A Remodelação do Sistema Nervoso Autônomo Cardíaco pode Desempenhar um Papel na Fibrilação Atrial: Um Estudo do Sistema Nervoso Autônomo e Receptores Miocárdicos / Cardiac Autonomic Nervous System Remodeling May Play a Role in Atrial Fibrillation: A Study of the Autonomic Nervous System and Myocardial Receptors

Resumo Fundamento Alterações do substrato elétrico e anatômico do coração são fatores que originam e perpetuam a fibrilação atrial (FA), porém, os mecanismos envolvidos não foram totalmente elucidados ainda. Objetivo: Avaliar o papel do remodelamento do sistema nervoso cardíaco intrínseco (SNCI), incluindo fibras nervosas e receptores muscarínicos e β-adrenérgicos, na FA permanente humana. Métodos Foram avaliadas 4 amostras em átrios de 13 corações obtidos em necrópsias de pacientes com doença cardíaca e FA permanente, e em 13 controles com as mesmas doenças, porém, sem FA. Utilizando imunoperoxidase e histomorfometria, quantificamos a densidade das fibras do SNCI, bem como a porcentagem positiva de miocárdio para receptores β-adrenérgicos 1, 2 e 3, receptor quinase 5 acoplado à proteína G (GRK-5), e receptores muscarínicos 1 a 5. Os resultados foram comparados usando ANOVA e ANOVA hierarquizada e ajustados pelo volume do átrio esquerdo e, para avaliação da expressão de receptores β e GRK-5, pelo uso de β-bloqueadores. Adotamos como significativo α = 0,05. Resultados Houve aumento na densidade das fibras ( p <0,01), especialmente nas fibras simpáticas ( p =0,02). Quanto aos receptores muscarínicos, só houve diferença nos M1, que estavam aumentados (5,87±4,52 vs 2,85±2,40; p =0,03). Quanto aos componentes do sistema adrenérgicos analisados, houve expressão aumentada de β-3 (37,41 vs 34,18, p =0,04) e GRK-5 (51,16 vs 47,66; p<0,01). O uso de β-bloqueadores não teve impacto na expressão de receptores beta. Conclusão O aumento na inervação do SNCI e a alteração na expressão de receptores em regiões suscetíveis de desencadear FA podem ter um papel na fibrilação atrial permanente.

Abstract Background The primary factors that originate and perpetuate atrial fibrillation (AF) are electrical and anatomical substrate alterations. However, the central mechanisms governing AF perpetuation have not been elucidated yet, which is reflected on the modest results of the treatment in patients with long persistent AF. Objective To evaluate if human intrinsic cardiac autonomic nervous system (ICANS) remodeling, including nervous system fibers and muscarinic and β-adrenergic receptors, play a role in permanent AF. Methods Heart necropsy samples from thirteen patients with heart disease and permanent AF and thirteen controls without AF were used. By using immunoperoxidase and histomorphometry quantification, we identified the following: the density of all fibers of the ICANS, sympathetic and parasympathetic fibers; and the percentage of myocardium positive for β-adrenergic receptors 1, 2 and 3; G protein-coupled receptor kinase-5 (GRK-5); and muscarinic receptors M1 to M5. The results were compared using ANOVA and nested ANOVA and were adjusted according to the left atrium volume for all variables, and β-blocker use to evaluate the expression of β-receptors and GRK-5. Results There was an overall increase in the density of fibers of the ICANS (p=0.006), especially in atrial sympathetic nerve fibers (p=0.017). Only M1 muscarinic receptors were increased (5.87 vs 2.35, p=0.032). For adrenergic receptors, the results were positive for increased expression of β-3 (37.41 vs 34.18, p=0.039) and GRK-5 (51.16 vs 47.66; p<0.001). β-blocker use had no impact on β-receptor expression. Conclusion Increased ICANS innervation and remodeling receptor expression in regions prone to triggering AF may play a role in permanent AF.

