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El presente artículo tiene como objetivo hacer una revisión comparativa de la literatura que permita obtener un panorama más claro respecto a la intervención de las instituciones de nivel superior para la detección de hábitos y técnicas de estudio en los estudiantes universitarios. El método es cualitativo y documental con un enfoque transversal simple, se utilizaron muestras homogéneas para la selección de los casos de estudio comparativo, eligiendo 17 autores. Respecto a las semejanzas encontradas, se pueden dividir en 4 rubros: Implementación de programas educativos, por parte de las instituciones de nivel superior, enfocados a desarrollar hábitos y técnicas de estudio en el alumno de nuevo ingreso; el educando y la ausencia de hábitos y técnicas de estudio; el papel del docente, y su influencia en el uso de hábitos y técnicas de estudio, por parte del estudiante y ventajas de la existencia de conocimientos en este rubro.

SUMMARYOne of the earliest pathophysiological perturbations in Alzheimer’s Disease (AD) may arise from dysfunction of fast-spiking parvalbumin (PV) interneurons (PV-INs). Defining early protein-level (proteomic) alterations in PV-INs can provide key biological and translationally relevant insights. Here, we use cell-type-specific in vivo biotinylation of proteins (CIBOP) coupled with mass spectrometry to obtain native-state proteomes of PV interneurons. PV-INs exhibited proteomic signatures of high metabolic, mitochondrial, and translational activity, with over-representation of causally linked AD genetic risk factors. Analyses of bulk brain proteomes indicated strong correlations between PV-IN proteins with cognitive decline in humans, and with progressive neuropathology in humans and mouse models of Aβ pathology. Furthermore, PV-IN-specific proteomes revealed unique signatures of increased mitochondrial and metabolic proteins, but decreased synaptic and mTOR signaling proteins in response to early Aβ pathology. PV-specific changes were not apparent in whole-brain proteomes. These findings showcase the first native state PV-IN proteomes in mammalian brain, revealing a molecular basis for their unique vulnerabilities in AD.

A substantial literature supports the notion that cancer is a metabolic disease. Mitochondria are sexually dimorphic, and progesterone (P4) plays a key regulatory role in mitochondrial functions. We investigated the effect of P4 on mitochondrial functions in three human glioblastoma multiforme (GBM) cell lines. In dose-response and time-response studies, GBM cells were exposed to different concentrations of P4 followed by mitochondrial stress-testing with a Seahorse analyzer. Data were analyzed for oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and spare respiratory capacity (SRC) to determine the effects of P4 exposure on mitochondrial respiration and rate of glycolysis. We also examined the effect of P4 on mitochondrial superoxide radical generation by confocal microscopy. As early as 1h post-P4 exposure, we found a substantial dose-dependent inhibitory effect of P4 on OCR, ECAR, and SRC in all GBM cell lines. P4 treatment altered the levels of basal respiration, maximum respiration, nonmitochondrial oxygen consumption, ATP production, and proton leak. P4 given at 80-μM concentration showed the maximum inhibitory effect compared to controls. Live imaging data showed an 11-22% increase in superoxide radical generation in all three GBM cell lines following 6h exposure to a high concentration of P4. Our data show that high-dose P4 exerts an inhibitory effect on both mitochondrial respiration and glycolysis in GBM cells. These effects would lead to decreased tumor size and rate of growth, representing a potential treatment to control the spread of GBM.

Desde marzo del 2020, implementó una modalidad de educación a distancia mediante el uso de tecnologías de la información y comunicación. A febrero del 2021, tal medida continuaba vigente. En una entidad federativa como Chiapas, donde un alto porcentaje de la población vive en situación de pobreza y el acceso y uso de las tecnologías es limitado, resulta pertinente un análisis con enfoque diferenciado que permita identificar cómo afectan tales medidas a las trayectorias educativas de infancias y adolescencias en condiciones de mayor desigualdad. El estudio analiza la información de una consulta telefónica a niñas, niños y adolescentes de 8 a 17 años tsotsiles, tsetales y mestizos de la Ciudad de San Cristóbal de las Casas, Chiapas en México realizada en marzo del 2020. Profundiza en las características de sus hogares, el acceso a servicios y el uso de tecnologías de la información para recuperar sus percepciones y preocupaciones en torno a sus trayectorias escolares. A partir de sus voces se evidencia las afectaciones, que medidas como la implementada por el gobierno mexicano, tienen sobre su derecho a la educación y su interdependencia con otros derechos como la alimentación, la salud física y mental, y el acceso a la información.

