Mitochondrial dysfunction in the pathophysiology of bipolar disorder: effects of pharmacotherapy

Bipolar disorder is a common, chronic, and complex mental illness. Bipolar disorder is frequently comorbid with primary mitochondrial and metabolic disorders, and studies have implicated mitochondrial dysfunction in its pathophysiology. In the brains of people with bipolar disorder, high-energy phosphates are decreased, lactate is elevated and pH decreased, which together suggest a shift toward glycolysis for energy production. Furthermore, oxidative stress is increased, and calcium signalling dysregulated. Additionally there is downregulation of the expression of mitochondrial complexes, especially complex I. The therapeutic effects of some bipolar disorder drugs have recently been shown to be related to these mechanisms. In this review we will evaluate current research on the interactions between mitochondrial dysfunction and bipolar disorder pathology. We will then appraise the current literature describing the effects of bipolar disorder drugs on mitochondrial function, and discuss ramifications for future research.

The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases

Many patients with systemic immune-inflammatory and neuro-inflammatory disorders, including depression, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, cancer, cardiovascular disorder, Parkinson's disease, multiple sclerosis, stroke, and chronic fatigue syndrome/myalgic encephalomyelitis, endure pathological levels of fatigue. The aim of this narrative review is to delineate the wide array of pathways that may underpin the incapacitating fatigue occurring in systemic and neuro-inflammatory disorders. A wide array of immune, inflammatory, oxidative and nitrosative stress (O&NS), bioenergetic, and neurophysiological abnormalities are involved in the etiopathology of these disease states and may underpin the incapacitating fatigue that accompanies these disorders. This range of abnormalities comprises: increased levels of pro-inflammatory cytokines, e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF) α and interferon (IFN) α; O&NS-induced muscle fatigue; activation of the Toll-Like Receptor Cycle through pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns, including heat shock proteins; altered glutaminergic and dopaminergic neurotransmission; mitochondrial dysfunctions; and O&NS-induced defects in the sodium-potassium pump. Fatigue is also associated with altered activities in specific brain regions and muscle pathology, such as reductions in maximum voluntary muscle force, downregulation of the mitochondrial biogenesis master gene peroxisome proliferator-activated receptor gamma coactivator 1-alpha, a shift to glycolysis and buildup of toxic metabolites within myocytes. As such, both mental and physical fatigue, which frequently accompany immune-inflammatory and neuro-inflammatory disorders, are the consequence of interactions between multiple systemic and central pathways.

Mechanisms underlying neurocognitive dysfunctions in recurrent major depression

Recent work shows that depression is intimately associated with changes in cognitive functioning, including memory, attention, verbal fluency, and other aspects of higher-order cognitive processing. Changes in cognitive functioning are more likely to occur when depressive episodes are recurrent and to abate to some degree during periods of remission. However, with accumulating frequency and duration of depressive episodes, cognitive deficits can become enduring, being evident even when mood improves. Such changes in cognitive functioning give depression links to mild cognitive impairment and thereby with neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, schizophrenia, and multiple sclerosis. Depression may then be conceptualized on a dimension of depression - mild cognitive impairment - dementia. The biological underpinnings of depression have substantial overlaps with those of neurodegenerative conditions, including reduced neurogenesis, increased apoptosis, reactive oxygen species, tryptophan catabolites, autoimmunity, and immune-inflammatory processes, as well as decreased antioxidant defenses. These evolving changes over the course of depressive episodes drive the association of depression with neurodegenerative conditions. As such, the changes in cognitive functioning in depression have important consequences for the treatment of depression and in reconceptualizing the role of depression in wider neuroprogressive conditions. Here we review the data on changes in cognitive functioning in recurrent major depression and their association with other central conditions.

