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Pellise F.,Hospital Universitario Vall dHebron | Barastegui D.,Hospital Universitario Vall dHebron | Hernandez-Fernandez A.,Hospital Universitario Donostia | Barrera-Ochoa S.,Institute Universitari Quiron Dexeus | And 4 more authors.
Spine Journal | Year: 2015

Background context Short-segment pedicle screw instrumentation constructs for the treatment of thoracolumbar fractures gained popularity in the 1980s. The load-sharing classification (LSC) is a straightforward way to describe the extent of bony comminution, amount of fracture displacement, and amount of correction of kyphotic deformity in a spinal fracture. There are no studies evaluating the relevance of fracture comminution/traumatic kyphosis on the long-term radiologic outcome of burst fractures treated by short-segment instrumentation with screw insertion in the fractured level. Purpose To evaluate the efficacy of the six-screw construct in the treatment of thoracolumbar junction burst fractures and the influence of the LSC score on the 2-year radiologic outcome. Study design Case series of consecutive patients of a single university hospital. Patient sample Consecutive patients from one university hospital with nonosteoporotic thoracolumbar burst fractures. Outcome measures Being a radiology-based study, the outcome measures are radiologic parameters (regional kyphosis [RK], local kyphosis, and thoracolumbar kyphosis [TLK]) that evaluate the degree and loss of correction. Methods Retrospective analysis of all consecutive patients with nonosteoporotic thoracolumbar burst fractures managed with a six-screw construct in a single university hospital, with more than 2 years' postoperative follow-up. Results Eighty-six patients met the inclusion criteria, and 72 (83.7%) with available data were ultimately included in the study. The sample included 53 men and 19 women, with a mean (standard deviation [SD]) age of 35.6 years (14.4 years) at the time of surgery. Mean LSC score was 6.3 (SD 1.6, range 3-9). Forty-four of 62 (70.9) fractures had a score greater than 6. Mean (SD) RK and TLK deteriorated significantly during the first 6 months of follow-up: 2.90° (4.54°) p=.005 and 2.78°(6.45°) p=.069, respectively. Surgical correction correlated significantly (r=0.521, p<.0001) with the time elapsed until surgery. Loss of surgical correction (postoperative to 6-month RK and TLK increase) correlated significantly with the LSC score (r=0.57, p=.004; r=0.51, p=.022, respectively). Further surgery because of correction loss was not required in any case. Conclusions The six-screw construct is effective for treating thoracolumbar junction burst fractures. The medium-to-long-term loss of correction is affected by the amount of bony comminution of the fracture, objectified through the LSC score. © 2015 Elsevier Inc. All rights reserved.

Alvarez I.,Autonomous University of Barcelona | Collado J.A.,Autonomous University of Barcelona | Colobran R.,Autonomous University of Barcelona | Colobran R.,Hospital Universitari Vall dHebron | And 10 more authors.
Journal of Autoimmunity | Year: 2015

Promiscuous gene expression (pGE) of tissue-restricted self-antigens (TRA) in medullary thymic epithelial cells (mTECs) is in part driven by the Autoimmune Regulator gene (AIRE) and essential for self-tolerance. The link between AIRE functional mutations and multi-organ autoimmunity in human and mouse supports the role of pGE. Deep sequencing of the transcriptome revealed that mouse mTECs potentially transcribe an unprecedented range of >90% of all genes. Yet, it remains unclear to which extent these low-level transcripts are actually translated into proteins, processed and presented by thymic APCs to induce tolerance. To address this, we analyzed the HLA-DR-associated thymus peptidome. Within a large panel of peptides from abundant proteins, two TRA peptides were identified: prostate-specific semenogelin-1 (an autoantigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome) and central nervous system-specific contactin-2 (an autoantigen in multiple sclerosis). Thymus expression of both genes was restricted to mTECs. SEMG1 expression was confined to mature HLA-DRhi mTECs of male and female donors and was AIRE-dependent, whereas CNTN2 was apparently AIRE-independent and was expressed by both populations of mTECs. Our findings establish a link between pGE, MHC-II peptide presentation and autoimmunity for bona fide human TRAs. © 2015 Elsevier Ltd.

Pampalona J.,Autonomous University of Barcelona | Pampalona J.,Barcelona Institute for Research in Biomedicine | Frias C.,Autonomous University of Barcelona | Frias C.,Vall Dhebron Institute Of Recerca | And 2 more authors.
PLoS Genetics | Year: 2012

