ESCLEROSE LATERAL AMIOTRÓFICA: NOVAS POSSIBILIDADES TERAPÊUTICAS EM UM ARCABOUÇO FISIOPATOLÓGICO AINDA EM CONSTRUÇÃO

Esclerose Lateral Amiotrófica (ELA) é definida como uma doença neurológica progressiva e inexorável, com cerca de 80% dos casos de etiologia desconhecida. Novos medicamentos têm emergido no tratamento de doenças neurodegenerativas, inclusive na ELA, redesenhando o modelo fisiopatológico. Dentre eles, destacam-se o uso da: Edaravone, Vitamina K2, Serina, Metilcobalamina, Pirroloquinolina quinona (PQQ), Ubiquinol e Glutationa. Especificamente na ELA, alguns já foram validados em estudos randomizados-controlados. Metodologia: Atualização da literatura (PUBMED, Medline) sobre a utilização desses fármacos em doenças neurológicas degenerativas, com enfoque para a Doença do Neurônio Motor (DNM-ELA), nos idiomas Português, Inglês, Espanhol e Francês, compreendidos entre os anos de (2010-2017). Discussão: A associação desses medicamentos tem mostrado resultados positivos em inúmeras doenças neurológicas. Alguns, como, por exemplo, a Metilcobalamina e o Edaravone,exerceriam mecanismos de ação capazes de interferir no processo de depleção dos neurônios motores da ponta anterior e do feixe piramidal em pacientes com ELA. Conclusão: Seria precipitado concluir que o uso associado desses fármacos poderia modificar ou mesmo restaurar os danos às unidades motoras; entretanto, faz-se necessário destacar seus mecanismos de ação e potencial capacidade de intervir na evolução da doença, principalmente, a partir de estudos em modelos fisiopatológico que culminam na degeneração dos neurônios motores

Pseudotumor Cerebri and Glymphatic Dysfunction

In contrast to virtually all organ systems of the body, the central nervous system was until recently believed to be devoid of a lymphatic system. The demonstration of a complex system of paravascular channels formed by the endfeet of astroglial cells ultimately draining into the venous sinuses has radically changed this idea. The system is subsidized by the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma along paravascular spaces (PVSs) and by exchanges with the interstitial fluid (IF). Aquaporin-4 channels are the chief transporters of water through these compartments. This article hypothesizes that glymphatic dysfunction is a major pathogenetic mechanism underpinning idiopathic intracranial hypertension (IIH). The rationale for the hypothesis springs from MRI studies, which have shown many signs related to IIH without evidence of overproduction of CSF. We propose that diffuse retention of IF is a direct consequence of an imbalance of glymphatic flow. This imbalance, in turn, may result from an augmented flow from the arterial PVS into the IF, by impaired outflow of the IF into the paravenous spaces, or both. Our hypothesis is supported by the facts that (i) visual loss, one of the main complications of IIH, is secondary to the impaired drainage of the optic nerve, a nerve richly surrounded by water channels and with a long extracranial course in its meningeal sheath; (ii) there is a high association between IIH and obesity, a condition related to paravascular inflammation and lymphatic disturbance, and (iii) glymphatic dysfunction has been related to the deposition of β-amyloid in Alzheimer’s disease. We conclude that the concept of glymphatic dysfunction provides a new perspective for understanding the pathophysiology of IIH; it may likewise entice the development of novel therapeutic approaches aiming at enhancing the flow between the CSF, the glymphatic system, and the dural sinuses

Cognitive Impairment in Neuromuscular Diseases: A Systematic Review

Neuromuscular diseases are multifactorial pathologies characterized by extensive muscle fiber damage that leads to the activation of satellite cells and to the exhaustion of their pool, with consequent impairment of neurobiological aspects, such as cognition and motor control. To review the knowledge and obtain a broad view of the cognitive impairment on Neuromuscular Diseases. Cognitive impairment in neuromuscular disease was explored; a literature search up to October 2017 was conducted, including experimental studies, case reports and reviews written in English. Keywords included Cognitive Impairment, Neuromuscular Diseases, Motor Neuron Diseases, Dystrophinopathies and Mitochondrial Disorders. Several cognitive evaluation scales, neuroimaging scans, genetic analysis and laboratory applications in neuromuscular diseases, especially when it comes to the Motor Neuron Diseases, Dystrophinopathies and Mitochondrial Disorders. In addition, organisms model using rats in the genetic analysis and laboratory applications to verify the cognitive and neuromuscular impacts. Several studies indicate that congenital molecular alterations in neuromuscular diseases promote cognitive dysfunctions. Understanding these mechanisms may in the future guide the proper management of the patient, evaluation, establishment of prognosis, choice of treatment and development of innovative interventions such as gene therapy

Alternative splicing originates different domain structure organization of Lutzomyia longipalpis chitinases

