Functional diversity for body actions in the mesencephalic locomotor region.

The mesencephalic locomotor region (MLR) is a key midbrain center with roles in locomotion. Despite extensive studies and clinical trials aimed at therapy-resistant Parkinson's disease (PD), debate on its function remains. Here, we reveal the existence of functionally diverse neuronal populations with distinct roles in control of body movements. We identify two spatially intermingled glutamatergic populations separable by axonal projections, mouse genetics, neuronal activity profiles, and motor functions. Most spinally projecting MLR neurons encoded the full-body behavior rearing. Loss- and gain-of-function optogenetic perturbation experiments establish a function for these neurons in controlling body extension. In contrast, Rbp4-transgene-positive MLR neurons project in an ascending direction to basal ganglia, preferentially encode the forelimb behaviors handling and grooming, and exhibit a role in modulating movement. Thus, the MLR contains glutamatergic neuronal subpopulations stratified by projection target exhibiting roles in action control not restricted to locomotion.

HMGB1 down-regulation mediates terameprocol vascular anti-proliferative effect in experimental pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in PAH pathophysiology, displaying a hyperproliferative, and apoptotic-resistant phenotype. In the present study, we evaluated the potential therapeutic role of terameprocol (TMP), an inhibitor of cellular proliferation and promoter of apoptosis, in a well-established pre-clinical model of PAH induced by monocrotaline (MCT) and studied the biological pathways modulated by TMP in PASMCs. Wistar rats injected with MCT or saline (SHAM group) were treated with TMP or vehicle. On day 21 after injection, we assessed bi-ventricular hemodynamics and cardiac and pulmonary morphometry. The effects of TMP on PASMCs were studied in a primary culture isolated from SHAM and MCT-treated rats, using an iTRAQ-based proteomic approach to investigate the molecular pathways modulated by this drug. In vivo, TMP significantly reduced pulmonary and cardiac remodeling and improved cardiac function in PAH. In vitro, TMP inhibited proliferation and induced apoptosis of PASMCs. A total of 65 proteins were differentially expressed in PASMCs from MCT rats treated with TMP, some of which involved in the modulation of transforming growth factor beta pathway and DNA transcription. Anti-proliferative effect of TMP seems to be explained, at least in part, by the down-regulation of the transcription factor HMGB1. Our findings support the beneficial role of TMP in PAH and suggest that it may be an effective therapeutic option to be considered in the clinical management of PAH.

Central nervous system circuits modified in heart failure: pathophysiology and therapeutic implications.

The pathophysiology of heart failure (HF) is characterized by an abnormal activation of neurohumoral systems, including the sympathetic nervous and the renin-angiotensin-aldosterone systems, which have long-term deleterious effects on the disease progression. Perpetuation of this neurohumoral activation is partially dependent of central nervous system (CNS) pathways, mainly involving the paraventricular nucleus of the hypothalamus and some regions of the brainstem. Modifications in these integrative CNS circuits result in the attenuation of sympathoinhibitory and exacerbation of sympathoexcitatory pathways. In addition to the regulation of sympathetic outflow, these central pathways coordinate a complex network of agents with an established pathophysiological relevance in HF such as angiotensin, aldosterone, and proinflammatory cytokines. Central pathways could be potential targets in HF therapy since the current mainstay of HF pharmacotherapy aims primarily at antagonizing the peripheral mechanisms. Thus, in the present review, we describe the role of CNS pathways in HF pathophysiology and as potential novel therapeutic targets.

DBScope as a versatile computational toolbox for the visualization and analysis of sensing data from deep brain stimulation.

Different neurostimulators for deep brain stimulation (DBS) come already with the ability to chronically sense local field potentials during stimulation. This invaluable new data has the potential to increase our understanding of disease-related brain activity patterns, their temporal evolution, and their modulation in response to therapies. It also gives the opportunity to unveil new electrophysiological biomarkers and ultimately bring adaptive stimulation therapies closer to clinical practice. Unfortunately, there are still very limited options on how to visualize, analyze, and exploit the full potential of the sensing data from these new DBS neurostimulators. To answer this need, we developed a free open-source toolbox, named DBScope, that imports data from neurostimulation devices and can be operated in two ways: via user interface and programmatically, as a library of functions. In this way, it can be used by both clinicians during clinical sessions (for instance, to visually inspect data from the current or previous in-clinic visits), and by researchers in their research pipelines (e.g., for pre-processing, feature extraction and biomarker search). All in all, the DBScope toolbox is set to facilitate the clinical decision-making process and the identification of clinically relevant biomarkers. The toolbox is already being used in clinical and research environments, and it is freely available to download at GitHub (where it is also fully documented).

