Neurochemical, histological, and behavioral profiling of the acute, sub-acute, and chronic MPTP mouse model of Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous multi-systemic disorder unique to humans characterized by motor and non-motor symptoms. Preclinical experimental models of PD present limitations and inconsistent neurochemical, histological, and behavioral readouts. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD is the most common in vivo screening platform for novel drug therapies; nonetheless, behavioral endpoints yielded amongst laboratories are often discordant and inconclusive. In this study, we characterized neurochemically, histologically, and behaviorally three different MPTP mouse models of PD to identify translational traits reminiscent of PD symptomatology. MPTP was intraperitoneally (i.p.) administered in three different regimens: (i) acute-four injections of 20 mg/kg of MPTP every 2 h; (ii) sub-acute-one daily injection of 30 mg/kg of MPTP for 5 consecutive days; and (iii) chronic-one daily injection of 4 mg/kg of MPTP for 28 consecutive days. A series of behavioral tests were conducted to assess motor and non-motor behavioral changes including anxiety, endurance, gait, motor deficits, cognitive impairment, circadian rhythm and food consumption. Impairments in balance and gait were confirmed in the chronic and acute models, respectively, with the latter showing significant correlation with lesion size. The sub-acute model, by contrast, presented with generalized hyperactivity. Both, motor and non-motor changes were identified in the acute and sub-acute regime where habituation to a novel environment was significantly reduced. Moreover, we report increased water and food intake across all three models. Overall, the acute model displayed the most severe lesion size, while across the three models striatal dopamine content (DA) did not correlate with the behavioral performance. The present study demonstrates that detection of behavioral changes following MPTP exposure is challenging and does not correlate with the dopaminergic lesion extent.

USim: A New Device and App for Case-Specific, Intraoperative Ultrasound Simulation and Rehearsal in Neurosurgery. A Preliminary Study.

BACKGROUND: Intraoperative ultrasound (iUS) is an excellent aid for neurosurgeons to perform better and safer operations thanks to real time, continuous, and high-quality intraoperative visualization. OBJECTIVE: To develop an innovative training method to teach how to perform iUS in neurosurgery. METHODS: Patients undergoing surgery for different brain or spine lesions were iUS scanned (before opening the dura) in order to arrange a collection of 3-dimensional, US images; this set of data was matched and paired to preoperatively acquired magnetic resonance images in order to create a library of neurosurgical cases to be studied offline for training and rehearsal purposes. This new iUS training approach was preliminarily tested on 14 European neurosurgery residents, who participated at the 2016 European Association of Neurosurgical Societies Training Course (Sofia, Bulgaria). RESULTS: USim was developed by Camelot and the Besta NeuroSim Center as a dedicated app that transforms any smartphone into a "virtual US probe," in order to simulate iUS applied to neurosurgery on a series of anonymized, patient-specific cases of different central nervous system tumors (eg, gliomas, metastases, meningiomas) for education, simulation, and rehearsal purposes. USim proved to be easy to use and allowed residents to quickly learn to handle a US probe and interpret iUS semiotics. CONCLUSION: USim could help neurosurgeons learn neurosurgical iUS safely. Furthermore, neurosurgeons could simulate many cases, of different brain/spinal cord tumors, that resemble the specific cases they have to operate on. Finally, the library of cases would be continuously updated, upgraded, and made available to neurosurgeons.

Role of Histone Deacetylases (HDACs) in Epilepsy and Epileptogenesis.

BACKGROUND: Emerging evidence suggests that epigenetic mechanisms are involved in different brain functions such as the development of the nervous system and normal neuronal function. At the same time, it has been proposed that several neurological diseases are in part, caused by aberrant epigenetic modifications. Nevertheless, the mechanisms underlying pathological alterations in the brain genome are not completely understood. METHODS AND RESULTS: Post-transcriptional histone acetylation is a major mechanism of chromatin remodeling, contributing to epigenetic regulation of gene transcription. Histone deacetylases (HDACs) are a family of proteins involved in both physiological and pathological conditions by regulating the status of chromatin histone acetylation. It is now becoming clear that epigenetic regulatory mechanisms may also play a major role in epilepsy; modulation of chromatin structure through histone modifications has emerged as an important regulator of gene transcription in the brain and altered histone acetylation seems to contribute to changes in gene expression associated with epilepsy and the epileptogenic process. Histone modification is crucial for regulating neurobiological processes such as neural network function, synaptic plasticity, and synaptogenesis which also contribute to the pathophysiology of epilepsy. CONCLUSIONS: The role of epigenetics in epilepsy development is a new and emerging research area; the present article reviews the recent findings on the role played by HDACs and the possible function of different histone modifications in epilepsy and epileptogenesis. Inhibitors of HDACs (HDACIs) have been tested in different experimental models of epilepsy with some success. We also review the results from these studies, which indicate HDACIs as potential new therapeutic agents for the treatment of human epilepsy.

