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Abstract Background HRASKO/NRASKO double knockout mice exhibit exceedingly high rates of perinatal lethality due to respiratory failure caused by a significant lung maturation delay. The few animals that reach adulthood have a normal lifespan, but present areas of atelectasis mixed with patches of emphysema and normal tissue in the lung. Methods Eight double knockout and eight control mice were analyzed using micro-X-ray computerized tomography and a Small Animal Physiological Monitoring system. Tissues and samples from these mice were analyzed using standard histological and Molecular Biology methods and the significance of the results analyzed using a Student´s T-test. Results The very few double knockout mice surviving up to adulthood display clear craniofacial abnormalities reminiscent of those seen in RASopathy mouse models, as well as thrombocytopenia, bleeding anomalies, and reduced platelet activation induced by thrombin. These surviving mice also present heart and spleen hyperplasia, and elevated numbers of myeloid-derived suppressor cells in the spleen. Mechanistically, we observed that these phenotypic alterations are accompanied by increased KRAS-GTP levels in heart, platelets and primary mouse embryonic fibroblasts from these animals. Conclusions Our data uncovers a new, previously unidentified mechanism capable of triggering a RASopathy phenotype in mice as a result of the combined removal of HRAS and NRAS.

The aging of the global population is a significant and complex phenomenon with far-reaching implications for healthcare systems and society. By 2030, it is projected that the number of individuals over the age of 65 will increase by nearly 1 billion, largely due to advancements in healthcare and improvements in quality of life. Aging is a multifaceted process that encompasses a wide array of changes, spanning from the cellular level to the intricate physiological systems of the human body. At the central nervous system level, aging represents a major risk factor for conditions such as depression and cognitive impairment, which are likely linked to neuroinflammatory processes and can potentially lead to more severe dementias, including Alzheimer’s disease (AD). The higher prevalence of AD in women compared to men has led to speculation that the onset of menopause and associated phenomena, particularly the decline in estrogen levels, may play a role in the development of the disease. Furthermore, research has shown that physical exercise confers both physical and mental health benefits to older adults, with women potentially experiencing the greatest advantages. Understanding the multifaceted nature of aging and its implications for health will ensure that older adults receive the support and care essential for maintaining their health and quality of life.

One of the diseases more related to the continuous aging of the population is Alzheimer's disease, which is a type of dementia currently without either effective diagnosis biomarkers or treatments. Its higher prevalence in women makes it necessary to study pathways/systems that could participate and/or be involved in its development, as well as those that could be affected by hormonal factors, which, in this case, are estradiol levels. In this sense, one of the systems under study that is gaining special relevance in the scientific community is the brain renin-angiotensin system and its regulatory proteolytic enzymes. This system is strongly modulated by estrogens, and it is also connected with the cerebral glucose metabolism through the angiotensin IV receptor, also recognized as the insulin-regulated aminopeptidase (IRAP). Due to the fact that the cerebral glucose metabolism is highly compromised in patients with Alzheimer's disease, it is necessary to know the elements of the systems and their functions in this process, namely, the cerebral renin-angiotensin system, estradiol and IRAP, an enzyme and receptor co-localized in brain tissue with the insulin-dependent glucose transporter 4 (GLUT4). Knowledge of the connection between them could shed light on the molecular mechanisms of this disease and also provide new diagnostic and therapeutic targets.

Abstract Background C3G is a guanine nucleotide exchange factor (GEF) that activates Rap1 to promote cell adhesion. Resting C3G is autoinhibited and the GEF activity is released by stimuli that signal through tyrosine kinases. C3G is activated by tyrosine phosphorylation and interaction with Crk adaptor proteins, whose expression is elevated in multiple human cancers. However, the molecular details of C3G activation and the interplay between phosphorylation and Crk interaction are poorly understood. Methods We combined biochemical, biophysical, and cell biology approaches to elucidate the mechanisms of C3G activation. Binding of Crk adaptor proteins to four proline-rich motifs (P1 to P4) in C3G was characterized in vitro using isothermal titration calorimetry and sedimentation velocity, and in Jurkat and HEK293T cells by affinity pull-down assays. The nucleotide exchange activity of C3G over Rap1 was measured using nucleotide-dissociation kinetic assays. Jurkat cells were also used to analyze C3G translocation to the plasma membrane and the C3G-dependent activation of Rap1 upon ligation of T cell receptors. Results CrkL interacts through its SH3N domain with sites P1 and P2 of inactive C3G in vitro and in Jurkat and HEK293T cells, and these sites are necessary to recruit C3G to the plasma membrane. However, direct stimulation of the GEF activity requires binding of Crk proteins to the P3 and P4 sites. P3 is occluded in resting C3G and is essential for activation, while P4 contributes secondarily towards complete stimulation. Tyrosine phosphorylation of C3G alone causes marginal activation. Instead, phosphorylation primes C3G lowering the concentration of Crk proteins required for activation and increasing the maximum activity. Unexpectedly, optimal activation also requires the interaction of CrkL-SH2 domain with phosphorylated C3G. Conclusion Our study revealed that phosphorylation of C3G by Src and Crk-binding form a two-factor mechanism that ensures tight control of C3G activation. Additionally, the simultaneous SH2 and SH3N interaction of CrkL with C3G, required for the activation, reveals a novel adaptor-independent function of Crk proteins relevant to understanding their role in physiological signaling and their deregulation in diseases. Video abstract

