CIMERA | Ancochea J.,CIBER ISCIII | And 6 more authors.
Respiratory Medicine | Year: 2013

Background Patients with COPD may share some clinical characteristics with asthma sufferers. This phenotypic overlap between COPD and asthma is not yet well characterised. Method We have analysed data from the EPI-SCAN study, an epidemiological, population-based study in Spain that included 3885 (40 to 80-year-old) subjects in order to investigate the clinical and systemic inflammatory characteristics of COPD patients previously diagnosed with asthma. Generic and COPD-specific quality of life, as well as physical activity, were also assessed through standardised and validated questionnaires. Results A total of 385 (10.1%) subjects were diagnosed with COPD, 67 (17.4%) being classified with the COPD-asthma overlap phenotype. Such patients were more likely to have dyspnea and wheezing (p < 0.001 in both comparisons) and more frequent exacerbations (p < 0.001). No differences in systemic inflammatory markers were observed except for lower NOx concentrations in overlap patients (p = 0.013). This overlap phenotype significantly worsened specific quality of life (11.1 units on the St. George's Respiratory Questionnaire (SGRQ), 95%CI: 4.88-17.36) and reduced physical activity (3.49 units on the London Chest Activities of Daily Living (LCADL) scale, 95%CI: 1.06-5.94). Conclusions In this population-based study, 17.4% of the individuals identified with COPD had an overlap COPD-asthma phenotype. This patient subgroup had more dyspnea, wheezing, exacerbations, worse respiratory-specific quality of life, and reduced levels of physical activity. Specific interventions may be required to adequately care for this subgroup of patients.© 2013 Elsevier Ltd. All rights reserved.


Vadasz I.,Justus Liebig University | Hubmayr R.D.,Thoracic Diseases Research Unit | Nin N.,CIBER ISCIII | Nin N.,Hospital Of Clinicas | And 3 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2012

Patients with severe acute and chronic lung diseases develop derangements in gas exchange thatmay result in increased levels of CO 2 (hypercapnia), the effects of which on human health are incompletely understood. It has been proposed that hypercapniamay have beneficial effects in patients with acute lung injury, and the concepts of "permissive" and even "therapeutic" hypercapnia have emerged. However, recent work suggests that CO 2 can act as a signaling molecule via pH- independentmechanisms, resulting in deleterious effects in the lung. Here we review recent research on how elevated CO 2 is sensed by cells in the lung and the potential harmful effects of hypercapnia on epithelial and endothelial barrier, lung edema clearance, innate immunity, and host defense. In viewof these findings,we raise concerns about the potentially deleterious effects hypercapnia may have in patients with acute and chronic lung diseases.


Corella D.,University of Valencia | Corella D.,CIBER ISCIII | Ordovas J.M.,Tufts University | Ordovas J.M.,IMDEA Madrid Institute for Advanced Studies
British Journal of Nutrition | Year: 2012

Nutritional genomics has undergone rapid development and the concept is now very popular with the general public. Therefore, there is increasing demand for knowledge on adapting dietary composition to the genome. Our aim has been to undertake a systematic review so as to find out the level of evidence existing on whether the effects of n-3 fatty acids on health can be modulated by genetic variation. A systematic literature search was conducted on studies that jointly analyse the effect of one or more genetic variants in candidate genes and n-3 fatty acids. Both observational and experimental studies were included. Results are classified in accordance with whether the study was undertaken on intermediate phenotypes (plasma lipid concentrations, glucose, inflammation markers, anthropometric measurements) or disease phenotypes (cancer, cardiovascular diseases, metabolic syndrome, etc) and whether it was experimental or observational. A wide diversity of genetic variants and little consistency in the publication of replication studies was found. Greater consistency was observed in studies that involved the FADS1 and FADS2 locus in the determination of n-3 fatty acid concentrations in biological samples. Most of the studies were designed to measure gene-diet interactions and not diet-gene interactions. Despite the fact that multiple studies have shown statistically significant interactions between n-3 fatty acids and certain genetic variants on intermediate and disease phenotypes, the individual level of evidence is very low and recommendations cannot be made on increasing or reducing the intake of n-3 fatty acids based on each individual's genotype. © 2012 The Authors.


Gonzalez-Dominguez R.,University of Huelva | Garcia-Barrera T.,University of Huelva | Vitorica J.,University of Seville | Vitorica J.,CIBER ISCIII | Gomez-Ariza J.L.,University of Huelva
Biochimie | Year: 2015

The transgenic mouse APP/PS1 is widely employed by neuroscientists because reproduces well some of the neuropathological and cognitive deficits observed in human Alzheimer's disease. In this study, serum samples from APP/PS1 mice (n = 30) and wild-type controls (n = 30) were analyzed using a metabolomic multiplatform based on the combination of gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry, in order to obtain wide information about serum metabolome. Metabolic profiles showed significant differences between the groups of study, and numerous metabolites were identified as potential players in the development of Alzheimer-type disorders in this transgenic model. Pathway analysis revealed the involvement of multiple metabolic networks in the underlying pathology, such as deficiencies in energy metabolism, altered amino acid homeostasis, abnormal membrane lipid metabolism, and other impairments related to the integrity of the central nervous system. It is noteworthy that some of these metabolomic markers are in accordance with pathological alterations observed in human Alzheimer's disease, while others have not been previously described. Therefore, these results demonstrate the potential of metabolomics and the use of transgenic animal models to understand the pathogenesis of Alzheimer's disease. © 2015 Elsevier B.V. and Société franc¸aise de biochimie et biologie Moléculaire (SFBBM). All rights reserved.


Brown R.S.,Columbia University | Verna E.C.,Columbia University | Pereira M.R.,Columbia University | Aguilar C.,Gilead Sciences Inc. | And 3 more authors.
Journal of Hepatology | Year: 2012

Background & Aims: Fetal safety of antiviral therapies is important given the long-term treatment of women with chronic hepatitis B (CHB) infection who may become pregnant. We analyzed neonatal safety data from the Antiretroviral Pregnancy Registry (APR), the largest safety database in pregnancy for antivirals used for HIV and CHB. Methods: Data were extracted from APR cases prospectively enrolled between 1989 and 2011. Primary outcomes were major birth defects rates with exposure to all antivirals, individual classes, and drugs compared to population-based controls. Relevant to CHB, only lamivudine (LAM) and tenofovir disoproxil fumarate (TDF) had sufficient individual data for review (≥200 cases). Results: Of 13,711 cases analyzed, the overall birth defect prevalence (2.8%, 95% CI 2.6-3.1%) was comparable to Centers for Disease Control population-based data (2.72%, 2.68-2.76%, p = 0.87) and two prospective antiretroviral exposed newborn cohorts (2.8%, 2.5-3.2%, p = 0.90 and 1.5%, 1.1-2.0%, p <0.001). The birth defects prevalence between first and second/third trimesters exposure was similar (3.0% vs. 2.7%). No increased risk of major birth defects with LAM or TDF exposure compared to population-based controls was observed. No specific pattern of major birth defects was observed for individual antivirals or overall. Conclusions: No increased risk of major birth defects including in non-live births was observed for pregnant women exposed to antivirals relevant to CHB treatment overall or to LAM or TDF compared to population-based controls. Continued safety and efficacy reporting on antivirals in pregnancy are essential to inform patients on their risks and benefits during pregnancy. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Solis O.,Instituto Cajal | Solis O.,CIBER ISCIII | Espadas I.,Instituto Cajal | Espadas I.,CIBER ISCIII | And 3 more authors.
Neurobiology of Disease | Year: 2015

Nitric oxide (NO), a gaseous messenger molecule synthesized by nitric oxide synthase (NOS), plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). To study the role of the nitrergic system in l-DOPA-induced dyskinesia (LID), we assessed the effect of the pharmacological manipulation of NO levels and NO/cyclic guanosine monophosphate (cGMP) signaling on LID in the Pitx3-/- aphakia mouse, a genetic model of PD. To evaluate the effect of decreased NO signaling on the development of LID, Pitx3-/- mice were chronically treated with l-DOPA and 7-nitroindazole (7-NI, a neuronal NOS inhibitor). To evaluate its effect on the expression of established LID, 7-NI was administered acutely to dyskinetic mice. The chronic 7-NI treatment attenuated the development of LID in the Pitx3-/- mice, and the sub-acute 7-NI treatment attenuated established dyskinesia without affecting the beneficial therapeutic effect of l-DOPA. Moreover, 7-NI significantly reduced FosB and pAcH3 expression in the acutely and chronically l-DOPA-treated mice. We also examined how increasing NO/cGMP signaling affects LID expression by acutely administering molsidomine (an NO donor) or zaprinast (a cGMP phosphodiesterase 5-PDE5 inhibitor) before l-DOPA in mice with established dyskinesia. Paradoxically, the administration of either of these drugs also significantly diminished the expression of established LID; however, the effect occurred at the expense of the antiparkinsonian l-DOPA properties. We demonstrate that targeting the NO/cGMP signaling pathway reduces dyskinetic behaviors and molecular markers, but only the 7-NI treatment preserved the antiparkinsonian effect of l-DOPA, indicating that NOS inhibitors represent a potential therapy to reduce LID. © 2014 Elsevier Inc.


Garcia-Blazquez V.,University Hospital Ramon y Cajal | Vicente-Bartulos A.,University Hospital Ramon y Cajal | Olavarria-Delgado A.,University Hospital Ramon y Cajal | Plana M.N.,University Hospital Ramon y Cajal | And 3 more authors.
European Radiology | Year: 2013

Objective: To assess the diagnostic accuracy of computed tomography (CT) angiography in the evaluation of patients with an episode of acute gastrointestinal haemorrhage. Methods: Systematic review and meta-analysis to estimate pooled accuracy indices. A bivariate random effects model was adjusted to obtain a summary receiver-operating characteristic (sROC) curve and the corresponding area under the curve (AUC). Results: Twenty-two studies were included and provided data on 672 patients (range of age 5-74) with a mean age of 65 years. The overall sensitivity of CT angiography for detecting active acute GI haemorrhage was 85.2 % (95 % CI 75.5 % to 91.5 %). The overall specificity of CT angiography was 92.1 % (95 % CI 76.7 % to 97.7 %). The likelihood ratios for positive and negative test results were 10.8 (95 % CI 3.4 to 34.4) and 0.16 (95 % CI 0.1 to 0.27) respectively, with an AUC of 0.935 (95 % CI 0.693 to 0.989). The sources of heterogeneity explored had no significant impact on diagnostic performance. Conclusions: CT shows high diagnostic accuracy and is an excellent diagnostic tool for detection and localising of intestinal bleeding sites. It is highly available, provides fast detection and localisation of the bleeding site, and is minimally invasive. Key Points: • CT angiography is increasingly used for investigating severe gastrointestinal bleeding. • This systematic review and meta-analysis updates previous ones. • In patients with massive gastrointestinal bleeding, CT angiography/MDCT detects bleeding accurately. • CT angiography is useful in locating the bleeding site and determining appropriate treatment. © 2012 European Society of Radiology.


Moscato G.,University of Pavia | Pala G.,Local Health Authority of Sassari | Sastre J.,CIBER ISCIII
Current Opinion in Allergy and Clinical Immunology | Year: 2014

Although scarce, available data suggest that immunotherapy and biological treatments may allow allergic workers to continue their work activity, but further studies are needed to standardize extracts and to evaluate the cost-effectiveness of these treatments, when exposure at the workplace cannot be avoided. Copyright © Lippincott Williams & Wilkins.


Gonzalez-Dominguez R.,University of Huelva | Garcia-Barrera T.,University of Huelva | Vitorica J.,University of Seville | Vitorica J.,CIBER ISCIII | Gomez-Ariza J.L.,University of Huelva
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide, but its etiology is still not completely understood. The identification of underlying pathological mechanisms is becoming increasingly important for the discovery of biomarkers and therapies, for which metabolomics presents a great potential. In this work, we studied metabolic alterations in different brain regions of the APP/PS1 mice by using a high-throughput metabolomic approach based on the combination of gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry. Multivariate statistics showed that metabolomic perturbations are widespread, affecting mainly the hippocampus and the cortex, but are also present in regions not primarily associated with AD such as the striatum, cerebellum and olfactory bulbs. Multiple metabolic pathways could be linked to the development of AD-type disorders in this mouse model, including abnormal purine metabolism, bioenergetic failures, dyshomeostasis of amino acids and disturbances in membrane lipids, among others. Interestingly, region-specific alterations were observed for some of the potential markers identified, associated with abnormal fatty acid composition of phospholipids and sphingomyelins, or differential regulation of neurotransmitter amino acids (e.g. glutamate, glycine, serine, N-acetyl-aspartate), not previously described to our knowledge. Therefore, these findings could provide a new insight into brain pathology in Alzheimer's disease. © 2014.


Sanchez-Dominguez M.,CIMAV | Pemartin K.,CIBER ISCIII | Boutonnet M.,KTH Royal Institute of Technology
Current Opinion in Colloid and Interface Science | Year: 2012

In this review, the synthesis of inorganic nanoparticles using oil-in-water (O/W) microemulsions as confined reaction media is discussed. Synthesis using (O/W) microemulsions has been demonstrated for a great variety of inorganic nanoparticles: metallic (Pt, Pd, Rh, Ag), single metal oxides (CeO 2, ZrO 2, TiO 2, Fe 2O 3), mixed and doped metal oxides (Ce 0.5Zr 0.5O 2, Ce 0.99Eu 0.01O 2, Zr 0.99Eu 0.01O 2, and Fe 2Mn 0.5Zn 0.5O 4), semiconductors (PbS, CdS, Ag 2S, ZnS, CdSe, PbSe, Ag 2Se), fluorides (CaF 2, YF 3, NdF 3, PrF 3), phosphates (CePO 4, HoPO 4), and chromates (BaCrO 4 and PbCrO 4). There are two synthetic strategies: 1) the use of oil-in water (O/W) microemulsions, in which the precursor is an ionic salt which is dissolved in the continuous aqueous phase; and 2) use of O/W microemulsions, in which the precursor is an organometallic salt dissolved in the oil droplets of the microemulsion. The latter approach keeps more resemblance to the typical W/O microemulsion reaction method, as it has the greatest level of precursor confinement. © 2012 Elsevier Ltd.


Orcau A.,CIBER ISCIII | Cayla J.A.,CIBER ISCIII | Martinez J.A.,Hospital Clinic Of Barcelona
Enfermedades Infecciosas y Microbiologia Clinica | Year: 2011

Tuberculosis (TB) has affected humanity since the beginning of the recorded time and is associated with poverty, malnutrition, overcrowding, and immunosuppression. Since Koch discovered the infectious nature of the disease in 1882, knowledge about its history and physiopathology has advanced, but it continues to be a global public health problem. More than 9 million new cases occurred in 2008 worldwide (with an incidence of 139/100,000 inhabitants), of whom more than one million died. Over half million of the cases presented with multidrug resistant-TB. Africa represents the continent with the highest incidence and the most HIV co-infection. The situation in Eastern Europe is also worrisome because of the high incidence and frequency drug resistance. In developed countries, TB has been localized in more vulnerable populations, such as immigrants and persons with social contention. There is an increase of extra-pulmonary presentation in this context, related to non-European ethnicity, HIV infection, and younger age. In Spain, the increasing immigrant population has presented a need to improve coordination between territories and strengthen surveillance The global control plan is based on the DOTS strategy, although the objectives and activities were redefined in 2006 to incorporate the measurement of global development, and community and healthcare strengthening. Adequate control measures in a more local context and continual activity evaluation are necessary to decrease the burden of suffering and economic loss that causes this ancient disease. © 2011 Elsevier España S.L.


Rayman M.P.,University of Surrey | Blundell-Pound G.,University of Surrey | Pastor-Barriuso R.,CIBER ISCIII | Guallar E.,Johns Hopkins University | And 3 more authors.
PLoS ONE | Year: 2012

Background: Evidence that selenium affects the risk of type-2 diabetes is conflicting, with observational studies and a few randomized trials showing both lower and higher risk linked to the level of selenium intake and status. We investigated the effect of selenium supplementation on the risk of type-2 diabetes in a population of relatively low selenium status as part of the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study. Plasma adiponectin concentration, a recognised independent predictor of type-2 diabetes risk and known to be correlated with circulating selenoprotein P, was the biomarker chosen. Methods: In a randomized, double-blind, placebo-controlled trial, five hundred and one elderly volunteers were randomly assigned to a six-month intervention with 100, 200 or 300 μg selenium/d as high-selenium or placebo yeast. Adiponectin concentration was measured by ELISA at baseline and after six months of treatment in 473 participants with one or both plasma samples available. Results: Mean (SD) plasma selenium concentration was 88.5 ng/g (19.1) at baseline and increased significantly in the selenium-treatment groups. In baseline cross-sectional analyses, the fully adjusted geometric mean of plasma adiponectin was 14% lower (95% CI, 0-27%) in the highest than in the lowest quartile of plasma selenium (P for linear trend = 0.04). In analyses across randomized groups, however, selenium supplementation had no effect on adiponectin levels after six months of treatment (P = 0.96). Conclusions: These findings are reassuring as they did not show a diabetogenic effect of a six-month supplementation with selenium in this sample of elderly individuals of relatively low selenium status. Trial Registration: Controlled-Trials.com ISRCTN25193534. © 2012 Rayman et al.


Beccari L.,CIBER ISCIII | Marco-Ferreres R.,CIBER ISCIII | Bovolenta P.,CIBER ISCIII
Mechanisms of Development | Year: 2013

The vertebrate forebrain or prosencephalon is patterned at the beginning of neurulation into four major domains: the telencephalic, hypothalamic, retinal and diencephalic anlagen. These domains will then give rise to the majority of the brain structures involved in sensory integration and the control of higher intellectual and homeostatic functions. Understanding how forebrain pattering arises has thus attracted the interest of developmental neurobiologists for decades. As a result, most of its regulators have been identified and their hierarchical relationship is now the object of active investigation. Here, we summarize the main morphogenetic pathways and transcription factors involved in forebrain specification and propose the backbone of a possible gene regulatory network (GRN) governing its specification, taking advantage of the GRN principles elaborated by pioneer studies in simpler organisms. We will also discuss this GRN and its operational logic in the context of the remarkable morphological and functional diversification that the forebrain has undergone during evolution. © 2012 Elsevier Ireland Ltd.


Lorenzo M.,Complutense University of Madrid | Fernandez-Veledo S.,Rovira i Virgili University | Fernandez-Veledo S.,CIBER ISCIII
Diabetes | Year: 2013

Adipose-derived stem cells (ASCs) are promising candidates for autologous cell-based regeneration therapies by virtue of their multilineage differentiation potential and immunogenicity; however,relatively little is known about their role in adipose tissue physiology and dysfunction. Here we evaluated whether ASCs isolated from nonobese and obese tissue differed in their metabolic characteristics and differentiation potential. During differentiation to mature adipocytes, mouse and human ASCs derived from nonobese tissues both increased their insulin sensitivity and inhibition of lipolysis, whereas obese-derived ASCs were insulin-resistant, showing impaired insulin-stimulated glucose uptake and resistance to the antilipolytic effect of insulin. Furthermore, obese-derived ASCs showed enhanced release of proinflammatory cytokines and impaired production of adiponectin. Interestingly, the delivery of cytosol from control ASCs into obese-derived ASCs using a lipid-based, protein-capture methodology restored insulin sensitivity on glucose and lipid metabolism and reversed the proinflammatory cytokine profile, in part due to the restoration of Lin28 protein levels. In conclusion, glucose and lipid metabolism as well as maturation of ASCs is uncated in an obese environment. The reversal of the altered pathways in obese cells by delivery of normal subcellular fractions offers a potential new tool for cell therapy. © 2013 by the American Diabetes Association.


Consiglio A.,University of Barcelona | Raya A.,Catalan Institution for Research and Advanced Studies | Raya A.,CIBER ISCIII | Raya A.,Institute for Bioengineering of Catalonia IBEC | And 2 more authors.
Genes and Development | Year: 2010

Human pluripotent stem cells, such as embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), have the unique abilities of differentiation into any cell type of the organism (pluripotency) and indefinite selfrenewal. Here, we show that the Rem2 GTPase, a suppressor of the p53 pathway, is up-regulated in hESCs and, by loss- and gain-of-function studies, that it is a major player in the maintenance of hESC self-renewal and pluripotency. We show that Rem2 mediates the fibroblastic growth factor 2 (FGF2) signaling pathway to maintain proliferation of hESCs. We demonstrate that Rem2 effects are mediated by suppressing the transcriptional activity of p53 and cyclin D1 to maintain survival of hESCs. Importantly, Rem2 does this by preventing protein degradation during DNA damage. Given that Rem2 maintains hESCs, we also show that it is as efficient as c-Myc by enhancing reprogramming of human somatic cells into iPSCs eightfold. Rem2 does this by accelerating the cell cycle and protecting from apoptosis via its effects on cyclin D1 expression/localization and suppression of p53 transcription. We show that the effects of Rem2 on cyclin D1 are independent of p53 function. These results define the cell cycle and apoptosis as a rate-limiting step during the reprogramming phenomena. Our studies highlight the possibility of reprogramming somatic cells by imposing hESC-specific cell cycle features for making safer iPSCs for cell therapy use. © 2010 by Cold Spring Harbor Laboratory Press.


Giralt M.,University of Barcelona | Giralt M.,CIBER ISCIII | Domingo P.,Hospital Of La Santa Creu I Sant Pau | Domingo P.,Institute Salud Carlos III | And 2 more authors.
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2011

HIV-1/highly active antiretroviral therapy-associated lipodystrophy syndrome (HALS) is an adipose tissue redistribution disorder characterized by subcutaneous adipose tissue lipoatrophy, sometimes including visceral adipose tissue hypertrophy and accumulation of dorsocervical fat ('buffalo hump'). The pathophysiology of HALS appears to be multifactorial and several key pathophysiological factors associated with HALS have been identified. These include mitochondrial dysfunction, adipocyte differentiation disturbances, high adipocyte lipolysis, and adipocyte apoptosis. These alterations in adipose tissue biology expand to involve systemic metabolism through alterations in endocrine functions of adipose tissue (via disturbed adipokine release), enhanced production of pro-inflammatory cytokines and excessive free fatty-acid release due to lipolysis. The deleterious action of some antiretroviral drugs is an important factor in eliciting these alterations in adipose tissue. However, HIV-1 infection-related events and HIV-1-encoded proteins also contribute directly to the complex development of HALS through effects on adipocyte biology, or indirectly through the promotion of local inflammation in adipose tissue. © 2010 Elsevier Ltd. All rights reserved.


Pope C.A.,Brigham Young University | Turner M.C.,University of Ottawa | Turner M.C.,Center for Research in Environmental Epidemiology | Turner M.C.,CIBER ISCIII | And 7 more authors.
Circulation Research | Year: 2015

Rationale: Growing evidence suggests that long-term exposure to fine particulate matter (PM2.5) air pollution contributes to risk of cardiovascular disease (CVD) morbidity and mortality. There is uncertainty about who are most susceptible. Individuals with underlying cardiometabolic disorders, including hypertension, diabetes mellitus, and obesity, may be at greater risk. PM2.5 pollution may also contribute to cardiometabolic disorders, augmenting CVD risk. Objective: This analysis evaluates relationships between long-term PM2.5 exposure and cardiometabolic disease on risk of death from CVD and cardiometabolic conditions. Methods and results: Data on 669 046 participants from the American Cancer Society Cancer Prevention Study II cohort were linked to modeled PM2.5 concentrations at geocoded home addresses. Cox proportional hazards regression models were used to estimate adjusted hazards ratios for death from CVD and cardiometabolic diseases based on death-certificate information. Effect modification by pre-existing cardiometabolic risk factors on the PM2.5-CVD mortality association was examined. PM2.5 exposure was associated with CVD mortality, with the hazards ratios (95% confidence interval) per 10 μg/m3 increase in PM2.5 equal to 1.12 (1.10-1.15). Deaths linked to hypertension and diabetes mellitus (mentioned on death certificate as either primary or contributing cause of death) were also associated with PM2.5. There was no consistent evidence of effect modification by cardiometabolic disease risk factors on the PM2.5-CVD mortality association. Conclusions: Pollution-induced CVD mortality risk is observed for those with and without existing cardiometabolic disorders. Long-term exposure may also contribute to the development or exacerbation of cardiometabolic disorders, increasing risk of CVD, and cardiometabolic disease mortality. © 2014 American Heart Association, Inc.


Roldan M.,Hospital Universitario Virgen Of La Victoria | Macias-Gonzalez M.,Hospital Universitario Virgen Of La Victoria | Macias-Gonzalez M.,CIBER ISCIII | Garcia R.,Hospital Universitario Virgen Of La Victoria | And 2 more authors.
FASEB Journal | Year: 2011

The discovery of adipose multipotent stem cells has provided new insights to explore cellular mechanisms involved in adipose tissue function. In the present work, we aimed to evaluate how the adipogenic environment influences the stemness of the resident multipotent stem cells. To achieve this goal, human omental multipotent stem cells (hO-MSCs) were isolated, expanded, and characterized in both healthy lean and morbidly obese individuals. We observed decreased cell proliferation, premature senescence, and increased cytokine secretion associated with increasing body mass index of the patients. Consistent with the latter finding, the hO-MSCs derived from patients with morbid obesity lose their multilineage differentiation capacity associated with a dysregulation in the Wnt, Notch, and Sonic Hedgehog signaling pathways. Moreover, microRNAs involved in the regulation of stemness, cell differentiation, and senescence were also up-regulated in obese individuals. Altogether, our data show that obesity causes a general short circuit in the stemness gene network of hO-MSCs.


Vaquero J.,University of Salamanca | Monte M.J.,University of Salamanca | Monte M.J.,CIBER ISCIII | Dominguez M.,Institute Salud Carlos III | And 4 more authors.
Biochemical Pharmacology | Year: 2013

The farnesoid X receptor (FXR) is a key sensor in bile acid homeostasis. Although four human FXR isoforms have been identified, the physiological role of this diversity is poorly understood. Here we investigated their subcellular localization, agonist sensitivity and response of target genes. Measurement of mRNA revealed that liver predominantly expressed FXRα1(+/-), whereas FXRα2(+/-) were the most abundant isoforms in kidney and intestine. In all cases, the proportion of FXRα(1/2)(+) and FXRα(1/2)(-) isoforms, i.e., with and without a 12 bp insert, respectively, was approximately 50%. When FXR was expressed in liver and intestinal cells the magnitude of the response to GW4064 and bile acids differs among FXR isoforms. In both cell types the strongest response was that of FXRα1(-). Different efficacy of bile acids species to activate FXR was found. The four FXR isoforms shared the order of sensitivity to bile acids species. When in FXR-deficient cells FXR was transfected, unconjugated, but not taurine- and glycine-amidated bile acids, were able to activate FXR. In contrast, human hepatocytes and cell lines showing an endogenous expression of FXR were sensitive to both unconjugated and conjugated bile acids. This suggests that to activate FXR conjugated, but not unconjugated, bile acids require additional component(s) of the intracellular machinery not related with uptake processes, which are missing in some tumor cells. In conclusion, cell-specific pattern of FXR isoforms determine the overall tissue sensitivity to FXR agonists and may be involved in the differential response of FXR target genes to FXR activation. © 2013 Elsevier Inc. All rights reserved.


Bosco A.,International School for Advanced Studies | Bosco A.,Elettra - Sincrotrone Trieste | Camunas-Soler J.,University of Barcelona | Camunas-Soler J.,CIBER ISCIII | And 2 more authors.
Nucleic Acids Research | Year: 2014

Single-stranded DNA (ssDNA) plays a major role in several biological processes. It is therefore of fundamental interest to understand how the elastic response and the formation of secondary structures are modulated by the interplay between base pairing and electrostatic interactions. Here we measure force-extension curves (FECs) of ssDNA molecules in optical tweezers set up over two orders of magnitude of monovalent and divalent salt conditions, and obtain its elastic parameters by fitting the FECs to semiflexible models of polymers. For both monovalent and divalent salts, we find that the electrostatic contribution to the persistence length is proportional to the Debye screening length, varying as the inverse of the square root of cation concentration. The intrinsic persistence length is equal to 0.7 nm for both types of salts, and the effectivity of divalent cations in screening electrostatic interactions appears to be 100-fold as compared with monovalent salt, in line with what has been recently reported for single-stranded RNA. Finally, we propose an analysis of the FECs using a model that accounts for the effective thickness of the filament at low salt condition and a simple phenomenological description that quantifies the formation of non-specific secondary structure at low forces. © 2013 The Author(s) 2013. Published by Oxford University Press.


Steven E.,Florida State University | Saleh W.R.,University of Baghdad | Lebedev V.,CIBER ISCIII | Acquah S.F.A.,Florida State University | And 2 more authors.
Nature Communications | Year: 2013

Understanding the compatibility between spider silk and conducting materials is essential to advance the use of spider silk in electronic applications. Spider silk is tough, but becomes soft when exposed to water. Here we report a strong affinity of amine-functionalised multi-walled carbon nanotubes for spider silk, with coating assisted by a water and mechanical shear method. The nanotubes adhere uniformly and bond to the silk fibre surface to produce tough, custom-shaped, flexible and electrically conducting fibres after drying and contraction. The conductivity of coated silk fibres is reversibly sensitive to strain and humidity, leading to proof-of-concept sensor and actuator demonstrations. © 2013 Macmillan Publishers Limited. All rights reserved.


Pemartin K.,CIBER ISCIII | Solans C.,CIBER ISCIII | Alvarez-Quintana J.,CIMAV | Sanchez-Dominguez M.,CIMAV
Colloids and Surfaces A: Physicochemical and Engineering Aspects | Year: 2014

The oil-in-water (O/W) microemulsion reaction method was used for the preparation of Mn-Zn ferrite magnetic nanoparticles (NPs). By variation of the precipitating agent and the oil phase concentration, Mn-Zn ferrite nanoparticles with different characteristics were obtained. HRTEM showed that at fixed microemulsion composition (surfactant:water weight ratio (S:W) 25:75, 12. wt% oil phase), the use of NaOH as precipitating agent resulted in smaller nanoparticle size than when tetramethylammonium hydroxide (TMAH) was used (2.4. nm vs. 5.2. nm, respectively). This is explained by the higher basic strength and concentration of NaOH compared to TMAH. When using two different oil phase concentrations (12 and 20. wt%) and TMAH as precipitating agent, particle size was increased upon increasing oil content (9.4. nm for 20. wt% oil); this is attributed to the higher concentration of precursor in the microemulsion as well as the higher processing temperature, which may favor growth and crystallization. X-ray diffraction patterns of as-obtained materials showed characteristic reflections of spinel structure, indicating that nanocrystalline materials were obtained at low temperature ( T= 25-40. °C). Crystallite size varied depending on microemulsion composition and precipitating agent. As a consequence, the magnetic characteristics (blocking temperature and saturation magnetization) also changed as a function of the precipitating agent and microemulsion composition. All samples were superparamagnetic. The estimated saturation magnetization values were slightly smaller than that of the bulk material, suggesting the presence of a disordered Spin layer on the surface. The thickness of this magnetically inert layer was estimated from the size dependence of the saturation magnetization at 9.1. Å. These results demonstrate the potential of the O/W microemulsion reaction method as greener alternative for the synthesis of complex ceramics such as mixed oxide spinels with magnetic properties under mild conditions. © 2014 Elsevier B.V.


Simmchen J.,Catalan Institute of Nanoscience and Nanotechnology | Baeza A.,CIBER ISCIII | Ruiz D.,Catalan Institute of Nanoscience and Nanotechnology | Esplandiu M.J.,Catalan Institute of Nanoscience and Nanotechnology | And 2 more authors.
Small | Year: 2012

An innovative self-propelled nanodevice able to perform motion, cargo transport, and target recognition is presented. The system is based on a mesoporous motor particle, which is asymmetrically functionalized by the attachment of single-stranded DNA onto one of its faces, while catalase is immobilized on the other face. This enzyme allows catalytic decomposition of hydrogen peroxide to oxygen and water, giving rise to the driving force for the motion of the whole system. Moreover the motor particles are able to capture and transport cargo particles functionalized with a noncomplementary single-stranded DNA molecule, only if a specific oligonucleotide sequence is present in the media. Functionalization with characteristic oligonucleotide sequences in the system implies a potential for further developments for lab-on-chip devices with applications in biomedical applications. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Rey-Lopez J.P.,University of Sao Paulo | de Rezende L.F.,University of Sao Paulo | Pastor-Valero M.,University Miguel Hernández | Pastor-Valero M.,CIBER ISCIII | Tess B.H.,University of Sao Paulo
Obesity Reviews | Year: 2014

We performed a systematic review of the prevalence of metabolically healthy obesity (MHO). Medline, Web of Science and EMBASE were searched for original articles from inception to November 2013. Only prospective and cross-sectional studies were included. After screening 478 titles, we selected 55 publications, of which 27 were population-based studies and were used in the narrative synthesis. From the 27 studies, we identified 30 definitions of metabolic health, mainly based on four criteria: blood pressure, high-density lipoprotein cholesterol, triglycerides and plasma glucose. Body mass index ≥30kgm-2 was the main indicator used to define obesity (74% of the studies). Overall, MHO prevalence ranged between 6% and 75%. In the studies that stratified the analysis by sex, prevalence was higher in women (seven out of nine studies) and in younger ages (all four studies). One-third of the studies (n=9) reported the response rate. Of these, four reported a response rate of ≥70% and they showed MHO prevalence estimates between 10% and 51%. The heterogeneity of MHO prevalence estimates described in this paper strengthens calls for the urgent need for a commonly established metabolic health definition. © 2014 The Authors.


Peris P.,CIBER ISCIII | Martinez de Osaba M.J.,Hormone Laboratory | Guanabens N.,CIBER ISCIII
Bone | Year: 2012

It remains unclear whether vitamin D sufficiency optimizes response to bisphosphonate (BP) treatment in postmenopausal osteoporosis. We evaluated the role and possible mechanisms of vitamin D in adequate response to standard BP treatment for postmenopausal osteoporosis. Methods: We included 120 postmenopausal osteoporotic women (aged 68 ± 8. years) receiving BP (alendronate or risedronate) at their annual follow-up, performing complete anamnesis, including treatment adherence, use of vitamin D supplements, and previous falls and fractures during the last year. We analyzed the evolution of bone mineral density (BMD) during this period and serum PTH and 25 hydroxyvitamin D (25(OH)D) and urinary NTx levels. Patients were classified as inadequate responders to antiosteoporotic treatment based on BMD loss > 2% and/or the presence of fragility fractures during the last year. Results: Thirty percent of patients showed inadequate response to BP treatment, with significantly lower levels of 25(OH)D (22.4 ± 1.3 vs. 26.6 ± 0.3. ng/ml, p = 0.01), a higher frequency of 25(OH)D levels < 30. ng/ml (91% vs. 69%, p = 0.019) and higher urinary NTx values (42.2 ± 3.9 vs. 30.9 ± 2.3 nM/mM, p = 0.01). Patients with 25(OH)D > 30. ng/ml had a greater significant increase in lumbar BMD than women with values < 30. ng/ml (3.6% vs. 0.8%, p < 0.05). The probability of inadequate response was 4-fold higher in patients with 25(OH)D < 30 (OR, 4.42; 95% CI, 1.22-15.97, p = 0.02). Conclusions: Inadequate response to BP treatment is frequent in postmenopausal women with osteoporosis as is vitamin D insufficiency, despite vitamin D supplementation. Maintenance of 25(OH)D levels > 30. ng/ml is especially indicated for adequate response to BP treatment. © 2012 Elsevier Inc.


Martinez-Martin P.,Carlos III Institute of Health | Martinez-Martin P.,CIBER ISCIII | Hernandez B.,Novartis
Parkinsonism and Related Disorders | Year: 2012

In Parkinson's disease (PD), wearing-off can be difficult to detect as it is very variable and may affect motor and non-motor symptoms. The Wearing-Off Questionnaire, WOQ-32 (Stacy et al., 2005), was introduced to help identify wearing-off and proved to be very efficient. Two short versions of the questionnaire (WOQ-19 or QUICK and WOQ-9) were later developed to decrease the respondent burden without loss of efficacy in terms of sensitivity. The objective of the present study was to check the ability of a new 10-item QUICK version, Q10, to identify patients with wearing-off. Q10 items were selected from the QUICK validation study data set through statistical analysis and it was then tested on a sample of 162 PD patients, 64.8% with wearing-off. Sensitivity, specificity, and accuracy were 96%, 63%, and 85% respectively with one positive response and 90%, 70%, and 83% respectively with two positive responses. The correlation with the gold standard (neurologist diagnosis of wearing-off) was substantial (kappa = 0.62-0.64). Comparison with the QUICK and WOQ-9 shows that the Q10 can be a new tool for detection of wearing-off with satisfactory properties and a good balance between brevity and performance. © 2011 Elsevier Ltd.


Gaulton K.J.,University of North Carolina at Chapel Hill | Nammo T.,Institute dInvestigacions Biomediques August Pi i Sunyer | Nammo T.,CIBER ISCIII | Pasquali L.,Institute dInvestigacions Biomediques August Pi i Sunyer | And 16 more authors.
Nature Genetics | Year: 2010

Tissue-specific transcriptional regulation is central to human disease. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). We identified 80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed 3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility. © 2010 Nature America, Inc. All rights reserved.


Viale L.,Centro Rosarino Of Estudios Perinatales | Allotey J.,Queen Mary, University of London | Cheong-See F.,Queen Mary, University of London | Arroyo-Manzano D.,Hospital Ramon y Cajal | And 8 more authors.
The Lancet | Year: 2015

Summary Background Antenatal care of women with epilepsy is varied. The association of epilepsy and antiepileptic drug exposure with pregnancy outcomes needs to be quantified to guide management. We did a systematic review and meta-analysis to investigate the association between epilepsy and reproductive outcomes, with or without exposure to antiepileptic drugs. Methods We searched MEDLINE, Embase, Cochrane, AMED, and CINAHL between Jan 1, 1990, and Jan 21, 2015, with no language or regional restrictions, for observational studies of pregnant women with epilepsy, which assessed the risk of obstetric complications in the antenatal, intrapartum, or postnatal period, and any neonatal complications. We used the Newcastle-Ottawa Scale to assess the methodological quality of the included studies, risk of bias in the selection and comparability of cohorts, and outcome. We assessed the odds of maternal and fetal complications (excluding congenital malformations) by comparing pregnant women with and without epilepsy and undertook subgroup analysis based on antiepileptic drug exposure in women with epilepsy. We summarised the association as odds ratio (OR; 95% CI) using random effects meta-analysis. The PROSPERO ID of this Systematic Review's protocol is CRD42014007547. Findings Of 7050 citations identified, 38 studies from low-income and high-income countries met our inclusion criteria (39 articles including 2 837 325 pregnancies). Women with epilepsy versus those without (2 809 984 pregnancies) had increased odds of spontaneous miscarriage (OR 1·54, 95% CI 1·02-2·32; I2=67%), antepartum haemorrhage (1·49, 1·01-2·20; I2=37%), post-partum haemorrhage (1·29, 1·13-1·49; I2=41%), hypertensive disorders (1·37, 1·21-1·55; I2=23%), induction of labour (1·67, 1·31-2·11; I2=64%), caesarean section (1·40, 1·23-1·58; I2=66%), any preterm birth (<37 weeks of gestation; 1·16, 1·01-1·34; I2=64%), and fetal growth restriction (1·26, 1·20-1·33; I2=1%). The odds of early preterm birth, gestational diabetes, fetal death or stillbirth, perinatal death, or admission to neonatal intensive care unit did not differ between women with epilepsy and those without the disorder. Interpretation A small but significant association of epilepsy, exposure to antiepileptic drugs, and adverse outcomes exists in pregnancy. This increased risk should be taken into account when counselling women with epilepsy. Funding EBM CONNECT Collaboration. © 2015 Elsevier Ltd.


