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Vidal E.,University of Cordoba, Spain | Torre-Cisneros J.,University of Cordoba, Spain | Blanes M.,University of Valencia | Montejo M.,University Hospital Of Cruces | And 11 more authors.
Transplant Infectious Disease | Year: 2012

Background: Urinary tract infection (UTI) is the most common infection in renal transplant patients, but it is necessary to determine the risk factors for bacterial UTI in recipients of other solid organ transplants (SOTs), as well as changes in etiology, clinical presentation, and prognosis. Methods: In total, 4388 SOT recipients were monitored in 16 transplant centers belonging to the Spanish Network for Research on Infection in Transplantation (RESITRA). The frequency and characteristics of bacterial UTI in transplant patients were obtained prospectively from the cohort (September 2003 to February 2005). Results: A total of 192 patients (4.4%) presented 249 episodes of bacterial UTI (0.23 episodes per 1000 transplantation days); 156 patients were kidney or kidney-pancreas transplant recipients, and 36 patients were liver, heart, and lung transplant recipients. The highest frequency was observed in renal transplants (7.3%). High frequency of cystitis versus pyelonephritis without related mortality was observed in both groups. The most frequent etiology was Escherichia coli (57.8%), with 25.7% producing extended-spectrum β-lactamase (ESBL). In all transplants but renal, most cases occurred in the first month after transplantation. Cases were uniformly distributed during the first 6 months after transplantation in renal recipients. Age (odds ratio [OR] per decade 1.1, 95% confidence interval [CI] 1.02-1.17), female gender (OR 1.74, 95% CI 1.42-2.13), and the need for immediate post-transplant dialysis (OR 1.63, 95% CI 1.29-2.05) were independent variables associated with bacterial UTI in renal and kidney-pancreas recipients. The independent risk factors identified in non-renal transplants were age (OR per decade 1.79, 95% CI 1.09-3.48), female gender (OR 1.7, 95% CI 1.43-2.49), and diabetes (OR 1.02, 95% CI 1.001-1.040). Conclusions: UTI was frequent in renal transplants, but also not unusual in non-renal transplants. Because E. coli continues to be the most frequent etiology, the emergence of ESBL-producing strains has been identified as a new problem. In both populations, most cases were cystitis without related mortality. Although the first month after transplantation was a risk period in all transplants, cases were uniformly distributed during the first 6 months in renal transplants. Age and female gender were identified as risk factors for UTI in both populations. Other particular risk factors were the need for immediate post-transplant dialysis in renal transplants and diabetes in non-renal transplants. © 2012 John Wiley & Sons A/S.


Lopez J.I.,University Hospital of Cruces | Andres L.,University Hospital of Cruces | Etxezarraga C.,University Hospital of Basurto | Santaolalla F.,University of the Basque Country | Zabala A.,University of the Basque Country
Regulatory Peptides | Year: 2010

Prolyl endopeptidase (EC 3.4.21.26) (PEP) is a serine peptidase that converts several biologically active peptides. This enzyme has been linked to several neurological, digestive, cardiovascular and infectous disorders. However, little is known about its involvement in neoplastic processes. This study analyzes fluorimetrically cytosolic and membrane-bound PEP activity in a large series (n=122) of normal and neoplastic tissues from the kidney, colon, oral cavity, larynx, thyroid gland and testis. Cytosolic PEP activity significantly increased in clear cell renal cell carcinoma, urothelial carcinoma of the renal pelvis and head and neck squamous cell carcinoma. Both cytosolic and membrane-bound PEP activity were also increased in colorectal adenomatous polyps. These data suggest the involvement of PEP in some mechanisms that underlie neoplastic processes. © 2010 Elsevier B.V.


San-Juan R.,Hospital General Universitario Doce Of Octubre | Aguado J.M.,Hospital General Universitario Doce Of Octubre | Lumbreras C.,Hospital General Universitario Doce Of Octubre | Fortun J.,University Hospital Ramon y Cajal | And 11 more authors.
Transplantation | Year: 2011

Background: Although antifungal prophylaxis in high-risk liver transplant recipients (LTR) seems to be clearly justified, the efficacy of universal prophylaxis (UP) including low-risk patients is controversial. Methods: From the study cohort RESITRA-REIPI, which prospectively analyzed 1010 LTR (September 2003 to February 2005) in 12 Spanish hospitals, we compared the incidence of early invasive fungal infection (IFI, first 90 days) between centers performing or not UP with fluconazole (for a minimum of 7 days) in low-risk LTR (none of the following: posttransplant renal failure, urgent transplant/retransplant, or choledochojejunostomy). RESULTS.: Three of 12 centers used UP. A total of 799 LTR were considered as low-risk patients (206 included in the UP group and 593 did not). We reported a total of 11 episodes of early IFI (six due to Candida albicans, one due to C. guillermondii, and three due to Aspergillus fumigatus) in 10 patients (incidence: 1.2%), with two cases of death attributable to IFI (18%) in both patients with invasive aspergillosis. There were no differences in the incidence of IFI between the patients receiving or not UP (4/206:1.9% vs. 6/593:1%, respectively; P=0.36). Conclusions: IFI is infrequent in LTR not fulfilling major high-risk factors criteria, and prophylaxis with fluconazole in this low-risk group does not seem to be justified. © 2011 by Lippincott Williams & Wilkins.


