Institute Investigacion Hospital 12 Of Octubre I12

Hospital de Órbigo, Spain

Institute Investigacion Hospital 12 Of Octubre I12

Hospital de Órbigo, Spain
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Llibre J.M.,Autonomous University of Barcelona | Pulido F.,Institute Investigacion Hospital 12 Of Octubre I12 | Garcia F.,Hospitales Universitarios Of Granada | Garcia Deltoro M.,Consorcio Hospital General Universitario Of Valencia | And 2 more authors.
AIDS reviews | Year: 2015

Dolutegravir is a novel integrase strand-transfer inhibitor that displays potent in vitro activity and a remarkably different resistance profile. Its robust pharmacokinetic/pharmacodynamic properties - long plasma t1/2, high plasma inhibition quotient, and slow dissociation rate from the integrase complex - suggest it should present a high barrier to resistance development. This has been confirmed in pivotal phase III studies of initial therapy, with none out of 1,118 treated individuals selecting resistance-associated mutations at the integrase or reverse transcriptase. In integrase-naive subjects with virological failure, a rescue intervention with dolutegravir has shown significantly higher rates of virological suppression than raltegravir, as well as significantly lower rates of selection of resistance both at the integrase and against the optimized background. Unexpectedly, a mutation rarely selected in this scenario (R263K) induces a fitness cost that prevents HIV-1 from evading drug pressure, and accumulation of further secondary mutations does not occur and has not been able to compensate the replication capacity deficit in the aftermath of the appearance of a single drug resistance mutation. Therefore, both in vitro and in vivo, it leads the virus to a previously unnoticed evolutionary pathway with low chances to develop resistance to both dolutegravir and other families of antiretrovirals present in the background. This high genetic barrier to resistance development in early stages of antiretroviral treatment can help preserve future treatment options in patients who fail antiretroviral therapy.


Lobo-Jarne T.,Institute Investigacion Hospital 12 Of Octubre I12 | Ugalde C.,Institute Investigacion Hospital 12 Of Octubre I12 | Ugalde C.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer
Seminars in Cell and Developmental Biology | Year: 2017

Over the past sixty years, researchers have made outmost efforts to clarify the structural organization and functional regulation of the complexes that configure the mitochondrial respiratory chain. As a result, the entire composition of each individual complex is practically known and, aided by notable structural advances in mammals, it is now widely accepted that these complexes stablish interactions to form higher-order supramolecular structures called supercomplexes and respirasomes. The mechanistic models and players that regulate the function and biogenesis of such superstructures are still under intense debate, and represent one of the hottest topics of the mitochondrial research field at present. Noteworthy, understanding the pathways involved in the assembly and organization of respiratory chain complexes and supercomplexes is of high biomedical relevance because molecular alterations in these pathways frequently result in severe mitochondrial disorders. The purpose of this review is to update the structural, biogenetic and functional knowledge about the respiratory chain supercomplexes and assembly factors involved in their formation, with special emphasis on their implications in mitochondrial disease. Thanks to the integrated data resulting from recent structural, biochemical and genetic approaches in diverse biological systems, the regulation of the respiratory chain function arises at multiple levels of complexity. © 2017 Elsevier Ltd.


Canete J.D.,Hospital Clinic of Barcelona and IDIBAPS | Pablos J.L.,Institute Investigacion Hospital 12 Of Octubre I12
Current Topics in Medicinal Chemistry | Year: 2013

Biologic therapies have notably improved the treatment of RA, making disease remission a realistic goal. After more than ten years of experience, the safety issues associated with these drugs are well characterized and can be avoided with careful patient selection and tight clinical control. Although the different biologic drugs (anti-TNF agents, anti-IL-6, anti-B cells and anti-costimulation of T-cells) have apparently different mechanisms of action, all biologic agents have demonstrated similar efficacy. In addition results of the combination of two biologic therapies have shown no additive clinical effects, although there is an increased risk of infection. Therefore, further research is needed to optimize the use of these and future targeted therapies in RA. © 2013 Bentham Science Publishers.


Fernandez-Ruiz J.,Complutense University of Madrid | Fernandez-Ruiz J.,CIBER ISCIII | Fernandez-Ruiz J.,Instituto Ramon Y Cajal Of Investigacion Sanitaria Irycis | Moro M.A.,Complutense University of Madrid | And 2 more authors.
Neurotherapeutics | Year: 2015

Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer’s disease, Parkinson’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects. © 2015, The American Society for Experimental NeuroTherapeutics, Inc.


Sierra-Hidalgo F.,Hospital Universitario 12 Of Octubre | Sierra-Hidalgo F.,Institute Investigacion Hospital 12 Of Octubre I12 | De Pablo-Fernandez E.,King's College
Clinical Neuropharmacology | Year: 2013

Palinopsia is an illusory visual phenomenon consisting in the persistence or recurrence of visual images after the exciting stimulus object has been removed. It has been reported in association with parietal and occipital lobe lesions, migraine auras, and related to the use of several drugs and illicit drugs. Here, we report the case of a 23-year-old woman with a 4-year history of episodic migraine with aura who developed palinopsia during sequential prophylactic therapies with topiramate and zonisamide. Although the exact physiopathology of this phenomenon remains unknown, topiramate-and zonisamide-induced palinopsia support an increase on serotonergic activity as a possible mechanism for this visual disorder. © 2013 by Lippincott Williams & Wilkins.


