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Objective: to evaluate the role of Epstein-Barr virus (EBV) on the intestinal mucosa in the evolution of inflammatory bowel disease (IBD). The risk factors for EBV infection and the frequency of EBV-associated lymphoproliferative disorders in IBD patients were also investigated.Methods: intestinal biopsies of IBD patients with available EBV status determined by Epstein-Barr-encoding RNA (EBER) in situ hybridization were identified in the Pathology Database of our center. Clinical information, including phenotypic characteristics of IBD, previous treatments, diagnosis of lymphoma and patient outcome were reviewed in all cases.Results: fifty-six patients with IBD (28 Crohn's disease, 27 ulcerative colitis and one unclassified colitis) were included. EBV in intestinal mucosa was positive in 26 patients (46 %) and was associated to a lymphoproliferative syndrome in one case. EBV positivity was associated with severe histological activity (52 % vs 17.2 %; p 0.007), the presence of a lymphoplasmacytic infiltrate (50 % vs 33.3 %; p 0.03) and active steroid treatment (61.5 % vs 33.3 %; p 0.03). Multi-variate analyses only found an association between EBV and lymphoplasmacytosis (p 0.001). Escalation in previous treatment was significantly more frequent in the EBER+ group (53.8 % vs 26.7 %; p 0.038). No cases developed lymphoma during follow-up.Conclusions: EBV on the intestinal mucosa is associated with a poor outcome of IBD and the need for escalation of therapy. Lymphoplasmacytic infiltrate is associated with EBV infection. EBER+ patients used steroids more frequently compared with EBER- patients. No EBER+ patients developed lymphoma during follow-up.

[Background] Detection of epidermal growth factor receptor (EGFR) mutations in exons 18–21 is recommended in all patients with advanced Non-small-cell lung carcinoma due to the demonstrated efficiency of the standard therapy with tyrosine kinase inhibitors in EGFR-mutated patients. Therefore, choosing a suitable technique to test EGFR mutational status is crucial to warrant a valid result in a short turnaround time using the lowest possible amount of tissue material. The Idylla™ EGFR Mutation Test is a simple, fast and reliable method designed for the detection of EGFR mutations from formalin-fixed paraffin-embedded samples. The aim of this study was the Clinical Performace Evaluation of the Idylla™ EGFR Mutation Test on the Idylla™ System., [Methods] EGFR mutational status was determined on 132 archived formalin-fixed paraffin-embedded tissue sections with Idylla™ technology. Results were compared with the results previously obtained by routine method in the reference lab (Therascreen® EGFR RGQ PCR v2, Qiagen in Molecular Pathology lab, Hospital Universitario Virgen del Rocío de Sevilla)., [Results] The overall agreement between results obtained with the Idylla™ EGFR Mutation Test and the Comparator test method was 95.38% (with 1-sided 95% lower limit of 91.7%) showing Positive Diagnostic Agreement of 93.22% and Negative Diagnostic Agreement of 97.18%, with a Limit Of Detection ≤5%., [Conclusions] The Idylla™ EGFR Mutation Test passed its clinical validity performance characteristics for accuracy., Supported by each clinical center. Biocartis provided free-of-charge Idylla™ EGFR Mutation Test cartridges.

[Background] Pancreatobiliary maljunction is a rare disease characterized by the junction of the pancreatic and biliary ducts outside of the duodenal wall, which normally results in a large common duct. As a result, there is a greater risk of acute pancreatitis and cancer of the gallbladder and biliary tract., [Case report] We present the case of a 43-year-old female diagnosed with a pancreatobiliary maljunction and an associated stenosis of the bile duct, secondary to an episode of acute pancreatitis. She underwent several endoscopic retrograde cholangiopancreatography procedures over the course of three years, without improvement of the stenosis, and therefore a surgical approach was taken. Prior to the surgical intervention, magnetic resonance imaging showed the presence of an 11-mm polyp in the gallbladder. A histological study of the surgical sample identified intramucosal adenocarcinoma over a tubular adenoma of the gallbladder., [Discussion] Pancreatobiliary maljunction can be considered as a premalignant entity due to the risk of developing cancer of the biliary tree and gallbladder. Therefore, these patients should undergo a prophylactic intervention, despite being asymptomatic.

