Entre neurônios e sinapses: as contribuições de Cajal e Athias para a medicina ibérica entre os séculos XIX e XX / Between neurons and synapses: the contributions of Cajal and Athias to Iberian medicine between the nineteenth and twentieth centuries

Resumo O presente estudo reflete sobre o trajeto da histologia na transição do século XIX para o XX, em Portugal e em Espanha, para estabelecer um paralelo entre as contribuições de Santiago Ramón y Cajal e Marck Athias, ambos determinantes para o desenvolvimento da medicina experimental na Península Ibérica, reconhecidos como pilares de uma nova mentalidade científica europeia, na alvorada do século XX. Neste estudo de caso, refletimos sobre as vicissitudes da construção da ciência na “periferia” europeia, no contexto da categoria historiográfica centro-periferia desenvolvida pelo grupo Science and Technology in the European Periphery (Step), confrontando a realidade ibérica com o modelo de ciência alemã, no período em estudo.

Abstract The trajectory of histology at the cusp of the twentieth century in Portugal and Spain is investigated to draw a parallel between the contributions of Santiago Ramón y Cajal and Marck Athias, both of whom were instrumental in the development of experimental medicine in the Iberian Peninsula and recognized as pillars of a new European scientific mindset at the dawn of the twentieth century. In this case study we reflect on the vicissitudes of the construction of science in the “periphery” of Europe, in the context of the historiographical category of center-periphery developed by STEP (Science and Technology in the European Periphery), contrasting the reality in Iberia with the model of German science in the period under study.

Microglia and neurons in the hippocampus of migratory sandpipers

The semipalmated sandpiper Calidris pusilla and the spotted sandpiper Actitis macularia are long- and short-distance migrants, respectively. C. pusilla breeds in the sub-arctic and mid-arctic tundra of Canada and Alaska and winters on the north and east coasts of South America. A. macularia breeds in a broad distribution across most of North America from the treeline to the southern United States. It winters in the southern United States, and Central and South America. The autumn migration route of C. pusilla includes a non-stop flight over the Atlantic Ocean, whereas autumn route of A. macularia is largely over land. Because of this difference in their migratory paths and the visuo-spatial recognition tasks involved, we hypothesized that hippocampal volume and neuronal and glial numbers would differ between these two species. A. macularia did not differ from C. pusilla in the total number of hippocampal neurons, but the species had a larger hippocampal formation and more hippocampal microglia. It remains to be investigated whether these differences indicate interspecies differences or neural specializations associated with different strategies of orientation and navigation.

Vulnerabilidade de famílias de idosos assistidos pela Estratégia Saúde da Família / Vulnerabilidad de las familias de adultos mayores asistidas por la Estrategia Salud de la Familia / Vulnerability of families of elderly citizens cared for by the Family Health Strategy

RESUMO Objetivo: estudo descritivo, exploratório, de corte transversal, cujo objetivo foi identificar a vulnerabilidade de famílias de idosos assistidos pela Estratégia Saúde da Família (ESF). Método: foi desenvolvido por meio de entrevistas domiciliárias realizadas com uma amostra de 500 famílias de idosos assistidas por 32 equipes da ESF da cidade de Dourados, MS. O Índice de Desenvolvimento da Família (IDF) foi adaptado para classificá-las em função da situação de vulnerabilidade. Resultados: os resultados revelaram a presença de famílias multigeracionais, com baixa escolaridade entre os indivíduos com idade superior a 20 anos e alta taxa de analfabetismo entre os idosos. Identificaram-se 403 famílias em situação de vulnerabilidade aceitável, 95 em vulnerabilidade grave e duas famílias em situação de vulnerabilidade muito grave. As dimensões mais críticas do IDF foram os acessos ao conhecimento e ao trabalho. Conclusão: conclui-se que há necessidade de mais investimentos no cuidado a esses idosos e suas famílias na Atenção Básica. .

RESUMEN Objetivo: estudio descriptivo, exploratorio, transversal, con el objetivo de identificar la vulnerabilidad de familias adultos mayores asistidas por la Estrategia Salud de la Familia (ESF). Método: fue desarrollado mediante entrevistas a una muestra de 500 familias de adultos mayores bajo la responsabilidad de 32 equipos de ESF en la ciudad de Dourados, MS, Brasil. El Índice de Desarrollo de la Familia (IDF) fue adaptado para clasificar las familias de acuerdo a la situación de vulnerabilidad. Resultados: los resultados revelaron la presencia de familias multigeneracionales con bajo nivel de educación entre las personas mayores de 20 años y las altas tasas de analfabetismo entre los adultos mayores. Se identificaron 403 familias en situación de vulnerabilidad aceptable, 95 con vulnerabilidad grave y dos familias en situación de vulnerabilidad muy grave. Las dimensiones más críticas en el IDF fueron el acceso al conocimiento y al trabajo. Conclusión: se concluye que existe la necesidad de una mayor inversión, con un enfoque en la atención primaria, con el fin de atender a las personas mayores y sus familias. .

