Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI)

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[Delay in the diagnosis and treatment of five types of cancer in two urban health centres].
(2022-02-07) Cañaveras León, Eugenio; Cano Fuentes, Gloria; Dastis Bendala, Carmen; Terrón Dastis, Pedro; Almeida González, Carmen V
To assess the diagnostic (ID) and treatment (IT) intervals of the most prevalent cancers in patients attached to two health centres and to analyse the influence of sociodemographic, clinical and health system (HS) organisational factors. Observational, retrospective, analytical cohort study. SITE: Primary care. Two urban health centres. Three hundred sixty-five patients diagnosed with colorectal cancer (CRC), breast, lung, prostate or bladder cancer between 1/1/2012 and 31/12/2017. The medians of ID and IT and the risk (OR) of ID and IT above those medians according to the above factors are compared. The contribution of each process step to ID is analysed. Median ID was 92 days, maximum in prostate cancer (395 days) and minimum in lung (54 days). Factors associated with prolonged ID (OR>92 days) were female sex, CRC or prostate location, localised stage, index primary care (AP) consultation and outpatient diagnostic pathway. Prolonged IT (OR>56 days) was related to CRC or prostate location and outpatient diagnostic route. ID components with the greatest influence on delay were: Primary Care Interval (IAP), Secondary Care Delay (DAS) and Secondary Care Adjunctive Test Delay (DPAS). The contribution of IAP was highest in patients with CRC, lung and bladder. ID and IT were 92 and 56 days respectively. The ID components with the highest contribution to delay were IAP, DAS and DPAS. Increasing diagnostic capacity in PC and organising specific diagnostic and treatment pathways would shorten these intervals and allow earlier detection.
Short-Term Pilot Study to Evaluate the Impact of Salbi Educa Nutrition App in Macronutrients Intake and Adherence to the Mediterranean Diet: Randomized Controlled Trial.
(2022-05-14) Gonzalez-Ramirez, Marina; Sanchez-Carrera, Rocio; Cejudo-Lopez, Angela; Lozano-Navarrete, Mauricio; Salamero Sánchez-Gabriel, Elena; Torres-Bengoa, M Alfonso; Segura-Balbuena, Manuel; Sanchez-Cordero, Maria J; Barroso-Vazquez, Mercedes; Perez-Barba, Francisco J; Troncoso, Ana M; Garcia-Parrilla, M Carmen; Cerezo, Ana B
Promoting a healthy diet is a relevant strategy for preventing non-communicable diseases. This study aims to evaluate the impact of an innovative tool, the SAlBi educa nutrition app, in primary healthcare dietary counseling to improve dietary profiles as well as adherence to the Mediterranean diet. A multi-center randomized control trial comprising 104 participants was performed. Both control (n = 49) and intervention (n = 55) groups attended four once-weekly sessions focusing on healthy eating habits and physical activity, over one month. As well as attending the meetings, the intervention group used the app, which provides self-monitoring and tailored dietary advice based on the Mediterranean diet model. In a second intervention (one arm trial), the potential of SAlBi educa was evaluated for three months during the COVID-19 pandemic. At 4 weeks, the intervention group had significantly increased their carbohydrate intake (7.7% (95% CI: 0.16 to 15.2)) and decreased their total fat intake (-5.7% (95% CI: -10.4 to -1.15)) compared to the control group. Significant differences were also found for carbohydrates (3.5% (95% CI: -1.0 to 5.8)), total fats (-5.9% (95% CI: -8.9 to -3.0)), fruits and vegetables (266.3 g/day (95% CI: 130.0 to 402.6)), legumes (7.7g/day (95% CI: 0.2 to 15.1)), starchy foods (36.4 g/day (95% CI: 1.1 to 71.7)), red meat (-17.5 g/day (95% CI: -34.0 to -1.1)), and processed meat (-6.6 g/day (95% CI: -13.1 to -0.1)) intakes during the COVID-19 pandemic. SAlBi educa is a useful tool to support nutrition counseling in primary healthcare, including in special situations such as the COVID-19 pandemic. Trial registration: ISRCTN57186362.
