The glutamatergic system in Alzheimer's disease: a systematic review with meta-analysis.

Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer's disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta-analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain. We searched PubMed and Web of Science (database origin-October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D-serine, metabotropic and ionotropic glutamate receptors in the AD human brain (PROSPERO #CDRD42022299518). The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain (cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I2 statistics. The search retrieved 6 936 articles, 63 meeting the inclusion criteria (N = 709CN/786AD; mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = -0.82; I2 = 74.54%; P < 0.001) and aspartate levels (SMD = -0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = -0.75; I2 = 83.04%; P < 0.001. We also found reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-GluA2/3 levels (SMD = -0.63; I2 = 95.55%; P = 0.046), hypofunctional N-methyl-D-aspartate receptor (NMDAR) (SMD = -0.60; I2 = 91.47%; P < 0.001) and selective reduction of NMDAR-GluN2B subunit levels (SMD = -1.07; I2 = 41.81%; P < 0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR-GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR-GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered. Our findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate-mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.

Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies.

INTRODUCTION: In Alzheimer's disease clinical research, glial fibrillary acidic protein (GFAP) released/leaked into the cerebrospinal fluid and blood is widely measured and perceived as a biomarker of reactive astrogliosis. However, it was demonstrated that GFAP levels differ in individuals presenting with amyloid-ß (Aß) or tau pathologies. The molecular underpinnings behind this specificity are little explored. Here we investigated biomarker and transcriptomic associations of hippocampal GFAP-positive astrocytes with Aß and tau pathologies in humans and mouse models. METHODS: We studied 90 individuals with plasma GFAP, Aß- and Tau-PET to investigate the association between biomarkers. Then, transcriptomic analysis in hippocampal GFAP-positive astrocytes isolated from mouse models presenting Aß (PS2APP) or tau (P301S) pathologies was conducted to explore differentially expressed genes (DEGs), Gene Ontology terms, and protein-protein interaction networks associated with each phenotype. RESULTS: In humans, we found that plasma GFAP associates with Aß but not tau pathology. Unveiling the unique nature of hippocampal GFAP-positive astrocytic responses to Aß or tau pathologies, mouse transcriptomics showed scarce overlap of DEGs between the Aß. and tau mouse models. While Aß GFAP-positive astrocytes were overrepresented with DEGs associated with proteostasis and exocytosis-related processes, tau hippocampal GFAP-positive astrocytes presented greater abnormalities in functions related to DNA/RNA processing and cytoskeleton dynamics. CONCLUSION: Our results offer insights into Aß- and tau-driven specific signatures in hippocampal GFAP-positive astrocytes. Characterizing how different underlying pathologies distinctly influence astrocyte responses is critical for the biological interpretation of astrocyte biomarkers and suggests the need to develop context-specific astrocyte targets to study AD. FUNDING: This study was supported by Instituto Serrapilheira, Alzheimer's Association, CAPES, CNPq and FAPERGS.

Astrocyte biomarker signatures of amyloid-ß and tau pathologies in Alzheimer's disease.

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-ß (Aß) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aß ([18F]AZD4694) and tau ([18F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aß-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aß-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aß and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aß and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.

p57Kip2 imposes the reserve stem cell state of gastric chief cells.

Adult stem cells constantly react to local changes to ensure tissue homeostasis. In the main body of the stomach, chief cells produce digestive enzymes; however, upon injury, they undergo rapid proliferation for prompt tissue regeneration. Here, we identified p57Kip2 (p57) as a molecular switch for the reserve stem cell state of chief cells in mice. During homeostasis, p57 is constantly expressed in chief cells but rapidly diminishes after injury, followed by robust proliferation. Both single-cell RNA sequencing and dox-induced lineage tracing confirmed the sequential loss of p57 and activation of proliferation within the chief cell lineage. In corpus organoids, p57 overexpression induced a long-term reserve stem cell state, accompanied by altered niche requirements and a mature chief cell/secretory phenotype. Following the constitutive expression of p57 in vivo, chief cells showed an impaired injury response. Thus, p57 is a gatekeeper that imposes the reserve stem cell state of chief cells in homeostasis.

Clozapine induces astrocyte-dependent FDG-PET hypometabolism.

PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.

Antidepressant-Like Effects of Chronic Guanosine in the Olfactory Bulbectomy Mouse Model.

Major depressive disorder (MDD) leads to pervasive changes in the health of afflicted patients. Despite advances in the understanding of MDD and its treatment, profound innovation is needed to develop fast-onset antidepressants with higher effectiveness. When acutely administered, the endogenous nucleoside guanosine (GUO) shows fast-onset antidepressant-like effects in several mouse models, including the olfactory bulbectomy (OBX) rodent model. OBX is advocated to possess translational value and be suitable to assess the time course of depressive-like behavior in rodents. This study aimed at investigating the long-term behavioral and neurochemical effects of GUO in a mouse model of depression induced by bilateral bulbectomy (OBX). Mice were submitted to OBX and, after 14 days of recovery, received daily (ip) administration of 7.5 mg/kg GUO or 40 mg/kg imipramine (IMI) for 45 days. GUO and IMI reversed the OBX-induced hyperlocomotion and recognition memory impairment, hippocampal BDNF increase, and redox imbalance (ROS, NO, and GSH levels). GUO also mitigated the OBX-induced hippocampal neuroinflammation (IL-1, IL-6, TNF-α, INF-γ, and IL-10). Brain microPET imaging ([18F]FDG) shows that GUO also prevented the OBX-induced increase in hippocampal FDG metabolism. These results provide additional evidence for GUO antidepressant-like effects, associated with beneficial neurochemical outcomes relevant to counteract depression.