A multidimensional inflammatory response ensues after status epilepticus (SE), driven partly by cyclooxygenase-2-mediated activation of prostaglandin EP2 receptors. The inflammatory response is typified by astrocytosis, microgliosis, erosion of the blood-brain barrier (BBB), formation of inflammatory cytokines, and brain infiltration of blood-borne monocytes. Our previous studies have shown that inhibition of monocyte brain invasion or systemic administration of an EP2 receptor antagonist relieves multiple deleterious consequences of SE. Here we identify those effects of EP2 antagonism that are reproduced by conditional ablation of EP2 receptors in immune myeloid cells and show that systemic EP2 antagonism blocks monocyte brain entry in male mice. The induction of hippocampal IL-6 after pilocarpine SE was nearly abolished in EP2 conditional KO mice. Serum albumin levels in the cortex, a measure of BBB breakdown, were significantly higher after SE in EP2-sufficient mice but not in EP2 conditional KOs. EP2 deficiency in innate immune cells accelerated the recovery from sickness behaviors following SE. Surprisingly, neurodegeneration was not alleviated in myeloid conditional KOs. Systemic EP2 antagonism prevented monocyte brain infiltration and provided broader rescue of SE-induced effects than myeloid EP2 ablation, including neuroprotection and broader suppression of inflammatory mediators. Reporter expression indicated that the cellular target of CD11b-driven Cre was circulating myeloid cells but, unexpectedly, not microglia. These findings indicate that activation of EP2 receptors on immune myeloid cells drives substantial deficits in behavior and disrupts the BBB after SE. The benefits of systemic EP2 antagonism can be attributed, in part, to blocking brain recruitment of blood-borne monocytes.SIGNIFICANCE STATEMENTUnabated seizures reduce quality of life, promote the development of epilepsy, and can be fatal. We previously identified activation of prostaglandin EP2 receptors as a driver of undesirable consequences of seizures. However, the relevant EP2-expressing cell types remain unclear. Here we identify peripheral innate immune cells as a driver of the EP2-related negative consequences of seizures. Removal of EP2 from peripheral immune cells was beneficial, abolishing production of a key inflammatory cytokine, accelerating weight regain, and limiting behavioral deficits. These findings provide evidence that EP2 engagement on peripheral immune and brain endothelia contributes to the deleterious effects of SE, and will assist in the development of beneficial therapies to enhance quality of life in individuals who suffer prolonged seizures.

Vitamin D deficiency (Ddef) alters morphology and outcomes after a stroke. We investigated the interaction of Ddef following post-stroke systemic inflammation and evaluated whether administration of progesterone (P) or vitamin D (D) will improve outcomes. Ddef rats underwent stroke with lipopolysaccharide (LPS)-induced systemic inflammation. Rats were randomly divided into 9 groups and treated with P, D, or vehicle for 4 days. At day 4, rats were tested on different behavioral parameters. Markers of neuronal inflammation, endoplasmic reticulum stress, oxidative stress, white matter integrity, and apoptosis were measured along with immune cell populations from the spleen, thymus, and blood. Severely altered outcomes were observed in the Ddef group compared to the D-sufficient (Dsuf) group. Stroke caused peripheral immune dysfunction in the Dsuf group which was worse in the Ddef group. Systemic inflammation exacerbated injury outcomes in the Dsuf group and these were worse in the Ddef group. Monotherapy with P/D showed beneficial functional effects but the combined treatment showed better outcomes than either alone. Ddef as a comorbid condition with stroke worsens stroke outcomes and can delay functional recovery. Combination treatment with P and D might be promising for future stroke therapeutics in Ddef.

This document is part of the “SHEA Neonatal Intensive Care Unit (NICU) White Paper Series.” It is intended to provide practical, expert opinion, and/or evidence-based answers to frequently asked questions about CLABSI detection and prevention in the NICU. This document serves as a companion to the CDC Healthcare Infection Control Practices Advisory Committee (HICPAC) Guideline for Prevention of Infections in Neonatal Intensive Care Unit Patients. Central line-associated bloodstream infections (CLABSIs) are among the most frequent invasive infections among infants in the NICU and contribute to substantial morbidity and mortality. Infants who survive CLABSIs have prolonged hospitalization resulting in increased healthcare costs and suffer greater comorbidities including worse neurodevelopmental and growth outcomes. A bundled approach to central line care practices in the NICU has reduced CLABSI rates, but challenges remain. This document was authored by pediatric infectious diseases specialists, neonatologists, advanced practice nurse practitioners, infection preventionists, members of the HICPAC guideline-writing panel, and members of the SHEA Pediatric Leadership Council. For the selected topic areas, the authors provide practical approaches in question-and-answer format, with answers based on consensus expert opinion within the context of the literature search conducted for the companion HICPAC document and supplemented by other published information retrieved by the authors. Two documents in the series precede this one: “Practical approaches to Clostridioides difficile prevention” published in August 2018 and “Practical approaches to Staphylococcus aureus prevention,” published in September 2020.