MedicalForms: Integrated Management of Semantics for Electronic Health Record Systems and Research Platforms
(Mdpi, 2022-05-01) Moreno-Conde, Jesus; Salas-Fernandez, Samuel; Moreno-Conde, Alberto; [Moreno-Conde, Jesus] Hosp Univ Virgen Macarena, Seville 41009, Spain; [Moreno-Conde, Alberto] Hosp Univ Virgen Macarena, Seville 41009, Spain; [Salas-Fernandez, Samuel] Fdn Publ Andaluza Gest Invest Salud Sevilla, Seville 41013, Spain; Andalusian Ministry of Health and Families
(1) Background: Clinical information modeling tools are software instruments designed to support the definition of semantic structures able to be implemented in health information systems. Based on the analysis of existing tools, this research developed a tool that proposes new approaches to promoting clinician involvement and supporting information modeling processes through mechanisms that ensure governance, information consistency and consensus building. (2) Method: This research developed the MedicalForms system, which is based on the requirements identified in both a Delphi study about tool requirements and the ISO/TS 13972 specifications. (3) Results: This system allows the management of projects, information structures and implementable forms related to clinical documentation. Users can easily define clinical documents in collaboration with the rest of the professionals in their team by being able to reuse previously defined forms, terminologies and information structures. The system is able to export the defined forms as interoperable specifications or as several implementable form formats compatible with multiple open source EHR systems and research platforms. End user perception of this tool was evaluated through the Technology Acceptance Questionnaire with satisfactory results. Finally, the system was applied to develop 12 research registries and 2 clinical trial research forms, 3 mobile applications and 1 decision support system.
SAlBi educa (Tailored Nutrition App for Improving Dietary Habits): Initial Evaluation of Usability
(Frontiers media sa, 2022-04-19) Gonzalez-Ramirez, Marina; Cejudo-Lopez, Angela; Lozano-Navarrete, Mauricio; Salamero Sanchez-Gabriel, Elena; Torres-Bengoa, M. Alfonso; Segura-Balbuena, Manuel; Sanchez-Cordero, Maria J.; Barroso-Vazquez, Mercedes; Perez-Barba, Francisco J.; Troncoso, Ana M.; Garcia-Parrilla, M. Carmen; Cerezo, Ana B.
In recent years, the use of applications to improve dietary habits has increased. Although numerous nutrition apps are available on the market, only few have been developed by health and nutrition professionals based on scientific evidence and subsequently tested to prove their usability. The main objective of this study was to design, develop, and evaluate the usability of a tailored nutrition application to be used to promote healthy eating habits. In order to decide app design and content, three focus groups took place with fifteen professionals from primary healthcare, nutrition, and food science and computer science, as well as expert users. For the general and feedback message design, a reference model based on the scientific literature was developed. To address the multi-perspective approach of users' and external healthcare professionals' feedback, a one-day pilot testing with potential users and healthcare professionals was conducted with four focus groups. To evaluate the relevance and potential usability of the app a 1-month pilot test was conducted in a real-life environment. A total of 42 volunteers participated in the one-day pilot testing, and 39 potential users participated in the 1-month pilot test. The SAlBi educa app developed includes an online dietary record, a self-monitoring tool to evaluate dietary patterns, general and feedback messages, and examples of traditional Mediterranean recipes. The usability study showed that volunteers think that SAlBi educa is pleasant (59%) and easy to learn to use (94%). Over 84% of the volunteers declared that the nutritional messages were clear and useful. Volunteers stated that general and tailored recommendations, as well as self-monitoring, were SAlBi educa's most motivating and useful features. SAlBi educa is an innovative, user-friendly nutritional education tool with the potential to engage and help individuals to follow dietary habits based on the Mediterranean model.
Inactivation of human plasma alters the structure and biomechanical properties of engineered tissues.
