PLASTAMINATION: Outcomes on the Central Nervous System and Reproduction.

BACKGROUND: Environmental exposures to non-biodegradable and biodegradable plastics are unavoidable. Microplastics (MPs) and nanoplastics (NPs) from the manufacturing of plastics (primary sources) and the degradation of plastic waste (secondary sources) can enter the food chain directly or indirectly and, passing biological barriers, could target both the brain and the gonads. Hence, the worldwide diffusion of environmental plastic contamination (PLASTAMINATION) in daily life may represent a possible and potentially serious risk to human health. OBJECTIVE: This review provides an overview of the effects of non-biodegradable and the more recently introduced biodegradable MPs and NPs on the brain and brain-dependent reproductive functions, summarizing the molecular mechanisms and outcomes on nervous and reproductive organs. Data from in vitro, ex vivo, non-mammalian and mammalian animal models and epidemiological studies have been reviewed and discussed. RESULTS: MPs and NPs from non-biodegradable plastics affect organs, tissues and cells from sensitive systems such as the brain and reproductive organs. Both MPs and NPs induce oxidative stress, chronic inflammation, energy metabolism disorders, mitochondrial dysfunction and cytotoxicity, which in turn are responsible for neuroinflammation, dysregulation of synaptic functions, metabolic dysbiosis, poor gamete quality, and neuronal and reproductive toxicity. In spite of this mechanistic knowledge gained from studies of non-biodegradable plastics, relatively little is known about the adverse effects or molecular mechanisms of MPs and NPs from biodegradable plastics. CONCLUSION: The neurological and reproductive health risks of MPs/NPs exposure warrant serious consideration, and further studies on biodegradable plastics are recommended.

The Other Side of Plastics: Bioplastic-Based Nanoparticles for Drug Delivery Systems in the Brain.

Plastics have changed human lives, finding a broad range of applications from packaging to medical devices. However, plastics can degrade into microscopic forms known as micro- and nanoplastics, which have raised concerns about their accumulation in the environment but mainly about the potential risk to human health. Recently, biodegradable plastic materials have been introduced on the market. These polymers are biodegradable but also bioresorbable and, indeed, are fundamental tools for drug formulations, thanks to their transient ability to pass through biological barriers and concentrate in specific tissues. However, this "other side" of bioplastics raises concerns about their toxic potential, in the form of micro- and nanoparticles, due to easier and faster tissue accumulation, with unknown long-term biological effects. This review aims to provide an update on bioplastic-based particles by analyzing the advantages and drawbacks of their potential use as components of innovative formulations for brain diseases. However, a critical analysis of the literature indicates the need for further studies to assess the safety of bioplastic micro- and nanoparticles despite they appear as promising tools for several nanomedicine applications.

The interplay between kisspeptin and endocannabinoid systems modulates male hypothalamic and gonadic control of reproduction in vivo.

Introduction: Male reproduction is under the control of the hypothalamus-pituitary-gonadal (HPG) axis. The endocannabinoid system (ECS) and the kisspeptin system (KS) are two major signaling systems in the central and peripheral control of reproduction, but their possible interaction has been poorly investigated in mammals. This manuscript analyzes their possible reciprocal modulation in the control of the HPG axis. Materials and methods: Adolescent male rats were treated with kisspeptin-10 (Kp10) and endocannabinoid anandamide (AEA), the latter alone or in combination with the type 1 cannabinoid receptor (CB1) antagonist rimonabant (SR141716A). The hypothalamic KS system and GnRH expression, circulating sex steroids and kisspeptin (Kiss1) levels, and intratesticular KS and ECS were evaluated by immunohistochemical and molecular methods. Non-coding RNAs (i.e., miR145-5p, miR-132-3p, let7a-5p, let7b-5p) were also considered. Results: Circulating hormonal values were not significantly affected by Kp10 or AEA; in the hypothalamus, Kp10 significantly increased GnRH mRNA and aromatase Cyp19, Kiss1, and Kiss1 receptor (Kiss1R) proteins. By contrast, AEA treatment affected the hypothalamic KS at the protein levels, with opposite effects on the ligand and receptor, and SR141716A was capable of attenuating the AEA effects. Among the considered non-coding RNA, only the expression of miR145-5p was positively affected by AEA but not by Kp10 treatment. Localization of Kiss1+/Kiss1R+ neurons in the arcuate nucleus revealed an increase of Kiss1R-expressing neurons in Kp10- and AEA-treated animals associated with enlargement of the lateral ventricles in Kp10-treated animals. In the brain and testis, the selected non-coding RNA was differently modulated by Kp10 or AEA. Lastly, in the testis, AEA treatment affected the KS at the protein levels, whereas Kp10 affected the intragonadal levels of CB1 and FAAH, the main modulator of the AEA tone. Changes in pubertal transition-related miRNAs and the intratesticular distribution of Kiss1, Kiss1R, CB1, and CB2 following KP and AEA treatment corroborate the KS-ECS crosstalk also showing that the CB1 receptor is involved in this interplay. Conclusion: For the first time in mammals, we report the modulation of the KS in both the hypothalamus and testis by AEA and revealed the KP-dependent modulation of CB1 and FAAH in the testis. KP involvement in the progression of spermatogenesis is also suggested.

