No description available.

Introduction: Bipolar disorder (BD) is a genetically heritable mood disorder typically characterized by manic and depressive episodes. Cognitive impairments experienced by people with BD are one of the best predictors of functional capacity in their daily lives. There are notable impairments in various domains, such as executive functioning, working memory, and processing speed, in both individuals diagnosed with BD as well as their first-degree unaffected relatives, which emphasizes the important role genetic factors play in the onset and presence of cognitive impairments. One commonly studied single nucleotide polymorphism (SNP) associated with BD and cognition is the CACNA1C rs1006737 SNP. Although there have been numerous studies investigating the effects of rs1006737 on cognitive functioning in BD, results have been inconclusive and mixed. Thus, we examined the involvement and impact of the CACNA1C rs1006737 risk SNP on cognitive functioning in the domains of executive functioning, working memory, and processing speed. Methods: A total of 70 euthymic BD-I participants and 76 healthy control (HC) participants were assessed on the cognitive domains of executive functioning, working memory, and processing speed and genotyped for the CACNA1C rs1006737 risk SNP. Results: No significant differences were observed in the scores for the cognitive domains of executive functioning, working memory, and processing between BD risk carriers vs. non-risk homozygotes, HC risk carriers vs. non-risk homozygotes, BD and HC risk carriers, and BD and HC non-risk homozygotes. Conclusion and Future Directions: The results suggest that the rs1006737 risk SNP does not have a significant impact on the cognitive domains investigated in BD and HC. However, our small sample size and lack of an age-matched control group are crucial limitations that must be taken into consideration. Future studies with larger sample sizes can help to further elucidate the role the CACNA1C rs1006737 risk SNP plays in cognitive functioning in BD. / Thesis / Master of Science (MSc)

No description available.

Bipolar Disorder (BD) is a debilitating mental illness that presents as mood alterations between manic and depressive states. There remain large gaps in the knowledge surrounding the disease, due to three main issues in understanding the illness. First is a lack of an appropriate animal model that mimics both manic and depressive symptoms. Second is a lack of knowledge on the biological cause of the disease. Finally, a lack of knowledge on the precise mechanism of action of lithium (Li), the main treatment for BD prevents more progressive research into the disease. Inflammation and a subsequent disruption of the blood-brain barrier (BBB) have recently been demonstrated in other psychiatric conditions, such as Alzheimer’s Disease (AD) and Schizophrenia (SZ). This mechanism remains to be fully investigated in BD. This thesis presents an inflammatory model of BBB disruption in rodents. A study examining gene expression in discordant sibling pairs with SZ or BD discovered that the Max gene was elevated two-fold in bipolar patients as compared to their non-BD siblings. We aim to elucidate on these findings and examine the effect of common BD treatments on Max gene expression. The first study utilized lipopolysaccharides (LPS) to induce an inflammatory response in the BBB, and sodium fluoroscein (NaF) to measure the levels of resulting disruption. It was shown that Li is unable to attenuate disruption of the BBB, and an LPS administration with Li pretreatment causes higher disruption than either substance alone in several brain regions. The second study examined Max gene expression levels in naïve rats as a result of Li or valproate (VPA) treatment. VPA was shown to significantly downregulate the expression of Max in a rodent model. These studies may provide insight into understanding the pathophysiology of BD, leading to better, more accurate animal models and more targeted therapies for the disorder. / Thesis / Master of Science (MSc)

Bipolar disorder (BD) is a chronic and often progressive illness that has a significant impact on quality of life and functioning. Pharmacological treatments are not effective for all patients, emphasizing the need to better understand the pathophysiology of the disorder. It is well known that patients with BD present with increased levels of inflammatory markers during mood episodes and often exhibit chronic low grade inflammation, implicating the immune system in the etiology of the disorder. Furthermore, patients with BD show deficits in neurotrophic factors suggesting that alterations in neurogenesis may precipitate clinical features. Recent evidence indicates that accelerated aging processes may underlie the pathophysiological changes observed in BD, implicating biomarkers related to aging. The chemokine C-C motif chemokine 11 (CCL11) and the cytokine growth differentiation factor 11 (GDF11) have been identified as proteins that increase and decrease with age, respectively. As such, this thesis presents research examining serum levels of these proteins in drug-naive young adults with BD and a matched healthy control group. We analyzed serum levels of CCL11 and GDF11 using enzyme linked immunosorbent assay (ELISA). Our results indicate that serum levels of CCL11 and GDF11 do not differ between the BD group and the healthy control group, however CCL11 levels were elevated in males and in individuals with tobacco abuse/dependence when considering the entire sample. Our results suggest that serum levels of these proteins do not differ between drug-naive young adults with BD and healthy controls, but that alterations may be due to demographic and lifestyle factors. Small sample size and low power should be considered when interpreting these results. / Thesis / Master of Science (MSc)

