Biomechanics of Exoskeleton-Assisted Treadmill Walking.

To exploit the benefits of treadmill-based exoskeletons, it is crucial to assess possible deviations from natural walking depending on assistive parameters. This study evaluated the biomechanics of exoskeleton-assisted treadmill walking by comparing it with free gait. Five healthy participants walked freely on a treadmill and with the assistance of the Lokomat gait trainer, while changing Body Weight Support (BWS), Gait Speed (GS), and Guidance Force (GF). Results showed that the hip and knee joint kinematics depended on BWS and GS, while changes due to GF were limited. Moreover, joint kinematics and the activity of related muscles were altered with respect to free gait, for any combination of robot parameters in the case of the ankle, and especially for low GS and with BWS in the case of hip and knee. Overall, walking with the Lokomat can mostly resemble free gait at high speed and without BWS.

Low-dose apixaban or rivaroxaban as secondary prophylaxis of upper extremity deep vein thrombosis.

Upper extremity deep vein thrombosis (UEDVT) may occur without inciting factor or may be secondary to malignancy, surgery, trauma, central venous catheter or related to thoracic outlet syndrome (TOS). International guidelines recommend anticoagulant treatment for at least three months, in particular the use of vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). No data on extended anticoagulant therapy and reduced dose of DOACs have been reported in patients affected by UEDVT with persistent thrombotic risk (active cancer, major congenital thrombophilia) or without affected vein recanalization. In our retrospective observational study, including 43 patients, we treated secondary UEDVT with DOACs. In the acute phase of thrombosis (median time of 4 months), we used therapeutic dose of DOACs; the 32 patients with permanent thrombotic risk factors or without recanalization of the UEDVT were shifted to low-dose DOACs (apixaban 2.5 mg twice daily or rivaroxaban 10 mg daily). During therapy with full-dose DOACs, 1 patient presented recurrence of thrombosis; no thromboembolic events were observed during treatment with low-dose DOACs. During full-dose treatment, 3 patients presented minor hemorrhagic complications; no hemorrhagic events were observed during DOACs at low dose. We think our preliminary data could support the indication to extend the anticoagulation with dose reduction of DOACs in patients affected by UEDVT and no-transient thrombotic risk. These data should be confirmed in randomized controlled prospective study.

Trastornos por déficit de atencional con hiperactividad en la población infantojuvenil / Attention deficit hyperactivity disorders in the child and adolescent population

El Trastorno por déficit atencional con hiperactividad (TDAH) es un trastorno crónico, del neurodesarrollo con una prevalencia de 5,29% en la población pediátrica. Las manifestaciones clínicas incluyen síntomas de hiperactividad, impulsividad y desatención que conducen a un deterioro funcional en el desarrollo social, familiar y escolar. Si bien en los últimos años ha habido un aumento en su reconocimiento, la heterogeneidad clínica y la alta comorbilidad pueden obstaculizar su diagnóstico. En el presente trabajo se revisarán diferentes aspectos de la presentación clínica y del abordaje terapéutico de este trastorno

The attention hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder with a prevalence of 5.24% in pediatric population. The clinical presentation includes symptoms of hyperactivity, impulsivity and inattention with a functional impairment in social, family and scholar development. Even though in the last years it has been well recognized, its clinical heterogeneity and high comorbidity hampers its diagnosis. In this article different aspects of the clinical presentation and therapeutic approach of this disorder will be reviewed

How long does it take to diagnose young-onset dementia? A comparison with late-onset dementia.

INTRODUCTION: Dementia occurring in young people may be difficult to recognize. We compared the time to diagnosis between young- (YOD, age < 65) and late-onset dementia (LOD). METHODS: Time between the onset of symptoms and the diagnosis was measured in YOD and LOD patients consecutively seen in a cognitive neurology clinic. Multivariable regression analyses were performed to identify determinants of time to diagnosis. RESULTS: Mean time to diagnosis in 95 YOD patients was 11.2 months longer than in 73 LOD patients (p = 0.022). The delay was driven by a longer time taken by YOD patients to be seen in the specialist centre, which in turn was related to the presence of language disturbances and coexisting depression. DISCUSSION: Young people take longer than elderly people to receive a dementia diagnosis because they take longer to be referred to dementia specialist centres. More awareness on YOD is needed in primary care and the public.

