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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.


Calon A.,Barcelona Institute for Research in Biomedicine | Espinet E.,Barcelona Institute for Research in Biomedicine | Palomo-Ponce S.,Barcelona Institute for Research in Biomedicine | Tauriello D.V.F.,Barcelona Institute for Research in Biomedicine | And 16 more authors.
Cancer Cell | Year: 2012

A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-β-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-β stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC. © 2012 Elsevier Inc.


Julia M.,University Pompeu Fabra | Catalina-Romero C.,Ibermutuamur | Calvo-Bonacho E.,Ibermutuamur | Benavides F.G.,University Pompeu Fabra | Benavides F.G.,CIBER ISCIII
Occupational and Environmental Medicine | Year: 2013

Objectives The aim of this study was to analyse the association between job stress and occupational injuries. Methods A prospective cohort study in a sample of 10 667 workers belonging to the insured population of the Mutual Insurance Company in Spain. Job stress was assessed with the Spanish version of the Job Stress Survey. A 1-year follow-up of the workers' clinical records was conducted to determine the incidence of occupational injuries, and the incidence rate per 1000 workers-year was calculated. The associations between the incidence of occupational injuries, job stress and job stress components ( job pressure ( JP) and lack of organisational support (LOS)) were assessed calculating the rate ratio (RR) and its CI of 95% using Poisson regression models. Results After adjusting for confounders, a significant association between LOS and increased incidence of occupational injuries was found. Such an association was observed for the LOS index (RRa=3.11, 95% CI 1.53 to 6.31), LOS severity (RRa=2.64, 95% CI 1.31 to 5.33) and LOS frequency (RRa=2.67, 95% CI 1.32 to 5.38) scales in women. There was no significant association between job stress or its components and the incidence of occupational injuries among men. Conclusions This prospective study found evidence of an association between the LOS and the incidence of occupational injuries in women, with potential implications for the prevention of accidents at work.


Different genome-wide linkage and association studies performed during the last 15 years have associated mutations and polymorphisms in complement genes with different diseases characterized by tissue damage and inflammation. These are complex disorders in which genetically susceptible individuals usually develop the pathology as a consequence of environmental triggers. Although complement dysregulation is a common feature of these pathologies, how the disease phenotype is determined is only partly understood. One way to advance understanding is to focus the research in the analysis of the peculiar genotype-phenotype correlations that characterize some of these diseases. I will review here how understanding the functional consequences of these disease-associated complement genetic variants is providing us with novel insights into the underpinning complement biology and a better knowledge of the pathogenic mechanisms underlying each of these pathologies. These advances have important therapeutic and diagnostic implications. © 2015 Elsevier GmbH.


de las Cuevas C.,Pharmacoepidemiology and Drug Use Studies Research Group | de las Cuevas C.,University of La Laguna | de las Cuevas C.,CIBER ISCIII
Current Clinical Pharmacology | Year: 2011

Medical terminology is at continuous process of change since the language of medicine needs the rapid incorporation of new terms or changing the existing ones to be in touch with new ideas, concepts and practices. The evolution of the terms "compliance", "adherence" and "concordance" in the field of medicine-taking represents a good example of this. Although these three terms are frequently used interchangeably generating some confusion, compliance, adherence and concordance mean different things and must be used in different ways. Compliance refers to the extent to which patients follow doctors' prescription about medicine taking; adherence refers to the extent to which patients follow through decisions about medicine taking; and concordance refers to the extent to which patients are successfully supported both in decision making partnerships about medicines and in their medicines taking. This terminology evolution may actually be more important than mere semantics since better adherence to a treatment regimen could be achieved through open-ended physician-patient communication, incorporating the beliefs and preferences of the patient in the decision-making process. At present time, concordance could be useful as a normative or aspirational term while compliance and adherence must be the terms used for scientific measurement in medicine-taking field. © 2011 Bentham Science Publishers Ltd.


Schouten J.N.,Rotterdam University | Garcia-Pagan J.C.,CIBER ISCIII | Valla D.C.,French Institute of Health and Medical Research | Janssen H.L.,Rotterdam University
Hepatology | Year: 2011

Idiopathic noncirrhotic portal hypertension (INCPH) is characterized by an increased portal venous pressure gradient in the absence of a known cause of liver disease and portal vein thrombosis. In contrast to the high prevalence of this disorder in India, INCPH is a rare disease in the Western world. The etiology of INCPH can be divided in five categories: chronic infections, exposure to medication or toxins, thrombophilia, immunological disorders, and genetic disorders. Multifactorial etiology can also be encountered. Chronic abdominal infection is incriminated as the most important etiological factor in Eastern patients and thrombophilia in Western patients. The majority of patients with INCPH initially present with signs or complications of portal hypertension (mainly variceal bleeding and splenomegaly). These patients usually have preserved liver function. Liver function impairment occurs mainly in the context of intercurrent conditions. Patients with INCPH are often clinically and radiologically misdiagnosed as liver cirrhosis, so that a liver biopsy is indispensable to discriminate cirrhosis from INCPH. Histopathological characteristics of INCPH are heterogeneous, demonstrating overlap between several pathological entities (e.g., hepatoportal sclerosis, nodular regenerative hyperplasia, and incomplete septal cirrhosis). Even though hemodynamical changes in INCPH patients are not comparable to those in cirrhotics, prophylaxis and treatment of variceal bleeding are recommended to be similar. Anticoagulation therapy must be considered only in patients who develop portal vein thrombosis. INCPH has been considered a disorder with a relatively benign disease course. However, liver failure, hepatic encephalopathy, and hepatopulmonary syndrome can occur and are considered indications for liver transplantation. © 2011 American Association for the Study of Liver Diseases.


Suarez D.,Autonomous University of Barcelona | Borras R.,Autonomous University of Barcelona | Basagana X.,Center for Research in Environmental Epidemiology | Basagana X.,Municipal Institute of Medical Research IMIM Hospital Del Mar | Basagana X.,CIBER ISCIII
Epidemiology | Year: 2011

Background: Marginal structural models were developed to address time-varying confounding in nonrandomized exposure effect studies. It is unclear how estimates from marginal structural models and conventional models might differ in real settings. Methods: We systematically reviewed the literature on marginal structural models since 2000. Results: Data to compare marginal structural models and conventional models were obtained from 65 papers reporting 164 exposureoutcome associations. In 58 (40%), estimates differed by at least 20%, and in 18 (11%), the 2 techniques resulted in estimates with opposite interpretations. In 88 papers, marginal structural models were used to analyze real data; only 53 (60%) papers reported the use of stabilized inverse-probability weights and only 28 (32%) reported that they verified that the mean of the stabilized inverseprobability weights was close to 1.0. Conclusions: We found important differences in results from marginal structural models and from conventional models in real studies. Furthermore, reporting of marginal structural models can be improved. © 2011 by Lippincott Williams & Wilkins.


Carod-Artal F.J.,International University of Catalonia | Martinez-Martin P.,CIBER ISCIII
Parkinsonism and Related Disorders | Year: 2013

Objective: Independent validation of the Non motor Symptoms Scale in Parkinson's disease (NMSS) based on a cross-culturally adapted Brazilian version. Methods: Parkinson's disease (PD) patients were evaluated by means of the Scales for Outcomes in Parkinson's disease-Motor (SCOPA-M), Autonomic, Cognition, and Psychosis; Hoehn and Yahr staging (H&Y); Berg Balance Scale; PD Sleep Scale; Clinical Impression of Severity Index for PD (CISI-PD); PDQ-39; and EQ-5D. The following clinimetric attributes were explored for the NMSS: acceptability, scaling assumptions, reliability, construct validity, and precision. Results: 150 patients were assessed (mean age 63.1 years; 56.7% males; mean duration of illness 8.7 years; HY median: 2). Mean NMSS was 48.9 (SD 36.3; median 42; skewness 1.3). Neither floor nor ceiling effect was observed on the NMSS total score. For domains, the Cronbach's alpha coefficient ranged from 0.40 to 0.82. The NMSS total score correlated significantly with SCOPA-AUT (rS = 0.65) and with those scales measuring related constructs (rS = 0.46-0.57). NMSS significantly increased as the H&Y stage increased (Kruskal-Wallis, p < 0.0001). These values were quite close to those from the original validation studies. Conclusions: The NMSS is a reliable and valid measure to evaluate non motor symptoms in Brazilian PD patients. © 2012 Elsevier Ltd.


Lalueza P.,University of Zaragoza | Monzon M.,University of Zaragoza | Arruebo M.,University of Zaragoza | Santamaria J.,University of Zaragoza | Santamaria J.,CIBER ISCIII
Materials Research Bulletin | Year: 2011

The evaluation of the bactericidal effect of different silver-containing materials where silver is available as Ag+ (silver nitrate and different silver-exchanged zeolites), as metallic Ag0 (commercial silver nanoparticles) or as oxide (silver (I) oxide) was carried out in order to elucidate the importance of the bioavailability of silver (i.e., as free ions, metallic particles, combination of them, clusters, complexes, partially soluble or insoluble salts, etc.) on its bactericidal action. For the different materials tested, their bactericidal effect is ordered in the following sequence: AgNO3 > Ag-ZSM-5 > Ag2O > commercial silver-exchanged zeolite (granular) > commercial silver-exchanged zeolite (pellets) > Ag nanoparticles. In general, as the content of bioavailable ionic silver increases, the biocidal effectiveness of the corresponding silver-releasing material increases too. © 2011 Elsevier Ltd. All rights reserved.


Garcia-Alonso L.,Research Center Principe Felipe | Alonso R.,Research Center Principe Felipe | Vidal E.,Research Center Principe Felipe | Amadoz A.,Research Center Principe Felipe | And 5 more authors.
Nucleic Acids Research | Year: 2012

Genomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network. © 2012 The Author(s).


Gozal D.,University of Chicago | Farre R.,University of Barcelona | Farre R.,CIBER ISCIII | Nieto F.J.,University of Wisconsin - Madison
Sleep Medicine Reviews | Year: 2016

Sleep disorders have emerged as highly prevalent conditions in the last 50-75 y. Along with improved understanding of such disorders, the realization that perturbations in sleep architecture and continuity may initiate, exacerbate or modulate the phenotypic expression of multiple diseases including cancer has gained increased attention. Furthermore, the intermittent hypoxia that is attendant to sleep disordered breathing, has recently been implicated in increased incidence and more adverse prognosis of cancer. The unifying conceptual framework linking these associations proposes that increased sympathetic activity and/or alterations in immune function, particularly affecting innate immune cellular populations, underlie the deleterious effects of sleep disorders on tumor biology. In this review, the epidemiological evidence linking disrupted sleep and intermittent hypoxia to oncological outcomes, and the potential biological underpinnings of such associations as illustrated by experimental murine models will be critically appraised. The overarching conclusion appears supportive in the formulation of an hypothetical framework, in which fragmented sleep and intermittent hypoxia may promote changes in multiple signalosomes and transcription factors that can not only initiate malignant transformation, but will also alter the tumor microenvironment, disrupt immunosurveillance, and thus hasten tumor proliferation and increase local and metastatic invasion. Future bench-based experimental studies as well as carefully conducted and controlled clinical epidemiological studies appear justified for further exploration of these hypotheses. © 2015 Elsevier Ltd.


Moreau R.,Service dHepatologie | Moreau R.,French Institute of Health and Medical Research | Moreau R.,University Paris Diderot | Jalan R.,Institute of Liver and Digestive Health | And 18 more authors.
Gastroenterology | Year: 2013

Background & Aims: Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD. Methods: We collected data from 1343 hospitalized patients with cirrhosis and AD from February to September 2011 at 29 liver units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score) and high 28-day mortality rate (>15%). Results: Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. The 28-day mortality rate among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholic, had more associated bacterial infections, and had higher numbers of leukocytes and higher plasma levels of C-reactive protein than patients without ACLF (P <.001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality compared with ACLF in patients with a prior history of AD. Conclusions: We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD. © 2013 AGA Institute.


El-Faham A.,Barcelona Institute for Research in Biomedicine | El-Faham A.,Alexandria University | Albericio F.,Barcelona Institute for Research in Biomedicine | Albericio F.,CIBER ISCIII | Albericio F.,University of Barcelona
Chemical Reviews | Year: 2011

The procedures used to combine two amino acid residues to form a peptide are referred to as coupling methods. Coupling involves attack by the amino group of one residue at the carbonyl carbon atom of the carboxy-containing component that has been activated by the introduction of an electron-withdrawing group. Several parameters are used to control racemization during peptide-coupling reactions. A key issue is the use of an appropriate N-protecting group. It is pertinent to remember that two types of acyl groups are involved in couplings, namely, those originating from an N-alkoxycarbonylamino acid and those from a peptide. The most traditional approach used to form peptide bonds is the carbodiimide method, using dicyclohexylcarbodiimide. A unique approach to peptide synthesis is the preparation of a derivative of the N- alkoxycarbonylamino acid that is stable enough to be stored and yet reactive enough to combine with an amino group when the two are mixed.


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.


Pena E.,Aragon Institute of Engineering Research | Pena E.,CIBER ISCIII
Computational Mechanics | Year: 2011

On the basis of continuum mechanics, a rate dependent directional damage model for fibred materials with application to soft biological tissues is presented. The structural model is formulated using the concept of internal variables that provides a very general description of materials involving irreversible effects. Continuum damage mechanics is used to describe the softening behavior of soft tissues under large deformation. To account for the rate dependency and to regularize the localization problems associated with strain-softening, a viscous damage mechanism is presented in this paper in decoupled form for matrix and fibers. The numerical implementation in the context of the finite element method is discussed in detail. In order to show the performance of the constitutive model and its algorithmic counterpart some simple examples are included. Results show that the model is able to capture the typical stress-strain behavior observed in fibrous soft tissues and appear to confirm the soundness of the proposed formulation. © 2011 Springer-Verlag.


Guxens M.,Erasmus Medical Center | Guxens M.,Center for Research in Environmental Epidemiology | Guxens M.,Hospital del Mar Research Institute IMIM | Guxens M.,CIBER ISCIII | And 9 more authors.
Journal of Allergy and Clinical Immunology | Year: 2014

Background: Maternal psychological distress during pregnancy might affect fetal lung development and subsequently predispose children to childhood asthma. Objective: We sought to assess the associations of maternal psychological distress during pregnancy with early childhood wheezing. Methods: We performed a population-based prospective cohort study among 4848 children. We assessed maternal and paternal psychological distress at the second trimester of gestation and 3 years after delivery and maternal psychological distress at 2 and 6 months after delivery by using the Brief Symptom Inventory questionnaire. Wheezing in the children was annually examined by using questionnaires from 1 to 4 years. Physician-diagnosed ever asthma was reported at 6 years. Results: Mothers with psychological distress during pregnancy had increased odds of wheezing in their children from 1 to 4 years of life (overall distress: odds ratio [OR], 1.60 [95% CI, 1.32-1.93]; depression: OR, 1.46 [95% CI, 1.20-1.77]; and anxiety: OR, 1.39 [95% CI, 1.15-1.67]). We observed similar positive associations with the number of wheezing episodes, wheezing patterns, and physician-diagnosed asthma at 6 years. Paternal distress during pregnancy and maternal and paternal distress after delivery did not affect these results and were not associated with childhood wheezing. Conclusion: Maternal psychological distress during pregnancy is associated with increased odds of wheezing in their children during the first 6 years of life independent of paternal psychological distress during pregnancy and maternal and paternal psychological distress after delivery. These results suggest a possible intrauterine programming effect of maternal psychological distress leading to respiratory morbidity. © 2013 American Academy of Allergy, Asthma & Immunology.


Santana N.,IIBB CSIC | Santana N.,Research Center Biomedica En Red Of Salud Mental Cibersam | Mengod G.,IIBB CSIC | Mengod G.,CIBER ISCIII | And 2 more authors.
International Journal of Neuropsychopharmacology | Year: 2013

The prefrontal cortex (PFC) is involved in behavioural control and cognitive processes that are altered in schizophrenia. The brainstem monoaminergic systems control PFC function, yet the cells/networks involved are not fully known. Serotonin (5-HT) and norepinephrine (NE) increase PFC neuronal activity through the activation of α1-adrenergic receptors (α1ARs) and 5-HT2A receptors (5-HT2ARs), respectively. Neurochemical and behavioural interactions between these receptors have been reported. Further, classical and atypical antipsychotic drugs share nm in vitro affinity for α1ARs while having preferential affinity for D2 and 5-HT2ARs, respectively. Using double in situ hybridization we examined the cellular expression of α1ARs in pyramidal (vGluT1-positive) and GABAergic (GAD65/67-positive) neurons in rat PFC and their co-localization with 5-HT2ARs. α1ARs are expressed by a high proportion of pyramidal (59-85%) and GABAergic (52-79%) neurons. The expression in pyramidal neurons exhibited a dorsoventral gradient, with a lower percentage of α1AR-positive neurons in infralimbic cortex compared to anterior cingulate and prelimbic cortex. The expression of α1A, α1B and α1D adrenergic receptors was segregated in different layers and subdivisions. In all them there is a high co-expression with 5-HT2ARs (∼80%). These observations indicate that NE controls the activity of most PFC pyramidal neurons via α1ARs, either directly or indirectly, via GABAergic interneurons. Antipsychotic drugs can thus modulate the activity of PFC via α1AR blockade. The high co-expression with 5-HT2ARs indicates a convergence of excitatory serotonergic and noradrenergic inputs onto the same neuronal populations. Moreover, atypical antipsychotics may exert a more powerful control of PFC function through the simultaneous blockade of α1ARs and 5-HT2ARs. © 2012 CINP.