ABSTRACT Objective: the present descriptive, exploratory, cross-sectional study aimed to identify the vulnerability of families of elderly citizens cared for by the Family Health Strategy (FHS). Method: the research employed home interviews and was developed with a sample of 500 families of aged people cared for by 32 FHS teams in the city of Dourados, MS, Brazil. The Family Development Index (FDI) was adapted in order to classify the families according to their degree of vulnerability. Results: the results revealed the presence of multigenerational families with low educational levels among individuals over the age of 20 and high illiteracy rates among elderly citizens. There were 403 families whose vulnerability was acceptable, 95 in severe vulnerability, and two families in a condition of very severe vulnerability. The most critical dimensions of the FDI were the access to knowledge and to work. Conclusion: the study identifi ed that there is still a need for further investments that can assist these aged people and their families in the Primary Health Care. .

Sobrevida de pacientes con cáncer gástrico en el Perú, 2009-2010 / Survival rate of patients with stomach cancer in Peru, 2009-2010

OBJETIVO: Determinar la sobrevida de pacientes con diagnóstico de cáncer gástrico en 2009-2010 en el Perú. MÉTODOS: Se realizó un estudio de tipo cohorte retrospectivo de pacientes con diagnóstico de cáncer gástrico registrados en el Sistema Nacional de Vigilancia Epidemiológica (SNVE) de la Dirección General de Epidemiología (DGE) y del Registro de Hechos Vitales (RHV) de la Oficina General de Estadística e Informática (OGEI) para los años 2009-2010. RESULTADOS: Se incluyeron 3 568 pacientes del SNVE, 51,5% eran hombres y 48,5% eran mujeres; la media de edad fue 63,9 años, 60,07% tenían 60 años o más. Se halló que 33,6% tenía adenocarcinoma de tipo intestinal, 18,7% tenía carcinoma de tipo difuso y 4,1% tenía linfoma gástrico primario. La sobrevida global fue de 29,7 ± 0,8 meses y fue mejor para los menores de 60 años (P = 0,034), para las mujeres (P = 0,014) y para el adenocarcinoma de tipo intestinal (P < 0,001). No hubo diferencias (P = 0,713) entre la sobrevida de los pacientes con linfoma gástrico y aquellos con adenocarcinoma. Para evaluar la tasa de mortalidad se incluyeron 6 069 registros de pacientes del RHV, la tasa de mortalidad nacional fue de 10,3 por cada 100 000 habitantes y las regiones con mayor mortalidad fueron Huánuco, Huancavelica y Junín. CONCLUSIONES: La sobrevida general fue de 29,7 ± 0,8 meses, las mujeres, los menores de 60 años y los pacientes con adenocarcinoma de tipo intestinal tienen mejor sobrevida. La mayor mortalidad por cáncer gástrico se concentra en las regiones más pobres del Perú, donde es probable que las condiciones de vida faciliten la alta transmisibilidad de Helicobacter pylori.

OBJECTIVE: Determine the survival rate of patients diagnosed with stomach cancer in 2009-2010 in Peru. METHODS: A retrospective cohort study was conducted of patients diagnosed with stomach cancer registered in the National Epidemiological Surveillance System (SNVE) of the Directorate General of Epidemiology (DGE) and the Register of Vital Statistics (RHV) of the General Office of Statistics and Information (OGEI) for the years 2009-2010. RESULTS: 3 568 patients of the SNVE were included; 51.5% were men and 48.5% were women; the average age was 63.9 years; 60.07% were 60 years old or older. It was found that 33.6% had intestinal type adenocarcinoma, 18.7% had diffuse type carcinoma, and 4.1% had primary gastric lymphoma. The overall survival rate was 29.7 ± 0.8 months and was better for those under 60 years (P = 0.034), for women (P = 0.014) and for intestinal type adenocarcinoma (P< 0.001). There was no difference (P = 0.713) between the survival rate of gastric lymphomas and adenocarcinomas. In order to evaluate mortality, 6 069 patient records from the RHV were included; national mortality was 10.3 per 100 000 population; the regions with the highest mortality were Huánuco, Huancavelica, and Junín. CONCLUSIONS: The general survival rate was 29.7 ± 0.8 months; women, those under 60 years, and patients with intestinal type adenocarcinoma had better survival rates. The highest mortality from stomach cancer is concentrated in the poorest regions of Peru, where it is probable that living conditions facilitate the high communicability of Helicobacter pylori.

