Targeting CEACAM5-positive solid tumors using NILK-2401, a novel CEACAM5xCD47 κλ bispecific antibody.

Background: Blocking the CD47 "don't eat me"-signal on tumor cells with monoclonal antibodies or fusion proteins has shown limited clinical activity in hematologic malignancies and solid tumors thus far. Main side effects are associated with non-tumor targeted binding to CD47 particularly on blood cells. Methods: We present here the generation and preclinical development of NILK-2401, a CEACAM5×CD47 bispecific antibody (BsAb) composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format). Results: NILK-2401 is a fully human BsAb binding the CEACAM5 N-terminal domain on tumor cells by its lambda light chain arm with an affinity of ≈4 nM and CD47 with its kappa chain arm with an intendedly low affinity of ≈500 nM to enabling tumor-specific blockade of the CD47-SIRPα interaction. For increased activity, NILK-2401 features a functional IgG1 Fc-part. NILK-2401 eliminates CEACAM5-positive tumor cell lines (3/3 colorectal, 2/2 gastric, 2/2 lung) with EC50 for antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity ranging from 0.38 to 25.84 nM and 0.04 to 0.25 nM, respectively. NILK-2401 binds neither CD47-positive/CEACAM5-negative cell lines nor primary epithelial cells. No erythrophagocytosis or platelet activation is observed. Quantification of the pre-existing NILK-2401-reactive T-cell repertoire in the blood of 14 healthy donors with diverse HLA molecules shows a low immunogenic potential. In vivo, NILK-2401 significantly delayed tumor growth in a NOD-SCID colon cancer model and a syngeneic mouse model using human CD47/human SIRPα transgenic mice and prolonged survival. In cynomolgus monkeys, single doses of 0.5 and 20 mg/kg were well tolerated; PK linked to anti-CD47 and Fc-binding seemed to be more than dose-proportional for Cmax and AUC0-inf. Data were validated in human FcRn TG32 mice. Combination of a CEACAM5-targeting T-cell engager (NILK-2301) with NILK-2401 can either boost NILK-2301 activity (Emax) up to 2.5-fold or allows reaching equal NILK-2301 activity at >600-fold (LS174T) to >3,000-fold (MKN-45) lower doses. Conclusion: NILK-2401 combines promising preclinical activity with limited potential side effects due to the tumor-targeted blockade of CD47 and low immunogenicity and is planned to enter clinical testing.

Sigilo profissional na relação médico-paciente: conhecimento de estudantes de medicina / Confidentiality in physician-patient relation: the knowledge of medical students / Secreto profesional en la relación médico-paciente: conocimientos de los estudiantes de medicina

Resumo A relação entre médico e paciente deve se estabelecer conforme parâmetros que garantam autonomia e liberdade a ambos. Entre tais parâmetros está o sigilo, que representa um direito essencial do paciente e uma obrigação do médico. Este estudo avalia o conhecimento de estudantes de medicina sobre o sigilo profissional mediante aplicação de um questionário a 409 alunos do primeiro ao quarto ano da graduação. Comparando a mediana de correspondência com as respostas esperadas, observou-se que o primeiro ano obteve notas menores nas situações-problemas. Concluiu-se que há diferença no grau de conhecimento entre os anos da graduação e que ele evolui no segundo ano, mantendo-se na mesma proporção até o quarto ano.

Abstract Physician-patient relations must follow parameters to ensure autonomy and liberty to both. One such parameter is confidentiality, recognized as a patient right and an obligation of physicians. Hence, this study evaluated student knowledge about medical confidentiality by applying a questionnaire to 409 medical undergraduates (first- to fourth-years). Comparing the median match to the expected answers revealed that first-years achieved the lowest scores on the problem-situations. Results show a clear difference in the degree of knowledge between years, increasing by the second year and maintained until the fourth year.

Resumen La relación entre el médico y el paciente debe basarse en parámetros que garanticen la autonomía y la libertad a ambos. Entre estos parámetros se destaca el secreto profesional, que es un derecho esencial del paciente y una obligación del médico. Este estudio evaluó los conocimientos de los estudiantes de medicina sobre el secreto profesional mediante la aplicación de un cuestionario a 409 estudiantes de primer a cuarto año de la carrera. La comparación entre la mediana de correspondencia y las respuestas esperadas dio como resultado que el primer año obtuvo puntuaciones más bajas en las situaciones problemáticas. Se concluyó que existe una diferencia en el nivel de conocimientos entre los años del grado y que evoluciona en el segundo año, manteniéndose en la misma proporción hasta el cuarto.