C3G is a Rap1 guanine nucleotide exchange factor that controls platelet activation, aggregation, and the release of α-granule content. Transgenic expression of C3G in platelets produces a net proangiogenic secretome through the retention of thrombospondin-1. In a physiological context, C3G also promotes megakaryocyte maturation and proplatelet formation, but without affecting mature platelet production. The aim of this work is to investigate whether C3G is involved in pathological megakaryopoiesis, as well as its specific role in platelet mediated angiogenesis and tumor metastasis. Using megakaryocyte-specific C3G knockout and transgenic mouse models, we found that both C3G overexpression and deletion promoted platelet-mediated angiogenesis, induced by tumor cell implantation or hindlimb ischemia, through differential release of proangiogenic and antiangiogenic factors. However, only C3G deletion resulted in a higher recruitment of hemangiocytes from the bone marrow. In addition, C3G null expression enhanced thrombopoietin (TPO)-induced platelet production, associated with reduced TPO plasma levels. Moreover, after 5-fluorouracil-induced platelet depletion and rebound, C3G knockout mice showed a defective return to homeostatic platelet levels, indicating impaired platelet turnover. Mechanistically, C3G promotes c-Mpl ubiquitination by inducing Src-mediated c-Cbl phosphorylation and participates in c-Mpl degradation via the proteasome and lysosome systems, affecting TPO internalization. We also unveiled a positive role of platelet C3G in tumor cell-induced platelet aggregation, which facilitated metastatic cell homing and adhesion. Overall, these findings revealed that C3G plays a crucial role in platelet-mediated angiogenesis and metastasis, as well as in platelet level modulation in response to pathogenic stimuli.

Wernicke’s encephalopathy (WE) is a neurologic disease caused by vitamin B1 or thiamine deficiency (TD), being the alcohol use disorder its main risk factor. WE patients present limiting motor, cognitive, and emotional alterations related to a selective cerebral vulnerability. Neuroinflammation has been proposed to be one of the phenomena that contribute to brain damage. Our previous studies provide evidence for the involvement of the innate immune receptor Toll-like (TLR)4 in the inflammatory response induced in the frontal cortex and cerebellum in TD animal models (animals fed with TD diet [TDD] and receiving pyrithiamine). Nevertheless, the effects of the combination of chronic alcohol consumption and TD on TLR4 and their specific contribution to the pathogenesis of WE are currently unknown. In addition, no studies on TLR4 have been conducted on WE patients since brains from these patients are difficult to achieve. Here, we used rat models of chronic alcohol (CA; 9 months of forced consumption of 20% (w/v) alcohol), TD hit (TDD + daily 0.25 mg/kg i.p. pyrithiamine during 12 days), or combined treatment (CA + TDD) to check the activation of the proinflammatory TLR4/MyD88 pathway and related markers in the frontal cortex and the cerebellum. In addition, we characterized for the first time the TLR4 and its coreceptor MyD88 signature, along with other markers of this proinflammatory signaling such as phospo-NFκB p65 and IκBα, in the postmortem human frontal cortex and cerebellum (gray and white matter) of an alcohol-induced WE patient, comparing it with negative (no disease) and positive (aged brain with Alzheimer’s disease) control subjects for neuroinflammation. We found an increase in the cortical TLR4 and its adaptor molecule MyD88, together with an upregulation of the proinflammatory signaling molecules p-NF-ĸB and IĸBα in the CA + TDD animal model. In the patient diagnosed with alcohol-induced WE, we observed cortical and cerebellar upregulation of the TLR4/MyD88 pathway. Hence, our findings provide evidence, both in the animal model and the human postmortem brain, of the upregulation of the TLR4/MyD88 proinflammatory pathway in alcohol consumption–related WE.

