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.

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.

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.

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.

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'.

Consensus Paper: Cerebellum and Emotion.

Over the past three decades, insights into the role of the cerebellum in emotional processing have substantially increased. Indeed, methodological refinements in cerebellar lesion studies and major technological advancements in the field of neuroscience are in particular responsible to an exponential growth of knowledge on the topic. It is timely to review the available data and to critically evaluate the current status of the role of the cerebellum in emotion and related domains. The main aim of this article is to present an overview of current facts and ongoing debates relating to clinical, neuroimaging, and neurophysiological findings on the role of the cerebellum in key aspects of emotion. Experts in the field of cerebellar research discuss the range of cerebellar contributions to emotion in nine topics. Topics include the role of the cerebellum in perception and recognition, forwarding and encoding of emotional information, and the experience and regulation of emotional states in relation to motor, cognitive, and social behaviors. In addition, perspectives including cerebellar involvement in emotional learning, pain, emotional aspects of speech, and neuropsychiatric aspects of the cerebellum in mood disorders are briefly discussed. Results of this consensus paper illustrate how theory and empirical research have converged to produce a composite picture of brain topography, physiology, and function that establishes the role of the cerebellum in many aspects of emotional processing.

Development of an improved Kelvin probe force microscope for accurate local potential measurements on biased electronic devices.

An improved setup for accurate near-field surface potential measurements and characterisation of biased electronic devices using the Kelvin Probe method has been developed. Using an external voltage source synchronised with the raster-scan of the KPFM-AM, this setup allows to avoid potential measurement errors of the conventional Kelvin Probe Force Microscopy in the case of in situ measurements on biased electronic devices. This improved KPFM-AM setup has been tested on silicon-based devices and organic semiconductor-based devices such as organic field effect transistors (OFETs), showing differences up to 25% compared to the standard KPFM-AM lift-mode measurement method.

Characterization of Gd loaded chitosan-TPP nanohydrogels by a multi-technique approach combining dynamic light scattering (DLS), asymetrical flow-field-flow-fractionation (AF4) and atomic force microscopy (AFM) and design of positive contrast agents for molecular resonance imaging (MRI).

Chitosan CS-tripolyphosphate TPP/hyaluronic acid HA nanohydrogels loaded with gadolinium chelates (GdDOTA ⊂ CS-TPP/HA NGs) synthesized by ionic gelation were designed for lymph node (LN) MRI. In order to be efficiently drained to LNs, nanogels (NGs) needed to exhibit a diameter ϕ < 100 nm. For that, formulation parameters were tuned, using (i) CS of two different molecular weights (51 and 37 kDa) and (ii) variable CS/TPP ratio (2 < CS/TPP < 8). Characterization of NG size distribution by dynamic light scattering (DLS) and asymetrical flow-field-flow-fractionation (AF4) showed discrepancies since DLS diameters were consistently above 200 nm while AF4 showed individual nano-objects with ϕ < 100 nm. Such a difference could be correlated to the presence of aggregates inherent to ionic gelation. This point was clarified by atomic force microscopy (AFM) in liquid mode which highlighted the main presence of individual nano-objects in nanosuspensions. Thus, combination of DLS, AF4 and AFM provided a more precise characterization of GdDOTA ⊂ CS-TPP/HA nanohydrogels which, in turn, allowed to select formulations leading to NGs of suitable mean sizes showing good MRI efficiency and negligible toxicity.

Altered Functionality, Morphology, and Vesicular Glutamate Transporter Expression of Cortical Motor Neurons from a Presymptomatic Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a lethal disorder characterized by the gradual degeneration of motor neurons in the cerebrospinal axis. Whether upper motor neuron hyperexcitability, which is a feature of ALS, provokes dysfunction of glutamate metabolism and degeneration of lower motor neurons via an anterograde process is undetermined. To examine whether early changes in upper motor neuron activity occur in association with glutamatergic alterations, we performed whole-cell patch-clamp recordings to analyze excitatory properties of Layer V cortical motor neurons and excitatory postsynaptic currents (EPSCs) in presymptomatic G93A mice modeling familial ALS (fALS). We found that G93A Layer V pyramidal neurons exhibited altered EPSC frequency and rheobase values indicative of their hyperexcitability status. Biocytin loading of these hyperexcitable neurons revealed an expansion of their basal dendrite arborization. Moreover, we detected increased expression levels of the vesicular glutamate transporter 2 in cortical Layer V of G93A mice. Altogether our data show that functional and structural neuronal alterations associate with abnormal glutamatergic activity in motor cortex of presymptomatic G93A mice. These abnormalities, expected to enhance glutamate release and to favor its accumulation in the motor cortex, provide strong support for the view that upper motor neurons are involved early on in the pathogenesis of ALS.