Genetic engineering in organoids.

Three-dimensional organoids have been widely used for developmental and disease modeling. Organoids are derived from both adult and pluripotent stem cells. Various types are available for mimicking almost all major organs and tissues in the mouse and human. While culture protocols for stepwise differentiation and long-term expansion are well established, methods for genetic manipulation in organoids still need further standardization. In this review, we summarized different methods for organoid genetics and provide the pros and cons of each method for designing an optimal strategy.

Vinte anos de experiência de mentoria na Faculdade de Medicina da UFMG: desafios enfrentados e soluções propostas / Twenty years of mentoring at the UFMG Medical School: challenges faced and proposed solutions

Resumo: Introdução: A mentoria na Faculdade de Medicina da Universidade Federal de Minas Gerais se iniciou em 2001, em resposta a dificuldades emocionais dos estudantes, mas foi precedida por um projeto experimental, fundamentado no modelo de ajuda, em 1983. Relato de experiência e discussão: Desde o seu início, muitos foram os desafios enfrentados, desde sua valorização e o entendimento de sua finalidade até a dificuldade de participação e manutenção dos mentores, bem como a ocorrência de uma mudança curricular nesse período. Para responder a esses desafios, algumas soluções foram propostas, como a educação continuada e a supervisão para os mentores, a criação da comentoria e da monitoria com o mentor júnior, e a busca de mentores voluntários. Novos desafios surgem a cada dia, mas a mentoria completou 20 anos de funcionamento no formato de disciplina obrigatória. Convive atualmente com dificuldades que a fragilizam e ameaçam, principalmente o fato de, embora institucional, ser dependente do esforço pessoal de um grupo de profissionais que nela acreditam. Conclusão: A difusão do conceito de mentoring e de sua importância na formação médica, a valorização de professores que se interessam pela atividade de mentoria, com reconhecimento de seu trabalho pela instituição, e a formação continuada de mentores foram e continuam sendo medidas necessárias para o fortalecimento da mentoria.

Abstract: Introduction: Mentoring at the Federal University of Minas Gerais Medical School started in 2001 in response to emotional difficulties reported by students, but was preceded by an experimental project based on the aid model in 1983. Experience report and discussion: Many challenges have been faced from the outset, from appreciating and understanding the purpose of the program, to ensuring the participation of and maintaining mentors, in addition to a curricular change that occurred in this period. In response to these challenges, some solutions have been proposed, such as continuing education and supervision for mentors, the creation of co-mentoring and undergraduate course monitoring, with the junior mentor and the search for volunteer mentors. New challenges arise every day, but the mentoring program is now twenty years' old as a compulsory subject of the medicine course. Mentoring currently has difficulties that weaken and threaten it, especially its dependence on the personal effort of a group of professionals who believe in it. Conclusion: The diffusion of the concept of mentoring and its importance in medical training; the appreciation of teachers who are interested in the mentoring activity, with recognition of their work by the institution, and the continued training of mentors have been and continue to be necessary measures to strengthen mentoring.

Análises das Demandas e Cenários de Apoio para Sobreviventes de Câncer: Revisão Integrativa / Analysis of the Demands and Scenarios of Support for Cancer Survivors: Integrative Review / Análisis de las Demandas y Escenarios de Apoyo para Sobrevivientes de Cáncer: Revisión Integrador

Introdução: A sobrevivência do câncer é um processo que começa no diagnóstico e continua por toda a vida, trazendo uma série de desafios adicionais à saúde. Objetivo: Analisar as demandas e o modelo de atendimento para o apoio ao sobrevivente de câncer. Método: Revisão integrativa de literatura sobre demandas e cenários de apoio para sobreviventes de câncer, nas bases de dados LILACS, MEDLINE, IBECS, SciELO e Biblioteca Cochrane, que buscou artigos publicados entre janeiro de 2015 a março de 2020. Resultados: Foram encontrados 90 artigos, sendo 20 compatíveis com o objetivo do estudo. A estrutura necessária para apoiar o sobrevivente de câncer é múltipla e dela participam: hospitais, centros oncológicos e espaços na comunidade. Houve unanimidade em relação a intervenções clínicas e educativas solicitadas pelos pacientes. Estudos apontam atuação multidisciplinar, com presença de sintomas nos domínios físico, psicológico e socioecológico. A atuação do enfermeiro foi citada por 19 estudos e envolveu desde o cuidado clínico até a coordenação e atuação quanto ao aconselhamento e orientação para a mudança de comportamentos prejudiciais à saúde. Verificaram-se oito estudos que citaram a American Society of Clinical Oncology como entidade norteadora das intervenções. Conclusão: As demandas dos sobreviventes incluem acompanhamento clínico, apoio psicológico, orientações de cuidados primários e estilo de vida saudável. As redes de apoio devem ser amplas e conduzidas principalmente por enfermeiros, embasadas em diretrizes sustentadas por evidências científicas e ou entidades especializadas com foco nos sintomas relacionados aos domínios físico, psicológico e socioecológico

