The metabolic and cardiovascular clinical manifestations in patients with Cushing's syndrome (CS) are generally well known. However, recent studies have broadened the perspective of the effects of ...hypercortisolism, showing that both endogenous and exogenous glucocorticoid excess alter brain functioning on several time scales. Consequently, cognitive deficits and neuropsychological symptoms are highly prevalent during both active CS and CS in remission, as well as during glucocorticoid treatment. In this review, we discuss the effects of endogenous hypercortisolism and exogenously induced glucocorticoid excess on the brain, as well as the prevalence of cognitive and neuropsychological deficits and their course after biochemical remission. Furthermore, we propose possible mechanisms that may underly neuronal changes, based on experimental models and in vitro studies. Finally, we offer recommendations for future studies.
Preventing neuropsychiatric adverse effects of dexamethasone with co‐administration of cortisol. Dexamethasone suppresses the HPA‐axis and thereby the adrenocortical cortisol production, leaving cortisol‐preferring MRs unoccupied. Re‐activating the MR using cortisol might reduce or prevent neuropsychiatric adverse effects of dexamethasone treatment via activation of brain MR. ACTH, adrenocorticotropic hormone; CRH, corticotrophin‐releasing hormone; GR, glucocorticoid receptor; HPA, hypothalamus‐pituitary‐adrenal; MR, mineralocorticoid receptor
ObjectiveTo test the hypothesis that systemic and inhaled glucocorticoid use is associated with changes in grey matter volume (GMV) and white matter microstructure.DesignCross-sectional ...study.SettingUK Biobank, a prospective population-based cohort study of adults recruited in the UK between 2006 and 2010.ParticipantsAfter exclusion based on neurological, psychiatric or endocrinological history, and use of psychotropic medication, 222 systemic glucocorticoid users, 557 inhaled glucocorticoid users and 24 106 controls with available T1 and diffusion MRI data were included.Main outcome measuresPrimary outcomes were differences in 22 volumetric and 14 diffusion imaging parameters between glucocorticoid users and controls, determined using linear regression analyses adjusted for potential confounders. Secondary outcomes included cognitive functioning (six tests) and emotional symptoms (four questions).ResultsBoth systemic and inhaled glucocorticoid use were associated with reduced white matter integrity (lower fractional anisotropy (FA) and higher mean diffusivity (MD)) compared with controls, with larger effect sizes in systemic users (FA: adjusted mean difference (AMD)=−3.7e-3, 95% CI=−6.4e-3 to 1.0e-3; MD: AMD=7.2e-6, 95% CI=3.2e-6 to 1.1e-5) than inhaled users (FA: AMD=−2.3e-3, 95% CI=−4.0e-3 to −5.7e-4; MD: AMD=2.7e-6, 95% CI=1.7e-7 to 5.2e-6). Systemic use was also associated with larger caudate GMV (AMD=178.7 mm3, 95% CI=82.2 to 275.0), while inhaled users had smaller amygdala GMV (AMD=−23.9 mm3, 95% CI=−41.5 to −6.2) than controls. As for secondary outcomes, systemic users performed worse on the symbol digit substitution task (AMD=−0.17 SD, 95% CI=−0.34 to −0.01), and reported more depressive symptoms (OR=1.76, 95% CI=1.25 to 2.43), disinterest (OR=1.84, 95% CI=1.29 to 2.56), tenseness/restlessness (OR=1.78, 95% CI=1.29 to 2.41), and tiredness/lethargy (OR=1.90, 95% CI=1.45 to 2.50) compared with controls. Inhaled users only reported more tiredness/lethargy (OR=1.35, 95% CI=1.14 to 1.60).ConclusionsBoth systemic and inhaled glucocorticoid use are associated with decreased white matter integrity and limited changes in GMV. This association may contribute to the neuropsychiatric side effects of glucocorticoid medication, especially with chronic use.
Glucocorticoids are powerful modulators of brain function. They act via mineralocorticoid and glucocorticoid receptors (MR and GR). These are best understood as transcription factors. Although many ...glucocorticoid effects depend on the modulation of gene transcription, it is a major challenge to link gene expression to function given the large‐scale, apparently pleiotropic genomic responses. The extensive sets of MR and GR target genes are highly specific per cell type, and the brain contains many different (neuronal and non‐neuronal) cell types. Next to the set “trait” of cellular context, the “state” of other active signaling pathways will affect MR and GR transcriptional activity. Here, we discuss receptor specificity and contextual factors that determine the transcriptional outcome of MR/GR signaling, experimental possibilities offered by single‐cell transcriptomics approaches, and reflect on how to make sense of lists of target genes in relation to understanding the functional effects of steroid receptor activation.
Glucocorticoid hormones affect the brain in the context of stress, medical treatment and disease. They have massive effects on gene expression in many different neuronal and non‐neuronal cell types in the brain. We discuss challenges and possible solutions in identifying those target genes that are responsible for particular adaptive, pathogenic of therapeutic effects.
