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Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease affecting the central nervous system (CNS) in animals that parallels several clinical and molecular traits of multiple sclerosis in humans. Herpes simplex virus type 1 (HSV-1) infection mainly causes cold sores and eye diseases, yet eventually, it can also reach the CNS, leading to acute encephalitis. Notably, a significant proportion of healthy individuals are likely to have asymptomatic HSV-1 brain infection with chronic brain inflammation due to persistent latent infection in neurons. Because cellular senescence is suggested as a potential factor contributing to the development of various neurodegenerative disorders, including multiple sclerosis, and viral infections may induce a premature senescence state in the CNS, potentially increasing susceptibility to such disorders, here we examine the presence of senescence-related markers in the brains and spinal cords of mice with asymptomatic HSV-1 brain infection, EAE, and both conditions. Across all scenarios, we find a significant increases of senescence biomarkers in the CNS with some differences depending on the analyzed group. Notably, some senescence biomarkers are exclusively observed in mice with the combined conditions. These results indicate that asymptomatic HSV-1 brain infection and EAE associate with a significant expression of senescence biomarkers in the CNS.
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Encéfalo , Senescencia Celular , Herpes Simple , Herpesvirus Humano 1 , Esclerosis Múltiple , Animales , Ratones , Encéfalo/virología , Encéfalo/patología , Encéfalo/metabolismo , Esclerosis Múltiple/virología , Esclerosis Múltiple/patología , Esclerosis Múltiple/metabolismo , Herpesvirus Humano 1/fisiología , Herpesvirus Humano 1/patogenicidad , Herpes Simple/virología , Herpes Simple/patología , Femenino , Ratones Endogámicos C57BL , Encefalomielitis Autoinmune Experimental/virología , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/metabolismo , Fenotipo , Sistema Nervioso Central/virología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Médula Espinal/virología , Médula Espinal/metabolismo , Médula Espinal/patología , Biomarcadores/metabolismo , Encefalitis por Herpes Simple/virología , Encefalitis por Herpes Simple/patología , Encefalitis por Herpes Simple/metabolismoRESUMEN
El artículo tiene como objetivo analizar la disponibilidad, acceso y asequibilidad de los medicamentos para niños con Enfermedad Renal Crónica (ERC) en tratamiento con hemodiálisis (HD) en un país de bajos a medianos ingresos. Se llevó a cabo un estudio transversal para determinar los medicamentos más utilizados en una unidad de hemodiálisis pediátrica, incluyendo el nombre del medicamento, dosis, frecuencia, forma farmacéutica y vía de administración. Dos farmacias dentro del perímetro del hospital, una pública y una privada, fueron consultadas para determinar el costoy disponibilidad de medicamentos genéricos y de marca. De un total de 30 pacientes de la unidad de hemodiálisis, 22 expedientes fueron revisados. En general 94% de marca se encontraban disponibles en las farmacias consultadas en comparación a un 52% de los medicamentos genéricos. En farmacias públicas, 41% de medicamentos de marca y 29% de medicamentos genéricos se encontraban disponibles. El costo promedio para un mes de tratamiento con medicamentos de marca adquiridos en una farmacia privada era de $495.00 vs $299.00 en una farmacia pública. Para medicamentos genéricos, el costo promedio correspondía a $414.00 y $239.00 en farmacias privadas y públicas respectivamente. En promedio, los medicamentos de marca adquiridos en una farmacia privada requieren 41 días de trabajo en un mes a comparación de 25 días si se adquieren en una farmacia pública. Los medicamentos genéricos adquiridos en farmacias privadas corresponden a 34 días de trabajo vs 20 días en farmacias públicas. En general existió un acceso limitado a medicamentos genéricos y los medicamentos poseen un costo general más elevado a comparación de otros países lo que implica un posible impacto en la adherencia terapéutica y los padecimientos secundarios de la ERC en los pacientes pediátricos en Guatemala. Esta realidad se puede aplicar a otros países de bajos a medianos ingresos.
