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Methylphenidate (MPH) is an amphetamine-like stimulant commonly prescribed for attention deficit hyperactivity disorder. Despite its widespread use, the cellular/molecular effects of MPH remain elusive. Here, we report a novel direct role of MPH on the regulation of macromolecular flux through human brain endothelial cells (ECs). MPH significantly increased caveolae-mediated transcytosis of horseradish peroxidase through ECs without affecting paracellular permeability. Using FRET-based live cell imaging, together with pharmacological inhibitors and lentiviral-mediated shRNA knockdown, we demonstrate that MPH promoted ROS generation via activation of Rac1-dependent NADPH oxidase (NOX) and c-Src activation at the plasma membrane. c-Src in turn was shown to mediate the phosphorylation of caveolin-1 (Cav1) on Tyr14 leading to enhanced caveolae formation and transendothelial transport. Accordingly, the inhibition of Cav1 phosphorylation by overexpression of a phosphodefective Cav1Y14F mutant or knocking down Cav1 expression abrogated MPH-induced transcytosis. In addition, both vitamin C and inhibition of NOX blocked MPH-triggered vesicular transport. This study, therefore, identifies Rac1/NOX/c-Src-dependent signaling in MPH-induced increase in transendothelial permeability of brain endothelial cell monolayers via caveolae-mediated transcytosis.

High-frequency activity (HFA) is believed to subserve a functional role in cognition, but these patterns are often not accessible to scalp EEG recordings. Intracranial studies provide a unique opportunity to link the all-encompassing range of high-frequency patterns with holistic perception. We tested whether the functional topography of HFAs (up to 250Hz) is related to perceptual decision-making. Human intracortical data were recorded (6 subjects; >250channels) during an ambiguous object-recognition task. We found a spatial topography of HFAs reflecting processing anterior dorsal and ventral streams, linked to decision independently of the type of processed object/stimulus category. Three distinct regional fingerprints could be identified, with lower gamma frequency patterns (

Robotics has been playing an important role in modern surgery, especially in procedures that require extreme precision, such as neurosurgery. This paper addresses the challenge of teaching robotics to undergraduate engineering students, through an experiential learning project of robotics fundamentals based on a case study of robot-assisted stereotactic neurosurgery. The project was integrated into the curriculum of a Biomedical Engineering and Electrical and Computer Engineering program, but can also be integrated in related courses. First, students are given a presentation on the planning and execution of a stereotactic neurosurgery procedure, with special attention being paid to the concepts involved, namely spatial transformations, kinematics, and trajectory planning. Students are then taught to use a robotics simulation tool for robot-assisted stereotactic neurosurgery. They are shown how this can be used as a specialized control application, providing direct feedback on the robot's motion in a neurosurgery scenario. They are then required to select a robotic manipulator, and to develop and implement its control code to make it perform as a robot assistant in this surgical procedure. Project efficacy was evaluated through student self-report data (with dedicated anonymous surveys) and through the impact on academic and pedagogical results (by means of statistical inference). The results of the student surveys show that the robotics simulator for stereotactic neurosurgery is well suited to its role as an experiential learning tool since it enhances the understanding and application of several robotics concepts in an appealing manner. The positive impact of the project learning experience is supported by a comparison to earlier years of student grades, pass rates, and feedback from an institutional survey., This work was supported by the POPH/FSE program under Grant SFRH/BD/86499/2012, the Foundation for Science and Technology, and the NETTProjectunderGrantFP7-PEOPLE-2011-ITN-289146., info:eu-repo/semantics/publishedVersion

The research of stereotactic apparatus to guide surgical devices began in 1908, yet a major part of today’s stereotactic neurosurgeries still rely on stereotactic frames developed almost half a century ago. Robots excel at handling spatial information, and are, thus, obvious candidates in the guidance of instrumentation along precisely planned trajectories. In this review, we introduce the concept of stereotaxy and describe a standard stereotactic neurosurgery. Neurosurgeons’ expectations and demands regarding the role of robots as assistive tools are also addressed. We list the most successful robotic systems developed specifically for or capable of executing stereotactic neurosurgery. A critical review is presented for each robotic system, emphasizing the differences between them and detailing positive features and drawbacks. An analysis of the listed robotic system features is also undertaken, in the context of robotic application in stereotactic neurosurgery. Finally, we discuss the current perspective, and future directions of a robotic technology in this field. All robotic systems follow a very similar and structured workflow despite the technical differences that set them apart. No system unequivocally stands out as an absolute best. The trend of technological progress is pointing toward the development of miniaturized cost-effective solutions with more intuitive interfaces.

Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood–brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF- α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF- κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF- α/NF- κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF- α and subsequent activation of NF- κB pathway culminating in barrier dysfunction.

