Institute Salud Carlos II

Madrid, Spain

Institute Salud Carlos II

Madrid, Spain
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Ardanuy C.,University of Barcelona | De La Campa A.G.,Centros de Investigacion Biomedica en Red de Enfermedades Respiratorias | De La Campa A.G.,Institute Salud Carlos II | Garcia E.,Centros de Investigacion Biomedica en Red de Enfermedades Respiratorias | And 10 more authors.
Emerging Infectious Diseases | Year: 2014

Streptococcus pneumoniae is a frequent cause of community- acquired pneumonia, meningitis, bacteremia, and otitis media in children. The diverse biochemical composition of the capsular polysaccharide results in >94 serotypes (1). However, only a few serotypes cause most invasive disease episodes worldwide. Serotype 8 pneumococci cause invasive pneumococcal disease in adults and have been occasionally associated with outbreaks. Nevertheless, isolates of this serotype are rarely found in children as a cause of invasive disease or as colonizers of the nasopharynx (2,3). Few lineages have been identified among serotype 8 pneumococci; the major clone is Netherlands 8-ST53, which has been detected worldwide and is typically susceptible to antimicrobial drugs (4).He capsular polysaccharide is the major virulence factor of pneumococci and usually determines their ability to act as invasive or colonizing microorganisms (3). In addition to exhibiting the capsule, pneumococci can show low or high genetic diversity, but genotype-serotype association is common. However, this association could be disrupted because of capsular switching caused mainly by recombination of capsular genetic loci. This finding could be a sporadic event, but the recombinant occasionally spreads and could cause pneumococcal disease.Capsular switching was associated with emergence of a serotype 19A variant of a formerly serotype 4 clone (5) related to immunity pressure sustained after a 7-valent pneumococcal conjugate vaccine was introduced into the United States. This well-known phenomenon was the origin of the major penicillin-resistant clone (serotype 14 variant of the Spain 9V-ST156 clone), which caused invasive pneumococcal disease in Spain in the 2000s (4,6).Data from the Spanish Reference Laboratory for Pneumococci, which has received pneumococci from Spain since 1979, showed rates of 2.5% to 6.5% for serotype 8 invasive isolates in the last 3 decades. These rates did not show any association with introduction of therapeutic or preventive measures (7,8). Over these decades, serotype 8 pneumococci were usually susceptible to antimicrobial drugs, although some isolates were resistant to erythromycin or tetracycline. Moreover, serotype 8 pneumococci were isolated mainly from adult patients (7,8). However, since 2004, serotype 8 pneumococci have been identified that showed resistance to erythromycin, clindamycin, tetracycline, and ciprofloxacin. © 2014, Centers for Disease Control and Prevention (CDC). All Rights Reserved.


Mata M.,University of Valencia | Mata M.,CIBER ISCIII | Sarrion I.,University of Valencia | Armengot M.,University of Valencia | And 7 more authors.
PLoS ONE | Year: 2012

Persistent respiratory syncytial virus (RSV) infections have been associated with the exacerbation of chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). This virus infects the respiratory epithelium, leading to chronic inflammation, and induces the release of mucins and the loss of cilia activity, two factors that determine mucus clearance and the increase in sputum volume. These alterations involve reactive oxygen species-dependent mechanisms. The antioxidant N-acetylcysteine (NAC) has proven useful in the management of COPD, reducing symptoms, exacerbations, and accelerated lung function decline. NAC inhibits RSV infection and mucin release in human A549 cells. The main objective of this study was to analyze the effects of NAC in modulating ciliary activity, ciliagenesis, and metaplasia in primary normal human bronchial epithelial cell (NHBEC) cultures infected with RSV. Our results indicated that RSV induced ultrastructural abnormalities in axonemal basal bodies and decreased the expression of β-tubulin as well as two genes involved in ciliagenesis, FOXJ1 and DNAI2. These alterations led to a decrease in ciliary activity. Furthermore, RSV induced metaplastic changes to the epithelium and increased the number of goblet cells and the expression of MUC5AC and GOB5. NAC restored the normal functions of the epithelium, inhibiting ICAM1 expression, subsequent RSV infection through mechanisms involving nuclear receptor factor 2, and the expression of heme oxygenase 1, which correlated with the restoration of the antioxidant capacity, the intracellular H2O2 levels and glutathione content of NHBECs. The results presented in this study support the therapeutic use of NAC for the management of chronic respiratory diseases, including COPD. © 2012 Mata et al.


