Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids

Background and aims: The mechanisms of interindividual variation of lipid regulation by statins, such as the low-density lipoprotein cholesterol (LDL) lowering effects, are not fully understood yet. Here, we used a gut microbiota depleted mouse model to investigate the relation between the gut microbiota and the regulatory property of atorvastatin on blood lipids. Methods: Mice (C57BL/6) with intact gut microbiota or antibiotic induced abiotic mice (ABS) were put on standard chow diet (SCD) or high fat diet (HFD) for six weeks. Atorvastatin (10 mg/kg body weight/day) or a control vehicle were applied per gavage for the last four weeks of dietary treatment. Blood lipids including total cholesterol, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and sphingolipids were measured to probe microbiota-dependent effects of atorvastatin. The expression of genes involved in hepatic and intestinal cholesterol metabolism was analyzed with qRT-PCR. The alteration of the microbiota profile was examined using 16S rRNA qPCR in mice with intact gut microbiota. Results: HFD feeding significantly increased total blood cholesterol and LDL levels, as compared to SCD in both mice with intact and depleted gut microbiota. The cholesterol lowering effect of atorvastatin was significantly attenuated in mice with depleted gut microbiota. Moreover, we observed a global shift in the abundance of several sphingolipids upon atorvastatin treatment which was absent in gut microbiota depleted mice. The regulatory effect of atorvastatin on the expression of distinct hepatic and intestinal cholesterol-regulating genes, including Ldlr, Srebp2 and Npc1l1 was altered upon depletion of gut microbiota. In response to HFD feeding, the relative abundance of the bacterial phyla Bacteroidetes decreased, while the abundance of Firmicutes increased. The altered ratio between Firmicutes to Bacteroidetes was partly reversed in HFD fed mice treated with atorvastatin. Conclusions: Our findings support a regulatory impact of atorvastatin on the gut microbial profile and, in turn, demonstrate a crucial role of the gut microbiome for atorvastatin-related effects on blood lipids. These results provide novel insights into potential microbiota-dependent mechanisms of lipid regulation by statins, which may account for variable response to statin treatment

Social instigation and aggressive behavior in mice: role of 5-HT 1A and 5-HT 1B receptors in the prefrontal cortex

Abstract Rationale Social instigation is used in rodents to induce high levels of aggression, a pattern of behavior with certain parallels to that of violent individuals. This procedure consists of a brief exposure to a provocative stimulus male, before direct confrontation with an intruder. Studies using 5-HT 1A and 5-HT 1B receptor agonists show an effective reduction in aggressive behavior. An important site of action for these drugs is the ventral orbitofrontal cortex (VO PFC), an area of the brain which is particularly relevant in the inhibitory control of aggressive and impulsive behavior. Objectives The objectives of the study are to assess the anti-aggressive effects of 5-HT 1A and 5-HT 1B agonist receptors [8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) and 129] in the VO PFC of socially provoked male mice. To confirm the specificity of the receptor, 5-HT 1A and 5-HT 1B antagonist receptors (WAY-100,635 and SB-224,289) were microinjected into the same area, in order to reverse the agonist effects. Results 8-OH-DPAT (0.56 and 1.0 μg) reduced the frequency of attack bites. The lowest dose of CP-93,129 (0.1 μg) also decreased the number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming, and the latter, increasing these acts. Specific participation of the 1A and 1B receptors was verified by reversal of anti-aggressive effects using selective antagonists WAY-100,635 (10.0 μg) and SB-224,289 (1.0 μg). Conclusions The decrease in aggressiveness observed with microinjections of 5-HT 1A and 5-HT 1B receptor agonists into the VO PFC of socially provoked mice, supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner

Déficits Primários e Secundários de Funções Executivas Pós-TCE: análise de dissociações

The present study evaluated the presence of associations and dissociations between impairments in episodic memory and executive functions in patients with traumatic brain injury (TBI), and verified whether these deficits were primary or secondary. Eighty-one patients with TBI were assessed using the Rey Auditory Verbal Learning Test and the Hayling Test. The results suggest that impairments in inhibition speed may contribute to deficits in episodic memory, and that initiation and inhibition abilities may be complementary and the first precedes the second. Our findings highlighted that primary executive impairment following TBI may lead to episodic memory deficits.Este estudo avaliou as associações e dissociações encontradas entre déficits de memória episódica em relação aos de funções executivas e verificou se estes déficits encontrados eram primários ou secundários. Os 81 pacientes pós-Traumatismo Cranioencefálico (TCE) foram avaliados por meio do Teste de Aprendizagem Auditivo-Verbal de Rey e do Teste Hayling. Os resultados sugerem que prejuízo na velocidade de controle inibitório pode contribuir para déficit na memória episódica e que as velocidades de iniciação e inibição parecem ser complementares, mas a primeira precede a segunda. Nossos achados ressaltam que os prejuízos executivos provavelmente sejam primários em nossa amostra de pacientes pós-TCE e que estes prejuízos podem causar déficits na memória episódica

Human-Centered Design Components in Spiral Model to Improve Mobility of Older Adults

As humans grow older, their cognitive needs change more frequently due to distal and proximal life events. Designers and developers need to come up with better designs that integrate older users’ needs in a short period of time with more interaction with the users. Therefore, the positioning of human end users in the center of the design itself is not the key to the success of design artifacts while designing applications for older adults to use a smartphone as a promising tool for journey planner while using public transportation. This study analyzed the use of human-centered design (HCD) components, the spiral model, and the design for failure (DfF) approach to improve the interactions between older users and designers/developers in gathering usability needs in the concept stage and during the development of the app with short iterative cycles. To illustrate the importance of the applied approach, a case study with particular focus on older adults is presented.The results presented in this study are based on “Assistant” project funded by AAL JP, co-funded by the European Union. The authors would like to thank Dr. Stefan Carmien, my colleague in Assistant, for mentoring and for reading and making comments in the earlier versions of this chapter; participating research institutes; funding agencies; and companies from Finland, Spain, Austria, France, and the United Kingdom for their active support throughout the project

