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Guillen-Navarro E.,Hospital Clinico Universitario Virgen Of La Arrixaca | Domingo-Jimenez M.R.,Hospital Clinico Universitario Virgen Of La Arrixaca | Alcalde-Martin C.,Hospital Universitario Rio Hortega | Cancho-Candela R.,Hospital Universitario Rio Hortega | And 3 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

Background: Mucopolysaccharidosis type II (MPS II) is an inherited X-linked disease associated with a deficiency in the enzyme iduronate 2-sulfatase due to iduronate 2-sulfatase gene (IDS) mutations. Recent studies in MPS II carriers did not find clinical involvement, but these were mainly performed by anamnesis and patients' self-reported description of signs and symptoms. So although it is rare in heterozygous carriers, investigations in other types of inherited X-linked disorders suggest that some clinical manifestations may be a possibility. The aim of this study was to evaluate the clinical pattern in female carriers of MPS II and to determine whether clinical symptoms were associated with the X-chromosome inactivation (XCI) pattern and age. Methods. Female carriers of MPS II were genetically identified by molecular analysis of IDS. The clinical evaluation protocol included pedigree analysis, a comprehensive anamnesis, complete physical examination, ophthalmological evaluation, brain-evoked auditory response, electrocardiogram, echocardiogram, pulmonary function tests, abdominal sonogram, skeletal survey, neurophysiological studies, blood cell counts and biochemistry, urine glycosaminoglycan (GAGs) quantification, karyotype and pattern of XCI. Results: Ten women were included in the study. The mean age of the participants was 40.2 ± 13.1 years. Six carriers presented a skewed XCI pattern, 3 of whom (aged 38, 42 and 52 years) had increased levels of GAGs in the urine and showed typical MPS II clinical manifestations, such as skeletal anomalies, liver abnormalities, carpal tunnel syndrome, recurrent ear infection, hypoacusia and more frequent severe odontological problems without coarse facial features. Conclusions: This is the first study performing a comprehensive evaluation of heterozygous MPS II carriers. Our results provide evidence of possible progressive, age-dependent, mild clinical manifestations in MPS II female carriers with a skewed XCI pattern, most likely affecting the normal allele. Further comparative studies with systematized clinical examinations in larger age-stratified populations of MPS II female carriers are required. © 2013 Guillén-Navarro et al.; licensee BioMed Central Ltd.

Montoro-Garcia S.,University of Birmingham | Montoro-Garcia S.,Hospital Clinico Universitario Virgen Of La Arrixaca | Shantsila E.,University of Birmingham | Hernandez-Romero D.,Hospital Clinico Universitario Virgen Of La Arrixaca | And 4 more authors.
British Journal of Haematology | Year: 2014

This study aimed to examine the mechanisms of cellular activation by small-size platelet microparticles (sPMP) and to present the performance of high-resolution flow cytometry for the analysis of subcellular entities from different origins. Plasma counts of sPMP were analysed in coronary artery disease patients (n = 40) and healthy controls (n = 40). The effect of sPMP and platelet debris (PD) in pathophysiologically relevant doses on platelet and monocyte activation parameters and thrombogenesis was investigated via flow cytometry and thromboelastometry. New generation flow cytometry identifies differences in size, levels and surface molecules of sPMP derived in the absence of stimulus, thrombin activation and platelet disruption. Addition of sPMP resulted in platelet degranulation and P-selectin redistribution to the membrane (P = 0·019) in a dose and time-dependent manner. Blood clotting time decreased after addition of sPMP (P = 0·005), but was not affected by PD. Blocking P-selectin (CD62P) in sPMP markedly reverted the effect on thrombus kinetics (P = 0·035). Exposure to sPMP stimulated monocyte expression of intercellular adhesion molecule-1 (P < 0·03) and decreased monocyte interleukin-6 receptor density (P < 0·01). These results implicate sPMP as a direct source of downstream platelet and monocyte activation. In pathological coronary artery disease conditions, higher levels of sPMP favour a prothrombotic state, partly through P-selectin expression. © 2014 John Wiley & Sons Ltd.