This article aims to analyze the availability, access, and affordability of medications for children with advanced Chronic Kidney Disease (CKD) treated with hemodialysis (HD) in a low to middle income country (LMIC). A cross- sectional chart review was carried out to determine the most common medications used in an HD pediatric unit, including medication name, dose, frequency, dosage form, and route of administration. Two pharmacies within the hospital perimeter, one public and one private, were consulted to determine medication cost and availability for generic and brand-name equivalents. From 30 patients attending the HD unit, 22 records were reviewed. Overall, 94 % of brand name medications were available at pharmacies consulted, versus and 52% of generic medications. In public pharmacies, 41% of brand name, and 29% of generic medications were available. The average cost for a full month´s treatment for brand name drugs in the private pharmacy was 495.00 USD versus 299.00 USD in the public pharmacy. For generic drugs, the average cost was 414.00 USD, and 239.00 USD in private and public pharmacies respectively. On average, brand-name drugs in the private pharmacy cost 41 days' wages versus 25 in the public pharmacy. Generic drugs in the private pharmacy cost 34 days' wages versus 20 in the public pharmacy. Overall, there was limited access to generic medications, medications had an overall high cost compared to other countries both of which have the potential to impact treatment adherence and overall outcomes of CKD5 pediatric patients in Guatemala. This reality can be translated to other LMIC.
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Introduction: Plica neuropathica (PN) is a rare, acquired, and irreversible condition characterized by the formation of a compacted mass of tangled hair held together by a hard keratin cement. Case Presentation: In case 1, a 50-year-old woman with history of contact dermatitis of the scalp presented with hair tangling and difficulty combing. Physical examination revealed a matted mass of hair with a dirty appearance and non-scarring alopecia. Case 2 involved a 46-year-old woman who experienced spontaneous hair matting after using various products, resulting in a dreadlock-like appearance. Clinical examination showed a compact and matted mass of hair with irregular twists, dirt, and yellowish exudate. Conclusion: PN's exact pathogenesis is not fully understood, but it is believed to involve physical and chemical insults to the hair shaft. Risk factors include self-neglect, hair felting or rubbing, certain substances, religious practices, chemotherapy, immunosuppressive drugs, infections, and contact dermatitis. Trichoscopy can provide valuable clues for an accurate diagnosis, such as fractured hairs, bent hair shafts, trichorrhexis nodosa, retained telogen hairs, and twisted hairs. Treatment involves cutting the matted hair, and early-stage manual separation may be beneficial.
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The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation.
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Our ability to learn and remember depends on the active formation, remodeling, and elimination of synapses. Thus, the development and growth of synapses as well as their weakening and elimination are essential for neuronal rewiring. The structural reorganization of synaptic complexes, changes in actin cytoskeleton and organelle dynamics, as well as modulation of gene expression, determine synaptic plasticity. It has been proposed that dysregulation of these key synaptic homeostatic processes underlies the synaptic dysfunction observed in many neurodegenerative diseases. Much is known about downstream signaling of activated N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoazolepropionate receptors; however, other signaling pathways can also contribute to synaptic plasticity and long-lasting changes in learning and memory. The non-receptor tyrosine kinase c-Abl (ABL1) is a key signal transducer of intra and extracellular signals, and it shuttles between the cytoplasm and the nucleus. This review focuses on c-Abl and its synaptic and neuronal functions. Here, we discuss the evidence showing that the activation of c-Abl can be detrimental to neurons, promoting the development of neurodegenerative diseases. Nevertheless, c-Abl activity seems to be in a pivotal balance between healthy synaptic plasticity, regulating dendritic spines remodeling and gene expression after cognitive training, and synaptic dysfunction and loss in neurodegenerative diseases. Thus, c-Abl genetic ablation not only improves learning and memory and modulates the brain genetic program of trained mice, but its absence provides dendritic spines resiliency against damage. Therefore, the present review has been designed to elucidate the common links between c-Abl regulation of structural changes that involve the actin cytoskeleton and organelles dynamics, and the transcriptional program activated during synaptic plasticity. By summarizing the recent discoveries on c-Abl functions, we aim to provide an overview of how its inhibition could be a potentially fruitful treatment to improve degenerative outcomes and delay memory loss.
