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Resumen: Introducción: Conocer y satisfacer las necesidades de pacientes (P) con cáncer de mama (CM) permite mejorar su calidad de vida y adherencia a tratamientos. Este estudio buscó identificar las necesidades de P con CM desde las perspectivas de tres agentes: ellos mismos, sus cuidadores (CU) y el personal de salud (PDS). Tras determinar esas necesidades desarrollamos y difundimos videos educativos para el PDS y evaluamos el impacto en la satisfacción del cuidado en salud de dicha intervención. Métodos: El estudio incluyó un centro académico (CA) y un hospital público (HP). Los datos se obtuvieron de entrevistas, focus group y encuestas autocompletadas. Se realizó un análisis de contenidos con el software Nvivo. Tras determinar las necesidades percibidas por los sujetos de estudio (P, CU, PDS) y debido a las restricciones impuestas debido al COVID19 se optó por presentar videos educativos al PDS describiendo las necesidades identificadas y su manejo. Se aplicaron encuestas de satisfacción antes (etapa I) y después de dicha intervención (etapa II). Resultados: Inicialmente, 22 participantes fueron entrevistados (7 P, 5 CU y 10 PDS). Identificamos 3 necesidades principales: 1) relacionadas con los cuidados de salud, 2) temas financieros y 3) apoyo social. En base a estas necesidades elaboramos y difundimos videos educativos para el PDS. El análisis de encuestas de satisfacción aplicadas antes (n = 93) y después (n = 71) de la intervención educativa reveló altos niveles de satisfacción, con la excepción de tópicos relacionados a las comodidades de la infraestructura y la atención psicológica en ambos centros (CA y HP). En la encuesta aplicada en la etapa II, aparecieron otras necesidades mayoritariamente relacionadas con nutrición e infraestructura. Conclusiones: Este estudio es la primera evaluación en Chile, simultánea, de necesidades de P con CM desde la perspectiva de ellos, sus CU y PDS. Todos los participantes indicaron que la información y el apoyo social/financiero son las necesidades más relevantes. Abstract: Introduction: Knowing and satisfying the needs of breast cancer (BC) patients (P) and their caregivers (CG) during treatment can help to improve their quality of life. This study assessed the needs of BC-P, their CG and health professionals (HP) and their perception before and after an intervention aiming to improve healthcare. Methods. The study included an academic center (AC) and a public hospital (PH). Data were obtained from interviews, focus groups and self-completed surveys. A content analysis was performed using Nvivo software. Due to COVID19 restrictions, educational videos were delivered to HPs describing the identified needs. Finally, satisfaction surveys were applied to P and CG, before and after this intervention. Results: A total of 22 participants were interviewed (7P, 5CG and 10HP). Three main needs were identified: 1) Healthcare related needs, 2) Financial issues and 3) Social support. Subsequently, a satisfaction survey was applied to users (stage I; n = 93) and the identified needs were used to design an intervention that consisted of educational videos directed towards HP. Following the intervention a second survey was applied (stage II; n = 71). Both surveys revealed high levels of satisfaction among users. Following the second survey, we noticed the emergence of other needs, mainly related to nutrition and the improvement of facilities. Conclusions: This is the first study in Chile assessing BC-P needs from the perspective of P, their CG and HP. All participants indicated that information and social/financial support were the most relevant needs.

Mitochondria's role as engines and beacons of metabolism and determinants of cellular health is being redefined through their therapeutic application as “Living Drugs” (LDs). Artificial mitochondrial transfer/transplant (AMT/T), encompassing various techniques to modify, enrich, or restore mitochondria in cells and tissues, is revolutionizing acellular therapies and the future of medicine. This article proposes a necessary definition for LDs within the Advanced Therapeutic Medicinal Products (ATMPs) framework. While recognizing different types of LDs as ATMPs, such as mesenchymal stem cells (MSCs) and chimeric antigen receptor T (CAR T) cells, we focus on mitochondria due to their unique attributes that distinguish them from traditional cell therapies. These attributes include their inherent living nature, diverse sources, industry applicability, validation, customizability for therapeutic needs, and their capability to adapt and respond within recipient cells. We trace the journey from initial breakthroughs in AMT/T to the current state-of-the-art applications by emerging innovative companies, highlighting the need for manufacturing standards to navigate the transition of mitochondrial therapies from concept to clinical practice. By providing a comprehensive overview of the scientific, clinical, and commercial landscape of mitochondria as LDs, this article contributes to the essential dialogue among regulatory agencies, academia, and industry to shape their future in medicine.

Obstructive sleep apnea (OSA) is quite prevalent during pregnancy and is associated with adverse perinatal outcomes, but its potential influence on fetal development remains unclear. This study investigated maternal OSA impact on the fetus by analyzing gene expression profiles in whole cord blood (WCB). Ten women in the third trimester of pregnancy were included, five OSA and five non-OSA cases. WCB RNA expression was analyzed by microarray technology to identify differentially expressed genes (DEGs) under OSA conditions. After data normalization, 3238 genes showed significant differential expression under OSA conditions, with 2690 upregulated genes and 548 downregulated genes. Functional enrichment was conducted using gene set enrichment analysis (GSEA) applied to Gene Ontology annotations. Key biological processes involved in OSA were identified, including response to oxidative stress and hypoxia, apoptosis, insulin response and secretion, and placental development. Moreover, DEGs were confirmed through qPCR analyses in additional WCB samples (7 with OSA and 13 without OSA). This highlighted differential expression of several genes in OSA (EGR1, PFN1 and PRKAR1A), with distinct gene expression profiles observed during rapid eye movement (REM)-OSA in pregnancy (PFN1, UBA52, EGR1, STX4, MYC, JUNB, and MAPKAP). These findings suggest that OSA, particularly during REM sleep, may negatively impact various biological processes during fetal development.