PubMed | University Hospital of Cruces, Achucarro Basque Center for Neuroscience, Baylor College of Medicine, University of Bordeaux Segalen and 2 more.
Type: Journal Article | Journal: PLoS biology | Year: 2016

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.


Larrinaga G.,University of the Basque Country | Perez I.,University of the Basque Country | Sanz B.,University of the Basque Country | Blanco L.,University of the Basque Country | And 6 more authors.
Regulatory Peptides | Year: 2010

The angiotensin-converting enzymes (ACE and ACE2) are highly expressed in renal tubules and play an important role in the regulation of renal function by the intrarenal renin-angiotensin system (iRAS). Dysregulation of these cell-surface peptidases has been associated with renal injury. Most of these studies, however, have focused on non-neoplastic kidney diseases. In the present study, ACE and ACE2 activity and protein and mRNA expression were analysed in a subset of clear-cell (CCRCC) and chromophobe (ChRCC) renal cell carcinomas, and in renal oncocytoma (RO). Enzyme activity was measured by spectrofluorometric (ACE2) and spectrophotometric assays (ACE), and protein and mRNA expression were determined by immunohistochemistry and qRT-PCR assays, respectively. The enzyme activities and immunohistochemistry showed that both enzymes are mainly downregulated in these neoplasms. qRT-PCR studies in CCRCC showed no positive correlation between ACE and ACE2 activity/protein expression and mRNA levels, whereas downregulation of ACE2 mRNA levels was observed in tumors from the distal nephron (ChRCC and RO). These findings suggest a metabolic imbalance in iRAS and a role of this system in renal neoplastic diseases, and point to ACE and ACE2 as potential prognostic/diagnostic markers. © 2010 Elsevier B.V.


Larrinaga G.,University of the Basque Country | Varona A.,University of the Basque Country | Perez I.,University of the Basque Country | Sanz B.,University of the Basque Country | And 5 more authors.
Histology and Histopathology | Year: 2010

The presence of CB1 and CB2 cannabinoid receptors and their physiological role in the kidney has been described in animal models but not in humans. Our aim in this study was to evaluate the presence of these receptors in human kidney, adult and fetal. For this purpose, RT-PCR, western-blot and immunohistochemical assays were performed. RT-PCR confirmed the presence of CB1 receptor mRNA receptor and the absence of the CB2 receptor mRNA in adult and fetal kidney. Western-blot and immunohistochemical assays revealed the presence of the CB1 cannabinoid receptor protein, which displayed a similar distribution in fetal and adult kidneys. Proximal and distal convoluted tubule cells and intercalated cells in the collecting ducts showed marked positivity. Conversely, the CB2 cannabinoid receptor protein was consistently negative in all cases. Our data suggest a possible implication of the endocannabinoid system in the physiology and development of the human kidney.


Varona A.,University of the Basque Country | Blanco L.,University of the Basque Country | Perez I.,University of the Basque Country | Gil J.,University of the Basque Country | And 5 more authors.
BMC Cancer | Year: 2010

Background: Cell-surface glycoproteins play critical roles in cell-to-cell recognition, signal transduction and regulation, thus being crucial in cell proliferation and cancer etiogenesis and development. DPP IV and NEP are ubiquitous glycopeptidases closely linked to tumor pathogenesis and development, and they are used as markers in some cancers. In the present study, the activity and protein and mRNA expression of these glycoproteins were analysed in a subset of clear-cell (CCRCC) and chromophobe (ChRCC) renal cell carcinomas, and in renal oncocytomas (RO).Methods: Peptidase activities were measured by conventional enzymatic assays with fluorogen-derived substrates. Gene expression was quantitatively determined by qRT-PCR and membrane-bound protein expression and distribution analysis was performed by specific immunostaining.Results: The activity of both glycoproteins was sharply decreased in the three histological types of renal tumors. Protein and mRNA expression was strongly downregulated in tumors from distal nephron (ChRCC and RO). Moreover, soluble DPP IV activity positively correlated with the aggressiveness of CCRCCs (higher activities in high grade tumors).Conclusions: These results support the pivotal role for DPP IV and NEP in the malignant transformation pathways and point to these peptidases as potential diagnostic markers. © 2010 Varona et al; licensee BioMed Central Ltd.


