Depósito Académico
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Results
- Ghrelin Reduces TNF-α-Induced Human Hepatocyte Apoptosis, Autophagy, and Pyroptosis: Role in Obesity-Associated NAFLD(Oxford University Press, 2019) Valenti, V. (Víctor); Ezquerro-Ezquerro, S. (Silvia); Colina, I. (Inmaculada); Catalan, V. (Victoria); Guzmán-Ruiz, R. (Rocío); Becerril, S. (Sara); Frühbeck, G. (Gema); Malagon, M.M. (María M.); Mugueta, C. (Carmen); Mocha, F. (Fátima); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia)Context: Human obesity is associated with increased circulating TNF-α, a proinflammatory cytokine that induces hepatocyte cell death. Objective: The potential beneficial effects of acylated and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-α-induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated. Design, settings, and participants: Plasma ghrelin isoforms and TNF-α were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-α-induced cell death was determined in vitro in human HepG2 hepatocytes. Results: Circulating TNF-α and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and improved hepatic function were found. Patients with obesity and type 2 diabetes showed increased hepatic ghrelin O-acyltransferase transcripts as well as an increased hepatic apoptosis, pyroptosis, and compromised autophagy. In HepG2 hepatocytes, acylated and desacyl ghrelin treatment reduced TNF-α-induced apoptosis, evidenced by lower caspase-8 and caspase-3 cleavage, as well as TUNEL-positive cells and pyroptosis, revealed by decreased caspase-1 activation and lower high-mobility group box 1 expression. Moreover, acylated ghrelin suppressed TNF-α-activated hepatocyte autophagy, as evidenced by a decreased LC3B-II/I ratio and increased p62 accumulation via AMPK/mTOR. Conclusions: Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-α-induced hepatocyte apoptosis, autophagy, and pyroptosis.
- Evaluation of the quality of multiple-choice questions according to the students’ academic level(BMC, 2022) Landecho, M.F. (Manuel F.); Lucena-Ramírez, J.F. (Juan Felipe); Fernandez-Ros, N. (Nerea); Iñarrairaegui, M. (Mercedes); Herrero, J.I. (José Ignacio); Garcia, N. (Nicolás); Quiroga, J. (Jorge)Background: One of the most important challenges in medical education is the preparation of multiple-choice questions able to discriminate between students with diferent academic level. Average questions may be very easy for students with good performance, reducing their discriminant power in this group of students. The aim of this study was to analyze if the discriminative power of multiple-choice questions is diferent according to the students’ academic performance. Methods: We retrospectively analyzed the difculty and discrimination indices of 257 multiple-choice questions used for the end of course examination of pathophysiology and analyzed whether the discrimination indices were lower in students with good academic performance (group 1) than in students with moderate/poor academic perfor‐ mance (group 2). We also evaluated whether case-based questions maintained their discriminant power better than factual questions in both groups of students or not. Comparison of the difculty and discrimination indices between both groups was based on the Wilcoxon test. Results: Difculty index was signifcantly higher in group 1 (median: 0.78 versus 0.56; P< 0.001) and discrimination index was signifcantly higher in group 2 (median: 0.21 versus 0.28; P< 0.001). Factual questions had higher discrimi‐ native indices in group 2 than in group 1 (median: 0.28 versus 0.20; P< 0.001), but discriminative indices of case- based questions did not difer signifcantly between groups (median: 0.30 versus 0.24; P=0.296). Conclusions: Multiple-choice question exams have lower discriminative power in the group of students with high scores. The use of clinical vignettes may allow to maintain the discriminative power of multiple-choice questions.
- Association of cystatin C with heart failure with preserved ejection fraction in elderly hypertensive patients: potential role of altered collagen metabolism(Lippincott Williams & Wilkins, 2016) Huerta, A. (Ana); Brugnolaro, C. (Cristina); Beloqui, O. (Óscar); Zubillaga, E. (Elena); Querejeta, R. (Ramón); Ravassa, S. (Susana); Gonzalez, A. (Arantxa); Rabago, G. (Gregorio); San-Jose, G. (Gorka); López, B. (Begoña); Diez, J. (Javier)Objectives: Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF. Methods: One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP- 1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts. Results: Compared with controls, cystatin C was increased (P < 0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P < 0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P < 0.01), TIMP-1 and osteopontin (P < 0.001) and inversely correlated with MMP-1:TIMP-1 (P < 0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP- 1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P < 0.01) and TIMP-1 (P < 0.001) increased in the supernatant of cardiac fibroblasts exposed to cystatin C. Conclusion: In patients with HFPEF of hypertensive origin, cystatin C is increased and associated with diastolic dysfunction and alterations in collagen metabolism independently of eGFR. An excess of cystatin C might contribute to diastolic dysfunction in HFPEF by facilitating myocardial fibrosis via accumulation of osteopontin and TIMP-1.
