Donostia / San Sebastián, Spain
Donostia / San Sebastián, Spain

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Munoz-Garrido P.,Donostia Universitary Hospital | Hijona E.,Donostia Universitary Hospital | Hijona E.,CIBER ISCIII | Carracedo M.,Donostia Universitary Hospital | And 7 more authors.
World Journal of Gastroenterology | Year: 2012

Cholangiopathies are a group of diseases primarily or secondarily affecting bile duct cells, and result in cholangiocyte proliferation, regression, and/or transformation. Their etiopathogenesis may be associated with a broad variety of causes of different nature, which includes genetic, neoplastic, immune-associated, infectious, vascular, and drug-induced alterations, or being idiopathic. miRNAs, small non-coding endogenous RNAs that post-transcriptionally regulate gene expression, have been associated with pathophysiological processes in different organs and cell types, and are postulated as potential targets for diagnosis and therapy. In the current manuscript, knowledge regarding the role of miRNAs in the development and/or progression of cholangiopathies has been reviewed and the most relevant findings in this promising field of hepatology have been highlighted. © 2012 Baishideng. All rights reserved.

Rodriguez-Arribas M.,University of Extremadura | Pedro J.M.B.-S.,University of Paris Pantheon Sorbonne | Gomez-Sanchez R.,University of Groningen | Yakhine-Diop S.M.S.,University of Extremadura | And 10 more authors.
Current Medicinal Chemistry | Year: 2016

Pompe disease or glycogen storage disease type II (OMIM: 232300) is a lysosomal storage disorder resulting from a partial or total lack of acid alphaglucosidase, which may produce muscle weakness, gait abnormalities, or even death by respiratory failure. In the last decade, autophagy has been proposed as a mechanism involved in the severity of symptoms related to this disorder and as a potential therapeutic target to alleviate disease progression. This review summarizes the relationship between autophagy and Pompe disease, including what information has been recently discovered and what remains unclear. © 2016 Bentham Science Publishers.

Fernandez-Torron R.,Neuromuscular Unit | Garcia-Puga M.,Donostia Universitary Hospital | Emparanza J.-I.,Neuromuscular Unit | Maneiro M.,Neurosciences Area | And 12 more authors.
Neurology | Year: 2016

Objective: Describe the incidence of cancer in a large cohort of patients with myotonic dystrophy type 1 (DM1) and to unravel the underlying molecular mechanisms. Methods: Standardized incidence ratios (SIRs) were calculated in the Gipuzkoa DM1 cohort (1985-2013), dividing observed numbers by expected numbers for all cancers combined and stratified by sex. An estimation of the expected incidence was achieved by multiplying the age- and sex-specific incidence rates from the Basque population cancer registry by the person-years observed in the study cohort. Large-scale gene expression of peripheral blood mononuclear cell samples derived from 10 individuals with DM1 (5 men, 5 women) and 10 healthy matched controls was analyzed by the Human Gene 1.0 ST Affymetrix microarray. Results: During 18,796 person-years of follow-up, corresponding to 424 patients with DM1, we observed 70 cancers in 62 patients giving a 1.81-fold risk (95% confidence interval [CI] 1.37-2.36), which was stronger in women than in men. Ovary (SIR 8.33, 95% CI 1.72-24.31) and endometrium (SIR 6.86, 95% CI 2.23-16.02) in women and thyroid (SIR 23.33, 95% CI 9.38-48.08) and brain (SIR 9.80, 95% CI 3.18-22.88) in both sexes were tumor sites with significantly higher risks in DM1. There were differences in gene expression between healthy controls and patients with DM1 and between men and women with DM1; all patients with DM1 combined and female patients with DM1 displayed significant downregulation of the microRNA (miRNA)-200c/141 tumor suppressor family. Conclusions: Oncologic risk is increased in DM1, especially in women and for gynecologic, brain, and thyroid cancer. Expression of the miRNA-200/miRNA-141 tumor suppressor family is decreased in women with DM1. © 2016 American Academy of Neurology.