Martinez-Gonzalez M.A.,Institute Salud Carlos II | Martinez-Gonzalez M.A.,Public University of Navarra | Garcia-Arellano A.,Institute Salud Carlos II | Garcia-Arellano A.,Public University of Navarra | And 34 more authors.
PLoS ONE | Year: 2014

Background: Different indexes of regional adiposity have been proposed for identifying persons at higher risk of death. Studies specifically assessing these indexes in large cohorts are scarce. It would also be interesting to know whether a dietary intervention may counterbalance the adverse effects of adiposity on mortality. Methods: We assessed the association of four different anthropometric indexes (waist-to-height ratio (WHtR), waist circumference (WC), body mass index (BMI) and height) with all-cause mortality in 7447 participants at high cardiovascular risk from the PREDIMED trial. Forty three percent of them were men (55 to 80 years) and 57% were women (60 to 80 years). All of them were initially free of cardiovascular disease. The recruitment took place in 11 recruiting centers between 2003 and 2009. Results: After adjusting for age, sex, smoking, diabetes, hypertension, intervention group, family history of coronary heart disease, and leisure-time physical activity, WC and WHtR were found to be directly associated with a higher mortality after 4.8 years median follow-up. The multivariable-adjusted HRs for mortality of WHtR (cut-off points: 0.60, 0.65, 0.70) were 1.02 (0.78-1.34), 1.30 (0.97-1.75) and 1.55 (1.06-2.26). When we used WC (cut-off points: 100, 105 and 110 cm), the multivariable adjusted Hazard Ratios (HRs) for mortality were 1.18 (0.88-1.59), 1.02 (0.74-1.41) and 1.57 (1.19-2.08). In all analyses, BMI exhibited weaker associations with mortality than WC or WHtR. The direct association between WHtR and overall mortality was consistent within each of the three intervention arms of the trial. Conclusions: Our study adds further support to a stronger association of abdominal obesity than BMI with total mortality among elderly subjects at high risk of cardiovascular disease. We did not find evidence to support that the PREDIMED intervention was able to counterbalance the harmful effects of increased adiposity on total mortality. Trial Registration: Controlled-Trials. com ISRCTN35739639 © 2014 Martínez-González et al.


Pozo-Rodriguez F.,Hospital 12 Of Octubre | Pozo-Rodriguez F.,Institute Salud Carlos II | Lopez-Campos J.L.,Institute Salud Carlos II | Lopez-Campos J.L.,Hospital Universitario Virgen del Rocio | And 15 more authors.
PLoS ONE | Year: 2012

Backgrounds: AUDIPOC is a nationwide clinical audit that describes the characteristics, interventions and outcomes of patients admitted to Spanish hospitals because of an exacerbation of chronic obstructive pulmonary disease (ECOPD), assessing the compliance of these parameters with current international guidelines. The present study describes hospital resources, hospital factors related to case recruitment variability, patients' characteristics, and adherence to guidelines. Methodology/Principal Findings: An organisational database was completed by all participant hospitals recording resources and organisation. Over an 8-week period 11,564 consecutive ECOPD admissions to 129 Spanish hospitals covering 70% of the Spanish population were prospectively identified. At hospital discharge, 5,178 patients (45% of eligible) were finally included, and thus constituted the audited population. Audited patients were reassessed 90 days after admission for survival and readmission rates. A wide variability was observed in relation to most variables, hospital adherence to guidelines, and readmissions and death. Median inpatient mortality was 5% (across-hospital range 0-35%). Among discharged patients, 37% required readmission (0-62%) and 6.5% died (0-35%). The overall mortality rate was 11.6% (0-50%). Hospital size and complexity and aspects related to hospital COPD awareness were significantly associated with case recruitment. Clinical management most often complied with diagnosis and treatment recommendations but rarely (<50%) addressed guidance on healthy life-styles. Conclusions/Significance: The AUDIPOC study highlights the large across-hospital variability in resources and organization of hospitals, patient characteristics, process of care, and outcomes. The study also identifies resources and organizational characteristics associated with the admission of COPD cases, as well as aspects of daily clinical care amenable to improvement. © 2012 Pozo-Rodríguez et al.


Henriquez-Sanchez P.,Institute Salud Carlos III | Henriquez-Sanchez P.,University of Las Palmas de Gran Canaria | Sanchez-Villegas A.,Institute Salud Carlos III | Sanchez-Villegas A.,University of Las Palmas de Gran Canaria | And 35 more authors.
European Journal of Nutrition | Year: 2016

Purpose: The aim of the present study was to assess the association between the dietary total antioxidant capacity, the dietary intake of different antioxidants and mortality in a Mediterranean population at high cardiovascular disease risk. Methods: A total of 7,447 subjects from the PREDIMED study (multicenter, parallel group, randomized controlled clinical trial), were analyzed treating data as an observational cohort. Different antioxidant vitamin intake and total dietary antioxidant capacity were calculated from a validated 137-item food frequency questionnaire at baseline and updated yearly. Deaths were ascertained through contact with families and general practitioners, review of medical records and consultation of the National Death Index. Cox regression models were fitted to assess the relationship between dietary total antioxidant capacity and mortality. Dietary total antioxidant capacity was estimated using ferric-reducing antioxidant power assays. Results: A total of 319 deaths were recorded after a median follow-up of 4.3 years. Subjects belonging to the upper quintile of antioxidant capacity were younger, ex-smokers, with high educational level, and more active and had higher alcohol intake. Multivariable-adjusted models revealed no statistically significant difference between total dietary antioxidant capacity and mortality (Q5 vs. Q1 ref HR 0.85; 95 % CI 0.60–1.20) neither for the intake of all the vitamins studied. Conclusions: No statistically significant association was found between antioxidant capacity and total mortality in elderly subjects at high cardiovascular risk. © 2015, Springer-Verlag Berlin Heidelberg.


