Dinámica mitocondrial en las enfermedades neurodegenerativas / Mitochondrial dynamics in neurodegenerative diseases

Resumen Las enfermedades neurodegenerativas son un grupo heterogéneo caracterizado por la disminución gradual, progresiva y selectiva de las funciones del sistema nervioso. La etiología de estas patologías aún se desconoce, sin embargo, se ha propuesto que la función mitocondrial pudiese estar participando en el establecimiento de estas enfermedades, debido al alto requerimiento energético que tienen las neuronas para realizar sus funciones fisiológicas. La mitocondria es un organelo dinámico que puede cambiar su morfología y función en respuesta a diferentes estímulos fisiológicos, por ello se ha empezado a estudiar a la dinámica mitocondrial como uno de los principales reguladores de la supervivencia celular. Este evento comprende diferentes procesos como la generación de nuevas mitocondrias y su eliminación cuando ya no son funcionales, así como los procesos de fusión y fisión mitocondrial y el tráfico de estos organelos en el entorno celular. Todos estos procesos son altamente regulados y tienen como finalidad la óptima funcionalidad de la mitocondria y la homeostasis celular.

Abstract Neurodegenerative diseases are a group of heterogeneous diseases characterized by a gradual, progressive and selective decrease in nervous system functions. The etiology of these pathologies remains unknown; however, mitochondrial function has been proposed as a common factor that could be involved in the establishment of these diseases, owing to the high energy requirement neurons have in order to carry out their physiological functions. Mitochondria are extremely dynamic organelles that can change their morphology and function in response to different physiological stimuli and, for this reason, mitochondrial dynamics have started being studied as one of cell survival main regulators. This event comprises different processes, such as the generation of new mitochondria and their elimination when they are no longer functional, as well as mitochondrial fusion and fission processes and the traffic of these organelles within the cellular environment. All these processes are highly regulated, and their main purpose is optimal functionality of mitochondria and cellular homeostasis.

Ataxina-2, nuevo blanco en enfermedades genéticas complejas / Ataxin-2, a new target in complex genetic diseases

Resumen El gen de la ataxina-2 es un blanco en la patogénesis de enfermedades complejas, entre ellas los factores de riesgo cardiovascular y enfermedades neurodegenerativas. El gen ATXN2 tiene un VNTR en el exón 1, cuya expansión por encima de las 30 repeticiones provoca al desarrollo de ataxia espinocerebelosa tipo 2; las repeticiones en rango menor se asocian con diabetes tipo 2 o esclerosis lateral amiotrófica. También este locus está ligado con fenotipos metabólicos e inflamatorios. En conclusión, el gen puede ser utilizado como marcador clínico de fenotipos metabólicos y neurológicos, lo cual está relacionado con su efecto pleiotrópico.

Abstract The ataxin 2 gene is a target in the pathogenesis of complex diseases, including cardiovascular risk factors and neurodegenerative diseases. ATXN2 gen has VNTR in exon 1, whose expansion exceeding 30 repetitions leads to the development of spinocerebellar ataxia type 2; lower-range repetitions are associated with type 2 diabetes or amyotrophic lateral sclerosis. This locus is also linked with metabolic and inflammatory phenotypes. In conclusion, this gene can be used as a clinical marker of metabolic and neurological phenotypes, which is related to its pleiotropic effect.

Complex proteinopathies and neurodegeneration: insights from the study of transmissible spongiform encephalopathies / Proteinopatías complejas y neurodegeneración: conocimientos obtenidos del estudio de las encefalopatías espongiformes transmisibles

ABSTRACT Protein misfolding diseases are usually associated with deposits of single "key" proteins that somehow drive the pathology; β-amyloid and hyperphosphorylated tau accumulate in Alzheimer's disease, α-synuclein in Parkinson's disease, or abnormal prion protein (PrPTSE) in transmissible spongiform encephalopathies (TSEs or prion diseases). However, in some diseases more than two proteins accumulate in the same brain. These diseases might be considered "complex" proteinopathies. We have studied models of TSEs (to explore deposits of PrPTSE and of "secondary proteins") infecting different strains and doses of TSE agent, factors that control incubation period, duration of illness and histopathology. Model TSEs allowed us to investigate whether different features of histopathology are independent of PrPTSE or appear as a secondary result of PrPTSE. Better understanding the complex proteinopathies may help to explain the wide spectrum of degenerative diseases and why some overlap clinically and histopathologically. These studies might also improve diagnosis and eventually even suggest new treatments for human neurodegenerative diseases.