Digital Devices Use and Fine Motor Skills in Children between 3-6 Years.

(1) Background: The principal aim of our research was to explore the relationship between digital devices use and fine motor skills in children aged three to six years and to explore the effect of some socio-demographic factors. (2) Methods: we enrolled 185 children aged between three to six years. The parents of all the participants fulfilled a questionnaire to explore the digital device use, and their children performed a standardized test to assess fine motor skills (APCM-2). We performed the Spearman correlation test to explore the relationship between different variables. (3) Results: the children spent an average of 3.08 ± 2.30 h/day on digital devices. We did not find a significant association between the time of use of digital devices and fine motor skills (p = 0.640; r = -0.036). The youngest children experienced digital tools earlier than older ones (p < 0.001; r = 0.424) and they were also the ones who used digital tools more time afterwards (p = 0.012; -0.202). The children who had working parents spent more time on digital devices (p = 0.028; r = 0.164/p = 0.037; r = 0.154) and used digital devices earlier (p = 0.023; r = 0.171). (4) Conclusions: This data suggest that it would be useful to monitor the use of digital tools, especially in the very first years of life. Future studies are needed to further explore this topic.

COVID-19 Pandemic: 1-Year Follow-Up in Children and Adolescents with Neuropsychiatric Disorders.

INTRODUCTION: Few studies have focused on the long-term effects of the COVID-19 pandemic on mental health. The objective of our work was to evaluate the changes in emotional and behavioral symptoms in patients with neuropsychiatric disorders and the impact on parenting stress 1 year after the first national lockdown. METHODS: We enrolled 369 patients aged 1.5-18 years of age referred to the Child and Adolescent Neuropsychiatry Unit of the University Hospital of Salerno (Italy) by their parents. We asked their parents to complete two standardized questionnaires for the assessment of emotional/behavioral symptoms (Child Behavior CheckList, CBCL) and parental stress (Parenting Stress Index, PSI) prior to the pandemic (Time 0), during the first national lockdown (Time 1) and after 1 year (Time 2), and we monitored the changes in symptoms over time. RESULTS: After 1 year from the start of the first national lockdown, we found a significant increase of internalizing problems, anxiety, depression, somatization, and social and oppositional-defiant problems in older children (6-18 years), and a significant increase of somatization, anxiety problems, and sleep problems in younger children (1.5-5 years). We also observed a significant relationship between emotional/behavioral symptoms and parental stress. CONCLUSION: Our study showed that parental stress levels increased compared to the pre-pandemic months and continues to persist over time, while internalizing symptoms of children and adolescents showed a significant worsening during 1 year follow-up from the first COVID-19 lockdown.

Epilepsy and Cognitive Impairment in Childhood and Adolescence: A Mini-Review.