(2022-08-23) Rosell-Valle, Cristina; Martín-López, María; Campos, Fernando; Chato-Astrain, Jesús; Campos-Cuerva, Rafael; Alaminos, Miguel; Santos González, Mónica
Fibrin is widely used for tissue engineering applications. The use of blood derivatives, however, carries a high risk of transmission of infectious agents, necessitating the application of pathogen reduction technology (PRT). The impact of this process on the structural and biomechanical properties of the final products is unknown. We used normal plasma (PLc) and plasma inactivated by riboflavin and ultraviolet light exposure (PLi) to manufacture nanostructured cellularized fibrin-agarose hydrogels (NFAHs), and then compared their structural and biomechanical properties. We also measured functional protein C, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and coagulation factors [fibrinogen, Factor (F) V, FVIII, FX, FXI, FXIII] in plasma samples before and after inactivation. The use of PLi to manufacture cellularized NFAHs increased the interfibrillar spacing and modified their biomechanical properties as compared with cellularized NFAH manufactured with PLc. PLi was also associated with a significant reduction in functional protein C, FV, FX, and FXI, and an increase in the international normalized ratio (derived from the PT), APTT, and TT. Our findings demonstrate that the use of PRT for fibrin-agarose bioartificial tissue manufacturing does not adequately preserve the structural and biomechanical properties of the product. Further investigations into PRT-induced changes are warranted to determine the applications of NFAH manufactured with inactivated plasma as a medicinal product.
GeoHealth: Geographic Information System for Health Management and Clinical, Epidemiological and Translational Research.
(2022) Moreno, Alberto; Moreno, Jesus; González, Victor; Salas, Samuel; Segura, Carmen; de Luque, Virginia; Cuadri, Pastora; Guardia, Pedro; Luque, Luis; Vilches, Ángel
This project aims to develop a system for clinical, epidemiological and translational research capable of associating contextual variables and geospatial data with clinical patient information. The GeoHealth system will include a section to perform exploratory analysis that will help identify risk factors to optimize clinical decision making.
CroniCare: Platform for the Design and Implementation of Follow-Up, Control and Self-Management Interventions for Chronic and Multimorbidity Patients Based on Mobile Technologies.
(2022) Moreno, Alberto; Moreno, Jesus; Salas, Samuel; González, Victor; Valido, Agustín; Guardia, Pedro; Luque, Luis; Reales, Ana; Machuca, Maria; Montblanc, Eva; Garcia, Clara; de la Vega, Juan M
The project proposes to facilitate the design and evaluation of interventions based on mobile technologies and information systems in order to improve the capacity for self-management, empowerment and control of chronic and multimorbidity patients. The system allows to create customizable apps according to the needs of primary care and specialized care. The project includes an evaluation of the impact of the care model, as well as the effectiveness and efficiency of the intervention through a study with 124 multimorbidity patients.
Influence of Performance Status on the Effectiveness of Pembrolizumab Monotherapy in First-Line for Advanced Non-Small-Cell Lung Cancer: Results in a Real-World Population.
(2021-09-09) Jiménez Galán, Rocío; Prado-Mel, Elena; Pérez-Moreno, María Antonia; Caballano-Infantes, Estefanía; Flores Moreno, Sandra
The KEYNOTE-024 clinical trial showed promising results for pembrolizumab in the first-line of treatment of advanced non-small-cell lung cancer (NSCLC). However, the profile of patients in real-world practice differs from those included in this clinical trial. Here, an observational single-center retrospective study was performed through a comparative analysis of clinical outcomes after pembrolizumab therapy according to the Eastern Cooperative Oncology Group Stage Performance Status (ECOG PS). Moreover, univariate and multivariate analyses were carried out to detect prognostic factors. In our cohort, 63.7% of patients had an ECOG PS of 0-1. Regarding response rate, 31.8% of patients had a partial response (PR), 19.3% had stable disease (SD) and 23.9% had progression disease. On the other hand, patients with ECOG PS ≥ 2 showed a significantly lower rate of PR and SD to pembrolizumab than patients with a PS of 0-1. The rate of response, median overall survival (OS) and progression-free survival (PFS) were significantly higher in patients with ECOG PS 0-1 than in those with ECOG PS ≥ 2. In the current study, we found ECOG PS as the only independent predictor of OS and PFS. Due to the ECOG PS scale being a subjective parameter, other tools are needed to identify treatment effectiveness to each patient.
Deficits in Early Sensory and Cognitive Processing Are Related to Phase and Nonphase EEG Activity in Multiple Sclerosis Patients.