Fibrosing mediastinitis (FM), also called sclerosing mediastinitis or mediastinal fibrosis, is a rare disease characterized by excessive fibrotic reaction in the mediastinum and may compromise the airway, the great vessels and other mediastinal structures, with a morbidity directly related to the location and extent of fibrosis. The cause is not always known but is often the result of a granulomatous disease, most often the histoplasmosis. We report a 43-year-old woman with a history of tuberculosis infection 23 years ago. She attended the pulmonology clinic for cough and dyspnea. Physical examination revealed jugular venous distention at 90°. In computed tomography scan of the chest with contrast (c/c), we observed a mediastinal nodal cast provoking cava compression and obliteration of main and intermediary right lobar bronchus. The pathological examination was FM.

Introduction: Image and metabolic techniques (CT, PET and EBUS) during the study of lung cancer set the pathway to sampling mediastinal LN using EBUS. Discrimination between benign or malignant nature of LN is complex, because there are inconsistent data on morphological and metabolic expression of NNLN. Findings integration from the diferents techniques may guide the probability of benign nature, direct the sampling method and estabish the priority to mediastinoscopy (MED) Aim: The aim of our study was describe the NNLN profile compared with CT, PET/CT and the EBUS in patient with CP and correlate those findings Methods: Period:January 2012-March 2015. We include 86 LN of 81 patients (31 NNLN and 55 NLN) with LC. All patients dispose TC and PET before EBUS-TBNA. The analyzed variables: CT/PET findings, location and size of primary tumor and LN ultrasound signs of studied LN. All results were confirmed by MED. We analyze and correlate findings in NNLN and neoplastic LN Results: No difference in size, SUV and localization of primary tumor between NNLN and NLN. The mean (x - ) size in NNLN and NLN were 17,97 mm vs 23,64 mm respectively. The x - SUV were 4,05 in NNLN (16,5% with - SUVratio (LN SUV / primary Tu SUV) were 0.46 in NNLN (54,1 with r = -0.43 p=0,03) and positive in NLN (r=0.41, p=0,02). The central hilliar sign was the only benign sign, with low sensivity (28%) Conclusions: The presentation of NNLN in patients with LC is heterogeneous with no correlation between image and metabolic test. Lack of concordance in all techniques is suggestive of a benign nature.

9 páginas., Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mtDNA. Here, we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from 2 patients with MELAS who harbored the A3243G mutation. Both mitochondrial respiratory chain enzyme activities and coenzyme Q(10) (CoQ) levels were significantly decreased in MELAS fibroblasts. A similar decrease in mitochondrial membrane potential was found in intact MELAS fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and the activation of mitochondrial permeability transition (MPT), which triggered the degradation of impaired mitochondria. Furthermore, we found defective autophagosome elimination in MELAS fibroblasts. Electron and fluorescence microscopy studies confirmed a massive degradation of mitochondria and accumulation of autophagosomes, suggesting mitophagy activation and deficient autophagic flux. Transmitochondrial cybrids harboring the A3243G mutation also showed CoQ deficiency and increased autophagy activity. All these abnormalities were partially restored by CoQ supplementation. Autophagy in MELAS fibroblasts was also abolished by treatment with antioxidants or cyclosporine, suggesting that both reactive oxygen species and MPT participate in this process. Furthermore, prevention of autophagy in MELAS fibroblasts resulted in apoptotic cell death, suggesting a protective role of autophagy in MELAS fibroblasts., This work was supported by Ministerio de Sanidad, Spain, grants FIS PI080500 and FIS EC08/00076, and by Asociación de Enfermos de Patología Mitocondrial (AEPMI) and Fundación Española de Enfermedades Lisosomales (FEEL). M. de la Mata is the recipient of a fellowship from Colegio Oficial de Farmacéuticos de Sevilla. This group was founded by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII).

