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This paper describes the reforms recommended by the Advisory Committee on the Financing of Pharmaceuticals (CAPF) for the National Health System (NHS) of Spain from 2019 to 2024 for the drug pricing and reimbursement process, to integrate economic evaluations and improve efficiency and sustainability. The CAPF has proposed a three-phase reform of the economic evaluation (EE) and budget impact analysis (BIA) processes. The first phase involves the mandatory submission of EE and BIA by applicants for new drugs. The second phase involves the assessment of these submissions, coordinated by the Directorate-General for Pharmaceuticals. The third phase focuses on the application of these assessments to decision-making on drug positioning, pricing and financing. The CAPF's recommendations emphasise improved regulation, transparency and the development of methodological guidelines for economic evaluations. These proposals include a dynamic appraisal system and the creation of official NHS guidance on EE and BIA. The process is designed to ensure compliance with established criteria and to incorporate efficiency into decision-making. The initiatives of the CAPF aim to make progress towards the integration of efficiency in Spanish pharmaceutical policy seeking to improve the methodological quality and transparency of economic evaluations, ultimately contributing to more informed decision-making and sustainable healthcare practices. Resumen: Este artículo describe las reformas recomendadas por el Comité Asesor para la Financiación de la Prestación Farmacéutica (CAPF) del Sistema Nacional de Salud (SNS) de España entre 2019 y 2024 en el proceso de fijación de precios y reembolso de medicamentos, con el fin de integrar evaluaciones económicas y mejorar la eficiencia y la sostenibilidad. El CAPF ha propuesto una reforma en tres fases de los procesos de evaluación económica (EE) y análisis de impacto presupuestario (AIP). La primera fase implica la presentación obligatoria de EE y AIP por parte de los solicitantes de nuevos medicamentos. La segunda fase implica la evaluación de estas presentaciones, coordinada por la Dirección General de Farmacia. La tercera fase se centra en la aplicación de estas evaluaciones en la toma de decisiones sobre el posicionamiento, la fijación de precios y la financiación de los medicamentos. Las recomendaciones del CAPF destacan la mejora de la regulación, la transparencia y el desarrollo de directrices metodológicas para las EE. Estas propuestas incluyen un sistema de evaluación dinámico y la creación de una guía oficial del SNS sobre EE y AIP. El proceso está diseñado para garantizar el cumplimiento de los criterios establecidos e incorporar la eficiencia en la toma de decisiones. Las propuestas del CAPF tienen como objetivo avanzar hacia la integración de la eficiencia en la política farmacéutica española y buscan mejorar la calidad metodológica y la transparencia de las EE, contribuyendo en última instancia a una toma de decisiones más informada y a prácticas de atención sanitaria sostenibles.

Abstract Introduction This paper outlines the design, implementation, and usability study results of the patient empowerment process for chronic disease management, using Patient Reported Outcome Measurements and Shared Decision-Making Processes. Background The ADLIFE project aims to develop innovative, digital health solutions to support personalized, integrated care for patients with severe long-term conditions such as Chronic Obstructive Pulmonary Disease, and/or Chronic Heart Failure. Successful long-term management of patients with chronic conditions requires active patient self-management and a proactive involvement of patients in their healthcare and treatment. This calls for a patient-provider partnership within an integrated system of collaborative care, supporting self-management, shared-decision making, collection of patient reported outcome measures, education, and follow-up. Methods ADLIFE follows an outcome-based and patient-centered approach where PROMs represent an especially valuable tool to evaluate the outcomes of the care delivered. We have selected 11 standardized PROMs for evaluating the most recent patients’ clinical context, enabling the decision-making process, and personalized care planning. The ADLIFE project implements the "SHARE approach’ for enabling shared decision-making via two digital platforms for healthcare professionals and patients. We have successfully integrated PROMs and shared decision-making processes into our digital toolbox, based on an international interoperability standard, namely HL7 FHIR. A usability study was conducted with 3 clinical sites with 20 users in total to gather feedback and to subsequently prioritize updates to the ADLIFE toolbox. Results User satisfaction is measured in the QUIS7 questionnaire on a 9-point scale in the following aspects: overall reaction, screen, terminology and tool feedback, learning, multimedia, training material and system capabilities. With all the average scores above 6 in all categories, most respondents have a positive reaction to the ADLIFE PEP platform and find it easy to use. We have identified shortcomings and have prioritized updates to the platform before clinical pilot studies are initiated. Conclusions Having finalized design, implementation, and pre-deployment usability studies, and updated the tool based on further feedback, our patient empowerment mechanisms enabled via PROMs and shared decision-making processes are ready to be piloted in clinal settings. Clinical studies will be conducted based at six healthcare settings across Spain, UK, Germany, Denmark, and Israel.

La depresión posparto comprende una complicación que ocurre en los primeros 4 meses previos al parto. El consumo de alcohol representa un problema social y de salud pública a nivel mundial. Casi 1 de cada 10 (9,8%) mujeres de la población general consume alcohol durante el embarazo, el cual durante la gestación o posparto puede desencadenar depresión al actuar como depresor del sistema nervioso central. Se realizó un estudio descriptivo transversal donde se entrevistaron a 657 puérperas hospitalizadas en el área de Ginecología y Obstetricia del Hospital General Guasmo Sur, se realizaron 2 pruebas: el Test de Edimburgo, para evaluar síntomas de depresión posparto y el Alcohol Use Disorders Identification Test para detectar problemas relacionados con el consumo de alcohol. La prevalencia de probable depresión posparto fue del 22.2% del cual el 85.6% de las mujeres tenían entre 18-30 años. También se observó que el 9.3% de las puérperas presentaban dependencia al consumo de alcohol, siendo que el 85.2% se encontraba en el rango de 18-30 años. Los resultados de diversos estudios similares son proporcionales a lo encontrado en la presente investigación, al describir que una paciente que presenta antecedentes de depresión asociados al consumo de alcohol tendría mayor riesgo a padecer depresión durante el período posparto. En nuestra comunidad se identificó que existe una tasa mayor de la esperada de depresión posparto y dependencia de alcohol, siendo el rango de edad más afectado en ambos casos entre los 18 a 30 años.