Conhecimento e percepção de estudantes de medicina sobre abortamento legal / Knowledge and perception of medical students on legal abortion / Conocimiento y percepción de estudiantes de medicina sobre el aborto legal

Resumo O abortamento é prática frequente no Brasil e importante causa de mortalidade materna. Mesmo em condições legais, as mulheres enfrentam diversas barreiras para acessar o procedimento, muitas vezes em decorrência do desconhecimento de médicos acerca dos marcos regulatórios. Este artigo objetiva avaliar o conhecimento de estudantes da Faculdade de Medicina da Bahia da Universidade Federal da Bahia sobre as leis que permitem o aborto no Brasil, bem como a percepção desses estudantes sobre o tema. Trata-se de estudo de corte transversal com análise qualitativa de dados obtidos pela aplicação de questionário a 237 estudantes. Apesar de os participantes demonstrarem conhecimento teórico adequado dos aspectos legais, houve incongruências e erros quando questionados sobre aplicação das leis em situações práticas de atendimento ao aborto legal. Os resultados demonstram a necessidade de fortalecer a abordagem do tema durante a graduação, de modo multidisciplinar e transversal. Vale ressaltar, por fim, que se observou entre os participantes inclinação favorável à descriminalização do aborto.

Abstract Abortion is a frequent practice in Brazil and a major cause of maternal mortality. Even under legal conditions, women face many barriers to access the procedure, often related to physicians' unfamiliarity with the legislation. This article assess the knowledge of medical students from Faculdade de Medicina da Bahia of Universidade Federal da Bahia about the laws that regulate abortion in Brazil and their perception on the topic. This qualitative cross-sectional study analyzed data collected from a questionnaire answered by 237 students. Although the participants showed adequate theoretical knowledge of legal aspects, discrepant and incorrect answers were observed when asked about law enforcement in situations of legal abortion care, showing that education focused on the topic is required using multidisciplinary and transversal discussions during the medical course. Finally, we observed that participants tended to favor decriminalization of abortion.

Resumen El aborto es una práctica frecuente en Brasil y una importante causa de mortalidad materna. Incluso cuando cumplen con las condiciones legales, las mujeres enfrentan varias barreras para acceder al procedimiento, a menudo debido a la falta de conocimiento de los médicos sobre los marcos regulatorios. Este artículo tiene como objetivo evaluar el conocimiento de los estudiantes de la Facultad de Medicina de la Universidad Federal de Bahía sobre las leyes que permiten el aborto en Brasil, así como la percepción de estos estudiantes sobre el tema. Se trata de un estudio transversal con análisis cualitativo de datos obtenidos mediante la aplicación de un cuestionario a 237 alumnos. Si bien los participantes demostraron un conocimiento teórico adecuado de los aspectos legales, hubo inconsistencias y errores cuando se les preguntó sobre la aplicación de las leyes en situaciones prácticas de atención al aborto legal. Los resultados demuestran la necesidad de fortalecer la enseñanza de la temática durante la graduación, de manera multidisciplinar y transversal. Finalmente, cabe mencionar que los participantes mostraron una inclinación favorable hacia la despenalización del aborto.

Significados de morte e morrer para profissionais de unidade de terapia intensiva / Meanings of death and dying for intensive care unit professionals

Ao longo do tempo, morte e morrer foram processos transferidos para o espaço do hospital e serviços de saúde especializados, como as unidades de terapia intensiva (UTI). Essa transição levou ao profissional da equipe de saúde a convivência constante com tais fenômenos. Nesse contexto, o presente estudo objetivou compreender como profissionais de uma unidade de terapia intensiva vivenciam a morte e o processo de morrer em seu cotidiano de trabalho, através dos significados que atribuem a esses fenômenos. Tratou-se de uma pesquisa qualitativa que utilizou como recursos empíricos as observações de campo e entrevista semiestruturada. Participaram do estudo 25 profissionais pertencentes à equipe da UTI, compreendendo médicos, enfermeiros, técnicos de enfermagem, fisioterapeutas, psicólogo e auxiliar administrativo. As unidades de análise morte e morrer são apresentadas de acordo com os conteúdos relatados e cenários que projetaram a marca da experiência vivenciada, analisados com base na fenomenologia social compreensiva de Alfred Schütz. Os resultados mostraram que a experiência com a morte de pacientes na unidade de cuidados intensivos é naturalizada por meio da adaptação ao contexto, apontada como dimensão que faz parte da vida; e, com o processo de morrer, a experiência engloba maior dificuldade de enfrentamento quando profissionais e pacientes estabelecem um vínculo duradouro. Por fim, ressaltou-se a necessidade de espaços para escuta dos profissionais da assistência, que trabalham em contextos exigentes e diante de fenômenos complexos, como são morte e morrer, em busca de acolhimento para a expressão da experiência.(AU)