Quercetin (Q) is one of the most frequently consumed flavonoids in the human diet. The purpose of this systematic review and meta-analysis was to determine the effects of Q supplementation on muscle damage, muscle soreness and biochemical markers of inflammation, antioxidant capacity and oxidative stress after intense exercise. A literature search of SPORTDiscus, PubMed, Web of Science and Scopus was performed from inception to May 31, 2022. Forest plots were generated with fixed or random-effect models and standardized mean differences (SMD). Data extraction and quality assessment were performed independently by two authors. After application of the inclusion and exclusion criteria, 13 studies with a total of 249 sedentary to well-trained participants were included. For all studies there were some concerns about the risk of bias. All but one study used a supplementation dosage of 1000 mg/day. Q supplementation accelerated recovery of muscle function and significantly decreased muscle soreness 0/24 h after exercise (SMD: -1.33; p = 0.03), creatine kinase levels 24/48 h after exercise (SMD: -1.15; p = 0.02), and post-exercise oxidative stress (SMD: -0.92; p = 0.03). However, Q supplementation had no effect on IL-6 concentration. Q supplementation with a dose of 1000 mg/day for periods of more than seven days and a maximum of 12 weeks appears to be a safe and efficacious strategy to reduce muscle damage and muscle soreness, as well as to enhance recovery after intense exercise in sedentary to well-trained young men. Systematic review registration: PROSPERO CRD42021266801.

Abstract Exposure to microgravity and ionizing radiation during spaceflight missions causes excessive reactive oxygen species (ROS) production that contributes to cellular stress and damage in astronauts. Average spaceflight mission time is expected to lengthen as humanity aims to visit other planets. However, longer missions or spaceflights will undoubtedly lead to an increment in microgravity, ionizing radiation and ROS production. Strategies to minimize ROS damage are necessary to maintain the health of astronauts, future space colonists, and tourists during and after spaceflight missions. An antioxidant cocktail formulated to prevent or mitigate ROS damage during space exploration could help maintain the health of space explorers. We propose key points to consider when developing an antioxidant cocktail. We discuss how ROS damages our body and organs, the genetic predisposition of astronauts to its damage, characteristics and evidence of the effectiveness of antioxidants to combat excess ROS, differences in drug metabolism when on Earth and in space that could modify antioxidant effects, and the characteristics and efficacy of common antioxidants. Based on this information we propose a workflow for assessing astronaut resistance to ROS damage, infight monitoring of ROS production, and an antioxidant cocktail. Developing an antioxidant cocktail represents a big challenge to translate current medical practices from an Earth setting to space. The key points presented in this review could promote the development of different antioxidant formulations to maintain space explorers’ health in the future.

The search for new therapeutic targets and their implications in drug development remains an emerging scientific topic. BRCT-bearing proteins are found in Archaea, Bacteria, Eukarya, and viruses. They are traditionally involved in DNA repair, recombination, and cell cycle control. To carry out these functions, BRCT domains are able to interact with DNA and proteins. Moreover, such domains are also implicated in several pathogenic processes and malignancies including breast, ovarian, and lung cancer. Although these domains exhibit moderately conserved folding, their sequences show very low conservation. Interestingly, sequence variations among species are considered positive traits in the search for suitable therapeutic targets, since non-specific drug interactions might be reduced. These main characteristics of BRCT, as well as its critical implications in key biological processes in the cell, have prompted the study of these domains as therapeutic targets. This review explores the possible roles of BRCT domains as therapeutic targets for drug discovery. We describe their common structural features and relevant interactions and pathways, as well as their implications in pathologic processes. Drugs commonly used to target these domains are also presented. Finally, based on their structures, we describe new drug design possibilities using modern and innovative techniques.

Leishmaniasis is spreading in Europe, especially in endemic countries such as Italy and Spain, in part due to ongoing climate change and the increase in travel and migration. Although Leishmania infantum is the main agent responsible for this disease in humans and animals, other species and hybrids have been detected. This highlights the need to continue isolating and characterizing Leishmania strains from biological samples of infected hosts. In this study, we characterized the recently isolated parasites L. infantum NAV and L. infantum TDL, obtained from naturally infected mammals (dogs), and we compared them with the widely distributed and studied strain L. infantum BCN 150. Both NAV and TDL promastigotes showed a slower growth rate than BCN 150 and were significantly more sensitive to amphotericin B and miltefosine. Furthermore, the expression of the CYCA gene (involved in cell cycle and proliferation) was significantly downregulated in NAV and TDL isolates. On the other hand, CYC6 (implicated in treatment resistance) and APG9 (related to the recycling of protein under stress conditions and/or while undergoing a differentiation process and treatment resistance) levels were upregulated, compared to those measured in BCN 150. Both isolates displayed a higher infection capacity (>3 amastigotes per macrophage and >70% of infected macrophages) compared to controls (Leishmania isolates that might be useful for in vitro and in vivo assays that will allow a better understanding of the parasite biology in Mediterranean areas.

Abstract Background Systematic reviews allow health decisions to be informed by the best available research evidence. However, their number is proliferating quickly, and many skills are required to identify all the relevant reviews for a specific question. Methods and findings We screen 10 bibliographic databases on a daily or weekly basis, to identify systematic reviews relevant for health decision-making. Using a machine-based approach developed for this project we select reviews, which are then validated by a network of more than 1000 collaborators. After screening over 1,400,000 records we have identified more than 300,000 systematic reviews, which are now stored in a single place and accessible through an easy-to-use search engine. This makes Epistemonikos the largest database of its kind. Conclusions Using a systematic approach, recruiting a broad network of collaborators and implementing automated methods, we developed a one-stop shop for systematic reviews relevant for health decision making.