Background: Floral microstructure, with multiple functions, is very important in pollination biology. Questions: Are the expected general characteristics of corolla micromorphology fulfilled in the selected species with different pollination systems? Studied species: Agave americana, Arbutus unedo, Aristolochia paucinervis, Cestrum nocturnum, Cytinus hypocistis subsp. macranthus, C. ruber, Dianthus lusitanus, Grevillea robusta, Musa x paradisiaca, Nicotiana glauca, Stellaria media and Teucrium fruticans. Study site and dates: Southern Spain, 2017-2019. Methods: Floral micromorphological characters were studied by light and scanning electron microscopy and analyzed using different statistical tests. Results: The adaxial side of the corolla lobes in melittophilous, myrmecophilous, psychophilous and sapromyophilous species showed papillose cells, and the same was true of the sphingophilous species Cestrum nocturnum and hummingbird-pollinated Nicotiana glauca. In contrast, tabular cells were observed in the perching-pollinator ornithophilous species Grevillea robusta, the two studied chiropterophilous species, and autogamous Stellaria media. In addition, corolla mesophyll was thicker in chiropterophilous species. Furthermore, differences were detected in cell turgidity (in protogynous Aristolochia paucinervis) and in mesophyll thickness between male and female flowers (Cytinus). Conclusions: Papillose cells were present in corollas in physical contact with pollinators, as expected, but also appeared in corollas of some other species without such contact. We recommend that studies of dichogamous and unisexual species include comparisons of corolla micromorphology between sexual states, as differences may exist in cell turgidity or mesophyll thickness. We also caution against the widespread view that certain types of pollinators do not mechanically interact with the epidermal surface of the corolla.

Summary: Nerve growth factor receptor (NGFR) is expressed by follicular dendritic cells (FDCs). However, the role of NGFR in the humoral response is not well defined. Here, we study the effect of Ngfr loss on lymph node organization and function, demonstrating that Ngfr depletion leads to spontaneous germinal center (GC) formation and an expansion of the GC B cell compartment. In accordance with this effect, stromal cells are altered in Ngfr−/− mice with a higher frequency of FDCs, characterized by CD21/35, MAdCAM-1, and VCAM-1 overexpression. GCs are located ectopically in Ngfr−/− mice, with lost polarization together with impaired high-affinity antibody production and an increase in circulating autoantibodies. We observe higher levels of autoantibodies in Bcl2 Tg/Ngfr−/− mice, concomitant with a higher incidence of autoimmunity and lower overall survival. Our work shows that NGFR is involved in maintaining GC structure and function, participating in GC activation, antibody production, and immune tolerance.

Objective Integrated care and digital health technology interventions are promising approaches to coordinate services for people living with chronic conditions, across different care settings and providers. The EU-funded ADLIFE project intends to provide digitally integrated personalized care to improve and maintain patients’ health with advanced chronic conditions. This study conducted a qualitative assessment of contextual factors prior to the implementation of the ADLIFE digital health platforms at the German pilot site. The results of the assessment are then used to derive recommendations for action for the subsequent implementation, and for evaluation of the other pilot sites. Methods Qualitative interviews with healthcare professionals and IT experts were conducted at the German pilot site. The interviews followed a semi-structured interview guideline, based on the HOT-fit framework, focusing on organizational, technological, and human factors. All interviews were audio recorded, transcribed, and subsequently analysed following qualitative content analysis. Results The results of the 18 interviews show the interviewees’ high openness and motivation to use new innovative digital solutions, as well as an apparent willingness of cooperation between different healthcare professionals. Challenges include limited technical infrastructure and large variability of software to record health data, lacking standards and interfaces. Conclusions Considering contextual factors on different levels is critical for the success of implementing innovations in healthcare and the transfer into other settings. In our study, the HOT-fit framework proved suitable for assessing contextual factors, when implementing IT innovations in healthcare. In a next step, the methodological approach will be transferred to the six other European pilot sites, participating in the project, for a cross-national assessment of contextual factors.

La producción agrícola en las Galápagos empezó a principios del siglo XX en las cuatro islas habitadas. Actualmente, se conoce muy poco acerca del número, abundancia y distribución de especies de insectos y plantas en el área agropecuaria. La información sobre la presencia de especies invasoras y sus impactos en la producción agrícola también es escasa. Para asegurar la sostenibilidad de la vida humana y la conservación de las especies de las Galápagos, es fundamental conocer esta biodiversidad terrestre y las interacciones con los sistemas socio-ecológicos. Con el propósito de llenar esta brecha de información, se levantó una línea base de insectos en 40 fincas de la Isla Santa Cruz. Para esto, se establecieron transectos en los que se realizaron barridos del follaje con redes entomológicas y colectas manuales de insectos en los cultivos de cada finca. Se colectaron e identificaron a diferentes niveles taxonómicos 16 533 individuos y de estos, 10 331 fueron identificados a nivel de especie. Se identificaron 135 especies de insectos, de estas el 18,7 % corresponde a insectos endémicos, el 13,3 % a nativos, y el 46,7 % a introducidos. Las especies: Bromeloecia wolverinei, Ceraeochrysa everes, Coproica bisphanta, Cosmosciara hartii, Dettopsomyia formosa, Pseudolycoriella cavatica, Psychoda alternata, Pullimosina heteroneura, Zagrammosoma lineaticeps son nuevos registros para Galápagos. Esta información constituye una herramienta útil a la hora de incorporar prácticas agrícolas sostenibles. Por esto, se recomienda reforzar el sistema de vigilancia entomológica y acompañamiento técnico en la zona agropecuaria de Santa Cruz.

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols.

Scrophularia arguta (Scrophulariaceae) is a rare amphicarpic annual species with a fragmented distribution in North Africa, part of the Arabian Peninsula, and Macaronesia, with several peripheral populations on the Iberian Peninsula (south-western Europe) as well. The Iberian populations have a disjunct distribution: several endangered or critically endangered populations are present in the southeast versus a few non-listed ones representing a relict lineage with a unique plastid haplotype inhabiting the west-central region (Extremadura). In this study, we examined the largest and most important population of this relict lineage to assess potential threats to its survival. We evaluated pollination and reproductive systems, floral rewards, fruit and seed set from chasmogamous and cleistogamous flowers, and population dynamics (i.e., phenology, survival, reproductive success, and predation level). We found that the main threats to the population are predation by wild herbivores, such as red deer and, to a lesser extent, Cucullia scrophulariae caterpillars. These threats decrease reproductive success to such an extent that population survival may be in jeopardy if no action is taken to reduce the effects of herbivores. In addition, the existence of nearby beehives alters the presence and density of wild pollinators that contribute to gene flow via pollen transfer and increase genetic variability. Cleistogamous seeds may help maintain the population in specific microhabitats (mainly quartzite rock cracks), although at the cost of reducing genetic variability. Finally, we recommend that regional/national administrations responsible for biodiversity matters adopt measures to ensure the conservation and survival of west-central populations.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal signals to control metabolism. Here the authors investigate the effects of constitutive nutrient signaling through genetic activation of RagA in adult mice and show that constitutive nutrient signaling regulates the response to feeding-fasting cycles and does not drive liver cancer.