Compan V.,University of Manchester | Compan V.,French National Center for Scientific Research | Martin-Sanchez F.,Hospital Clinico Universitario Virgen Of La Arrixaca | Baroja-Mazo A.,Hospital Clinico Universitario Virgen Of La Arrixaca | And 6 more authors.
Journal of Immunology | Year: 2015

Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is a key adaptor molecule required for the inflammatory processes. ASC acts by bridging NLRP proteins, such as NLRP3, with procaspase-1 within the inflammasome complex, which subsequently results in the activation of caspase-1 and the secretion of IL-1β and IL-18. In response to bacterial infection, ASC also forms specks by self-oligomerization to activate caspase-1 and induce pyroptosis. Hitherto, the role of these specks in NLRP3 inflammasome activation in response to danger signals, such as a hypotonic environment, largely has been unexplored. In this article, we report that, under hypotonic conditions and independently of NLRP3, ASC was able to form specks that did not activate caspase-1. These specks were not associated with pyroptosis and were controlled by transient receptor potential vanilloid 2 channel-mediated signaling. However, interaction with NLRP3 enhanced ASC speck formation, leading to fully functional inflammasomes and caspase-1 activation. This study reveals that the ASC speck can present different oligomerization assemblies and represents an essential step in the activation of functional NLRP3 inflammasomes. Copyright © 2015 by The American Association of Immunologists, Inc.

Sanchez-de la Rosa R.,Teva Pharmaceutical Industries | Garcia-Bujalance L.,Teva Pharmaceutical Industries | Meca-Lallana J.,Hospital Clinico Universitario Virgen Of La Arrixaca
Health Economics Review | Year: 2015

Objective: The Escala Study evidenced that the administration of glatiramer acetate for relapsing-remitting multiple sclerosis improved the spasticity of patients previously treated with interferon-β. However, whether such an improvement was translated into cost savings remained unclear. We therefore conducted a cost analysis of glatiramer acetate versus interferon-β in these patients with multiple sclerosis and spasticity. Methods: This cost analysis encompassed data from the observational Escala Study, which included patients with relapsing-remitting multiple sclerosis and spasticity whose treatment had been switched from interferon-β to glatiramer acetate. Costs prior to starting glatiramer acetate (interferon-β period) were compared to the subsequent six months on glatiramer acetate (glatiramer acetate period). The analysis was carried out following the recommendations for conducting pharmacoeconomic studies and from the Spanish National Health System perspective. Costs associated with multiple sclerosis treatment, spasticity treatment and relapse management were expressed in 2014 euros (€); a 7.5 % discount was applied—when needed—as stipulated in Spanish law. Results: The management of relapsing-remitting multiple sclerosis, spasticity and relapses accounted for a 6-month cost per patient of 7,078.02€ when using interferon-β and 4,671.31€ when using glatiramer acetate. Switching from interferon-β to glatiramer acetate therefore represented a cost saving of 2,406.72€ per patient in favour of glatiramer acetate, which resulted from savings in treatment costs, relapse management and spasticity treatment of 1,890.02€, 430.48€ and 86.21€, respectively. The ratio of the costs during interferon-β was 1.5 times the costs during glatiramer acetate; thus, a fixed budget of 5,000,000€ would enable 1,070 patients to be treated with glatiramer acetate and only 706 patients with interferon-β. Conclusions: The treatment of relapsing-remitting multiple sclerosis with glatiramer acetate entailed cost savings when compared to interferon-β in patients with spasticity, which not only resulted from its lower costs of therapy and relapse management but also from its favourable effect on reducing spasticity. Thus, glatiramer acetate may be regarded as a more efficient alternative than interferon-β from the perspective of the Spanish National Health System. © 2015, Sánchez-de la Rosa et al.