Melatonin inhibits nicotinic acetylcholine receptor functions in bovine chromaffin cells

Melatonin is a neurotransmitter that modulates various physiological phenomena including regulation and maintenance of the circadian rhythm. Nicotinic acetylcholine receptors (nAChRs) play an important role in oral functions including orofacial muscle contraction, salivary secretion, and tooth development. However, knowledge regarding physiological crosstalk between melatonin and nAChRs is limited. In the present study, the melatonin-mediated modulation of nAChR functions using bovine adrenal chromaffin cells, a representative model for the study of nAChRs, was investigated. Melatonin inhibited the nicotinic agonist dimethylphenylpiperazinium (DMPP) iodide-induced cytosolic free Ca²⁺ concentration ([Ca²⁺](i)) increase and norepinephrine secretion in a concentration-dependent manner. The inhibitory effect of melatonin on the DMPP-induced [Ca²⁺](i) increase was observed when the melatonin treatment was performed simultaneously with DMPP. The results indicate that melatonin inhibits nAChR functions in both peripheral and central nervous systems.

Trastorno depresivo mayor: una mirada genética / Major depressive disorder: a genetic view

Resumen El trastorno depresivo mayor es una enfermedad que se caracteriza por la presencia de diferentes síntomas, que van desde no poder comer o dormir, hasta el no disfrute de las actividades que antes resultaban placenteras, ideas de minusvalía y suicidio. Las investigaciones del campo de las neurociencias y de las enfermedades psiquiátricas en especial, tienden cada vez más a buscar los posibles orígenes genéticos que expliquen su desarrollo y progresión. En esta revisión de la literatura se presenta lo reportado en estudios que no solo describen la enfermedad desde los trastornos neurofisiológicos, sino también desde alteraciones genéticas y epigenéticas, con el fin de brindar un mayor entendimiento de las bases moleculares y fisiopatológicas de esta patología psiquiátrica.

Abstract Major depressive disorder is a disease that is characterized by the presence of different symptoms, ranging from not being able to eat or sleep, to not enjoy activities that were previously pleasurable, ideas of disability and suicide. Research in the field of neurosciences and psychiatric diseases in particular, increasingly tend to seek the possible genetic origins that explain the development and progression of them. In this review of the literature, is presented what has been reported in studies, that not only describe the disease from its neurophysiological disorders, but also from the genetic and epigenetic alterations, in order to provide a better understanding of the molecular and physiopathological bases of this psychiatric pathology.

El tabaquismo: una adicción / Smoking, an addiction

Resumen El tabaquismo es factor de riesgo y a la vez una adicción compleja con componentes físicos, psicológicos y sociales. Adicción es la necesidad compulsiva de volver a consumir una droga para experimentar sus efectos, en el caso la nicotina, estimulación, euforia, placer, aumento de la atención concentración y memoria, además de disminución de la ansiedad, estrés y apetito. El Manual Diagnóstico y Estadístico de los Trastornos Mentales (DSM V) cataloga el tabaquismo como una adicción, la nicotina es una de las drogas más adictivas que existen, junto con la cocaína y la heroína, además demora 10 segundos en llegar al cerebro cuando se fuma. La nicotina se relaciona con distintos sistemas de neurotransmisión en el sistema nervioso central, es agonista de los receptores α4β2 de acetilcolina, siendo la unión receptor- neurotransmisor de alta sensibilidad. Las vías neurofisiológicas más importes implicadas en la dependencia por la nicotina son dopaminérgica (la más importante), noradrenérgica, GABA-érgica, glutamatérgica y endocanabinoide. El síndrome de abstinencia es una característica básica de la adicción, y es un conjunto de síntomas y signos, físicos y psíquicos que aparecen como consecuencia de la interrupción, reducción o abandono del tabaco. El síndrome de abstinencia se produce como consecuencia de varios factores: disminución de los niveles de cortisol plasmáticos, disminución de los niveles de noradrenalina en el Locus Coeruleous (LC) y principalmente disminución de los niveles de dopamina en el Núcleo Accumbens.

