Instituições hospitalares brasileiras: revisão integrativa sobre absenteísmo de trabalhadores de enfermagem / Brazilian hospital institutions: integrative review on nursing workers' absenteeism

Objetivo: analisar fatores relacionados ao absenteísmo dos profissionais de enfermagem em hospitais brasileiros. Fonte de dados: trata-se de um estudo de abordagem qualitativa, que adota o método de revisão integrativa da literatura para a identificação de produções sobre o tema do absenteísmo dos profissionais de enfermagem nas instituições hospitalares brasileiras, publicados entre os anos de 2005 e 2015. A amostra final para o estudo foi constituída por 24 artigos. Resumo das conclusões: identificou-se que as licenças de saúde são as principais causas do absenteísmo. Os profissionais de enfermagem que mais se ausentam do trabalho são do sexo feminino, com faixa etária de 30 a 50 anos, das categorias dos técnicos e auxiliares. Como medidas para redução do absenteísmo aponta-se: o dimensionamento adequado de pessoal; avaliações sistemáticas e individualizadas das taxas e causas do absenteísmo; ações preventivas de controle de riscos ocupacionais; promoção da saúde do trabalhador; gestão democrática e participativa; suporte terapêutico e alterações nas políticas de contratação. Conclui-se que cabe aos gestores a organização de estratégias que estimulem a participação dos trabalhadores nos processos decisórios e de readequação de serviços ou de processos produtivos.

Acompanhamento Terapêutico e Direitos Sociais: Territórios existenciais e sujeito biopsico-político-social / Therapeutic Accompaniment and Social Rights: Existential territories and biopsico-political-social subject / Acompañamiento Terapéutico y Derechos Sociales: Territorios existenciales y sujeto biopsico-político-social

Este artigo surge da pesquisa de doutorado que teve como objetivo analisar como o exercício de Direitos Sociais (DS) incide nos processos subjetivos e terapêuticos em curso, na clínica em Psicologia, articulada às políticas públicas brasileiras. Subsidiado por registros de experiências de 28 casos clínicos em Acompanhamento Terapêutico (AT), além de documentos institucionais, registros em diário de campo, imagens, dentre outros, focaliza a discussão na relação entre o Acompanhamento Terapêutico, como modalidade da clínica, e o exercício dos Direitos Sociais. A pesquisa analisou o modo como o discurso dos DS - educação, saúde, alimentação, trabalho, moradia, transporte, lazer, segurança, previdência social, proteção à maternidade e à infância e assistência aos desamparados - emergiu nos materiais e forneceu elementos para pensar como os sujeitos produzem e conduzem a si, na vida e nos processos terapêuticos, como seres subjetivos. Mediante os resultados, em interlocução com autoras da área, propõem-se três linhas de pensamentos integrados: (1) o AT como via, em ato, de exercício do Direito Social à saúde; (2) a relação entre território, processos terapêuticos e os DS; e (3) a radicalidade da clínica do sujeito biopsico-político-social, que a prática do AT explicita.

This article arises from the doctoral research that aimed to analyze how the exercise of Social Rights (SD) affects the subjective and therapeutic processes in progress, in the Psychology clinic, linked to Brazilian public policies. Subsidized by records of experiences of 28 clinical cases in Therapeutic Accompaniment (TA), in addition to institutional documents, field diary records, images, among others, focuses the discussion on the relationship between Therapeutic Accompaniment, as a modality of the clinic, and exercise Social Rights. The research analyzed how the DS discourse - education, health, food, work, housing, transportation, leisure, security, social security, maternity and childhood protection and assistance to the destitute - emerged in the materials and provided elements to think about how the subjects produce and conduct themselves, in life and in therapeutic processes, as subjective beings. Through the results, in interlocution with authors from the area, three integrated lines of thoughts are proposed: (1) the TA as a way, in action, of exercising the Social Right to health; (2) the relationship between territory, therapeutic processes and SD; and (3) the radicality of the clinic of the biopsico-political-social subject, which the TA practice makes explicit.

