Multiscale In Silico Modeling of Cartilage Injuries.

Injurious loading of the joint can be accompanied by articular cartilage damage and trigger inflammation. However, it is not well-known which mechanism controls further cartilage degradation, ultimately leading to post-traumatic osteoarthritis. For personalized prognostics, there should also be a method that can predict tissue alterations following joint and cartilage injury. This chapter gives an overview of experimental and computational methods to characterize and predict cartilage degradation following joint injury. Two mechanisms for cartilage degradation are proposed. In (1) biomechanically driven cartilage degradation, it is assumed that excessive levels of strain or stress of the fibrillar or non-fibrillar matrix lead to proteoglycan loss or collagen damage and degradation. In (2) biochemically driven cartilage degradation, it is assumed that diffusion of inflammatory cytokines leads to degradation of the extracellular matrix. When implementing these two mechanisms in a computational in silico modeling workflow, supplemented by in vitro and in vivo experiments, it is shown that biomechanically driven cartilage degradation is concentrated on the damage environment, while inflammation via synovial fluid affects all free cartilage surfaces. It is also proposed how the presented in silico modeling methodology may be used in the future for personalized prognostics and treatment planning of patients with a joint injury.

Cyclic loading regime considered beneficial does not protect injured and interleukin-1-inflamed cartilage from post-traumatic osteoarthritis.

Injurious overloading and inflammation perturbate homeostasis of articular cartilage, leading to abnormal tissue-level loading during post-traumatic osteoarthritis. Our objective was to gain time- and cartilage depth-dependent insights into the early-stage disease progression with an in vitro model incorporating for the first time the coaction of (1) mechanical injury, (2) pro-inflammatory interleukin-1 challenge, and (3) cyclic loading mimicking walking and considered beneficial for cartilage health. Cartilage plugs (n = 406) were harvested from the patellofemoral grooves of young calves (N = 6) and subjected to injurious compression (50% strain, rate 100%/s; INJ), interleukin-1α-challenge (1 ng/ml; IL), and cyclic loading (intermittent 1 h loading periods, 15% strain, 1 Hz; CL). Plugs were assigned to six groups (control, INJ, IL, INJ-IL, IL-CL, INJ-IL-CL). Bulk and localized glycosaminoglycan (GAG) content (DMMB assay, digital densitometry), aggrecan biosynthesis (35S-sulfate incorporation), and chondrocyte viability (fluorescence microscopy) were assessed on days 3-12. The INJ, IL, and INJ-IL groups exhibited rapid early (days 2-4) GAG loss in contrast to CL groups. On day 3, deep cartilage of INJ-IL-CL group had higher GAG content than INJ group (p < 0.05). On day 12, INJ-IL-CL group showed more accumulated GAG loss (normalized with control) than INJ-IL group (average fold changes 1.97 [95% CI: 1.23-2.70]; 1.66 [1.42-1.89]; p = 0.007). Aggrecan biosynthesis increased in CL groups on day 12 compared to day 0. Despite promoting aggrecan biosynthesis, this cyclic loading protocol seems to be beneficial early-on to deep cartilage, but later becoming incapable of restricting further degradation triggered by marked but non-destructive injury and cytokine transport.

Evaluation of a Low-Cost Commercial Actigraph and Its Potential Use in Detecting Cultural Variations in Physical Activity and Sleep.

The purpose of the present study was to evaluate the performance of a low-cost commercial smartwatch, the Xiaomi Mi Band (MB), in extracting physical activity and sleep-related measures and show its potential use in addressing questions that require large-scale real-time data and/or intercultural data including low-income countries. We evaluated physical activity and sleep-related measures and discussed the potential application of such devices for large-scale step and sleep data acquisition. To that end, we conducted two separate studies. In Study 1, we evaluated the performance of MB by comparing it to the GT3X (ActiGraph, wGT3X-BT), a scientific actigraph used in research, as well as subjective sleep reports. In Study 2, we distributed the MB across four countries (Austria, Germany, Cuba, and Ukraine) and investigated physical activity and sleep among these countries. The results of Study 1 indicated that MB step counts correlated highly with the scientific GT3X device, but did display biases. In addition, the MB-derived wake-up and total-sleep-times showed high agreement with subjective reports, but partly deviated from GT3X predictions. Study 2 revealed similar MB step counts across countries, but significant later wake-up and bedtimes for Ukraine than the other countries. We hope that our studies will stimulate future large-scale sensor-based physical activity and sleep research studies, including various cultures.