RESUMEN La acumulación de proteínas con conformación anormal es observada en numerosas enfermedades degenerativas del sistema nervioso. Tales enfermedades están generalmente asociadas con el depósito de una proteína que es importante para la patogenia de la enfermedad; amiloide-β e hiperfosforilación de tau en la Enfermedad de Alzheimer, α-sinucleína en la Enfermedad de Parkinson, y acúmulo de proteína prion anormal (PrPTSE) en las encefalopatías espongiformes transmisibles (EET). Sin embargo, en algunas enfermedades más de dos proteínas se acumulan en el sistema nervioso central. Estas enfermedades pueden considerarse "proteinopatías complejas". Hemos estudiado varios modelos de EET para analizar los depósitos de PrPTSE y la posible acumulación de otras proteínas (que podríamos llamar "proteínas secundarias"). La relación entre proteínas mal plegadas y neurodegeneración no es claro. La mayor parte de las enfermedades neurodegenerativas evolucionan por décadas; por lo tanto los acúmulos proteicos podrían generar diferentes efectos patogénicos en los diferentes estadios de la enfermedad. Alternativamente los acúmulos proteicos podrían ser el resultado de alteraciones del sistema nervioso y no su causa. Dado que la etiología de las ETT es relativamente bien conocido y es atribuido a infección por agentes autoreplicantes que generan malformacion de la proteína prion normal (la isoforma patologica, PrPTSE, propuesta como el agente infeccioso) hemos estudiado varios modelos animales, cepas de agente infectante y dosis del agente causal de ETT. Estos factores controlan el período de incubación, duración de la enfermedad e histopatología. Los modelos animales estudiados nos han permitido investigar si las diferentes características histopatológicas son independientes de PrPTSE o podrían ser secundarias a la acumulación de la misma. Un mejor conocimiento de las proteinopatías complejas podría ayudar a analizar el espectro de enfermedades degenerativas y a su vez, investigar el motivo de la superposición clínico-patológico en algunas de ellas. Estos estudios podrían ayudar en el diagnóstico y eventualmente sugerir nuevas posibles terapéuticas para las enfermedades neurodegenerativas humanas.

The Glymphatic System: A Review

The brain represents 2% of the adult body mass; conversely, it is responsible for 20% to 25% of the glucose and 20% of the oxygen consumption, receiving 15% of the cardiac output. This substantial metabolic rate is associated with a significant production of biological debris, which is potentially toxic. Therefore, a complex and efficient clearance system is required to prevent the accumulation of byproducts and ensure optimal function. However, until today, there is little knowledge about this topic. The glymphatic system, also known as perivascular pathway, is a recently described glialdependent network that is responsible for the clearance of metabolites from the central nervous system (CNS), playing a role equivalent to the one played by the lymphatic vessels present in other organs. Studies have demonstrated that the glymphatic pathway has a paramount role in protein homeostasis, and that the malfunction of this system may be related to the development of neurodegenerative disorders such as Alzheimer disease and normal pressure hydrocephalus. They also showed that body posture, exercise and the state of consciousness influence the glymphatic transport. In this context, the understanding of this clearance system could not only clarify the pathophysiology of several diseases, but also contribute to future therapeutic interventions. In the present article, we will evaluate the glymphatic pathway, focusing on the factors that regulate its flow, as well as on its role in CNS physiology and in disease initiation and progression, including dementia, hydrocephalus, glaucoma and traumatic brain injury. Ultimately, this review also aims to encourage further research on novel therapeutic targets.