Ortin J.,CIBER ISCIII | Martin-Benito J.,CSIC - National Center for Biotechnology
Virology | Year: 2015

The group of Negative-Stranded RNA Viruses (NSVs) includes many human pathogens, like the influenza, measles, mumps, respiratory syncytial or Ebola viruses, which produce frequent epidemics of disease and occasional, high mortality outbreaks by transmission from animal reservoirs. The genome of NSVs consists of one to several single-stranded, negative-polarity RNA molecules that are always assembled into mega Dalton-sized complexes by association to many nucleoprotein monomers. These RNA-protein complexes or ribonucleoproteins function as templates for transcription and replication by action of the viral RNA polymerase and accessory proteins. Here we review our knowledge on these large RNA-synthesis machines, including the structure of their components, the interactions among them and their enzymatic activities, and we discuss models showing how they perform the virus transcription and replication programmes. © 2015.


Marino Z.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Crespo G.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | D'Amato M.,Rottapharm S.p.A. | Brambilla N.,Rottapharm S.p.A. | And 5 more authors.
Journal of Hepatology | Year: 2013

Background & Aims: Hepatitis C recurrence after liver transplantation (LT) is the main problem of most transplant programs. We aimed at assessing the antiviral activity and safety of intravenous silibinin (SIL) administered daily during the peri-transplant period. Methods: This was a single-centre, prospective, randomized, double-blind, placebo-controlled study including 14 HCV-infected patients awaiting LT. Eleven patients received SIL and 3 placebo, for a maximum of 21 days before LT and 7 days after LT. Results: Among the patients who received more than 14 days of pre-LT treatment, the median decrease in viral load (VL) was 2.31 log10 (range 0.6-4.2) in the SIL-treated group (n = 9) versus 0.30 log10 (0.1-0.6) in the placebo group (n = 3) (p = 0.016). During the post-LT treatment, HCV-RNA levels were consistently and significantly (p = 0.002) lower in the SIL group compared to placebo and decreased below the limit of quantification in 2 patients and below the limit of detection in 2 additional patients (all in the SIL-treated group). Peri-transplant treatment with SIL was well tolerated. Conclusions: This proof-of-concept study in patients in the waiting list for LT indicates that daily intravenous silibinin has evident antiviral properties and is well tolerated in the peri-LT period. A longer treatment regimen with silibinin (alone or in combination with other agents) should be assessed in clinical trials for the prevention of hepatitis C recurrence. © 2012 European Association for the Study of the Liver.


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.


Emerich D.F.,Nsgene Inc. | Orive G.,University of the Basque Country | Orive G.,CIBER ISCIII | Thanos C.,Cytosolve Inc. | And 2 more authors.
Advanced Drug Delivery Reviews | Year: 2014

Delivering therapeutic molecules, including trophic factor proteins, across the blood brain barrier to the brain parenchyma to treat chronic neurodegenerative diseases remains one of the great challenges in biology. To be effective, delivery needs to occur in a long-term and stable manner at sufficient quantities directly to the target region in a manner that is selective but yet covers enough of the target site to be efficacious. One promising approach uses cellular implants that produce and deliver therapeutic molecules directly to the brain region of interest. Implanted cells can be precisely positioned into the desired region and can be protected from host immunological attack by encapsulating them and by surrounding them within an immunoisolatory, semipermeable capsule. In this approach, cells are enclosed within a semiporous capsule with a perm selective membrane barrier that admits oxygen and required nutrients and releases bioactive cell secretions while restricting passage of larger cytotoxic agents from the host immune defense system. Recent advances in human cell line development have increased the levels of secreted therapeutic molecules from encapsulated cells, and membrane extrusion techniques have led to the first ever clinical demonstrations of long-term survival and function of encapsulated cells in the brain parenchyma. As such, cell encapsulation is capable of providing a targeted, continuous, de novo synthesized source of very high levels of therapeutic molecules that can be distributed over significant portions of the brain. © 2013 Elsevier B.V.


Lurbe E.,CIBER ISCIII | Alvarez J.,University of Valencia | Redon J.,INCLIVA
Current Hypertension Reports | Year: 2010

Hypertension is a global problem, affecting both developed and developing nations. In children and adolescents, hypertension has gained ground in cardiovascular medicine, thanks to the progress made in several areas of pathophysiologic and clinical research. Childhood hypertension is often asymptomatic and is easily missed, even by health professionals. Target organ damage is detectable in children and adolescents. Management of hypertension includes lifestyle changes and pharmacologic treatment. In the case of secondary hypertension, pharmacologic treatment usually is required. In essential hypertension, assessment of early organ damage provides a useful tool for treatment decisions. © 2010 Springer Science+Business Media, LLC.


During the 10th HUPO Annual World Congress held in Geneva (Switzerland) from 4th to 7th September, a workshop on Human Liver Proteome Project (HLPP) Initiative took place. Four research groups presented their latest results from different ongoing projects. Later on, during the HLPP executive members' meeting, the status of current projects and the next possible steps to be taken were discussed. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Gallego J.A.,Bioengineering Group | Rocon E.,Bioengineering Group | Belda-Lois J.M.,Polytechnic University of Valencia | Belda-Lois J.M.,CIBER ISCIII | Pons J.L.,Bioengineering Group
Journal of NeuroEngineering and Rehabilitation | Year: 2013

Background: Pathological tremor is the most prevalent movement disorder. Current treatments do not attain a significant tremor reduction in a large proportion of patients, which makes tremor a major cause of loss of quality of life. For instance, according to some estimates, 65% of those suffering from upper limb tremor report serious difficulties during daily living. Therefore, novel forms for tremor management are required. Since muscles intrinsically behave as a low pass filter, and tremor frequency is above that of volitional movements, the authors envisioned the exploitation of these properties as a means of developing a novel treatment alternative. This treatment would rely on muscle co-contraction for tremor management, similarly to the strategy employed by the intact central nervous system to stabilize a limb during certain tasks. Methods. We implemented a neuroprosthesis that regulated the level of muscle co-contraction by injecting current at a pair of antagonists through transcutaneous neurostimulation. Co-contraction was adapted to the instantaneous parameters of tremor, which were estimated from the raw recordings of a pair of solid state gyroscopes with a purposely designed adaptive algorithm. For the experimental validation, we enrolled six patients suffering from parkinsonian or essential tremor of different severity, and evaluated the effect of the neuroprosthesis during standard tasks employed for neurological examination. Results: The neuroprosthesis attained significant attenuation of tremor (p<0.001), and reduced its amplitude up to a 52.33±25.48%. Furthermore, it alleviated both essential and parkinsonian tremor in spite of their different etiology and symptomatology. Tremor severity was not a limiting factor on the performance of the neuroprosthesis, although there was a subtle trend towards larger attenuation of more severe tremors. Tremor frequency was not altered during neurostimulation, as expected from the central origin of Parkinson's disease and essential tremor. All patients showed a good tolerance to neurostimulation in terms of comfort and absence of pain, and some spontaneously reported that they felt that tremor was reduced when the neuroprosthesis was activated. Conclusions: The results presented herein demonstrate that the neuroprosthesis provides systematic attenuation of the two major types of tremor, irrespectively from their severity. This study sets the basis for the validation of the neuroprosthesis as an alternative, non-invasive means for tremor management. © 2013 Gallego et al.; licensee BioMed Central Ltd.


Llamedo M.,Aragon Institute of Engineering Research | Martinez J.P.,CIBER ISCIII
Computing in Cardiology | Year: 2014

Automatic QRS detection remains a challenging task in certain types of recordings, limiting the capacity of automating subsequent tasks that heavily depends on proper heartbeat location. Performance estimation of these algorithms is calculated almost exclusively in a few databases, ignoring the generalization to other more complex situations. In this work, we evaluated six QRS detection algorithms in 13 ECG databases. Four out of the six algorithms, and 11 out of 13 databases are publicly available. The databases were categorized into 5 groups: normal sinus rhythm, arrhythmia, ST and T morphology changes, stress-test and long-term. The best evaluated algorithm was gqrs, achieving S of 95 (85-98) (median and percentile range 5-95) and P+of 93 (90-96) across all databases. When analyzing the performance by groups of databases, this algorithm obtained the first rank in 4 out of 5 groups. The algorithm developed in our group achieved a performance close to gqrs, and obtained the best performance in the stress group. This evaluation setup includes a broad variety of recordings, being useful to estimate the actual performance of QRS detection algorithms, not only in a global sense but also specific to specific type of recordings.


Hawser S.P.,IHMA Europe Sarl | Bouchillon S.K.,International Health Management Associates Inc. | Lascols C.,International Health Management Associates Inc. | Hackel M.,International Health Management Associates Inc. | And 3 more authors.
Clinical Microbiology and Infection | Year: 2012

A total of 3160 clinical isolates of Escherichia coli from intra-abdominal infections were collected during 2008-2009 from 13 European countries. The frequency of extended-spectrum β-lactamase (ESBL)-producing isolates in Europe was 11%. The most active antibiotics tested were typically imipenem, ertapenem, and amikacin, although the activity of all non-carbapenem antibiotics was lower when tested against ESBL-positive isolates than when tested against ESBL-negative isolates. Ertapenem exhibited 99.3% susceptibility with all isolates, and 96.8% susceptibility with ESBL-positive isolates. With application of the ertapenem CLSI clinical breakpoint for resistance (MIC ≥1mg/L), only six isolates (0.2%) were ertapenem-resistant, and only three of these were available for molecular characterization. Of those three, only one was ESBL-positive (CTX-M-14), and two were carbapenemase-positive (OXA-48). All three were negative for, VIM, NDM and KPC carbapenemases. Although the level of ertapenem resistance in E. coli is very low, further monitoring of ertapenem susceptibility and molecular characterization of ertapenem-resistant isolates is needed. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.


Human respiratory syncytial virus (hRSV) remains one of the most prevalent human pathogens for which a vaccine is still missing. After several decades of hesitant efforts, particularly after the harmful effects of a formalin-inactivated hRSV vaccine trial in the 1960s, hRSV vaccine development has received new impetus from structure-based studies of its main protective antigen: the fusion (F) glycoprotein. This article reviews studies done with hRSV F, either in pieces (e.g. epitopes) or as soluble or membrane-anchored molecules folded in different conformations or presented under different forms. Knowledge gained from these studies has provided the basis for novel vaccines that are now in different phases of development and has generated tools and reagents for developing other control measures such as prophylactic or therapeutic antibodies against this virus, which remains the most important cause of hospitalization in infants and one of the leading global causes of infant mortality. © 2016 Informa UK Limited, trading as Taylor & Francis Group


Rodriguez M.M.,CIBER ISCIII
International Journal of Obesity | Year: 2016

Context:Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is strongly associated with obesity, dyslipidaemia and altered glucose regulation. Previous data demonstrated that low circulating levels of tumour necrosis factor weak inducer of apoptosis (sTWEAK) were associated with obesity, diabetes and insulin resistance, all traits associated with an increased risk of NALFD. Circulating sTWEAK levels are expected to be reduced in the presence of NAFLD.Objective:We aimed to explore the relationship between NAFLD and circulating sTWEAK levels in obese patients, and to evaluate the effect of sTWEAK on hepatocyte triglyceride accumulation.Design setting and patients:This is an observational case–control study performed in n=112 severely obese patients evaluated for NAFLD by abdominal ultrasound and n=32 non-obese patients without steatosis. Serum sTWEAK concentrations were measured by ELISA. Multivariable analyses were performed to determine the independent predictors of NAFLD. We analysed TWEAK and Fn14 protein expression in liver biopsies by western blotting and immunohistochemistry. An immortalized primary human hepatocyte cell line (HHL) was used to evaluate the effect of sTWEAK on triglyceride accumulation.Results:We observed a reduction in serum circulating sTWEAK concentrations with the presence of liver steatosis. On multivariable analysis, lower sTWEAK concentrations were independently associated with the presence of NAFLD (odds ratio (OR)=0.023; 95% confidence interval: 0.001–0.579; P<0.022). In human hepatocytes, sTWEAK administration reduced fat accumulation as demonstrated by the reduction in palmitic acid-induced accumulation of triglyceride and the decreased expression of cluster of differentiation 36 (CD36) and perilipin 1 and 2 (PLIN1 and PLIN2) genes.Conclusions:Decreased sTWEAK concentrations are independently associated with the presence of NAFLD. This is concordant with the observation that TWEAK reduces lipid accumulation in human liver cells.International Journal of Obesity advance online publication, 7 June 2016; doi:10.1038/ijo.2016.73. © 2016 Macmillan Publishers Limited


Guerra S.,University of Arizona | Guerra S.,CIBER ISCIII | Stern D.A.,University of Arizona | Zhou M.,University of Arizona | And 4 more authors.
Thorax | Year: 2013

Background Cross-sectional reports have suggested that, among active smokers, previous exposure to parental smoking may increase susceptibility to development of chronic obstructive pulmonary disease. We assessed prospectively whether parental smoking enhances the effects of active smoking on early deficits of lung function in young adults. Methods We used data from the prospective birth cohort, the Tucson Children's Respiratory Study. Maternal and paternal smoking was assessed via questionnaires completed by the parents at the time of the participant's birth. Active smoking by participants was assessed via personal questionnaires completed at ages 16 (YR16), 22 and 26 years. Four groups were generated based on the combination of parental and active smoking. Lung function parameters, including forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio, were assessed by spirometry before and after inhalation of 180 μg of albuterol at YR11, YR16, YR22 and YR26. Results Complete data were available for 519 participants. Pre-bronchodilator FEV1/FVC values did not differ at YR11, YR16 or YR22 by parental or active smoking. However, at YR26 participants with exposure to parental and active smoking had pre-bronchodilator FEV1/FVC levels that were, on average, 2.8% (0.9% to 4.8%; p=0.003) lower than participants who were not exposed to parental or active smoking. In contrast, subjects who were only exposed to active smoking or only exposed to parental smoking did not differ from those who were not exposed to either. Between YR11 and YR26, participants with exposure to parental and active smoking had the steepest decline in sex, age and height adjusted residuals of FEV1/FVC, FEV1, forced expiratory flow between 25% and 75% of the FVC (FEF25-75) and FEF25-75/FVC (all p values between 0.03 and <0.001). Conclusions Parental and active smoking act synergistically to affect early lung function deficits in young adulthood.


Carod-Artal F.J.,International University of Catalonia | Mesquita H.M.,Matsumoto Medical Center | Ziomkowski S.,Sarah Hospital | Martinez-Martin P.,CIBER ISCIII
Parkinsonism and Related Disorders | Year: 2013

Purpose: To analyze the main determinants of burden and health-related quality-of-life (HRQoL) in caregivers of Brazilian Parkinson's disease (PD) patients. Methods: Caregivers answered Hospital Anxiety and Depression Scale (HADS), Zarit caregiver burden interview (ZCBI) and EQ-5D, a generic measure of HRQoL. Patients were assessed with Hoehn and Yahr (H&Y) staging; Scales for Outcomes in Parkinson's disease (SCOPA) Motor, Cognition, Psychosocial and Sleep scales; Non-Motor Symptoms Scale; HADS; Clinical Impression of Severity Index; EQ-5D and Parkinson's Psychosis Rating Scale. Results: 50 Caregiver-patient dyads were assessed. Caregivers were significantly younger (55.7 vs. 65.4 years), p<0.0001. Eighty-eight per cent of caregivers were females, and 78% were spouses. The proportion of caregivers who scored ≥11 points in the HADS-anxiety or HADS-depression subscales was 12% and 14% respectively. ZCBI mean score was 20.2 (SD 12.8), and significantly worsened as severity of disease, based on H&Y, increased (H&Y 1-2: 16.4, H&Y 3-5: 24.6; p=0.02). Caregiver's EQ-5D Index and visual analog scale mean scores were 0.7 (SD: 0.26) and 76.3 (SD: 16.2) respectively. Weak to moderate association (r=-0.27 to-0.39) between EQ-5D Index and ZBCI mean scores was observed in caregivers. Patient outcomes (sleep disorders and behavioral-psychotic symptoms) and caregiver outcomes (mood, time of caregiving) were independent predictors of caregiver burden (adjusted R2=0.55; p<0.0001) in the multivariate regression analysis. Caregiver's mood status was a significant determinant of caregiver's HRQoL, as measured by the EQ-5D Index (adjusted R2=0.28; p=0.006). Conclusions: Patients' psychiatric and sleep disorders and caregiver's mood significantly influenced burden and HRQoL in Brazilian PD caregivers. © 2013 Elsevier Ltd.


Muttenthaler M.,Barcelona Institute for Research in Biomedicine | Muttenthaler M.,University of Queensland | Albericio F.,Barcelona Institute for Research in Biomedicine | Albericio F.,CIBER ISCIII | And 2 more authors.
Nature Protocols | Year: 2015

Solid-phase peptide synthesis (SPPS) using tert-butyloxycarbonyl (Boc)/benzyl (Bzl) chemistry is an indispensable technique in many laboratories around the globe, and it provides peptides to the pharmaceutical industry and to thousands of scientists working in basic research. The Boc/Bzl strategy has several advantages, including reliability in the synthesis of long and difficult polypeptides, alternative orthogonality regarding protecting groups and ease of producing C-terminal thioesters for native chemical ligation applications. In this process, anhydrous hydrogen fluoride (HF) is used to remove the side chain protecting groups of the assembled peptide and to release the peptide from the resin, a process typically described as 'HF cleavage'. This protocol describes the general methodology, apparatus setup and safe handling of HF, with the aim of providing comprehensive information on the safe use of this valuable, well-studied and validated cleavage technique. We explain the cleavage mechanism, the physicochemical properties and risks of HF, first aid measures and the correct use of the apparatus. In addition, we provide advice on scavenger selection, as well as a troubleshooting section and video material illustrating key steps of the procedure. The protocol comprises precleavage sample preparation (30 min-2.5 h), complete HF cleavage procedure (2 h) and reaction workup (30 min). © 2015 Nature America, Inc. All rights reserved.