Fernandez-Ruiz M.,Institute Investigacion Hospital 12 Of Octubre I12 | Silva J.T.,Complejo Hospitalario Universitario Of Badajoz | San-Juan R.,Institute Investigacion Hospital 12 Of Octubre I12 | De Dios B.,Institute Investigacion Hospital 12 Of Octubre I12 | And 4 more authors.
Medicine (United States) | Year: 2012

Aspergillus tracheobronchitis (AT) is an infrequent but severe form of invasive pulmonary aspergillosis in which the fungal infection is entirely or predominantly confined to the tracheobronchial tree. We reviewed 8 cases of AT diagnosed in our tertiary care center during an 18-year period, as well as 148 cases previously reported in the English literature from 1985 to July 2011. The demographic, clinical, imaging, bronchoscopic, and outcome characteristics of every eligible patient were excerpted, and predictors of inhospital mortality were identified by logistic regression. Solid organ transplantation (SOT) (44.2%), hematologic malignancy (21.2%), neutropenia (18.7%), and chronic obstructive pulmonary disease (15.4%) were the most common underlying conditions reported. Most cases occurred in patients receiving long-term corticosteroid treatment (71.8%) or chemotherapy (25.0%). Fever and respiratory complaints (cough, dyspnea, stridor, or wheezing) were the most frequent symptoms; one-third of patients developed acute respiratory distress at presentation, and 15.1% were asymptomatic at the time of diagnosis. Initial imaging studies were not informative in 47.4% of the cases. Aspergillus fumigatus was the predominant species (74.4%). The pseudomembranous form was the most commonly observed (31.9% of cases) and was more frequent in neutropenic patients (p = 0.007), whereas ulcerative AT (31.2%) was associated with SOT (p = 0.001). The most frequent antifungal monotherapy regimens were amphotericin B deoxycholate (23.1%) and itraconazole (18.6%), whereas combined therapy was administered in 35.9% of the cases. Overall inhospital mortality was 39.1%, with neutropenia (odds ratio [OR], 20.47; p < 0.001) and acute respiratory distress at presentation (OR, 9.54; p = 0.002) as independent prognostic factors. Our pooled analysis of the literature shows that AT remains a rare opportunistic infection with a nonspecific presentation and a variable course depending on the nature of the predisposing factor. Copyright © 2012 by Lippincott Williams &Wilkins.


Del Rey M.J.,Institute Investigacion Hospital 12 Of Octubre I12 | Usategui A.,Institute Investigacion Hospital 12 Of Octubre I12 | Izquierdo E.,Institute Investigacion Hospital 12 Of Octubre I12 | Canete J.D.,Hospital Clinic Of Barcelona | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objective: Changes in rheumatoid arthritis synovial fibroblast (RASF) gene expression are usually defined by a comparison to osteoarthritis synovial fibroblasts (OASFs). This study was undertaken to analyse the transcriptome of OASFs as compared to RASFs and healthy synovial fibroblasts (HSFs). Methods: The authors used microarray messenger RNA expression profiling of synovial fibroblasts cultured from osteoarthritis (OA), rheumatoid arthritis and normal synovial tissues. Quantitative real-time PCR of selected genes was performed to validate microarray data. Analysis of variance, Student t test and the Benjamini-Hochberg multiple testing correction method for multiple testing correction were used to determine the statistical significance of the changes between the three groups. Results: Larger numbers of transcripts showed a differential expression in OASFs versus the other groups, rather than in RASFs versus HSFs. Cluster analysis confirmed that the differences between the three groups were mostly due to the differences between OA and the other groups. Functional classification identified a significant number of genes related to growth factor activities, cell adhesion, neurotransmission and Ras signalling that are differentially expressed in OASFs. Classical proinflammatory factors or proteases involved in cartilage degradation were not found to be overexpressed in OASFs. Conclusion: Cultured OASFs display a more homogeneous transcriptomic profile than RASFs when compared to HSFs. This supports the participation of synovial fibroblasts in the pathogenesis of OA and may reflect global defects in the mesenchyma-derived lineages of the different tissues in OA joints. These data support individual heterogeneity among RASFs and advise against the use of OASFs as controls.