- Association of low GLP-1 with oxidative stress is related to cardiac disease and outcome in patients with type 2 diabetes mellitus: A pilot study(Elsevier, 2015) Huerta, A. (Ana); Ravassa, S. (Susana); Barba, J. (Joaquín); Gonzalez, A. (Arantxa); Coma-Canella, I. (Isabel); Beaumont, J. (Javier); López, B. (Begoña); Diez, J. (Javier)Oxidative stress (OS) contributes to cardiovascular damage in type 2 diabetes mellitus (T2DM). The peptide glucagon-like peptide-1 (GLP-1) inhibits OS and exerts cardiovascular protective actions. Our aim was to investigate whether cardiac remodeling (CR) and cardiovascular events (CVE) are associated with circulating GLP-1 and biomarkers of OS in T2DM patients. We also studied GLP-1 antioxidant effects in a model of cardiomyocyte lipotoxicity. We examined 72 T2DM patients with no coronary or valve heart disease and 14 nondiabetic subjects. A median of 6 years follow-up information was obtained in 60 patients. Circulating GLP- 1, dipeptidyl peptidase-4 activity, and biomarkers of OS were quantified. In T2DM patients, circulating GLP-1 decreased and OS biomarkers increased, compared with nondiabetics. Plasma GLP-1 was inversely correlated with serum 3-nitrotyrosine in T2DM patients. Patients showing high circulating 3-nitrotyrosine and low GLP- 1 levels exhibited CR and higher risk for CVE, compared to the remaining patients. In palmitate-stimulated HL-1 cardiomyocytes, GLP-1 reduced cytosolic and mitochondrial oxidative stress, increased mitochondrial ATP synthase expression, partially restored mitochondrial membrane permeability and cytochrome c oxidase activity, blunted leakage of creatine to the extracellular medium, and inhibited oxidative damage in total and mitochondrial DNA. These results suggest that T2DM patients with reduced circulating GLP-1 and exacerbated OS may exhibit CR and be at higher risk for CVE. In addition, GLP-1 exerts antioxidant effects in HL-1 palmitate-overloaded cardiomyocytes. It is proposed that therapies aimed to increase GLP-1 may counteract OS, protect from CR, and prevent CVE in patients with T2DM.
- Mortality Prediction in Patients Undergoing Non-Invasive Ventilation in Intermediate Care(San Francisco CA: Public Library of Science, 2015) Landecho, M.F. (Manuel F.); Garcia-Mouriz, A. (Alberto); Lucena-Ramírez, J.F. (Juan Felipe); Huerta, A. (Ana); Alegre, F. (Félix); Fernandez-Ros, N. (Nerea); Martinez-Urbistondo, D. (Diego); Carmona-Torre, F. (Francisco de A.); Garcia, N. (Nicolás); Quiroga, J. (Jorge); Nuñez-Cordoba, J.M. (Jorge M.)Background Intermediate Care Units (ImCU) have become an alternative scenario to perform Non-Inva- sive Ventilation (NIV). The limited number of prognostic studies in this population support the need of mortality prediction evaluation in this context. Objective The objective of this study is to analyze the performance of Simplified Acute Physiology Score (SAPS) II and 3 in patients undergoing NIV in an ImCU. Additionally, we searched for new variables that could be useful to customize these scores, in order to improve mortality prediction. Design Cohort study with prospectively collected data from all patients admitted to a single center ImCU who received NIV. The SAPS II and 3 scores with their respective predicted mortality rates were calculated. Discrimination and calibration were evaluated by calculating the area under the receiver operating characteristic curve (AUC) and with the Hosmer-Lemeshow goodness of fit test for the models, respectively. Binary logistic regression was used to iden- tify new variables to customize the scores for mortality prediction in this setting. Patients The study included 241 patients consecutively admitted to an ImCU staffed by hospitalists from April 2006 to December 2013. Key Results The observed in-hospital mortality was 32.4% resulting in a Standardized Mortality Ratio (SMR) of 1.35 for SAPS II and 0.68 for SAPS 3. Mortality discrimination based on the AUC was 0.73 for SAPS II and 0.69 for SAPS 3. Customized models including immunosuppres- sion, chronic obstructive pulmonary disease (COPD), acute pulmonary edema (APE), lactic acid, pCO2 and haemoglobin levels showed better discrimination than old scores with simi- lar calibration power. Conclusions These results suggest that SAPS II and 3 should be customized with additional patient-risk factors to improve mortality prediction in patients undergoing NIV in intermediate care.