Este artículo surge de la investigación doctoral que tuvo como objetivo analizar cómo el ejercicio de los Derechos Sociales (DS) afecta los procesos subjetivos y terapéuticos en progreso, en la clínica de Psicología, vinculados a las políticas públicas brasileñas. Subsidiado por registros de experiencias de 28 casos clínicos en Acompañamiento Terapéutico (AT), además de documentos institucionales, registros de diario de campo, imágenes, entre otros, enfoca la discusión sobre la relación entre el Acompañamiento Terapéutico, como una modalidad de la clínica, y el ejercicio Derechos sociales. La investigación analizó cómo el discurso de DS (educación, salud, alimentación, trabajo, vivienda, transporte, ocio, seguridad, seguridad social, protección de la maternidad y la infancia y asistencia a los indigentes) surgió en los materiales y proporcionó elementos para pensar cómo los sujetos producen y conducense, en la vida y en los procesos terapéuticos, como seres subjetivos. A través de los resultados, en la interlocución con los autores del área, son propuestas tres líneas de pensamientos integradas: (1) el AT como una forma, en acción, de ejercer el Derecho Social a la salud; (2) la relación entre territorio, procesos terapéuticos y DS; y (3) la radicalidad de la clínica del sujeto biopsico-político-social, que la práctica de TA hace explícita.

Direito social à educação no Brasil pós-1988: Programa Mais Educação e a PNAS na gestão da pobreza / Social law to education in Brazil post-1988: More Education Program and PNAS in poverty management / Derecho social a la educación en Brasil post-1988: Programa Más Educación y la PNAS en la gestión de la pobreza

O artigo versa sobre a articulação entre o Programa Mais Educação (PME) e a Política Nacional de Assistência Social (PNAS) como via de garantia do direito social à Educação no Brasil pós-1988. Para isso, analisa a Constituição Federal de 1988, a Lei de Diretrizes e Bases da Educação Nacional de 1996, a PNAS e o Programa Mais Educação, situando como os discursos da estatística, justiça, economia e território, que foram, nos documentos e historicamente, sendo integrados na formulação das políticas e programas de garantia do direito à Educação pós-1988. Por meio dos resultados, infere que as estratégias do Estado para o acesso universal ao direito à Educação entre o PME e PNAS, amparado sob o discurso da esfera pública como via para alteração das desigualdades sociais, possibilitaram gerir uma parcela específica da população: sujeitos carentes, pobres, vulneráveis ou em risco.

The article deals with the articulation between the More Education Program (PME) and the National Social Assistance Policy (PNAS) as a way of guaranteeing social law to Education in Brazil after 1988. For this, it analyzes the jurisdiction of the Federal Constitution of 1988, the Law on Guidelines and Bases of National Education of 1996, the PNAS and the More Education Program, situating as the discourses of statistics, justice, economy and territory were, in the documents and historically, integrated into the formulation of policies and programs to guarantee the right to Education after 1988. By means of the results show that the State's strategies for universal access to the right to Education between PMEs and PNAS, supported by the discourse of the public sphere, as a way to change social inequalities, made it possible to manage a certain part of the population: poor, vulnerable or at risk.

El artículo versa sobre la articulación entre el Programa Más Educación (PME) y la Política Nacional de Asistencia Social (PNAS) como vía de garantía del derecho social a la Educación en Brasil post-1988. Para ello, analiza la Constitución Federal de 1988, de la Ley de Directrices y Bases de la Educación Nacional de 1996, de la PNAS y del Programa Más Educación, situando como los discursos de la estadística, justicia, economía y territorio fueron, en los documentos e históricamente, siendo integrados en la formulación de las políticas y programas de garantía del derecho a la Educación, después de 1988. Por medio de los resultados se desprende que las estrategias del Estado para el acceso universal al derecho a la Educación entre la PME y el PNAS, amparado bajo el discurso de la esfera pública como vía para alteración de las desigualdades sociales, posibilitaron gestionar una parte de la población: sujetos carentes, pobres, vulnerables o en riesgo.

Paradoxos nos 'benefícios' aos incapacitados: biopolítica e saúde mental / The paradoxes of government 'benefits' in individual considered incapable: biopolitics and mental health / Las paradojas de los 'beneficios' gubernamentales cedidos a los individuos considerados incapacitados: biopolítica e salud mental