Hernandez-Palazon J.,Hospital Clinico Universitario Virgen Of La Arrixaca
Journal of Neurosurgical Anesthesiology | Year: 2015

BACKGROUND:: The authors investigated the effect of equiosmolar, equivolemic solutions of 3% hypertonic saline (HS) and 20% mannitol on blood coagulation assessed by rotational thromboelastometry (ROTEM) and standard coagulation tests during elective craniotomy. METHODS:: In a prospective, randomized, double-blind trial, 40 patients undergoing elective craniotomy were randomized to receive 5 mL/kg of either 20% mannitol or 3% HS for intraoperative brain relaxation. Fibrinogen, activated partial thromboplastin time, prothrombin time, hemoglobin, hematocrit, and platelet count were simultaneously measured intraoperatively with ROTEM for EXTEM, INTEM, and FIBTEM analysis. ROTEM parameters were: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and α-angle. RESULTS:: No significant differences between groups were found in ROTEM variables CT, CFT, MCF, α-angle (EXTEM and INTEM), and MCF (FIBTEM) nor standard coagulation tests. ROTEM parameters did not show changes after administration of hyperosmolar solutions relating to basal values, except for an increase of CFT EXTEM (118±28 vs. 128±26 s) and decrease of CT INTEM (160±18 vs. 148±15 s) with values within normal range. Significant decreases from baseline levels were observed for hematocrit (−7%), platelet count (−10%), and fibrinogen (−13%) after HS infusion, and hematocrit (−9%), platelet count (−13%), and fibrinogen (−9%) after mannitol infusion, but remaining normal. CONCLUSIONS:: The use of 5 mL/kg of equiosmolar solutions of 3% HS and 20% mannitol applied to reach a brain relaxation during elective craniotomy does not induce coagulation impairment as evidenced by ROTEM and standard coagulation tests. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved

Pinero-Madrona A.,Hospital Clinico Universitario Virgen Of La Arrixaca
Revisiones en Cancer | Year: 2015

Surgical treatment of the breast cancer is still a basic element in the management of this disease although, currently, it is ununderstandable without a multidisciplinary approach. Similarly, the more radical first surgeries have been replaced by more conservative techniques, supported by adjuvant systemic or locoregional treatments that allowed equivalent survival rates with much less secondary morbidity. As in the case of primary tumor treatment, axillary treatment has also become more conservative using the selective biopsy of the sentinel node as diagnostic procedure. This allows, besides avoiding unnecessary lymphadenectomy, a more effective and efficient staging of the disease and a better selection of adjuvant treatments. Copyright © 2015 ARAN EDICIONES, S.L.

Cascales-Campos P.,Hospital Clinico Universitario Virgen Of La Arrixaca | Gil J.,Hospital Clinico Universitario Virgen Of La Arrixaca | Feliciangeli E.,Hospital Clinico Universitario Virgen Of La Arrixaca | Parrilla P.,Hospital Clinico Universitario Virgen Of La Arrixaca
Gynecologic Oncology | Year: 2015

Ovarian cancer is the leading cause of death from gynecological cancer in western countries. The absence of an effective screening program as well as specific symptoms, makes the diagnosis difficult and often made in advanced stages of the disease, in the presence of peritoneal dissemination. The complete cytoreduction of the disease and tumor sensitivity to systemic chemotherapy based on platinums, are the two main prognostic factors. However in patients with complete cytoreduction the recurrence rate is high. The microscopic component of the disease at the end of the cytoreduction is responsible for these recurrences and the use of intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) in the same time of surgery has been proposed as a reasonable therapeutic option for treatment. However, the absence of sufficient levels of scientific evidence to support the use of HIPEC in patients with ovarian cancer with peritoneal dissemination does not allow a general recommendation outside of clinical trials. The main objective of this study is to identify the strengths and weaknesses of HIPEC treatment in ovarian cancer with peritoneal dissemination, and to know which points can be improved in the future. © 2015 Elsevier Inc.

Egea-Valenzuela J.,Hospital Clinico Universitario Virgen Of La Arrixaca | Alberca-de-las-Parras F.,Hospital Clinico Universitario Virgen Of La Arrixaca | Carballo-Alvarez F.,Hospital Clinico Universitario Virgen Of La Arrixaca
Revista Espanola de Enfermedades Digestivas | Year: 2015

