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Background: Healthcare workers represent one of the most affected categories by the adverse effects of the COVID-19 pandemic on mental health. Excessive stress and anxiety are critical factors that could compromise work performance. Besides, high levels of stress and anxiety may have long-term physical and psychological consequences. Recent studies investigated virtual reality to reduce stress and anxiety among healthcare workers during the COVID-19 pandemic. However, the proposed virtual reality interventions have important limitations related to their location (i.e., research lab and hospitals) and content (i.e., virtual experiences only for relaxation). Within this context, this randomized controlled trial aims to investigate the efficacy and acceptability of a brief home-based virtual reality training for managing stress and anxiety during the COVID-19 crisis in a sample of Italian healthcare workers., Methods: The study is a randomized controlled trial. It includes two groups of 30 individuals recruited from healthcare workers: (1) the experimental group and (2) the control group. Participants in the experimental group will receive a training consisting of three home sessions performed in a week. In each session, participants will try through an immersive virtual reality standalone system (i.e., Oculus Quest 2) a virtual psychoeducation experience on stress and anxiety (i.e., MIND-VR). Subsequently, they will try the virtual relaxation content (i.e., The Secret Garden). The control group will receive no training and will be reassessed one week and one month after the initial evaluation., Discussion: If the proposed brief home-based virtual reality training will result helpful and easy to use, it could become an empirically assessed viable option for protecting healthcare workers' mental health both during the COVID-19 pandemic and once it will be over. Furthermore, the intervention might be easily adapted for other categories of people who need support in managing stress and anxiety., Trial Registration: ClinicalTrials.gov NCT04611399 ., (© 2022. The Author(s).)

Objectives: Delirium is commonly seen in older adults with multimorbidity, during a hospitalization, resulting from the interplay between predisposing factors such as advanced age, frailty, and dementia, and a series of precipitating factors. The association between delirium and specific multimorbidity is largely unexplored so far although of potential key relevance for targeted interventions. The aim of the study was to check for a potential association of multimorbidity with delirium in a large cohort of older patients hospitalized for an acute medical or surgical condition., Design: This is a cross-sectional study nested in the 2017 Delirium Day project., Setting and Participants: The study includes 1829 hospitalized patients (age: 81.8, SD: 5.5). Of them, 419 (22.9%) had delirium., Methods: Sociodemographic and medical history were collected. The 4AT was used to assess the presence of delirium. The Charlson Comorbidity index was used to assess multimorbidity., Results: The results identified neurosensorial multimorbidity as the most prevalent, including patients with dementia, cerebrovascular diseases, and sensory impairments. In light of the highest co-occurrence of 3 neurosensorial chronic conditions, we could hypothesize that a baseline altered brain functional and neural connectivity might determine the vulnerability signature for incipient overall system disruption in presence of acute insults., Conclusions and Implications: Eventually, our findings moved a step forward in supporting the key importance of routine screening for sensory impairments and cognitive status of older patients for the highest risk of in-hospital delirium. In fact, preventive interventions could be particularly relevant and effective in preventing delirium in such vulnerable populations and might help refining this early diagnosis., (Copyright © 2021. Published by Elsevier Inc.)

Parkinson's disease is mainly characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Together with the small number, the high vulnerability of the dopaminergic neurons is a major pathogenic culprit of Parkinson's disease. Our previous findings of a higher survival of dopaminergic neurons in the substantia nigra co-expressing Nogo-A in an animal model of Parkinson's disease suggested that Nogo-A may be associated with dopaminergic neurons resilience against Parkinson's disease neurodegeneration. In the present study, we have addressed the expression of Nogo-A in the dopaminergic neurons in the substantia nigra in postmortem specimens of diseased and non-diseased subjects of different ages. For this purpose, in a collaborative effort we developed a tissue micro array (TMA) that allows for simultaneous staining of many samples in a single run. Interestingly, and in contrast to the observations gathered during normal aging and in the animal model of Parkinson's disease, increasing age was significantly associated with a lower co-expression of Nogo-A in nigral dopaminergic neurons of patients with Parkinson's disease. In sum, while Nogo-A expression in dopaminergic neurons is higher with increasing age, the opposite is the case in Parkinson's disease. These observations suggest that Nogo-A might play a substantial role in the vulnerability of dopaminergic neurons in Parkinson's disease.

Early brain injury (EBI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia (DCI) are common complications of subarachnoid hemorrhage (SAH). Inflammatory processes in the cerebrospinal fluid (CSF) are one of the causes for such complications. Our aim to study the effects of an IL-6 receptor antagonist (Tocilizumab) examines the occurrence of DCVS, neuronal cell death, and microclot formation in an acute SAH rabbit model. Twenty-nine New Zealand white rabbits were randomized into one of three groups as the SAH, SAH + Tocilizumab, and sham groups. In SAH groups, hemorrhage was induced by extracranial-intracranial arterial blood shunting from the subclavian artery into the cisterna magna under intracranial pressure (ICP) monitoring. In the second group, Tocilizumab was given once intravenously 1 h after SAH induction. Digital subtraction angiography was performed, and CSF and blood were sampled before and after (day 3) SAH induction. IL-6 plasma and CSF levels were measured. TUNEL, FJB, NeuN, and caspase-3 immunostaining were used to assess cell apoptosis, neurodegeneration, and neuronal cell death, respectively. Microclot formation was detected by fibrinogen immunostaining. Between baseline and follow-up, there was a significant reduction of angiographic DCVS (p < 0.0001) in the Tocilizumab compared with the SAH group. Tocilizumab treatment resulted in decreased neuronal cell death in the hippocampus (p = 0.006), basal cortex (p = 0.001), and decreased microclot formation (p = 0.02). Tocilizumab reduced DCVS, neuronal cell death, and microclot formation in a rabbit SAH model, and could be a potential treatment to prevent DCVS and DCI in SAH patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: although frailty and delirium are among the most frequent and burdensome geriatric syndromes, little is known about their association and impact on short-term mortality., Objective: to examine, in hospitalized older persons, whether frailty is associated with delirium, and whether these two conditions, alone or in combination, affect these patients' 30-day survival., Design: observational study nested in the Delirium Day project, with 30-day follow-up., Setting: acute medical wards (n = 118) and rehabilitation wards (n = 46) in Italy., Subjects: a total of 2,065 individuals aged 65+ years hospitalized in acute medical (1,484 patients, 71.9%) or rehabilitation (581 patients, 28.1%) wards., Methods: a 25-item Frailty Index (FI) was created. Delirium was assessed using the 4AT test. Vital status was ascertained at 30 days., Results: overall, 469 (22.7%) patients experienced delirium on the index day and 82 (4.0%) died during follow-up. After adjustment for potential confounders, each FI score increase of 0.1 significantly increased the odds of delirium (odds ratio, OR: 1.66 [95% CI: 1.45-1.90]), with no difference between the acute (OR: 1.65 [95% CI: 1.41-1.93]) and rehabilitation ward patients (OR: 1.71 [95% CI: 1.27-2.30]). The risk of dying during follow-up also increased significantly for every FI increase of 0.1 in the overall population (OR: 1.65 [95% CI: 1.33-2.05]) and in the acute medical ward patients (OR: 1.61 [95% CI: 1.28-2.04]), but not in the rehabilitation patients. Delirium was not significantly associated with 30-day mortality in either hospital setting., Conclusions: in hospitalized older patients, frailty is associated with delirium and with an increased risk of short-term mortality., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: None