PURPOSE Like other malignancies, GI stromal tumors (GIST) are highly heterogeneous. This not only applies to histologic features and malignant potential, but also to geographic incidence rates. Several studies have reported GIST incidence and prevalence in Europe and North America. In contrast, GIST incidence rates in South America are largely unknown, and only a few studies have reported GIST prevalence in Latin America. PATIENTS AND METHODS Our study was part of a collaborative effort between Chile and Mexico, called Salud con Datos. We sought to determine GIST prevalence and patients’ clinical characteristics, including survival rates, through retrospective analysis. RESULTS Overall, 624 patients were included in our study. Our results found significant differences between Mexican and Chilean registries, such as stage at diagnosis, primary tumor location, CD117-positive immunohistochemistry status, mitotic index, and tumor size. Overall survival (OS) times for Chilean and Mexican patients with GIST were 134 and 156 months, respectively. No statistically significant differences in OS were detected by sex, age, stage at diagnosis, or recurrence status in both cohorts. As expected, patients categorized as being at high risk of recurrence displayed a trend toward poorer progression-free survival in both registries. CONCLUSION To the best of our knowledge, this is the largest report from Latin America assessing the prevalence, clinical characteristics, postsurgery risk of recurrence, and outcomes of patients with GIST. Our data confirm surgery as the standard treatment of localized disease and confirm a poorer prognosis in patients with regional or distant disease. Finally, observed differences between registries could be a result of registration bias.

We introduce a general debiasing Bayesian formalism to brightness-limited surveys of solar system objects that constrains the statistical distribution of a population’s physical characteristics such as size, albedo, heliocentric distance, or others to account for the survey detections and measured properties such as brightness. We reanalyze the Dark Energy Camera search for main-belt asteroids of Peña et al. and fit a smooth double power-law size to its size distribution. Using only detections with reliable distances and accurate orbital information, we find no evidence for a significant difference in size distribution between the inner, middle, and outer belts for objects between 0.1 and 1 km in diameter, with q _2 = 2.27 ± 0.05 a good fit for the small-end slope. We show that the intrinsic number density of objects is consistent between these populations and is compatible with observational biases. As spectral classes are distributed unevenly throughout the main belt, these results support the ongoing collisional reprocessing of the asteroid belt for objects smaller than 5 km.

The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-parasitic and anti-tumoral. In the present study, the approach of repurposing AMPs as antileishmanial drugs was applied. The leishmanicidal activity of two synthetic anti-lipopolysaccharide peptides (SALPs), so-called 19-2.5 and 19-4LF was characterized in Leishmania major. In vitro, both peptides were highly active against intracellular Leishmania major in mouse macrophages without exerting toxicity in host cells. Then, q-PCR-based gene profiling, revealed that this activity was related to the downregulation of several genes involved in drug resistance (yip1), virulence (gp63) and parasite proliferation (Cyclin 1 and Cyclin 6). Importantly, the treatment of BALB/c mice with any of the two AMPs caused a significant reduction in L. major infective burden. This effect was associated with an increase in Th1 cytokine levels (IL-12p35, TNF-α, and iNOS) in the skin lesion and spleen of the L. major infected mice while the Th2-associated genes were downregulated (IL-4 and IL-6). Lastly, we investigated the effect of both peptides in the gene expression profile of the P2X7 purinergic receptor, which has been reported as a therapeutic target in several diseases. The results showed significant repression of P2X7R by both peptides in the skin lesion of L. major infected mice to an extent comparable to that of a common anti-leishmanial drug, Paromomycin. Our in vitro and in vivo studies suggest that the synthetic AMPs 19-2.5 and 19-4LF are promising candidates for leishmaniasis treatment and present P2X7R as a potential therapeutic target in cutaneous leishmaniasis (CL).

Around 15% of cancer cases are attributable to infectious agents. Epidemiological studies suggest that an association between leishmaniasis and cancer does exist. Recently, the homologue of PES1 in Leishmania major (LmjPES) was described to be involved in parasite infectivity. Mammalian PES1 protein has been implicated in cellular processes like cell cycle regulation. Its BRCT domain has been identified as a key factor in DNA damage-responsive checkpoints. This work aimed to elucidate the hypothetical oncogenic implication of BRCT domain from LmjPES in host cells. We generated a lentivirus carrying this BRCT domain sequence (lentiBRCT) and a lentivirus expressing the luciferase protein (lentiLuc), as control. Then, HEK293T and NIH/3T3 mammalian cells were infected with these lentiviruses. We observed that the expression of BRCT domain from LmjPES conferred to mammal cells in vitro a greater replication rate and higher survival. In in vivo experiments, we observed faster tumor growth in mice inoculated with lentiBRCT respect to lentiLuc HEK293T infected cells. Moreover, the lentiBRCT infected cells were less sensitive to the genotoxic drugs. Accordingly, gene expression profiling analysis revealed that BRCT domain from LmjPES protein altered the expression of proliferation- (DTX3L, CPA4, BHLHE41, BMP2, DHRS2, S100A1 and PARP9), survival- (BMP2 and CARD9) and chemoresistance-related genes (DPYD, Dok3, DTX3L, PARP9 and DHRS2). Altogether, our results reinforced the idea that in eukaryotes, horizontal gene transfer might be also achieved by parasitism like Leishmania infection driving therefore to some crucial biological changes such as proliferation and drug resistance.

Purpose: The objective of the present study was to determine whether a denervated muscle extract (DmEx) could stimulate satellite cell response in denervated muscle. Methods: Wistar rats were divided into 4 groups: normal rats, normal rats treated with DmEx, denervated rats, and denervated rats treated with DmEx. The soleus muscles were examined using immunohistochemical techniques for proliferating cell nuclear antigen, desmin, and myogenic differentiation antigen (MyoD), and electron microscopy was used for analysis of the satellite cells. Results: The results indicate that while denervation causes activation of satellite cells, DmEx also induces myogenic differentiation of cells localized in the interstitial space and the formation of new muscle fibers. Although DmEx had a similar effect in nature on innervated and denervated muscles, this response was of greater magnitude in denervated vs. intact muscles. Conclusion: Our study shows that treatment of denervated rats with DmEx potentiates the myogenic response in atrophic denervated muscles. Keywords: Muscle atrophy, Muscle denervation, Muscle extract, Myogenic response, Satellite cell, Skeletal muscle

INTRODUCTION Gallbladder cancer is the most common malignancy of the biliary tract. Given the lack of therapeutic alternatives for advanced stage patients studies have suggested that palliative chemotherapy could benefit these patients. METHODS We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis, and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS We identified two systematic reviews including two studies overall, of which one was a randomized trial. We concluded that palliative chemotherapy may increase survival in advanced gallbladder cancer patients. However, palliative chemotherapy probably increases adverse effects. In addition, it is essential to carry out a new systematic review, since methodological errors were identified in the analysis and there is new evidence that has not been included in the previous reviews.

