Institute Investigacion Sanitaria INCLIVA

Valencia, Spain

Institute Investigacion Sanitaria INCLIVA

Valencia, Spain

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Belghiti M.,Research Center Principe Felipe | Agusti A.,Institute Investigacion Sanitaria INCLIVA | Hernandez-Rabaza V.,Research Center Principe Felipe | Cabrera-Pastor A.,Research Center Principe Felipe | And 2 more authors.
Neurochemical Research | Year: 2016

Pruritus is a common symptom in chronic liver diseases, which may also alter thermal sensitivity. The underlying mechanisms remain unclear and treatments are not satisfactory. Portal-systemic shunting has been proposed to alter thermal sensitivity in cirrhotics. Inflammation-induced enhanced activity of the Transient Receptor Potential Vanilloid 1 (TRPV1) may contribute to pruritus and thermal hyperalgesia. Sildenafil reduces neuroinflammation in portacaval shunt (PCS) rats. The aims were to assess whether: (1) PCS rats show enhanced scratching or thermal sensitivity; (2) TRPV1 activity is enhanced in PCS rats; (3) treatment with sildenafil reduces TRPV1 activation, scratching and thermal hyperalgesia. Rats were treated with sildenafil beginning 3 weeks after surgery. The number of scratches performed were counted. Thermal hyperalgesia was analyzed using the Hargreaves’ Plantar Test. TRPV1 activation by measuring the increase in Ca2+ induced by capsaicin in dorsal root ganglia neurons. PCS rats show enhanced scratching behavior, reaching 66 ± 5 scratches/h (p < 0.01) at 21 days after surgery, while controls show 37 ± 2 scratches/h. PCS rats show thermal hyperalgesia. Paw withdrawal latency was reduced (p < 0.05) to 10 ± 1 s compared to controls (21 ± 2 s). Capsaicin-induced calcium increase was higher in dorsal root ganglia cultures from PCS rats, indicating TRPV1functional increase. PCS rats show enhanced scratching behavior and thermal sensitivity and are a good model to study these alterations in chronic liver diseases. Enhanced sensitivity and activity of TRPV1 channel underlies these alterations. Treatment with sildenafil reduces TRPV1 channel sensitivity and activity and normalizes scratching behavior and thermal sensitivity. © 2016 Springer Science+Business Media New York


Gomez-Navarro N.,University of Valencia | Peiro-Chova L.,University of Valencia | Peiro-Chova L.,Institute Investigacion Sanitaria INCLIVA | Rodriguez-Navarro S.,Research Center Principe Felipe | And 2 more authors.
Molecular and Cellular Biology | Year: 2013

The assembly and nuclear transport of RNA polymerase II (RNA pol II) are processes that require the participation of many auxiliary factors. In a yeast genetic screen, we identified a previously uncharacterized gene, YMR185w (renamed RTP1), which encodes a protein required for the nuclear import of RNA pol II. Using protein affinity purification coupled to mass spectrometry, we identified interactions between Rtp1p and members of the R2TP complex. Rtp1p also interacts, to a different extent, with several RNA pol II subunits. The pattern of interactions is compatible with a role for Rtp1p as an assembly factor that participates in the formation of the Rpb2/Rpb3 subassembly complex and its binding to the Rpb1p-containing subcomplex. Besides, Rtp1p has a molecular architecture characteristic of karyopherins, composed of HEAT repeats, and is able to interact with phenylalanine- glycine-containing nucleoporins. Our results define Rtp1p as a new component of the RNA pol II biogenesis machinery that plays roles in ubunit assembly and likely in transport through the nuclear pore complex. © 2013, American Society for Microbiology.


Navarro-Perez J.,Institute Investigacion Sanitaria INCLIVA | Peiro S.,Centro Superior Of Investigacion En Salud Publica Csisp Fisabio | Lopez-Alcina E.,Consorcio Hospital General Universitario Of Valencia | Real-Romaguera A.,Consorcio Hospital General Universitario Of Valencia
Atencion Primaria | Year: 2014