Cocaine-related cervical spinal cord infarction: a case report and review of the literature.

STUDY DESIGN: Case report. OBJECTIVES: To report a clinical case of spinal cord infarction due to cocaine use. SETTING: Spinal Center, IRCCS Fondazione S. Lucia, Rome (Italy). CASE PRESENTATION: Two days after recreational use of cocaine, a 27-year-old Caucasic man was admitted to the emergency department for acute cervical pain, weakness in all four limbs, and urinary retention. A cervical spinal magnetic resonance imaging scan, performed after 2 days, showed a "pencil-like" lesion extending from C4 to T1 metamer, compatible with acute ischemia in the anterior spinal artery territory. Other causes of vascular disorders, as well as inflammatory and infectious disorders were ruled out. At admission in our department, the patient had an incomplete tetraplegia at level C6, an indwelling catheter, and was unable to stand and walk. After 3 months of rehabilitation, he had an AIS score D tetraplegia at level C7, was able to stand and walk using parallel bars, and indwelling catheter was replaced by intermittent catheterization. DISCUSSION AND CONCLUSIONS: The etiology of medullary infarction may remain unexplained in nearly 30-40% of cases. Even if rare, cocaine-induced ischemic myelopathy should be considered and ruled out in the differential diagnosis of any acute nontraumatic myelopathy, especially in young patients.

Quantitative and time-resolved monitoring of organelle and protein delivery to the lysosome with a tandem fluorescent Halo-GFP reporter.

Lysosomal degradative compartments hydrolyze macromolecules to generate basic building blocks that fuel metabolic pathways in our cells. They also remove misfolded proteins and control size, function, and number of cytoplasmic organelles via constitutive and regulated autophagy. These catabolic processes attract interest because their defective functioning is linked to human disease and their molecular components are promising pharmacologic targets. The capacity to quantitatively assess them is highly sought-after. Here we present a tandem-fluorescent reporter consisting of a HaloTag-GFP chimera appended at the C- or at the N-terminus of select polypeptides to monitor protein and organelle delivery to the lysosomal compartment. The Halo-GFP changes color on fluorescent pulse with cell-permeable HaloTag ligands and, again, on delivery to acidic, degradative lysosomal compartments, where the fluorescent ligand-associated HaloTag is relatively stable, whereas the GFP portion is not, as testified by loss of the green fluorescence and generation of a protease-resistant, fluorescent HaloTag fragment. The Halo-GFP tandem fluorescent reporter presented in our study allows quantitative and, crucially, time-resolved analyses of protein and organelle transport to the lysosomal compartment by high resolution confocal laser scanning microscopy, antibody-free electrophoretic techniques and flow cytometry.

Tomographic Study of Mesopore Formation in Ceria Nanorods.

Porosity in functional oxide nanorods is a recently discovered new type of microstructure, which is not yet fully understood and still under evaluation for its impact on applications in catalysis and gas/ion storage. Here we explore the shape and distribution of pores in ceria in three dimensions using a modified algorithm of geometric tomography as a reliable tool for reconstructing defective and strained nanoobjects. The pores are confirmed as "negative-particle" or "inverse-particle" cuboctahedral shapes located exclusively beneath the flat surface of the rods separated via a sub-5 nm thin ceria wall from the outside. New findings also comprise elongated "negative-rod" defects, seen as embryonic nanotubes, and pores in cube-shaped ceria. Furthermore, we report near-sintering secondary heat treatment of nanorods and cubes, confirming persistence of pores beyond external surface rounding. We support our experiments with molecular modeling and predict that the growth history of voids is via diffusion and aggregation of atomic point defects. In addition, we use density functional theory to show that the relative stability of pore (shape) increases in the order "cuboidal" < "hexagonal-prismatic" < "octahedral". The results indicate that by engineering voids into nanorods, via a high-temperature postsynthetic heat treatment, a potential future alternative route of tuning catalytic activities might become possible.