Este ensaio objetiva problematizar os paradoxos dos 'benefícios' governamentais, cedidos aos indivíduos considerados incapacitados ao trabalho, devido algum diagnóstico em saúde mental. Para tanto, utiliza do conceito de Biopolítica, proposto por Michel Foucault, contrapondo a relatos de usuários e usuárias de serviços de saúde mental. Através dessas experiências, analisam-se impasses produzidos entre os princípios da Reforma Psiquiátrica Brasileira e os métodos utilizados pelos programas de seguridade social para garantia dos 'benefícios'. Na discussão, aponta-se que o paradoxo dos direitos se torna ainda mais intenso quando as reivindicações emancipatórias no campo da subjetividade estão localizadas numa sociedade em que os Direitos Sociais, previstos em Constituição, não foram conquistados pela maioria da população brasileira. Assim, se os 'benefícios' se colocam de forma paradoxal é, também, porque boa parte da população não tem direitos garantidos e precisam obter alimentação, moradia, saúde, dentre outros, à custa da manutenção de patologias como justificativa para garantir direitos.

This essay aims to discuss the paradoxes of government 'benefits', given to individuals considered incapable of work, due to some diagnosis in mental health. For this, use the concept of Biopolitics, proposed by Michel Foucault, in opposition to reports of users of mental health services. Through these experiences, analyze impasses produced between the principles of the brazilian Psychiatric Reform and the methods used by the social security programs to guarantee benefits. In the discussion, it is pointed out that the rights paradox becomes even more intense when the emancipatory claims in the field of subjectivity are located in a society in which the Social Rights, foreseen in Constitution, were not won by the majority of the brazilian population. Thus, if the benefits are paradoxical, it is also because a large part of the population does not have guaranteed rights and needs to obtain food, shelter, health, among others, at the expense of maintaining pathologies as justification for ensure rights.

Este ensayo objetiva discutir las paradojas de los 'beneficios' gubernamentales, cedidos a los individuos considerados incapacitados al trabajo, debido a algún diagnóstico en la salud mental. Para ello, se utiliza el concepto de Biopolítica, propuesto por Michel Foucault, en contrapunto a relatos de usuarios de servicios de salud mental. A través de esas experiencias, se analizan impasses producidos entre los principios de la Reforma Psiquiátrica brasileña y los métodos utilizados por los programas de seguridad social para garantizar los beneficios. En la discusión, se apunta que la paradoja de los derechos se vuelve aún más intenso cuando las reivindicaciones emancipatorias en el campo de la subjetividad están localizadas en una sociedad en la que los Derechos Sociales, previstos en la Constitución, no fueron conquistados por la mayoría de la población brasileño. Así, si los beneficios se plantean de forma paradójal es, también, porque buena parte de la población no tiene derechos garantizados y necesitan obtener alimentación, vivienda, salud, entre otros, a costa del mantenimiento de patologías como justificación para asegurar derechos.

The GRK2 Promoter Is Regulated by Early-Growth Response Transcription Factor EGR-1.

The G-protein-coupled receptor kinase 2 (GRK2) plays a major role in cardiovascular diseases, and its expression is increased in heart failure. However, only little is known about factors being involved in up-regulation of GRK2 expression through transcriptional regulation of its promoter. Since the transcription factor early-growth response 1 (EGR-1) is also up-regulated in patients with heart failure, we tested the hypothesis that EGR-1 regulates GRK2 transcription. Stimulation of immortalized rat cardiomyocytes (H9c2) with phorbol 12-myristate 13-acetate (PMA) resulted in up-regulation of Egr-1 and subsequently of Grk2 mRNA expression, with maximum Grk2 expression (p = 0.008) 5 hr after PMA stimulation and being abolished by actinomycin D, indicating a transcriptional mechanism. To identify naturally occurring variants affecting promoter transcriptional activity, we identified a novel G(-43)A polymorphism (rs182084609), which surrounded a putative EGR-1-binding site. While the minor A allele frequency was rare (0.02), this variant was used to explore regulation by EGR-1 and promoter construct with altered alleles at nt-43 were subjected of reporter assays in human embryonic kidney cells (Hek293). Here, EGR-1 over-expression resulted in a more than twofold increase in GRK2 promoter activity but only in the presence of the G-allele (p = 0.04). In electrophoretic mobility shift assays, EGR-1 over-expression resulted in a specific binding of transcription factors only to the G oligonucleotide. Finally, EGR-1 over-expression resulted in increased GRK2 mRNA expression (p = 0.03). We identified EGR-1 as a regulator of GRK2 transcription. Suppression of GRK2 expression by inhibition of EGR-1 binding to GRK2 might be a promising approach to mitigate adrenergic desensitization.