Background and Purpose: Endovascular aneurysm treatment relies on a biological process, including cell migration for thrombus organization and growth of a neointima. To better understand aneurysm healing, our study explores the origin of neointima-forming and thrombus-organizing cells in a rat saccular sidewall aneurysm model., Methods: Saccular aneurysms were transplanted onto the abdominal aorta of male Lewis rats and endovascularly treated with coils (n=28) or stents (n=26). In 34 cases, GFP+ (green fluorescent protein)-expressing vital aneurysms were sutured on wild-type rats, and in 23 cases, decellularized wild-type aneurysms were sutured on GFP+ rats. Follow-up at 3, 7, 14, 21, and 28 days evaluated aneurysms by fluorescence angiography, macroscopic inspection, and microscopy for healing and inflammation status. Furthermore, the origin of cells was tracked with fluorescence histology., Results: In animals with successful functional healing, histological studies showed a gradually advancing thrombus organization over time characterized by progressively growing neointima from the periphery of the aneurysm toward the center. Cell counts revealed similar distributions of GFP+ cells for coil or stent treatment in the aneurysm wall (54.4% versus 48.7%) and inside the thrombus (20.5% versus 20.2%) but significantly more GFP+ cells in the neointima of coiled (27.2 %) than stented aneurysms (10.4%; P =0.008)., Conclusions: Neointima formation and thrombus organization are concurrent processes during aneurysm healing. Thrombus-organizing cells originate predominantly in the parent artery. Neointima formation relies more on cell migration from the aneurysm wall in coiled aneurysms but receives greater contributions from cells originating in the parent artery in stent-treated aneurysms. Cell migration, which allows for a continuous endothelial lining along the parent artery's lumen, may be a prerequisite for complete aneurysm healing after endovascular therapy. In terms of translation into clinical practice, these findings may explain the variability in achieving complete aneurysm healing after coil treatment and the improved healing rate in stent-assisted coiling.

Recently, there has been increasing interest in techniques for enhancing working memory (WM), casting a new light on the classical picture of a rigid system. One reason is that WM performance has been associated with intelligence and reasoning, while its impairment showed correlations with cognitive deficits, hence the possibility of training it is highly appealing. However, results on WM changes following training are controversial, leaving it unclear whether it can really be potentiated. This study aims at assessing changes in WM performance by comparing it with and without training by a professional mnemonist. Two groups, experimental and control, participated in the study, organized in two phases. In the morning, both groups were familiarized with stimuli through an N-back task, and then attended a 2-hour lecture. For the experimental group, the lecture, given by the mnemonist, introduced memory encoding techniques; for the control group, it was a standard academic lecture about memory systems. In the afternoon, both groups were administered five tests, in which they had to remember the position of 16 items, when asked in random order. The results show much better performance in trained subjects, indicating the need to consider such possibility of enhancement, alongside general information-theoretic constraints, when theorizing about WM span.

Aim: Pathological complete response (pCR) and clinical outcomes [overall survival (OS), disease-free survival (DFS), locoregional control (LC)] were evaluated in a single-institution experience of different schedules of neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC)., Patients and Methods: Data for 322 patients with LARC were retrospectively analyzed. pCR was evaluated according to Mandard tumor regression grade (TRG). The Kaplan-Meier method was used to estimate OS, DFS and LC., Results: Three hundred and three (94.1%) patients underwent surgery. pCR was observed in 81 patients (26.7%), with TRG1-2 rate of 41.8%. The 5- and 10-year OS, DFS and LC rates were 82.5%±2.5% and 65.5%±3.8%, 81.2%±2.4% and 79.3%±2.9%, 93.1%±1.7% and 90.5%±2.1%, respectively., Conclusion: Neoadjuvant CRT in LARC patients resulted in favorable long-term oncological outcomes, with a high pCR rate and acceptable toxicity., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background : Delayed cerebral vasospasm (DCVS) due to aneurysmal subarachnoid hemorrhage (aSAH) and its sequela, delayed cerebral ischemia (DCI), are associated with poor functional outcome. Endothelin-1 (ET-1) is known to play a major role in mediating cerebral vasoconstriction. Angiotensin-II-type-1-receptor antagonists such as Sartans may have a beneficial effect after aSAH by reducing DCVS due to crosstalk with the endothelin system. In this review, we discuss the role of Sartans in the treatment of stroke and their potential impact in aSAH. Methods : We conducted a literature research of the MEDLINE PubMed database in accordance with PRISMA criteria on articles published between 1980 to 2019 reviewing: "Sartans AND ischemic stroke". Of 227 studies, 64 preclinical and 19 clinical trials fulfilled the eligibility criteria. Results : There was a positive effect of Sartans on ischemic stroke in both preclinical and clinical settings (attenuating ischemic brain damage, reducing cerebral inflammation and infarct size, increasing cerebral blood flow). In addition, Sartans reduced DCVS after aSAH in animal models by diminishing the effect of ET-1 mediated vasoconstriction (including cerebral inflammation and cerebral epileptogenic activity reduction, cerebral blood flow autoregulation restoration as well as pressure-dependent cerebral vasoconstriction). Conclusion : Thus, Sartans might play a key role in the treatment of patients with aSAH.

Background: Alzheimer's disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease., Objective: The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations., Methods: Mild to moderate AD patients were enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls., Results: Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation., Conclusion: This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients.