Flumazenil therapy for a gabapentin-induced coma: a case report.

BACKGROUND: Spasticity and neuropathic pain are common in patients after spinal cord injury and negatively affect patients' quality of life. Gabapentin and baclofen are frequently used to treat these conditions. We present a flumazenil-reversed gabapentin-induced coma case, which, to our knowledge, is the second one described in scientific literature. CASE PRESENTATION: A 70-year-old Caucasian man was admitted to our neurorehabilitation ward following a fall with cervical trauma that resulted in immediate tetraplegia. During his stay, he suffered from lower limb pain, both neuropathic and due to severe spasticity. Gradual baclofen and gabapentin administration was prescribed, with reduction in both pain and spasticity. One morning, the patient was found unresponsive, with a Glasgow Coma Score of 3. Head computerized tomography, electrocardiogram, electroencephalogram, vital signs, blood tests, breathing, and blood oxygenation were normal. Renal and liver failure were ruled out. Intravenous 0.25 mg of flumazenil (Anexate) was administered, resulting in complete neurocognitive recovery with a Glasgow Coma Score of 15. DISCUSSION AND CONCLUSIONS: This case report highlights the importance of the individual response to certain pharmacological agents and suggests that further studies need to be conducted both on flumazenil and gabapentin pharmacodynamics to better understand their molecular-receptor activity, and on possible multiple flumazenil mechanisms of action, beyond its classical strict benzodiazepine antagonist action.

Symbitron Exoskeleton: Design, Control, and Evaluation of a Modular Exoskeleton for Incomplete and Complete Spinal Cord Injured Individuals.

In this paper, we present the design, control, and preliminary evaluation of the Symbitron exoskeleton, a lower limb modular exoskeleton developed for people with a spinal cord injury. The mechanical and electrical configuration and the controller can be personalized to accommodate differences in impairments among individuals with spinal cord injuries (SCI). In hardware, this personalization is accomplished by a modular approach that allows the reconfiguration of a lower-limb exoskeleton with ultimately eight powered series actuated (SEA) joints and high fidelity torque control. For SCI individuals with an incomplete lesion and sufficient hip control, we applied a trajectory-free neuromuscular control (NMC) strategy and used the exoskeleton in the ankle-knee configuration. For complete SCI individuals, we used a combination of a NMC and an impedance based trajectory tracking strategy with the exoskeleton in the ankle-knee-hip configuration. Results of a preliminary evaluation of the developed hardware and software showed that SCI individuals with an incomplete lesion could naturally vary their walking speed and step length and walked faster compared to walking without the device. SCI individuals with a complete lesion, who could not walk without support, were able to walk with the device and with the support of crutches that included a push-button for step initiation Our results demonstrate that an exoskeleton with modular hardware and control allows SCI individuals with limited or no lower limb function to receive tailored support and regain mobility.

Incomplete penetrance in familial Alzheimer's disease with PSEN1 Ala260Gly mutation.

Presenilin1 (PSEN1) gene is the most common known genetic cause of early-onset familial Alzheimer's disease. We describe an Italian family with the known p.Ala260Gly mutation in PSEN1 gene. The presence of an asymptomatic 64-year-old male carrying the mutation provides evidence of a possible incomplete penetrance leading to a wider range of age at onset. In order to evaluate whether or not epigenetic modifications could contribute to the phenotypic heterogeneity, we assessed global DNA methylation levels which resulted significantly higher in the three females than in their presymptomatic brother. The study suggests that DNA methylation can contribute to slowing down or possibly protecting from the manifestation of symptoms even in monogenic diseases, emphasizing the great complexity of familial Alzheimer's disease.