Cognitive comorbidities can substantially reduce quality of life in people with epilepsy. Inflammation is a component of all chronic diseases including epilepsy, as well as acute events like status epilepticus (SE). Neuroinflammation is the consequence of several broad signaling cascades including cyclooxygenase-2 (COX-2)-associated pathways. Activation of the EP2 receptor for prostaglandin E2 appears responsible for blood-brain barrier leakage and much of the inflammatory reaction, neuronal injury and cognitive deficit that follows seizure-provoked COX-2 induction in brain. Here we show that brief exposure of mice to TG11-77, a potent, selective, orally available and brain permeant EP2 antagonist, eliminates the profound cognitive deficit in Y-maze performance after SE and reduces delayed mortality and microgliosis, with a minimum effective i.p. dose (as free base) of 8.8 mg/kg. All in vitro studies required to submit an investigational new drug (IND) application for TG11-77 have been completed, and non-GLP dose range-finding toxicology in the rat identified no overt, organ or histopathology signs of toxicity after 7 days of oral administration at 1000 mg/kg/day. Plasma exposure in the rat was dose-linear between 15 and 1000 mg/kg dosing. TG11-77 thus appears poised to continue development towards the initial clinical test of the hypothesis that EP2 receptor modulation after SE can provide the first preventive treatment for one of the chief comorbidities of epilepsy.

Sleep disturbances, such as insomnia, obstructive sleep apnea, and daytime sleepiness, are common in people diagnosed with epilepsy. These disturbances can be attributed to nocturnal seizures, psychosocial factors, and/or the use of anti-epileptic drugs with sleep-modifying side effects. Epilepsy patients with poor sleep quality have intensified seizure frequency and disease progression compared to their well-rested counterparts. A better understanding of the complex relationship between sleep and epilepsy is needed, since approximately 20% of seizures and more than 90% of sudden unexpected deaths in epilepsy occur during sleep. Emerging studies suggest that neuroinflammation, (e.g., the CNS immune response characterized by the change in expression of inflammatory mediators and glial activation) may be a potential link between sleep deprivation and seizures. Here, we review the mechanisms by which sleep deprivation induces neuroinflammation and propose that neuroinflammation synergizes with seizure activity to worsen neurodegeneration in the epileptic brain. Additionally, we highlight the relevance of sleep interventions, often overlooked by physicians, to manage seizures, prevent epilepsy-related mortality, and improve quality of life.

Epilepsy, one of the most common neurological disorders worldwide, is characterized by recurrent seizures and subsequent brain damage. Despite strong evidence supporting a deleterious impact on seizure occurrence and outcome severity, stress is an overlooked component in people with epilepsy. With regard to stressor duration and timing, acute stress can be protective in epileptogenesis, while chronic stress often promotes seizure occurrence in epilepsy patients. Preclinical research suggests that chronic stress promotes neuroinflammation and leads to a depressive state. Depression is the most common psychiatric comorbidity in people with epilepsy, resulting in a poor quality of life. Here, we summarize studies investigating acute and chronic stress as a seizure trigger and an important factor that worsens epilepsy outcomes and psychiatric comorbidities. Mechanistic insight into the impact of stress on epilepsy may create a window of opportunity for future interventions targeting neuroinflammation-related disorders.

A substantial literature supports the notion that cancer is a metabolic disease. Mitochondria are sexually dimorphic, and progesterone (P4) plays a key regulatory role in mitochondrial functions. We investigated the effect of P4 on mitochondrial functions in three human glioblastoma multiforme (GBM) cell lines. In dose-response and time-response studies, GBM cells were exposed to different concentrations of P4 followed by mitochondrial stress-testing with a Seahorse analyzer. Data were analyzed for oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and spare respiratory capacity (SRC) to determine the effects of P4 exposure on mitochondrial respiration and rate of glycolysis. We also examined the effect of P4 on mitochondrial superoxide radical generation by confocal microscopy. As early as 1h post-P4 exposure, we found a substantial dose-dependent inhibitory effect of P4 on OCR, ECAR, and SRC in all GBM cell lines. P4 treatment altered the levels of basal respiration, maximum respiration, nonmitochondrial oxygen consumption, ATP production, and proton leak. P4 given at 80-μM concentration showed the maximum inhibitory effect compared to controls. Live imaging data showed an 11-22% increase in superoxide radical generation in all three GBM cell lines following 6h exposure to a high concentration of P4. Our data show that high-dose P4 exerts an inhibitory effect on both mitochondrial respiration and glycolysis in GBM cells. These effects would lead to decreased tumor size and rate of growth, representing a potential treatment to control the spread of GBM.

Vitamin D deficiency (D

NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1&beta, production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1&beta, production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone&rsquo, s (PROG&rsquo, s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.

La Moringa oleifera es altamente valorada a nivel mundial debido a sus propiedades. Una de las partes aprovechables del árbol son las semillas. En el presente trabajo se desarrolló la extracción de aceite mediante un extractor Soxhlet a partir de semillas de Moringa oleifera Lam. variedad Plain de origen cubano. El porcentaje de extracción se estableció como variable respuesta en el diseño de experimentos. Los factores temperatura de extracción y relación soluto-solvente influyeron de manera significativa en la variable respuesta, teniendo asociados valores de probabilidades menores que 0,05. El modelo matemático obtenido explicó 94,03% de la variabilidad en la variable respuesta. La mejor condición para la extracción de aceite se alcanzó operando a una relación solutosolvente 1:6 y a una temperatura de extracción de 65 °C.