Identificação das alterações de deglutição: percepção de pacientes com doenças neurodegenerativas / Identification of swallowing disorders: the perception of patients with neurodegenerative diseases

RESUMO Objetivo Verificar a percepção de indivíduos com doenças neurodegenerativas quanto às alterações de deglutição, e conhecer as sensações ao deglutir que podem favorecer a identificação precoce de disfagia. Método Trata-se de um estudo transversal com 44 sujeitos com doenças neurodegenerativas. Todos responderam a um questionário para investigação da sensação percebida ao deglutir e mensuração da intensidade da sensação. Foram questionados quanto à presença de fadiga por meio da Fatigue Severity Scale. Para detecção de queixas de deglutição, foi utilizada a versão traduzida e adaptada para o português brasileiro do Swallowing Disturbance Questionaire. A Funcional Oral Intake Scale foi utilizada para classificar o nível de ingestão oral. Realizou-se videofluoroscopia da deglutição para verificar a correspondência entre a percepção dos participantes e a fisiopatologia da deglutição. Foi realizada análise estatística descritiva e exploratória. Resultados Houve correspondência entre os achados da videofluoroscopia e a percepção dos sujeitos em 76,5% casos. Sensações como desconforto, cansaço e incômodo foram percebidas ao engolir, especialmente, na consistência sólida. Tais sensações foram referidas, predominantemente, na região da garganta, da metade para o final das refeições. Houve associação entre fadiga durante a alimentação e odinofagia. A fadiga durante a deglutição foi associada à pior funcionalidade oral. Conclusão A maioria dos participantes percebeu as alterações presentes em sua deglutição. Sensações como ardor, desconforto, incômodo, cansaço, dor, câimbra ou irritação foram referidas pelos participantes e se mostraram associadas com sinais e sintomas que sugerem risco de aspiração laringotraqueal, especialmente, devido à fadiga muscular decorrente de fraqueza, incoordenação e/ou rigidez da musculatura.

ABSTRACT Purpose To verify the perception of patients with neurodegenerative diseases regarding swallowing changes and to know the perceptions of swallowing sensations that can promote the early identification of dysphagia. Methods It is a cross-sectional study with 44 patients with neurodegenerative diseases. All of them answered a questionnaire to know the sensation perceived during swallowing and its intensity. The Fatigue Severity Scale was applied to measure fatigue and the Swallowing Disturbance Questionnaire was applied to detect swallowing complaints. The Functional Oral Intake Scale was used to classify the swallowing functionality. Videofluoroscopic swallowing study (VFSS) was performed to verify the correspondence between the patient's perceptions and swallowing physiopathology. A descriptive and exploratory statistical analysis was performed. Results There was correspondence between VFSS findings and the patient's perception in 76.5% of the cases. Sensations such as discomfort and fatigue were perceived during swallowing, especially with solids. Such feelings have predominantly been reported in the throat, from the half to the end of the meal. There was association between fatigue and odynophagia. Fatigue during swallowing was associated with worse functionality of oral intake. Conclusion Most participants perceived the disorders in their swallowing. Sensations such as burning, discomfort, tiredness, pain, cramp, or irritation were perceived by participants and were associated with symptoms that may suggest risk of aspiration due to fatigue resulting from weakness, incoordination, and/or stiffness of muscles.

Autofagia, una estrategia de supervivencia celular / Autophagy. A strategy for cell survival

La autofagia es un proceso de reciclado de partes de la célula. Como se describe en esta revisión, ocurre naturalmente preservando a las células de la acumulación de toxinas, moléculas y organelas dañadas y además permite los procesos de desarrollo y diferenciación de los tejidos. En el transcurso de la autofagia, el procesamiento de los sustratos a reciclar genera ATP, lo que constituye una fuente alternativa de energía en situaciones de estrés. En este sentido, bajo condiciones hostiles como hipoxia o falta de nutrientes, el proceso puede dispararse de modo exacerbado llevando a la muerte celular. Algunas alteraciones en su funcionamiento pueden involucrar el desarrollo de diversas patologías, tales como el daño hepático, el cáncer y las enfermedades neurodegenerativas.

Autophagy is a process of recycling parts of the cell. As described in this review, it occurs naturally in order to preserve cells from the accumulation of toxins, damaged molecules and organelles, and to allow processes of tissue development and differentiation. In the course of autophagy, the processing of the substrates to be recycled generates ATP, thus providing an alternative source of energy in stress situations. In this sense, under hostile conditions such as hypoxia or lack of nutrients, the autophagy process can be exacerbated leading to cell death. Some alterations in its functioning may involve the development of various pathologies, including liver damage, cancer and neurodegenerative diseases.

Are astrocytes executive cells within the central nervous system? / ¿Son los astrocitos células ejecutivas dentro del Sistema Nervioso Central?