Abstract Glioblastoma (GBM) is the most aggressive tumor from the central nervous system (CNS). The current lack of efficient therapies makes essential to find new treatment strategies. C3G, a guanine nucleotide exchange factor for some Ras proteins, plays a dual role in cancer, but its function in GBM remains unknown. Database analyses revealed a reduced C3G mRNA expression in GBM patient samples. C3G protein levels were also decreased in a panel of human GBM cell lines as compared to astrocytes. Based on this, we characterized C3G function in GBM using in vitro and in vivo human GBM models. We report here that C3G downregulation promoted the acquisition of a more mesenchymal phenotype that enhanced the migratory and invasive capacity of GBM cells. This facilitates foci formation in anchorage-dependent and -independent growth assays and the generation of larger tumors in xenografts and chick chorioallantoic membrane (CAM) assays, but with a lower cell density, as proliferation was reduced. Mechanistically, C3G knock-down impairs EGFR signaling by reducing cell surface EGFR through recycling inhibition, while upregulating the activation of several other receptor tyrosine kinases (RTKs) that might promote invasion. In particular, FGF2, likely acting through FGFR1, promoted invasion of C3G-silenced GBM cells. Moreover, ERKs mediate this invasiveness, both in response to FGF2- and serum-induced chemoattraction. In conclusion, our data show the distinct dependency of GBM tumors on C3G for EGF/EGFR signaling versus other RTKs, suggesting that assessing C3G levels may discriminate GBM patient responders to different RTK inhibition protocols. Hence, patients with a low C3G expression might not respond to EGFR inhibitors.

Introducción: La formación inicial docente de maestros de inglés como categoría de análisis comporta una historicidad, que posibilita identificar formas particulares de ver y pensar al maestro de inglés en formación y al inglés como objeto de enseñanza. Objetivo: Explorar las tendencias imperantes en las normas producidas para regular la formación inicial de maestros de inglés y las relaciones de poder-conocimiento que se instalan en los currículos y discursos de formación docente. Metodología: Se utilizaron algunos procedimientos de arqueología foucaultiana para organizar temáticamente algunos discursos dominantes e identificar giros y desplazamientos en la historia de la formación de profesores de Inglés en Colombia entre 1990 y 2020. Resultados y Conclusiones: Los resultados permiten identificar giros y desplazamientos en las formas de pensar la formación inicial de maestros de inglés. Se produjo entonces un esquema de especificación que marcó dos trayectos equidistantes: Uno ligado al ideal de la formación profesional, la pedagogía y la investigación y otro, marcado por mecanismos de control y certificación de competencias.

The dentate gyrus (DG) of the human hippocampus is a complex and dynamic structure harboring mature and immature granular neurons in diverse proliferative states. While most mammals show persistent neurogenesis through adulthood, human neurogenesis is still under debate. We found nuclear alterations in granular cells in autopsied human brains, detected by immunohistochemistry. These alterations differ from those reported in pyramidal neurons of the hippocampal circuit. Aging and early AD chromatin were clearly differentiated by the increased epigenetic markers H3K9me3 (heterochromatin suppressive mark) and H3K4me3 (transcriptional euchromatin mark). At early AD stages, lamin B2 was redistributed to the nucleoplasm, indicating cell-cycle reactivation, probably induced by hippocampal nuclear pathology. At intermediate and late AD stages, higher lamin B2 immunopositivity in the perinucleus suggests fewer immature neurons, less neurogenesis, and fewer adaptation resources to environmental factors. In addition, senile samples showed increased nuclear Tau interacting with aged chromatin, likely favoring DNA repair and maintaining genomic stability. However, at late AD stages, the progressive disappearance of phosphorylated Tau forms in the nucleus, increased chromatin disorganization, and increased nuclear autophagy support a model of biphasic neurogenesis in AD. Therefore, designing therapies to alleviate the neuronal nuclear pathology might be the only pathway to a true rejuvenation of brain circuits.

Abstract Background Megakaryopoiesis allows platelet formation, which is necessary for coagulation, also playing an important role in different pathologies. However, this process remains to be fully characterized. C3G, an activator of Rap1 GTPases, is involved in platelet activation and regulates several differentiation processes. Methods We evaluated C3G function in megakaryopoiesis using transgenic mouse models where C3G and C3GΔCat (mutant lacking the GEF domain) transgenes are expressed exclusively in megakaryocytes and platelets. In addition, we used different clones of K562, HEL and DAMI cell lines with overexpression or silencing of C3G or GATA-1. Results We found that C3G participates in the differentiation of immature hematopoietic cells to megakaryocytes. Accordingly, bone marrow cells from transgenic C3G, but not those from transgenic C3GΔCat mice, showed increased expression of the differentiation markers CD41 and CD61, upon thrombopoietin treatment. Furthermore, C3G overexpression increased the number of CD41+ megakaryocytes with high DNA content. These results are supported by data obtained in the different models of megakaryocytic cell lines. In addition, it was uncovered GATA-1 as a positive regulator of C3G expression. Moreover, C3G transgenic megakaryocytes from fresh bone marrow explants showed increased migration from the osteoblastic to the vascular niche and an enhanced ability to form proplatelets. Although the transgenic expression of C3G in platelets did not alter basal platelet counts, it did increase slightly those induced by TPO injection in vivo. Moreover, platelet C3G induced adipogenesis in the bone marrow under pathological conditions. Conclusions All these data indicate that C3G plays a significant role in different steps of megakaryopoiesis, acting through a mechanism dependent on its GEF activity.