Despite the fact that stress is associated with increased risk of stroke and worsened outcome, most preclinical studies have ignored this comorbid factor, especially in the context of testing neuroprotective treatments. Preclinical research suggests that stress primes microglia, resulting in an enhanced reactivity to a subsequent insult and potentially increasing vulnerability to stroke. Ischemia-induced activated microglia can be polarized into a harmful phenotype, M1, which produces pro-inflammatory cytokines, or a protective phenotype, M2, which releases anti-inflammatory cytokines and neurotrophic factors. Selective modulation of microglial polarization by inhibiting M1 or stimulating M2 may be a potential therapeutic strategy for treating cerebral ischemia. Our laboratory and others have shown progesterone to be neuroprotective against ischemic stroke in rodents, but it is not known whether it will be as effective under a comorbid condition of chronic stress. Here we evaluated the neuroprotective effect of progesterone on the inflammatory response in the hippocampus after exposure to stress followed by global ischemia. We focused on the effects of microglial M1/M2 polarization and pro- and anti-inflammatory mediators in stressed ischemic animals. Male Sprague-Dawley rats were exposed to 8 consecutive days of social defeat stress and then subjected to global ischemia or sham surgery. The rats received intraperitoneal injections of progesterone (8mg/kg) or vehicle at 2h post-ischemia followed by subcutaneous injections at 6h and once every 24h post-injury for 7days. The animals were killed at 7 and 14days post-ischemia, and brains were removed and processed to assess outcome measures using histological, immunohistochemical and molecular biology techniques. Pre-ischemic stress (1) exacerbated neuronal loss and neurodegeneration as well as microglial activation in the selectively vulnerable CA1 hippocampal region, (2) dysregulated microglial polarization, leading to upregulation of both M1 and M2 phenotype markers, (3) increased pro-inflammatory cytokine expression, and (4) reduced anti-inflammatory cytokine and neurotrophic factor expression in the ischemic hippocampus. Treatment with progesterone significantly attenuated stress-induced microglia priming by modulating polarized microglia and the inflammatory environment in the hippocampus, the area most vulnerable to ischemic injury. Our findings can be taken to suggest that progesterone holds potential as a candidate for clinical testing in ischemic stroke where high stress may be a contributing factor.

This article presents a work that we have done through the Self Study methodology and it is part of a project awarded by the OEI. We are two academics who participated in this research, we performed within the ambit of the Initial Formation of future kindergarten educators in private Catholic Universities of Chile, belonging to the Cruch (Council of Rectors of Chilean Universities). The aim of the study is to investigate our own practices, in order to visualize how to analize it affects the reflection processes of the students attending the practical courses. From the narration of our classes, the analysis of videos and the use of the Stiket Out applied to students, we managed to identify that to enhance a better capacity for reflection, feedback and accompaniment in the initial training must include affective aspects, attention to diversity, generation of questions and learning spaces that favour participation. We have become aware that these elements are relevant and we must incorporate them into our training practices, intentionally and systematically. El presente artículo presenta un trabajo que hemos realizado a través de la metodología Self Study y se enmarca en un proyecto adjudicado por la OEI. Somos dos académicas lasque participamos de esta investigación, nos desempeñamos dentro del ámbito de la Formación Inicial de futuras educadoras de párvulos en Universidades Católicas privadas de Chile, pertenecientes al CRUCH (Consejo de Rectores de Universidades chilenas). El estudio tiene como objetivo investigar sobrenuestras propias prácticas, con el fin de visualizar cómo éstas inciden en los procesos de reflexión de las alumnas que asisten a los cursos de práctica. A partir de la narración de nuestras clases, el análisis de videos y el uso de los Stiket Out aplicados a las estudiantes, logramos identificar que, para potenciar una mejor capacidad de reflexión,la retroalimentación y el acompañamiento en la formación inicial debe contemplar aspectos afectivos, atención a la diversidad, generación de preguntas y espacios de aprendizaje que favorezcan la participación. Hemos tomado conciencia de que estos elementos son relevantes y debemos incorporarlos en nuestras prácticas formadoras, de manera intencionada y sistemática. O presente artigo apresenta um trabalho realizado através da metodologia de autoestudo (self study) e faz parte de um projeto promovido pela OEI. Participamos nesta pesquisa duas professoras, trabalhamos no âmbito da Formação Inicial de futuras educadoras de crianças em fase pré-escolar em Universidades Católicas particulares de Chile, pertencentes ao CRUCH (Conselho de Reitores de Universidades Chilenas). O estudo tem como objetivo pesquisar sobre as nossas próprias práticas, visando visualizar como estas incidem nos processos de reflexão das alunas dos cursos de prática. A partir da narração das nossas aulas, da análise de vídeos e do uso dos bilhetes de saída (“ticket out”) realizados pelas estudantes, conseguimos identificar que, para potencializar uma melhor capacidade de reflexão, a retroalimentação e o acompanhamento na formação inicial, devem ser contemplados aspectos afetivos, atenção à diversidade, formulação de perguntas que induzam à reflexão e espaços de aprendizagem que favoreçam à participação. Reconhecemos que estes elementos são relevantes e devemos incorporá-los nas nossas práticas de formação, intencional e sistematicamente. O presente artigo apresenta um trabalho realizado através da metodologia de autoestudo (self study) e faz parte de um projeto promovido pela OEI. Participamos nesta pesquisa duas professoras, trabalhamos no âmbito da Formação Inicial de futuras educadoras de crianças em fase pré-escolar em Universidades Católicas particulares de Chile, pertencentes ao CRUCH (Conselho de Reitores de Universidades Chilenas). O estudo tem como objetivo pesquisar sobre as nossas próprias práticas, visando visualizar como estas incidem nos processos de reflexão das alunas dos cursos de prática. A partir da narração das nossas aulas, da análise de vídeos e do uso dos bilhetes de saída (“ticket out”) realizados pelas estudantes, conseguimos identificar que, para potencializar uma melhor capacidade de reflexão, a retroalimentação e o acompanhamento na formação inicial, devem ser contemplados aspectos afetivos, atenção à diversidade, formulação de perguntas que induzam à reflexão e espaços de aprendizagem que favoreçam à participação. Reconhecemos que estes elementos são relevantes e devemos incorporá-los nas nossas práticas de formação, intencional e sistematicamente.