Balasch J.,University of Barcelona | Gratacos E.,University of Barcelona | Gratacos E.,CIBER ISCIII
Fetal Diagnosis and Therapy | Year: 2011

In modern societies, the proportion of women who delay childbearing beyond the age of 35 years has greatly increased in recent decades. They are falsely reassured by popular beliefs that advances in new reproductive technologies can compensate for the age-related decline in fertility. Yet age remains the single most important determinant of male and female fertility, either natural or treated. The consequences of advancing maternal age are not only relevant for the risk of natural and assisted conception, but also for the outcome of pregnancy. Although the absolute rate of poor pregnancy outcomes may be low from an individual standpoint, the impact of delaying childbearing from a public health perspective cannot be overestimated and should be in the agenda of public health policies for the years to come. This review summarizes available evidence regarding the impact of delaying childbearing on fertility and pregnancy outcomes. Copyright © 2011 S. Karger AG.


Fernandez-Real J.M.,University of Girona | Fernandez-Real J.M.,CIBER ISCIII | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona Idibgi | Pickup J.C.,Diabetes Research Group
Diabetologia | Year: 2012

In this edition of 'Then and now' the initial studies by J.C. Pickup and colleagues supporting the hypothesis that type 2 diabetes is caused by activated innate immunity, published in Diabetologia in 1997 (40:1286-1292), are discussed. These initial findings led to research that has uncovered links between insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to the altered production or function of circulating innate immune proteins, cellular pattern recognition receptors and inflammatory cytokines are linked to obesity, insulin resistance and type 2 diabetes. Components of the innate immune system in the muscle, bone, liver and adipose tissue, as well as macrophages, have been revealed to play a role in systemic insulin action. Evolutionary pressures, such as acute infections at the population level (pandemics) and chronic low exposure to environmental products or infectious agents, may have contributed to increased susceptibility and to the current increase in the prevalence of insulin resistance and type 2 diabetes. © 2011 Springer-Verlag.


Borrell-Pages M.,Cardiovascular Research Center | Romero J.C.,Cardiovascular Research Center | Badimon L.,Cardiovascular Research Center | 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.


Arboix A.,University of Barcelona | Arboix A.,CIBER ISCIII | Alio J.,Hospital Universitari Of Bellvitge
Current Cardiology Reviews | Year: 2010

This article provides the reader with an overview and up-date of clinical features, specific cardiac disorders and prognosis of cardioembolic stroke. Cardioembolic stroke accounts for 14-30% of ischemic strokes and, in general, is a severe condition; patients with cardioembolic infarction 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 cardioembolic infarction, 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 more common high risk cardioembolic conditions are atrial fibrillation, recent myocardial infarction, mechanical prosthetic valve, dilated myocardiopathy, and mitral rheumatic stenosis. Transthoracic and transesophageal echocardiogram can disclose structural heart diseases. Paroxysmal atrial dysrhyhtmia can be detected by Holter monitoring. In-hospital mortality in cardioembolic stroke (27.3%, in our series) is the highest as compared with other subtypes of cerebral infarction. In our experience, in-hospital mortality in patients with early embolic recurrence (within the first 7 days) was 77%. Patients with alcohol abuse, hypertension, valvular heart disease, nausea and vomiting, and previous cerebral infarction are at increased risk of early recurrent systemic embolization. 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. © 2010 Bentham Science Publishers Ltd.


Trujillo M.L.,University of Santiago de Compostela | Spuch C.,University of Vigo | Carro E.,CIBER ISCIII | Senaris R.,University of Santiago de Compostela
Endocrinology | Year: 2011

The purpose of this work was to study the central mechanisms involved in food intake regulation and leptin resistance during gestation in the rat. Sprague Dawley rats of 7, 13, and 18 d of pregnancy [days of gestation (G) 7, G13, and G18] were used and compared with nonpregnant animals in diestrus-1. Food intake was already increased in G7, before hyperleptinemia and central leptin resistance was established in midpregnancy. Leptin resistance was due to a reduction in leptin transport through the blood-brain barrier (BBB) and to alterations in leptin signaling within the hypothalamus based on an increase in suppressor of cytokine signaling 3 levels and a blockade of signal transducer and activator of transcription-3 phosphorylation (G13), followed by a decrease in LepRb and of Akt phosphorylation (G18). In earlygestation (G7), no change in hypothalamic neuropeptideY (NPY),agouti-relatedpeptide (AgRP), or proopiomelanocortin (POMC) expression was shown. Nevertheless, an increase in NPY and AgRP and a decrease in POMC mRNA were observed in G13 and G18 rats, probably reflecting the leptin resistance. To investigate the effect of maternal vs. placental hormones on these mechanisms,we used a model of pseudogestation. Rats of 9 d of pseudogestation were hyperphagic, showing an increase in body and adipose tissue weight, normoleptinemia, and normal responses to iv/intracerebroventricular leptin on hypothalamic leptin signaling, food intake, and body weight. Leptin transport through the BBB, and hypothalamic NPY, AgRP and POMC expression were unchanged. Finally, the transport of leptin through the BBB was assessed using a double-chamber culture system of choroid plexus epithelial cells or brain microvascular endothelial cells. We found that sustained high levels of prolactin significantly reduced leptin translocation through the barrier, whereas progesterone and β-estradiol did not show any effect. Our data demonstrate a dual mechanism of leptin resistance during mid/late-pregnancy, which is not due to maternal hormones and which allows the maintenance of hyperphagia in the presence of hyperleptinemia driven by an increase in NPY and AgRP and a decrease in POMC mRNA. By contrast, in early pregnancy maternal hormones induce hyperphagia without the regulation of hypothalamic NPY, AgRP, or POMC and in the absence of leptin resistance. Copyright © 2011 by The Endocrine Society.


Perez-Poyato M.S.,Hospital Sant Joan de Deu | Pineda M.,Hospital Sant Joan de Deu | Pineda M.,CIBER ISCIII
Current Pharmaceutical Biotechnology | Year: 2011

Niemann-Pick disease type C is an autosomal recessive disorder caused by mutations in either one of the two genes, NPC1 or NPC2, which encode proteins involved in the regulation of normal transport and/or processing of free cholesterol. Several types of lipids including free cholesterol (unesterified), sphingosine, sphingomyelin, phospholipids and glycosphingolipids (glucosylceramide and gangliosides GM2 and GM3) are accumulated in lysosomes and late endosomes of cells, with pronounced concentrations in the liver and the spleen. The key laboratory diagnostic test for NP-C is filliping staining of cultured skin fibroblasts from the patient, to demonstrate free cholesterol accumulation in lysosomes secondary to impaired intracellular cholesterol transport. The symptomatology and rate of disease progression are strongly influenced by age at disease onset and different clinical forms have been described on this basis: Perinatal,Early-infantile (EI), late-infantile (LI), juvenile and adult forms. Clinical symptoms include progressive neurological deterioration and visceral organomegaly. Nowadays there is no fully effective treatment, only supportive measures for relief of specific manifestations of the disease. The intervention to slow disease progression is the most promising therapy. A number of experimental disease - specific therapies, based on the molecular pathology of NP-C, have been tested in cell culture and animal models including neurosteroids, cholesterol - binding agents, curcumin and Miglustat. This paper summarizes the recent developments that have been investigated for the treatment in patients and animal models with NPC. Current therapeutic approaches have been classified based on the targeting of cellular function, the anti - apoptotic cellular mechanisms and the stem cells therapy. © 2011 Bentham Science Publishers Ltd.


Lott I.T.,University of California at Irvine | Dierssen M.,CIBER ISCIII
The Lancet Neurology | Year: 2010

Improvements in medical interventions for people with Down's syndrome have led to a substantial increase in their longevity. Diagnosis and treatment of neurological complications are important in maintaining optimal cognitive functioning. The cognitive phenotype in Down's syndrome is characterised by impairments in morphosyntax, verbal short-term memory, and explicit long-term memory. However, visuospatial short-term memory, associative learning, and implicit long-term memory functions are preserved. Seizures are associated with cognitive decline and seem to cause additional decline in cognitive functioning, particularly in people with Down's syndrome and comorbid disorders such as autism. Vision and hearing disorders as well as hypothyroidism can negatively impact cognitive functioning in people with Down's syndrome. Dementia that resembles Alzheimer's disease is common in adults with Down's syndrome. Early-onset dementia in adults with Down's syndrome does not seem to be associated with atherosclerotic complications. © 2010 Elsevier Ltd. All rights reserved.


Mokkink L.B.,VU University Amsterdam | Terwee C.B.,VU University Amsterdam | Patrick D.L.,University of Washington | Alonso J.,Institute Municipal dInvestigacio Medica IMIM Hospital del Mar | And 5 more authors.
Journal of Clinical Epidemiology | Year: 2010

Objective: Lack of consensus on taxonomy, terminology, and definitions has led to confusion about which measurement properties are relevant and which concepts they represent. The aim was to clarify and standardize terminology and definitions of measurement properties by reaching consensus among a group of experts and to develop a taxonomy of measurement properties relevant for evaluating health instruments. Study Design and Setting: An international Delphi study with four written rounds was performed. Participating experts had a background in epidemiology, statistics, psychology, and clinical medicine. The panel was asked to rate their (dis)agreement about proposals on a five-point scale. Consensus was considered to be reached when at least 67% of the panel agreed. Results: Of 91 invited experts, 57 agreed to participate and 43 actually participated. Consensus was reached on positions of measurement properties in the taxonomy (68-84%), terminology (74-88%, except for structural validity [56%]), and definitions of measurement properties (68-88%). The panel extensively discussed the positions of internal consistency and responsiveness in the taxonomy, the terms "reliability" and "structural validity," and the definitions of internal consistency and reliability. Conclusions: Consensus on taxonomy, terminology, and definitions of measurement properties was reached. Hopefully, this will lead to a more uniform use of terms and definitions in the literature on measurement properties. © 2010 Elsevier Inc. All rights reserved.


Delaye L.,Instituto Cavanilles | Delaye L.,National Autonomous University of Mexico | Moya A.,Instituto Cavanilles | Moya A.,CIBER ISCIII
BioEssays | Year: 2010

Prokaryotic genomes of endosymbionts and parasites are examples of naturally evolved minimal cells, the study of which can shed light on life in its minimum form. Their diverse biology, their lack of a large set of orthologous genes and the existence of essential linage (and environmentally) specific genes all illustrate the diversity of genes building up naturally evolved minimal cells. This conclusion is reinforced by the fact that sometimes the same essential function is performed by genes from different evolutionary origins. Nevertheless, all cells perform a set of life-essential functions however different their cell machinery and environment in which they thrive. An upcoming challenge for biologists will be to discern, by studying differences and similarities in current biodiversity, how cells with reduced genomes have adapted while retaining all basic life-supporting functions. © 2010 Wiley Periodicals, Inc.


Guerra S.,University of Arizona | Guerra S.,CIBER ISCIII | Sherrill D.L.,University of Arizona | Venker C.,University of Arizona | And 3 more authors.
Thorax | Year: 2010

Background: Recent studies have suggested that a restrictive pattern assessed with a single spirometric test is associated with increased morbidity and mortality. This study was undertaken to determine demographic, clinical and mortality profiles of subjects with either a recurrent or an inconsistent restrictive spirometric pattern assessed prospectively. Methods: Data from 2048 adult participants in the population-based TESAOD study were analysed. Normal (forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio ≥70% and FVC ≥80% predicted), restrictive (FEV1/FVC ≥70% and FVC <80% predicted) and obstructive (FEV1/FVC <70%) patterns were assessed at the enrolment survey in 1972 and in 11 subsequent follow-up surveys up to 1996. Demographic and clinical characteristics were measured at enrolment and vital status and cause of death were assessed at January 2005. Results: Overall, 12% of participants had a restrictive spirometric pattern at enrolment. They were less likely to be male, to smoke and to have asthma, and had lower IgE levels than subjects in the obstructive group. Among subjects with a restrictive pattern at enrolment, 38% developed an obstructive pattern during follow-up. The remaining 62% had either a recurrent (restrictive pattern ≥50% of follow-up surveys) or inconsistent (restrictive pattern <50% of follow-up surveys) longitudinal restrictive pattern. The recurrent and inconsistent restrictive groups had increased mortality risk for all-cause (adjusted HR 1.7 (95% CI 1.3 to 2.3) and 1.9 (95% CI 1.4 to 2.6), respectively), heart disease (2.0 (95% CI 1.3 to 3.1) and 2.7 (95% CI 1.7 to 4.3)), stroke (2.4 (95% CI 0.9 to 6.3) and 3.5 (95% CI 1.2 to 9.8)) and diabetes (8.0 (95% CI 2.9 to 21.8) and 6.0 (95% CI 1.9 to 19.2)). Conclusions: The restrictive spirometric pattern identifies a pulmonary condition that is distinguishable from obstructive lung disease and is associated with an increased risk of life-threatening comorbidities.


Tena-Sempere M.,University of Cordoba, Spain | Tena-Sempere M.,CIBER ISCIII
Molecular and Cellular Endocrinology | Year: 2010

Kisspeptins, a family of peptides encoded by the KISS1 gene which binds GPR54 (or KISS1 receptor), have recently emerged as essential neuropeptide regulators of key aspects of reproductive maturation and function, including puberty onset, neuroendocrine control of ovulation and metabolic regulation of fertility. Yet, while the neuroanatomy of kisspeptin system has begun to be deciphered, and the involvement of kisspeptins in the above phenomena has been experimentally documented in recent years, precise information on the signaling events underlying these functions has remained scarce. Similarly, the nature and mechanisms of action of most of the regulatory signals of KISS1 expression in the brain are largely unknown. In this review, we will comprehensively summarize some of the recent developments in these areas of kisspeptin physiology, with the ultimate aim to delineate unresolved questions and future pathways for the progression of this active field of Neuroendocrinology. © 2009 Elsevier Ireland Ltd. All rights reserved.


Garcia De Viedma D.,Hospital General Universitario Gregorio Maranon | Garcia De Viedma D.,CIBER ISCIII | Mokrousov I.,St Petersburg Pasteur Institute | Rastogi N.,Institute Pasteur Of Guadeloupe Morne Joliviere
Enfermedades Infecciosas y Microbiologia Clinica | Year: 2011

The application of genotyping tools to the analysis of tuberculosis (TB) has allowed us to identify clinical isolates of Mycobacterium tuberculosis to strain level. M. tuberculosis fingerprinting has been applied at different levels: a) in the laboratory, to optimize identification of cross-contamination events which can lead to a false diagnosis; b) in the patient, to determine whether recurrences are due to reactivations or exogenous reinfections or to identify cases coinfected by more than one strain; c) at the micropopulation level, to identify clusters of cases infected by the same strains (recent transmission) and to differentiate them from orphan cases that are most probably due to reactivations; and d) at the macropopulation level, to define the global distribution of M. tuberculosis lineages, to monitor the international spread of high-risk strains, and to explore the evolutionary features of M. tuberculosis. In recent years, important methodological and strategic advances have been applied at these different levels of analysis. Rather than provide an exhaustive review, the present study focuses on specific advances in micropopulation and macropopulation analysis. © 2011 Elsevier España S.L.


Farre R.,Catholic University of Leuven | Farre R.,CIBER ISCIII
Neurogastroenterology and Motility | Year: 2013

Background: Gastro-esophageal reflux disease (GERD) is very prevalent and has a high burden on health security system costs. Nevertheless, pathophysiology is complex and not well-understood. Several mechanisms have been proposed: decreased salivation, impaired esophageal clearance, decreased lower esophageal sphincter pressure resting tone, presence of hiatal hernia, increased number of transient lower esophageal sphincter relaxations (TLESRs), increased acid, and pepsin secretion, pyloric incompetence provoking duodeno-gastro-esophageal reflux of bile acids and trypsin. Independent of the relevance of each mechanism, the ultimate phenomenon is that mucosal epithelium is exposed for a longer time to agents as acid and pepsin or is in contact to luminal agents not commonly present in gastric refluxate as trypsin or bile acids. This leads to a visible damage of the epithelium (erosive esophagitis -EE) or impairing mucosal integrity without any sign of macroscopic alteration as occurs in non-erosive reflux disease (NERD). Luminal factors are not the only responsible for such impairment; more recent data indicate that endogenous factors may also play a role. Purpose: This review will update the most recent findings on the putative pathophysiological mechanisms and specially will focus on the role of esophageal mucosal integrity in GERD. Methodologies used for the evaluation of mucosal integrity, its relevance in EE and NERD, its involvement in symptoms perception and the effect of luminal and endogenous factors will be discussed. Gastro-esophageal reflux disease (GERD) is very prevalent. Nevertheless, pathophysiology is complex and not well understood. Several mechanisms have been proposed but the ultimate phenomenon is that mucosal epithelium is most of the times abnormally exposed to luminal agents leading to an impaired mucosal integrity. Methodologies used for the evaluation of mucosal integrity, its relevance in erosive esophagitis and non-erosive reflux disease, its involvement in symptoms perception and the effect of luminal and endogenous factors will be discussed. © 2013 John Wiley & Sons Ltd.