Marques V.P.,Institute Salud Carlos II | Gonzalez-Rodriguez A.,Institute Salud Carlos II | Valverde A.M.,Institute Salud Carlos II
Anales de la Real Academia Nacional de Farmacia | Year: 2016

Chronic low-grade inflammation in adipose tissue during obesity is associated to an impairment of the insulin signaling cascade. In this study we have evaluated the impact of palmitate or oleate overload of macrophages in triggering lipoapotosis and in the cross-talk with insulin signaling in hepatocytes. Macrophages were stimulated with oleate or palmitate and levels of M1/M2 polarization markers was analyzed. Whereas proinflammatory cytokines were elevated in macrophages stimulated with palmitate, enhanced M2 markers levels was detected in macrophages stimulated with oleate. When hepatocytes were pretreated with conditioned medium from macrophages loaded with palmitate (CM-P) phosphorylation of stress kinases and endoplasmic reticulum (ER) stress signaling was increased, insulin signaling was impaired and lipoapoptosis was detected. Conversely, enhanced insulin receptor (IR)-mediated signaling and reduced levels of the phosphatase protein tyrosine phosphatase 1B (PTP1B) was found in hepatocytes treated with CM from macrophages stimulated with oleate (CM-O). In conclusion, oleate and palmitate elicit an opposite cross-talk between macrophages and hepatocytes. Whereas CM-P interferes at the early steps of insulin signaling, CM-O increases insulin sensitization by decreasing PTP1B. Therefore, targeting PTP1B is a therapeutic strategy to combat hepatic insulin resistance in obesity.


Molmeret M.,University of Louisville | Jones S.,University of Louisville | Santic M.,University of Louisville | Santic M.,University of Rijeka | And 4 more authors.
Environmental Microbiology | Year: 2010

During late stages of infection and prior to lysis of the infected macrophages or amoeba, the Legionella pneumophila-containing phagosome becomes disrupted, followed by bacterial escape into the host cell cytosol, where the last few rounds of bacterial proliferation occur prior to lysis of the plasma membrane. This coincides with growth transition into the postexponential (PE) phase, which is controlled by regulatory cascades including RpoS and the LetA/S two-component regulator. Whether the temporal expression of flagella by the regulatory cascades at the PE phase is exhibited within the phagosome or after bacterial escape into the host cell cytosol is not known. We have utilized fluorescence microscopybased phagosome integrity assay to differentiate between vacuolar and cytosolic bacteria/or bacteria within disrupted phagosomes. Our data show that during late stages of infection, expression of FlaA is triggered after bacterial escape into the macrophage cytosol and the peak of FlaA expression is delayed for few hours after cytosolic residence of the bacteria. Importantly, bacterial escape into the host cell cytosol is independent of flagella, RpoS and the twocomponent regulator LetA/S, which are all triggered by L. pneumophila upon growth transition into the PE phase. Disruption of the phagosome and bacterial escape into the cytosol of macrophages is independent of the bacterial pore-forming activity, and occurs prior to the induction of apoptosis during late stages of infection. We conclude that the temporal and spatial engagement of virulence-associated regulatory cascades by L. pneumophila at the PE phase is temporally and spatially triggered after phagosomal escape and bacterial residence in the host cell cytosol. © 2009 Society for Applied Microbiology and Blackwell Publishing Ltd.


Vanuytsel T.,Catholic University of Leuven | Vanormelingen C.,Catholic University of Leuven | Vanheel H.,Catholic University of Leuven | Masaoka T.,Catholic University of Leuven | And 9 more authors.
PLoS ONE | Year: 2014

Background: Impaired intestinal barrier function, low-grade inflammation and altered neuronal control are reported in functional gastrointestinal disorders. However, the sequence of and causal relation between these events is unclear, necessitating a spontaneous animal model. The aim of this study was to describe the natural history of intestinal permeability, mucosal and neuromuscular inflammation and nitrergic motor neuron function during the lifetime of the BioBreeding (BB) rat. Copyright:Methods: Normoglycemic BB-diabetes prone (DP) and control rats were sacrificed at different ages and jejunum was harvested to characterize intestinal permeability, inflammation and neuromuscular function.Results: Both structural and functional evidence of increased intestinal permeability was found in young BB-DP rats from the age of 50 days. In older animals, starting in the mucosa from 70 days and in half of the animals also in the muscularis propria from 110 days, an inflammatory reaction, characterized by an influx of polymorphonuclear cells and higher myeloperoxidase activity, was observed. Finally, in animals older than 110 days, coinciding with a myenteric ganglionitis, a loss of nitrergic neurons and motor function was demonstrated.Conclusion: In the BB-rat, mucosal inflammatory cell infiltration is preceded by intestinal barrier dysfunction and followed by myenteric ganglionitis and loss of nitrergic function. This sequence supports a primary role for impaired barrier function and provides an insightful model for the pathogenesis of functional gastrointestinal disorders. © 2014 Gjoni et al.


PubMed | Institute Salud Carlos II
Type: Journal Article | Journal: Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society | Year: 2013

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.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.

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