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Introduction: The development of new materials and tools for radiology is key to the implementation of this diagnostic technique in clinics. In this work, we evaluated the differential accumulation of peptide-functionalized GNRs in a transgenic animal model (APPswe/PSENd1E9) of Alzheimer's disease (AD) by computed tomography (CT) and measured the pharmacokinetic parameters and bioaccumulation of the nanosystem. Methods: The GNRs were functionalized with two peptides, Ang2 and D1, which conferred on them the properties of crossing the blood-brain barrier and binding to amyloid aggregates, respectively, thus making them a diagnostic tool with great potential for AD. The nanosystem was administered intravenously in APPswe/PSEN1dE9 model mice of 4-, 8- and 18-months of age, and the accumulation of gold nanoparticles was observed by computed tomography (CT). The gold accumulation and biodistribution were determined by atomic absorption. Results: Our findings indicated that 18-month-old animals treated with our nanosystem (GNR-D1/Ang2) displayed noticeable differences in CT signals compared to those treated with a control nanosystem (GNR-Ang2). However, no such distinctions were observed in younger animals. This suggests that our nanosystem holds the potential to effectively detect AD pathology. Discussion: These results support the future development of gold nanoparticle-based technology as a more effective and accessible alternative for the diagnosis of AD and represent a significant advance in the development of gold nanoparticle applications in disease diagnosis.
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Enfermedad de Alzheimer , Nanopartículas del Metal , Nanotubos , Ratones , Animales , Oro/química , Bioacumulación , Distribución Tisular , Nanopartículas del Metal/química , Péptidos/química , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Tomografía Computarizada por Rayos X , Nanotubos/química , Tomografía , Péptidos beta-Amiloides/metabolismo , Ratones Transgénicos , Modelos Animales de Enfermedad , Encéfalo/metabolismoRESUMEN
Gaucher disease (GD) is an inherited disorder caused by recessive mutations in the GBA1 gene that encodes the lysosomal enzyme ß-glucocerebrosidase (ß-GC). ß-GC hydrolyzes glucosylceramide (GluCer) into glucose and ceramide in the lysosome, and the loss of its activity leads to GluCer accumulation in different tissues. In severe cases, enzymatic deficiency triggers inflammation, organomegaly, bone disease, and neurodegeneration. Neuronopathic Gaucher disease (nGD) encompasses two different forms of the disease, characterized by chronic or acute damage to the central nervous system (CNS). The cellular and molecular studies that uncover the pathological mechanisms of nGD mainly focus on lysosomal dysfunction since the lysosome is the key organelle affected in GD. However, new studies show alterations in other organelles that contribute to nGD pathology. For instance, abnormal accumulation of GluCer in lysosomes due to the loss of ß-GC activity leads to excessive calcium release from the endoplasmic reticulum (ER), activating the ER-associated degradation pathway and the unfolded protein response. Recent evidence indicates mitophagy is altered in nGD, resulting in the accumulation of dysfunctional mitochondria, a critical factor in disease progression. Additionally, nGD patients present alterations in mitochondrial morphology, membrane potential, ATP production, and increased reactive oxygen species (ROS) levels. Little is known about potential dysfunction in other organelles of the secretory pathway, such as the Golgi apparatus and exosomes. This review focuses on collecting evidence regarding organelle dysfunction beyond lysosomes in nGD. We briefly describe cellular and animal models and signaling pathways relevant to uncovering the pathological mechanisms and new therapeutic targets in GD.