The unmet need for a safe treatment that significantly improves the overall survival, as well as the quality of life of patients with brain tumors, has urged researchers to work out new treatment modalities. About 15 years ago, it was shown that alternating electric fields significantly impair the growth of cancer cells. Recently, this potentially revolutionary approach called Tumor Treating Fields (TTFs) has been FDA-approved for the treatment of glioblastoma as well as mesothelioma. However, despite the promising reports on the potential of TTFs, the precise knowledge of the mechanisms of action is still lacking. The purpose of this review is, thus, to present the current state of research and to highlight the variety of ultrastructural effects of TTFs. Moreover, the aim is to bring to the foreground less discussed mechanisms of action of TTFs, which might develop into novel therapeutic approaches. Therefore, a systematic literature search in Ovid Medline and Embase was performed on clinical and preclinical data concerning TTFs. The alternating electric fields force cellular components to aberrant dynamics, among which the most evident is the inhibition of the mitotic spindle assembly leading to impaired cancer cell division and cell death. However, a variety of other microstructural events induced by TTFs, such as inhibition of DNA repair and cell migration, as well as an enhancement of anti- tumor immune response and membrane permeability, have been reported. In addition, apart from a suggested interference with angiogenesis, no TTF-induced effects on normal cells have been described so far., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Epilepsy has a growing frequency, particularly in the elderly. Several triggers may cause late-onset epilepsy; however, more than 20% of epilepsies, manifesting in the elderly, has an unknown etiology. Although cognition is frequently altered in patients affected by epilepsy, there is a paucity of studies specifically evaluating cognition in patients affected by late-onset epilepsy. The aim of the present study was to assess the cognitive profile of patients affected by late-onset epilepsy with an unknown etiology and followed for 12 months., Methods: Patients affected by diagnosed late-onset epilepsy with unknown etiology were included in this observation. All patients were evaluated at the time of diagnosis (baseline) and at follow-up (12 months later). We distributed patients in subgroups based on seizure type (focal seizures [FS], secondarily generalized seizures [SGS], primarily generalized seizures [GS]) and antiepileptic drug (AED) regimen (mono- vs. polytherapy). Cognition was evaluated through standardized neuropsychological testing., Results: Fifty-eight patients were included in this observation and distributed in three groups: 29 affected by FS, 14 affected by SGS, 15 affected by GS. Forty-five patients were in monotherapy, and 13 in polytherapy. The most frequent treatments were levetiracetam (n = 12), valproic acid (VPA) (n = 9), carbamazepine (n = 9), and oxcarbazepine (n = 7). We documented a significant decrease of Mini-Mental State Examination (MMSE) and memory scores at follow-up in the whole group. Verbal learning decreased exclusively in VPA users., Conclusion: Patients affected by late-onset epilepsy with unknown etiology showed a significant decline of cognition at follow-up, independently from number and efficacy of AEDs received. These results deserve verification in larger longitudinal cohorts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cortical networks are shaped by the combined action of excitatory and inhibitory interactions. Among other important functions, inhibition solves the problem of the all-or-none type of response that comes about in purely excitatory networks, allowing the network to operate in regimes of moderate or low activity, between quiescent and saturated regimes. Here, we elucidate a noise-induced effect that we call "Jensen's force" -stemming from the combined effect of excitation/inhibition balance and network sparsity- which is responsible for generating a phase of self-sustained low activity in excitation-inhibition networks. The uncovered phase reproduces the main empirically-observed features of cortical networks in the so-called asynchronous state, characterized by low, un-correlated and highly-irregular activity. The parsimonious model analyzed here allows us to resolve a number of long-standing issues, such as proving that activity can be self-sustained even in the complete absence of external stimuli or driving. The simplicity of our approach allows for a deep understanding of asynchronous states and of the phase transitions to other standard phases it exhibits, opening the door to reconcile, asynchronous-state and critical-state hypotheses, putting them within a unified framework. We argue that Jensen's forces are measurable experimentally and might be relevant in contexts beyond neuroscience.

Transplantation of stem and progenitor cells offers a promising tool for brain repair in the context of neuropathological disorders including Parkinson's disease. There is growing proof that the capacity of adult stem and progenitor cells for tissue regeneration relies rather on the release of paracrine factors than on their cell replacement properties. In line with this notion, we have previously reported that conditioned medium (CM) collected from cultured Endothelial Progenitor Cells (EPC) stimulated survival of striatal neurons. In the present study we investigated whether EPC-CM promotes survival of cultured midbrain progenitor cells. For that purpose primary cultures from fetal rat embryonic ventral mesencephalon (VM) were prepared and grown for 7 days in vitro (DIV). EPC-CM was administered from DIV5-7. First, we found that EPC-CM treatment resulted in significantly increased cell densities of TH-ir neurons. Interestingly, this effect was no longer seen after proteolytic digestion of the EPC-CM. EPC-CM also significantly increased densities of beta-III-tubulin positive neurons and lba-1-ir microglial cells. The effect on dopaminergic neurons was not due to higher cell proliferation as no incorporation of EdU was observed in TH-ir cells. Importantly, EPC-CM exerted neuroprotection against MPP+ induced toxicity as in vitro model of Parkinson's disease. Taken together, our findings identified EPC-CM as a powerful tool to promote survival of cultured VM neurons and further support the importance of paracrine factors in the actions of stem and progenitor cells for brain repair., (Copyright © 2019. Published by Elsevier B.V.)

Progress in stem cell research demonstrates stem cells' potential for treating neurodegenerative diseases. Stem cells have proliferative/differentiative properties and produce a variety of paracrine factors that can potentially be used to regenerate nervous tissue. Previous studies have shown the positive regenerative effects of endothelial progenitor cells (EPCs), and thus, they may be used as a tool for regeneration. A study by Di Santo et al . explored whether EPC-derived conditioned medium (EPC-CM) promotes the survival of cultured striatal progenitor cells and attempted to find the paracrine factors and signaling pathways involved with EPC-CM's effects. The neuronal progenitor cells that were cultured with EPC-CM had much higher densities of GABA-immunoreactive (GABA-ir) neurons. It was shown that phosphatidylinositol-3-kinase/AKT and mitogen-activated protein kinase/ERK signaling pathways are involved in the proliferation of GABAergic neurons, as inhibition of these pathways decreased GABAergic densities. In addition, the results suggest that paracrine factors from EPC, both proteinaceous and lipidic, significantly elevated the viability and/or differentiation in the cultures. Importantly, it was found that EPC-CM provided neuroprotection against toxins from 3-nitropropionic acid. In sum, EPC-CM engendered proliferation and regeneration of the cultured striatal cells through paracrine factors and imparted neuroprotection. Furthermore, the effects of EPC-CM may generate a cell-free therapeutic strategy to address neurodegeneration., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Brain Circulation.)

Background: The inflammatory pathway in cerebrospinal fluid (CSF) leads to delayed cerebral vasospasm (DCVS) and delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). The role of IL-1α has never been evaluated in a rabbit SAH model. The aim of our study is to analyze systemic and CSF changes of IL-1α, and to evaluate potential associations with the onset of DCVS in a rabbit closed cranium SAH model. Methods : 17 New Zealand white rabbits were randomized into two groups, SAH ( n = 12) and sham ( n = 5). In the first group, SAH was induced by extracranial-intracranial shunting from the subclavian artery into the cerebral cistern of magna under intracranial pressure (ICP) monitoring. The sham group served as a control. The CSF and blood samples for IL-1α measurement were taken at day zero before SAH induction and at day three., Results: There was a significant increase of ICP ( p = 0.00009) and a decrease of cerebral perfusion pressure (CPP) ( p = 0.00089) during SAH induction. At follow up, there was a significant increase of systemic IL-1α in the SAH as compared with the sham group ( p = 0.042) . There was no statistically significant difference in the CSF values in both groups. The CSF IL-1α values showed a correlation trend of DCVS., Conclusions: Systemic IL-1α levels are elevated after SAH induction in a rabbit SAH model., Competing Interests: The authors have no financial or other conflict of interest to declare.

Avalanches whose sizes and durations are distributed as power laws appear in many contexts, from physics to geophysics and biology. Here we show that there is a hidden peril in thresholding continuous times series-from either empirical or synthetic data-for the identification of avalanches. In particular, we consider two possible alternative definitions of avalanche size used, e.g., in the empirical determination of avalanche exponents in the analysis of neural-activity data. By performing analytical and computational studies of an Ornstein-Uhlenbeck process (taken as a guiding example) we show that (1) if relatively large threshold values are employed to determine the beginning and ending of avalanches and (2) if-as sometimes done in the literature-avalanche sizes are defined as the total area (above zero) of the avalanche, then true asymptotic scaling behavior is not seen, instead the observations are dominated by transient effects. This problem-that we have detected in some recent works-leads to misinterpretations of the resulting scaling regimes.

The presence of pain in elderly persons with cognitive decline is often neglected, under-reported, underestimated, misdiagnosed and not adequately treated, with consequences that have a strong impact on health, independence in activities of daily living and quality of life. There is no empirical evidence that people with dementia experience less pain; therefore, in patients with severe cognitive impairment the progression of cognitive decline dramatically affects the ability to verbalize the presence of pain. Self-assessment scales are considered the "gold standard" for pain assessment, but the presence of cognitive impairment is likely to reduce the reliability of these measures. Treatment of pain in elderly with cognitive decline or dementia is based on non-pharmacological and pharmacological strategies. Pharmacological treatment should consider physiological changes, high comorbidity and drug interactions that occur frequently in the elderly. This narrative review aims to describe current knowledge, methods of detection and treatment approaches for chronic pain in elderly persons with cognitive deficits.