Abnormally increased signaling by the GTPase RAP1 favors progression of diverse tumors. We have characterized the auto-regulation and activation of C3G (RAPGEF1), an activator of RAP1. This led us to discover mutations in non-Hodgkin’s lymphomas that activate C3G-RAP1 constitutively, suggesting that deregulation of C3G may favor the dissemination of tumor cells.

Potassium (K+) acquisition, translocation and cellular homeostasis are mediated by various membrane transport systems in all organisms. We identified and described an ion channel in the ectomycorrhizal fungus Hebeloma cylindrosporum (HcSKC) that harbors features of animal voltage-dependent Shaker-like K+ channels, and investigated its role in both free-living hyphae and symbiotic conditions. RNAi lines affected in the expression of HcSKC were produced and used for in vitro mycorrhizal assays with the maritime pine as host plant, under standard or low K+ conditions. The adaptation of H. cylindrosporum to the downregulation of HcSKC was analyzed by qRT-PCR analyses for other K+-related transport proteins: the transporters HcTrk1, HcTrk2, and HcHAK, and the ion channels HcTOK1, HcTOK2.1, and HcTOK2.2. Downregulated HcSKC transformants displayed greater K+ contents at standard K+ only. In such conditions, plants inoculated with these transgenic lines were impaired in K+ nutrition. Taken together, these results support the hypothesis that the reduced expression of HcSKC modifies the pool of fungal K+ available for the plant and/or affects its symbiotic transfer to the roots. Our study reveals that the maintenance of K+ transport in H. cylindrosporum, through the regulation of HcSKC expression, is required for the K+ nutrition of the host plant.

C3G (RAPGEF1) is a guanine nucleotide exchange factor (GEF) for GTPases from the Ras superfamily, mainly Rap1, although it also acts through GEF-independent mechanisms. C3G regulates several cellular functions. It is expressed at relatively high levels in specific brain areas, playing important roles during embryonic development. Recent studies have uncovered different roles for C3G in cancer that are likely to depend on cell context, tumour type, and stage. However, its role in brain tumours remained unknown until very recently. We found that C3G expression is downregulated in GBM, which promotes the acquisition of a more mesenchymal phenotype, enhancing migration and invasion, but not proliferation. ERKs hyperactivation, likely induced by FGFR1, is responsible for this pro-invasive effect detected in C3G silenced cells. Other RTKs (Receptor Tyrosine Kinases) are also dysregulated and could also contribute to C3G effects. However, it remains undetermined whether Rap1 is a mediator of C3G actions in GBM. Various Rap1 isoforms can promote proliferation and invasion in GBM cells, while C3G inhibits migration/invasion. Therefore, other RapGEFs could play a major role regulating Rap1 activity in these tumours. Based on the information available, C3G could represent a new biomarker for GBM diagnosis, prognosis, and personalised treatment of patients in combination with other GBM molecular markers. The quantification of C3G levels in circulating tumour cells (CTCs) in the cerebrospinal liquid and/or circulating fluids might be a useful tool to improve GBM patient treatment and survival.

Cellular identity is determined through complex patterns of gene expression. Chromatin, the dynamic structure containing genetic information, is regulated through epigenetic modulators, mainly by the histone code. One of the main challenges for the cell is maintaining functionality and identity, despite the accumulation of DNA damage throughout the aging process. Replicative cells can remain in a senescent state or develop a malign cancer phenotype. In contrast, post-mitotic cells such as pyramidal neurons maintain extraordinary functionality despite advanced age, but they lose their identity. This review focuses on tau, a protein that protects DNA, organizes chromatin, and plays a crucial role in genomic stability. In contrast, tau cytosolic aggregates are considered hallmarks of Alzheimer´s disease (AD) and other neurodegenerative disorders called tauopathies. Here, we explain AD as a phenomenon of chromatin dysregulation directly involving the epigenetic histone code and a progressive destabilization of the tau–chromatin interaction, leading to the consequent dysregulation of gene expression. Although this destabilization could be lethal for post-mitotic neurons, tau protein mediates profound cellular transformations that allow for their temporal survival.