Exploring the role of post-translational modifications on protein-protein interactions with survivin.

Survivin is a member of the inhibitor of apoptosis protein (IAP) family with crucial roles in apoptosis and cell cycle regulation. Post-translational modifications (PTMs) have a ubiquitous role in the regulation of a diverse range of proteins' cellular functions and survivin is not an exception. Phosphorylation, acetylation and ubiquitination seem to regulate survivin anti-apoptotic and mitotic roles and also its nuclear localization. In the present review we explore the role of PTMs on protein-protein interactions focused on survivin to provide new insights into the functions and cell localization of this IAP in pathophysiological conditions, which might help the envisioning of novel targeted therapies for diseases characterized by impaired survivin activity. Protein-protein interaction analysis was performed with bioinformatics tools based on published data aiming to give an integrated perspective of this IAP's role in the cell.

Bilateral deep brain stimulation of the subthalamic nucleus: Targeting differences between the first and second side.

INTRODUCTION AND OBJECTIVES: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a recognized treatment for drug-refractory Parkinson's disease (PD). However, the therapeutic success depends on the accuracy of targeting. This study aimed to evaluate potential accuracy differences in the placement of the first and second electrodes implanted, by comparing chosen electrode trajectories, STN activity detected during microelectrode recording (MER), and the mismatch between the initially planned and final electrode positions on each side. MATERIALS AND METHODS: In this retrospective cohort study, we analyzed data from 30 patients who underwent one-stage bilateral DBS. For most patients, three arrays of microelectrodes were used to determine the physiological location of the STN. Final target location depended also on the results of intraoperative stimulation. The choice of central versus non-central channels was compared. The Euclidean vector deviation was calculated using the initially planned coordinates and the final position of the tip of the electrode according to a CT scan taken at least a month after the surgery. RESULTS: The central channel was chosen in 70% of cases on the first side and 40% of cases on the second side. The mean length of high-quality STN activity recorded in the central channel was longer on the first side than the second (3.07±1.85mm vs. 2.75±1.94mm), while in the anterior channel there were better MER recordings on the second side (1.59±2.07mm on the first side vs. 2.78±2.14mm on the second). Regarding the mismatch between planned versus final electrode position, electrodes on the first side were placed on average 0.178±0.917mm lateral, 0.126±1.10mm posterior and 1.48±1.64mm inferior to the planned target, while the electrodes placed on the second side were 0.251±1.08mm medial, 0.355±1.29mm anterior and 2.26±1.47mm inferior to the planned target. CONCLUSION: There was a tendency for the anterior trajectory to be chosen more frequently than the central on the second side. There was also a statistically significant deviation of the second electrodes in the anterior and inferior directions, when compared to the electrodes on the first side, suggesting that another cause other than brain shift may be responsible. We should therefore factor this during planning for the second implanted side. It might be useful to plan the second side more anteriorly, possibly reducing the number of MER trajectories tested and the duration of surgery.

Machine learning for adaptive deep brain stimulation in Parkinson's disease: closing the loop.

Parkinson's disease (PD) is the second most common neurodegenerative disease bearing a severe social and economic impact. So far, there is no known disease modifying therapy and the current available treatments are symptom oriented. Deep Brain Stimulation (DBS) is established as an effective treatment for PD, however current systems lag behind today's technological potential. Adaptive DBS, where stimulation parameters depend on the patient's physiological state, emerges as an important step towards "smart" DBS, a strategy that enables adaptive stimulation and personalized therapy. This new strategy is facilitated by currently available neurotechnologies allowing the simultaneous monitoring of multiple signals, providing relevant physiological information. Advanced computational models and analytical methods are an important tool to explore the richness of the available data and identify signal properties to close the loop in DBS. To tackle this challenge, machine learning (ML) methods applied to DBS have gained popularity due to their ability to make good predictions in the presence of multiple variables and subtle patterns. ML based approaches are being explored at different fronts such as the identification of electrophysiological biomarkers and the development of personalized control systems, leading to effective symptom relief. In this review, we explore how ML can help overcome the challenges in the development of closed-loop DBS, particularly its role in the search for effective electrophysiology biomarkers. Promising results demonstrate ML potential for supporting a new generation of adaptive DBS, with better management of stimulation delivery, resulting in more efficient and patient-tailored treatments.