Background: Sedentarism is a risk factor for mortality that is independent of physical exercise. As indicated in the literature, there is negative compensation of non-exercise physical activity due to exercise training. The aim was to investigate potential predictor variables of physical activity compensation in post-menopausal women beginning aerobic physical exercise training., Methods: One hundred and three post-menopausal women (mean age, 58.31±5.33 years) were eligible for the study. Metabolic markers were measured (plasma leptin, insulin, glucose), together with cardiovascular parameters and body composition. Daily physical activity was recorded objectively. Following baseline measurements, participants walked at moderate intensity on 4 days/week, for 13 weeks., Results: Baseline mean intensity of daily physical activity and leptin-to-fat mass ratio (L/FMkg) were independently and negatively correlated with variations in non-exercise physical activity. High L/FMkg was associated with negative compensation of non-exercise physical activity due to aerobic physical exercise. The same was shown for participants starting their exercise training who showed high daily physical activity., Conclusions: Knowledge of both L/FMkg and baseline spontaneous physical activity of participants in exercise training are important to programme physical exercise interventions and to prevent negative non-exercise physical activity compensation due to exercise training.

Parkinson's disease (PD) is a neurodegenerative disorder that presents with hallmark clinical symptoms of tremor at rest, bradykinesia, and muscle rigidity. Stem cell therapy has emerged as an experimental treatment for PD. However, optimizing the cell culture condition that allows enhanced survival and differentiation of cells toward the dopaminergic phenotype remains a logistical challenge. Here, we discuss the utility of a combination of neurotrophin-4/5 (NT-4/5) and glial cell line-derived neurotrophic factor (GDNF) in increasing the dopaminergic phenotypic expression of rat ventral mesencephalic (VM) tissue. Using organotypic explant cultures of fetal human ventral mesencephalon, we observed that NT-4/5 and GDNF as single factors, or in combination on DAergic neurons, increased survival and number of tyrosine hydroxylase immunoreactive neurons as well as the dopamine content in the culture medium. The application of specific neurotrophic factors, such as NT-4/5 and GDNF, as cell culture supplements or as adjunctive therapy to cell transplantation may achieve improved functional outcomes when contemplating cell-based regenerative medicine for PD., Competing Interests: There are no conflicts of interest.

Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder, clinically manifested by cardinal motor symptoms including tremor at rest, bradykinesia, and muscle rigidity. Transplantation of dopaminergic (DAergic) neurons is an experimental therapy for PD, however, it is limited by suboptimal integration and low survival of grafts. Pretreatment of donor tissue may offer a strategy to improve properties of transplanted DAergic neurons and thereby clinical outcome. We have previously shown that a combination of neurotrophin-4/5 (NT-4/5) and glial cell line-derived neurotrophic factor (GDNF) demonstrated additive effects on rat ventral mesencephalic (VM) tissue. The present study investigated the effects of NT-4/5 and GDNF as single factors, or in combination on DAergic neurons, in organotypic explant cultures of fetal human ventral mesencephalon. For that purpose, free-floating roller-tube cultures were prepared from VM and the equally sized pieces grown for 1 week in the presence or absence of neurotrophic factors. Both neurotrophic factors increased dopamine content in the culture medium and in the number of tyrosine hydroxylase immunoreactive neurons, most prominently after combined GDNF + NT-4/5 treatment. Culture volumes did not differ between groups while content of lactate dehydrogenase in the culture medium was moderately reduced in all treated groups. In conclusion, we identified that a combination of GDNF and NT-4/5 robustly promoted differentiation and survival of human fetal VM DAergic neurons, an observation with potential promising impact for cell replacement approaches in PD.

The literature indicates that the plasma cortisol-to-dehydroepiandrosterone-sulfate (DHEA-S) ratio is a marker of health status after menopause, when a decline in both estrogen and DHEA-S and an increase in cortisol occur. An increase in the cortisol-to-DHEA-S ratio has been positively correlated with metabolic syndrome, all-cause mortality, cancer, and other diseases. The aim of this study was to investigate the effects of a walking program on the plasma cortisol-to-DHEA-S ratio in postmenopausal women. Fifty-one postmenopausal women participated in a 13-week supervised walking program, in the metropolitan area of Pescara (Italy), from June to September 2013. Participants were evaluated in April-May and September-October of the same year. The linear mixed model showed that the variation of the log 10 Cortisol-to-log 10 DHEA-S ratio was associated with the volume of exercise (p = .03). Participants having lower adherence to the walking program did not have a significantly modified log 10 Cortisol or log 10 DHEA-S, while those having the highest adherence had a significant reduction in log 10 Cortisol (p = .016) and a nearly significant increase in log 10 DHEA-S (p = .084). Walking training appeared to reduce the plasma log 10 Cortisol-to-log 10 DHEA-S ratio, although a minimum level of training was necessary to achieve this significant reduction.

Understanding the origin, nature, and functional significance of complex patterns of neural activity, as recorded by diverse electrophysiological and neuroimaging techniques, is a central challenge in neuroscience. Such patterns include collective oscillations emerging out of neural synchronization as well as highly heterogeneous outbursts of activity interspersed by periods of quiescence, called "neuronal avalanches." Much debate has been generated about the possible scale invariance or criticality of such avalanches and its relevance for brain function. Aimed at shedding light onto this, here we analyze the large-scale collective properties of the cortex by using a mesoscopic approach following the principle of parsimony of Landau-Ginzburg. Our model is similar to that of Wilson-Cowan for neural dynamics but crucially, includes stochasticity and space; synaptic plasticity and inhibition are considered as possible regulatory mechanisms. Detailed analyses uncover a phase diagram including down-state, synchronous, asynchronous, and up-state phases and reveal that empirical findings for neuronal avalanches are consistently reproduced by tuning our model to the edge of synchronization. This reveals that the putative criticality of cortical dynamics does not correspond to a quiescent-to-active phase transition as usually assumed in theoretical approaches but to a synchronization phase transition, at which incipient oscillations and scale-free avalanches coexist. Furthermore, our model also accounts for up and down states as they occur (e.g., during deep sleep). This approach constitutes a framework to rationalize the possible collective phases and phase transitions of cortical networks in simple terms, thus helping to shed light on basic aspects of brain functioning from a very broad perspective., Competing Interests: The authors declare no conflict of interest.

Several studies reported that cancer is less frequent in persons with Alzheimer's and Parkinson's Diseases (AD/PD) and vice-versa. We evaluated whether a different distribution of known nongenetic risk factors for cancer and AD/PD, might explain their inverse relationship of occurrence. We nested 2 case-control studies in a subsample of a large cohort of 1,000,000 resident in Lombardy Region in Italy (n=1515), followed-up for cancer and AD/PD occurrence since 1991 until 2012. Conditional logistic regression was performed to determine the odds ratios (OR) and 95% confidence intervals (CI) of AD/PD in subjects with and without cancer and the risk of cancer in those with and without AD/PD. A total of 54 incident cases of AD/PD and 347 cancer cases were matched with 216 and 667 controls, respectively. After controlling for low education, obesity, history of hypertension, diabetes, dyslipidemia, physical activity, smoking habit, alcohol consumption, and dietary habit, cancer was found inversely associated with the risk of AD/PD (OR, 0.66; 95% CI, 0.32-1.38), and the risk of cancer in AD/PD was similarly reduced (OR, 0.42; 95% CI, 0.20-0.91). Different exposures to nongenetic risk factors of both diseases do not explain their competitive relationship of occurrence.