Giglio R.E.,Barnard College | Rodriguez-Blazquez C.,CIBER ISCIII | De Pedro-Cuesta J.,CIBER ISCIII | Forjaz M.J.,Carlos III Institute of Health
International Psychogeriatrics | Year: 2015

Background: In light of the demographic aging trend in Europe, investigation into successful aging is a public health priority. This paper describes the sense of coherence (SOC) of a sample of community-dwelling older adults in Spain and analyzes the relationship between SOC and both health and sociodemographic variables. SOC measures the extent to which an individual conceptualizes the world as comprehensible, manageable, and meaningful. Strong SOC may promote good health. Methods: The study followed a cross-sectional design involving a nationally representative sample of 1,106 community-dwelling adults aged 60 years and older in Spain. The sample was collected by geographically based proportional stratified sampling. Results are based on responses to a questionnaire requesting sociodemographic information and including the following validated scales: SOC, Barthel index (BI), functional independence scale (FIS), personal wellbeing index (PWI), EQ-5D dimensions (mobility, personal care, daily activities, pain/discomfort, anxiety/depression), and the depression subscale of the hospital anxiety and depression scale (HADS-D). A multivariate linear regression model analyzed determinants of SOC. Results: Personal wellbeing (b = -0.32), depression (b = 0.26), and educational level (b = -0.06) were significant determinants of SOC. Lower SOC was associated with problems in all EQ-5D dimensions and moderate/severe disability as measured by the BI. Conclusions: SOC in older adults is related to functional status, mental health status, personal wellbeing, and educational level. Public health initiatives should work to reduce the psychological and physiological impact of aging by focusing on the conditions that facilitate the coping of older adults. Copyright © International Psychogeriatric Association 2014.


Aubery C.,CIBER ISCIII | Solans C.,CIBER ISCIII | Sanchez-Dominguez M.,CIBER ISCIII | Sanchez-Dominguez M.,CIMAV
Langmuir | Year: 2011

In this work, the formation of water-in-oil (w/o) microemulsions with high aqueous phase uptake in a nonionic surfactant system is investigated as potential media for the synthesis of Mn-Zn ferrite nanoparticles. A comprehensive study based on the phase behavior of systems containing precursor salts, on one hand, and precipitating agent, on the other hand, was carried out to identify key regions on (a) pseudoternary phase diagrams at constant temperature (50 °C), and (b) pseudobinary phase diagrams at constant surfactant (S):oil(O) weight ratio (S:O) as a function of temperature. The internal structure and dynamics of microemulsions were studied systematically by conductivity and self-diffusion coefficient determinations (FT PGSE 1H NMR). It was found that nonpercolated w/o microemulsions could be obtained by appropriate tuning of composition variables and temperature, with aqueous phase concentrations as high as 36 wt % for precursor salts and 25 wt % for precipitating agent systems. Three compositions with three different dynamic behaviors (nonpercolated and percolated w/o, as well as bicontinuous microemulsions) were selected for the synthesis of Mn-Zn ferrites, resulting in nanoparticles with different characteristics. Spinel structure and superparamagnetic behavior were obtained. This study sets firm basis for a systematic study of Mn-Zn ferrite nanoparticle synthesis via different scenarios of microemulsion dynamics, which will contribute to a better understanding on the relationship of the characteristics of the obtained materials with the properties of the reaction media. © 2011 American Chemical Society.


Nueda M.J.,University of Alicante | Medina I.,CIBER ISCIII
Nucleic Acids Research | Year: 2010

Serial transcriptomics experiments investigate the dynamics of gene expression changes associated with a quantitative variable such as time or dosage. The statistical analysis of these data implies the study of global and gene-specific expression trends, the identification of significant serial changes, the comparison of expression profiles and the assessment of transcriptional changes in terms of cellular processes. We have created the SEA (Serial Expression Analysis) suite to provide a complete web-based resource for the analysis of serial transcriptomics data. SEA offers five different algorithms based on univariate, multivariate and functional profiling strategies framed within a user-friendly interface and a projectoriented architecture to facilitate the analysis of serial gene expression data sets from different perspectives. SEA is available at sea.bioinfo.cipf.es. © The Author(s) 2010. Published by Oxford University Press.


Alonso-Coello P.,CIBER ISCIII | Bellmunt S.,Hospital Of La Santa Creu I Sant Pau | McGorrian C.,Materials Misericordiae University Hospital | Anand S.S.,McMaster University | And 7 more authors.
Chest | Year: 2012

Background: This guideline focuses on antithrombotic drug therapies for primary and secondary prevention of cardiovascular disease as well as for the relief of lower-extremity symptoms and critical ischemia in persons with peripheral arterial disease (PAD). Methods: The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines in this supplement. Results: The most important of our 20 recommendations are as follows. In patients aged ≥ 50 years with asymptomatic PAD or asymptomatic carotid stenosis, we suggest aspirin (75-100 mg/d) over no therapy (Grade 2B) for the primary prevention of cardiovascular events. For secondary prevention of cardiovascular disease in patients with symptomatic PAD (including patients before and after peripheral arterial bypass surgery or percutaneous transluminal angioplasty), we recommend long-term aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 1A). We recommend against the use of warfarin plus aspirin in patients with symptomatic PAD (Grade 1B). For patients undergoing peripheral artery percutaneous transluminal angioplasty with stenting, we suggest single rather than dual antiplatelet therapy (Grade 2C). For patients with refractory claudication despite exercise therapy and smoking cessation, we suggest addition of cilostazol (100 mg bid) to aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 2C). In patients with critical limb ischemia and rest pain unable to undergo revascularization, we suggest the use of prostanoids (Grade 2C). In patients with acute limb ischemia due to acute thrombosis or embolism, we recommend surgery over peripheral arterial thrombolysis (Grade 1B). Conclusions: Recommendations continue to favor single antiplatelet therapy for primary and secondary prevention of cardiovascular events in most patients with asymptomatic PAD, symptomatic PAD, and asymptomatic carotid stenosis. Additional therapies for relief of limb symptoms should be considered only after exercise therapy, smoking cessation, and evaluation for peripheral artery revascularization. © 2012 American College of Chest Physicians.


Medina M.,CIBER ISCIII | Avila J.,CIBER ISCIII
Biochemical Pharmacology | Year: 2014

Alzheimer's disease (AD) and related dementias constitute a major public health issue due to an increasingly aged population as a consequence of generally improved medical care and demographic changes. Current drug treatment of AD, the most prevalent dementia, with cholinesterase inhibitors or NMDA antagonists have demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. While drug development efforts in the last two decades have primarily focused on the amyloid cascade hypothesis, so far with disappointing results, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. The discovery of mutations within the tau gene that cause fronto-temporal dementia demonstrated that tau dysfunction, in the absence of amyloid pathology, was sufficient to cause neuronal loss and clinical dementia. Abnormal levels and hyperphosphorylation of tau protein have been reported to be the underlying cause of a group of neurodegenerative disorders collectively known as 'tauopathies'. The detrimental consequence is the loss of affinity between this protein and the microtubules, increased production of fibrillary aggregates and the accumulation of insoluble intracellular neurofibrillary tangles. However, it has become clear in recent years that tau is not only a microtubule interacting protein, but rather has additional roles in cellular processes. This review focuses on emerging therapeutic strategies aimed at treating the underlying causes of the tau pathology in tauopathies and AD, including some novel approaches on the verge of providing new treatment paradigms within the coming years. © 2014 Elsevier Inc.


Cardona F.,Laboratorio Of Investigaciones Biomedicas Del Hospital Virgen Of La Victoria Fimabis | Cardona F.,CIBER ISCIII | Andres-Lacueva C.,University of Barcelona | Tulipani S.,Laboratorio Of Investigaciones Biomedicas Del Hospital Virgen Of La Victoria Fimabis | And 4 more authors.
Journal of Nutritional Biochemistry | Year: 2013

The biological properties of dietary polyphenols are greatly dependent on their bioavailability that, in turn, is largely influenced by their degree of polymerization. The gut microbiota play a key role in modulating the production, bioavailability and, thus, the biological activities of phenolic metabolites, particularly after the intake of food containing high-molecular-weight polyphenols. In addition, evidence is emerging on the activity of dietary polyphenols on the modulation of the colonic microbial population composition or activity. However, although the great range of health-promoting activities of dietary polyphenols has been widely investigated, their effect on the modulation of the gut ecology and the two-way relationship "polyphenols ↔ microbiota" are still poorly understood.Only a few studies have examined the impact of dietary polyphenols on the human gut microbiota, and most were focused on single polyphenol molecules and selected bacterial populations. This review focuses on the reciprocal interactions between the gut microbiota and polyphenols, the mechanisms of action and the consequences of these interactions on human health. © 2013 Elsevier Inc.


Objective To identify potentially inappropriate prescriptions (PPI) and prescribing omissions (OP) by means of the STOPP/START criteria, as well as associated factors in ≥ 65 year old patients in a Primary Care setting in Spain. Study design A cross-sectional, descriptive study. Setting Centro de Salud Monóvar, Primary Health Care. Study period: 6 months. Patients Random sample 247 patients. Eligibility criteria: ≥ 65 years patients who attended an urban Primary Care clinic 2 or more times were studied. Terminally ill and nursing home residents were excluded. Methods Data were collected from electronic clinical records. STOPP and START criteria were evaluated in each clinical record, including age, sex, co-morbidity, number of chronic prescriptions. Main outcomes: PPI and OP identified by STOPP and START criteria, respectively. Results A total of 81 patients (32.8%) had PPI, with the most common being the long-term use of long-acting benzodiazepines in 17 (6.9%). OP was found in 73 (29.6%) patients, with the most common being the omission of statins in patients diagnosed with diabetes mellitus and/or one or more major cardiovascular risk factors in 21 (8.5%). After adjustment by gender and age, correlations were found between PPI and multiple medication (OR: 2.02; 95% CI: 1.15-3.53; P =.014), and OP and polypharmacy (OR: 2.37; 95% CI: 1.32-4.24; P = 0.004). Conclusions Inappropriate prescribing in older people is frequent, and is mainly associated with long-acting benzodiazepines. There are diabetic patients who do not have statins prescribed. Multiple medication is associated with PPI and OP. © 2014 Elsevier España, S.L. All rights reserved.


Garcia-Camara B.,Catalan Institute of Nanoscience and Nanotechnology | Garcia-Camara B.,Charles III University of Madrid | Gomez-Medina R.,Autonomous University of Madrid | Saenz J.J.,Autonomous University of Madrid | And 2 more authors.
Optics Express | Year: 2013

In this work we propose two novel sensing principles of detection that exploit the magnetic dipolar Mie resonance in high-refractiveindex dielectric nanospheres. In particular, we theoretically investigate the spectral evolution of the extinction and scattering cross sections of these nanospheres as a function of the refractive index of the external medium (next). Unlike resonances in plasmonic nanospheres, the spectral position of magnetic resonances in high-refractive-index nanospheres barely shifts as next changes. Nevertheless, there is a drastic reduction in the extinction cross section of the nanospheres when next increases, especially in the magnetic dipolar spectral region, which is accompanied with remarkable variations in the radiation patterns. Thanks to these changes, we propose two new sensing parameters, which are based on the detection of: i) the intensity variations in the transmitted or backscattered radiation by the dielectric nanospheres at the magnetic dipole resonant frequency, and ii) the changes in the radiation pattern at the frequency that satisfies Kerker's condition of near-zero forward radiation. To optimize the sensitivity, we consider several semiconductor materials and particles sizes. © 2013 Optical Society of America.


Tena-Sempere M.,University of Cordoba, Spain | Tena-Sempere M.,CIBER ISCIII | Tena-Sempere M.,Hospital Universitario Reina Sofia
Current Topics in Developmental Biology | Year: 2013

Puberty is the culmination of a complex series of maturational events that lead to the completion of sexual and somatic maturation and the acquisition of reproductive competence. This key developmental transition, which defines the boundary between immaturity and adulthood, is under the control of sophisticated regulatory networks that impinge upon the brain centers governing the reproductive axis. These networks are sensitive to earlier maturational events, such as brain sex differentiation, and dynamically regulated by a plethora of hormonal factors and environmental signals, which are essential for the fine-tuning of the tempo of puberty. While much knowledge on mammalian puberty had been gleaned during the last decades, important recent developments have substantially expanded our understanding of the neuroendocrine and molecular mechanisms governing puberty onset. We will provide here a synoptic account of some of these important advancements, including the identification of the essential roles of hypothalamic kisspeptin signaling, and some of its putative partners, in pubertal maturation, the characterization of novel mechanisms involved in the metabolic regulation of puberty, and the recognition of the potential roles of epigenetics and miRNA-related pathways in the central control of puberty. It is expected that further progress in these and related areas will follow in the coming years. This will permit a better understanding of the physiological mechanisms responsible for pubertal timing and will help to decipher the pathophysiological basis for pubertal alterations in humans and wildlife species. © 2013 Elsevier Inc.


Farooqi A.A.,Rashid Latif Medical College | ur Rehman Z.,Kohat University of Science and Technology | Muntane J.,University of Seville | Muntane J.,CIBER ISCIII
OncoTargets and Therapy | Year: 2014

There is increasing progress in translational oncology and tremendous breakthroughs have been made as evidenced by preclinical and clinical trials. Data obtained from high-throughput technologies are deepening our understanding about the molecular and gene network in cancer cells and rapidly emerging in vitro and in vivo evidence is highlighting the role of antisense agents as specific inhibitors of the expression of target genes, thus modulating the response of cancer cells to different therapeutic strategies. Much information is continuously being added into various facets of molecular oncology and it is now understood that over expression of antiapoptotic proteins, oncogenes, oncogenic microRNAs (miRNA), and fusion proteins make cancer cells difficult to target. Delivery of antisense oligonucleotides has remained a challenge and technological developments have helped in overcoming hurdles by improving the ability to penetrate cells, effective and targeted binding to gene sequences, and down regulation of target gene function. Different delivery systems, including stable nucleic acid lipid particles, have shown potential in enhancing the delivery of cargo to the target site. In this review, we attempt to summarize the current progress in the development of antisense therapeutics and their potential in medical research. We partition this multi component review into introductory aspects about recent breakthroughs in antisense therapeutics. We also discuss how antisense therapeutics have shown potential in resensitizing resistant cancer cells to apoptosis by targeted inhibition of antiapoptotic proteins, oncogenic miRNAs, and BCR-ABL. © 2014 Farooqi et al.


Miravitlles M.,CIBER ISCIII | Garcia-Sidro P.,Hospital Of La Plana | Fernandez-Nistal A.,Takeda Farmaceutica Espana S.A | Buendia M.J.,Hospital Universitario Infanta Leonor | Espinosa de los Monteros M.J.,Hospital Universitario Virgen Of La Salud
Health and Quality of Life Outcomes | Year: 2013

Introduction: COPD exacerbations have a negative impact on lung function, decrease quality of life (QoL) and increase the risk of death. The objective of this study was to assess the course of health status after an outpatient or inpatient exacerbation in patients with COPD.Methods: This is an epidemiological, prospective, multicentre study that was conducted in 79 hospitals and primary care centres in Spain. Four hundred seventy-six COPD patients completed COPD assessment test (CAT) and Clinical COPD Questionnaire (CCQ) questionnaires during the 24 hours after presenting at hospital or primary care centres with symptoms of an exacerbation, and also at weeks 4-6. The scores from the CAT and CCQ were evaluated and compared at baseline and after recovery from the exacerbation.Results: A total of 164 outpatients (33.7%) and 322 inpatients (66.3%) were included in the study. The majority were men (88.2%), the mean age was 69.4 years (SD = 9.5) and the mean FEV1 (%) was 47.7% (17.4%). During the exacerbation, patients presented high scores in the CAT: [mean: 22.0 (SD = 7.0)] and the CCQ: [mean: 4.4 (SD = 1.2)]. After recovery there was a significant reduction in the scores of both questionnaires [CAT: mean: -9.9 (SD = 5.1) and CCQ: mean: -3.1 (SD = 1.1)]. Both questionnaires showed a strong correlation during and after the exacerbation and the best predictor of the magnitude of improvement in the scores was the severity of each score at onset.Conclusions: Due to their good correlation, CAT and CCQ can be useful tools to measure health status during an exacerbation and to evaluate recovery. However, new studies are necessary in order to identify which factors are influencing the course of the recovery of health status after a COPD exacerbation. © 2013 Miravitlles et al.; licensee BioMed Central Ltd.


Palomar F.J.,University of Seville | Palomar F.J.,CIBER ISCIII | Mir P.,University of Seville | Mir P.,CIBER ISCIII
Clinical Neurophysiology | Year: 2012

Botulinum toxin (BT) acts peripherally by inhibiting acetylcholine release from the presynaptic neuromuscular terminals and by weakening muscle contraction. Therefore, its clinical benefit is primarily due to its peripheral action. As a result, local injection of BT has become a successful and safe tool in the treatment of several neurological and non-neurological disorders. Studies in animals have also shown that the toxin can be retrogradely transported and even transcytosed to neurons in the central nervous system (CNS). Further human studies have suggested that BT could alter the functional organisation of the CNS indirectly through peripheral mechanisms. BT can interfere with and modify spinal, brainstem and cortical circuits, including cortical excitability and plasticity/organisation by altering spindle afferent inflow directed to spinal motoneurons or to the various cortical areas. It is well demonstrated that the distant CNS effects of BT treatment parallel the peripheral effect, although there is limited evidence as to the cause of this. Therefore, further studies focussed on central changes after BT treatment is needed for a better understanding of these non-peripheral effects of BT. © 2011 International Federation of Clinical Neurophysiology.


Pena E.,Hospital Of La Santa Creu I Sant Pau | Pena E.,CIBER ISCIII | Arderiu G.,Hospital Of La Santa Creu I Sant Pau | Arderiu G.,CIBER ISCIII | And 3 more authors.
Journal of Thrombosis and Haemostasis | Year: 2012

Background:Tissue factor (TF) is the most relevant physiological trigger of thrombosis. Additionally TF is a transmembrane receptor with cell signaling functions. Objectives:The aim of this study was to investigate TF subcellular localization, function and signaling in human coronary artery smooth muscle cell migration. Methods:Coronary arteries and primary cultures of vascular smooth muscle cells (HVSMC) were obtained from human explanted hearts. Wound repair and Boyden chamber assays were used to measure migration in vitro. TF-pro-coagulant activity (TF-PCA) was measured in extracted cellular membranes. Analysis of TF distribution was performed by confocal microscopy. A nucleofector device was used for TF and protease activated receptor 2 (PAR2) silencing. mRNA levels were analyzed by RT-PCR. Results:In migrating HVSMC TF translocates to the leading edge of the cells showing an intense patch-like staining in the lamellipodia. In the migrating front TF colocalizes with filamin (FLN) in the polarized lipid rafts. TF-PCA was increased in migrating cells. Silencing of the TF gene inhibits RSK-induced FLN-Ser-2152 phosphorylation, down-regulates CDC42, RhoA, and Rac1 protein expression and significantly inhibits cell migration. Silencing PAR2 also inhibits cell migration; however, silencing both TF and PAR2 induces a significantly higher effect on migration. Smooth muscle cells expressing TF have been identified in non-lipid-rich human coronary artery atherosclerotic plaques. Conclusions:TF translocates to the cell front in association with cytoskeleton proteins and regulates HVSMC migration by mechanisms dependent and independent of factor (F)VIIa/PAR2. These results extend the functional role of TF to smooth muscle cell trafficking in vessel wall remodeling. © 2012 International Society on Thrombosis and Haemostasis.


Jones P.,University of London | Miravitlles M.,CIBER ISCIII | van der Molen T.,University of Groningen | Kulich K.,Novartis
International Journal of COPD | Year: 2012

Patients with chronic obstructive pulmonary disease (COPD) present with a variety of symptoms and pathological consequences. Although primarily viewed as a respiratory disease, COPD has both pulmonary and extrapulmonary effects, which have an impact on many aspects of physical, emotional, and mental well-being. Traditional assessment of COPD relies heavily on measuring lung function, specifically forced expiratory volume in 1 second (FEV1). However, the evidence suggests that FEV1 is a relatively poor correlate of symptoms such as breathlessness and the impact of COPD on daily life. Furthermore, many consequences of the disease, including anxiety and depression and the ability to perform daily activities, can only be described and reported reliably by the patient. Thus, in order to provide a comprehensive view of the effects of interventions in clinical trials, it is essential that spirometry is accompanied by assessments using patient-reported outcome (PRO) instruments. We provide an overview of patient-reported outcome concepts in COPD, such as breathlessness, physical functioning, and health status, and evaluate the tools used for measuring these concepts. Particular attention is given to the newly developed instruments emerging in response to recent regulatory guidelines for the development and use of PROs in clinical trials. We conclude that although data from the development and validation of these new PRO instruments are emerging, to build the body of evidence that supports the use of a new instrument takes many years. Furthermore, new instruments do not necessarily have better discriminative or evaluative properties than older instruments. The development of new PRO tools, however, is crucial, not only to ensure that key COPD concepts are being reliably measured but also that the relevant treatment effects are being captured in clinical trials. In turn, this will help us to understand better the patient's experience of the disease. © 2012 Jones et al, publisher and licensee Dove Medical Press Ltd.


Blanco-Munoz J.,Instituto Nacional Of Salud Publica National Institute Of Public Health | Lacasana M.,CIBER ISCIII
Journal of Agromedicine | Year: 2011

Practices related to the safe handling of pesticides and use of personal protective equipment (PPE) are largely unknown among agricultural workers in developing countries. The authors obtained information from 99 Mexican agricultural workers (35 women and 64 men) who answered questions on sociodemographic data, agricultural practices, use of pesticides, use of PPE, and risk perception. As expected, men handled pesticides more frequently than women (67% versus 20%). The workers carried out several agricultural tasks, as is customary in the case of fieldworkers who (1) work in small agricultural enterprises; use a great number of pesticide products (59 commercial brands of pesticides, 33 active ingredients, and 20 chemical families); (2) use mostly manual application equipment; (3) have a low rate of correct usage of PPE (2%), which does not vary according to the education level, the time of year, or the risk perception; and (4) have insufficient hygienic practices. In addition, storage of pesticide products and application equipment at home is frequent among this group of workers (42%), and provides a significant source of para-occupational exposure for the workers' families. These results show the need to develop prevention programs to reduce risks posed by pesticides to agricultural workers and their families.


Miravitlles M.,Hospital Universitari Vall dHebron | Miravitlles M.,CIBER ISCIII | Anzueto A.,University of Texas Health Science Center at San Antonio | Anzueto A.,Audie L Murphy Memorial Veterans Hospital Division
Pulmonary Pharmacology and Therapeutics | Year: 2015

One of the main goals of treatment of chronic obstructive pulmonary disease (COPD) is the prevention of exacerbations. Bronchodilators and anti-inflammatories are the first line therapy for treatment of COPD; however, these drugs are not effective in suppressing all infective exacerbations. In fact, the use of inhaled corticosteroids in patients with COPD and chronic bronchial infection may even increase the bacterial load in the airways and increase the risk of pneumonia. In this context, the use of long-term or intermittent antibiotic treatment has shown to prevent COPD exacerbations and hospitalizations. These effects may be achieved by reducing bacterial load in the airways in stable state and/or bronchial inflammation. The drugs more extensively studied are macrolides, followed by quinolones. The long-term use of antibiotics is associated with an increased risk of potentially serious adverse events and development of bacterial resistance. Therefore, the indication of long-term antibiotic therapy must be determined on a case by case basis taking into account the potential risks and benefits. In general, this treatment may be indicated in patients with severe or very severe COPD with frequent or severe exacerbations despite optimal pharmacological and non pharmacological treatment. These patients should be carefully monitored based on clinical and microbiological assessments. The most appropriate drug and regime administration, as well as the optimal duration of therapy are issues that still require further investigation. © 2014 Elsevier Ltd.


Lopez-Campos J.L.,University of Seville | Lopez-Campos J.L.,CIBER ISCIII | Tan W.,University of British Columbia | Soriano J.B.,Autonomous University of Madrid
Respirology | Year: 2016

It is estimated that the world population will reach a record 7.3 billion in 2015, and the high burden of chronic conditions associated with ageing and smoking will increase further. Respiratory diseases in general receive little attention and funding in comparison with other major causes of global morbidity and mortality. In particular, chronic obstructive pulmonary disease (COPD) has been a major public health problem and will remain a challenge for clinicians within the 21st century. Worldwide, COPD is in the spotlight, since its high prevalence, morbidity and mortality create formidable challenges for health-care systems. This review emphasizes the magnitude of the COPD problem from a clinician's standpoint by drawing extensively from the new findings of the Global Burden of Disease study. Updated, distilled information on the population distribution of COPD is useful for the clinician to help provide an appreciation of the relative impact of COPD in daily practice compared with other chronic conditions, and to allocate minimum resources in anticipation of future needs in care. Despite recent trends in reduction of COPD standardized mortality rates and some recent successes in anti-smoking efforts in a number of Western countries, the overarching demographic impact of ageing in an ever-expanding world population, joined with other factors such as high rates of smoking and air pollution in Asia, will ensure that COPD will continue to pose an ever-increasing problem well into the 21st century. © 2015 Asian Pacific Society of Respirology.


Blanco C.,Columbia University | Morcillo C.,Columbia University | Alegria M.,Center for Multicultural Mental Health Research | Dedios M.C.,Catholic University of Peru | And 4 more authors.
Journal of Psychiatric Research | Year: 2013

The authors' objective was to examine the relationship between degree of acculturation across five different dimensions of acculturation and risk of drug use disorders (DUD) among US Hispanics.Data were derived from a large national sample of the US adult population, the National Epidemiological Survey on Alcohol and Related Conditions, collected using face-to-face interviews. The sample included civilian non-institutionalized U.S. population aged 18 years and older, with oversampling of Hispanics, Blacks and those aged 18-24 years. Interviews of more than 34,000 adults were conducted during 2004-2005 using the Alcohol Use Disorder and Associated Disabilities Interview Schedule - DSM-IV Version. A total of 6359 subjects who identified themselves as Hispanics were included in this study. Acculturation measures used in this study assessed:, time spent in the U.S., age at immigration, language preference, social network composition, and ethnic identification.Among Hispanics, there was an inverse relationship between five complementary dimensions of acculturation and DUD. Moreover, this relationship showed a significant gradient across all acculturation dimensions and DUD.The prevalence of DUD increases with acculturation in Hispanics, across several measures of acculturation in a dose-response relationship. Hispanic cultural features and values exert a protective effect on risk of DUD. Preservation and promotion of Hispanic values may be an important component of preventive interventions for Hispanics. © 2012 Elsevier Ltd.


Aubery C.,CIBER ISCIII | Solans C.,CIBER ISCIII | Prevost S.,TU Berlin | Prevost S.,Helmholtz Center Berlin | And 3 more authors.
Langmuir | Year: 2013

Phase behavior, dynamics, and structure of W/O microemulsions of the system aqueous solution/Synperonic 13-6.5/1-hexanol/isooctane were studied, with the goal of determining their effect on Mn-Zn ferrite nanoparticle formation, kinetics and characteristics. Microemulsion structure and dynamics were studied systematically by conductivity, dynamic light scattering (DLS), differential scanning calorimetry (DSC), and small-angle neutron scattering (SANS). The main effect of cosurfactant 1-hexanol was a decrease in microemulsion regions as compared to the systems without cosurfactant; nevertheless, overlap of microemulsion regions in the systems with precursor salts (PS) and precipitating agent (PA) was achieved at lower S/O ratios, compared to the system without cosurfactant. At 50 C, PA microemulsions are nonpercolated, while PS microemulsions are percolated. SANS indicates small prolate ellipsoidal micelles with the absence of free water up to 18 wt % PS solution; DSC studies confirm the absence of free water in this composition range. Kinetic studies show an increase in the reaction rate with increasing concentration of the aqueous solution; but the most significant effect in reaction kinetics was noted when cosurfactant was used, regardless of microemulsion dynamics and structure. On the other hand, the main difference regarding the characteristics of the obtained nanoparticles was observed when bicontinuous microemulsions were used as reaction media which resulted in 8 nm nanoparticles, versus a constant size of ∼4 nm obtained with all other microemulsions regardless of aqueous solution content, dynamics, and presence or absence of cosurfactant. The latter effect of constant size is attributed to the fact that the water present is dominantly bound to the EO units of the surfactant. © 2013 American Chemical Society.


Pastor-Barriuso R.,Carlos III Institute of Health | Pastor-Barriuso R.,CIBER ISCIII | Lopez-Abente G.,Carlos III Institute of Health | Lopez-Abente G.,CIBER ISCIII
BMC Cancer | Year: 2014

Background: In contrast to other haematological cancers, mortality from non-Hodgkin's lymphoma and multiple myeloma increased dramatically during the second half of the 20th century in most developed countries. This widespread upward trend remains controversial, as it may be attributable either to progressive improvements in diagnosis and certification or to increasing exposures to little-known but relevant risk factors.Methods: To assess the relative contribution of these factors, we analysed the independent effects of age, death period, and birth cohort on haematological cancer mortality rates in Spain across the period 1952-2006. Weighted joinpoint regression analyses were performed to detect and estimate changes in period and cohort curvatures.Results: Although mortality rates were consistently higher among men, trends across periods and cohorts were virtually identical in both sexes. There was an early period trend reversal in the 1960s for Hodgkin's disease and leukaemia, which was delayed to the 1980s for multiple myeloma and the 1990s for non-Hodgkin's lymphoma. Birth cohort patterns showed a first downturn for generations born in the 1900s and 1910s for all haematological cancers, and a second trend reversal for more recent cohorts born in the 1950s and 1960s for non-Hodgkin's lymphoma and leukaemia.Conclusions: The sustained decline in Hodgkin's disease mortality and the levelling off in leukaemia seem to be driven by an early period effect linked to improvements in disease treatment, whereas the steep upward trends in non-Hodgkin's lymphoma and multiple myeloma mortality in Spain are more likely explained by a cohort effect linked to better diagnosis and death certification in the elderly. The consistent male excess mortality across all calendar periods and age groups points to the importance of possible sex-related genetic markers of susceptibility in haematological cancers. © 2014 Pastor-Barriuso and López-Abente; licensee BioMed Central Ltd.


Medina M.,CIBER ISCIII | Avila J.,CIBER ISCIII
Expert Opinion on Therapeutic Targets | Year: 2014

Introduction: Glycogen synthase kinase-3 (GSK-3) is recognized as a crucial player in many cellular functions and its activity is tightly controlled by complex mechanisms that are each dependent upon specific signaling pathways. Furthermore, GSK-3 dysfunction has been linked to a number of pathologies, including Alzheimer's disease (AD). In particular, the involvement of GSK-3 in several key pathophysiological pathways leading to AD and neurodegenerative diseases has placed this enzyme in a central position in this disorder. Areas covered: This article offers a review of the relationship between GSK-3 and AD with a special focus on recent evidence showing a key role of GSK-3 activity in modulating cellular pathways controlling amyloid formation, especially through the control of β-site APP-cleaving enzyme 1 gene expression, as well as its role as a key regulator of neurogenesis. Expert opinion: GSK-3 appears to be a cellular nexus, integrating several signaling systems, including several second messengers and a wide selection of cellular stimulants. The next few years will certainly bring us further insights into the cellular functions of this fascinating enzyme and its potential as a therapeutic target in AD and other neurological disorders. © 2014 Informa UK, Ltd.


Llorente-Cortes V.,Hospital Of La Santa Creu I Sant Pau | Barbarigo V.,Hospital Of La Santa Creu I Sant Pau | Badimon L.,Hospital Of La Santa Creu I Sant Pau | Badimon L.,CIBER ISCIII
Journal of Cellular Physiology | Year: 2012

Human hepatic stellate cells (HHSCs) proliferation and migration play a key role in the pathogenesis of liver inflammation and fibrogenesis. Low density lipoprotein receptor-related protein (LRP1) is an endocytic receptor involved in intracellular signal transduction. The aim of this work was to analyse the role of low density lipoprotein receptor-related protein (LRP1) in HHSCs proliferation and migration and the mechanisms involved. Human LRP1 deficient-HHSCs were generated by nucleofecting the line HHSCs with siRNA anti-LRP1. HHSCs DNA synthesis was measured by [ 3H]-thymidine incorporation and cell cycle progression by flow cytometry after annexin V and iodure propidium staining. Cell migration was assessed using a wound repair model system. LRP1 expression and extracellular matrix-regulated kinase (ERK1,2) phosphorylation were analysed by Western blot analysis. Transforming growth factor-β (TGF-β) extracellular levels were analysed by ELISA. siRNA-antiLRP1 treatment almost completely inhibited LRP1 mRNA and protein expression. LRP1 deficient HHSCs showed higher proliferative response (172±19 vs. 93±8 [ 3H]-thymidine incorporation; 78.68% vs. 82.69% in G0/G1, 21.32% vs. 17.30% in G2/S) and higher migration rates than control HHSCs. LRP1 deficient cells showed higher levels of phosphorylated ERK1,2. TGF-β extracellular levels were threefold higher in LRP1-deficient than in control HHSCs cells. These results demonstrate that LRP1 regulates HHSCs proliferation and migration through modulation of ERK1,2 phosphorylation and TGF-β extracellular levels. These results suggest that HHSCs-LRP1 may play a key role in the modulation of factors determining hepatic fibrosis. J. Cell. Physiol. 227: 3528-3533, 2012. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.


Anasagasti A.,Instituto Biodonostia | Irigoyen C.,Hospital Universitario Donostia | Barandika O.,Instituto Biodonostia | Lopez de Munain A.,Instituto Biodonostia | And 4 more authors.
Vision Research | Year: 2013

With a worldwide prevalence of about 1 in 3500-5000 individuals, Retinitis Pigmentosa (RP) is the most common form of hereditary retinal degeneration. It is an extremely heterogeneous group of genetically determined retinal diseases leading to progressive loss of vision due to impairment of rod and cone photoreceptors. RP can be inherited as an autosomal-recessive, autosomal-dominant, or X-linked trait. Non-Mendelian inheritance patterns such as digenic, maternal (mitochondrial) or compound heterozygosity have also been reported. To date, more than 65 genes have been implicated in syndromic and non-syndromic forms of RP, which account for only about 60% of all RP cases. Due to this high heterogeneity and diversity of inheritance patterns, the molecular diagnosis of syndromic and non-syndromic RP is very challenging, and the heritability of 40% of total RP cases worldwide remains unknown. However new sequencing methodologies, boosted by the human genome project, have contributed to exponential plummeting in sequencing costs, thereby making it feasible to include molecular testing for RP patients in routine clinical practice within the coming years. Here, we summarize the most widely used state-of-the-art technologies currently applied for the molecular diagnosis of RP, and address their strengths and weaknesses for the molecular diagnosis of such a complex genetic disease. © 2012 Elsevier Ltd.


Recuero M.,CIBER ISCIII | Bullido M.J.,CIBER ISCIII | Valdivieso F.,CIBER ISCIII | Aldudo J.,CIBER ISCIII
Neurobiology of Aging | Year: 2012

Mounting evidence suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer's disease (AD). Epidemiological analyses have shown that HSV-1 is a risk factor for AD in people with at least 1 type 4 allele of the apolipoprotein E gene. Recent studies have also suggested that HSV-1 contributes to the appearance of the biochemical anomalies characteristic of AD brains. In addition, autophagic activity appears to be reduced with aging, and the final stages of autophagy in neurodegenerative process appear to be impaired. The present work reports that HSV-1 provokes the strong intracellular accumulation of both the main species of β-amyloid (Aβ) in the autophagic compartments and that it is associated with a marked inhibition of Aβ secretion. Autophagosomes containing Aβ failed to fuse with lysosomes in HSV-1-infected cells, indicating the impaired degradation of Aβ localized in the autophagic vesicles. In addition, HSV-1 infection was associated with the inhibition of the nonamyloidogenic pathway of amyloid precursor protein (APP) processing without significantly affecting the activity of the secretases involved in the amyloidogenic pathway. Taken together, these data suggest that HSV-1 infection modulates autophagy and amyloid precursor protein processing, contributing to the accumulation of Aβ characteristic of AD. © 2012 Elsevier Inc.


Xia Y.,Salk Institute for Biological Studies | Nivet E.,Salk Institute for Biological Studies | Sancho-Martinez I.,La Jolla Salk Institute | Gallegos T.,Salk Institute for Biological Studies | And 8 more authors.
Nature Cell Biology | Year: 2013

Diseases affecting the kidney constitute a major health issue worldwide. Their incidence and poor prognosis affirm the urgent need for the development of new therapeutic strategies. Recently, differentiation of pluripotent cells to somatic lineages has emerged as a promising approach for disease modelling and cell transplantation. Unfortunately, differentiation of pluripotent cells into renal lineages has demonstrated limited success. Here we report on the differentiation of human pluripotent cells into ureteric-bud-committed renal progenitor-like cells. The generated cells demonstrated rapid and specific expression of renal progenitor markers on 4-day exposure to defined media conditions. Further maturation into ureteric bud structures was accomplished on establishment of a three-dimensional culture system in which differentiated human cells assembled and integrated alongside murine cells for the formation of chimeric ureteric buds. Altogether, our results provide a new platform for the study of kidney diseases and lineage commitment, and open new avenues for the future application of regenerative strategies in the clinic.


Soler-Botija C.,Heart Health | Bago J.R.,CIBER ISCIII | Bago J.R.,Cardiovascular Research Center | Bayes-Genis A.,Heart Health | And 2 more authors.
Annals of the New York Academy of Sciences | Year: 2012

Complete recovery of ischemic cardiac muscle after myocardial infarction is still an unresolved concern. In recent years, intensive research efforts have focused on mimicking the physical and biological properties of myocardium for cardiac repair. Here we show how heart regeneration approaches have evolved from cell therapy to refined tissue engineering. Despite progressive improvements, the best cell type and delivery strategy are not well established. Our group has identified a new population of cardiac adipose tissue-derived progenitor cells with inherent cardiac and angiogenic potential that is a promising candidate for cell therapy to restore ischemic myocardium. We also describe results from three strategies for cell delivery into a murine model of myocardial infarction: intramyocardial injection, implantation of a fibrin patch loaded with cells, and an engineered bioimplant (a combination of chemically designed scaffold, peptide hydrogel, and cells); dual-labeling noninvasive bioluminescence imaging enables in vivo monitoring of cardiac-specific markers and cell survival. © 2012 New York Academy of Sciences.


Kulisevsky J.,Hospital Of La Santa Creu I Sant Pau | Kulisevsky J.,CIBER ISCIII | Pagonabarraga J.,Hospital Of La Santa Creu I Sant Pau | Pagonabarraga J.,CIBER ISCIII
Drug Safety | Year: 2010

Background: Dopamine agonists have a well established role in the treatment of Parkinson's disease. The choice of a particular dopamine agonist requires assessing the benefit-risk balance of each available medication. Objective: The present study evaluated the tolerability and safety of ropinirole against those of other dopamine agonists (bromocriptine, cabergoline, pramipexole, rotigotine, pergolide) and placebo in monotherapy and adjuvant therapy with levodopa in the treatment of Parkinson's disease, as reported in the peer reviewed medical literature. Methods: A systematic review of the medical literature was carried out for relevant English language articles in the MEDLINE database and Cochrane Library from January 1975 to November 2008. The searches were limited to either double-blind clinical trials or randomized clinical trials that included both patients with early Parkinson's disease receiving dopamine agonist monotherapy, and patients at a later stage on combined treatment with levodopa. The Cochrane Collaboration guidelines were followed and the following data were extracted from each study: identifier (title and bibliographical reference), classification of the quality of the evidence (Jadad criteria), type and design of the study, number of patients, patient demographics (average age, sex), Parkinson's disease stage (Hoehn and Yahr Scale), treatment (monotherapy or adjuvant to levodopa), drugs used (including dosage and duration), study objective (safety or tolerability), method of evaluation of results, randomization and blinding, and description of all the adverse events in all treatment groups. A meta-analysis was performed, calculating relative risks (RRs) and confidence intervals for the 12 most relevant adverse events. On the basis of incidence and clinical importance criteria, the final selection of 12 adverse events was made by consensus between the investigators. Results: Forty randomized clinical trials were included. Direct comparison of ropinirole with bromocriptine showed a lower RR of constipation for ropinirole (0.55 [95% CI 0.35, 0.89]), while the direct comparison with levodopa showed a lower RR of dyskinesia for ropinirole (0.25 [95% CI 0.09, 0.71]); no significant differences for either dyskinesia or constipation were found when a direct comparison of ropinirole and rotigotine was made. For nausea, ropinirole, pergolide and rotigotine versus placebo all demonstrated similar RRs (2.25 [95%CI 1.85, 2.74]; 2.28 [95%CI 1.54, 3.37]; and 2.08 [95%CI 1.30, 3.34], respectively). On indirect comparison of ropinirole with pramipexole, ropinirole showed a higher RR for nausea (2.25 [95% CI 1.85, 2.74] vs 1.48 [95% CI 1.24, 1.76]), dizziness (1.87 [95% CI 1.48, 2.37] vs 1.20 [95% CI 1.01, 1.43]), somnolence (2.45 [95% CI 1.30, 4.61] vs 1.68 [95% CI 1.25, 2.25]), and dyskinesia (2.71 [95% CI 1.74, 4.21] vs 2.27 [95% CI 1.58, 3.27]). Pramipexole (3.36 [95% CI 2.41, 4.68], pergolide (4.80 [95% CI 2.24, 10.29]), ropinirole (2.84 [95% CI 1.34, 5.99]), and rotigotine (4.02 [95% CI 1.23, 13.11]) all had a higher RR of hallucinations compared with placebo. Pramipexole also showed a higher RR of confusion (2.64 [95% CI 1.18, 5.91]) and constipation (2.23 [95% CI 1.53, 3.25]) compared with placebo. Conclusions: In all the included studies, dopamine agonists, including ropinirole, exhibited a higher incidence of adverse events than placebo. Ropinirole showed an adverse event profile similar to other dopamine agonists. Consideration of the clinical characteristics of each patient and the differences in the incidence of adverse events related to each dopamine agonist, may help to optimize the dopamine agonist therapy. © 2010 Adis Data Information BV. All rights reserved.