Borque A.,University of Zaragoza | Del Amo J.,Progenika Biopharma S.A. | Esteban L.M.,University of Zaragoza | Ars E.,Puigvert Foundation | And 16 more authors.
BJU International | Year: 2013

What's known on the subject? and What does the study add? Currently available nomograms to predict preoperative risk of early biochemical recurrence (EBCR) after radical prostatectomy are solely based on classic clinicopathological variables. Despite providing useful predictions, these models are not perfect. Indeed, most researchers agree that nomograms can be improved by incorporating novel biomarkers. In the last few years, several single nucleotide polymorphisms (SNPs) have been associated with prostate cancer, but little is known about their impact on disease recurrence. We have identified four SNPs associated with EBCR. The addition of SNPs to classic nomograms resulted in a significant improvement in terms of discrimination and calibration. The new nomogram, which combines clinicopathological and genetic variables, will help to improve prediction of prostate cancer recurrence. Objectives To evaluate genetic susceptibility to early biochemical recurrence (EBCR) after radical prostatectomy (RP), as a prognostic factor for early systemic dissemination. To build a preoperative nomogram to predict EBCR combining genetic and clinicopathological factors. Patients and Methods We evaluated 670 patients from six University Hospitals who underwent RP for clinically localized prostate cancer (PCa), and were followed-up for at least 5 years or until biochemical recurrence. EBCR was defined as a level prostate-specific antigen >0.4 ng/mL within 1 year of RP; preoperative variables studied were: age, prostate-specific antigen, clinical stage, biopsy Gleason score, and the genotype of 83 PCa-related single nucleotide polymorphisms (SNPs). Univariate allele association tests and multivariate logistic regression were used to generate predictive models for EBCR, with clinicopathological factors and adding SNPs. We internally validated the models by bootstrapping and compared their accuracy using the area under the curve (AUC), net reclassification improvement, integrated discrimination improvement, calibration plots and Vickers' decision curves. Results Four common SNPs at KLK3, KLK2, SULT1A1 and BGLAP genes were independently associated with EBCR. A significant increase in AUC was observed when SNPs were added to the model: AUC (95% confidence interval) 0.728 (0.674-0.784) vs 0.763 (0.708-0.817). Net reclassification improvement showed a significant increase in probability for events of 60.7% and a decrease for non-events of 63.5%. Integrated discrimination improvement and decision curves confirmed the superiority of the new model. Conclusions Four SNPs associated with EBCR significantly improved the accuracy of clinicopathological factors. We present a nomogram for preoperative prediction of EBCR after RP. © 2012 BJU International.


Garcia-Zapirain B.,University of Deusto | Garcia-Chimeno Y.,University of Deusto | Saralegui I.,Galdakao Hospital | Fernandez-Ruanova B.,Osatek | Martinez R.,University Hospital of Cruces
Biomedical Signal Processing and Control | Year: 2016

Non-invasive quantitative MRI methods, such as Diffusion Tensor Imaging (DTI) can offer insights into diverse developmental brain disorders such as dyslexia, the most prevalent reading disorder in childhood. In this article, we quantified the microstructural attributes of the main fascicles of both hemispheres related to the reading network in three groups of Spanish children: typically developing readers (TDR or controls), dyslexic readers (DXR) and readers with monocular vision due to ocular motility disorders (MVR), to assess whether the dyslexic children neuronal network for reading shares similarities with the neuronal network for reading in children with impaired binocular vision due to ocular motility disorders or not. Diffusion anisotropy, and mean, radial and axial diffusivity of cross-sectional subregions of the main fascicles studied were computed using a validated DTI methodology. Our results reveal differences in fractional anisotropy (FA) values between the DXR and the non-dyslexic readers, with a decreased FA for the DXR and no significant differences between TDR and MVR groups in the left Arcuate fasciculus, and a tendency to higher FA values in the DXR group compared to the other two groups in the genu of the Corpus Callosum (CC). In the splenium of the CC a trend towards higher FA values was observed in the DXR and MVR groups versus the TDR. This study reveals a different brain connectivity pattern for reading in Spanish children with dyslexia from those with impaired binocular vision due to ocular motility disorders, which would support the hypothesis that ocular motility disorders are not a causal factor of dyslexia. © 2015 Elsevier Ltd.


PubMed | University Hospital of Cruces and Center for Cooperative Research in Biosciences bio
Type: | Journal: Expert opinion on drug metabolism & toxicology | Year: 2016

Ammonia-scavenging drugs, benzoate and phenylacetate (PA)/phenylbutyrate (PB), modulate hepatic nitrogen metabolism mainly by providing alternative pathways for nitrogen disposal. Areas covered: We review the major findings and potential novel applications of ammonia-scavenging drugs, focusing on urea cycle disorders and liver disease. Expert opinion: For over 40years, ammonia-scavenging drugs have been used in the treatment of urea cycle disorders. Recently, the use of these compounds has been advocated in acute liver failure and cirrhosis for reducing hyperammonemic-induced hepatic encephalopathy. The efficacy and mechanisms underlying the antitumor effects of these ammonia-scavenging drugs in liver cancer are more controversial and are discussed in the review. Overall, as ammonia-scavenging drugs are usually safe and well tolerated among cancer patients, further studies should be instigated to explore the role of these drugs in liver cancer. Considering the relevance of glutamine metabolism to the progression and resolution of liver disease, we propose that ammonia-scavenging drugs might also be used to non-invasively probe liver glutamine metabolism in vivo. Finally, novel derivatives of classical ammonia-scavenging drugs with fewer and less severe adverse effects are currently being developed and used in clinical trials for the treatment of acute liver failure and cirrhosis.

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