Smoking is a risk factor and at the same time a complex addiction with physical, psychological and social components. Addiction is the compulsive need to re-consume a drug to experience its effects, in the case of nicotine, stimulation, euphoria, pleasure, increased attention concentration and memory, plus decreased anxiety, stress and appetite. The Diagnostic and Statistical Manual of Mental Disorders (DSM V) lists smoking as an addiction, nicotine is one of the most addictive existing drugs, along with cocaine and heroin, and it takes 10 seconds to reach the brain when people smokes. Nicotine is related to different neurotransmission systems in the central nervous system, it is an agonist of acetylcholine α4β2 receptors, being the receptor-neurotransmitter junction of high sensitivity. The most important neurophysiological pathways involved in nicotine dependence are dopaminergic (most important), noradrenergic, GABA-ergic, glutamatergic and endocannabinoid. Abstinence syndrome is a basic characteristic of addiction, and is a set of physical and psychological symptoms and signs that appear because of interruption, reduction, or smoking cessation. Abstinence syndrome occurs as a consequence of several factors: decreased plasma cortisol levels, decreased levels of noradrenaline in the Locus Coeruleous and mainly decreased dopamine levels in Nucleous Accumbens.

In Silico Model-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology

OBJECTIVE: Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA. METHODS: Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)-Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm. RESULTS: Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network. CONCLUSION: The study presents in silico quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current understanding of the disorder.

Trabalhadores usuários de drogas em recuperação em uma região industrial do Brasil / Workers recovering from drug addiction in an industrial region of Brazil

Contexto: O número de usuários de drogas ilícitas é estimado globalmente em 210 milhões de pessoas ao ano, das quais pelo menos 200.000 morrem em decorrência do uso. O consumo de drogas afeta não apenas o usuário, mas também a família, os amigos, os colegas de trabalho e a comunidade. Objetivo: O presente estudo traçou um perfil sociodemográfico de trabalhadores em tratamento para recuperação da dependência química na região de Campinas (SP). Método: Estudo transversal exploratório com dados colhidos por meio de questionário autoaplicado e anônimo em centros de recuperação para tratamento de dependência química no município de Campinas. A pesquisa foi conduzida entre julho de 2011 e julho de 2012 e analisou as condições de saúde e trabalho. A população estudada constituía-se de trabalhadores que estiveram em acompanhamento por mais de 30 dias, totalizando 200 pessoas. Resultados: A faixa etária de 18 a 54 anos representou 87,8% da amostra, com predominância de participantes com ensino médio completo e que desenvolviam alguma atividade remunerada, sendo que 54,5% estavam empregados formalmente, 48,4% com contratos inferiores a um ano, e 42,1% com faixa salarial abaixo de R$ 1.020,00. Conclusão: Este estudo apresenta informações pouco exploradas em outras pesquisas e com potencial para aprimorar as intervenções relacionadas à prevenção, ao tratamento e à reabilitação de trabalhadores em situação semelhante.

Context: The number of illicit drug users is estimated at 210 million people a year worldwide, of which at least 200,000 die as a consequence of the use. Drug use affects not only the user but also the family, friends, coworkers, and the community. Objective: This study outlines a sociodemographic profile of workers undergoing treatment for chemical dependency recovery in Campinas (SP). Method: Cross-sectional, exploratory study with data collected in rehabilitation centers for chemical dependency treatment in Campinas by means of a self-administered and anonymous questionnaire. The research was conducted between July 2011 and July 2012 and focused on the analysis of health and work conditions. The study included workers who were followed up for more than 30 days (n=200). Results: 87.8% of the population were aged 18­54 years, most of them had completed high school, had a remunerated activity, and of which 54.5% were formally employed, 48.4% with less than one year contracts and 42.1% with salary range below R$1,020.00 (Brazilian real). Conclusion: This study provides information not explored in other researches and has a potential value related to the prevention, treatment, and rehabilitation of workers in similar conditions.