Balsells M.,Hospital Universitari Mutua Of Terrassa | Garcia-Patterson A.,Hospital Of La Santa Creu I Sant Pau | Gich I.,Hospital Of La Santa Creu I Sant Pau | Corcoy R.,Hospital Of La Santa Creu I Sant Pau | Corcoy R.,CIBER ISCIII
Diabetes/Metabolism Research and Reviews | Year: 2012

Background: The risk of major congenital malformations (MCM) is increased in women with pregestational diabetes mellitus (PGDM). Whether this risk is increased in gestational diabetes mellitus (GDM) is still debated. The aim of this study was to perform a systematic review (and meta-analysis) of major congenital malformations in women with gestational diabetes versus a reference population. Methods: We conducted a MEDLINE search (1 January 1995 to 31 December 2009) of original studies reporting data on major congenital malformations in women with gestational diabetes and a reference group. Information on pregestational diabetes was collected when available. Two investigators considered studies for inclusion and extracted data; discrepancies were solved by consensus. Meta-analysis tools were used to summarize results. MOOSE and PRISMA guidelines were followed. Results: Two case control and 15 cohort studies were selected out of 3488 retrieved abstracts. A higher risk of major congenital malformations was observed in offspring of women with gestational diabetes with the following relative risk (RR)/odds ratios (OR) and 95% confidence intervals (CI): RR 1.16 (1.07-1.25) in cohort studies and OR 1.4 (1.22-1.62) in case control studies. Risk of major congenital malformations was much higher in offspring of women with PGDM than in those of the reference group: RR 2.66 (2.04-3.47) in cohort studies and OR 4.7 (3.01-6.95) in the single case control study providing information. Conclusion: There is a slightly higher risk of major congenital malformations in women with gestational diabetes than in the reference group. The contribution of women with overt hyperglycemia and other factors could not be ascertained. This risk, however, is much lower than in women with pregestational diabetes. © 2011 John Wiley & Sons, Ltd.


Gomez-Lechon M.J.,CIBER ISCIII | Donato M.T.,CIBER ISCIII | Donato M.T.,University of Valencia
Expert Opinion on Drug Metabolism and Toxicology | Year: 2014

Introduction: The liver is the most important target for drug-induced toxicity. This vulnerability results from functional liver features and its role in the metabolic elimination of most drugs. Drug-induced liver injury is a significant leading cause of acute, chronic liver disease and an important safety issue when developing new drugs. Areas covered: This review describes the advantages and limitations of hepatic cell-based models for early safety risk assessment during drug development. These models include hepatocytes cultured as monolayer, collagen-sandwich; emerging complex 3D configuration; liver-derived cell lines; stem cell-derived hepatocytes. Expert opinion: In vitro toxicity assays performed in hepatocytes or hepatoma cell lines can potentially provide rapid and cost-effective early feedback to identify toxic candidates for compound prioritization. However, their capacity to predict hepatotoxicity depends critically on cells' functional performance. In an attempt to improve and prolong functional properties of cultured cells, different strategies to recreate the in vivo hepatocyte environment have been explored. 3D cultures, co-cultures of hepatocytes with other cell types and microfluidic devices seem highly promising for toxicological studies. Moreover, hepatocytes derived from human pluripotent stem cells are emerging cell-based systems that may provide a stable source of hepatocytes to reliably screen metabolism and toxicity of candidate compounds. © 2014 Informa UK, Ltd.


Llorens R.,Polytechnic University of Valencia | Llorens R.,Servicio Of Neurorrehabilitacion Y Dano Cerebral Of Los Hospitales Nisa | Noe E.,Servicio Of Neurorrehabilitacion Y Dano Cerebral Of Los Hospitales Nisa | Colomer C.,Servicio Of Neurorrehabilitacion Y Dano Cerebral Of Los Hospitales Nisa | And 2 more authors.
Archives of Physical Medicine and Rehabilitation | Year: 2015

Objectives First, to evaluate the clinical effectiveness of a virtual reality (VR)-based telerehabilitation program in the balance recovery of individuals with hemiparesis after stroke in comparison with an in-clinic program; second, to compare the subjective experiences; and third, to contrast the costs of both programs. Design Single-blind, randomized, controlled trial. Setting Neurorehabilitation unit. Participants Chronic outpatients with stroke (N=30) with residual hemiparesis. Interventions Twenty 45-minute training sessions with the telerehabilitation system, conducted 3 times a week, in the clinic or in the home. Main Outcome Measures First, Berg Balance Scale for balance assessment. The Performance-Oriented Mobility Assessment balance and gait subscales, and the Brunel Balance Assessment were secondary outcome measures. Clinical assessments were conducted at baseline, 8 weeks (posttreatment), and 12 weeks (follow-up). Second, the System Usability Scale and the Intrinsic Motivation Inventory for subjective experiences. Third, cost (in dollars). Results Significant improvement in both groups (in-clinic group [control] and a home-based telerehabilitation group) from the initial to the final assessment in the Berg Balance Scale (ηp2=.68; P=.001), in the balance (ηp2=.24; P=.006) and gait (ηp2=.57, P=.001) subscales of the Tinetti Performance-Oriented Mobility Assessment, and in the Brunel Balance Assessment (control: χ2=15.0; P=.002; experimental: χ2=21.9; P=.001). No significant differences were found between the groups in any balance scale or in the feedback questionnaires. With regard to subjective experiences, both groups considered the VR system similarly usable and motivating. The in-clinic intervention resulted in more expenses than did the telerehabilitation intervention ($654.72 per person). Conclusions First, VR-based telerehabilitation interventions can promote the reacquisition of locomotor skills associated with balance in the same way as do in-clinic interventions, both complemented with a conventional therapy program; second, the usability of and motivation to use the 2 interventions can be similar; and third, telerehabilitation interventions can involve savings that vary depending on each scenario. © 2015 American Congress of Rehabilitation Medicine.


Grande-Perez A.,University of Malaga | Domingo E.,CIBER ISCIII | Martin V.,Research Center en Sanidad Animal
Viruses | Year: 2012

Lymphocytic choriomeningitis virus (LCMV) has contributed to unveil some of the molecular mechanisms of lethal mutagenesis, or loss of virus infectivity due to increased mutation rates. Here we review these developments, and provide additional evidence that ribavirin displays a dual mutagenic and inhibitory activity on LCMV that can be relevant to treatment designs. Using 5-fluorouracil as mutagenic agent and ribavirin either as inhibitor or mutagen, we document an advantage of a sequential inhibitor-mutagen administration over the corresponding combination treatment to achieve a low LCMV load in cell culture. This advantage is accentuated in the concentration range in which ribavirin acts mainly as an inhibitor, rather than as mutagen. This observation reinforces previous theoretical and experimental studies in supporting a sequential inhibitor-mutagen administration as a possible antiviral design. Given recent progress in the development of new inhibitors of arenavirus replication, our results suggest new options of ribavirin-based anti-arenavirus treatments. © 2012 by the authors; licensee MDPI, Basel, Switzerland.


Perales C.,CIBER ISCIII | Iranzo J.,CSIC - National Institute of Aerospace Technology | Manrubia S.C.,CSIC - National Institute of Aerospace Technology | Domingo E.,CIBER ISCIII | Domingo E.,CSIC - National Institute of Aerospace Technology
Trends in Microbiology | Year: 2012

The application of quasispecies theory to viral populations has boosted our understanding of how endogenous and exogenous features condition their adaptation. Mounting empirical evidence demonstrates that internal interactions within mutant spectra may cause unexpected responses to antiviral treatments. In this scenario, increased mutagenesis could be efficient at low mutagen doses due to the lethal action of defective genomes, whereas sequential administration of antiviral drugs might be superior to combination therapies. Our ability to predict the outcome of a particular therapy takes advantage of the complementary use of in vivo observations, in vitro experiments, and mathematical models. © 2012 Elsevier Ltd.


Leal-Egana A.,Friedrich - Alexander - University, Erlangen - Nuremberg | Leal-Egana A.,CEA Grenoble | Diaz-Cuenca A.,University of Seville | Diaz-Cuenca A.,CIBER ISCIII | Boccaccini A.R.,Friedrich - Alexander - University, Erlangen - Nuremberg
Advanced Materials | Year: 2013

Which mechanisms mediate cell attachment to biomaterials? What role does the surface charge or wettability play on cell-material anchorage? What are the currently investigated strategies to modify cell-matrix adherence spatiotemporally? Considering the development of scaffolds made of biocompatible materials to temporarily replace the structure and/or function of the extracellular matrix, focus is given to the analysis of the specific (i.e., cell adhesive peptide sequences) and unspecific (i.e., surface charge, wettability) mechanisms mediating cell-matrix interactions. Furthermore, because natural tissue regeneration is characterized by the dynamic attachment/detachment of different cell populations, the design of advanced scaffolds for tissue engineering, based in the spatiotemporal tuning of cell-matrix anchorage is discussed. Focus is given on the analysis of the specific and unspecific mechanisms mediating cell-matrix interactions. Furthermore, because natural tissue regeneration is characterized by the dynamic attachment/detachment of different cell populations, the advanced design of scaffolds for tissue engineering, based in the spatiotemporal tuning of cell-matrix anchorage, is discussed. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Baba T.,Catholic University of Louvain | Benitez-Ribas D.,CIBER ISCIII | Croockewit S.,Radboud University Nijmegen | Winkels G.,Miltenyi Biotec GmbH | And 2 more authors.
Cancer Research | Year: 2013

Vaccination against cancer by using dendritic cells has for more than a decade been based on dendritic cells generated ex vivo from monocytes or CD34+ progenitors. Here, we report on the first clinical study of therapeutic vaccination against cancer using naturally occurring plasmacytoid dendritic cells (pDC). Fifteen patients with metastatic melanoma received intranodal injections of pDCs activated and loaded with tumor antigen-associated peptides ex vivo. In vivo imaging showed that administered pDCs migrated and distributed over multiple lymph nodes. Several patients mounted antivaccine CD4+ and CD8+ T-cell responses. Despite the limited number of administered pDCs, an IFN signature was observed after each vaccination. These results indicate that vaccination with naturally occurring pDC is feasible with minimal toxicity and that in patients with metastatic melanoma, it induces favorable immune responses. © 2012 American Association for Cancer Research.


Ares-Santos S.,Instituto Cajal | Ares-Santos S.,CIBER ISCIII | Granado N.,Instituto Cajal | Granado N.,CIBER ISCIII | And 6 more authors.
Neuropsychopharmacology | Year: 2014

Methamphetamine is a widely abused illicit drug. Recent epidemiological studies showed that methamphetamine increases the risk for developing Parkinson's disease (PD) in agreement with animal studies showing dopaminergic neurotoxicity. We examined the effect of repeated low and medium doses vs single high dose of methamphetamine on degeneration of dopaminergic terminals and cell bodies. Mice were given methamphetamine in one of the following paradigms: three injections of 5 or 10 mg/kg at 3 h intervals or a single 30 mg/kg injection. The integrity of dopaminergic fibers and cell bodies was assessed at different time points after methamphetamine by tyrosine hydroxylase immunohistochemistry and silver staining. The 3 × 10 protocol yielded the highest loss of striatal dopaminergic terminals, followed by the 3 × 5 and 1 × 30. Some degenerating axons could be followed from the striatum to the substantia nigra pars compacta (SNpc). All protocols induced similar significant degeneration of dopaminergic neurons in the SNpc, evidenced by amino-cupric-silver-stained dopaminergic neurons. These neurons died by necrosis and apoptosis. Methamphetamine also killed striatal neurons. By using D1-Tmt/D2-GFP BAC transgenic mice, we observed that degenerating striatal neurons were equally distributed between direct and indirect medium spiny neurons. Despite the reduced number of dopaminergic neurons in the SNpc at 30 days after treatment, there was a partial time-dependent recovery of dopamine terminals beginning 3 days after treatment. Locomotor activity and motor coordination were robustly decreased 1-3 days after treatment, but recovered at later times along with dopaminergic terminals. These data provide direct evidence that methamphetamine causes long-lasting loss/degeneration of dopaminergic cell bodies in the SNpc, along with destruction of dopaminergic terminals in the striatum. © 2014 American College of Neuropsychopharmacology.


Berg M.V.D.,Carlos III Institute of Health | Castellote J.M.,Carlos III Institute of Health | Castellote J.M.,Complutense University of Madrid | Mahillo-Fernandez I.,Carlos III Institute of Health | And 2 more authors.
Journal of Neurotrauma | Year: 2011

Long-term incidence studies are required to identify high-risk groups, establish trends, and forecast needs, and thus contribute to health care planning in spinal cord injury (SCI). This study aimed to determine the incidence of traumatic SCI over a 36-year period in Aragón, Spain, and compare rates with other published European estimates. Hospital records from the Servet Hospital, the only specialized SCI unit in the region, of a retrospective cohort with traumatic SCI between January 1972 and December 2008 were reviewed. Specification of SCI patient demographics, injury causes, and related factors was achieved by utilizing medical records available for inpatients, hospital archives, and central databases. A total of 540 cases were reported over the 36-year study period (79% were male). The age-and sex-adjusted incidence rate was 15.5 per million population (18.8 for males and 4.9 for females). Two incidence peaks were suggested, in the 20-to 29-year and 60-to 69-year age groups. Traffic accidents and falls were the main causes of injury. The highest peak occurs in young adults, mainly caused by traffic accidents. The majority of the lesions were at cervical or thoracic level, and ASIA grade A was most frequently observed. The proportion of SCI cases in persons older than 60 years, mostly due to falls, is increasing. The age-adjusted incidence rates found for the region of Aragón in Spain fall within the range of other published European estimates. Comparative epidemiological features for 2001-2008 suggest that there is room for prevention. © Copyright 2011, Mary Ann Liebert, Inc.


Medina M.,CIBER ISCIII | Avila J.,CIBER ISCIII
Expert Review of Neurotherapeutics | Year: 2013

Originally discovered because of its role in the regulation of glucose metabolism, GSK-3 is now widely recognized as a crucial player in many cellular functions. Control of GSK-3 activity occurs by complex mechanisms that are each dependent upon specific signaling pathways. Furthermore, GSK-3 dysfunction has been linked to a number of pathologies, including Alzheimer's disease (AD). In particular, the involvement of GSK-3 in several key pathophysiological pathways leading to AD and neurodegenerative diseases has placed this enzyme in a central position in this disorder. In this article, the authors will specifically focus on the role of this enzyme as a key regulator of synaptic plasticity and how alterations in the GSK-3 synaptic functions may be a major factor in AD and other neurodegenerative disorders. © 2013 2013 Expert Reviews Ltd.


Cantoni J.,BioClever | Miravitlles M.,CIBER ISCIII
Respiratory Medicine | Year: 2012

Background: There is ample evidence of the differences between genders in chronic obstructive pulmonary disease (COPD). The purpose of this study was to identify the factors that contribute to these differences. Methods: This was a multi-center, cross-sectional observational study including 4574 patients of 40 years of age and older who attended primary care and pulmonary clinics. Data were collected on COPD characteristics, comorbidities, quality of life as assessed by both the EuroQoL 5D questionnaire (EQ-5D) and the Airways Questionnaire 20 (AQ20), and prevalence of anxiety and depression. Data collected were compared between males and females. Results: Mean age was 67 years and 740 patients (16.7%) were female. Women were significantly younger, had better pulmonary function, and smoked less; however, they showed poorer quality of life (EQ-5D: 0.6 [SD = 0.3] versus 0.7 [0.3]; p < 0.001; and AQ20: 10.4 [SD = 4.6] versus 9.2 [SD = 4.5]; p < 0.001) and a higher rate of anxiety (34.5% versus 20.6%; p < 0.001) and depression (31.7% versus 22.1%; p < 0.001). In a multivariate analysis, female gender was significantly associated to poorer quality of life (AQ20) but not to a higher rate of dyspnea. Conclusion: Women with COPD are younger and have lower rates of impaired lung function; however, they show poorer quality of life and more frequent COPD-associated anxiety and depression. © 2011 Elsevier Ltd. All rights reserved.


Martinez-Martin P.,CIBER ISCIII | Martinez-Martin P.,Carlos III Institute of Health | Rodriguez-Blazquez C.,CIBER ISCIII | Kurtis M.M.,Ruber International Hospital | And 2 more authors.
Movement Disorders | Year: 2011

Background: Non-motor symptoms are detrimental to health-related quality of life (HRQoL) of Parkinson's disease patients. In this study, the Non-Motor Symptoms Scale (NMSS) was used to assess the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. Methods: In a multicenter, international, cross sectional study on 411 Parkinson's disease patients, the NMSS was applied along with clinical (Hoehn and Yahr staging and SCOPA-Motor) and HRQoL measures (PDQ-39, and EQ-5D). Prevalence of non-motor symptoms was determined also through the NMSS. The association of NMSS and SCOPA-Motor with HRQoL measures and the differences in HRQoL scores between patients with and without non-motor symptoms in each NMSS domain were estimated by non-parametric statistics. Predictors of HRQoL were sought through multiple linear regression analyses. Results: Nocturia (68.4% of the sample), fatigue (65.9%), and dribbling saliva (56.7%), were the most frequent complaints. Total NMSS score: (1) showed a higher correlation coefficient (rS = 0.70) with the PDQ-39 Summary Index (SI) than SCOPA-Motor (rS = 0.58); (2) showed high-moderate correlation (rS = 0.60 - 0.38) with all PDQ-39 domains; and (3) was the best predictor of HRQoL as measured by the PDQ-39 SI. For each NMSS domain, patients with symptoms had significantly worse HRQoL scores than patients without symptoms. Discussion: To our knowledge, this is the first study to determine in a holistic manner the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. The results show that non-motor symptoms have, as a whole, a greater impact on HRQoL than motor symptoms and non-motor symptoms progression contributes importantly to HRQoL decline in patients with Parkinson's disease. © 2011 Movement Disorder Society.


Sicuri E.,University of Barcelona | Sicuri E.,CIBER ISCIII | Vieta A.,IMS Health | Lindner L.,IMS Health | Sauboin C.,Glaxosmithkline
Malaria Journal | Year: 2013

Background: Malaria causes significant mortality and morbidity in sub-Saharan Africa (SSA), especially among children less than five years of age (U5 children). Although the economic burden of malaria in this region has been assessed previously, the extent and variation of this burden remains unclear. This study aimed to estimate the economic costs of malaria in U5 children in three countries (Ghana, Tanzania and Kenya). Methods. Health system and household costs previously estimated were integrated with costs associated with co-morbidities, complications and productivity losses due to death. Several models were developed to estimate the expected treatment cost per episode per child, across different age groups, by level of severity and with or without controlling for treatment-seeking behaviour. Total annual costs (2009) were calculated by multiplying the treatment cost per episode according to severity by the number of episodes. Annual health system prevention costs were added to this estimate. Results: Household and health system costs per malaria episode ranged from approximately US$ 5 for non-complicated malaria in Tanzania to US$ 288 for cerebral malaria with neurological sequelae in Kenya. On average, up to 55% of these costs in Ghana and Tanzania and 70% in Kenya were assumed by the household, and of these costs 46% in Ghana and 85% in Tanzania and Kenya were indirect costs. Expected values of potential future earnings (in thousands) lost due to premature death of children aged 0-1 and 1-4 years were US$ 11.8 and US$ 13.8 in Ghana, US$ 6.9 and US$ 8.1 in Tanzania, and US$ 7.6 and US$ 8.9 in Kenya, respectively. The expected treatment costs per episode per child ranged from a minimum of US$ 1.29 for children aged 2-11 months in Tanzania to a maximum of US$ 22.9 for children aged 0-24 months in Kenya. The total annual costs (in millions) were estimated at US$ 37.8, US$ 131.9 and US$ 109.0 nationwide in Ghana, Tanzania and Kenya and included average treatment costs per case of US$ 11.99, US$ 6.79 and US$ 20.54, respectively. Conclusion: This study provides important insight into the economic burden of malaria in SSA that may assist policy makers when designing future malaria control interventions. © 2013 Sicuri et al.; licensee BioMed Central Ltd.


De Tassigny X.D.,University of Seville | Pascual A.,University of Seville | Lopez-Barneo J.,University of Seville | Lopez-Barneo J.,CIBER ISCIII
Frontiers in Neuroanatomy | Year: 2015

The glial cell line-derived neurotrophic factor (GDNF) is a well-established trophic agent for dopaminergic (DA) neurons in vitro and in vivo. GDNF is necessary for maintenance of neuronal morphological and neurochemical phenotype and protects DA neurons from toxic damage. Numerous studies on animal models of Parkinson's disease (PD) have reported beneficial effects of GDNF on nigrostriatal DA neuron survival. However, translation of these observations to the clinical setting has been hampered so far by side effects associated with the chronic continuous intra-striatal infusion of recombinant GDNF In addition, double blind and placebo-controlled clinical trials have not reported any clinically relevant effect of GDNF on PD patients. In the past few years, experiments with conditional Gdnf knockout mice have suggested that GDNF is necessary for maintenance of DA neurons in adulthood. In parallel, new methodologies for exogenous GDNF delivery have been developed. Recently, it has been shown that a small population of scattered, electrically interconnected, parvalbumin positive (PV+) GABAergic interneurons is responsible for most of the GDNF produced in the rodent striatum. In addition, cholinergic striatal interneurons appear to be also involved in the modulation of striatal GDNF In this review, we summarize current knowledge on brain GDNF delivery, homeostasis, and its effects on nigrostriatal DA neurons. Special attention is paid to the therapeutic potential of endogenous GDNF stimulation in PD. © 2015 d’Anglemont de Tassigny, Pascual and López-Barneo.


Hernando-Arizaleta L.,Direccion General de Planificacion | Rajmil L.,Catalan Agency for Health Information | Rajmil L.,Institute Municipal Dinvestigacio Medica Imim Parc Of Salut Mar | Rajmil L.,CIBER ISCIII
Pediatrics | Year: 2012

OBJECTIVES: To assess mental health and health-related quality of life (HRQoL) of children and adolescents in Spain and to investigate the existence of a social gradient in mental health and HRQoL. METHODS: Within the Spanish National Health Survey (2006), the parents' version of the Strengths and Difficulties Questionnaire was administered to a population aged 4 to 15 years, and the parents' version of the modified KIDSCREEN-10 Index was given to a population aged 8 to 15 years. Sociodemographic data and information on family structure, socioeconomic status, health status, and discrimination were collected. Regression models were developed to analyze associations of socioeconomic status with mental health and HRQoL. RESULTS: A total of 6414 children and adolescents aged 4 to 15 years participated. Mean Strengths and Difficulties Questionnaire score was 9.38 (SD, 5.84) and mean KIDSCREEN-10 Index score (n = 4446) was 85.21 (SD, 10.73). Children whose mothers had a primary school education (odds ratio [OR]: 1.37; 95% con fidence interval [CI]: 1.29 - 1.46) or a secondary education (OR: 1.21; 95% CI: 1.14 - 1.29) presented poorer mental health than those whose mothers had a university degree. Children from disadvantaged social classes (IV-V) showed slightly poorer HRQoL scores (OR: 0.98; CI: 0.97 -0.99) than the remaining children. CONCLUSIONS: There is a social gradient in the mental health of children and young adolescents in Spain. No social gradient was found for HRQoL, although children from families of disadvantaged social classes had slightly worse HRQoL scores than their counterparts from more advantaged classes. Copyright © 2012 by the American Academy of Pediatrics.


Castellano J.,Hospital Of La Santa Creu I Sant Pau | Aledo R.,Hospital Of La Santa Creu I Sant Pau | Aledo R.,CIBER ISCIII | Sendra J.,Hospital Of La Santa Creu I Sant Pau | And 5 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective- Hypoxia is considered a key factor in the progression of atherosclerotic lesions. Low-density lipoprotein receptor-related protein (LRP1) plays a pivotal role in the vasculature. The aim of this study was to investigate the effect of hypoxia on LRP1 expression and function in vascular smooth muscle cells (VSMC) and the role of hypoxia-inducible factor-α (HIF-1α). Methods and Results- Real-time polymerase chain reaction and Western blot analysis demonstrated that hypoxia (1% O2) time-dependently induced LRP1 mRNA (maximum levels at 1 to 2 hours) and protein expression (maximum levels at 12 to 24 hours). The delayed hypoxic upregulation of LRP1 protein versus mRNA may be explained by the long half-life of LRP1 protein. Luciferase assays demonstrated that hypoxia and HIF-1α overaccumulation induced LRP1 promoter activity and that 2 consensus hypoxia response element sites located at -1072/-1069 and -695/-692 participate in the induction. Chromatin immunoprecipitation showed the in vivo binding of HIF-1α to LRP1 promoter in hypoxic VSMC. Hypoxia effects on LRP1 protein expression were functionally translated into an increased cholesteryl ester (CE) accumulation from aggregated low-density lipoprotein (agLDL) uptake. The blockade of HIF-1α expression inhibited the upregulatory effect of hypoxia on LRP1 expression and agLDL-derived intracellular CE overaccumulation, suggesting that both LRP1 overexpression and CE overaccumulation in hypoxic vascular cells are dependent on HIF-1α. Immunohistochemical analysis showed the colocalization of LRP1 and HIF-1α in vascular cells of human advanced atherosclerotic plaques. Conclusion- Hypoxia upregulates LRP1 expression and agLDL-derived intracellular CE accumulation in human VSMC through HIF-1α induction. © 2011 American Heart Association, Inc.


Soler-Cataluna J.J.,Hospital Arnau Of Vilanova | Soler-Cataluna J.J.,CIBER ISCIII | Alcazar-Navarrete B.,Hospital Of Alta Resolucion | Miravitlles M.,CIBER ISCIII | Miravitlles M.,Hospital Universitari Vall Dhebron
International Journal of COPD | Year: 2014

Treatment of chronic obstructive pulmonary disease (COPD) requires a personalized approach according to the clinical characteristics of the patients, the level of severity, and the response to the different therapies. Furthermore, patients with the same level of severity measured by the degree of airflow obstruction or even with multidimensional indices may have very different symptoms and limitations for daily activities. The concept of control has been extensively developed in asthma but has not been defined in COPD. Here, we propose a definition of COPD control based on the concepts of impact and stability. Impact is a cross-sectional concept that can be measured by questionnaires such as the COPD Assessment Test or the Clinical COPD Questionnaire. Alternatively, impact can be assessed by the degree of dyspnea, the use of rescue medication, the level of physical activity, and sputum color. Stability is a longitudinal concept that requires the absence of exacerbations and deterioration in the aforementioned variables or in the COPD Assessment Test or Clinical COPD Questionnaire scores. Control is defined by low impact (adjusted for severity) and stability. The concept of control in COPD can be useful in the decision making regarding an increase or decrease in medication in the stable state. © 2014 Soler-Cataluña et al.


Codner E.,University of Chile | Merino P.M.,University of Chile | Tena-Sempere M.,University of Cordoba, Spain | Tena-Sempere M.,CIBER ISCIII | Tena-Sempere M.,Hospital Universitario Reina Sofia
Human Reproduction Update | Year: 2012

Background: The functional reproductive alterations seen in women with type 1 diabetes (T1D) have changed as therapy has improved. Historically, patients with T1D and insufficient metabolic control exhibited a high prevalence of amenorrhea, hypogonadism and infertility. This paper reviews the impact of diabetes on the reproductive axis of female T1D patients treated with modern insulin therapy, with special attention to the mechanisms by which diabetes disrupts hypothalamic-pituitary-ovarian function, as documented mainly by animal model studies. Methods: A comprehensive MEDLINE search of articles published from 1966 to 2012 was performed. Animal model studies on experimental diabetes and human studies on T1D were examined and cross-referenced with terms that referred to different aspects of the gonadotropic axis, gonadotrophins and gonadal steroids. Results: Recent studies have shown that women with T1D still display delayed puberty and menarche, menstrual irregularities (especially oligomenorrhoea), mild hyperandrogenism, polycystic ovarian syndrome, fewer live born children and possibly earlier menopause. Animal models have helped us to decipher the underlying basis of these conditions and have highlighted the variable contributions of defective leptin, insulin and kisspeptin signalling to the mechanisms of perturbed reproduction in T1D. Conclusions: Despite improvements in insulin therapy, T1D patients still suffer many reproductive problems that warrant specific diagnoses and therapeutic management. Similar to other states of metabolic stress, T1D represents a challenge to the correct functioning of the reproductive axis. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Pomarol-Clotet E.,Germanes Hospitalaries Del Sagrat Cor Of Jesu S | Canales-Rodriguez E.J.,Germanes Hospitalaries Del Sagrat Cor Of Jesu S | Salvador R.,Germanes Hospitalaries Del Sagrat Cor Of Jesu S | Sarro S.,Germanes Hospitalaries Del Sagrat Cor Of Jesu S | And 8 more authors.
Molecular Psychiatry | Year: 2010

Neuroimaging studies have found evidence of altered brain structure and function in schizophrenia, but have had complex findings regarding the localization of abnormality. We applied multimodal imaging (voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) combined with tractography) to 32 chronic schizophrenic patients and matched healthy controls. At a conservative threshold of P0.01 corrected, structural and functional imaging revealed overlapping regions of abnormality in the medial frontal cortex. DTI found that white matter abnormality predominated in the anterior corpus callosum, and analysis of the anatomical connectivity of representative seed regions again implicated fibres projecting to the medial frontal cortex. There was also evidence of convergent abnormality in the dorsolateral prefrontal cortex, although here the laterality was less consistent across techniques. The medial frontal region identified by these three imaging techniques corresponds to the anterior midline node of the default mode network, a brain system which is believed to support internally directed thought, a state of watchfulness, and/or the maintenance of one's sense of self, and which is of considerable current interest in neuropsychiatric disorders. © 2010 Macmillan Publishers Limited All rights reserved.


Roa J.,University of Cordoba, Spain | Roa J.,CIBER ISCIII | Roa J.,Hospital Universitario Reina Sofia | Tena-Sempere M.,University of Cordoba, Spain | And 2 more authors.
Molecular and Cellular Endocrinology | Year: 2014

It is well established that pubertal activation of the reproductive axis and maintenance of fertility are critically dependent on the magnitude of body energy reserves and the metabolic state of the organism. Hence, conditions of impaired energy homeostasis often result in deregulation of puberty and reproduction, whereas gonadal dysfunction can be associated with the worsening of the metabolic profile and, eventually, changes in body weight. While much progress has taken place in our knowledge about the neuroendocrine mechanisms linking metabolism and reproduction, our understanding of how such dynamic interplay happens is still incomplete. As paradigmatic example, much has been learned in the last two decades on the reproductive roles of key metabolic hormones (such as leptin, insulin and ghrelin), their brain targets and the major transmitters and neuropeptides involved. Yet, the molecular mechanisms whereby metabolic information is translated and engages into the reproductive circuits remain largely unsolved. In this work, we will summarize recent developments in the characterization of the putative central roles of key cellular energy sensors, such as mTOR, in this phenomenon, and will relate these with other molecular mechanisms likely contributing to the brain coupling of energy balance and fertility. In doing so, we aim to provide an updated view of an area that, despite still underdeveloped, may be critically important to fully understand how reproduction and metabolism are tightly connected in health and disease. © 2014 Elsevier Ireland Ltd.


Ndiaye C.,University of Montréal | Ndiaye C.,Sainte Justine Hospital Research Center | Mena M.,Catalan Institute of Nanoscience and Nanotechnology | Alemany L.,Catalan Institute of Nanoscience and Nanotechnology | And 11 more authors.
The Lancet Oncology | Year: 2014

Background: We aimed to provide updated information about the global estimates of attributable fraction and type distribution of human papillomavirus (HPV) in head and neck squamous cell carcinomas by doing a systematic review and meta-analysis. Methods: We did a literature search on PubMed to identify studies that used PCR for detection of HPV DNA in head and neck squamous cell carcinomas with information about HPV genotype distribution. We included studies that tested 20 or more biopsies per cancer site and were published between July 15, 1990, and Feb 29, 2012. We collected information about sex, risk factors, HPV detection methods, and biomarkers of potentially HPV-induced carcinogenesis (E6/E7 mRNA and p16INK4a). If it was not possible to abstract the required information directly from the paper, we contacted the authors. We did a meta-analysis to produce pooled prevalence estimates including a meta-regression to explore sources of heterogeneity. Findings: 148 studies were included, contributing data for 12 163 cases of head and neck squamous cell carcinoma from 44 countries. HPV DNA was detected in 3837 cases. HPV16 accounted for 82.2% (95% CI 77.7-86.4) of all HPV DNA positive cases. By cancer site, pooled HPV DNA prevalence estimates were 45.8% (95% CI 38.9-52.9) for oropharynx, 22.1% (16.4-28.3) for larynx (including hypopharynx), and 24.2% (18.7-30.2) for oral cavity. The percent positivity of p16INK4a positive cases in HPV-positive oropharyngeal cancer cases was 86.7% (95% CI 79.2-92.9) and of E6/E7 mRNA positive cases was 86.9% (73.2-96.8). The estimate of HPV attributable fraction in oropharyngeal cancer defined by expression of positive cases of E6/E7 mRNA was 39.8% and of p16INK4a was 39.7%. Of subsites, tonsils (53.9%, 95% CI 46.4-61.3) had the highest HPV DNA prevalence. HPV DNA prevalence varied significantly by anatomical site, geographic region, but not by sex or tobacco or alcohol consumption. Interpretation: The contribution of HPV prevalence in head and neck squamous cell carcinoma and in particular that of HPV16 in the oropharynx shows the potential benefit of prophylactic vaccines. Funding: European Commission. © 2014 Elsevier Ltd.


Alemany A.,University of Barcelona | Mossa A.,University of Aarhus | Ritort F.,University of Barcelona | Ritort F.,CIBER ISCIII
Nature Physics | Year: 2012

Recent advances in non-equilibrium statistical mechanics and single-molecule technologies have made it possible to use irreversible work measurements to extract free-energy differences associated with the mechanical (un)folding of molecules. To date, free-energy recovery has been focused on native (or equilibrium) molecular states, but free-energy measurements of kinetic states have remained unexplored. Kinetic states are metastable, finite-lifetime states that are generated dynamically, and play important roles in diverse physical processes. In biophysics, there are many examples in which these states determine the fate of molecular reactions, including protein binding, enzymatic reactions, as well as the formation of transient intermediate states during molecular-folding processes. Here we demonstrate that it is possible to obtain free energies of kinetic states by applying extended fluctuation relations, using optical tweezers to mechanically unfold and refold deoxyribonucleic acid (DNA) structures exhibiting intermediate and misfolded kinetic states. © 2012 Macmillan Publishers Limited. All rights reserved.


Delclos G.L.,University of Houston | Delclos G.L.,University Pompeu Fabra | Delclos G.L.,CIBER ISCIII
Occupational and Environmental Medicine | Year: 2012

Objectives: Work-related asthma (WRA) is an important public health problem affecting one quarter of adults with asthma. Although cleaning substances are routinely used in hospitals, few studies have addressed their potential adverse respiratory health effects on healthcare professionals (HCPs). This study attempts to identify relationship between work-related exposure to cleaning-related chemicals and development of WRA among HCPs. Methods: Of 5600 HCPs surveyed, 3650 responded to a validated questionnaire about their occupation, asthma diagnosis, variability of asthma symptoms at and away from work, and exposure to individual cleaning substances. Workplace asthma was defined as a categorical variable with four mutually exclusive categories: work-related asthma symptoms (WRAS), work-exacerbated asthma (WEA), occupational asthma (OA) and none. Multivariable logistic regression analysis was used to evaluate the association between self-reported use of cleaning substances and asthma outcomes among HCPs. Results: Prevalences of WRAS, WEA and OA were 3.3%, 1.1% and 0.8%, respectively. The prevalence estimates were generally higher among female than male HCPs. The odds of WRAS and WEA increased in a dose-dependent manner for exposure in the longest job to cleaning agents and disinfectants/sterilants, respectively. For exposure in any job, the odds of WRAS were significantly elevated for both factor 1 (bleach, cleaners/abrasives, toilet cleaners, detergents and ammonia) and factor 2 (glutaraldehyde/ortho- phtaldehyde, chloramines and ethylene oxide). Significantly elevated odds of WEA were observed for exposure to bleach, factor 2 and formalin/formaldehyde. Exposure to chloramines was significantly associated with an almost fivefold elevated odds of OA. Conclusions: HCPs are at risk of developing WRA from exposure to cleaning substances.


Roa J.,University of Cordoba, Spain | Roa J.,CIBER ISCIII | Roa J.,Hospital Universitario Reina Sofia
International Journal of Endocrinology | Year: 2013

Reproductive function is regulated by a plethora of signals that integrate physiological and environmental information. Among others, metabolic factors are key components of this circuit since they inform about the propitious timing for reproduction depending on energy availability. This information is processed mainly at the hypothalamus that, in turn, modulates gonadotropin release from the pituitary and, thereby, gonadal activity. Metabolic hormones, such as leptin, insulin, and ghrelin, act as indicators of the energy status and convey this information to the reproductive axis regulating its activity. In this review, we will analyse the central mechanisms involved in the integration of this metabolic information and their contribution to the control of the reproductive function. Particular attention will be paid to summarize the participation of GnRH, Kiss1, NPY, and POMC neurons in this process and their possible interactions to contribute to the metabolic control of reproduction. © 2013 Juan Roa.


Mullerova H.,Glaxosmithkline | Maselli D.J.,Audie L Murphy Hospital | Maselli D.J.,University of Texas Health Science Center at San Antonio | Locantore N.,Glaxosmithkline | And 9 more authors.
Chest | Year: 2015

OBJECTIVE: Exacerbations of COPD requiring hospital admission have important clinical and societal implications. We sought to investigate the incidence, recurrence, risk factors, and mortality of patients with COPD exacerbations requiring hospital admission compared with those without hospital admission during 3-year follow-up. Patients with COPD (N=2,138) were identified from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) observational cohort. METHODS: An analysis of time to first event of hospital admission was performed using Kaplan-Meier curves and Cox proportional hazard regression adjusting for possible confounders. RESULTS: Of the 2,138 patients, 670 (31%) reported a total of 1,452 COPD exacerbations requiring hospital admission during the study period; 313 patients (15%) reported multiple events. A prior history ofexacerbation of COPD requiring hospital admission was the factor associated with the highest risk of a new hospitalization for exacerbation (hazard ratio, 2.71; 95% CI, 2.24-3.29; P <.001). Other risk factors included more severe airfl ow limitation, poorer health status, older age, radiologic evidence ofemphysema, and higher WBC count. Having been hospitalized for exacerbation significantly increased the risk of mortality (P , <001). CONCLUSIONS: Exacerbations of COPD requiring hospital admission occur across all stages of airfl ow limitation and are a significant prognostic factor ofreduced survival across all COPD stages. Patients with COPD at a high risk for hospitalization can be identified by their past history for similar events, and other factors, including the severity of airfl ow limitation, poor health status, age, presence ofemphysema, and leukocytosis. © 2015 American College of Chest Physicians.