Funcionamento executivo no traumatismo cranioencef?lico : estudos neuropsicol?gicos de desempenho e de neuroimagem estrutural

Made available in DSpace on 2015-04-14T13:22:15Z (GMT). No. of bitstreams: 1 449211.pdf: 158484 bytes, checksum: 16db88bea9b358e2895521faa0ba81c3 (MD5) Previous issue date: 2013-03-08TBI individuals may present great functional disability. Most of these dysfunctions is related to clinical manifestations of cognitive impairment, which creates several losses in different areas, such as work, autonomy and, as a consequence, on the quality of life of individuals and their relatives. In this context, studies have discussed the heterogeneity of clinical manifestations in TBI, which challenges research of clinical trials and characterization studies as a whole. One of the main issues in the field of clinical and cognitive neuropsychology is the understanding of executive functions (EF) post-TBI and their neural correlates. For this reason, it is of great interest to integrate neuropsychological evaluation, classical methods of clinical neuropsychology and neuroimaging. This dissertation aimed to investigate EF in TBI individuals by means of two studies. The first study investigated the profile of executive functioning in a sample of TBI individuals. This study included an extensive neuropsychological evaluation with a primary focus in FE. Results showed three different profiles of FE: Cluster 1 was characterized by difficulties in processing speed, phonemic verbal fluency and inhibition; Cluster 2 was formed by multiple deficits in FE, such as processing speed, working memory, planning, cognitive flexibility and verbal fluency; finally Cluster 3 had no or very mild difficulties on the EF examined. The second study investigated the two cases of adults with mild TBI with different education levels on EF performance and brain structures volumetry and cortical thickness. The patient with high education surpassed the patient with low education in four variables of FE and different structures of brain volume and cortical thickness. The results suggest that education seems to be a feature of cognitive reserve in mild TBI. Together, these studies contribute for answers to an important question about heterogeneity of TBI and clinical studies. Our findings reinforce the importance of group interventions constituted according to sociocultural variables and cognitive profiles, rather than sociocultural, individual and clinical variables. However, when considering case analysis, sociocultural variables seem to be important for cognitive performance and brain reorganization in mild TBI.Os indiv?duos que sofrem TCE podem ter grande incapacidade funcional. A maior parte dessas disfun??es tem rela??o com manifesta??es cl?nicas de preju?zos cognitivos, o que cria diversas perdas em diferentes ?reas, tais como, trabalho, autonomia e como conseq??ncia uma qualidade de vida n?o apenas o indiv?duo, mas tamb?m todos aqueles que est?o envolvidos com ele. Neste contexto, os estudos t?m discutido a heterogeneidade das manifesta??es cl?nicas do TCE, ainda um grande desafio em ensaios cl?nicos e estudos de caracteriza??o como um todo. A maior lacuna na ?rea de neuropsicologia cl?nica e cognitiva ? a compreens?o das fun??es executivas (FE) p?s-TCE e de seus correlatos neurais. ? de grande interesse integrar a avalia??o neuropsicol?gica, os m?todos cl?ssicos cl?nicos da neuropsicologia, e t?cnicas avan?adas de neuroimagem. A presente disserta??o visou ainvestigar FE no contexto cl?nico do TCE. Dois estudos foram realizados nesta disserta??o. O primeiro estudo avaliou o perfil de funcionamento executivo de uma amostra de TCE. Este panorama executivo foi baseado em uma extensa avalia??o neuropsicol?gica com foco principal em FE. Os resultados apontaram tr?s perfis diferentes de FE: o Cluster 1 foi caracterizado por dificuldades em velocidade de processamento, flu?ncia verbal fon?mica e inibi??o; o Cluster 2 foi formado por m?ltiplos d?ficits em FE, tais como, de velocidade de processamento, mem?ria de trabalho, planejamento, flexibilidade cognitiva e flu?ncia verbal; finalmente o Cluster 3 n?o apresentou dificuldades executivas objetivamente examinadas. O segundo estudo investigou o desempenho em tarefas de FE e ?ndices de volumetria e de espessura cortical em regi?es de interesse por seu correlato com FE em dois casos de adultos com TCE leve com diferentes escolaridades. O paciente com alta escolaridade superou o paciente de baixa escolaridade em quatro vari?veis das FE e em diferentes estruturas de volume cerebral e espessura cortical. Os resultados sugerem que a educa??o parece ser uma caracter?stica de reserva cognitiva no TCE leve. Juntos, esses estudos contribuem com respostas a uma pergunta importante sobre poss?veis solu??es para a heterogeneidade neuropsicol?gica do TCE. Nossos achados refor?am a relev?ncia de interven??es em grupo constitu?do de acordo com vari?veis socioculturais e perfis cognitivos. Para a forma??o de subgrupos cl?nicos de TCE, seu funcionamento executivo parece ser sido a principal vari?vel, na medida em que n?o houve diferen?as quanto a fatores socioculturais,m individuais nem cl?nicos. No entanto, quando se considera an?lise de casos, vari?veis socioculturais parecem importantes para o desempenho cognitivo e para a reorganiza??o cerebral no TCE leve