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Background: SARS-CoV-2 is the coronavirus responsible for the COVID-19 pandemic. Even though we are no longer in a pandemic situation, people are still getting infected, some of them need hospitalization and a few of them die. Methods: We conducted a retrospective study including 445 patients who accessed the Emergency Section of Policlinico Umberto I, Rome, Italy, where they had routine blood exams. In this study, we focused on the complete blood count, serum creatinine and azotemia. The data were analyzed using ANOVA, Spearman correlation and ROC analyses. They were divided into four groups based on their clinical outcomes: (1) the emergency group (patients who had mild forms and were quickly discharged); (2) the hospital ward group (patients who were admitted to the emergency section and were then hospitalized in a COVID-19 ward); (3) the intensive care unit (ICU) group (patients who required intensive assistance after the admission in the emergency section); (4) the deceased group (patients who had a fatal outcome after admission to the emergency section). Results: We found significant changes for creatinine, azotemia, hematocrit, mean corpuscular hemoglobin concentration, basophils, monocytes, red blood cell distribution width, hemoglobin, hematocrit and red blood cell numbers using ANOVA according to their clinical outcomes, particularly for the deceased group. Also, we found linear correlations of clinical outcomes with eosinophils, hemoglobin, hematocrit, mean corpuscular hemoglobin concentration, lymphocyte, neutrophil, platelet and red blood cell number and red blood cell distribution width. Conclusions: This study discloses an early association between “classical” routine blood biomarkers and the severity of clinical outcomes in Omicron patients.

Nerve growth factor (NGF) plays a dual role both in inflammatory states and cancer, acting both as a pro-inflammatory and oncogenic factor and as an anti-inflammatory and pro-apoptotic mediator in a context-dependent way based on the signaling networks and its interaction with diverse cellular components within the microenvironment. This report aims to provide a summary and subsequent review of the literature on the role of NGF in regulating the inflammatory microenvironment and tumor cell growth, survival, and death. The role of NGF in inflammation and tumorigenesis as a component of the inflammatory system, its interaction with the various components of the respective microenvironments, its ability to cause epigenetic changes, and its role in the treatment of cancer have been highlighted in this paper.

NGF plays a crucial immunomodulatory role and increased levels are found in numerous tissues during autoimmune states. NGF directly modulates innate and adaptive immune responses of B and T cells and causes the release of neuropeptides and neurotransmitters controlling the immune system activation in inflamed tissues. Evidence suggests that NGF is involved in the pathogenesis of numerous immune diseases including autoimmune thyroiditis, chronic arthritis, multiple sclerosis, systemic lupus erythematosus, mastocytosis, and chronic granulomatous disease. Furthermore, as NGF levels have been linked to disease severity, it could be considered an optimal early biomarker to identify therapeutic approach efficacy. In conclusion, by gaining insights into how these molecules function and which cells they interact with, future studies can devise targeted therapies to address various neurological, immunological, and other disorders more effectively. This knowledge may pave the way for innovative treatments based on NGF manipulation aimed at improving the quality of life for individuals affected by diseases involving neurotrophins.

Pediatric acute-onset neuropsychiatric syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), represent an overlapping group of disorders which is characterized by acute-onset obsessive compulsive disorders, eating restriction, tics, cognitive and behavioral deterioration which typically follows a relapsing-remitting course but some patients have a primary or secondary persistent progress. This condition is likely caused by heterogeneous inflammatory mechanisms (autoantibodies, complement activation, pro-inflammatory cytokine production) involving the basal ganglia as evidenced by imaging studies (patients vs. controls), sleep studies that found movements and/or atonia during REM sleep, and neurological soft signs that go along with basal ganglia dysfunction. The condition causes significant psychiatric and behavioral symptoms, caregiver burden and sleep abnormalities. Autoantibodies resulting from molecular mimicry of infectious agents (namely group A Streptococcus) and neuronal autoantigens that map to the basal ganglia play also a subtle role. This narrative review aims to describe the key immunological features documented thus far and that likely play a role in the pathogenesis and clinical manifestations of this disorder.