The metabolic syndrome includes changes in blood glucose levels, arterial hypertension, triglycerides, dyslipidemia and central obesity. Countless reports have described the correlation between the metabolic syndrome and cognitive impairment. However, only a few reports have assessed cognitive impairment associated with the metabolic syndrome in animals of both sexes. For this purpose, Sprague-Dawley male and female rats were fed either with a hypercaloric diet as model of the metabolic syndrome or with a standard chow diet as controls. Subsequently, spatial learning and memory (Morris water maze) as well as short- and long-term memory (passive avoidance task) were evaluated. Body weight, blood pressure, triglycerides, and total cholesterol significantly increased (F(1, 36) = 94.89, p < .001) in rats fed with hypercaloric diet compared to control rats. Furthermore, cognitive impairment was observed in spatial learning and spatial memory on male rats but not on female rats fed with hypercaloric diet. In addition, a long-term memory impairment was observed in both groups fed with hypercaloric diet in comparison to their respective control group (F(1, 32) = 10.61, p = .0027). Immunohistochemistry results showed no changes in the number of positive cells for NeuN, GFAP and Ox-42. In males fed with a hypercaloric diet, a decrease in testosterone levels was observed, whereas estradiol levels decreased in females when compared with their respective control group (p < .0001). In this MetS animal model, metabolic and cognitive differences were observed in males and females, which demonstrates that sex hormones play a significant role in metabolic regulation and neuroprotection related to the CA1 region of the hippocampus.

Introduction: We investigated whether vitamin D (VDH) deficiency is associated with worsened outcomes after stroke with lipopolysaccharide (LPS)-induced inflammation as evaluated by measures of behavioral function, inflammation, endoplasmic reticulum (ER) stress, white matter integrity and peripheral immune response and whether combined progesterone (P) and VDH treatment would improve outcomes under these conditions. Methods: After 8 weeks on a VDH-deficient diet, adult, male Sprague-Dawley rats underwent transient ischemic stroke (tMCAO). Systemic inflammation was induced 24h post-stroke via 3 doses of LPS (50 μg/kg at 4h intervals). P (8 mg/kg; i.p.) and VDH (1 μg/kg; i.p.) were given 5 min before reperfusion followed by s.c. injections on days 1-7 post-stroke. Groups (n=6) were: Sham VDH-deficient; Sham VDH-sufficient; VDH-deficient tMCAO treated with vehicle; VDH-deficient tMCAO+LPS; VDH-deficient tMCAO+LPS treated with P; VDH-deficient tMCAO+LPS treated with VDH; VDH-deficient tMCAO+LPS treated with P and VDH. At day 7 post-stroke, rats were tested on behavioral parameters, measures of peripheral immune dysfunction, markers of neuronal inflammation (GFAP, Iba-1, IL-6), apoptosis (cleaved caspase-3, TUNEL), ER stress (PERK, eIF2α, CHOP) and white matter integrity (axonal and myelin injury markers SMI-32 and MBP, respectively) in brain. Data were analyzed using ANOVA and the Tukey-HSD post hoc test. Statistical significance was set at P Results: We found significant behavioral deficits in MCAO and MCAO+LPS animals compared to controls. P+VDH significantly improved behavioral outcomes and reduced neuronal inflammation, apoptosis, ER stress and white matter injury compared to the MCAO and MCAO+LPS groups. β cell numbers were significantly reduced in both the MCAO and MCAO+LPS compared to the two sham groups. Peripheral immune dysfunctions revealed by flow cytometric analyses of immune cells in blood, spleen and thymus were significantly restored by combinatorial treatment with P and VDH. P+VDH improved all outcomes significantly more than monotherapy. Conclusion: The current standard of care for stroke has limited benefit, while combinatorial treatment with P+VDH shows promise for future stroke therapeutics.