Objective To assess quality of care indicators for benign prostatic hyperplasia (BPH), and to evaluate their strengths and weaknesses for incorporation into health information systems. Design Structured expert meeting, using procedures adapted from the nominal group techniques and the Rand consensus method. Setting Valencian School of Health Studies. Participants and/or contexts Forty panellists (74% doctors, 70% from primary care settings) with experience in the management of BPH from 15 departments of the Valencia Health Agency. Method Three workshops were held simultaneously (examination and diagnosis, drug therapy, and appropriateness and results), and the 15 quality indicators selected by the coordination group were assessed. Results Eleven of the 15 indicators scored in the range of high relevance. The 5 best rated were: the use of alpha-blockers + 5-alpha reductase inhibitor from certain severity level, digital rectal examination in the initial assessment, follow-up with the International Prostate Symptoms Score (IPSS), the rate of urgent catheterization in Hospital Accident & Emergency Units, initial assessment with the IPSS and the use of alpha-blockers prior to catheter removal for acute retention of urine. Conclusions Some of the assessed indicators can be useful for incorporation into health information systems. © 2013 Elsevier España, S.L. All rights reserved.


Rodriguez-Berna G.,Polytechnic University of Valencia | Mangas-Sanjuan V.,University Miguel Hernández | Gonzalez-Alvarez M.,University Miguel Hernández | Gonzalez-Alvarez I.,University Miguel Hernández | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2014

Oral administration of camptothecin (CPT) derivatives and other antitumoral agents is being actively developed in order to improve the quality of life of patients with cancer. Though several lipophilic derivatives of CPT have shown interesting oral bioavailability in preclinical and clinical studies, only Topotecan has been approved for this route of administration. Semisynthesis, antitumor activity, biological inhibition mechanism, and in situ intestinal permeability of 9, 10-[1,3]-Dioxinocamptothecin (CDiox), an unexplored CPT derivative, have been studied in this paper. The hexacyclic analog was as effective as Topotecan and CPT in different tumor cell lines, showing an expected similar apoptosis cell mechanism and high ability to inhibit DNA synthesis in HeLa, Caco-2, A375 and MDA-MB-231 cell lines. Furthermore, in vitro and in situ pharmacokinetics transport values obtained for CDiox displayed more favorable absorption profile than CPT and Topotecan. © 2014 Elsevier Masson SAS. All rights reserved.


Ampuero J.,University of Seville | Simon M.,Hospital Universitari Vall dHebron | Montoliu C.,Institute Investigacion Sanitaria INCLIVA | Jover R.,Hospital General Universitario | And 3 more authors.
Gastroenterology | Year: 2015

Background and Aims Minimal hepatic encephalopathy (MHE) is associated with falls, traffic accidents, and overt HE. However, the association with survival is controversial. We assessed the effects of MHE on the long-term survival of patients with cirrhosis. Methods We performed a prospective study of 117 consecutive patients with cirrhosis seen at a tertiary hospital in Seville, Spain (estimation cohort), followed by a validation study of 114 consecutive patients with cirrhosis seen at 4 hospitals in Spain from January 2004 through December 2007. Patients were examined every 6 months at outpatient clinics through December 2013 (follow-up periods of 5 ± 2.8 y and 4.4 ± 3.9 y for each group, respectively). Cirrhosis was identified by liver biopsy, ultrasound, endoscopic analysis, and biochemical parameters. Liver dysfunction was determined based on model for end-stage liver disease (MELD) and Child-Pugh scores. All patients were administered the critical flicker frequency (CFF) test and psychometric hepatic encephalopathy scores were used to detect MHE. Survival curves were compared using the log-rank test and multivariable analysis was performed using Cox proportional hazards models. Results The distributions of Child-Pugh scores were as follows: 66% class A, 31% class B, and 3% class C in the estimation cohort, and 50% class A, 32% class B, and 18% class C in the validation cohort. In the estimation cohort, 24 of 35 patients (68.6%) with a CFF score less than 39 Hz survived for 5 years, whereas 50 of 61 patients (82%) with a CFF score of 39 Hz or higher survived during the follow-up period (log-rank score, 5.07; P =.024). Psychometric hepatic encephalopathy scores did not correlate with survival. In multivariable analysis, older age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02-1.12; P =.009), CFF score less than 39 Hz (HR, 4.36; 95% CI, 1.67-11.37; P =.003), and MELD score (HR, 1.40; 95% CI, 1.21-1.63; P =.0001) were associated independently with survival during the follow-up period. In the validation cohort, CFF score less than 39 Hz and MELD score also were associated with patient survival during the follow-up period. MHE had no effect on the survival of patients with MELD scores less than 10 (among patients with CFF scores ≥39 Hz, 94.5% survived for 5 years vs 91.9% of patients with CFF scores <39 Hz; log-rank score, 0.64; P =.423). Fewer patients with MELD scores of 10-15 and MHE survived for 5 years (44.4%; 12 of 27) than those with MELD scores greater than 15 without MHE (61.5%; 8 of 13) (P <.05). Only 2 of 12 patients (16.7%) with MELD scores of 15 or higher and MHE survived for 5 years (log-rank score, 90.56; P =.0001). Conclusions MHE is associated with a reduced 5-year survival rate of patients with cirrhosis. Evaluation of MHE could help predict survival times and outcomes of patients with specific MELD scores. The CFF could help physicians determine prognoses of patients with cirrhosis. © 2015 AGA Institute.


Izarra A.,CSIC - National Center for Biotechnology | Moscoso I.,University of Santiago de Compostela | Levent E.,University of Gottingen | Canon S.,CSIC - National Center for Biotechnology | And 9 more authors.
Stem Cell Reports | Year: 2014

miR-133a and miR-1 are known as muscle-specific microRNAs that are involved in cardiac development and pathophysiology. We have shown that both miR-1 and miR-133a are early and progressively upregulated during in vitro cardiac differentiation of adult cardiac progenitor cells (CPCs), but only miR-133a expression was enhanced under in vitro oxidative stress. miR-1 was demonstrated to favor differentiation of CPCs, whereas miR-133a overexpression protected CPCs against cell death, targeting, among others, the proapoptotic genes Bim and Bmf. miR-133a-CPCs clearly improved cardiac function in a rat myocardial infarction model by reducing fibrosis and hypertrophy and increasing vascularization and cardiomyocyte proliferation. The beneficial effects of miR-133a-CPCs seem to correlate with the upregulated expression of several relevant paracrine factors and the plausible cooperative secretion of miR-133a via exosomal transport. Finally, an in vitro heart muscle model confirmed the antiapoptotic effects of miR-133a-CPCs, favoring the structuration and contractile functionality of the artificial tissue. © 2014 The Authors.


PubMed | Servicio Of Dano Cerebral Del Hospital Valencia Al Mar, Hospital Arnau Of Vilanova, Centro Investigacion Principe Felipe Of Valencia, University of Valencia and Institute Investigacion Sanitaria INCLIVA
Type: | Journal: Liver international : official journal of the International Association for the Study of the Liver | Year: 2016

Cognitive dysfunction in cirrhotic patients with minimal hepatic encephalopathy (MHE) is associated with falls. Alterations in postural control and stability could contribute to increase falls risk in these patients. We aimed to assess whether postural control and direction-specific limits of stability are altered in cirrhotic patients with MHE compared to patients without MHE and controls. We also assessed if alterations in postural control correlate with neurological impairment and/or blood biomarkers.Posturography analysis, attention Stroop test and bimanual and visuo-motor coordination tests were performed in 18 controls, 19 patients with cirrhosis without MHE and 17 with MHE, diagnosed by PHES. Posturography was assessed by NedSVEMHE patients show impaired balance, mainly on unstable surface with eyes open, with longer reaction and confinement times and lower success in Limits of Stability test compared to patients without MHE. Performance in attention and motor coordination tests correlated with most posturography parameters alterations. Logistic regression analysis shows that posturography parameters and bimanual coordination test are good predictors of falls.Balance patterns and limits of stability in MHE patients are impaired compared to patients without MHE and controls. This seems to contribute to a higher falls risk. Attention and motor coordination deficits could contribute to balance impairment in patients with MHE. This article is protected by copyright. All rights reserved.


PubMed | Centro Superior Of Investigacion En Salud Publica Csisp Fisabio, Consorcio Hospital General Universitario Of Valencia and Institute Investigacion Sanitaria INCLIVA
Type: Journal Article | Journal: Atencion primaria | Year: 2014

To assess quality of care indicators for benign prostatic hyperplasia (BPH), and to evaluate their strengths and weaknesses for incorporation into health information systems.Structured expert meeting, using procedures adapted from the nominal group techniques and the Rand consensus method.Valencian School of Health Studies.Forty panellists (74% doctors, 70% from primary care settings) with experience in the management of BPH from 15 departments of the Valencia Health Agency.Three workshops were held simultaneously (examination and diagnosis, drug therapy, and appropriateness and results), and the 15 quality indicators selected by the coordination group were assessed.Eleven of the 15 indicators scored in the range of high relevance. The 5 best rated were: the use of alpha-blockers + 5-alpha reductase inhibitor from certain severity level, digital rectal examination in the initial assessment, follow-up with the International Prostate Symptoms Score (IPSS), the rate of urgent catheterization in Hospital Accident & Emergency Units, initial assessment with the IPSS and the use of alpha-blockers prior to catheter removal for acute retention of urine.Some of the assessed indicators can be useful for incorporation into health information systems.