Insulin-like growth factor (IgF)-I, IgF binding protein-3, and prostate cancer: correlation with gleason score

Introduction Non-androgenic growth factors are involved in the growth regulation of prostate cancer (PCa). Objective This is the first Brazilian study to correlate, in a population of patients operated for PCa, PSA, total testosterone, insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) with Gleason score and to compare with a control group with benign prostate hyperplasia (BPH). Materials and Methods This retrospective single-center study included 49 men with previously diagnosed PCa and 45 with previously diagnosed BPH. PSA, testosterone, IGF-I, IGFBP-3 were determined in both groups. Results PSA and IGFBP-3 levels were significantly higher in the PCa group as compared to the BPH group (p<0.001 and p=0.004, respectively). There was a significant difference when we compared the PSA before surgery (p<0.001) and at the inclusion in the study (p<0.001) and IGFBP3 (0.016) among patients with Gleason <7, ≥7 and BPH. In the PCa group, PSA, testosterone, IGF-I and IGFBP-3 levels were comparable between Gleason <7 and ≥7. Conclusions Our data suggest that in localized PCa, the quantification of PSA and, not of IGF-1, may provide independent significant information in the aggressiveness. IGFBP-3 could be a biochemical marker of disease control in PCa patients. .

Perioperative myocardial infarction in patients undergoing myocardial revascularization surgery / Infarto do miocárdio perioperatório em pacientes submetidos à cirurgia de revascularização miocárdica

Introduction: Perioperative myocardial infarction adversely affects the prognosis of patients undergoing coronary artery bypass graft and its diagnosis was hampered by numerous difficulties, because the pathophysiology is different from the traditional instability atherosclerotic and the clinical difficulty to be characterized. Objective: To identify the frequency of perioperative myocardial infarction and its outcome in patients undergoing coronary artery bypass graft. Methods: Retrospective cohort study performed in a tertiary hospital specialized in cardiology, from May 01, 2011 to April 30, 2012, which included all records containing coronary artery bypass graft records. To confirm the diagnosis of perioperative myocardial infarction criteria, the Third Universal Definition of Myocardial Infarction was used. Results: We analyzed 116 cases. Perioperative myocardial infarction was diagnosed in 28 patients (24.1%). Number of grafts and use and cardiopulmonary bypass time were associated with this diagnosis and the mean age was significantly higher in this group. The diagnostic criteria elevated troponin I, which was positive in 99.1% of cases regardless of diagnosis of perioperative myocardial infarction. No significant difference was found between length of hospital stay and intensive care unit in patients with and without this complication, however patients with perioperative myocardial infarction progressed with worse left ventricular function and more death cases. Conclusion: The frequency of perioperative myocardial infarction found in this study was considered high and as a consequence the same observed average higher troponin I, more cases of worsening left ventricular function and death. .

Introdução: O infarto do miocárdio perioperatório afeta negativamente o prognóstico dos pacientes submetidos à cirurgia de revascularização do miocárdio e seu diagnóstico esbarra em inúmeras dificuldades, pois a fisiopatologia é diferente da tradicional instabilidade aterosclerótica e o quadro clínico de difícil caracterização. Objetivo: Identificar a frequência de infarto do miocárdio perioperatório e seu desfecho em pacientes submetidos à cirurgia de revascularização do miocárdio. Métodos: Coorte retrospectiva realizada em hospital terciário especializado em cardiologia, de 1 de maio de 2011 a 30 de abril de 2012, que incluiu todos os prontuários contendo registros de cirurgia de revascularização do miocárdio. Para confirmação diagnóstica do infarto do miocárdio perioperatório, foram utilizados os critérios da Third Universal Definition of Myocardial Infarction Resultados: Foram analisados 116 casos. Foi diagnosticado infarto do miocárdio perioperatório em 28 pacientes (24,1%). Número de enxertos e utilização e tempo de circulação extracorpórea foram fatores associados a este diagnóstico e a média de idade foi significativamente mais elevada neste grupo. O critério diagnóstico elevação de troponina I foi positivo em 99,1% dos casos, independentemente do diagnóstico de infarto do miocárdio perioperatório. Não foi encontrada diferença significativa entre tempo de internação hospitalar e em unidade de terapia intensiva nos grupos com e sem esta complicação, porém pacientes com infarto do miocárdio perioperatório evoluíram com pior função ventricular esquerda e mais casos de óbito. Conclusão: A frequência de infarto do miocárdio perioperatório encontrada neste trabalho foi considerada alta e como consequência do mesmo observou-se média mais elevada de troponina I, mais casos de piora da função ventricular esquerda e óbito. .

Para além do combate à ancilostomíase: o diário do médico norte-americano Alan Gregg / Looking beyond the campaign to eradicate ancylostomiasis: the diary of the American physician Alan Gregg

Entre 1916 e 1923, o Distrito Federal e 11 estados brasileiros estabeleceram acordos de cooperação com a divisão internacional de saúde – International Health Board – da Fundação Rockefeller para combater uma endemia rural, a ancilostomíase. Este breve texto apresenta o diário de Alan Gregg, um dos médicos norte-americanos que trabalharam no Brasil entre 1919-1922. Fonte interessante para discutir questões relativas à história da saúde pública no Brasil, o diário do médico, além das informações sobre as atividades de combate à ancilostomíase desenvolvidas pela Fundação Rockefeller no país, apresenta suas impressões relativas à natureza, à cultura, à política e à sociedade brasileiras. Na seleção de trechos do diário ora apresentado, priorizamos, porém, aspectos relativos às atividades profissionais realizadas por Gregg.