Correction: Understanding and supporting law enforcement professionals working with distressing material: Findings from a qualitative study.

[This corrects the article DOI: 10.1371/journal.pone.0242808.].

Sleep during COVID-19 lockdown: A cross-cultural study investigating job system relevance.

Our study aimed to assess the change in the sleep patterns during the Coronavirus lockdown in five regions (Austria/Germany, Ukraine, Greece, Cuba and Brazil), using online surveys, translated in each language. Part of the cohort (age 25-65, well-educated) was collected directly during lockdown, to which retrospective cross-sectional data from and after lockdown (retrospective) questionnaires were added. We investigated sleep times and sleep quality changes from before to during lockdown and found that, during lockdown, participants had (i) worse perceived sleep quality if worried by COVID-19, (ii) a shift of bedtimes to later hours during workdays, and (iii) a sleep loss on free days (resulting from more overall sleep during workdays in non-system relevant jobs), leading to (iv) a marked reduction of social jetlag across all cultures. For further analyses we directly compared system relevant and system irrelevant jobs, because it was assumed that the nature of the lockdown's consequences is dependent upon system relevance. System relevant jobs were found to have earlier wake-up times as well as shorter total sleep times on workdays, leading to higher social jetlag for people in system relevant jobs. Cultural differences revealed a general effect that participants from Greece and Ukraine had later bedtimes (on both work and free days) and wake-up times (on workdays) than Cuba, Brazil and Austria, irrespective of COVID-19 lockdown restrictions.

Understanding and supporting law enforcement professionals working with distressing material: Findings from a qualitative study.

This study aimed to extend previous research on the experiences and factors that impact law enforcement personnel when working with distressing materials such as child sexual abuse content. A sample of 22 law enforcement personnel working within one law enforcement organisation in England, United Kingdom participated in anonymous semi-structured interviews. Results were explored thematically and organised in the following headings: "Responses to the material", "Impact of working with distressing evidence", "Personal coping strategies" and "Risks and mitigating factors". Law enforcement professionals experienced heightened affective responses to personally relevant material, depictions of violence, victims' displays of emotions, norm violations and to various mediums. These responses dampened over time due to desensitisation. The stress experienced from exposure to the material sometimes led to psychological symptoms associated with Secondary Traumatic Stress. Job satisfaction, self-care activities, the coping strategies used when viewing evidence, detachment from work outside working hours, social support and reducing exposure to the material were found to mediate law enforcement professionals' resilience. Exposure to distressing material and the risks associated with this exposure were also influenced by specific organisational procedures implemented as a function of the funding available and workload. Recommendations for individual and organisational practices to foster resilience emerged from this research. These recommendations are relevant to all organisations where employees are required to view distressing content.

Mechanobiological model for simulation of injured cartilage degradation via pro-inflammatory cytokines and mechanical stimulus.

Post-traumatic osteoarthritis (PTOA) is associated with cartilage degradation, ultimately leading to disability and decrease of quality of life. Two key mechanisms have been suggested to occur in PTOA: tissue inflammation and abnormal biomechanical loading. Both mechanisms have been suggested to result in loss of cartilage proteoglycans, the source of tissue fixed charge density (FCD). In order to predict the simultaneous effect of these degrading mechanisms on FCD content, a computational model has been developed. We simulated spatial and temporal changes of FCD content in injured cartilage using a novel finite element model that incorporates (1) diffusion of the pro-inflammatory cytokine interleukin-1 into tissue, and (2) the effect of excessive levels of shear strain near chondral defects during physiologically relevant loading. Cytokine-induced biochemical cartilage explant degradation occurs near the sides, top, and lesion, consistent with the literature. In turn, biomechanically-driven FCD loss is predicted near the lesion, in accordance with experimental findings: regions near lesions showed significantly more FCD depletion compared to regions away from lesions (p<0.01). Combined biochemical and biomechanical degradation is found near the free surfaces and especially near the lesion, and the corresponding bulk FCD loss agrees with experiments. We suggest that the presence of lesions plays a role in cytokine diffusion-driven degradation, and also predisposes cartilage for further biomechanical degradation. Models considering both these cartilage degradation pathways concomitantly are promising in silico tools for predicting disease progression, recognizing lesions at high risk, simulating treatments, and ultimately optimizing treatments to postpone the development of PTOA.

