Escetamina na Depressão Resistente ao Tratamento: O Caminho para a Remissão

Major depressive disorder affects an estimate of 5% of the population with nearly 1‑third of patients failing to achieve remission with conventional pharmacological treatment. Esketamine, a novel rapid‑acting antidepressant, with a noncompetitive antagonism on N‑methyl‑D‑Aspartate receptor, have been recently approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment‑resistant depression. Here, we report a clinical case of a 42‑year‑old Caucasian woman who endured many years with severe depressive symptoms and high functional impairment. Previous treatments included cognitive behavioral therapy, numerous pharmacological trials with antidepressants and augmentation agents, and neurostimulation approaches. Upon treatment with esketamine, the patient presented remarkable clinical recovery. Psychometric assessments determined an acute reduction on the MADRS score after 1 week and progressive recovery of the depressive symptoms on the following weeks. Likewise, PHQ‑9 scale assessments, evaluating the relative frequency of depressive symptoms. and the Sheehan scale, assessing functional recovery, also determined a pronounced symptomatic relief.A perturbação depressiva major afeta cerca de 5% da população e quase 1‑terço dos doentes não consegue atingir remissão com o tratamento farmacológico convencional. Escetamina, um novo antidepressivo de ação rápida, com antagonismo não competitivo do receptor N‑metil‑D‑aspartato, foi recentemente aprovado pela Food and Drug Administration (FDA) e European Medicines Agency (EMA) para o tratamento de depressão resistente ao tratamento. Aqui, relatamos o caso clínico de uma mulher caucasiana de 42 anos que padeceu durante muitos anos de sintomas depressivos graves e de grande compromisso funcional. Os tratamentos anteriores incluíram terapia cognitivo‑comportamental, vários ciclos de tratamento farmacológico com antidepressivos e agentes de aumento e técnicas de neuroestimulação. Após tratamento com escetamina, a doente apresentou uma notável recuperação clínica. Avaliações psicométricas determinaram uma redução considerável na pontuação MADRS após uma semana e recuperação progressiva dos sintomas depressivos nas semanas seguintes. Da mesma forma, as avaliações com a escala de PHQ‑9, que avalia a frequência relativa de sintomas depressivos, e a escala de Sheehan, que avalia a recuperação funcional, também determinaram alívio sintomático muito pronunciado

Lurasidona: Dez Anos de Utilização no Tratamento da Depressão Bipolar em Adultos

Lurasidone is an atypical antipsychotic approved in 2010 in Canada and in the USA for the treatment of adults with schizophrenia or bipolar type I disorder. In 2014 it was approved in the European Union for the treatment of patients with 13 years‑old or older, with schizophrenia. Lurasidone is a benzisothiazole derivative with a binding profile that makes it an antidepressant candidate with a low metabolic impact. In patients with bipolar disorder, depressive episodes tend to be present for the majority of the time and are difficult to treat, as shown in multiple surveys indicating that more than three quarters of patients with bipolar depression receive at least two pharmaceutical drugs and more than one third receive three or more. Some relevant international guidelines include different first‑line options in the treatment of bipolar depression, among which is lurasidone. Considering the difficulties in treating depressive episodes in bipolar disorder, the EU marketing authorization limiting the use of lurasidone in schizophrenia only and the expectable commercialization in Portugal by 2021, we aim to review the literature regarding the efficacy and advantages of lurasidone for depressive episodes of bipolar disorder and to discuss the usefulness of approving this medication as an alternative treatment approach.A lurasidona é um antipsicótico atípico, aprovado em 2010 no Canadá e Estados Unidos da América para o tratamento de doentes com o diagnóstico de esquizofrenia ou doença bipolar tipo I. Em 2014 obteve autorização de comercialização na União Europeia (UE), para o tratamento de doentes com 13 anos ou mais, com o diagnóstico de esquizofrenia. É um antipsicótico com estrutura derivada de benzisotiazol, com um perfil de ligação singular, que faz deste um candidato a antidepressivo com pouco impacto metabólico. Em doentes com diagnóstico de doença bipolar, os episódios depressivos tendem a estar presentes a maioria do tempo e a ser difíceis de tratar, como revelam vários estudos que indicam que mais de três quartos de doentes com depressão bipolar experimentam pelo menos dois fármacos e mais de um terço, três ou mais. Em linhas orientadoras de tratamento internacionais, as indicações de primeira linha no tratamento de episódios depressivos de doença bipolar são variadas, sendo a lurasidona considerada uma opção. Considerando a dificuldade na prática clínica em tratar os episódios depressivos na doença bipolar, a autorização de comercialização na UE exclusiva para utilização em esquizofrenia e a expectável disponibilidade do fármaco em Portugal no decurso do ano 2021, pretendemos realizar uma revisão de literatura com enfoque na eficácia e vantagens da utilização de lurasidona em episódios depressivos de doença bipolar e discutir a utilidade da sua aprovação como alternativa de tratamento

Loss of Ccbe1 affects cardiac-specification and cardiomyocyte differentiation in mouse embryonic stem cells