The UP4FUN intervention effect on breaking up sedentary time in 10- to 12-year-old Belgian children: the ENERGY project

There are currently no studies available reporting intervention effects on breaking up children's sedentary time. This study examined the UP4FUN intervention effect on objectively measured number of breaks in sedentary time, number of sedentary bouts (≥ 10 mins) and total and average amount of time spent in those sedentary bouts among 10- to 12-year-old Belgian children. The total sample included 354 children (mean age: 10.9 ± 0.7 years; 59% girls) with valid ActiGraph accelerometer data at pre- and posttest. Only few and small intervention effects were found, namely on total time spent in sedentary bouts immediately after school hours (4-6PM; β = -3.51mins) and on average time spent in sedentary bouts before school hours (6-8.30AM; β = -4.83mins) and immediately after school hours in favor of children from intervention schools (β = -2.71mins). Unexpectedly, girls from intervention schools decreased the number of breaks during school hours (8.30AM-4PM; β = -23.45breaks) and increased the number of sedentary bouts on a weekend day (β = +0.90bouts), whereas girls in control schools showed an increase in number of breaks and a decrease in number of bouts. In conclusion, UP4FUN did not have a consistent or substantial effect on breaking up children's sedentary time and these data suggest that more intensive and longer lasting interventions are needed.

The putative role of viruses, bacteria, and chronic fungal biotoxin exposure in the genesis of intractable fatigue accompanied by cognitive and physical disability

Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation. Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms. More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.

Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways

The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut–brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression.

The deleterious effects of oxidative and nitrosative stress on palmitoylation, membrane lipid rafts and lipid-based cellular signalling : new drug targets in neuroimmune disorders

Oxidative and nitrosative stress (O&NS) is causatively implicated in the pathogenesis of Alzheimer’s and Parkinson’s disease, multiple sclerosis, chronic fatigue syndrome, schizophrenia and depression. Many of the consequences stemming from O&NS, including damage to proteins, lipids and DNA, are well known, whereas the effects of O&NS on lipoprotein-based cellular signalling involving palmitoylation and plasma membrane lipid rafts are less well documented. The aim of this narrative review is to discuss the mechanisms involved in lipid-based signalling, including palmitoylation, membrane/lipid raft (MLR) and n-3 polyunsaturated fatty acid (PUFA) functions, the effects of O&NS processes on these processes and their role in the abovementioned diseases. S-palmitoylation is a post-translational modification, which regulates protein trafficking and association with the plasma membrane, protein subcellular location and functions. Palmitoylation and MRLs play a key role in neuronal functions, including glutamatergic neurotransmission, and immune-inflammatory responses. Palmitoylation, MLRs and n-3 PUFAs are vulnerable to the corruptive effects of O&NS. Chronic O&NS inhibits palmitoylation and causes profound changes in lipid membrane composition, e.g. n-3 PUFA depletion, increased membrane permeability and reduced fluidity, which together lead to disorders in intracellular signal transduction, receptor dysfunction and increased neurotoxicity. Disruption of lipid-based signalling is a source of the neuroimmune disorders involved in the pathophysiology of the abovementioned diseases. n-3 PUFA supplementation is a rational therapeutic approach targeting disruptions in lipid-based signalling.

Autobiographical memory dysfunctions in depressive disorders

Autobiographical memory is a ubiquitous human experience which belongs to long-term declarative memory. It plays interpersonal and intrapsychic functions. The main aim of this study is to present results of contemporary research on autobiographical memory in recurrent depressive disorders (rDD). The available research literature suggests that autobiographical memory dysfunctions are a precursor and risk factor for rDD and that they also appear to be a consequence of depressive symptoms in a bidirectional and interacting manner. These data suggest that autobiographical memory might be a viable therapeutic target for cognitive remediation strategies, given the impact of cognition on diverse clinical outcomes.