ABSTRACT Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS) by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson’s disease, Alzheimer’s dementia, Huntington’s dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction. This hypothesis is supported by observations that demonstrated that the killing of neurons by non-neural cells plays a major role in the pathogenesis of those diseases, at both their onset and their progression. Furthermore, recent findings suggest that astrocytes might be involved in the pathogenesis of some psychiatric disorders as well.

RESUMEN Evidencias experimentales sugieren que los astrocitos desempeñan un rol crucial en la fisiología del sistema nervioso central (SNC) modulando la actividad y plasticidad sináptica. En base a lo actualmente conocido creemos que los astrocitos participan, en pie de igualdad con las neuronas, en los procesos de información del SNC. Además, observaciones experimentales y humanas encontraron que algunas de las enfermedades degenerativas primarias del SNC: la demencia fronto-temporal; las enfermedades de Parkinson, de Alzheimer, y de Huntington, las ataxias cerebelosas primarias y la esclerosis lateral amiotrófica, que afectan solo a los humanos, pueden deberse a astroglíopatía. Esta hipótesis se sustenta en hallazgos que demostraron que la muerte neuronal que en ellas ocurre es debida al compromiso de células no-neuronales que juegan rol principal en su iniciación y desarrollo. Más aún, observaciones recientes señalan que los astrocitos podrían estar implicados en la patogenia de algunas enfermedades psiquiátricas.

Degeneración corticobasal: reporte de un caso / Corticobasal degeneration: a case report

Se presenta un caso de Degeneración Corticobasal en una paciente chilena de 48 años de edad. La evolución clínica fue progresiva, con parkinsonismo (rigidez, acinesia, alteraciones posturales, disartria), deterioro cognitivo, apraxia del vestir, apraxia constructiva e hipomimia. Además, la paciente presentaba afasia no fluente. Adicionalmente, fue diagnosticada con Síndrome Depresivo Crónico (SDC) y Trombosis Venosa Profunda (TVP) de la extremidad inferior izquierda. Se han descrito varios tipos de enfermedades neurodegenerativas en las últimas décadas, las cuales cumplen con distintas características patológicas y clínicas. Sin embargo, la diferenciación de estas, en la práctica, es compleja y se necesita de una apreciación clínica entrenada, evaluaciones clínicas detalladas, neuroimágenes y estudios de laboratorio para lograr llegar a un diagnóstico adecuado. Dentro de las principales enfermedades neurodegenerativas que se presentan con parkinsonismo encontramos las llamadas “taupatías”, que son la Degeneración Corticobasal (DCB) y la Parálisis Supranuclear Progresiva*(PSP)...

A case study of corticobasal degeneration in a Chilean 48 year old female patient is reported. The clinical course was progressive and included Parkinsonism (rigidity, akinesia, postural abnormalities, dysarthria), cognitive impairment, dressing apraxia, constructive apraxia and hypomimia. In addition, the patienth ad non Mfluent aphasia. Also, the patient was diagnosed with Chronic Depressive Syndrome and Deep Venous Thrombosis (DVT) of the left lower extremity. In recent decades, several types of neurodegenerative diseases* have been described. These diseases have different clinical and pathologic features. However, in practice, it is difficult to differentiate them from one another and, to reach an accurate diagnosis, advanced medical skills, detailed clinical evaluations of neuroimaging and laboratory studies are needed. “Tauopathies”, which are Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) are among the major neurodegenerative diseases occurring with Parkinsonism...

Memory deficit associated with increased brain proinflammatory cytokine levels and neurodegeneration in acute ischemic stroke / Déficit de memória associado ao aumento dos níveis cerebrais de citocinas pró-inflamatórias e neurodegeneração na isquemia cerebral aguda

The present study aimed to investigate behavioral changes and neuroinflammatory process following left unilateral common carotid artery occlusion (UCCAO), a model of cerebral ischemia. Post-ischemic behavioral changes following 15 min UCCAO were recorded 24 hours after reperfusion. The novel object recognition task was used to assess learning and memory. After behavioral test, brains from sham and ischemic mice were removed and processed to evaluate central nervous system pathology by TTC and H&E techniques as well as inflammatory mediators by ELISA. UCCAO promoted long-term memory impairment after reperfusion. Infarct areas were observed in the cerebrum by TTC stain. Moreover, the histopathological analysis revealed cerebral necrotic cavities surrounded by ischemic neurons and hippocampal neurodegeneration. In parallel with memory dysfunction, brain levels of TNF-a, IL-1b and CXCL1 were increased post ischemia compared with sham-operated group. These findings suggest an involvement of central nervous system inflammatory mediators and brain damage in cognitive impairment following unilateral acute ischemia.