Transplantation of fetal ventral mesencephalic (VM) neurons for Parkinson's disease (PD) is limited by poor survival and suboptimal integration of grafted tissue into the host brain. In a 6-hydroxydopamine rat model of PD, we investigated the feasibility of simultaneous transplantation of rat fetal VM tissue and polymer-encapsulated C2C12 myoblasts genetically modified to produce glial cell line-derived neurotrophic factor (GDNF) or mock-transfected myoblasts on graft function. Amphetamine-induced rotations were assessed prior to transplantation and 2, 4, 6 and 9 wk posttransplantation. We found that rats grafted with VM transplants and GDNF capsules showed a significant functional recovery 4 wk after implantation. In contrast, rats from the VM transplant and mock-capsule group did not improve at any time point analyzed. Moreover, we detected a significantly higher number of tyrosine hydroxylase immunoreactive (TH-ir) cells per graft (2-fold), a tendency for a larger graft volume and an overall higher TH-ir fiber outgrowth into the host brain (1.7-fold) in the group with VM transplants and GDNF capsules as compared to the VM transplant and mock-capsule group. Most prominent was the TH-ir fiber outgrowth toward the capsule (9-fold). Grafting of GDNF-pretreated VM transplants in combination with the implantation of GDNF capsules resulted in a tendency for a higher TH-ir fiber outgrowth into the host brain (1.7-fold) as compared to the group transplanted with untreated VM transplants and GDNF capsules. No differences between groups were observed for the number of surviving TH-ir neurons or graft volume. In conclusion, our findings demonstrate that simultaneous transplantation of fetal VM tissue and encapsulated GDNF-releasing cells is feasible and support the graft survival and function. Pretreatment of donor tissue with GDNF may offer a way to further improve cell transplantation approaches for PD.

Resveratrol is a natural polyphenol with antioxidant, anti-inflammatory, and antiproliferative properties. We have shown previously that resveratrol decreases sodium/iodide symporter expression and iodide uptake in thyrocytes, both in vitro and in vivo. In the present study, we further investigated the effects of resveratrol, with evaluation of the expression of additional thyroid-specific genes in the FRTL-5 rat thyroid cell line: thyroglobulin, thyroid peroxidase, TSH receptor, Nkx2-1, Foxe1 and Pax8. We observed decreased expression of these genes in FRTL-5 cells treated with 10 μM resveratrol. The effects of resveratrol was further evaluated in vivo using Sprague-Dawley rats treated with resveratrol 25 mg/kg body weight intraperitoneally, for 60 days. No clinical signs of hypothyroidism were seen, although the treated rats showed significant increase in thyroid size. Serum TSH and thyroid hormone levels were in the normal range, with significantly higher TSH seen in resveratrol-treated rats, compared with control rats. Histological and immunohistochemical analyses confirmed increased proliferative activity in the thyroid from resveratrol-treated rats. These data suggest that resveratrol acts as a thyroid disruptor and a goitrogen, which indicates the need for caution as a supplement and for therapeutic uses., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cell transplantation using ventral mesencephalic tissue is an experimental approach to treat Parkinson's disease. This approach is limited by poor survival of the transplants and the high number of dopaminergic neurons needed for grafting. Increasing the yield of dopaminergic neurons in donor tissue is of great importance. We have previously shown that antagonization of the Nogo-receptor 1 by NEP1-40 promoted survival of cultured dopaminergic neurons and exposure to neurotrophin-4/5 increased dopaminergic cell densities in organotypic midbrain cultures. We investigated whether a combination of both treatments offers a novel tool to further improve dopaminergic neuron survival. Rat embryonic ventral mesencephalic neurons grown as organotypic free-floating roller tube or primary dissociated cultures were exposed to neurotrophin-4/5 and NEP1-40. The combined and single factor treatment resulted in significantly higher numbers of tyrosine hydroxylase positive neurons compared to controls. Significantly stronger tyrosine hydroxylase signal intensity was detected by Western blotting in the combination-treated cultures compared to controls but not compared to single factor treatments. Neurotrophin-4/5 and the combined treatment showed significantly higher signals for the neuronal marker microtubule-associated protein 2 in Western blots compared to control while no effects were observed for the astroglial marker glial fibrillary acidic protein between groups, suggesting that neurotrophin-4/5 targets mainly neuronal cells. Finally, NEP1-40 and the combined treatment significantly augmented tyrosine hydroxylase positive neurite length. Summarizing, our findings substantiate that antagonization of the Nogo-receptor 1 promotes dopaminergic neurons but does not further increase the yield of dopaminergic neurons and their morphological complexity when combined with neurotrophin-4/5 hinting to the idea that these treatments might exert their effects by activating common downstream pathways., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Intrastriatal transplantation of fetal human ventral mesencephalic dopaminergic neurons is an experimental therapy for patients suffering from Parkinson's disease. The success of this approach depends on several host brain parameters including neurotrophic factors and growth inhibitors that guide survival and integration of transplanted neurons. While the potential of neurotrophic factors has been extensively investigated, repression of growth inhibitors has been neglected, despite the significant effects reported in various CNS injury models. Recently, we demonstrated that infusion of neutralizing antibodies against Nogo-A into the lateral ventricles of hemi-parkinsonian rats significantly enhanced graft function. Since the Nogo-receptor 1 also interacts with other neurite growth inhibitors, we investigated whether a direct antagonization of the receptor would result in more robust effects. Therefore, rats with unilateral striatal 6-hydroxydopamine lesions were grafted with ventral mesencephalic tissue in combination with intraventricular infusions of the Nogo-receptor 1 antagonist NEP1-40. Transplanted rats receiving saline infusions served as controls. To test whether NEP1-40 treatment alone affects the remaining dopaminergic striatal fibers, rats with unilateral striatal 6-hydroxydopamine lesions were infused with NEP1-40 or saline without receiving a transplant. Motor behavior was assessed prior to the lesion as well as prior and 1, 3, and 5 weeks after the transplantations. At the end of the experimental period the number of graft-derived dopaminergic fibers growing into the host brain, the number of surviving dopaminergic neurons and graft volume were analyzed. In rats without a transplant, the density of dopaminergic fibers in the striatum was analyzed. We detected that NEP1-40 treatment significantly enhanced graft-derived dopaminergic fiber outgrowth as compared to controls while no effects were detected for graft volume and survival of grafted dopaminergic neurons. Notably, the enhanced dopaminergic fiber outgrowth was not sufficient to improve the functional recovery as compared to controls. Moreover, NEP1-40 infusions in hemi-parkinsonian rats without a transplant did not result in enhanced striatal dopaminergic fiber densities and consequently did not improve behavior. In sum, our findings demonstrate that antagonization of the Nogo-receptor 1 has the capacity to support the engraftment of transplanted mesencephalic tissue in an animal model of Parkinson's disease.