Introduction: Cancer survival is a process beginning at diagnosis and continuing for life, bringing a series of additional health challenges. Objective: To analyze the demands and the care model to support cancer survivors. Method: Study of integrative literature review through search of articles published between January 2015 and March 2020 in the databases LILACS, MEDLINE, IBECS, SciELO and Cochrane Library about demands and support scenarios for cancer survivors. Results: Ninety articles were found, 20 of which are consistent with the objective of the study. The structure necessary to support the cancer survivor is multiple, and it includes: hospitals, cancer centers and spaces in the community. There was unanimity in meeting the needs of patients requiring clinical and educational interventions. Studies point out multidisciplinary performance, with the presence of symptoms in the physical, psychological, and socioecological domains. The role of the nurse was mentioned by 19 studies and involves clinical care up to coordination and initiatives related to counseling and guidance to change behaviors that are harmful to health. It was found that 8 studies cited the American Society of Clinical Oncology, as the guiding entity for the interventions. Conclusion: Survivors demands include clinical follow-up, psychological support, primary care guidelines and a healthy lifestyle. The support networks should be extensive, conducted mainly by nurses, based on guidelines supported by scientific evidence and/or specialized entities focused to symptoms related to the physical, psychological, and socioecological domains

Introducción: La supervivencia del cáncer es un proceso que comienza en el momento del diagnóstico y continúa durante toda la vida, lo que conlleva una serie de desafíos de salud adicionales. Objetivo: Analizar las demandas de necesidades y el modelo de atención para apoyar a los sobrevivientes de cáncer. Método: Estudio de revisión integradora de la literatura, sobre demandas y escenarios de apoyo para sobrevivientes de cáncer, en las bases de datos LILACS, MEDLINE, IBECS, SciELO y Cochrane Library, en la que se buscaron artículos publicados entre enero de 2015 y marzo de 2020. Resultados: Se encontraron noventa artículos, 20 de los cuales son consistentes con el objetivo del estudio. La estructura necesaria para apoyar al sobreviviente de cáncer es múltiple e incluye: hospitales, centros oncológicos y espacios en la comunidad. Hubo unanimidad en la satisfacción de las necesidades de los pacientes que requieren intervenciones clínicas y educativas. Los estudios apuntan a un desempeño multidisciplinario, con presencia de síntomas en los dominios físico, psicológico y socioecológico. El rol de la enfermera fue mencionado por 19 estudios, e incluye la atención clínica hasta la coordinación y desempeño en el asesoramiento y orientación para cambios de conducta que son perjudiciales para la salud. Se encontró que ocho estudios citaron a la American Society of Clinical Oncology, como entidad rectora de las intervenciones. Conclusión: Las demandas de los sobrevivientes incluyen seguimiento clínico, apoyo psicológico, pautas de atención primaria y un estilo de vida saludable. Las redes de apoyo deben ser desarrolladas de manera amplia principalmente por enfermeras, con base en pautas sustentadas en evidencia científica y/o entidades especializadas con foco en síntomas relacionados con los dominios físico, psicológico y socioecológico

Guanosine Neuroprotection of Presynaptic Mitochondrial Calcium Homeostasis in a Mouse Study with Amyloid-ß Oligomers.

Amyloid-ß oligomers (AßOs) toxicity causes mitochondrial dysfunction, leading to synaptic failure in Alzheimer's disease (AD). Considering presynaptic high energy demand and tight Ca2+ regulation, impairment of mitochondrial function can lead to deteriorated neural activity and cell death. In this study, an AD mouse model induced by ICV (intracerebroventricular) injection of AßOs was used to investigate the toxicity of AßOs on presynaptic function. As a therapeutic approach, GUO (guanosine) was given by oral route to evaluate the neuroprotective effects on this AD model. Following 24 h and 48 h from the model induction, behavioral tasks and biochemical analyses were performed, respectively. AßOs impaired object recognition (OR) short-term memory and reduced glutamate uptake and oxidation in the hippocampus. Moreover, AßOs decreased spare respiratory capacity, reduced ATP levels, impaired Ca2+ handling, and caused mitochondrial swelling in hippocampal synaptosomes. Guanosine crossed the BBB, recovered OR short-term memory, reestablished glutamate uptake, recovered mitochondrial Ca2+ homeostasis, and partially prevented mitochondrial swelling. Therefore, this endogenous purine presented a neuroprotective effect on presynaptic mitochondria and should be considered for further studies in AD models.

Structural and biochemical analysis of phosphoethanolamine methyltransferase from the pine wilt nematode Bursaphelenchus xylophilus.

In free-living and parasitic nematodes, the methylation of phosphoethanolamine to phosphocholine provides a key metabolite to sustain phospholipid biosynthesis for growth and development. Because the phosphoethanolamine methyltransferases (PMT) of nematodes are essential for normal growth and development, these enzymes are potential targets of inhibitor design. The pine wilt nematode (Bursaphelenchus xylophilus) causes extensive damage to trees used for lumber and paper in Asia. As a first step toward testing BxPMT1 as a potential nematicide target, we determined the 2.05 Å resolution x-ray crystal structure of the enzyme as a dead-end complex with phosphoethanolamine and S-adenosylhomocysteine. The three-dimensional structure of BxPMT1 served as a template for site-directed mutagenesis to probe the contribution of active site residues to catalysis and phosphoethanolamine binding using steady-state kinetic analysis. Biochemical analysis of the mutants identifies key residues on the ß1d-α6 loop (W123F, M126I, and Y127F) and ß1e-α7 loop (S155A, S160A, H170A, T178V, and Y180F) that form the phosphobase binding site and suggest that Tyr127 facilitates the methylation reaction in BxPMT1.