Usategui A.,Institute Investigacion Hospital 12 Of Octubre I12 | Criado G.,Institute Investigacion Hospital 12 Of Octubre I12 | Izquierdo E.,Institute Investigacion Hospital 12 Of Octubre I12 | Del Rey M.J.,Institute Investigacion Hospital 12 Of Octubre I12 | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objetive: Systemic sclerosis (SSc) is an autoimmune disease characterised by progressive fibrosis. Although SSc shares pathogenetic features with other autoimmune diseases, the participation of profibrotic Th2 cytokines is unique to SSc, but the mechanisms of Th2 skewing are unknown. We have analysed the expression and function of thymic stromal lymphopoietin (TSLP), a central regulator of Th2-mediated allergic inflammation, in human SSc, primary lung fibrosis and in a mouse model of scleroderma. Methods: TSLP expression was analysed by immunohistochemistry in human SSc skin, primary lung fibrosis and mouse bleomycin-induced skin fibrosis, and by quantitative RT-PCR in mouse skin and cultured fibroblasts. The regulation of TSLP expression by specific toll-like receptors (TLR)-2, -3 and -4 agonists was analysed in human dermal fibroblast cultures. The role of TSLP in skin fibrosis and local cytokine expression was analysed in TSLP receptor (TSLPR)-deficient mice. Results: TSLP was overexpressed by epithelial cells, mast cells and fibroblasts in human SSc skin and lung fibrosis, and in the bleomycin model of scleroderma. In cultured human and mouse skin fibroblasts, TSLP expression was inducible by activation of TLR, particularly TLR3. In TSLPR-deficient mice, bleomycininduced fibrosis was significantly reduced in parallel with significantly reduced local expression of IL-13. Conclusions: These data provide the first evidence of TSLP overexpression in SSc and other non-allergic fibrotic conditions, and demonstrate a profibrotic role that is potentially meditated by specific changes in the local cytokine milieu. Thus, modulating TSLP may have antifibrotic therapeutic implications.


de Andres M.C.,Complejo Hospitalario Universitario runa CHUAC | Maneiro E.,Complejo Hospitalario Universitario runa CHUAC | Martin M.A.,Institute Investigacion Hospital 12 Of Octubre I12 | Arenas J.,Institute Investigacion Hospital 12 Of Octubre I12 | Blanco F.J.,Complejo Hospitalario Universitario runa CHUAC
Arthritis Research and Therapy | Year: 2013

Introduction: The pathogenesis of osteoarthritis (OA) is characterized by the production of high amounts of nitric oxide (NO), as a consequence of up-regulation of chondrocyte-inducible nitric oxide synthase (iNOS) induced by inflammatory cytokines. NO donors represent a powerful tool for studying the role of NO in the cartilage in vitro. There is no consensus about NO effects on articular cartilage in part because the differences between the NO donors available. The aim of this work is to compare the metabolic profile of traditional and new generation NO donors to see which one points out the osteoarthritic process in the best way. Methods: Human healthy and OA chondrocytes were isolated from patients undergoing joint replacement surgery, and primary cultured. Cells were stimulated with NO donors (NOC-12 or SNP). NO production was evaluated by the Griess method, and apoptosis was quantified by flow cytometry. Mitochondrial function was evaluated by analysing respiratory chain enzyme complexes, citrate synthase (CS) activities by enzymatic assay, mitochondrial membrane potential (Δψm) by JC-1 using flow cytometry, and ATP levels were measured by luminescence assays. Glucose transport was measured as the uptake of 2-deoxy-[3H]glucose (2-[3H]DG). Statistical analysis was performed using the Mann-Whitney U test. Results: NOC-12 liberates approximately ten times more NO2 -than SNP, but the level of cell death induced was not as profound as that produced by SNP. Normal articular chondrocytes stimulated with NOC-12 had reduced activity from complexes I, III y IV, and the mitochondrial mass was increased in these cells. Deleterious effects on ΔΨm and ATP levels were more profound with SNP, and this NO donor was able to reduce 2-[3H]DG levels. Both NO donors had opposite effects on lactate release, SNP diminished the levels and NOC-12 lead to lactate accumulation. OA chondrocytes incorporate significantly more 2-[3H]DG than healthy cells. Conclusions: These findings suggest that the new generation donors, specifically NOC-12, mimic the OA metabolic process much better than SNP. Previous results using SNP have to be considered prudently since most of the effects observed can be induced by the interactions of secondary products of NO. © 2013 de Andrés et al.; licensee BioMed Central Ltd.


Usategui A.,Institute Investigacion Hospital 12 Of Octubre I12 | Del Rey M.J.,Institute Investigacion Hospital 12 Of Octubre I12 | Pablos J.L.,Institute Investigacion Hospital 12 Of Octubre I12
Expert Review of Clinical Immunology | Year: 2011

Systemic sclerosis (SSc) is a chronic systemic disease characterized by autoimmunity, vascular lesions and progressive fibrosis. The fibrotic component is dominant in SSc compared with other vascular or autoimmune diseases and determines its prognosis and therapeutic refractoriness. Fibroblasts are responsible for abnormal extracellular matrix accumulation. Studies in cultured SSc skin fibroblasts have facilitated the identification of potential pathways involved in their profibrotic phenotype. Profibrotic fibroblasts characterized by abnormal growth and extracellular matrix synthesis may differentiate or expand from normal resident fibroblasts. Recruitment of bone marrow-derived progenitors and transdifferentiation of different cell lineages might also be involved. Multiple factors and signaling pathways appear to be involved in the development or persistence of the SSc fibroblast phenotype. Although their relative relevance and interplay are unclear, aberrant TGF-β signaling seems pivotal and constitutes the best characterized therapeutic target. © 2011 Expert Reviews Ltd.

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