This piece of research presents the concepts of Ethics and Morals in relation to the achievement of Sustainable Development Goal targets 8.5 and 8.8 of the 2030 Agenda. Specifically, this work develops an explanation for some possible conflicts generated by the challenges of an ethical and moral nature in the implementation of business policies oriented toward economic sustainability. To this end, first, a reflection of the basic concepts is provided. Second, these two concepts are polemically pitted against each other. Finally, some solutions are suggested as a synthesis of a dialectical process. Additionally, throughout this study, both terms are presented in accordance with the idea of sustainability from a socio-economic and political context, which are generated by the ideological system of their culture.

Diabetic nephropathy is a major complication in diabetic patients. Podocytes undergo loss and detachment from the basal membrane. Intra- and intercellular communication through exosomes are key processes for maintaining function, and the Rab3A/Rab27A system is an important counterpart. Previously, we observed significant changes in the Rab3A/Rab27A system in podocytes under glucose overload, demonstrating its important role in podocyte injury. We investigated the implication of silencing the Rab3A/Rab27A system in high glucose-treated podocytes and analysed the effect on differentiation, apoptosis, cytoskeletal organisation, vesicle distribution, and microRNA expression in cells and exosomes. For this, we subjected podocytes to high glucose and transfection through siRNAs, and we isolated extracellular vesicles and performed western blotting, transmission electron microscopy, RT-qPCR, immunofluorescence and flow cytometry assays. We found that silencing RAB3A and RAB27A generally leads to a decrease in podocyte differentiation and cytoskeleton organization and an increase in apoptosis. Moreover, CD63-positive vesicles experienced a pattern distribution change. Under high glucose, Rab3A/Rab27A silencing ameliorates some of these detrimental processes, suggesting a differential influence depending on the presence or absence of cellular stress. We also observed substantial expression changes in miRNAs that were relevant in diabetic nephropathy upon silencing and glucose treatment. Our findings highlight the Rab3A/Rab27A system as a key participant in podocyte injury and vesicular traffic regulation in diabetic nephropathy.

Assessment of disease burden and drug efficacy is achieved preclinically using high resolution micro computed tomography (CT). However, micro-CT is not applicable to clinical human imaging due to operating at high dose. In addition, the technology differences between micro-CT and standard clinical CT prevent direct translation of preclinical applications. The current proof-of-concept study presents spectral photon-counting CT as a clinically translatable, molecular imaging tool by assessing contrast uptake in an ex-vivo mouse model of pulmonary tuberculosis (TB). Iodine, a common contrast used in clinical CT imaging, was introduced into a murine model of TB. The excised mouse lungs were imaged using a standard micro-CT subsystem (SuperArgus) and the contrast enhanced TB lesions quantified. The same lungs were imaged using a spectral photoncounting CT system (MARS small-bore scanner). Iodine and soft tissues (water and lipid) were materially separated, and iodine uptake quantified. The volume of the TB infection quantified by spectral CT and micro-CT was found to be 2.96 mm3 and 2.83 mm3, respectively. This proof-of-concept study showed that spectral photon-counting CT could be used as a predictive preclinical imaging tool for the purpose of facilitating drug discovery and development. Also, as this imaging modality is available for human trials, all applications are translatable to human imaging. In conclusion, spectral photon-counting CT could accelerate a deeper understanding of infectious lung diseases using targeted pharmaceuticals and intrinsic markers, and ultimately improve the efficacy of therapies by measuring drug delivery and response to treatment in animal models and later in humans.

Background/purpose: There are few studies comparing the expression of enamel proteins, such as amelogenin, and cytokeratins in cyst and odontogenic tumors like in ameloblastoma and odontogenic keratocyst, indicating that amelogenin could be a potential biomarker for the aggressiveness in the odontogenic tumors. The aim of this study was to evaluate if the expression of amelogenin, cytokeratin AE1/AE3 (CKAE1/AE3) and cytokeratin 14 (CK14) in cysts and odontogenic tumors with calcified matrices such as calcifying odontogenic cyst (COC), compound (CdO) and complex (CxO) odontomas, adenomatoid odontogenic tumor (AOT) and calcifying epithelial odontogenic tumor (CEOT) as an aggressiveness indicator. Materials and methods: Three COC, eight CxO, three CdO, twelve AOT, two CEOT and three dental germs were submitted to an immunohistochemistry panel of antibodies composed of amelogenin, CKAE1/AE3 and CK14. Results: CKAE1/AE3 and CK14 was present in all odontogenic epithelia. The amelogenin protein was detected in prismatic and amorphous calcified matrices of epithelial origin belonging to CxO, CdO, AOT, COC and the tooth germs used as controls. On the other hand, the CEOT was the only tumor or cyst studied that did not present immunostaining for amelogenin in calcified matrices. Conclusion: Amelogenin was detected in pathologies with a low or absent recurrence rate and excellent prognosis. CEOT was the lesion of greater clinical aggressiveness which did not express amelogenin. The presence of amelogenin in calcified matrices of odontogenic arise could be an indicator of low aggressiveness.

Objective: Patients included in MAINRITSAN2 trial received either an individually tailored or a fixed-schedule therapy with rituximab as maintenance treatment of antineutrophil cytoplasm antibody associated vasculitides. The aim of this study was to compare the real-world costs of both arms. Method: We performed a cost-minimization analysis over an 18-month time period, estimating direct costs –drug acquisition, preparation, administration and monitoring costs– from the health system perspective. We conducted a number of additional sensitivity analyses with different assumptions for unit costs, with further scenarios including the interquartile range of the tailored-infusion group results, different number of monitoring visits for fixed-schedule regimen and different number of reported severe adverse events. A cost- effectiveness analysis was conducted as a sensitivity analysis using the absolute difference in the relapse rate and its confidence interval. Results: The individually tailored maintenance therapy with rituximab was shown to be a cost-saving treatment compared to the fixed-schedule therapy (6,049 euros vs. 7,850 euros). Savings resulted primarily from lower drug acquisition costs (2,861 vs. 4,768 euros) and lower preparation and administration costs (892 vs. 1,486 euros), due to the lower number of infusions per patient in the tailored-infusion regimen. The tailoredinfusion regimen presented higher monitoring costs (2,296 vs. 1,596 euros). This result was replicated in all assumptions considered in the sensitivity analysis of cost-minimization approach. Conclusions: From the perspective of the health system, the tailoredtherapy regimen seems to be the preferable option in terms of direct costs. Further studies assessing all the effects and costs associated to vasculitides maintenance treatment with rituximab are needed to support clinical management and healthcare planning.