Introduction: The levels of calprotectin in the stools are proportional to neutrophil activity in the enteric lumen, so fecal calprotectin is a useful intestinal inflammatory biomarker. It is an extended tool as predictor of colonic pathology but there is scare evidence about its utility in the small bowel. Objective: To test the yield of fecal calprotectin to detect lesions in the small bowel. Material and methods: We have retrospectively included 71 patients sent for small bowel capsule endoscopy in study for suspected inflammatory bowel disease. All of them had a determination of fecal calprotectin and had been sent to colonoscopy with no findings. Patients have been divided in groups: A, fecal calprotectin < 50 μg/g; B, fecal calprotectin: 50-100 μg/g; C, fecal calprotectin > 100 μg/g, and we have analyzed which of them presented inflammatory lesions in capsule endoscopy studies. Results: The rate of patients with signi ficative lesions was 1 out of 10 (10%) in group A, 6 out of 24 (25%) in group B, and 21 out of 34 (62%) in group C. If we consider levels over 50 μg/g pathologic, fecal calprotectin presents sensitivity: 96%, specificity: 23%, NPV: 90% and PPV: 56%. If we consider levels over 100 μg/g pathologic these values are sensitivity: 75%, specificity: 67%, NPV: 79% and PPV: 62%. Conclusions: Fecal calprotectin has high sensitivity but not so good specificity for predicting small bowel lesions after a normal colonoscopy. In daily practice it will be more useful to establish in 100 μg/g the limit to indicate capsule endoscopy studies. © 2015 Arán Ediciones, S. L.

Martin-Sanchez F.,Hospital Clinico Universitario Virgen Of La Arrixaca
Cell Death and Differentiation | Year: 2016

Interleukin-1β (IL-1β) is a critical regulator of the inflammatory response. IL-1β is not secreted through the conventional ER–Golgi route of protein secretion, and to date its mechanism of release has been unknown. Crucially, its secretion depends upon the processing of a precursor form following the activation of the multimolecular inflammasome complex. Using a novel and reversible pharmacological inhibitor of the IL-1β release process, in combination with biochemical, biophysical, and real-time single-cell confocal microscopy with macrophage cells expressing Venus-labelled IL-1β, we have discovered that the secretion of IL-1β after inflammasome activation requires membrane permeabilisation, and occurs in parallel with the death of the secreting cell. Thus, in macrophages the release of IL-1β in response to inflammasome activation appears to be a secretory process independent of nonspecific leakage of proteins during cell death. The mechanism of membrane permeabilisation leading to IL-1β release is distinct from the unconventional secretory mechanism employed by its structural homologues fibroblast growth factor 2 (FGF2) or IL-1α, a process that involves the formation of membrane pores but does not result in cell death. These discoveries reveal key processes at the initiation of an inflammatory response and deliver new insights into the mechanisms of protein release.Cell Death and Differentiation advance online publication, 12 February 2016; doi:10.1038/cdd.2015.176. © 2016 Macmillan Publishers Limited

Lopez-Picazo Ferrer J.J.,Hospital Clinico Universitario Virgen Of La Arrixaca | Tomas Garcia N.,Hospital Clinico Universitario Virgen Of La Arrixaca
Cirugia Espanola | Year: 2016

Introduction: The information contained in a good informed consent form (ICF) must be understood by the patients. The aim of this study is to assess and improve the readability of the ICF submitted for accreditation in a tertiary hospital. Methods: Study of assessment and improvement of the quality of 132 ICF from 2 departments of a public tertiary hospital, divided into 3 phases: Initial assessment, intervention and reassessment. Both length and readability are assessed. Length is measured in words (adequate to 470, excessive over 940), and readability in INFLESZ points (suitable if over 55). The ICF contents initially proposed by departments were adapted by non-health-related trained persons, whose doubts about medical terms were resolved by the authors. To compare results between evaluations, relative improvement (in both length and INFLESZ) and statistical significances were calculated. Results: Baseline data: 78.8% of the ICFs showed a desired length (CI95% 86,5-71,1) and a mean of 44.1 INFLESZ points (3.8% >55 points, CI95% 6,0-1,6). After the intervention, INFLESZ raised to 61.9 points (improvement 40.3%, P<.001), all ICF showing >55 points. The resulting ICFs had a longer description of the nature of the procedure (P<.0001) and a shorter description of their consequences, risks (P <.0001) and alternatives (P <.05). Conclusions: The introduction of improvement dynamics in the design of ICFs is possible and necessary because it produces more effective and easily readable ICFs. © 2015 AEC.

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