O presente estudo teve como objetivo investigar alterações comportamentais e processos inflamatórios na isquemia cerebral induzida pela oclusão unilateral da carótida comum esquerda (UCCAO) em camundongos. As alterações comportamentais foram avaliadas após 15 minutos de isquemia e 24 horas de reperfusão. O teste de reconhecimento de objetos foi utilizado para avaliação da memória e do aprendizado. Em seguida, os animais foram mortos e os encéfalos foram coletados e processados para avaliação das alterações patológicas pelas técnicas de TTC e H&E, assim como da dosagem de mediadores inflamatórios por ELISA. A UCCAO promoveu alterações de memória após a reperfusão. Foram visualizadas áreas de infarto cerebral pela coloração de TTC e cavidades necróticas circundadas por neurônios isquêmicos no cérebro e neurodegeneração hipocampal. A UCCAO causou aumento dos níveis encefálicos de TNF-a, IL-1b e CXCL1. Estes achados demonstraram o envolvimento dos mediadores inflamatórios no sistema nervoso central e da neurodegeneração no déficit cognitivo após isquemia cerebral aguda.

Wilson?s disease presenting as rapid eye movement sleep behavior disorder: a possible window to early treatment / Doença de Wilson apresentando-se com transtorno comportamental do sono REM: uma janela possível para instituição de tratamento precoce

Objective To describe characteristics of REM sleep behavior disorder in Wilson’s disease. Method Questionnaire-based interviews (patients and relatives), neurological examinations, two-week prospective dream-diary, video-polysomnography, transcranial sonography, MRI. Results Four Wilson’s disease cases with REM sleep behavior disorder were described; three had REM sleep behavior disorder as initial symptom. All showed mesencephalic tegmental/tectal sonographic hyperechogenicities and two presented ponto-mesencephalic tegmental MRI hyperintensities. Conclusion This first description of REM sleep behavior disorder in Wilson’s disease in literature documents REM sleep behavior disorder as a possible presenting symptom of Wilson’s disease and adds further evidence to the parallelism of Parkinson’s disease and Wilson’s disease in phenotype and brainstem topography, which ought to be further studied. REM sleep behavior disorder has prognostic relevance for neurodegeneration in α-synucleinopathies. In Wilson’s disease, usefulness of early diagnosis and treatment are already well established. REM sleep behavior disorder in Wilson’s disease offers a possible theoretical model for potential early treatment in this extrapyramidal and brainstem paradigm syndrome, previewing the possibility of neuroprotective treatment for REM sleep behavior disorder in “pre-clinical” Parkinson’s disease. .

Objetivo Descrever características do transtorno comportamental do sono REM (TCSR) na doença de Wilson (DW). Método Aplicação de entrevistas, vídeo-polissonografia, sonografia transcraniana (STC), ressonância magnética (RM), diário de sonhos. Resultados Descrevemos quatro casos de DW com TCSR. Três apresentaram o TCSR como primeira manifestação. Todos mostraram hiperecogenicidades mesencefálicas na STC, dois apresentaram hiperintensidades ponto-mesencefálicas na RM. Conclusão Esta é a primeira descrição do TCSR na DW. Relatamos o TCSR como um sintoma inicial da DW. Acrescentamos prova para o paralelismo entre a doença de Parkinson e DW, com relação aos fenótipos e localização das lesões cerebrais. Nas alfa-sinucleinopatias, o TCSR tem relevância prognóstica quanto à neurodegeneração. Na DW, já conhecemos a importância de diagnóstico e tratamento precoces. O TCSR na DW oferece um modelo para antecipar o tratamento desta síndrome de acometimento dos núcleos basais e tronco, vislumbrando a possibilidade de tratamento neuroprotetor para a fase “pré-clínica” da DP. .

