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Gonzalez-Mateo G.,Hospital Universitario La Paz | Jimenez-Heffernan J.,Hospital Universitario Of La Princesa | Selgas R.,Hospital Universitario La Paz | Aguilera Peralta A.,Institute Investigacion Sanitaria Princesa IP
International Journal of Nephrology | Year: 2013

Mesothelial-to-mesenchymal transition (MMT) is an autoregulated physiological process of tissue repair that in uncontrolled conditions, such as peritoneal dialysis (PD), can lead to peritoneal fibrosis. The maximum expression of sclerotic peritoneal syndromes (SPS) is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. The SPS includes a wide range of peritoneal fibrosis that appears progressively and is considered as a reversible process, while EPS does not. EPS is a serious complication of PD characterized by a progressive intra-abdominal inflammatory process that results in bridles and severe fibrous tissue formation which cover and constrict the viscera. Recent studies show that transdifferentiated mesothelial cells isolated from the PD effluent correlate very well with the clinical events such as the number of hemoperitoneum and peritonitis, as well as with PD function (lower ultrafiltration and high Cr-MTC). In addition, in peritoneal biopsies from PD patients, the MMT correlates very well with anatomical changes (fibrosis and angiogenesis). However, the pathway to reach EPS from SPS has not been fully and completely established. Herein, we present important evidence pointing to the MMT that is present in the initial peritoneal fibrosis stages and it is perpetual over time, with at least theoretical possibility that MMT initiated the fibrosing process to reach EPS. © 2013 Jesús Loureiro et al.


PubMed | Clinico de Santiago, Fuenlabrada, Consorci Sanitari de Terrassa, Germans Trias i Pujol and 2 more.
Type: Journal Article | Journal: Gastroenterologia y hepatologia | Year: 2016

Dose intensification is a recommended strategy to recover therapeutic benefit in Crohns disease (CD) patients who have lost initial response to anti-TNF therapy. Once patients have achieved remission, dose de-intensification can be used for cost and safety reasons.The primary aim of this study was to evaluate the long-term durability of remission after stepping down anti-TNF therapy. The secondary aim was to identify predictive factors associated with loss of response after de-intensification and to evaluate the effectiveness of a second re-intensification in patients who lost response after the treatment was stepped down.We evaluated CD patients who received at least one standard anti-TNF dosage after achieving remission with intensified anti-TNF therapy.Twenty-four patients were included. The treatment was intensified because of partial response in 11 patients, loss of response in 10, and primary lack of response in 3. Eight of the 24 patients had lost response after a median follow-up of only 7 months after de-intensification of the anti-TNF therapy. The anti-TNF drug was intensified again in all 8 patients. Three patients did not respond to the new intensification, two had partial response and three achieved remission. On univariate analysis, no predictive factors were identified for loss of response after treatment de-intensification.After only 7 months of follow-up, one-third of the CD patients who received de-intensification therapy lost response; of these, two-thirds did not achieve response after subsequent re-intensification.


Martinez-deMena R.,Institute Investigaciones Biomedicas IIB | Anedda A.,Institute Investigacion Sanitaria Princesa IP | Cadenas S.,Institute Investigacion Sanitaria Princesa IP | Cadenas S.,Autonomous University of Madrid | Obregon M.-J.,Institute Investigaciones Biomedicas IIB
Molecular and Cellular Endocrinology | Year: 2015