Odontogenic fibromyxomas are benign odontogenic tumors of mesenchymal origin of rare presentation in the oral cavity, which exhibit locally aggressive behavior and are prone to local recurrence. The controversy has mainly been on therapeutic management with recommendations varying, depending on the clinical cases, from simple curettage of lesion to segmental bone resection. We present a case report describing the reconstruction of an osseous defect in the maxilla and the restoration with dental implants in a 32 year old female patient after radical surgical excision due to an odontogenic fibromyxoma with locally aggressive behavior. The primary reconstruction of maxillary discontinuity defect was carried out by an immediate non-vascularized cortico-cancellous iliac crest graft. Using a computer-guided system for the implant treatment-planning, three dental implants were secondary placed in the bone graft by means of flapless implant surgery. The patient was subsequently restored with an implant-supported fixed prosthesis that has remained in continuous function for a period of three years. The surgical, reconstructive and restorative treatment sequence and techniques are discussed. © Medicina Oral S. L.

Summary Background Cryptogenic organizing pneumonia (COP) is a rare disease, and its diagnosis requires histological confirmation. The objective of our study was to describe the findings of the thoracic high-resolution computed tomography (HR-CT) and bronchoalveolar lavage (BAL) in patients with confirmed COP and evaluate the complementary diagnostic use of BAL and thoracic HR-CT. Methods Patients recorded in the registry of interstitial pulmonary diseases between 1991 and 2008 were located and the COP patients selected. Results We identified 21 patients with histological confirmation of COP. The median age was 58.0 ± 15.9 years, and 61.9% of patients were female. The most frequent thoracic HR-CT profile was patchy infiltrate (71.4%), followed by parenchymatous consolidation (42.9%). The most frequent BAL profile was mixed alveolitis (62%) with lymphocyte predominance, a CD4/CD8 index of 0.4 and foamy macrophages. The effectiveness of transbronchial biopsy was 66.6%. The diagnostic utility of Poletti’s BAL criteria gives us a specificity of 88.8%, although the sensitivity obtained was low. The specificity of certain HR-CT profiles is 99%. In addition, we observed a complementary use of the HR-CT and the BAL. Conclusions The imaging findings and BAL could be useful for patients with appropriate clinical presentation and for those whose transbronchial biopsy is negative or for whom a confirmatory biopsy cannot be performed.

Objective Study of the bronchoalveolar lavage (BAL) fluid in some interstitial lung diseases can reveal patterns typical to each disease and that can support the diagnosis. The objective of this study was to perform a descriptive analysis of the cytologic study and of the lymphocyte subpopulations in BAL fluid from patients with interstitial lung disease. Material and methods In this prospective, observational study of 562 patients between January 1991 and January 2005, BAL fluid was analyzed to determine the distribution of cell populations and of lymphocyte subsets: CD3, CD4, CD8, CD3+CD4−CD8−, and CD56. Results The mean age was 53.4 years and 53.3% of the patients were women. The following diseases were studied: idiopathic pulmonary fibrosis (n=132), sarcoidosis (n=123), connective tissue diseases (n=133), cryptogenic organizing pneumonia (n=89), and extrinsic allergic alveolitis (n=85). Isolated lymphocytic alveolitis was common in sarcoidosis and extrinsic allergic alveolitis. Mixed alveolitis was the most common pattern in the other interstitial lung diseases. The CD4:CD8 ratio was the most useful parameter. It was high in sarcoidosis (median, 2.3); the ratio was low or inverted in the other interstitial lung diseases, with median values of 1.76 in idiopathic pulmonary fibrosis, 0.45 in extrinsic allergic alveolitis, 0.35 in cryptogenic organizing pneumonia, and 0.33 in the connective tissue diseases. Conclusions BAL parameters, in association with clinical and radiologic data, help to discriminate between interstitial lung diseases. BAL should therefore be considered a very useful tool in clinical management, particularly when pulmonary biopsy is not conclusive or is not possible.