"Due to the high variation of critical device parameters inherent in integrated circuit manufacturing, modern integrated circuit designs have evolved to rely on the ratios of similar devices for their performance rather than on the absolute characteristics of any individual device. Today's high performance analog integrated circuits depend on the ability to make identical or matched devices. Circuits are designed using a tolerance based on the overall matching characteristics of their particular manufacturing process. Circuit designers also follow a general rule of thumb that larger devices offer better matching characteristics. This results in circuits that are over designed and circuit layouts that are generally larger than necessary. In this project we develop a model to predict the mismatch in a pair of NPN bipolar transistors. Precise prediction of device mismatch will result in more efficient circuit deigns, smaller circuit layouts and higher test yields, all of which lead to into more reliable and less expensive products."

Alteração da fosfolipase A2 tem sido descrita em diversas doenças neuropsiquiátricas. Esta enzima é responsável pelo metabolismo dos fosfolípides de membrana e parece estar envolvida na fisiopatologia do transtorno bipolar. Neste estudo, foram analisados os três principais subtipos da PLA2 (sPLA2, cPLA2 e iPLA2) em plaquetas de pacientes e indivíduos controles. A atividade de subtipos de PLA2 foi determinada em 20 pacientes TB sem tratamento com estabilizadores de humor e após seis semanas de tratamento com lítio; 72 pacientes medicados e 65 controles (16 pareados com os pacientes sem tratamento e 49 com os pacientes previamente medicados), pelo método radioenzimático. Os pacientes foram diagnosticados e classificados de acordo com os critérios estabelecidos no DSM-IV-TR. Foi verificado que Os pacientes no estágio inicial da doença apresentaram menor atividade de iPLA2, sPLA2 e cPLA2 quando comparadas ao grupo controle. Seis semanas de tratamento com o lítio não foram suficientes para observar alterações nos resultados obtidos. No entanto, o lítio diminuiu a sintomatologia maníaca e a depressiva, avaliadas pelas escalas de Hamilton e Young, respectivamente (p < 0,01 para as duas comparações). Os pacientes medicados não diferiram do grupo controle para os três subtipos de PLA2 avaliados. Estes resultados sugerem que no estágio inicial do TB há uma diminuição da atividade das PLA2, e que a ação de um ou mais medicamentos que são incluídos na terapêutica para este transtorno podem reverter essa diminuição. Sugere-se ainda que a diminuição da atividade da iPLA2 no estágio inicial do transtorno bipolar, além de alterar o remodelamento da membrana, possa ser um fator de risco para o desenvolvimento de demência nestes pacientes. / Changes in phospholipase A2 have been reported in several psychiatric disorders. This enzyme is responsible for the metabolism of membrane phospholipids and has been suggested to play a role in bipolar disorder physiopathology. In this study, the activity of the three main subtypes of phospholipase A2 (PLA2) were analyzed (sPLA2, cPLA2 and iPLA2) in platelets of BD patients and health subjects. Subjects enrolled were: 20 drug-naïve and drug free BD patients, who were treated with lithium for six weeks; 72 BD long-term treatment patients and 65 controls (16 for the drug-naïve and drug free and 49 for the long term group). PLA2 subtype activities were determined by the radio enzymatic method. Patients\' diagnostic and classification were made according to DSM-IV-TR criteria. Patients at the early stage of the disease presented lower iPLA2, sPLA2 and cPLA2 activity than the control group. Six weeks treatment with lithium did not change these activities. However, lithium reduced the maniac and depressive symptoms, evaluated with Hamilton and Young scales, respectively (p < 0.01, for both comparisons). Long-term treated patients presented similar PLA2 activities to control group. The results suggest that at the early stage of BD iPLA2 activity is decreased and that the adequate treatment of BD could reverse this reduction. We suggest that a reduction of iPLA2 activity at the early stage of BD can modify the membrane metabolism, and could be a risk for the development of dementia in BD patients.