Relato de experiência da aproximação do CREPOP-RS ao meio acadêmico: formação em psicologia e políticas públicas / Experience report on the approximation of CREPOP-RS to the academic environment: training in psychology and public policy / Relato de experiencia de la aproximación del CREPOP-RS al entorno académico: formación en psicología y políticas públicas / Rapport d'expérience de l'approximation du centre de réference technique en psychologie et politiques publiques de l'état brésilien rio grande do sul (CREPOP-RS) au milieu académique: formation en psychologie et politiques publiques

Este relato de experiência discute o desenvolvimento de um projeto-piloto de aproximação do Centro de Referência Técnica em Psicologia e Políticas Públicas (CREPOP), do Conselho Regional de Psicologia do Rio Grande do Sul (CRP/RS), ao meio acadêmico. A aproximação objetivou fomentar a discussão sobre a formação em psicologia e as políticas públicas junto a estudantes e professores de graduação de duas universidades do estado do Rio Grande do Sul. O projeto foi executado em duas etapas: encontro com os estudantes inseridos em estágios e discussão sobre a temática seguida da sistematização dos dados obtidos; debate dos dados sistematizados com os professores que compõem o corpo docente do curso de psicologia de cada instituição. A partir dos resultados foi possível organizar os relatos dos estudantes nas seguintes categorias: 1) Presença da temática na formação; 2) Espaços de prática profissional; 3) Formação crítica; 4) Interdisciplinaridade; 5) Qualificação do corpo docente; 6) Atuação política; 7) Protagonismo estudantil. Por fim, avaliamos o projeto-piloto como um espaço potente de reflexão sobre a interface entre a formação em psicologia e as políticas públicas.

This experience report discusses the development of a pilot project for the approximation of the Centro de Referência Técnica em Psicologia e Políticas Públicas/Center for Technical Reference in Psychology and Public Policy (CREPOP), from the Conselho Regional de Psicologia do Rio Grande do Sul/Regional Council of Psychology of Rio Grande do Sul (CRP / RS), to the academic environment. The aim of this study was to foster a discussion about training in psychology and public policies among undergraduate students and professors from two universities in the state of Rio Grande do Sul. The project was carried out in two stages: a meeting with internship students and a discussion about the thematic followed by the systematization of the obtained data; discussion of systematized data with the professors who make up the faculty of the psychology course of each institution. From the results it was possible to organize the students' reports in the following categories: 1) Presence of the theme in training; 2) Spaces of professional practice; 3) Critical training; 4) Interdisciplinarity; 5) Qualification of teaching staff; 6) Political action; 7) Student protagonism. Finally, we evaluated the pilot project as a powerful space for reflection on the interface between training in psychology and public policy.

Este relato de experiencia discute el desarrollo de un proyecto-piloto de aproximación del Centro de Referencia Técnica en Psicología y Políticas Públicas (CREPOP), del 'Conselho Regional de Psicologia do Rio Grande do Sul' (CRP/RS), al entorno académico. La aproximación tuvo el objetivo de estimular la discusión sobre la formación en psicología y las políticas públicas junto a Estudiantes y profesores del grado de dos universidades del Estado del Rio Grande do Sul. El proyecto fue ejecutado en dos etapas: encuentro con estudiantes en pasantías y discusión sobre la temática seguida de la sistematización de los datos obtenidos; debate de los datos sistematizados con los profesores que componen el cuerpo docente del curso de psicología de cada institución. Con los resultados fue posible organizar los relatos de los estudiantes en las siguientes categorías: 1) Presencia de la temática en la formación; 2) Espacios de práctica profesional; 3) Formación crítica; 4) Interdisciplinaridad; 5) Cualificación del cuerpo docente; 6) Actuación política; 7) Protagonismo estudiantil. Por fin, evaluamos el proyecto-piloto como un potente espacio de reflexión sobre la interface entre la formación en psicología y las políticas públicas.