Introduction Red cell distribution width (RDW) is a parameter included in the complete blood count which informs about the size of the circulating red blood cell population and its distribution. In adults, an increase in RDW was shown to be associated both with obstructive sleep apnoea (OSA) and with an increase in cardiovascular mortality. The aim of this study was to determine whether RDW is a potential biomarker for screening children with moderate–severe OSA. Methods An observational study in snoring patients was performed. All patients underwent a sleep study and were classified either as simple snorers (apnoea–hypopnoea index (AHI) 13.1% values, adjusting for body mass index z-score and age (area under the curve 0.657; p=0.004). In addition, differences were found in eosinophil count and C-reactive protein concentrations among the three subgroups. Conclusions In children, RDW stands out as a biomarker associated with the severity of OSA. The use of RDW and MCHC could be a simple but useful tool for the severity prediction of paediatric OSA in snoring patients.

Countries should ensure equitable access to quality medicines. Regulatory systems for medicines and other health technologies are an essential part of well-functioning health systems and are a requisite for achieving Universal Health and the Sustainable Development Goals. The Pan American Health Organization, the World health Organization (WHO) regional office for the Americas, has assessed national regulatory capacities using a precursor of WHO Global Benchmarking Tool, and conducted an analysis of the data which suggests an association of regulatory capacity with population and the size of the economy. Regulatory capacity tends to decrease as population and gross domestic product decreases. This predominantly impacts the Caribbean sub-region in the Americas, which includes many states with small populations and economies. This paper will use the World Bank’s term ‘small states’ to refer to countries with 1.5 million people or less and other larger countries that face similar challenges. The regulatory challenges of small states include small markets and limited human and financial resources. However, small states can build regulatory systems with a narrower scope that are less resource intensive and still ensure appropriate regulation and oversight. The approach should be tailored to accomplish a subset of WHO recommended essential functions, including marketing authorisation, licensing of establishments and postmarket surveillance/pharmacovigilance, depending on the need to oversee local manufacturing, which requires a comprehensive system. The approach should also include adoption of efficiencies, such as regionalisation and reliance. This model is currently being put in practice in the small states of the Caribbean Community and Pacific Islands and can inform other small states around the world.

Leishmaniasis is a neglected tropical disease caused by Leishmania spp. The improvement of existing treatments and the discovery of new drugs remain ones of the major goals in control and eradication of this disease. From the parasite genome, we have identified the homologue of the human oncogene PES1 in Leishmania major (LmjPES). It has been demonstrated that PES1 is involved in several processes such as ribosome biogenesis, cell proliferation and genetic transcription. Our phylogenetic studies showed that LmjPES encodes a highly conserved protein containing three main domains: PES N-terminus (shared with proteins involved in ribosomal biogenesis), BRCT (found in proteins related to DNA repair processes) and MAEBL-type domain (C-terminus, related to erythrocyte invasion in apicomplexan). This gene showed its highest expression level in metacyclic promastigotes, the infective forms; by fluorescence microscopy assay, we demonstrated the nuclear localization of LmjPES protein. After generating mutant parasites overexpressing LmjPES, we observed that these clones displayed a dramatic increase in the ratio of cell infection within macrophages. Furthermore, BALB/c mice infected with these transgenic parasites exhibited higher footpad inflammation compared to those inoculated with non-overexpressing parasites.

Since many of the currently available antileishmanial treatments exhibit toxicity, low effectiveness, and resistance, search and validation of new therapeutic targets allowing the development of innovative drugs have become a worldwide priority. This work presents a structure-based drug discovery strategy to validate the Lmj_04_BRCT domain as a novel therapeutic target in Leishmania spp. The structure of this domain was explored using homology modeling, virtual screening, and molecular dynamics studies. Candidate compounds were validated in vitro using promastigotes of Leishmania major, L. amazonensis, and L. infantum, as well as primary mouse macrophages infected with L. major. The novel inhibitor CPE2 emerged as the most active of a group of compounds against Leishmania, being able to significantly reduce the viability of promastigotes. CPE2 was also active against the intracellular forms of the parasites and significantly reduced parasite burden in murine macrophages without exhibiting toxicity in host cells. Furthermore, L. major promastigotes treated with CPE2 showed significant lower expression levels of several genes (α-tubulin, Cyclin CYCA, and Yip1) related to proliferation and treatment resistance. Our in silico and in vitro studies suggest that the Lmj_04_BRCT domain and its here disclosed inhibitors are new potential therapeutic options against leishmaniasis.

Background: Axial spondyloarthritis (axSpA) affects spinal muscles, due to inflammation and structural damage. The mechanical properties of the muscles, such as tone or stiffness, could be altered in axSpA. The aim of this work is to analyze the mechanical properties of cervical and lumbar spine muscles in axSpA patients and their relationship with metrology measures, function, disease activity, structural damage and quality of life. Methods: axSpA patients and age/gender/BMI matched healthy controls were recruited. The muscle mechanical properties (MMPs), such as tone or frequency, stiffness, decrement (linear elastic properties), relaxation and creep (viscoelastic properties), of cervical (semispinalis capitis) and lumbar (erector spinae) muscles were bilaterally measured at rest using myotonometry. Additionally, conventional metrology, BASMI (metrology index), BASDAI (disease activity index), mSASSS (radiological structural damage index) and SF-12 (health-related quality of life questionnaire) were used in the axSpA group. Between-groups comparison, intra-group correlations and multivariable regression analyses were performed to achieve the study aims. Results: Thirty-four axSpA patients (mean age: 46.21 ± 8.53 y) and 34 healthy volunteers (mean age: 43.97 ± 8.49 y) were recruited. Both in cervical and lumbar spine, linear elastic parameters were significantly higher in axSpA patients in comparison with controls, while viscoelastic parameters were significantly lower. Lumbar muscle frequency, stiffness, relaxation, creep and cervical muscle elasticity were fair to strongly correlated (|0.346| < r < |0.774|) with age, functional status, activity of disease, structural damage and quality of life in axSpA patients. Furthermore, moderate to good fitted multivariate models (0.328 < R2 < 0.697) were obtained combining age, conventional metrology, activity of the disease and function for the estimation of cervical and lumbar MMPs. Conclusion: Mechanical properties of spinal muscles of axSpA patients differ from controls. Lumbar and cervical muscles exhibit greater linear elastic properties and lower viscoelastic properties, which are related with age, clinical and psychophysiological features of axSpA.