(2021-05-13) Sarrias-Arrabal, Esteban; Eichau, Sara; Galvao-Carmona, Alejandro; Domínguez, Elvira; Izquierdo, Guillermo; Vázquez-Marrufo, Manuel
Currently, there is scarce knowledge about the relation between spectral bands modulations and the basis of cognitive impairment in multiple sclerosis (MS). In this sense, analyzing the evoked or phase activity can confirm results from traditional event-related potential (ERP) studies. However, studying the induced or nonphase activity may be necessary to elucidate hidden compensatory or affected cognitive mechanisms. In this study, 30 remitting-relapsing multiple sclerosis patients and 30 healthy controls (HCs) matched in sociodemographic variables performed a visual oddball task. The main goal was to analyze phase and nonphase alpha and gamma bands by applying temporal spectral evolution (TSE) and its potential relation with cognitive impairment in these patients. The behavioural results showed slower reaction time and poorer accuracy in MS patients compared to controls. In contrast, the time-frequency analysis of electroencephalography (EEG) revealed a delay in latency and lower amplitude in MS patients in evoked and induced alpha compared to controls. With respect to the gamma band, there were no differences between the groups. In summary, MS patients showed deficits in early sensorial (evoked alpha activity) and cognitive processing (induced alpha activity in longer latencies), whereas the induced gamma band supported the hypothesis of its role in translation of attentional focus (induced activity) and did not show strong activity in this paradigm (visual oddball).
Genotype-phenotype correlation of 17 cases of Pompe disease in Spanish patients and identification of 4 novel GAA variants.
(2021-05-21) Hernández-Arévalo, Paula; Santotoribio, José D; Delarosa-Rodríguez, Rocío; González-Meneses, Antonio; García-Morillo, Salvador; Jiménez-Arriscado, Pilar; Guerrero, Juan M; Macher, Hada C
Pompe disease (PD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the acid α-glucosidase gene (GAA) that produces defects in the lysosomal acid α-1,4-glucosidase. We aimed to identify genetic variations and clinical features in Spanish subjects to establish genotype-phenotype correlation. A total of 2637 samples of patients who showed symptoms or susceptible signs of PD were enrolled in this observational study. Enzymatic activity was detected by fluorometric techniques and the genetic study was carried out using Next-Generation Sequencing. Fourteen different variants from 17 diagnosed patients were identified, seven males and nine females with LOPD (mean age 36.07, SD 20.57, range 7-64) and a 2-day-old boy with IOPD, four genetic variants had not been described in the literature previously, including a homozygous variant. In all of them α-glucosidase activity was decreased. Muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia and myalgia were commonly observed in patients. This study report four new genetic variants that contribute to the pathogenic variants spectrum of the GAA gene. We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T>G being the most prevalent variant. Furthermore, it was confirmed that the c.236_246delCCACACAGTGC pathogenic variant in homozygosity is associated with early disease and a worse prognosis.
The placenta protects the fetal circulation from anxiety-driven elevations in maternal serum levels of brain-derived neurotrophic factor.
(2021-01-18) Dingsdale, Hayley; Nan, Xinsheng; Garay, Samantha M; Mueller, Annett; Sumption, Lorna A; Chacón-Fernández, Pedro; Martinez-Garay, Isabel; Ghevaert, Cedric; Barde, Yves-Alain; John, Rosalind M
Brain-derived neurotrophic factor (BDNF) plays crucial roles in brain function. Numerous studies report alterations in BDNF levels in human serum in various neurological conditions, including mood disorders such as depression. However, little is known about BDNF levels in the blood during pregnancy. We asked whether maternal depression and/or anxiety during pregnancy were associated with altered serum BDNF levels in mothers (n = 251) and their new-born infants (n = 212). As prenatal exposure to maternal mood disorders significantly increases the risk of neurological conditions in later life, we also examined the possibility of placental BDNF transfer by developing a new mouse model. We found no association between maternal symptoms of depression and either maternal or infant cord blood serum BDNF. However, maternal symptoms of anxiety correlated with significantly raised maternal serum BDNF exclusively in mothers of boys (r = 0.281; P = 0.005; n = 99). Serum BDNF was significantly lower in male infants than female infants but neither correlated with maternal anxiety symptoms. Consistent with this observation, we found no evidence for BDNF transfer across the placenta. We conclude that the placenta protects the developing fetus from maternal changes in serum BDNF that could otherwise have adverse consequences for fetal development.
A proprietary GMP human platelet lysate for the expansion of dermal fibroblasts for clinical applications.