Understanding the molecular pathways regulating cardiogenesis is crucial for the early diagnosis of heart diseases and improvement of cardiovascular disease. During normal mammalian cardiac development, collagen and calcium-binding EGF domain-1 (Ccbe1) is expressed in the first and second heart field progenitors as well as in the proepicardium, but its role in early cardiac commitment remains unknown. Here we demonstrate that during mouse embryonic stem cell (ESC) differentiation Ccbe1 is upregulated upon emergence of Isl1- and Nkx2.5- positive cardiac progenitors. Ccbe1 is markedly enriched in Isl1-positive cardiac progenitors isolated from ESCs differentiating in vitro or embryonic hearts developing in vivo. Disruption of Ccbe1 activity by shRNA knockdown or blockade with a neutralizing antibody results in impaired differentiation of embryonic stem cells along the cardiac mesoderm lineage resulting in a decreased expression of mature cardiomyocyte markers. In addition, knockdown of Ccbe1 leads to smaller embryoid bodies. Collectively, our results show that CCBE1 is essential for the commitment of cardiac mesoderm and consequently, for the formation of cardiac myocytes in differentiating mouse ESCs.Fundacao para a Ciencia e Tecnologia (FCT) [SFRH/BD/82280/2011]; FCT [SFRH/BPD/46506/2008, CEDOC/2015/36/iNOVA4Health/Multi/04462, SFRH/BPD/87114/2012, PTDC/SAU-ENB/121095/2010, HMSP-ICT/0039/2013]; Fundacao para a Ciencia e Tecnologia / Ministerio da Educacao e Ciencia [UID/Multi/04462/2013]; FEDER under the PT2020 Partnership Agreemen

COVID‑19, Saúde Mental, e Nutrição: Uma Revisão Narrativa

Since the pandemic was declared in March 2020 by World Health Organization, COVID‑19 has been responsible for a disruptive impact on health, economy, and interpersonal relationships, with significant repercussions on mental health and the eating habits. A bibliographic review was carried out through the PubMed database, which aimed to study the implications of COVID‑19 on the mental health and eating habits of individuals. The association between increased psychopathological symptoms and pandemics has been established throughout human history. During the COVID‑19 pandemic, studies that sought to assess the mental health of individuals who had been infected with SARS‑CoV‑2 and/or were in quarantine found an increased prevalence of psychopathological symptoms such as anxiety, sadness or fear. The duration of the quarantine, socioeconomic problems, false and/or inappropriate information and the neurotropism of the virus, were some of the risk factors pointed to the appearance of these symptoms. Likewise, the scientific community has also found a relationship between the quarantine period and depressive symptoms with increased consumption of comfort foods, with high energy density and low in nutrients. This not only increases the risk of developing chronic non‑communicable diseases, such as obesity and type 2 diabetes mellitus, but it also seems to influence the hypothalamic‑pituitary‑adrenal axis, with impairment of the immune system and an increase in mental illnesses such as depression. The immune response is, ultimately, the only way we have to overcome this pandemic. SARS‑CoV‑2 has had an important negative impact both on the mental health of the population and on their food choices, which conditions out immune response. Thus, more than only measures to prevent contamination, also to promote a healthy lifestyle seem to be the best strategies against COVID‑19, with a view to increase our “psychoneuroimmunity” to better overcome this pandemic.Desde que foi declarada pandemia em março de 2020 pela Organização Mundial de Saúde, a COVID‑19 tem sido responsável por um impacto disruptivo na saúde, economia e relacionamentos interpessoais, com impacto negativo ao nível da saúde mental, com repercussão nos hábitos alimentares na população. Foi realizada pesquisa bibliográfica, através da base de dados PubMed, que pretendeu estudar implicações da COVID‑19 na saúde mental e hábitos alimentares dos indivíduos. A associação entre o aumento dos sintomas psicopatológicos e as pandemias tem sido estabelecida ao longo da história da humanidade. Estudos realizados durante a pandemia COVID‑19, em indivíduos que tinham sido infetados por SARS‑CoV‑2 e/ou em quarentena, encontraram um aumento significativo, da prevalência de sintomas psicopatológicos como a ansiedade, tristeza ou medo. A duração da quarentena, problemas socioeconómicos, informações falsas e/ou inadequadas e o neurotropismo do vírus, são alguns dos fatores de risco apontados como responsáveis pelo surgimento destes sintomas. Da mesma maneira, a comunidade científica têm também encontrado uma relação entre o período de quarentena e dos sintomas angodepressivos com o aumento do consumo de alimentos conforto, de elevada densidade energética e pobre em nutrientes. Este facto, não só aumenta o risco de desenvolvimento de doenças crónicas não transmissíveis, como a obesidade e a diabetes mellitus tipo 2, como também parece influenciar o eixo hipotálamo‑hipófise‑suprarrenal, com comprometimento do sistema imunitário e aumento das doenças mentais como a depressão. A resposta imunitária é, em última instância, a única maneira que temos para ultrapassar esta pandemia. O SARS‑CoV‑2, tem tido um importante impacto negativo quer na saúde mental da população quer nas suas escolhas alimentares o que, condiciona a nossa resposta imunitária. Deste modo, para além das medidas de prevenção da contaminação, também a promoção de um estilo de vida saudável, parecem ser as melhores estratégias contra a COVID‑19, com vista a aumentar a nossa “psiconeuroimunidade” para melhor ultrapassarmos esta pandemia