Abstract Gender dysphoria is a clinical condition characterized by significant distress due to the discordance between biological sex and gender identity. Currently, gender dysphoria is also found more frequently in children and adolescents, thanks to greater social sensibleness and new therapeutic possibilities. In fact, it is estimated that the prevalence of gender dysphoria in pediatric age is between 0.5% and 2% based on the statistics of the various countries. Therefore, the pediatrician cannot fail to update himself on these issues and above all should be the reference figure in the management of these patients. Even if the patient must be directed to a referral center and be followed up by a multidisciplinary team, the treating pediatrician will care to coordinate the clinical and therapeutic framework. The aim of the present report is therefore to integrate literature data with our clinical experience to propose a new clinical approach in which the pediatrician should be the reference in the care of these patients, directing them towards the best therapeutic approach and staying in contact with the specialists of the referral center.

Klinefelter syndrome (KS), characterized by an additional X-chromosome in males, manifests in a wide range of neuroendocrine and psychiatric symptoms. Individuals with KS often face increased risks of hormonal dysfunction, leading to depression and anxiety, although extended research during pediatric and adolescent age is still limited. This critical phase, decisive for KS children, is influenced by a combination of genetic, environmental and familial factors, which impact brain plasticity. In this report, we reviewed, in a narrative form, the crucial KS psychopathological hallmarks in children. To better describe neuroendocrine and neuropsychiatric outcomes in children with KS, we presented the case of an 11-year-old prepubertal child with mosaic KS who was referred to our Center of Developmental Psychopathology due to a decline in his academic performance, excessive daytime fatigue and increased distractibility over the past few months. Family history revealed psychiatric conditions among first- and second-degree relatives, including recently divorced parents and a 15-year-old sister. Early-onset persistent depressive disorder and anxious traits were diagnosed. Timely identification of susceptible children, with thorough examination of familial psychiatric history, environmental influences and neurocognitive profile, alongside targeted interventions, could potentially mitigate lifelong psychopathology-related disabilities in pediatric and adolescent KS cases, including those with mosaic KS.

Fetal alcohol spectrum disorders (FASD) represent a continuum of lifelong impairments resulting from prenatal exposure to alcohol, with significant global impact. The “spectrum” of disorders includes a continuum of physical, cognitive, behavioral, and developmental impairments which can have profound and lasting effects on individuals throughout their lives, impacting their health, social interactions, psychological well-being, and every aspect of their lives. This narrative paper explores the intricate relationship between oxidative stress and epigenetics in FASD pathogenesis and its therapeutic implications. Oxidative stress, induced by alcohol metabolism, disrupts cellular components, particularly in the vulnerable fetal brain, leading to aberrant development. Furthermore, oxidative stress is implicated in epigenetic changes, including alterations in DNA methylation, histone modifications, and microRNA expression, which influence gene regulation in FASD patients. Moreover, mitochondrial dysfunction and neuroinflammation contribute to epigenetic changes associated with FASD. Understanding these mechanisms holds promise for targeted therapeutic interventions. This includes antioxidant supplementation and lifestyle modifications to mitigate FASD-related impairments. While preclinical studies show promise, further clinical trials are needed to validate these interventions’ efficacy in improving clinical outcomes for individuals affected by FASD. This comprehensive understanding of the role of oxidative stress in epigenetics in FASD underscores the importance of multidisciplinary approaches for diagnosis, management, and prevention strategies. Continued research in this field is crucial for advancing our knowledge and developing effective interventions to address this significant public health concern.