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Resumen Introducción: A nivel latinoamericano el suicidio en jóvenes y adolescente representa una problemática grave, por lo que es necesario trabajar en su prevención. En ese sentido, este trabajo presenta una revisión teórica narrativa sobre la temática. Objetivo: Conocer las principales experiencias de prevención de la suicidalidad en jóvenes y adolescentes de Latinoamérica en los últimos 15 años. Método: Se revisaron y analizaron 44 estudios empíricos, realizando búsquedas bibliográficas en revistas científicas indexadas en Scopus, Scielo, WoS, REDALYC y ERIH PLUS y motores de búsqueda como Google Académico y EBSCO. Resultados: Los hallazgos obtenidos en los 44 estudios se organizaron en tres categorías: 1) diagnósticos sobre suicidalidad realizados en población juvenil y adolescente; 2) intervenciones psicoterapéuticas destinadas a tratamiento en suicidalidad; y 3) intervenciones en base a programas, estrategias y técnicas enfocadas en la prevención del suicidio juvenil y adolescente. Discusión: Los principales diagnósticos asociados a la suicidalidad están vinculados a disfuncionalidades emocionales, donde las mujeres son las principales afectadas, la familia y el entorno surgen como principales factores protectores o de riesgo dependiendo de su funcionalidad y cohesión. Además, las intervenciones más valoradas están asociadas a los modelos clásicos de psicoterapia y las estrategias psicoeducativas aparecen como los principales focos de los programas preventivos. Conclusión: Por la multifactoriedad del fenómeno, se debería realizar un cambio paradigmal en el enfrentamiento de la suicidalidad.
Abstract Introduction: At the Latin American level, suicide in young people and adolescents represents a serious problem, so it is necessary to work on its prevention. In this sense, this work presents a narrative theoretical review on the subject. Objective: To know the main experiences of suicide prevention in young people and adolescents in Latin America in the last 15 years. Method: 44 empirical studies were reviewed and analyzed, performing bibliographic searches in scientific journals indexed in Scopus, Scielo, WoS, REDALYC and ERIH PLUS and search engines such as Google Scholar and EBSCO. Results: The findings obtained in the 44 studies were organized into three categories: 1) diagnoses of suicidality made in the youth and adolescent population; 2) psychotherapeutic interventions aimed at treating suicidality; and 3) interventions based on programs, strategies and techniques focused on the prevention of youth and adolescent suicide. Discussion: The main diagnoses associated with suicidality are linked to emotional dysfunctionalities, where women are the main affected, the family and the environment appear as the main protective or risk factors depending on their functionality and cohesion. In addition, the most valued interventions are associated with the classic models of psychotherapy and psychoeducational strategies appear as the main focuses of preventive programs. Conclusion: Due to the multifactorial nature of the phenomenon, a paradigm shift should be made in the confrontation of suicidality.
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The ß-amyloid (Aß) peptide is one of the key etiological agents in Alzheimer's disease (AD). The in vivo detection of Aß species is challenging in all stages of the illness. Currently, the development of fluorescent probes allows the detection of Aß in animal models in the near-infrared region (NIR). However, considering future applications in biomedicine, it is relevant to develop strategies to improve detection of amyloid aggregates using NIR probes. An innovative approach to increase the fluorescence signal of these fluorophores is the use of plasmonic gold nanoparticles (surface-enhanced fluorescence effect). In this work, we improved the detection of Aß aggregates in C. elegans and mouse models of AD by co-administering functionalized gold nanorods (GNRs-PEG-D1) with the fluorescent probes CRANAD-2 or CRANAD-58, which bind selectively to different amyloid species (soluble and insoluble). This work shows that GNRs improve the detection of Aß using NIR probes in vivo.
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Enfermedad de Alzheimer , Nanopartículas del Metal , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/metabolismo , Animales , Caenorhabditis elegans , Colorantes Fluorescentes/química , Oro , Nanopartículas del Metal/química , RatonesRESUMEN
Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder caused by the deficiency in acid sphingomyelinase (ASM) activity. NPA patients present severe and progressive neurodegeneration starting at an early age. Currently, there is no effective treatment for this disease and NPA patients die between 2 and 3 years of age. NPA is characterized by an accumulation of sphingomyelin in lysosomes and dysfunction in the autophagy-lysosomal pathway. Recent studies show that c-Abl tyrosine kinase activity downregulates autophagy and the lysosomal pathway. Interestingly, this kinase is also activated in other lysosomal neurodegenerative disorders. Here, we describe that c-Abl activation contributes to the mechanisms of neuronal damage and death in NPA disease. Our data demonstrate that: 1) c-Abl is activated in-vitro as well as in-vivo NPA models; 2) imatinib, a clinical c-Abl inhibitor, reduces autophagy-lysosomal pathway alterations, restores autophagy flux, and lowers sphingomyelin accumulation in NPA patient fibroblasts and NPA neuronal models and 3) chronic treatment with nilotinib and neurotinib, two c-Abl inhibitors with differences in blood-brain barrier penetrance and target binding mode, show further benefits. While nilotinib treatment reduces neuronal death in the cerebellum and improves locomotor functions, neurotinib decreases glial activation, neuronal disorganization, and loss in hippocampus and cortex, as well as the cognitive decline of NPA mice. Our results support the participation of c-Abl signaling in NPA neurodegeneration and autophagy-lysosomal alterations, supporting the potential use of c-Abl inhibitors for the clinical treatment of NPA patients.