Bone and Energy Metabolism / 임상당뇨병

Bone remodeling requires a large amount of energy, and is regulated by various hormones. Leptin, produced by adipocytes, is a well-known regulator of energy balance and is also involved in controlling bone mass through interaction with the central nervous system. Serotonin, downstream of leptin, is also emerging as a candidate for controlling energy balance and bone metabolism. Currently, bone is also considered to be an endocrine regulator of energy metabolism. Osteocalcin, secreted from osteoblasts, is known to be a key regulator of glucose and fat metabolism. In this review, we describe a novel concept that asserts that there exists a biological link between bone and energy metabolism, and we summarize what is currently known about the relationship between bone and energy metabolism.

Role of M3 muscarinic acetylcholine receptor in glycinergic neurotransmitter release in spinal lamina Ⅰneurons in rats / 中华麻醉学杂志

Objective To evaluate the role of M3 muscarinic acetylcholine receptor (M3 mAChR) in the release of glycinergic neurotransmitter by using oxotremorine-M (Oxo-M: a nonselective mAChR agonist) and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP: a highly selective M3mAChR antagonist). Methods Twenty male 3-4 weeks old SD rats weighing 160-180 g after successful intrathecal catheterization were randomized into 2 groups (n = 10 each): normal saline group (group NS) and pertussis toxin (group PTX).Pertussis toxin 1.5 μg/10 μl was injected IT in group PTX, while in group NS normal saline 10 μl was injected IT instead. The animals were killed at day 7 after injection. The spinal cords were removed and sliced and placed in artificial CSF. Glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs) were measured in spinal lamina Ⅱneurons using whole-cell voltage-clamp technique. Five minutes after sealing, Oxo-M (final concentration 3 μ mol/L) was added. Oxo-M was then completely washed out 3 min later and 4-DAMP (final concentration 25 nmol/L) was added after 5 min of stabilization. In the presence of 4-DAMP, Oxo-M (final concentration 3 μmol/L) was added again 3 min later. sIPSCs were recorded before addition of Oxo-M (T1), 3 min after addition of Oxo-M (T2), 3 min after addition of 4-DAMP (T3), 3 min after the second addition of Oxo-M (T4). Results Compared with the baseline value at T1 , Oxo-M significantly increased the frequency of glycinergic sIPSCs at T2without changing the amplitude at T2-4 in both groups. The frequency of sIPSCs was significantly lower at T4 than at T2 in both groups (P ＜ 0.05 or 0.01). There was no significant difference in both frequency and amplitude of glycinergic sIPSCs between the two groups. Conclusion M3 mAChR plays a predominant role in the release of glycinergic transmitter in the spinal lamina Ⅱ neurons in rats.

Aripiprazole en el tratamiento sintomático del síndrome de Gilíes de la Tourette (enfermedad de los tics) / Aripiprazole for the treatment of Tourette syndrome. Experience in 10 patients

Background: Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics, attentional deficit, poor control of impulses and obsessive compulsive disorder. Pharmacological treatment is often disappointing due to partial response and frequent poor tolerance to neuroleptic drugs which are otherwise the most effective therapy so far. Aim: To report a lasting improvement obtained with a new drug, aripiprazole that acts modulating both dopaminergic and serotoninergic neurotransmission. Material and methods: Ten patients refractory to their usual therapy, aged 10 to 35 years, were switched to aripiprazole in an open trial. Results: Nine of the 10 patients showed a significant response assessed by the Yale severity tics rating scale and the clinical global impression scale (p <0.01). No relevant adverse effects were observed. Conclusions: Aripiprazole may be a good pharmacological option for patients with Tourette syndrome.