Agusti A.,University of Barcelona | Agusti A.,CIBER ISCIII | MacNee W.,nter for Inflammation Research
Thorax | Year: 2013

Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease whose assessment and management have traditionally been based on the severity of airflow limitation (forced expiratory volume in 1 s (FEV1)). Yet, it is now clear that FEV1 alone cannot describe the complexity of the disease. In fact, the recently released Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011 revision has proposed a new combined assessment method using three variables (symptoms, airflow limitation and exacerbations). Methods Here, we go one step further and propose that in the near future physicians will need a 'control panel' for the assessment and optimal management of individual patients with complex diseases, including COPD, that provides a path towards personalised medicine. Results We propose that such a 'COPD control panel' should include at least three different domains of the disease: severity, activity and impact. Each of these domains presents information on different 'elements' of the disease with potential prognostic value and/or with specific therapeutic requirements. All this information can be easily incorporated into an 'app' for daily use in clinical practice. Conclusion We recognise that this preliminary proposal needs debate, validation and evolution (eg, including 'omics' and molecular imaging information in the future), but we hope that it may stimulate debate and research in the field.


Velasco G.,Catholic University of Leuven | Velasco G.,Complutense University of Madrid | Verfaillie T.,Catholic University of Leuven | Salazar M.,Complutense University of Madrid | Agostinis P.,CIBER ISCIII
International Journal of Cell Biology | Year: 2010

Different physiological and pathological conditions can perturb protein folding in the endoplasmic reticulum, leading to a condition known as ER stress. ER stress activates a complex intracellular signal transduction pathway, called unfolded protein response (UPR). The UPR is tailored essentially to reestablish ER homeostasis also through adaptive mechanisms involving the stimulation of autophagy. However, when persistent, ER stress can switch the cytoprotective functions of UPR and autophagy into cell death promoting mechanisms. Recently, a variety of anticancer therapies have been linked to the induction of ER stress in cancer cells, suggesting that strategies devised to stimulate its prodeath function or block its prosurvival function, could be envisaged to improve their tumoricidial action. A better understanding of the molecular mechanisms that determine the final outcome of UPR and autophagy activation by chemotherapeutic agents, will offer new opportunities to improve existing cancer therapies as well as unravel novel targets for cancer treatment. © 2010 Guillermo Velasco.


Colom C.,Autonomous University of Barcelona | Corcoy R.,Autonomous University of Barcelona | Corcoy R.,CIBER ISCIII
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2010

Three and a half decades after the clinical description of "Maturity Onset Diabetes of the Young" (MODY), and despite its low prevalence, important knowledge has been gathered concerning its genetic basis, molecular pathways, clinical phenotypes and pharmacogenetic issues. This knowledge has proved to be important not only for the attention of subjects carrying a mutation but also for the insight provided in Type 2 diabetes mellitus. In recent years, a shift from the term "MODY" to "monogenic diabetes" has taken place, the latter term being a better and more comprehensive descriptor. We stick to the "old" term because information on other types of monogenic diabetes and pregnancy is scarce. In this review we perform an overview of the entity, the prevalence rates reported in women with gestational diabetes mellitus and the specific impact of each type on pregnancy outcome. © 2010 Elsevier Ltd. All rights reserved.


Armengol C.,French Institute of Health and Medical Research | Armengol C.,CIBER ISCIII | Cairo S.,French Institute of Health and Medical Research | Fabre M.,University Paris - Sud | Buendia M.A.,French Institute of Health and Medical Research
International Journal of Biochemistry and Cell Biology | Year: 2011

The Wnt/β-catenin pathway plays a key role in liver development, regeneration and tumorigenesis. Among human cancers tightly linked to abnormal Wnt/β-catenin signaling, hepatoblastoma (HB) presents with the highest rate (50-90%) ofβ-catenin mutations. HB is the most common malignant tumor of the liver in childhood. This embryonic tumor differs from hepatocellular carcinoma by the absence of viral etiology and underlying liver disease, and by distinctive morphological patterns evoking hepatoblasts, the bipotent precursors of hepatocytes and cholangiocytes. Recent studies of the molecular pathogenesis of hepatoblastoma have led to identify two major tumor subclasses resembling early and late phases of prenatal liver development and presenting distinctive chromosomal alterations. It has been shown that the molecular signature of Wnt/β-catenin signaling in hepatoblastoma is mainly imposed by liver context, but differs according to developmental stage. Finally, the differentiation stage of tumor cells strongly influences their invasive and metastatic properties, therefore affecting clinical behavior. © 2009 Elsevier Ltd. All rights reserved.


Martinez-Frias M.L.,Institute of Health Carlos III ISCIII | Martinez-Frias M.L.,CIBER ISCIII | Martinez-Frias M.L.,Complutense University of Madrid
Journal of Medical Genetics | Year: 2010

Having identified teratogenic factors, primary prevention of congenital defects is possible by the implementation of specific measures in pregnant women or those planning pregnancy. Our current understanding of the epigenetic processes acting during reproductive events raises new possibilities to prevent both heritable and sporadic congenital anomalies. Cell differentiation during embryonice - fetal development involves different epigenetic processes which, if altered, may affect either somatic or germ cells. Epigenetic alterations can occur in somatic cells at different stages of life, from fecundation to adulthood, and when germ cells are affected, such changes can even be passed on to future generations. This review summarises the main epigenetic processes that influence gene expression and cell specification at different stages of development. The experimental and epidemiological evidence of environmental agents that cause epigenetic alterations is evaluated, as well as their effects in males and females. As a result, new avenues for primary prevention are proposed.


Roa J.,University of Cordoba, Spain | Roa J.,University of Otago | Tena-Sempere M.,University of Cordoba, Spain | Tena-Sempere M.,CIBER ISCIII | Tena-Sempere M.,Instituto Maimonides Of Investigaciones Biomedicas Imibic
Trends in Endocrinology and Metabolism | Year: 2010

The onset of puberty is gated by body energy reserves and nutritional cues. The adipose hormone leptin is an essential signal for the metabolic control of puberty, through mechanisms that are yet to be fully characterized. Mammalian target of rapamycin (mTOR), an energetic cell sensor, operates at specific hypothalamic nuclei as a transducer for leptin effects on feeding and energy homeostasis. This review summarizes recent experimental evidence supporting a role for central mTOR signaling in puberty onset. These findings are discussed in the context of topical developments in the field, such as recognition of the roles of the cAMP responsive element-binding protein regulated transcription coactivator-1 (Crtc1) and kisspeptins in the metabolic control of reproduction, thus highlighting novel mechanisms responsible for coupling puberty and energy homeostasis. © Elsevier Ltd.


Ros E.,CIBER ISCIII
Nutrients | Year: 2010

Nuts (tree nuts and peanuts) are nutrient dense foods with complex matrices rich in unsaturated fatty and other bioactive compounds: high-quality vegetable protein, fiber, minerals, tocopherols, phytosterols, and phenolic compounds. By virtue of their unique composition, nuts are likely to beneficially impact health outcomes. Epidemiologic studies have associated nut consumption with a reduced incidence of coronary heart disease and gallstones in both genders and diabetes in women. Limited evidence also suggests beneficial effects on hypertension, cancer, and inflammation. Interventional studies consistently show that nut intake has a cholesterol-lowering effect, even in the context of healthy diets, and there is emerging evidence of beneficial effects on oxidative stress, inflammation, and vascular reactivity. Blood pressure, visceral adiposity and the metabolic syndrome also appear to be positively influenced by nut consumption. Thus it is clear that nuts have a beneficial impact on many cardiovascular risk factors. Contrary to expectations, epidemiologic studies and clinical trials suggest that regular nut consumption is unlikely to contribute to obesity and may even help in weight loss. Safety concerns are limited to the infrequent occurrence of nut allergy in children. In conclusion, nuts are nutrient rich foods with wide-ranging cardiovascular and metabolic benefits, which can be readily incorporated into healthy diets. © 2010 by the authors.


Klaus A.,University of Regensburg | Tiddy G.J.T.,University of Manchester | Solans C.,CIBER ISCIII | Harrar A.,University of Regensburg | And 2 more authors.
Langmuir | Year: 2012

For many decades, the solubilization of long-chain triglycerides in water has been a challenge. A new class of amphiphiles has been created to overcome this solubilization problem. The so-called "extended" surfactants contain a hydrophilic-lipophilic linker to reduce the contrast between the surfactant-water and surfactant-oil interfaces. In the present contribution, the effects of different anions and cations on the phase behavior of a mixture containing an extended surfactant (X-AES), a hydrotrope (sodium xylene sulfonate, SXS), water, and rapeseed oil were determined as a function of temperature. Nanoemulsions were obtained and characterized by conductivity measurements, light scattering, and optical microscopy. All salting-out salts show a transition from a clear region (O/W nanoemulsion), to a lamellar liquid crystalline phase region, a clear phase (bicontinuous L 3), and again to a lamellar liquid crystalline phase region with increasing temperature. For the phase diagrams with NaSCN and Na 2SO 4, only one clear region (O/W nanoemulsion) was observed, which turns into a lamellar phase region at elevated temperatures. Furthermore, the stability of the nanoemulsions was investigated by time-dependent measurements: the visual observation of phase separation, droplet size by dynamic light scattering (DLS), and optical microscopy. The mechanism of the different phase transitions is also discussed. © 2012 American Chemical Society.


Saldana L.,Hospital Universitario La Paz | Vilaboa N.,Hospital Universitario La Paz | Vilaboa N.,CIBER ISCIII
Acta Biomaterialia | Year: 2010

Titanium (Ti) and its alloys are widely used in biomedical devices as bone tissue replacements due to their advantageous bulk mechanical properties and biocompatibility. It is known that particles released from Ti-based implants impair essential functions of osteoblasts, which for survival require attachment to specific extracellular matrix proteins at the bone surface. This study investigates whether Ti particles of micrometric sizes affect the osteoblast attachment machinery. Exposure of human osteoblastic Saos-2 cells to Ti particles impaired their adhesion strength, migration and proliferation. Attenuation of these functions was associated with reduced cell spreading, cell membrane disruptions and loss of cell shape. Cell exposure to Ti particles led to changes in cytoskeletal structures, including reduced ventral stress fibers combined with a disorderly arrangement of β-tubulin and acetylated α-tubulin fibers. Cytoskeleton disassembly was associated with a reduction in overall cell adhesion area, characterized by fewer centrally localized focal adhesions and shorter focal contacts at the periphery. Paxillin adaptor protein redistributed to peripheral corner regions, colocalizing with poorly organized actin fibers at attachment sites. Total focal adhesion kinase (FAK) protein amounts, as well as its degree of phosphorylation on the active form p-FAK (Tyr-397), decreased, which was accompanied by a lesser extent of co-localization with paxillin in focal contacts. On the other hand, p-FAK (Tyr-407), an inhibitory form of FAK, accumulated in the focal contacts of Ti-treated cells. Pyk2 phosphorylated on Tyr-402 colocalized with paxillin in focal contacts of untreated cells, while it was barely detected upon exposure to particles. In summary, changes in the phosphorylation states of both FAK and Pyk2 tyrosine kinases at focal contacts underlie impaired bone-forming cell attachment after exposure to Ti particles of micrometric sizes. © 2009 Acta Materialia Inc.


Essau C.A.,Roehampton University | Olaya B.,CIBER ISCIII | Pasha G.,Islamic Azad University at Ahvaz | O'Callaghan J.,Roehampton University | Bray D.,Roehampton University
Journal of Anxiety Disorders | Year: 2012

The present study examined the psychometric properties of the Iranian translation of the Spence Children's Anxiety Scale (SCAS) in a large community sample of adolescents (N= 1984), aged 12-17 years, in Ahvaz City, Iran. In addition to the SCAS, all participants completed the Strengths and Difficulties Questionnaire (SDQ), and the Centre for Epidemiological Studies Depression Scale for Children (CES-DC). The internal consistency (Cronbach Alpha =. 92) and the validity of the Iranian translation of the SCAS was excellent. The SCAS total scores correlated significantly with the CES-DC, as well as with the emotional, conduct problems, hyperactivity-inattention, and peer problems subscales of the SDQ. However, Steiger's Z test demonstrated that correlations between the SCAS scores and the SDQ conduct problems or hyperactivity-inattention subscales were significantly lower than the correlations between the SCAS scores and the SDQ emotional symptoms subscale. Confirmatory factor analyses revealed the same 6-factor structure as the original SCAS. The SCAS proved to be a reliable and valid measure of anxiety symptoms among adolescents in Iran. © 2012 Elsevier Ltd.


Liviac D.,Autonomous University of Barcelona | Creus A.,Autonomous University of Barcelona | Marcos R.,Autonomous University of Barcelona | Marcos R.,CIBER ISCIII
Water Research | Year: 2010

Drinking water contains disinfection byproducts, generated by the interaction of chlorine (or other disinfecting chemicals) with organic matter, anthropogenic contaminants, and bromide/iodide naturally present in most source waters. One class of these chemicals is the halogenated acetaldehydes (HAs), identified in high quantities when ozone is used as primary or secondary disinfectant. In this study, an analysis of the genotoxic potential of two HAs, namely tribromoacetaldehyde (TBA) and chloral hydrate (CH) has been conducted in human cells (TK6 cultured cells and peripheral blood lymphocytes). The comet assay was used to 1) measure the induction of single and double-strand DNA breaks, 2) evaluate the capacity of inducing oxidative DNA damage, and 3) determine the DNA repair kinetics of the induced primary genetic damage. In addition, chromosome damage, as a measure of fixed damage, was evaluated by means of the micronucleus test. The results of the comet assay show that both compounds are clearly genotoxic, inducing high levels of DNA breaks, TBA being more effective than CH. According to the comet results, both HAs produce high levels of oxidized bases, and the induced DNA damage is rapidly repaired over time. Contrarily, the results obtained in the micronucleus test, which measures the capacity of genotoxic agents to induce clastogenic and aneugenic effects, are negative for the two HAs tested, either using TK6 cells or human peripheral blood lymphocytes. This would indicate that the primary damage induced by the two HAs is not fixed as chromosome damage, possibly due to an efficient repair or the death of damaged cells, which is an important point in terms of risk assessment of DBPs exposure. © 2010.


Magan P.,Hospital Universitario 12 Of Octubre | Magan P.,CIBER ISCIII | Otero A.,Red de Envejecimiento y Fragilidad RETICEF | Otero A.,Autonomous University of Madrid | And 2 more authors.
Medical Care | Year: 2011

Background: Hospitalizations for ambulatory care sensitive conditions (ACSH) have been proposed as an indirect indicator of the effectiveness and quality of care provided by primary health care. OBJECTIVE:: To investigate the association of ACSH rates with population socioeconomic factors and with characteristics of primary health care. Research design: Cross-sectional, ecologic study. Using hospital discharge data, ACSH were selected from the list of conditions validated for Spain. SETTING:: All 34 health districts in the Region of Madrid, Spain. Subjects: Individuals aged 65 years or older residing in the region of Madrid between 2001 and 2003, inclusive. Measures: Age- and gender-adjusted ACSH rates in each health district. Results: The adjusted ACSH rate per 1000 population was 35.37 in men and 20.45 in women. In the Poisson regression analysis, an inverse relation was seen between ACSH rates and the socioeconomic variables. Physician workload was the only health care variable with a statistically significant relation (rate ratio of 1.066 [95% CI; 1.041-1.091]). These results were similar in the analyses disaggregated by gender. In the multivariate analyses that included health care variables, none of the health care variables were statistically significant. Conclusions: ACSH may be more closely related with socioeconomic variables than with characteristics of primary care activity. Therefore, other factors outside the health system must be considered to improve health outcomes in the population. © 2010 by Lippincott Williams & Wilkins.


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.


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.


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.


Martinez-Martin P.,CIBER ISCIII | Kurtis M.M.,Ruber International Hospital
Parkinsonism and Related Disorders | Year: 2010

Dopamine receptor agonists have demonstrated effectiveness in managing Parkinson's disease both as monotherapy and as adjunctive treatment to l-dopa. Dopamine receptor agonist therapy may reduce the risk of developing motor complications; however, it can also produce undesirable side-effects. Patient health-related quality of life (HRQoL) is a comprehensive outcome that may be useful in evaluating these complex effects. This is a systematic review of the reported clinical trials that have investigated the effect of dopamine receptor agonists on HRQoL. A literature search was carried out using Medline, cut-off date 30 June 2009. Identified manuscripts were classified according to level of evidence; Level I studies were rated for quality; relative change (RC) and effect size (ES) were calculated when possible; and dopamine receptor agonist efficacy in improving HRQoL was assigned accordingly. Overall, 18 manuscripts reporting clinical trial outcomes on seven dopamine receptor agonists were reviewed. Six studies were randomized and double-blinded; five were controlled with placebo; and 10 were comparative. Sample sizes ranged from 4 to 506 patients (mean, 181.1 ± 143.7), and follow-up ranged from 1.5 to 48 months (11.8 ± 14.2). Level I was reached by six of eight pramipexole studies (mean quality, 79%), one of four cabergoline studies (quality, 83.3%), and one study with the following: ropinirole prolonged release (quality, 88.9%), pergolide (quality, 86.0%), and rotigotine (quality, 77.8%). Quantifying HRQoL improvement by RC and ES was only possible for five of the 18 studies. The reviewed trials were highly variable in design, objectives and presentation of results. Therefore, specific evaluation of intervention impact in each of the tested clinical settings was required. © 2009 Elsevier Ltd. All rights reserved.