Objective: To identify which genes are associated with the clinical phenotype of amelogenesis Imperfecta (AI) and to elucidate which of these genes participate in the determination of isolated and syndromic forms.Methods: In this review, all data on mutations described in AI-related genes were obtained from HGMD® Professional. The data in relation to the mutations, inheritance, phenotype, type of AI and country were supplemented with information from the literature. The identity codes and frequency values were obtained from the dbSNP, ClinVar and OMIM databases. The percentage of specificity (PE) was determined for each gene.Results: HGMD® describes 27 genes involved in AI, which we propose to group into 5 categories: (1) genes whose mutations are associated only with isolated AI, (2) genes whose mutations cause only syndromic AI, (3) genes with both mutations that cause isolated AI and mutations responsible for other pathologies, (4) genes with mutations responsible for syndromic AI and mutations that cause other pathologies, and (5) genes with mutations that cause isolated AI and mutations that cause AI associated with syndromes and other pathologies. Using the PE calculation, the genes were ranked into 5 specificity groups. The genes of category 1 are specific for isolated AI, while the genes of categories 2 and 4 are non-specific. Interestingly, we observed that mutations in some genes were associated with different types of cancer.Conclusion: The ACP4, AMTN, MMP20, ODAPH, RELT, SLC24A4 and SP6 genes participate in causing isolated AI, and the CNNM4, DLX3 and FAM20A genes participate in causing syndromic forms of AI.

The identification of the Rag GTPases initiated the deciphering of the molecular puzzle of nutrient signaling to the mechanistic target of rapamycin (mTOR), and spurred interest in targeting this pathway to combat human disease. Recent mouse genetic studies have provided pathophysiological insight and pointed to potential indications for inhibitors of the Rag GTPase pathway.

Background: Epidermolysis bullosa (EB) corresponds to a series of conditions characterized by extreme fragility of the skin and/or mucous membranes. Of the four main types of EB, junctional EB (JEB) is the most associated with alterations in the teeth. The purposes of this study were to determine the clinical, histopathological, and ultrastructural characteristics of teeth with amelogenesis imperfecta (AI) in a patient with JEB, and compare them with control teeth, and correlate the findings with the mutations present in the patient.Case Report: The study was conducted on a 10-year-old patient with JEB carrier of two recessive mutations in the LAMB3 gene and absence of the laminin-332 protein (LM-332), determined by immunofluorescence on a skin biopsy. The patient presents hypoplastic AI with very thin and yellow-brown colored enamel. Extraction of two permanent molars was performed due to pain and soft tissue covering the crown, resembling pulp polyp or hyperplastic gingiva. Light and scanning electron microscopy (SEM) revealed very thin enamel varying from complete absence to 60 μm, absence of normal prismatic structure, and presence of a cross-banding with a laminated appearance. The histopathological study revealed granulation tissue causing external crown resorption.Conclusion: Although coronary resorption has been reported in patients with syndromic and non-syndromic AI, this is the first clinicopathological report of coronary resorption in partially erupted teeth in patients with JEB with mutations in the LAMB3 gene and hypoplastic AI. In patients with this condition, the presence of partially erupted teeth with soft tissue covering part of the crown, without a periodontal pocket, and with a radiographic image of partial coronal radiolucency should lead to suspicion of external coronary resorption.

The addition of a fourth year to the hospital pharmacy residency program has allowed trainees to rotate through various inpatient clinical units where they can, under the supervision of a specialist pharmacist, work shoulder to shoulder with other healthcare providers to ensure that patients receive the care they need. In addition to sharing their pharmacotherapeutic and pharmacokinetic knowledge (among others) with their colleagues, hospital pharmacists can and should contribute with their expertise in the areas of drug evaluation, selection and positioning. As no other healthcare professional masters like a pharmacist the intricacies of treatment efficacy or effectiveness, or of therapeutic safety, conveying this knowledge is yet another of the many clinical activities a hospital pharmacist must perform as a member of a multidisciplinary team, while assisting fellow-team members in deciding what medications are best suited to each patient. Both the public authorities and the pharmaceutical profession as a whole should make sure the pharmacist’s role is rightfully valued and given the recognition it deserves.

This study aimed to evaluate the ages of attainment of the different stages of third molar development in Chileans. We evaluated of 1236 panoramic radiographs of individuals aged between 13 and 26 years. Demirjian's stages of dental development for the upper and lower third molars were recorded in relation to chronological age, and further statistical analysis was performed. The maxillary third molars reached almost all stages of development earlier than the mandibular third molars in both male and female individuals, but with significant differences in the chronological mean ages only at stages F and H for male individuals, and F, G, and H for females. The third molar tended to mature faster in male than in female individuals, but significant differences were found only at stage H for both the maxilla and mandible, and at stages F and G for the mandible. Comparison between the mean ages of Chileans with the mean ages reported previously in a Caucasian North American population showed that the Chilean sample had an earlier maturation of the third molar in stages D to G, up to 2.52 years. The data obtained in this study might be useful for the identification of modern Chilean human remains with incomplete third molar development.

Summary: B lymphocytes are exquisitely sensitive to fluctuations in nutrient signaling by the Rag GTPases, and 15% of follicular lymphomas (FLs) harbor activating mutations in RRAGC. Hence, a potential therapeutic approach against malignant B cells is to inhibit Rag GTPase signaling, but because such inhibitors are still to be developed, efficacy and safety remain unknown. We generated knockin mice expressing a hypomorphic variant of RagC (Q119L); RagCQ119L/+ mice are viable and show attenuated nutrient signaling. B lymphocyte activation is cell-intrinsically impaired in RagCQ119L/+ mice, which also show significant suppression of genetically induced lymphomagenesis and autoimmunity. Surprisingly, no overt systemic trade-offs or phenotypic alterations caused by partial suppression of nutrient signaling are seen in other organs, and RagCQ119L/+ mice show normal longevity and normal age-dependent health decline. These results support the efficacy and safety of moderate inhibition of nutrient signaling against pathological B cells.

Autoimmune diseases (ADs) are characterized by the activation of the immune system against self-antigens. More common in women than in men and with an early onset, their incidence is increasing worldwide, and this, combined with their chronic nature, is contributing to an enlarged medical and economic burden. Conventional immunosuppressive agents are designed to alleviate symptoms but do not constitute an effective therapy, highlighting a need to develop new alternatives. In this regard, mesenchymal stem cells (MSCs) have demonstrated powerful immunosuppressive and regenerative effects. MSC-derived extracellular vesicles (MSC-EVs) have shown some advantages, such as less immunogenicity, and are proposed as novel therapies for ADs. In this review, we summarize current perspectives on therapeutic options for ADs based on MSCs and MSC-EVs, focusing particularly on their mechanism of action exerted through their non-coding RNA (ncRNA) cargo. A complete state-of-the-art review was performed, centralized on some of the most severe ADs (rheumatoid arthritis, autoimmune type 1 diabetes mellitus, and systemic lupus erythematosus), giving evidence that a promising field is evolving to overcome the current knowledge and provide new therapeutic possibilities centered on MSC-EVs and their role as ncRNA delivery vehicles for AD gene therapy.