Expression and Function of Ccbe1 in the Chick Early Cardiogenic Regions Are Required for Correct Heart Development

During the course of a differential screen to identify transcripts specific for chick heart/hemangioblast precursor cells, we have identified Ccbe1 (Collagen and calcium-binding EGF-like domain 1). While the importance of Ccbe1 for the development of the lymphatic system is now well demonstrated, its role in cardiac formation remained unknown. Here we show by whole-mount in situ hybridization analysis that cCcbe1 mRNA is initially detected in early cardiac progenitors of the two bilateral cardiogenic fields (HH4), and at later stages on the second heart field (HH9-18). Furthermore, cCcbe1 is expressed in multipotent and highly proliferative cardiac progenitors. We characterized the role of cCcbe1 during early cardiogenesis by performing functional studies. Upon morpholino-induced cCcbe1 knockdown, the chick embryos displayed heart malformations, which include aberrant fusion of the heart fields, leading to incomplete terminal differentiation of the cardiomyocytes. cCcbe1 overexpression also resulted in severe heart defects, including cardia bifida. Altogether, our data demonstrate that although cardiac progenitors cells are specified in cCcbe1 morphants, the migration and proliferation of cardiac precursors cells are impaired, suggesting that cCcbe1 is a key gene during early heart development.FCT [SFRH/BD/65628/2009, SFRH/BPD/86497/2012, SFRH/BPD/41081/2007]; F.C.T.B.I. fellowship [PTDC/SAU-BID/114902/ 2009]; FCT; Institute for Biotechnology Bioengineering (Centro Biomedicina Molecular e Celular (IBB/CBME), Laboratorio Associado (LA) in the frame of Project [PestOE/EQB/LA0023/2013]info:eu-repo/semantics/publishedVersio

The analysis of mitochondria and mitochondrial DNA in human embryonic stem cells.

As human embryonic stem cells (hESCs) undergo differentiation, they express genes characteristic of the lineage for which they are destined. However, fully differentiated individual cell types can be characterized by the number of mitochondria they possess and the copies of the mitochondrial genome per mitochondrion. These characteristics are indicative of a specific cell's requirement for adenosine triphosphate (ATP) and therefore cellular viability and function. Consequently, failure for an ESC to possess the full complement of mitochondria and mitochondrial DNA (mtDNA) could limit its final commitment to a particular fate. We describe a series of protocols that analyze the process of cellular mitochondrial and mtDNA differentiation during hESC differentiation. In addition, mtDNA transcription and replication are key events in cellular differentiation that require interaction between the nucleus and the mitochondrion. To this extent, we describe a series of protocols that analyze the initiation of these key events as hESCs progress from their undifferentiated state to the fully committed cell. Last, we describe real-time polymerase chain reaction protocols that allow both the identification of mtDNA copy number and determine whether mtDNA copy is uniform (homoplasmy) in its transmission or heterogeneous (heteroplasmy)

Inhibition of Mitochondrial Complex III Blocks Neuronal Differentiation and Maintains Embryonic Stem Cell Pluripotency

The mitochondrion is emerging as a key organelle in stem cell biology, acting as a regulator of stem cell pluripotency and differentiation. In this study we sought to understand the effect of mitochondrial complex III inhibition during neuronal differentiation of mouse embryonic stem cells. When exposed to antimycin A, a specific complex III inhibitor, embryonic stem cells failed to differentiate into dopaminergic neurons, maintaining high Oct4 levels even when subjected to a specific differentiation protocol. Mitochondrial inhibition affected distinct populations of cells present in culture, inducing cell loss in differentiated cells, but not inducing apoptosis in mouse embryonic stem cells. A reduction in overall proliferation rate was observed, corresponding to a slight arrest in S phase. Moreover, antimycin A treatment induced a consistent increase in HIF-1α protein levels. The present work demonstrates that mitochondrial metabolism is critical for neuronal differentiation and emphasizes that modulation of mitochondrial functions through pharmacological approaches can be useful in the context of controlling stem cell maintenance/ differentiation.Fundação para a Ciência e a Tecnologia (FCT) Portugal for grant support (PTDC/EBB-EBI/101114/2008, PTDC/EBB-EBI/ 120634/2010 and PDTC/QUI-BIQ/120652/2010 co-funded by Compete/FEDER/National Funds; and a PhD scholarship attributed to SP (SFRH/BD/ 37933/2007). Center for Neuroscience and Cell Biology (CNC) funding is also supported by FCT (PEst-C/SAU/LA0001/2011). EA’s work was supported by the Swedish Foundation for Strategic Research (SRL Program), Swedish Research Council (DBRM), Karolinska Institutet (SFO Thematic Center in Stem Cells and Regenerative Medicine), and Hjärnfonden