Human prion and non-prion neurodegenerative diseases share pathogenic mechanisms and neuropathological features. The lesion profile of a particular entity results from specific involvement of vulnerable neuron populations and connectivity circuits by a pathogenic protein isoform with strain-like properties. The lesion profile of the medial temporal lobe (MTL) was studied in postmortem tissue of 143 patients with human prion disease (HPD) including sporadic, genetic, and acquired forms. Most cases (90%) were classified according to PrPres type and/or PRNP codon 129 status, in addition to a full neuropathological profile. Mixed histotypes represented 29.4% of total sporadic Creutzfeldt-Jakob disease (sCJD) cases. An intensity score of involvement including spongiosis and astrogliosis was determined for the amygdala, presubiculum, subiculum, entorhinal cortex, CA1 to CA4 sectors of the hippocampal cortex, and dentate gyrus. Connectivity hubs within the MTL presented the highest scores. Diverse lesion profiles were obtained for different types and subtypes of HPD. Impact of mixed PrPres types on the MTL lesion profile was higher for sCJDMV2K cases than in other histotypes. Differences between MTL profiles was globally consistent with current evidence on specific strains in HPD. These results may be relevant for the analysis of possible strain effects in focal non-prion neurodegenerative conditions limited to the MTL.

Background: An epidemiological study of Streptococcus pneumoniae nasopharyngeal carriage in healthy children was carried out five years after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13). Objectives: Study the impact of pediatric vaccination with PCV13, and other associated epidemiological factors on the status of nasopharyngeal carriage, the circulating pneumococcal serotypes, and the antibiotic susceptibility to more frequently used antibiotics. Methods: A multi-center study was carried out in Primary Health Care, which included 1821 healthy children aged 1 to 4 years old. All isolates were sent to the Spanish Pneumococcal Reference Laboratory for serotyping and antimicrobial susceptibility testing. Results: At least one dose of PCV13 had been received by 71.9% of children and carriage pneumococcal prevalence was 19.7%. The proportion of PCV13 serotypes was low (14.4%), with an observed predominance of non-vaccine serotypes, 23B, 11A, 10A, 35B/F, and 23A were the five most frequent. A high rate of resistance to penicillin, erythromycin, and trimethoprim sulfamethoxazole was found. Conclusions: A low proportion of PCV13 serotypes were detected, confirming the impact of pediatric vaccination for reducing the serotypes vaccine carriage. High resistance rates to clinically important antibiotics were observed.

El embarazo múltiple es una entidad que está estrechamente ligada a estudios genéticos, especialmente en el caso de gemelos univitelinos en el área médica de la obstetricia. Su incidencia es baja, sin embargo, representa un factor de alto riesgo obstétrico y por ende, se encuentra sujeto a complicaciones durante el embarazo tanto como para la madre como para el feto (mutaciones, anomalías o incompatibilidad con la vida). En la actualidad aún se pueden encontrar alteraciones en el desarrollo normal de este tipo de embarazos, aunque desafortunadamente el conocimiento que se tiene respecto a su origen sigue imposibilitando su prevención o tratamiento. En el presente trabajo se describe el caso clínico de primigesta de 17 años de edad quien cursa con embarazo gemelar monocorial, biamniótico atendido en la consulta de Alto Riesgo Obstétrico del Instituto Autónomo Hospital Universitario de Los Andes (IAHULA); en el cual se diagnostica a partir de Ultrasonografía pélvica 2D, un feto con múltiples malformaciones, caracterizadas por acranea, hepato-onfalocele y tumor en cordón umbilical; se realizan estudios genéticos donde no se evidencia algún tipo de alteración.

Background and objectives: Screening colonoscopy with polipectomy reduces colonorectal cancer incidence and mortality. An adequate bowel cleansing is one of the keys to achieving best results with this technique. Oral sodium phosphate solution (OSP) had a widespread use in the 90s decade. Its efficacy was similar to polyethylene glycol (PEG) solution, but with less cost and convenient administration. Series of patients with acute renal failure due to OSP use have been reported. However, large cohorts of patients found no difference in the incidence of renal damage between these two solutions. Methods: From 2006 to 2009 we identified twelve cases of phosphate nephropathy after colonoscopy prepared with OSP. All patients were followed up to six months. All patients had received just a single dose. Results: We analyzed 12 cases with phosphate nephropathy; three patients debuted with AKI and nine patients had chronic renal injury. Four cases were confirmed with renal biopsy. One patient with AKI needed hemodialysis at diagnosis without subsequent recovery. Two patients (both with chronic damage) fully recovered their previous renal function. The remaining patients (nine) had an average loss of estimated glomerular filtration rate of 24 ml/min/1.73 m2. Conclusions: The use of OSP can lead to both acute and chronic renal damage. However, chronic injury was the most common pattern. Both forms of presentation imply a significant and irreversible loss of renal function. Further studies analyzing renal damage secondary to bowel cleaning should consider these two different patterns of injury.