Resumen Objetivo en determinadas enfermedades pulmonares intersticiales difusas (EPID), el estudio del lavado broncoalveolar (LBA) define patrones tipicos de cada enfermedad y tiene valor como apoyo al diagnostico. El objetivo del estudio ha sido realizar un analisis descriptivo del estudio citologico y de las subpoblaciones linfocitarias en el LBA efectuado a pacientes con EPID. Pacientes y metodos estudio prospectivo de 562 pacientes con EPID desde 1991 hasta 2005. Se realizo un estudio de la distribucion celular y de la subpoblaciones linfocitarias en el LBA: CD3, CD4, CD8, CD3 + CD4 − CD8 − y CD56. Resultados la edad media de los pacientes era de 53,4 anos y el 53,3% eran mujeres. Se estudiaron las siguientes enfermedades: fibrosis pulmonar idiopatica (n=132), sarcoidosis (n=123), enfermedades del colageno (n=133), neumonia organizada criptogenetica (n=89) y alveolitis alergica extrinseca (n=85). Tanto en los casos de sarcoidosis como en los de alveolitis alergica extrinseca fue frecuente la alveolitis linfocitaria aislada. En el resto de enfermedades la alveolitis mixta fue el patron habitual. El indice CD4/CD8 fue el parametro mas util, con un incremento en la sarcoidosis (mediana: 2,3). En el resto de las enfermedades el indice estaba invertido, con una mediana para la fibrosis pulmonar idiopatica, la alveolitis alergica extrinseca, la neumonia organizada criptogenetica y la enfermedad del colageno de 1,76; 0,45; 0,35, y 0,33, respectivamente. Conclusiones los parametros del LBA, junto a los datos clinicorradiologicos, ayudan a discriminar entre las EPID. Por lo tanto, debe considerarse una tecnica de gran utilidad en el manejo clinico, sobre todo cuando la biopsia pulmonar no resulta diagnostica o no es posible realizarla.

Introduction: The diagnostic profitability of EBUS-TBNA is highly variable between different studies. Failure to identify those factors depending on the technique and the underlying neoplasia which can determine it. Materials and Methods: We included 162 patients with LC between the periods January 2010 to September 2014. The analyzed variables: histology, CT/PET findings, location and size of primary tumor, ultrasound descriptions of mediastinal lymph nodes (LN), technical aspects of EBUS-TBNA. The diagnostic accuracy was expressed as sensitivity, specificity, PPV and NPV.Cervical mediastinoscopy and surgical resection were considered as reference standard. Due the important diagnostic implication of the NPV, we focus on analyze the factors which can condition it. Results: Of the 162 patients included, 153 were NSCLC and 9 SCLC. The prevalence was 72% and NPV 72%. The total of false negative results (FN) was 18 patients . On 7/18 FN, a systematic sampling was not performed. In 4/18 FN, the cytology was reported as not representative of lymphadenopathy (LN), these being predominantly left LN. In 7/18, a FN result was obtained even with adequate sampling and representative cytology. Most of these LN were accessible on the right side and showed ultrasound evidence of necrosis in five of them. In one of those cases the diagnosis was by EUS-TBNA. Conclusions: During EBUS-TBNA, it´s necessary to execute a systematic sampling of all visible LN. The access of left nodes stations could be improved complementing the study with EUS-TBNA. In the absence of ROSE, with ultrasound evidence of necrosis, the LN sampling area should be better selected and / or increase the number of punctures.

Fibrosing mediastinitis (FM), also called sclerosing mediastinitis or mediastinal fibrosis, is a rare disease characterized by excessive fibrotic reaction in the mediastinum and may compromise the airway, the great vessels and other mediastinal structures, with a morbidity directly related to the location and extent of fibrosis. The cause is not always known but is often the result of a granulomatous disease, most often the histoplasmosis. We report a 43-year-old woman with a history of tuberculosis infection 23 years ago. She attended the pulmonology clinic for cough and dyspnea. Physical examination revealed jugular venous distention at 90°. In computed tomography scan of the chest with contrast (c/c), we observed a mediastinal nodal cast provoking cava compression and obliteration of main and intermediary right lobar bronchus. The pathological examination was FM.