Amyloid-ß oligomers in cellular models of Alzheimer's disease.

Amyloid-ß (Aß) dysmetabolism is tightly associated with pathological processes in Alzheimer's disease (AD). Currently, it is thought that, in addition to Aß fibrils that give rise to plaque formation, Aß aggregates into non-fibrillar soluble oligomers (AßOs). Soluble AßOs have been extensively studied for their synaptotoxic and neurotoxic properties. In this review, we discuss physicochemical properties of AßOs and their impact on different brain cell types in AD. Additionally, we summarize three decades of studies with AßOs, providing a compelling bulk of evidence regarding cell-specific mechanisms of toxicity. Cellular models may lead us to a deeper understanding of the detrimental effects of AßOs in neurons and glial cells, putatively shedding light on the development of innovative therapies for AD.

Stress ocupacional e comportamentos de saúde: intervenção em profissionais de um centro hospitalar / Occupational stress and health behaviors: intervention in professionals from a hospital center

Os fatores de risco psicossociais relacionam-se com o stress ocupacional, reconhecido como causa de doenças e comportamentos não saudáveis. As intervenções sustentadas na metodologia do Planeamento em Saúde realizadas pelo Enfermeiro Especialista em Enfermagem Comunitária, através da implementação de projetos para a gestão do stress ocupacional e promoção da saúde dão resposta às necessidades dos profissionais. O projeto de intervenção comunitária foi desenvolvido no âmbito do Programa Nacional de Saúde Ocupacional, num Serviço de Saúde Ocupacional de um Centro Hospitalar. Teve como objetivo contribuir para o bem-estar dos profissionais de saúde, através de estratégias de gestão do stress ocupacional. Na revisão bibliográfica fez-se revisão scoping. O projeto seguiu a metodologia do Planeamento em Saúde e foi estruturado numa abordagem sistémica de acordo com o modelo de sistema de Neuman. Para diagnostico de situação usaram-se os instrumentos: Atitudes e Comportamentos de Saúde (QACS), Índice de bem-estar da OMS, Stress nos Profissionais de Saúde (QSPS) e Brief COPE. A amostra foi de 87 profissionais que prestam cuidados à pessoa com doença hemato-oncológica. O tratamento estatístico foi feito por SPSS. Percecionaram o stress como moderado a elevado 95,4% dos profissionais. Apresentaram níveis reduzidos de bem-estar 52,9%. Os principais stressores foram: "Lidar com clientes" (96,5%), "Excesso de trabalho" (94,3%) e "Carreira e remuneração" (91,9%). Os comportamentos de saúde mais prevalentes: sedentarismo (44,8% - 47,1%) e alterações no padrão de sono (57,4%). Os diagnósticos de enfermagem foram priorizados por grelha de análise, sendo as intervenções em: Status psicológico comprometido e Sobrecarga por stress devido a lidar com clientes atual. A educação para a saúde, através de intervenções breves baseadas no mindfulness, a formação para a capacitação dos profissionais em lidar com o sofrimento dos doentes e o marketing social, foram as principais estratégias selecionadas. A adesão ao projeto e respetiva satisfação ultrapassaram as metas determinadas e a maioria dos profissionais que participaram nas sessões referiram diminuição do nível de stress e aumento do bem-estar.

Psychosocial risk factors are related to occupational stress, recognized as a cause of illness and unhealthy behaviour. Interventions based on the Health Planning methodology carried out by the Nurse Specialist in Community Nursing, through the implementation of projects for the occupational stress management and health promotion, responds to the needs of professionals. The community intervention project was developed under the National Occupational Health Program, in an Occupational Health Service of a Central Hospital. It aimed to contribute to the well-being of health professionals, through occupational stress management strategies. In the bibliographic review, a scoping review was carried out. The project followed the Health Planning methodology and was structured in a systemic approach according to the Neuman system Model. To diagnose the situation, the following instruments were used: Health Attitudes and Behaviours, WHO Well-Being Index, Stress in Health Professionals and Brief COPE. The sample consisted of 87 professionals who provide care to people with haemato-oncological disease. The statistical treatment was done by SPSS. 95.4% of professionals perceived stress as moderate to high. 52.9% presented reduced levels of well-being. The main stressors were: "Dealing with customers" (96.5%), "Overwork" (94.3%) and "Career and remuneration" (91.9%). The most prevalent health behaviours: sedentary lifestyle (44,8% - 47,1%) and sleep patterns changes (57.4%). Nursing diagnoses were prioritized by an analysis grid, with interventions in: Compromised psychological status and Actual stress overload due to dealing with clients. Health education, through brief interventions based on mindfulness, training of professionals in dealing with the suffering of patients and social marketing, were the main strategies selected. Adherence to the project and its satisfaction exceeded the determined goals and most professionals who participated in the sessions reported a decrease in the level of stress and an increase in well-being.