(2021-01-03) Fernández Muñoz, Beatriz; Lopez-Navas, Luis; Gonzalez Bermejo, María; Lomas Romero, Isabel María; Montiel Aguilera, Miguel Ángel; Campos Cuerva, Rafael; Arribas Arribas, Blanca; Nogueras, Sonia; Carmona Sánchez, Gloria; Santos González, Mónica
Recent years have witnessed the introduction of ex vivo expanded dermal fibroblasts for several cell therapy and tissue-engineering applications, including the treatment of facial scars and burns, representing a promising cell type for regenerative medicine. We tested different in-house produced human platelet lysate (HPL) solutions against fetal bovine serum as supplements for in vitro fibroblast expansion by comparing cell yield, molecular marker expression, extracellular matrix (ECM) generation, genomic stability and global gene expression. Our in-house produced HPL supported fibroblast growth at levels similar to those for FBS and commercial HPL products and was superior to AB human serum. Cells grown in HPL maintained a fibroblast phenotype (VIM+, CD44+, CD13+, CD90+), ECM generation capacity (FN+, COL1+) and a normal karyotype, although gene expression profiling revealed changes related to cell metabolism, adhesion and cellular senescence. The HPL manufacturing process was validated within a GMP compliant system and the solution was stable at -80ºC and -20ºC for 2 years. Dermal fibroblasts expanded in vitro with HPL maintain a normal karyotype and expression of fibroblast markers, with only minor changes in their global gene expression profile. Our in-house produced GMP-HPL is an efficient, safe and economical cell culture supplement that can help increase the healthcare activity of blood transfusion centers through the re-use of transfusional plasma and platelets approaching their expiration date. Currently, our HPL solution is approved by the Spanish Agency of Medicines and Medical Devices and is being used in the manufacture of cell therapy products.Abbreviations: AB plasma: plasma group AB; ABHS: AB Human Serum; ABHS+GF: AB Human Serum supplemented with growth factors; ANOVA: Analysis of variance; ATMPs: Advanced Therapies for Medicinal Products; CPE: cytopathic effect; DEGs: Differentially expressed genes; DMEM: Dulbecco's modified Eagle's Medium; ECM: Extracellular matrix; ELISA: enzyme-linked immunosorbent assay; FBS: Fetal bovine serum; FDR: False discovery rate; FGF: Fibroblast growth factor; GMP: Good manufacturing practice; HPL: Human platelet lysate; HPL-CM: commercial human platelet lysate; MSCs: mesenchymal stem cells; NEAA: non-essential amino acids; P/S: penicillin/streptomycin; PBS: phosphate buffered saline; PC: leukodepleted platelet concentrate; PCR: polymerase chain reaction; PDGF: Platelet-derived growth factor; PDGFRA: Platelet-derived growth factor receptor alpha; qPCR: quantitative polymerase chain reaction; RNA: Ribonucleic acid; RT: Room temperature; TAC: Transcriptome analysis console; TGF-β: Transforming growth factor beta.
COVID-19 natural herd immunity and risk of neuropsychiatric disorders.
(2020-08-24) Losilla-Rodríguez, Beatriz; Maldonado, Natalia; Moreno-Mellado, Elisa; López-Díaz, Álvaro
Prevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid: The PREDIABOLE study, a randomized controlled trial.
(2019-08-28) Santos-Lozano, José M; Rada, Mirela; Lapetra, José; Guinda, Ángeles; Jiménez-Rodríguez, María C; Cayuela, José A; Ángel-Lugo, Antonio; Vilches-Arenas, Ángel; Gómez-Martín, Ana M; Ortega-Calvo, Manuel; Castellano, José M
To assess whether the regular intake of an oleanolic acid (OA)-enriched olive oil is effective in the prevention of diabetes. In the PREDIABOLE study, prediabetic individuals (impaired fasting glucose and impaired glucose tolerance) of both sexes (176 patients, aged 30-80 years) were randomized to receive 55 mL/day of OA-enriched olive oil (equivalent dose 30 mg OA/day) [intervention group (IG)] or the same oil not enriched [control group (CG)]. The main outcome was the incidence of new-onset type 2 diabetes in both groups. Forty-eight new diabetes cases occurred, 31 in the CG and 17 in the IG. The multivariate-adjusted hazard ratio was 0.45 (95% CI, 0.24-0.83) for the IG compared with the CG. Intervention-related adverse effects were not reported. The intake of OA-enriched olive oil reduces the risk of developing diabetes in prediabetic patients. The results of the PREDIABOLE study promote the use of OA in new functional foods and drugs for the prevention of diabetes in individuals at risk of developing it.