Managing epilepsy in people with an intellectual disability remains a therapeutic challenge and must take into account additional issues such as diagnostic difficulties and frequent drug resistance. Advances in genomic technologies improved our understanding of epilepsy and raised the possibility to develop patients-tailored treatments acting on the key molecular mechanisms involved in the development of the disease. In addition to conventional antiseizure medications (ASMs), ketogenic diet, hormone therapy and epilepsy surgery play an important role, especially in cases of drugresistance. This review aims to provide a comprehensive overview of the mainfactors influencing cognition in children and adolescents with epilepsy and the main therapeutic options available for the epilepsies associated with intellectual disability.

Reading and writing difficulties in third- and sixth-grade students: a cross-sectional survey.

BACKGROUND: In Southern Italy and, specifically, in the region of Campania, many surveys show that the average of students with reading difficulties is much higher than in northern Italy and abroad. On the other hand, specific learning disorders (SLDs) in Campania are much less certified. Since there are no etiological reasons that can explain this apparent inconsistency, an objective of this cross-sectional study was to evaluate the extent of reading/writing difficulties in students from a province of Campania and then to assess the ability of teachers to identify such difficulties in their students. METHODS: Of a total of 241 enrolled students, 155 (64.31%), including 73 from primary school and 82 from secondary school, belonging to 5 schools in the province of Salerno (Italy), took part in the survey. Students' reading and writing skills were assessed through standardized tests. The tests results were then compared with teacher judgments and context-related variables. RESULTS: At the reading test, 28.7% of primary school and 13.4% of lower secondary school students fell below the 5th percentile for age. Results of the writing test were even more significant: almost half of the students of both levels of education performed below the 5th percentile. Teacher judgments showed higher agreement with standardized assessments in primary (88%, K of Cohen=0.68) than in secondary school (78%, K=0.23). CONCLUSIONS: Reading and writing difficulties were common in our sample. While reading skills tended to improve with age, writing difficulties apparently persisted to some extent in third and sixth-grade classes. The accuracy of teacher judgments on reading skills is relatively high, but teachers seem to hardly report reading difficulties "requiring attention." Although less "severe" than others, such difficulties should be considered, mainly because of their potential developmental trajectories.

Neuroinflammation: Molecular Mechanisms And Therapeutic Perspectives.

BACKGROUND: Neuroinflammation is a key component in the etiopathogenesis of neurological diseases and brain aging. This process involves the brain immune system that modulates synaptic functions and protects neurons from infection or damage. Hence, the knowledge of neuroinflammation related pathways and modulation by drugs or natural compounds is functional to developing therapeutic strategies aimed at preserving, maintaining and restoring brain health. OBJECTIVE: This review article summarizes the basics of neuroinflammation and related signaling pathways, the success of the dietary intervention in clinical practice and the possible development of RNA-based strategies for treating neurological diseases. METHODS: Pubmed search from 2012 to 2022 with the keywords neuroinflammation and molecular mechanisms in combination with diet, miRNA and non-coding RNA. RESULTS: Glial cells-play a crucial role in neuroinflammation, but several pathways can be activated in response to different inflammatory stimuli, inducing cell death by apoptosis, pyroptosis or necroptosis. The dietary intervention has immunomodulatory effects and could limit the inflammatory process induced by microglia and astrocytes. Thus by inhibiting neuroinflammation and improving the symptoms of a variety of neurological diseases, diet exerts pleiotropic neuroprotective effects independently from the spectrum of pathophysiological mechanisms underlying the specific disorder. Furthermore, data from animal models revealed that altered expression of specific noncoding RNAs, in particular microRNAs, contributes to neuroinflammatory diseases; consequently, RNA-based strategies may be promising to alleviate the consequences of neuroinflammation. CONCLUSION: Further studies are needed to identify the molecular pathways and the new pharmacological targets in neuroinflammation to lay the basis for more effective and selective therapies to be applied, in parallel to dietary intervention, in the treatment of neuroinflammation-based diseases.

Impact of COVID-19 Pandemic on Children and Adolescents with Neuropsychiatric Disorders: Emotional/Behavioral Symptoms and Parental Stress.