Tratamento Psíquico Prévio ao Ingresso na Universidade: Experiência de um Serviço de Apoio ao Estudante / Mental Health Treatment prior to University Admission: Experience of a Student Support Service

Resumo: Introdução: Dados da literatura apontam para um aumento da frequência de sofrimento mental entre estudantes de Medicina. Entretanto, os fatores responsáveis ou que têm contribuído para isso ainda não estão completamente esclarecidos. Conhecê-los é fundamental para o planejamento de um serviço de apoio que acolha, identifique, acompanhe e, se necessário, encaminhe o estudante com sofrimento mental. Método: Avaliamos, neste trabalho, o relato de tratamento psíquico, anterior ao ingresso na universidade, de estudantes do curso de Medicina da Universidade Federal de Minas Gerais que buscaram atendimento no Núcleo de Apoio Psicopedagógico aos Estudantes da Faculdade de Medicina (Napem). Os relatos, os dados sociodemográficos e os motivos que levaram o aluno a procurar o serviço foram obtidos de uma ficha de inscrição preenchida pelo estudante. Resultados: No ano avaliado, 87 estudantes (47 homens, média de idade 23,3 anos) procuraram os serviços do Napem. Desses alunos, 42 (48,3%) cursavam os dois primeiros anos; 24 (27,6%), o terceiro e quarto anos; e 21 (24,1%), o quinto e sexto anos. Tratamento psíquico antes do ingresso na universidade foi relatado por 53 (60,9%) alunos: 37 (42,5%) declararam ter feito uso de medicamentos psicoativos e 16 relataram tratamento com psicoterapia sem medicação. Os relatos de tratamento psíquico e de uso de medicamentos psicoativos antes do ingresso na universidade foram significativamente mais frequentes (p = 0,04 e p = 0,04, respectivamente) entre os estudantes que cursavam os dois primeiros anos do curso do que entre os dos demais anos. Não se observaram diferenças estatisticamente significativas em relação à média de idade (p = 0,06), à distribuição por sexo (p = 0,87), à procedência (p = 0,68) ou ao tipo de moradia em Belo Horizonte (p = 0,96) quando se compararam os grupos com e sem relato de tratamento psíquico. Dentre os motivos apontados para a busca de atendimento no Napem, "ansiedade", "depressão/sintomas depressivos" e "instabilidade de humor" foram relatados por 59 (67,8%) estudantes. Problemas relacionados ao curso foram declarados por cinco (5,7%) alunos. Conclusão: Os resultados do estudo sugerem que o tratamento psíquico prévio ao ingresso na universidade pode ser um dos fatores que contribuem para o sofrimento mental do estudante de Medicina durante o curso.

Abstract: Introduction: Data published in literature point to an increased frequency of psychological distress among medical students. However, the causes or potentially contributory factors for this scenario are not completely understood. Understanding these factors is essential for planning a support service that welcomes, identifies, monitors and, if necessary, guides the student with mental suffering. Methods: We evaluated the pre-university admission mental health treatment report on medical students at the Federal University of Minas Gerais who sought care at the Psychopedagogical Support Center. These data, as well as demographic data and the reasons that led the student to seek the service were obtained from an enrollment form filled out by the student. Results: A total of 87 students (47 males, mean age 23.3 years) were received support from the NAPEM in the year under study. Of those, 42 (48.3%) were in the first two years of the course, 24 (27.6%) in the 3rd/4th year and 21 (24.1%) in the 5th/6th year. Mental Health treatment prior to university admission was reported by 53 (60.9%) students: 37 (42.5%) reported the use of psychoactive drugs and 16 reported psychotherapies without the use of medication. Mental Health treatment and medication prior to university admission were significantly more frequent (p = 0.04 and p = 0,04, respectively) among students in the first two years of the course than among those in other years. No statistically significant differences in relation to the average age (p = 0.06), distribution by sex (p = 0.87), origin (p = 0.68) or type of housing in Belo Horizonte (p = 0.96) were found when comparing those who had undergone psychic treatment with those who had not. Anxiety, depression/depressive symptoms and mood swings were reported by 59 (67.8%) students as reasons to seek help. Problems related to the course were reported by five (5.7%) students. Conclusion: The results of the present study suggest that Mental Health treatment prior to university admission may be one of the factors that contribute to the medical student's mental suffering during the course.

Activated peripheral blood mononuclear cell mediators trigger astrocyte reactivity.