Abstract Background There is increasing interest in using extracellular vesicle-derived microRNAs (miRNAs) as biomarkers in renal dysfunction and injury. Preliminary evidence indicates that miRNAs regulate the progression of glomerular disease. Indeed, exosomes from the renal system have provided novel evidence in the clinical setting of albuminuria. Thus, the aim of this study was to quantify the urinary miRNAs present in exosome and microvesicles (MVs), and to assess their association with the presence of increased urinary albumin excretion in essential hypertension. Methods Exosomes were collected from urine specimens from a cohort of hypertensive patients with (n = 24) or without albuminuria (n = 28), and from 20 healthy volunteers as a control group. Urinary exosomes were phenotyped by Western blot, tunable resistive pulse sensing, and electronic microscopy. Expression of miR-146a and miR-335* was analysed by qRT-PCR and any associations between albuminuria and exosomal miRNAs were analysed. Results Urinary miRNAs are highly enriched in exosome subpopulations compared to MVs, both in patients with or without increased albuminuria (p

Based on our study of 4,845 herbarium sheets of the genus Poa from the area covered by Flora iberica, namely, the Iberian Peninsula and the Balearic Islands, we recognise 24 taxa (17 species, 1 subspecies and 8 varieties), mostly perennials. Most of these taxa have wide global and/or European distributions, while two (P. legionensis and P. minor subsp. nevadensis) are Spanish endemics and two have restricted distributions (P. ligulata, Iberia–North Africa; P. flaccidula, Iberia–North Africa and the Balearic Islands, extending to Provence, France). We have studied the original publications of more than 225 names considered as synonyms, with those more historically cited in Flora iberica taken into account in this paper; a total of 26 are new synonyms. The following names are typified: P. alpina var. involucrata Lange, P. annua var. lanuginosa Sennen, P. minor subsp. nevadensis Nannf., P. paui Font Quer, P. sulcata Lag. and P. trivialis var. flaccida Willk. ex J.J. Rodr. We include P. compressa L. in the flora of Portugal for the first time and present detailed illustrations of three very interesting taxa (P. legionensis, P. minor subsp. nevadensis and P. ligulata). In addition to a general species key, we provide the following information for each taxon: synonyms, types, typification, the most relevant iconography, regional flowering time, regional and general distribution and, as supplementary material, the number of sheets examined and a list of selected materials.

El presente estudio analiza la construcción y de la representación del califato como Estado por parte del Estado Islámico. Para ello, se ha utilizado la revista Dabiq al completo. En el análisis se establecerá la forma en la que ISIS se autoproyecta hacia el exterior, incidiendo sobre todo en la ecuación nosotros-otros y nutriéndose de los imaginarios sociales y colectivos allegados a esta. En definitiva, este trabajo pretende acercarse al instrumento propagandístico de una organización que se plasma a sí misma como la salvadora de la sociedad y que, por ende, se ha diseñado y autoproclamado a través de unas instituciones sociales y unas formas de gobierno que refuerzan esa hegemonía cultural particular.

Abstract Purpose To determine the frequency of limitations on life support techniques (LLSTs) on admission to intensive care units (ICU), factors associated, and 30-day survival in patients with LLST on ICU admission. Methods This prospective observational study included all patients admitted to 39 ICUs in a 45-day period in 2011. We recorded hospitals’ characteristics (availability of intermediate care units, usual availability of ICU beds, and financial model) and patients’ characteristics (demographics, reason for admission, functional status, risk of death, and LLST on ICU admission (withholding/withdrawing; specific techniques affected)). The primary outcome was 30-day survival for patients with LLST on ICU admission. Statistical analysis included multilevel logistic regression models. Results We recruited 3042 patients (age 62.5 ± 16.1 years). Most ICUs (94.8%) admitted patients with LLST, but only 238 (7.8% [95% CI 7.0–8.8]) patients had LLST on ICU admission; this group had higher ICU mortality (44.5 vs. 9.4% in patients without LLST; p

Abstract: Orofacial granulomatosis is a nonspecific term that contains a wide variety of granulomatous entities, which share a clinical and histopathological presentation. It manifests as persistent or recurrent orofacial swelling, amongst other findings. Idiopathic orofacial granulomatosis, characterized by an absence of systemic granulomatous disease, is a diagnosis of exclusion. The main differential diagnosis is Crohn's disease. Its pathogenesis is unknown, however, it seems to be immune-mediated. Patch-test sensitivity to multiple allergens is well documented. Currently, therapeutic options consider restrictive diets, topical, intralesional, and systemic agents. First-line therapy is currently a matter of debate. We present a review of the value of diet therapy in this syndrome, along with two illustrative cases.

The removal of necrotic and vital pulp substrates and microorganisms and their toxins from the root canal system (RCS) has been found to be the basis for a successful endodontic treatment. In this study, our aim was to evaluate the effect of passive ultrasonic irrigation (PUI) on the elimination of the organic remnant tissue from infected, narrow and curved mandibular root canals during their instrumentation. For this purpose, mesiobuccal canals from mandibular first molars were instrumented with the RaCe rotary system, using PUI activation or conventional irrigation (CI) and two apical diameters (#25 and #35). The root canal cleanness of the samples was evaluated by microscopy and using a modified Langeland’s ordinal scale. Parametric and non-parametric statistical analyses and principal coordinates analysis (PCoA) of the samples were performed. When PUI was used, there was a significant reduction of the organic remnant in the apical enlargement of 25 at 2 mm from the apex (p < 0.001). After pooling the groups, regardless of the depth of the observation (2 and 4 mm from the apex), the pair #35 + PUI vs. #25 + CI showed statistically significant differences (p < 0.001). The effect of PUI explained 65% of the overall variance when compared with the CI samples. The use of PUI reduced the organic material of narrow infected and curved root canals with an apical enlargement of #25 and #35. When PUI is not used, a biomechanical instrumentation up to a diameter ≥#35 is recommended.