Off-label use of ketamine for treatment-resistant depression in clinical practice: European perspective.
(2019-04-29) López-Díaz, Álvaro; Murillo-Izquierdo, Manuel; Moreno-Mellado, Elisa
Ketamine therapy for treatment-resistant depression in European national health systems may only be considered after attempting all evidence-based antidepressant strategies outlined in clinical guidelines. This paper seeks to explain the ethical, regulatory and procedural framework for the off-label use of ketamine for treatment-resistant depression within a public healthcare system.Declaration of interestNone.
Exercises using a touchscreen tablet application improved functional ability more than an exercise program prescribed on paper in people after surgical carpal tunnel release: a randomised trial.
(2019-03-26) Blanquero, Jesús; Cortés-Vega, María Dolores; García-Frasquet, María Ángeles; Sánchez-Laulhé, Pablo Rodríguez; Nieto Díaz de Los Bernardos, María Isabel; Suero-Pineda, Alejandro
In people who have undergone surgical carpal tunnel release, do sensorimotor-based exercises performed on the touchscreen of a tablet device improve outcomes more than a conventional home exercise program prescribed on paper? Randomised, parallel-group trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Fifty participants within 10 days of surgical carpal tunnel release. Each participant was prescribed a 4-week home exercise program. Participants in the experimental group received the ReHand tablet application, which administered and monitored exercises via the touchscreen. The control group was prescribed a home exercise program on paper, as is usual practice in the public hospital system. The primary outcome was functional ability of the hand, reported using the shortened form of the Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire. Secondary outcomes were grip strength, pain intensity measured on a 10-cm visual analogue scale, and dexterity measured with the Nine-Hole Peg Test. Outcomes were measured by a blinded assessor at baseline and at the end of the 4-week intervention period. At Week 4, functional ability improved significantly more in the experimental group than the control group (MD -21, 95% CI -33 to -9) on the QuickDASH score (0 to 100). Although the mean estimates of effect on the secondary outcome also all favoured the experimental group, none reached statistical significance: grip strength (MD 5.6 kg, 95% CI -0.5 to 11.7), pain (MD -1.4 cm, 95% CI -2.9 to 0.1), and dexterity (MD -1.3 seconds, 95% CI -3.7 to 1.1). Use of the ReHand tablet application for early rehabilitation after carpal tunnel release is more effective in the recovery of functional ability than a conventional home exercise program. It remains unclear whether there are any benefits in grip strength, pain or dexterity. ACTRN12618001887268.
Reply to: prediction of bilateral cerebral oxygen desaturation from a single sensor in adult cardiac surgery.
(2019) de la Matta, Manuel; Praena, Juan M; Domínguez, Alejandro
Loss of Sarcomeric Scaffolding as a Common Baseline Histopathologic Lesion in Titin-Related Myopathies.
(2018) Ávila-Polo, Rainiero; Malfatti, Edoardo; Lornage, Xavière; Cheraud, Chrystel; Nelson, Isabelle; Nectoux, Juliette; Böhm, Johann; Schneider, Raphaël; Hedberg-Oldfors, Carola; Eymard, Bruno; Monges, Soledad; Lubieniecki, Fabiana; Brochier, Guy; Thao Bui, Mai; Madelaine, Angeline; Labasse, Clémence; Beuvin, Maud; Lacène, Emmanuelle; Boland, Anne; Deleuze, Jean-François; Thompson, Julie; Richard, Isabelle; Taratuto, Ana Lía; Udd, Bjarne; Leturcq, France; Bonne, Gisèle; Oldfors, Anders; Laporte, Jocelyn; Romero, Norma Beatriz
Titin-related myopathies are heterogeneous clinical conditions associated with mutations in TTN. To define their histopathologic boundaries and try to overcome the difficulty in assessing the pathogenic role of TTN variants, we performed a thorough morphological skeletal muscle analysis including light and electron microscopy in 23 patients with different clinical phenotypes presenting pathogenic autosomal dominant or autosomal recessive (AR) mutations located in different TTN domains. We identified a consistent pattern characterized by diverse defects in oxidative staining with prominent nuclear internalization in congenital phenotypes (AR-CM) (n = 10), ± necrotic/regenerative fibers, associated with endomysial fibrosis and rimmed vacuoles (RVs) in AR early-onset Emery-Dreifuss-like (AR-ED) (n = 4) and AR adult-onset distal myopathies (n = 4), and cytoplasmic bodies (CBs) as predominant finding in hereditary myopathy with early respiratory failure (HMERF) patients (n = 5). Ultrastructurally, the most significant abnormalities, particularly in AR-CM, were multiple narrow core lesions and/or clear small areas of disorganizations affecting one or a few sarcomeres with M-band and sometimes A-band disruption and loss of thick filaments. CBs were noted in some AR-CM and associated with RVs in HMERF and some AR-ED cases. As a whole, we described recognizable histopathological patterns and structural alterations that could point toward considering the pathogenicity of TTN mutations.