Over time, the processes of death and dying have been transferred to the space of hospitals and specialized health services, such as intensive care units (ICU). This transition has led health team professionals to constantly live with these phenomena. In this context, the present study had as an objective to understand how intensive care unit professionals experience death and the process of dying in their working daily lives, by the meanings they attribute to these phenomena. It was a piece of qualitative research which used as empirical sources field observations and semi-structured interviews. Twenty-five members of the ICU team took part in the study, among them were doctors, nurses, nursing technicians, physiotherapists, a psychologist, and an administrative assistant. The units of analysis death and dying are presented according to contents reported and scenarios that predicted the imprint of the experience, analyzed based on the comprehensive social phenomenology approach by Alfred Schütz. The results show that the experience on the death of patients in intensive care units have been made natural by means of adaptation to context, being identified as an aspect that is part of life; and, for the process of dying, the experience involves greater difficulty in facing it when professionals and patients establish a long-term relationship. Finally, it was highlighted the need for space for healthcare professionals, who work in demanding contexts and facing complex phenomena, such as death and dying, to be heard in search for a receptive environment for the expression of the experience.(AU)

Lipid-laden cells differentially distributed in the aging brain are functionally active and correspond to distinct phenotypes.

We characterized cerebral Oil Red O-positive lipid-laden cells (LLC) of aging mice evaluating their distribution, morphology, density, functional activities and inflammatory phenotype. We identified LLC in meningeal, cortical and neurogenic brain regions. The density of cerebral LLC increased with age. LLC presenting small lipid droplets were visualized adjacent to blood vessels or deeper in the brain cortical and striatal parenchyma of aging mice. LLC with larger droplets were asymmetrically distributed in the cerebral ventricle walls, mainly located in the lateral wall. We also found that LLC in the subventricular region co-expressed beclin-1 or LC3, markers for autophagosome or autophagolysosome formation, and perilipin (PLIN), a lipid droplet-associated protein, suggesting lipophagic activity. Some cerebral LLC exhibited ß galactosidase activity indicating a senescence phenotype. Moreover, we detected production of the pro-inflammatory cytokine TNF-α in cortical PLIN(+) LLC. Some cortical NeuN(+) neurons, GFAP(+) glia limitans astrocytes, Iba-1(+) microglia and S100ß(+) ependymal cells expressed PLIN in the aging brain. Our findings suggest that cerebral LLC exhibit distinct cellular phenotypes and may participate in the age-associated neuroinflammatory processes.

O direito fundamental de acesso a medicamentos e a função social da propriedade imaterial no Brasil / The fundamental right of access to medicines and the social function of intangible property in Brazil

O objetivo do presente trabalho é estudar as relações entre o direito de acesso a medicamentos e o direito de exclusividade na exploração de inventos farmacêuticos, a partir do direito fundamental à saúde em suas várias dimensões. Este objetivo será buscado por intermédio de pesquisa bibliográfica e documental. O presente estudo é justificado tendo em vista que o acesso a medicamentos constitui, atualmente, parcela indispensável do direito fundamental à saúde, devendo ser equilibrado com o direito de patente, considerando-se que toda propriedade,inclusive a imaterial, tem uma função social. Conclui-se que é necessário harmonizar o direito à preservação da propriedade imaterial – e, consequentemente, à exclusividade na exploração econômica do produto desenvolvido e patenteado – com o direito de acesso aos medicamentos, sob pena de se esvaziarem ambas as garantias constitucionais...

This is a literature and documental research aiming at studying the relationship between the right of access to medicines and the right to exclusivity in the exploitation of pharmaceutical inventions, from the fundamental right to health in its various dimensions. This study is justified by the increasing importance that the access to medicines currently has in the fundamental right to health, and by the necessity of balancing this right with the patents, if seen that all property, including intangible, has a social function. We conclude that it is necessary to harmonize the right to preserve intangible property –and, as a consequence, to preserve the economic exclusive exploitation of a developed and patented product- with the right of access to medicines, at risk of losing both constitutional guarantees...