Abstract Amelogenesis imperfecta (AI) is a group of enamel development disorders that alter the structure and chemical composition of the tissue. There is great variability in the clinical presentation; according to Witkop, AI can be categorized into 14 subtypes, which makes its diagnosis extremely complex. Objective: This study aimed to describe and determine the frequency of clinical and radiographic features and inheritance patterns found in 41 Chilean families diagnosed with diverse types of AI. Material and Methods: We analyzed the clinical records, photographs, pedigrees and radiographs of 121 individuals recruited between 2003 and 2016. All of the information was included in a database that was analyzed using the application Stata 14. Results: The 72 affected individuals had average age of 16 years, and no sex association with the presence of AI was found. The most frequent clinical subtypes were as follows: 43% hypomature, 25% hypoplastic, 21% hypomature/hypoplastic, 7% hypocalcified and 4% hypocalcified/hypoplastic. The number of severely affected teeth was 22, which occurred in the patients with hypocalcified and hypocalcified/hypoplasic AI who presented the highest number of damaged teeth. Caries and periodontal disease were found in 47 and 32% of the patients, respectively. Malocclusions were observed in 43% of the individuals with AI, with open bite being the most frequent. Radiographically, the thickness of the enamel decreased in 51% of the patients, and 80% showed decreased radiopacity of the enamel compared to that of dentin. Autosomal dominant inheritance pattern was found in 37% of the families with hypoplastic AI, and autosomal recessive pattern was present in 56% of the other clinical subtypes, but more frequently in those affected with hypomature and hypocalcified AI. Conclusion: Of the five clinical subtypes, autosomal recessive hypomature, autosomal dominant hypoplastic and autosomal recessive hypomature/hypoplastic AI were the most prevalent subtypes in this group.

Exosomes, nanometer-sized lipid-bilayer-enclosed extracellular vesicles (EVs), have attracted increasing attention due to their inherent ability to shuttle proteins, lipids and genes between cells and their natural affinity to target cells. Their intrinsic features such as stability, biocompatibility, low immunogenicity and ability to overcome biological barriers, have prompted interest in using exosomes as drug delivery vehicles, especially for gene therapy. Evidence indicates that exosomes play roles in both immune stimulation and tolerance, regulating immune signaling and inflammation. To date, exosome-based nanocarriers delivering small molecule drugs have been developed to treat many prevalent autoimmune diseases. This review highlights the key features of exosomes as drug delivery vehicles, such as therapeutic cargo, use of targeting peptide, loading method and administration route with a broad focus. In addition, we outline the current state of evidence in the field of exosome-based drug delivery systems in systemic lupus erythematosus (SLE), evaluating exosomes derived from various cell types and engineered exosomes.

Objective: to determine the incidence of linezolid-induced haematological toxicity and study the influence of renal clearance on its appearance and the preventive effect of pyridoxine. Methods: a retrospective observational study was conducted. Every patient treated with linezolid in a university hospital during 6 months was included. Haematological toxicity was defined as a decrease of 25% in hemoglobin, of 25% in platelets and/or 50% in neutrophils from baseline. The incidence of haematological toxicity and the percentage decrease in analytical variables were compared in patients with and without renal failure (creatinine clearance lower than 50 mL/min), using the 30 mL/min threshold, and with or without pyridoxine; using Chi -Square and U Mann-Whitney tests, respectively. Results: thirty-eight patients were evaluated. Sixteen (42%) presented haematological toxicity (2 due to a decrease in haemoglobin, 9 in platelets and 8 in neutrophils). Two patients (5%) discontinued treatment due to thrombocytopenia. Toxicity incidence was similar in patients with and without renal failure, 42% vs 42%, p = 0.970, with more or less than 30 ml/min, 67% vs 40%, p = 0.369, or with or without pyridoxine, 47.8% vs 33%, p = 0.376. Patients with renal failure had a significantly greater reduction in platelet count, p = 0.0185. Conclusion: forty-two percent of patients had haematological toxicity, being more frequent platelets and neutrophils reduction. This was not significantly higher in patients with renal failure or in those without pyridoxine. Greater reduction in platelet count was observed in patients with renal failure

Objective: economic evaluation is a fundamental criterion when deciding a drug’s place in therapy. The MADRE method (Method for Assistance in making Decisions and Writing Drug Evaluation Reports) is widely used for drug evaluation. This method was developed by the GENESIS group of the Spanish Society of Hospital Pharmacy (SEFH), including economic evaluation. We intend to improve the economic aspects of this method. As for the direction to take, we have to first analyze our previous experiences with the current methodology and propose necessary improvements. Method: economic evaluation sections in collaboratively conducted drug evaluation reports (as the scientific society, SEFH) with the MADRE method were reviewed retrospectively. Results: thirty-two reports were reviewed, 87.5% of them included an economic evaluation conducted by authors and 65.6% contained published economic evaluations. In 90.6% of the reports, a Budget impact analysis was conducted. The cost per life year gained or per Quality Adjusted Life Year gained was present in 14 reports. Twenty-three reports received public comments regarding the need to improve the economic aspect. Main difficulties: low quality evidence in the target population, no comparative studies with a relevant comparator, non-final outcomes evaluated, no quality of life data, no fixed drug price available, dosing uncertainty, and different prices for the same drug. Conclusions: proposed improvements: incorporating different forms of aid for non-drug costs, survival estimation and adapting published economic evaluations; establishing criteria for drug price selection, decision-making in conditions of uncertainty and poor quality evidence, dose calculation and cost-effectiveness thresholds depending on different situations.

The association between dilated cardiomyopathy (DCM) and low thyroid hormone (TH) levels has been previously described. In these patients abnormal thyroid function is significantly related to impaired left ventricular (LV) function and increased risk of death. Although TH was originally thought to be produced exclusively by the thyroid gland, we recently reported TH biosynthesis in the human ischemic heart.Based on these findings, we evaluated whether the genes required for TH production are also altered in patients with DCM.Twenty-three LV tissue samples were obtained from patients with DCM (n = 13) undergoing heart transplantation and control donors (n = 10), and used for RNA sequencing analysis. The number of LV DCM samples was increased to 23 to determine total T4 and T3 tissue levels by ELISA.We found that all components of TH biosynthesis are expressed in human dilated heart tissue. Expression of genes encoding thyroperoxidase (-2.57-fold, P < 0.05) and dual oxidase 2 (2.64-fold, P < 0.01), the main enzymatic system of TH production, was significantly altered in patients with DCM and significantly associated with LV remodeling parameters. Thyroxine (T4) cardiac tissue levels were significantly increased (P < 0.01), whilst triiodothyronine (T3) levels were significantly diminished (P < 0.05) in the patients.Expression of TH biosynthesis machinery in the heart and total tissue levels of T4 and T3, are altered in patients with DCM. Given the relevance of TH in cardiac pathology, our results provide a basis for new gene-based therapeutic strategies for treating DCM.

