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Barrancabermeja, Colombia

Court F.,Bellvitge Institute for Biomedical Research IDIBELL | Martin-Trujillo A.,Bellvitge Institute for Biomedical Research IDIBELL | Romanelli V.,Bellvitge Institute for Biomedical Research IDIBELL | Garin I.,Hospital Universitario Araba Txagorritxu | And 6 more authors.
Human Mutation

Genomic imprinting is the parent-of-origin-specific allelic transcriptional silencing observed in mammals, which is governed by DNA methylation established in the gametes and maintained throughout the development. The frequency and extent of epimutations associated with the nine reported imprinting syndromes varies because it is evident that aberrant preimplantation maintenance of imprinted differentially methylated regions (DMRs) may affect multiple loci. Using a custom Illumina GoldenGate array targeting 27 imprinted DMRs, we profiled allelic methylation in 65 imprinting defect patients. We identify multilocus hypomethylation in numerous Beckwith-Wiedemann syndrome, transient neonatal diabetes mellitus (TNDM), and pseudohypoparathyroidism 1B patients, and an individual with Silver-Russell syndrome. Our data reveal a broad range of epimutations exist in certain imprinting syndromes, with the exception of Prader-Willi syndrome and Angelman syndrome patients that are associated with solitary SNRPN-DMR defects. A mutation analysis identified a 1 bp deletion in the ZFP57 gene in a TNDM patient with methylation defects at multiple maternal DMRs. In addition, we observe missense variants in ZFP57, NLRP2, and NLRP7 that are not consistent with maternal effect and aberrant establishment or methylation maintenance, and are likely benign. This work illustrates that further extensive molecular characterization of these rare patients is required to fully understand the mechanism underlying the etiology of imprint establishment and maintenance. © 2013 Wiley Periodicals, Inc. Source

Moreno J.C.,University Institute of La Paz | Visser T.J.,Erasmus Medical Center
Molecular and Cellular Endocrinology

Iodotyrosine deiodinase is a thyroidal enzyme that deiodinates mono- and di-iodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to hypothyroidism, goiter and mental retardation, a clinical phenotype yet described in the 1950s, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine.DEHAL1, the gene responsible for this activity, was recently isolated and the molecular basis for the iodotyrosine deiodinase deficiency (ITDD) unraveled. The current clinical picture of mutations in DEHAL1 mostly recapitulates the " classical" phenotype of ITDD, including the psychomotor deficits. This is probably due to the lack of expression of the disease at the beginning of life, which causes ITDD being undetected in current screening programs for congenital hypothyroidism. This worrying feature calls for efforts to improve the preclinical detection of iodotyrosine deiodinase deficiency in the neonatal time. © 2010 Elsevier Ireland Ltd. Source

The efficacy of intra-articular tranexamic acid (TXA) to decrease blood loss after total knee replacement (TKR) has been confirmed in randomised clinical trials (RCTs) and meta-analysis. However, insufficient data are still available about the efficacy in clinical practice of intra-articular TXA administration in reducing the rate of postoperative blood transfusion. To prove the efficacy of a low-volume formulation of intra-articular TXA in current clinical practice, and the role of preoperative variables to influence the transfusion risk after primary TKR. We performed a retrospective study (using data that were gathered concurrently with the treatments but without a specific protocol to address the research question) in patients undergoing cemented TKR and receiving a low-volume formulation (2.5?g-25?ml TXA plus 20-ml saline) of intra-articular TXA (group B, study group, N?=?85), and compared it with a cohort of high volume (3?g-30?ml TXA plus 70-ml saline) half topical half intra-articular TXA (group A, N?=?39). Lower volume may diffuse less into the knee joint, and effectiveness assessment is required. To further confirm the effectiveness of the strategy, we compared this cohort with the historical cohort in our centre without TXA (group C, N?=?393). End-point variables were compared and a multiple regression model was adjusted to obtain the odds ratio for confounding preoperative variables. Transfusion rates significantly differed between groups B (7%) and C (30%), but not between group A and group B, proving effectiveness of the low-volume formulation of intra-articular administration of TXA, despite in group B 18% of patients has less than 13?g/dl haemoglobin (Hb) vs. 0% in group A. The effectiveness of intra-articular TXA after TKR has been confirmed for a low-volume formulation (2.5?g-25?ml TXA plus 20?ml saline) even if Hb is less than 13?g/dl. Preoperative HB optimization (>13?g/dl) is also important.Level of evidence: Level IV. Copyright © 2016 YEAR Wolters Kluwer Health, Inc. All rights reserved. Source