Kabuki syndrome (KS) is a rare multisystemic disease due to mutations in the KMT2D or KDM6A genes, which act as epigenetic modulators of different processes, including immune response. The syndrome is characterized by anomalies in multiple organ systems, and it is associated with autoimmune and inflammatory disorders, and an underlying immunological phenotype characterized by immunodeficiency and immune dysregulation. Up to 17% of KS patients present with immune thrombocytopenia characterized by a severe, chronic or relapsing course, and often associated to other hematological autoimmune diseases including autoimmune hemolytic anemia, eventually resulting in Evans syndrome (ES). A 23-year-old woman, clinically diagnosed with KS and presenting from the age of 3 years with ES was referred to the Rare Diseases Centre of our Pediatric Department for corticosteroid-induced hyperglycemia. Several ES relapses and recurrent respiratory infections in the previous years were reported. Severe hypogammaglobulinemia, splenomegaly and signs of chronic lung inflammation were diagnosed only at the time of our observation. Supportive treatment with amoxicillin-clavulanate prophylaxis and recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin replacement were immediately started. In KS patients, the failure of B-cell development and the lack of autoreactive immune cells suppression can lead to immunodeficiency and autoimmunity that may be undiagnosed for a long time. Our patient's case is paradigmatic since she presented with preventable morbidity and severe lung disease years after disease onset. This case emphasizes the importance of suspecting immune dysregulation in KS. Pathogenesis and immunological complications of KS are discussed. Moreover, the need to perform immunologic evaluations is highlighted both at the time of KS diagnosis and during disease follow-up, in order to allow proper treatment while intercepting avoidable morbidity in these patients.

Klinefelter syndrome (KS) is a male genetic disease caused by the presence of an extra X chromosome, causing endocrine disorders mainly responsible for a high rate of infertility and metabolic disorders in adulthood. Scientific research is interested in identifying new biomarkers that can be predictive or prognostic of alterations strictly connected to KS. Lipocalin-2 (LCN-2, also known as NGAL) is a small protein initially identified within neutrophils as a protein related to innate immunity. Serum LCN-2 estimation seems to be a useful tool in predicting the metabolic complications caused by several pathological conditions. However, little is known about its potential role in infertility conditions. The present pilot study aims to investigate the presence of LCN-2 in the serum of a group of pre-pubertal and post-pubertal children affected by KS, compared to healthy controls. We demonstrated for the first time the presence of elevated levels of LCN-2 in the serum of KS patients, compared to controls. This increase was accompanied, in pre-pubertal KS patients, by the loss of correlation with LH and HDL, which instead was present in the healthy individuals. Moreover, in all KS individuals, a positive correlation between LCN-2 and inhibin B serum concentration was found. Despite the limited size of the sample analyzed, our preliminary data encourage further studies to confirm the findings and to extend the study to KS adult patients, to verify the predictive/prognostic value of LCN-2 as new biomarker for metabolic diseases and infertility associated with the pathology.

Abstract Background COVID toes or chilblain-like skin lesions have been widely reported during COVID-19 pandemic. Most cases were described in patients with negative microbiological tests for SARS-CoV-2, therefore the possible relationship with SARS-CoV-2 infection, as well as with the nowadays broadly available mRNA-based vaccination, has not been fully elucidated. Case presentation We here describe the case of a 14-year-old male who developed chilblain-like skin eruptions during SARS-CoV-2 infection despite two mRNA-based vaccine doses and review the clinical and epidemiological characteristics of chilblain-like lesions as a cutaneous presentation of COVID-19 in children. Conclusions Most children and adolescent with COVID toes have a mild or asymptomatic SARS-CoV-2 infection. Our report aims to highlight the possible onset of these skin lesions in vaccinated children, if infection has occurred, and the potential use of systemic corticosteroids as a first line treatment. Additional evidence is required to better understand SARS-CoV-2 infection and cutaneous manifestations in children and determine the relationship between chilblain-like lesions and COVID-19 vaccination.