The aim of this study was to analyse the health status of breast cancer survivors and the effects of 12 weeks of aerobic training. Twenty-three breast cancer survivors (51.71 ± 3.17 years) and 23 healthy women (50.73 ± 2.97 years) were investigated for body composition, daily physical activity, quality of life, salivary cortisol, and DHEA-S. Breast cancer survivors were then aerobically trained for 12 weeks. Breast cancer survivors have a worse psychophysical health than healthy women. Aerobic training increased salivary DHEA-S, aerobic fitness, self-reported health, and nocturnal sleeping time and reduced salivary cortisol in breast cancer survivors. Salivary cortisol variation correlated with change of sleeping time and self-reported health. Salivary DHEA-S correlated with change of self-reported physical pain and general health as well. Breast cancer survivors can live in a situation of continuous distress, requiring a multidisciplinary approach. Twelve weeks of aerobic training improve the psychophysical health of breast cancer survivors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cell replacement therapy is a promising avenue into the investigation and treatment of Parkinson's disease (PD), and in some cases, significant long-term motor improvements have been demonstrated. The main source of donor tissue is the human fetal ventral mesencephalon (FVM), which consists of a mixed neuronal population, and its heterogeneity likely contributes to the inconsistent outcome observed in clinical trials. Therefore, detailed knowledge about the neuronal subpopulations in the VM seems essential for successful cell transplantation. Interestingly, it has been reported that some tyrosine hydroxylase-positive (TH+) neurons in the VM of adult rats and in cultured midbrain-derived neuroblasts coexpress additional neurotransmitters. Thus, the present study investigated, by means of colocalization analyses, the possible expression of GABA or serotonin in TH+ neurons. For that purpose, both fetal rat and human dissociated, organotypic and neurosphere FVM cultures as well as an animal model of PD were investigated. In dissociated rat FVM cultures, approximately 30% of the TH+ neurons coexpressed serotonin, while no colocalization with GABA was observed. Interestingly, coexpression of TH and serotonin was found to be dependent on the time in culture, the plating density, and the exposure to neurotrophic factors, that is, higher cell densities and treatment with brain-derived neurotrophic factor resulted in a significantly reduced coexpression rate. Notably, even though approximately 30% of the dopaminergic neurons in the donor tissue coexpressed serotonin, no colocalization could be detected in grafts 1 month after intrastriatal transplantation into hemiparkinsonian rats. In conclusion, a significant and susceptible subpopulation of dopaminergic neurons in FVM tissues coexpresses serotonin. This might have potential implications for the future selection and handling of cells prior to transplantation in PD.

We revisit the problem of deriving the mean-field values of avalanche exponents in systems with absorbing states. These are well known to coincide with those of unbiased branching processes. Here we show that for at least four different universality classes (directed percolation, dynamical percolation, the voter model or compact directed percolation class, and the Manna class of stochastic sandpiles) this common result can be obtained by mapping the corresponding Langevin equations describing each of them into a random walker confined to the origin by a logarithmic potential. We report on the emergence of nonuniversal continuously varying exponent values stemming from the presence of small external driving - that might induce avalanche merging - that, to the best of our knowledge, has not been noticed in the past. Many of the other results derived here appear in the literature as independently derived for individual universality classes or for the branching process itself. Still, we believe that a simple and unified perspective as the one presented here can help (1) clarify the overall picture, (2) underline the superuniversality of the behavior as well as the dependence on external driving, and (3) avoid the common existing confusion between unbiased branching processes (equivalent to a random walker in a balanced logarithmic potential) and standard (unconfined) random walkers.

Purpose: Prospective detection of patients with advanced rectal cancer (LARC) who have a higher probability of responding to preoperative chemoradiotherapy (CRT) may provide individualized therapy. Lipidomics is an emerging science dedicated to the characterization of lipid fingerprint involved in different pato-physiological conditions. The purpose of this study is to highlight a typical lipid signature able to predict the tumor response to CRT., Experimental Design: A prospective global analysis of lipids in 54 sera from 18 LARC patients treated with preoperative CRT was performed. Samples were collected at 3 time points: before (T0), at 14th day and at 28th day of CRT. An open LC-MS/MS analysis was performed to characterize lipid expression at T0. Differential lipids were validated by an independent approach and studied during treatment., Results: From 65 differential lipids highlighted between responder (RP) vs not responder (NRP) patients, five lipids were validated to predict response at T0: SM(d18:2/18:1), LysoPC (16:0/0:0), LysoPC (15:1(9z)/0:0), Lyso PE (22:5/0:0) and m/z= 842.90 corresponding to a PC containing 2 fatty acids of 40 carbons totally. The levels of these lipids were lower in NRP before treatment. The ROC curve obtained by combining these five lipid signals showed an AUC of 0.95, evidence of good sensitivity and specificity in discriminating groups., Conclusion: Our results are in agreement with previous evidences about the role of lipids in determining the tumor response to therapy and suggest that the study of serum lipid could represent a useful tool in prediction of CRT response and in personalizing treatment.

Background: The most common cause of hospitalization for children younger than age one is bronchiolitis. Several prenatal and environmental risk factors may affect the incidence of hospitalization for bronchiolitis. The aim of this study was to investigate the relation between exposure to vehicular traffic and the incidence of hospitalization for bronchiolitis in children during their first year of life in Italy., Methods: A multicenter prospective birth cohort study, where equal numbers of newborns of 33-34, 35-37 and ≥38 wGA were recruited at birth (1814 children) in 30 Italian neonatology units. Two interviewer-administered questionnaires were used to collect data. The first interview was carried out at the end of the Italian epidemic season. The second interview was carried out when the child was one year old. Data on possible prenatal, perinatal, and postnatal/environmental risk factors and on vehicular traffic density in the zone of residence were collected. On each interview, parents were also asked about any hospitalizations of the child. The outcome measure was the hospitalization for bronchiolitis (International Health Service ICD-9 code 466)., Results: Univariate analysis demonstrated that exposure to air pollution due to vehicular traffic, was significantly associated with an increased risk of hospitalization for bronchiolitis. The adjusted risk from logistic regression model confirmed that children exposed to air pollution due to vehicular traffic were at increased risk of hospitalization for bronchiolitis., Conclusions: Exposure to air pollution due to vehicular traffic may increase the risk of hospitalization for bronchiolitis in the first year of life.

Background: The negative side effects of breast cancer treatments can include upper limb lymphoedema. The growing literature indicates that Nordic walking is an effective discipline against several disease symptoms. The aim of this study was to determine whether introduction to Nordic walking alone is effective against total body extracellular water and upper limb circumferences in breast cancer survivors compared to its combination with a series of specifically created exercises (i.e. the Isa method)., Methods: 16 breast cancer survivors (49.09 ± 2.24 years) were recruited and randomly assigned to 1 of 2 different training groups., Results: 10 lessons on Nordic walking technique plus the Isa method significantly reduced both extracellular body water and the extracellular-to-total body water ratio (p = 0.01 for both), and also the circumference of the upper limb, (both relaxed arm and forearm circumferences) (p = 0.01 for all), whereas Nordic walking alone did not., Conclusions: Introduction to Nordic walking does not seem to affect lymphoedema in breast cancer survivors. This might be because novice Nordic Walkers do not adequately generate an effective muscular pump through coordination of the alternated bimanual open-close cycle. The Isa method appears to close this gap.