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Parkinson's disease is the second most common neurodegenerative disorder. Although it is clear that dopaminergic neurons degenerate, the underlying molecular mechanisms are still unknown, and thus, successful treatment is still elusive. One pro-apoptotic pathway associated with several neurodegenerative diseases is the tyrosine kinase c-Abl and its target p73. Here, we evaluated the contribution of c-Abl and p73 in the degeneration of dopaminergic neurons induced by the neurotoxin 6-hydroxydopamine as a model for Parkinson's disease. First, we found that in SH-SY5Y cells treated with 6-hydroxydopamine, c-Abl and p73 phosphorylation levels were up-regulated. Also, we found that the pro-apoptotic p73 isoform TAp73 was up-regulated. Then, to evaluate whether c-Abl tyrosine kinase activity is necessary for 6-hydroxydopamine-induced apoptosis, we co-treated SH-SY5Y cells with 6-hydroxydopamine and Imatinib, a c-Abl specific inhibitor, observing that Imatinib prevented p73 phosphorylation, TAp73 up-regulation, and protected SH-SY5Y cells treated with 6-hydroxydopamine from apoptosis. Interestingly, this observation was confirmed in the c-Abl conditional null mice, where 6-hydroxydopamine stereotaxic injections induced a lesser reduction of dopaminergic neurons than in the wild-type mice significantly. Finally, we found that the intraperitoneal administration of Imatinib prevented the death of dopaminergic neurons induced by injecting 6-hydroxydopamine stereotaxically in the mice striatum. Thus, our findings support the idea that the c-Abl/p73 pathway is involved in 6-hydroxydopamine degeneration and suggest that inhibition of its kinase activity might be used as a therapeutical drug in Parkinson's disease.
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La presente investigación buscó caracterizar la población suicida de la Región de Atacama entre los años 2010-2017. Asimismo, pretendió describir los casos en los cuales se constató intentos previos que pasaron por la atención del Sistema de Salud. Se realizó un estudio de tipo epidemiológico descriptivo donde se revisaron estadísticas del Servicio Médico Legal y del Servicio de Salud. El análisis se realizó a partir de los 266 casos registrados y tipificados como suicidios por el Servicio Médico Legal en el periodo estudiado. Se describieron las tasas anuales regionales y comunales, y se compararon los casos por sexo, edad, causa de muerte, estado civil, actividad laboral, nacionalidad, fecha de muerte y presencia de sustancias. Se constató un comportamiento semejante al nacional, evidenciándose una primacía de hombres, solteros, con un promedio de edad de 38,8 años, dedicado a oficios, quienes usaron preferentemente como método el ahorcamiento. Se destaca de manera significativa la ocurrencia de suicidios en el periodo octubre-enero. Se discute respecto a la necesidad de profundizar esta problemática a partir de variables socioambientales, con el fin de explicar las diferencias comunales detectadas, y problematizar los datos a nivel local, en búsqueda de favorecer la prevención.
Suicide is a major global, national, and regional public health problem. The present investigation sought to characterise the suicidal population of the Atacama Region between 2010-2017. It also describes the cases with previous attempts detected by the Health System. The analysis is based on 266 registered cases classified as suicides by the Legal Medical Service in the studied period. The annual regional and city rates are described, and the cases are compared by gender, age, cause of death, marital status, work activity, nationality, date of death and presence of substances. The behaviour observed is similar to the national one, which reflects evidence of a predominance of single men with an average age of 38.8 years, of different trades, who preferably used hanging. The study underscores the occurrence of suicides in the period October-January. The study raises the need to go deep into this problem, considering socio-environmental variables to explain the detected differences between cities and analysing the local data to favour prevention.
