RESUMEN
Cardiac fibroblasts (CF) are mesenchymal-type cells responsible for maintaining the homeostasis of the heart's extracellular matrix (ECM). Their dysfunction leads to excessive secretion of ECM proteins, tissue stiffening, impaired nutrient and oxygen exchange, and electrical abnormalities in the heart. Additionally, CF act as sentinel cells in the cardiac tissue microenvironment, responding to various stimuli that may affect heart function. Deleterious stimuli induce an inflammatory response in CF, increasing the secretion of cytokines such as IL-1ß and TNF-α and the expression of cell adhesion molecules like ICAM1 and VCAM1, initially promoting damage resolution by recruiting immune cells. However, constant harmful stimuli lead to a chronic inflammatory process and heart dysfunction. Therefore, it is necessary to study the mechanisms that govern CF inflammation. NFκB is a key regulator of the cardiac inflammatory process, making the search for mechanisms of NFκB regulation and CF inflammatory response crucial for developing new treatment options for cardiovascular diseases. SGK1, a serine-threonine protein kinase, is one of the regulators of NFκB and is involved in the fibrotic effects of angiotensin II and aldosterone, as well as in CF differentiation. However, its role in the CF inflammatory response is unknown. On the other hand, many bioactive natural products have demonstrated anti-inflammatory effects, but their role in CF inflammation is unknown. One such molecule is boldine, an alkaloid obtained from Boldo (Peumus boldus), a Chilean endemic tree with proven cytoprotective effects. However, its involvement in the regulation of SGK1 and CF inflammation is unknown. In this study, we evaluated the role of SGK1 and boldine in the inflammatory response in CF isolated from neonatal Sprague-Dawley rats. The involvement of SGK1 was analyzed using GSK650394, a specific SGK1 inhibitor. Our results demonstrate that SGK1 is crucial for LPS- and IFN-γ-induced inflammatory responses in CF (cytokine expression, cell adhesion molecule expression, and leukocyte adhesion). Furthermore, a conditioned medium (intracellular content of CF subject to freeze/thaw cycles) was used to simulate a sterile inflammation condition. The conditioned medium induced a potent inflammatory response in CF, which was completely prevented by the SGK1 inhibitor. Finally, our results indicate that boldine inhibits both SGK1 activation and the CF inflammatory response induced by LPS, IFN-γ, and CF-conditioned medium. Taken together, our results position SGK1 as an important regulator of the CF inflammatory response and boldine as a promising anti-inflammatory drug in the context of cardiovascular diseases.
Asunto(s)
Aporfinas , Fibroblastos , Proteínas Inmediatas-Precoces , FN-kappa B , Proteínas Serina-Treonina Quinasas , Transducción de Señal , Animales , FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Inmediatas-Precoces/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ratas , Aporfinas/farmacología , Inflamación/metabolismo , Inflamación/patología , Miocardio/patología , Miocardio/metabolismo , Células Cultivadas , Ratas Sprague-DawleyRESUMEN
En el último tiempo, la inmunoterapia se ha convertido en una opción terapéutica para diversos tipos de neoplasias, aumentando la sobrevida en muchos casos, pero también los efectos adversos asociados. Existen tres tipos de inmunoterapia utilizados en cáncer: Terapia de células T con receptor de antígeno quimérico (CAR-T), destacando como reacciones adversas el síndrome liberador de citoquinas (CRS) y el síndrome de neurotoxicidad (ICANS); Anticuerpos monoclonales (AcM), cuyos efectos adversos más comunes están relacionados con reacciones de hipersensibilidad; y los Inhibidores de puntos de control inmunitario (ICI) con toxicidad pulmonar claramente reportada. Para un correcto manejo de estas reacciones adversas se requiere un alto índice de sospecha, un adecuado diagnóstico diferencial y un tratamiento oportuno, basado principalmente en corticoides y guiado por criterios de gravedad. Se presenta el caso de un paciente con reacción granulomatosa sarcoidea posterior al uso de Nivolumab.
In recent times, immunotherapy has emerged as a therapeutic option for various neoplasms, significantly improving survival rates in many cases, albeit with associated adverse effects. There are three types of immunotherapy commonly used in cancer treatment: Chimeric Antigen Receptor T-cell Therapy (CAR-T), notable for adverse reactions such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS); Monoclonal Antibodies (mAbs), with the most common adverse effects being hypersensitivity reactions; and Immune Checkpoint Inhibitors (ICI), with well-documented pulmonary toxicity. Adequate management of these adverse reactions requires a high index of suspicion, accurate differential diagnosis, and timely treatment, primarily based on corticosteroids and guided by severity criteria. We present a case of a patient with granulomatous sarcoid-like reaction following the use of Nivolumab.