[Purpose] The aims of this study were to verify the effects on upper limb circumferences and total body extracellular water of 10 weeks of Nordic Walking (NW) and Walking (W), both alone and combined with a series of exercises created for breast cancer survivors, the ISA method. [Subjects and Methods] Twenty breast cancer survivors were randomly assigned to 4 different training groups and evaluated for upper limb circumferences, total body and extracellular water. [Results] The breast cancer survivors who performed NW, alone and combined with the ISA method, and Walking combined with the ISA method (but not alone) showed significantly reduced arm and forearm circumferences homolateral to the surgical intervention. [Conclusion] For breast cancer survivors, NW, alone and combined with the ISA method, and Walking combined with the ISA method should be prescribed to prevent the onset and to treat light forms of upper limb lymphedema because Walking training practiced alone had no significant effect on upper limb circumference reduction.

Self-organized criticality elucidates the conditions under which physical and biological systems tune themselves to the edge of a second-order phase transition, with scale invariance. Motivated by the empirical observation of bimodal distributions of activity in neuroscience and other fields, we propose and analyze a theory for the self-organization to the point of phase coexistence in systems exhibiting a first-order phase transition. It explains the emergence of regular avalanches with attributes of scale invariance that coexist with huge anomalous ones, with realizations in many fields.

Transplantation of fetal human ventral mesencephalic (VM) dopaminergic neurons into the striatum is a promising strategy to compensate for the characteristic dopamine deficit observed in Parkinson's disease (PD). This therapeutic approach, however, is currently limited by the high number of fetuses needed for transplantation and the poor survival and functional integration of grafted dopaminergic neurons into the host brain. Accumulating evidence indicates that contrasting inhibitory signals endowed in the central nervous system (CNS) might support neuronal regeneration. Hence, in the present study we aimed at improving survival and integration of grafted cells in the host brain by neutralizing Nogo-A, one of the most potent neurite growth inhibitors in the CNS. For that purpose, VM tissue cultures were transplanted into rats with a partial 6-hydroxydopamine (6-OHDA) lesion causing a hemi-PD model and concomitantly treated for 2 weeks with intra-ventricular infusion of neutralizing anti-Nogo-A antibodies. Motor behavior using the cylinder test was assessed prior to and after transplantation as functional outcome. At the end of the experimental period the number of dopaminergic fibers growing into the host brain, the number of surviving dopaminergic neurons in the grafts as well as graft size was examined. We found that anti-Nogo-A antibody infusion significantly improved the asymmetrical forelimb use observed after lesions as compared to controls. Importantly, a significantly three-fold higher dopaminergic fiber outgrowth from the transplants was detected in the Nogo-A antibody treated group as compared to controls. Furthermore, Nogo-A neutralization showed a tendency for increased survival of dopaminergic neurons (by two-fold) in the grafts. No significant differences were observed for graft volume and the number of dopaminergic neurons co-expressing G-protein-coupled inward rectifier potassium channel subunit two between groups. In sum, our findings support the view that neutralization of Nogo-A in the host brain may offer a novel and therapeutically meaningful intervention for cell transplantation approaches in PD.

Background: The use of high-intensity interval training (HIIT) is widely diffused as strategy to enhance aerobic fitness and body composition. In order to offer a more complete training, resistance exercises have been added to HIIT (HIIRT). Aims of our study were to characterize both heart rate and hormonal responses elicited by three different protocols of HIIRT having the same exercises, the same load and number of repetitions for each exercise., Methods: Eight healthy trained men (28.61±3.51 years) performed three different workouts: exercise order, recovery and speed of execution were differently organized according to workout. Salivary samples were collected before and after each workout, at 11:00 p.m. and at 7:00 a.m. of the following day. Salive was also collected during a non-training day. Before and after the workout, plasma lactate was measured while a beat-to-beat heart rate recording was executed during each workout. Cortisol (C) and testosterone (T) were measured in salivary samples., Results: Workouts elicited the same heart rate response while random organization seems to elicit the highest lactate, C and T increases. Also when we studied the effects of workouts on prolonged hormones production we observed that workout organization influenced post-exercise hormonal production until the following morning modifying their physiological trend., Conclusions: Even if exercises, load and number of repetitions were maintained fixed, exercise order, structured recovery and speed of execution determined different acute and prolonged effects. The knowledge of these responses is very important because may positively or negatively influence performance and health.

Nogo-A is a myelin associated protein and one of the most potent neurite growth inhibitors in the central nervous system. Interference with Nogo-A signaling has thus been investigated as therapeutic target to promote functional recovery in CNS injuries. Still, the finding that Nogo-A presents a fairly ubiquitous expression in many types of neurons in different brain regions, in the eye and even in the inner ear suggests for further functions besides the neurite growth repression. Indeed, a growing number of studies identified a variety of functions including regulation of neuronal stem cells, modulation of microglial activity, inhibition of angiogenesis and interference with memory formation. Aim of the present commentary is to draw attention on these less well-known and sometimes controversial roles of Nogo-A. Furthermore, we are addressing the role of Nogo-A in neuropathological conditions such as ischemic stroke, schizophrenia and neurodegenerative diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The spread of carbapenemase-producing Enterobacteriaceae (CPE) has become a worldwide problem. Early identification and isolation of asymptomatic carriers are important for infection prevention and control measures. All inpatients (N=1427) admitted to 'Fondazione Santa Lucia' Rehabilitation Hospital in 2014 were screened by rectal swab; 10.2% of them were CPE-colonized. The multivariate analysis on anamnestic data showed that both previous admission to an intensive care unit (odds ratio: 4.04; 95% confidence interval: 2.20-7.44; P<0.001) or post-acute care hospitals (2.88; 1.74-4.77; P<0.001) and presence of a central venous catheter (2.19; 1.34-3.59; P<0.001) were significant risk factors., (Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Endothelial progenitor cells (EPCs) promote revascularization and tissue repair mainly by paracrine actions. In the present study, we investigated whether EPC-secreted factors in the form of conditioned medium (EPC-CM) can protect cultured brain microvascular endothelial cells against an ischemic insult. Furthermore, we addressed the type of factors that are involved in the EPC-CM-mediated functions. For that purpose, rat brain-derived endothelial cells (rBCEC4 cell line) were exposed to EPC-CM pretreated with proteolytic digestion, heat inactivation, and lipid extraction. Moreover, the involvement of VEGF and IL-8, as canonical angiogenic factors, was investigated by means of neutralizing antibodies. We demonstrated that EPC-CM significantly protected the rBCEC4 cells against an ischemic insult mimicked by induced oxygen-glucose deprivation followed by reoxygenation. The cytoprotective effect was displayed by higher viable cell numbers and reduced caspase 3/7 activity. Heat inactivation, proteolytic digestion, and lipid extraction resulted in a significantly reduced EPC-CM-dependent increase in rBCEC4 viability, tube formation, and survival following the ischemic challenge. Notably, VEGF and IL-8 neutralization did not affect the actions of EPC-CM on rBCEC4 under both standard and ischemic conditions. In summary, our findings show that paracrine factors released by EPCs activate an angiogenic and cytoprotective response on brain microvascular cells and that the activity of EPC-CM relies on the concerted action of nonproteinaceous and proteinaceous factors but do not directly involve VEGF and IL-8.