Puberty identifies the transition from childhood to adulthood. Precocious puberty is the onset of signs of pubertal development before age eight in girls and before age nine in boys, it has an incidence of 1/5000–1/10,000 with an F:M ratio ranging from 3:1 to 20:1. Precocious puberty can be divided into central, also known as gonadotropin-dependent precocious puberty or true precocious puberty, and peripheral, also recognized as gonadotropin-independent precocious puberty or precocious pseudopuberty. Thus, the main aim of this narrative report is to describe the standard clinical management and therapy of precocious puberty according to the experience and expertise of pediatricians and pediatric endocrinologists at Policlinico Umberto I, Sapienza University of Rome, Italy. In the suspicion of early sexual maturation, it is important to collect information regarding the age of onset, the speed of maturation of secondary sexual features, exposure to exogenous sex steroids and the presence of neurological symptoms. The objective examination, in addition to the evaluation of secondary sexual characteristics, must also include the evaluation of auxological parameters. Initial laboratory investigations should include serum gonadotropin levels (LH and FSH) and serum levels of the sex steroids. Brain MRI should be performed as indicated by the 2009 Consensus Statement in all boys regardless of chronological age and in all girls with onset of pubertal signs before 6 years of age. The gold standard in the treatment of central precocious puberty is represented by GnRH analogs, whereas, as far as peripheral forms are concerned, the triggering cause must be identified and treated. At the moment there are no reliable data establishing the criteria for discontinuation of GnRH analog therapy. However, numerous pieces of evidence suggest that the therapy should be suspended at the physiological age at which puberty occurs.

Fetal alcohol spectrum disorder (FASD) is a set of conditions resulting from prenatal alcohol exposure (PAE). FASD is estimated to affect between 2% and 5% of people in the United States and Western Europe. The exact teratogenic mechanism of alcohol on fetal development is still unclear. Ethanol (EtOH) contributes to the malfunctioning of the neurological system in children exposed in utero by decreasing glutathione peroxidase action, with an increase in the production of reactive oxygen species (ROS), which causes oxidative stress. We report a case of a mother with declared alcohol abuse and cigarette smoking during pregnancy. By analyzing the ethyl glucuronide (EtG, a metabolite of alcohol) and the nicotine/cotinine in the mother’s hair and meconium, we confirmed the alcohol and smoking abuse magnitude. We also found that the mother during pregnancy was a cocaine abuser. As a result, her newborn was diagnosed with fetal alcohol syndrome (FAS). At the time of the delivery, the mother, but not the newborn, had an elevation in oxidative stress. However, the infant, a few days later, displayed marked potentiation in oxidative stress. The clinical complexity of the events involving the infant was presented and discussed, underlining also the importance that for cases of FASD, it is crucial to have more intensive hospital monitoring and controls during the initial days.

Alcohol consumption is associated with oxidative stress and an increased risk of carcinoma of the upper aero-digestive tract (UADT). Recently, it has been found that some microorganisms in the human oral cavity may locally metabolize ethanol, forming acetaldehyde, a carcinogenic metabolite of alcohol. In a cohort of patients first visited for UADT cancers, we estimated their alcohol consumption by measuring Ethyl Glucuronide/EtG (a long-lasting metabolite of ethanol) in the hair and carbohydrate-deficient transferrin/CDT (short-term index of alcohol intake) in the serum. Moreover, we analyzed, by culture-based methods, the presence of Neisseria subflava, Streptococcus mitis, Candida albicans, and glabrata (microorganisms generating acetaldehyde) in the oral cavity. According to the EtG values, we correlated drinking alcohol with endogenous oxidative stress and the investigated microorganism’s presence. We found that 55% of heavy drinkers presented microorganisms generating acetaldehyde locally. Moreover, we found that the presence of oral acetaldehyde-producing bacteria correlates with increased oxidative stress compared to patients without such bacteria. As for the study of alcohol dehydrogenase gene polymorphisms (the enzyme that transforms alcohol to acetaldehyde), we found that only the “CGTCGTCCC” haplotype was more frequent in the general population than in carcinoma patients. This pilot study suggests the importance of estimating alcohol consumption (EtG), the presence of bacteria producing acetaldehyde, and oxidative stress as risk factors for the onset of oral carcinomas.

Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which confers specificity of biological action by interacting with its surface receptor (FSHR), predominantly located in granulosa and Sertoli cells. However, FSHRs also exist in extra-gonadal tissues, indicating potential effects beyond male fertility. Emerging evidence suggests that FSH may have extra-gonadal effects, including on bone metabolism, where it appears to stimulate bone resorption by binding to specific receptors on osteoclasts. Additionally, higher FSH levels have been associated with worse metabolic and cardiovascular outcomes, suggesting a possible impact on the cardiovascular system. FSH has also been implicated in immune response modulation, as FSHRs are expressed on immune cells and may influence inflammatory response. Furthermore, there is growing interest in the role of FSH in prostate cancer progression. This paper aims to provide a comprehensive analysis of the literature on the extra-gonadal effects of FSH in men, with a focus on the often-conflicting results reported in this field. Despite the contradictory findings, the potential for future development in this area is substantial, and further research is needed to elucidate the mechanisms underlying these effects and their clinical implications.