The Glutathione System: a new drug target in neuroimmune disorders

Glutathione (GSH) has a crucial role in cellular signaling and antioxidant defenses either by reacting directly with reactive oxygen or nitrogen species or by acting as an essential cofactor for GSH S-transferases and glutathione peroxidases. GSH acting in concert with its dependent enzymes, known as the glutathione system, is responsible for the detoxification of reactive oxygen and nitrogen species (ROS/RNS) and electrophiles produced by xenobiotics. Adequate levels of GSH are essential for the optimal functioning of the immune system in general and T cell activation and differentiation in particular. GSH is a ubiquitous regulator of the cell cycle per se. GSH also has crucial functions in the brain as an antioxidant, neuromodulator, neurotransmitter, and enabler of neuron survival. Depletion of GSH leads to exacerbation of damage by oxidative and nitrosative stress; hypernitrosylation; increased levels of proinflammatory mediators and inflammatory potential; dysfunctions of intracellular signaling networks, e.g., p53, nuclear factor-κB, and Janus kinases; decreased cell proliferation and DNA synthesis; inactivation of complex I of the electron transport chain; activation of cytochrome c and the apoptotic machinery; blockade of the methionine cycle; and compromised epigenetic regulation of gene expression. As such, GSH depletion has marked consequences for the homeostatic control of the immune system, oxidative and nitrosative stress (O&NS) pathways, regulation of energy production, and mitochondrial survival as well. GSH depletion and concomitant increase in O&NS and mitochondrial dysfunctions play a role in the pathophysiology of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson’s disease, suggesting that depleted GSH is an integral part of these diseases. Therapeutical interventions that aim to increase GSH concentrations in vivo include N-acetyl cysteine; Nrf-2 activation via hyperbaric oxygen therapy; dimethyl fumarate; phytochemicals, including curcumin, resveratrol, and cinnamon; and folate supplementation.

A review of vulnerability and risks for schizophrenia: beyond the two hit hypothesis

Schizophrenia risk has often been conceptualized using a model which requires two hits in order to generate the clinical phenotype-the first as an early priming in a genetically predisposed individual and the second a likely environmental insult. The aim of this paper was to review the literature and reformulate this binary risk-vulnerability model. We sourced the data for this narrative review from the electronic database PUBMED. Our search terms were not limited by language or date of publication. The development of schizophrenia may be driven by genetic vulnerability interacting with multiple vulnerability factors including lowered prenatal vitamin D exposure, viral infections, smoking intelligence quotient, social cognition cannabis use, social defeat, nutrition and childhood trauma. It is likely that these genetic risks, environmental risks and vulnerability factors are cumulative and interactive with each other and with critical periods of neurodevelopmental vulnerability. The development of schizophrenia is likely to be more complex and nuanced than the binary two hit model originally proposed nearly thirty years ago. Risk appears influenced by a more complex process involving genetic risk interfacing with multiple potentially interacting hits and vulnerability factors occurring at key periods of neurodevelopmental activity, which culminate in the expression of disease state. These risks are common across a number of neuropsychiatric and medical disorders, which might inform common preventive and intervention strategies across non-communicable disorders.

Modelo de sacola quiral com superfície difusa : um estudo das propriedades dos hádrons

o modelo de sacola difusa é um modelo hadrônico que possui aspectos tanto do modelo de sacola do MIT (conservação da energia e momentum, energia de vácuo da QCD) quanto dos modelos de potencial relativísticos (confinamento obtido através de um potencial). O modelo desenvolvido também é um modelo quiral, com a propriedade única de que o campo piônico é suprimido no interior da sacola por meio de um potencial escalar, e no entanto a simetria quiral é preservada. O modelo também é único em que podese controlar o quanto o campo piônico pode penetrar no interior da sacola (em todos os outros modelos, os píons ou entram livremente na sacola ou permanecem totalmente excluídos de seu interior). Nós calculamos as massas do octeto fundamental dos bárions levando em conta as correções de centro de massa, troca de um glúon e troca de um píon. Também calculamos a constante de acoplamento píon-núcleon, a carga axial do núcleon, assim como os raios de carga, momentos magnéticos e fatores de forma eletromagnéticos do próton e do neutron. Exceto pelos fatores de forma eletromagnéticos, a concordância com os resultados experimentais foi excelente, e os resultados indicam que o campo piônico é suprimido somente na vizinhança do centro da sacola.