Non-alcoholic fatty liver disease (NAFLD) is characterized by intra-hepatic fat accumulation and mechanisms involved in its pathogenesis are not fully explained. Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism. We investigated its activity in patients with fatty liver. LAL activity (nmol/spot/h) was measured in 100 adult healthy subjects (HS) and in 240 NAFLD patients. A sub-analysis on 35 patients with biopsy-proven non-alcoholic steatohepatitis (NASH) was performed. Median LAL activity was 1.15 (0.95-1.72) in HS. It was significantly reduced in NAFLD [0.78 (0.61-1.01), p < 0.001 vs. HS]. A further reduction was observed in the subgroup of NASH [0.67 (0.51-0.77), p < 0.001 vs. HS]. Patients with LAL activity below median had higher values of serum total cholesterol (p < 0.05) and LDL-c (p < 0.05), and increased serum liver enzymes (ALT, p < 0.001; AST, p < 0.01; GGT, p < 0.01). At multivariable logistic regression analysis, factors associated with LAL activity below median were ALT (OR: 1.018, 95% CI 1.004-1.032, p = 0.011) and metabolic syndrome (OR: 2.551, 95% CI 1.241-5.245, p = 0.011), whilst statin use predicted a better LAL function (OR: 0.464, 95% CI 0.248-0.866, p = 0.016). Our findings suggest a strong association between impaired LAL activity and NAFLD. A better knowledge of the role of LAL may provide new insights in NAFLD pathogenesis.

Fetal antigen 1/delta-like 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a non-canonical ligand for the Notch receptor. Interactions between Notch and its ligands are crucial for the development of various tissues. Moreover, FA1/dlk1 has been suggested as a potential supplementary marker of dopaminergic neurons. The present study aimed at investigating the distribution of FA1/dlk1-immunoreactive (-ir) cells in the early postnatal and adult midbrain as well as in the nigrostriatal system of 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata as compared to unlesioned controls. The higher number of FA1/dlk1-ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was up-regulated in intrinsic cells in response to the 6-OHDA-mediated loss of FA1/dlk1-expressing SNc dopaminergic neurons and/or due to the stab wound. Our findings hint to a significant role of FA1/dlk1 in the SNc during early postnatal development. The differential expression of FA1/dlk1 in the SNc and the striatum of dopamine-depleted rats could indicate a potential involvement of FA1/dlk1 in the cellular response to the degenerative processes.

Aim: Main endpoint was a response rate to therapy; secondary endpoints were disease-free survival, overall survival, acute and late toxicities, specially in terms of anorectal and urinary continence., Background: Radiochemotherapy for anal cancer achieves a good clinical response, locoregional control, anal function preservation. However, oncologic outcomes can differ using radiotherapy plus fluorouracil and mytomicin vs. cisplatin and fluorouracil., Methods: Between 2000 and 2012, 27 anal cancer patients receiving radiotherapy combined with two different radiochemotherapy schedules, fluorouracil and mytomicin (group A) and cisplatin plus fluorouracil (group B). The Kaplan-Meier method was also used to estimate local control, overall survival and disease free survival. Statistical significance between curves was evaluated using the Log-rank test., Results: Complete pathological response was found in 85.2% of patients, with higher rates of response in the group A (100% vs. 63.6%, p = 0.039). No significantly difference was found between the two groups for the other endpoints. Low rates of both acute and late toxicities were recorded., Conclusion: Radiotherapy plus fluorouracil and mytomicin provide a better complete pathological response than radiotherapy plus cisplatin and fluorouracil and a greater rate of anal sphincter function preservation. Globally, radiochemotherapy of the anal cancer provides excellent clinical outcomes with a good profile of acute and late toxicity, without difference between the two groups studied.

Objectives: Platelets generate oxidized LDL (ox-LDL) via NOX2-derived oxidative stress. We investigated if once generated by activated platelets ox-LDL can propagate platelet activation., Methods: Experiments were performed in platelets from healthy subjects (HS), hyper-cholesterolemic patients and patients with NOX2 hereditary deficiency., Results: Agonist-stimulated platelets from HS added with LDL were associated with a dose-dependent increase of reactive oxidant species and ox-LDL. Agonist-stimulated platelets from HS added with a fixed dose of LDL (57.14 μmol/L) or added with homogenized human atherosclerotic plaque showed enhanced ox-LDL formation (approximately +50% and +30% respectively), which was lowered by a NOX2 inhibitor (approximately -35% and -25% respectively). Compared to HS, ox-LDL production was more pronounced in agonist-stimulated platelet rich plasma (PRP) from hyper-cholesterolemic patients but was almost absent in PRP from NOX2-deficient patients. Platelet aggregation and 8-iso-PGF2α-ΙΙΙ formation increased in LDL-treated washed platelets (+42% and +53% respectively) and PRP (+31% and +53% respectively). Also, LDL enhanced platelet-dependent thrombosis at arterial shear rate (+33%) but did not affect platelet activation in NOX2-deficient patients. Platelet activation by LDL was significantly inhibited by CD36 or LOX1 blocking peptides, two ox-LDL receptor antagonists, or by a NOX2 inhibitor. LDL-added platelets showed increased p38MAPK (+59%) and PKC (+51%) phosphorylation, p47(phox) translocation to platelet membrane (+34%) and NOX2 activation (+30%), which were inhibited by ox-LDL receptor antagonists., Conclusion: Platelets oxidize LDL, which in turn amplify platelet activation via specific ox-LDL receptors; both effects are mediated by NOX2 activation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Self-organized quasiperiodicity is one of the most puzzling dynamical phases observed in systems of nonlinear coupled oscillators. The single dynamical units are not locked to the periodic mean field they produce, but they still feature a coherent behavior, through an unexplained complex form of correlation. We consider a class of leaky integrate-and-fire oscillators on random sparse and massive networks with dynamical synapses, featuring self-organized quasiperiodicity, and we show how complex collective oscillations arise from constructive interference of microscopic dynamics. In particular, we find a simple quantitative relationship between two relevant microscopic dynamical time scales and the macroscopic time scale of the global signal. We show that the proposed relation is a general property of collective oscillations, common to all the partially synchronous dynamical phases analyzed. We argue that an analogous mechanism could be at the origin of similar network dynamics.

Resveratrol is a polyphenol found in grapes and berries that has antioxidant, antiproliferative and anti-inflammatory properties. For these reasons, it is available as a dietary supplement, and it is under investigation in several clinical trials. Few data are available regarding the effects of resveratrol on thyroid function. A previous study showed that resveratrol transiently increases iodide influx in FRTL-5 rat thyroid cells. Indeed, this increase arises after short treatment times (6-12 h), and no further effects are seen after 24 h. The aim of the present study was to investigate the effects of resveratrol on iodide uptake and sodium/iodide symporter expression in thyroid cells after longer times of treatment. For this purpose, the effects of resveratrol were evaluated both in vitro and in vivo using the rat thyroid FRTL-5 cell line and Sprague-Dawley rats, respectively. In FRTL-5 cells, resveratrol decreased the sodium/iodide symporter RNA and protein expression as a function of time. Furthermore, resveratrol decreased cellular iodide uptake after 48 h of treatment. The inhibitory effect of resveratrol on iodide uptake was confirmed in vivo in Sprague-Dawley rats. This study demonstrates that with longer-term treatment, resveratrol is an inhibitor of sodium/iodide symporter gene expression and function in the thyroid. These data suggest that resveratrol can act as a thyroid disruptor, which indicates the need for caution as a supplement and in therapeutic use.