Introduction: Post-stroke systemic inflammation due to in-hospital infections increases patient morbidity and mortality. We examined the immunomodulatory effects of progesterone (P4) either alone or in combination with vitamin D hormone (VDH) on post-stroke systemic inflammation-induced peripheral immune dysfunction and functional deficits. Methods: Adult male Sprague-Dawley rats underwent transient middle cerebral artery occlusion/reperfusion (tMCAO) or sham surgery. Delayed systemic inflammation was induced by injections of lipopolysaccharide (LPS; 50 μg/kg; IP) at 24, 28 and 32 h post-occlusion. P4 (8 mg/kg; IP) and VDH (1 μg/kg; IP) were given 5 min prior to reperfusion followed by SC injections on days 1, 2 and 3 post-stroke. Power analysis specified a sample size of 6 rats/group to detect a 30% difference between treatment groups with a power of 80% at alpha 0.05. There were 6 groups (n=6/gp): 1) Sham + vehicle (SHAM); 2) tMCAO + vehicle (VEH); 3) tMCAO + vehicle + LPS (VEH + LPS); 4) tMCAO + LPS + P4 (P4); 5) tMCAO + LPS + VDH (VDH); 6) tMCAO + LPS + P4 + VDH (P4 + VDH). At day 4 post-stroke, rats were tested on spontaneous locomotor activity, grip strength and sensory neglect; peripheral immune dysfunctions were assessed by flow cytometric analysis of subsets of immune cells in blood, spleen and thymus. We measured markers of neuronal inflammation (GFAP, Iba-1, IL-6), apoptosis (cleaved caspase-3, TUNEL), and endoplasmic reticulum (ER) stress (PERK, eIF2α, CHOP) in brain. Data were analyzed using ANOVA with the Tukey-HSD post hoc test. Statistical significance was set at p Results: The worst stroke outcomes were seen in the VEH + LPS group. Peripheral immune dysfunctions revealed by flow cytometry were significantly ( p combination of P4 + VDH improved outcomes significantly ( p Conclusions: Our findings may have translational relevance because the current standard of care for stroke and post-stroke infections is largely ineffective and our P4+VDH combination therapy may hold promise for stroke therapeutics.

Introduction: Exposure to stress primes microglia and the NLRP3 inflammasome, resulting in an exaggerated inflammatory response to a secondary insult such as stroke. NLRP3-mediated inflammation can be regulated by the autophagic removal of inflammasome activators, components, or cytokines. We hypothesized that progesterone (PROG), a neuroprotective neurosteroid, would enhance autophagy in a rodent model of cerebral ischemia combined with stress, and in an in vitro inflammasome assay. Methods: Adult male rats were exposed to social defeat stress for 8 days and then subjected to global ischemia. PROG (8 mg/Kg) was administered 2 and 6 h after occlusion, then daily for 7 days. At 7 and 14 days post-ischemia, hippocampi were dissected and autophagic flux was evaluated by western blot using LC3-II and p62 as indicators. To activate the NLRP3 inflammasome in vitro , cultured primary mouse microglia were primed with 1 ug/mL LPS for 2 h prior to stimulation with 5 mM ATP (a classical inflammasome activator) for 1h, and concomitantly treated with PROG. IL-1b production was measured by ELISA, while LC3 puncta were detected by immunofluorescence. Results: After social defeat, no changes in LC3-II levels were observed, but p62 levels slightly decreased. Global ischemia impaired autophagy as evidenced by decreased LC3 and p62 levels compared to non-ischemic controls. Stressed ischemic animals showed lower LC3 and p62 levels than ischemic animals. Notably, PROG enhanced autophagy, LC3 levels were increased and p62 reduced in both stressed and non-stressed ischemic animals. LPS and ATP synergized in compromising microglial autophagy and worsened IL-1b production. LPS-primed microglia treated with PROG showed enhanced autophagy, a larger number of LC3 puncta, and reduced IL-1b production compared to untreated controls. PROG’s beneficial effects were blocked by 3-methyladenine, an autophagy inhibitor. We conclude that PROG reduced the neurotoxic potential of primed microglia via autophagy, and attenuated NLRP3 inflammasome overactivation. These findings provide new insight into the mechanisms underlying PROG’s protective effects on the excessive inflammatory response, particularly important for improving outcome in stroke patients with comorbid stress.