Functional Magnetic Resonance Imaging in the Final Stage of Creutzfeldt-Jakob Disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare fatal degenerative disease of the central nervous system. The clinical course is characterized by rapid progression of neurological and neuromuscular symptoms. The late stage with loss of consciousness is not well characterized. We report a 62-year-old male patient with sCJD with the clinical picture of a vegetative state/apallic syndrome, in whom we studied cortical responses using a vibration paradigm. The functional magnetic resonance imaging (fMRI) investigation demonstrated a clear response within the sensorimotor cortex, the cerebellum, the parietal cortex, the insular, and frontal inferior region. The finding of persistent cortical activity on fMRI in a patient with CJD in a state of unconsciousness has implications for the clinical management and for ethical considerations.

Therapy of Dysphagia by Prolonged Pharyngeal Electrical Stimulation (Phagenyx) in a Patient with Brainstem Infarction.

Dysphagia after stroke impacts quality of life and is a risk factor for respiratory infections. Patients frequently require prophylactic measures including nasogastric tube or percutaneous endoscopic gastrostomy. Until recently, therapy for dysphagia was limited to training with a speech and language specialist. Intraluminal pharyngeal electrical stimulation (PES) is a new technique that stimulates the pharyngeal sensory afferents to the higher swallowing center in cortex. The clinical trials published to date involved stimulation for 10 minutes over three days. We present a case of brainstem infarction with severe dysphagia in a 53-year-old woman with preserved cognitive functions. For airway protection, she had a surgical tracheotomy. The initial swallowing training achieved slight improvements, but stagnated after three months so PES was tried. Under good PES tube tolerance, a prolonged and repeated stimulation protocol was administered, with the main purpose of relieving her of the tracheal tube. Although the swallowing improved, she stayed tube-dependent with minimal attempts with puréed food during therapy, and could not be decannulated. Further studies are required to assess the value of this promising approach for the treatment of dysphagia.

Spinal cord involvement in Lewy body-related α-synucleinopathies.

Context: Lewy body (LB)-related α-synucleinopathy (LBAS) is the neuropathological hallmark of several neurodegenerative diseases such as Parkinson disease (PD), but it is also found in neurologically asymptomatic subjects. An abnormal accumulation of α-synuclein has been reported also in the spinal cord, but extent and significance of the spinal cord involvement are still poorly defined. Objective: We aimed to review the studies addressing the spinal cord involvement of LBAS in healthy subjects and in patients with PD or other neurodegenerative diseases. Methods: A MEDLINE search was performed using following terms: "spinal cord", " α-synucleinopathy", "α-synuclein", "Lewy body", "Parkinson's disease", "multiple system atrophy", "neurodegenerative disorder". Results: LBAS in the spinal cord is associated with that of the medullary reticular formation and locus ceruleus in the brainstem but not with that in the olfactory bulb and amygdala. The intermediolateral columns of the thoracic and sacral cord are the most frequently and severely affected region of the spinal cord. LBAS occurs in centrally projecting spinal cord neurons integrating pain, in particular from lower body periphery. It also involves the sacral parasympathetic nucleus innervating the smooth muscles of the bladder and distal colon and the Onuf's nucleus innervating the striated sphincters. The spinal cord lesions may thus play a crucial role in the genesis of frequent non-motor symptoms such as pain, urinary symptoms, bowel dysfunction, autonomic failure including orthostatic hypotension and sexual disturbances. Moreover, these may also contribute to the motor symptoms, since α-synuclein inclusions have been observed in the pyramidal tracts of patients with PD and multiple system atrophy. Conclusion: Recognition of this peculiar spinal cord pathology may help in the management of the related symptoms in subjects affected by α-synucleinopathies.

Epidemiology of status epilepticus in adults: A population-based study on incidence, causes, and outcomes.

OBJECTIVE: In 2015, the International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus (SE): 5 minutes of ongoing seizure activity to diagnose convulsive SE (CSE, ie, bilateral tonic-clonic SE) and 10 minutes for focal SE and absence SE, rather than the earlier criterion of 30 minutes. Based on semiology, several types of SE with prominent motor phenomena at any time (including CSE) were distinguished from those without (ie, nonconvulsive SE, NCSE). We present the first population-based incidence study applying the new 2015 ILAE definition and classification of SE and report the impact of the evolution of semiology and level of consciousness (LOC) on outcome. METHODS: We conducted a retrospective population-based incidence study of all adult patients with SE residing in the city of Salzburg between January 2011 and December 2015. Patients with hypoxic encephalopathy were excluded. SE was defined and classified according to the ILAE 2015. RESULTS: We identified 221 patients with a median age of 69 years (range 20-99 years). The age- and sex-adjusted incidence of a first episode of SE, NCSE, and SE with prominent motor phenomena (including CSE) was 36.1 (95% confidence interval [CI] 26.2-48.5), 12.1 (95% CI 6.8-20.0), and 24.0 (95% CI 16.0-34.5; including CSE 15.8 [95% CI 9.4-24.8]) per 100 000 adults per year, respectively. None of the patients whose SE ended with or consisted of only bilateral tonic-clonic activity died. In all other clinical presentations, case fatality was lower in awake patients (8.2%) compared with patients with impaired consciousness (33%). SIGNIFICANCE: This first population-based study using the ILAE 2015 definition and classification of SE found an increase of incidence of 10% compared to previous definitions. We also provide epidemiologic evidence that different patterns of status evolution and LOCs have strong prognostic implications.