Montaner D.,Research Center Principe Felipe | Dopazo J.,Research Center Principe Felipe | Dopazo J.,CIBER ISCIII
PLoS ONE | Year: 2010

Understanding the functional implications of changes in gene expression, mutations, etc., is the aim of most genomic experiments. To achieve this, several functional profiling methods have been proposed. Such methods study the behaviour of different gene modules (e.g. gene ontology terms) in response to one particular variable (e.g. differential gene expression). In spite to the wealth of information provided by functional profiling methods, a common limitation to all of them is their inherent unidimensional nature. In order to overcome this restriction we present a multidimensional logistic model that allows studying the relationship of gene modules with different genome-scale measurements (e.g. differential expression, genotyping association, methylation, copy number alterations, heterozygosity, etc.) simultaneously. Moreover, the relationship of such functional modules with the interactions among the variables can also be studied, which produces novel results impossible to be derived from the conventional unidimensional functional profiling methods. We report sound results of gene sets associations that remained undetected by the conventional one-dimensional gene set analysis in several examples. Our findings demonstrate the potential of the proposed approach for the discovery of new cell functionalities with complex dependences on more than one variable. © 2010 Montaner, Dopazo.


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.


Miro J.M.,University of Barcelona | Stock P.,University of California at San Francisco | Teicher E.,AP HP Hopital Kremlin Bicetre | Duclos-Vallee J.-C.,University Paris - Sud | And 2 more authors.
Journal of Hepatology | Year: 2015

Summary Liver transplantation is increasingly performed in selected HIV-infected patients in most developed countries, with excellent results reported in patients with liver diseases unrelated to HCV. In contrast, survival in HCV/HIV-coinfected liver recipients is poorer than in HCV-monoinfected patients, due to more aggressive recurrence of HCV and consequent graft loss and death. Results from American, French, and Spanish cohort studies showed a 5-year survival rate of only 50-55%. Therefore, it is debated whether liver transplantation should be offered to HCV/HIV-coinfected patients. Studies have shown that the variables more consistently associated with poor outcome are: (1) the use of old or HCV-positive donors, (2) dual liver-kidney transplantation, (3) recipients with very low body mass index and (4) less site experience. However, the most effective factor influencing transplantation outcome is the successful treatment of HCV recurrence with anti-HCV. Survival is 80% in patients whose HCV infection resolves. Unfortunately, the rates of sustained virological response with pegylated-interferon plus ribavirin in coinfected recipients are low, particularly for genotype 1 (only 10%). Here we present a non-systematic review of the literature based on our own experience in different liver transplant scenarios. This review covers selection criteria in HIV-infected patients, pre- and post-LT management, donor selection, anti-HCV treatment, drug interactions with antiretrovirals and anti-HCV direct antiviral agents, hepatocellular carcinoma, and liver retransplantation. Recommendations are rated. Finally, we explain how the introduction of new effective and more tolerable direct antiviral agents may improve significantly the outcome of HCV/HIV-coinfected liver recipients. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Gomez de Barreda E.,Autonomous University of Madrid | Dawson H.N.,Duke University | Vitek M.P.,Duke University | Avila J.,Autonomous University of Madrid | Avila J.,CIBER ISCIII
FEBS Letters | Year: 2010

Although tau is mainly located in the cell cytoplasm, mostly bound to tubulin, it may also be found in the nucleus of neurons. Hence, we tested whether tau might play a role in regulating the expression of certain genes by comparing gene expression in mice containing or lacking the tau protein. Our results identified a significant difference in the expression of the smarce1 gene, which codes for the BAF-57 protein, a protein involved in the repression of neuron specific genes. These data suggest a role for tau in neuron maturation. © 2010 Federation of European Biochemical Societies.


Ortiz-Barreda G.,University of Alicante | Vives-Cases C.,University of Alicante | Vives-Cases C.,CIBER ISCIII
Gaceta Sanitaria | Year: 2012

Objectives: To identify and describe the responsibilities attributed to health administrations in preventing and addressing violence against women in the international legislation on this issue. Methods: We carried out a content analysis of the laws on violence against women collected in the following legal databases: the Annual Review of Law of Harvard University, the United Nations' Secretary-General's database on Violence against Women, the International Digest of Health Legislation and Stop Violence against Women. All legal documents explicitly mentioning the participation of the health sector in interventions against violence against women were identified. Subsequently, the interventions selected were classified into primary, secondary and tertiary prevention, as defined by the World Health Organization in its first World Report on Violence and Health (2002). Results: Of the 115 countries analyzed, 55 have laws on violence against women that include the participation of the health sector in interventions concerning this phenomenon. In most of these countries, this participation focusses on reporting detected cases and on providing healthcare and assistance to women referred from police services. We identified 24 laws that explicitly mention the interventions developed by the health sector, mainly consisting of tertiary prevention. The laws of Mexico, Colombia, Argentina, El Salvador, Spain and the Philippines include interventions involving the three levels of prevention. Conclusions: One-fourth of the laws concerning violence against women studied incorporate specific interventions in the health sector, suggesting that a comprehensive approach to the problem is still required. Greater utilization of the potential of this sector is required in interventions to prevent violence against women. © 2011 SESPAS.


Penas-Cazorla R.,Institute Dinvestigacions Biomediques Of Barcelona Iibb Csic | Vilaro M.T.,Institute Dinvestigacions Biomediques Of Barcelona Iibb Csic | Vilaro M.T.,CIBER ISCIII
Brain Structure and Function | Year: 2015

Activation of serotonin 5-HT4 receptors has pro-cognitive effects on memory performance. The proposed underlying neurochemical mechanism is the enhancement of acetylcholine release in frontal cortex and hippocampus elicited by 5-HT4 agonists. Although 5-HT4 receptors are present in brain areas related to cognition, e.g., hippocampus and cortex, the cellular localization of the receptors that might modulate acetylcholine release is unknown at present. We have analyzed, using dual label in situ hybridization, the cellular localization of 5-HT4 receptor mRNA in identified neuronal populations of the rat basal forebrain, which is the source of the cholinergic innervation to cortex and hippocampus. 5-HT4 receptor mRNA was visualized with isotopically labeled oligonucleotide probes, whereas cholinergic, glutamatergic, GABAergic and parvalbumin-synthesizing neurons were identified with digoxigenin-labeled oligonucleotide probes. 5-HT4 receptor mRNA was not detected in the basal forebrain cholinergic cell population. In contrast, basal forebrain GABAergic, parvalbumin synthesizing, and glutamatergic cells contained 5-HT4 receptor mRNA. Hippocampal and cortical glutamatergic neurons also express this receptor. These results indicate that 5-HT4 receptors are not synthesized by cholinergic cells, and thus would be absent from cholinergic terminals. In contrast, several non-cholinergic cell populations within the basal forebrain and its target hippocampal and cortical areas express these receptors and are thus likely to mediate the enhancement of acetylcholine release elicited by 5-HT4 agonists. © 2014, Springer-Verlag Berlin Heidelberg.


Beer R.L.,Johns Hopkins University | Parsons M.J.,Johns Hopkins University | Rovira M.,CIBER ISCIII
Developmental Biology | Year: 2016

The process of regeneration serves to heal injury by replacing missing cells. Understanding regeneration can help us replace cell populations lost during disease, such as the insulin-producing β cells lost in diabetic patients. Centroacinar cells (CACs) are a specialized ductal pancreatic cell type that act as progenitors to replace β cells in the zebrafish. However, whether CACs contribute to β-cell regeneration in adult mammals remains controversial. Here we review the current understanding of the role of CACs as endocrine progenitors during regeneration in zebrafish and mammals. © 2016 Elsevier Inc.


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.


Dominguez-Almendros S.,Fundacion para la Investigacion Biosanitaria de Andalucia Oriental FIBAO | Benitez-Parejo N.,CIBER ISCIII | Gonzalez-Ramirez A.R.,Hospital Universitario San Cecilio
Allergologia et Immunopathologia | Year: 2011

In the health sciences it is quite common to carry out studies designed to determine the influence of one or more variables upon a given response variable. When this response variable is numerical, simple or multiple regression techniques are used, depending on the case. If the response variable is a qualitative variable (dichotomic or polychotomic), as for example the presence or absence of a disease, linear regression methodology is not applicable, and simple or multinomial logistic regression is used, as applicable. © 2011 SEICAP.


de Pedro M.,Nuevo Belen University Hospital | Baeza S.,Hospital Nuestra Senora de Sonsoles | Escudero M.-T.,Santander University | Dierssen-Sotos T.,University of Cantabria | And 3 more authors.
Breast Cancer Research and Treatment | Year: 2015

Evidence on non-steroidal anti-inflammatory drugs (NSAID) use and breast cancer risk shows a slightly protective effect of these drugs, but previous studies lack randomized clinical trial results and present high heterogeneity in exposure measurement. This systematic review and meta-analysis widens the knowledge about NSAID use and breast cancer risk, updating the information from the last meta-analysis, focusing on evidence on specific effects of COX-2 inhibitors and differential expression patterns of hormonal receptors. A PubMed-database search was conducted to include all entries published with the keywords “BREAST CANCER NSAID ANTI-INFLAMMATORY” until 10/24/2013 providing original results from cohort studies, case–control studies, or randomized clinical trials with at least one reported relative risk (RR) or odds ratio (OR) on the association between any NSAID use and incidence of invasive breast cancer. This resulted in 49 publications, from which the information was retrieved about type of study, exposure characteristics, breast cancer characteristics, and breast cancer-NSAID association. Meta-analyses were performed separately for case–control and cohort studies and for different hormone-receptor status. NSAID use reduced invasive breast cancer risk by about 20 %. A similar effect was found for aspirin, acetaminophen, COX-2 inhibitors and, to a lesser extent, ibuprofen. The effect of aspirin was similar in preventing hormone-receptor-positive breast cancer. This meta-analysis suggests a slightly protective effect of NSAIDs-especially aspirin and COX-2 inhibitors- against breast cancer, which seems to be restricted to ER/PR+tumors. © 2015, Springer Science+Business Media New York.


D'Urzo A.,University of Toronto | Donohue J.F.,University of North Carolina at Chapel Hill | Kardos P.,Red Cross | Miravitlles M.,CIBER ISCIII | Price D.,University of Aberdeen
Expert Opinion on Pharmacotherapy | Year: 2015

Introduction: Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β2-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary disease (COPD), outside their labeled indications and recommended treatment strategies and guidelines, despite having the potential to cause significant side effects.Areas covered: Although the existence of asthma in patients with asthma-COPD overlap syndrome (ACOS) clearly supports the use of anti-inflammatory treatment (typically an ICS/LABA combination, as ICS monotherapy is usually not indicated for COPD), the current level of ICS/LABA use is not consistent with the prevalence of ACOS in the COPD population. Data have recently become available showing the comparative efficacy of fixed bronchodilator combinations (long-acting muscarinic antagonist [LAMA]/LABA with ICS/LABA combinations). Additionally, new information has emerged on ICS withdrawal without increased risk of exacerbations, under cover of effective bronchodilation.Expert opinion: For patients with COPD who do not have ACOS, a LAMA/LABA combination may be an appropriate starting therapy, apart from those with mild disease who can be managed with a single long-acting bronchodilator. Patients who remain symptomatic or present with exacerbations despite effectively delivered LAMA/LABA treatment may require additional drug therapy, such as ICS or phosphodiesterase-4 inhibitors. When prescribing an ICS/LABA, the risk:benefit ratio should be considered in individual patients. © 2015 Informa UK, Ltd.


Subirana I.,University of Barcelona | Sanz H.,University of Barcelona | Vila J.,CIBER ISCIII
Journal of Statistical Software | Year: 2014

The R package compareGroups provides functions meant to facilitate the construction of bivariate tables (descriptives of several variables for comparison between groups) and generates reports in several formats (LATEX, HTML or plain text CSV). Moreover, bivariate tables can be viewed directly on the R console in a nice format. A graphical user interface (GUI) has been implemented to build the bivariate tables more easily for those users who are not familiar with the R software. Some new functions and methods have been incorporated in the newest version of the compareGroups package (version 1.x) to deal with time-to-event variables, stratifying tables, merging several tables, and revising the statistical methods used. The GUI interface also has been improved, making it much easier and more intuitive to set the inputs for building the bivariate tables. The first version (version 0.x) and this version were presented at the 2010 useR! conference (Sanz, Subirana, and Vila 2010) and the 2011 useR! conference (Sanz, Subirana, and Vila 2011), respectively.


Martinez-Garcia M.A.,Pneumology Unit | Martinez-Garcia M.A.,University of Valencia | Martinez-Garcia M.A.,CIBER ISCIII | Soler-Cataluna J.J.,Pneumology Unit | And 3 more authors.
Chest | Year: 2012

Background: The aim of this study is to evaluate the efficacy and safety of medium-dose formoterolbudesonide combined inhaled treatment in a single inhaler compared with high-dose budesonide treatment in patients with non-cystic fibrosis (non-CF) bronchiectasis. Methods: This is a 12-month randomized, double-blind, parallel-groups clinical trial, to run in 40 patients with non-CF bronchiectasis diagnosed by high-resolution CT scan of the chest, receiving formoterol-budesonide combined treatment (18/640 μg daily) or budesonide treatment (1,600 μg daily). Variables concerning clinical condition, health-related quality of life (HRQL), lung function, β 2- adrenergic agonist use, potentially pathogenic microorganism (PPM) isolates, and medication side effects were analyzed by intention-to-treat analysis. Results: The study group receiving a formoterol-budesonide combined treatment showed a significant improvement, both clinically and statistically, of symptoms(dyspnea, number of coughs, and rescue β 2-adrenergic agonist-free days). Furthermore, we observed an HRQL improvement, with no changes in functional parameters or in PPM isolates, together with an important reduction in overall side effects, especially for those related to inhaled steroids, compared with the high-dose budesonide treatment group. Conclusions: Inhaled medium-dose formoterol-budesonide combined treatment in a single inhaler is more effective and safe compared with high-dose budesonide treatment in patients with non-CF bronchiectasis. Trial registry: ClinicalTrials.gov; No.: NCT00728715; URL: www.clinicaltrials.gov. ©2012 American College of Chest Physicians.


Gane E.J.,New Zealand Liver Transplant Unit | 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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


Ortiz-Barreda G.,University of Alicante | Vives-Cases C.,CIBER ISCIII
Revista Panamericana de Salud Publica/Pan American Journal of Public Health | Year: 2013

This study aimed to determine if legislation on violence against women (VAW) worldwide contains key components recommended by the Pan American Health Organization (PAHO) and the United Nations (UN) to help strengthen VAW prevention and provide better integrated victim protection, support, and care. A systematic search for VAW legislation using international legal databases and other electronic sources plus data from previous research identified 124 countries/territories with some type of VAW legislation. Full legal texts were found for legislation from 104 countries/territories. Those available in English, Portuguese, and Spanish were downloaded and compiled and the selection criteria applied (use of any of the common terms related to VAW, including intimate partner violence (IPV), and reference to at least two of six sectors (education, health, judicial system, mass media, police, and social services) with regard to VAW interventions (protection, support, and care). A final sample from 80 countries/territories was selected and analyzed for the presence of key components recommended by PAHO and the UN (reference to the term "violence against women" in the title; definitions of different types of VAW; identification of women as beneficiaries; and promotion of (reference to) the participation of multiple sectors in VAW interventions). Few countries/territories specifically identified women as the beneficiaries of their VAW legislation, including those that labeled their legislation "domestic violence" law (n = 51), of which only two explicitly mentioned women as complainants/survivors. Only 28 countries/territories defined the main forms of VAW (economic, physical, psychological, and sexual) in their VAW legislation. Most highlighted the role of the judicial system, followed by that of social services and the police. Only 28 mentioned the health sector. Despite considerable efforts worldwide to strengthen VAW legislation, most VAW laws do not incorporate the key recommended components. Significant limitations were found in the legislative content, its application, and the extent to which it provided women with integrated protection, support, and care. In developing new VAW legislation, policymakers should consider the vital role of health services.


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.


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.


Chaudhuri K.R.,Kings 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.


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.


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.


Gatta G.,Evaluative Epidemiology Unit | Botta L.,Evaluative Epidemiology Unit | Rossi S.,Centro Nazionale Of Epidemiologia | 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.


Garcia-Esparcia P.,University of Barcelona | Llorens F.,University of Barcelona | Carmona M.,University of Barcelona | Ferrer I.,University of Barcelona | Ferrer I.,CIBER ISCIII
Brain Pathology | Year: 2014

Neuroinflammation is common in neurodegenerative diseases including Parkinson disease (PD). Expression of 25 mRNAs was assessed with TaqMan-PCR including members of the complement system, colony stimulating factors, Toll family, cytokines IL-8, IL-6, IL-6ST, IL-1B, TNF-α family, IL-10, TGFβ family, cathepsins and integrin family, in the substantia nigra pars compacta, putamen, frontal cortex area 8 and angular gyrus area 39, in a total of 43 controls and 56 cases with PD-related pathology covering stages 1-6 of Braak. Up-regulation of IL-6ST was the only change in the substantia nigra at stages 1-2. Down-regulation of the majority of members examined occurred in the substantia nigra from stage 4 onwards. However, region-dependent down- and up-regulation of selected mRNAs occurred in the putamen and frontal cortex, whereas only mRNA up-regulated mRNAs were identified in the angular cortex from stage 3 onwards in PD cases. Protein studies in frontal cortex revealed increased IL6 expression and reduced IL-10 with ELISA, and increased IL-6 with western blotting in PD. Immunohistochemistry revealed localization of IL-5, IL-6 and IL-17 receptors in glial cells, mainly microglia; IL-5, IL-10 and M-CSF in neurons; TNF-α in neurons and microglia; and active NF-κB in the nucleus of subpopulations of neurons and glial cells in PD. Distinct inflammatory responses, involving pro- and anti-inflammatory cytokines, and variegated mediators of the immune response occur in different brain regions at the same time in particular individuals. Available information shows that altered α-synuclein solubility and aggregation, Lewy body formation, oxidative damage and neuroinflammation converge in the pathogenesis of PD. © 2014 International Society of Neuropathology.