Post-stroke systemic inflammation, due to the injury itself and exacerbated by in-hospital infections, can increase morbidity and mortality in stroke patients. In this study, we examined the immunomodulatory effects of progesterone (P4) alone and in combination with vitamin D hormone (VDH) on acute phase post-stroke peripheral immune dysfunction and functional/behavioral deficits. Adult rats underwent transient middle cerebral artery occlusion/reperfusion (tMCAO) and delayed systemic inflammation was induced by injections of lipopolysaccharide (LPS) beginning 24 h post-stroke. Animals were tested for behavioral outcomes and immune function at day 4 post-stroke. We also measured infarction volume and markers of neuronal inflammation (GFAP, IL-6) and apoptosis (cleaved caspase-3) in brain post-stroke. We observed the worst stroke outcomes in the stroke + systemic inflammation group compared to the stroke-alone group. Flow cytometric analysis of different subsets of immune cells in blood, spleen and thymus revealed peripheral immune dysfunction which was restored by both P4 and VDH monotherapy. P4 monotherapy reduced infarction volume, behavioral/functional deficits, peripheral immune dysfunction, neuronal inflammation, and apoptosis induced by post-stroke systemic inflammation. Combination treatment with P4+VDH improved outcomes better than monotherapy. Our findings can be taken to suggest that the current standard of care for stroke and post-stroke infection can be substantially improved by P4 and VDH combination therapy.

Solithromycin is a novel fluoroketolide antibiotic which was under investigation for the treatment of community-acquired bacterial pneumonia (CABP). A phase 1 study was performed to characterize the pharmacokinetics (PK) and safety of solithromycin in children. Eighty-four subjects (median age, 6 years [age range, 4 days to 17 years]) were administered intravenous (i.v.) or oral (capsules or suspension) solithromycin (i.v., 6 to 8 mg/kg of body weight; capsules/suspension, 14 to 16 mg/kg on days 1 and 7 to 15 mg/kg on days 2 to 5). PK samples were collected after the first and multidose administration. Data from 83 subjects (662 samples) were combined with previously collected adolescent PK data (n = 13; median age, 16 years [age range, 12 to 17 years]) following capsule administration to perform a population PK analysis. A 2-compartment PK model characterized the data well, and postmenstrual age was the only significant covariate after accounting for body size differences. Dosing simulations suggested that 8 mg/kg i.v. daily and oral dosing of 20 mg/kg on day 1 (800-mg adult maximum) followed by 10 mg/kg on days 2 to 5 (400-mg adult maximum) would achieve a pediatric solithromycin exposure consistent with the exposures observed in adults. Seventy-six treatment-emergent adverse events (TEAEs) were reported in 40 subjects. Diarrhea (6 subjects) and infusion site pain or phlebitis (3 subjects) were the most frequently reported adverse events related to treatment. Two subjects experienced TEAEs of increased hepatic enzymes that were deemed not to be related to the study treatment. (The phase 1 pediatric studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01966055 and NCT02268279.).

In adult mice with unilateral optic nerve crush injury (ONC), we studied visual response plasticity in the visual cortex following stimulation with sinusoidal grating. We examined visually evoked potentials (VEP) in the primary visual cortex ipsilateral and contralateral to the crushed nerve. We found that unilateral ONC induces enhancement of visual response on the side ipsilateral to the injury that is evoked by visual stimulation to the intact eye. This enhancement was associated with supranormal spatial frequency thresholds in the intact eye when tested using optomotor response. To probe whether injury-induced disinhibition caused the potentiation, we treated animals with the neurosteroid allopregnanolone, a potent agonist of the GABA(A) receptor, one hour after crush and on post-injury days 3, 8, 13, and 18. Allopregnanolone diminished enhancement of the VEP and this effect was associated with the upregulated synthesis of the δ-subunit of the GABA(A) receptor. Our study shows a new aspect of experience-dependent plasticity following unilateral ONC. This hyper-activity in the ipsilateral visual cortex is prevented by upregulation of GABA inhibition with allopregnanolone. Our findings suggest the therapeutic potential of allopregnanolone for modulation of plasticity in certain eye and brain disorders and a possible role for disinhibition in ipsilateral hyper-activity following unilateral ONC.

We examined the effect of progesterone treatments on glycolytic metabolism and senescence as possible mechanisms in controlling the growth of glioblastoma multiforme (GBM). In an orthotopic mouse model, after tumor establishment, athymic nude mice received treatment with progesterone or vehicle for 40 days. Compared to controls, high-dose progesterone administration produced a significant reduction in tumor size (~47%) and an increased survival rate (~43%) without any demonstrable toxicity to peripheral organs (liver, kidney). This was accompanied by a significant improvement in spontaneous locomotor activity and reduced anxiety-like behavior. In a follow-up in vitro study of U87MG-luc, U87dEGFR and U118MG tumor cells, we observed that high-dose progesterone inhibited expression of Glut1, which facilitated glucose transport into the cytoplasm; glyceraldehyde 3-phosphate dehydrogenase (GAPDH; a glycolysis enzyme); ATP levels; and cytoplasmic FoxO1 and Phospho-FoxO1, both of which control glycolytic metabolism through upstream PI3K/Akt/mTOR signaling in GBM. In addition, progesterone administration attenuated EGFR/PI3K/Akt/mTOR signaling, which is highly activated in grade IV GBM. High-dose progesterone also induced senescence in GBM as evidenced by changes in cell morphology and β-galactocidase accumulation. In conclusion, progesterone inhibits the modulators of glycolytic metabolism and induces premature senescence in GBM cells and this can help to reduce/slow tumor progression.