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Enfermedades Pulmonares/inducido químicamente , Neoplasias/tratamiento farmacológico , Sarcoidosis Pulmonar/inducido químicamente , Inmunoterapia/efectos adversosRESUMEN
El oxígeno (O2) es una de las drogas más utilizadas en clínica, su uso no está exento de riesgos. Existen guias internacionales para su uso, pero en nuestro medio no sabemos si se aplican. Nuestro objetivo fue describir la forma en que se utiliza y controla la oxígenoterapia en los 3 hospitales de la red del Servicio de Salud Talcahuano. Aplicamos una encuesta un día de agosto de 2016 a los pacientes hospitalizados en las instituciones de la red que recibían O2 en ese momento. Se recolectaron datos sobre la prescripción, administración y seguimiento de la terapia de O2. De los 381 pacientes auditados, un 13,7% recibía oxígenoterapia. Los diagnósticos más frecuentes fueron de causa respiratoria (46,15%) y cardiológica (25%). La indicación la dio un médico en 88,5% de los casos y en un 3,8% no había registro. En un 17,3% de los pacientes no había fundamento para la indicación. Se indicó una dosis fija en el 75% con una meta de SaO2 en el 50%, siendo naricera y máscara de Venturi los métodos de administración más frecuentes monitorizándose con oximetría de pulso en los hospitales menos complejos y gasometría arterial en el hospital terciario. La duración media de la oxígenoterapia fue de 7,8 días. Habiendo un buen fundamento y control de la oxígenoterapia aún no se indican metas a obtener. No hay un buen registro de la indicación ni de los cambios realizados. Creemos útil la realización periódica de este tipo de control para optimizar su uso evitando los potenciales efectos adversos en los pacientes.
Abstract Oxygen is a commonly used drug in clinics and its use must be judicious. There are guidelines for oxygen therapy but we ignore if these are respected in our country. We conducted an audit of oxygen therapy by applying a survey to 381 patients in the three hospitals of Talcahuano Public Health Service. The day of the audit 13.7% of the hospitalized patients were on oxygen, most of them with respiratory (46.15%) or cardiovascular (25%) diseases. Indication of O2 administration was given by a physician in 88.5% and there was not registry in 3.8% of the cases. There was not foundation for supplying O2 in 13.3% of patients. A fixed dose was indicated in 75% of cases and 50% had an oximetry value as a target. Oxygen was administered in most of the cases by nasal prongs and Venturi masks. Monitoring was based on pulse oximetry in the less complex hospitals and on arterial blood gases in the tertiary hospital. 100% of patients at urgency ward were receiving a different dose from that indicated at their admission time and none of them had a registry of the new dose. Mean duration of therapy was 7.8 days. We believe our results might represent what is going on with oxygen therapy in our country; having a good foundation and monitoring, we still don t use targets and there is a bad system of registry. We think that it would be advisably to carry out audits on oxygen therapy at national level on regular basis.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Terapia por Inhalación de Oxígeno/métodos , Auditoría Clínica/métodos , Servicios de Salud , Terapia por Inhalación de Oxígeno/estadística & datos numéricos , Chile , Encuestas y Cuestionarios , Monitoreo FisiológicoRESUMEN
Methylphenidate (MPH, Ritalin©) is widely used in the treatment of Attention Deficit Hyperactivity Disorder and recently as a drug of abuse. Although the effect of MPH has been studied in brain regions such as striatum and prefrontal cortex (PFC), the hippocampus has received relatively little attention. It is known that MPH increases the TBS-dependent Long Term Potentiation (LTP) in the CA1 area. However, the cellular and molecular mechanisms involved in this process are still unknown. Using field potential recordings and western blot analysis in rat hippocampal slices of young rats, we found that acute application of MPH enhances LTP in CA3-CA1 synapses in a dose-dependent manner with an EC50 of 73.44±6.32 nM. Using specific antagonists and paired-pulse facilitation protocols, we observed that the MPH-dependent increase of LTP involves not only ß-adrenergic receptors activation but also post-synaptic D1/D5 dopamine receptors. The inhibition of PKA with PKI, suppressed the facilitation of LTP induced by MPH consistent with an involvement of the adenyl cyclase-cAMP-PKA dependent cascade downstream of the activation of D1/D5 receptors. In addition, samples of CA1 areas taken from slices potentiated with MPH presented an increase in the phosphorylation of the Ser845 residue of the GluA1 subunit of AMPA receptors compared to control slices. This effect was reverted by SCH23390, antagonist of D1/D5 receptors, and PKI. Moreover, we found an increase of surface-associated functional AMPA receptors. We propose that MPH increases TBS-dependent LTP in CA3-CA1 synapses through a polysynaptic mechanism involving activation of ß-adrenergic and D1/D5 dopaminergic receptors and promoting the trafficking and insertion of functional AMPA receptors to the plasma membrane.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Metilfenidato/farmacología , Animales , Transporte Biológico Activo/efectos de los fármacos , Membrana Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Técnicas de Placa-Clamp , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores Adrenérgicos beta/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/metabolismo , Transducción de Señal/efectos de los fármacos , Técnicas de Cultivo de TejidosRESUMEN