Most cancer cells accumulate genomic abnormalities at a remarkably rapid rate, as they are unable to maintain their chromosome structure and number. Excessively short telomeres, a known source of chromosome instability, are observed in early human-cancer lesions. Besides telomere dysfunction, it has been suggested that a transient phase of polyploidization, in most cases tetraploidization, has a causative role in cancer. Proliferation of tetraploids can gradually generate subtetraploid lineages of unstable cells that might fire the carcinogenic process by promoting further aneuploidy and genomic instability. Given the significance of telomere dysfunction and tetraploidy in the early stages of carcinogenesis, we investigated whether there is a connection between these two important promoters of chromosomal instability. We report that human mammary epithelial cells exhibiting progressive telomere dysfunction, in a pRb deficient and wild-type p53 background, fail to complete the cytoplasmatic cell division due to the persistence of chromatin bridges in the midzone. Flow cytometry together with fluorescence in situ hybridization demonstrated an accumulation of binucleated polyploid cells upon serial passaging cells. Restoration of telomere function through hTERT transduction, which lessens the formation of anaphase bridges by recapping the chromosome ends, rescued the polyploid phenotype. Live-cell imaging revealed that these polyploid cells emerged after abortive cytokinesis due to the persistence of anaphase bridges with large intervening chromatin in the cleavage plane. In agreement with a primary role of anaphase bridge intermediates in the polyploidization process, treatment of HMEC-hTERT cells with bleomycin, which produces chromatin bridges through illegimitate repair, resulted in tetraploid binucleated cells. Taken together, we demonstrate that human epithelial cells exhibiting physiological telomere dysfunction engender tetraploid cells through interference of anaphase bridges with the completion of cytokinesis. These observations shed light on the mechanisms operating during the initial stages of human carcinogenesis, as they provide a link between progressive telomere dysfunction and tetraploidy. © 2012 Pampalona et al.

Gregori J.,Autonomous University of Barcelona | Gregori J.,University of Barcelona | Villarreal L.,Autonomous University of Barcelona | Sanchez A.,University of Barcelona | And 3 more authors.
Journal of Proteomics | Year: 2013

The microarray community has shown that the low reproducibility observed in gene expression-based biomarker discovery studies is partially due to relying solely on p-values to get the lists of differentially expressed genes. Their conclusions recommended complementing the p-value cutoff with the use of effect-size criteria. The aim of this work was to evaluate the influence of such an effect-size filter on spectral counting-based comparative proteomic analysis. The results proved that the filter increased the number of true positives and decreased the number of false positives and the false discovery rate of the dataset. These results were confirmed by simulation experiments where the effect size filter was used to evaluate systematically variable fractions of differentially expressed proteins. Our results suggest that relaxing the p-value cut-off followed by a post-test filter based on effect size and signal level thresholds can increase the reproducibility of statistical results obtained in comparative proteomic analysis. Based on our work, we recommend using a filter consisting of a minimum absolute log2 fold change of 0.8 and a minimum signal of 2-4 SpC on the most abundant condition for the general practice of comparative proteomics. The implementation of feature filtering approaches could improve proteomic biomarker discovery initiatives by increasing the reproducibility of the results obtained among independent laboratories and MS platforms. Biological significance: Quality control analysis of microarray-based gene expression studies pointed out that the low reproducibility observed in the lists of differentially expressed genes could be partially attributed to the fact that these lists are generated relying solely on p-values. Our study has established that the implementation of an effect size post-test filter improves the statistical results of spectral count-based quantitative proteomics. The results proved that the filter increased the number of true positives whereas decreased the false positives and the false discovery rate of the datasets. The results presented here prove that a post-test filter applying a reasonable effect size and signal level thresholds helps to increase the reproducibility of statistical results in comparative proteomic analysis. Furthermore, the implementation of feature filtering approaches could improve proteomic biomarker discovery initiatives by increasing the reproducibility of results obtained among independent laboratories and MS platforms.This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics. © 2013 Elsevier B.V.

Michelena J.,Liver Unit | Michelena J.,University of Barcelona | Altamirano J.,Liver Unit | Altamirano J.,University of Barcelona | And 25 more authors.
Hepatology | Year: 2015

Alcoholic hepatitis (AH) frequently progresses to multiple organ failure (MOF) and death. However, the driving factors are largely unknown. At admission, patients with AH often show criteria of systemic inflammatory response syndrome (SIRS) even in the absence of an infection. We hypothesize that the presence of SIRS may predispose to MOF and death. To test this hypothesis, we studied a cohort including 162 patients with biopsy-proven AH. The presence of SIRS and infections was assessed in all patients, and multivariate analyses identified variables independently associated with MOF and 90-day mortality. At admission, 32 (19.8%) patients were diagnosed with a bacterial infection, while 75 (46.3%) fulfilled SIRS criteria; 58 patients (35.8%) developed MOF during hospitalization. Short-term mortality was significantly higher among patients who developed MOF (62.1% versus 3.8%, P<0.001). The presence of SIRS was a major predictor of MOF (odds ratio=2.69, P=0.025) and strongly correlated with mortality. Importantly, the course of patients with SIRS with and without infection was similar in terms of MOF development and short-term mortality. Finally, we sought to identify serum markers that differentiate SIRS with and without infection. We studied serum levels of high-sensitivity C-reactive protein, procalcitonin, and lipopolysaccharide at admission. All of them predicted mortality. Procalcitonin, but not high-sensitivity C-reactive protein, serum levels identified those patients with SIRS and infection. Lipopolysaccharide serum levels predicted MOF and the response to prednisolone. Conclusion: In the presence or absence of infections, SIRS is a major determinant of MOF and mortality in AH, and the mechanisms involved in the development of SIRS should be investigated; procalcitonin serum levels can help to identify patients with infection, and lipopolysaccharide levels may help to predict mortality and the response to steroids. (Hepatology 2015;62:762-772) © 2015 by the American Association for the Study of Liver Diseases.

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