Lopez-Campos J.L.,University of Seville | Lopez-Campos J.L.,CIBER ISCIII | 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.


Molina-Infante J.,Hospital San Pedro de 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.


Girn M.,University Miguel Hernandez | 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.


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.


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.


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.


Miravitlles M.,CIBER ISCIII | Moragas A.,Rovira i Virgili University | Hernandez S.,Rovira i Virgili University | Bayona C.,Primary Care Center Valls | Llor C.,Rovira i Virgili University
Chest | Year: 2013

Background: Anthonisen criteria are widely used to guide the use of antibiotics in exacerbations of COPD. We evaluated the best predictors of outcomes in exacerbations of mild to moderate COPD not treated with antibiotics. Methods: We used data from 152 patients of the placebo arm of a randomized trial of amoxicillin/clavulanate for exacerbations of mild to moderate COPD. Clinical response in relation to Anthonisen criteria and point-of-care serum C-reactive protein (CRP) tests (cutoff, 40 mg/L) was assessed with multivariate logistic regression analysis. Results: Clinical failure without antibiotics was 19.9% compared with 9.5% with amoxicillin/clavulanate (P =.022). The only factors significantly associated with an increased risk of failure without antibiotics were the increase in sputum purulence (OR, 6.1; 95% CI, 1.5-25.0; P =.005) and a CRP concentration ≥40 mg/L (OR, 13.4; 95% CI, 4.6-38.8; P<.001). When both factors were present, the probability of failure without antibiotics was 63.7%. The Anthonisen criteria showed an area under the curve of 0.708 (95% CI, 0.616-0.801) for predicting clinical outcome. With the addition of CRP level, the area under the curve rose significantly to 0.842 (95% CI, 0.76-0.924; P<.001). Conclusions: Among the Anthonisen criteria, only an increase in sputum purulence is a significant predictor of failure without antibiotics. The use of a point-of-care CRP test significantly increases the predictive accuracy of failure. Both of these easy-to-obtain factors may help clinicians to identify patients with exacerbated mild to moderate COPD who can be safely treated without antibiotics in an ambulatory setting. © 2013 American College of Chest Physicians.


Herrero M.A.,University of Castilla - La Mancha | Herrero M.A.,University of Trieste | Guerra J.,University of Castilla - La Mancha | Guerra J.,Campus Universitario | And 5 more authors.
ACS Nano | Year: 2010

In this paper, we report the functionalization of the surface of multiwalled carbon nanotubes (MWNTs) with Au dendrimer encapsulated nanoparticles (DENs). The results show that, when pristine MWNTs having hydrophobic surfaces are exposed to DENs, the dendrimers aggregate on the MWNT surface. However, when the MWNTs are oxidized in acid prior to exposure to DENs, well-dispersed submonolayer coverages of Au nanoparticles are observed on the MWNT surface. This suggests that acid-induced debundling of the nanotubes is an essential prerequisite for attachment of nearly monodisperse DENs. Electron microscopy and NMR spectroscopy confirm that the structures of the DENs and dendrimers are retained after immobilization on the surface of acid-functionalized MWNTs. © 2010 American Chemical Society..


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.


Pena E.,Aragon Institute of Engineering Research | Pena E.,CIBER ISCIII
Journal of the Mechanics and Physics of Solids | Year: 2011

Deformation induced softening is an inelastic phenomenon frequently accompanying mechanical response of soft biological tissues. Inelastic phenomena which occur in mechanical testing of biological tissues are very likely to be associated with alterations in the internal structure of these materials. In this study, a novel structural constitutive model is formulated to describe the inelastic effects in soft biological tissues such as Mullins type behavior, damage and permanent set as a result of residual strains after unloading. Anisotropic softening is considered by evolution of internal variables governing the anisotropic properties of the material. We consider two weight factors wi (softening) and sk (discontinuous damage) as internal variables characterizing the structural state of the material. Numerical simulations of several soft tissues are used to demonstrate the performance of the model in reproducing the inelastic behavior of soft biological tissues. © 2011 Elsevier Ltd.


Bruix J.,BCLC Group | 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.


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.


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..


Bermudez-Silva F.J.,University of Bordeaux Segalen | Bermudez-Silva F.J.,Laboratorio Of Medicina Regenerativa | Bermudez-Silva F.J.,CIBER ISCIII | Cardinal P.,University of Bordeaux Segalen | Cota D.,University of Bordeaux Segalen
Journal of Psychopharmacology | Year: 2012

Animal and human studies carried out so far have established a role for the endocannabinoid system (ECS) in the regulation of energy balance. Here we critically discuss the role of the endocannabinoid signalling in brain structures, such as the hypothalamus and reward-related areas, and its interaction with neurotransmitter and neuropeptide systems involved in the regulation of food intake and body weight. The ECS has been found to interact with peripheral signals, like leptin, insulin, ghrelin and satiety hormones and the resulting effects on both central and peripheral mechanisms affecting energy balance and adiposity will be described. Furthermore, ECS dysregulation has been associated with the development of dyslipidemia, glucose intolerance and obesity; phenomena that are often accompanied by a plethora of neuroendocrine alterations which might play a causal role in determining ECS dysregulation.Despite the withdrawal of the first generation of cannabinoid type 1 receptor (CB1) antagonists from the pharmaceutical market due to the occurrence of psychiatric adverse events, new evidence suggests that peripherally restricted CB1 antagonists might be efficacious for the treatment of obesity and its associated metabolic disorders. Thus, a perspective on new promising strategies to selectively target the ECS in the context of energy balance regulation is given. © British Association for Psychopharmacology 2012.


Adefuye P.O.,Olabisi Onabanjo University | Broutet N.J.,World Health Organization | de Sanjose S.,Institute Catala dOncologia Catalan Institute of Oncology ICO | de Sanjose S.,CIBER ISCIII | Denny L.A.,University of Cape Town
Vaccine | Year: 2013

Cervical cancer is the leading cause of cancer morbidity and mortality in women in sub-Saharan Africa (SSA), accounting for about 50,000 deaths annually. Until recently, cytology was the gold standard for screening and prevention of cervical cancer. This method of screening has not been successful in SSA due to a lack of human, financial and material resources and poor health care infrastructure. It is estimated that less than 5% of at risk women have ever being screened. In the past two decades alternative approaches to cytology for cervical cancer screening have been evaluated in low- and medium-income countries. Visual inspection with acetic acid (VIA) and/or Lugol's iodine (VILI) have been shown to have adequate sensitivity, although low specificity, in a number of cross-sectional research and demonstration projects. Visual inspection methods require minimal resources, are technologically accessible, and are feasible for screening for precancerous lesions. Linking screening with VIA/VILI to treatment with cryotherapy may enable screening and treatment to take place in one visit, but this is likely to result in large numbers of women being subjected to unnecessary treatment. A number of studies have shown that cryotherapy is not associated with significant side effects or complications and is well tolerated. Creating the infrastructure for screening of older women is considered desirable, despite the limitations of visual inspection methods as screening tests. Understanding the role of human papillomavirus (HPV) infection in the etiology of cervical cancer and the discovery of HPV rapid test kits, as well as the development of vaccines against the HPV oncogenic types, have created new opportunities for prevention of cervical cancer. Trials and projects have established (and are still ongoing) the feasibility of using these molecular tests for screening. The ultimate in prevention method is primary prevention, offered by the advent of prophylactic vaccines against the most important oncogenic types, namely HPV16 and 18.This article forms part of a regional report entitled ". Comprehensive Control of HPV Infections and Related Diseases in the Sub-Saharan Africa Region" Vaccine Volume 31, Supplement 5, 2013. Updates of the progress in the field are presented in a separate monograph entitled ". Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012. © 2012 Elsevier Ltd.


Kacmarek R.M.,Harvard University | Kacmarek R.M.,Massachusetts General Hospital | Villar J.,CIBER ISCIII | Villar J.,A+ Network
Minerva Anestesiologica | Year: 2011

Although significant advances have been made in approaches to manage the acute respiratory distress syndrome (ARDS), reported overall mortality for ARDS is still high. Recruitment maneuvers (RM) have been recommended by some as potential adjuncts to lung protective ventilatory approaches in ARDS. In this point of view issues surrounding the use of RM in ARDS are addressed. Specifically, the ability of RM to open the lung, the safety of RM, and their affect on outcome are addressed. Finally, a specific approach to performing RM with the use of a decremental PEEP trial is outlined. (Minerva Anestesiol 2011;77:85-9).


Molina-Infante J.,Hospital San Pedro de Alcantara | Ferrando-Lamana L.,Hospital San Pedro de Alcantara | Ripoll C.,CIBER ISCIII | Hernandez-Alonso M.,Hospital San Pedro de Alcantara | And 6 more authors.
Clinical Gastroenterology and Hepatology | Year: 2011

Background & Aims: Despite consensus recommendations, eosinophilic esophagitis (EoE) is commonly diagnosed upon esophageal eosinophilic infiltration (EEI; based on ≥15 eosinophils per high power field; eo/HPF). We evaluated the prevalence of EEI before and after proton pump inhibitor (PPI) therapy and assessed the accuracy of EEI and pH monitoring analyses. Methods: Biopsies were taken from the upper-middle esophagus of 712 adults with upper gastrointestinal symptoms who were referred for endoscopy due to upper gastrointestinal symptoms. Patients with EEI were treated with rabeprazole (20 mg, twice daily) for 2 months. EoE was defined by persistent symptoms and >15 eo/HPF following PPI therapy. Results: Thirty-five patients (4.9%) had EEI, of whom 55% had a history of allergies, and 70% had food impaction or dysphagia as their primary complaint. Twenty-six EEI patients (75%) achieved clinicopathological remission with PPI therapy; of these, 17 had GERD-like profile (EEI <35 eo/HPF and objective evidence of reflux, based on endoscopy or pH monitoring), and 9 had EoE-like profile (EEI 35-165 eo/HPF, typical EoE symptoms and endoscopic findings). The PPI response was 50% in the EoE-like profile patients. The PPI-response was 50% in EoE-like profile patients. Likewise, PPI-responsive EEI occurred with normal (33%) and pathologic (80%) pH monitoring. Higher histologic cut-off values improved specificity and positive predictive for EoE (35%-35% for >20 eo/HPF; 46%-39% for >24 eo/HPF; 65%-50% for 35 eo/HPF). Conclusions: In adults with EEI, 75% of unselected patients and 50% with an EoE phenotype respond to PPI therapy; pH monitoring is poorly predictive of response. Patients with PPI-responsive EEI >35 eo/HPF are phenotypically undistinguishable from EoE patients. EoE might be overestimated without clinical and pathologic follow-up of patient response to PPI. © 2011 AGA Institute.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


Serrano A.J.,University of the Basque Country | Cobos R.,Health Research Unit of Alava | Orive G.,University of the Basque Country | Orive G.,CIBER ISCIII
Gynecological Endocrinology | Year: 2013

The aim of this meta-analysis was to evaluate the efficacy and safety of two bisphosphonates (alendronate and zoledronate) in the treatment of postmenopausal osteoporosis. The incidence of fractures was considered as primary endpoint. Only randomized trials with a follow-up period of 1 year or more were included in this systematic review and meta-analysis. We excluded studies that included patients with secondary osteoporosis especially in relation to therapy with corticosteroids or other drugs or diseases known to affect bone mineral density. Studies published as subgroup analysis, extension studies, economic evaluations, and comparisons with active control were excluded. The methodological quality of controlled clinical trials that met these inclusion criteria was evaluated. No studies were excluded from analysis due to lack of quality. The risk ratio of hip, vertebral and wrist fractures for alendronate were 0.61 [95% confidence interval (CI) 0.40-0.93], 0.54 (95% CI 0.44-0.66) and 0.65 (95% CI 0.33-1.25), respectively. Zoledronate risk ratio was 0.62 (95% CI 0.46-0.82) and 0.38 (95% CI 0.22-0.67) for hip and vertebral fractures, respectively. © 2013 Informa UK Ltd.


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.


Hosseinpoor A.R.,World Health Organization | Parker L.A.,University Miguel Hernandez | 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.


Laleman W.,University Hospital Gasthuisberg | Simon-Talero M.,Autonomous University of Barcelona | Maleux G.,University Hospital Gasthuisberg | Perez M.,Autonomous University of Barcelona | And 11 more authors.
Hepatology | Year: 2013

Refractory hepatic encephalopathy (HE) remains a major cause of morbidity in cirrhosis patients. Large spontaneous portosystemic shunts (SPSSs) have been previously suggested to sustain HE in these patients. We aimed to retrospectively assess the efficacy and safety of patients treated with embolization of large SPSSs for the treatment of chronic therapy-refractory HE in a European multicentric working group and to identify patients who may benefit from this procedure. Between July 1998 and January 2012, 37 patients (Child A6-C13, MELD [Model of Endstage Liver Disease] 5-28) with refractory HE were diagnosed with single large SPSSs that were considered eligible for embolization. On a short-term basis (i.e., within 100 days after embolization), 22 out of 37 patients (59.4%) were free of HE (P < 0.001 versus before embolization) of which 18 (48.6% of patients overall) remained HE-free over a mean follow-up period of 697 ± 157 days (P < 0.001 versus before embolization). Overall, we noted improved autonomy, decreased number of hospitalizations, and severity of the worst HE episode after embolization in three-quarters of the patients. Logistic regression identified the MELD score as strongest positive predictive factor of HE recurrence with a cutoff of 11 for patient selection. As to safety, we noted one major nonlethal procedure-related complication. There was no significant increase in de novo development or aggravation of preexisting varices, portal hypertensive gastropathy, or ascites. Conclusion: This multicenter European cohort study demonstrated a role for large SPSSs in chronic protracted or recurrent HE and substantiated the effectiveness and safety of embolization of these shunts, provided there is sufficient functional liver reserve. © 2013 American Association for the Study of Liver Diseases.


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.


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.


Palassini M.,University of Barcelona | Ritort F.,University of Barcelona | Ritort F.,CIBER ISCIII
Physical Review Letters | Year: 2011

We derive analytical expressions for the bias of the Jarzynski free-energy estimator from N nonequilibrium work measurements, for a generic work distribution. To achieve this, we map the estimator onto the random energy model in a suitable scaling limit parametrized by (log N)/μ, where μ measures the width of the lower tail of the work distribution, and then compute the finite-N corrections to this limit with different approaches for different regimes of (log N)/μ. We show that these expressions describe accurately the bias for a wide class of work distributions and exploit them to build an improved free-energy estimator from unidirectional work measurements. We apply the method to optical tweezers unfolding and refolding experiments on DNA hairpins of varying loop size and dissipation, displaying both near-Gaussian and non-Gaussian work distributions. © 2011 American Physical Society.


Trichopoulou A.,National and Kapodistrian University of Athens | Martinez-Gonzalez M.A.,Public University of Navarra | Martinez-Gonzalez M.A.,CIBER ISCIII | Tong T.Y.N.,University of Cambridge | And 3 more authors.
BMC Medicine | Year: 2014

The Mediterranean diet has been linked to a number of health benefits, including reduced mortality risk and lower incidence of cardiovascular disease. Definitions of the Mediterranean diet vary across some settings, and scores are increasingly being employed to define Mediterranean diet adherence in epidemiological studies. Some components of the Mediterranean diet overlap with other healthy dietary patterns, whereas other aspects are unique to the Mediterranean diet. In this forum article, we asked clinicians and researchers with an interest in the effect of diet on health to describe what constitutes a Mediterranean diet in different geographical settings, and how we can study the health benefits of this dietary pattern. © 2014 Trichopoulou et al.; licensee BioMed Central Ltd.


Perez-Vizcaino F.,Complutense University of Madrid | Perez-Vizcaino F.,CIBER ISCIII | Duarte J.,Complutense University of Madrid | Santos-Buelga C.,University of Salamanca
Journal of the Science of Food and Agriculture | Year: 2012

Flavonoids have been proposed to exert beneficial effects in the prevention of a large number of diseases, including cancer, cardiovascular disease, and neurodegenerative disorders. Paradoxically, despite the most representative flavonoid-quercetin-exerting biologically demonstrable systemic effects, it is not found in plasma after oral administration and its circulating metabolites show weak activity in vitro. The current available evidence indicates that quercetin is extensively metabolized into methylated and glucurono- and sulfo-conjugated metabolites, which are the plasma circulating forms; and glucurono-, but not sulfo-conjugates, can be hydrolyzed at the vascular level, yielding the parent aglycone which accumulates in tissues. Thus conjugation is a reversible process and, at least regarding the vasodilator and antihypertensive effects, the conjugation-deconjugation cycle appears to be an absolute requirement. Glucuronidated derivatives transport quercetin and its methylated form, and deliver to the tissues the free aglycone, which is the final effector. © 2012 Society of Chemical Industry.