Mitochondrial DNA mutations are an important cause of human disease for which there is no effective treatment. Myoclonic epilepsy with ragged-red fibers (MERRF) is a mitochondrial disease usually caused by point mutations in transfer RNA genes encoded by mitochondrial DNA. The most common mutation associated with MERRF syndrome, m.8344A > G in the gene MT-TK, which encodes transfer RNA Lysine, affects the translation of all mitochondrial DNA encoded proteins. This impairs the assembly of the electron transport chain complexes leading to decreased mitochondrial respiratory function. Here we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from patients harboring the A8344G mutation. Coenzyme Q 10 (CoQ) levels, as well as mitochondrial respiratory chain activity, and mitochondrial protein expression levels were significantly decreased in MERRF fibroblasts. Mitotracker staining and imaging analysis of individual mitochondria indicated the presence of small, rounded, depolarized mitochondria in MERRF fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and increased degradation of impaired mitochondria by mitophagy. Transmitochondrial cybrids harboring the A8344G mutation also showed CoQ deficiency, mitochondrial dysfunction, and increased mitophagy activity. All these abnormalities in patient-derived fibroblasts and cybrids were partially restored by CoQ supplementation, indicating that these cell culture models may be suitable for screening and validation of novel drug candidates for MERRF disease. © 2012 The American Society for Experimental NeuroTherapeutics, Inc., DYT1 dystonia is a childhood-onset movement disorder with autosomal dominant inheritance. The disease is caused by a 3-bp deletion (ΔGAG) in the TOR1A gene that removes a glutamic acid residue (ΔE) of the encoded protein, torsin A. Interestingly, the ΔGAG mutation shows reduced penetrance of only 30%. Thus, additional genetic and enviromental modifiers affecting the manifestation of DYT1 dystonia symptoms are likely to exist. A recent hypothesis proposed a molecular link between DYT1 and DYT6 dystonia based on the possible regulation of torsin A transcription by THAP1.1, 2 Aiming to expand on prior analysis testing whether THAP1 is a genetic modifier for DYT1 dystonia,3, 4 we performed a genetic screen for sequence variations in the THAP1 gene and also in THAP1-binding sites of the TOR1A promoter in carriers of the ΔGAG DYT1 deletion., This work was supported by FIS PI10/00543 grant, FIS EC08/00076 grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), SAS 111242 grant, Servicio Andaluz de Salud-Junta de Andalucía, Proyecto de Investigación de Excelencia de la Junta de Andalucía CTS-5725, International Coenzyme Q Association Grant and by AEPMI (Asociación de Enfermos de Patología Mitocondrial), FEEL (Fundación Española de Enfermedades Lisosomales) and Federación Andaluza de Fibromialgia y Fatiga Crónica (ALBA Andalucía). Mario de la Mata is granted with a fellowship from Colegio Oficial de Farmacéuticos de Sevilla. We also thank Elena Garcia from Hospital Vall d´Hebron (Barcelona, Spain) for her help with the cybrid clones. This group is founded by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII.

Aquaporin-1 (AQP1) is the main water channel responsible for water transport through many epithelia and endothelia. The latest evidence pointed toward an important role of this protein also in gas permeation, angiogenesis, cell proliferation and migration. In the present work we studied the expression of AQP1 by immunohistochemical staining of 92 lung biopsies from patients diagnosed with a pleuro-pulmonary tumor (71 lung and 21 pleural neoplasms). AQP1 expression was analyzed comparing the results among the different histological patterns and against 9 control cases (5 parenchyma and 4 healthy pleura). Clear staining of AQP1 was detected in 39 of the 92 tumors analyzed. In parenchyma, AQP1 was more frequently detected in primary lung adenocarcinomas (55%, P0.001); in contrast, small cell carcinomas were the least AQP1 expressive tumors studied (93% of negative staining, P0.05). Carcinomas analyzed in pleura (mesotheliomas and metastatic adenocarcinomas) also revealed strong expression of AQP1. High expression of this protein was detected in small capillaries in areas near or surrounding the tumor, and novel intense AQP1 immunostaining was detected over thicker alveolar walls in alveoli inside or next to the tumoral tissue regardless of the tumor type. An important role of AQP1 in tumor angiogenesis is sustained by the abundant expression of this protein in the endothelia of tumor capillaries. Further studies are necessary to elucidate the potential pathophysiological role of this protein in pleuro-pulmonary neoplasms.