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Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Suicidio/estadística & datos numéricos , Estaciones del Año , Autopsia , Chile/epidemiología , Factores Sexuales , Estudios Retrospectivos , Causas de Muerte , Distribución por Edad y Sexo , Factores SociodemográficosRESUMEN
Resumen Introducción: La pandemia de la COVID-19 ha venido a cambiar de forma abrupta las formas de vida de buena parte de la población mundial. Conocer la presencia de psicopatología en este contexto se hace relevante para generar políticas públicas de promoción y prevención en salud mental. Objetivo: Establecer la presencia de psicopatología en habitantes de Copiapó, Chile, y determinar su relación con las variables sexo, edad, ocupación y apoyo social percibido. Método: El estudio, de tipo transversal, se efectuó en una muestra de 523 personas, habitantes de la ciudad de Copiapó, Chile. Se aplicaron la Escala de Salud General, GHQ-12, la Escala de Apoyo Social percibido, MSPSS, y un cuestionario de caracterización sociodemográfica. Las técnicas de análisis de datos fueron estadísticos descriptivos de frecuencia, tendencia central y variabilidad, y estadígrafos de asociación no paramétricos, chi-cuadrado y Eta. También se utilizó t de Student y Anova, para los datos de nivel escalar. Resultados: Se evidencia que un 51,82 % de los evaluados presenta sospecha o presencia de psicopatología, asociada a sintomatología de depresión, ansiedad y/o disfunción social. Se constatan diferencias significativas según sexo, edad y ocupación de los sujetos. Junto a ello, se aprecian niveles estadísticamente significativos de apoyo social entre quienes tienen ausencia y presencia de psicopatología. Conclusiones: El estudio logra describir los niveles de psicopatología en el grupo estudiado en tiempos de la COVID 19, evidenciándose su relación con variables de género, edad y ocupación, lo cual tiene implicancias para la focalización de intervenciones considerando los grupos más afectados: mujeres, jóvenes y estudiantes. Además, se destaca el apoyo social como un factor protector de la salud mental.
Abstract Introduction: The COVID-19 pandemic has come to abruptly change the ways of life of a large part of the world population. Knowing the presence of psychopathology in this context becomes relevant to generate public politics to promote and prevent mental health. Objective: To establish the presence of psychopathology in the inhabitants of Copiapó, Chile, and determine its relationship with the variables sex, age, occupation and perceived social support. Method: The cross-sectional study was carried out on a sample of 523 people, inhabitants of the city of Copiapó, Chile. The General Health Scale, GHQ-12, the Perceived Social Support Scale, MSPSS, and a questionnaire of sociodemographic characterization were applied. Data analysis techniques were descriptive statistics of frequency, central tendency and variability, and non-parametric association statistic, chi-square, and Eta. T Student and Anova were also used for the scalar level data. Results: It is evident that 51,82% of those evaluated show suspicion or presence of psychopathology, associated with symptoms of depression, anxiety and/or social dysfunction. Significant differences were found according to sex, age, and occupation subjects' occupation. Along with this, there are statistically significant levels of social support among those who have absence and presence of psychopathology. Conclusions: The study achieve to describe the levels of psychopathology in the group studied at time of COVID-19, evidencing its relationship with variables of gender, age and occupation, which has implications for targeting interventions considering the most affected groups: women, youth and students. In addition, social support is highlighted as a protective factor of mental health.
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Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1-/- mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.