A novel mechanobiological model can predict how physiologically relevant dynamic loading causes proteoglycan loss in mechanically injured articular cartilage.

Cartilage provides low-friction properties and plays an essential role in diarthrodial joints. A hydrated ground substance composed mainly of proteoglycans (PGs) and a fibrillar collagen network are the main constituents of cartilage. Unfortunately, traumatic joint loading can destroy this complex structure and produce lesions in tissue, leading later to changes in tissue composition and, ultimately, to post-traumatic osteoarthritis (PTOA). Consequently, the fixed charge density (FCD) of PGs may decrease near the lesion. However, the underlying mechanisms leading to these tissue changes are unknown. Here, knee cartilage disks from bovine calves were injuriously compressed, followed by a physiologically relevant dynamic compression for twelve days. FCD content at different follow-up time points was assessed using digital densitometry. A novel cartilage degeneration model was developed by implementing deviatoric and maximum shear strain, as well as fluid velocity controlled algorithms to simulate the FCD loss as a function of time. Predicted loss of FCD was quite uniform around the cartilage lesions when the degeneration algorithm was driven by the fluid velocity, while the deviatoric and shear strain driven mechanisms exhibited slightly discontinuous FCD loss around cracks. Our degeneration algorithm predictions fitted well with the FCD content measured from the experiments. The developed model could subsequently be applied for prediction of FCD depletion around different cartilage lesions and for suggesting optimal rehabilitation protocols.

Perampanel in patients with refractory and super-refractory status epilepticus in a neurological intensive care unit: A single-center audit of 30 patients.

In refractory status epilepticus (SE), γ-aminobutyric acidergic drugs become less effective and glutamate plays a major role in seizure perpetuation. Data on the efficacy of perampanel (PER) in treatment of refractory SE in humans are limited. Here, we present a single-center case series of patients with refractory SE who received PER orally in an intensive care unit. We retrospectively analyzed treatment response, outcome, and adverse effects of all patients with refractory SE in our Neurological Intensive Care Unit who received add-on PER between September 2012 and February 2018. Thirty patients with refractory SE (median = 72 years, range = 18-91, 77% women) were included. In 14 patients (47%), a high-dose approach was used, with a median initial dose of 24 mg (range = 16-32). In five patients (17%), SE could be terminated after PER administration (median dose = 6 mg, range = 6-20 mg, 2/5 patients in high-dose group). Clinical response was observed after a median of 24 hours (range = 8-48 hours), whereas electroencephalogram resolved after a median of 60 hours (range = 12-72 hours). Time to treatment response tended to be shorter in patients receiving high-dose PER (median clinical response = 16 hours vs 18 hours; electroencephalographic response = 24 hours vs 72 hours), but groups were too small for statistical analysis. Continuous cardiorespiratory monitoring showed no changes in cardiorespiratory function after "standard" and "high-dose" treatment. Elevated liver enzymes without clinical symptoms were observed after a median of 6 days in seven of 30 patients (23%; 57% high dose vs 43% standard dose), of whom six also received treatment with phenytoin (PHT). Outcome was unfavorable (death, persistent vegetative state) in 13 patients (43%; 39% high dose vs 61% standard dose), and good recovery (no significant disability, moderate disability) was achieved in nine patients (56% high dose vs 44% standard dose). Oral PER in loading doses up to 32 mg were well tolerated but could terminate SE only in a few patients (5/30; 17%). Long duration of SE, route of administration, and severe underlying brain dysfunction might be responsible for the modest result. An intravenous formulation is highly desired to explore the full clinical utility in the treatment of refractory SE.

Characterizing human subchondral bone properties using near-infrared (NIR) spectroscopy.