The long-term risk of malignancy associated with stem cell therapies is a significant concern in the clinical application of this exciting technology. We report a cancer-selective strategy to enhance the safety of stem cell therapies. Briefly, using a cell engineering approach, we show that aggressive cancers derived from human or murine induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) are strikingly sensitive to temporary MYC blockade. On the other hand, differentiated tissues derived from human or mouse iPSCs can readily tolerate temporary MYC inactivation. In cancer cells, endogenous MYC is required to maintain the metabolic and epigenetic functions of the embryonic and cancer-specific pyruvate kinase M2 isoform (PKM2). In summary, our results implicate PKM2 in cancer’s increased MYC dependence and indicate dominant MYC inhibition as a cancer-selective fail-safe for stem cell therapies.

Alterations in myocardial structure and reduced cardiomyocyte adhesions have been previously described in dilated cardiomyopathy (DCM). We studied the transcriptome of cell adhesion molecules in these patients and their relationships with left ventricular (LV) function decay. We also visualized the intercalated disc (ID) structure and organization. The transcriptomic profile of 23 explanted LV samples was analyzed using RNA-sequencing (13 DCM, 10 control [CNT]), focusing on cell adhesion genes. Electron microscopy analysis to visualize ID structural differences and immunohistochemistry experiments of ID proteins was also performed. RT-qPCR and western blot experiments were carried out on ID components. We found 29 differentially expressed genes, most of all, constituents of the ID structure. We found that the expression of GJA3, DSP and CTNNA3 was directly associated with LV ejection fraction (r = 0.741, P = 0.004; r = 0.674, P = 0.011 and r = 0.565, P = 0.044, respectively), LV systolic (P = 0.003, P = 0.003, P = 0.028, respectively) and diastolic dimensions (P = 0.006, P = 0.001, P = 0.025, respectively). Electron microscopy micrographs showed a reduced ID convolution index and immunogold labeling of connexin 46 (GJA gene), desmoplakin (DSP gene) and catenin α-3 (CTNNA3 gene) proteins in DCM patients. Moreover, we observed that protein and mRNA levels analyzed by RT-qPCR of these ID components were diminished in DCM group. In conclusion, we report significant gene and protein expression changes and found that the ID components GJA3, DSP and CTNNA3 were highly related to LV function. Microscopic observations indicated that ID is structurally compromised in these patients. These findings give new data for understanding the ventricular depression that characterizes DCM, opening new therapeutic perspectives for these critically diseased patients.

The Macaronesian Scrophularia lowei is hypothesized to have arisen from the widespread S. arguta on the basis of several phylogenetic studies of the genus, but sampling has been limited. Although these two annual species are morphologically distinct, the origin of S. lowei is unclear because genetic studies focused on this Macaronesian species are lacking. We studied 5 S. lowei and 25 S. arguta populations to determine the relationship of both species and to infer the geographical origin of S. lowei. The timing of S. lowei divergence and differentiation was inferred by dating analysis of the ITS region. A phylogenetic analysis of two nuclear (ITS and ETS) and two chloroplast (psbJ-petA and psbA-trnH) DNA regions was performed to study the relationship between the two species, and genetic differentiation was analysed by AMOVA. Haplotype network construction and Bayesian phylogeographic analysis were conducted using chloroplast DNA regions and a spatial clustering analysis was carried out on a combined dataset of all studied regions. Our results indicate that both species constitute a well-supported clade that diverged in the Miocene and differentiated in the Late Miocene-Pleistocene. Although S. lowei constitutes a well-supported clade according to nDNA, cpDNA revealed a close relationship between S. lowei and western Canarian S. arguta, a finding supported by the spatial clustering analysis. Both species have strong population structure, with most genetic variability explained by inter-population differences. Our study therefore supports a recent peripatric speciation of S. lowei-a taxon that differs morphologically and genetically at the nDNA level from its closest relative, S. arguta, but not according to cpDNA, from the closest Macaronesian populations of that species. In addition, a recent dispersal of S. arguta to Madeira from Canary Islands or Selvagens Islands and a rapid morphological differentiation after the colonization to generate S. lowei is the most likely hypothesis to explain the origin of the last taxon.

Aims: The knowledge of parameters as the quantity of anthocyanins and tannins present during grape maturation, their evolution during the ripening period and extractability data could improve the management of red wine fermentation and help predict the color of wines. Methods and results: Grapes from Vitis vinifera var. Cabernet Sauvignon, Syrah, Merlot and Monastrell were harvested in 2002, 2003 and 2004 from a commercial vineyards and their physicochemical characteristics together with the anthocyanin and tannin evolution during ripening were followed. The results showed that differences were found in the evolution of these compounds due to variety and year. Conclusions: Some of the studied parameters seemed to be clearly related to variety (berry weight and extractability index) and others seemed to be clearly affected by soil and edaphoclimatic conditions. The high extractability index in Monastrell reflects the difficulty involved in extracting their anthocyanins. The short maturation period observed for Merlot grapes and the high seed tannin index could lead to excessively astringent wines. Significance and impact of the study: This study demonstrate that the ripening period of some varieties (Merlot) in very warm conditions is too short, promoting the rapid accumulation of sugar in the pulp and an incomplete seed maturation that may lead to excessively astringent wines. Other varieties, e.g. Monastrell, show longer maturation period that usually permits pulp and seed maturity to be reached at the moment of harvest. The extractability index seems to be closely related to the grape variety and this is also an important fact to take into account when planning a vinification process.

Intercalated disks are unique structures in cardiac tissue, in which adherens junctions, desmosomes, and GAP junctions co-localize, thereby facilitating cardiac muscle contraction and function. Protocadherins are involved in these junctions; however, their role in heart physiology is poorly understood. We aimed to analyze the transcriptomic profile of adhesion molecules in patients with ischemic cardiomyopathy (ICM) and relate the changes uncovered with the hemodynamic alterations and functional depression observed in these patients.Twenty-three left ventricular tissue samples from patients diagnosed with ICM (n = 13) undergoing heart transplantation and control donors (CNT, n = 10) were analyzed using RNA sequencing. Forty-two cell adhesion genes involved in cellular junctions were differentially expressed in ICM myocardium. Notably, the levels of protocadherin PCDHGA3 were related with the stroke volume (r = -0.826, P = 0.003), ejection fraction (r = -0.793, P = 0.004) and left ventricular end systolic and diastolic diameters (r = 0.867, P = 0.001; r = 0.781, P = 0.005, respectively).Our results support the importance of intercalated disks molecular alterations, closely involved in the contractile function, highlighting its crucial significance and showing gene expression changes not previously described. Specifically, altered PCDHGA3 gene expression was strongly associated with reduced stroke volume and ventricular dysfunction in ICM, suggesting a relevant role in hemodynamic perturbations and cardiac performance for this unexplored protocadherin.