Alemany M.,University of Barcelona | Alemany M.,CIBER ISCIII
Nutrition Research Reviews | Year: 2012

Amino-N is preserved because of the scarcity and nutritional importance of protein. Excretion requires its conversion to ammonia, later incorporated into urea. Under conditions of excess dietary energy, the body cannot easily dispose of the excess amino-N against the evolutively adapted schemes that prevent its wastage; thus ammonia and glutamine formation (and urea excretion) are decreased. High lipid (and energy) availability limits the utilisation of glucose, and high glucose spares the production of ammonium from amino acids, limiting the synthesis of glutamine and its utilisation by the intestine and kidney. The amino acid composition of the diet affects the production of ammonium depending on its composition and the individual amino acid catabolic pathways. Surplus amino acids enhance protein synthesis and growth, and the synthesis of non-protein-N-containing compounds. But these outlets are not enough; consequently, less-conventional mechanisms are activated, such as increased synthesis of NO2 followed by higher nitrite (and nitrate) excretion and changes in the microbiota. There is also a significant production of N2 gas, through unknown mechanisms. Health consequences of amino-N surplus are difficult to fathom because of the sparse data available, but it can be speculated that the effects may be negative, largely because the fundamental N homeostasis is stretched out of normalcy, forcing the N removal through pathways unprepared for that task. The unreliable results of hyperproteic diets, and part of the dysregulation found in the metabolic syndrome may be an unwanted consequence of this N disposal conflict. © 2012 The Author.


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.


Vadasz I.,Justus Liebig University | Hubmayr R.D.,Thoracic Diseases Research Unit | Nin N.,CIBER ISCIII | Sporn P.H.S.,Northwestern University | And 2 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.


Torrens M.,Autonomous University of Barcelona | Fonseca F.,Autonomous University of Barcelona | Castillo C.,Autonomous University of Barcelona | Domingo-Salvany A.,CIBER ISCIII
Bulletin of the World Health Organization | Year: 2013

Problem During the 1980s, Spain had very strict laws limiting access to opioid agonist maintenance treatment (OAMT). Because of this, mortality among people who used illicit opioids and other illicit drugs was high. Spain was also the European country with the highest number of cases of acquired immunodeficiency syndrome transmitted through illicit drug injection. Approach The rapid spread of human immunodeficiency virus (HIV) infection among people using heroin led to a shift from a drug-free approach to the treatment of opioid dependence to one focused on harm reduction. A substantial change in legislation made it possible to meet public health needs and offer OAMT as part of harm reduction programmes in the public health system, including prisons. Local setting Legislative changes were made throughout the country, although at a different pace in different regions. Relevant changes Legal changes facilitated the expansion of OAMT, which has achieved a coverage of 60%. A parallel reduction in the annual incidence of HIV infection has been reported. Reductions in morbidity and mortality and improved health-related quality of life have been described in patients undergoing OAMT. Lessons learnt The treatment of opioid dependence has been more heavily influenced by moral concepts and prejudices that hinder legislation and interfere with the implementation of OAMT than by scientific evidence. To fulfil public health needs, OAMT should be integrated in harm reduction programmes offered primarily in public facilities, including prisons. Longitudinal studies are needed to detect unmet needs and evaluate programme impact and suitability.


Llor C.,Rovira i Virgili University | Moragas A.,Primary Care Center Jaume I | Hernandez S.,Primary Care Center Jaume I | Bayona C.,Primary Care Center Valls | Miravitlles M.,CIBER ISCIII
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Rationale: Antimicrobial therapy remains a controversial issue in nonsevere exacerbations of chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of antibiotic therapy in moderate exacerbations of mild-to-moderate COPD. Methods: This study involved a multicenter, parallel, double-blind, placebo-controlled, randomized clinical trial. Patients aged 40 years or older, smokers, or ex-smokers of 10 pack-years or more with spirometrically confirmed mild-to-moderate COPD (FEV1 > 50% predicted and FEV1/FVC ratio < 0.7) and diagnosed with an exacerbation were enrolled in the study. The patients were randomized to receive amoxicillin/clavulanate 500/125 mg three times a day or placebo three times a day for 8 days. Measurements and Main Results: The primary outcome measure was clinical cure at end of therapy visit (EOT) at Days 9 to 11. A total of 310 subjects fulfilled all the criteria for efficacy analysis. A total of 117 patients with amoxicillin/clavulanate (74.1%) and 91 with placebo (59.9%) were considered cured at EOT (difference, 14.2%; 95% confidence interval, 3.7-24.3). The median time to the next exacerbation was significantly longer in patients receiving antibiotic compared with placebo (233 d [interquartile range, 110-365] compared with 160 d [interquartile range, 66-365]; P < 0.05). The best C-reactive protein serum cut-off for predicting clinical failure with placebo was 40 mg/L, with an area under the curve of 0.732 (95% confidence interval, 0.614-0.851). Conclusions: Treatment of ambulatory exacerbations of mild-to-moderate COPD with amoxicillin/clavulanate is more effective and significantly prolongs the time to the next exacerbation compared with placebo. Clinical trial registered with www.clinical.gov (NCT00495586). Copyright © 2012 by the American Thoracic Society.


Serra T.,Institute for Bioengineering of Catalonia IBEC | Planell J.A.,Institute for Bioengineering of Catalonia IBEC | Planell J.A.,University of Barcelona | Planell J.A.,CIBER ISCIII | Navarro M.,Institute for Bioengineering of Catalonia IBEC
Acta Biomaterialia | Year: 2013

Fabrication of new biodegradable scaffolds that guide and stimulate tissue regeneration is still a major issue in tissue engineering approaches. Scaffolds that possess adequate biodegradability, pore size, interconnectivity, bioactivity and mechanical properties in accordance with the injured tissue are required. This work aimed to develop and characterize three-dimensional (3-D) scaffolds that fulfill the aforementioned requirements. For this, a nozzle-based rapid prototyping system was used to combine polylactic acid and a bioactive CaP glass to fabricate 3-D biodegradable scaffolds with two patterns (orthogonal and displaced double layer). Scanning electron microscopy and micro-computer tomography showed that 3-D scaffolds had completely interconnected porosity, uniform distribution of the glass particles, and a controlled and repetitive architecture. Surface properties were also assessed, showing that the incorporation of glass particles increased both the roughness and the hydrophilicity of the scaffolds. Mechanical tests indicated that compression strength is dependent on the scaffold geometry and the presence of glass. Preliminary cell response was studied with primary mesenchymal stem cells (MSC) and revealed that CaP glass improved cell adhesion. Overall, the results showed the suitability of the technique/materials combination to develop 3-D porous scaffolds and their initial biocompatibility, both being valuable characteristics for tissue engineering applications. © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Hanhan M.E.,Zonguldak Karaelmas University | Martinez-Manez R.,Polytechnic University of Valencia | Martinez-Manez R.,CIBER ISCIII | Ros-Lis J.V.,Polytechnic University of Valencia
Tetrahedron Letters | Year: 2012

The Suzuki coupling of aryl chlorides with boronic acids using a ferrocene-containing Pd(II)-diimine complex as catalyst, in aqueous media, under microwave heating is reported. A small amount of the catalyst (0.1%) was found to be highly effective for coupling unactivated aryl chlorides with boronic acids to form sterically hindered ortho-substituted biaryls. The same catalyst also enabled the coupling of aryl bromides and iodides with various boronic acids in very high yields. The catalyst is air stable and the catalytic reaction can be completed in 15 min. © 2012 Elsevier Ltd. All rights reserved.


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.


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.


Llamedo M.,Aragon Institute of Engineering Research | Martinez J.P.,Aragon Institute of Engineering Research | Martinez J.P.,CIBER ISCIII
IEEE Transactions on Biomedical Engineering | Year: 2012

In this paper, we present a patient-adaptable algorithm for ECG heartbeat classification, based on a previously developed automatic classifier and a clustering algorithm. Both classifier and clustering algorithms include features from the RR interval series and morphology descriptors calculated from the wavelet transform. Integrating the decisions of both classifiers, the presented algorithm can work either automatically or with several degrees of assistance. The algorithm was comprehensively evaluated in several ECG databases for comparison purposes. Even in the fully automatic mode, the algorithm slightly improved the performance figures of the original automatic classifier; just with less than two manually annotated heartbeats (MAHB) per recording, the algorithm obtained a mean improvement for all databases of 6.9% in accuracy A, of 6.5% in global sensitivity S and of 8.9% in global positive predictive value P +. An assistance of just 12 MAHB per recording resulted in a mean improvement of 13.1\% in A, of 13.9\% in S, and of 36.1\% in P+. For the assisted mode, the algorithm outperformed other state-of-the-art classifiers with less expert annotation effort. The results presented in this paper represent an improvement in the field of automatic and patient-adaptable heartbeats classification, concluding that the performance of an automatic classifier can be improved with an efficient handling of the expert assistance. © 2012 IEEE.


Franco R.,University of Barcelona | Franco R.,CIBER ISCIII | Fernandez-Suarez D.,Karolinska Institutet
Progress in Neurobiology | Year: 2015

Macrophages are important players in the fight against viral, bacterial, fungal and parasitic infections. From a resting state they may undertake two activation pathways, the classical known as M1, or the alternative known as M2. M1 markers are mostly mediators of pro-inflammatory responses whereas M2 markers emerge for resolution and cleanup. Microglia exerts in the central nervous system (CNS) a function similar to that of macrophages in the periphery. Microglia activation and proliferation occurs in almost any single pathology affecting the CNS. Often microglia activation has been considered detrimental and drugs able to stop microglia activation were considered for the treatment of a variety of diseases. Cumulative evidence shows that microglia may undergo the alternative activation pathway, express M2-type markers and contribute to neuroprotection. This review focuses on details about the role of M2 microglia and in the approaches available for its identification. Approaches to drive the M2 phenotype and data on its potential in CNS diseases are also reviewed. © 2015 Elsevier Ltd.


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.


Postma T.M.,Barcelona Institute for Research in Biomedicine | Postma T.M.,CIBER ISCIII | Albericio F.,Barcelona Institute for Research in Biomedicine | Albericio F.,University of Barcelona | Albericio F.,University of KwaZulu - Natal
Organic Letters | Year: 2013

N-Chlorosuccinimide is described as a widely applicable on-resin disulfide-forming reagent. Disulfide bond formation was completed within 15 min in DMF. This strategy was successfully used in the synthesis of oxytocin and a regioselective synthesis of an α-conotoxin. Moreover, disulfide formation with N-chlorosuccinimide was found to be compatible with oxidation-prone methionine and tryptophan. © 2013 American Chemical Society.


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.


Castells A.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Castells A.,CIBER ISCIII
Gastroenterologia y Hepatologia | Year: 2011

Colorectal cancer is the most frequent neoplasm in the Western countries and the second cause of death from cancer. This situation is due to the underuse of screening or early detection strategies. In the American Gastroenterological Association's congress, several studies reported major advances in the efficacy and efficiency of diverse approaches. Notable among these was evaluation of new fecal occult blood tests through immunological methods, especially with regard to the number of determinations, the cut-off point for positivity, age range of the target population and periodicity. One of the main contributions to the congress were the results of a UK controlled randomized trial showing the benefit of a single sigmoidoscopy performed in persons aged approximately 60 years on reducing the incidence of distal colorectal cancer and colorectal cancer overall and associated mortality. In this trial, the protective effect of sigmoidoscopy was maintained for a minimum of 10 years. © 2011 Elsevier España S.L.


Hartwig S.,Sanofi S.A. | Syrjanen S.,Medicity | Dominiak-Felden G.,Sanofi S.A. | Brotons M.,Institute Catala Doncologia Ico Idibell | And 2 more authors.
BMC Cancer | Year: 2012

Background: The role of human papillomavirus (HPV) in malignant and non-malignant genital diseases in women is well known and the corresponding epidemiological burden has been widely described. However, less is known about the role of HPV in anal, penile and head and neck cancer, and the burden of malignant and non-malignant HPV-related diseases in men. The objective of this review is to estimate the epidemiological burden of HPV-related cancers and non-malignant diseases in men in Europe.Methods: The annual number of new HPV-related cancers in men in Europe was estimated using Eurostat population data and applying cancer incidence rates published by the International Agency for Research on Cancer. The number of cancer cases attributable to HPV, and specifically to HPV16/18, was calculated based on the most relevant prevalence estimates. The annual number of new cases of genital warts was calculated from the most robust European studies; and latest HPV6/11 prevalence estimates were then applied. A literature review was also performed to retrieve exhaustive data on HPV infection at all anatomical sites under study, as well as incidence and prevalence of external genital warts, recurrent respiratory papillomatosis and HPV-related cancer trends in men in Europe.Results: A total of 72, 694 new cancer cases at HPV-related anatomical sites were estimated to occur each year in men in Europe. 17,403 of these cancer cases could be attributable to HPV, with 15,497 of them specifically attributable to HPV16/18. In addition, between 286,682 and 325,722 new cases of genital warts attributable to HPV6/11were estimated to occur annually in men in Europe.Conclusions: The overall estimated epidemiological burden of HPV-related cancers and non-malignant diseases is high in men in Europe. Approximately 30% of all new cancer cases attributable to HPV16/18 that occur yearly in Europe were estimated to occur in men. As in women, the vast majority of HPV-positive cancer in men is related to HPV16/18, while almost all HPV-related non-malignant diseases are due to HPV6/11. A substantial number of these malignant and non-malignant diseases may potentially be prevented by quadrivalent HPV vaccination. © 2011 Hartwig et al; licensee BioMed Central Ltd..


Leentjens A.F.G.,Maastricht University | Dujardin K.,Lille University Medical Center | Pontone G.M.,Johns Hopkins University | Starkstein S.E.,University of Western Australia | And 2 more authors.
Movement Disorders | Year: 2014

Existing anxiety rating scales have limited construct validity in patients with Parkinson's disease (PD). This study was undertaken to develop and validate a new anxiety rating scale, the Parkinson Anxiety Scale (PAS), that would overcome the limitations of existing scales. The general structure of the PAS was based on the outcome of a Delphi procedure. Item selection was based on a canonical correlation analysis and a Rasch analysis of items of the Hamilton Anxiety Rating Scale (HARS) and the Beck Anxiety Inventory (BAI) from a previously published study. Validation was done in a cross-sectional international multicenter study involving 362 patients with idiopathic PD. Patients underwent a single screening session in which the PAS was administered, along with the Hamilton Depression Rating Scale, the HARS, and the BAI. The Mini International Neuropsychiatric Interview was administered to establish Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses of anxiety and depressive disorders. The PAS is a 12-item observer or patient-rated scale with three subscales, for persistent, episodic anxiety and avoidance behavior. Properties for acceptability and reliability met predetermined criteria. The convergent and known groups validity was good. The scale has a satisfactory factorial structure. The area under the receiver operating characteristics curve and Youden index of the PAS are higher than that of existing anxiety rating scales. The PAS is a reliable and valid anxiety measure for use in PD patients. It is easy and brief to administer, and has better clinimetric properties than existing anxiety rating scales. The sensitivity to change of the PAS remains to be assessed. © 2014 International Parkinson and Movement Disorder Society.


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.


Alemany M.,University of Barcelona | Alemany M.,CIBER ISCIII
Nutrition Research | Year: 2013

Metabolic syndrome (MS) is a widespread pathologic state that manifests as multiple intertwined diseases affecting the entire body. This review analyzes the contribution of adipose tissue inflammation to its development. The main factor in the appearance of MS is an excess of dietary energy (largely fats), eliciting insulin resistance and creating the problem of excess energy disposal. Under these conditions, amino acid catabolism is diminished, which indirectly alters the production of nitric oxide and affects blood flow regulation. The oxidation of nitric oxide to nitrite and nitrate affects microbiota composition and functions. Adipose tissue cannot incorporate excessive nutrients after cell enlargement and loss of function. Tissue damage is a form of aggression, and the response is proinflammatory cytokine release. Cytokines favor the massive penetration of immune system cells, such as macrophages, which unsuccessfully try to fight an elusive danger for which they are not prepared. The consequence is low-level maintenance of the inflammatory state, which affects endoplasmic reticulum function and the endothelial response to excess regulatory mechanisms affecting blood flow and substrate/oxygen supply. When inflammation becomes chronic, the pathologic consequences are disseminated throughout the body because unused substrates and signals from adipose tissue affect energy partitioning and organ function. This maintenance of an unbalanced state ultimately results in the establishment of MS and associated pathologies. New research should focus on identifying ways to disarm the inflammatory response of adipose tissue when the dangers of dietary excess have already been controlled. © 2013 .


Sanchez-Ruiz A.,CIC Biomagune | Serna S.,CIC Biomagune | Ruiz N.,CIC Biomagune | Martin-Lomas M.,CIC Biomagune | And 2 more authors.
Angewandte Chemie - International Edition | Year: 2011

Active arrays: Complex lipid-tagged oligosaccharides, including large multiantennary species, can be efficiently immobilized on self-assembled monolayers of alkyl mercaptans . These arrays can be used to follow the action of a galactosyltransferase (GalT) and a hydrolase. The utility of the system for the selective trapping and identification of a lectin from a complex mixture was also demonstrated. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Parkinson disease (PD) has a premotor stage where neurodegeneration occurs before parkinsonism becomes apparent. Identification of individuals at this stage provides an opportunity to study early disease progression and test disease-modifying interventions. Hyposmia, constipation, depression and hypersomnia are part of this premotor phase and predictive of future development of PD. However, these features are common in the general population, and they are most often the result of causes other than incipient PD. In contrast, most individuals with idiopathic REM sleep behavior disorder (IRBD) eventually develop PD and other synucleinopathies. IRBD individuals with hyposmia, substantia nigra hyperechogenicity, and abnormal striatal dopamine transporter imaging findings have increased short-term risk of developing a synucleinopathy. IRBD is an optimal target to test disease-modifying agents in the PD prodromal phase. Serial dopamine transporter imaging, but not olfactory tests, may serve to monitor the disease process in future disease-modifying trials in IRBD. © 2013 Springer Science+Business Media New York.