The objective of our study was to evaluate the impact of the COVID-19 pandemic on the emotional and behavioral symptoms in minors with neuropsychiatric disorders and on parental stress through a standardized neuropsychological assessment, comparing the data collected before the pandemic with those collected during the lock-down. Another goal of our study was to analyze the relationship between parental stress and behavioral/emotional symptoms in children. Our study was conducted on 383 families of patients who had already been referred at the Child Neuropsychiatry Unit of the University Hospital of Salerno for different neuropsychiatric conditions. All the parents completed two neuropsychological standardized questionnaires for the assessment of parental stress (PSI-Parenting Stress Index-Short Form) and the emotional/behavioral problems of their children (Child Behaviour CheckList). The data collected during the pandemic were compared with those collected from questionnaires administered during the six months preceding the pandemic, as is our usual clinical practice. The comparison between the mean scores of PSI and CBCL before and after the pandemic showed a statistically significant increase in all subscales analyzed in the total sample. The correlation analysis showed significant positive relationship between the subscale Total Stress of PSI and the subscales Total Problems and Internalizing Problems of CBCL. Our study suggested that the COVID-19 pandemic and the corresponding measures adopted led to an increase in internalizing and externalizing symptoms in children and adolescents with neuropsychiatric disorder. Similarly, parental stress increased during COVID-19 and ahigher level of stress in parents can be related to the internalizing symptoms of their children.

Differential Expression of Kisspeptin System and Kisspeptin Receptor Trafficking during Spermatozoa Transit in the Epididymis.

The hypothalamus-pituitary-testis axis controls the production of spermatozoa, and the kisspeptin system, comprising Kiss1 and Kiss1 receptor (Kiss1R), is the main central gatekeeper. The activity of the kisspeptin system also occurs in testis and spermatozoa, but currently the need of peripheral kisspeptin to produce gametes is not fully understood. Hence, we characterized kisspeptin system in rat spermatozoa and epididymis caput and cauda and analyzed the possible presence of Kiss1 in the epididymal fluid. The presence of Kiss1 and Kiss1R in spermatozoa collected from epididymis caput and cauda was evaluated by Western blot; significant high Kiss1 levels in the caput (p < 0.001 vs. cauda) and constant levels of Kiss1R proteins were observed. Immunofluorescence analysis revealed that the localization of Kiss1R in sperm head shifts from the posterior region in the epididymis caput to perforatorium in the epididymis cauda. In spermatozoa-free epididymis, Western blot revealed higher expression of Kiss1 and Kiss1R in caput (p < 0.05 vs. cauda). Moreover, immunohistochemistry revealed that Kiss1 and Kiss1R proteins were mainly localized in the secretory epithelial cell types and in contractile myoid cells, respectively. Finally, both dot blot and Elisa revealed the presence of Kiss1 in the epididymal fluid collected from epididymis cauda and caput, indicating that rat epididymis and spermatozoa possess a complete kisspeptin system. In conclusion, we reported for the first time in rodents Kiss1R trafficking in spermatozoa during the epididymis transit and Kiss1 measure in the epididymal fluid, thus suggesting a possible role for the system in spermatozoa maturation and storage within the epididymis.

Pleiotropic Outcomes of Glyphosate Exposure: From Organ Damage to Effects on Inflammation, Cancer, Reproduction and Development.

Glyphosate is widely used worldwide as a potent herbicide. Due to its ubiquitous use, it is detectable in air, water and foodstuffs and can accumulate in human biological fluids and tissues representing a severe human health risk. In plants, glyphosate acts as an inhibitor of the shikimate pathway, which is absent in vertebrates. Due to this, international scientific authorities have long-considered glyphosate as a compound that has no or weak toxicity in humans. However, increasing evidence has highlighted the toxicity of glyphosate and its formulations in animals and human cells and tissues. Thus, despite the extension of the authorization of the use of glyphosate in Europe until 2022, several countries have begun to take precautionary measures to reduce its diffusion. Glyphosate has been detected in urine, blood and maternal milk and has been found to induce the generation of reactive oxygen species (ROS) and several cytotoxic and genotoxic effects in vitro and in animal models directly or indirectly through its metabolite, aminomethylphosphonic acid (AMPA). This review aims to summarize the more relevant findings on the biological effects and underlying molecular mechanisms of glyphosate, with a particular focus on glyphosate's potential to induce inflammation, DNA damage and alterations in gene expression profiles as well as adverse effects on reproduction and development.

Multi-Systemic Alterations by Chronic Exposure to a Low Dose of Bisphenol A in Drinking Water: Effects on Inflammation and NAD+-Dependent Deacetylase Sirtuin1 in Lactating and Weaned Rats.

Bisphenol A (BPA) is largely used as a monomer in some types of plastics. It accumulates in tissues and fluids and is able to bypass the placental barrier, affecting various organs and systems. Due to huge developmental processes, children, foetuses, and neonates could be more sensitive to BPA-induced toxicity. To investigate the multi-systemic effects of chronic exposure to a low BPA dose (100 µg/L), pregnant Wistar rats were exposed to BPA in drinking water during gestation and lactation. At weaning, newborn rats received the same treatments as dams until sex maturation. Free and conjugated BPA levels were measured in plasma and adipose tissue; the size of cerebral ventricles was analysed in the brain; morpho-functional and molecular analyses were carried out in the liver with a focus on the expression of inflammatory cytokines and Sirtuin 1 (Sirt1). Higher BPA levels were found in plasma and adipose tissue from BPA treated pups (17 PND) but not in weaned animals. Lateral cerebral ventricles were significantly enlarged in lactating and weaned BPA-exposed animals. In addition, apart from microvesicular steatosis, liver morphology did not exhibit any statistically significant difference for morphological signs of inflammation, hypertrophy, or macrovesicular steatosis, but the expression of inflammatory cytokines, Sirt1, its natural antisense long non-coding RNA (Sirt1-AS LncRNA) and histone deacetylase 1 (Hdac1) were affected in exposed animals. In conclusion, chronic exposure to a low BPA dose could increase the risk for disease in adult life as a consequence of higher BPA circulating levels and accumulation in adipose tissue during the neonatal period.

Vitamin C Acutely Affects Brain Perfusion and Mastication-Induced Perfusion Asymmetry in the Principal Trigeminal Nucleus.

Prolonged mastication may induce an asymmetric modification of the local perfusion of the trigeminal principal nucleus. The aim of the present study was to evaluate the possible influence of vitamin C (vit. C) on such effect. Four groups of healthy volunteers underwent arterial spin labeling magnetic resonance imaging (ASL-MRI) to evaluate the local perfusion of the trigeminal nuclei after a vit. C-enriched lunch or a control lunch. Two ASL-MRI scans were acquired, respectively, before and after a 1 h-long masticating exercise or a 1 h long resting period. The results showed (i) an increased global perfusion of the brain in the vit. C-enriched lunch groups, (ii) an increased local perfusion of the right principal trigeminal nucleus (Vp) due to mastication, and (iii) a reduction of the rightward asymmetry of the Vp perfusion, due to mastication, after the vit C-enriched meal compared to the control meal. These results confirmed a long-lasting effect of prolonged mastication on Vp perfusion and also suggest a possible effect of vit. C on cerebral vascular tone regulation. Moreover, the data strongly draw attention on the side-to-side relation in Vp perfusion as a possible physiological parameter to be considered to understand the origin of pathological conditions like migraine.

Sirt1 Activity in the Brain: Simultaneous Effects on Energy Homeostasis and Reproduction.

Diet deeply impacts brain functions like synaptic plasticity and cognitive processes, neuroendocrine functions, reproduction and behaviour, with detrimental or protective effects on neuronal physiology and therefore consequences for health. In this respect, the activity of metabolic sensors within the brain is critical for the maintenance of health status and represents a possible therapeutic target for some diseases. This review summarizes the main activity of Sirtuin1 (Sirt1), a metabolic sensor within the brain with a focus on the link between the central control of energy homeostasis and reproduction. The possible modulation of Sirt1 by natural phytochemical compounds like polyphenols is also discussed.

The Complex Interplay between Endocannabinoid System and the Estrogen System in Central Nervous System and Periphery.

The endocannabinoid system (ECS) is a lipid cell signaling system involved in the physiology and homeostasis of the brain and peripheral tissues. Synaptic plasticity, neuroendocrine functions, reproduction, and immune response among others all require the activity of functional ECS, with the onset of disease in case of ECS impairment. Estrogens, classically considered as female steroid hormones, regulate growth, differentiation, and many other functions in a broad range of target tissues and both sexes through the activation of nuclear and membrane estrogen receptors (ERs), which leads to genomic and non-genomic cell responses. Since ECS function overlaps or integrates with many other cell signaling systems, this review aims at updating the knowledge about the possible crosstalk between ECS and estrogen system (ES) at both central and peripheral level, with focuses on the central nervous system, reproduction, and cancer.

Digital Devices Use and Language Skills in Children between 8 and 36 Month.

Background: Over the past decade, the use of digital tools has grown and research evidence suggests that traditional media and new media offer both benefits and health risks for young children. The abilities to understand and use language represent two of the most important competencies developed during the first 3 years of life through the interaction of the child with people, objects, events, and other environmental factors. The main goal of our study is to evaluate the relationship between digital devices use and language abilities in children between 8 and 36 month, also considering the influence of several factors. Materials and Methods: We conducted a cross-sectional observational study on digital devices use and language abilities in260 children (140 males = 54%) aged between 8 and 36 months (mean = 23.5 ± 7.18 months). All the parents completed a self-report questionnaire investigating the use of digital devices by their children, and a standardized questionnaire for the assessment of language skills (MacArthur-Bates). Linear regression analysis was used to evaluate the relation between different variables. Subsequent moderation analysis were performed to verify the influence of other factors. Results: We found a statistically significant negative relation between the total daily time of exposure to digital devices and the Actions and Gestures Quotient (ß = -0.397) in children between 8 and 17 months, and between the total daily time of exposure to digital devices and Lexical Quotient (ß = -0.224) in children between 18 and 36 months. Gender, level of education/job of parents, modality of use/content of digital device did not significantly affect the result of the regression analysis. Conclusion: In our study we found that a longer time of exposure to digital devices was related to lower mimic-gestural skills in children from 8-17 months and to lower language skills in children between 18 and 36 months, regardless of age, gender, socio-economic status, content, and modality of use. Further studies are needed to confirm and better understand this relation, but parents and pediatricians are advised to limit the use of digital devices by children and encourage the social interaction to support the learning of language and communication skills in this age group.

Facial Emotion Recognition in Children and Adolescents with Specific Learning Disorder.

BACKGROUND: Some recent studies suggest that children and adolescents with different neurodevelopmental disorders perform worse in emotions recognition through facial expressions (ER) compared with typically developing peers. This impairment is also described in children with Specific Learning Disorders (SLD), compromising their scholastic achievement, social functioning, and quality of life. The purpose of our study is to evaluate ER skills in children and adolescents with SLD compared to a control group without learning disorders, and correlate them with intelligence and executive functions. MATERIALS AND METHODS: Our work is a cross-sectional observational study. Sixty-three children and adolescents aged between 8 and 16 years, diagnosed with SLD, and 32 sex/age-matched controls without learning disorders were recruited. All participants were administered standardized neuropsychological tests, evaluating facial emotion recognition (NEPSY-II), executive functions (EpiTrack Junior), and intelligence profile (WISC-IV). RESULTS: Emotion recognition mean score was significantly lower in the SLD group than in the controls group on the Mann-Whitney U test for unpaired samples (p < 0.001). The SLD group performed significantly lower than the control group in their abilities to identify neutral expressions, happiness, sadness, anger, and fear compared to controls (p < 0.001). ER scores were positively correlated to the executive functions scores. There was no correlation with the Total Intelligence Quotient scores but there is a significant positive correlation with Working Memory Index and Processing Speed Index measured by WISC.IV. CONCLUSION: Our study showed that children and adolescents with Specific Learning Disorders have facial emotion recognition impairment when compared with a group of peers without learning disorders. ER abilities were independent of their global intelligence but potentially related to executive functions.

Bisphenol A induces DNA damage in cells exerting immune surveillance functions at peripheral and central level.

Bisphenol A (BPA) is a synthetic xenoestrogen diffused worldwide. Humans are chronically exposed to low doses of BPA from food and drinks, thus BPA accumulates in tissues posing human health risk. In this study, we investigated the effects of BPA on peripheral blood mononuclear cells (PBMC) from human healthy donors, and in glia and microglia of rat offspring at postnatal day 17 (17PND) from pregnant females who received BPA soon after coupling and during lactation and weaning. Results indicated that BPA affected Phytoemagglutinin (PHA) stimulated PBMC proliferation causing an S-phase cell cycle accumulation at nanomolar concentrations while BPA was almost ineffective in resting PBMC. Furthermore, BPA induced chromosome aberrations and the appearance of shattered cells characterized by high number of fragmented and pulverized chromosomes, suggesting that the compound could cause a massive genomic rearrangement by inducing catastrophic events. The BPA-induced DNA damage was observed mainly in TCD4+ and TCD8+ subsets of T lymphocytes and was mediated by the increase of ERK1/2 phosphorylation, p21/Waf1 and PARP1 protein expression. Intriguingly, we observed for the first time that BPA-induced effects were associated to a sex specific modulation of ERα and ERß in human PBMC. Immunofluorescence analysis of rat hippocampus corroborated in vitro findings showing that BPA induced É£H2AX phosphorylation in microglia and astrocytosis by decreasing ERα expression within the dentate gyrus. Overall these results suggest that BPA can alter immune surveillance functions at both peripheral and central level with a potential risk for cancer, neuroinflammation and neurodegeneration.

The Epigenetics of the Endocannabinoid System.

The endocannabinoid system (ES) is a cell-signalling system widely distributed in biological tissues that includes endogenous ligands, receptors, and biosynthetic and hydrolysing machineries. The impairment of the ES has been associated to several pathological conditions like behavioural, neurological, or metabolic disorders and infertility, suggesting that the modulation of this system may be critical for the maintenance of health status and disease treatment. Lifestyle and environmental factors can exert long-term effects on gene expression without any change in the nucleotide sequence of DNA, affecting health maintenance and influencing both disease load and resistance. This potentially reversible "epigenetic" modulation of gene expression occurs through the chemical modification of DNA and histone protein tails or the specific production of regulatory non-coding RNA (ncRNA). Recent findings demonstrate the epigenetic modulation of the ES in biological tissues; in the same way, endocannabinoids, phytocannabinoids, and cannabinoid receptor agonists and antagonists induce widespread or gene-specific epigenetic changes with the possibility of trans-generational epigenetic inheritance in the offspring explained by the transmission of deregulated epigenetic marks in the gametes. Therefore, this review provides an update on the epigenetics of the ES, with particular attention on the emerging role in reproduction and fertility.

Perampanel tolerability in children and adolescents with focal epilepsy: Effects on behavior and executive functions.

OBJECTIVES: Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist recently approved for focal and generalized epilepsies as an add-on therapy. It is well tolerated and effective as treatment of various pediatric epilepsy syndromes; PER does not seem to negatively affect the cognitive profile of children and adolescents, but its influence on executive functions is still to be assessed. METHODS: Our sample included 37 children aged 12-18 years, with focal pharmacoresistant epilepsy already in therapy with 2 or 3 antiepileptic drug (AED); PER was added with 1 mg/week increments up to a dose of 2-4 mg/day. Changes in executive functions were assessed by the EpiTrack Junior test. Emotional and behavioral aspects were evaluated through the interview for parents Child Behavior Checklist (CBCL). Both tests were performed before taking PER and after 6 and 12 months of treatment. RESULTS: After 12 months of PER in 22/30 patients, global score of the EpiTrack Junior test remained almost unchanged; in 7/30 patients, this score improved. The CBCL did not show significant changes in emotional or behavioral problems. CONCLUSIONS: Adjunctive treatment with PER did not negatively affect executive functions that could also be improved. No emotional/behavioral negative effects have been reported, and this suggests a good tolerability in the middle/long term.