14 páginas, 11 figuras, 1 tabla., Coenzyme Q10 (CoQ) is a small lipophilic molecule critical for the transport of electrons from complexes I and II to complex III in the mitochondrial respiratory chain. CoQ deficiency is a rare human genetic condition that has been associated with a variety of clinical phenotypes. With the aim of elucidating how CoQ deficiency affects an organism, we have investigated the pathophysiologic processes present within fibroblasts derived from 4 patients with CoQ deficiency. Assays of cultured fibroblasts revealed decreased activities of complex II+III, complex III, and complex IV, reduced expression of mitochondrial proteins involved in oxidative phosphorylation, decreased mitochondrial membrane potential, increased production of reactive oxygen species (ROS), activation of mitochondrial permeability transition (MPT), and reduced growth rates. These abnormalities were partially restored by CoQ supplementation. Moreover, we demonstrate that CoQ deficient fibroblasts exhibited increased levels of lysosomal markers (β-galactosidase, cathepsin, LC3, and Lyso Tracker), and enhanced expression of autophagic genes at both transcriptional and translational levels, indicating the presence of autophagy. Electron microscopy studies confirmed a massive degradation of the altered mitochondria by mitophagy. Autophagy in CoQ deficient fibroblasts was abolished by antioxidants or cyclosporin treatments suggesting that both ROS and MPT participate in this process. Furthermore, prevention of autophagy in CoQ deficient fibroblasts by 3-methyl adenine or wortmannin, as well as the induction of CoQ deficiency in cells lacking autophagy (by means of genetic knockout of the Atg5 gene in mouse embryonic fibroblasts) resulted in apoptotic cell death, suggesting a protective role of autophagy in CoQ deficiency., This work was supported by grants PI041617 from the FIS, Ministerio de Sanidad, Spain, and European Union contract LSHBCT-2004-005151 (UBIGENES). This group is founded by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII.

This is an open access article distributed under the terms of the Creative Commons Attribution License., [Introduction]: Fibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress may have a role in the pathophysiology of fibromyalgia. However, it is still not clear whether oxidative stress is the cause or the effect of the abnormalities documented in fibromyalgia. Furthermore, the role of mitochondria in the redox imbalance reported in fibromyalgia also is controversial. We undertook this study to investigate the role of mitochondrial dysfunction, oxidative stress, and mitophagy in fibromyalgia. [Methods]: We studied 20 patients (2 male, 18 female patients) from the database of the Sevillian Fibromyalgia Association and 10 healthy controls. We evaluated mitochondrial function in blood mononuclear cells from fibromyalgia patients measuring, coenzyme Q10 levels with high-performance liquid chromatography (HPLC), and mitochondrial membrane potential with flow cytometry. Oxidative stress was determined by measuring mitochondrial superoxide production with MitoSOX™ and lipid peroxidation in blood mononuclear cells and plasma from fibromyalgia patients. Autophagy activation was evaluated by quantifying the fluorescence intensity of LysoTracker™ Red staining of blood mononuclear cells. Mitophagy was confirmed by measuring citrate synthase activity and electron microscopy examination of blood mononuclear cells. [Results]: We found reduced levels of coenzyme Q10, decreased mitochondrial membrane potential, increased levels of mitochondrial superoxide in blood mononuclear cells, and increased levels of lipid peroxidation in both blood mononuclear cells and plasma from fibromyalgia patients. Mitochondrial dysfunction was also associated with increased expression of autophagic genes and the elimination of dysfunctional mitochondria with mitophagy. [Conclusions]: These findings may support the role of oxidative stress and mitophagy in the pathophysiology of fibromyalgia., This work was supported by grants FIS PI080500 and FIS EC08/00076, Ministerio de Sanidad, Spain. The authors dedicate this manuscript to FM patients and AFIBROSE (Asociación de Fibromialgia de Sevilla) for their unconditional help.

Male, aged 74, with chronic respiratory disease and degenerative aortic stenosis, operated 45 days ago to replace the valve with a biological prosthetic valve. The patient came for a consultation due to class III dyspnoea and long-term oppressive retrosternal pain. Transthoracic echocardiography was carried out showing normal prosthetic functioning, good contractility in all segments, and …