Between 1916 and 1923, the Federal District and 11 Brazilian states entered into cooperation agreements with the International Health Board of the Rockefeller Foundation to combat a rural endemic disease, namely ancylostomiasis. This paper presents the diary of Alan Gregg, one of the American physicians who worked in Brazil from 1919 to 1922. An interesting source to discuss issues relating to the history of public health in Brazil, in addition to information about the activities to combat ancylostomiasis developed by the Rockefeller Foundation in the country, the diary of the physician presents his impressions concerning nature, culture, politics and society in Brazil. In the diary excerpts presented here, however, aspects related to the professional activities performed by Gregg are prioritized.

Encuesta nacional de ceguera y deficiencia visual evitables en Honduras / National survey of blindness and avoidable visual impairment in Honduras

OBJETIVO: Determinar la prevalencia de ceguera y deficiencia visual en Honduras, sus causas y la respuesta que los servicios de salud están dando a la creciente demanda. MÉTODOS: Estudio poblacional transversal realizado entre junio y diciembre de 2013 mediante la metodología estándar de evaluación rápida de ceguera evitable. Se realizó un muestreo aleatorio en 63 conglomerados de 50 personas de 50 años o más, representativo de todo el país. Se evaluó la agudeza visual (AV) mediante una cartilla de Snellen y el estado del cristalino y del polo posterior por oftalmoscopía directa. Se calculó la cobertura de cirugía de catarata y se evaluó su calidad, las causas de tener AV < 20/60 y las barreras para acceder al tratamiento quirúrgico. RESULTADOS: Se examinaron 2 999 personas (95,2% del total previsto). La prevalencia de ceguera fue de 1,9% (intervalo de confianza de 95%: 1,4-2,4%) y 82,2% de esos casos era evitable. La catarata no operada fue la causa principal de ceguera (59,2%), seguida del glaucoma (21,1%). Los errores de refracción no corregidos fueron la principal causa de deficiencia visual, tanto severa (19,7%) como moderada (58,6%). La cobertura de cirugía de catarata fue de 75,2%. De los ojos operados de catarata, 62,5% alcanzó una AV ≥ 20/60 con la corrección disponible. Las principales barreras para someterse a la cirugía de catarata fueron el costo (27,7%) y la falta de disponibilidad o de acceso geográfico al tratamiento (24,6%). CONCLUSIONES: La prevalencia de ceguera y deficiencia visual en Honduras es similar a la de otros países latinoamericanos. Mejorar la capacidad resolutiva de los servicios oftalmológicos, especialmente de cirugía de catarata, desarrollar los servicios ópticos y la atención ocular incorporada en la atención primaria en salud, podrían resolver el 67% de los casos de ceguera.

OBJECTIVES: To determine the prevalence of blindness and visual impairment in Honduras, its causes and the response by the health services to growing demand. METHODS: A cross-sectional population study was conducted between June and December 2013 using the standard methodology of the Rapid Assessment of Avoidable Blindness. A random sample survey was done in 63 clusters of 50 individuals aged ≥ 50, representative of the country as a whole. Visual acuity (VA) was assessed using a Snellen eye chart, and the condition of the lens and posterior pole was examined by direct ophthalmoscopy. Cataract surgical coverage was calculated and an assessment made of its quality, the causes of VA < 20/60 and the barriers to accessing surgical treatment. RESULTS: A total of 2 999 people were examined (95.2% of the forecast total). Blindness prevalence was 1.9% (confidence interval of 95%: 1.4-2.4%) and 82.2% of these cases were avoidable. The main causes of blindness were unoperated cataracts (59.2%) and glaucoma (21.1%). Uncorrected refraction error was the main cause of severe (19.7%) and moderate (58.6%) visual impairment. Cataract surgical coverage was 75.2%. 62.5% of the eyes operated for cataracts achieved a VA > 20/60 with available correction. The main barriers against cataract surgery were cost (27.7%) and the lack of availability or difficulty of geographical access to the treatment (24.6%). CONCLUSIONS: The prevalence of blindness and visual impairment in Honduras is similar to that of other Latin American countries. 67% of cases of blindness could be resolved by improving the response capacity of the ophthalmological services, especially of cataract surgery, improving optician services and incorporating eye care in primary health care.

CDK5-dependent inhibitory phosphorylation of Drp1 during neuronal maturation

Mitochondrial functions are essential for the survival and function of neurons. Recently, it has been demonstrated that mitochondrial functions are highly associated with mitochondrial morphology, which is dynamically changed by the balance between fusion and fission. Mitochondrial morphology is primarily controlled by the activation of dynamin-related proteins including dynamin-related protein 1 (Drp1), which promotes mitochondrial fission. Drp1 activity is regulated by several post-translational modifications, thereby modifying mitochondrial morphology. Here, we found that phosphorylation of Drp1 at serine 616 (S616) is mediated by cyclin-dependent kinase 5 (CDK5) in post-mitotic rat neurons. Perturbation of CDK5 activity modified the level of Drp1S616 phosphorylation and mitochondrial morphology in neurons. In addition, phosphorylated Drp1S616 preferentially localized as a cytosolic monomer compared with total Drp1. Furthermore, roscovitine, a chemical inhibitor of CDKs, increased oligomerization and mitochondrial translocation of Drp1, suggesting that CDK5-dependent phosphorylation of Drp1 serves to reduce Drp1's fission-promoting activity. Taken together, we propose that CDK5 has a significant role in the regulation of mitochondrial morphology via inhibitory phosphorylation of Drp1S616 in post-mitotic neurons.