O Transtorno Afetivo Bipolar (TAB) é um transtorno mental crônico e recorrente. Está situado entre as principais doenças que causam incapacitação e morbidade em todo mundo. A substituição do modelo de atendimento ao doente mental centrado no hospital, por uma rede de serviços prestados na comunidade, tem como conseqüência o aumento do número de pacientes vivendo em família. Estas famílias são solicitadas a oferecer apoio emocional, tolerar estigma, lidar com perdas financeiras e laboral, interrupções na rotina do lar, entre outras. Tais implicações correspondem à sobrecarga que são as conseqüências que o familiar enfrenta ao conviver com pessoa portadora de transtorno mental. O objetivo deste estudo foi identificar e descrever a sobrecarga do TAB nas famílias que convivem com algum portador deste transtorno. Foram entrevistados 15 familiares, sendo três filhos, quatro irmãs, duas cunhadas, uma ex- cunhada, três cônjuges, uma tia e uma mãe. Foram utilizados para a coleta de dados um questionário com informações sobre dados clínicos do paciente com TAB, Critério Padrão de Classificação Econômica Brasil 2008 e roteiro de entrevista semi-estruturado adaptado por Koga (1997) que engloba a sobrecarga familiar. As respostas foram analisadas utilizando-se a técnica de análise de conteúdo de Bardin. O impacto do TAB sobre a família foi descrito nos seguintes aspectos: trabalho, gastos, lazer, relacionamento interpessoal, futuro, recursos e adoecimento do familiar como expressão de sobrecarga. Observou-se que a família se sente mais sobrecarregada nos períodos de crise da doença. Nos períodos estáveis somente os aspectos trabalho e relacionamento interpessoal permanecem como ponto de preocupação e sofrimento familiar. O fato de não se conhecer as causas e tampouco a cura, faz com que apareçam insegurança e temor quanto ao futuro. Este estudo contribuiu para compreender que TAB também sobrecarrega a família que necessita e solicita apoio dos profissionais de saúde para obter melhora na qualidade de vida. A principal limitação do presente estudo é o número pequeno de familiares entrevistados e o fato de todos terem sido recrutados em um único serviço de saúde. Pesquisas semelhantes deverão ser realizadas a fim de verificar se outras famílias manifestam sobrecarga semelhante as apresentadas pelos familiares deste estudo. / The bipolar disorder (BD) is a chronic and recurring mental disorder. Nowadays, it is one of most important disease that is responsible for incapacity and morbidity worldwide. The replacement treatment model of mental illness that was focus at hospital for services accessible to community is responsible for increase of number of patients living in family contexts. These families are responsible to offer emotional support, sometimes tolerate stigma, deal with financial and work loses, disruption at home routine and other ones. These implications are the result of relationship with a person with mental illness. The aim of this study was to identify and describe the burden of bipolar disorder in the family that lives with a person that has this disorder. Questioners were applied for fifteen relatives: tree children, four sisters, tree sistersin- law, tree spouse, 1 aunt and 1 mother. The data were collected using questionnaires with information about clinic data of BD patients, Standard Economic Classification Brazil 2008 and semi structured interview adapted by Koga. The results were analyzed by Bardins content technique. The impact in the family resulting of the relationship with BD patients was described following these aspects: work, costs with daily life, leisure, interpersonal relationship, future, resource and falling ill like expression of burden. As a result BD patients family reported that they were burdensome in the severe periods of disease. In the stable periods, only work and interpersonal aspects are continuous factors of worry and familiar suffer. Ignore the causes and the cure emerge insecurity and fear about the future. This study contributed to comprehension of that BD also burdensome the family of the patients. In addition, this people require support of health professionals to provide quality of life. The limits of this study were the short number of relatives submitted to questioners and they were come from the one source. More studies will be necessary to analyze other families and the pattern of BD illness burdensome.