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Hepatocitos/metabolismo , Hígado/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismo , Proteoma/metabolismo , Animales , Western Blotting , Células Cultivadas , Hígado/patología , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , RatonesRESUMEN
BACKGROUND: Brain metastases (BM) occur in almost one third of patients with systemic malignancies. Only a small number of studies focus on infratentorial location and whole brain radiotherapy (WBRT) as the main non-surgical management. The aim of the study was to compare the prognosis of patients treated with WBRT among patients with supra- or infratentorial lesions. MATERIALS AND METHODS: At a single center, 263 patients with either breast (BC) or lung (LC) cancer, that had developed BM and received treatment with WBRT, were analyzed during an 8-year period. RESULTS: A total of 152 patients with BC and 111 with LC were analyzed, median age at the time of BM was 50.7 years, systemic activity other than BM was detected in 91%. Newly diagnosed BM were supratentorial in 40%, infratentorial in 10% and 51% in both locations. Median overall survival was 13 months (95% CI: 11.1-14.8 months), without significant difference between supra- or infratentorial location. WBRT alone was administered in 79% of patients, whereas WBRT with chemtoreapy was provided for 21%. CONCLUSION: In patients with BM from LC or BC that were not candidates for surgical resection, palliative WBRT appears to be equally effective in those with supra- or infratentorial locations.
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Memory consolidation requires activation of a gene expression program that allows de novo protein synthesis. But the molecular mechanisms that favour or restrict that program are poorly understood. The kinase c-Abl can modulate gene expression through transcription factors and chromatin modifiers. Here, we show that c-Abl ablation in the brain improves learning acquisition and memory consolidation in mice. Its absence also affects gene expression profiles in the mouse hippocampus. We found that genes involved in synaptic plasticity and actin cytoskeleton dynamics, such as Arp2 and Thorase, are up-regulated at the mRNA and protein levels in trained c-Abl KO mice and by a chemical-LTP stimulus. Trained c-Abl KO mice also show that dendritic spines are larger than in wild-type mice and present at a higher density. These results indicate that c-Abl kinase is an important part of the mechanism that limits or restricts signalling of relevant gene programs involved in morphological and functional spine changes upon neuronal stimulation.
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Aprendizaje , Plasticidad Neuronal , Animales , Espinas Dendríticas , Genes abl , Hipocampo , Consolidación de la Memoria , Ratones , Neuronas , SinapsisRESUMEN
Satellite cells (SCs) are tissue-specific stem cells responsible for adult skeletal muscle regeneration and maintenance. SCs function is critically dependent on two families of transcription factors: the paired box (Pax) involved in specification and maintenance and the Muscle Regulatory Factors (MRFs), which orchestrate myogenic commitment and differentiation. In turn, signaling events triggered by extrinsic and intrinsic stimuli control their function via post-translational modifications, including ubiquitination and phosphorylation. In this context, the Abelson non-receptor tyrosine kinase (c-Abl) mediates the activation of the p38 α/ß MAPK pathway, promoting myogenesis. c-Abl also regulates the activity of the transcription factor MyoD during DNA-damage stress response, pausing differentiation. However, it is not clear if c-Abl modulates other key transcription factors controlling SC function. This work aims to determine the role of c-Abl in SCs myogenic capacity via loss of function approaches in vitro and in vivo. Here we show that c-Abl inhibition or deletion results in a down-regulation of Pax7 mRNA and protein levels, accompanied by decreased Pax7 transcriptional activity, without a significant effect on MRF expression. Additionally, we provide data indicating that Pax7 is directly phosphorylated by c-Abl. Finally, SC-specific c-Abl ablation impairs muscle regeneration upon acute injury. Our results indicate that c-Abl regulates myogenic progression in activated SCs by controlling Pax7 function and expression.
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The transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis, and autophagy, promoting the clearance of substrates stored in cells. c-Abl is a tyrosine kinase that participates in cellular signaling in physiological and pathophysiological conditions. In this study, we explored the connection between c-Abl and TFEB. Here, we show that under pharmacological and genetic c-Abl inhibition, TFEB translocates into the nucleus promoting the expression of its target genes independently of its well-known regulator, mammalian target of rapamycin complex 1. Active c-Abl induces TFEB phosphorylation on tyrosine and the inhibition of this kinase promotes lysosomal biogenesis, autophagy, and exocytosis. c-Abl inhibition in Niemann-Pick type C (NPC) models, a neurodegenerative disease characterized by cholesterol accumulation in lysosomes, promotes a cholesterol-lowering effect in a TFEB-dependent manner. Thus, c-Abl is a TFEB regulator that mediates its tyrosine phosphorylation, and the inhibition of c-Abl activates TFEB promoting cholesterol clearance in NPC models.