This dissertation objective is to contribute for the development of a robotic system towards neurosurgery assistance in Deep Brain Stimulation (DBS) stereotactic procedures. Being DBS neurosurgery typically a long, physically and cognitively demanding procedure; the introduction of a robotic assistant to hold, manipulate and position instrumentation would improve the medical team working conditions and lead to better surgery outcomes. Upon understanding how could the robot be used and what robotic systems were adequate to the task, we implemented a simulation environment to emulate several industrial robot manipulators and the operating room. It was also developed each robot geometric and differential kinematic equations, and control algorithms specifically oriented for DBS neurosurgery assistance. Taking into account the operating room arrangement, the robot characteristics and task requirements, we selected the most apt industrial robotic manipulator and further elaborated on its placement and orientation to achieve utmost performance., This work has been partially financed by projects FP7 Marie Curie ITN - NETT (project no289146), FCT FCOMP-01-0124-FEDER-022674, Pest-C/MAT-UI0013/2011 (FCT grant ref. UMINHO/BIC/8/2012) and FCT PhD grant (ref. SFRH/BD/86499/2012).

The advantages of Deep Brain Stimulation (DBS) lead to an increasing number of stereotactic DBS surgeries, which are extensive procedures that require extreme precision and steadiness of tool handling. Robotic manipulators known for their consistency, movement precision and steadiness have the potential to be remarkable tools to assist the neurosurgeons and can refine the quality/working conditions, while improving surgery outcome. Currently, robotic systems for stereotactic neurosurgeries with simple/pragmatic low budget solutions that fulfil the surgeons' needs are not yet available. Thus, we have been asked to develop such robotic system. In this paper we present our first steps toward such endeavour. Specifically, we implemented a simulation environment for robotic assisted DBS neurosurgery that allows emulating several hardware setups within the operating room, and to test and assess their performance. The simulator is useful not only as tool for developing specialized control applications, but also for training clinicians. First results support the viability of the sought solution and open way to future developments., This work has been partially financed by projects FP7 Marie Curie ITN - NETT (project no 289146), FCT FCOMP-01-0124-FEDER-022674 and Pest-C/MATUI0013/2011 (FCT grant ref. UMINHO/BIC/8/2012).

A 29 years old patient was sent to our Outpatient Clinic of Endocrinology presenting clinic of hypercortisolism. Laboratorial study: High urinary free cortisol (UFC); serum cortisol - 25 microg/dl (8 am) (5-25) and 20 microg/dL (11pm); ACTH - 20 pg/mL (9-52) (8 am) and 14 pg/mL (11 pm); serum cortisol after dexamethasone suppression test: 14,9 mg/dL; CRH test: elevation of ACTH; Pituitary MRI: microadenoma; abdominal CT: nodule on the left adrenal. During inferior petrosal sinus sampling with CRH stimulation, ACTH reached 368 pg/mL on the right and 136 pg/mL on the left side. The patient was submitted to transsphenoidal surgery. After surgery, hypertension and physical stigmata improved. In 2006, a relapse of Cushing syndrome was suspected due to worsening of hypertension and increase of weight. A slight increase of UFC, undetectable ACTH and serum cortisol after dexamethasone suppression test equal to 16 microg/dL were found. On abdominal CT, the adrenal nodule kept the same characteristics. In December 2006, the patient was submitted to left adrenalectomy. After surgery, blood pressure normalized, UFC and serum cortisol were reduced, needing substitutive therapy. Progressive tapering of hydrocortisone doses lead to discontinuation in March 2007. He is clinically well, without any treatment. This is an unusual case, in which after surgical cure of Cushing disease, secretory autonomy of a coexisting adrenal nodule occurred. This clinical case is relevant, pointing out the complexity of hypercortisolism cases and the need of long follow-up.

To evaluate the characteristics and outcomes of the patients diagnosed as ACTH-dependent Cushing syndrome, registered in the department.We reviewed the files of forty-three patients followed from 1974 to 2002.A progressive rise in the number of patients diagnosed was found, being 80% females. Clinical suspicion was based mostly on the typical fat distribution; hirsutism and amenorrhoea were important in women. The more reliable diagnostic tests were: 11 pm cortisol, day curve of ACTH and cortisol, and dexamethasone suppression tests. The ACTH response to CRH during inferior petrosal sinus sampling permitted the diagnosis of ectopic source. In thirty-seven patients a pituitary adenoma was diagnosed. The three patients diagnosed before 1985 went for bilateral adrenalectomy (Nelson's syndrome in two); the others were submitted to transsphenoidal pituitary adenomectomy, obtaining remission in twenty six at the first operation and in two others at the second. Three patients had a recidive. Of the six patients with persistent disease (all treated with metyrapone or ketoconazole), three were submitted to radiotherapy, two to bilateral adrenalectomy, and one was waiting for surgery. Four patients had a bronchial carcinoid, successfully removed in three. One patient was lost to follow-up and another was still being evaluated.We found a positive evolution in the capacity to diagnose and treat these patients. Neurosurgical ability to achieve remission was 80% in the operated cases. More effective technical methods and drugs, as well as a multidisciplinary and dedicated medical team, lead to long lasting remissions in most of the patients.