O Transtorno Bipolar (TB) é uma doença psiquiátrica grave, altamente incapacitante que está associada com diversas comorbidades médicas e altas taxas de suicídio. Embora sua fisiopatologia não esteja completamente elucidada, inúmeros estudos têm mostrado alterações no sistema imune de indivíduos com TB. A resposta crônica destes indivíduos ao estresse parece gerar um aumento da inflamação sistêmica bem como da neuroinflamação. A micróglia ativada devido aos estímulos inflamatórios contínuos deve ocasionar diferentes prejuízos tanto bioquímicos quanto funcionas. Os macrófagos, primeira linha de defesa, são células de característica plástica de extrema importância do sistema imune e podem ser estimulados a polarizar para diferentes formas com liberação de fatores pró e antiinflamatórios, estimulando ou mantendo a homeostase no ambiente agredido de alguma forma. Desta forma, nosso trabalho buscou investigar a resposta fenotípica dos macrófagos contra o meio ambiente pró-inflamatório sistêmico observado no plasma de pacientes bipolares eutímicos, maníacos e depressivos em comparação aos controles. A amostra incluiu 5 controles saudáveis, 8 pacientes bipolares remetidos, 5 pacientes maníacos e 5 pacientes depressivos. As citocinas e quimiocinas de RNAm em células U937 tratadas com plasma mostraram um padrão de expressão diferente relativo entre controles saudáveis e pacientes com TB. As citoquinas inflamatórias tais como IL-1β e TNF-α, em pacientes bipolares maníacos e depressivos demonstram maiores quantidades de IL-1β mRNA do que os pacientes eutímicos e pacientes depressivos induziram maiores quantidades de RNAm de TNF-α do que os pacientes eutímicos em células U937. Já a expressão das quimiocinas CXCL9 e CXCL10 no plasma de pacientes com TB depressivos, demostraram ser de menor expressão significativa no grupo de pacientes maníacos quando comparados a controles e pacientes bipolares eutímicos. Nossos resultados sugerem que as citocinas periféticas devem modular a polarização M1 ou M2 de macrófagos no TB. / Bipolar Disorder (BD) is a severe and highly incapacitating psychiatric disorder which is associated with the presence of medical comorbidities. The progression of BD is related to an important cognitive deficit and also to biological and clinical manifestations that lead to treatment resistance and worse prognosis. Immune disturbances have been widely observed and investigated in BD patients. Chronic inflammatory responses induce neuroinflammation, mainly by pro-inflammatory microglial activation, and result in biochemical and functional impairment. Macrophages are the first line of defense of the immune system and exhibit cell plasticity. As well, microglia represents the resident macrophage of the central nervous system been responsible for its protection. Both cells can be stimulated to polarize into two different phenotypes, mainly pro- and anti-inflammatory, maintaining the homeostasis under physiologic and pathologic conditions. Therefore, we aimed to investigate macrophages phenotypical response when submitted to BD patients plasma in different episodes, which is considered a pro-inflammatory environment, and healthy controls plasma. Subjects included healthy controls (n=5), remitted BD patients (n=8), manic patients (n=5) and depressive patients (n=5). The mRNA expression of chemokynes and cytokines from U937 cells treated with BD patients plasma were different from those submitted to healthy controls plasma. Higher mRNA expression of IL-1β was observed in those cells submitted to manic and depressive BD patients plasma when compared to euthymic patients. Also, depressive BD patients plasma induced higher expression of TNF-α compared to euthymic patients. However, chemokynes expression, such as CXCL9 and CXCL10, were reduced in depressive BD patients. However, chemokynes expression, such as CXCL9 and CXCL10, were reduced in depressive BD patients. Inflammatory cytokines such as IL-1β and TNF-α in bipolar manic and depressive patients demonstrate higher amounts of IL-1β mRNA that euthymic patients and depressive patients induced higher amounts of TNF-α mRNA levels than the patients in euthymic U937. Since the expression of CXCL9 and CXCL10 chemokines in plasma from patients with depressive TB, proved less significant expression in the group of manic patients when compared to controls and euthymic bipolar patients.