Resumen Objetivo: evaluar efecto genotóxico y mutagénico en linfocitos humanos expuestos a nanotubos de carbono (NTC) prístinos y dopados con Nitrógeno. Métodos: linfocitos humanos fueron expuestos a NTC dopados y prístinos (0.08, 0.09, 0.1mg/mL), se evaluó alteraciones cromosómicas e intercambio de cromátidas hermanas (ICH). Resultados: se presentaron rupturas cromatídicas y cromosómicas en linfocitos expuestos a 0.1mg/mL y 0.08mg/mL de NTC prístinos. NTC dopados, indujeron cromosomas dicéntricos y anillos cromosómicos. Se presentó diferencia significativa en el porcentaje de ICH de células tratadas con NTC dopados versus control negativo y NTC prístinos (p

Introduction: Cerebral ischemia, a consequence of cardiac arrest and stroke, is a leading cause of death and disability in the U.S. To improve translational studies, STAIR recommends augmenting animal models with comorbidities that “better reproduce the pathophysiological state” of stroke patients. Therefore, we incorporated social stress into our ischemia model (Espinosa-Garcia et al., 2017). Prior exposure to social stress upregulates the inflammatory status of microglia. They become primed—sensitized to activation by subsequent ischemia—worsening outcome. Such potentiated activation may result from the release of danger signals in the brain, such as HMGB-1, which binds to TLR4 receptors and activates inflammasomes. The NLRP3 inflammasome consists of a sensor molecule, NLRP3, the ASC adaptor, and caspase-1, whose activation leads to pro-inflammatory IL-1β production. We hypothesized that progesterone (P4) administration will reduce NLRP3 inflammasome activation, one of the molecular mechanisms underlying P4’s neuroprotective effects against ischemia combined with stress. Methods: Adult male rats were exposed to social defeat stress for 8 days and then subjected to global ischemia. P4 was administered 2 and 6h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia and their hippocampi dissected for western blots. The hippocampus is highly sensitive to stress and selectively vulnerable to global ischemia. Results: Consistent with previous reports, stress primed microglia and increased ( p p p Conclusion: Our data show that P4 can modulate stress-induced microglial priming to subsequent ischemic injury by counteracting NLRP3 inflammasome activation in the hippocampus. P4 may thus prove a promising neuroprotective agent to reduce inflammation associated with poor outcome in stroke patients with comorbid stress.

Dear Editor,In “Prehospital Intubation is Associated with Favorable Outcomes and Lower Mortality in ProTECT III,” Denninghoff et al. (1) evaluated the relationship between prehospital intubation, f...

Carbon nanotubes (CNTs) have gained popularity due to their many characteristics which make them the promising material for biomedical applications. A major challenge when working with CNTs is the difficulty to distribute them evenly throughout liquids. This research is a comparative analysis of the dispersion of multi wall CNTs (MWCNTs) in different liquid media (distilled water, ultrapure water of type I [Milli-Q], ethanol, dimethyl sulfoxide [DMSO] and cell culture medium [RPMI-1640]) by using two different sonication techniques (probe-type sonication and ultrasonic bath sonication) as well as determining the effect of sterilization in the presence and absence of fluid before dispersion. The results indicate that the best method to achieve a CNTs dispersion is to use a probe-type sonicator as well as to sterilize the CNTs samples in the presence of fluid. Los nanotubos de carbono (CNTs) han atraído un enorme interés debido a sus muchas características que los convierten en un material prometedor para aplicaciones biomedicas. Un desafío importante cuando se trabaja con CNTs es la dificultad de dispersarlos homogéneamente en un fluido. Esta investigación es un análisis comparativo de la dispersión de nanotubos de carbono de pared múltiple (MWCNTs) en diferentes fluidos (agua destilada, agua ultrapura de tipo I [Milli-Q], etanol, dimetilsulfóxido [DMSO] y medio de cultivo celular [RPMI-1640]). Utilizando dos diferentes técnicas de sonicación (sonicación con lanza ultrasónica y sonicación ultrasónica de baño), así como la determinación del efecto de la esterilización en presencia y ausencia de fluido antes de la dispersión. Los resultados indican que el mejor método de dispersión de los CNTs es usando un sonicador tipo lanza y esterilizarlos en presencia de fluido.