The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors.

Background. Recent reports point to a nuclear origin of Alzheimer’s disease (AD). Aged postmitotic neurons try to repair their damaged DNA by entering the cell cycle. This aberrant cell cycle re-entry involves chromatin modifications where nuclear Tau and the nuclear lamin are involved. The purpose of this work was to elucidate their participation in the nuclear pathological transformation of neurons at early AD. Methodology. The study was performed in hippocampal paraffin embedded sections of adult, senile, and AD brains at I-VI Braak stages. We analyzed phospho-Tau, lamins A, B1, B2, and C, nucleophosmin (B23) and the epigenetic marker H4K20me3 by immunohistochemistry. Results. Two neuronal populations were found across AD stages, one is characterized by a significant increase of Lamin A expression, reinforced perinuclear Lamin B2, elevated expression of H4K20me3 and nuclear Tau loss, while neurons with nucleoplasmic Lamin B2 constitute a second population. Conclusions. The abnormal cell cycle reentry in early AD implies a fundamental neuronal transformation. This implies the reorganization of the nucleo-cytoskeleton through the expression of the highly regulated Lamin A, heterochromatin repression and building of toxic neuronal tangles. This work demonstrates that nuclear Tau and lamin modifications in hippocampal neurons are crucial events in age-related neurodegeneration.

Rap proteins regulate liver physiopathology. For example, Rap2B promotes hepatocarcinoma (HCC) growth, while Rap1 might play a dual role. The RapGEF, Epac1, activates Rap upon cAMP binding, regulating metabolism, survival, and liver regeneration. A liver specific Epac2 isoform lacking cAMP-binding domain also activates Rap1, promoting fibrosis in alcoholic liver disease. C3G (RapGEF1) is also present in the liver, but mainly as shorter isoforms. Its function in the liver remains unknown. Information from different public genetic databases revealed that C3G mRNA levels increase in HCC, although they decrease in metastatic stages. In addition, several mutations in RapGEF1 gene are present, associated with a reduced patient survival. Based on this, C3G might represent a new HCC diagnostic and prognostic marker, and a therapeutic target.