Connecting Circuits for Supraspinal Control of Locomotion.

Locomotion is regulated by distributed circuits and achieved by the concerted activation of body musculature. While the basic properties of executive circuits in the spinal cord are fairly well understood, the precise mechanisms by which the brain impacts locomotion are much less clear. This Review discusses recent work unraveling the cellular identity, connectivity, and function of supraspinal circuits. We focus on their involvement in the regulation of the different phases of locomotion and their interaction with spinal circuits. Dedicated neuronal populations in the brainstem carry locomotor instructions, including initiation, speed, and termination. To align locomotion with behavioral needs, brainstem output structures are recruited by midbrain and forebrain circuits that compute and infer volitional, innate, and context-dependent locomotor properties. We conclude that the emerging logic of supraspinal circuit organization helps to understand how locomotor programs from exploration to hunting and escape are regulated by the brain.

[Career Satisfaction of Medical Residents in Portugal]. / Satisfação com a Especialidade entre os Internos da Formação Específica em Portugal.

INTRODUCTION: The satisfaction with the medical profession has been identified as an essential factor for the quality of care, the wellbeing of patients and the healthcare systems' stability. Recent studies have emphasized a growing discontent of physicians, mainly as a result of changes in labor relations. OBJECTIVES: To assess the perception of Portuguese medical residents about: correspondence of residency with previous expectations; degree of satisfaction with the specialty, profession and place of training; reasons for dissatisfaction; opinion regarding clinical practice in Portugal and emigration intents. MATERIAL AND METHODS: Cross-sectional study. Data collection was conducted through the "Satisfaction with Specialization Survey", created in an online platform, designed for this purpose, between May and August 2014. RESULTS: From a total population of 5788 medical residents, 804 (12.25 %) responses were obtained. From this sample, 77% of the responses were from residents in the first three years. Results showed that 90% of the residents are satisfied with their specialty, 85% with the medical profession and 86% with their place of training. Nevertheless, results showed a decrease in satisfaction over the final years of residency. The overall assessment of the clinical practice scenario in Portugal was negative and 65% of residents have plans to emigrate after completing their residency. CONCLUSION: Portuguese residents revealed high satisfaction levels regarding their profession. However, their views on Portuguese clinical practice and the results concerning the intent to emigrate highlight the need to take steps to reverse this scenario.

Introdução: A satisfação com a profissão médica tem sido apontada como um fator essencial para a qualidade assistencial, o bemestar dos doentes e a estabilidade dos sistemas de saúde. Estudos recentes têm vindo a enfatizar um crescente descontentamento dos médicos, principalmente como consequência das alterações das relações laborais.Objetivos: Avaliar a perceção dos médicos de formação específica em Portugal, sobre as expectativas e grau de satisfação com a profissão, especialidade e local de formação; razões da insatisfação e intenção de emigrar.Material e Métodos: Estudo transversal. A colheita de dados foi efetuada entre Maio e Agosto de 2014 através de um Inquérito online sobre a âÄúSatisfação com a EspecialidadeâÄù.Resultados: De uma população total de 5788 médicos, foram obtidas 804 respostas (12,25% do total de médicos internos). Desta amostra, 77% das respostas correspondem a internos dos três primeiros anos de formação. Verificou-se que 90% dos médicos se encontram satisfeitos com a especialidade, tendo-se encontrado também níveis elevados de satisfação com a profissão (85%) e local de formação (86%). Por outro lado, constatou-se que estes diminuíam com a progressão ao longo dos anos de internato. A avaliação global sobre o panorama da prática médica foi negativa e 65% dos médicos responderam que consideram emigrar após conclusão do internato.Conclusão: Os médicos internos em Portugal apresentam níveis positivos de satisfação com a sua profissão. No entanto, a sua opinião sobre o panorama da Medicina e os resultados relativos à intenção de emigrar alertam para a necessidade de tomada de medidas para inverter este cenário.

Adiponectin levels are elevated in patients with pulmonary arterial hypertension.