Almendros I.,University of Chicago | Wang Y.,University of Chicago | Becker L.,University of Chicago | Lennon F.E.,University of Chicago | And 9 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: An increased cancer aggressiveness and mortality have been recently reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), a hallmark of OSA, enhances melanoma growth and metastasis in mice. Objectives: To assess whether OSA-related adverse cancer outcomes occur via IH-induced changes in host immune responses, namely tumor-associated macrophages (TAMs). Measurements and Main Results: Lung epithelial TC1 cell tumors were 84% greater in mice subjected to IH for 28 days compared with room air (RA). In addition, TAMs in IH-exposed tumors exhibited reductions in M1 polarity with a shift toward M2 protumoral phenotype. Although TAMs fromtumors harvested from RA-exposed mice increased TC1 migration and extravasation, TAMs from IHexposed mice markedly enhanced such effects and also promoted proliferative rates and invasiveness of TC1 cells. Proliferative rates of melanoma (B16F10)andTC1cells exposed to IHeither in single culture or in coculture with macrophages (RAW 264.7) increased only when RAW 264.7 macrophages were concurrently present. Conclusions: Our findings support the notion that IH-induced alterations in TAMs participate in the adverse cancer outcomes reported in OSA.Copyright © 2014 by the American Thoracic Society.


Huy N.T.,Nagasaki University | Van Giang T.,Nagasaki University | Thuy D.H.D.,PharmaCo Cell Co. | Kikuchi M.,Nagasaki University | And 3 more authors.
PLoS Neglected Tropical Diseases | Year: 2013

Background:The pathogenesis of dengue shock syndrome (DSS, grade 3 and 4) is not yet completely understood. Several factors are reportedly associated with DSS, a more severe form of dengue infection that reportedly causes 50 times higher mortality compared to that of dengue patients without DSS. However, the results from these reports remain inconclusive. To better understand the epidemiology, clinical manifestation, and pathogenesis of DSS for development of new therapy, we systematically reviewed and performed a meta-analysis of relevant studies that reported factors in both DSS and dengue hemorrhagic fever (DHF, grade 1 and 2) patients.Methods and Findings:PubMed, EMBASE, Scopus, Google Scholar, Dengue Bulletin, Cochrane Library, Virtual Health Library, and a manual search of reference lists of articles published before September 2010 were used to retrieve relevant studies. A meta-analysis using fixed- or random-effects models was used to calculate pooled odds ratios (OR) or event rate with corresponding 95% confidence intervals. Assessment of heterogeneity and publication bias, meta-regression analysis, subgroup analysis, sensitivity analysis, and analysis of factor-specific relationships were further performed. There were 198 studies constituting 203 data sets that met our eligibility criteria. Our meta-regression analysis showed a sustained reduction of DSS/dengue hemorrhagic fever (DHF) ratio over a period of 40 years in Southeast Asia, especially in Thailand. The meta-analysis revealed that age, female sex, neurological signs, nausea/vomiting, abdominal pain, gastrointestinal bleeding, hemoconcentration, ascites, pleural effusion, hypoalbuminemia, hypoproteinemia, hepatomegaly, levels of alanine transaminase and aspartate transaminase, thrombocytopenia, prothrombin time, activated partial thromboplastin time, fibrinogen level, primary/secondary infection, and dengue virus serotype-2 were significantly associated with DSS when pooling all original relevant studies.Conclusions:The results improve our knowledge of the pathogenesis of DSS by identifying the association between the epidemiology, clinical signs, and biomarkers involved in DSS. © 2013 Huy et al.


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.


Martin F.,CIBER ISCIII
Advances in Experimental Medicine and Biology | Year: 2010

Over the last years, there has been great success in driving stem cells toward insulin-expressing cells. However, the protocols developed to date have some limitations, such as low reliability and low insulin production. The most successful protocols used for generation of insulin-producing cells from stem cells mimic in vitro pancreatic organogenesis by directing the stem cells through stages that resemble several pancreatic developmental stages. Islet cell fate is coordinated by a complex network of inductive signals and regulatory transcription factors that, in a combinatorial way, determine pancreatic organ specification, differentiation, growth, and lineage. Together, these signals and factors direct the progression from multipotent progenitor cells to mature pancreatic cells. Later in development and adult life, several of these factors also contribute to maintain the differentiated phenotype of islet cells. A detailed understanding of the processes that operate in the pancreas during embryogenesis will help us to develop a suitable source of cells for diabetes therapy. In this chapter, we will discuss the main transcription factors involved in pancreas specification and β-cell formation. © Springer Science+Business Media B.V. 2010.


Montuschi P.,University Hospital Agostino Gemelli | Malerba M.,University of Brescia | Santini G.,University of Brescia | Miravitlles M.,CIBER ISCIII
Drug Discovery Today | Year: 2014

Chronic obstructive pulmonary disease (COPD) is characterized by large phenotype variability, reflected by a highly variable response to pharmacological treatment. Nevertheless, current guidelines suggest that patients with COPD of similar severity should be treated in the same way. The phenotype-based pharmacotherapeutic approach proposes bronchodilators alone in the nonfrequent exacerbator phenotype and a combination of bronchodilators and inhaled corticosteroids in patients with asthma-COPD overlap syndrome (ACOS) and moderate-to-severe exacerbator phenotype. The clinical importance of phenotypes is changing the paradigm of COPD management from evidence-based to personalized medicine. However, the personalized pharmacological strategy of COPD has to be validated in future clinical studies. © 2014 Elsevier Ltd.


Binefa G.,CIBER ISCIII | Binefa G.,University of Barcelona | Rodriguez-Moranta F.,University of Barcelona | Teule A.,Catalan Institute of Nanoscience and Nanotechnology | Medina-Hayas M.,Autonomous University of Barcelona
World Journal of Gastroenterology | Year: 2014

Colorectal cancer (CRC) is a very heterogeneous disease that is caused by the interaction of genetic and environmental factors. CRC develops through a gradual accumulation of genetic and epigenetic changes, leading to the transformation of normal colonic mucosa into invasive cancer. CRC is one of the most prevalent and incident cancers worldwide, as well as one of the most deadly. Approximately 1235108 people are diagnosed annually with CRC, and 609051 die from CRC annually. The World Health Organization estimates an increase of 77% in the number of newly diagnosed cases of CRC and an increase of 80% in deaths from CRC by 2030. The incidence of CRC can benefit from different strategies depending on its stage: health promotion through health education campaigns (when the disease is not yet present), the implementation of screening programs (for detection of the disease in its early stages), and the development of nearly personalized treatments according to both patient characteristics (age, sex) and the cancer itself (gene expression). Although there are different strategies for screening and although the number of such strategies is increasing due to the potential of emerging technologies in molecular marker application, not all strategies meet the criteria required for screening tests in population programs; the three most accepted tests are the fecal occult blood test (FOBT), colonoscopy and sigmoidoscopy. FOBT is the most used method for CRC screening worldwide and is also the primary choice in most population-based screening programs in Europe. Due to its non-invasive nature and low cost, it is one of the most accepted techniques by population. CRC is a very heterogeneous disease, and with a few exceptions (APC, p53, KRAS), most of the genes involved in CRC are observed in a small percentage of cases. The design of genetic and epigenetic marker panels that are able to provide maximum coverage in the diagnosis of colorectal neoplasia seems a reasonable strategy. In recent years, the use of DNA, RNA and protein markers in different biological samples has been explored as strategies for CRC diagnosis. Although there is not yet sufficient evidence to recommend the analysis of biomarkers such as DNA, RNA or proteins in the blood or stool, it is likely that given the quick progression of technology tools in molecular biology, increasingly sensitive and less expensive, these tools will gradually be employed in clinical practice and will likely be developed in mass. © 2014 Baishideng Publishing Group Inc. All rights reserved.


Fernandez-Alvarez A.,Institute Biomedicina Of Valencia Ibv Csic | Alvarez M.S.,Institute Biomedicina Of Valencia Ibv Csic | Cucarella C.,Institute Biomedicina Of Valencia Ibv Csic | Casado M.,Institute Biomedicina Of Valencia Ibv Csic | Casado M.,CIBER ISCIII
Journal of Biological Chemistry | Year: 2010

Insulin-induced gene 2 (INSIG2) and its homolog INSIG1 encode closely related endoplasmic reticulum proteins that regulate the proteolytic activation of sterol regulatory element-binding proteins, transcription factors that activate the synthesis of cholesterol and fatty acids in animal cells. Several studies have been carried out to identify INSIG2 genetic variants associated with metabolic diseases. However, few data have been published regarding the regulation of INSIG2 gene expression. Two Insig2 transcripts have been described in rodents through the use of different promoters that produce different noncoding first exons that splice into a common second exon. Herein we report the cloning and characterization of the human INSIG2 promoter and the detection of an INSIG2-specific transcript homologous to the Insig2b mouse variant in human liver. Deletion analyses on 3 kb of 5′-flanking DNA of the human INSIG2 gene revealed the functional importance of a 350-bp region upstream of the transcription start site. Mutated analyses, chromatin immunoprecipitation assays, and RNA interference analyses unveiled the significance of an Ets-consensus motif in the proximal region and the interaction of the Ets family member SAP1a (serum response factor (SRF) accessory protein-1a) with this region of the human INSIG2 promoter. Moreover, our findings suggest that insulin activated the human INSIG2 promoter in a process mediated by phosphorylated SAP1a. Overall, these results map the functional elements in the human INSIG2 promoter sequence and suggest an unexpected regulation of INSIG2 gene expression in human liver. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Kennedy A.S.,North Carolina State University | Sangro B.,University of Navarra | Sangro B.,CIBER ISCIII
Current Oncology Reports | Year: 2014

The most common non-surgical approaches for the treatment of localized hepatocellular carcinoma remain hepatic artery-delivered particles laden with chemotherapy (TACE), or radioactive microparticles (TARE). External beam radiotherapy has been an effective option in many parts of the world for selected HCC patients, but now has an expanded role with stereotactic and proton beam technologies. This review focuses on existing evidence and current guidance for utilizing these modalities for localized, but unresectable, non-transplantable HCC patients.x © 2014 The Author(s).


Ruiz J.,University of Barcelona | Ruiz J.,CIBER ISCIII | Pons M.J.,University of Barcelona | Gomes C.,University of Barcelona
International Journal of Antimicrobial Agents | Year: 2012

Quinolones were introduced into clinical practice in the late 1960s. Although quinolone resistance was described early, no transferable mechanism of quinolone resistance (TMQR) was confirmed until 1998. To date, five different TMQRs have been described in the literature, including target protection (Qnr), quinolone modification (AAC(6′)-Ib-cr), plasmid-encoded efflux systems (e.g. QepA or OqxAB, amongst others), effect on bacterial growth rates and natural transformation. Although TMQRs usually only result in a slight increase in the minimum inhibitory concentrations of quinolones, they possess an additive effect and may facilitate the acquisition of full quinolone resistance. The emergence of new related genes may continue in the next years. © 2012 Elsevier B.V. and the International Society of Chemotherapy.


Sia D.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Sia D.,Italian National Cancer Institute | Alsinet C.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Newell P.,Earle A Chiles Research Institute | And 3 more authors.
Current Pharmaceutical Design | Year: 2014

Induction of angiogenesis represents one of the major hallmarks of cancer. The growth of new vessels is crucial to provide malignant cells with an adequate supply of oxygen and nutrients. It is generally accepted that vascular endothelial growth factor (VEGF) is a major driver of the angiogenic process in physiological and pathological processes in both embryo and adult. VEGF is often found overexpressed in tumors, as well as its receptors VEGFR1 and VEGFR2. Hence, several different strategies have been designed to target VEGF signal transduction. In the last decades, multiple inhibitors have been therapeutically validated in preclinical models and several clinical trials. Neutralizing monoclonal antibodies against VEGF and small molecule tyrosine kinase inhibitors targeting VEGFRs have been shown to block its angiogenic activity, resulting in tumor vascular regression, anti-tumor effects and improvements in patient survival. However, side effects and lack of efficacy in some instances challenge the potential clinical impact of these therapies. This review examines the role of VEGF signaling in cancer and outlines the current status of anti-angiogenic therapies against VEGF pathway. © 2014 Bentham Science Publishers.


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.


Llorens R.,Polytechnic University of Valencia | Noe E.,Servicio de Neurorrehabilitacion y Dano Cerebral de los Hospitales NISA | Colomer C.,Servicio de Neurorrehabilitacion y Dano Cerebral de los Hospitales NISA | Alcaniz M.,Polytechnic University of Valencia | Alcaniz M.,CIBER ISCIII
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.


Gonzalez de Molina F.J.,University of Barcelona | Ferrer R.,University of Barcelona | Ferrer R.,CIBER ISCIII
Critical Care | Year: 2011

Severe sepsis and septic shock cause considerable morbidity and mortality. Early appropriate empiric broad-spectrum antibiotics and advanced resuscitation therapy are the cornerstones of treatment for these conditions. In prescribing an antibiotic regimen in septic patients with acute renal failure treated with continuous renal replacement therapy, several factors should be considered: pharmacokinetics, weight, residual renal function, hepatic function, mode of renal replacement therapy (membrane and surface area, sieving coefficient, effluent and dialysate rate, and blood flow rate), severity of illness, microorganism, minimum inhibitory concentration, and others. Studies that determine the serum antibiotic concentrations are very useful in establishing the correct dosage in critical patients. © 2011 BioMed Central Ltd.


Ribezzi-Crivellari M.,University of Barcelona | Ritort F.,University of Barcelona | Ritort F.,CIBER ISCIII
Biophysical Journal | Year: 2012

Dual-trap optical tweezers are often used in high-resolution measurements in single-molecule biophysics. Such measurements can be hindered by the presence of extraneous noise sources, the most prominent of which is the coupling of fluctuations along different spatial directions, which may affect any optical tweezers setup. In this article, we analyze, both from the theoretical and the experimental points of view, the most common source for these couplings in dual-trap optical-tweezers setups: the misalignment of traps and tether. We give criteria to distinguish different kinds of misalignment, to estimate their quantitative relevance and to include them in the data analysis. The experimental data is obtained in a, to our knowledge, novel dual-trap optical-tweezers setup that directly measures forces. In the case in which misalignment is negligible, we provide a method to measure the stiffness of traps and tether based on variance analysis. This method can be seen as a calibration technique valid beyond the linear trap region. Our analysis is then employed to measure the persistence length of dsDNA tethers of three different lengths spanning two orders of magnitude. The effective persistence length of such tethers is shown to decrease with the contour length, in accordance with previous studies. © 2012 Biophysical Society.


Campos-Rodriguez F.,Hospital Universitario Of Valme | Martinez-Garcia M.A.,Polytechnic University of Valencia | Martinez-Garcia M.A.,CIBER ISCIII | Reyes-Nunez N.,Hospital Universitario Of Valme | And 3 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: It is unknown whether obstructive sleep apnea (OSA) may be a risk factor for incident cardiovascular events in women. Objectives: We sought to investigate whether OSA increases the incidence of a composite of stroke or coronary heart disease (CHD) in women, and the role of continuous positive airway pressure (CPAP) treatment on this association. Methods: This was a prospective, observational study conducted in two Spanish teaching hospitals between 1998 and 2007. Consecutive women referred for suspected OSA and free of previous stroke and CHD were analyzed. Women with an apnea - hypopnea index (AHI) less than 10 comprised the control group, and those with an AHI greater than or equal to 10 were diagnosed with OSA and classi fi ed as CPAP-treated (adherence ≥ 4 h/d) or untreated (adherence < 4 h/d or not prescribed). The follow-up ended in December 2010. Measurements and Main Results: A total of 967 women were studied (median follow-up, 6.8 yr; interquartile range, 5.2-8.2). The untreated OSA group showed a greater incidence rate of the composite outcome than the control group (2.19 vs. 0.54 per 100 person-years; P < 0.0005). Compared with the control group, the fully adjusted hazard ratios for the composite outcome incidence were 2.76 (95% confidence interval [CI], 1.35-5.62) for the untreated OSA group, and 0.91 (95% CI, 0.43-1.95) for the CPAP-treated group.Whenthe type of cardiovascular event was separately assessed, untreated OSA showed a stronger association with incident stroke (adjusted hazard ratio, 6.44; 95% CI, 1.46-28.3) than with CHD (adjusted hazard ratio, 1.77; 95% CI, 0.76-4.09). Conclusions: In women, untreatedOSAis associated with increased incidence of serious cardiovascular outcomes, particularly incident stroke. Adequate CPAP treatment seems to reduce this risk. Copyright © 2014 by the American Thoracic Society.


Serra F.,Research Center Principe Felipe | Arbiza L.,Research Center Principe Felipe | Dopazo J.,Research Center Principe Felipe | Dopazo J.,CIBER ISCIII | Dopazo H.,Research Center Principe Felipe
PLoS Computational Biology | Year: 2011

Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species. © 2011 Serra et al.