TSH receptor (TSHR) is present in the thyroid and other tissues, as adipose tissue. In brown adipose tissue (BAT) TSH increases UCP1 expression and lipolysis. We have studied the regulation of Tshr mRNA expression and the effect of TSH on Ucp1 and Dio2 mRNA, on D2 activity and O2 consumption in rat brown adipocytes and the TSH signaling pathways. Tshr increased during brown adipocyte differentiation, was up-regulated by insulin and low TSH concentrations and down-regulated by high TSH concentrations, T3 and/or NE. TSH increased basal Ucp1 mRNA in a dose-dependent way acting synergistically with T3, while had no effect when NE was present. High TSH concentrations increased basal Dio2 mRNA (12-fold) and were synergistic with T3 (100-fold), but decreased Dio2 mRNA in T3+NE-treated cells. TSH increased D2 activities in T3-treated cells and inhibition of ERK pathway decreased the TSH effect by 55%. In T3+NE treated-cells TSH decreased D2 activity by 50%, in a dose-dependent manner. TSH activated Akt and Erk phosphorylation, while inhibition of PKA promoted Akt phosphorylation. TSH inhibited leptin mRNA. TSH increased O2 consumption by 20% and T3 enhanced its effect. Tshr is expressed in brown adipocytes and is regulated by insulin, TSH, T3 and NE. TSH increases basal and T3-stimulated Ucp1 and Dio2 expression and D2 activity only when T3 is present, but decreases Dio2 mRNA and D2 activity stimulated by NE+T3. TSH increases O2 consumption, confirming the role of TSH in the maintenance of thermogenesis. © 2015 Elsevier Ireland Ltd.


Calderon J.,Autonomous University of Madrid | Calderon J.,Institute Investigacion Sanitaria Princesa IP | Maganto-Garcia E.,Autonomous University of Madrid | Maganto-Garcia E.,Harvard University | And 7 more authors.
PLoS Pathogens | Year: 2012

Trypanosoma cruzi, the protozoan parasite responsible for Chagas' disease, causes severe myocarditis often resulting in death. Here, we report that Slamf1-/- mice, which lack the hematopoietic cell surface receptor Slamf1, are completely protected from an acute lethal parasite challenge. Cardiac damage was reduced in Slamf1-/- mice compared to wild type mice, infected with the same doses of parasites, as a result of a decrease of the number of parasites in the heart even the parasitemia was only marginally less. Both in vivo and in vitro experiments reveal that Slamf1-defIcient myeloid cells are impaired in their ability to replicate the parasite and show altered production of cytokines. Importantly, IFN-γ production in the heart of Slamf1 deficient mice was much lower than in the heart of wt mice even though the number of infiltrating dendritic cells, macrophages, CD4 and CD8 T lymphocytes were comparable. Administration of an anti-Slamf1 monoclonal antibody also reduced the number of parasites and IFN-γ in the heart. These observations not only explain the reduced susceptibility to in vivo infection by the parasite, but they also suggest human Slamf1 as a potential target for therapeutic target against T. cruzi infection. © 2012 Calderón et al.


Sanoja C.,Central University of Venezuela | Carbajosa S.,Autonomous University of Madrid | Fresno M.,Autonomous University of Madrid | Fresno M.,Institute Investigacion Sanitaria Princesa IP | And 2 more authors.
PLoS ONE | Year: 2013

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects several million people in Latin America. Myocarditis, observed during both the acute and chronic phases of the disease, is characterized by an inammatory mononuclear cell infiltrate that includes CD4+ T cells. It is known that Th1 cytokines help to control infection. The role that Treg and Th17 cells may play in disease outcome, however, has not been completely elucidated. We performed a comparative study of the dynamics of CD4+ T cell subsets after infection with the T. cruzi Y strain during both the acute and chronic phases of the disease using susceptible BALB/c and non-susceptible C57BL/6 mice infected with high or low parasite inocula. During the acute phase, infected C57BL/6 mice showed high levels of CD4+ T cell infiltration and expression of Th1 cytokines in the heart associated with the presence of Treg cells. In contrast, infected BALB/c mice had a high heart parasite burden, low heart CD4+ T cell infiltration and low levels of Th1 and inflammatory cytokines, but with an increased presence of Th17 cells. Moreover, an increase in the expression of IL-6 in susceptible mice was associated with lethality upon infection with a high parasite load. Chronically infected BALB/c mice continued to present higher parasite burdens than C57BL/6 mice and also higher levels of IFN-γ, TNF, IL-10 and TGF-β. Thus, the regulation of the Th1 response by Treg cells in the acute phase may play a protective role in non-susceptible mice irrespective of parasite numbers. On the other hand, Th17 cells may protect susceptible mice at low levels of infection, but could, in association with IL-6, be pathogenic at high parasite loads. © 2013 Sanoja et al.