Development of a shear-force scanning near-field cathodoluminescence microscope for characterization of nanostructures' optical properties.

An original scanning near-field cathodoluminescence microscope for nanostructure characterization has been developed and successfully tested. By using a bimorph piezoelectric stack both as actuator and detector, the developed setup constitutes a real improvement compared to previously reported SEM-based solutions. The technique combines a scanning probe and a scanning electron microscope in order to simultaneously offer near-field cathodoluminescence and topographic images of the sample. Share-force topography and cathodoluminescence measurements on GaN, SiC and ZnO nanostructures using the developed setup are presented showing a nanometric resolution in both topography and cathodoluminescence images with increased sensitivity compared to classical luminescence techniques.

Validation of the Italian version of the Spinal Cord Independence Measure (SCIM III) Self-Report.

STUDY DESIGN: Cross-sectional validation study. OBJECTIVES: To validate the Italian version of the Spinal Cord Independence Measure Self-Report (SCIM SR). SETTING: Two spinal cord injury (SCI) rehabilitation facilities in Italy. METHODS: The SCIM III comprises items on 19 daily tasks, grouped into three subscales: 'Self-care,' 'Respiration and sphincter management' and 'Mobility'. The total SCIM score ranges between 0 and 100. The Italian self-reported version (SCIM SR) was translated from the German tool. We studied 116 patients on their first hospitalization for rehabilitation after an SCI. At the time of discharge, patients were evaluated by the rehabilitation team using the SCIM III and self-assessed their independence with regard to activities of daily living using the SCIM SR. Pearson's correlation, Bland-Altman method, and stratified and regression analyses were used to examine the differences between evaluations. RESULTS: On the basis of Pearson's correlation, there was good agreement between the data from the SCIM III and SCIM SR (r=0.918 for 'Self-care,' 0.806 for 'Respiration and sphincter management,' 0.906 for 'Mobility' and 0.934 for total scores). By Bland-Altman analysis, patients rated their functioning nearly the same as professionals-the mean difference between SCIM III and SCIM SR scores was approximately 0 for all subscales and total scores. The stratified and regression analyses failed to identify any specific factor that was associated with differences between SCIM III and SCIM SR scores. CONCLUSIONS: These results support the validity of the Italian version of the SCIM SR, which can facilitate longer-term evaluations of the independence of individuals with SCIs.

Observational study of the effectiveness of spinal cord injury rehabilitation using the Spinal Cord Injury-Ability Realization Measurement Index.

STUDY DESIGN: Retrospective observational study. OBJECTIVES: The objective of this study was to determine the rehabilitation potential and the extent to which it is realized in a cohort of spinal cord injury patients using the Spinal Cord Injury-Ability Realization Measurement Index (SCI-ARMI) and to study the clinical factors that influence this realization. SETTING: Two spinal units in Italy. METHODS: Consecutive patients were assessed at the end of an in-patient rehabilitation program using the Spinal Cord Independence Measure and the International Standards for Neurological Classification of Spinal Cord Injury. On the basis of these data and of the age and gender of the patients, we calculated the SCI-ARMI score. Regression analyses were performed to study the relationship between clinical factors and the extent to which rehabilitation potential is realized. RESULTS: We examined the data for 306 patients. Most patients were discharged without having reached their rehabilitation potential, with an SCI-ARMI score <80%. SCI-ARMI scores at discharge were positively influenced by etiology and the lesion level and correlated negatively with lesion severity and the presence of complications during rehabilitation. CONCLUSION: The SCI-ARMI is an effective tool that can be used to measure the achievement of rehabilitation potential in SCI patients and to identify groups of patients who are at risk of not meeting their rehabilitative potential.

Cerebellar sequencing: a trick for predicting the future.