In dilated cardiomyopathy (DCM), cardiac failure is accompanied by profound alterations of extracellular matrix associated with the progression of cardiac dilation and left ventricular (LV) dysfunction. Recently, we reported alterations of non-fibrillar collagen expression in ischemic cardiomyopathy linked to fibrosis and cardiac remodeling. We suspect that expression changes in genes coding for non-fibrillar collagens may have a potential role in DCM development.This study sought to analyze changes in the expression profile of non-fibrillar collagen genes in patients with DCM and to examine relationships between cardiac remodeling parameters and the expression levels of these genes.Twenty-three human left ventricle tissue samples were obtained from DCM patients (n = 13) undergoing heart transplantation and control donors (n = 10) for RNA sequencing analysis. We found increased mRNA levels of six non-fibrillar collagen genes, such as COL4A5, COL9A1, COL21A1, and COL23A1 (P < 0.05 for all), not previously described in DCM. Protein levels of COL8A1 and COL16A1 (P < 0.05 for both), were correspondingly increased. We also identified TGF-β1 significantly upregulated and related to both COL8A1 and COL16A1. Interestingly, we found a significant relationship between LV mass index and the gene expression level of COL8A1 (r = 0.653, P < 0.05).In our research, we identified new non-fibrillar collagens with altered expression in DCM, being COL8A1 overexpression directly related to LV mass index, suggesting that they may be involved in the progression of cardiac dilation and remodeling.

RESUMEN El objetivo del trabajo es considerar el desarrollo alcanzado por el conocimiento en estrategia empresarial en Castilla y León y su posición en el conjunto nacional, ofreciendo una visión complementaria a la de anteriores estudios. Para dicho análisis se han considerado, durante la década de los 90, congresos y revistas de alcance regional y nacional. Los resultados obtenidos nos muestran la necesidad de contar con más foros de encuentro en Castilla y León y con medios especializados en el campo de la estrategia. Además, los investigadores castellano-leoneses parecen mostrar un interés poco frecuente por la ejecución estratégica y por los aspectos de delimitación teórica, un tanto marginados en el conjunto nacional. Palabras clave: Dirección estratégica, investigación, medios de difusión, España, Castilla y León.

Disruptions in cardiac ion channels have shown to influence the impaired cardiac contraction in heart failure. We sought to determine the altered gene expression profile of this category in dilated cardiomyopathy (DCM) patients and relate the altered gene expression with the clinical signs present in our patients, such as ventricular dysfunction and sustained monomorphic ventricular tachycardia (SMVT).Left ventricular (LV) tissue samples were used in RNA-sequencing technique to elucidate the transcriptomic changes of 13 DCM patients compared to controls (n = 10). We analyzed the differential gene expression of cardiac ion channels, and we found a total of 34 altered genes. We found that the calcium channel CACNG8 mRNA and protein levels were down-regulated and highly and inversely related with LV ejection fraction (LVEF) (r = -0.78, P

BACKGROUND: The endoplasmic reticulum (ER) is a multifunctional organelle responsible for the synthesis and folding of proteins as well as for signalling and calcium storage, that has been linked to the contraction-relaxation process. Perturbations of its homeostasis activate a stress response in diseases such as heart failure (HF). To elucidate the alterations in ER molecular components, we analyze the levels of ER stress and structure proteins in human dilated (DCM) and ischemic (ICM) cardiomyopathies, and its relationship with patient's functional status. METHODS AND RESULTS: We examined 52 explanted human hearts from DCM (n = 21) and ICM (n = 21) subjects and 10 non-failing hearts as controls. Our results showed specific changes in stress (IRE1, p

Dilated cardiomyopathy (DCM) is a public health problem with no available curative treatment, and mitochondrial dysfunction plays a critical role in its development. The present study is the first to analyze the mitochondrial proteome in cardiac tissue of patients with DCM to identify potential molecular targets for its therapeutic intervention.16 left ventricular (LV) samples obtained from explanted human hearts with DCM (n = 8) and control donors (n = 8) were extracted to perform a proteomic approach to investigate the variations in mitochondrial protein expression. The proteome of the samples was analyzed by quantitative differential electrophoresis and Mass Spectrometry. These changes were validated by classical techniques and by novel and precise selected reaction monitoring analysis and RNA sequencing approach increasing the total heart samples up to 25. We found significant alterations in energy metabolism, especially in molecules involved in substrate utilization (ODPA, ETFD, DLDH), energy production (ATPA), other metabolic pathways (AL4A1) and protein synthesis (EFTU), obtaining considerable and specific relationships between the alterations detected in these processes. Importantly, we observed that the antioxidant PRDX3 overexpression is associated with impaired ventricular function. PRDX3 is significantly related to LV end systolic and diastolic diameter (r = 0.73, p value

BACKGROUND: The atrium is the major site of ANP synthesis, which has been said to increase in heart failure as a result of increased production in the left ventricular (LV) myocardium. This is a key issue related to its diagnostic and prognostic capabilities. We aimed to evaluate protein levels of proANP and ANP and the enzymes that cleave the natriuretic peptides, corin and furin, in the LV tissue of heart transplant patients with dilated (DCM) and ischemic (ICM) cardiomyopathy compared with control donors (CNT). We also evaluate mRNA levels of ANP gene (NPPA) by RNA sequencing in the same tissue. METHODS AND RESULTS: Seventy-three human LV tissue samples from ICM (n=30) and DCM (n=33) patients and CNT (n=10) were analyzed by Western blot and RNA sequencing. Comparing protein levels according to etiology, neither DCM nor ICM showed levels of proANP or ANP different from those of CNT. However, NPPA was increased in both groups compared to CNT (DCM 32 fold, p

BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by idiopathic dilation and systolic contractile dysfunction of the cardiac chambers. The present work aimed to study the alterations in gene expression of ion channels involved in cardiomyocyte function. METHODS AND RESULTS: Microarray profiling using the Affymetrix Human Gene® 1.0 ST array was performed using 17 RNA samples, 12 from DCM patients undergoing cardiac transplantation and 5 control donors (CNT). The analysis focused on 7 cardiac ion channel genes, since this category has not been previously studied in human DCM. SCN2B was upregulated, while KCNJ5, KCNJ8, CLIC2, CLCN3, CACNB2, and CACNA1C were downregulated. The RT-qPCR (21 DCM and 8 CNT samples) validated the gene expression of SCN2B (p < 0.0001), KCNJ5 (p < 0.05), KCNJ8 (p < 0.05), CLIC2 (p < 0.05), and CACNB2 (p < 0.05). Furthermore, we performed an IPA analysis and we found a functional relationship between the different ion channels studied in this work. CONCLUSION: This study shows a differential expression of ion channel genes involved in cardiac contraction in DCM that might partly underlie the changes in left ventricular function observed in these patients. These results could be the basis for new genetic therapeutic approaches.

Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability.