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Competing Interests: Declaration of Competing Interest The authors of this editorial wish to acknowledge that they are co-authors of the articles by Gotti et al. (2024) and Sala and Gotti (2023) included in this special issue.

Over the years, different solutions were developed and tested to reduce the emissions of ammonia and particulate matter from the livestock facilities. The environmental performances of these solutions were not always evaluated in detail. This study examines the environmental footprint of pig production at farm gate, with a focus on emissions from housing. Using Life Cycle Assessment, the environmental impact of pig production in a transition farm in Spain and in two finishing farms in Italy was evaluated considering three scenarios (one baseline and two of them involving an air treatment technology: wet scrubber or dry scrubber). The study goal was to quantify the environmental footprint of pig production in different scenarios, identify key environmental hotspots, and to assess impact reduction efficiency due to the two assessed technologies, analyze the environmental trade-offs that come with the use of these technologies, and identify potential for improvements. Both wet and dry scrubbers showed potential for reducing emissions in pig housing, affecting environmental impact categories related to air pollutants such as particulate matter, acidification and eutrophication. However, there were trade-offs between emissions reduction and categories related to energy and resource use. The infrastructure and consumables required to operate the scrubber added to the impacts compared to the baseline. The dry scrubber showed a more favorable balance between emission reduction and trade-offs. In this regard, results were similar for the Spanish and Italian farms, although there were slight variations. Scrubbers had a greater effect in the Italian farms due to their use along longer periods of the pig fattening (closed cycle farms) compared to the Spanish farm (transition farm). Scrubbers are environmentally promising, especially where acidification, eutrophication and particulate matter are local problems. However, they alone cannot fully address the complex environmental impacts of pig production, which require comprehensive interventions across the supply chain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of pentameric, ligand-gated ion channels that are located on the surface of neurons and non-neuronal cells and have multiple physiological and pathophysiological functions. In order to reach the cell surface, many nAChR subtypes require the help of chaperone and/or auxiliary/accessory proteins for their assembly, trafficking, pharmacological modulation, and normal functioning in vivo. The use of powerful genome-wide cDNA screening has led to the identification and characterisation of the molecules and mechanisms that participate in the assembly and trafficking of receptor subtypes, including chaperone and auxiliary or accessory proteins. The aim of this review is to describe the latest findings concerning nAChR chaperones and auxiliary proteins and pharmacological chaperones, and how some of them control receptor biogenesis or regulate channel activation and pharmacology. Some auxiliary proteins are subtype selective, some regulate various subtypes, and some not only modulate nAChRs but also target other receptors and signalling pathways. We also discuss how changes in auxiliary proteins may be involved in nAChR dysfunctions., Competing Interests: Declaration of Competing Interest The authors declare that there is no financial/personal interest or belief that could affect their objectivity., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in AD has been recently postulated. Here, we first investigated the effects of PCSK9 on neuroinflammation in vitro. Then, we examined the impact of a genetic ablation of PCSK9 on cognitive performance in a severe mouse model of AD. Finally, in the same animals we evaluated the effect of PCSK9 loss on Aβ pathology, neuroinflammation, and brain lipids., Methods: For in vitro studies, U373 human astrocytoma cells were treated with Aβ fibrils and human recombinant PCSK9. mRNA expression of the proinflammatory cytokines and inflammasome-related genes were evaluated by q-PCR, while MCP-1 secretion was measured by ELISA. For in vivo studies, the cognitive performance of a newly generated mouse line - obtained by crossing 5XFAD Het with PCSK9 KO mice - was tested by the Morris water maze test. After sacrifice, immunohistochemical analyses were performed to evaluate Aβ plaque deposition, distribution and composition, BACE1 immunoreactivity, as well as microglia and astrocyte reactivity. Cholesterol and hydroxysterols levels in mouse brains were quantified by fluorometric and LC-MS/MS analyses, respectively. Statistical comparisons were performed according to one- or two-way ANOVA, two-way repeated measure ANOVA or Chi-square test., Results: In vitro, PCSK9 significantly increased IL6, IL1B and TNFΑ mRNA levels in Aβ fibrils-treated U373 cells, without influencing inflammasome gene expression, except for an increase in NLRC4 mRNA levels. In vivo, PCSK9 ablation in 5XFAD mice significantly improved the performance at the Morris water maze test; these changes were accompanied by a reduced corticohippocampal Aβ burden without affecting plaque spatial/regional distribution and composition or global BACE1 expression. Furthermore, PCSK9 loss in 5XFAD mice induced decreased microgliosis and astrocyte reactivity in several brain regions. Conversely, knocking out PCSK9 had minimal impact on brain cholesterol and hydroxysterol levels., Conclusions: In vitro studies showed a pro-inflammatory effect of PCSK9. Consistently, in vivo data indicated a protective role of PCSK9 ablation against cognitive impairments, associated with improved Aβ pathology and attenuated neuroinflammation in a severe mouse model of AD. PCSK9 may thus be considered a novel pharmacological target for the treatment of AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Feeding is one of the most important factors influencing production efficiency and the environmental impact of livestock production. This study evaluates the possibility of reducing the impact of beef cattle production by optimizing the fertilization management of home-grown forage on the same farms. To this end, two scenarios were compared on two beef cattle farms in northern Italy, a baseline scenario (BS) and a scenario with optimized management (OMS) in terms of nitrogen fertilizer use. The cradle-to-gate LCA (Life Cycle Assessment) approach was used to compare the environmental performances in the different scenarios. Two different functional units (1 t dry matter of forage self-produced and 1 kg live weight of beef cattle produced) were used to express the results in relation to different stages of the supply chain. Inventory data were translated into indicators to reflect environmental pressures as well as resource scarcity by means of the ReCiPe 2016 Midpoint (H) method. The reduction of synthetic nitrogen fertilization, particularly during top fertilization, maintain yields at satisfactory levels while substantially reducing most of the evaluated impacts (e.g., Climate change from 17 % to 23 %). On the other hand, trade-offs among the different impact categories can be identified (e.g., terrestrial acidification grows up to 52 % for wheat silage). The optimization of the fertilization also involves a reduction in the impact of the feed as a whole and then of the beef cattle produced, even though the increasing number of external inputs, not affected by best fertilization practices, for each of these two phases leads to increasingly smaller reductions in impact. Ultimately, the optimization of internal crop production practices is important from an environmental point of view for farms but represents only one of the possible mitigation interventions necessary to mitigate the entire agricultural supply chain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: A minimally invasive option of colloid cyst surgical treatment is endoscopic resection, well validated in various reports and clinical practice. A rare complication of the surgical treatment, previously reported only once in literature, is the entrapment of the lateral ventricle. In this study we aim to outline our experience in the management of this occurrence, hypothesizing possible etiopathogenetic causes., Methods: Among patients who underwent neuroendoscopic resection for a colloid cysts at our Institution between 2013 and 2022, cases who developed a postoperative lateral ventricle entrapment were retrospectively reviewed and included. Clinical history, imaging and treatment were reported., Results: Among 34 patients treated for a colloid cysts, two (5.9 %) patients developed an ipsilateral ventricular entrapment with dilation from two to five months after the resection. Both patients were substantially asymptomatic and neurologically intact, and therefore treated conservatively. One case underwent complete spontaneous radiological resolution one month later, and the other one has remained neurological asymptomatic at follow-up., Conclusions: Isolated asymptomatic ventricular entrapment with significant dilation after endoscopic colloid cyst resection is a rare occurrence which can be plausibly caused by scar tissue at the level of the foramen of Monro. Because they can have an indolent course with spontaneous resolution, conservative treatment is a viable option, with strict radiological and clinical follow - up. Given the rarity of the occurrence, further studies with larger cohorts are warranted to confirm the etiopathogenetic hypothesis and validate the clinical management., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Transorbital neuroendoscopic surgery (TONES) comprises a group of approaches with indications expanding from orbital tumors to more complex skull base lesions. We analyzed the role of the endoscopic transorbital approach (eTOA) for spheno-orbital tumors, reporting the results of our clinical series and of a systematic review of the literature., Materials and Methods: All patients operated on from 2016 to 2022 at our institution for a spheno-orbital tumor through an eTOA were included in a clinical series, and a systematic review of the literature was performed., Results: Our series consisted of 22 patients (16 females, mean age 57 ± 13 years). Gross tumor removal was achieved in 8 patients (36.4%) after the eTOA and in 11 (50.0%) after a multistaged strategy combining the eTOA with the endoscopic endonasal approach. Complications included 1 chronic subdural hematoma and 1 permanent extrinsic ocular muscle deficit. Patients were discharged after 2.4 ± 1.3 days. The most common histotype was meningioma (86.4%). Proptosis improved in all cases, visual deficit in 66.6%, and diplopia in 76.9%. These results were confirmed by the review of the 127 cases reported in the literature., Conclusions: Despite its recent introduction, a significant number of spheno-orbital lesions treated with an eTOA are being reported. Its main advantages are favorable patient outcome and optimal cosmetic results, with minimal morbidity and quick recovery. This approach can be combined with other surgical routes or adjuvant therapies for complex tumors. However, it is a technically demanding procedure, requiring specific skills in endoscopic surgery, that should be reserved to dedicated centers., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The agri-food sector needs both water and energy and it also contributes to greenhouse gas (GHG) emissions; among the various activities within this sector, rice production has a particularly significant impact on the environment. Life Cycle Assessment (LCA) is one of the widely used approaches for evaluating the environmental impacts of a product, and as such, it is useful for examining the impacts of the rice industry. In recent years, LCA has been increasingly utilized to provide detailed insight into rice production processes. This review focuses on the application of LCA in rice production. Rice LCA studies were gathered in Scopus®. A total of 76 papers were examined up to the end of 2022. Most studies have evaluated the environmental impact of rice production and identified problem areas and opportunities for improvement. But there is a discrepancy in inputs considered, multifunctionality, emissions estimation and use of FU, which makes it challenging to compare LCA results, while some key aspects such as loss of biodiversity and variation of soil organic carbon and fertility are often not considered or roughly modelled. Only a small number (13 studies) evaluated economic consequences and investigated the impact of rice production on biodiversity (4 studies), indicating a stronger focus on environmental rather than socioeconomic aspects and limitations in evaluating certain environmental effects such as biodiversity and soil fertility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The anterior optic pathway (AOP) is a system of three structures (optic nerves, optic chiasma, and optic tracts) that convey visual stimuli from the retina to the lateral geniculate nuclei. A successful reconstruction of the AOP using tractography could be helpful in several clinical scenarios, from presurgical planning and neuronavigation of sellar and parasellar surgery to monitoring the stage of fiber degeneration both in acute (e.g., traumatic optic neuropathy) or chronic conditions that affect AOP structures (e.g., amblyopia, glaucoma, demyelinating disorders or genetic optic nerve atrophies). However, its peculiar anatomy and course, as well as its surroundings, pose a serious challenge to obtaining successful tractographic reconstructions. Several AOP tractography strategies have been adopted but no standard procedure has been agreed upon. We performed a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines in order to find the combinations of acquisition and reconstruction parameters that have been performed previously and have provided the highest rate of successful reconstruction of the AOP, in order to promote their routine implementation in clinical practice. For this purpose, we reviewed data regarding how the process of anatomical validation of the tractographies was performed. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias and thus the study quality We identified thirty-nine studies that met our inclusion criteria, and only five were considered at low risk of bias and achieved over 80% of successful reconstructions. We found a high degree of heterogeneity in the acquisition and analysis parameters used to perform AOP tractography and different combinations of them can achieve satisfactory levels of anterior optic tractographic reconstruction both in real-life research and clinical scenarios. One thousand s/mm 2 was the most frequently used b value, while both deterministic and probabilistic tractography algorithms performed morphological reconstruction of the tract satisfactorily, although probabilistic algorithms estimated a more realistic percentage of crossing fibers (45.6%) in healthy subjects. A wide heterogeneity was also found regarding the method used to assess the anatomical fidelity of the AOP reconstructions. Three main strategies can be found: direct visual direct visual assessment of the tractography superimposed to a conventional MR image, surgical evaluation, and computational methods. Because the latter is less dependent on a priori knowledge of the anatomy by the operator, computational methods of validation of the anatomy should be considered whenever possible., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: An enhanced surveillance schedule has been proposed for cirrhotics with viral etiology, who are considered at extremely high-risk of hepatocellular carcinoma (HCC)., Aims: We compared the 3- and 6-months surveillance interval, evaluating cancer stage at diagnosis and patient survival., Methods: Data of 777 HBV and HCV cirrhotic patients with HCC diagnosed under a 3-months (n = 109, 3MS group) or a 6-months (n = 668, 6MS group) surveillance were retrieved from the Italian Liver Cancer database. Survival in the 3MS group was considered as observed and adjusted for lead-time bias, and survival analysis was repeated after a propensity score matching., Results: The 3-months surveillance interval neither reduced the share of patients diagnosed outside the Milano criteria, nor increased their probability to receive curative treatments. The median survival of 6MS patients (55.0 months [45.9-64.0]) was not significantly different from the observed (47.0 months [35.0-58.9]; p = 0.43) and adjusted (44.9 months [33.4-56.4]; p = 0.30) survival of 3MS patients. A propensity score analysis confirmed the absence of a survival advantage for 3MS patients., Conclusions: A tightening of surveillance schedule does not increase the diagnosis of early-stage tumors, the feasibility of curative treatments and the survival. Therefore, we should maintain the 6-months interval in the surveillance of viral cirrhotics., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Technological advancement in neurosurgery is a continuous process aimed at improving existing devices and implementing innovative ones. Recently, artificial intelligence (AI)-derived technologies (i.e., machine learning and virtual or augmented reality) have been entering this field, promising to significantly change its future. The acquisition of technological skills should be a goal of training for young neurosurgeons. The aim of this study is the analysis of competence and attitude toward intraoperative devices of young neurosurgeons., Methods: An online electronic survey was sent to 256 members of the Young Neurosurgeons Section of the Italian Society of Neurosurgery (Società Italiana di Neurochirurgia, SINch), inquiring about their competences and attitude toward surgical technologies and AI-derived devices., Results: A total of 152 neurosurgeons participated in the survey. Most participants reported sufficient skills in autonomously setting up and using the optic neuronavigator (93.4% and 92.1%, respectively), advanced microscope (80.3% and 76.3%), magnetic neuronavigator (75% and 72.4%), ultrasonography (63.2% and 60.5%) and high-definition endoscope (55.3% and 46%). Most (92.1%) considered operative devices useful and 89.5% reported a high motivation to acquire technological skills. AI-derived devices have already been used by 56.6% of participants but only 31.6% received proper dedicated training., Conclusions: Italian young neurosurgeons have acquired technical skills sufficient for the autonomous use of the most common operative devices, reporting a positive attitude toward technology with high motivation to learn and awareness of their potential harmfulness. A promising number of participants had already used AI-derived technologies, although only a few had received focused training for these devices., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Glioblastomas (GBMs), the most frequent brain tumours, are highly invasive and their prognosis is still poor despite the use of combination treatment. MG624 is a 4-oxystilbene derivative that is active on α7- and α9-containing neuronal nicotinic acetylcholine receptor (nAChR) subtypes. Hybridisation of MG624 with a non-nicotinic resveratrol-derived pro-oxidant mitocan has led to two novel compounds (StN-4 and StN-8) that are more potent than MG624 in reducing the viability of GBM cells, but less potent in reducing the viability of mouse astrocytes. Functional analysis of their activity on α7 receptors showed that StN-4 is a silent agonist, whereas StN-8 is a full antagonist, and neither alters intracellular [Ca 2+ ] levels when acutely applied to U87MG cells. After 72 h of exposure, both compounds decreased U87MG cell proliferation, and pAKT and oxphos ATP levels, but only StN-4 led to a significant accumulation of cells in phase G 1 /G 0 and increased apoptosis. One hour of exposure to either compound also decreased the mitochondrial and cytoplasmic ATP production of U87MG cells, and this was not paralleled by any increase in the production of reactive oxygen species. Knocking down the α9 subunit (which is expressed at relatively high levels in U87MG cells) decreased the potency of the effects of both compounds on cell viability, but cell proliferation, ATP production, pAKT levels were unaffected by the presence of the noncell-permeable α7/α9-selective antagonist αBungarotoxin. These last findings suggest that the anti-tumoral effects of StN-4 and StN-8 on GBM cells are not only due to their action on nAChRs, but also to other non-nicotinic mechanisms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Phosphoinositide-specific phospholipases C (PLCs) are a class of enzymes involved in several cell activities, such as cell cycle regulation, proliferation, differentiation and cytoskeletal dynamics. Among these enzymes, PLCγ1 is one of the most expressed PLCs in the brain, contributing to a complex network in the developing nervous system. Several studies have shown that PLCγ1 signaling imbalance is linked to several brain disorders, including glioblastoma, the most aggressive brain tumor in adults. Indeed, it has been demonstrated a link between PLCγ1 inhibition and the arrest of glioma cell motility of fetal rat brain aggregates and the impairment of cell invasion abilities following its down-regulation. This study aims to determine the pathological influence of PLCγ1 in glioblastoma, through a translational study which combines in silico data, data from glioblastoma patients' samples and data on engineered cell lines. We found out that PLCγ1 gene expression correlates with the pathological grade of gliomas, and it is higher in fifty patients' glioblastoma tissue samples compared to twenty healthy controls. Moreover, it was demonstrated that PLCγ1 silencing in U87-MG leads to a reduction in cell migration and invasion abilities. The opposite trend was observed following PLCγ1 overexpression, suggesting an interesting possible involvement of PLCγ1 in gliomas' aggressiveness., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Northern Italy represents the most important rice-growing district in Europe. In this area, rice is the main annual crop and the main revenues source for farmers. However, Italian climatic condition led to a traditional cultivation characterized by continuous flooding, causing emissions of methane into the atmosphere due to the organic matter fermentation in anaerobic conditions, and, consequently, a high environmental impact. The water conditions of paddy fields also affect heavy metals uptake by rice plants. In this context, this study focuses on the evaluation of environmental impact and of heavy metal content in paddy rice, and it may represent an important step in mitigating the environmental impact of rice production. In detail, this study quantifies the environmental benefits related to the adoption of an alternative water management characterized by an additional aeration period during stem elongation. To this purpose, field trials were carried out and the Life Cycle Assessment (LCA) approach was applied with a cradle-to-farm gate perspective. The potential environmental impact of the production of two rice varieties (Carnaroli and Caravaggio) was analysed in terms of 12 different impact categories and dehulled rice grain were analysed for arsenic and cadmium content. Alternative flooding decreases CH 4 emissions in all cases evaluated (from 15% to 52%), resulting in a reduction in the climate change impact of rice cultivation (from 12% to 32%). Furthermore, the alternative water management does not influence grain yield and it reduces all the other environmental impact categories in 2 out of 4 cases. Regarding the heavy metals contents, the arsenic content in the grain decreases in all alternative scenarios, whereas the cadmium content increases, while remaining well below the legal limits., Competing Interests: Declaration of competing interest In order to ensure that all authors of papers submitted to Science of the Total Environment follow the journal's ethical guidelines, the lead or corresponding author should sign this form on behalf of all of the paper's authors, and return it to the Editor handling their paper. This paper has not been submitted to another journal for simultaneous consideration. All authors are aware of, and accept responsibility for, the manuscript. All authors have made a significant intellectual contribution to the research and have permission (if required) to submit the manuscript for possible publication. The authors have not plagiarized any parts of this manuscript; this includes the verbatim copying of text, the uncited use of another's work, or the use of information gained during a confidential manuscript or proposal review process. None of the data, tables, figures, or text in this paper have been published elsewhere (in any language), with the exception of abstracts of papers presented at conferences and figures or tables for which permission to use them has been obtained from the copyright holder. Any authors who have a financial interest in the results of the paper have disclosed this interest to the Editors in the manuscript submittal letter. These financial interests may include, but are not limited to, paid consultancies, patent interests, stock holdings, professional affiliations, advisory positions, board memberships, and other financial holdings. Interests that might detract from an author's objectivity in the presentation of study results should be disclosed. The Editors will determine whether the material disclosed to them should be published as part of the paper. The authors have accurately listed their affiliations. This list must include academic, significant corporate and industrial, and non-governmental organization (NGO) affiliations. As the Editors deem appropriate, items in this list will be included in the author affiliations printed in the paper. The authors have accurately listed the funding sources for the work presented in the paper in the acknowledgements section. All financial contributions to the work being reported, including contributions “in kind”, must be reported. All funding sources will be listed in the published paper. The authors declare that they have read the current Instructions to Authors and understand Science of the Total Environment full Conflict of Interest Policy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The specific role of the striatum, especially its dorsolateral (DLS) and dorsomedial (DMS) parts, in male copulatory behavior is still debated. In order to clarify their contribution to male sexual behavior, we specifically ablated the major striatal neuronal subpopulations, direct and indirect medium spiny neurons (dMSNs and iMSNs) in DMS or DLS, and dMSNs, iMSNs and cholinergic interneurons in nucleus accumbens (NAc), The main results of this study can be summarized as follows: In DMS, dMSN ablation causes a reduction in the percent of mice that mount a receptive female, and a complex alteration in the parameters of the copulatory performance, that is largely opposite to the alterations induced by iMSN ablation. In DLS, dMSN ablation causes a widespread alteration in the copulatory behavior parameters, that tends to disappear at repetition of the test; iMSN ablation induces minor copulatory behavior alterations that are complementary to those observed after dMSN ablation. In NAc, dMSN ablation causes a marked reduction in the percent of mice that mount a receptive female and a disruption of copulatory behavior, while iMSN ablation induces minor copulatory behavior alterations that are opposite to those observed with dMSN ablation, and cholinergic neuron ablation induces a selective decrease in mount latency. Overall, present data point to a complex region and cell-specific contribution to copulatory behavior of the different neuronal subpopulations of both dorsal and ventral striatum, with a prominent role of the dMSNs of the different subregions., Competing Interests: Conflict of Interest All the authors have no competing financial interest in this study., (Copyright © 2021. Published by Elsevier B.V.)

Background: Sorafenib is the gold standard therapy for the advanced hepatocellular carcinoma (HCC). No scoring/staging is universally accepted to predict the survival of these patients., Aims: To evaluate the accuracy of the available prognostic models for HCC to predict the survival of advanced HCC patients treated with Sorafenib included in the Italian Liver Cancer (ITA.LI.CA.) multicenter cohort., Methods: The performance of several prognostic scores was assessed through a Cox regression-model evaluating the C-index and the Akaike Information Criterion (AIC)., Results: Data of 1129 patients were analyzed. The mean age of patients was 61.6 years, and 80.8% were male. During a median follow-up period of 13 months, 789 patients died. The median period of Sorafenib administration was 4 months. All the prognostic scores were able to predict the overall survival (p<0.001) at univariate analysis, except the Albumin-Bilirubin score. The Italian Liver Cancer score (CLIP) yielded the highest accuracy (C-index 0.604, AIC 9898), followed by the ITA.LI.CA. prognostic score (C-index 0.599, AIC 9915)., Conclusions: The CLIP score had the highest accuracy in predicting the overall survival of HCC patients treated with Sorafenib, although its performance remained poor. Further studies are needed to refine the current ability to predict the outcome of HCC patients undergoing Sorafenib., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Phosphoinositide-specific phospholipases C (PI-PLCs) are a class of enzymes involved in the phosphatidylinositol metabolism, which is implicated in the activation of several signaling pathways and which controls several cellular processes. The scientific community has long accepted the existence of a nuclear phosphoinositide (PI) metabolism, independent from the cytoplasmic one, critical in nuclear function control. Indeed, nuclear PIs are involved in many activities, such as cell cycle regulation, cell proliferation, cell differentiation, membrane transport, gene expression and cytoskeletal dynamics. There are several types of PIs and enzymes implicated in brain activities and among these enzymes, PI-PLCs contribute to a specific and complex network in the developing nervous system. Moreover, considering the abundant presence of PI-PLCβ1, PI-PLCγ1 and PI-PLCβ4 in the brain, a specific role for each PLC subtype has been suggested in the control of neuronal activity, which is important for synapse function, development and other mechanisms. The focus of this review is to describe the latest research about the involvement of PI-PLC signaling in the nervous system, both physiologically and in pathological conditions. Indeed, PI-PLC signaling imbalance seems to be also linked to several brain disorders including epilepsy, movement and behavior disorders, neurodegenerative diseases and, in addition, some PI-PLC subtypes could become potential novel signature genes for high-grade gliomas., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Glioblastomas (GBMs), the most frequent and aggressive human primary brain tumours, have altered cell metabolism, and one of the strongest indicators of malignancy is an increase in choline compounds. Choline is also a selective agonist of some neuronal nicotinic acetylcholine receptor (nAChR) subtypes. As little is known concerning the expression of nAChR in glioblastoma cells, we analysed in U87MG human grade-IV astrocytoma cell line and GBM5 temozolomide-resistant glioblastoma cells selected from a cancer stem cell-enriched culture, molecularly, pharmacologically and functionally which nAChR subtypes are expressed and,whether choline and nicotine can affect GBM cell proliferation. We found that U87MG and GBM5 cells express similar nAChR subtypes, and choline and nicotine increase their proliferation rate and activate the anti-apoptotic AKT and pro-proliferative ERK pathways. These effects are blocked by the presence of non-cell-permeable peptide antagonists selective for α7- and α9-containing nicotinic receptors. siRNA-mediated silencing of α7 or α9 subunit expression also selectively prevents the effects of nicotine and choline on GBM cell proliferation. Our findings indicate that nicotine and choline activate the signalling pathways involved in the proliferation of GBM cells, and that these effects are mediated by α7 and α9-containing nAChRs. This suggests that these nicotinic receptors may contribute to the aggressive behaviour of this tumor and may indicate new therapeutic strategies against high-grade human brain tumours., (Copyright © 2020. Published by Elsevier Ltd.)

Smoking cessation induces a withdrawal syndrome associated with anxiety, depression, and impaired neurocognitive functions, but much less is known about the withdrawal of e-cigarettes (e-CIG). We investigated in Balb/c mice the behavioural and neurochemical effects of withdrawal for up to 90 days after seven weeks' intermittent exposure to e-CIG vapour or cigarette smoke (CIG). The withdrawal of e-CIG and CIG induced early behavioural alterations such as spatial memory deficits (spatial object recognition task), increased anxiety (elevated plus maze test) and compulsive-like behaviour (marble burying test) that persisted for 60-90 days. Notably, attention-related (virtual object recognition task) and depression-like behaviours (tail suspension and sucrose preference tests) appeared only 15-30 days after withdrawal and persisted for as long as up to 90 days. At hippocampal level, the withdrawal-induced changes in the levels of AMPA receptor GluA1 and GluA2/3 subunits, PSD 95 protein, corticotropin-releasing factor (Crf) and Crf receptor 1 (CrfR1) mRNA were biphasic: AMPA receptor subunit and PSD95 protein levels initially remained unchanged and decreased after 60-90 days, whereas Crf/CrfR1 mRNA levels initially increased and then markedly decreased after 60 days. These late reductions correlated with the behavioural impairments, particularly the appearance of depression-like behaviours. Our findings show that major behavioural and neurochemical alterations persist or even first appear late after the withdrawal of chronic CIG smoke or e-CIG vapour exposure, and underline importance of conducting similar studies of humans, including e-CIG vapers., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest, (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Central nervous system (CNS) compartments remain one of the most difficult districts for drug delivery. This is due to the presence of the blood-brain barrier (BBB) that hampers 90% of drug passage, dramatically requiring non-invasive treatment strategies. Here, for the first time, the use of opioid-derived deltorphin-derivative peptides to drive biodegradable and biocompatible polymeric (i.e. poly-lactide-co-glycolide, PLGA) nanomedicines delivery across the BBB was described. Opioid-derived peptides were covalently conjugated to furnish activated polymers which were further used for fluorescently tagged nanoformulations. Beyond reporting production, formulation methodology and full physico-chemical characterization, in vivo tests generated clear proof of BBB crossing and CNS targeting by engineered nanomedicines opening the research to further applications of drug delivery and targeting in CNS disease models., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In the last years, few reports have shown the feasibility of the endoscopic endonasal approach (EEA) for craniopharyngiomas in pediatric patients. For these tumors, recent studies have suggested less aggressive surgery, favoring the preservation of the patient's quality of life., Objective: The aim of this study was to assess the outcome of the EEA in a large series with specific attention on the long-term functional sequelae., Materials: All consecutive pediatric craniopharyngiomas operated on through this approach since 2000 were included in the study. Preoperative and postoperative operative clinical, radiologic, and pathologic features were retrieved from patient records (mean follow-up, 72 ± 67 months)., Results: The series included 25 patients (12 female; mean age, 8.9 ± 4.1 years). Most of the tumors presented with a supradiaphragmatic extension (88%). Removal was radical in 23 patients (92%). Complications consisted of 6 cerebrospinal fluid leaks (24%). One patient (4%) died of postoperative respiratory complications. Most patients (92%) developed panhypopituitarism and visual disturbances normalized or improved in 6 patients (43%). At follow-up, 9 patients (36%) were overweight/obese (6 were already overweight before surgery). The tumor recurrence rate was 19%., Conclusions: EEA can be an effective approach for midline craniopharyngiomas in children older than 3 years. It gives a satisfactory exposure of the suprasellar region and an adequate assessment of the brain-tumor interface. Its main limitations are age-related anatomic features of nasal/paranasal sinuses and the risk of cerebrospinal fluid leak., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Human induced pluripotent stem cells (hiPSCs) have become indispensable for disease modelling. They are an important resource to access patient cells harbouring disease-causing mutations. Derivation of midbrain dopaminergic (DAergic) neurons from hiPSCs of PD patients represents the only option to model physiological processes in a cell type that is not otherwise accessible from human patients. However, differentiation does not produce a homogenous population of DA neurons and contaminant cell types may interfere with the readout of the in vitro system. Here, we use CRISPR/Cas9 to generate novel knock-in reporter lines for DA neurons, engineered with an endogenous fluorescent tyrosine hydroxylase - enhanced green fluorescent protein (TH-eGFP) reporter. We present a reproducible knock-in strategy combined with a highly specific homologous directed repair (HDR) screening approach using digital droplet PCR (ddPCR). The knock-in cell lines that we created show a functioning fluorescent reporter system for DA neurons that are identifiable by flow cytometry., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Cigarette (CIG) smoking often precedes the use of illegal drugs. Electronic-cigarettes (e-CIGs) have been promoted as a means of stopping smoking and reducing the harmful effects of CIGs on the population. However, although e-CIGs eliminate some of the morbidity associated with combustible tobacco, they are still nicotine-delivery devices. In order to study whether the nicotine delivered via e-CIG acts as "a gateway drug" to the use of cannabis, we analysed the behavioural and molecular effects of 7 weeks' pre-exposure to air (AIR), e-CIGs or CIGs on addiction-related conditioned place preference (CPP) in mice using a sub-threshold (0.01 mg/kg) dose of delta-9-tetrahydrocannabinol (Δ 9 -THC), the principal psychoactive constituent of cannabis. After 8 and 66 days of withdrawal, this Δ 9 -THC dose was ineffective in inducing CPP in mice pre-exposed to pump-driven AIR, but very effective in mice pre-exposed to e-CIGs or CIGs. Exposure to e-CIGs or CIGs increases the expression of ΔFosB in the nucleus accumbens (NAc), which remains high during short-term e-CIG or CIG withdrawal and long-term CIG withdrawal and is not influenced by treatment with Δ 9 -THC. At the end of e-CIG or CIG exposure and during withdrawal, the mice also had a higher AMPA receptors GluA1/GluA2-3 ratio in the NAc. Chronic nicotine exposure increases sensitivity to rewarding effects of Δ 9 -THC in mice and produces long-lasting neurobiological changes regardless of the delivery method (CIG vs. e-CIG). The exposure to passive tobacco smoke or e-CIG vapours can similarly increase vulnerability to the effects of cannabis and possibly other drugs of abuse., (Copyright © 2019. Published by Elsevier B.V.)

Epigenetic modifications of DNA and histone proteins are emerging as fundamental mechanisms by which neural cells adapt their transcriptional response to environmental cues, such as, immune stimuli or stress. In particular, histone H3 phospho(Ser10)-acetylation(Lys14) (H3S10phK14ac) has been linked to activation of specific gene expression. The purpose of this study was to investigate the role of H3S10phK14ac in a neuroinflammatory condition. Adult male rats received a intraperitoneal injection of lipopolysaccharide (LPS) (830 μg/Kg/i.p., n = 6) or vehicle (saline 1 mL/kg/i.p., n = 6) and were sacrificed 2 or 6 h later. We showed marked region- and time-specific increases in H3S10phK14ac in the hypothalamus and hippocampus, two principal target regions of LPS. These changes were accompanied by a marked transcriptional activation of interleukin (IL) 1β, IL-6, Tumour Necrosis Factor (TNF) α, the inducible nitric oxide synthase (iNOS) and the immediate early gene c-Fos. By means of chromatin immunoprecipitation, we demonstrated an increased region- and time-specific association of H3S10phK14ac with the promoters of IL-6, c-Fos and iNOS genes, suggesting that part of the LPS-induced transcriptional activation of these genes is regulated by H3S10phK14ac. Finally, by means of multiple immunofluorescence approach, we showed that increased H3S10phK14ac is cell type-specific, being neurons and reactive microglia, the principal histological types involved in this response. Present data point to H3S10phK14ac as a principal epigenetic regulator of neural cell response to systemic LPS and underline the importance of distinct time-, region- and cell-specific epigenetic mechanisms that regulate gene transcription to understand the mechanistic complexity of neuroinflammatory response to immune challenges., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A novel fully organic bioelectronic device is presented and validated as electronic transducer and current stimulator for brain implants. The device integrates polymeric electrodes made of poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) on paper thin foils, resulting in a high surface-to-volume ratio architecture that exhibits high sensitivity to interfacial ionic transport phenomena. The prototyping technique herein presented yields devices for the bidirectional communication with biological systems whose dimensionality can be controlled according to the desired application. Transduction of ultra-low local-field potentials and delivery of voltage pulse-trains alike those used in deep-brain stimulation are herein assessed, paving the way towards novel theranostic strategies for the treatment of Parkinson's Disease and other severe neurodegenerative and/or traumatic pathologies of the central nervous system., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Nicotine addiction supports tobacco smoking, a main preventable cause of disease and death in Western countries. It develops through long-term neuroadaptations in the brain reward circuit by modulating intracellular pathways and regulating gene expression. This study assesses the regional expression of the transcripts of the CRF transmission in a nicotine sensitization model, since it is hypothesised that the molecular neuroadaptations that mediate the development of sensitization contribute to the development of addiction., Methods: Rats received intraperitoneal nicotine administrations (0.4 mg/kg) once daily for either 1 day or over 5 days. Locomotor activity was assessed to evaluate the development of sensitization. The mRNA expression of CRF and CRF1 and CRF2 receptors was measured by qPCR in the ventral mesencephalon, ventral striatum, dorsal striatum (DS), prefrontal cortex (PFCx), and hippocampus (Hip)., Results: Acute nicotine administration increased locomotor activity in rats. In the sub-chronic group, locomotor activity progressively increased and reached a clear sensitization. Significant effects of sensitization on CRF mRNA levels were detected in the DS (increasing effect). Significantly higher CRF1 and CRF2 receptor levels after sensitization were detected in the Hip. Additionally, CRF2 receptor levels were augmented by sensitization in the PFCx, and treatment and time-induced increases were detected in the DS. Nicotine treatment effects were observed on CRF1R levels in the DS., Conclusions: This study suggests that the CRF transmission, in addition to its role in increasing withdrawal-related anxiety, may be involved in the development of nicotine-habituated behaviours through reduced control of impulses and the aberrant memory plasticity characterising addiction., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study aimed to quantify 24h body core temperature (BcT°) and sleep-wake cycle rhythm alterations in craniopharyngioma (CP) patients and to identify markers related to the postsurgical outcomes. Ten consecutive CP patients underwent neuroradiological, endocrinological and ophthalmological evaluations, 24h BcT° and sleep-wake cycle recordings before and after endoscopic endonasal surgery. The sample included four women and six men. Nocturnal sleep efficiency was pathologically reduced in eight patients before surgery. Seven out of ten patients presented one to three daytime naps. 24h BcT° rhythm was pathological in six out of ten cases. Post-surgery sleep efficiency normalized in four out of eight patients, whereas nine out of ten patients presented with two to six longer daytime naps. Diurnal naps were mainly present in patients showing pre-operative involvement of the third ventricle floor. 24h BcT° remained pathological in only one out of six cases, returned to normal in two and improved in three. 24h BcT° rhythm improved more in papillary CPs than in adamantomatous CPs. Our data confirmed that both CP and surgery frequently disrupt the sleep-wake cycle and BcT° rhythms. Tumour location and histotype may be related to a worse postsurgical outcome. Therefore, in-depth investigation including circadian monitoring is crucial for surgical outcome., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The optimal management of pituitary apoplexy (PA) remains debated. The aim of this study was to assess the outcome of the transsphenoidal approach for PA in a large surgical experience., Materials: Each consecutive case of PA consecutively operated by endoscopic endonasal approach from our tertiary care center, from 1998 to 2015, was included in this series., Results: Seventy-five patients (47 male; mean age 52.4 ± 16.2 years) were included. Mean follow-up was 69.3 ± 46.7 months. On admission, all patients presented with abrupt severe headache (100%), associated with anterior hypopituitarism in 51 patients (68%), visual disturbances in 55 (73.4%), ophthalmoplegia in 38 (50.7%), and a remarkable reduction of consciousness in 2 (2.6%). Apoplexy proved to be ischemic in 35 patients (46.7%) and hemorrhagic in 40 (53.3%). Patients with hemorrhagic necrosis presented more often with major suprasellar expansion (P = 0.012) Radical removal was achieved in 60 cases (80%). Surgical morbidity consisted in one case of postoperative cerebrospinal fluid leak (1.3%). Anterior hypopituitarism worsened in 15 cases (20%), and diabetes insipidus occurred in 4 cases (5.3%). Ophthalmoplegia improved/normalized in 71% and visual symptoms in 85.5% of the patients, with better results achieved in ischemic forms (P = 0.043). The 2 comatose patients regained normal consciousness., Conclusions: The endoscopic endonasal approach represents a valid, effective, and safe technique in the management of PA. Favorable outcomes can be achieved by referring patients to dedicated pituitary centers with a multidisciplinary team. Further studies are still needed to define criteria for surgical indication and to identify outcome predictors., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Postoperative infection is a potentially dramatic consequence in endoscopic endonasal surgery. The aim of this study was to assess the efficacy of our intraoperative antibiotic prophylaxis by analyzing the risk factors of postoperative meningitis in our series., Methods: Each endoscopic endonasal procedure performed since 1998 in patients with no preoperative infections and a follow-up longer than 30 days were included and retrospectively reviewed. Antibiotic protocol consisted in single antibiotic administration of ampicillin/sulbactam 3 g or cefazolin 2 g on induction; no postoperative administrations were performed after 2005. All cases of cerebrospinal fluid (CSF) leak, meningitis, and systemic infection were recorded., Results: Two thousand thirty-two procedures matched the inclusion criteria (median age 50 years; range: 1-89 years, male/female ratio: 1:1.12). Intraoperative CSF leak occurred in 32.8% of the cases and postoperative CSF leak in 3.4%. The rate of meningitis was 0.69%; other systemic infections were observed in 0.44% of cases. Meningitis was statistically associated with intra- and postoperative CSF leak (P < 0.001). Other risk factors were the intradural extension of the tumors and their malignant histology. Extended approaches producing wide osteodural defects were correlated with a greater risk of meningitis (P < 0.001)., Conclusions: All surgical maneuvers to prevent, detect, and quickly repair intra- and postoperative CSF leak are crucial to avoid postoperative meningitis. The proposed prophylaxis protocol is comparable in safety to those recommended in literature as assessed by the low rate of meningitis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background & Aims: Assessment of long-term outcome is required in hepatitis C virus (HCV)-infected patients with cirrhosis, who have been successfully treated for Barcelona Clinic Liver Cancer (BCLC) stage A hepatocellular carcinoma (HCC). However, problems arise due to the lack of models accounting for early changes during follow-up. The aim of this study was to estimate the impact of early events (HCC recurrence or hepatic decompensation within 12months of complete radiological response) on 5-year overall survival (OS) in a large cohort of patients with HCV and cirrhosis, successfully treated HCC., Methods: A total of 328 consecutive Caucasian patients with HCV-related cirrhosis and BCLC stage 0/A HCC who had complete radiological response after curative resection or thermal ablation were prospectively recruited to this study. Primary endpoint of the study was 5-year OS. Independent baseline and time-dependent predictors of 5-year OS were identified by Cox model., Results: The observed 5-year survival rate was 44%. The observed HCC early recurrence and early hepatic decompensation rate were 21% and 10%, respectively. Early hepatic decompensation (Hazard Ratio [HR] 7.52; 95% confidence intervals (CI): 1.23-13.48) and HCC early recurrence as time-dependent covariates (HR 2.50; 95%CI: 1.23-5.05), presence of esophageal varices at baseline (HR 1.66; 95% CI: 1.02-2.70) and age (HR 1.04; 95% CI: 1.02-1.07) were significantly associated with the 5-year OS., Conclusion: Survival in HCV-infected patients with cirrhosis and successfully treated HCC is influenced by early hepatic decompensation. Our study indirectly suggests that direct-acting antiviral agents could improve OS of HCC patients through long-term preservation of liver function, resulting in a lower cirrhosis-related mortality and a greater change of receiving curative treatments., Lay Summary: Survival in hepatitis C virus (HCV) infected patients with cirrhosis and successfully treated hepatocellular carcinoma (HCC), is mainly influenced by early hepatic decompensation. HCV eradication after treatment with new direct-acting antiviral agents could improve overall survival of HCC patients through long-term preservation of liver function., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The collection of the greatest possible amount of pathologic tissue is of paramount importance in neurosurgery to achieve the most accurate histopathologic diagnosis, to perform all of the necessary biomolecular tests on the pathologic specimen, and to collect biological material for basic or translational science studies. This problem is particularly relevant in pituitary surgery because of the possible small size and soft consistency of tumors, which make them suitable for removal through suction, reducing the amount of available pathologic tissue. To solve this issue, we adopted a filter connected to the suction tube, which allows the surgeon to collect all of the tissue aspirated during surgery., Methods: Our experience of 1734 endoscopic endonasal procedures, performed adopting this device since 1998 to December 2015, has been revised to assess its advantages and limitations., Results: This system is easy-to-use, does not impair the surgical maneuvers, and does not add any relevant cost to the surgery. The tissue collected through the filter proved useful for diagnostic histologic and biomolecular analyses and for research purposes, without any relevant artifacts as a result of this method of collection., Conclusions: The use of a filter has allowed us to obtain the greatest amount possible of pathologic tissue at each surgery. This surgical material has revealed to be helpful both for diagnostic and basic science purposes. The use of the filter has proven to be of particular importance for microadenomas, soft tumors, and supradiaphragmatic or skull base lesions with heterogeneous features, improving the accuracy of histopathologic diagnosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Nicotine dependence is maintained by neurobiological adaptations in the dopaminergic brain reward pathway with the contribution of opioidergic circuits. This study assessed the role of opioid peptides and receptors on the molecular changes associated with nicotine dependence. To this aim we analysed nicotine effects on opioid gene and receptor expression in the reward pathway in a nicotine sensitization model., Methods: Sprague-Dawley rats received nicotine administrations for five days and locomotor activity assessment showed the development of sensitization. The mRNA expression of prodynorphin (pdyn), pronociceptin (pnoc) and the respective receptors was measured by quantitative PCR in the ventral midbrain (VM), the nucleus accumbens (NAc), the caudate-putamen (CPu), the pre-frontal cortex (PFCx), and the hippocampus., Results: A significant positive effect of sensitization on pdyn mRNA levels was detected in the CPu. This effect was supported by a significant and selective correlation between the two parameters in this region. Moreover, chronic but not acute nicotine treatment significantly decreased pdyn mRNA levels in the NAc and increased expression in the PFCx. Pnoc mRNA was significantly increased in the VM and the PFCx after sub-chronic administration of nicotine, whereas no alterations were observed after acute treatment. No treatment associated changes were detected in κ-opioid receptor or nociceptin receptor mRNAs., Conclusions: This experiment revealed an effect of nicotine administration that was distinguishable from the effect of nicotine sensitization. While several pnoc and pdyn changes were associated to nicotine administration, the only significant effect of sensitization was a significant increase in pdyn in the CPu., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug concentration in whole brain tissue and provides continuous monitoring of extracellular concentrations of single chiral drug enantiomers along with its metabolites in specific brain regions at each selected time point for a desired period by using a single animal., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Meningocele and meningoencephalocele of the lateral wall of the sphenoidal sinus (LWSS) are rare lesions, crossing the borders of multiple disciplines such as ear-nose-throat, maxillofacial, and neurologic surgery. We reviewed our surgical experience to analyze the role of the endoscopic endonasal approach and consider these pathologies from different perspectives., Methods: All consecutive cases of meningocele and meningoencephalocele of LWSS operated through an endoscopic endonasal approach from 1998 to 2015 in our institutions were collected. Medical history, focusing on previous episodes of cerebrospinal fluid leak, meningitis or seizures, was considered. The outcome was assessed considering the medical condition and the postoperative neuroimaging., Results: The series includes 23 patients (7 male, 16 female). Mean age was 52 years (26-73 years). Eleven cases were meningoencephaloceles and 12 meningoceles. A clear cerebrospinal fluid leak occurred on in 19 patients and was associated with meningitis in 3. Two were presenting a history of epilepsy. No complications were observed, but 1 case presented seizures on waking. At follow-up (mean 84 months, 4-167) each patient is in good clinical condition with no further episodes of leaking or seizures., Conclusions: Endoscopic endonasal surgery is a safe and effective approach for meningocele and meningoencephalocele of LWSS; it allows resection of herniated tissue and repair of the osteodural defect. The favorable clinical outcome and the possible effectiveness on seizures lead us to support this approach as first minimally invasive treatment also in presence of epilepsy, as a first low risk epilepsy surgical procedure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Tobacco addiction is a complex form of dependence process that leads high relapse rates in people seeking to stop smoking. Nicotine elicits its primary effects on neuronal nicotinic cholinergic receptors (nAChRs), alters brain reward systems, and induces long-term changes during chronic nicotine use and withdrawal. We analysed the effects of chronic nicotine treatment and withdrawal on the mesocorticolimbic pathway (a brain reward circuit in which addictive drugs induce widespread adaptations) by analysing the expression of nAChRs in the midbrain, striatum and prefrontal cortex (PFC) of mice receiving intravenous infusions of nicotine (4mg/kg/h) or saline (control) for 14 days and mice sacrified two hours, and one, four and 14 days after treatment withdrawal. We biochemically fractionated whole tissue homogenates in order to obtain crude synaptosomal membranes. Western blotting analyses of these membrane fractions, ligand binding and immunoprecipitation studies, showed that chronic nicotine up-regulates heteromeric β2* nAChRs in all three mesocorticolimbic areas, and that these receptors are rapidly removed from synapses upon the cessation of nicotine treatment. The extent of nicotine-induced nAChR up-regulation, and the time course of its reversal were comparable in all three areas. We also analysed the expression of glutamate receptor subunits (GluRs) and scaffold proteins, and found that it was altered in an area-specific manner during nicotine exposure and withdrawal. As the functional properties of GluRs are determined by their subunit composition, the observed changes in subunit expression may indicate alterations in the excitability of mesocorticolimbic circuitry, and this may underlie the long-term biochemical and behavioural effects of nicotine dependence., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Nicotine is the primary addictive substance in tobacco smoke and electronic cigarette (e-cig) vapour. Methodological limitations have made it difficult to compare the role of the nicotine and non-nicotine constituents of tobacco smoke. The aim of this study was to compare the effects of traditional cigarette smoke and e-cig vapour containing the same amount of nicotine in male BALB/c mice exposed to the smoke of 21 cigarettes or e-cig vapour containing 16.8 mg of nicotine delivered by means of a mechanical ventilator for three 30-min sessions/day for seven weeks. One hour after the last session, half of the animals were sacrificed for neurochemical analysis, and the others underwent mecamylamine-precipitated or spontaneous withdrawal for the purposes of behavioural analysis. Chronic intermittent non-contingent, second-hand exposure to cigarette smoke or e-cig vapour led to similar brain cotinine and nicotine levels, similar urine cotinine levels and the similar up-regulation of α4β2 nicotinic acetylcholine receptors in different brain areas, but had different effects on body weight, food intake, and the signs of mecamylamine-precipitated and spontaneous withdrawal episodic memory and emotional responses. The findings of this study demonstrate for the first time that e-cig vapour induces addiction-related neurochemical, physiological and behavioural alterations. The fact that inhaled cigarette smoke and e-cig vapour have partially different dependence-related effects indicates that compounds other than nicotine contribute to tobacco dependence., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)