- Design and Performance of a New Severity Score for Intermediate Care(San Francisco CA: Public Library of Science, 2015) Landecho, M.F. (Manuel F.); Lucena-Ramírez, J.F. (Juan Felipe); Huerta, A. (Ana); Alegre, F. (Félix); Fernandez-Ros, N. (Nerea); Martinez-Urbistondo, D. (Diego); Garcia, N. (Nicolás)Background Application of illness-severity scores in Intermediate Care Units (ImCU) shows conflicting results. The aim of the study is to design a severity-of-illness score for patients admitted to an ImCU. Methods We performed a retrospective observational study in a single academic medical centre in Pamplona, Spain. Demographics, past medical history, reasons for admission, physiologi- cal parameters at admission and during the first 24 hours of ImCU stay, laboratory variables and survival to hospital discharge were recorded. Logistic regression analysis was per- formed to identify variables for mortality prediction. Results A total of 743 patients were included. The final multivariable model (derivation cohort = 554 patients) contained only 9 variables obtained at admission to the ImCU: previous length of stay 7 days (6 points), health-care related infection (11), metastatic cancer (9), immunosup- pressive therapy (6), Glasgow comma scale 12 (10), need of non-invasive ventilation (14), platelets 50000/mcL (9), urea 0.6 g/L (10) and bilirubin 4 mg/dL (9). The ImCU severity score (ImCUSS) is generated by summing the individual point values, and the formula for determining the expected in-hospital mortality risk is: eImCUSS points*0.099 – 4,111 / (1 + eImCUSS points*0.099 – 4,111). The model showed adequate calibration and discrimination. Performance of ImCUSS (validation cohort = 189 patients) was comparable to that of SAPS II and 3. Hos- mer-Lemeshow goodness-of-fit C test was χ2 8.078 (p=0.326) and the area under receiver operating curve 0.802. Conclusions ImCUSS, specially designed for intermediate care, is based on easy to obtain variables at admission to ImCU. Additionally, it shows a notable performance in terms of calibration and mortality discrimination.
- Enterococcal bloodstream infection. Design and validation of a mortality prediction rule(John Wiley & Sons Ltd, 2016) Landecho, M.F. (Manuel F.); Lucena, F. (Felipe); Huerta, A. (Ana); Alegre, F. (Félix); Pérez-García, A. (Alejandra); Conde-Estevez, D. (David); Pozo, J.L. (José Luis) del; Gómez, J. (J.); Mauleón, E. (E.); Beunza, J.J. (Juan José); Grau, S. (Santiago); Terradas-Robledo, R. (Roser); Gea, A. (Alfredo)Background: To develop a prediction rule to describe the risk of death as a result of enterococcal bloodstream infection. Methods: A prediction rule was developed by analysing data collected from 122 patients diagnosed with entero- coccal BSI admitted to the Clınica Universidad de Navarra (Pamplona, Spain); and validated by confirming its accuracy with the data of an external population (Hospital del Mar, Barcelona). Results: According to this model, independent sig- nificant predictors for the risk of death were being diabetic, have received appro- priate treatment, severe prognosis of the underlying diseases, have renal failure, received solid organ transplant, malignancy, source of the bloodstream infection and be immunosuppressed. The prediction rule showed a very good calibration (Hosmer–Lemeshow statistic, P = 0.93) and discrimination for both training and testing sets (area under ROC curve = 0.84 and 0.83 respectively). Conclusions: The predictive rule was able to predict risk of death as a result of enterococcal bloodstream infection as well as to identify patients, who being below the thresh- old value, will have a low risk of death with a negative predictive value of 96%.
- El índice neutrófilo/linfocito como marcador de disfunción sistémica endotelial en sujetos asintomáticos(Sociedad Española de Nefrología, 2016) Huerta, A. (Ana); Beloqui, O. (Óscar); Martinez-Urbistondo, D. (Diego); Beltrán, A. (Almudena)Fundamento y objetivo: El índice neutrófilo/linfocito es un marcador inflamatorio de valor pronóstico en enfermedades cardiovasculares. El objetivo del presente trabajo es valorar la asociación entre el índice neutrófilo/linfocito y la alteración del cociente albú- mina/creatinina urinario como marcador precoz de disfunción endotelial sistémica asociada a enfermedad microvascular y riesgo cardiovascular, en sujetos asintomáticos. Materiales y métodos: Se realizó un estudio transversal en 1.816 sujetos asintomáticos. Se excluyó del a estudio aquellos pacientes que presentaron antecedentes de enfermedad car- diovascular, los que recibían tratamiento con fármacos antiproteinúricos (inhibidores de la enzima conversora de angiotensina y antagonistas de los receptores de la angiotensina II) y aquellos que presentaron un cociente albúmina/creatinina superior a 300mg/dL. La variable desenlace del estudio fue la alteración del cociente albúmina/creatinina urinario. Resultados: El índice neutrófilo/linfocito resultó significativamente asociado a la alteración del cociente albúmina/creatinina urinario, tanto en el estudio univariante como en el mul- tivariante, independientemente de otros cofactores como la edad, la hipertensión arterial, la diabetes, la dislipidemia o el filtrado glomerular patológico. El análisis de la sensibilidad y la especificidad de distintos niveles del índice neutrófilo/linfocito permitió generar 3 grupos de riesgo de alteración del cociente albúmina/creatina urinario: riesgo bajo con un cociente neutrófilo/linfocito < 1,5, riesgo intermedio con cociente neutrófilo/linfocito entre 1,5y3y riesgo alto con un cociente neutrófilo/linfocito > 3. La proporción relativa de alteración del cociente albúmina/creatinina urinario, en los 3 grupos de riesgo, aumentaba en razón del valor del índice neutrófilo/linfocito de forma independiente al resto de cofactores. Conclusiones: El índice neutrófilo/linfocito surge como un potencial marcador de disfun- ción endotelial sistémica económico, rápido, no invasivo e independiente de otros factores conocidos, en sujetos asintomáticos.