"Looking into the future" well depicts one of the most significant concepts in cognitive neuroscience: the brain is constantly predicting future events. Such directedness toward the future has been recognized to be relevant to and beneficial for many aspects of information processing in humans, such as perception, motor and cognitive control, decision-making, theory of mind, and other cognitive processes. Because one of the most adaptive characteristics of the brain is to correct errors, the ability to look into the future represents the best chance to avoid repeating errors. Within the structures that constitute the "predictive brain," the cerebellum has been proposed to have a central function, based on its ability to generate internal models. We suggested that "sequence detection" is the operational mode of the cerebellum in predictive processing. According to this hypothesis, the cerebellum detects and simulates repetitive patterns of temporally or spatially structured events and generates internal models that can be used to make predictions. Consequently, we demonstrate that the cerebellum recognizes serial events as a sequence, detects a sequence violation, and successfully reconstructs the correct sequence of events. Thus, we hypothesize that pattern detection and prediction and processing of anticipation are cerebellum-specific functions within the brain and that the sequence detection hypothesis links the multifarious impairments that are reported in patients with cerebellar damage. We propose that this cerebellar operational mode can advance our understanding of the pathophysiological mechanisms in various clinical conditions, such as schizophrenia and autism.

A new magnetic resonance imaging contrast agent loaded into poly(lacide-co-glycolide) nanoparticles for long-term detection of tumors.

The incorporation of a lipophilic Gd chelate (GdDO3A-C12) in biocompatible PLGA poly(D, L-lactide-co-glycolide) nanoparticles was explored as an approach to increase the relaxivity of contrast agents for magnetic resonance imaging. By nanoprecipitation, it was possible to obtain PEGylated gadolinium nanoparticles (mean diameter of 155 nm) with high Gd loading (1.1 × 10(4) Gd centers per nanoparticle). The corresponding GdDO3AC12 ⊂ NPs nanoparticles exhibited an enhanced relaxivity (up to sixfold greater than DOTAREM® at 40 MHz) because the nanoparticle framework constrained the lipophilic Gd chelate motion and favorably impacted the Gd chelate rotational correlation time. T1-weighted imaging at 3 T on phantoms showed enhanced contrast for the GdDO3AC12 ⊂ NPs. Importantly, Gd chelate leakage was almost nonexistent, which suggested that these GdDO3AC12 ⊂ NPs could be useful for long-term MRI detection.

Walking Index for Spinal Cord Injury version II in acute spinal cord injury: reliability and reproducibility.

STUDY DESIGN: Administration of the walking index for SCI (WISCI) II is recommended to assess walking in spinal cord injury (SCI) patients. Determining the reliability and reproducibility of the WISCI II in acute SCI would be invaluable. OBJECTIVES: The objective of this study is to assess the reliability and reproducibility of the WISCI II in patients with traumatic, acute SCI. DESIGN: Test-retest analysis and calculation of reliability and smallest real difference (SRD). SETTING: SCI unit of a rehabilitation hospital. METHODS: Thirty-three patients, median age 44 years, median time since onset of SCI 40 days. Level: 20 cervical, 8 thoracic, 5 lumbar; ASIA (American Spinal Injury Association) impairment scale (AIS) grade: 32 D/1 C. Assessment of maximum WISCI II levels by two trained, blinded raters to evaluate interrater (IRR) and intrarater reliability. RESULTS: The intrarater reliability was 0.999 for therapists A and 0.979 for therapists B, for the maximum WISCI II level. The IRR for the maximum WISCI II score was 0.996 on day 1 and 0.975 on day 2. The SRD for the maximum WISCI II score was 1.147 for tetraplegics and 1.682 for paraplegics. These results suggest that a change of two WISCI II levels could be considered real. CONCLUSIONS: The WISCI II has high IRR and intrarater reliability and good reproducibility in the acute and subacute phase when administered by trained raters.

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.

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.

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.

Multidrug-resistant Pseudomonas aeruginosa bloodstream infections: risk factors and mortality.

We retrospectively studied patients diagnosed with P. aeruginosa bloodstream infections (BSIs) in two Italian university hospitals. Risk factors for the isolation of multidrug-resistant (MDR) or non-MDR P. aeruginosa in blood cultures were identified by a case-case-control study, and a cohort study evaluated the clinical outcomes of such infections. We identified 106 patients with P. aeruginosa BSI over the 2-year study period; 40 cases with MDR P. aeruginosa and 66 cases with non-MDR P. aeruginosa were compared to 212 controls. Independent risk factors for the isolation of MDR P. aeruginosa were: presence of central venous catheter (CVC), previous antibiotic therapy, and corticosteroid therapy. Independent risk factors for non-MDR P. aeruginosa were: previous BSI, neutrophil count <500/mm3, urinary catheterization, and presence of CVC. The 21-day mortality rate of all patients was 33·9%. The variables independently associated with 21-day mortality were presentation with septic shock, infection due to MDR P. aeruginosa, and inadequate initial antimicrobial therapy.