Objetivo • La planificación de la comunicación interna sugiere la necesidad de un análisis de la percepción de esta materia, tanto desde el punto de vista de los directivos como desde la perspectiva de los propios profesionales, con el fin de conocer las posibles coincidencias y divergencias entre la percepción de unos y otros y poder así dirigirnos a una mejor sintonización. Este estudio se plantea conocer dicha percepción por parte de los dos actores del sistema, directivos y profesionales y a demás en dos entornos, hospitales y atención primaria. Material y métodos • La opinión de los directivos se obtuvo a través de un cuestionario de Comunicación Interna, diseñado y pilotado para este contexto. El cuestionario fue autoadministrado, con preguntas con una escala de respuesta de Likert entre 1 y 7, y otras de respuesta múltiple, utilizándose el email como medio de envío y recolección de estos cuestionarios. Ámbito: España. Universo: Directivos de hospitales públicos de todo el territorio nacional. Tamaño de la muestra: 135 entrevistas (Tasa de respuesta alcanzada 63%). Procedimiento de muestreo: aleatorio estratificado, con afijación proporcional. Los estratos se han formado tomando como elemento diferenciador el tamaño del hospital según número de camas. Análisis: Se hizo un análisis descriptivo de las variables del cuestionario, junto a la Prueba T para la comparación de medias entre muestras independientes. Se realizó un análisis de alpha de Cronbach del cuestionario, que fue de 0,85. Además, se hizo un análisis discriminante. Opinión de los profesionales: La información se obtuvo a través de un cuestionario de Clima, Cultura y Comunicación Interna, que incluía un apartado específico sobre Comunicación Interna. Algunas variables se midieron a través de una escala de respuesta de Likert con puntuaciones entre 1 y 7, mientras que otras preguntas eran de respuesta múltiple. El cuestionario fue autoadministrado y se distribuyó a todos los profesionales (facultativos, personal de enfermería y personal no sanitario) y mandos intermedios (subdirectores, jefes de servicio y supervisores de enfermería) de 6 hospitales del Servicio Andaluz de Salud (SAS), uno regional (H5), tres de especialidades (H1, H2 y H3) y dos comarcales (H6 y H7), junto a dos áreas de atención primaria. N = 2156. % de respuesta = 42%. Análisis: Análisis descriptivo univariante y bivariante. Resultados • Existen diferencias significativas en la valoración de las características examinadas de la Comunicación Interna entre los profesionales de base y los directivos. Sin embargo, no se observan diferencias significativas para ninguna de estas variables entre el personal de base sanitario y el no sanitario, ni entre mandos intermedios y directivos. En la valoración de los directivos, se observan diferencias significativas a favor de los hospitales de menos de 500 camas en cuanto a la claridad y formalidad de la información. Asimismo existen diferencias significativas para todas las variables comparadas entre jefes de servicio y facultativos y entre jefes de bloque y supervisoras con respecto a las enfermeras. Los compañeros son la fuente por la que los profesionales reciben la mayor parte de la información, con un rango entre hospitales que oscila entre el 58% y el 67% (al preguntarles de donde les gustaría recibir la información, los compañeros ocupan entre el 1% y 14%) mientras que los directivos son la fuente principal para un % de profesionales que varia entre 4 y 14 según hospitales (en el deseo de los profesionales varia entre el 32 y el 71%) y los responsables intermedios que oscilan como fuente principal entre el 7 y el 22% (esperarían porcentajes entre el 43 y el 71%). Por otra parte, los gerentes creen que son los directivos, incluyendo al propio gerente, la fuente más importante por la que los profesionales reciben la información (44%), seguido de los compañeros (32%) y los cargos intermedios (19%). Se detectó como en los hospitales de 500 camas y menos, para los gerentes, la importancia de los mandos intermedios, las Juntas facultativas y de Enfermería o el uso de los tablones de anuncios tienen un papel significativamente mayor como transmisores de información descendente que el que juegan en los hospitales de mayor tamaño, en los cuales tienen un papel significativamente superior el correo electrónico o los compañeros. Entre los canales a través de los cuales los directivos afirman recibir la opinión de los profesionales, destacan las reuniones de equipo y las entrevistas con los responsables con un 86,2%, seguido por las entrevistas con la dirección con un 82,8%.. Por su parte, los profesionales señalan las reuniones de equipo como canal preferido tanto para dar su opinión (el 45,5% opinó así) como para recibir información sobre el hospital (71% opinó así). Las entrevistas personales tienen también un peso importante tanto para dar (38,5%) como para recibir (28%). Además, encontramos las encuestas, los grupos de discusión y los buzones de sugerencias como canales preferidos para dar su opinión, mientras que el boletín y las cartas lo son para recibir. Si miramos lo que ocurre en los centros de salud, encontramos que la información es clara, creíble, llega por canales formales, periódica y en cantidad suficiente. Además, respecto a las fuentes de información de los profesionales, destacan que la mayoría llega por canales formales, sea el coordinador del centro, el adjunto de enfermería, el responsable de enfermería o el Director del Área. Al analizar la relación entre variables, los profesionales que reciben información de sus compañeros tienen una satisfacción laboral más baja, perciben que su centro ofrece una imagen al exterior peor de lo que piensan sus compañeros, consideran que la calidad de la información que reciben es baja. Por otra parte, los que reciben la información de los coordinadores o responsables, se caracterizan por todo lo contrario. Además los que reciben la información a través de las reuniones de equipo o las entrevistas individuales, tienen una satisfacción más alta y una percepción positiva del centro hacia el exterior. Además, hemos encontrado una relación entre la satisfacción laboral, el contenido del trabajo (ligado al ambiente del trabajo) y la comunicación. Conclusiones • La comunicación interna es valorada de forma positiva por los directivos y negativa por parte de los profesionales. Existe un bloqueo entre la Dirección y los trabajadores y entre los cargos intermedios y los responsables y el personal de base. Por tanto, la comunicación interna es valorada de forma diferente en diferentes contextos hospitalarios y muy diferente en los hospitales que en atención primaria.

Attempts to discover genes that are involved in the pathogenesis of major psychiatric disorders have been frustrating and often fruitless. Concern is building about the need to understand the complex ways in which nature and nurture interact to produce mental illness. We analyze the epigenome in several brain regions from schizophrenic patients with severe cognitive impairment using high-resolution (450k) DNA methylation array. We identified 159 differentially methylated CpG sites included in known and novel candidate genes sequences as well as in and intergenic sequences wich functions remain unknown. We found that altered DNA methylation is not restricted to a particular region, but includes others such as CpG shelves and gene bodies, indicating the presence of different DNA methylation signatures depending on the brain area analyzed. Our findings suggest that epimutations are not relatables between different tissues or even between tissues’ regions, highlighting the need to adqueately study brain samples to obtain reliable data concerning the epigenetics of schizophrenia.