In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease which can be attenuated by glycyrrhizin.

High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells - including microglia and neurons. HMGB1 can contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There is increasing evidence from in vitro studies that HMGB1 may link the two main pathophysiological components of Parkinson's disease (PD), i.e. progressive dopaminergic degeneration and chronic neuroinflammation which underlie the mechanistic basis of PD progression. Analysis of tissue and biofluid samples from PD patients, showed increased HMGB1 levels in human postmortem substantia nigra specimens as well as in the cerebrospinal fluid and serum of PD patients. In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), systemic administration of neutralizing antibodies to HMGB1 partly inhibited the dopaminergic cell death, and reduced the increase of RAGE and tumour necrosis factor-alpha. The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to HMGB1, both suppressed MPTP-induced HMGB1 and RAGE upregulation while reducing MPTP-induced dopaminergic cell death in a dose dependent manner. These results provide first in vivo evidence that HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, suggesting that HMGB1 is a suitable target for neuroprotective trials in PD.

Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post-mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In wild-type mice MHC II levels in the ventral midbrain were upregulated 1-2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP-induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon-γ or tumour necrosis factor-α in the brain after MPTP treatment, as was found in wild-type mice. However, interleukin-1ß was significantly increased in both wild-type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II-mediated T cell activation is required for the full expression of pathology in this model of PD.

Self-reported adherence to a home-based exercise program among patients affected by psoriatic arthritis with minimal disease activity.

More than half of all patients with psoriatic arthritis (PsA) exhibit progressive erosive arthritis, associated with severe functional impairment and psychosocial disability. Biologics have been suggested to be more effective in inducing minimal disease activity" (MDA) than disease-modifying antirheumatic drugs (DMARDs). Behavioral patient education appears to be more effective in encouraging patients to increase their physical activity (PA) levels. The aim of the study was to evaluate the benefits of home-based exercises program on disease activity and quality of life in MDA-PsA patients treated with an anti-tumor necrosis factor (TNF) and DMARD therapy. We observed a self-reported adherence rate to home-based exercise of 76.6% and data showed the impact of the exercise program on self-reported health and mental assessment. A positive relationship between patient and therapist is crucial, influencing the quality of the performance, the emotional support, and increasing motivation in PsA patients.

A connectionist architecture for view-independent grip-aperture computation.

This paper addresses the problem of extracting view-invariant visual features for the recognition of object-directed actions and introduces a computational model of how these visual features are processed in the brain. In particular, in the test-bed setting of reach-to-grasp actions, grip aperture is identified as a good candidate for inclusion into a parsimonious set of hand high-level features describing overall hand movement during reach-to-grasp actions. The computational model NeGOI (neural network architecture for measuring grip aperture in an observer-independent way) for extracting grip aperture in a view-independent fashion was developed on the basis of functional hypotheses about cortical areas that are involved in visual processing. An assumption built into NeGOI is that grip aperture can be measured from the superposition of a small number of prototypical hand shapes corresponding to predefined grip-aperture sizes. The key idea underlying the NeGOI model is to introduce view-independent units (VIP units) that are selective for prototypical hand shapes, and to integrate the output of VIP units in order to compute grip aperture. The distinguishing traits of the NEGOI architecture are discussed together with results of tests concerning its view-independence and grip-aperture recognition properties. The overall functional organization of NEGOI model is shown to be coherent with current functional models of the ventral visual stream, up to and including temporal area STS. Finally, the functional role of the NeGOI model is examined from the perspective of a biologically plausible architecture which provides a parsimonious set of high-level and view-independent visual features as input to mirror systems.