Chronic exposure to high circulating levels of glucocorticoids has detrimental effects on health, including metabolic abnormalities, as exemplified in Cushing's syndrome (CS). Magnetic resonance ...imaging (MRI) studies have found volumetric changes in gray and white matter of the brain in CS patients during the course of active disease, but also in remission. In order to explore this further, we performed MRI-based brain volumetric analyses in the AdKO mouse model for CS, which presents its key traits. AdKO mice had reduced relative volumes in several brain regions, including the corpus callosum and cortical areas. The medial amygdala, bed nucleus of the stria terminalis, and hypothalamus were increased in relative volume. Furthermore, we found a lower immunoreactivity of myelin basic protein (MBP, an oligodendrocyte marker) in several brain regions but a paradoxically increased MBP signal in the male cingulate cortex. We also observed a decrease in the expression of glial fibrillary acidic protein (GFAP, a marker for reactive astrocytes) and ionized calcium-binding adapter molecule 1 (IBA1, a marker for activated microglia) in the cingulate regions of the anterior corpus callosum and the hippocampus. We conclude that long-term hypercorticosteronemia induced brain region-specific changes that might include aberrant myelination and a degree of white matter damage, as both repair (GFAP) and immune (IBA1) responses are decreased. These findings suggest a cause for the changes observed in the brains of human patients and serve as a background for further exploration of their subcellular and molecular mechanisms.
Excess glucocorticoid exposure affects emotional and cognitive brain functions. The extreme form, Cushing's syndrome, is adequately modelled in the AdKO2.0 mouse, consequential to adrenocortical ...hypertrophy and hypercorticosteronemia. We previously reported that the AdKO2.0 mouse brain undergoes volumetric changes that resemble closely those of Cushing's syndrome human patients, as well as changes in expression of glial related marker proteins. In the present work, the expression of genes related to glial and neuronal cell populations and functions was assessed in regions of the anterior brain, hippocampus, amygdala and hypothalamus. Glucocorticoid target genes were consistently regulated, including CRH mRNA suppression in the hypothalamus and induction in amygdala and hippocampus, even if glucocorticoid receptor protein was downregulated. Expression of glial genes was also affected in the AdKO2.0 mouse brain, indicating a different activation status in glial cells. Generic markers for neuronal cell populations, and cellular integrity were only slightly affected. Our findings highlight the vulnerability of glial cell populations to chronic high levels of circulating glucocorticoids.
Glucocorticoids are key executors of the physiological response to stress. Previous studies in mice showed that the androgen receptor (AR) influenced the transcriptional outcome of glucocorticoid ...treatment in white and brown adipocytes and in the liver. In the brain, we observed that chronic hypercorticism induced changes in gene expression that tended to be more pronounced in male mice. In the present study, we investigated if glucocorticoid signaling in the brain could be modulated by androgen. After chronic treatment with corticosterone, dihydrotestosterone, a combination of both, and corticosterone in combination with the AR antagonist enzalutamide, we compared the expression of glucocorticoid receptor (NR3C1, also abbreviated GR) target genes in brain regions where AR and GR are co-expressed, namely: prefrontal cortex, hypothalamus, hippocampus, ventral tegmental area and substantia nigra. We observed that androgen affected glucocorticoid signaling only in the prefrontal cortex and the substantia nigra. Dihydrotestosterone and corticosterone independently and inversely regulated expression of
and
in prefrontal cortex. AR antagonism with enzalutamide attenuated corticosterone-induced expression of
in the prefrontal cortex and of
and
in the substantia nigra. Additionally, in the substantia nigra, AR antagonism increased expression of
and
, two genes coding for key components of the dopaminergic system. Our data indicate that androgen influence over glucocorticoid stimulation in the brain is not a dominant phenomenon in the context of high corticosterone levels, but can occur in the prefrontal cortex and substantia nigra.
With the creation of the European Higher Education Area (EHEA) universities have integrated their tutorial projects into their teaching and learning processes. The evaluation of the impact of these ...projects shows the need for their continued improvement so that they can become even more effective. After analyzing annually the results of tutoring activities in each of the six years since San Jorge University’s tutoring project was implemented, a descriptive research has been carried out which analyses the appraisal of various aspects of university tutoring activities from the point of view of San Jorge University’s undergraduate student. These aspects include the consideration of the university tutoring project as part of the learning process, the identification of needs that this project should cover, the most valued factors in a tutor and a number of proposals for improvement based on the experiences of other national and international universities. This paper presents a general descriptive analysis of the mentioned variables across the University. Results show that students consider professional development issues to be more important than both academic and personal development issues, close personal contact as the tutor’s most widely valued aspect and personal interview as the most effective form of communicating with tutors. In addition, most valued proposals for improvement have been the incorporation of final year students as tutors (peer-tutoring) and the possibility of maintaining the same tutor throughout the whole student’s stay at University.
Con la implantación del Espacio Europeo de Educación Superior, las universidades han integrado los planes de acción tutorial dentro del proceso de enseñanza aprendizaje. La evaluación de los ...resultados de la implantación de estos planes pondría de manifiesto la necesidad de mejorarlos de forma continua para que sean cada vez más efectivos.