Sepsis is characterized by a severe and disseminated inflammation. In the central nervous system, sepsis promotes synaptic dysfunction and permanent cognitive impairment. Besides sepsis-induced neuronal dysfunction, glial cell response has been gaining considerable attention with microglial activation as a key player. By contrast, astrocytes' role during acute sepsis is still underexplored. Astrocytes are specialized immunocompetent cells involved in brain surveillance. In this context, the potential communication between the peripheral immune system and astrocytes during acute sepsis still remains unclear. We hypothesized that peripheral blood mononuclear cell (PBMC) mediators are able to affect the brain during an episode of acute sepsis. With this in mind, we first performed a data-driven transcriptome analysis of blood from septic patients to identify common features among independent clinical studies. Our findings evidenced pronounced impairment in energy-related signaling pathways in the blood of septic patients. Since astrocytes are key for brain energy homeostasis, we decided to investigate the communication between PBMC mediators and astrocytes in a rat model of acute sepsis, induced by cecal ligation and perforation (CLP). In the CLP animals, we identified widespread in vivo brain glucose hypometabolism. Ex vivo analyses demonstrated astrocyte reactivity along with reduced glutamate uptake capacity during sepsis. Also, by exposing cultured astrocytes to mediators released by PBMCs from CLP animals, we reproduced the energetic failure observed in vivo. Finally, by pharmacologically inhibiting phosphoinositide 3-kinase (PI3K), a central metabolic pathway downregulated in the blood of septic patients and reduced in the CLP rat brain, we mimicked the PBMC mediators effect on glutamate uptake but not on glucose metabolism. These results suggest that PBMC mediators are capable of directly mediating astrocyte reactivity and contribute to the brain energetic failure observed in acute sepsis. Moreover, the evidence of PI3K participation in this process indicates a potential target for therapeutic modulation.

Avaliação da Demanda Preliminar de Atendimento Dirigida pelo Aluno ao Núcleo de Apoio Psicopedagógico ao Estudante da Faculdade de Medicina (Napem) da Universidade Federal de Minas Gerais / Evaluation of the Student's Preliminary Request for Assistance to the School of Medicine Psychopedagogical Student Support Center (NAPEM) of the Federal University of Minas Gerais

RESUMO O sofrimento psíquico do estudante universitário, particularmente do estudante de Medicina, é conhecido e tem sido motivo de preocupação. O Núcleo de Apoio Psicopedagógico ao Estudante da Faculdade de Medicina (Napem) da Universidade Federal de Minas Gerais tem como função acolher o estudante que demanda ajuda espontaneamente. O objetivo deste trabalho foi analisar os motivos da busca por atendimento descritos pelos próprios estudantes ao preencherem a ficha de inscrição no Napem. Foram catalogadas 273 fichas, que representam o total de inscrições de novos estudantes em dois anos da última década. Para preservar a identidade dos estudantes, os anos analisados não foram identificados. Desse grupo, 235 eram estudantes de Medicina, 28 de Fonoaudiologia, 4 do curso superior de Tecnologia em Radiologia e 6 eram estudantes de outros cursos. A metodologia utilizada para análise dos dados foi qualitativa, com análise de conteúdo, e o teste do qui-quadrado foi empregado para a comparação de frequências. Os motivos descritos pelos estudantes foram alocados em cinco categorias estabelecidas pelos pesquisadores - distúrbios do humor, problemas pessoais, características de personalidade, questões acadêmicas e outros. Os resultados mostraram que os distúrbios do humor foram os mais frequentemente relatados (44,3%), seguidos por características de personalidade (26,4%) e por problemas pessoais (13,9%). As questões acadêmicas foram as que apresentaram menor frequência (5,5%). O desejo de morrer foi descrito por 17 (6,2%) estudantes. Quando os estudantes de Medicina foram comparados aos dos demais cursos, não foi observada diferença estatisticamente significativa entre as categorias (p = 0,21), sendo também observado o predomínio de motivos alocados na categoria distúrbios do humor (41,7%). Entretanto, quando considerados separadamente os dois períodos analisados, a frequência de distúrbios do humor nos alunos do curso de Medicina foi significativamente maior (p = 0,0005) entre os inscritos no segundo ano, comparados aos inscritos no primeiro ano do estudo. Deve ser ressaltado, ainda, que quase 50% do total de estudantes que se inscreveu no segundo ano analisado neste estudo cursavam os períodos iniciais, resultado significativamente maior (p = 0,002) quando comparado ao dos inscritos no primeiro ano do estudo. Embora reconhecendo as limitações referentes à análise da demanda preliminar de atendimento formulada pelo aluno ao procurar ajuda, particularmente quando expressa de forma escrita, acredita-se que os resultados deste estudo possam contribuir para a organização dos serviços de apoio psíquico e servir de alerta para essa questão. Pela magnitude do problema, fica evidente a necessidade da existência de espaços de acolhimento para os estudantes e de atuação precoce no início do curso, com atividades que possam recebê-los e escutá-los quando do ingresso na faculdade, como, por exemplo, os programas de tutoria.

ABSTRACT The psychological distress experienced by university students, particularly medical students, is well-known and has long been a cause for concern. In the School of Medicine of the Universidade Federal de Minas Gerais, the School of Medicine Psychopedagogical Student Support Center (Núcleo de Apoio Psicopedagógico ao Estudante da Faculdade de Medicina - NAPEM) provides care to students who spontaneously seek help. The purpose of this study was to analyze the reasons described when completing the Napem application form by students for their seeking the assistance. A total of 273 students enrolled in the two years studied, which were both in the last decade. To preserve the identity of the students, the years analyzed were not identified. Of this group, 235 were medical students, 28 students of Speech Therapy, four undergraduate students of Technology in Radiology and six were students of other courses. The methodology used for data analysis was qualitative, with content analysis and the frequency comparison was performed using the chi-square test. The reasons to seek care written by the students in the application form were placed in five categories established by the researchers - "mood disorders," "personal problems," "personality traits," "academic issues" and others. The results showed that "mood disorders" were the most frequently reported (44.3%), followed by "personality traits" (26.4%) and "personal problems" (13.9%). The "academic questions" presented the lowest frequency (5.5%). The desire to die was described by 17 (6.2%) students. When the medical students were compared to the students of the other courses, there was no statistically significant difference among the frequencies of the five categories (p = 0.21) with motives allocated in the category "mood disorders" (41.7%) being predominantly observed. However, when considering two studied periods separately, the frequency of the category "mood disorders" for medical students was significantly higher (p = 0.0005) in the second year than in the first year of study. It should be emphasized that almost 50% of the students enrolled in the second year analyzed attended the centre for first two years, a significantly higher result (p = 0.002) when compared to those enrolled in the first year of the study. Even recognizing the limitations regarding the analysis of the student's preliminary demand for care when seeking help, particularly when expressed in written form, it is believed that the results of this study can contribute to the organization of psychological support services. Due to the magnitude of the problem, there is a clear need to have welcome spaces for the students with activities that can receive them and listen to them when they enter college, such as mentoring programs.