Systematic Screening of Ubiquitin/p62 Aggregates in Cerebellar Cortex Expands the Neuropathological Phenotype of the C9orf72 Expansion Mutation.
(2018) Ramos-Campoy, Oscar; Ávila-Polo, Rainiero; Grau-Rivera, Oriol; Antonell, Anna; Clarimón, Jordi; Rojas-García, Ricardo; Charif, Sara; Santiago-Valera, Veronica; Hernandez, Isabel; Aguilar, Miquel; Almenar, Consuelo; Lopez-Villegas, Dolores; Bajo, Lorena; Pastor, Pau; Van der Zee, Julie; Lladó, Albert; Sanchez-Valle, Raquel; Gelpi, Ellen
The neuropathological hallmark of the C9orf72 intronic hexanucleotide expansion in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the presence of small ubiquitin/p62-positive and transactive response DNA binding protein 43 kDa (TDP-43)-negative cytoplasmic inclusions in several brain areas. The identification of this histopathological signature is highly predictive of an underlying mutation. In this study, we screened 1800 cases of the Barcelona IDIBAPS Brain Bank, independently of the clinical and final neuropathological diagnosis of the brain donor, for the presence of ubiquitin/p62-positive inclusions in the cerebellum (UPPI). Positive cases were also stained for dipeptide repeats. We identified a total of 21 donors with UPPI and in all of them the C9orf72 hexanucleotide expansion was genetically confirmed. Most donors had an FTLD or to a lesser extent ALS clinico-pathological phenotype. However, 3 cases had been previously classified as having clinically and neuropathologically Lewy body disease. Other co-existing pathologies, especially of the PART-type, were also frequently encountered. This study highlights the importance of the evaluation of ubiquitin/p62-positive cytoplasmic inclusions in all neurodegenerative diseases as a good screening method for the detection of C9orf72 expansion mutation, since this mutation is not rare and can overlap with other neurodegenerative entities.
Sex Differences in Patients With Occult Cancer After Venous Thromboembolism.
(2017-07-06) Jara-Palomares, Luis; Otero, Remedios; Jiménez, David; Praena-Fernández, Juan Manuel; Rivas, Agustina; Font, Carme; Wells, Philip S; López-Reyes, Raquel; González-Martínez, José; Monreal, Manuel
In patients with venous thromboembolism (VTE), male sex has been associated with an increased risk of occult cancer. The influence of sex on clinical characteristics, treatment, cancer sites, and outcome has not been thoroughly investigated yet. We used the Registro Informatizado Enfermedad TromboEmbólica registry to compare the clinical characteristics, treatment strategies, cancer sites, and clinical outcomes in patients with VTE having occult cancer, according to sex. As of June 2014, 5864 patients were recruited, of whom 444 (7.6%; 95% confidence interval: 6.8-8.2) had occult cancer. Of these, 246 (55%) were men. Median time elapsed from VTE to occult cancer was 4 months (interquartile range: 2-8.4), with no sex differences. Women were older, weighed less, and were less likely to have chronic lung disease than men. The most common cancer sites were the lung (n = 63), prostate (n = 42), and colorectal (n = 29) in men and colorectal (n = 38), breast (n = 23), uterine (n = 18), hematologic (n = 17), or pancreas (n = 15) in women. Men were more likely to have lung cancer than women (2.18% vs 0.30%; P 50 years.

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