- Estimation of fatty liver disease clinical role on glucose metabolic remodelling phenotypes and T2DM onset(Wiley, 2023) Landecho, M.F. (Manuel F.); Martinez, J.A. (José Alfredo); Navarro-Gonzalez, D. (David); Huerta, A. (Ana); Martinez-Urbistondo, D. (Diego); Sanchez-Iñigo, L. (Laura); Fernandez-Montero, A. (Alejandro); Pastrana-Delgado, J. (Juan)Introduction: Metabolic syndrome (MetS), prediabetes (PreDM) and Fatty Liver Disease (FLD) share pathophysiological pathways concerning type 2 diabetes mellitus (T2DM) onset. The non-invasive assessment of fatty liver combined with PreDM and MetS features screening might provide further accuracy in predicting hyperglycemic status in the clinical setting with the putative description of singu- lar phenotypes. The objective of the study is to evaluate and describe the links of a widely available FLD surrogate -the non-invasive serological biomarker Hepatic Steatosis Index (HSI)- with previously described T2DM risk predictors, such as preDM and MetS in forecasting T2DM onset. Patients and methods: A retrospective ancillary cohort study was performed on 2799 patients recruited in the Vascular-Metabolic CUN cohort. The main out- come was the incidence of T2DM according to ADA criteria. MetS and PreDM were defined according to ATP III and ADA criteria, respectively. Hepatic stea- tosis index (HSI) with standardized thresholds was used to discriminate patients with FLD, which was referred as estimated FLD (eFLD). Results: MetS and PreDM were more common in patients with eFLD as com- pared to those with an HSI < 36 points (35% vs 8% and 34% vs. 18%, respectively). Interestingly, eFLD showed clinical effect modification with MetS and PreDM in the prediction of T2DM [eFLD-MetS interaction HR = 4.48 (3.37-5.97) and eFLD-PreDM interaction HR = 6.34 (4.67-8.62)]. These findings supported thedescription of 5 different liver status-linked phenotypes with increasing risk of T2DM: Control group (1,5% of T2DM incidence), eFLD patients (4,4% of T2DM incidence), eFLD and MetS patients (10,6% of T2DM incidence), PreDM patients (11,1% of T2DM incidence) and eFLD and PreDM patients (28,2% of T2DM inci- dence). These phenotypes provided independent capacity of prediction of T2DM incidence after adjustment for age, sex, tobacco and alcohol consumption, obesity and number of SMet features with a c-Harrell=0.84. Conclusion: Estimated Fatty Liver Disease using HSI criteria (eFLD) interplay with MetS features and PreDM might help to discriminate patient risk of T2DM in the clinical setting through the description of independent metabolic risk phenotypes. [Correction added on 15 June 2023, after first online publication: The abstract section was updated in this current version.]
- Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial(Lancet Pub. Group, 2022) Yau, T. (Thomas); El-Khoueiry, A. (Anthony); Edeline, J. (Julien); Chen, G. (Gong); Park, J.W. (Joong-Won); Wyrwicz, L. (Lucjan); Choo, S.P. (Su-Pin); Wisniewski, T. (Tami); Harding, J.J. (James J.); Schott, E. (Eckart); Begic, D. (Damir); Furuse, J. (Junji); Assenat, E. (Eric); Sieghart, W. (Wolfgang); Kate-Kelley, R. (Robin); Sangro, B. (Bruno); Kudo, M. (Masatoshi); Neely, J. (Jaclyn); Zaucha, R. (Renata); Melero, I. (Ignacio); Rosmorduc, O. (Olivier); Merle, P. (Philippe); Tschaika, M. (Marina); Finn, R.S. (Richard S.); Cheng, A.L. (Ann-Lii); Mathurin, P. (Philippe); Abou-Alfa, G.K. (Ghassan K.)Background: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. Methods: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. Findings: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. Interpretation: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.