Luengo-Oroz M.A.,Technical University of Madrid | Luengo-Oroz M.A.,CIBER ISCIII | Arranz A.,Nebutek Soluciones SL | Frean J.,South African National Institute for Communicable Diseases | Frean J.,University of Witwatersrand
Journal of Medical Internet Research | Year: 2012

Background: There are 600,000 new malaria cases daily worldwide. The gold standard for estimating the parasite burden and the corresponding severity of the disease consists in manually counting the number of parasites in blood smears through a microscope, a process that can take more than 20 minutes of an expert microscopist's time. Objective: This research tests the feasibility of a crowdsourced approach to malaria image analysis. In particular, we investigated whether anonymous volunteers with no prior experience would be able to count malaria parasites in digitized images of thick blood smears by playing a Web-based game. Methods: The experimental system consisted of a Web-based game where online volunteers were tasked with detecting parasites in digitized blood sample images coupled with a decision algorithm that combined the analyses from several players to produce an improved collective detection outcome. Data were collected through the MalariaSpot website. Random images of thick blood films containing Plasmodium falciparum at medium to low parasitemias, acquired by conventional optical microscopy, were presented to players. In the game, players had to find and tag as many parasites as possible in 1 minute. In the event that players found all the parasites present in the image, they were presented with a new image. In order to combine the choices of different players into a single crowd decision, we implemented an image processing pipeline and a quorum algorithm that judged a parasite tagged when a group of players agreed on its position. Results: Over 1 month, anonymous players from 95 countries played more than 12,000 games and generated a database of more than 270,000 clicks on the test images. Results revealed that combining 22 games from nonexpert players achieved a parasite counting accuracy higher than 99%. This performance could be obtained also by combining 13 games from players trained for 1 minute. Exhaustive computations measured the parasite counting accuracy for all players as a function of the number of games considered and the experience of the players. In addition, we propose a mathematical equation that accurately models the collective parasite counting performance. Conclusions: This research validates the online gaming approach for crowdsourced counting of malaria parasites in images of thick blood films. The findings support the conclusion that nonexperts are able to rapidly learn how to identify the typical features of malaria parasites in digitized thick blood samples and that combining the analyses of several users provides similar parasite counting accuracy rates as those of expert microscopists. This experiment illustrates the potential of the crowdsourced gaming approach for performing routine malaria parasite quantification, and more generally for solving biomedical image analysis problems, with future potential for telediagnosis related to global health challenges.


Andino R.,University of California at San Francisco | Domingo E.,CIBER ISCIII
Virology | Year: 2015

New generation sequencing is greatly expanding the capacity to examine the composition of mutant spectra of viral quasispecies in infected cells and host organisms. Here we review recent progress in the understanding of quasispecies dynamics, notably the occurrence of intra-mutant spectrum interactions, and implications of fitness landscapes for virus adaptation and de-adaptation. Complementation or interference can be established among components of the same mutant spectrum, dependent on the mutational status of the ensemble. Replicative fitness relates to an optimal mutant spectrum that provides the molecular basis for phenotypic flexibility, with implications for antiviral therapy. The biological impact of viral fitness renders particularly relevant the capacity of new generation sequencing to establish viral fitness landscapes. Progress with experimental model systems is becoming an important asset to understand virus behavior in the more complex environments faced during natural infections. © 2015.


Calvillo J.,University of Seville | Calvillo J.,CIBER ISCIII | Roman I.,University of Seville | Roman I.,CIBER ISCIII | And 2 more authors.
International Journal of Medical Informatics | Year: 2013

Background: Advancements in information and communication technologies have allowed the development of new approaches to the management and use of healthcare resources. Nowadays it is possible to address complex issues such as meaningful access to distributed data or communication and understanding among heterogeneous systems. As a consequence, the discussion focuses on the administration of the whole set of resources providing knowledge about a single subject of care (SoC). New trends make the SoC administrator and responsible for all these elements (related to his/her demographic data, health, well-being, social conditions, etc.) and s/he is granted the ability of controlling access to them by third parties. The subject of care exchanges his/her passive role without any decision capacity for an active one allowing to control who accesses what. Purpose: We study the necessary access control infrastructure to support this approach and develop mechanisms based on semantic tools to assist the subject of care with the specification of access control policies. This infrastructure is a building block of a wider scenario, the Person-Oriented Virtual Organization (POVO), aiming at integrating all the resources related to each citizen's health-related data. The POVO covers the wide range and heterogeneity of available healthcare resources (e.g., information sources, monitoring devices, or software simulation tools) and grants each SoC the access control to them. Methods: Several methodological issues are crucial for the design of the targeted infrastructure. The distributed system concept and focus are reviewed from the service oriented architecture (SOA) perspective. The main frameworks for the formalization of distributed system architectures (Reference Model-Open Distributed Processing, RM-ODP; and Model Driven Architecture, MDA) are introduced, as well as how the use of the Unified Modelling Language (UML) is standardized. The specification of access control policies and decision making mechanisms are essential keys for this approach and they are accomplished by using semantic technologies (i.e., ontologies, rule languages, and inference engines). Results: The results are mainly focused on the security and access control of the proposed scenario. An ontology has been designed and developed for the POVO covering the terminology of the scenario and easing the automation of administration tasks. Over that ontology, an access control mechanism based on rule languages allows specifying access control policies, and an inference engine performs the decision making process automatically. The usability of solutions to ease administration tasks to the SoC is improved by the Me-As-An-Admin (M3A) application. This guides the SoC through the specification of personal access control policies to his/her distributed resources by using semantic technologies (e.g., metamodeling, model-to-text transformations, etc.). All results are developed as services and included in an architecture in accordance with standards and principles of openness and interoperability. Conclusions: Current technology can bring health, social and well-being care actually centered on citizens, and granting each person the management of his/her health information. However, the application of technology without adopting methodologies or normalized guidelines will reduce the interoperability of solutions developed, failing in the development of advanced services and improved scenarios for health delivery. Standards and reference architectures can be cornerstones for future-proof and powerful developments. Finally, not only technology must follow citizen-centric approaches, but also the gaps needing legislative efforts that support these new paradigms of healthcare delivery must be identified and addressed. © 2012 Elsevier Ireland Ltd.


Peinado J.R.,University of Sfax | Diaz-Ruiz A.,University of Cordoba, Spain | Diaz-Ruiz A.,CIBER ISCIII | Fruhbeck G.,CIBER ISCIII | And 3 more authors.
Proteomics | Year: 2014

Mitochondria play a key role as major regulators of cellular energy homeostasis, but in the context of mitochondrial dysfunction, mitochondria may generate reactive oxidative species and induce cellular apoptosis. Indeed, altered mitochondrial status has been linked to the pathogenesis of several metabolic disorders and specially disorders related to insulin resistance, such as obesity, type 2 diabetes, and other comorbidities comprising the metabolic syndrome. In the present review, we summarize information from various mitochondrial proteomic studies of insulin-sensitive tissues under different metabolic states. To that end, we first focus our attention on the pancreas, as mitochondrial malfunction has been shown to contribute to beta cell failure and impaired insulin release. Furthermore, proteomic studies of mitochondria obtained from liver, muscle, and adipose tissue are summarized, as these tissues constitute the primary insulin target metabolic tissues. Since recent advances in proteomic techniques have exposed the importance of PTMs in the development of metabolic disease, we also present information on specific PTMs that may directly affect mitochondria during the pathogenesis of metabolic disease. Specifically, mitochondrial protein acetylation, phosphorylation, and other PTMs related to oxidative damage, such as nitrosylation and carbonylation, are discussed. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Molina-Montes E.,CIBER ISCIII | Donadio D.,University of California at Davis | Hernaandez-Laguna A.,University of Granada | Sainz-Diiaz C.I.,University of Granada
Journal of Physical Chemistry B | Year: 2010

We have investigated the process of rehydroxylation of pyrophyllite as a limiting factor to the dehydroxylation upon thermal treatment. Car-Parrinello molecular dynamics simulations based on density functional theory have been used along with the metadynamics algorithm. Two possible rehydroxylation mechanisms reaction have been characterized, related to two possible intermediate structures along the rehydroxylation paths, and both involve the interaction of the apical oxygen atoms. At high temperature, the rehydroxylation reaction is highly competitive (free energy barrier (δF) = 1.5 kcal/mol) and inhibits the progress of the dehydroxylation reaction (δF = 40 kcal/mol). In addition to the rehydroxylation of the dehydroxylated structure, the water molecule supports the interconversion of the cross and on-site intermediates as well. Thus, rehydroxylation and interconversion among intermediates can justify the wide range of transformations as a function of the temperature observed experimentally. © 2010 American Chemical Society.


Tinahones F.J.,CIBER ISCIII | Onaca A.,Pelican Hospital of Oradea | Cleall S.,Eli Lilly and Company | Rodriguez A.,Lilly Spain
Diabetes, Obesity and Metabolism | Year: 2014

Aims: To compare the efficacy and safety of two insulin intensification strategies in patients with type 2 diabetes inadequately controlled on basal insulin glargine with metformin and/or pioglitazone. Methods: A multinational, randomized, open-label trial that compared insulin lispro low mixture (LM25; n=236) twice daily with a basal-prandial regimen of insulin glargine once daily and insulin lispro once daily (IGL; n=240) over 24weeks in patients with HbA1c 7.5-10.5% and fasting plasma glucose =6.7 mmol/l. The primary objective was to assess non-inferiority [per-protocol (PP) population], and then superiority [intention-to-treat (ITT) population], of LM25 versus IGL according to change in HbA1c after 24weeks (non-inferiority margin 0.4%, two-sided significance level 0.05). Results: Estimated change [least squares (LS) mean (95% CI)] in HbA1c after 24 weeks: -1.30 (-1.44, -1.16)% with LM25 and -1.08 (-1.22, -0.94)%with IGL. Non-inferioritywas shown [LSmean (95% CI) HbA1c treatment difference-0.21 (-0.38,-0.04) (PP population)]; gated superiority assessment showed a statistically significant advantage for LM25 (p=0.010; ITT population). Mean blood glucose, glycaemic variability, overall tolerability and hypoglycaemic episodes per patient-year did not show significant differences between treatments during the study. Conclusions: In patients with type 2 diabetes inadequately controlled on once-daily basal insulin glargine and metformin and/or pioglitazone, intensification with LM25 was superior to a basal-prandial approach in terms of reduction in HbA1c after 24 weeks and did not increase hypoglycaemia episodes. © 2014 John Wiley & Sons Ltd.


Leentjens A.F.G.,Maastricht University | Dujardin K.,Lille University Hospital Center | Marsh L.,Johns Hopkins University | Marsh L.,Baylor College of Medicine | And 3 more authors.
Movement Disorders | Year: 2011

Anxiety is understudied in Parkinson's disease (PD), which is not justified by the prevalence and impact of anxiety disorders on quality of life in PD patients. In this cross-sectional study, 342 patients suffering from idiopathic PD underwent a research-based assessment including DSM IV criteria for anxiety disorders, the Hamilton anxiety rating scale (HARS) and the beck anxiety inventory (BAI). Thirty-four percent (34%) of subjects met the DSM IV criteria for at least one anxiety disorder; 11.8% met criteria for multiple anxiety disorders; and 11.4% had clinically relevant anxiety symptoms without meeting the criteria for any specific anxiety disorder. Score profiles on the HARS and BAI differed significantly between the disorders, but these differences were associated with different scores on a limited number of items, and the respective symptom profiles were not readily interpretable. Female sex, the presence of motor fluctuations, as well as a previous history of an anxiety disorder were markers for anxiety disorders. The use of a mono-amino oxidase (MAO)-B inhibitor was associated with a reduced prevalence of anxiety disorders. Research into anxiety in PD is hampered by the questionable validity of DSM IV defined anxiety disorders in this population. A first focus for research should therefore be the identification of clinically useful anxiety presentations and their validation in PD. © 2011 Movement Disorder Society.


Tortosa E.,CIBER ISCIII | Tortosa E.,University Utrecht | Galjart N.,Erasmus University Rotterdam | Avila J.,CIBER ISCIII | Sayas C.L.,CIBER ISCIII
EMBO Journal | Year: 2013

MAP1B, a structural microtubule (MT)-associated protein highly expressed in developing neurons, plays a key role in neurite and axon extension. However, not all molecular mechanisms by which MAP1B controls MT dynamics during these processes have been revealed. Here, we show that MAP1B interacts directly with EB1 and EB3 (EBs), two core 'microtubule plus-end tracking proteins' (+TIPs), and sequesters them in the cytosol of developing neuronal cells. MAP1B overexpression reduces EBs binding to plus-ends, whereas MAP1B downregulation increases binding of EBs to MTs. These alterations in EBs behaviour lead to changes in MT dynamics, in particular overstabilization and looping, in growth cones of MAP1B-deficient neurons. This contributes to growth cone remodelling and a delay in axon outgrowth. Together, our findings define a new and crucial role of MAP1B as a direct regulator of EBs function and MT dynamics during neurite and axon extension. Our data provide a new layer of MT regulation: a classical MAP, which binds to the MT lattice and not to the end, controls effective concentration of core +TIPs thereby regulating MTs at their plus-ends. © 2013 European Molecular Biology Organization.


Diez-Domingo J.,Centro Superior Of Investigaciones En Salud Publica Of Valencia Csisp | San-Martin-Rodriguez M.,Sanofi S.A. | Puig-Barbera J.,Centro Superior Of Investigaciones En Salud Publica Of Valencia Csisp | Navarro-Perez J.,CIBER ISCIII
BMC Infectious Diseases | Year: 2011

Background: Data on the epidemiology and costs related to herpes zoster (HZ) and postherpetic neuralgia (PHN) in Spain are scarce; therefore, studies are needed to evaluate the epidemiological and economic impact of HZ and its most common complication, PHN. The present study aimed to estimate the clinical and economic burden of HZ and PHN in Valencia (Spain).Methods: We prospectively analyzed the burden of HZ and PHN and their attributable costs in patients from 25 general practices in the Autonomous Community of Valencia serving 36,030 persons aged > 14 years. All patients with a clinical diagnosis of HZ who attended these centers between December 1 st2006 and November 30 th2007 were asked to participate. Patients included were followed for 1 year.Results: Of the 130 cases of HZ followed up, continued pain was experienced by 47.6% (95% confidence interval (CI) = 35.6-56.7%) at 1 month after rash onset, by 14.5% (95% CI = 7.8-1.2%) at 3 months, by 9.0% (95% CI = 3.7-14.3%) at 6 months, and by 5.9% (95% CI = 1.5-10.3%) at 12 months. The percentage of patients with PHN increased with age, from 21.4% (95% CI = 8.3-40) in patients < 50 years to 59.2% (95% CI = 44.4-74) in patients ≥ 70 years. The estimated total cost for the 130 HZ cases during the follow-up period was €49,160 ($67,349). Mean cost per patient was €378 (range 53-2,830) ($517, range 73-3,877).Conclusions: This study shows that PHN is a relatively common complication of HZ and that both conditions combined give rise to a significant clinical and economic burden for patients and providers. © 2011 Cebrián-Cuenca et al; licensee BioMed Central Ltd.


Ballesteros I.,Complutense University of Madrid | Cuartero M.I.,Complutense University of Madrid | Rossaint J.,University of Munster | Bilbao I.,CIBER ISCIII | And 9 more authors.
Science | Year: 2014

Immune and inflammatory responses require leukocytes to migrate within and through the vasculature, a process that is facilitated by their capacity to switch to a polarized morphology with an asymmetric distribution of receptors. We report that neutrophil polarization within activated venules served to organize a protruding domain that engaged activated platelets present in the bloodstream.The selectin ligand PSGL-1 transduced signals emanating from these interactions resulting in the redistribution of receptors that drive neutrophil migration. Consequently, neutrophils unable to polarize or to transduce signals through PSGL-1 displayed aberrant crawling and blockade of this domain protected mice against thromboinflammatory injury. These results reveal that recruited neutrophils scan for activated platelets and they suggest that the neutrophils' bipolarity allows the integration of signals present at both the endothelium and the circulation before inflammation proceeds. ©2014 by the American Association for the Advancement of Science; all rights reserved.


Conte I.,Telethon Institute of Genetics and Medicine | Banfi S.,Telethon Institute of Genetics and Medicine | Banfi S.,The Second University of Naples | Bovolenta P.,CIBER ISCIII
Cellular and Molecular Life Sciences | Year: 2013

Genomes are transcribed well beyond the conventionally annotated protein-encoding genes and produce many thousands of regulatory non-coding RNAs (ncRNAs). In the last few years, ncRNAs, especially microRNAs and long non-coding RNA, have received increasing attention because of their implication in the function of chromatin-modifying complexes and in the regulation of transcriptional and post-transcriptional events. The morphological events and the genetic networks responsible for the development of sensory organs have been well delineated and therefore sensory organs have provided a useful scenario to address the role of ncRNAs. In this review, we summarize the current information on the importance of microRNAs and long non-coding RNAs during the development of the eye, inner ear, and olfactory system in vertebrates. We will also discuss those cases in which alteration of ncRNA expression has been linked to pathological conditions affecting these organs. © 2013 Springer Basel.


Lucas R.,University of Seville | Gomez-Pinto I.,CSIC - Institute of Physical Chemistry "Rocasolano" | Avino A.,CIBER ISCIII | Reina J.J.,University of Seville | And 3 more authors.
Journal of the American Chemical Society | Year: 2011

Carbohydrate-nucleic acid contacts are known to be a fundamental part of some drug-DNA recognition processes. Most of these interactions occur through the minor groove of DNA, such as in the calicheamicin or anthracycline families, or through both minor and major groove binders such as in the pluramycins. Here, we demonstrate that carbohydrate-DNA interactions are also possible through sugar capping of a DNA double helix. Highly polar mono- and disaccharides are capable of CH/π stacking onto the terminal DNA base pair of a duplex as shown by NMR spectroscopy. The energetics of the carbohydrate-DNA interactions vary depending on the stereochemistry, polarity, and contact surface of the sugar involved and also on the terminal base pair. These results reveal carbohydrate-DNA base stacking as a potential recognition motif to be used in drug design, supramolecular chemistry, or biobased nanomaterials. © 2011 American Chemical Society.


Ruano E.G.,CIBER ISCIII | Ruano E.G.,Diabetes and Obesity Research Laboratory | Canivell S.,Diabetes and Obesity Research Laboratory | Vieira E.,CIBER ISCIII | Vieira E.,Diabetes and Obesity Research Laboratory
PLoS ONE | Year: 2014

REV-ERB ALPHA has been shown to link metabolism with circadian rhythms. We aimed to identify new polymorphisms in the promoter of REV-ERB ALPHA and tested whether these polymorphisms could be associated with obesity in the Spanish population. Of the 1197 subjects included in our study, 779 were obese (BMI 34.38±3.1 kg/m2) and 418 lean (BMI 23.27±1.5 kg/m2). In the obese group, 469 of the 779 had type 2 diabetes. Genomic DNA from all the subjects was obtained from peripheral blood cells and the genotyping in the REV-ERB ALPHA promoter was analyzed by High Resolution Melting. We found six polymorphisms in the REV-ERB ALPHA promoter and identified rs939347 as a SNP with the highest frequency in the total population. We did not find any association between rs939347 and type 2 diabetes (p = 0.101), but rs939347 was associated with obesity (p = 0.036) with the genotype AA exhibiting higher frequency in the obese (5.2% in total obese vs 2.4% in lean). This association was found only in men (p = 0.031; 6.5% AA-carriers in obese men vs 1.9% AA-carriers in lean men), with no association found in the female population (p = 0.505; 4.4% AA-carriers in obese women vs 2.7% AA-carriers in lean women). Our results suggest that the REV-ERB ALPHA rs939347 polymorphism could modulate body fat mass in men. The present work supports the role of REV-ERB ALPHA in the development of obesity as well as a potential target for the treatment of obesity. © 2014 Ruano et al.


Patent
University of Seville and Ciber Isciii | Date: 2016-09-14

The invention relates to an intelligent bioimpedance sensor for biomedical applications, which can carry out bioimpedance measurements in a plurality of configurable frequencies, process data in order to obtain the modulus and the phase of the bioimpedance (or real and imaginary part of the bioimpedance) in each of the frequencies, and wirelessly transmit the results of the processing, configured by means of a device that is in contact with the biological means to be measured by means of a series of electrodes in such a way that the device injects electrical current, via said electrodes, into the biological means, in the different frequencies, and measures the tension generated by the circulation of said current based on the joint operation of various subsystems.


Marco A.,Health Services of Barcelona Mens Penitentiary Center | Esteban J.I.,CIBER ISCIII | Sole C.,Health Services of Brians 1 Penitentiary Center | Da Silva A.,Health Services of Quatre Camins Penitentiary Center | And 6 more authors.
Journal of Hepatology | Year: 2013

Background & Aims We estimated HCV reinfection rate and its associated risk factors in inmates with chronic hepatitis C who had achieved sustained virological response (SVR) after completing combination therapy while in prison. Methods Individuals who had achieved an SVR after treatment provided from January 2003 to December 2009 at four prisons in Catalonia, had been tested annually for HCV RNA and were in prison during 2010, were invited to complete a questionnaire regarding risk factors for reinfection. Incidence rate was calculated as 100 person-years of follow-up. Risk factors potentially associated with reinfection were evaluated by bivariate log-rank test and multivariate Cox regression analysis. Results One hundred and nineteen subjects who had achieved an SVR agreed to participate. 98% were male, with a median age of 33.3 ± 6.3 years and 81% had a history of injection drug use (IDU). After a mean follow-up of 1.4 years, HCV reinfection was identified in nine former IDUs, seven with HCV genotype switch, for an overall reinfection rate of 5.27 cases per 100 person-years. Reinfection incidence was significantly higher among active drug users (HR = 12.47; 95% CI: 2.90-53.71), HIV co-infected (HR = 9.95; 95% CI: 1.73-57.34), and those engaging in more than one risk behaviors after treatment (HR = 7.47; 95% CI: 1.19-46.89). Conclusions HCV reinfection among inmates after successful treatment is high especially in those with ongoing IDU. Preventative interventions at diagnosis and during and after HCV treatment should be strongly reinforced. © 2013 European Association for the Study of the Liver. Published.


Lopez-Campos J.L.,University of Seville | Lopez-Campos J.L.,CIBER ISCIII | Hartl S.,Ludwig Boltzmann Institute of COPD and Respiratory Epidemiology | Pozo-Rodriguez F.,CIBER ISCIII | And 2 more authors.
European Respiratory Journal | Year: 2014

Studies have suggested that larger hospitals have better resources and provide better care than smaller ones. This study aimed to explore the relationship between hospital size, resources, organisation of care and adherence to guidelines. The European COPD Audit was designed as a pilot study of clinical care and a survey of resources and organisation of care. Data were entered by clinicians to a multilingual web tool and analysed centrally. Participating hospitals were divided into tertiles on the basis of bed numbers and comparisons made of the resources, organisation of care and adherence to guidelines across the three size groups. 13 national societies provided data on 425 hospitals. The mean number of beds per tertile was 220 (lower), 479 (middle), and 989 (upper). Large hospitals were more likely to have resources and increased numbers of staff; hospital performance measures were related in a minority of indicators only. Adherence to guidelines also varied with hospital size, but the differences were small and inconsistent. There is a wide variation in the size, resources and organisation of care across Europe for hospitals providing chronic obstructive pulmonary disease care. While larger hospitals have more resources, this does not always equate to better accessibility or quality of care for patients.


Rodriguez-Munoz M.,CIBER ISCIII | De La Torre-Madrid E.,Cajal Institute | Sanchez-Blazquez P.,CIBER ISCIII | Sanchez-Blazquez P.,Cajal Institute | And 3 more authors.
Antioxidants and Redox Signaling | Year: 2011

In the brain, the mu-opioid receptor (MOR) activates neural nitric oxide synthase (nNOS) through the PI3K/Akt pathway. The resulting nitric oxide (NO) enhances the function of the glutamate N-methyl-d-aspartate receptor (NMDAR)/calcium and calmodulin-dependent serine/threonine kinase (CaMKII), which subsequently diminishes MOR signaling strength. Because the ERK1/2 cascade is implicated in opioid tolerance, we analyzed the role of morphine-generated NO in this negative regulation. We found that NO-released endogenous zinc ions recruit the Ras/Raf-1/ERK1/2 cassette to histidine triad nucleotide-binding protein 1 (HINT1). A-Raf and B-Raf showed little or no MOR association. The zinc ions bridge the Raf-1 cysteine-rich domain (CRD) with HINT1 at the MOR C-terminus. Morphine also recruits PKCγ via NO/zinc to the MOR-HINT1 complex. Both Raf-1 and PKCγ CRDs bind simultaneously to HINT1, enabling PKCγ to enhance Raf-1 function to intensify MEK/ERK1/2 activation. Thus, through attached HINT1, the MOR facilitates the cross-talk of two NO- and zinc-regulated signal-transduction pathways, PKC/Src and Raf-1/ERK1/2, implicated in the negative control of morphine effects. This study reveals new aspects of ERK1/2 regulation by the MOR without requiring the transactivation of a receptor tyrosine kinase. © 2011 Mary Ann Liebert, Inc.


Gonzalez-Dominguez R.,University of Huelva | Garcia-Barrera T.,University of Huelva | Vitorica J.,University of Seville | Vitorica J.,CIBER ISCIII | Gomez-Ariza J.L.,University of Huelva
Molecular BioSystems | Year: 2015

There is growing evidence that Alzheimer's disease may be a widespread systemic disorder, so peripheral organs could be affected by pathological mechanisms occurring in this neurodegenerative disease. For this reason, a double metabolomic platform based on the combination of gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry was used for the first time to investigate metabolic changes in liver and kidney from the transgenic mice APP/PS1 against wild-type controls. Multivariate statistics showed significant differences in levels of numerous metabolites including phospholipids, sphingolipids, acylcarnitines, steroids, amino acids and other compounds, which denotes that multiple pathways might be associated with systemic pathogenesis of Alzheimer's in this mouse model, such as bioenergetic failures, oxidative stress, altered metabolism of membrane lipids, hyperammonemia or impaired homeostasis of steroids. Furthermore, it is noteworthy that some novel pathological mechanisms were found, such as impaired gluconeogenesis, polyol pathway or metabolism of branched chain amino acids, not previously described for Alzheimer's disease. Therefore, these findings clearly support the hypothesis that Alzheimer's disease may be considered as a systemic disorder. © The Royal Society of Chemistry 2015.


Bratov A.,CSIC - National Center of Microelectronics | Abramova N.,CSIC - National Center of Microelectronics | Marco M.P.,CIBER ISCIII | Sanchez-Baeza F.,CIBER ISCIII
Electroanalysis | Year: 2012

Possible applications of a new transducer based on a three dimensional interdigitated electrode array (3D-IDEA) with electrode digits separated by an insulating barrier are discussed. Due to the presence of insulating barriers that separate the adjacent digits of the electrodes the main portion of the probing electrical current goes close to the surface of the barrier. Chemical modification of the barrier surface with the probe molecules permits to realise direct detection of subsequent target analytes in solution. The functional mechanism of the device is based on registration of changes in conductivity at the surface of the barrier provoked by electrical charge redistribution caused by surface chemical reactions. Three-dimensional sensor shows considerable improvement in sensitivity compared with a standard planar IDEA design sensors. The potential of the developed device as a sensor transducer to detect various chemical and bio chemical reactions is demonstrated. Examples include enzyme immobilisation, polyelectrolytes layer-by-layer deposition, covalent chemical modification with molecules containing reactive thiol groups. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Boggs D.A.,Boston University | Rosenberg L.,Boston University | Rodriguez-Bernal C.L.,Center for Public Health Research | Rodriguez-Bernal C.L.,CIBER ISCIII | Palmer J.R.,Boston University
Journal of Nutrition | Year: 2013

The prevalence of obesity [body mass index (BMI) ≥30 kg/m2] is high among African American women, with most weight gain occurring before middle age. We assessed diet quality, as measured by the Alternate Healthy Eating Index-2010 (AHEI-2010) and the Dietary Approaches to Stop Hypertension (DASH) diet score in relation to incident obesity in the Black Women's Health Study. Prospective data were collected via biennial questionnaires from 1995 to 2011. AHEI-2010 and DASH scores were calculated from food-frequency questionnaire data collected in 1995 and 2001. We restricted the analysis to 19,885 nonobese women aged 21-39 y at baseline. Multivariable Cox regression was used to estimate HRs and 95% CIs. Among women with consistent diet scores in 1995 and 2001, higher diet quality scores were inversely associated with obesity incidence: the multivariable HRs comparing highest with lowest quintiles of the AHEI-2010 and DASH scores were 0.76 (95% CI: 0.58, 0.98) and 0.68 (95% CI: 0.53, 0.88), respectively, among women with a BMI in the normal range (18.5-24.9 kg/m2) at baseline. There were no significant associations among women who were overweight at baseline. The findings suggest that a high-quality diet that is sustained over time is associated with reduced obesity risk among young African American women with a normal BMI at baseline. © 2013 American Society for Nutrition.


Nazelle A.D.,University of North Carolina at Chapel Hill | Nazelle A.D.,Center for Research in Environmental Epidemiology | Nazelle A.D.,Municipal Institute of Medical Research IMIM Hospital Del Mar | Nazelle A.D.,CIBER ISCIII | And 2 more authors.
Environmental Science and Technology | Year: 2010

States in the USA are required to demonstrate future compliance of criteria air pollutant standards by using both air quality monitors and model outputs. In the case of ozone, the demonstration tests aim at relying heavily on measured values, due to their perceived objectivity and enforceable quality. Weight given to numerical models is diminished by integrating them in the calculations only in a relative sense. For unmonitored locations, the EPA has suggested the use of a spatial interpolation technique to assign current values. We demonstrate that this approach may lead to erroneous assignments of nonattainment and may make it difficult for States to establish future compliance. We propose a method that combines different sources of information to map air pollution, using the Bayesian Maximum Entropy (BME) Framework. The approach gives precedence to measured values and integrates modeled data as a function of model performance. We demonstrate this approach in North Carolina, using the States ozone monitoring network in combination with outputs from the Multiscale Air Quality Simulation Platform (MAQSIP) modeling system. We show that the BME data integration approach, compared to a spatial interpolation of measured data, improves the accuracy and the precision of ozone estimations across the State. © 2010 American Chemical Society.


Chowdhry S.,University of Dundee | Zhang Y.,University of Dundee | McMahon M.,University of Dundee | Sutherland C.,Ninewells Hospital and Medical School | And 2 more authors.
Oncogene | Year: 2013

Identification of regulatable mechanisms by which transcription factor NF-E2 p45-related factor 2 (Nrf2) is repressed will allow strategies to be designed that counter drug resistance associated with its upregulation in tumours that harbour somatic mutations in Kelch-like ECH-associated protein-1 (Keap1), a gene that encodes a joint adaptor and substrate receptor for the Cul3-Rbx1/Roc1 ubiquitin ligase. We now show that mouse Nrf2 contains two binding sites for β-transducin repeat-containing protein (β-TrCP), which acts as a substrate receptor for the Skp1-Cul1-Rbx1/Roc1 ubiquitin ligase complex. Deletion of either binding site in Nrf2 decreased β-TrCP-mediated ubiquitylation of the transcription factor. The ability of one of the two β-TrCP-binding sites to serve as a degron could be both increased and decreased by manipulation of glycogen synthase kinase-3 (GSK-3) activity. Biotinylated-peptide pull-down assays identified DSGIS 338 and DSAPGS 378 as the two β-TrCP-binding motifs in Nrf2. Significantly, our pull-down assays indicated that β-TrCP binds a phosphorylated version of DSGIS more tightly than its non-phosphorylated counterpart, whereas this was not the case for DSAPGS. These data suggest that DSGIS, but not DSAPGS, contains a functional GSK-3 phosphorylation site. Activation of GSK-3 in Keap1-null mouse embryonic fibroblasts (MEFs), or in human lung A549 cells that contain mutant Keap1, by inhibition of the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)/Akt pathway markedly reduced endogenous Nrf2 protein and decreased to 10-50% of normal the levels of mRNA for prototypic Nrf2-regulated enzymes, including the glutamate-cysteine ligase catalytic and modifier subunits, glutathione S-transferases Alpha-1 and Mu-1, haem oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Pre-treatment of Keap1-/-MEFs or A549 cells with the LY294002 PI3K inhibitor or the MK-2206 PKB/Akt inhibitor increased their sensitivity to acrolein, chlorambucil and cisplatin between 1.9-fold and 3.1-fold, and this was substantially attenuated by simultaneous pre-treatment with the GSK-3 inhibitor CT99021. © 2013 Macmillan Publishers Limited.


Martinez-Martin P.,CIBER ISCIII | Leentjens A.F.G.,Maastricht University | de Pedro-Cuesta J.,CIBER ISCIII | Chaudhuri K.R.,King's College London | And 3 more authors.
Movement Disorders | Year: 2016

Parkinson's disease includes neuropsychiatric manifestations, such as depression, anxiety, apathy, psychosis, and impulse control disorders, which often are unreported by patients and caregivers or undetected by doctors. Given their substantial impact on patients and caregivers as well as the existence of effective therapies for some of these disorders, screening for neuropsychiatric symptoms is important. Instruments for screening have a particular methodology for validation, and their performance is expressed in terms of accuracy compared with formal diagnostic criteria. The present study reviews the attributes of the screening instruments applied for detection of the aforementioned major neuropsychiatric symptoms in Parkinson's disease. A quasi-systematic review (including predefined selection criteria, but not evaluating the quality of the reviewed studies) was carried out on the basis of previous systematic reviews (commissioned by the American Academy of Neurology and the Movement Disorder Society) and made current by conducting a literature search (2005-2014). For depression, 11 scales and questionnaires were shown to be valid for Parkinson's disease screening. The recently developed Parkinson Anxiety Scale and the Geriatric Anxiety Inventory demonstrate satisfactory properties as screening instruments for anxiety, and the Lille Apathy Rating Scale for detection of apathy. No scale adequately screens for psychosis, so a specific psychosis instrument should be developed. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (Questionnaire and Rating Scale) are valid for comprehensive screening of impulse control disorders, and the Parkinson's Disease-Sexual Addiction Screening Test for hypersexuality specifically. © 2015 International Parkinson and Movement Disorder Society.


Sanchez-Cruz J.-J.,Escuela Andaluza de Salud Publica | Jimenez-Moleon J.J.,University of Granada | Jimenez-Moleon J.J.,CIBER ISCIII | Fernandez-Quesada F.,Hospital Universitario San Cecilio | And 2 more authors.
Revista Espanola de Cardiologia | Year: 2013

Introduction and objectives: Obesity is a major cardiovascular risk factor. In Spain, few studies have physically measured height and weight to estimate the magnitude of the problem. The aim of this study was to determine the prevalence of child and adolescent obesity in Spain in 2012. Methods: We performed a cross-sectional probability sample of 1018 children, representative of the Spanish population aged between 8 and 17 years old, with objectively measured height and weight, along with other sociodemographic variables. We calculated the prevalence of overweight and obesity according to the criteria of the World Health Organization, the International Obesity Task Force, and the enKid study. Results: In the group aged 8 to 17 years old, the prevalence of overweight and obesity was 26% and 12.6%, respectively; 4 in 10 young people were overweight or obese. Excess weight was found in 45% of the group aged 8 to 13 years and in 25.5% of that aged 14 to 17 years. This cardiovascular risk factor was associated with lower social class and lower educational level. Conclusions: The prevalence of overweight and obesity in children and adolescents in Spain remains high (close to 40%), but has not increased in the last 12 years. © 2012 Sociedad Española de Cardiología. Publicado por Elsevier España, S.L. Todos los derechos reservados.


Plans-Rubio P.,Public Health Agency of Catalonia | Plans-Rubio P.,CIBER ISCIII
Expert Review of Anti-Infective Therapy | Year: 2014

Elimination of measles and rubella in Europe is a feasible objective, but it requires achieving a maintaining a high prevalence of protected individuals in order to prevent cases and outbreaks from imported cases. The epidemiology of measles and rubella in Europe in the period 2003-2013 suggests that we are far away from the elimination target for measles, while the situation is better for rubella. In this situation, a new preventive strategy based on serological surveillance systems should be developed in Europe in order to identify and immunise individuals in population groups without sufficient herd immunity against measles and rubella. © 2014 Informa UK, Ltd..


Girn M.,University Miguel Hernández | Fernndez-Yaez A.,Babel Health | Ma-Alvarenga S.,Petrer Mental Health Center | Molina-Habas A.,Ciutat Jard Mental Health Center | And 3 more authors.
Psychological Medicine | Year: 2010

Background Empirical evidence of the efficacy and effectiveness of psychosocial family intervention and of the specificity of its effects on the course of schizophrenia is limited. The aim was to study the efficacy and effectiveness of psychosocial family intervention with regard to clinical and social functioning and family burden after controlling for compliance and several prognostic factors.Method A 2-year randomized controlled trial with blind assessments. Fifty patients with DSM-IV schizophrenia and persistent positive symptoms and/or previous clinical relapse were allocated to psychosocial family intervention, individual counselling and standard treatment versus individual counselling and standard treatment.Results Family intervention was associated with fewer clinical relapses, hospitalizations and major incidents, and an improvement in positive and negative symptoms, social role performance, social relations, employment and family burden. The reduction in hospitalizations in the family intervention group was significantly greater than that observed in the group of patients who refused to participate but this was not the case for the control group. The effects of family intervention were independent of compliance and prognostic factors.Conclusions Family intervention is effective in severe schizophrenia independently of compliance and prognostic factors. © Copyright Cambridge University Press 2009.


Teresa Donato M.,Hospital La Fe | Teresa Donato M.,CIBER ISCIII | Teresa Donato M.,University of Valencia | Gomez-Lechon M.J.,Hospital La Fe | Gomez-Lechon M.J.,CIBER ISCIII
Current Drug Metabolism | Year: 2012

The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spectrum of lesions, e.g., steatosis and phospholipidosis. Steatosis is increased lipid accumulation, mainly as triglycerides, in the liver, while phospholipidosis is a lysosomal storage disorder characterised by intracellular accumulation of phospholipids. These alterations can be induced by several factors, including exposure to certain drugs. Drug-induced steatosis is often reversible, and prolonged exposure to certain drugs can cause macrovacuolar steatosis, a benign hepatic lesion, that can evolve into steatohepatitis and cirrhosis in some patients. Some drugs may acutely induce microvesicular steatosis which, despite having a good short-term prognosis, can lead to chronic lipid peroxidation and to the development of steatohepatitis lesions with time. Over 50 marketed drugs have been reported to induce phospholipidosis in different tissues, including the liver. Although drug-induced phospholipidosis is often reversible and there is no definitive evidence for its toxicological implications, it is considered an adverse side finding by regulatory agencies. As developing new drugs is a complex, lengthy and expensive process that aims to identify pharmacologically active, low-toxicity drug candidates among closely related compounds, it could be advantageous to determine which drugs are able to induce lipid metabolic disorders in early developmental stages. To this end, in vitro predictive screening assays, particularly cell-based approaches in which many drug candidates are evaluated, have been developed to identify and rule out compounds with a strong liver steatosis and/or phospholipidosis-inducing potential. © 2012 Bentham Science Publishers.