Ce rapport d'expérience discute le développement d'un projet-pilote d'approximation entre le Centre de Référence Technique en Psychologie et Politiques Publiques, le Conseil régional de Psychologie de l'état brésilien Rio Grande do Sul, et le milieu académique. L'approximation a eu l'objectif d'encourager le débat sur la formation en psychologie et les politiques publiques chez les élèves et les enseignants du premier cycle de deux universités dans l'état Rio Grande do Sul. Le projet a été réalisé en deux étapes: rencontre avec les étudiants stagiaires et débat sur le thème, suivi par la systématisation des données obtenues; discussion des données organisées avec les enseignants qui composent la faculté du cours de psychologie de chaque institution. D'après les résultats, il a été possible d'organiser les rapports d'étudiants dans les catégories suivantes: 1) Présence thématique dans la formation; 2) Espaces de pratique professionnelle; 3) Formation critique; 4) Interdisciplinarité; 5) Qualification du corps enseignant; 6) Action politique; 7) Le rôle central de l'étudiant. Enfin, nous avons évalué le projet-pilote comme un espace puissant de réflexion sur l'interface entre la formation en psychologie et les politiques publiques.

São todas as causas potencialmente causadoras de doença mental? os archivos brasileiros de hygiene mental e o esboço do homem moderno / Can any cause be a potential cause of mental illness? brazilian archives of mental hygiene and the outline of the modern man / ¿son todas las causas potencialmente causadoras de enfermedad mental? los archivos brasileños de hygiene mental y el esbozo del hombre moderno

Este artigo tem como objetivo discutir a noção de higiene mental preconizada no documento Archivos Brasileiros de Hygiene Mental, com base na abordagem foucaultiana de "governamentalidade" e estratégias de biopoder. Para isso, analisamos um periódico de saúde pública veiculado no Brasil entre as décadas de 1920 e 1940 pela Liga Brasileira de Hygiene Mental, no qual a noção de higiene mental se converte em certa profilaxia do comportamento, em prol de um ideal de progresso coletivo para o Brasil daquela época. A discussão de tal material evidencia que os processos de governo da vida se sustentam em verdades sobre os sujeitos que legitimam as necessidades da urbanização emergente e, como efeito, constituem elementos para o ideal de homem moderno

This paper aims at discussing the notion of mental hygiene advocated by the document Brazilian Archives of Mental Hygiene by considering the Foucauldian approach of govern mentality and bio-power strategies. We have analyzed a public health journal published by the Brazilian League of Mental Hygiene in Brazil from the 1920s to the 1940s in which the notion of mental hygiene was converted into a certain behavioral prophylaxis, in favor of a collective ideal of progress in Brazil at that time. The discussion about such material has evidenced that the process of government of life grounded in truths about the subjects who both legitimate the needs of the emerging urbanization and, as a result, constitute elements for the ideal of the modern man

Este artículo pretende discutir la noción de la higiene mental preconizada en el documento Archivos Brasileiros de Hygiene Mental a partir del abordaje de Foucault sobre a gobernabilidad y estrategias de biopoder. Para eso, analizamos una revista de salud pública divulgada en Brasil entre las décadas de 1920 y 1940 por la Liga Brasileira de Hygiene Mental donde la noción de higiene mental se convierte en cierta profilaxis del comportamiento, a favor de un ideal de progreso colectivo para Brasil en ese momento. La discusión de tal material demuestra que los procesos de gobierno de la vida son apoyados por verdades sobre los procesos que legitiman las necesidades de la urbanización emergente y, como efecto, constituyen elementos para el ideal del hombre moderno

A internação compulsória como estratégia de governamentalização de adolescentes usuários de drogas / The compulsory hospitalization as a governmentalization strategy for the adolescent drug users / El internamiento como estrategia de gobernamentalización de adolescentes consumidores de drogas

Resumo Este artigo tem como objetivo problematizar a internação compulsória de adolescentes usuários de drogas em um serviço de saúde mental de Porto Alegre/RS a partir da noção de Biopolítica, proposta por Michel Foucault. Assim, primeiramente, descrevemos o processo de internação compulsória e os percursos dos jovens no serviço para depois avançarmos na análise da internação compulsória como uma estratégia de governamentalização da vida. Esta análise leva para a desnaturalização das ações contemporâneas do Estado direcionadas aos adolescentes usuários de drogas e aos atravessamentos dos interesses de mercado que operam no contexto dessa política. Por fim, apontamos a suspensão dos elementos universais que permeiam a temática das drogas como possibilidade de ruptura dos padrões de cuidado até então colocados no campo da saúde.