Sex differences in the effects of pre- and postnatal caffeine exposure on behavior and synaptic proteins in pubescent rats.

Few studies have addressed the effects of caffeine in the puberty and/or adolescence in a sex dependent manner. Considering that caffeine intake has increased in this population, we investigated the behavioral and synaptic proteins changes in pubescent male and female rats after maternal consumption of caffeine. Adult female Wistar rats started to receive water or caffeine (0.1 and 0.3g/L in drinking water; low and moderate dose, respectively) during the active cycle at weekdays, two weeks before mating. The treatment lasted up to weaning and the offspring received caffeine until the onset of puberty (30-34days old). Behavioral tasks were performed to evaluate locomotor activity (open field task), anxious-like behavior (elevated plus maze task) and recognition memory (object recognition task) and synaptic proteins levels (proBDNF, BDNF, GFAP and SNAP-25) were verified in the hippocampus and cerebral cortex. While hyperlocomotion was observed in both sexes after caffeine treatment, anxiety-related behavior was attenuated by caffeine (0.3g/L) only in females. While moderate caffeine worsened recognition memory in females, an improvement in the long-term memory was observed in male rats for both doses. Coincident with memory improvement in males, caffeine increased pro- and BDNF in the hippocampus and cortex. Females presented increased proBDNF levels in both brain regions, with no effects of caffeine. While GFAP was not altered, moderate caffeine intake increased SNAP-25 in the cortex of female rats. Our findings revealed that caffeine promoted cognitive benefits in males associated with increased BDNF levels, while females showed less anxiety. Our findings revealed that caffeine promotes distinct behavioral outcomes and alterations in synaptic proteins during brain development in a sex dependent manner.

Impacto da "Disciplina Relação Médico-Paciente" sobre Atitudes Centradas no Paciente / The Impact of a "Doctor-Patient Relationship" Discipline on Patient-Centred Attitudes

RESUMO Vários estudos têm demonstrado que as atitudes centradas no paciente entre os estudantes de Medicina decaem ao longo do curso de graduação. A relação médico-paciente sofre influência profunda da contemporaneidade, e, cada vez mais, comunicar-se na prática clínica torna-se um desafio. O processo de educar em medicina deve encorajar os estudantes a compartilhar o processo de tomada de decisão com seus pacientes. Os estudantes devem compreender não somente o que preocupa seus pacientes, mas também o que os motiva no cuidado em saúde. No processo ensino-aprendizagem, a adoção de medidas eficazes direcionadas ao aprimoramento da escuta e das habilidades de comunicação torna-se a pedra angular na construção da relação médico-paciente de alta qualidade. O objetivo deste estudo foi avaliar o impacto da disciplina "relação médico-paciente" nas atitudes centradas no paciente entre os estudantes de Medicina. Também foi avaliada a influência de variáveis demográficas e do período do curso de Medicina nessas atitudes. Metodologia Foram incluídos 279 estudantes de Medicina que responderam ao questionário Patient-Practitioner Orientation Scale (PPOS): 128 (45,9%) estudantes matriculados na disciplina "Relação médico-paciente" e 151 (54,1%) estudantes voluntários, que não cursaram a disciplina, pareados por sexo e idade aos que frequentaram a disciplina. Os dados foram analisados no software SPSS 17.0 (SPSS Inc., Chicago IL, EUA). Regressão linear múltipla foi realizada para determinar se variáveis demográficas e o período do curso de Medicina estavam independentemente associados aos escores do PPOS (escore total; dimensões sharing e caring). Modelos logísticos foram criados para avaliar associação entre a disciplina "Relação médico-paciente" e os escores das subescalas do PPOS. Resultados Na análise de regressão linear, sexo feminino (p ≤ 0,01), idade mais avançada (p ≤ 0,02) e estar cursando os primeiros anos da faculdade de Medicina (p ≤ 0,02) estavam significativamente associados às atitudes mais centradas no paciente. Maior pontuação na subescala sharing estava independentemente associada à participação na disciplina "Relação médico-paciente" (4,50 ± 0,65 para aqueles que frequentaram vs. 4,33 ± 0,65 para aqueles não matriculados na disciplina, p = 0,03) em modelo logístico ajustado por sexo, idade e período do curso de Medicina. Educadores da área da saúde devem buscar estratégias inovadoras que estimulem atitudes humanísticas, melhorem as habilidades de comunicação e influenciem de forma decisiva as atitudes adotadas pelos estudantes de Medicina, que devem estar focadas no cuidado centrado no paciente/pessoa.