A disfunção do sistema imune inato e a neuroinflamação tem sido cada vez mais reconhecidas como elementos importantes na fisiopatologia do transtorno bipolar (TB). Como componentes essenciais da imunidade inata, os macrófagos tem múltiplas funções tanto na inibição como na promoção da proliferação celular e na reparação tecidual, sendo a diversidade e a plasticidade características marcantes deste tipo celular. A polarização M1 clássica e a polarização alternativa M2 de macrófagos representam dois extremos de um estado dinâmico na mudança da ativação dos mesmos. Os macrófagos do tipo M1 sintetizam citocinas próinflamatórias que inibem a proliferação de células circundantes e danificam tecidos, enquanto os macrófagos do fenótipo M2 liberam citocinas antiinflamatórias que podem promover reparo tecidual. Um desequilíbrio da polarização M1-M2 dos macrófagos é frequentemente associado a várias doenças ou condições inflamatórias. O objetivo desta tese foi, além de revisar a importância da inflamação sistêmica na modulação da resposta inflamatória da microglia/macrófagos e consequentemente seu potencial envolvimento na fisiopatologia do TB, avaliar o perfil de polarização M1/M2 em cultura de macrófagos de sujeitos com TB comparados a indivíduos saudáveis. Monócitos foram isolados a partir de sangue periférico de dez sujeitos com TB e dez indivíduos saudáveis e diferenciados em macrófagos através da adição de fator estimulante de colônia de macrófagos (MCSF) ao meio de cultura. Para induzir a polarização M1 ou M2, as culturas foram incubadas com IFN-y e LPS ou IL-4 respectivamente. Após a incubação, recolheram-se os sobrenadantes e mediram-se as citocinas (IL-1β, IL-6, IL-10 e TNF-α) por ensaio multiplex. A secreção das citocinas IL-1β, TNF-α e IL-6 características do protótipo M1 e citocinas IL-10 do protótipo M2 foram semelhantes entre os pacientes e os controles. Utilizou-se a razão TNF-α / IL-10 do fenótipo M1 para refletir o estado inflamatório dos participantes. Não foi observada diferença entre os grupos (p=0,627). Duas hipóteses diferentes poderiam explicar esses resultados: todos os pacientes incluídos neste estudo representam um estágio inicial da doença como evidenciado pela pontuação FAST total inferior a 11. De acordo com o modelo de estadiamento em TB, as alterações biológicas (incluindo a inflamação) parecem estar relacionadas com os episódios de humor e progressão da doença. Juntamente com estudos anteriores, os nossos dados sugerem que os pacientes nos estágios iniciais ainda preservam a função do sistema imunológico sem apresentar um desequilíbrio a favor do perfil de macrófagos M1 como tem sido observado em pacientes no estágio tardio, destacando a relevância da intervenção precoce no TB. Ainda, estes pacientes estavam em tratamento com estabilizadores de humor e é plausível especular que esses fármacos exerçam efeitos sobre a polarização de macrófagos. Estudos futuros em pacientes drug-free são essenciais para avaliar esta questão. Em conclusão, nossos achados sugerem que os pacientes TB não apresentam desequilíbrio na polarização dos macrófagos em favor do fenótipo pró-inflamatório M1. O fato de todos estes pacientes estarem em estágios iniciais da doença reforça os efeitos protetores da intervenção precoce no TB na prevenção de alterações do sistema imune e, consequentemente, na progressão da doença. / Innate immune system dysfunction and neuroinflammation have been recognized as important elements in the pathophysiology of bipolar disorder (BD). As essential players of innate immunity, macrophages have multiple roles in inhibition and promotion of cell proliferation and tissue repair. The classical M1 polarization and the M2 alternative polarization of macrophages represent two extremes of a dynamic state in their change of activation. M1 macrophages synthesize proinflammatory cytokines that inhibit the proliferation of surrounding cells and damage tissues, whereas macrophages of the M2 phenotype release antiinflammatory cytokines that may promote tissue repair. An imbalance of the M1-M2 polarization of macrophages is often associated with various diseases or inflammatory conditions. The aim of this thesis was to review the importance of systemic inflammation in modulating the inflammatory response of microglia/ macrophages and consequently their potential involvement in the pathophysiology of BD, and also evaluate the M1/M2 polarization profile in macrophages of patients with BD compared to healthy individuals. Blood monocytes were obtained from ten BD patients and ten healthy controls. These cells were activated/polarized into the M1 (IFNγ + LPS) or M2(IL-4) phenotype. Supernatants were collected and the cytokines (IL-1β, IL-6, IL-10 and TNF-α) were measured by multiplex assay. Secretion of the IL- 1β, TNF-α, IL-6 and IL-10 were similar between patients and controls. The TNF-α/IL- 10 ratio of the M1 phenotype was used to reflect the inflammatory state of the participants. There was no difference between groups (p = 0.627). Two hypotheses could explain these results: all patients included in this study represent an early stage of disease as evidenced by the FAST score below 11. According to the BD staging model, biological changes (including inflammation) appear to be related to mood episodes and disease progression. Together with previous studies, our data suggest that patients in early stages of BD still preserve immune system function without presenting an imbalance in favor of M1 macrophages as has been observed in latestage patients, highlighting the relevance of early intervention. Moreover, these patients were under treatment with mood stabilizers and it is plausible to speculate that these drugs have effects on macrophage polarization. Future studies in drug-free patients are essential to assess this issue. In conclusion, our findings suggest that BD patients do not present imbalance in macrophage polarization in favor of the M1 proinflammatory phenotype. The fact that all these patients are in the early stages of the disease reinforces the protective effects of early intervention in BD to prevent changes in the immune system and, consequently, prevent the progression of the disease.