An immunocompetent 82-year-old female was admitted to our hospital due to fever without clear origin and hyponatremia. In the following days, an acute and bilateral pulmonary infiltrate appeared with a progressive worsening in respiratory function. Chest x-ray and CT (Computed tomography) showed bilateral reticulonodular infiltrates. Bronchoscopic aspiration and bronchoalveolar lavage (BAL), and transbronchial lung biopsy (TBBX) studies did not reveal microbiological and histopathological diagnosis. Broad-spectrum antibiotics were non-effective, and the patient died due to respiratory failure. Necropsy study revealed a miliary tuberculosis affecting lungs, liver, bone marrow, spleen, kidney, arteries, pancreas, and adrenal glands. Some weeks after the patient´s death, mycobacterial cultures from sputum, BAL and TBBX samples were positive for Mycobacterium tuberculosis.

Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P

Studies on family care giving within hospitals are not frequent. This situation contributes to make these people underconsidered by the health system. The aim of this study is to analyze the profile of family caregivers, the needs they attend and how they are considered by the health professionals in a traumatology and rehabilitation hospital.Methodology: Descriptive and cross-sectional study, which included one hundred interviews performed between September and October 2002 in traumatology, maxillofacial surgery, neurology, and neurosurgery wards. Results: The family caregiver profile corresponds to a female with a median age of 48 years who spends a mean of 20 hours per day in the hospital. Surveillance and company were the main contributions to the patient care according to caregivers’ answers. Conclusions: Wives or mothers become the main family caregivers. Their contribution implies monetary and time costs as well as physic, psychological and social impact. The care offered by the family caregivers is scarcely supported by professional help. Increasing the professionals’ recognition of the family caregivers is a social requirement.

Resumen: Los estudios de cuidadores familiares realizados dentro de las instituciones hospitalarias son escasos. Esta situación determina su invisibilidad y su no reconocimiento por parte del sistema institucional sanitario. Los objetivos de este estudio son estudiar el perfil de los cuidadores familiares en el Hospital Universitario de Traumatología y Rehabilitación de Granada, conocer el tipo de necesidades que cubren, las repercusiones y su valoración por los profesionales sanitarios. Metodología: Investigación de tipo descriptivo y transversal, mediante 100 encuestas realizadas entre septiembre y octubre de 2002, en las plantas de traumatología, maxilofacial, neurología, neurocirugía. Se efectuó un análisis descriptivo y bivariante a través de tablas de contingencia y diferencias de media. Las variables fueron edad, sexo, ingresos económicos, vivienda conjunta, trabajo y localidad del cuidador. Resultados: El perfil del cuidador informal corresponde a una mujer, con una media de edad de 48 años y que permanece 20 horas de media al día en el hospital. Las necesidades que el cuidador percibe como más importantes para el paciente estuvieron relacionadas con la compañía y la vigilancia. Conclusiones: El perfil del cuidador familiar es de cónyuges o madres. La realización de las tareas de cuidador supone un gasto de tiempo, dinero, desgaste físico, psicológico y social. Parte de las necesidades del paciente son cubiertas por los cuidadores informales, los cuales reciben poca información y asesoramiento del personal de enfermería sobre cómo realizarlas. Ampliar por tanto la mirada enfermera es una exigencia y demanda de nuestra sociedad. Abstract: Studies on family care giving within hospitals are not frequent. This situation contributes to make these people underconsidered by the health system. The aim of this study is to analyze the profile of family caregivers, the needs they attend and how they are considered by the health professionals in a traumatology and rehabilitation hospital. Methodology: Descriptive and cross-sectional study, which included one hundred interviews performed between September and October 2002 in traumatology, maxillofacial surgery, neurology, and neurosurgery wards. Results: The family caregiver profile corresponds to a female with a median age of 48 years who spends a mean of 20 hours per day in the hospital. Surveillance and company were the main contributions to the patient care according to caregivers’ answers. Conclusions: Wives or mothers become the main family caregivers. Their contribution implies monetary and time costs as well as physic, psychological and social impact. The care offered by the family caregivers is scarcely supported by professional help. Increasing the professionals’ recognition of the family caregivers is a social requirement. Centro de Trabajo: EUE “Virgen de las Nieves”, Granada Fecha del Trabajo: 15/06/2003 Palabra Clave: Cuidador familiar, cuidador informal, hospital, traumatologia, rehabilitación, enfermería Key Words: Family caregiver, hospital, traumatology, rehabilitation, nursing