BACKGROUND: In addition to insulin-sensitizing effects, adiponectin influences several mechanisms involved in pulmonary arterial hypertension (PAH) pathobiology. Insulin resistance has been associated with PAH, and elevated adiponectin levels have been described in left heart failure (HF) as a response to the increased metabolic stress. No studies have been performed in right HF or PAH patients. HYPOTHESIS: Compared to healthy controls, PAH patients have a different plasma adipocytokine profile, higher insulin resistance, and higher inflammatory systemic activation. METHODS: A case-control study was conducted in PAH patients individually matched for sex, age, and body mass index. We characterized the clinical features, functional status (6-minute walking test), and hemodynamic profile of cases (n=25). We measured insulin resistance (homeostasis model assessment and high-density lipoprotein/triglycerides ratio), inflammatory systemic activation (high-sensitivity C-reactive protein), and plasma adipocytokine profile (adiponectin, leptin, visfatin, and resistin) in cases and controls. RESULTS: PAH patients had significantly higher adiponectin levels than controls (12.4±6.9 vs 8.1±4.5 µg/mL; P<0.05) and higher high-sensitivity C-reactive protein (2.96±3.2 vs 1.08±1.1; P<0.05). No statistically significant differences were found in plasma levels of leptin, visfatin, and resistin between groups. CONCLUSIONS: Adiponectin levels are increased in PAH patients compared to controls. Further studies are needed to study the potential role of adiponectin as a PAH biomarker.

Bilateral deep brain stimulation of the subthalamic nucleus: Targeting differences between the first and second side / Estimulación cerebral profunda bilateral del núcleo subtalámico: diferencias de posicionamiento entre el primer y el segundo lado

Introduction and objectives Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a recognized treatment for drug-refractory Parkinson's disease (PD). However, the therapeutic success depends on the accuracy of targeting. This study aimed to evaluate potential accuracy differences in the placement of the first and second electrodes implanted, by comparing chosen electrode trajectories, STN activity detected during microelectrode recording (MER), and the mismatch between the initially planned and final electrode positions on each side. Materials and methods In this retrospective cohort study, we analyzed data from 30 patients who underwent one-stage bilateral DBS. For most patients, three arrays of microelectrodes were used to determine the physiological location of the STN. Final target location depended also on the results of intraoperative stimulation. The choice of central versus non-central channels was compared. The Euclidean vector deviation was calculated using the initially planned coordinates and the final position of the tip of the electrode according to a CT scan taken at least a month after the surgery. Results The central channel was chosen in 70% of cases on the first side and 40% of cases on the second side. The mean length of high-quality STN activity recorded in the central channel was longer on the first side than the second (3.07±1.85mm vs. 2.75±1.94mm), while in the anterior channel there were better MER recordings on the second side (1.59±2.07mm on the first side vs. 2.78±2.14mm on the second). Regarding the mismatch between planned versus final electrode position, electrodes on the first side were placed on average 0.178±0.917mm lateral, 0.126±1.10mm posterior and 1.48±1.64mm inferior to the planned target (AU)

Introducción y objetivos La estimulación cerebral profunda (ECP) del núcleo subtalámico (NST) es reconocida como un tratamiento para la enfermedad de Parkinson (EP) refractaria al tratamiento farmacológico. Sin embargo, el éxito de esta intervención depende de la precisión de la colocación de los electrodos. Este estudio tuvo como objetivo evaluar las posibles diferencias de precisión entre la colocación del primer y segundo electrodo, comparando las trayectorias elegidas para cada lado, la actividad del NST detectada durante el microrregistro (MER) y la discrepancia entre las posiciones inicialmente planeadas y las finales. Materiales y métodos En este estudio retrospectivo analizamos datos de 30 pacientes sometidos a ECP bilateral. En la mayoría de los casos se usaron tres conjuntos de microelectrodos para determinar la ubicación fisiológica del NST. El posicionamiento final del electrodo estuvo asimismo condicionado por los resultados de la estimulación intraoperatoria. Se comparó la elección de canales centrales vs. no centrales. El vector euclidiano del desvío se calculó a partir de las coordenadas planeadas inicialmente y la posición final de la punta del electrodo, según una tomografía computarizada realizada al menos un mes después de la cirugía. Resultados La trayectoria central se eligió en 70% de los casos en el primer lado y en el 40% de los casos en el segundo lado. La duración media de la actividad de alta calidad del NST registrada en el canal central fue mayor en el primer lado que en el segundo (3,07±1,85mm vs. 2,75±1,94mm), mientras que en el canal anterior hubo mejores registros de MER en el segundo lado (1,59±2,07mm en el primer lado vs. 2,78±2,14mm en el segundo) (AU)