Avaliação da satisfação e motivação dos técnico-administrativos em uma instituição de ensino superior : um estudo de caso

A busca pela satisfação e motivação de uma categoria de funcionários públicos de uma instituição de ensino superior é o tema do presente trabalho, o qual aborda as seguintes questões: como motivar funcionários que estão com o seu salário defasado? Será que um reajuste salarial irá motivá-Ios? Ou há outros fatores que determinam a satisfação e motivação dos funcionários? Visando responder essas questões e elaborar um plano de ação que aumente a satisfação e motivação dos funcionários, o presente trabalho apresenta um estudo sobre a satisfação no trabalho e as principais teorias motivacionais. As particularidades de uma organização pública também são abordadas. O trabalho envolve um estudo aplicado, o qual inicia apresentando o perfil da categoria de funcionários públicos que será estudada: os técnico-administrativos da Escola de Engenharia da Universidade Federal do Rio Grande do Sul. Através de pesquisas, foi possível aprofundar o conhecimento relativo aos 116 funcionários da instituição, identificando o seu nível de satisfação e os fatores de trabalho que consideram mais importantes. A participação da Direção da Escola de Engenharia da UFRGS no estudo aplicado foi relevante, na medida em que foram estudadas as propostas contidas no Plano de Gestão 2001 - 2004 da Direção da Escola, que possuem potencial para afetar a satisfação e motivação dos seus funcionários. Finalizando o estudo aplicado, o plano de ação para motivar e satisfazer os funcionários da Escola de Engenharia da UFRGS foi apresentado e questionado com relação ao seu potencial motivacional.

A singularidade humana sob a ótica de Baruch Spinoza : uma contribuição à reflexão sobre a ética e a prática educativa do professor

A problemática delineada e discutida nessa dissertação surgiu da necessidade suscitada pelas experiências e percepções de que por mais que o professor se esforce para mudar sua atitude e sua práxis educativa de modo significativo, na prática, não consegue, concretizar a ação de se engendrar e agir de modo diferente; muda muito pouco ou, às vezes, de modo contrário ao proposto. Para tentar dar sustentação a uma possível justificação sobre o como se dá esse engendramento, o caminho escolhido foi o de uma ação reflexiva da proto-modernidade, traçada por Spinoza. Esse filósofo sugere, mesmo atualmente, o modo como conservamos a nós mesmo e como é possível nos relacionarmos democraticamente em sociedade apesar, e devido, essa mesma necessidade de conservação. Filósofo que viveu e se engendrou singularmente por meio da própria ação de produzir conhecimentos e teses sobre o engendramento da singularidade humana, dentro dos paradoxos do limiar de uma nova era – Séc. XVII. Época em que se inaugura um novo modo de pensar, agir e de relação entre os que são de uma mesma natureza que a nossa: a modernidade – tal qual, agora vivemos e nos engendramos singularmente como seres humanos e profissionais da educação. Isto é, dentro de um contexto repleto de questionamentos proporcionados pela era pós-moderna, pós-capitalista e de globalização.

Uma análise da construção do Museu de Arte do Espírito Santo e de seus reflexos

Esta pesquisa apresenta alguns dados do processo de construção do Museu de Arte do Espírito Santo- MAES até a sua inauguração e uma análise atual, refletindo sobre o papel do poder público através do estudo de matérias de jornais e entrevistas com alguns atores participantes do processo de discussão e instalação do MAES, e o posicionamento adotado pelo governo ao longo deste período, bem como o da classe artística e da sociedade em geral. Pretendeu-se reconhecer os atores participantes de todo esse processo recorrendo a documentos que explicitassem as relações que existiram nesse período entre os poderes públicos, os interesses da classe artística e da coletividade que fez e faz uso da Instituição. Ao final, mostra-se como esses discursos influenciam o museu até os dias de hoje. Para tal, inscrevemos nossa discussão sobre o MAES no âmbito de uma reflexão mais geral sobre os museus na atualidade.