Abstract This article aims to discuss the compulsory hospitalization of adolescent drug users in a mental health service in the city of Porto Alegre/RS from the notion of Bio-politics, proposed by Michel Foucault. So, first, we describe the process of compulsory hospitalization and the passages of young people in the service, and thus we move to the analysis of compulsory hospitalization as a strategy of governmentalization of life. This analysis leads to the denaturalization of contemporary state actions directed to adolescent's drug users and the crossings market interests operating in the context of this policy. Finally, we point to the suspension of the universal elements that permeate the theme of drugs as a possibility to break off the standards of care placed in the health field.

Resumen Ese artículo tiene como objetivo problematizar el internamiento forzado de adolescentes consumidores de drogas en un servicio de salud mental de Porto Alegre/RS a partir de la noción de la Biopolítica, propuesta por Michel Foucault. Así, primero, describimos el proceso de internamiento forzado y el camino de los jóvenes en el servicio investigado como un fenómeno inherente al campo de la problemática de las racionalidades del gobierno de las conductas. Análisis que desnaturaliza las acciones de hoy día del Estado dirigidas a los adolescentes consumidores de drogas al discutir los intereses del mercado que operan en el contexto de esa política. Por último, apuntamos la suspensión de los elementos universales que permean la temática como posibilidad de rotura de los patrones de cuidado hasta el momento colocados en el campo.

Velhice e Identidade: Significações de Mulheres Idosas / Aging and Identity: Meanings of Elderly Women

Este estudo é de caráter qualitativo e propõe reflexões sobre a construção da identidade em mulheres idosas. Foram realizadas entrevistas semi-estruturadas com seis idosas, e os dados foram analisados por meio da Análise Compreensiva de Base Fenomenológica. Constatou-se que a mulher idosa pode estar ressignificando seu papel na sociedade, e, hoje, ruma para a construção de um espaço social onde haja igualdade de direitos e deveres...

This paper presents the results of a survey that focus on reflections on the construction of identity in elderly women. Interviews were conducted by semi-structured form with six elderly women and the data were analyzed based on the Comprehensive Review of Phenomenological Base. Not reduce the subject to biological, genetic, social allows us to develop these projects and achievements in this time of life where the experience can lead to a better well-being and quality of life...

Ketamine effects on brain function--simultaneous fMRI/EEG during a visual oddball task.

BACKGROUND: Behavioral and electrophysiological human ketamine models of schizophrenia are used for testing compounds that target the glutamatergic system. However, corresponding functional neuroimaging models are difficult to reconcile with functional imaging and electrophysiological findings in schizophrenia. Resolving the discrepancies between different observational levels is critical to understand the complex pharmacological ketamine action and its usefulness for modeling schizophrenia pathophysiology. METHODS: We conducted a within-subject, randomized, placebo-controlled pharmacoimaging study in twenty-four male volunteers. Subjects were given low-dose S-ketamine (bolus prior to functional imaging: 0.1mg/kg during 5min, thereafter continuous infusion: 0.015625mg/kg/min reduced by 10% every ten minutes) or placebo while performing a visual oddball task during simultaneous functional magnetic resonance imaging (fMRI) with continuous recording of event-related potentials (P300) and electrodermal activity (EDA). Before and after intervention, psychopathological status was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale. RESULTS: P300 amplitude and corresponding BOLD responses were diminished in the ketamine condition in cortical regions being involved in sensory processing/selective attention. In both measurement modalities separation of drug conditions was achieved with area under the curve (AUC) values of up to 0.8-0.9. Ketamine effects were also observed in the clinical, behavioral and peripheral physiological domains (Positive and Negative Syndrome Scale, reaction hit and false alarm rate, electrodermal activity and heart rate) which were in part related to the P300/fMRI measures. CONCLUSION: The findings from our ketamine experiment are consistent across modalities and directly related to observations in schizophrenia supporting the validity of the model. Our investigation provides the first prototypic example of a pharmacoimaging study using simultaneously acquired fMRI/EEG.

Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate.

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.

Dopamine Agonists and their risk to induce psychotic episodes in Parkinson's disease: a case-control study.

BACKGROUND: Psychosis is rare in untreated patients with Parkinson's disease (PD) but the prevalence rises to 40% during dopaminergic treatment. So far, no systematic comparison of the psychogenic potential of different dopaminergic drugs had been performed. METHODS: Eighty PD patients with psychotic episodes were compared to an age-matched control group of PD patients without psychotic episodes (n = 120) in a cross-sectional retrospective study. RESULTS: We found a positive correlation between psychotic episodes and dementia, number of concomitant medication, and pergolide intake. Odds ratio calculation confirmed the association with dementia. With respect to dopaminergic treatment, pergolide showed the highest odds ratio, levodopa the lowest. An adjusted logistic regression model confirmed the strong association with psychotic episodes and pergolide and no association with levodopa (adjusted odds ratio 2.01 and 0.11, respectively). CONCLUSION: The analysis indicates that dementia and concomitant medication are factors in PD associated with psychotic symptoms. Furthermore, different dopaminergic drugs showed markedly different associations with psychotic symptoms.