Después de analizar anualmente los resultados de la acción tutorial en los seis años que lleva implantado el Plan de acción tutorial en la Universidad San Jorge, se lleva a cabo una investigación tipo descriptivo en la que se analizan las valoraciones de los estudiantes de grado de la Universidad San Jorge sobre varios aspectos de la acción tutorial universitaria: su consideración como parte del proceso de aprendizaje, las necesidades que debe cubrir, los factores más valorados en el tutor y una serie de propuestas de mejora basadas en las experiencias de otras universidades nacionales e internacionales.
Se presenta un análisis descriptivo de las variables indicadas a nivel general de la universidad. Entre los resultados obtenidos se observa que los estudiantes consideran más importantes cubrir las necesidades de desarrollo profesional que las de desarrollo académico y personal, el trato humano es el aspecto más valorado del tutor y prefieren la entrevista personal como medio de comunicación con su tutor. Las propuestas de mejora más valoradas han sido la incorporación de estudiantes de cursos superiores como mentores (tutoría entre iguales) y mantener el mismo tutor a lo largo de toda la carrera.
Con la implantación del Espacio Europeo de Educación Superior, las universidades han integrado los planes de acción tutorial dentro del proceso de enseñanza aprendizaje. La evaluación de los ...resultados de la implantación de estos planes pondría de manifiesto la necesidad de mejorarlos de forma continua para que sean cada vez más efectivos.
Después de analizar anualmente los resultados de la acción tutorial en los seis años que lleva implantado el Plan de acción tutorial en la Universidad San Jorge, se lleva a cabo una investigación tipo descriptivo en la que se analizan las valoraciones de los estudiantes de grado de la Universidad San Jorge sobre varios aspectos de la acción tutorial universitaria: su consideración como parte del proceso de aprendizaje, las necesidades que debe cubrir, los factores más valorados en el tutor y una serie de propuestas de mejora basadas en las experiencias de otras universidades nacionales e internacionales.
Se presenta un análisis descriptivo de las variables indicadas a nivel general de la universidad. Entre los resultados obtenidos se observa que los estudiantes consideran más importantes cubrir las necesidades de desarrollo profesional que las de desarrollo académico y personal, el trato humano es el aspecto más valorado del tutor y prefieren la entrevista personal como medio de comunicación con su tutor. Las propuestas de mejora más valoradas han sido la incorporación de estudiantes de cursos superiores como mentores (tutoría entre iguales) y mantener el mismo tutor a lo largo de toda la carrera.ABSTRACT
University students and the quality of the tutorial project. Evaluation and improvements.
With the creation of the European Higher Education Area (EHEA) universities have integrated their tutorial projects into their teaching and learning processes. The evaluation of the impact of these projects shows the need for their continued improvement so that they can become even more effective.
After analyzing annually the results of tutoring activities in each of the six years since San Jorge University's tutoring project was implemented, a descriptive research has been carried out which analyses the appraisal of various aspects of university tutoring activities from the point of view of San Jorge University's undergraduate student. These aspects include the consideration of the university tutoring project as part of the learning process, the identification of needs that this project should cover, the most valued factors in a tutor and a number of proposals for improvement based on the experiences of other national and international universities.
This paper presents a general descriptive analysis of the mentioned variables across the University. Results show that students consider professional development issues to be more important than both academic and personal development issues, close personal contact as the tutor's most widely valued aspect and personal interview as the most effective form of communicating with tutors. In addition, most valued proposals for improvement have been the incorporation of final year students as tutors (peer-tutoring) and the possibility of maintaining the same tutor throughout the whole student's stay at University.
Background
The question of an optimal strategy and outcomes in COVID-19 tracheostomy has not been answered yet. The critical focus in our case study is to evaluate the outcomes of tracheostomy on ...intubated COVID-19 patients.
Methods
A multicentric prospective observational study of 1890 COVID-19 patients undergoing tracheostomy across 120 hospitals was conducted over 7 weeks in Spain (March 28 to May 15, 2020). Data were collected with an innovative approach: instant messaging via WhatsApp. Outcome measurements: complications, achieved weaning and decannulation and survival.
Results
We performed 1,461 surgical (81.3%) and 429 percutaneous tracheostomies. Median timing of tracheostomy was 12 days (4–42 days) since orotracheal intubation. A close follow-up of 1616/1890 (85.5%) patients at the cut-off time of 1-month follow-up showed that in 842 (52.1%) patients, weaning was achieved, while 391 (24.2%) were still under mechanical ventilation and 383 (23.7%) patients had died from COVID-19. Decannulation among those in whom weaning was successful (
n
= 842) was achieved in 683 (81%) patients.
Conclusion
To the best of our knowledge, this is the largest cohort of COVID-19 patients undergoing tracheostomy. The critical focus is the unprecedented amount of tracheostomies: 1890 in 7 weeks. Weaning could be achieved in over half of the patients with follow-up. Almost one out of four tracheotomized patients died from COVID-19.
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