Garin N.,University of Barcelona | Garin N.,Institute Salud Carlos III | Olaya B.,University of Barcelona | Olaya B.,Institute Salud Carlos III | And 9 more authors.
PLoS ONE | Year: 2014

Background: In the context of population aging, multimorbidity has emerged as a growing concern in public health. However, little is known about multimorbidity patterns and other issues surrounding chronic diseases. The aim of our study was to examine multimorbidity patterns, the relationship between physical and mental conditions and the distribution of multimorbidity in the Spanish adult population. Methods: Data from this cross-sectional study was collected from the COURAGE study. A total of 4,583 participants from Spain were included, 3,625 aged over 50. An exploratory factor analysis was conducted to detect multimorbidity patterns in the population over 50 years of age. Crude and adjusted binary logistic regressions were performed to identify individual associations between physical and mental conditions. Results: Three multimorbidity patterns rose: 'cardio-respiratory' (angina, asthma, chronic lung disease), 'mental-arthritis' (arthritis, depression, anxiety) and the 'aggregated pattern' (angina, hypertension, stroke, diabetes, cataracts, edentulism, arthritis). After adjusting for covariates, asthma, chronic lung disease, arthritis and the number of physical conditions were associated with depression. Angina and the number of physical conditions were associated with a higher risk of anxiety. With regard to multimorbidity distribution, women over 65 years suffered from the highest rate of multimorbidity (67.3%). Conclusion: Multimorbidity prevalence occurs in a high percentage of the Spanish population, especially in the elderly. There are specific multimorbidity patterns and individual associations between physical and mental conditions, which bring new insights into the complexity of chronic patients. There is need to implement patient-centered care which involves these interactions rather than merely paying attention to individual diseases. © 2014 Garin et al.


PubMed | Autonomous University of Madrid, Institute Investigaciones Biomedicas IIB and Institute Investigacion Sanitaria Princesa IP
Type: | Journal: Molecular and cellular endocrinology | Year: 2015

TSH receptor (TSHR) is present in the thyroid and other tissues, as adipose tissue. In brown adipose tissue (BAT) TSH increases UCP1 expression and lipolysis. We have studied the regulation of Tshr mRNA expression and the effect of TSH on Ucp1 and Dio2 mRNA, on D2 activity and O2 consumption in rat brown adipocytes and the TSH signaling pathways. Tshr increased during brown adipocyte differentiation, was up-regulated by insulin and low TSH concentrations and down-regulated by high TSH concentrations, T3 and/or NE. TSH increased basal Ucp1 mRNA in a dose-dependent way acting synergistically with T3, while had no effect when NE was present. High TSH concentrations increased basal Dio2 mRNA (12-fold) and were synergistic with T3 (100-fold), but decreased Dio2 mRNA in T3+NE-treated cells. TSH increased D2 activities in T3-treated cells and inhibition of ERK pathway decreased the TSH effect by 55%. In T3+NE treated-cells TSH decreased D2 activity by 50%, in a dose-dependent manner. TSH activated Akt and Erk phosphorylation, while inhibition of PKA promoted Akt phosphorylation. TSH inhibited leptin mRNA. TSH increased O2 consumption by 20% and T3 enhanced its effect. Tshr is expressed in brown adipocytes and is regulated by insulin, TSH, T3 and NE. TSH increases basal and T3-stimulated Ucp1 and Dio2 expression and D2 activity only when T3 is present, but decreases Dio2 mRNA and D2 activity stimulated by NE+T3. TSH increases O2 consumption, confirming the role of TSH in the maintenance of thermogenesis.