Cortical dysfunction in patients with Huntington's disease during working memory performance.

Previous functional neuroimaging studies on executive function suggested multiple functionally aberrant cortical regions in patients with Huntington's disease (HD). However, little is known about the neural mechanisms of working memory (WM) function in this patient population. The objective of this study was to investigate the functional neuroanatomy of WM in HD patients. We used event-related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in 16 healthy control subjects and 12 mild to moderate stage HD patients. We excluded incorrectly performed trials to control for potential accuracy-related activation confounds. Voxel-based morphometry (VBM) was used to control for confounding cortical and subcortical atrophy. We found that HD patients were slower and less accurate than healthy controls across all WM load levels. In addition, HD patients showed lower activation in the left dorso- and ventrolateral prefrontal cortex, the left inferior parietal cortex, the left putamen, and the right cerebellum at high WM load levels only. VBM revealed gray matter differences in the bilateral caudate nucleus and the thalamus, as well as in inferior parietal and right lateral prefrontal regions. However, volumetric abnormalities in the patient group did not affect the activation differences obtained during WM task performance. These findings demonstrate that WM-related functional abnormalities in HD patients involve distinct WM network nodes associated with cognitive control and subvocal rehearsal. Moreover, aberrant cortical function in HD patients may occur in brain regions, which are relatively well preserved in terms of brain atrophy.

Aberrant connectivity of lateral prefrontal networks in presymptomatic Huntington's disease.

In clinically presymptomatic individuals with the Huntington's disease (HD) gene mutation, functional neuroimaging data have suggested a dysfunction of multiple cortical and subcortical regions including the prefrontal and parietal cortex, as well as the striatum. Although it has been hypothesized that these activation differences most likely reflect aberrant corticostriatal circuits, the functional coupling of neural networks associated with cognitive performance has not been investigated so far. In this study, we used functional magnetic resonance imaging (fMRI) and multivariate analytic techniques to investigate memory-related patterns of functional connectivity in healthy controls (n=16) and pre-HD individuals (n=16). Independent component analyses (ICA) revealed distinct bilateral frontostriatal and frontoparietal networks that were activated during a verbal working memory paradigm in both healthy controls and pre-HD subjects. Compared with healthy controls, pre-HD individuals exhibited lower functional connectivity in left lateral prefrontal and parietal regions as well as in the bilateral putamen. Functional connectivity indices in the left putamen were negatively correlated with the CAG repeat size and the UHDRS behavioral score, and positively correlated with the predicted years to manifest symptom onset. The connectivity of the right putamen was negatively correlated with the UHDRS motor score. In pre-HD individuals, these results suggest an early frontostriatal and frontoparietal deficit of dissociable functional networks associated with executive processing.

Dorsolateral prefrontal cortex dysfunction in presymptomatic Huntington's disease: evidence from event-related fMRI.

Evidence from magnetic resonance imaging (MRI) suggests early structural and functional brain changes in individuals with the Huntington's disease (HD) gene mutation who are presymptomatic for the motor symptoms of the disorder (pre-HD subjects). The objective of this study was to investigate the functional neuroanatomy of verbal working memory (WM) in pre-HD subjects. By means of event-related functional MRI, we studied healthy controls (n = 16) and pre-HD subjects (n = 16) with a parametric WM paradigm comprising three different WM load levels. Voxel-based morphometry (VBM) was used to control potentially confounding brain atrophy. Although WM performance did not significantly differ between pre-HD subjects and healthy controls, pre-HD subjects showed a significantly decreased activation of the left dorsolateral prefrontal cortex (DLPFC) at intermediate and high WM load levels only. This region was not affected by early cortical atrophy, as revealed by VBM. Pre-HD individuals close to the onset of motor symptoms showed an increased activation of the left inferior parietal lobule and the right superior frontal gyrus compared with both pre-HD subjects far from symptom onset and healthy controls. In addition, the activation level in the left DLPFC was positively correlated with the UHDRS cognitive subscore in pre-HD subjects. Our findings demonstrate that early functional brain changes in pre-HD subjects may occur in the DLPFC before manifest cortical atrophy, and support a role of this region in the expression of clinical symptoms. Compensatory brain responses in pre-HD individuals may occur with closer proximity to the onset of manifest clinical symptoms.