Ortega F.J.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Ortega F.J.,CIBER ISCIII | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Fernandez-Real J.M.,CIBER ISCIII
Hormone and Metabolic Research | Year: 2013

Recent findings in adipose tissue (AT) have uncovered negative interactions among obesity, lipogenesis, and fatty acid (FA) storage, perhaps in response to the increased production of proinflammatory cytokines and transcription factors. Emerging evidence highlights that local hypoxia, generation of reactive oxygen and nitrogen species, increased immune cells infiltration and activation, senescence, inflammation, energy consumption, and decreased lipogenesis in the AT are interrelated and may lead to impaired cytokine and hormonal secretion by adipocytes, and ectopic fat deposition in obesity that strengths the increased risk of suffering metabolic disorders in obese subjects. The information summarized in this review attempts to defend the interdependent relationship of these proofs of concept, supporting the idea that inflamed and dysfunctional AT are synonymous when referring to obesity. This may happen in severe obese subjects with a large and long-lasting fat excess, when fat depots have reached the point in which excessive fat storage, cell density, and diminished oxygen availability promote decreased lipo/adipogenesis and increased lipolysis and FA release. This response may be induced by an important inflammatory component that promotes angiogenesis and insulin resistance, but also by leptin and the increase of T3 in hyperplastic AT. © 2013 Georg Thieme Verlag KG Stuttgart New York.


Garcia I.,CIBER ISCIII | Gallo J.,CIBER ISCIII | Genicio N.,CIBER ISCIII | Padro D.,CIBER ISCIII | Penades S.,CIBER ISCIII
Bioconjugate Chemistry | Year: 2011

A versatile nanoplatform based on magnetic glyconanoparticles (glyco-ferrites) to attach well-oriented antibodies is described. An efficient ligand exchange process has been used to prepare water-soluble 6-nm-sized core-shell Fe3O4@Au nanoparticles bearing amphiphilic carbohydrates and aliphatic ethylene glycol chains ended in a carboxyl group. The covalent immobilization through the carboxyl group of an Fc receptor (protein G) enables successful well-oriented capture of immunoglobulins G onto the magnetic glyconanoparticle. A thorough characterization of structure and biofunctionality of the constructs is carried out by different techniques. The selective immunolabeling of cells by the antibody-magnetic glyconanoparticle conjugates is demonstrated by magnetic resonance imaging (MRI), as well as by fluorescence techniques. © 2011 American Chemical Society.


Franco-Pons N.,CIBER ISCIII | Casas J.,CSIC - Institute of Advanced Chemistry of Catalonia | Fabrias G.,CSIC - Institute of Advanced Chemistry of Catalonia | Gea-Sorli S.,CIBER ISCIII | And 3 more authors.
Annals of Surgery | Year: 2013

OBJECTIVE: To evaluate the generation of halogenated fatty acids in the areas of fat necrosis during acute pancreatitis and to evaluate the effects of these molecules on the ensuing inflammatory process. BACKGROUND: Lipid mediators derived from adipose tissue have been implicated in the progression of acute pancreatitis, although their precise role remains unknown. METHODS: Acute pancreatitis was induced in rats by intraductal infusion of 3.5% sodium taurocholate. Fatty acid chlorohydrins (FA-Cl) were measured in adipose tissue, ascitic fluid, and plasma by mass spectrometry. Chlorohydrins were also instilled in the rats' peritoneal cavity, and their effects on peritoneal macrophages activation and in systemic inflammation were evaluated. Finally, they have also been measured in plasma from human patients with acute pancreatitis. RESULTS: Induced acute pancreatitis results in a substantial release not only of free fatty acids but also of the chlorohydrins of both oleic and linoleic acids from adipose tissue. In plasma, only the chlorohydrin of oleic acid was detected. Administration of 250-μM lipid chlorohydrins, which is the concentration found in ascitic fluid, induces the expression of TNFα and interleukin-1β in peritoneal macrophages and increases the systemic inflammatory response in pancreatitis. Finally, increased concentrations of oleic acid chlorohydrin have been found in plasma of human patients with pancreatitis. CONCLUSIONS: During acute pancreatitis, adipose tissue release FA-Cl, which exacerbate the systemic inflammatory response. Copyright © 2013 by Lippincott Williams & Wilkins.


Lopez M.,University of Santiago de Compostela | Lopez M.,CIBER ISCIII | Alvarez C.V.,University of Santiago de Compostela | Nogueiras R.,University of Santiago de Compostela | And 3 more authors.
Trends in Molecular Medicine | Year: 2013

Classically, medical textbooks taught that most effects of thyroid hormones (THs) on energy homeostasis are directly exerted in peripheral tissues. However, current evidence is changing (and challenging) our perspective about the role of THs from a 'peripheral' to a 'central' vision, implying that they affect food intake, energy expenditure, and metabolism by acting, to a large extent, at the central level. Interestingly, effects of THs are interrelated with global energy sensors in the central nervous system (CNS), such as uncoupling protein 2 (UCP2), AMP-activated protein kinase (AMPK; the 'AMPK-BAT axis'), and mechanistic target of rapamycin (mTOR). Here, we review what is currently known about THs and their regulation of energy balance and metabolism in both peripheral and central tissues. © 2013 Elsevier Ltd.


Quintero E.,University of La Laguna | Carrillo M.,University of La Laguna | Gimeno-Garcia A.Z.,University of La Laguna | Hernandez-Guerra M.,University of La Laguna | And 5 more authors.
Gastroenterology | Year: 2014

Background & Aims Colonoscopy is the recommended screening procedure for first-degree relatives of patients with colorectal cancer (CRC), but few studies have compared its efficacy for CRC detection with that of other screening strategies. We conducted a controlled randomized trial to compare the efficacy of repeated fecal immunochemical tests (FITs) and colonoscopy in detecting advanced neoplasia (advanced adenoma or CRC) in family members of patients with CRC.Methods In a prospective study, 1918 first-degree relatives of patients with CRC were randomly assigned (1:1 ratio) to receive a single colonoscopy examination or 3 FITs (1/year for 3 years; OC-Sensor; cutoff ≤10 μg hemoglobin/g feces, corresponding to 50 ng hemoglobin/mL buffer). The strategies were considered to be equivalent if the 95% confidence interval of the difference for the detection of advanced neoplasia was ±3%. Follow-up analyses were performed to identify false-negative FIT results and interval CRCs.Results Of all eligible asymptomatic first-degree relatives, 782 were included in the colonoscopy group and 784 in the FIT group. In the intention-to-screen analysis, advanced neoplasia was detected in 33 (4.2%) and 44 (5.6%) first-degree relatives in the FIT and colonoscopy groups, respectively (odds ratio = 1.41; 95% confidence interval: 0.88-2.26; P =.14). In the per-protocol analysis, 28 first-degree relatives (3.9%) in the FIT group and 43 (5.8%) in the colonoscopy group had advanced neoplasia (odds ratio = 1.56; 95% confidence interval: 0.95-2.56; P =.08). FIT missed 16 of 41 advanced adenomas but no CRCs. The FIT strategy required endoscopic evaluation of 4-fold fewer individuals to detect 1 advanced neoplasia than the colonoscopy strategy.Conclusions Repeated FIT screening (1/year for 3 years) detected all CRCs and proved equivalent to colonoscopy in detecting advanced neoplasia in first-degree relatives of patients with CRC. This strategy should be considered for populations where compliance with FITs is higher than with colonoscopy. ClinicalTrials.gov number: NCT01075633 (COLONFAM Study). © 2014 by the AGA Institute.


Minones-Moyano E.,Genetic Causes of Disease Group | Minones-Moyano E.,University of Barcelona | Porta S.,Genetic Causes of Disease Group | Porta S.,University of Barcelona | And 10 more authors.
Human Molecular Genetics | Year: 2011

MicroRNAs (miRNAs) are post-transcriptional gene expression regulators, playing key roles in neuronal development, plasticity and disease. Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the presence of protein inclusions or Lewy bodies and a progressive loss of dopaminergic neurons in the midbrain. Here, we have evaluated miRNA expression deregulation in PD brain samples. MiRNA expression profiling revealed decreased expression of miR-34b and miR-34c in brain areas with variable neuropathological affectation at clinical (motor) stages (Braak stages 4 and 5) of the disease, including the amygdala, frontal cortex, substantia nigra and cerebellum. Furthermore, misregulation of miR-34b/c was detected in pre-motor stages (stages 1-3) of the disease, and thus in cases that did not receive any PD-related treatment during life. Depletion of miR-34b or miR-34c in differentiated SH-SY5Y dopaminergic neuronal cells resulted in a moderate reduction in cell viability that was accompanied by altered mitochondrial function and dynamics, oxidative stress and reduction in total cellular adenosin triphosphate content. MiR-34b/c downregulation was coupled to a decrease in the expression of DJ1 and Parkin, two proteins associated to familial forms of PD that also have a role in idiopathic cases. Accordingly, DJ1 and Parkin expression was reduced in PD brain samples displaying strong miR-34b/c downregulation. We propose that early deregulation of miR-34b/c in PD triggers downstream transcriptome alterations underlying mitochondrial dysfunction and oxidative stress, which ultimately compromise cell viability. A better understanding of the cellular pathways controlling and/or controlled by miR-34b/c should allow identification of targets for development of therapeutic approaches. © The Author 2011. Published by Oxford University Press. All rights reserved.


Gea J.,University Pompeu Fabra | Gea J.,CIBER ISCIII | Agusti A.,CIBER ISCIII | Agusti A.,University of Barcelona | And 2 more authors.
Journal of Applied Physiology | Year: 2013

Muscle dysfunction often occurs in patients with chronic obstructive pulmonary disease (COPD) and may involve both respiratory and locomotor (peripheral) muscles. The loss of strength and/or endurance in the former can lead to ventilatory insufficiency, whereas in the latter it limits exercise capacity and activities of daily life. Muscle dysfunction is the consequence of complex interactions between local and systemic factors, frequently coexisting in COPD patients. Pulmonary hyperinflation along with the increase in work of breathing that occur in COPD appear as the main contributing factors to respiratory muscle dysfunction. By contrast, deconditioning seems to play a key role in peripheral muscle dysfunction. However, additional systemic factors, including tobacco smoking, systemic inflammation, exercise, exacerbations, nutritional and gas exchange abnormalities, anabolic insufficiency, comorbidities and drugs, can also influence the function of both respiratory and peripheral muscles, by inducing modifications in their local microenvironment. Under all these circumstances, protein metabolism imbalance, oxidative stress, inflammatory events, as well as muscle injury may occur, determining the final structure and modulating the function of different muscle groups. Respiratory muscles show signs of injury as well as an increase in several elements involved in aerobic metabolism (proportion of type I fibers, capillary density, and aerobic enzyme activity) whereas limb muscles exhibit a loss of the same elements, injury, and a reduction in fiber size. In the present review we examine the current state of the art of the pathophysiology of muscle dysfunction in COPD. Copyright © 2013 the American Physiological Society.


Gomez-Barroso D.,CIBER ISCIII | Rodriguez-Valin E.,CIBER ISCIII | Ramis R.,CIBER ISCIII | Cano R.,CIBER ISCIII
International Journal of Tuberculosis and Lung Disease | Year: 2013

BACKGROUND: The characteristics of respiratory tuberculosis (TB) favour the appearance of clusters of cases in space and time. It is important for public health authorities to know which clusters occur randomly and which merit further investigation. OBJECTIVE: To detect spatial and spatio-temporal clusters of respiratory TB in Spain during the period from 1 January 2008 to 31 December 2010. MATERIALS AND METHODS: Retrospective spatiotemporal study of respiratory TB cases reported to Spain's National Epidemiological Surveillance Network from 2008 to 2010, at a municipal level. We used the purely spatial and space-time Scan statistic estimators. All analyses were adjusted for age and sex. RESULTS: The spatial cluster analysis detected 28 significant clusters and the spatio-temporal cluster analysis detected 20 significant clusters. The most likely spatial cluster comprised seven municipalities in the Greater Barcelona Area. Most space-time clusters were situated in the same area, and were detected between 1 April 2008 and 31 March 2009. CONCLUSION: The distribution of TB clusters as shown by the proposed models furnishes a spatial pattern of the distribution of the disease. The two methods used can be a useful tool for analysing the distribution of respiratory TB in Spain. © 2013 The Union.


Sia D.,HCC Translational Research Laboratory | Sia D.,Italian National Cancer Institute | Villanueva A.,HCC Translational Research Laboratory | Villanueva A.,CIBER ISCIII
Oncology | Year: 2011

Hepatocellular carcinoma (HCC) is the sixth most common cancer, and its mortality rate is the third highest after lung and colon cancer. Its incidence has significantly increased in the last two decades in close relation with the ubiquitous spread of viral hepatitis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Molecular therapies such as sorafenib, a BRAF/ VEGFR/PDGFR tyrosine kinase inhibitor, have shown to improve survival in patients with advanced HCC. This recent success has spurred intensive research aimed at identifying aberrant activation of signaling pathways. This approach will probably aid to define previously unrecognized oncogenic addiction loops in HCC and in developing more effective targeted therapies. Copyright © 2011 S. Karger AG.


Marin C.,Institute dInvestigacions Biomdiques August Pi i Sunyer IDIBAPS | Marin C.,CIBER ISCIII | Aguilar E.,Institute dInvestigacions Biomdiques August Pi i Sunyer IDIBAPS
Neurochemistry International | Year: 2011

Numerous reports suggest the involvement of oxidative stress in the pathogenesis of Parkinson's disease (PD), however, the crucial mechanism of the degenerative process remain unclear. Emerging evidence supports a critical role for autophagy in the pathogenic process of dopaminergic neurodegeneration. However, the definitive in vivo proof of it is currently lacking. Due to the relevance oxidative stress and chaperone-mediated autophagy (CMA) in PD pathogenesis, we investigated the expression of nigral CMA markers in 6-OHDA-lesioned hemiparkinsonian rats. Male Sprague-Dawley rats received a 6-OHDA injection (8 μg in 4 μl of saline with 0.02% ascorbate over 8 min) into the left medial forebrain bundle by means of a Harvard infusion pump. Following a three-week recovery period, rats exhibiting a vigorous rotational response (>100 total turns) to apomorphine (0.05 mg/kg, sc) were selected for further study. Western blotting analyses showed a decrease by 88% in TH expression levels in the striatum ipsilateral to 6-OHDA lesion (p < 0.01) associated to an increase in nigral lysosomal membrane protein receptor type 2A (LAMP2A, p < 0.01) and heat shock protein 90 (HSP90, p < 0.01). The present results provide in vivo evidence of CMA activation in the animal model of parkinsonism in rats with a unilateral lesion of the nigrostriatal pathway induced by 6-OHDA. This widely used model offers great potential for future studies regarding new potential treatments for neurodegenerative conditions and in the investigation of signaling pathways regulating autophagy. © 2011 Elsevier Ltd. All rights reserved.


Maeso S.,Health Technology Assessment Unit | Reza M.,Health Technology Assessment Unit | Mayol J.A.,Hospital Clinico San Carlos | Blasco J.A.,Health Technology Assessment Unit | And 3 more authors.
Annals of Surgery | Year: 2010

Aim: The main aim of this review was to compare the safety and efficacy of the Da Vinci Surgical System (DVSS) and conventional laparoscopic surgery (CLS) in different types of abdominal intervention. Summary of background data: DVSS is an emerging laparoscopic technology. The surgeon directs the robotic arms of the system through a console by means of hand controls and pedals, making use of a stereoscopic viewing system. DVSS is currently being used in general, urological, gynecologic, and cardiothoracic surgery. Methods: This systematic review analyses the best scientific evidence available regarding the safety and efficacy of DVSS in abdominal surgery. The results found were subjected to meta-analysis whenever possible. Results: Thirty-one studies, 6 of them randomized control trials, involving 2166 patients that compared DVSS and CLS were examined. The procedures undertaken were fundoplication (9 studies, one also examining cholecystectomy), Heller myotomy (3 studies), gastric bypass (4), gastrectomy (2), bariatric surgery (1), cholecystectomy (4), splenectomy (1), colorectal resection (7), and rectopexy (1). DVSS was found to be associated with fewer Heller myotomy-related perforations, a more rapid intestinal recovery time after gastrectomy-and therefore a shorter hospital stay, a shorter hospital stay following cholecystectomy (although the duration of surgery was longer), longer colorectal resection surgery times, and a larger number of conversions to open surgery during gastric bypass. Conclusions: The publications reviewed revealed DVSS to offer certain advantages with respect to Heller myotomy, gastrectomy, and cholecystectomy. However, these results should be interpreted with caution until randomized clinical trials are performed and, with respect to oncologic indications, studies include variables such as survival. Copyright © 2010 by Lippincott Williams & Wilkins.


Mullol J.,Hospital Clinic | Mullol J.,CIBER ISCIII
Clinical and Experimental Allergy Reviews | Year: 2012

Allergic rhinitis (AR) is a major health problem with high and ever-increasing prevalence worldwide. At least one-fifth of adults in industrialized countries are estimated to have AR, defined as nasal and eye symptoms that are sufficiently severe to have a substantial negative impact on the quality of life (QoL). The former classification of AR comprised seasonal AR (SAR) and perennial AR (PAR), which did not adequately reflect the presentation and clinical course of the disease. The Allergic Rhinitis and its Impact on Asthma (ARIA) classification is based on the duration of symptoms and the disease severity. Both intermittent AR (IAR: symptoms ≤ 4 days/week or ≤ 4 consecutive weeks) and persistent AR (PER: symptoms > 4 days/week and > 4 consecutive weeks) may be mild, moderate, or severe based on the QOL impairment (sleep, daily activities/leisure, work productivity/school performance) and bothersome symptoms. Despite its disabling effects, AR remains a condition where affected individuals do not seek appropriate treatment, are undertreated and do not adhere well to treatment, which all lead to low disease control and high societal costs. The four pillars of AR treatment are allergen and pollutant avoidance, patient education, pharmacotherapy and allergen-specific immunotherapy. Oral antihistamines, together with intranasal corticosteroids and leucotriene antagonists, constitute important pharmacological options for the treatment of AR at all levels of severity. New second-generation antihistamines are H1-receptor antagonists with high efficacy (rapid onset of action for AR symptoms, sometimes even on nasal congestion, improvement of QoL and additional anti-allergic effects) and safety (low sedation rates). Although new antihistamines have been studied and approved for SAR and PAR, only some of them have been reported to show efficacy and safety for treatment of AR under the ARIA classification: levocetirizine (high efficacy) and rupatadine (dual antihistamine and anti-PAF effects) for PER, and desloratadine (high safety) for both IAR and PER. © 2012 Blackwell Publishing Ltd.


Saulyte J.,University of Santiago de Compostela | Saulyte J.,CIBER ISCIII | Regueira C.,University of Santiago de Compostela | Regueira C.,CIBER ISCIII | And 5 more authors.
PLoS Medicine | Year: 2014

Background:Allergic rhinitis, allergic dermatitis, and food allergy are extremely common diseases, especially among children, and are frequently associated to each other and to asthma. Smoking is a potential risk factor for these conditions, but so far, results from individual studies have been conflicting. The objective of this study was to examine the evidence for an association between active smoking (AS) or passive exposure to secondhand smoke and allergic conditions.Methods and Findings:We retrieved studies published in any language up to June 30th, 2013 by systematically searching Medline, Embase, the five regional bibliographic databases of the World Health Organization, and ISI-Proceedings databases, by manually examining the references of the original articles and reviews retrieved, and by establishing personal contact with clinical researchers. We included cohort, case-control, and cross-sectional studies reporting odds ratio (OR) or relative risk (RR) estimates and confidence intervals of smoking and allergic conditions, first among the general population and then among children.We retrieved 97 studies on allergic rhinitis, 91 on allergic dermatitis, and eight on food allergy published in 139 different articles. When all studies were analyzed together (showing random effects model results and pooled ORs expressed as RR), allergic rhinitis was not associated with active smoking (pooled RR, 1.02 [95% CI 0.92-1.15]), but was associated with passive smoking (pooled RR 1.10 [95% CI 1.06-1.15]). Allergic dermatitis was associated with both active (pooled RR, 1.21 [95% CI 1.14-1.29]) and passive smoking (pooled RR, 1.07 [95% CI 1.03-1.12]). In children and adolescent, allergic rhinitis was associated with active (pooled RR, 1.40 (95% CI 1.24-1.59) and passive smoking (pooled RR, 1.09 [95% CI 1.04-1.14]). Allergic dermatitis was associated with active (pooled RR, 1.36 [95% CI 1.17-1.46]) and passive smoking (pooled RR, 1.06 [95% CI 1.01-1.11]). Food allergy was associated with SHS (1.43 [1.12-1.83]) when cohort studies only were examined, but not when all studies were combined.The findings are limited by the potential for confounding and bias given that most of the individual studies used a cross-sectional design. Furthermore, the studies showed a high degree of heterogeneity and the exposure and outcome measures were assessed by self-report, which may increase the potential for misclassification.Conclusions:We observed very modest associations between smoking and some allergic diseases among adults. Among children and adolescents, both active and passive exposure to SHS were associated with a modest increased risk for allergic diseases, and passive smoking was associated with an increased risk for food allergy. Additional studies with detailed measurement of exposure and better case definition are needed to further explore the role of smoking in allergic diseases.Please see later in the article for the Editors' Summary. © 2014 Saulyte et al.


Pons-Vigues M.,CIBER ISCIII
Health & place | Year: 2012

This study describes the concept of prevention and identifies the knowledge, perceived benefits and barriers, as well as the practices of early detection of breast cancer among women from different cultural backgrounds and socioeconomic levels. A socioconstructivist qualitative study was conducted in Barcelona. The study population consisted of women who were either native (Spanish) or immigrants from low income countries, aged 40 to 69 years. Narrations of the 68 informants were subjected to sociological discourse analysis. Place and culture of origin, social class and the migratory process can either facilitate or constitute barriers to breast cancer prevention. Copyright © 2012 Elsevier Ltd. All rights reserved.


Chaudhuri K.R.,King's College | Odin P.,Central Hospital | Odin P.,Lund University | Antonini A.,University of Padua | Martinez-Martin P.,CIBER ISCIII
Parkinsonism and Related Disorders | Year: 2011

Non-motor symptoms (NMS) of Parkinson's disease remain the most under-appreciated and under-researched when taken as a whole. Data is emerging that it is the "totaL" burden of NMS that is the major determinant of quality of life not a single NMS such as depression for instance. Only recently validated tools such as the NMSQuest which empowers patients to declare NMS and the NMS scale, the SCOPA scales, and the modified version of the MDS-UPDRS have become available and validated for bedside clinical assessment of NMS. For the first time clinical trials have been incorporating non-motor measures as outcome measures and clinical recommendations for treatment of non-motor symptoms of PD are being published. This review aims to address some of these topical and "real life" aspects of modern day management of Parkinson's. © 2011.


Fernandez-Tajes J.,Complejo Hospitalario Universitario runa CHUAC | Soto-Hermida A.,Complejo Hospitalario Universitario runa CHUAC | Vazquez-Mosquera M.E.,Complejo Hospitalario Universitario runa CHUAC | Cortes-Pereira E.,Complejo Hospitalario Universitario runa CHUAC | And 8 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objective: Alterations in DNA methylation patterns have been found to correlate with several diseases including osteoarthritis (OA). The aim of this study was to identify, for the first time, the genome-wide DNA methylation profiles of human articular chondrocytes from OA cartilage and healthy control cartilage samples. Methods: DNA methylation profiling was performed using Illumina Infinium HumanMethylation27 in 25 patients with OA and 20 healthy controls. Subsequent validation was performed by genome-wide expression analysis using the Affymetrix Human Gene 1.1 ST array in an independent cohort of 24 patients with OA. Finally, the most consistent genes in both assays were amplified by quantitative reverse transcriptase PCR in a validation cohort of 48 patients using microfluidic real-time quantitative PCR. Appropriate bioinformatics analyses were carried out using R bioconductor software packages and qBase plus software from Biogazelle. Results: We found 91 differentially methylated (DM) probes, which permitted us to separate patients with OA from healthy controls. Among the patients with OA, we detected 1357 DM probes that identified a tight cluster of seven patients who were different from the rest. This cluster was also identified by genome-wide expression in which 450 genes were differentially expressed. Further validation of the most consistent genes in an independent cohort of patients with OA permitted us to identify this cluster, which was characterised by increased inflammatory processes. Conclusions: We were able to identify a tight subgroup of patients with OA, characterised by an increased inflammatory response that could be regulated by epigenetics. The identification and isolation of this subgroup may be critical for the development of effective treatment and disease prevention.


Delgado-Lista J.,University of Cordoba, Spain | Delgado-Lista J.,CIBER ISCIII | Perez-Martinez P.,University of Cordoba, Spain | Perez-Martinez P.,CIBER ISCIII | And 4 more authors.
British Journal of Nutrition | Year: 2012

Introduction: Cardiovascular disease remains the commonest health problem in developed countries, and residual risk after implementing all current therapies is still high. The use of marine omega-3 fatty acids (DHA and EPA) has been recommended to reduce cardiovascular risk by multiple mechanisms. Objectives: To update the current evidence on the influence of omega-3 on the rate of cardiovascular events. Review Methods: We used the MEDLINE and EMBASE databases to identify clinical trials and randomized controlled trials of omega-3 fatty acids (with quantified quantities) either in capsules or in dietary intake, compared to placebo or usual diet, equal to or longer than 6 months, and written in English. The primary outcome was a cardiovascular event of any kind and secondary outcomes were all-cause mortality, cardiac death and coronary events. We used RevMan 5•1 (Mantel-Haenszel method). Heterogeneity was assessed by the I2 and Chi2 tests. We included 21 of the 452 pre-selected studies. Results: We found an overall decrease of risk of suffering a cardiovascular event of any kind of 10 % (OR 0•90; [0•85-0•96], p = 0•001), a 9 % decrease of risk of cardiac death (OR 0•91; [0•83-0•99]; p = 0•03), a decrease of coronary events (fatal and non-fatal) of 18 % (OR 0•82; [0•75-0•90]; p < 1 p-10-4), and a trend to lower total mortality (5 % reduction of risk; OR 0•95; [0•89-1•02]; p = 0•15. Most of the studies analyzed included persons with high cardiovascular risk. Conclusions: marine omega-3 fatty acids are effective in preventing cardiovascular events, cardiac death and coronary events, especially in persons with high cardiovascular risk. © 2012 The Authors.


Benach J.,University Pompeu Fabra | Benach J.,CIBER ISCIII | Malmusi D.,CIBER ISCIII | Yasui Y.,University of Alberta | And 2 more authors.
Journal of Epidemiology and Community Health | Year: 2013

The last decade has witnessed a surge in interest for policies to tackle health inequalities. Adequate theoretical development of policy models is needed to understand how to design and evaluate equity-oriented health policies. In this paper we review Graham's typology of policies (focused on the worst-off, on the gap, or on the gradient) and propose an adaptation (targeted, universal with additional targeting, redistributive, and proportionate universalism). For each type, potential scenarios of impact on population health and health inequalities are depicted following the idea of Geoffrey Rose's population curves and strategies, policy examples are given and a simulation with survey data is shown. The proposed typology of scenarios of health inequality reduction can serve as an effective tool to interpret the differential impact of interventions and to reflect on how to adequately design or re-orient a policy and which measures to use to evaluate it.


Tena-Sempere M.,University of Cordoba, Spain | Tena-Sempere M.,CIBER ISCIII
Hormone and Metabolic Research | Year: 2013

Reproductive maturation and function are sensitive to the metabolic state of the organism and the magnitude of body fuel reserves; hence, conditions ranging from energy insufficiency to morbid obesity impact the timing of puberty and are frequently linked to fertility problems. This phenomenon is the result of the close interplay between a diversity of nutritional cues and metabolic signals (including hormones) with different elements of the so-called hypothalamic-pituitary-gonadal (HPG) axis. In this review, we will focus our attention on the 'reproductive' roles of 2 key metabolic hormones, namely, the adipose signal, leptin, and the gut hormone, ghrelin. These 2 factors, which have been proposed to operate as functional antagonists in the control of metabolism and energy homeostasis, are also provided with important, and in many cases opposite, roles in the regulation of puberty onset and gonadal function. We will provide herein an update view of the reproductive effects of leptin and ghrelin, with a major emphasis on the actions of these 2 key hormones upon the central elements of the HPG axis, including their putative effects on Kiss1 and other reproductive neuronal networks. This will help to understand the mechanisms whereby reproductive function is gated and dynamically regulated by metabolic signals at different key developmental stages, such as puberty and adulthood. © Georg Thieme Verlag KG Stuttgart, New York.


Quilez M.E.,CIBER ISCIII | Lopez-Aguilar J.,CIBER ISCIII | Lopez-Aguilar J.,Critical Care Center | Blanch L.,CIBER ISCIII | Blanch L.,Critical Care Center
Current Opinion in Critical Care | Year: 2012

Purpose of Review: Multiple organ failure is the main cause of morbidity and mortality in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) patients. Moreover, survivors of both ALI and ARDS often show significant neurocognitive decline at discharge. These data suggest a deleterious organ crosstalk between lungs and distal organs. This article reviews the recent literature concerning the role of this organ crosstalk during ALI, ARDS, and mechanical ventilation, especially focusing on brain-lung communication. Recent Findings: Numerous pulmonary and extrapulmonary disorders could predispose critically ill patients to ALI and ARDS. Mechanical ventilation, although a lifesaving intervention, could contribute by modulating the mechanisms involved in the pathophysiology of lung damage and their impact on remote organs. Emerging clinical and experimental evidence supports the hypothesis of a multidirectional organ crosstalk between lungs and distal organs. Summary: Organ crosstalk is an emerging area of research in lung disease in critically ill patients. The findings of these studies are clinically relevant and show the importance of an integrative approach in the management of critical patients. However, further studies are necessary to understand the complex interactions concurring in these pathologies. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Mato J.M.,CIBER ISCIII | Lu S.C.,University of Southern California
Alcoholism: Clinical and Experimental Research | Year: 2011

Normal differentiated hepatocytes primarily metabolize methionine, via homocysteine synthesis, through the transsulfuration pathway. In addition to glutathione, this pathway produces α-ketobutyrate that is further metabolized in the mitochondria. It is only under low methionine conditions that differentiated hepatocytes predominantly regenerate methionine from homocysteine. In contrast, proliferating hepatocytes and liver cancer cells regenerate methionine from homocysteine regardless of the availability of methionine. Here we propose that this less efficient metabolism of methionine in proliferating hepatocytes and cancer cells is an adaptation to the "Warburg effect" that is, to the well known phenomenon that cancer cells rely on aerobic glycolysis instead of oxidative phosphorylation to generate energy. The observation that knockout mice with impaired S-adenosylmethionine (SAMe) synthesis (the first step in methionine metabolism) or catabolism spontaneously develop fatty liver and hepatocellular carcinoma, together with the observation that SAMe administration induces apoptosis in hepatoma cells and prevents liver cancer support this hypothesis. Copyright © 2011 by the Research Society on Alcoholism.


Arboix A.,University of Barcelona | Arboix A.,CIBER ISCIII | Alio J.,Hospital Universitari Of Bellvitge
Current Cardiology Reviews | Year: 2012

Cardioembolic cerebral infarction (CI) is the most severe subtype of ischaemic stroke but some clinical aspects of this condition are still unclear. This article provides the reader with an overview and up-date of relevant aspects related to clinical features, specific cardiac disorders and prognosis of CI. CI accounts for 14-30% of ischemic strokes; patients with CI are prone to early and long-term stroke recurrence, although recurrences may be preventable by appropriate treatment during the acute phase and strict control at follow-up. Certain clinical features are suggestive of CI, including sudden onset to maximal deficit, decreased level of consciousness at onset, Wernicke's aphasia or global aphasia without hemiparesis, a Valsalva manoeuvre at the time of stroke onset, and co-occurrence of cerebral and systemic emboli. Lacunar clinical presentations, a lacunar infarct and especially multiple lacunar infarcts, make cardioembolic origin unlikely. The most common disorders associated with a high risk of cardioembolism include atrial fibrillation, recent myocardial infarction, mechanical prosthetic valve, dilated myocardiopathy and mitral rheumatic stenosis. Patent foramen ovale and complex atheromatosis of the aortic arch are potentially emerging sources of cardioembolic infarction. Mitral annular calcification can be a marker of complex aortic atheroma in stroke patients of unkown etiology. Transthoracic and transesophageal echocardiogram can disclose structural heart diseases. Paroxysmal atrial dysrhyhtmia can be detected by Holter monitoring. Magnetic resonance imaging, transcranial Doppler, and electrophysiological studies are useful to document the source of cardioembolism. In-hospital mortality in cardioembolic stroke (27.3%, in our series) is the highest as compared with other subtypes of cerebral infarction. Secondary prevention with anticoagulants should be started immediately if possible in patients at high risk for recurrent cardioembolic stroke in which contraindications, such as falls, poor compliance, uncontrolled epilepsy or gastrointestinal bleeding are absent. Dabigatran has been shown to be non-inferior to warfarin in the prevention of stroke or systemic embolism. All significant structural defects, such as atrial septal defects, vegetations on valve or severe aortic disease should be treated. Aspirin is recommended in stroke patients with a patent foramen ovale and indications of closure should be individualized. CI is an important topic in the frontier between cardiology and vascular neurology, occurs frequently in daily practice, has a high impact for patients, and health care systems and merits an update review of current clinical issues, advances and controversies. © 2012 Bentham Science Publishers.


Mata M.,University of Valencia | Mata M.,CIBER ISCIII | Morcillo E.,CIBER ISCIII | Morcillo E.,University of Valencia | And 3 more authors.
Biochemical Pharmacology | Year: 2011

64% of chronic obstructive pulmonary disease (COPD) exacerbations are caused by respiratory infections including influenza (strains A and B) and respiratory syncytial virus (RSV). They affect the airway epithelium increasing inflammatory and apoptosis events through mechanisms involving ROS generation, and induce the release of mucins from epithelial cells that are involved in the deterioration of the patient's health during the course of the disease. The antioxidant NAC has proved useful in the management of COPD reducing symptoms, exacerbations and accelerated lung function decline. It has been shown to inhibit influenza virus replication and to diminish the release of inflammatory and apoptotic mediators during virus infection. The main objective of this study is to analyze the effects of NAC in modulating MUC5AC over-expression and release in an in vitro infection model of alveolar type II A549 cells infected with influenza (strains A and B) and RSV. We have also analyzed virus replication and different pro-inflammatory responses. Our results indicate a significant induction of MUC5AC, IL8, IL6 and TNF-alpha that is strongly inhibited by NAC at the expression and at the release level. It also decreased the intracellular H 2O 2 concentration and restored the intracellular total thiol contents. Mechanisms of NAC included inhibition of NF-κB translocation to the cellular nucleus and phosphorylation of MAPK p38. NAC also inhibited replication of the three viruses under study. This work supports the use of antioxidants in order to ameliorate the inflammatory effects of different viral infections during COPD exacerbations. © 2011 Elsevier Inc. All rights reserved.


Vera F.,CIBER ISCIII | Mas-Torrent M.,CIBER ISCIII | Esquena J.,CIBER ISCIII | Rovira C.,CIBER ISCIII | And 3 more authors.
Chemical Science | Year: 2012

The different weak non-covalent interactions established between "hydrophobic-amphiphilic" fluorescent and paramagnetic organic free-radical molecules, and solvents result in the formation of hierarchically self-assembled multifunctional superhydrophobic materials with very unusual shapes. © 2012 The Royal Society of Chemistry.


Muntane J.,University of Cordoba, Spain | Muntane J.,CIBER ISCIII
Anti-Cancer Agents in Medicinal Chemistry | Year: 2011

Hepatocarcinoma (HCC) is the fifth most common neoplasia in the world, and the first cause of death by cancer in some areas. The clinical course of HCC patients has improved greatly owing to the use of the oral multikinase inhibitor, Sorafenib. The expression of receptors belonging to the superfamily of tumor necrosis factor receptors (TNF-R), such as TNF-R1, CD95 and TNF-related apoptosis inducing ligand (TRAIL) receptor -1 (TRAIL-R1) and -2 (TRAIL-R2) are altered in patients with HCC, especially those in advanced stages of de-differentiation. The disruption of death receptor (DR)-dependent cell signaling is related to poor survival in patients with HCC. These observations, together with the lack of antitumoral therapy alternatives, have stimulated research on DR-targeted therapies. The increasing research progress in cell death shows the intense crosstalk among DR and cell survival pathways in cancer cells. In consequence, new potential therapeutic strategies involving antibodies or small molecules specifically targeted to DR pathways either in monotherapy or in combination with other therapeutic strategies may be envisaged in the future to treat HCC. © 2011 Bentham Science Publishers Ltd.


Luengo-Oroz M.A.,Technical University of Madrid | Luengo-Oroz M.A.,CIBER ISCIII | Ledesma-Carbayo M.J.,Technical University of Madrid | Ledesma-Carbayo M.J.,CIBER ISCIII | And 3 more authors.
Current Opinion in Genetics and Development | Year: 2011

The digital reconstruction of the embryogenesis of model organisms from 3D. +. time data is revolutionizing practices in quantitative and integrative Developmental Biology. A manual and fully supervised image analysis of the massive complex data acquired with new microscopy technologies is no longer an option and automated image processing methods are required to fully exploit the potential of imaging data for biological insights. Current developments and challenges in biological image processing include algorithms for microscopy multiview fusion, cell nucleus tracking for quasi-perfect lineage reconstruction, segmentation, and validation methodologies for cell membrane shape identification, single cell gene expression quantification from in situ hybridization data, and multidimensional image registration algorithms for the construction of prototypic models. These tools will be essential to ultimately produce the multilevel in toto reconstruction that combines the cell lineage tree, cells, and tissues structural information and quantitative gene expression data in its spatio-temporal context throughout development. © 2011 Elsevier Ltd.


Garcia-Fruitos E.,Autonomous University of Barcelona | Garcia-Fruitos E.,CIBER ISCIII | Sabate R.,Autonomous University of Barcelona | De Groot N.S.,Autonomous University of Barcelona | And 3 more authors.
FEBS Journal | Year: 2011

Inclusion bodies are insoluble protein aggregates usually found in recombinant bacteria when they are forced to produce heterologous protein species. These particles are formed by polypeptides that cross-interact through sterospecific contacts and that are steadily deposited in either the cell's cytoplasm or the periplasm. An important fraction of eukaryotic proteins form inclusion bodies in bacteria, which has posed major problems in the development of the biotechnology industry. Over the last decade, the fine dissection of the quality control system in bacteria and the recognition of the amyloid-like architecture of inclusion bodies have provided dramatic insights on the dynamic biology of these aggregates. We discuss here the relevant aspects, in the interface between cell physiology and structural biology, which make inclusion bodies unique models for the study of protein aggregation, amyloid formation and prion biology in a physiologically relevant background. Many eukaryotic polypeptides form inclusion bodies when producedin bacteria. The dissection of the quality control machinery in bacteria and the discovery of the amyloid-like nature of bacterial aggregates have provided an excitingand new view on their dynamic biology, suggesting thatthey may serve as models to study the mechanisms of amyloid aggregation in physiologically relevant conditions. © 2011 The Authors Journal compilation © 2011 FEBS.


Palomo G.M.,Autonomous University of Madrid | Palomo G.M.,CIBER ISCIII | Cerrato T.,Autonomous University of Madrid | Cerrato T.,CIBER ISCIII | And 3 more authors.
Human Molecular Genetics | Year: 2011

Friedreich's ataxia (FRDA) is an autosomal recessive disease caused by mutations that produce a deficiency in frataxin. Despite the importance of neurodegeneration in FRDA, little is known about the consequences of frataxin deficiency in neuronal cells. Here we describe a neuronal cell model for FRDA based on the use of lentiviral vectors that carry minigenes encoding frataxin-specific shRNAs that silence the expression of this gene. These lentivectors can knockdown frataxin expression in human neuroblastoma SH-SY5Y cells, which results in large-scale cell death in differentiated neuron-like cells but not in undifferentiated neuroblas- toma cells. Frataxin-deficient neuron-like cells appear to die through apoptosis that is accompanied by up-regulation of p53, PUMA and Bax and activation of caspase-3. No significant autophagy is observed in frataxin-deficient neuron-like cells and the pharmacological activation of autophagy does not significantly increase neuronal cell death in response to the frataxin deficiency. Cell death triggered by frataxin knock- down can be impaired by interference with p53, caspase inhibitors and gene transfer of FXN. These results suggest that frataxin gene silencing in human neuron-like cells may constitute a useful cell model to charac- terize the molecular changes triggered by frataxin deficiency in neurons, as well as to search for therapies that may protect against neurodegeneration. © The Author 2011. Published by Oxford University Press. All rights reserved.