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a drug of abuse that induces learning and memory deficit. However, there are no experimental data that correlate the behavioral evidence with models of synaptic plasticity such as long-term potentiation (LTP) or long-term depression (LTD). Using field potential recordings in rat hippocampal slices of young rats, we found that acute application of MDMA enhances LTP in CA3-CA1 synapses without affecting LTD. Using specific antagonists and paired-pulse facilitation protocols we observed that the MDMA-dependent increase of LTP involves presynaptic 5-HT2 serotonin receptors and postsynaptic D1/D5 dopamine receptors. In addition, the inhibition of PKA suppresses the MDMA-dependent increase in LTP, suggesting that dopamine receptor agonism activates cAMP-dependent intracellular pathways. We propose that MDMA exerts its LTP-altering effect involving a polysynaptic interaction between serotonergic and dopaminergic systems in hippocampal synapses. Our results are compatible with the view that the alterations in hippocampal LTP could be responsible for MDMA-dependent cognitive deficits observed in humans and animals.
Asunto(s)
Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Neuronas/efectos de los fármacos , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina 5-HT2/metabolismo , Serotoninérgicos/farmacología , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/química , Antagonistas de Dopamina/farmacología , Activación Enzimática/efectos de los fármacos , Potenciales Evocados/efectos de los fármacos , Alucinógenos/farmacología , Hipocampo/enzimología , Hipocampo/metabolismo , Técnicas In Vitro , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/enzimología , Neuronas/metabolismo , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/enzimología , Terminales Presinápticos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/antagonistas & inhibidores , Receptores de Dopamina D5/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Transmisión Sináptica/efectos de los fármacosRESUMEN
La recolección de datos se llevó a cabo a través de la revisión de la literatura existente sobre el tema y una entrevista semiestructurada a siete Terapeutas Ocupacionales, con experiencia en el área de estudio. La entrevista se centró en los siguientes temas: Componentes Ocupacionales evaluados por terapeutasocupacionales durante el proceso de Tratamiento y Rehabilitación, modelos y evaluaciones utilizadas por terapeutas ocupacionales y Componentes Ocupacionales que muestran mayor déficit. Los resultados de esta investigación revelaron que la mayoría de los terapeutas ocupacionales evalúan los componentes ocupacionales de rutina/hábitos, roles, volición, tiempo libre e historia laboral en la etapa de ingreso a Centros de Tratamiento y Rehabilitación. Los resultados también revelaron una carencia de modelos y evaluaciones adecuadas y específicas desde la Terapia Ocupacional en el tema de estudio. Este estudio concluye en que existe una carencia de homogeneidad en el lenguaje, instrumentos de evaluación y los modelos utilizados entre Terapeutas Ocupacionales en los distintos Centros de Tratamiento y Rehabilitación.
This research topic is framed within the field of occupational therapy and problematic drug abuse. The purpose of this qualitative study is to explore what occupational components occupational therapists assess in the process of treatment and rehabilitation of problematic drug abuse. The study also explores the models and assessments used during this process. The participants were selected out of the list of Treatment and Rehabilitation Centers, that provides Occupational Therapy intervention in an Intensive Outpatient Program. This list was obtained from thedatabase of the National Council for Narcotics Control (CONACE). Data was collected through literature review on the topic and semi-structured interviews with seven Occupational Therapists with experience in the field of Drug Addiction Treatment and Rehabilitation. Theinterviews focused on the following topics: occupational components that are assessed for occupational therapists during the process of Treatment and Rehabilitation, models or theoretical frameworks and assessments used during this process and occupational components most affected. The results revealed that the majority of occupational therapists evaluate the occupational components of routine / habits, roles, volition, leisure and work history at the stage of admission to Treatment and Rehabilitation Centers. In addition, the results reveal a lack of appropriate and specific models andassessments from the occupational therapy perspective within the field of drug abuse. This study concludes that there is a lack of homogeneity in language, assessment tools and models used between the Occupational Therapists working in the Treatment and Rehabilitation Centers.