PubMed | Research Center Principe Felipe and Institute Investigacion Sanitaria INCLIVA
Type: | Journal: Neurochemical research | Year: 2016

Pruritus is a common symptom in chronic liver diseases, which may also alter thermal sensitivity. The underlying mechanisms remain unclear and treatments are not satisfactory. Portal-systemic shunting has been proposed to alter thermal sensitivity in cirrhotics. Inflammation-induced enhanced activity of the Transient Receptor Potential Vanilloid 1 (TRPV1) may contribute to pruritus and thermal hyperalgesia. Sildenafil reduces neuroinflammation in portacaval shunt (PCS) rats. The aims were to assess whether: (1) PCS rats show enhanced scratching or thermal sensitivity; (2) TRPV1 activity is enhanced in PCS rats; (3) treatment with sildenafil reduces TRPV1 activation, scratching and thermal hyperalgesia. Rats were treated with sildenafil beginning 3weeks after surgery. The number of scratches performed were counted. Thermal hyperalgesia was analyzed using the Hargreaves Plantar Test. TRPV1 activation by measuring the increase in Ca


PubMed | Hospital Clinico Universitario, Hospital Universitari Vall dHebron, Hospital General Universitario, University of Seville and Institute Investigacion Sanitaria INCLIVA
Type: Journal Article | Journal: Gastroenterology | Year: 2015

Minimal hepatic encephalopathy (MHE) is associated with falls, traffic accidents, and overt HE. However, the association with survival is controversial. We assessed the effects of MHE on the long-term survival of patients with cirrhosis.We performed a prospective study of 117 consecutive patients with cirrhosis seen at a tertiary hospital in Seville, Spain (estimation cohort), followed by a validation study of 114 consecutive patients with cirrhosis seen at 4 hospitals in Spain from January 2004 through December 2007. Patients were examined every 6 months at outpatient clinics through December 2013 (follow-up periods of 5 2.8 y and 4.4 3.9 y for each group, respectively). Cirrhosis was identified by liver biopsy, ultrasound, endoscopic analysis, and biochemical parameters. Liver dysfunction was determined based on model for end-stage liver disease (MELD) and Child-Pugh scores. All patients were administered the critical flicker frequency (CFF) test and psychometric hepatic encephalopathy scores were used to detect MHE. Survival curves were compared using the log-rank test and multivariable analysis was performed using Cox proportional hazards models.The distributions of Child-Pugh scores were as follows: 66% class A, 31% class B, and 3% class C in the estimation cohort, and 50% class A, 32% class B, and 18% class C in the validation cohort. In the estimation cohort, 24 of 35 patients (68.6%) with a CFF score less than 39 Hz survived for 5 years, whereas 50 of 61 patients (82%) with a CFF score of 39 Hz or higher survived during the follow-up period (log-rank score, 5.07; P= .024). Psychometric hepatic encephalopathy scores did not correlate with survival. In multivariable analysis, older age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02-1.12; P= .009), CFF score less than 39 Hz (HR, 4.36; 95% CI, 1.67-11.37; P= .003), and MELD score (HR, 1.40; 95% CI, 1.21-1.63; P= .0001) were associated independently with survival during the follow-up period. In the validation cohort, CFF score less than 39 Hz and MELD score also were associated with patient survival during the follow-up period. MHE had no effect on the survival of patients with MELD scores less than 10 (among patients with CFF scores 39 Hz, 94.5% survived for 5 years vs 91.9% of patients with CFF scores <39 Hz; log-rank score, 0.64; P= .423). Fewer patients with MELD scores of 10-15 and MHE survived for 5 years (44.4%; 12 of 27) than those with MELD scores greater than 15 without MHE (61.5%; 8 of 13) (P < .05). Only 2 of 12 patients (16.7%) with MELD scores of 15 or higher and MHE survived for 5 years (log-rank score, 90.56; P= .0001).MHE is associated with a reduced 5-year survival rate of patients with cirrhosis. Evaluation of MHE could help predict survival times and outcomes of patients with specific MELD scores. The CFF could help physicians determine prognoses of patients with cirrhosis.

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