Lechuga L.M.,CIBER ISCIII
Optics InfoBase Conference Papers | Year: 2013

We have recently proposed the use of plasmonic biosensing as an unconventional strategy for deciphering main cell pathways influencing diseases progression in order to improve diagnosis and follow-up of therapies for several diseases as cancer. © OSA 2013.


Hosseinpoor A.R.,World Health Organization | Parker L.A.,University Miguel Hernández | Parker L.A.,CIBER ISCIII | Tursan d'Espaignet E.,World Health Organization | Chatterji S.,World Health Organization
PLoS ONE | Year: 2012

Objectives: To assess the magnitude and pattern of socioeconomic inequality in current smoking in low and middle income countries. Methods: We used data from the World Health Survey [WHS] in 48 low-income and middle-income countries to estimate the crude prevalence of current smoking according to household wealth quintile. A Poisson regression model with a robust variance was used to generate the Relative Index of Inequality [RII] according to wealth within each of the countries studied. Results: In males, smoking was disproportionately prevalent in the poor in the majority of countries. In numerous countries the poorest men were over 2.5 times more likely to smoke than the richest men. Socioeconomic inequality in women was more varied showing patterns of both pro-rich and pro-poor inequality. In 20 countries pro-rich relative socioeconomic inequality was statistically significant: the poorest women had a higher prevalence of smoking compared to the richest women. Conversely, in 9 countries women in the richest population groups had a statistically significant greater risk of smoking compared to the poorest groups. Conclusion: Both the pattern and magnitude of relative inequality may vary greatly between countries. Prevention measures should address the specific pattern of smoking inequality observed within a population. © 2012 Hosseinpoor et al.


Alemany M.,University of Barcelona | Alemany M.,CIBER ISCIII
Reproductive Biology and Endocrinology | Year: 2011

After birth, the body shifts from glucose as primary energy substrate to milk-derived fats, with sugars from lactose taking a secondary place. At weaning, glucose recovers its primogeniture and dietary fat role decreases. In spite of human temporary adaptation to a high-fat (and sugars and protein) diet during lactation, the ability to thrive on this type of diet is lost irreversibly after weaning. We could not revert too the lactating period metabolic setting because of different proportions of brain/muscle metabolism in the total energy budget, lower thermogenesis needs and capabilities, and absence of significant growth in adults. A key reason for change was the limited availability of foods with high energy content at weaning and during the whole adult life of our ancestors, which physiological adaptations remain practically unchanged in our present-day bodies. Humans have evolved to survive with relatively poor diets interspersed by bouts of scarcity and abundance. Today diets in many societies are largely made up from choice foods, responding to our deeply ingrained desire for fats, protein, sugars, salt etc. Consequently our diets are not well adjusted to our physiological needs/adaptations but mainly to our tastes (another adaptation to periodic scarcity), and thus are rich in energy roughly comparable to milk. However, most adult humans cannot process the food ingested in excess because our cortical-derived craving overrides the mechanisms controlling appetite. This is produced not because we lack the biochemical mechanisms to use this energy, but because we are unprepared for excess, and wholly adapted to survive scarcity. The thrifty mechanisms compound the effects of excess nutrients and damage the control of energy metabolism, developing a pathologic state. As a consequence, an overflow of energy is generated and the disease of plenty develops. © 2011 Alemany; licensee BioMed Central Ltd.


Leon Z.,Institute Investigacion Sanitaria Fundacion Hospital La Fe | Garcia-Canaveras J.C.,University of Valencia | Garcia-Canaveras J.C.,Institute Investigacion Sanitaria Fundacion Hospital La Fe | Donato M.T.,University of Valencia | And 3 more authors.
Electrophoresis | Year: 2013

Metabolomics represents the global assessment of metabolites in a biological sample and reports the closest information to the phenotype of the biological system under study. Mammalian cell metabolomics has emerged as a promising tool with potential applications in many biotechnology and research areas. Metabolomics workflow includes experimental design, sampling, sample processing, metabolite analysis, and data processing. Given their influence on metabolite content and biological interpretation of data, a good experimental design and the appropriate choice of a sample processing method are prerequisites for success in any metabolomic study. The use of mammalian cells in the metabolomics field involves harder sample processing methods, including metabolism quenching and metabolite extraction, as compared to the use of body fluids, although such critical issues are frequently overlooked. This review aims to overview the common experimental procedures used in mammalian cell metabolomics based on mass spectrometry, by placing special emphasis on discussing sample preparation approaches, although other aspects, such as cell metabolomics applications, culture systems, cellular models, analytical platforms, and data analysis, are also briefly covered. This review intends to be a helpful tool to assist researchers in addressing decisions when planning a metabolomics study involving the use of mammalian cells. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Pico C.,University of the Balearic Islands | Pico C.,CIBER ISCIII | Jilkova Z.M.,Academy of Sciences of the Czech Republic | Kus V.,Academy of Sciences of the Czech Republic | And 3 more authors.
American Journal of Clinical Nutrition | Year: 2011

Breastfeeding, compared with infant-formula feeding, confers later protection against obesity. Leptin represents a candidate for the programming of the lean phenotype as suggested by 1) the presence of leptin in breast milk and its absence in infant formula, 2) a human study that showed a negative correlation between leptin concentrations in breast milk and body weights of infants until 2 y of age, and 3) intervention studies in animals. Milk-borne leptin and leptin synthesized in adipose tissue and the stomach may contribute to leptinemia in newborns. Studies in rodents suggested that early leptin treatment may program either a lean or obese phenotype, probably depending on the dose, route of administration, and timing of exposure to high leptin concentrations, whereas these studies also suggested the importance of the physiologic postnatal surge in leptinemia for the programming effect. Leptin oral administration at physiologic doses to neonate rats during the entire lactation period had later positive effects that prevented the animals from overweight and obesity and other metabolic alterations, which were particularly associated with feeding of a high-fat diet. High leptin sensitivity, which is associated with leanness, and leptin resistance in obesity may be programmed by the early life environment. The differential sensitivity to leptin implies a contribution of leptin-inducible energy expenditure to the adult phenotype. Available data have suggested the involvement of nonshivering thermogenesis induced by a leptin-AMP-activated protein kinase axis in oxidative muscles, which is based on lipid metabolism. Additional studies on the programming effects of leptin, mainly in response to the oral intake of leptin, are required. © 2011 American Society for Nutrition.


Llorens N.,Ministry of Health and Social Policy | Barrio G.,CIBER ISCIII | Sanchez A.,Ministry of Health and Social Policy | Suelves J.M.,University of Barcelona
Prevention Science | Year: 2011

Adolescent drinking has an important health and social impact in many countries. In Spain, this behavior often takes place in groups and in open areas (known as "botellón"). The aim of this study is to describe the prevalence of excessive drinking among Spanish adolescents and its association with socialization and family factors. A national school survey was conducted in 2006 among 26,454 students aged 14-18 years who were selected by two-stage cluster sampling (schools and classrooms). The questionnaire was self-completed with paper and pencil. The outcomes were: habitual excessive drinking or HED (average consumption ≥30 g/day of alcohol among men, and ≥20 g/day among women), binge drinking (drinking 5 or more standard alcohol units in a 2-hour interval), and drunkenness. Logistic regression models were used to estimate the effect of socialization and family factors. Monthly prevalence of HED, binge drinking and drunkenness was 11.2%, 30.9% and 25.6%, respectively. The main factors positively associated with HED were: frequently going out for fun in the evenings, high proportion of friends who drink or get drunk, early onset of alcohol use, low perceived risk of drinking, truancy, illegal drug use, and amount of money spent for personal needs. Family factors were weakly associated with outcomes. Socialization in leisure environments with friends who drink excessively is an important predictor of adolescent excessive drinking in Spain. Thus, prevention must also focus on the community level, limiting alcohol access, building socialization environments without alcohol, and increasing adolescents' risk perception of drinking. © 2010 Society for Prevention Research.


Tomasi M.L.,University of Southern California | Li T.W.,University of Southern California | Li M.,University of Southern California | Mato J.M.,CIBER ISCIII | Lu S.C.,University of Southern California
Journal of Cellular Physiology | Year: 2012

Two genes (MAT1A and MAT2A) encode for the essential enzyme methionine adenosyltransferase (MAT). MAT1A is silenced in hepatocellular carcinoma (HCC), and absence of MAT1A leads to spontaneous development of HCC in mice. Previous report correlated promoter methylation to silencing of MAT1A but definitive proof was lacking. Here we investigated the role of methylation in regulating MAT1A expression. There are three MspI/HpaII sites from -1,913 to +160 of the human MAT1A gene (numbered relative to the translational start site) at position -977, +10, and +88. Bisulfite treatment and DNA sequencing, and Southern blot analysis showed that methylation at +10 and +88, but not -977, correlated with lack of MAT1A expression. MAT1A promoter construct methylated at -977, +10 or +88 position has 0.7-fold, 3-fold, and 1.6-fold lower promoter activity, respectively. Methylation at -977 and +10 did not inhibit the promoter more than methylation at +10 alone; while methylation at +10 and +88 reduced promoter activity by 60%. Mutation of +10 and +88 sites also resulted in 40% reduction of promoter activity. Reactivation of MAT1A correlated with demethylation of +10 and +88. In vitro transcription assay showed that methylation or mutation of +10 and +88 sites reduced transcription. In conclusion, our data support the novel finding that methylation of the MAT1A coding region can inhibit gene transcription. This represents a key mechanism for decreased MAT1A expression in HCC and a target for therapy. To our knowledge, this is the first example of coding region methylation inhibiting transcription of a mammalian gene. © 2011 Wiley Periodicals, Inc.


Rodriguez-Perez A.I.,University of Santiago de Compostela | Rodriguez-Perez A.I.,CIBER ISCIII | Borrajo A.,University of Santiago de Compostela | Borrajo A.,CIBER ISCIII | And 6 more authors.
GLIA | Year: 2015

Previous studies have shown that the brain renin-angiotensin system may play a major role, via angiotensin type 1 (AT1) receptors, in the regulation of neuroinflammation, oxidative stress and progression of dopaminergic degeneration. Angiotensin-induced activation of the microglial nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase complex and microglial Rho-kinase are particularly important in this respect. However, it is not known whether crosstalk between Rho-kinase and NADPH-oxidase leads to microglial activation. In the present study, we found that, in the substantia nigra of rats, NADPH-oxidase activation was involved in angiotensin-induced Rho-kinase activation, which, in turn, was involved in angiotensin-induced NADPH-oxidase activation. In N9 microglial cell line and primary microglial cultures, a crosstalk signaling between NADPH-oxidase and Rho-kinase occurred in a positive feedback fashion during angiotensin-induced microglial activation. Angiotensin-induced NADPH-oxidase activation and superoxide generation led to NF-k{cyrillic}B translocation and Rho-kinase activation. Rho-kinase activation was involved in regulation of NADPH-oxidase activation via p38 mitogen-activated protein kinase. Moreover, Rho-kinase activation, via NF-k{cyrillic}B, upregulated AT1 receptor expression in microglial cells through a feed-forward mechanism. NADPH-oxidase and Rho-kinase pathways are known to be responsible for major components of the microglial response, such as changes involving microglial motility and phagocytosis, generation of superoxide, and release of inflammatory cytokines. The present results show that both pathways are linked by a common mechanism that may constitute a basic means of coordinating the microglial response. © 2014 Wiley Periodicals, Inc.


Kacmarek R.M.,Massachusetts General Hospital | Kacmarek R.M.,Harvard University | Villar J.,CIBER ISCIII | Villar J.,Hospital Universitario Dr Negrin | Villar J.,Li Ka Shing Knowledge Institute
Minerva Anestesiologica | Year: 2013

Severe hypoxemia is the hallmark of ARDS. However, unmanageable refractory hypoxemia fortunately is a rare occurrence in patients with ARDS and an infrequent cause of death in ARDS. However, in some patients, in spite of the application of lung protective ventilation with moderate to high levels of end-expiratory pressure (PEEP), refractory hypoxemia remains unresolved. When refractory hypoxemia persists, we first recommend the use of lung recruitment maneuvers and a decremental PEEP trial, if this does not resolve the refractory hypoxemia prone positioning should be attempted. The use of aerosolized pulmonary vasodilators can be used to buy time when these approaches fail as the patient is transitioned to extracorporeal membrane oxygenation. We also find that there is now sufficient evidence to recommend against the use of high frequency oscillation in the management of refractory hypoxemia.


Cardona P.-J.,Autonomous University of Barcelona | Cardona P.-J.,CIBER ISCIII
Clinical and Developmental Immunology | Year: 2011

Liquefaction is one of the most intriguing aspects of human tuberculosis. It is a major cause of the transition from the infection to active disease (tuberculosis, TB) as well as the transmission of M. tuberculosis to other persons. This paper reviews the natural history of liquefaction in humans from a pathological and radiological point of view and discusses how the experimental models available can be used to address the topic of liquefaction and cavity formation. Different concepts that have been related to liquefaction, from the influence of immune response to mechanical factors, are reviewed. Synchronic necrosis or apoptosis of infected macrophages in a close area, together with an ineffective fibrosis, appears to be clue in this process, in which macrophages, the immune response, and bacillary load interact usually in a particular scenario: the upper lobes of the lung. The summary would be that even if being a stochastic effect, liquefaction would result if the organization of the intragranulomatous necrosis (by means of fibrosis) would be disturbed. Copyright © 2011 Pere-Joan Cardona.


Chen Z.,Nanjing Medical University | Cao M.,Nanjing Medical University | Plana M.N.,CIBER ISCIII | Liang J.,Nanjing Medical University | And 3 more authors.
Arthritis Care and Research | Year: 2013

Objective To assess the utility of anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody measurement for predicting a risk for developing rapidly progressive interstitial lung disease (RP-ILD) in patients with polymyositis/dermatomyositis (PM/DM). Methods A single-center cohort of 64 consecutive Chinese patients with PM/DM was examined. Serum anti-MDA5 antibody was measured by enzyme-linked immunosorbent assay. For meta-analysis, we searched PubMed and the Institute for Scientific Information Web of Knowledge for original studies that measured anti-MDA5 antibodies in patients with PM/DM. We calculated pooled sensitivity, specificity, diagnostic odds ratio (DOR), and the summary receiver operating characteristic (sROC) curve. Results In Chinese patients, anti-MDA5 antibodies were detected in 26 patients with classic DM or clinically amyopathic DM (CADM). Compared with anti-MDA5-negative patients, anti-MDA5-positive patients showed a higher prevalence of RP-ILD (P = 0.001). In a total of 233 patients with anti-MDA5 antibody, derived from 16 studies, a higher frequency of CADM was found in Japanese than in non-Japanese patients (74.7% versus 39.2%; P = 1.2 × 10-7). Meta-analysis revealed that the pooled sensitivity and specificity of anti-MDA5 antibody for RP-ILD was 77% (95% confidence interval [95% CI] 64-87%) and 86% (95% CI 79-90%), respectively. The pooled DOR was 20.41 (95% CI 9.02-46.20) with a favorable area under the sROC curve of 0.89 (95% CI 0.63-0.98). Conclusion Detection of anti-MDA5 antibody is a valuable tool for identifying DM patients with a high risk for developing RP-ILD, but the distribution of classic DM and CADM in patients with this antibody varies among ethnic groups. Copyright © 2013 by the American College of Rheumatology.


Wilson R.,Royal Brompton Hospital | Sethi S.,State University of New York at Buffalo | Anzueto A.,University of Texas Health Science Center at San Antonio | Miravitlles M.,CIBER ISCIII
Journal of Infection | Year: 2013

Acute exacerbations (AE) can be recurrent problems for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) increasing morbidity and mortality. Evidence suggests that ≥50% of acute exacerbations involve bacteria requiring treatment with an antibiotic which should have high activity against the causative pathogens. However, sputum analysis is not a pre-requisite for antibiotic prescription in outpatients as results are delayed and patients are likely to be colonised with bacteria in the stable state. Clinicians rely on the clinical symptoms, sputum appearance and the patient's medical history to decide if an AE-COPD should be treated with antibiotics. This article reviews the available data of antibiotic trials in AE-COPD. Management of frequent exacerbators is particularly challenging for physicians. This may include antibiotic prophylaxis, especially macrolides because of anti-inflammatory properties; though successful in reducing exacerbations, concerns about resistance development remain. Inhalation of antibiotics achieves high local concentrations and minimal systemic exposure; therefore, it may represent an attractive alternative for antibiotic prophylaxis in certain COPD patients. Inhaled antibiotic prophylaxis has been successfully used in other respiratory conditions such as non-cystic fibrosis bronchiectasis which itself might be present in COPD patients who have chronic bacterial infection, particularly with Pseudomonas aeruginosa. © 2013 The British Infection Association.


Riveiro-Barciela M.,Autonomous University of Barcelona | Rodriguez-Frias F.,Vall dHebron Hospital | Rodriguez-Frias F.,CIBER ISCIII | Buti M.,Autonomous University of Barcelona | Buti M.,CIBER ISCIII
Annals of Hepatology | Year: 2013

Hepatitis E virus is one of the most common causes of acute hepatitis worldwide, with the majority of cases occurring in Asia. In recent years, however, an increasing number of acute and chronic hepatitis E virus infections have been reported in industrialized countries. The importance of this infection resides in the associated morbidity and mortality. In acute cases, a high mortality rate has been reported in patients with previously undiagnosed alcoholic liver disease. Hepatitis E infection can become chronic in immunocompromised patients, such as solid organ transplant recipients, patients receiving chemotherapy, and HIV-infected patients, and lead to the development of hepatic fibrosis and cirrhosis. Hence, treatment strategies involving reductions in immunosuppressive regimens and therapy with ribavirin or peg-interferon have been evaluated. In terms of prevention, a promising new vaccine was recently licensed in China, although its efficacy is uncertain and potential adverse effects in risk groups such as chronic liver disease patients and pregnant women require investigation. In conclusion, physicians should be aware of hepatitis E as a cause of both acute and chronic hepatitis in immunocompromised patients. The best treatment option for HEV infection remains to be defined, but both ribavirin and peg-interferon may have a role in therapy for this condition.


Perez-Domper P.,Cajal Institute CSIC | Perez-Domper P.,CIBER ISCIII | Gradari S.,Cajal Institute CSIC | Trejo J.L.,Cajal Institute CSIC
Ageing Research Reviews | Year: 2013

The decision between cellular survival and death is governed by a balance between proapoptotic versus antiapoptotic signaling cascades. Growth factors are key actors, playing two main roles both at developmental and adult stages: a supporting antiapoptotic role through diverse actions converging in the mitochondria, and a promoter role of cell maturation and plasticity through dendritogenesis and synaptogenesis, especially relevant for the adult hippocampal neurogenesis, a case of development during adulthood. Here, both parallel roles mutually feed forward each other (the success in avoiding apoptosis lets the cell to grow and differentiate, which in turn lets the cell to reach new targets and form new synapses accessing new sources of growth factors to support cell survival) in a circular cause and consequence, or a "the chicken or the egg" dilemma. While identifying the first case of this dilemma makes no sense, one possible outcome might have biological relevance: the decision between survival and death in the adult hippocampal neurogenesis is mainly concentrated at a specific time window, and recent data suggest some divergences between the survival and the maturational promoter effect of growth factors. This review summarizes these evidences suggesting how growth factors might contribute to the live-or-die decision of adult-born immature granule neurons through influencing the maturation of the young neuron by means of its connectivity into a mature functional circuit. © 2013 Elsevier B.V.


Cunha B.A.,Winthrop University | Cunha B.A.,State University of New York at Stony Brook | Burillo A.,Hospital General Universitario Gregorio Maranon | Burillo A.,Complutense University of Madrid | And 3 more authors.
The Lancet | Year: 2016

Summary Since first identified in early 1977, bacteria of the genus Legionella are recognised as a common cause of community-acquired pneumonia and a rare cause of hospital-acquired pneumonia. Legionella bacteria multisystem manifestations mainly affect susceptible patients as a result of age, underlying debilitating conditions, or immunosuppression. Water is the major natural reservoir for Legionella, and the pathogen is found in many different natural and artificial aquatic environments such as cooling towers or water systems in buildings, including hospitals. The term given to the severe pneumonia and systemic infection caused by Legionella bacteria is Legionnaires' disease. Over time, the prevalence of legionellosis or Legionnaires' disease has risen, which might indicate a greater awareness and reporting of the disease. Advances in microbiology have led to a better understanding of the ecological niches and pathogenesis of the condition. Legionnaires' disease is not always suspected because of its non-specific symptoms, and the diagnostic tests routinely available do not offer the desired sensitivity. However, effective antibiotics are available. Disease notification systems provide the basis for initiating investigations and limiting the scale and recurrence of outbreaks. This report reviews our current understanding of this disease. © 2016 Elsevier Ltd.


Jimenez R.,University of Granada | Duarte J.,University of Granada | Perez-Vizcaino F.,Complutense University of Madrid | Perez-Vizcaino F.,CIBER ISCIII
Journal of Agricultural and Food Chemistry | Year: 2012

Epidemiological studies indicate an inverse relationship between flavanol intake and the risk of cardiovascular disease. Potential mechanisms include their effects on endothelial function and hypertension. A number of studies have shown that flavanol-rich cocoa reduces blood pressure and endothelial dysfunction, whereas black tea may have opposite effects. These results highlight the importance of the different effects of the multitude of phytochemical constituents in these foods and the need for studying the individual flavanols. Epicatechin seems to be a major bioactive constituent of cocoa and other flavanol-rich foods and beverages. It has been shown to improve endothelial function in animals and humans. In salt-sensitive animal models of hypertension, epicatechin lowers blood pressure and the associated end-organ damage. Nitric oxide (NO) seems to play a key role in the protection of both hypertension and endothelial dysfunction. © 2012 American Chemical Society.


Barbe F.,Coordinator Center | Duran-Cantolla J.,Hospital Universitario La Paz | Sanchez-De-La-Torre M.,Coordinator Center | Martinez-Alonso M.,Coordinator Center | And 14 more authors.
JAMA - Journal of the American Medical Association | Year: 2012

Context: Continuous positive airway pressure (CPAP) is the first-line treatment for patients with symptomatic obstructive sleep apnea (OSA). However, its indication for all patients with sleep-disordered breathing, regardless of daytime symptoms, is unclear. Objective: To evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA. Design, Setting, and Patients: Multicenter, parallel-group, randomized controlled trial in 14 teaching hospitals in Spain. Between May 2004 and May 2006, 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h -1 or greater and an Epworth Sleepiness Scale score of 10 or less (scores range from 0-24, with values <10 suggesting no daytime sleepiness). Exclusion criteria were previous cardiovascular event, physical or psychological incapacity, chronic disease, or drug or alcohol addiction. Follow-up ended in May 2009. Intervention: Patients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice. Main Outcome Measures: Incidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for unstable angina or arrhythmia, heart failure, or cardiovascular death). Results: Seven hundred twenty-three patients underwent follow-up for a median of 4 (interquartile range, 2.7-4.4) years (1 patient from each group did not receive allocated treatment); 357 in the CPAP group and 366 in the control group were included in the analysis. In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events (17 unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal myocardial infarction, 2 transient ischemic attack, 1 cardiovascular death). In the control group there were 79 patients with new hypertension and 31 cardiovascular events (11 unstable angina or arrhythmia, 8 nonfatal myocardial infarction, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years (95% CI, 7.36-11.04) in the CPAP group and 11.02 per 100 person-years (95% CI, 8.96-13.08) in the control group. The incidence density ratio was 0.83 (95% CI, 0.63-1.1; P=.20). Conclusions: In patients with OSA without daytime sleepiness, the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events. However, the study may have had limited power to detect a significant difference. Trial Registration: clinicaltrials.gov Identifier: NCT00127348. ©2012 American Medical Association. All rights reserved.


Vidorreta M.,University of Navarra | Wang Z.,University of Pennsylvania | Rodriguez I.,Complutense University of Madrid | Rodriguez I.,CIBER ISCIII | And 3 more authors.
NeuroImage | Year: 2013

Arterial spin labeling (ASL) can be implemented by combining different labeling schemes and readout sequences. In this study, the performance of 2D and 3D single-shot pulsed-continuous ASL (pCASL) sequences was assessed in a group of young healthy volunteers undergoing a baseline perfusion and a functional study with a sensory-motor activation paradigm. The evaluated sequences were 2D echo-planar imaging (2D EPI), 3D single-shot fast spin-echo with in-plane spiral readout (3D FSE spiral), and 3D single-shot gradient-and-spin-echo (3D GRASE). The 3D sequences were implemented with and without the addition of an optimized background suppression (BS) scheme. Labeling efficiency, signal-to-noise ratio (SNR), and gray matter (GM) to white matter (WM) contrast ratio were assessed in baseline perfusion measurements. 3D acquisitions without BS yielded 2-fold increments in spatial SNR, but no change in temporal SNR. The addition of BS to the 3D sequences yielded a 3-fold temporal SNR increase compared to the unsuppressed sequences. 2D EPI provided better GM-to-WM contrast ratio than the 3D sequences. The analysis of functional data at the subject level showed a 3-fold increase in statistical power for the BS 3D sequences, although the improvement was attenuated at the group level. 3D without BS did not increase the maximum t-values, however, it yielded larger activation clusters than 2D. These results demonstrate that BS 3D single-shot imaging sequences improve the performance of pCASL in baseline and activation studies, particularly for individual subject analyses where the improvement in temporal SNR translates into markedly enhanced power for task activation detection. © 2012 Elsevier Inc.


Cardenas A.,CIBER ISCIII | Gines P.,CIBER ISCIII | Gines P.,Hospital Clinic
Current Opinion in Critical Care | Year: 2011

Purpose of review: Acute-on-chronic liver failure (ACLF) is defined as an abrupt deterioration of liver function in patients with established liver disease. Kidney function is almost universally altered in patients with ACLF due to underlying circulatory abnormalities. We review current advances during the past year in the diagnosis and management of renal failure in ACLF. Recent findings: The adequate measurement of renal function by means of clearance methods remains the gold standard for estimation of the glomerular filtration rate in patients with cirrhosis. The new definition of acute kidney injury needs to be specifically studied in patients with cirrhosis. Alternative kidney biomarkers of renal function in cirrhosis are promising and need further investigation. The most common cause of renal failure in cirrhosis is that associated with infections followed by hypovolemia-induced renal failure, intrinsic renal diseases, hepatorenal syndrome, and drug-induced renal failure. Adrenal insufficiency commonly occurs in patients with cirrhosis and hemodynamic instability. The proper diagnosis relies on corticotropin stimulation testing and the role of hydrocortisone therapy in these patients merits further investigation. Hyponatremia in cirrhosis is a major risk factor for the development of hepatic encephalopathy and is associated with a poor outcome in patients with ACLF and also after deceased donor and living-related liver transplantation. Vasoconstrictor drugs, particularly terlipressin, are effective for the management of hepatorenal syndrome. Predictive factors of response to terlipressin include serum bilirubin levels and the presence of an early increase in mean arterial pressure. SUMMARY: The ongoing advances in the diagnosis and management of patients with ACLF and renal failure will improve the diagnosis, therapy and outcome of these patients. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Raoul J.-L.,French Institute of Health and Medical Research | Sangro B.,Liver Unit | Sangro B.,CIBER ISCIII | Forner A.,University of Barcelona | And 4 more authors.
Cancer Treatment Reviews | Year: 2011

Transarterial chemoembolization (TACE) is considered the gold standard for treating intermediate-stage hepatocellular carcinoma (HCC). However, intermediate-stage HCC includes a heterogeneous population of patients with varying tumour burdens, liver function (Child-Pugh A or B) and disease aetiology. This suggests that not all patients with intermediate-stage HCC will derive similar benefit from TACE, and that some patients may benefit from other treatment options. Results of an extensive literature review into the treatment of unresectable HCC with TACE were combined with our own clinical experience to identify factors that may predict survival after TACE. We also report contraindications to TACE and propose a treatment algorithm for the repetition of TACE. In addition, we have constructed a number of expert opinions that may be used as a guide to help physicians make treatment decisions for their patients with intermediate-stage HCC. The data included in the literature review related almost exclusively to conventional TACE, rather than to TACE with drug-eluting beads. Therefore, the findings and conclusions of the literature review are only applicable to the treatment of HCC with conventional TACE. Treating physicians may want to consider other treatment options for patients with intermediate-stage HCC who are not suitable for or do not respond to TACE. By distinguishing those patients who represent good candidates for TACE from those where little or no benefit might be expected, it may be possible to make better use of current treatment options and improve outcomes for patients. © 2010.


Benito M.,Complutense University of Madrid | Benito M.,CIBER ISCIII
Archives of Physiology and Biochemistry | Year: 2011

Insulin resistance is the most important pathophysiological feature in many pre-diabetic states. Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion by pancreatic beta cells. The creation of monogenic or polygenic genetically manipulated mice models in a tissue-specific manner was of great help to elucidate the tissue-specificity of insulin action and its contribution to the overall insulin resistance. However, complete understanding of the molecular bases of the insulin action and resistance requires the identification of the intracellular pathways that regulate insulin-stimulated proliferation, differentiation and metabolism. Accordingly, cell lines derived from insulin target tissues such as brown adipose tissue, liver and beta islets lacking insulin receptors or sensitive candidate genes such as IRS-1, IRS-2, IRS-3, IR and PTP1B were developed. Indeed, these cell lines have been also very useful to understand the tissue-specificity of insulin action and inaction. © 2011 Informa UK, Ltd.


Pathak N.,Blizard Institute | Dodds J.,Blizard Institute | Zamora J.,Blizard Institute | Zamora J.,CIBER ISCIII | Khan K.,Blizard Institute
BMJ (Online) | Year: 2014

Objective: To determine the accuracy of testing for human papillomavirus (HPV) DNA in urine in detecting cervical HPV in sexually active women.Design: Systematic review and meta-analysis.Data sources: Searches of electronic databases from inception until December 2013, checks of reference lists, manual searches of recent issues of relevant journals, and contact with experts.Eligibility criteria: Test accuracy studies in sexually active women that compared detection of urine HPV DNA with detection of cervical HPV DNA.Data extraction and synthesis: Data relating to patient characteristics, study context, risk of bias, and test accuracy. 2×2 tables were constructed and synthesised by bivariate mixed effects meta-analysis.Results: 16 articles reporting on 14 studies (1443 women) were eligible for meta-analysis. Most used commercial polymerase chain reaction methods on first void urine samples. Urine detection of any HPV had a pooled sensitivity of 87% (95% confidence interval 78% to 92%) and specificity of 94% (95% confidence interval 82% to 98%). Urine detection of high risk HPV had a pooled sensitivity of 77% (68% to 84%) and specificity of 88% (58% to 97%). Urine detection of HPV 16 and 18 had a pooled sensitivity of 73% (56% to 86%) and specificity of 98% (91% to 100%). Metaregression revealed an increase in sensitivity when urine samples were collected as first void compared with random or midstream (P=0.004).Limitations: The major limitations of this review are the lack of a strictly uniform method for the detection of HPV in urine and the variation in accuracy between individual studies.


Sanchez-Buso L.,University of Valencia | Sanchez-Buso L.,CIBER ISCIII | Comas I.,University of Valencia | Comas I.,CIBER ISCIII | And 3 more authors.
Nature Genetics | Year: 2014

Legionella pneumophila is a strictly environmental pathogen and the etiological agent of legionellosis. It is known that non-vertical processes have a major role in the short-term evolution of pathogens, but little is known about the relevance of these and other processes in environmental bacteria. We report the whole-genome sequencing of 69 L. pneumophila strains linked to recurrent outbreaks in a single location (Alcoy, Spain) over 11 years. We found some examples where the genome sequences of isolates of the same sequence type and outbreak did not cluster together and were more closely related to sequences from different outbreaks. Our analyses identify 16 recombination events responsible for almost 98% of the SNPs detected in the core genome and an apparent acceleration in the evolutionary rate. These results have profound implications for the understanding of microbial populations and for public health interventions in Legionella outbreak investigations. © 2014 Nature America, Inc. All rights reserved.


Villaescusa L.A.,Polytechnic University of Valencia | Villaescusa L.A.,CIBER ISCIII | Camblor M.A.,CSIC - Institute of Materials Science
Chemistry of Materials | Year: 2016

Calcination in air of GeO2 zeolites with AST-topology causes reduction of the framework, hence structural destruction, in a notable extension. This is due to the impossibility for the organic cation occluded inside to react with ambient oxygen. As the temperature increases, reoxidation in air of the reduced framework causes episodes of weight-gain. When calcination is carried out in N2, weight losses close to 70% imply a loss of Ge due to sublimation of germanium monoxide, GeO. The nature of the organic cation occluded determines the nature and oxidation state of the final residue after calcination in N2: for tetramethylammonium the residue is GeO2 while trimethyl-terc-butylammonium, thanks to its larger C content, yields metallic Ge. Framework organoreduction is not unique to GeO2-AST zeolites but also occurs during the calcination in air of other germanium-containing zeolites with larger pore openings. © 2016 American Chemical Society.


Tomasi M.L.,University of Southern California | Tomasi I.,University of London | Ramani K.,University of Southern California | Pascale R.M.,University of Sassari | And 4 more authors.
Hepatology | Year: 2012

Ubiquitin-conjugating enzyme 9 (Ubc9) is required for sumoylation and is overexpressed in several malignancies, but its expression in hepatocellular carcinoma (HCC) is unknown. Hepatic S-adenosyl methionine (SAMe) levels decrease in methionine adenosyltransferase 1A (Mat1a) knockout (KO) mice, which develop HCC, and in ethanol-fed mice. We examined the regulation of Ubc9 by SAMe in murine liver and human HCC, breast, and colon carcinoma cell lines and specimens. Real-time polymerase chain reaction and western blotting measured gene and protein expression, respectively. Immunoprecipitation followed by western blotting examined protein-protein interactions. Ubc9 expression increased in HCC and when hepatic SAMe levels decreased. SAMe treatment in Mat1a KO mice reduced Ubc9 protein, but not messenger RNA (mRNA) levels, and lowered sumoylation. Similarly, treatment of liver cancer cell lines HepG2 and Huh7, colon cancer cell line RKO, and breast cancer cell line MCF-7 with SAMe or its metabolite 5′-methylthioadenosine (MTA) reduced only Ubc9 protein level. Ubc9 posttranslational regulation is unknown. Ubc9 sequence predicted a possible phosphorylation site by cell division cycle 2 (Cdc2), which directly phosphorylated recombinant Ubc9. Mat1a KO mice had higher phosphorylated (phospho)-Ubc9 levels, which normalized after SAMe treatment. SAMe and MTA treatment lowered Cdc2 mRNA and protein levels, as well as phospho-Ubc9 and protein sumoylation in liver, colon, and breast cancer cells. Serine 71 of Ubc9 was required for phosphorylation, interaction with Cdc2, and protein stability. Cdc2, Ubc9, and phospho-Ubc9 levels increased in human liver, breast, and colon cancers. Conclusion: Cdc2 expression is increased and Ubc9 is hyperphosphorylated in several cancers, and this represents a novel mechanism to maintain high Ubc9 protein expression that can be inhibited by SAMe and MTA. © 2012 American Association for the Study of Liver Diseases.


Porlan E.,CIBER ISCIII | Porlan E.,University of Valencia | Porlan E.,Cell Division and Cancer Group | Marti-Prado B.,CIBER ISCIII | And 13 more authors.
Nature Cell Biology | Year: 2014

The identification of mechanisms that maintain stem cell niche architecture and homeostasis is fundamental to our understanding of tissue renewal and repair. Cell adhesion is a well-characterized mechanism for developmental morphogenetic processes, but its contribution to the dynamic regulation of adult mammalian stem cell niches is still poorly defined. We show that N-cadherin-mediated anchorage of neural stem cells (NSCs) to ependymocytes in the adult murine subependymal zone modulates their quiescence. We further identify MT5-MMP as a membrane-type metalloproteinase responsible for the shedding of the N-cadherin ectodomain in this niche. MT5-MMP is co-expressed with N-cadherin in adult NSCs and ependymocytes and, whereas MT5-MMP-mediated cleavage of N-cadherin is dispensable for the regulation of NSC generation and identity, it is required for proper activation of NSCs under physiological and regenerative conditions. Our results indicate that the proliferative status of stem cells can be dynamically modulated by regulated cleavage of cell adhesion molecules. © 2014 Macmillan Publishers Limited. All rights reserved.


Vallverdu-Queralt A.,University of Barcelona | Vallverdu-Queralt A.,CIBER ISCIII | Medina-Remon A.,University of Barcelona | Medina-Remon A.,CIBER ISCIII | And 3 more authors.
Food Chemistry | Year: 2012

The present study aims to compare the phenolic and hydrophilic antioxidant profiles of organically and conventionally produced tomato juices. Comparisons of analyses of archived samples from conventional and organic production systems demonstrated statistically higher levels (P < 0.05) of phenolic compounds in organic tomato juices. This increase corresponds not only with increasing amounts of soil organic matter accumulating in organic plots but also with reduced manure application rates once soils in the organic systems had reached equilibrium levels of organic matter. Using principal component analysis, results show that phenolic compounds and hydrophilic antioxidant capacity were responsible for the differentiation between organic and conventional tomato juices. Thus, there appear to be genuine differences in the bioactive components of organic and conventional tomato juices not previously reported. © 2011 Elsevier Ltd. All rights reserved.


Acebo P.,Institute Salud Carlos III | Martin-Galiano A.J.,Institute Salud Carlos III | Navarro S.,Institute Salud Carlos III | Navarro S.,CIBER ISCIII | And 3 more authors.
RNA | Year: 2012

Streptococcus pneumoniae is the main etiological agent of community-acquired pneumonia and a major cause of mortality and morbidity among children and the elderly. Genome sequencing of several pneumococcal strains revealed valuable information about the potential proteins and genetic diversity of this prevalent human pathogen. However, little is known about its transcriptional regulation and its small regulatory noncoding RNAs. In this study, we performed deep sequencing of the S. pneumoniae TIGR4 strain RNome to identify small regulatory RNA candidates expressed in this pathogen. We discovered 1047 potential small RNAs including intragenic, 5′- and/or 3′-overlapping RNAs and 88 small RNAs encoded in intergenic regions. With this approach, we recovered many of the previously identified intergenic small RNAs and identified 68 novel candidates, most of which are conserved in both sequence and genomic context in other S. pneumoniae strains. We confirmed the independent expression of 17 intergenic small RNAs and predicted putative mRNA targets for six of them using bioinformatics tools. Preliminary results suggest that one of these six is a key player in the regulation of competence development. This study is the biggest catalog of small noncoding RNAs reported to date in S. pneumoniae and provides a highly complete view of the small RNA network in this pathogen. Published by Cold Spring Harbor Laboratory Press. Copyright © 2012 RNA Society.


Mengod G.,CIBER ISCIII | Palacios J.M.,Frontera Biotechnology | Cortes R.,CIBER ISCIII
ACS Chemical Neuroscience | Year: 2015

Since the development of chemical neuroanatomical tools in the 1960s, a tremendous wealth of information has been generated on the anatomical components of the serotonergic system, at the microscopic level in the brain including the prefrontal cortex (PFC). The PFC receives a widespread distribution of serotonin (5-hydroxytryptamine, 5-HT) terminals from the median and dorsal raphe nuclei. 5-HT receptors were first visualized using radioligand autoradiography in the late 1980s and early 1990s and showed, in contrast to 5-HT innervation, a differential distribution of binding sites associated with different 5-HT receptor subtypes. Due to the cloning of the different 5-HT receptor subtype genes in the late 1980s and early 1990s, it was possible, using in situ hybridization histochemistry, to localize cells expressing mRNA for these receptors. Double in situ hybridization histochemistry and immunohistochemistry allowed for the chemical characterization of the phenotype of cells expressing 5-HT receptors. Tract tracing technology allowed a detailed cartography of the neuronal connections of PFC and other brain areas. Based on these data, maps have been constructed that reflect our current understanding of the different circuits where 5-HT receptors can modulate the electrophysiological, pharmacological, and behavioral functions of the PFC. We will review current knowledge regarding the cellular localization of 5-HT1A and 5-HT2A receptors in mammalian PFC and their possible functions in the neuronal circuits of the PFC. We will discuss data generated in our laboratory as well as in others, focusing on localization in the pyramidal and GABAergic neuronal cell populations in different mammalian species using molecular neuroanatomy and on the connections with other brain regions. © 2015 American Chemical Society.