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Nanostructured films with electrical conductivity in the semiconductor region were prepared in a polymeric matrix of poly(vinyl alcohol) (PVA) with nanostructures of chitosan-gold nanoparticles (AuNPs)/single-wall carbon nanotubes carboxylic acid functionalized (SWCNT-COOH) (chitosan-AuNPs/SWCNT-COOH) self-assembled. Dispersion light scattering (DLS) was used to determine the average particle sizes of chitosan-AuNPs, z-average particle size (Dz) and number average particle size (Dn), and the formation of crystalline domains of AuNPs was demonstrated by X-ray diffraction (XRD) patterns and observed by means of transmission electron microscopy (TEM). The electrostatic interaction was verified by Fourier transform infrared spectroscopy (FTIR). The electrical conductivity of PVA/chitosan-AuNPs/SWCNT-COOH was determined by the four-point technique and photocurrent. The calculated Dn values of the chitosan-AuNPs decreased as the concentration of gold (III) chloride trihydrate (HAuCl4·3H2O) increased: the concentrations of 0.4 and 1.3 mM were 209 and 90 nm, respectively. Average crystal size (L) and number average size (D) of the AuNPs were calculated in the range of 13 to 24 nm. Electrical conductivity of PVA/chitosan-AuNPs/SWCNT-COOH films was 3.7 × 10-5 σ/cm determined by the four-point technique and 6.5 × 10-4 σ/cm by photocurrent for the SWCNT-COOH concentration of 0.5 wt.% and HAuCl4·3H2O concentration of 0.4 mM. In this investigation, the protonation of the amine group of chitosan is fundamental to prepare PVA films with nanostructures of self-assembled chitosan-AuNPs/SWCNT-COOH.
RESUMEN
RESUMEN El origen del pseudotumor orbitario no es del todo conocido. Se admite su naturaleza inflamatoria granulomatosa e inespecífica en diferentes localizaciones. El pseudotumor orbitario se define como una respuesta inflamatoria celular pleomórfica, que está usualmente confinado a estructuras de la órbita y tiene una evolución limitada. En este trabajo se presenta una paciente femenina de 16 años, con diagnóstico de pseudotumor orbitario corroborado por biopsia y tomografía axial computarizada, refractaria al tratamiento con esteroides sistémicos, por lo que se decide iniciar con la aplicación de hialuronidasa y triamcinolona en el espacio peribulbar. Los casos agudos casi siempre responden rápidamente al tratamiento con cortocoesteroides, como prednisona, pero debemos tener en cuenta que existen pacientes que son refractarios al tratamiento, por lo que es necesario buscar procedimientos alternativos. Una opción es el uso de hialuronidasa para destruir las uniones extracelulares, y difundir un esteroide de manera local, como la triamcinolona, más efectiva dentro del tejido inflamatorio para provocar un efecto localizado de este. A los tres meses del tratamiento hubo una regresión total del cuadro en esta paciente(AU)
ABSTRACT The exact etiology of orbital pseudotumor is unknown, but its granulomatous unspecific inflammatory nature at various locations has been recognized. Orbital pseudotumor is defined as a cellular pleomorphic inflammatory response of limited evolution often confined to orbital structures. A case is presented of a female 16-year-old patient diagnosed with orbital pseudotumor confirmed by biopsy and computerized axial tomography, refractory to treatment with systemic steroids, due to which it is decided to start treatment with hyaluronidase and triamcinolone in the peribulbar space. Acute cases often respond fast to treatment with corticosteroids such as prednisone. It should be borne in mind that there are patients who are refractory to treatment for whom alternative treatments should be sought. An option is the use of hyaluronidase to destroy extracellular junctions and locally spread a steroid such as triamcinolone, most effectively within the inflammatory tissue to ensure its localized effect. Total regression of the patient's status was observed at three months of treatment(AU)