Neuromuscular Controller Embedded in a Powered Ankle Exoskeleton: Effects on Gait, Clinical Features and Subjective Perspective of Incomplete Spinal Cord Injured Subjects.

Powered exoskeletons are among the emerging technologies claiming to assist functional ambulation. The potential to adapt robotic assistance based on specific motor abilities of incomplete spinal cord injury (iSCI) subjects, is crucial to optimize Human-Robot Interaction (HRI). Achilles, an autonomous wearable robot able to assist ankle during walking, was developed for iSCI subjects and utilizes a NeuroMuscular Controller (NMC). NMC can be used to adapt robotic assistance based on specific residual functional abilities of subjects. The main aim of this pilot study was to analyze the effects of the NMC-controlled Achilles, used as an assistive device, on chronic iSCI participants' performance, by assessing gait speed during 10-session training of robot-aided walking. Secondary aims were to assess training impact on participants' motion, clinical and functional features and to evaluate subjective perspective in terms of attitude towards technology, workload, usability and satisfaction. Results showed that 5 training sessions were necessary to significantly improve robot-aided gait speed on short paths and consequently to optimize HRI. Moreover, the training allowed participants who initially were not able to walk for 6 minutes, to improve gait endurance during Achilles-aided walking and to reduce perceived fatigue. Improvements were obtained also in gait speed during free walking, thus suggesting a potential rehabilitative impact, even if Achilles-aided walking was not faster than free walking. Participants' subjective evaluations indicated a positive experience.

Functional Changes of Mentalizing Network in SCA2 Patients: Novel Insights into Understanding the Social Cerebellum.

In recent years, increasing evidence of the cerebellar role in social cognition has emerged. The cerebellum has been shown to modulate cortical activity of social brain regions serving as a regulator of function-specific mentalizing and mirroring processes. In particular, a mentalizing area in the posterior cerebellum, specifically Crus II, is preferentially recruited for more complex and abstract forms of social processing, together with mentalizing cerebral areas including the dorsal medial prefrontal cortex (dmPFC), the temporo-parietal junction (TPJ), and the precuneus. In the present study, the network-based statistics approach was used to assess functional connectivity (FC) differences within this mentalizing cerebello-cerebral network associated with a specific cerebellar damage. To this aim, patients affected by spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease specifically affecting regions of the cerebellar cortex, and age-matched healthy subjects have been enrolled. The dmPFC, left and right TPJ, the precuneus, and the cerebellar Crus II were used as regions of interest to construct the mentalizing network to be analyzed and evaluate pairwise functional relations between them. When compared with controls, SCA2 patients showed altered internodal connectivity between dmPFC, left (L-) and right (R-) TPJ, and right posterior cerebellar Crus II.The present results indicate that FC changes affect a function-specific mentalizing network in patients affected by cerebellar damage. In particular, they allow to better clarify functional alteration mechanisms driven by the cerebellar damage associated with SCA2 suggesting that selective cortico-cerebellar functional disconnections may underlie patients' social impairment in domain-specific complex and abstract forms of social functioning.

Gait training with Achilles ankle exoskeleton in chronic incomplete spinal cord injury subjects.

Powered exoskeletons (EXOs) have emerged as potential devices for Spinal Cord Injury (SCI) to support the intervention of physical therapists during therapy (rehabilitation EXOs) as well as to assist lower limb motion during the daily life (assistive EXOs). Although the ankle is considered a key joint for gait restoration after SCI, very few ankle exoskeletons were developed and tested in incomplete SCI (iSCI) population. Among those, the Achilles ankle exoskeleton is the only one embedding a Controller inspired by the neuromuscular system (NeuroMuscular Controller, NMC). In a previous study we demonstrated that a period dedicated to train iSCI subjects in using the Achilles EXO as an assistive aid, improved robot-aided walking speed and surprisingly also generated a positive trend in free walking speed on long and short distances thus suggesting a possible unexpected rehabilitation effect. To further investigate this result, a case-control longitudinal study was conducted in the present work. The aim of this study was to test the hypothesis that Achilles-aided training could improve performance of free walking of chronic iSCI people more than conventional intensity-matched gait rehabilitation. Before and after conventional and robot-aided rehabilitation a number of variables were analyzed, including spatiotemporal parameters, joint kinematics, ground reaction forces, muscle force, spasticity and its related symptoms, balance and personal experience about the training. Results showed that only the NMC-controlled Achilles training allowed participants to significantly walk faster, with a longer step length and a reduced gait cycle time. A slight force and spasticity improvements were also experienced. In terms of subjects' personal experience, Achilles training was perceived more interesting and less physically demanding than conventional rehabilitation.