Toxic effects of methylmercury, arsanilic acid and danofloxacin on the differentiation of mouse embryonic stem cells into neural cells

This study was performed to assess the neurotoxic effects of methylmercury, arsanilic acid and danofloxacin by quantification of neural-specific proteins in vitro. Quantitation of the protein markers during 14 days of differentiation indicated that the mouse ESCs were completely differentiated into neural cells by Day 8. The cells were treated with non-cytotoxic concentrations of three chemicals during differentiation. Low levels of exposure to methylmercury decreased the expression of GABAA-R and Nestin during the differentiating stage, and Nestin during the differentiated stage. In contrast, GFAP, Tuj1, and MAP2 expression was affected only by relatively high doses during both stages. Arsanilic acid affected the levels of GABA(A)-R and GFAP during the differentiated stage while the changes of Nestin and Tuj1 were greater during the differentiating stage. For the neural markers (except Nestin) expressed during both stages, danofloxacin affected protein levels at lower concentrations in the differentiated stage than the differentiating stage. Acetylcholinesterase activity was inhibited by relatively low concentrations of methylmercury and arsanilic acid during the differentiating stage while this activity was inhibited only by more than 40 microM of danofloxacin in the differentiated stage. Our results provide useful information about the different toxicities of chemicals and the impact on neural development.

Relationships between dendritic morphology, spatial distribution and firing patterns in rat layer 1 neurons

The cortical layer 1 contains mainly small interneurons, which have traditionally been classified according to their axonal morphology. The dendritic morphology of these cells, however, has received little attention and remains ill defined. Very little is known about how the dendritic morphology and spatial distribution of these cells may relate to functional neuronal properties. We used biocytin labeling and whole cell patch clamp recordings, associated with digital reconstruction and quantitative morphological analysis, to assess correlations between dendritic morphology, spatial distribution and membrane properties of rat layer 1 neurons. A total of 106 cells were recorded, labeled and subjected to morphological analysis. Based on the quantitative patterns of their dendritic arbor, cells were divided into four major morphotypes: horizontal, radial, ascendant, and descendant cells. Descendant cells exhibited a highly distinct spatial distribution in relation to other morphotypes, suggesting that they may have a distinct function in these cortical circuits. A significant difference was also found in the distribution of firing patterns between each morphotype and between the neuronal populations of each sublayer. Passive membrane properties were, however, statistically homogeneous among all subgroups. We speculate that the differences observed in active membrane properties might be related to differences in the synaptic input of specific types of afferent fibers and to differences in the computational roles of each morphotype in layer 1 circuits. Our findings provide new insights into dendritic morphology and neuronal spatial distribution in layer 1 circuits, indicating that variations in these properties may be correlated with distinct physiological functions.

Otras posibles aplicaciones clínicas de fármacos con efecto 5HT2A y 3 en psiquiatría de enlace: reporte de casos / Other Possible Clinical Applications of Drugs with 5HT2A effect in Liaison Psychiatry: Cases Report

Introducción: En psiquiatría de enlace se logra obtener una visión integral del tratamiento y de las necesidades de cada paciente prestando especial atención a las interacciones medicamentosas y a las contraindicaciones. Algunos casos particulares motivaron la descripción, reporte y revisión bibliográfica acerca de otras posibles aplicaciones de fármacos antagonistas de los recetores 5HT2A y 3, particularmente mirtazapina y olanzapina, en síndrome de hiperalgesia, tinitus y leucoencefalopatía multifocal progresiva por virus JC. Método: reporte de casos. Resultados y Conclusiones: Se describen los casos de tres pacientes en los cuales fue necesario usar mirtazapina y olanzapina no solo para el control de los síntomas psiquiátricos (afectivos, comportamentales y trastorno del sueño), sino también como coadyuvantes en las patologías de base de cada paciente. El uso de cualquier medicamento en psiquiatría de enlace debe tener en cuenta el contexto del paciente, la comorbilidad, las contraindicaciones y las interacciones farmacológicas para garantizar un desenlace positivo, además de promover el trabajo multidisciplinario entre especialistas.