Resumen INTRODUCCIÓN En pacientes con cáncer testicular avanzado tipo seminoma que tienen lesiones residuales post quimioterapia de más de 3 cm, el PET-CT podría seleccionar un subgrupo susceptible de ser manejado con seguimiento, evitando una resección quirúrgica innecesaria de tumor no viable. MÉTODOS Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES Identificamos tres revisiones sistemáticas que en conjunto incluyeron 11 estudios primarios, de los cuales, ninguno es un ensayo aleatorizado. Concluimos que el uso de PET-CT en la evaluación de masas residuales post quimioterapia en pacientes con cáncer testicular tipo seminoma podría evitar un porcentaje importante de cirugías innecesarias (certeza de la evidencia baja). Además, el uso de PET-CT podría presentar balances riesgo/beneficio y costo/beneficio favorables en el manejo de pacientes con cáncer testicular tipo seminoma. Sin embargo, se requieren revisiones sistemáticas y estudios primarios que evalúen directamente el impacto diagnóstico del test.

Axial spondyloarthritis (axSpA) is a chronic rheumatic disease characterized by the presence of inflammatory back pain. In patients with chronic low back pain, the lumbar flexion relaxation phenomenon measured by surface electromyography (sEMG) differs from that in healthy individuals. However, sEMG activity in axSpA patients has not been studied. The purpose of this study was to analyze the flexion relaxation phenomenon in axSpA patients. A study evaluating 39 axSpA patients and 35 healthy controls was conducted. sEMG activity at the erector spinae muscles was measured during lumbar full flexion movements. sEMG activity was compared between axSpA patients and the controls, as well as between active (BASDAI ≥ 4) and non-active (BASDAI < 4) patients. The reliability (using intraclass correlation coefficients (ICC)), criterion validity and discriminant validity using the area Under the curve (AUC) for the inverse flexion/relaxation ratio (1/FRR) were evaluated. Significant differences (p < 0.05) were observed between axSpA patients and the control group in lumbar electric activity, especially during flexion, relaxation, and extension and in FRR and 1/FRR (0.66 ± 0.39 vs. 0.25 ± 0.19, respectively). In addition, significant differences were found between active and non-active but also between non-active and healthy subjects. The sEMG showed good reliability (ICC > 0.8 for 1/FRR) and criterion validity. ROC analysis showed good discriminant validity for axSpA patients (AUC = 0.835) vs. the control group using 1/FRR. An abnormal flexion/relaxation phenomenon exists in axSpA patients compared with controls. sEMG could be an additional objective tool in the evaluation of patient function and disease activity status.

Background: Near-peer teaching is an educational method based on being taught by one or more students who are more advanced in one specific area of the same curriculum. The aim of this study was to analyze outcomes and medical students’ reactions to near-peer teaching in Histology Laboratory session. Methods: Histology Laboratory session was firstly designed as a practical session driven by academic staff, while in our new approach was driven by Histology intern students, which are upper year students in Medicine curriculum. Our near-peer teaching was evaluated using a multiple choice test when half of students had attended the session, the results of which were compared with those from traditional teaching. A reaction evaluation survey was also administered at the end of the course. Results: Multiple choice test results did not showed statistical differences between near-peer and traditional teaching strategies. Results from the reaction evaluation were mostly positive, especially with regard to feeling comfortable in the session taught by intern students and how intern students managed to transmit the information properly. Conclusion: Near-peer teaching in Histology Laboratory practical session is an effective alternative teaching method, with outcomes equivalent to traditional design, and highly valued by undergraduate medical students

A novel serine/threonine protein kinase, LmjF.22.0810, was recently described in Leishmania major. After generating an L. major cell line overexpressing LmjF.22.0810 (named LmJ3OE), the ability of this novel protein to modulate the Th2-type immune response was analyzed. Our results suggest that the protein kinase LmjF.22.0810 might be involved in leishmaniasis outcomes. Indeed, our study outlined the LmJ3OE parasites infectivity in vitro and in vivo. Transgenic parasites displayed lower phagocytosis rates in vitro, and their promastigote forms exhibited lower expression levels of virulence factors compared to their counterparts in control parasites. In addition, LmJ3OE parasites developed significantly smaller footpad swelling in susceptible BALB/c mice. Hematoxylin–eosin staining allowed the observation of a lower inflammatory infiltrate in the footpad from LmJ3OE-infected mice compared to animals inoculated with control parasites. Gene expression of Th2-associated cytokines and effectors revealed a dramatically lower induction in interleukin (IL)-4, IL-10, and arginase 1 (ARG1) mRNA levels at the beginning of the swelling; no expression change was found in Th1-associated cytokines except for IL-12. Accordingly, such results were validated by immunohistochemistry studies, illustrating a weaker expression of ARG1 and a similar induction for inducible NO synthase (iNOS) in footpads from LmJ3OE-infected mice compared to control L. major infected animals. Furthermore, the parasite burden was lower in footpads from LmJ3OE-infected mice. Our analysis indicated that such significant smaller footpad swellings might be due to an impairment of the Th2 immune response that subsequently benefits Th1 prevalence. Altogether, these studies depict LmjF.22.0810 as a potential modulator of host immune responses to Leishmania. Finally, this promising target might be involved in the modulation of infection outcome.