The Implementation of Predictions During Sequencing.

Optimal control mechanisms require prediction capabilities. If one cannot predict the consequences of a motor act or behavior, one will continually collide with walls or become a social pariah. "Looking into the future" is thus one of the most important prerequisites for smooth movements and social interactions. To achieve this goal, the brain must constantly predict future events. This principle applies to all domains of information processing, including motor and cognitive control, as well as the development of decision-making skills, theory of mind, and virtually all cognitive processes. Sequencing is suggested to support the predictive capacity of the brain. To recognize that events are related, the brain must discover links among them in the spatiotemporal domain. To achieve this, the brain must often hold one event in working memory and compare it to a second one, and the characteristics of the two must be compared and correctly placed in space and time. Among the different brain structures involved in sequencing, the cerebellum has been proposed to have a central function. We have suggested that the operational mode of the cerebellum is based on "sequence detection" and that this process is crucial for prediction. Patterns of temporally or spatially structured events are conveyed to the cerebellum via the pontine nuclei and compared with actual ones conveyed through the climbing fibers olivary inputs. Through this interaction, data on previously encountered sequences can be obtained and used to generate internal models from which predictions can be made. This mechanism would allow the cerebellum not only to recognize sequences but also to detect sequence violations. Cerebellar pattern detection and prediction would thus be a means to allow feedforward control based on anticipation. We will argue that cerebellar sequencing allows implementation of prediction by setting the correct excitatory levels in defined brain areas to implement the adaptive response for a given pattern of stimuli that embeds sufficient information to be recognized as a previously encountered template. Here, we will discuss results from human and animal studies and correlate them with the present understanding of cerebellar function in cognition and behavior.

Defect segregation facilitates oxygen transport at fluorite UO2 grain boundaries.

An important challenge for modelling transport in materials for energy applications is that in most applications they are polycrystalline, and hence it is critical to understand the properties in the presence of grain boundaries. Moreover, most grain boundaries are not pristine stoichiometric interfaces and hence dopants are likely to play a significant role. In this paper, we describe our recent work on using atomistic molecular dynamics simulations to model the effect of doped grain boundaries on oxygen transport of fluorite structured UO2. UO2, much like other fluorite grain boundaries, are found to be sinks for oxygen vacancy segregation relative to the grain interior, thus facilitating oxygen transport. Fission products further enhance diffusivity via strong interactions between the impurities and oxygen defects. Doping produces a striking structural alteration in the Σ5 class of grain boundaries that enhances oxygen diffusivity even further. This article is part of a discussion meeting issue 'Energy materials for a low carbon future'.

High speed atomic force microscopy to investigate the interactions between toxic Aß1-42 peptides and model membranes in real time: impact of the membrane composition.

Due to an aging population, neurodegenerative diseases have become a major health issue, the most common being Alzheimer's disease. The mechanisms leading to neuronal loss still remain unclear but recent studies suggest that soluble Aß oligomers have deleterious effects on neuronal membranes. Here, high-speed atomic force microscopy was used to assess the effect of oligomeric species of a variant of Aß1-42 amyloid peptide on model membranes with various lipid compositions. Results showed that the peptide does not interact with membranes composed of phosphatidylcholine and sphingomyelin. Ganglioside GM1, but not cholesterol, is required for the peptide to interact with the membrane. Interestingly, when they are both present, a fast disruption of the membrane was observed. It suggests that the presence of ganglioside GM1 and cholesterol in membranes promotes the interaction of the oligomeric Aß1-42 peptide with the membrane. This interaction leads to the membrane's destruction in a few seconds. This study highlights the power of high-speed atomic force microscopy to explore lipid-protein interactions with high spatio-temporal resolution.