Asunto(s)
Humanos , Evaluación de Procesos y Resultados en Atención de Salud , Terapia Ocupacional/instrumentación , Trastornos Relacionados con Sustancias/rehabilitación , Modelos Teóricos , Ocupaciones , Centros de Rehabilitación , Trastornos Relacionados con Sustancias/terapiaRESUMEN
INTRODUCTION AND DEVELOPMENT: Alterations of sensory experience cause large-scale re-arrangements of cortical connectivity only early in life. After a critical period that roughly ends by puberty, comparable modifications requires more invasive manipulations, including deafferentation and cortical lesions. At a cellular level, the elementary mechanisms responsible for synaptic modification appear to be available throughout life. Thus, in adults, experience dependent plasticity might be constrained additional factors, like the maturation of inhibition or changes in the extra cellular matrix. Such view is consistent with a limited, but not absent, modifiability of adult cortical circuits. This view also has interesting therapeutical implications. CONCLUSION: In this scenario, manipulation of these limiting factors, for example reducing synaptic inhibition, might be a useful strategy to enhance plasticity and to restore function in the adult cortex.
Asunto(s)
Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Corteza Visual/fisiología , Animales , Humanos , Factores de Crecimiento Nervioso/metabolismo , Vías Nerviosas , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The optic tectum of the pigeon is a highly organized, multilayered structure that receives a massive polystratified afference of at least five different populations of retinal ganglion cells and gives rise to various anatomically segregated efferent systems. The synaptic organization of retino-tectal circuitry is, at present, mostly unknown. To investigate the spatiotemporal profile of synaptic activation produced by differential (electrical and visual) stimulation of the retinal inputs, we performed a high-spatial-resolution current source density analysis in the optic tectum of the anaesthetized pigeon. Electrical stimuli consisted of brief pulses of different durations applied to the optic nerve head, while visual stimuli consisted of light flashes of different intensities. Electrical stimulation generated sinks confined to retinorecipient layers. The temporal structure, spatial location and thresholds of these sinks indicated that they are all due to primary tectal synapses of retinal fibers with different conduction velocities. Sinks evoked by the fastest retinal axons were more superficially located than sinks produced by slower retinal fibers. Visual stimulation, on the other hand, resulted in a more complex pattern of current sinks, with various sinks located in the retinorecipient layers and also well below. Visual stimulation induced action potentials at superficial as well as deep tectal levels. We conclude that electrical stimulation activates most of the populations of ganglion cells as well as their primary tectal synapses, but is unable to elicit a significant activation of secondary tectal synapses. Visual stimulation, on the contrary, activates just some of the incoming retinal populations, but in a way that produces noticeable secondary activation of intratectal circuits. Laminar segregation of retinally evoked tectal activity, as reported here, has also been found in other vertebrates. Similarities and differences with previous studies are discussed.
Asunto(s)
Columbidae/fisiología , Nervio Óptico/fisiología , Retina/fisiología , Colículos Superiores/fisiología , Sinapsis/fisiología , Vías Visuales/fisiología , Animales , Gatos , Estimulación Eléctrica , Potenciales Evocados , Potenciales Evocados Visuales , Femenino , Masculino , Fibras Nerviosas/fisiología , Conducción Nerviosa , Estimulación Luminosa , Ranidae , Tiempo de Reacción , Células Ganglionares de la Retina/fisiologíaRESUMEN
Potency tests of a total of 658 foot-and-mouth disease (FMD) vaccine batches by bovine protective dose (PD50) showed that 22% of the tests did not follow the expected theoretical model and the results could not be interpreted because of the lack of a dose-response relationship. The protection against generalization (PG) method, using undiluted vaccine, proved to be highly reliable from the analysis of the results of 65 replicate potency tests of three hydroxide-saponin (HS) vaccines and two oil-adjuvanted (OL) vaccines. The PG results were consistent in 64 out of the total of 65 tests. The data obtained indicated that, with regard to direct tests in cattle, the PG test is the preferred method for FMD vaccine potency control. This study also showed that the incorporation of a reference vaccine in routine potency tests is essential to ensure normality of the test system and that good quality HS and OL FMD vaccines may maintain immunogenic stability for at least 27 and 36 months, respectively, when stored at 2-8 degrees C.
Asunto(s)
Aphthovirus/inmunología , Enfermedades de los Bovinos/prevención & control , Fiebre Aftosa/prevención & control , Vacunas Virales/uso terapéutico , Animales , Bovinos , Relación Dosis-Respuesta a Droga , Valores de Referencia , Vacunación/normasRESUMEN
Forty two saliva samples from rabid dogs were examined by intracerebral inoculation of weanling and suckling mice. Although rabies virus assay were successful in all of the samples in both groups of mice used, a significant higher death proportion (p < 0.01) were observed in the suckling mice group.