Resumen INTRODUCCIÓN El tratamiento de las náuseas y vómitos inducidos por quimioterapia podría mejorar la calidad de vida de los pacientes oncológicos; para lograrlo se ha propuesto la adición de cannabinoides a los esquemas de antieméticos habituales. MÉTODOS Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES Identificamos 16 revisiones sistemáticas que en conjunto incluyen 61 estudios primarios, de los cuales cuatro son ensayos aleatorizados que responden a la pregunta de interés. Concluimos que no hay claridad respecto a si los cannabinoides otorgan un beneficio al añadirlos a esquemas antieméticos habituales para el control de náuseas y vómitos inducidos por quimioterapia, porque la certeza de la evidencia es muy baja. Probablemente aumentan los efectos adversos de manera sustantiva.

A modified vaccinia Ankara-based HIV-1 vaccine clade B (MVA-B) has been tested for safety and immunogenicity in low-risk human immunodeficiency virus (HIV)-uninfected individuals and as a therapeutic vaccine in HIV-1-infected individuals on combined antiretroviral therapy (cART). As a therapeutic vaccine, MVA-B was safe and broadly immunogenic; however, patients still showed a viral rebound upon treatment interruption. Monocytes are an important part of the viral reservoir and several studies suggest that they are partly responsible for the chronic inflammation observed in cART-treated HIV-infected people. The CD300 family of receptors has an important role in several diseases, including viral infections. Monocytes express CD300a, c, e, and f molecules and lipopolysaccharide (LPS) and other stimuli regulate their expression. However, the expression and function of CD300 receptors on monocytes in HIV infection is still unknown. In this work, we investigated for the first time the expression of CD300 molecules and the cytokine production in response to LPS on monocytes from HIV-1-infected patients before and after vaccination with MVA-B. Our results showed that CD300 receptors expression on monocytes from HIV-1-infected patients correlates with markers of HIV infection progression and immune inflammation. Specifically, we observed a positive correlation between the expression of CD300e and CD300f receptors on monocytes with the number of CD4+ T cells of HIV-1-infected patients before vaccination. We also saw a positive correlation between the expression of the inhibitory receptor CD300f and the expression of CD163 on monocytes from HIV-1-infected individuals before and after vaccination. In addition, monocytes exhibited a higher cytokine production in response to LPS after vaccination, almost at the same levels of monocytes from healthy donors. Furthermore, we also described a correlation in the expression of CD300e and CD300f receptors with TNF-α production in response to LPS, only in monocytes of HIV-1-infected patients before vaccination. Altogether, our results describe the impact of HIV-1 and of the MVA-B vaccine in cytokine production and monocytes phenotype.

Resumen Los pacientes con tumores cerebrales, primarios o metastásicos, presentan riego de desarrollar convulsiones durante la evolución de su enfermedad, por lo que se ha propuesto el uso profiláctico de anticonvulsivantes. Sin embargo, el efecto de esta intervención no está claro. Para responder esta pregunta utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos. Identificamos 12 revisiones sistemáticas que en conjunto incluyen ochenta estudios primarios. Doce corresponden a estudios aleatorizados, pero sólo dos responden la pregunta de interés. Extrajimos los datos, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. Concluimos que la prevención primaria con anticonvulsivantes podría no disminuir el riesgo de convulsiones en tumores o metástasis cerebrales, y se asocia a efectos adversos frecuentes.

Leishmania is the causative agent of leishmaniasis, a neglected tropical disease that affects more than 12 million people around the world. Current treatments are toxic and poorly effective due to the acquisition of resistance within Leishmania populations. Thus, the pursuit for new antileishmanial drugs is a priority. The available methods for drug screening based on colorimetric assays using vital dyes are time-consuming. Currently, the use of fluorescent reporter proteins is replacing the use of viability indicator dyes. We have constructed two plasmids expressing the red fluorescent protein mCherry with multiple cloning sites (MCS), adequate for N- and C-terminal fusion protein constructs. Our results also show that the improved pXG-mCherry plasmid can be employed for drug screening in vitro. The use of the red fluorescent protein, mCherry, is an easier tool for numerous assays, not only to test pharmacological compounds, but also to determine the subcellular localization of proteins.

The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania.

El papiloma invertido es un tumor infrecuente que ha recibido múltiples interpretaciones histológicas. Es localizado, agresivo, recidivante y potencialmente maligno. De etiología oscura, aún cuando la teoría por virus papiloma humano es la más firmemente aceptada; microscópicamente tiene la característica de invaginarse en el corion, respetando la membrana basal. Este tumor se maligniza, generalmente, por esta causa se comporta con una gran agresividad provocando una gran destrucción por desplazamiento de las estructuras. Se presentó un caso de papiloma invertido en estadio 2, según la clasificación de Krause, analizando las manifestaciones clínicas y hallazgos radiológicos. El síntoma más frecuente es la obstrucción nasal unilateral. El método diagnóstico en este caso se basó en la tomografía axial computarizada de senos perinatales y en la biopsia, las cuales permitió conocer la extensión del tumor y su naturaleza. Se programó la intervención y se realizó una rinotomía lateral con exéresis total del tumor. La modalidad de tratamiento dependerá de la localización y extensión de la enfermedad, aunque el tratamiento quirúrgico radical es el factor más importante en la prevención de la invasión intracraneal.

Resumen El uso de cannabinoides ha sido propuesto para el tratamiento de pacientes con dolor oncológico, principalmente para aquellos en quienes el tratamiento habitual no es suficiente. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, identificamos nueve revisiones sistemáticas que en conjunto incluyen siete estudios que responden la pregunta de interés, de los cuáles seis corresponden a estudios aleatorizados. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que no está claro si los cannabinoides producen una disminución del dolor o una mejoría en la calidad de vida en pacientes con dolor oncológico refractario porque la certeza de la evidencia es muy baja, pero probablemente se asocian a efectos adversos importantes.