Sanchez-Cuellar S.,Hospital Universitario Of La Princesa | Bermudez J.A.,Institute Investigacion Sanitaria Princesa IP
Revista de Patologia Respiratoria | Year: 2012

Biological markers are being used in the diagnosis and treatment of disease as prevalent as cardiovascular or cancer. Biomarkers are a useful in clinical practice as a non invasive methods for the accurate diagnosis of the disease, monitor disease and create personalized treatment regimes. Asthma is a heterogeneous disease with different phenotypes. Pulmonary function test are most often used to confirm the diagnosis, but not reflect the pathological processes responsible for different phenotypes that present the disease. Inhaled corticosteroids and beta 2 agonists have been mainstay of asthma therapy for over 30 years, but the heterogeneity of the disease means not all asthmatics respond to the same treatment. Biomarkers are useful tools to identify these specific phenotypes. This review focuses on the utility of biomarkers of inflammation of the airway in the management of asthma patients obtained by noninvasive tecniques including sputum, exhaled breath or serum. © 2012 Elsevier and Sociedad Madrileña de Neumología y Cirugía Torácica.


Cabaleiro T.,Hospital Universitario Of La Princesa | Lopez-Rodriguez R.,Institute Investigacion Sanitaria Princesa IP | Lopez-Rodriguez R.,Institute Salud Carlos III | Ochoa D.,Hospital Universitario Of La Princesa | And 4 more authors.
Human Psychopharmacology | Year: 2013

Objective: The pharmacokinetics of olanzapine and response to treatment could be affected by polymorphisms in genes coding for drug-metabolizing enzymes, transporters, or receptors. The aim of this study was to identify genetic markers predictive of pharmacokinetics, pharmacodynamics, and adverse effects of olanzapine. Methods: Sixty-three healthy volunteers receiving a single 5-mg oral dose of olanzapine were genotyped for 39 genetic variants that could be related to the response to olanzapine. All genetic variants were analyzed by PharmaChip, but DRD2 Taq1A polymorphism was determined by real-time polymerase chain reaction. Olanzapine was measured using high-performance liquid chromatography combined with tandem mass spectrometry. The relationship of gender and polymorphisms with olanzapine pharmacokinetics, the change in prolactin levels, and the incidence of adverse effects were evaluated by multiple regression analysis. Results: The pharmacokinetics of olanzapine was influenced by polymorphisms in CYP3A5, GSTM3, and GRIN2B. Prolactin levels were affected by gender and polymorphisms in DRD2 and 5-HTR2A. Polymorphisms in CYP2C9, TPMT, UGT1A1, MDR1, and 5-HTR2A were related to some adverse effects of olanzapine. Conclusions: Several polymorphisms can explain differences in the pharmacokinetics, pharmacodynamics, and safety of olanzapine in healthy subjects. Whether these genetic factors influence the risk of therapeutic failure or tolerability in patients remains to be established. Copyright © 2013 John Wiley & Sons, Ltd.


Segrelles Calvo G.,Hospital Universitario La Paz | Segrelles Calvo G.,Institute Investigacion Sanitaria Princesa IP | Zamora Garcia E.,Hospital Universitario La Paz | Ancochea J.,Hospital Universitario La Paz
Revista de Patologia Respiratoria | Year: 2014

The aim of the study was to evaluate the usefulness of non-invasive ventilation (NIV) in elderly with multiple comorbidities that was taken to hospital with respiratory acidosis (RA) due to heart failure (HF) and survivor after one year follow-up. Design: Observational prospective trial made at the Monitoring Respiratory Unit (MRU) in the Hospital Universitario La Princesa (Madrid) between 2009th October and 2010th December. We included 28 elderly (≥70 years) patients with HF and AR that needed NIV. Results: 64.3% was women. The median age was 79.6 years. Charlson Index was 3.8 and the median of drugs that patients taken was about 6. The aim complication during income was cardiovascular disease. 25% died during admission. The principal diagnosed of re-admission was HF. Global survivor was 60,7%. Discussion: NIV is a good treatment for elderly patients with HF and non-intubation orders. The principal factor associated with mortality was: low pH and high PaCO2 at Emergency department, high respiratory frequency, bad basal situation, home oxygen and previous income with RA.

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