Dysfunctions of the stomatognathic system and vocal aspects in Fahr disease: case report / Disfunções do sistema estomatognático e aspectos vocais na doença de Fahr: relato de caso

The aim of this study is to report the case of a patient with Fahr's Disease in order to describe the main stomatognathic and vocal changes that can be found in individuals with this disease. In order to establish the diagnosis, an assessment of the conditions of orofacial motor system and speech production, as well the efficiency of swallowing, was realized. Based on these assessments, there were difficulties in coordinating and sustaining muscle during speech and presence of oropharyngeal dysphagia. Speech disorders found in Fahr's disease manifest themselves in complex and cover various aspects of phonological knowledge and the diseases that affect the basal ganglia have similar frames of speech-language disorders of the stomatognathic system, being able to present a picture of dysarthria.

O objetivo deste estudo consiste em relatar o caso de uma paciente com Doença de Fahr buscando descrever as principais alterações estomatognáticas e vocais que podem ser encontradas em indivíduos com essa doença. A fim de estabelecer o diagnóstico fonoaudiológico, foi realizada avaliação das condições motoras orofaciais e produção da fala, além de eficiência da deglutição. Com base nessas avaliações, observaram-se dificuldades na coordenação e na sustentação muscular durante a fala e presença de disfagia orofaríngea. Os achados fonoaudiológicos na Doença de Fahr manifestam-se de forma complexa, incluindo disfagias e disartria e as doenças que acometem os núcleos da base apresentam quadros semelhantes de alterações fonoaudiológicas do sistema estomatognático, podendo apresentar quadro de disartria.

Agregados amiloides: rol en desórdenes de conformación proteica / Amyloid aggregates: role in protein misfolding disorders

Misfolding and aggregation of proteins are the main features of a group of diseases termed Protein Misfolding Disorders (PMDs). PMDs include Alzheimer's disease and Transmissible Spongiform Encephalopathies, among many others. The deposition of protein aggregates is the main responsible for tissue damage and the consequent clinical signs generated in such disorders. In this review, we will focus in the role of protein aggregates in these diseases and in the putative mechanisms by which they exert their toxicity.

Os possíveis papéis da S100B na esquizofrenia / Potential roles of S100B in schizophrenia

Evidências científicas do aumento da concentração da proteína S100B no sangue de pacientes esquizofrênicos são muito consistentes. No passado essa informação era principalmente considerada como reflexo da disfunção astroglial ou da barreira hematoencefálica. MÉTODOS: Pesquisa de publicações no PubMed até o dia 15 de junho de 2011 visando estabelecer potenciais ligações entre a proteína S100B e as hipóteses correntes da esquizofrenia. RESULTADOS: A S100B está potencialmente associada com as hipóteses dopaminérgica e glutamatérgica. O aumento da expressão de S100B tem sido detectado em astrócitos corticais em casos de esquizofrenia paranoide, enquanto se observa uma redução da expressão em oligodendrócitos na esquizofrenia residual, dando suporte à hipótese glial. Recentemente, a hipótese da neuroinflamação da esquizofrenia tem recebido atenção crescente. Nesse sentido, a S100B pode funcionar como uma citocina secretada por células gliais, linfócitos CD8+ e células NK, levando à ativação de monócitos e microglia. Além disso, a S100B apresenta propriedades do tipo adipocina e pode estar desregulada na esquizofrenia, devido a distúrbios da sinalização de insulina, levando ao aumento da liberação de S100B e ácidos graxos do tecido adiposo. CONCLUSÃO: A expressão de S100B em diferentes tipos celulares está envolvida em muitos processos regulatórios. Atualmente, não pode ser respondido qual mecanismo relacionado à esquizofrenia é o mais importante

Scientific evidence for increased S100B concentrations in the peripheral blood of acutely ill schizophrenia patients is consistent. In the past, this finding was mainly considered to reflect astroglial or blood-brain barrier dysfunction. METHODS: Using Entrez, PubMed was searched for articles published on or before June 15, 2011, including electronic early release publications, in order to determine other potential links between S100B and current hypotheses for schizophrenia. RESULTS: S100B is potentially associated with the dopamine and glutamate hypotheses. Supporting the glial hypothesis, an increased expression of S100B has been detected in cortical astrocytes of paranoid schizophrenia cases, while decreased oligodendrocytic expression has been observed in residual schizophrenia. Recently, the neuroinflammation hypothesis of schizophrenia has gained attention. S100B may act as a cytokine after secretion from glial cells, CD8+ lymphocytes and NK cells, activating monocytes and microglial cells. Moreover, S100B exhibits adipokine-like properties and may be dysregulated in schizophrenia due to disturbances in insulin signaling, leading to the increased release of S100B and free fatty acids from adipose tissue. DISCUSSION: Dysregulation of pathways related to S100B appears to play a role in schizophrenia. However, S100B is expressed in different cell types and is involved in many regulatory processes. Currently, "the most important" mechanism related to schizophrenia cannot be determined