Gallo J.,CIC Biomagune | Garcia I.,CIC Biomagune | Garcia I.,CIBER ISCIII | Genicio N.,CIC Biomagune | And 3 more authors.
Biomaterials | Year: 2011

Current performance of iron oxide nanoparticle-based contrast agents in clinical use is based on the unspecific accumulation of the probes in certain organs or tissues. Specific targeted biofunctional nanoparticles would significantly increase their potential as diagnostic and therapeutic tools in vivo. In this study, multimodal fluorescent/magnetic glyco-nanoparticles were synthesized from gold-coated magnetite (glyco-ferrites) and converted into specific probes by the covalent coupling of protein G and subsequent incubation with an IgG antibody. The immuno-magnetic-fluorescent nanoparticles were applied to the specific labelling of peripheral blood mononuclear cells (PBMCs) in a complex biological medium, as human blood. We have been able to label specifically PBMCs present in blood in a percentage as low as 0.10-0.17%. Red blood cells (RBCs) were also clearly labelled, even though the inherent T 2 contrast arising from the high iron content of these cells (coming mainly from haemoglobin). The labelling was further assessed at cellular level by fluorescence microscopy. In conclusion, we have developed new contrast agents able to label specifically a cell population under adverse biological conditions (low abundance, low intrinsic T 2, high protein content). These findings open the door to the application of these probes for the labelling and tracking of endogenous cell populations like metastatic cancer cells, or progenitor stem cells that exist in very low amount in vivo. © 2011 Elsevier Ltd.


Burillo A.,Hospital Universitario Of Mostoles | Bouza E.,Complutense University of Madrid | Bouza E.,Hospital General Universitario Gregorio Maranon | Bouza E.,CIBER ISCIII
Infectious Disease Clinics of North America | Year: 2010

Chlamydophila pneumoniae is estimated to cause about 10% of community-acquired pneumonia (CAP) cases and 5% of bronchitis cases, although most patients with C pneumoniae infection are asymptomatic, and the course of respiratory illness is relatively mild. The incubation period of C pneumoniae infection is around 21 days, and such symptoms as cough and malaise show a gradual onset, yet may persist for several weeks or months despite appropriate antibiotic therapy. Diagnosis by nasopharyngeal specimen culture, serum antibody titers, or molecular techniques is usually delayed with respect to the onset of symptoms, antibiotic treatment, or disease resolution and there is no accurate, standardized, commercial US Food and Drug Administration-cleared diagnostic method available. Erythromycin, tetracycline, and doxycycline are used as first-line therapy, although some investigators report no clinical or survival benefits from treating CAP caused by atypical pathogens. Meanwhile, adequate prospective studies have met with ethical and logistic barriers. Despite these limitations, North American guidelines recommend the antimicrobial treatment of patients with acute C pneumoniae respiratory infection. © 2010.


Gonzalez-Candelas F.,University of Valencia | Gonzalez-Candelas F.,CIBER ISCIII | Bracho M.A.,University of Valencia | Bracho M.A.,CIBER ISCIII | And 5 more authors.
BMC Biology | Year: 2013

Background: Molecular phylogenetic analyses are used increasingly in the epidemiological investigation of outbreaks and transmission cases involving rapidly evolving RNA viruses. Here, we present the results of such an analysis that contributed to the conviction of an anesthetist as being responsible for the infection of 275 of his patients with hepatitis C virus.Results: We obtained sequences of the NS5B and E1-E2 regions in the viral genome for 322 patients suspected to have been infected by the doctor, and for 44 local, unrelated controls. The analysis of 4,184 cloned sequences of the E1-E2 region allowed us to exclude 47 patients from the outbreak. A subset of patients had known dates of infection. We used these data to calibrate a relaxed molecular clock and to determine a rough estimate of the time of infection for each patient. A similar analysis led to an estimate for the time of infection of the source. The date turned out to be 10 years before the detection of the outbreak. The number of patients infected was small at first, but it increased substantially in the months before the detection of the outbreak.Conclusions: We have developed a procedure to integrate molecular phylogenetic reconstructions of rapidly evolving viral populations into a forensic setting adequate for molecular epidemiological analysis of outbreaks and transmission events. We applied this procedure to a large outbreak of hepatitis C virus caused by a single source and the results obtained played a key role in the trial that led to the conviction of the suspected source. © 2013 González-Candelas et al.; licensee BioMed Central Ltd.


Canton R.,CIBER ISCIII | Gonzalez-Alba J.M.,CIBER ISCIII | Galan J.C.,CIBER ISCIII
Frontiers in Microbiology | Year: 2012

CTX-M β-lactamases are considered a paradigm in the evolution of a resistance mechanism. Incorporation of different chromosomal blaCTX-M related genes from different species of Kluyvera has derived in different CTX-M clusters. In silico analyses have shown that this event has occurred at least nine times; in CTX-M-1 cluster (3), CTX-M-2 and CTX-M-9 clusters (2 each), and CTX-M-8 and CTX-M-25 clusters (1 each). This has been mainly produced by the participation of genetic mobilization units such as insertion sequences (ISEcp1 or ISCR1) and the later incorporation in hierarchical structures associated with multifaceted genetic structures including complex class 1 integrons and transposons. The capture of these blaCTX-M genes from the environment by highly mobilizable structures could have been a random event. Moreover, after incorporation within these structures, β-lactam selective force such as that exerted by cefotaxime and ceftazidime has fueled mutational events underscoring diversification of different clusters. Nevertheless, more variants of CTX-M enzymes, including those not inhibited by β-lactamase inhibitors such as clavulanic acid (IR-CTX-M variants), only obtained under in in vitro experiments, are still waiting to emerge in the clinical setting. Penetration and the later global spread of CTX-M producing organisms have been produced with the participation of the so-called "epidemic resistance plasmids" often carried in multi-drug resistant and virulent high-risk clones. All these facts but also the incorporation and co-selection of emerging resistance determinants within CTX-M producing bacteria, such as those encoding carbapenemases, depict the currently complex pandemic scenario of multi-drug resistant isolates.© 2012 Cantón, González-Alba and Galán.


Several epidemiological studies have shown that consumption of tree nuts is associated with lower cardiovascular risk, specific cause of mortality and total mortality. Clinical feeding trials have demonstrated that tree nuts protect from cardiovascular disease risk through different mechanisms: regulating inflammatory processes, oxidative stress and endothelial function, thereby improving various cardiovascular risk factors. In the context of meals high in carbohydrates, tree nuts reduce the postprandial glucose peaks, improving insulin resistance. Frequent consumption of nuts has been associated with a lower risk of diabetes in women, but the effect was not yet elucidated in men. Although tree nuts are energetically dense and they are high in fat, nut consumption does not imply appreciable weight gain nor has been associated with a higher risk of abdominal obesity. Tree nut consumption reduces LDL cholesterol levels, but its effects on atherogenic dyslipidemia associated to metabolic syndrome (MetS) are less clear. The effect of consumption of nuts on LDL cholesterol in subjects with MetS neither has been well established, but it seems that in these patients could lower plasma triglyceride levels. Some studies suggest an inverse association between tree nut consumption and blood pressure or endothelial function, especially in non-diabetic individuals. Nut consumption was inversely related to the prevalence and incidence of MetS. Including tree nuts in the context of a healthy dietary pattern way increase the health benefits. It has been observed a lower prevalence of MetS and a lower incidence of diabetes in people who adhered to a Mediterranean diet supplemented with nuts. Future nutrition intervention studies are needed on large samples of subjects and long follow-up to affirm that tree nut consumption has beneficial effects on the prevention and treatment of MetS. © 2015, Grupo Aula Medica S.A. All rights reserved.


Fan E.,University of Toronto | Fan E.,Sinai University | Villar J.,CIBER ISCIII | Villar J.,Hospital Universitario Dr Negrin | And 3 more authors.
BMC Medicine | Year: 2013

Despite over 40 years of research, there is no specific lung-directed therapy for the acute respiratory distress syndrome (ARDS). Although much has evolved in our understanding of its pathogenesis and factors affecting patient outcome, supportive care with mechanical ventilation remains the cornerstone of treatment. Perhaps the most important advance in ARDS research has been the recognition that mechanical ventilation, although necessary to preserve life, can itself aggravate or cause lung damage through a variety of mechanisms collectively referred to as ventilator-induced lung injury (VILI). This improved understanding of ARDS and VILI has been important in designing lung-protective ventilatory strategies aimed at attenuating VILI and improving outcomes. Considerable effort has been made to enhance our mechanistic understanding of VILI and to develop new ventilatory strategies and therapeutic interventions to prevent and ameliorate VILI with the goal of improving outcomes in patients with ARDS. In this review, we will review the pathophysiology of VILI, discuss a number of novel physiological approaches for minimizing VILI, therapies to counteract biotrauma, and highlight a number of experimental studies to support these concepts. © 2013 Fan et al.; licensee BioMed Central Ltd.


Sostres C.,Universitario Lozano Blesa | Sostres C.,Aragon Health science Institute | Gargallo C.J.,Universitario Lozano Blesa | Gargallo C.J.,Aragon Health science Institute | And 4 more authors.
Arthritis Research and Therapy | Year: 2013

NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with gastrointestinal (GI) adverse events. NSAIDs can damage the whole GI tract including a wide spectrum of lesions. About 1 to 2% of NSAID users experienced a serious GI complication during treatment. The relative risk of upper GI complications among NSAID users depends on the presence of different risk factors, including older age (>65 years), history of complicated peptic ulcer, and concomitant aspirin or anticoagulant use, in addition to the type and dose of NSAID. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge. NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract. Selective cyclooxygenase-2 inhibitors have the same beneficial effects as nonselective NSAIDs but with less GI toxicity in the upper GI tract and probably in the lower GI tract. Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies. © 2013 BioMed Central Ltd.


Vales G.,Autonomous University of Barcelona | Demir E.,Akdeniz University | Kaya B.,Akdeniz University | Creus A.,Autonomous University of Barcelona | And 3 more authors.
Nanotoxicology | Year: 2013

Nanogenotoxicology is an emergent area of research, relevant for estimating the potential carcinogenic risk of nanomaterials. Since most of the approaches use in vitro studies, and neglecting the whole organism limits the accuracy of the obtained results, we have used Drosophila melanogaster to study the possible genotoxic potential of cobalt nanoparticles (Co NPs). The wing somatic mutation and recombination test has been the test of choice. This test is based on the principle that the loss of heterozygosis and the corresponding expression of the suitable recessive markers, multiple wing hairs and flare-3 can lead to the formation of mutant clone cells in growing up larvae, which are expressed as mutant spots on the wings of adult flies. Co NPs, as well as the ionic form cobalt chloride, were given to third instar larvae through the food, at concentrations ranging from 0.1 to 10 mM. The results obtained indicate that both cobalt forms are able to induce significant increases in the frequency of mutant clones. Although at low concentrations only Co NPs were genotoxic, the level of genetic damage obtained at the highest dose tested of cobalt chloride (10 mM) showed a significant higher increase in the frequency of total spots than those observed after the treatment with cobalt nanoparticles. As conclusion, our results indicate that Co NPs were able to induce genotoxic activity in the wing-spot assay of D. melanogaster, mainly via the induction of somatic recombination. The differences observed in the behaviour of the two selected cobalt forms may result from differences in the uptake. © 2013 Informa UK, Ltd.


Novelle M.G.,U.S. National Institute on Aging | Novelle M.G.,University of Santiago de Compostela | Novelle M.G.,CIBER ISCIII | Wahl D.,U.S. National Institute on Aging | And 4 more authors.
Ageing Research Reviews | Year: 2015

Pre-clinical findings have provided mounting evidence that resveratrol, a dietary polyphenol, may confer health benefits and protect against a variety of medical conditions and age-related complications. However, there is no consistent evidence of an increased protection against metabolic disorders and other ailments when comparing studies in laboratory animals and humans. A number of extraneous and potential confounding variables can affect the outcome of clinical research. To date, most of the studies that have investigated the effect of resveratrol administration on patient outcomes have been limited by their sample sizes. In this review, we will survey the latest advances regarding the timing, dosage, formulation, bioavailability, toxicity of resveratrol, and resveratrol-drug interactions in human studies. Moreover, the present report focuses on the actions of resveratrol treatment in combating diseases, such as cancer, diabetes, neurodegeneration, cardiovascular disease, and other age-related ailments. © 2015 .


Basagana X.,Center for Research in Environmental Epidemiology | Basagana X.,Municipal Institute of Medical Research IMIM Hospital del Mar | Basagana X.,CIBER ISCIII | Spiegelman D.,Harvard University
Statistics in Medicine | Year: 2010

Existing study design formulas for longitudinal studies have assumed that the exposure is time-invariant. We derived sample size formulas for studies comparing rates of change by exposure when the exposure varies with time within a subject, focusing on observational studies where this variation is not controlled by the investigator. Two scenarios are considered, one assuming that the effect of exposure on the response is acute and the other assuming that it is cumulative. We show that accurate calculations can often be obtained by providing the intraclass correlation of exposure and the exposure prevalence at each time point. When comparing rates of change, studies with a time-varying exposure are, in general, less efficient than studies with a time-invariant one. We provide a public access program to perform the calculations described in the paper (http://www.hsph.harvard.edu/faculty/spiegelman/optitxs.html). Copyright © 2009 John Wiley & Sons, Ltd.


Barrecheguren M.,CIBER ISCIII | Roman-Rodriguez M.,Primary Health Care Center Son Pisa | Miravitlles M.,CIBER ISCIII
International Journal of COPD | Year: 2015

Background: Some patients share characteristics of both COPD and asthma. As yet, there is no gold standard to identify patients with the so-called asthma–COPD overlap syndrome (ACOS). Objective: To describe the differences between ACOS patients and the remaining COPD patients, and to compare the clinical characteristics of patients diagnosed with ACOS by two different criteria: previous diagnosis of asthma before the age of 40 years; and the diagnostic criteria of the Spanish guidelines of COPD. Methods: Multicenter, observational, cross-sectional study performed in 3,125 COPD patients recruited in primary care and specialized outpatient clinics. Patients with COPD and a history of asthma before the age of 40 years were diagnosed with ACOS and compared to the remaining COPD patients. Subsequently, ACOS patients were subdivided based on whether they fulfilled the Spanish guidelines of the COPD diagnostic criteria or not, and they were compared. Results: ACOS was diagnosed in 15.9% of the patients. These patients had different basal characteristics compared to the remaining COPD patients, including a higher frequency of women and more exacerbations despite lower tobacco exposure and better lung function. They were more likely to have features of asthma, such as a positive bronchodilator test, higher peripheral eosinophilia, and higher total immunoglobulin E. Within the ACOS group, only one-third fulfilled the diagnostic criteria of the Spanish guidelines of COPD; these individuals were not significantly different from the remaining ACOS patients, except for having more exacerbations and poorer lung function. Conclusion: ACOS patients diagnosed on the basis of a previous diagnosis of asthma differed from the remaining COPD patients, but they were similar to ACOS patients diagnosed according to more restrictive criteria, suggesting that a history of asthma before the age of 40 years could be a useful criterion to suspect ACOS in a patient with COPD. © 2015 Barrecheguren et al.


Perez-Martinez F.C.,S.L. Parque Cientifico y Tecnologico | Guerra J.,University of Castilla - La Mancha | Guerra J.,S.L. Parque Cientifico y Tecnologico | Posadas I.,University of Castilla - La Mancha | And 3 more authors.
Pharmaceutical Research | Year: 2011

Efficient methods for cell line transfection are well described, but, for primary neurons, a high-yield method different from those relying on viral vectors is lacking. Viral transfection has several drawbacks, such as the complexity of vector preparation, safety concerns, and the generation of immune and inflammatory responses when used in vivo. However, one of the main problems for the use of non-viral gene vectors for neuronal transfection is their low efficiency when compared with viral vectors. Transgene expression, or siRNA delivery mediated by non-viral vectors, is the result of multiple processes related to cellular membrane crossing, intracellular traffic, and/or nuclear delivery of the genetic material cargo. This review will deal with the barriers that different nanoparticles (cationic lipids, polyethyleneimine, dendrimers and carbon nanotubes) must overcome to efficiently deliver their cargo to central nervous system cells, including internalization into the neurons, interaction with intracellular organelles such as lysosomes, and transport across the nuclear membrane of the neuron in the case of DNA transfection. Furthermore, when used in vivo, the nanoparticles should efficiently cross the blood-brain barrier to reach the target cells in the brain. © 2011 The Author(s).


Pneumococcal disease (including community-acquired pneumonia and invasive pneumococcal disease) poses a burden to the community all year round, especially in those with chronic underlying conditions. Individuals with COPD, asthma or who smoke, and those with chronic heart disease or diabetes mellitus have been shown to be at increased risk of pneumococcal disease compared with those without these risk factors. These conditions, and smoking, can also adversely affect patient outcomes, including short-term and long-term mortality rates, following pneumonia. Community-acquired pneumonia, and in particular pneumococcal pneumonia, is associated with a significant economic burden, especially in those who are hospitalised, and also has an impact on a patient's quality of life. Therefore, physicians should target individuals with COPD, asthma, heart disease or diabetes mellitus, and those who smoke, for pneumococcal vaccination at the earliest opportunity at any time of the year.


Diebold Y.,University of Valladolid | Diebold Y.,CIBER ISCIII | Calonge M.,University of Valladolid | Calonge M.,CIBER ISCIII
Progress in Retinal and Eye Research | Year: 2010

Nanocarriers, such as nanoparticles, have the capacity to deliver ocular drugs to specific target sites and hold promise to revolutionize the therapy of many eye diseases. Results to date strongly suggest that ocular medicine will benefit enormously from the use of this nanometric scale technology. One of the most important handicaps of the eye as a target organ for drugs is the presence of several barriers that impede direct and systemic drug access to the specific site of action. Superficial barriers include the ocular surface epithelium and the tear film, and internal barriers include the blood-aqueous and blood-retina barriers. Topical application is the preferred route for most drugs, even when the target tissues are at the back part of the eye where intraocular injections are currently the most common route of administration. Direct administration using any of these two routes faces many problems related to drug bioavailability, including side effects and repeated uncomfortable treatments to achieve therapeutic drug levels. In this regard, the advantages of using nanoparticles include improved topical passage of large, poorly water-soluble molecules such as glucocorticoid drugs or cyclosporine for immune-related, vision-threatening diseases. Other large and unstable molecules, such as nucleic acids, delivered using nanoparticles offer promising results for gene transfer therapy in severe retinal diseases. Also, nanoparticle-mediated drug delivery increases the contact time of the administered drug with its target tissue, such as in the case of brimonidine, one of the standard treatments for glaucoma, or corticosteroids used to treat autoimmune uveitis, a severe intraocular inflammatory process. In addition, nanocarriers permit the non-steroidal anti-inflammatory drug indomethacin to reach inner eye structures using the transmucosal route. Finally, nanoparticles allow the possibility of targeted delivery to reach specific types of cancer, such as melanoma, leaving normal cells untouched.This review summarizes experimental results from our group and others since the beginnings of nanocarrier technology to deliver drugs to different locations in the eye. Also, it explores the future possibilities of nanoparticles not only as drug delivery systems but also as aides for diagnostic purposes. © 2010 Elsevier Ltd.


Rajmil L.,Institute Hospital del Mar dInvestigacions Mediques | Rajmil L.,CIBER ISCIII | Lopez A.R.,Institute Hospital del Mar dInvestigacions Mediques | Lopez-Aguila S.,Agencia dinformacio | And 2 more authors.
Health and Quality of Life Outcomes | Year: 2013

Background: Few studies have evaluated changes on parent-child agreement in HRQOL over time. The objectives of the study were to assess parent-child agreement on child's HRQOL in a 3-year longitudinal study, and to identify factors associated with possible disagreement.Methods: A sample of Spanish children/adolescents aged 8-18 years and their parents both completed the KIDSCREEN-27 questionnaire. Data on age, gender, family socioeconomic status (SES), and mental health (Strengths and Difficulties Questionnaire, SDQ) was also collected at baseline (2003), and again after 3 years (2006). Changes in family composition were collected at follow-up. Agreement was assessed through intraclass correlation coefficient (ICC), and Bland and Altman plots. Generalizing Estimating Equation (GEE) models were built to analyze factors associated with parent-child disagreement.Results: A total of 418 parent-child pairs were analyzed. At baseline the level of agreement on HRQOL was low to moderate and it was related to the level of HRQOL reported. Physical well-being at baseline showed the highest level of parent-child agreement (ICC=0.59; 0.53-0.65) while less " observable" dimensions presented lower levels of agreement, (i.e. Psychological well-being: ICC= 0.46; 0.38-0.53). Agreement parent-child was lower at follow-up. Some interactions were found between rater and child's age; with increasing age, child scored lower than parents on Parents relationships and Autonomy (Beta [B] -0.47; -0.71 / -0.23) and the KIDSCREEN-10 (-0.49; -0.73 /-0.25).Conclusions: Parent-child agreement on child's HRQOL is moderate to low and tends to diminish with children age. Measuring HRQOL of children/adolescents mainly in healthy population samples might require direct self-assessments. © 2013 Rajmil et al.; licensee BioMed Central Ltd.


Pagan I.,Technical University of Madrid | Holguin A.,CIBER ISCIII
PLoS ONE | Year: 2013

The Caribbean and Central America are among the regions with highest HIV-1B prevalence worldwide. Despite of this high virus burden, little is known about the timing and the migration patterns of HIV-1B in these regions. Migration is one of the major processes shaping the genetic structure of virus populations. Thus, reconstruction of epidemiological network may contribute to understand HIV-1B evolution and reduce virus prevalence. We have investigated the spatio-temporal dynamics of the HIV-1B epidemic in The Caribbean and Central America using 1,610 HIV-1B partial pol sequences from 13 Caribbean and 5 Central American countries. Timing of HIV-1B introduction and virus evolutionary rates, as well as the spatial genetic structure of the HIV-1B populations and the virus migration patterns were inferred. Results revealed that in The Caribbean and Central America most of the HIV-1B variability was generated since the 80 s. At odds with previous data suggesting that Haiti was the origin of the epidemic in The Caribbean, our reconstruction indicated that the virus could have been disseminated from Puerto Rico and Antigua. These two countries connected two distinguishable migration areas corresponding to the (mainly Spanish-colonized) Easter and (mainly British-colonized) Western islands, which indicates that virus migration patterns are determined by geographical barriers and by the movement of human populations among culturally related countries. Similar factors shaped the migration of HIV-1B in Central America. The HIV-1B population was significantly structured according to the country of origin, and the genetic diversity in each country was associated with the virus prevalence in both regions, which suggests that virus populations evolve mainly through genetic drift. Thus, our work contributes to the understanding of HIV-1B evolution and dispersion pattern in the Americas, and its relationship with the geography of the area and the movements of human populations. © 2013 Pagán, Holguín.


Gonzalez-Cabo P.,Research Center Principe Felipe | Gonzalez-Cabo P.,Institute Biomedicina Of Valencia Csic | Gonzalez-Cabo P.,CIBER ISCIII | Palau F.,Research Center Principe Felipe | And 3 more authors.
Journal of Neurochemistry | Year: 2013

Neurological examination indicates that Friedreich's ataxia corresponds to a mixed sensory and cerebellar ataxia, which affects the proprioceptive pathways. Neuropathology and pathophysiology of Friedreich's ataxia involves the peripheral sensory nerves, dorsal root ganglia, posterior columns, the spinocerebellar, and corticospinal tracts of the spinal cord, gracile and cuneate nuclei, dorsal nuclei of Clarke, and the dentate nucleus. Involvement of the myocardium and pancreatic islets of Langerhans indicates that it is also a systemic disease. The pathophysiology of the disease is the consequence of frataxin deficiency in the mitochondria and cells. Some of the biological consequences are currently recognized such as the effects on iron-sulfur cluster biogenesis or the oxidative status, but others deserve to be studied in depth. Among physiological aspects of mitochondria that have been associated with neurodegeneration and may be interesting to investigate in Friedreich's ataxia we can include mitochondrial dynamics and movement, communication with other organelles especially the endoplasmic reticulum, calcium homeostasis, apoptosis, and mitochondrial biogenesis and quality control. Changes in the mitochondrial physiology and transport in peripheral and central axons and mitochondrial metabolic functions such as bioenergetics and energy delivery in the synapses are also relevant functions to be considered. Thus, to understand the general pathophysiology of the disease and fundamental pathogenic mechanisms such as dying-back axonopathy, and determine molecular, cellular and tissue therapeutic targets, we need to discover the effect of frataxin depletion on mitochondrial properties and on specific cell susceptibility in the nervous system and other affected organs. © 2013 International Society for Neurochemistry.


Medina M.A.,University of Malaga | Medina M.A.,CIBER ISCIII
Cellular and Molecular Life Sciences | Year: 2013

Modern systems biology is already contributing to a radical transformation of molecular life sciences and biomedicine, and it is expected to have a real impact in the clinical setting in the next years. In this review, the emergence of systems biology is contextualized with a historic overview, and its present state is depicted. The present and expected future contribution of systems biology to the development of molecular medicine is underscored. Concerning the present situation, this review includes a reflection on the " inflation" of biological data and the urgent need for tools and procedures to make hidden information emerge. Descriptions of the impact of networks and models and the available resources and tools for applying them in systems biology approaches to molecular medicine are provided as well. The actual current impact of systems biology in molecular medicine is illustrated, reviewing two cases, namely, those of systems pharmacology and cancer systems biology. Finally, some of the expected contributions of systems biology to the immediate future of molecular medicine are commented. © 2012 Springer Basel AG.


Lanas A.,University Hospital | Lanas A.,University of Zaragoza | Lanas A.,CIBER ISCIII | Gargallo C.J.,University Hospital
Journal of Gastroenterology | Year: 2015

Low-dose aspirin, alone or combined with other antiplatelet agents, is increasingly prescribed for cardiovascular prevention. However, the cardiovascular benefits should be evaluated together with the gastrointestinal risks. Low-dose aspirin is associated with upper and lower gastrointestinal injury, although lower gastrointestinal effects are poorly characterized. This gastrointestinal risk differs among antiplatelets drugs users. The most important risk factors are history of peptic ulcer, older age, and concomitant use of non-steroidal anti-inflammatory drugs or dual antiplatelet therapy. Effective upper gastrointestinal prevention strategies are available and should be used in at-risk patients taking low-dose aspirin or clopidogrel. Proton pump inhibitors seem to be the best gastroprotective agents, whereas the benefits of Helicobacter pylori eradication are still unclear. Low-dose aspirin has additional effects in the gastrointestinal tract. A large body of evidence indicates that it can protect against different cancers, in particular colorectal cancer. This effect could modify the future indications for use of low-dose aspirin and the risk–benefit balance. © 2015, Springer Japan.


Lumbreras B.,University Miguel Hernández | Lumbreras B.,CIBER ISCIII | Donat L.,CIBER ISCIII | Hernandez-Aguado I.,University Miguel Hernández | Hernandez-Aguado I.,CIBER ISCIII
British Journal of Radiology | Year: 2010

The objective of this review is to summarise the available evidence on the frequency and management of incidental findings in imaging diagnostic tests. Original articles were identified by a systematic search of the MEDLINE, EMBASE and Cochrane Library Plus databases using appropriate medical headings. Extracted variables were study design; sample size; type of imaging test; initial diagnosis; frequency and location of incidental findings; whether clinical follow-up was performed; and whether a definitive diagnosis was made. Study characteristics were assessed by one reviewer and checked by a second reviewer. Any disagreement was solved by consensus. The relationship between the frequency of incidental findings and the study characteristics was assessed using a one-way ANOVA test, as was the frequency of follow-up of incidental findings and the frequency of confirmation. 251 potentially relevant abstracts were identified and 44 articles were finally included in the review. Overall, the mean frequency of incidental findings was 23.6% (95% confidence interval (CI) 15.8-31.3%). The frequency of incidental findings was higher in studies involving CT technology (mean 31.1%, 95% CI 20.1-41.9%), in patients with an unspecific initial diagnosis (mean 30.5, 95% CI 0-81.6) and when the location of the incidental findings was unspecified (mean 33.9%, 95% CI 18.1-49.7). The mean frequency of clinical follow-up was 64.5% (95% CI 52.9-76.1%) and mean frequency of clinical confirmation was 45.6% (95% CI 32.1-59.2%). Although the optimal strategy for the management of these abnormalities is still unclear, it is essential to be aware of the low clinical confirmation in findings of moderate and major importance. © 2010 The British Institute of Radiology.


Etchevers M.J.,CIBER ISCIII | Ords I.,CIBER ISCIII | Ricart E.,CIBER ISCIII
Drugs | Year: 2010

Crohns disease is a chronic, disabling, inflammatory condition of the gastrointestinal tract that has a segmental distribution and can affect the entire gastrointestinal tract. Treatment of patients with Crohns disease represents a difficult challenge to physicians. Conventional therapy includes corticosteroids and immunosuppressants. Corticosteroids are highly effective for inducing response and remission, but the results in the long-term are disappointing and are associated with serious adverse events. Immunosuppressants are effective, but have a slow onset of action and are associated with intolerance and adverse events. In the last decade, as a result of a better understanding of the immunopathology of inflammatory bowel disease, novel therapeutic agents have been developed to target crucial components of the inflammatory cascade. Tumour necrosis factor (TNF) inhibitors (infliximab, adalimumab and certolizumab pegol) offer an effective alternative therapy, and are widely used in clinical practice for the management of Crohns disease and ulcerative colitis. This article focuses on the latest evidence-based data on clinical effectiveness, mucosal healing, immunogenicity, dose optimization for induction and maintenance of response and remission, and step-up versus top-down approaches of the available TNF inhibitors for the treatment of Crohns disease. © 2010 Adis Data Information BV. All rights reserved.


Otte M.A.,CIBER ISCIII | Estevez M.-C.,CIBER ISCIII | Carrascosa L.G.,CIBER ISCIII | Gonzalez-Guerrero A.B.,CIBER ISCIII | And 2 more authors.
Journal of Physical Chemistry C | Year: 2011

In this work, we provide a theoretical and experimental study of the adverse effects that inherently arise when plasmonic nanoparticles are attached to a solid support. Using the example of short-ordered arrays of gold nanodisks, we show that the right choice for the thin metal adhesion layer that is used to ensure stable binding of the nanodisks to the substrate is extremely important to achieve competitive limits of detection. Furthermore, we show that the presence of the high refractive index support undisputedly results in lower bulk and surface sensing sensitivities. To minimize this effect, we propose an isotropic chemical etch of the supporting substrate, resulting in dielectric nanopillars which distance the nanodisks from this high refractive index material. We demonstrate that this novel method not only preserves the mechanical stability but also strongly increases the sensing performance of these suspended nanodisk arrays. This is demonstrated via the label-free detection of DNA hybridization, reflecting the robustness and the surface-regenerative capabilities of these pillar-supported nanodisk arrays. Furthermore, through the successful implementation of this sensitivity enhancing method to more complex nanostructures, such as arrays of closely distanced nanodisk dimers, this method profiles itself as a simple strategy to improve the limits of detection of a wide variety of nanoplasmonic sensors. © 2011 American Chemical Society.


Molina-Infante J.,Hospital San Pedro Of Alcantara | Santolaria S.,Hospital San Jorge | Sanders D.S.,Royal Hallamshire Hospital | Fernandez-Banares F.,Hospital Universitario Mutua Terrassa | Fernandez-Banares F.,CIBER ISCIII
Alimentary Pharmacology and Therapeutics | Year: 2015

Background: Noncoeliac gluten sensitivity (NCGS) is a controversial emerging disorder. Despite reported symptoms related to the ingestion of gluten, NCGS remains a diagnosis based on the exclusion of coeliac disease, given the absence of reliable biomarkers. Aim: To evaluate the prevalence, diagnostic exclusion of coeliac disease and the efficacy of a gluten-free diet (GFD) for NCGS patients. Methods: A PubMed search was performed up to December 2014. According to consensus diagnostic criteria, NCGS was defined as self-reported gluten intolerance, negative coeliac serology and absence of villous atrophy. Studies evaluating the impact of a GFD on patients with irritable bowel syndrome (IBS) were also included. Results: Prevalence rates of NCGS (0.5-13%) differed widely. Seventeen studies, including 1561 patients (26 children), met the inclusion criteria for NCGS. HLA haplotypes could not be linked to histology [normal or lymphocytic enteritis (LE)] in 1123 NCGS patients. HLADQ2/DQ8 haplotypes were present in 44% of NCGS patients. After advanced diagnostic techniques in 189 NCGS patients combining LE and HLADQ2/DQ8 haplotypes, 39 (20%) were reclassified as coeliac disease. There was a higher than expected family history of coeliac disease and autoimmune disorders in NCGS patients. A GFD resulted in variable results for variable, but significantly improved stool frequency in HLADQ2 positive diarrhoea-predominant IBS patients. Conclusions: Prevalence rates for NCGS are extremely variable. A subset of NCGS patients might belong in the so-called 'coeliac-lite' disease. The benefit of a GFD for NCGS patients is currently controversial. HLADQ2 positive diarrhoea-type IBS patients might gain symptom improvement from a GFD. © 2015 John Wiley & Sons Ltd.


Vestbo J.,University of Southern Denmark | Vestbo J.,University of Manchester | Hurd S.S.,Global Initiative for Chronic Obstructive Lung Disease | Rodriguez-Roisin R.,Thorax Institute | And 2 more authors.
Clinical Respiratory Journal | Year: 2012

Introduction: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published a strategy for diagnosis and for management of chronic obstructive pulmonary disease (COPD) since 2001 and this has formed the basis for numerous national and regional guidelines. Objectives: We describe the background for the 2011 revision of the GOLD document. Methods: The GOLD document is updated annually and revised every 5 years based on published research as well as an evaluation by an expert panel of how to best formulate and disseminate knowledge on COPD. Results: The GOLD 2011 revision states that spirometry is required for making a clinical diagnosis of COPD. At the same time, the document has less emphasis on spirometric evaluation of disease severity and launches a combined assessment taking symptoms, spirometry and history of exacerbations into account. This is matched with initial treatment for COPD where smoking cessation, pulmonary rehabilitation and physical activity in general are given high priority followed by pharmacologic treatment guided by the novel assessment scheme. Comorbidities are often present in COPD and the GOLD 2011 revision gives some guidance in how to manage these as well as how to manage COPD in the presence of comorbidities. Conclusion: A more clinically oriented GOLD document will hopefully improve assessment and management of COPD. © 2012 Blackwell Publishing Ltd.


Miravitlles M.,CIBER ISCIII | Calle M.,Hospital Clinico San Carlos | Soler-Cataluna J.J.,Hospital Of Requena
Archivos de Bronconeumologia | Year: 2012

The term phenotype in the field of COPD is defined as "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes" Among all phenotypes described, there are three that are associated with prognosis and especially are associated with a different response to currently available therapies. There phenotypes are: the exacerbator, the overlap COPD-asthma and the emphysema-hyperinflation. The exacerbator is characterised by the presence of, at least, two exacerbations the previous year, and on top of long-acting bronchodilators, may require the use of antiinflammatory drugs. The overlap phenotype presents symptoms of increased variability of airflow and incompletely reversible airflow obstruction. Due to the underlying inflammatory profile, it uses to have a good therapeutic response to inhaled corticosteroids in addition to bronchodilators. Lastly, the emphysema phenotype presents a poor therapeutic response to the existing antiinflammatory drugs and long-acting bronchodilators together with rehabilitation are the treatments of choice. Identifying the peculiarities of the different phenotypes of COPD will allow us to implement a more personalised treatment, in which the characteristics of the patients, together with their severity will be key to choose the best treatment option. © 2011 SEPAR.


Perez-Martinez F.C.,S.L. Parque Cientifico y Tecnologico | Carrion B.,S.L. Parque Cientifico y Tecnologico | Lucio M.I.,University of Castilla - La Mancha | Rubio N.,University of Castilla - La Mancha | And 4 more authors.
Biomaterials | Year: 2012

We synthesized a non-viral delivery system (f-CNH3) for small interfering RNA (siRNA) by anchoring a fourth-generation polyamidoamine dendrimer (G4-PAMAM) to carbon nanohorns (CNHs). Using this new compound, we delivered a specific siRNA designed to knockdown cofilin-1, a key protein in the regulation of cellular cytoskeleton, to human prostate cancer (PCa) cells. The carbon nanohorn (CNH) derivative was able to bind siRNA and release it in the presence of an excess of the polyanion heparin. Moreover, this hybrid nanomaterial protected the siRNA from RNAse-mediated degradation. Synthetic siRNA delivered to PCa cells by f-CNH3 decreased the cofilin-1 mRNA and protein levels to about 20% of control values. Docetaxel, the drug of choice for the treatment of PCa, produced a concentration-dependent activation of caspase-3, an increase in cell death assessed by lactate dehydrogenase release to the culture medium, cell cycle arrest and inhibition of tumor cell proliferation. All of these toxic effects were potentiated when cofilin-1 was down regulated in these cells by a siRNA delivered by the nanoparticle. This suggests that knocking down certain proteins involved in cancer cell survival and/or proliferation may potentiate the cytotoxic actions of anticancer drugs and it might be a new therapeutic approach to treat tumors. © 2012 Elsevier Ltd.


Roura S.,Health science Research Institute Germans Trias i Pujol IGTP | Pujal J.-M.,Health science Research Institute Germans Trias i Pujol IGTP | Bayes-Genis A.,Health science Research Institute Germans Trias i Pujol IGTP | Bayes-Genis A.,University of Barcelona | And 2 more authors.
Annals of the New York Academy of Sciences | Year: 2012

Endothelial recovery and cell replacement are therapeutic challenges for cardiovascular medicine. Initially employed in the treatment of blood malignancies due to its high concentration of hematological precursors, umbilical cord blood (UCB) is now a non-controversial and accepted source of both hematopoietic and non-hematopoietic progenitors for a variety of emerging cell therapies in clinical trials. Here, we review the current therapeutic potential of UCB, focusing in recent evidence demonstrating the ability of UCB-derived mesenchymal stem cells to differentiate into the endothelial lineage and to develop new vasculature in vivo. © 2012 New York Academy of Sciences.


Alberdi E.,University of the Basque Country | Sanchez-Gomez M.V.,University of the Basque Country | Cavaliere F.,University of the Basque Country | Perez-Samartin A.,University of the Basque Country | And 4 more authors.
Cell Calcium | Year: 2010

Amyloid beta (Aβ) oligomers accumulate in brain tissue of Alzheimer disease patients and are related to pathogenesis. The precise mechanisms by which Aβ oligomers cause neurotoxicity remain unresolved. In this study, we investigated the role of ionotropic glutamate receptors on the intracellular Ca2+ overload caused by Aβ. Using rat cortical neurons in culture and entorhinal-hippocampal organotypic slices, we found that Aβ oligomers significantly induced inward currents, intracellular Ca2+ increases and apoptotic cell death through a mechanism requiring NMDA and AMPA receptor activation. The massive entry of Ca2+ through NMDA and AMPA receptors induced by Aβ oligomers caused mitochondrial dysfunction as indicated by mitochondrial Ca2+ overload, oxidative stress and mitochondrial membrane depolarization. Importantly, chronic treatment with nanomolar concentration of Aβ oligomers also induced NMDA- and AMPA receptor-dependent cell death in entorhinal cortex and hippocampal slice cultures. Together, these results indicate that overactivation of NMDA and AMPA receptor, mitochondrial Ca2+ overload and mitochondrial damage underlie the neurotoxicity induced by Aβ oligomers. Hence, drugs that modulate these events can prevent from Aβ damage to neurons in Alzheimer's disease. © 2009 Elsevier Ltd. All rights reserved.