Cocaine- and amphetamine-regulated transcript is increased in Huntington disease.

Weight loss and anxiety frequently occur in individuals with Huntington's disease (HD) but the underlying mechanisms are not well-understood. Peptides produced in the hypothalamus are involved in regulating energy homeostasis and emotion. Recent data suggest that changes in neuropeptide levels may be reflected in the cerebrospinal fluid (CSF), and could therefore serve as biomarkers for HD. Cocaine- and amphetamine-regulated transcript (CART) is a neuropetide expressed in several brain regions such as the hypothalamus, amygdala, and hippocampus. CART has been shown to increase anxiety and reduce food intake in rodents by as yet unknown mechanisms. Individuals with a CART mutation exhibit increased anxiety. In cross-sectional CSF samples from HD patients (n = 39), we found that levels of CART peptide were significantly increased by 23% compared to control subjects (n = 28). Increased CART levels in HD therefore hold promise as a biomarker as well as a potential pathogenic mediator of symptoms.

Thalamic atrophy in Huntington's disease co-varies with cognitive performance: a morphometric MRI analysis.

The pattern of motor, behavioral and cognitive symptoms in Huntington's disease (HD) implicates dysfunction of basal-ganglia-thalamo-cortical circuits. This study explored if cognitive performance in HD is correlated with localized cerebral changes. Psychomotor functions were investigated by verbal fluency, Stroop color word and Digit Symbol tests in 44 HD patients and 22 controls. Three-dimensional magnetic resonance imaging (MRI) data were analyzed with regard to regional gray matter changes by use of the observer-independent whole-brain-based approach of voxel-based morphometry (VBM). Using statistical parametric mapping, the MRI data of the HD patients were analyzed in an ANCOVA including the individual results of the neuropsychological tests. Besides striatal areas, symmetrical regional atrophy of the thalamus was found to co-vary significantly with cognitive performance (P < 0.001, corrected for multiple comparisons). In particular, thalamic subnuclei projecting to prefrontal areas (dorsomedial subnucleus) and connected to the striatum (centromedian/parafascicular and ventrolateral nuclear complex) displayed volume loss, in agreement with neuropathological studies. These results suggest that thalamic degeneration contributes in an important way to the impairment of executive function in early HD. Patients who are impaired in executive tests display structural double lesions of the basal-ganglia-thalamo-cortical circuitry both at the striatal and at the thalamic level.

Global cerebral atrophy in early stages of Huntington's disease: quantitative MRI study.

Global brain atrophy was determined in 70 patients suffering from Huntington's disease (HD) and 70 healthy controls, using brain parenchymal fractions calculated from 3D MRI data in a standardized procedure. In HD patients, brain parenchymal fractions were significantly reduced compared to controls in all age groups; the physiological decline with age was less pronounced in HD. However, brain parenchymal fraction values did not allow the prediction of clinical impairment (as assessed by clinical scores). Global brain parenchyma reduction seems to be an early or even constitutional feature of HD, but clinical symptoms appear to reflect regional rather than global atrophy. Overall, MRI-based brain volume quantification correlated with clinical scores clarifies the functional impact of morphological brain alterations.

Amyotrophic lateral sclerosis: disease stage related changes of tau protein and S100 beta in cerebrospinal fluid and creatine kinase in serum.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to progressive cell death of upper and lower motor neurons and reactive astrogliosis. Two proteins which may be relevant in this respect (tau and S100 beta) were studied in cerebrospinal fluid (CSF) next to routine parameters in 20 patients with sporadic ALS and 20 age-matched controls. Serum levels of creatine kinase (CK) were also determined to monitor the muscular involvement. S100 beta showed a significant decrease in CSF over the disease course (P=0.024). CSF tau as well as serum CK were elevated in 70% of the ALS patients. While highest CSF tau levels were found rather in the early disease stages, serum CK showed a shift of the peak values to several months later. Elevation of the CSF/serum albumin quotient occurred in 20% of the cases most likely representing a non-specific finding in ALS.