Degenerative joint conditions are often characterized by changes in articular cartilage and subchondral bone properties. These changes are often associated with subchondral plate thickness and trabecular bone morphology. Thus, evaluating subchondral bone integrity could provide essential insights for diagnosis of joint pathologies. This study investigates the potential of optical spectroscopy for characterizing human subchondral bone properties. Osteochondral samples (n = 50) were extracted from human cadaver knees (n = 13) at four anatomical locations and subjected to NIR spectroscopy. The samples were then imaged using micro-computed tomography to determine subchondral bone morphometric properties, including: plate thickness (Sb.Th), trabecular thickness (Tb.Th), volume fraction (BV/TV), and structure model index (SMI). The relationship between the subchondral bone properties and spectral data in the 1st (650-950 nm), 2nd (1100-1350 nm) and 3rd (1600-1870 nm) optical windows were investigated using partial least squares (PLS) regression multivariate technique. Significant correlations (p < 0.0001) and relatively low prediction errors were obtained between spectral data in the 1st optical window and Sb.Th (R2 = 92.3%, error = 7.1%), Tb.Th (R2 = 88.4%, error = 6.7%), BV/TV (R2 = 83%, error = 9.8%) and SMI (R2 = 79.7%, error = 10.8%). Thus, NIR spectroscopy in the 1st tissue optical window is capable of characterizing and estimating subchondral bone properties, and can potentially be adapted during arthroscopy.

Proximal flow to middle cerebral artery is associated with higher thrombus density in terminal internal carotid artery occlusion.

Proximal collaterals may determine the composition of occluding thrombi in acute ischemic stroke (AIS) in addition to source, hematocrit, time, and medication. Here, we performed a retrospective study of 39 consecutive patients with radiological evidence of I-, L-, and T-type terminal internal carotid artery occlusion. Middle cerebral artery (MCA) thrombus density was assessed on noncontrast enhanced CT and proximal collaterals on CT angiography. In patients with presence of proximal collaterals to the MCA we detected more hyperdense clots (P = 0.003) and a higher frequency of leptomeningeal collaterals (P = 0.008). We expand the spectrum of factors that potentially determine clot perviousness and evolution of ischemic stroke.

Rodent, large animal and non-human primate models of spinal cord injury.

In this narrative review we aimed to assess the usefulness of the different animal models in identifying injury mechanisms and developing therapies for humans suffering from spinal cord injury (SCI). Results obtained from rodent studies are useful but, due to the anatomical, molecular and functional differences, confirmation of these findings in large animals or non-human primates may lead to basic discoveries that cannot be made in rodent models and that are more useful for developing treatment strategies in humans. SCI in dogs can be considered as intermediate between rodent models and human clinical trials, but the primate models could help to develop appropriate methods that might be more relevant to humans. Ideally, an animal model should meet the requirements of availability and repeatability as well as reproduce the anatomical features and the clinical pathological changing process of SCI. An animal model that completely simulates SCI in humans does not exist. The different experimental models of SCI have advantages and disadvantages for investigating the different aspects of lesion development, recovery mechanisms and potential therapeutic interventions. The potential advantages of non-human primate models include genetic similarities, similar caliber/length of the spinal cord as well as biological and physiological responses to injury which are more similar to humans. Among the potential disadvantages, high operating costs, infrastructural requirements and ethical concerns should be considered. The translation from experimental repair strategies to clinical applications needs to be investigated in future carefully designed studies.

A combined experimental atomic force microscopy-based nanoindentation and computational modeling approach to unravel the key contributors to the time-dependent mechanical behavior of single cells.

Cellular responses to mechanical stimuli are influenced by the mechanical properties of cells and the surrounding tissue matrix. Cells exhibit viscoelastic behavior in response to an applied stress. This has been attributed to fluid flow-dependent and flow-independent mechanisms. However, the particular mechanism that controls the local time-dependent behavior of cells is unknown. Here, a combined approach of experimental AFM nanoindentation with computational modeling is proposed, taking into account complex material behavior. Three constitutive models (porohyperelastic, viscohyperelastic, poroviscohyperelastic) in tandem with optimization algorithms were employed to capture the experimental stress relaxation data of chondrocytes at 5 % strain. The poroviscohyperelastic models with and without fluid flow allowed through the cell membrane provided excellent description of the experimental time-dependent cell responses (normalized mean squared error (NMSE) of 0.003 between the model and experiments). The viscohyperelastic model without fluid could not follow the entire experimental data that well (NMSE = 0.005), while the porohyperelastic model could not capture it at all (NMSE = 0.383). We also show by parametric analysis that the fluid flow has a small, but essential effect on the loading phase and short-term cell relaxation response, while the solid viscoelasticity controls the longer-term responses. We suggest that the local time-dependent cell mechanical response is determined by the combined effects of intrinsic viscoelasticity of the cytoskeleton and fluid flow redistribution in the cells, although the contribution of fluid flow is smaller when using a nanosized probe and moderate indentation rate. The present approach provides new insights into viscoelastic responses of chondrocytes, important for further understanding cell mechanobiological mechanisms in health and disease.