Inmaculada Tasset1, José Peña2, Ignacio Jimena2, Montserrat Feijóo1, María del Carmen Muñoz1, Pedro Montilla1, Isaac Túnez11Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Córdoba, Córdoba, Spain; 2Departamento de Ciencias Morfológicas, Sección de Histología, Facultad de Medicina, Universidad de Córdoba, SpainAbstract: The present study evaluated 17β-estradiol (17βE2) (2.5 mg/kg sc) effects on bilateral OBX-induced behavioral changes and oxidative stress. OBX in male Wistar rats produced an increase in lipid peroxidation products and a decline in reduced glutathione (GSH) content and glutathione peroxidase (GSH-Px) activity, together with an increase in caspase-3 activity. Additionally, OBX triggered changes of behavior such as an enhancement of immobility time in the forced swim test and hyperactivity in the open field test. These changes were reversed by treatment with 17βE2 (14 days). Our results reveled that 17βE2 has a protective effect against oxidative stress, cell damage and behavioral changes induced by OBX, and present antidepressant and antianxiety properties.Keywords: behavioral, depression, 17β-estradiol, oxidative stress

Resumen Este resumen Epistemonikos (Living FRISBEE: Living FRIendly Summary of the Body of Evidence using Epistemonikos) es una actualización del resumen publicado en Agosto de 2014, basado en dos nuevas revisiones sistemáticas aparecidas en Enero y Febrero de 2015. Existe controversia sobre los efectos del uso de antibióticos profilácticos en pacientes con pancreatitis aguda. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, identificamos 18 revisiones sistemáticas que en conjunto incluyen 19 estudios aleatorizados. Los combinamos mediante un metanálisis y generamos tablas de resumen de resultados utilizando el método GRADE. Concluimos que el uso de antibióticos profilácticos podría disminuir la mortalidad y el tiempo de hospitalización en pacientes con pancreatitis aguda, pero la certeza de la evidencia es baja. La probabilidad que la aparición de nueva evidencia cambie lo que sabemos es alta.

El virus del Oeste del Nilo (VON) género Flavivirus, familia Flaviviridae, es mantenido en la naturaleza en un cicloenzoótico ave-mosquito-ave. Las aves son los hospederos amplificadores primarios. Humanos y caballos sonhospederos incidentales finales. En humanos las infecciones se manifiestan como enfermedad febril autolimitada.También puede presentarse encefalitis o meningoencefalitis. El virus se ha establecido en Norte América y se hadocumentado su circulación en México, Jamaica, República Dominicana, Guadalupe, Cuba, Puerto Rico, ElSalvador y recientemente en Colombia. Se realizó una vigilancia centinela en culícidos y aves domésticas parahacer un seguimiento a la circulación en el departamento de Córdoba e identificar que especies de mosquitosestaban infectadas con el virus. Se analizaron 4942 mosquitos en 99 pooles por la técnica Vec TestTM (MedicalSystem, Inc. Camarillo, CA) y 162 sueros de aves de corral fueron enviadas al Centers for Disease Control andPrevention Division of Vector-Borne Infectious Diseases Fort Collins, USA, para ser analizadas por MAC-ELISA ydebido a las reacciones cruzadas que se dan entre el VON y otros virus del serocomplejo de la encefalitis japonesase utilizó el test de reducción de la neutralización en placa (PRNT). No se obtuvieron mosquitos o aves positivos

El virus del Oeste del Nilo (VON) pertenece a la familia Flaviviridae, género Flavivirus, es transmitido porartrópodos en un ciclo que involucra a mosquitos y aves. Por muchas décadas había sido reconocido enÁfrica, Asia y el sur de Europa. El virus apareció por primera vez en Estados Unidos en año de 1999 y seha documentado su circulación en México, Islas Caimán, Jamaica, República Dominicana, Martinica,Guadalupe, Cuba, Puerto Rico, El Salvador y Colombia. Sólo recientemente fue asociado con un crecientenúmero de brotes de encefalitis en humanos y equinos, además de infecciones en vertebrados de una granvariedad de especies. Muchos animales, incluyendo más de 150 especies de aves y al menos 30 vertebradosde otras especies son susceptibles a la infección por VON. El resultado de las infecciones depende de laespecie, la edad del animal, su estado inmune y la patogenicidad de la cepa del virus. La infección ocurreen aves, como passeriformes, pollos jóvenes y gansos domésticos, lo que resulta en altos títulos de viremiaque permite la transmisión a los artrópodos. Está menos caracterizado el rol de los vertebrados en latransmisión indirecta, como por órganos contaminados, tejidos o excreciones. La creciente importancia dela infección por VON ha conducido al desarrollo de vacunas veterinarias con virus muertos, atenuados,quiméricos y vacunas de ADN recombinante. En esta revisión se discute en forma general la importanciade infección por VON en vertebrados, su rol en medicina veterinaria y su posible impacto en salud animalpor su reciente introducción a Colombia.

The ability to track changes in gene expression following viral infection is paramount to understanding viral pathogenesis. This study was undertaken to evaluate the nCounter, a high throughput digital gene expression system, as a means to better understand West Nile virus (WNV) dissemination and the inflammatory response against WNV in the outbred Swiss Webster (SW) mouse model over the course of infection.The nCounter Mouse Inflammation gene expression kit containing 179 inflammation related genes was used to analyze gene expression changes in multiple tissues over a nine day course of infection in SW mice following intraperitoneal injection with WNV. Protein expression levels for a subset of these cytokine/chemokine genes were determined using a multiplex protein detection system (BioPlex) and comparisons of protein/RNA expression levels made.Expression analysis of spleen, lung, liver, kidney and brain of SW mice infected with WNV revealed that Cxcl10 and Il12b are differentially expressed in all tissues tested except kidney. Data stratification of positively confirmed infected (WNV (+)) versus non-infected (WNV (-) tissues allowed differentiation of the systemic inflammatory gene response from tissue-specific responses arising from WNV infection. Significant (p

En pacientes con cáncer gástrico aparentemente localizado, la resección quirúrgica con intención curativa tiene pobres resultados a largo plazo, por lo que el uso de quimioterapia perioperatoria se ha planteado como alternativa. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 19 bases de datos, identificamos cuatro revisiones sistemáticas que en conjunto incluyen dos estudios aleatorizados pertinentes. Los combinamos mediante un metanálisis y generamos tablas de resumen de resultados utilizando el método GRADE. Concluimos que la adición de quimioterapia perioperatoria a la resección quirúrgica del cáncer gástrico aumenta la sobrevida, probablemente en una magnitud importante, y podría no aumentar la morbimortalidad perioperatoria.