Evaluation of mTHPC-loaded PLGA nanoparticles for in vitro photodynamic therapy on C6 glioma cell line.

Photodynamic therapy (PDT) is a very attractive strategy to complement or replace common cancer treatments such as radiotherapy, surgery, and chemotherapy. Some molecules have shown their efficiency as photosensitizers (PS), still many issues have to be solved such as the inherent cytotoxicity of the PS or its hydrophobic properties causing limitation in their solubility, leading to side effects. In this study, the encapsulation of an approved PS, the meso-tetra hydroxyphenylchlorine (mTHPC, Foscan®) within biocompatible and biodegradable poly(D, l-lactide-co-glycolide) acid (PLGA) NPs prepared by the nanoprecipitation method was studied. The mTHPC-loaded NPs (mTHPC ⊂ PLGA NPs) were analyzed by UV-vis spectroscopy to determine the efficiency of mTHPC encapsulation, and by dynamic light scattering (DLS) and atomic force microscopy (AFM) to determine mTHPC ⊂ PLGA NPs sizes, morphologies and surface charges. The longitudinal follow-up of mTHPC release from the NPs indicated that 50% of the encapsulated PS was retained within the NP matrix after a period of five days. Finally, the cytotoxicity and the phototoxicity of the mTHPC ⊂ PLGA NPs were determined in murine C6 glioma cell lines and compared to the ones of mTHPC alone. The studies showed a strong decrease of mTHPC cytotoxicity and an increase of mTHPC photo-cytotoxicity when mTHPC was encapsulated. In order to have a better insight of the underlying cellular mechanisms that governed cell death after mTHPC ⊂ PLGA NPs incubation and irradiation, annexin V staining tests were performed. The results indicated that apoptosis was the main cell death mechanism.

Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment. The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients' cognitive performances. Cerebellar GM maps were extracted and compared between SCA2 patients (n = 9) and controls (n = 33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components. Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation.

Interaction of Aß1-42 peptide or their variant with model membrane of different composition probed by infrared nanospectroscopy.

Toxicity of Aß peptides involved in Alzheimer's disease is linked to the interaction of intermediate species with membranes. Nanoscale Infrared Spectroscopy enhances the study of the morphology and the secondary structure of the peptides as fibers or oligomers interacting with membranes of different compositions, with nanometer scale resolution. Membrane models are used to investigate the role of different lipids in their interactions with Aß peptides. This work clearly brings to light that the presence of cholesterol in membranes is favorable to the interaction with Aß peptides in oligomers or aggregates.

A strain-induced exciton transition energy shift in CdSe nanoplatelets: the impact of an organic ligand shell.

We study the influence of surface passivating ligands on the optical and structural properties of zinc blende CdSe nanoplatelets. Ligand exchange of native oleic acid with aliphatic thiol or phosphonic acid on the surface of nanoplatelets results in a large shift of exciton transition energy for up to 240 meV. Ligand exchange also leads to structural changes (strain) in the nanoplatelet's core analysed by wide-angle X-ray diffraction. By correlating the experimental data with theoretical calculations we demonstrate that the exciton energy shift is mainly caused by the ligand-induced anisotropic transformation of the crystalline structure altering the well width of the CdSe core. Further the exciton reduced mass in these CdSe quantum wells is determined by a new method and this agrees well with the expected values substantiating that ligand-strain induced changes in the colloidal quantum well thickness are responsible for the observed spectral shifts. Our findings are important for theoretical modeling of other anisotropically strained systems and demonstrate an approach to tune the optical properties of 2D semiconductor nanocrystals over a broad region thus widening the range of possible applications of AIIBVI nanoplatelets in optics and optoelectronics.