ABSTRACT Several studies have demonstrated that medical students' attitudes toward patient-centred care tend to decline throughout undergraduate education. At present, the adequate translation of the communication skills among medical students into clinical practice remains a challenge. Regardless of the increased efforts of educators to improve the provision of patient care, learning to communicate as a professional physician remains a complex process. Objectives To evaluate the impact of the "doctor-patient relationship" discipline on medical students' attitudes towards patient-centred care, and to examine whether variables related to demographic characteristics and different stages of education are associated to medical student's patient-centred attitudes. Methods Two-hundred and seventy nine medical students who responded a Patient-Practitioner Orientation Scale (PPOS), a validated instrument exploring attitudes towards the doctor-patient relationship were enrolled: 128 (45.9%) who attended the "Doctor-Patient Relationship" discipline and 151 (54.1%) volunteer students, matched by sex and age, who have not taken the discipline. Multiple linear regression analyses were used to quantify the independent association between PPOS scores (overall PPOS, 'sharing' and 'caring' dimensions), demographic variables and year of medical school. Logistic models were created to quantify the independent association between the "doctor-patient relationship" discipline and PPOS and the sub-scales scores. Results In the linear regression analysis, female gender (p ≤ 0.01), older age (p ≤ 0.02) and earliest years of medical school (p ≤ 0.02) were significantly associated with more patient-centred attitudes. Higher score on the 'sharing' sub-scale was independently associated with attending the "doctor-patient relationship" discipline (4.50 ± 0.65 for those who have studied the discipline vs. 4.33 ± 0.65 for those who have not studied the discipline, p = 0.03) after adjustment, in logistic models, for student's age, gender and years on the medical course. Medical educators should be focused on innovative strategies that stimulate humanistic attitudes, improve communication skills and truly change medical students' behaviour towards patient-centred care.

Altered sleep and EEG power in the P301S Tau transgenic mouse model.

OBJECTIVE: Sleep disturbances are prevalent in human tauopathies yet despite the importance of sleep, little is known about its relationship with tau pathology. Here, we investigate this interaction by analyzing sleep and tau pathology throughout tauopathy disease progression in P301S human tau transgenic mice. METHODS: P301S and wild-type mice were analyzed by electroencephalography (EEG)/electromyography at 3, 6, 9, and 11 months of age for sleep/wake time, EEG power, and homeostatic response. Cortical volume and tau pathology was also assessed by anti-phospho-tau AT8 staining. RESULTS: P301S tau mice had significantly decreased rapid eye movement (REM) sleep at 9 months of age and decreased REM and non-REM (NREM) sleep as well as increased wakefulness at 11 months. Sleep loss was characterized by fewer wake, REM, and NREM bouts, increased wake bout duration, and decreased sleep bout duration. Decreased REM and NREM sleep was associated with increased brainstem tau pathology in the sublaterodorsal area and parafacial zone, respectively. P301S mice also showed increased EEG power at 6 and 9 months of age and decreased power at 11 months. Decreased EEG power was associated with decreased cortical volume. Despite sleep disturbances, P301S mice maintained homeostatic response to sleep deprivation. INTERPRETATION: Our results indicate that tau pathology is associated with sleep disturbances that worsen with age and these changes may be related to tau pathology in brainstem sleep regulating regions as well as neurodegeneration. Tau-induced sleep changes could affect disease progression and be a marker for therapeutic efficacy in this and other tauopathy models.

Aged mice receiving caffeine since adulthood show distinct patterns of anxiety-related behavior.

Caffeine is the psychostimulant most consumed worldwide. Anxiogenic effects of caffeine have been described in adult animals with controversial findings about its anxiogenic potential. Besides, the effects of caffeine on anxiety with aging are still poorly known. In this study, adult mice (6months old) started to receive caffeine (0.3 and 1.0mg/mL, drinking water) during 12-14months only in the light cycle and at weekdays. The open field (OF) and elevated plus maze (EPM) testing were used to determine the effects of caffeine on anxiety-related behavior in adult and aged mice (18-20months old). Because aging alters synaptic proteins, we also evaluated SNAP-25 (as a nerve terminals marker), GFAP (as an astrocyte marker) and adenosine A1 and A2A receptors levels in the cortex. According to the OF analysis, caffeine did not change both hypolocomotion and anxiety with aging. However, aged mice showed less anxiety behavior in the EPM, but after receiving caffeine (0.3mg/mL) during adulthood they were anxious as adult mice. While SNAP-25 and adenosine A2A receptors increased with aging, both GFAP and adenosine A1 receptors were not affected. Caffeine at moderate dose prevented the age-related increase of the SNAP-25, with no effect on adenosine A2A receptors. The absence of effect for the highest dose suggests that tolerance to caffeine may have developed over time. Aged mice showed high responsiveness to the OF, being difficult to achieve any effect of caffeine. On the other hand this substance sustained the adult anxious behavior over time in a less stressful paradigm, and this effect was coincident with changes in the SNAP-25, suggesting the involvement of this synaptic protein in the ability of caffeine to preserve changes related to emotionality with aging.