Bioética e literatura: relato de experiência do Eixo ético-humanístico FMB-UFBA / Bioética y literatura: relato de experiencia del Eje Ético-humanístico FMB-UFBA / Bioethics and literature: the experience report of Ethical-humanistic axis - FMB-UFBA

O ensino médico brasileiro tem-se transformado para atender às demandas do modelo assistencial em saúde e à implementação do Sistema Único de Saúde, bem como formar profissionais com atuação generalista, capazes de prestar assistência integral e humanizada. A reforma curricular da Faculdade de Medicina da Universidade Federal da Bahia, marco no ensino médico no estado, implantou o Eixo ético-humanístico do primeiro ao oitavo semestre do curso médico. Neste Eixo, diversas ferramentas são utilizadas no ensino da ética médica e bioética, inclusive literatura narrativa. A partir de observação empreendida no período de 2009 a 2012 este trabalho relata a experiência do referido Eixo com o uso dessa forma de literatura para o ensino médico. A literatura pode ser usada como ferramenta para viabilizar o debate sobre questões político-sociais, necessárias à formação do médico, e induzir reflexões sobre o sofrimento humano e as relações humanas imanentes à prática médica.

La educación médica en Brasil ha sido objeto de reforma con el fin de atender a las demandas del modelo de atención de salud y a la implementación del Sistema Único de Salud y de formar médicos generalistas capaces de proporcionar la atención médica integral y humanizada. La reforma curricular de la Facultad de Medicina de la Universidad Federal de Bahía (FMB-UFBA), hito em la educación médica en el Estado, há implementado el Eje Ético-humanístico, desde el primer al octavo semestre del plan de estudios médicos. En dicho Eje, se utilizan diversas herramientas para la estúdio de la ética médica y bioética, incluso literatura narrativa. Desde observación tomada en el período de 2009 a 2012. Este trabajo relata la experiência del referido Eje con el uso de este tipo de literatura para el estúdio médico. La literatura puede ser utilizada como una herramienta que permite el debate sobre los planteamientos políticos y sociales, necesarios a la formación del médico e inducen a las reflexiones acerca del sufrimiento humano y las relaciones humanas inherentes a la práctica médica.

Medical education in Brazil has been reconstructed in order to attend demands of the health care model, the implementation of the Unified Health System and to form generalist physicians that are able to provide humanistic and integral health care. The curricular reform, a turning point in medical education in the Faculty of Medicine, Federal University of Bahia (FMB-UFBA), has implemented its Ethical-humanistic axis, from the first to the eighth semester of medical school curriculum. Many tools are applied in the teaching of medical ethics and bioethics, including the use of literature. This work aims to report the experience of Ethical-humanistic axis of FMB-UFBA in the use of literature in medical education during the period from 2009 to 2012. Literature can be used as a tool that enables the debate on political and social issues, necessary in medical education and allow the reflection on human suffering and human relations inherent to medical practice.

Permissivity of fish cell lines to three Chlamydia-related bacteria: Waddlia chondrophila, Estrella lausannensis and Parachlamydia acanthamoebae.

Epitheliocystis is an infectious disease affecting gills and skin of various freshwater and marine fishes, associated with high mortality and reduced growth of survivors. Candidatus Piscichlamydia salmonis and Clavochlamydia salmonicola have recently been identified as aetiological agents of epitheliocystis in Atlantic Salmon. In addition, several other members of the Chlamydiales order have been identified in other fish species. To clarify the pathogenicity of Chlamydia-like organisms towards fishes, we investigated the permissivity of two fish cell lines, EPC-175 (Fathead Minnow) and RTG-2 (rainbow trout) to three Chlamydia-related bacteria: Waddlia chondrophila, Parachlamydia acanthamoebae and Estrella lausannensis. Quantitative PCR and immunofluorescence demonstrated that W. chondrophila and, to a lesser extent, E. lausannensis were able to replicate in the two cell lines tested. Waddlia chondrophila multiplied rapidly in its host cell and a strong cytopathic effect was observed. During E. lausannensis infection, we observed a limited replication of the bacteria not followed by host cell lysis. Very limited replication of P. acanthamoebae was observed in both cell lines tested. Given its high infectivity and cytopathic effect towards fish cell lines, W. chondrophila represents the most interesting Chlamydia-related bacteria to be used to develop an in vivo model of epitheliocystis disease in fishes.