Introduction: In liaison psychiatry it is possible to get an integral view of patient's treatment and needs, paying special attention to pharmacological interactions and contraindications. Some particular cases motivated the description, report and review about other possible applications of 5HT2A and 5HT3 antagonist, particularly Mirtazapine and Olanzapine, in hyperalgesia syndrome, tinnitus and Progressive Multifocal Leukoencephalopathy by JC virus. Method: Cases report. Results: We describe 3 cases of patients in which Mirtazapine and Olanzapine were necessary not only to control psychiatric symptoms (affective / behavioral symptoms and insomnia) but to act as adjuvant therapy in axis III diseases. The use of any drug in psychiatry must take in to account the context of the patient, the presence of comorbidity, contraindications and pharmacological interactions so as to grant a positive outcome also promoting the multidisciplinary work between specialists.

Neuronal autophagy and neurodegenerative diseases

Autophagy is a dynamic cellular pathway involved in the turnover of proteins, protein complexes, and organelles through lysosomal degradation. The integrity of postmitotic neurons is heavily dependent on high basal autophagy compared to non-neuronal cells as misfolded proteins and damaged organelles cannot be diluted through cell division. Moreover, neurons contain the specialized structures for intercellular communication, such as axons, dendrites and synapses, which require the reciprocal transport of proteins, organelles and autophagosomes over significant distances from the soma. Defects in autophagy affect the intercellular communication and subsequently, contributing to neurodegeneration. The presence of abnormal autophagic activity is frequently observed in selective neuronal populations afflicted in common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. These observations have provoked controversy regarding whether the increase in autophagosomes observed in the degenerating neurons play a protective role or instead contribute to pathogenic neuronal cell death. It is still unknown what factors may determine whether active autophagy is beneficial or pathogenic during neurodegeneration. In this review, we consider both the normal and pathophysiological roles of neuronal autophagy and its potential therapeutic implications for common neurodegenerative diseases.

Role of PPAR, a Nuclear Hormone Receptor in Neuroprotection.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily. PPAR-alpha is involved in wound healing, stimulation of lipid and folic acid catabolism, inflammation control, inhibition of ureagenesis and peroxisome proliferation. The PPAR/ is involved wound healing, cell proliferation, embryo implantation, adipocyte differentiation, myelination alteration and apoptosis. The PPAR is involved in fat, lipid and calorie utilization, sugar control, inflammation control and macrophage (MQ) matutation. Homocysteine (Hcy) binds to nuclear peroxisome proliferator activated receptor. Increase in PPAR expression decreases the level of nitrotyrosine and increases endothelial nitric oxide concentration, decreases metalloproteinase activity and expression as well as elastinolysis and reverses Hcy-mediated vascular dysfunction. The PPAR initially recognized as a regulator of adipocyte development has become a potential therapeutic target for the treatment of diverse disorders. In addition, the activation of PPAR receptor ameliorates neurodegenerative disease. This review focuses on the recent knowledge of PPAR in neuroprotection and deals with the mechanism of neuroprotection of central nervous system disorder by PPAR.

Condução nervosa sensorial no nervo caudal de ratos com diabetes experimental / Sensory nerve conduction in the caudal nerves of rats with diabetes

PURPOSE: To investigate sensory nerve conduction of the caudal nerve in normal and diabetic rats. METHODS: Diabetes was induced in twenty 8-weeks old Wistar male rats. Twenty normal rats served as controls. Caudal nerve conduction studies were made before diabetes induction and the end of each week for six consecutive weeks. The caudal nerve was stimulated distally and nerve potentials were recorded proximally on the animal's tail using common "alligator" clips as surface electrodes. RESULTS: After induction, nerve conduction velocities (NCV) increased slower in the diabetic than in the control group. Sensory nerve action potentials (SNAP) conduction velocities increased slower in the diabetic than in the control group (slope of regression line: 0.5 vs 1.3m/s per week; NCV in the 15th week = 39±3m/s vs 44±4m/s). Tukey's tests showed differences between groups at the 11th, 13th and 15th weeks old. From the 10th week on, SNAP amplitudes increased faster in the diabetic than in the control group (slopes of the regression line: 10 vs 8µV per week; SNAP amplitudes in the 15th week: 107±23µV vs 85±13µV). Differences at the 12th, 13th and 15th weeks were significant. CONCLUSION: In diabetic rats nerve conduction velocities were slower whereas amplitudes were larger than in normal rats.

OBJETIVO: Investigar a condução nervosa sensorial do nervo caudal em ratos normais e diabéticos. MÉTODOS: O diabetes foi induzido em vinte ratos Wistar com idade de oito semanas. Vinte ratos serviram como controle. Os estudos da condução do nervo caudal foram feitos antes da indução do diabetes e ao final de cada semana, durante seis semanas consecutivas. O nervo caudal foi estimulado distalmente e potenciais foram registrados proximalmente na cauda do animal, usando clipes comuns "jacaré" como eletrodos de superfície. RESULTADOS: Após a indução, a velocidade de condução nervosa (VCN) aumentou mais lentamente no grupo diabético que no controle. Potenciais de ação dos nervos sensitivos (PANS) aumentaram a velocidade de condução mais lentamente no grupo diabético que no controle (linha de regressão: 0,5 vs 1,3m/s por semana; VCN na 15ª semana = 39±3m/s vs 44±4m/s). O teste de Tukey mostrou diferenças entre os grupos nas 11ª, 13ª e 15ª semanas de vida. A partir da semana 10, os PANS aumentaram mais rapidamente no grupo diabético que no controle (linha de regressão: 10 vs 8µV por semana; PANS na 15ª semana: 107±23µV vs 85±13µV). Diferenças na semana 12, 13 e 15 foram significativas. CONCLUSÃO: Nos ratos diabéticos a velocidade de condução nervosa foi mais lenta enquanto que as amplitudes foram maiores que em ratos normais.