Gordo-Gilart R.,University Institute of La Paz | Andueza S.,University Institute of La Paz | Hierro L.,University Institute of La Paz | Hierro L.,La Paz Childrens University Hospital | And 5 more authors.

Objective: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a potentially lethal autosomal recessive liver disease associated with mutations in ABCB4, the gene encoding the canalicular translocator of phosphatidylcholine MDR3. While some affected children benefit from ursodeoxycholic acid (UDCA) therapy, others evolve to end-stage liver disease. We aimed to evaluate whether these different outcomes are related to the impact of ABCB4 mutations.Design: Six children with PFIC3 were investigated by sequencing of ABCB4 exons and flanking intron-exon boundaries and by immunohistochemistry. ABCB4 missense mutations were phenotyped in vitro by assessing their effects on MDR3 expression, subcellular localisation, and phosphatidylcholine-translocating activity. The resulting data were contrasted with the clinical outcomes.Results: Eight distinct ABCB4 mutations were identified: one nonsense, one splicing and six missense mutations, four of which (G68R, T201M, P479L, D459H) affected MDR3 expression level. G68R and D459H also led to retention of the protein in endoplasmic reticulum. Phosphatidylcholine efflux assays indicated that T201M, P479L, S978P and E1118K mutations impaired MDR3 activity to variable degrees. Three children with mutations that caused a total loss of MDR3 expression/function manifested progressive liver disease refractory to UDCA treatment. This was also the case in a patient carrying two different mutations that, in combination, resulted in a 90% reduction in total MDR3 activity. A favourable response to UDCA was achieved in two patients with estimated MDR3 activities of 50% and 33%, respectively.Conclusions: These data provide experimental evidence of the correlation between the degree of MDR3 floppase activity and the clinical outcomes of PFIC3. Source

Arnalich-Montiel F.,Ramon y Cajal University Hospital | Munoz-Negrete F.J.,Ramon y Cajal University Hospital | De Miguel M.P.,University Institute of La Paz
Eye (Basingstoke)

ObjectiveTo study endothelial injury from a newly designed asymmetric double port Descemet Membrane Endothelial Keratoplasty (DMEK) injector, both ex-vivo and in clinical practice.DesignLaboratory investigation with an interventional case series study.MethodSixteen rabbit endothelial rolls were tested for injection using a no-touch technique. For each pair of rolls, one endothelial graft underwent injection with a single port Pasteur pipette twice, wheras the other was injected with a novel asymmetric double port injector with a larger diameter entry port than the exit port also twice. Each graft was stained with 4-6-diamidino-2-phenylinidole dihydrochloride and was counted under a fluorescence-inverted microscope before and after injection. The proportion of graft injury was calculated and the differences were analyzed. Subsequently, six patients requiring DMEK underwent surgery using this novel insertion device and endothelial cell loss was calculated 3 months after the surgery.ResultsAfter injection, the mean proportion of endothelial cell survival with the single port pipette was 78.8% (n=8; SD: ±20.9%), whereas the double port injector yielded a survival rate of 96.8% (n=8; SD: ±8.4%). This difference was statistically significant (P=0.008), representing less endothelial injury with the double port device. Early endothelial cell loss after 3 months in the DMEK patients was 26.1% (SD: ±6.1%).ConclusionIn our injection model, using a double port injector created significantly less endothelial cell damage than with the single port pipette. Clinically, this device yielded early endothelial cell loss comparable to that of the series performed by experienced DMEK surgeons. © 2014 Macmillan Publishers Limited. Source

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