BACKGROUND The insect chitinase gene family is composed by more than 10 paralogs, which can codify proteins with different domain structures. In Lutzomyia longipalpis, the main vector of visceral leishmaniasis in Brazil, a chitinase cDNA from adult female insects was previously characterized. The predicted protein contains one catalytic domain and one chitin-binding domain (CBD). The expression of this gene coincided with the end of blood digestion indicating a putative role in peritrophic matrix degradation. OBJECTIVES To determine the occurrence of alternative splicing in chitinases of L. longipalpis. METHODS We sequenced the LlChit1 gene from a genomic clone and the three spliced forms obtained by reverse transcription polymerase chain reaction (RT-PCR) using larvae cDNA. FINDINGS We showed that LlChit1 from L. longipalpis immature forms undergoes alternative splicing. The spliced form corresponding to the adult cDNA was named LlChit1A and the two larvae specific transcripts were named LlChit1B and LlChit1C. The B and C forms possess stop codons interrupting the translation of the CBD. The A form is present in adult females post blood meal, L4 larvae and pre-pupae, while the other two forms are present only in L4 larvae and disappear just before pupation. Two bands of the expected size were identified by Western blot only in L4 larvae. MAIN CONCLUSIONS We show for the first time alternative splicing generating chitinases with different domain structures increasing our understanding on the finely regulated digestion physiology and shedding light on a potential target for controlling L. longipalpis larval development

Transcranial electrical stimulation modulates emotional experience and metabolites in the prefrontal cortex in a donation task

Understanding the neural, metabolic, and psychological mechanisms underlying human altruism and decision-making is a complex and important topic both for science and society. Here, we investigated whether transcranial Direct Current Stimulation (tDCS) applied to two prefrontal cortex regions, the ventromedial prefrontal cortex (vmPFC, anode) and the right dorsolateral prefrontal cortex (DLPFC, cathode) can induce changes in self-reported emotions and to modulate local metabolite concentrations. We employed in vivo quantitative MR Spectroscopy in healthy adult participants and quantified changes in GABA and Glx (glutamate + glutamine) before and after five sessions of tDCS delivered at 2 mA for 20 min (active group) and 1 min (sham group) while participants were engaged in a charitable donation task. In the active group, we observed increased levels of GABA in vmPFC. Glx levels decreased in both prefrontal regions and self-reported happiness increased significantly over time in the active group. Self-reported guiltiness in both active and sham groups tended to decrease. The results indicate that self-reported happiness can be modulated, possibly due to changes in Glx concentrations following repeated stimulation. Therefore, local changes may induce remote changes in the reward network through interactions with other metabolites, previously thought to be unreachable with noninvasive stimulation techniques

Anti-musk positive myasthenia gravis and three semiological cardinal signs

Myasthenia gravis (MG) is a relatively uncommon disorder with an annual incidence of approximately 7 to 9 new cases per million. The prevalence is about 70 to 165 per million. The prevalence of the disease has been increasing over the past five decades. This is thought to be due to better recognition of the condition, aging of the population, and the longer life span of affected patients. MG causes weakness, predominantly in bulbar, facial, and extra-ocular muscles, often fluctuating over minutes to weeks, in the absence of wasting, sensory loss, or reflex changes. The picture of fluctuating, asymmetric external ophthalmoplegia with ptosis and weak eye closure is virtually diagnostic of myasthenia. We report an atypical MG case with three semiological cardinal signs

Alternative splicing originates different domain structure organization of Lutzomyia longipalpis chitinases

<div><p> BACKGROUND The insect chitinase gene family is composed by more than 10 paralogs, which can codify proteins with different domain structures. In Lutzomyia longipalpis, the main vector of visceral leishmaniasis in Brazil, a chitinase cDNA from adult female insects was previously characterized. The predicted protein contains one catalytic domain and one chitin-binding domain (CBD). The expression of this gene coincided with the end of blood digestion indicating a putative role in peritrophic matrix degradation. OBJECTIVES To determine the occurrence of alternative splicing in chitinases of L. longipalpis. METHODS We sequenced the LlChit1 gene from a genomic clone and the three spliced forms obtained by reverse transcription polymerase chain reaction (RT-PCR) using larvae cDNA. FINDINGS We showed that LlChit1 from L. longipalpis immature forms undergoes alternative splicing. The spliced form corresponding to the adult cDNA was named LlChit1A and the two larvae specific transcripts were named LlChit1B and LlChit1C. The B and C forms possess stop codons interrupting the translation of the CBD. The A form is present in adult females post blood meal, L4 larvae and pre-pupae, while the other two forms are present only in L4 larvae and disappear just before pupation. Two bands of the expected size were identified by Western blot only in L4 larvae. MAIN CONCLUSIONS We show for the first time alternative splicing generating chitinases with different domain structures increasing our understanding on the finely regulated digestion physiology and shedding light on a potential target for controlling L. longipalpis larval development.</p></div

Frontotemporal Dementia in Amyotrophic Lateral Sclerosis: From Rarity to Reality?

Amyotrophic lateral sclerosis (ALS) was initially described in 1869 by Jean-Martin Charcot [...