Cortical afferent inhibition reflects cognitive impairment in obstructive sleep apnea syndrome: a TMS study.

OBJECTIVES: Patients with obstructive sleep apnea syndrome (OSAS) show neurocognitive impairment, but the exact mechanisms that cause cognitive dysfunctions remain unknown. The cholinergic system is known to play a key role in all attentional processes and cognitive functions. A transcranial magnetic stimulation (TMS) protocol may give direct information about the function of some cholinergic circuits in the human brain; this technique relies on short latency afferent inhibition (SAI) of the motor cortex. The objective of this exploratory study was to test the hypothesis that impaired cognitive performances in OSAS patients are associated with a dysfunction of the cholinergic system, as assessed by SAI. METHODS: We applied SAI technique in a group of 13 patients with OSAS and compared the data with those from a group of 13 age-matched healthy subjects. All the patients underwent a sleep study, an extensive neuropsychological evaluation, and TMS examination. RESULTS: Mean SAI was significantly reduced in our OSAS patients when compared with controls. The neuropsychological evaluation showed impairments in most cognitive areas in the OSAS patients. SAI values were strongly correlated with the neuropsychological test scores. CONCLUSIONS: These findings suggest that the cognitive deficits in OSAS may be, at least in part, secondary to alterations in cholinergic neurotransmission, presumably caused by nocturnal hypoxemia. TMS studies may shed light on the pathophysiological mechanisms of the cognitive disturbances in OSAS patients.

Abnormal cortical synaptic plasticity in minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) represents the earliest stage of hepatic encephalopathy (HE). MHE is characterized by cognitive function impairment in the domains of attention, vigilance and integrative function, while obvious clinical manifestations are lacking. In the present study, we aimed at assessing whether subjects with MHE showed alterations in synaptic plasticity within the motor cortex. Previous findings suggest that learning in human motor cortex occurs through long-term potentiation (LTP)-like mechanisms. We employed therefore the paired associative stimulation (PAS) protocol by transcranial magnetic stimulation (TMS), which is able to induce LTP-like effects in the motor cortex of normal subjects. Fifteen patients with MHE and 15 age- and sex-matched cirrhotic patients without MHE were recruited. PAS consisted of 180 electrical stimuli of the right median nerve paired with a single TMS over the hotspot of right abductor pollicis brevis (APB) at an ISI of 25ms (PAS25). We measured motor evoked potentials (MEPs) before and after each intervention for up to 30min. In healthy subjects the PAS25 protocol was followed by a significant increase of the MEP amplitude. On the contrary, in patients with MHE the MEP amplitude was slightly reduced after PAS. These findings demonstrated that associative sensorimotor plasticity, an indirect probe for motor learning, is impaired in MHE patients.

Improved stability and biocompatibility of nanostructured silicon drug carrier for intravenous administration.

Nanotechnology has attracted considerable interest in the field of biomedicine, where various nanoparticles (NPs) have been introduced as efficient drug carrier systems. Mesoporous silicon (PSi) is one of the most promising materials in this field due to its low toxicity, good biodegradability, high surface area, tunable pore size and controllable surface functionality. However, recognition by the reticuloendothelial system and particle agglomeration hinder the use of PSi for intravenous applications. The present paper describes a dual-PEGylation method, where two PEG molecules with different sizes (0.5 and 2 kDa) were grafted simultaneously in a single process onto thermally oxidized PSi NPs to form a high-density PEG coating with both brush-like and mushroom-like conformation. The material was characterized in detail and the effects of the dual-PEGylation on cell viability, protein adsorption and macrophage uptakes were evaluated. The results show that dual-PEGylation improves the colloidal stability of the NPs in salt solutions, prolongs their half-lives, and minimizes both protein adsorption and macrophage uptake. Therefore, these new dual-PEGylated PSi NPs are potential candidates for intravenous applications.