Banales J.M.,Donostia Universitary Hospital | Banales J.M.,CIBER ISCIII | Banales J.M.,Ikerbasque | Munoz-Garrido P.,Donostia Universitary Hospital | And 2 more authors.
World Journal of Gastroenterology | Year: 2013

Polycystic liver diseases (PCLDs) are a heterogeneous group of genetic disorders characterized by the development of multiple fluid-filled cysts in the liver, which derive from cholangiocytes, the epithelial cells lining the bile ducts. When these cysts grow, symptoms such as abdominal distension, nausea, and abdominal pain may occur. PCLDs may exist isolated (i.e., autosomal dominant polycystic liver disease, ADPLD) or in combination with renal cystogenesis (i.e., autosomal dominant polycystic kidney disease and autosomal recessive polycystic liver disease). The exact prevalence of PCLDs is unknown, but is estimated to occur in approximately 1:1000 persons. Although the pathogenesis of each form of PCLD appears to be different, increasing evidences indicate that hepatic cystogenesis is a phenomenon that may involve somatic loss of heterozygosity (LOH) in those pathological conditions inherited in a dominant form. A recent report, using highly sophisticated methodology, demonstrated that ADPLD patients with a germline mutation in the protein kinase C substrate 80K-H (PRKCSH) gene mostly develop hepatic cystogenesis through a second somatic mutation. While hepatocystin, the PRKCSH-encoding protein, was absent in the hepatic cysts with LOH, it was still expressed in the heterozygous cysts. On the other hand, no additional trans-heterozygous mutations on the SEC63 homolog (S. cerevisiae /SEC63) gene (also involved in the development of PCLDs) were observed. These data indicate that PCLD is recessive at the cellular level, and point out the important role of hepatocystin loss in cystogenesis. In this commentary, we discuss the knowledge regarding the role of somatic second-hit mutations in the development of PCLDs, and the most relevant findings have been highlighted. © 2013 Baishideng. All rights reserved.

Arranz L.,Donostia Universitary Hospital | Arranz L.,University of the Basque Country | Aldamiz-Echevarria L.,University of the Basque Country | Aldamiz-Echevarria L.,Cruces Universitary Hospital
Molecular Genetics and Metabolism Reports | Year: 2015

The most severe form of Mucopolysaccharosidosis type I (MPS-I), Hurler syndrome, presents with progressive respiratory, cardiac and musculoskeletal symptoms and cognitive deterioration. Treatment includes enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). We describe the case of an 8-year old boy with MPS-I, homozygous for W402X, treated at 10 months of age with HSCT and after failure of the transplant, with ERT during 2 years showing good results, including a positive neuropsychological development. © 2015 Published by Elsevier Inc.

PubMed | Policlinica Gipuzkoa, University of the Basque Country, Quiron Donostia Hospital, Mendaro Hospital and 3 more.
Type: | Journal: BioMed research international | Year: 2015

The objectives were (i) construction of a phantom to reproduce the behavior of iron overload in the liver by MRI and (ii) assessment of the variability of a previously validated method to quantify liver iron concentration between different MRI devices using the phantom and patients.A phantom reproducing the liver/muscle ratios of two patients with intermediate and high iron overload. Nine patients with different levels of iron overload were studied in 4 multivendor devices and 8 of them were studied twice in the machine where the model was developed. The phantom was analysed in the same equipment and 14 times in the reference machine.FeCl3 solutions containing 0.3, 0.5, 0.6, and 1.2mgFe/mL were chosen to generate the phantom. The average of the intramachine variability for patients was 10% and for the intermachines 8%. For the phantom the intramachine coefficient of variation was always below 0.1 and the average of intermachine variability was 10% for moderate and 5% for high iron overload.The phantom reproduces the behavior of patients with moderate or high iron overload. The proposed method of calculating liver iron concentration is reproducible in several different 1.5 T systems.

Llorenc V.,Hospital Clinic of Barcelona | Mesquida M.,Hospital Clinic of Barcelona | Sainz De La Maza M.,Hospital Clinic of Barcelona | Blanco R.,Marques Of Valdecilla Hospital | And 5 more authors.
Ocular Immunology and Inflammation | Year: 2016

Purpose: To study the efficacy and tolerance of certolizumab pegol (CZP) in active uveitis.Methods: Retrospective case series at 4 referral centers. Patients treated with CZP for active uveitis during at least 6 months were eligible. Inflammation by SUN scores, visual acuity (VA) (logMAR), and central macular thickness (CMT) were compared from baseline until final follow-up. Quiescence was defined as 0+ to 0.5+ in anterior chamber and vitreous haze scores and no CMT increase.Results: Four males and 3 females (14 eyes) were included, mean age 42.4 ± 8.8 years. All were long-lasting chronic-relapsing uveitis with prior failure to other anti-TNF-α. After a mean follow-up of 10.4 ± 4.8 months, 5/7 patients (71.4%) achieved quiescence with CZP. VA improved significantly from +0.52 ± 0.68 to +0.45 ± 0.68 (p = 0.032) at 1 month and to +0.44 ± 0.64 (p = 0.035) at 6 months. No adverse events were found.Conclusion: CZP can be an effective alternative in refractory uveitis. © 2016 Taylor & Francis Group, LLC.