Aspectos fisiológicos do cálcio e sua disfunção em patologias neurodegenerativas / Physiological aspects of calcium and its dysfunction in neurodegenerative diseases

O íon cálcio funciona como um segundo mensageiro que regula um amplo espectro de processos celulares. A diminuição ou perda do controle dos mecanismos que regulam a concentração intracelular desse íon está associada, respectivamente, ao envelhecimento dos neurônios e a doenças neurodegenerativas. A gênese dessas modificações é desconhecida. Entretanto, estudos recentes apontam para uma provável correlação entre expressão gênica alterada, estresse do retículo endoplasmático e os processos patológicos associados à disfunção na concentração intracelular de cálcio. O esclarecimento dessas questões poderá trazer novos alvos terapêuticos capazes de frear ou reverter tais alterações, combatendo, dessa forma, tanto o envelhecimento neuronal quanto as doenças neurodegenerativas.

Calcium is a second messenger that regulates a lot of cellular functions. The following mechanisms regulate the intracellular concentrations of the ion: influx, release, extrusion and storage. Decrease or loss in control of these mechanisms is related to aging of neurons and neurodegenerative diseases, respectively. The genesis of these alterations is unknown. However, recent studies point to a correlation between calcium dysfunction and altered gene expression. There is also a correlation between endoplasmic reticulum stress and pathological processes. Further investigations may reveal new therapeutical targets that can block or revert these alterations.

Calcium and cell death signaling in neurodegeneration and aging

Transient increase in cytosolic (Cac2+) and mitochondrial Ca2+ (Ca m2+) are essential elements in the control of many physiological processes. However, sustained increases in Ca c2+ and Ca m2+ may contribute to oxidative stress and cell death. Several events are related to the increase in Ca m2+, including regulation and activation of a number of Ca2+ dependent enzymes, such as phospholipases, proteases and nucleases. Mitochondria and endoplasmic reticulum (ER) play pivotal roles in the maintenance of intracellular Ca2+ homeostasis and regulation of cell death. Several lines of evidence have shown that, in the presence of some apoptotic stimuli, the activation of mitochondrial processes maylead to the release of cytochrome c followed by the activation of caspases, nuclear fragmentation and apoptotic cell death. The aim of this review was to show how changes in calcium signaling can be related to the apoptotic cell death induction. Calcium homeostasis was also shown to be an important mechanism involved in neurodegenerative and aging processes.

Aumentos transientes no cálcio citosólico (Ca c2+) e mitocondrial (Ca m2+) são elementos essenciais no controle de muitos processos fisiológicos. No entanto, aumentos sustentados do Ca c2+ e do Ca m2+ podem contribuir para o estresse oxidativo ea morte celular. Muitos eventos estão relacionados ao aumentono Ca c2+, incluindo a regulação e ativação de várias enzimas dependentes de Ca2+ como as fosfolipases, proteases e nucleases. A mitocôndria e o retículo endoplasmático têm um papel central na manutenção da homeostase intracellular de Ca c2+ e na regulação da morte celular. Várias evidências mostraram que, na presença de certos estímulos apoptóticos, a ativação dos processos mitocondriais pode promover a liberação de citocromo c, seguida da ativação de caspases, fragmentação nuclear e morte celular por apoptose. O objetivo desta revisão é mostrar como aumentos na sinalização de Ca2+ podem estar relacionados aos eventos de indução da morte celular apoptótica. Além disso, evidenciar como a homeostase de Ca2+ pode ser importante e está envolvida nos mecanismos presentes nos processos de neurodegeneração e envelhecimento.

Astrocyte, the star avatar: redefined.