Lack of association between PSA-NCAM expression and migration in the rostral migratory stream of a Huntington's disease transgenic mouse model.

Huntington's disease is a neurodegenerative autosomal disorder characterized by selective loss of striatal and cortical neurons. The mammalian brain subventricular zone contains a population of neural precursors involved in postnatal neurogenesis. These newly generated cells migrate from the subventricular zone along the rostral migratory stream and differentiate into mature olfactory bulb neurons throughout adulthood. The establishment of this pathway depends upon a variety of molecules, including polysialylated neural cell adhesion molecule (PSA-NCAM). We used a murine model of Huntington's disease, the R6/2 transgenic mouse, and in vivo bromodeoxyuridine administration to label cells undergoing proliferation and to follow their migration along the rostral migratory stream. Bromodeoxyuridine labeling did not show any significant increase in proliferation of progenitor cells in symptomatic R6/2 mice, but migration of neuroblasts along the rostral migratory stream was significantly diminished. The decrease in neuroblast migration was not due to an alteration in the expression of PSA-NCAM along the rostral migratory stream since immunohistochemical analysis showed no significant differences between R6/2 and wild type mice. In addition, we used Fluoro-Jade C to evaluate apoptosis and demonstrated that the number of apoptotic cells in the rostral migratory stream is similar in affected and wild type animals, suggesting that cell death is not responsible for the differences observed in neuroblast migration. We conclude that in R6/2 mice, progenitor cells have an impaired migration in their route to the olfactory bulb, with accumulation of cells in the caudal rostral migratory stream that does not result from changes in PSA-NCAM expression and/or cell death.

A critical survey on nitric oxide synthase expression and nitric oxide function in the retinotectal system.

The ongoing research on the roles of the gas nitric oxide (NO) in the nervous system has demonstrated its involvement in neurotransmission, synaptic plasticity, learning, excitotoxicity, neurodegenerative diseases and regulation of the cerebral blood flow. Thus, this molecule has been currently considered an important neuromodulator in CNS. Studies carried out in the visual system, particularly in the retinotectal component, have contributed to this current concept about NO. In the present work, we reviewed critically current data about nitric oxide synthase (NOS) expression in the superior colliculus/optic tectum, as well as the roles of NO in the formation of the retinotopic map and in synaptic plasticity. Several vertebrate species have been used in studies about the NOS expression in the retinotectal system and most of the available results are in agreement with the involvement of NO in the developmental refinement of the retinotectal projections, and its role as a neuromodulator of synaptic function during the processing of visual information. However, the few studies about the functional linkage between NOS expression/NO synthesis and retinotectal topographic refinement/tectal synaptic plasticity are not conclusive and/or sometimes inconsistent, indicating that more experimental data are necessary to improve the understanding about NO functions in this visual subsystem. Predictive models for the involvement of NO as a retrograde messenger in the developmental retinotectal refinement are discussed.

Embryonic cortical neural stem cells migrate ventrally and persist as postnatal striatal stem cells.

Embryonic cortical neural stem cells apparently have a transient existence, as they do not persist in the adult cortex. We sought to determine the fate of embryonic cortical stem cells by following Emx1(IREScre); LacZ/EGFP double-transgenic murine cells from midgestation into adulthood. Lineage tracing in combination with direct cell labeling and time-lapse video microscopy demonstrated that Emx1-lineage embryonic cortical stem cells migrate ventrally into the striatal germinal zone (GZ) perinatally and intermingle with striatal stem cells. Upon integration into the striatal GZ, cortical stem cells down-regulate Emx1 and up-regulate Dlx2, which is a homeobox gene characteristic of the developing striatum and striatal neural stem cells. This demonstrates the existence of a novel dorsal-to-ventral migration of neural stem cells in the perinatal forebrain.

A progressive and cell non-autonomous increase in striatal neural stem cells in the Huntington's disease R6/2 mouse.