Obeso J.A.,University of Navarra | Obeso J.A.,CIBER ISCIII | Rodriguez-Oroz M.C.,CIBER ISCIII | Rodriguez-Oroz M.C.,University Hospital Donostia | And 4 more authors.
The Lancet | Year: 2014

Summary The basal ganglia were originally thought to be associated purely with motor control. However, dysfunction and pathology of different regions and circuits are now known to give rise to many clinical manifestations beyond the association of basal ganglia dysfunction with movement disorders. Moreover, disorders that were thought to be caused by dysfunction of the basal ganglia only, such as Parkinson's disease and Huntington's disease, have diverse abnormalities distributed not only in the brain but also in the peripheral and autonomic nervous systems; this knowledge poses new questions and challenges. We discuss advances and the unanswered questions, and ways in which progress might be made. © 2014 Elsevier Ltd.


Aguirre A.,Institute for Bioengineering of Catalonia IBEC | Planell J.A.,University of Barcelona | Engel E.,CIBER ISCIII
Biochemical and Biophysical Research Communications | Year: 2010

Tissue engineering aims to regenerate tissues and organs by using cell and biomaterial-based approaches. One of the current challenges in the field is to promote proper vascularization in the implant to prevent cell death and promote host integration. Bone marrow endothelial progenitor cells (BM-EPCs) and mesenchymal stem cells (MSCs) are bone marrow resident stem cells widely employed for proangiogenic applications. In vivo, they are likely to interact frequently both in the bone marrow and at sites of injury. In this study, the physical and biochemical interactions between BM-EPCs and MSCs in an in vitro co-culture system were investigated to further clarify their roles in vascularization. BM-EPC/MSC co-cultures established close cell-cell contacts soon after seeding and self-assembled to form elongated structures at 3. days. Besides direct contact, cells also exhibited vesicle transport phenomena. When co-cultured in Matrigel, tube formation was greatly enhanced even in serum-starved, growth factor free medium. Both MSCs and BM-EPCs contributed to these tubes. However, cell proliferation was greatly reduced in co-culture and morphological differences were observed. Gene expression and cluster analysis for wide panel of angiogenesis-related transcripts demonstrated up-regulation of angiogenic markers but down-regulation of many other cytokines. These data suggest that cross-talk occurs in between BM-EPCs and MSCs through paracrine and direct cell contact mechanisms leading to modulation of the angiogenic response. © 2010 Elsevier Inc.


Murri M.,Virgen Of La Victoria Hospital | Leiva I.,Carlos Haya Materno Infantil Hospital | Gomez-Zumaquero J.M.,Civil Hospital IMABIS foundation | Tinahones F.J.,CIBER ISCIII | And 7 more authors.
BMC Medicine | Year: 2013

Background: A recent study using a rat model found significant differences at the time of diabetes onset in the bacterial communities responsible for type 1 diabetes modulation. We hypothesized that type 1 diabetes in humans could also be linked to a specific gut microbiota. Our aim was to quantify and evaluate the difference in the composition of gut microbiota between children with type 1 diabetes and healthy children and to determine the possible relationship of the gut microbiota of children with type 1 diabetes with the glycemic level.Methods: A case-control study was carried out with 16 children with type 1 diabetes and 16 healthy children. The fecal bacteria composition was investigated by polymerase chain reaction-denaturing gradient gel electrophoresis and real-time quantitative polymerase chain reaction.Results: The mean similarity index was 47.39% for the healthy children and 37.56% for the children with diabetes, whereas the intergroup similarity index was 26.69%. In the children with diabetes, the bacterial number of Actinobacteria and Firmicutes, and the Firmicutes to Bacteroidetes ratio were all significantly decreased, with the quantity of Bacteroidetes significantly increased with respect to healthy children. At the genus level, we found a significant increase in the number of Clostridium, Bacteroides and Veillonella and a significant decrease in the number of Lactobacillus, Bifidobacterium, Blautia coccoides/Eubacterium rectale group and Prevotella in the children with diabetes. We also found that the number of Bifidobacterium and Lactobacillus, and the Firmicutes to Bacteroidetes ratio correlated negatively and significantly with the plasma glucose level while the quantity of Clostridium correlated positively and significantly with the plasma glucose level in the diabetes group.Conclusions: This is the first study showing that type 1 diabetes is associated with compositional changes in gut microbiota. The significant differences in the number of Bifidobacterium, Lactobacillus and Clostridium and in the Firmicutes to Bacteroidetes ratio observed between the two groups could be related to the glycemic level in the group with diabetes. Moreover, the quantity of bacteria essential to maintain gut integrity was significantly lower in the children with diabetes than the healthy children. These findings could be useful for developing strategies to control the development of type 1 diabetes by modifying the gut microbiota. © 2013 Murri et al; licensee BioMed Central Ltd.


Bueno M.J.,Cell Division and Cancer Group | Bueno M.J.,Autonomous University of Madrid | De Cedron M.G.,Cell Division and Cancer Group | Laresgoiti U.,University of the Basque Country | And 4 more authors.
Molecular and Cellular Biology | Year: 2010

Transcription of microRNAs (miRNAs) is thought to be regulated similarly to that of protein-coding genes. However, how miRNAs are regulated during the cell division cycle is not well understood. We have analyzed the transcription profiles of miRNAs in response to mitogenic stimulation in primary fibroblasts. About 33% of the miRNAs expressed in these cells are induced upon exit from quiescence. Many of these miRNAs are specifically induced by E2F1 or E2F3 during the G1/S transition and are repressed in E2F1/3-knockout cells. At least four miRNA clusters, let-7a-d, let-7i, mir-15b-16-2, and mir-106b-25, are direct targets of E2F1 and E2F3 during G1/S and are repressed in E2F1/3-null cells. Interestingly, these miRNAs do not contribute to E2F-dependent entry into S phase but rather inhibit the G1/S transition by targeting multiple cell cycle regulators and E2F targets. In fact, E2F1 expression results in a significant increase in S-phase entry and DNA damage in the absence of these microRNAs. Thus, E2F-induced miRNAs contribute to limiting the cellular responses to E2F activation, thus preventing replicative stress. Given the known function of E2F of inducing other oncogenic miRNAs, control of miRNAs by E2F is likely to play multiple roles in cell proliferation and in proliferative diseases such as cancer. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Van Arensbergen J.,Institute dInvestigacions Biomediques August Pi i Sunyer | Van Arensbergen J.,CIBER ISCIII | Garcia-Hurtado J.,Institute dInvestigacions Biomediques August Pi i Sunyer | Garcia-Hurtado J.,CIBER ISCIII | And 11 more authors.
Genome Research | Year: 2010

The epigenome changes that underlie cellular differentiation in developing organisms are poorly understood. To gain insights into how pancreatic beta-cells are programmed, we profiled key histone methylations and transcripts in embryonic stem cells, multipotent progenitors of the nascent embryonic pancreas, purified beta-cells, and 10 differentiated tissues. We report that despite their endodermal origin, beta-cells show a transcriptional and active chromatin signature that is most similar to ectoderm-derived neural tissues. In contrast, the beta-cell signature of trimethylated H3K27, a mark of Polycomb-mediated repression, clusters with pancreatic progenitors, acinar cells and liver, consistent with the epigenetic transmission of this mark from endoderm progenitors to their differentiated cellular progeny. We also identified two H3K27 methylation events that arise in the beta-cell lineage after the pancreatic progenitor stage. One is a wave of cell-selective de novo H3K27 trimethylation in non-CpG island genes. Another is the loss of bivalent and H3K27me3-repressed chromatin in a core program of neural developmental regulators that enables a convergence of the gene activity state of beta-cells with that of neural cells. These findings reveal a dynamic regulation of Polycomb repression programs that shape the identity of differentiated beta-cells. © 2010 by Cold Spring Harbor Laboratory Press.


Del Rio J.A.,Cellular Bioengineering | Del Rio J.A.,University of Barcelona | Del Rio J.A.,CIBER ISCIII | Soriano E.,University of Barcelona | And 2 more authors.
Nature Protocols | Year: 2010

We present a method for using long-term organotypic slice co-cultures of the entorhino-hippocampal formation to analyze the axon-regenerative properties of a determined compound. The culture method is based on the membrane interphase method, which is easy to perform and is generally reproducible. The degree of axonal regeneration after treatment in lesioned cultures can be seen directly using green fluorescent protein (GFP) transgenic mice or by axon tracing and histological methods. Possible changes in cell morphology after pharmacological treatment can be determined easily by focal in vitro electroporation. The well-preserved cytoarchitectonics in the co-culture facilitate the analysis of identified cells or regenerating axons. The protocol takes up to a month. © 2010 Nature Publishing Group.


Lloveras V.,CIBER ISCIII | Vidal-Gancedo J.,CIBER ISCIII | Figueira-Duarte T.M.,CNRS Molecular Chemistry Laboratory | Nierengarten J.-F.,CNRS Molecular Chemistry Laboratory | And 5 more authors.
Journal of the American Chemical Society | Year: 2011

Radical anions 1-•-5-•, showing different lengths and incorporating up to five p-phenylenevinylene (PPV) bridges between two polychlorinated triphenylmethyl units, have been prepared by chemical or electrochemical reductions from the corresponding diradicals 1-5 which were prepared using Wittig-Horner-type chemistry. Such radical anions enabled us to study, by means of UV-vis-NIR and variable-temperature electron spin resonance spectroscopies, the long-range intramolecular electron transfer (IET) phenomena in their ground states, probing the influence of increasing the lengths of the bridges without the need of using an external bias to promote IET. The temperature dependence of the IET rate constants of mixed-valence species 1 -•-5-• revealed the presence of two different regimes at low and high temperatures in which the mechanisms of electron tunneling via superexchange and thermally activated hopping are competing. Both mechanisms occur to different extents, depending on the sizes of the radical anions, since the lengths of the oligo-PPV bridges notably influence the tunneling efficiency and the activation energy barriers of the hopping processes, the barriers diminishing when the lengths are increased. The nature of solvents also modifies the IET rates by means of the interactions between the oligo-PPV bridges and the solvents. Finally, in the shortest compounds 1 -• and 2-•, the IET induced optically through the superexchange mechanism can also be observed by the exhibited intervalence bands, whose intensities decrease with the length of the PPV bridge. © 2011 American Chemical Society.


Miravitlles M.,CIBER ISCIII | Pena-Longobardo,University of Castilla - La Mancha | Oliva-Moreno J.,University of Castilla - La Mancha | Hidalgo-Vega A.,University of Castilla - La Mancha
International Journal of COPD | Year: 2015

Objective: Chronic obstructive pulmonary disease (COPD) is a very prevalent and invalidating disease. The aim of this study was to analyze the burden borne by informal caregivers of patients with COPD. Methods: We used the Survey on Disabilities, Personal Autonomy, and Dependency Situations (Encuesta sobre Discapacidad, Autonomía personal y Situaciones de Dependencia [EDAD]-2008) to obtain information on the characteristics of disabled individuals with COPD and their caregivers in Spain. Additionally, statistical multivariate analyses were performed to analyze the impact that an increase in dependence would have on the problems for which caregivers provide support, in terms of health, professional, and leisure/social dimensions. Results: A total of 461,884 individuals with one or more disabilities and with COPD were identified, and 220,892 informal caregivers were estimated. Results showed that 35% of informal caregivers had health-related problems due to the caregiving provided; 83% had leisure/social-related problems; and among caregivers of working age, 38% recognized having profession-related problems. The probability of a problem arising was significantly associated with the degree of dependence of the patient receiving care. Caregivers of patients with great dependence showed a 39% higher probability of presenting health-related problems, 27% more professional problems, and 23% more leisure problems compared with those with nondependent patients. Conclusion: The results show the large impact on society in terms of the welfare of informal caregivers of patients with COPD. A higher level of dependence was associated with more severe problems in caregivers, in all dimensions. © 2015 Miravitlles et al.


Betous R.,Vanderbilt University | Couch F.,Vanderbilt University | Mason A.,Vanderbilt University | Eichman B.,Vanderbilt University | And 3 more authors.
Cell Reports | Year: 2013

Stalled replication forks are sources of genetic instability. Multiple fork-remodeling enzymes are recruited to stalled forks, but how they work to promote fork restart is poorly understood. By combining ensemble biochemical assays and single-molecule studies with magnetic tweezers, we show that SMARCAL1 branch migration and DNA-annealing activities are directed by the single-stranded DNA-binding protein RPA to selectively regress stalled replication forks caused by blockage to the leading-strand polymerase and to restore normal replication forks with a lagging-strand gap. We unveil the molecular mechanisms by which RPA enforces SMARCAL1 substrate preference. E.coli RecG acts similarly to SMARCAL1 in the presence of E.coli SSB, whereas the highly related human protein ZRANB3 has different substrate preferences. Our findings identify the important substrates of SMARCAL1 in fork repair, suggest that RecG and SMARCAL1 are functional orthologs, and provide a comprehensive model of fork repair by these DNA translocases. © 2013 The Authors.


Louis E.D.,Columbia University | Benito-Leon J.,University Hospital 12 Of Octubre | Benito-Leon J.,CIBER ISCIII | Vega-Quiroga S.,Arevalo Health Center | And 2 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2010

Background: Many investigators have observed mild cognitive deficits in essential tremor (ET), yet the functional significance of these deficits is unclear. Also, there are very few data in which functional activity in ET has been divided into cognitively based activities (remembering appointments) versus motor-based activities (writing cheques). Objective: The authors (1) compared functional level in ET cases versus controls, assessing functional activities that are cognitively based and those that are dependent upon both motor and cognitive factors, and (2) determined whether lower mini mental status test scores in ET cases have a functional correlate. Methods: In a population-based study of people ≥65 years in central Spain (NEDICES), a 37-item version of the Mini-Mental State Examination (37-MMSE) and an 11-item version of the Pfeffer Functional Activities Questionnaire (FAQ) were administered to non-demented ET cases and controls. Results: The FAQ was 55.5% higher (ie, lower function) in 208 cases than 3616 controls (2.8±4.8 vs 1.8±4.2, p<0.001). Cases reported more difficulty (ie, higher FAQ scores) with FAQ items that were cognitive measures as well as FAQ items that were cognitive-motor in nature. In cases, a lower 37-MMSE was associated with more difficulty on both cognitively based and cognitive-motor-based FAQ items (p<0.001). Discussion: In this large, population-based study, ET cases reported more functional difficulty than controls, and this functional difficulty was present in both cognitive and cognitive-motor domains. Lower cognitive test scores were associated with more reported functional difficulty, indicating that lower cognitive test scores in ET, rather than being inconsequential, have a clear clinical-functional correlate.


Tintore M.,CIBER ISCIII | Eritja R.,CIBER ISCIII | Fabrega C.,CIBER ISCIII
ChemBioChem | Year: 2014

DNA's remarkable molecular recognition properties, flexibility, and structural features make it one of the most promising scaffolds to design a variety of nanostructures. During recent decades, two major methods have been developed for the construction of DNA nanomaterials in a programmable way; both generate nanostructures in one, two, and three dimensions. The tile-based assembly process is a useful tool to construct large and simple structures; the DNA origami method is suitable for the production of smaller, more sophisticated and well-defined structures. Proteins, nanoparticles and other functional elements have been specifically positioned into designed patterns on these structures. They can also act as templates to study chemical reactions, help in the structural determination of proteins, and be used as platform for genomic and drug delivery applications. In this review we examine recent progresses towards the potential use of DNA nanostructures in molecular and cellular biology. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Martinez-Ceron E.,Hospital Universitario La Paz | Fernandez-Navarro I.,Hospital Universitario La Paz | Garcia-Rio F.,Hospital Universitario La Paz | Garcia-Rio F.,Autonomous University of Madrid | Garcia-Rio F.,CIBER ISCIII
Sleep Medicine Reviews | Year: 2016

A possible association between obstructive sleep apnea (OSA) and type 2 diabetes (T2DM) has been suggested. OSA could alter glucose metabolism, generating insulin resistance and favoring the development of T2DM. In addition, our greater understanding of intermediate disorders produced by intermittent hypoxia and sleep fragmentation, such as sympathetic activation, oxidative stress, systemic inflammation and alterations in appetite-regulating hormones, provides biological plausibility to this possible association. Nevertheless, there are still few data available about the consequences of suppressing apnea. Therefore, the objective of this review was to analyze current knowledge about the effect of continuous positive airway pressure (CPAP) on glucose metabolism. A global interpretation of the studies evaluated shows that CPAP could improve insulin resistance, and perhaps also glycemic control, in OSA patients who still have not developed diabetes. In addition, it seems possible that the effect of CPAP is still greater in patients with OSA and T2DM, particularly in those patients with more severe and symptomatic OSA, in those with poorer baseline glycemic control and with greater compliance and duration of CPAP treatment. In conclusion, although the current information available is limited, it suggests that apnea reversion by means of CPAP could improve the control of glucose metabolism. © 2015 Elsevier Ltd.


Curto-Reyes V.,University of Oviedo | Llames S.,CIBER ISCIII | Hidalgo A.,University of Oviedo | Menendez L.,University of Oviedo | Baamonde A.,University of Oviedo
British Journal of Pharmacology | Year: 2010

Background and purpose: The activation of CB2 receptors induces analgesia in experimental models of chronic pain. The present experiments were designed to study whether the activation of peripheral or spinal CB2 receptors relieves thermal hyperalgesia and mechanical allodynia in two models of bone cancer pain. Experimental approach: NCTC 2472 osteosarcoma or B16-F10 melanoma cells were intratibially inoculated to C3H/He and C57BL/6 mice. Thermal hyperalgesia was assessed by the unilateral hot plate test and mechanical allodynia by the von Frey test. AM1241 (CB2 receptor agonist), AM251 (CB1 receptor antagonist), SR144528 (CB2 receptor antagonist) and naloxone were used. CB2 receptor expression was measured by Western blot. Key results: AM1241 (0.3-10 mg·kg-1) abolished thermal hyperalgesia and mechanical allodynia in both tumour models. The antihyperalgesic effect was antagonized by subcutaneous, intrathecal or peri-tumour administration of SR144528. In contrast, the antiallodynic effect was inhibited by systemic or intrathecal, but not peri-tumour, injection of SR144528. The effects of AM1241 were unchanged by AM251 but were prevented by naloxone. No change in CB2 receptor expression was found in spinal cord or dorsal root ganglia. Conclusions and implications: Spinal CB2 receptors are involved in the antiallodynic effect induced by AM1241 in two neoplastic models while peripheral and spinal receptors participate in the antihyperalgesic effects. Both effects were mediated by endogenous opiates. The use of drugs that activate CB2 receptors could be a useful strategy to counteract bone cancer-induced pain symptoms. © 2010 The British Pharmacological Society All rights reserved.


Levato R.,CIBER ISCIII | Mateos-Timoneda M.A.,CIBER ISCIII | Planell J.A.,CIBER ISCIII | Planell J.A.,University of Barcelona
Macromolecular Bioscience | Year: 2012

PLA MPs are prepared via a novel and toxic-chemical-free fabrication route using ethyl lactate, a green solvent and FDA-approved aroma. MPs are obtained by a solution jet break-up and solvent displacement method. Adjusting flow parameters allows the tuning of MPs size between 60 and 180μm, with reduced polydispersity. Morphological analysis shows microporous particles with Janus-like surface. A fluorophore is successfully loaded into the MPs during their formation step. This versatile green solvent-based procedure is proven to be suitable for drug encapsulation and delivery applications. The method may be extended to different droplet generation techniques. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Just-Baringo X.,University of Barcelona | Just-Baringo X.,CIBER ISCIII | Albericio F.,University of Barcelona | Albericio F.,CIBER ISCIII | And 3 more authors.
Angewandte Chemie - International Edition | Year: 2014

The recent development of thiopeptide analogues of antibiotics has allowed some of the limitations inherent to these naturally occurring substances to be overcome. Chemical synthesis, semisynthetic derivatization, and engineering of the biosynthetic pathway have independently led to complementary modifications of various thiopeptides. Some of the new substances have displayed improved profiles, not only as antibiotics, but also as antiplasmodial and anticancer drugs. The design of novel molecules based on the thiopeptide scaffold appears to be the only strategy to exploit the high potential they have shown invitro. Herein we present the most relevant achievements in the production of thiopeptide analogues and also discuss the way the different approaches might be combined in a multidisciplinary strategy to produce more sophisticated structures. Making a complement: Modification of the structure of thiopeptides has produced numerous analogues that overcome some of their inherent limitations. The combined use of chemical synthesis, semisynthesis, and biosynthetic pathway engineering will allow the development of future thiopeptide-based drugs. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Valles Y.,University of Valencia | Artacho A.,University of Valencia | Pascual-Garcia A.,Autonomous University of Madrid | Ferrus M.L.,University of Valencia | And 5 more authors.
PLoS Genetics | Year: 2014

In spite of its major impact on life-long health, the process of microbial succession in the gut of infants remains poorly understood. Here, we analyze the patterns of taxonomic and functional change in the gut microbiota during the first year of life for a birth cohort of 13 infants. We detect that individual instances of gut colonization vary in the temporal dynamics of microbiota richness, diversity, and composition at both functional and taxonomic levels. Nevertheless, trends discernible in a majority of infants indicate that gut colonization occurs in two distinct phases of succession, separated by the introduction of solid foods to the diet. This change in resource availability causes a sharp decrease in the taxonomic richness of the microbiota due to the loss of rare taxa (p = 2.06e-9), although the number of core genera shared by all infants increases substantially. Moreover, although the gut microbial succession is not strictly deterministic, we detect an overarching directionality of change through time towards the taxonomic and functional composition of the maternal microbiota. Succession is however not complete by the one year mark, as significant differences remain between one-year-olds and their mothers in terms of taxonomic (p = 0.009) and functional (p = 0.004) microbiota composition, and in taxonomic richness (p = 2.76e-37) and diversity (p = 0.016). Our results also indicate that the taxonomic composition of the microbiota shapes its functional capacities. Therefore, the observed inter-individual variability in taxonomic composition during succession is not fully compensated by functional equivalence among bacterial genera and may have important physiological consequences. Finally, network analyses suggest that positive interactions among core genera during community assembly contribute to ensure their permanence within the gut, and highlight an expansion of complexity in the interactions network as the core of taxa shared by all infants grows following the introduction of solid foods. © 2014 Vallès et al.


Giraldez T.,University Hospital Ns Candelaria | Rojas P.,University of Santiago de Chile | Jou J.,University of Notre Dame | Flores C.,University Hospital Ns Candelaria | And 2 more authors.
American Journal of Physiology - Renal Physiology | Year: 2012

Amiloride-sensitive epithelial Na_ channels (ENaCs) can be formed by different combinations of four homologous subunits, named α, β, γ, and δ. In addition to providing an apical entry pathway for transepithelial Na_ reabsorption in tight epithelia such as the kidney distal tubule and collecting duct, ENaCs are also expressed in nonepithelial cells, where they may play different functional roles. The δ-subunit of ENaC was originally identified in humans and is able to form amiloride-sensitive Na_ channels alone or in combination with β and γ, generally resembling the canonical kidney ENaC formed by α, β, and γ. However, δ differs from α in its tissue distribution and channel properties. Despite the low sequence conservation between α and δ (37% identity), their similar functional characteristics provide an excellent model for exploring structural correlates of specific ENaC biophysical and pharmacological properties. Moreover, the study of cellular mechanisms modulating the activity of different ENaC subunit combinations provides an opportunity to gain insight into the regulation of the channel. In this review, we examine the evolution of ENaC genes, channel subunit composition, the distinct functional and pharmacological features that δ confers to ENaC, and how this can be exploited to better understand this ion channel. Finally, we briefly consider possible functional roles of the ENaC δ-subunit. © 2012 the American Physiological Society.


Cuatrecasas G.,CPEN S.L | Alegre C.,Institute Universitari Dexeus | Casanueva F.F.,CIBER ISCIII
Pituitary | Year: 2014

Fibromyalgia Syndrome (FMS) is a frequent idiopathic condition in which patients experience intense pain in specific tender points, profound fatigue and sleep disturbances. Although pain had not account so far in growth hormone deficiency syndrome (GHD) description, symptoms of FMS are very similar; and there is strong evidence of decreased GH secretion at least in a subset of FMS patients. Is there an overlap of the two diseases? A systematic Medline/Embase search for preliminary proof-of-concept trials, but also larger placebo-controlled studies, have shown that GH replacement in low-IGF1 patients can significantly improve some symptoms of FMS and quality of life, suggesting a direct causal effect of GH deficiency. Despite the use of relatively high doses of GH in these patients, treatment seems to be well tolerated. Several mechanisms of action for GH in FMS relief have been suggested, including both central modulation of pain and peripheral musculo-tendinous effects, as already described in classic GHD. © Springer Science+Business Media 2013.


Perez M.A.,Aragon Institute of Engineering Research | Perez M.A.,CIBER ISCIII | Palacios J.,University of Zaragoza
Annals of Biomedical Engineering | Year: 2010

Damage accumulation in the cement mantle and debonding of the bone-cement interface are basic events that contribute to the long-term failure of cemented hip reconstructions. In this work, a numerical study with these two process coupled is presented. Previously uniform bone- cement interface mechanical properties were only considered. In this work, a new approach assuming nonuniform and random bone-cement interface mechanical properties was applied to investigate its effect on cement degradation. This methodology was also applied to simulate and compare the degradation process of the cement and bone-cement interface in three different concepts of design: Exeter, Charnley, and ABG II stems. Nonuniform and random mechanical properties of the bone-cement interface implied a simulation closer to reality. The predicted results showed that the cement deterioration and bone-cement interface debonding is different for each implant depending on the stem geometry. Lower cement deterioration was obtained for the Charnley stem and lower bone-cement interface debonding was predicted for the Exeter stem, while the highest deterioration (cement and bone-cement interface) was produced for the ABG II stem. © 2010 Biomedical Engineering Society.


Seruggia D.,CSIC - National Center for Biotechnology | Seruggia D.,CIBER ISCIII | Montoliu L.,CSIC - National Center for Biotechnology | Montoliu L.,CIBER ISCIII
Transgenic Research | Year: 2014

The CRISPR–Cas system is the newest targeted nuclease for genome engineering. In less than 1 year, the ease, robustness and efficiency of this method have facilitated an immense range of genetic modifications in most model organisms. Full and conditional gene knock-outs, knock-ins, large chromosomal deletions and subtle mutations can be obtained using combinations of clustered regularly interspaced short palindromic repeats (CRISPRs) and DNA donors. In addition, with CRISPR–Cas compounds, multiple genetic modifications can be introduced seamlessly in a single step. CRISPR–Cas not only brings genome engineering capacities to species such as rodents and livestock in which the existing toolbox was already large, but has also enabled precise genetic engineering of organisms with difficult-to-edit genomes such as zebrafish, and of technically challenging species such as non-human primates. The CRISPR–Cas system allows generation of targeted mutations in mice, even in laboratories with limited or no access to the complex, time-consuming standard technology using mouse embryonic stem cells. Here we summarize the distinct applications of CRISPR–Cas technology for obtaining a variety of genetic modifications in different model organisms, underlining their advantages and limitations relative to other genome editing nucleases. We will guide the reader through the many publications that have seen the light in the first year of CRISPR–Cas technology. © 2014, Springer International Publishing Switzerland.


Bruix J.,Hospital Clinic | Bruix J.,CIBER ISCIII | Gores G.J.,Rochester College | Mazzaferro V.,Italian National Cancer Institute
Gut | Year: 2014

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and is currently the main event leading to death in patients with cirrhosis. Evolving information suggests that the metabolic syndrome with non-alcoholic liver disease may be an important cause of HCC in addition to viral hepatitis and alcohol-induced liver disease. The molecular pathogenesis is extremely complex and heterogeneous. To date the molecular information has not impacted on treatment decisions. Periodic surveillance imaging of patients with cirrhosis is widely practiced, especially because diagnostic, radiographic criteria for early-stage HCC have been defined (including nodules between 1 and 2 cm) and effective treatment is available for tumours detected at an early stage. Worldwide the approach to resection versus transplantation varies depending upon local resources, expertise and donor availability. The criteria for transplantation are discussed, and the controversial areas highlighted with evidence-based recommendations provided. Several approaches are available for intermediate stage disease, including radiofrequency ablation, transarterial chemoembolisation and radioembolisation; the rationale for these therapies is buttressed by appropriate outcome-based studies. For advanced disease, systemic therapy with sorafenib remains the option best supported by current data. Thus, while several trials have failed to improve the benefits of established therapies, studies assessing the sequential or combined application of those already known to be beneficial are needed. Also, new concepts are provided in regards to selecting and stratifying patients for second-line studies, which may help explain the failure of prior studies.


Villena J.A.,Autonomous University of Barcelona | Villena J.A.,CIBER ISCIII
FEBS Journal | Year: 2015

Members of the PGC-1 family of coactivators have been revealed as key players in the regulation of energy metabolism. Early gain- and loss-of-function studies led to the conclusion that all members of the PGC-1 family (PGC-1α, PGC-1β and PRC) play redundant roles in the control of mitochondrial biogenesis by regulating overlapping gene expression programs. Regardless of this, all PGC-1 coactivators also appeared to differ in the stimuli to which they respond to promote mitochondrial gene expression. Although PGC-1α was found to be induced by different physiological or pharmacological cues, PGC-1β appeared to be unresponsive to such stimuli. Consequently, it has long been widely accepted that PGC-1α acts as a mediator of mitochondrial biogenesis induced by cues that signal high-energy needs, whereas the role of PGC-1β is restricted to the maintenance of basal mitochondrial function. By contrast, the function of PRC appears to be restricted to the regulation of gene expression in proliferating cells. However, recent studies using tissue-specific mouse models that lack or overexpress different PGC-1 coactivators have provided emerging evidence not only supporting new roles for PGC-1s, but also redefining some of the paradigms related to the precise function and mode of action of PGC-1 coactivators in mitochondrial biogenesis. The present review discusses some of the new findings regarding the control of mitochondrial gene expression by PGC-1 coactivators in a tissue-specific context, as well as newly-uncovered functions of PGC-1s beyond mitochondrial biogenesis, and their link to pathologies, such as diabetes, muscular dystrophies, neurodegenerative diseases or cancer. © 2014 FEBS.


Lopez M.,University of Santiago de Compostela | Lopez M.,CIBER ISCIII | Tena-Sempere M.,CIBER ISCIII | Tena-Sempere M.,University of Cordoba, Spain | Tena-Sempere M.,University of Turku
Trends in Endocrinology and Metabolism | Year: 2015

Despite their prominent roles in the control of reproduction, estrogens pervade many other bodily functions. Key metabolic pathways display marked sexual differences, and estrogens are potent modulators of energy balance, as evidenced in extreme conditions of estrogen deficiency characterized by hyperphagia and decreased energy expenditure, and leading to obesity. Compelling evidence has recently demonstrated that, in addition to their peripheral effects, the actions of estrogens on energy homeostasis are exerted at central levels, to regulate almost every key aspect of metabolic homeostasis, from feeding to energy expenditure, to glucose and lipid metabolism. We review herein the state-of-the-art of the role of estrogens in the regulation of energy balance, with a focus on their central effects and modes of action. © 2015 Elsevier Ltd.


Martin-Benito J.,CSIC - National Center for Biotechnology | Ortin J.,CSIC - National Center for Biotechnology | Ortin J.,CIBER ISCIII
Advances in Virus Research | Year: 2013

The influenza A viruses cause yearly epidemics and occasional pandemics of respiratory disease, which constitute a serious health and economic burden. Their genome consists of eight single-stranded, negative-polarity RNAs that associate to the RNA polymerase and many nucleoprotein monomers to form ribonucleoprotein complexes (RNPs). Here, we focus on the organization of these RNPs, as well as on the structure and interactions of its constitutive elements and we discuss the mechanisms by which the RNPs transcribe and replicate the viral genome. © 2013 Elsevier Inc.


Kluwe J.,Columbia University | Pradere J.,Columbia University | Gwak G.,Columbia University | Mencin A.,Columbia University | And 6 more authors.
Gastroenterology | Year: 2010

Background & Aims: c-Jun N-terminal kinase (JNK) is activated by multiple profibrogenic mediators; JNK activation occurs during toxic, metabolic, and autoimmune liver injury. However, its role in hepatic fibrogenesis is unknown. Methods: JNK phosphorylation was detected by immunoblot analysis and confocal immunofluorescent microscopy in fibrotic livers from mice after bile duct ligation (BDL) or CCl4 administration and in liver samples from patients with chronic hepatitis C and non-alcoholic steatohepatitis. Fibrogenesis was investigated in mice given the JNK inhibitor SP600125 and in JNK1- and JNK2-deficient mice following BDL or CCl4 administration. Hepatic stellate cell (HSC) activation was determined in primary mouse HSCs incubated with pan-JNK inhibitors SP600125 and VIII. Results: JNK phosphorylation was strongly increased in livers of mice following BDL or CCl4 administration as well as in human fibrotic livers, occurring predominantly in myofibroblasts. In vitro, pan-JNK inhibitors prevented transforming growth factor (TGF) β-, platelet-derived growth factor-, and angiotensin II-induced murine HSC activation and decreased platelet-derived growth factor and TGF-β signaling in human HSCs. In vivo, pan-JNK inhibition did not affect liver injury but significantly reduced fibrosis after BDL or CCl4. JNK1-deficient mice had decreased fibrosis after BDL or CCl4, whereas JNK2-deficient mice displayed increased fibrosis after BDL but fibrosis was not changed after CCl4. Moreover, patients with chronic hepatitis C who displayed decreased fibrosis in response to the angiotensin receptor type 1 blocker losartan showed decreased JNK phosphorylation. Conclusions: JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches. © 2010 AGA Institute.


Martinez-Vicente M.,CIBER ISCIII | Martinez-Vicente M.,Autonomous University of Barcelona
Seminars in Cell and Developmental Biology | Year: 2015

Neuronal homeostasis depends on the proper functioning of quality control systems like autophagy. This mechanism is responsible of the clearance of misfolded proteins, aggregates and the turnover of organelles within the neuron. Autophagic dysfunction has been described in many neurodegenerative diseases. It can occur at several steps of the autophagic machinery and can contribute to the formation of intracellular aggregates and ultimately to neuronal death. Accordingly restoring autophagy activity in affected neurons can be an attractive therapeutic approach to fight neurodegeneration. In this review we summarize the present encouraging strategies that have been achieved with pharmacological and genetic treatments aimed to induce neuronal autophagy in experimental models of neurodegenerative diseases. © 2015 Elsevier Ltd.


Navarro-Mateu F.,CIBER ISCIII | Escamez T.,IMIB BIOBANC MUR | Koenen K.C.,Columbia University | Alonso J.,CIBER ISCIII | Sanchez-Meca J.,University of Murcia
PLoS ONE | Year: 2013

Objective:To conduct a meta-analysis of all published genetic association studies of 5-HTTLPR polymorphisms performed in PTSD casesMethods Data Sources:Potential studies were identified through PubMed/MEDLINE, EMBASE, Web of Science databases (Web of Knowledge, WoK), PsychINFO, PsychArticles and HuGeNet (Human Genome Epidemiology Network) up until December 2011. Study Selection: Published observational studies reporting genotype or allele frequencies of this genetic factor in PTSD cases and in non-PTSD controls were all considered eligible for inclusion in this systematic review. Data Extraction: Two reviewers selected studies for possible inclusion and extracted data independently following a standardized protocol. Statistical analysis: A biallelic and a triallelic meta-analysis, including the total S and S' frequencies, the dominant (S+/LL and S'+/L'L') and the recessive model (SS/L+ and S'S'/L'+), was performed with a random-effect model to calculate the pooled OR and its corresponding 95% CI. Forest plots and Cochran's Q-Statistic and I2 index were calculated to check for heterogeneity. Subgroup analyses and meta-regression were carried out to analyze potential moderators. Publication bias and quality of reporting were also analyzed.Results:13 studies met our inclusion criteria, providing a total sample of 1874 patients with PTSD and 7785 controls in the biallelic meta-analyses and 627 and 3524, respectively, in the triallelic. None of the meta-analyses showed evidence of an association between 5-HTTLPR and PTSD but several characteristics (exposure to the same principal stressor for PTSD cases and controls, adjustment for potential confounding variables, blind assessment, study design, type of PTSD, ethnic distribution and Total Quality Score) influenced the results in subgroup analyses and meta-regression. There was no evidence of potential publication bias.Conclusions:Current evidence does not support a direct effect of 5-HTTLPR polymorphisms on PTSD. Further analyses of gene-environment interactions, epigenetic modulation and new studies with large samples and/or meta-analyses are required. © 2013 Navarro-Mateu et al.


Dehay B.,CIBER ISCIII | Bove J.,CIBER ISCIII | Rodriguez-Muela N.,CSIC - Biological Research Center | Perier C.,CIBER ISCIII | And 4 more authors.
Journal of Neuroscience | Year: 2010

Mounting evidence suggests a role for autophagy dysregulation in Parkinson's disease (PD). The bulk degradation of cytoplasmic proteins (including α-synuclein) and organelles (such as mitochondria) is mediated by macroautophagy, which involves the sequestration of cytosolic components into autophagosomes (AP) and its delivery to lysosomes. Accumulation of AP occurs in postmortem brain samples from PD patients, which has been widely attributed to an induction of autophagy. However, the cause and pathogenic significance of these changes remain unknown. Here we found in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine mouse model of PD that AP accumulation and dopaminergic cell death are preceded by a marked decrease in the amount of lysosomes within dopaminergic neurons. Lysosomal depletion was secondary to the abnormal permeabilization of lysosomal membranes induced by increased mitochondrial-derived reactive oxygen species. Lysosomal permeabilization resulted in a defective clearance and subsequent accumulation of undegraded AP and contributed directly to neurodegeneration by the ectopic release of lysosomal proteases into the cytosol. Lysosomal breakdown and AP accumulation also occurred in PD brain samples, where Lewy bodies were strongly immunoreactive for AP markers. Induction of lysosomal biogenesis by genetic or pharmacological activation of lysosomal transcription factor EB restored lysosomal levels, increased AP clearance and attenuated 1-methyl-4- phenylpyridinium-induced cell death. Similarly, the autophagy-enhancer compound rapamycin attenuated PD-related dopaminergic neurodegeneration, both in vitro and in vivo, by restoring lysosomal levels. Our results indicate that AP accumulation in PD results from defective lysosomal-mediated AP clearance secondary to lysosomal depletion. Restoration of lysosomal levels and function may thus represent a novel neuroprotective strategy in PD. Copyright © 2010 the authors.


Salmeron-Sanchez M.,Polytechnic University of Valencia | Salmeron-Sanchez M.,CIBER ISCIII | Salmeron-Sanchez M.,Regenerative Medicine Unit | Rico P.,Polytechnic University of Valencia | And 5 more authors.
Biomaterials | Year: 2011

Fibronectin (FN) is a ubiquitous extracellular matrix protein (ECM) protein that is organized into fibrillar networks by cells through an integrin-mediated process that involves contractile forces. This assembly allows for the unfolding of the FN molecule, exposing cryptic domains that are not available in the native globular FN structure and activating intracellular signalling complexes. However, organization of FN into a physiological fibrillar network upon adsorption on a material surface has not been observed. Here we demonstrate cell-free, material-induced FN fibrillogenesis into a biological matrix with enhanced cellular activities. We found that simple FN adsorption onto poly(ethyl acrylate) surfaces, but not control polymers, triggered FN organization into a fibrillar network via interactions in the amino-terminal 70 kDa fragment, which is involved in the formation of cell-mediated FN fibrils. Moreover, the material-driven FN fibrils exhibited enhanced biological activities in terms of myogenic differentiation compared to individual FN molecules and even type I collagen. Our results demonstrate that molecular assembly of FN can take place at the material interface, giving rise to a physiological protein network similar to fibrillar matrices assembled by cells. This research identifies material surfaces that trigger the organization of extracellular matrix proteins into biological active fibrils and establishes a new paradigm to engineer ECM-mimetic biomaterials. © 2010 Elsevier Ltd.


Marin J.M.,University Institute of Health Sciences | Marin J.M.,CIBER ISCIII | Soriano J.B.,CIBER ISCIII | Soriano J.B.,Program of Epidemiology and Clinical Research |