PubMed | Donostia Universitary Hospital, Marques Of Valdecilla Hospital, Txagorritxu Hospital and Hospital Clinic of Barcelona
Type: Journal Article | Journal: Ocular immunology and inflammation | Year: 2016

To study the efficacy and tolerance of certolizumab pegol (CZP) in active uveitis.Retrospective case series at 4 referral centers. Patients treated with CZP for active uveitis during at least 6 months were eligible. Inflammation by SUN scores, visual acuity (VA) (logMAR), and central macular thickness (CMT) were compared from baseline until final follow-up. Quiescence was defined as 0+ to 0.5+ in anterior chamber and vitreous haze scores and no CMT increase.Four males and 3 females (14 eyes) were included, mean age 42.48.8 years. All were long-lasting chronic-relapsing uveitis with prior failure to other anti-TNF-. After a mean follow-up of 10.44.8 months, 5/7 patients (71.4%) achieved quiescence with CZP. VA improved significantly from +0.520.68 to +0.450.68 (p=0.032) at 1 month and to +0.440.64 (p=0.035) at 6 months. No adverse events were found.CZP can be an effective alternative in refractory uveitis.

Goni N.,Donostia Universitary Hospital | Bidaguren A.,Donostia Universitary Hospital | Macias-Murelaga B.,Donostia Universitary Hospital | Alberdi T.,Donostia Universitary Hospital | And 2 more authors.
Cornea | Year: 2015

Purpose: To analyze objective optical quality changes after pterygium surgical excision using the Optical Quality Analysis System.Methods: Forty eyes with primary pterygium suitable for surgical treatment were included. Uncorrected distance visual acuity, corrected distance visual acuity (CDVA), objective scattering index (OSI), and cutoff frequency of the modulation transfer function (MTFcutoff) were recorded preoperatively and at 1 and ± months postoperatively. Slit-lamp measurement of pterygium size was performed to classify them: small in group 1 and medium size/large in group 2. A paired comparative study of all data that included preoperative with 1-month results (comparison A), preoperative with 6- month results (comparison B), and 1 month with sixth-month results (comparison C) was performed.Results: In global analysis, uncorrected distance visual acuity and OSI showed significant changes in comparison A, all parameters in comparison B, and CDVA, OSI, and MTFcutoff in comparison C. When subdividing into groups, in group 1, there was significant improvement between preoperative uncorrected distance visual acuity value and those at 1 and ± months. Significant improvement in CDVA, OSI, and MTFcutoff values were observed in comparisons B and C. In group 2, MTFcutoff values significantly improved in comparisons B and C. The comparison of mean values between each group at each evaluation showed a lower value for MTFcutoff at 1 month after surgery. A comparative analysis of the evolution between both groups based on pterygium size did not reveal significant differences.Conclusions: Pterygium can undermine visual quality, and its excision provides significant improvement even at ± months after surgery. Optical Quality Analysis System proved useful for postoperative outcomes. Copyright © 2014 by Lippincott Williams & Wilkins.

PubMed | Laboratory of Ubiquitylation and Cancer Molecular Biology, Biodonostia Research Institute, Donostia Universitary Hospital and Laboratory of Stem Cells and Neural Repair
Type: Journal Article | Journal: Journal of neuroinflammation | Year: 2016

Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both familial and idiopathic forms of Parkinsons disease (PD). Neuroinflammation is a key event in neurodegeneration and aging, and there is mounting evidence of LRRK2 involvement in inflammatory pathways. In a previous study, we described an alteration of the inflammatory response in dermal fibroblasts from PD patients expressing the G2019S and R1441G mutations in LRRK2.Taking advantage of cellular reprogramming, we generated induced pluripotent stem cell (iPSC) lines and neurons thereafter, harboring LRRK2LRRK2 silencing decreased -synuclein protein levels in mutated neurons and modified NF-B transcriptional targets, such as PTGS2 (COX-2) and TNFAIP3 (A20). We next tested whether NF-B and -synuclein pathways converged and found that TNF modulated -synuclein levels, although we could not detect an effect of LRRK2 mutations, partly because of the individual variability. Nevertheless, we confirmed NF-B dysregulation in mutated neurons, as shown by a protracted recovery of IB and a clear impairment in p65 nuclear translocation in the LRRK2 mutants.Altogether, our results show that LRRK2 mutations affect -synuclein regulation and impair NF-B canonical signaling in iPSC-derived neurons. TNF modulated -synuclein proteostasis but was not modified by the LRRK2 mutations in this paradigm. These results strengthen the link between LRRK2 and the innate immunity system underscoring the involvement of inflammatory pathways in the neurodegenerative process in PD.

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