Neural stem and progenitor cells are located in the subependyma of the adult forebrain. An increase in adult subependymal cell proliferation is reported after various kinds of brain injury. We demonstrate an expansion of neural precursor cells in the postnatal subependyma in a murine genetic disease model of Huntington's disease (HD), the R6/2 mouse. We used the in vitro neurosphere assay as an index of the number of neural stem cells in vivo and to assess proliferation kinetics in vitro and in vivo bromodeoxyuridine labeling to assess the progenitor cell population and their fates. Disease progression in this model leads to an increase in the numbers of neural stem cells in the adult striatal subependyma. This increase is produced cell non-autonomously by events in the R6/2 brains as the mice become increasingly symptomatic. Once the neural stem cell increase is induced in vivo, it is maintained during in vitro passaging of neural stem cells, but the neural stem cell increase is not reproduced during in vitro passaging of neural stem cells from presymptomatic R6/2 mice. In addition, we show that some of the R6/2 neural progenitor cells show a change from their normal migration destiny toward the olfactory bulb. Instead, some of these cells migrate into the striatum, one of the main affected areas in HD. Our findings demonstrate that HD damage recruits precursor cells in two ways: expansion of neural stem cells and altered migration of progenitor cells.

Nitrergic dendrites in the superficial layers of the rat superior colliculus: retinal afferents and alternatively spliced isoforms in normal and deafferented animals.

The superficial layers of the rat superior colliculus (sSC) receive innervation from the retina and include nitrergic neurons. We have shown previously that in sSC, eye enucleation reduces NADPH diaphorase staining considerably in all but the most proximal dendrites of nitrergic neurons. We have used immunocytochemistry for neuronal nitric oxide synthase (nNOS) at light and electron microscopic levels and bilateral eye enucleation with varied survival times to determine the regulatory changes imposed by the direct and indirect loss of retinal input on apparent nNOS amount and subcellular distribution. In addition, we have used SDS-PAGE and immunoblotting to test alternatively spliced isoforms in normal and deafferented animals. Our results show that unambiguously identified retinal terminals contact nitrergic neurons. In normal dendrites, nNOS immunoreactivity was distributed almost completely within the cytoplasm of the dendrite and along the postsynaptic membrane at synaptic junctions, in association with endoplasmic reticulum, ribosomes and external mitochondrial membranes. In contrast, nNOS labeling was greatly reduced in sSC deprived of retinal projections, and could only be observed in association with mitochondrial membranes and postsynaptic densities. Immunoblots of the soluble fraction from sSC revealed a surprisingly high proportion of the beta isoform with respect to the alpha counterpart in normal colliculi, suggesting an increase in isoform proportion after enucleation, or at least maintenance of the same proportion. It is suggested that ultrastructural alterations observed in sSC cells of enucleated animals may be consequent to plastic reactions of the sSC cells in response to the removal of retinal afferents.

Patters of nitric oxide synthase expression in the developing superior colliculus

Nitric oxide (NO) is synthesized in cells of both the central and peripheral nervous system and has been implicated in several forms of synaptic plasticity. The enzyme that produces NO, nitric oxide synthase (NOS), can be visualized in the brain by the reduced nicotinamide adenine dinucleotide phosphate diaphorase histochemistry technique (NADPH-d). We have used NADPH-d activity to detect the presence of NOS-positive cells in the developing rat superior colliculus. Our results showed that NOS is present in cells and neuropil in the developing and adult rat superior colliculus. The first NOS-positive cells appeared at postnatal day 7 and were weakly stained. The number and intensity of the NOS-positive cells increased progressively during the following days reaching a maximum at postnatal day 15. By the end of the third postnatal week, both the number and intensity of stained cells showed an adult-like pattern. The NOS-positive cells showed a Golgi-like mosphology and we have found that all cell types present in the superior colliculus express the enzyme. The expression of NOS by tectal cells parallels the functional development of the retino-collicular and cortico-tectal projections and suggest that nitric oxide synthase-positive cells might be involved in this process. In this review we highlighted some of the recent descriptions of the expression of NOS in the mammalian visual system with emphasis in the superior colliculus and correlate these findings with several developmental events taking place in this structure.

O programa de implantaçäo do Sistema Unico de Saúde em Minas Gerais: modalidade de atençäo, participaçäo dos usuários, acesso aos serviços de saúde e grau de satisfaçäo / The establishing process of the Sistema Unico de Saúde (Unified Health System) in Minas Gerais: modality of care, user participation, access to health services and degree of satisfaction

Discute questöes relacionadas com a modalidade de atençäo expressa em açöes preventivas e assistenciais, durante a implantaçäo do Sistema Unico de Saúde, em municípios selecionados do estado de Minas Gerais, no âmbito da Secretaria de Estado da Saúde (SES/MG). Aborda questöes como participaçäo dos usuários no processo de implantaçäo do sistema, acesso aos serviços oferecidos pelo setor público e grau de satisfaçäo