Until recently, the neuroscience community held the belief that glial cells such as astrocytes and oligodendrocytes functioned solely as "support" cells of the brain. In this role, glial cells simply provide physical support and housekeeping functions for the more important cells of the brain, the neurons. However, this view has changed radically in recent years with the discovery of previously unrecognized and surprising functions for this underappreciated cell type. In the past decade or so, emerging evidence has provided new insights into novel glial cell activities such as control of synapse formation and function, communication,cerebrovascular tone regulation, immune regulation and adult neurogenesis. Such advances in knowledge have effectively elevated the role of the astrocyte to one that is more important than previously realized. This review summarizes the past and present knowledge of glial cell functions that has evolved over the years, and has resulted in a new appreciation of astrocytes and their value in studying the neurobiology of human brain cells and their functions. In this review, we highlight recent advances in the role of glial cells in physiology, pathophysiology and, most importantly, in adult neurogenesis and "stemness", with special emphasis on astrocytes.

Results of Charité artificial lumbar disc replacement: experience in 43 Thais.

OBJECTIVE: To demonstrate the results of artificial lumbar disc replacement in Thai patients with degenerative disc disease. MATERIAL AND METHOD: A prospective study had been conducted to evaluate the efficacy and safety of artificial lumbar disc replacement in patients from October 2004 to December 2007. Oswestry disability index (ODI) score and visual analogic scale (VAS) for pain had been used to assess the clinical result before and after surgery. RESULTS: Forty three patients diagnosed as degenerative lumbar disc disease underwent 50 artificial lumbar disc replacement. All patients markedly improved in both ODI and VAS. The mean ODI score decreased from 60.9% preoperative to only 9.8% postoperative. The VAS score also decreased from 7.44 to 1.3 at the final follow up period. No serious complication found from this procedure. CONCLUSION: We demonstrated a good short term, a critical outcome of Charité artificial lumbar disc replacement in Thai patient with degenerative lumbar disc disease.

Anartria o apraxia del habla progresiva / Progressive anarthria or speech apraxia

Two cases of progressive anarthria are reported; we remark their close but distinct relation with speech apraxia. Both of them were older female, with a progressive loss of speech, bilateral paresis of lower face, tongue and palatal muscles. They also had mild pyramidal signs and a fronto-subcortical cognitive deterioration. Brain TC and MRI were within normal limits. One of them had a possible progressive supranuclear palsy, the other one a possible corticobasal degeneration. The analysis of similar cases reports let us to conclude than there are several pathologies that can cause a progressive pseudobulbar palsy. The final diagnosis must be by postmortem examination of the brain.

Se presentan dos casos de anartria progresiva, discutiendo la relación o el diagnóstico diferencial con la apraxia del habla progresiva. En ambos casos se trataba de mujeres mayores de 65 años con un cuadro de pérdida progresiva del lenguaje oral, con diparesia facial, lingual y velar, deterioro cognitivo de tipo frontal y discretos signos piramidales. Las imágenes cerebrales estructurales fueron normales. Uno de ellos pudo corresponder a una parálisis supranuclear progresiva, la otra a una degeneración corticobasal. Se analiza la literatura, llegando a la conclusión de que existen una serie de cuadros que pueden presentarse con un síndrome pseudobulbar progresivo. El diagnóstico definitivo debiera ser patológico.

Mecanismos moleculares de transducción de señales en patologías neurodegenerativas: enfermedad de Alzheimer como modelo de neurodegeneración / Molecular mechanism of signal transduction in neurodegenerative pathologies: Alzheimer diseases as neurodegeneration model

Las patologías neurodegenerativas corresponden a un grupo heterogéneo de desordenes caracterizados por cambios moleculares que desencadenan alteraciones morfológicas, asociadas a modificaciones de la conducta y disminución progresiva de la capacidad cognitiva. El notable avance en el esclarecimiento de los mecanismos moleculares implicados en la neurodegeneración, ha demostrado que existen alteraciones importantes en diversos mecanismos de transducción de señales como consecuencia de neurotoxicidad, injuria oxidativa y alteraciones moleculares en genes que codifican para proteínas claves en los mecanismos fisiológicos de aprendizaje, memoria y plasticidad neuronal. La comprensión de la fisiología y fisiopatología de estas vías de señalización, ejemplificada en la enfermedad de Alzheimer, permitiría enfocar de mejor manera el estudio de estas patologías y la búsqueda de un tratamiento efectivo para combatir estos desordenes cada vez más frecuentes debido al aumento de las expectativas de vida de la población.