Morphoquantitative study of the submucous plexus (of Meissner) of the jejunum-ileum of young and old guinea pigs / Estudo morfoquantitativo do plexo submucoso (de Meissner) do jejuno-íleo de cobaias jovens e velhas

OBJECTIVE: To study the aging of submucous plexus of the small intestine (jejunum-ileum) of the guinea pigs from the quantitative, structural and ultrastructural perspective. METHOD: Chemical preparations of membrane of the jejunum-ileum of old and young animals with the use of light and electronic microscope. RESULTS: The ganglia of young animals presented between 1 and 56 neurons and the old animals presented from 1 to 30 neurons. The mean density of the ganglia by cm² in the young jejunum-ileum was of 551±36.89 and in the old one 413±11.86. The density of the neurons was 5011±291.11 neurons/cm² average in young animals and 2918±120.70 neurons/cm² in the old ones. The size of the neurons varied in both age groups. The collagen fibers in the ganglia of old animals they were condensed. Degenerated mitochondrias in the interior of the cell were frequent in the old animals. CONCLUSION: In submucous plexus of the jejunum-ileum there is a loss of 38 percent of the neurons with aging.

OBJETIVO: Estudar o envelhecimento do plexo submucoso do intestino delgado (jejuno-íleo) das cobaias do ponto de vista quantitativo, estrutural e ultra-estrutural. MÉTODO: Preparados de membrana do jejuno-íleo de animais jovens e velhos com a utilização de microscopia de luz e eletrônica. RESULTADOS: Os gânglios de animais jovens apresentaram entre 1 e 56 neurônios e os animais velhos apresentaram de 1 a 30 neurônios. A densidade média dos gânglios por cm² no jejuno-íleo jovem foi de 551±36,89 e no velho foi de 413±11,86. A densidade dos neurônios foi de 5011±291,11 neurônios/cm² em média nos animais jovens e 2918±120,70 neurônios/cm² nos velhos. O tamanho dos neurônios variou em ambos os grupos etários. As fibras colágenas nos gânglios de animais velhos estavam mais condensadas. Mitocôndrias degeneradas no interior da célula foram freqüentes nos animais velhos. CONCLUSÃO: No plexo submucoso do jejuno-íleo há uma perda de 38 por cento dos neurônios com o envelhecimento.

Histological, biochemical and pharmacologycal characterization of the gastric muscular layer in Chagas disease / Caracterização histológica, bioquímica e farmacológica da musculatura gástrica na doença de Chagas

PURPOSE: To assess in vitro the correlation between the number of neurons and the sensitivity to cholinergic drugs and acetylcholinesterase activity in chagasic patients. METHODS: A 3x1 cm strip of the muscle layer of the anterior part of the stomach, always close to the angular incisure, was removed from 10 chronic chagasic patients (6 men) submitted to megaesophagus or megacolon surgery and from 10 non-chagasic patients (4 men) submitted to other types of surgery (control group), aged on average 52.3 and 50.1 years, respectively, for histological and pharmacological studies. The action of cholinergic drugs was investigated in isolated preparations according to the superfusion method of Ferreira and Costa, and acetylcholinesterase activity was determined by the method of Ellman. For neuron count, the strips were cut into 8 µm sections according to the method standardized by Alcântara. RESULTS: There was a difference in number of neurons between the chagasic (5,6) and control (7,3) groups. Acetylcholinesterase activity, in moles of hydrolyzed substrate per minute per gram tissue, was reduced in chagasic patients (4,32) compared to the controls (7,30). No hypersensitivity of the gastric musculature to cholinergic drugs was detected, with a reduced maximum response to carbachol and betanechol in the chagasic group. CONCLUSIONS: The reduction of neurons in the myenteric plexus of the stomach of chronic chagasic patients can be demonstrated even in the absence of clinical chagasic gastropathy. The hypersensitivity of the gastric musculature to cholinergic drugs probably depends on intense denervation. The reduced acetylcholinesterase activity demonstrates the involvement of the cholinergic innervation in the stomach of chronic chagasic patients. There was no correlation between number of neurons, sensitivity to cholinergic drugs and acetylcholinesterase activity in the gastric musculature of chagasic and non-chagasic patients.