There is controversy about the effects of prophylactic antibiotics in acute pancreatitis. Searching in Epistemonikos database, which is maintained by screening 19 databases, we identified 15 systematic reviews including 19 randomised studies overall. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded that prophylactic antibiotics may reduce mortality and length of hospitalization in patients with acute pancreatitis, but the quality of the evidence is low. The probability that future evidence change what we know is high.

Problem. Aldosterone antagonist therapy in patients with advanced heart failure and reduced ejection fraction is widely recommended as it decreases mortality and hospitalizations. However, it is unclear how useful this class of drugs is in patients with mild to moderate heart failure. Key messages. - The addition of aldosterone antagonists to chronic treatment of patients with mild to moderate heart failure reduces mortality and hospitalizations for heart failure decompensation. - Aldosterone antagonists have a similar benefit across the spectrum of patients, regardless of their functional capacity and ejection fraction. - Major clinical practice guidelines have not considered much of the existing evidence, and therefore the recommendations of these drugs are more restrictive in the type of heart failure patients. - Spironolactone, a widely available and low cost drug, seems to be the best choice for the vast majority of patients with heart failure requiring an aldosterone antagonist.

Background and aimsSeveral studies have reported that a significant number of HIV patients not co-infected with HCV/HBV develop liver damage of uncertain origin (LDUO). The objective of our study was to evaluate the incidence of and risk factors for the development of LDUO in HIV infected patients not co-infected with HCV/HBV.MethodsProspective longitudinal study that included HIV-infected patients free of previous liver damage and viral hepatitis B or C co-infections. Patients were followed up at 6-monthly intervals. Liver stiffness was measured at each visit. Abnormal liver stiffness (ALS) was defined as a liver stiffness value greater than 7.2 kPa at two consecutive measurements. For patients who developed ALS, a protocol was followed to diagnose the cause of liver damage. Those patients who could not be diagnosed with any specific cause of liver disease were diagnosed as LDUO and liver biopsy was proposed.Results210 patients matched the inclusion criteria and were included. 198 patients completed the study. After a median (Q1-Q3) follow-up of 18 (IQR 12-26) months, 21 patients (10.6%) developed ALS. Of these, fifteen patients were diagnosed as LDUO. The incidence of LDUO was 7.64 cases/100 patient-years. Histological studies were performed on ten (66.6%) patients and all showed liver steatosis. A higher HOMA-IR value and body mass index were independently associated with the development of LDUO.ConclusionWe found a high incidence of LDUO in HIV-infected patients associated with metabolic risk factors. The leading cause of LDUO in our study was non-alcoholic fatty liver disease.

AIM: To evaluate the influence of the presence of the killer cell immunoglobulin-like receptor (KIR) 3DS1 on HCV treatment response in HIV/HCV genotype 1 co-infected patients. METHODS: HIV/HCV co-infected patients were included. KIR3DS1, their specific HLA-B ligands and IL28B gene were genotyped. Reductions of plasma HCV RNA levels between baseline and week 1, week 2 and week 4 were analyzed for IL28B genotype and KIR3DS1 (HLA Bw4 or Bw6). Rapid and sustained virological response (RVR and SVR) rates were also analyzed. RESULTS: Sixty HIV/HCV genotype 1 co-infected patients were included. Patients with KIR3DS1 and Bw4 had higher rates of HCV viral decline than those who were not carriers of KIR3DS1 (week 1: p = 0.01; week 2: p = 0.038; week 4: p = 0.03). Patients carrying KIR3DS1/Bw4 had higher rates of RVR and SVR than those who did not carry KIR3DS1 (RVR: 46.15% versus 17.02%, p = 0.012; SVR: 63.6% versus 13 26.5%, p = 0.031). With respect to patients carrying the IL28B-CC genotype, those with KIR3DS1/Bw4 had greater rates of HCV viral clearance (week 1: p

The rearrangement of intracellular membranes has been long reported to be a common feature in diseased cells. In this study, we used dengue virus (DENV) to study the role of the unfolded protein response (UPR) and sterol-regulatory-element-binding-protein-2 (SREBP-2) pathway in the rearrangement and expansion of the endoplasmic reticulum (ER) early after infection. Using laser scanning confocal and differential interference contrast microscopy, we demonstrate that rearrangement and expansion of the ER occurs early after DENV-2 infection. Through the use of mouse embryonic fibroblast cells deficient in XBP1 and ATF6, we show that ER rearrangement early after DENV infection is independent of the UPR. We then demonstrate that enlargement of the ER is independent of the SREBP-2 activation and upregulation of 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway. We further show that this ER rearrangement is not inhibited by the treatment of DENV-infected cells with the cholesterol-inhibiting drug lovastatin. Using the transcription inhibitor actinomycin D and the translation elongation inhibitor cycloheximide, we show that de novo viral protein synthesis but not host transcription is necessary for expansion and rearrangement of the ER. Lastly, we demonstrate that viral infection induces the reabsorption of lipid droplets into the ER. Together, these results demonstrate that modulation of intracellular membrane architecture of the cell early after DENV-2 infection is driven by viral protein expression and does not require the induction of the UPR and SREBP-2 pathways. This work paves the way for further study of virally-induced membrane rearrangements and formation of cubic membranes.

Análisis de las causas que hicieron posible la Constitución de 1812, las consecuencias de las mismas, la incidencia de la guerra junto a un proceso revolucionario, el papel e los intelectuales en este proceso, las contradicciones del momento histórico y de sus protagonistas, y en cierto modo el planteamiento de lo que años mas tarde se conocería como el llamado «problema de España». Analysis of the causes which lead to the Constitution of 1812, their consequences, the incidence of war along with a revolutionary process, the role of intellectuals in this process, the contradictions of that historical time and its main characters. In a way, the beginning of what later on became known as «the Spanish problem».