OBJETIVO: Avaliar in vitro a correlação entre o número de neurônios e a sensibilidade a drogas colinérgicas e a atividade da acetilcolinesterase em pacientes chagásicos. MÉTODOS: Em 10 pacientes chagásicos crônicos (6 homens) submetidos à cirurgia de megaesôfago ou de megacólon e em 10 pacientes não chagásicos (4 homens) submetidos a outros tipos de cirurgia (grupo controle), respectivamente com idade média de 52,3 e 50,1 anos, retirou-se uma tira de 3x1 cm da camada muscular da parede anterior do estômago, sempre junto á cisura angular, que serviu para os estudos histológicos e farmacológicos. A ação de drogas colinérgicas foi feita em preparação isolada de acordo com o método de superfusão de Ferreira e Costa, e a determinação da atividade da acetilcolinesterase pelo método de Ellman. Para a contagem de neurônios a tira muscular foi submetida a cortes de 8 micra segundo método padronizado por Alcântara. RESULTADOS: Houve diferença do número de neurônios entre os grupos chagásico (5,6) e controle (7,3). A atividade da acetilcolinesterase mostrou-se diminuída nos chagásicos (4,32) expressa como número de moles do substrato hidrolisado por minuto por grama de tecido, em relação aos controles (7,30). Não se encontrou hipersensibilidade da musculatura gástrica a drogas colinérgicas, encontrando-se inclusive efeito máximo reduzido ao carbacol e betanecol no grupo chagásico. CONCLUSÕES: A redução de neurônios no plexo mioentérico do estômago de pacientes chagásicos crônicos pode ser demonstrada mesmo na ausência de gastropatia chagásica clínica. A hipersensibilidade da musculatura gástrica a drogas colinérgicas provavelmente depende de desnervação intensa. A redução da atividade da acetilcolinesterase demonstra o comprometimento da inervação colinérgica no estômago de pacientes chagásicos crônicos. Não houve correlação entre número de neurônios, sensibilidade a drogas colinérgicas e atividade da acetilcolinesterase na musculatura gástrica de pacientes chagásicos ou não chagásicos.

Regulation of cell polarity by controlled proteolytic systems

Epithelial and neuronal cells are highly asymmetric, with discrete regions responsible for different roles that underlie the generation of specific compartments within cells that are distinct in biochemical composition, structure, and morphology that ultimately lead to distinct functions. Controlled and specific molecular targeting and sorting have been studied to understand the generation of asymmetric domains inside cells. Recently, a new and complementary explanation has emerged to account for the generation of domains that are enriched by a subset of proteins or polarization determinants: local proteolysis. In this review, we discuss the most conspicuous proteolytic systems that may contribute to the generation of cell polarity, namely the ubiquitin-proteosome and the calpain systems. Specifically, we focus this review on two cellular processes that depend on the acquisition of cell polarity; cell migration and the establishment of an axon in a neuronal cell.

Cytotoxicity of gamma-ray in rat immature hippocampal neurons

This in vitro study evaluated the detrimental effect of acute gamma (gamma)-irradiation on rat immature hippocampal neurons. Rat immature hippocampal neurons (0.5 day in vitro) were irradiated with 0~4 Gy gamma-rays. Cytotoxicity was analyzed using a lactate dehydrogenase release assay at 24 h after gamma-irradiation. Radiation-induced cytotoxicity in immature hippocampal neurons increased in a dose-dependent manner. Pre-treatments of pro-apoptotic caspase inhibitors and anti-oxidative substances significantly blocked gamma-irradiation-induced cytotoxicity in immature hippocampal neurons. The results suggest that the caspase-dependent cytotoxicity of gamma-rays in immature hippocampal cultured neurons may be caused by oxidative stress.

Neuron-Like Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells

PURPOSE: Mesenchymal stem cells (MSCs) are multipotent and give rise to distinctly differentiated cells from all three germ layers. Neuronal differentiation of MSC has great potential for cellular therapy. We examined whether the cluster of mechanically made, not neurosphere, could be differentiated into neuron-like cells by growth factors, such as epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: BMSCs grown confluent were mechanically separated with cell scrapers and masses of separated cells were cultured to form cluster BMSCs. As described here cluster of BMSCs were differentiated into neuron-like cells by EGF, HGF, and VEGF. Differentiated cells were analyzed by means of phase-contrast inverted microscopy, reverse transcriptase-polymerase chain reaction (RT-PCR), immunofluorescence, and immunocytochemistry to identify the expression of neural specific markers. RESULTS: For the group with growth factors, the shapes of neuron-like cells was observable a week later, and two weeks later, most cells were similar in shape to neuron-like cells. Particularly, in the group with chemical addition, various shapes of filament structures were seen among the cells. These culture conditions induced MSCs to exhibit a neural cell phenotype, expressing several neuro-glial specific markers. CONCLUSION: bone marrow-derived mesenchymal stem cells (BMSCs) could be easily induced to form clusters using mechanical scraping, not neurospheres, which in turn could differentiate further into neuron-like cells and might open an attractive possibility for clinical cell therapy for neurodegenerative diseases. In the future, we consider that neuron-like cells differentiated from clusters of BMSCs are needed to be compared and analyzed on a physiological and molecular biological level with preexisting neuronal cells, and studies on the possibility of their transplantation and differentiation capability in animal models are further required.