Background: Since its outbreak, Coronavirus disease 2019 (COVID-19), a life-threatening respiratory illness, has rapidly become a public health emergency with a devastating social impact. Lately, the Omicron strain is considered the main variant of concern. Routine blood biomarkers are, indeed, essential for stratifying patients at risk of severe outcomes, and a huge amount of data is available in the literature, mainly for the previous variants. However, only a few studies are available on early routine biochemical blood biomarkers for Omicron-afflicted patients. Thus, the aim and novelty of this study were to identify routine blood biomarkers detected at the emergency room for the early prediction of severe morbidity and/or mortality. Methods: 449 COVID-19 patients from Sapienza University Hospital of Rome were divided into four groups: (1) the emergency group (patients with mild forms who were quickly discharged); (2) the hospital ward group (patients that after the admission in the emergency department were hospitalized in a COVID-19 ward); (3) the intensive care unit (ICU) group (patients that after the admission in the emergency department required intensive assistance); (4) the deceased group (patients that after the admission in the emergency department had a fatal outcome). Results: ANOVA and ROC data showed that high-sensitivity troponin-T (TnT), fibrinogen, glycemia, C-reactive protein, lactate dehydrogenase, albumin, D-dimer myoglobin, and ferritin for both men and women may predict lethal outcomes already at the level of the emergency department. Conclusions: Compared to previous Delta COVID-19 parallel emergency patterns of prediction, Omicron-induced changes in TnT may be considered other early predictors of severe outcomes.

Autoimmune polyendocrine syndromes (APSs) encompass a heterogeneous group of rare diseases characterized by autoimmune activity against two or more endocrine or non-endocrine organs. Three types of APSs are reported, including both monogenic and multifactorial, heterogeneous disorders. The aim of this manuscript is to present the main clinical and epidemiological characteristics of APS-1, APS-2, and IPEX syndrome in the pediatric age, describing the mechanisms of autoimmunity and the currently available treatments for these rare conditions.

Abstract Background Poland syndrome (OMIM: 173800) is a disorder in which affected individuals are born with missing or underdeveloped muscles on one side of the body, resulting in abnormalities that can affect the chest, breast, shoulder, arm, and hand. The extent and severity of the abnormalities vary among affected individuals. Main body The aim of this work is to provide recommendations for the diagnosis and management of people affected by Poland syndrome based on evidence from literature and experience of health professionals from different medical backgrounds who have followed for several years affected subjects. The literature search was performed in the second half of 2019. Original papers, meta-analyses, reviews, books and guidelines were reviewed and final recommendations were reached by consensus. Conclusion Being Poland syndrome a rare syndrome most recommendations here presented are good clinical practice based on the consensus of the participant experts.

Abstract Background Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children. Results In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. Conclusions These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.

DiGeorge syndrome (DGS) is a rare genetic disease caused by microdeletions of the 22q11.2 region (DGS1). A haploinsufficiency at 10p level has been proposed also as a DGS cause (DGS2). Clinical manifestations are variable. The most frequent features are thymic hypoplasia or aplasia with consequent immune deficiency, cardiac malformations, hypoparathyroidism, facial and palatine abnormalities, variable degrees of cognitive impairment and psychiatric disorders. The specific aim of this descriptive report is to discuss the correlation between oxidative stress and neuroinflammation in DGS patients with microdeletions of the 22q11.2 region. The deleted chromosomic region maps various genes involved in mitochondrial metabolisms, such as DGCR8 and TXNRD2, that could lead to reactive oxygen species (ROS) increased production and antioxidant depletion. Furthermore, increased levels of ROS in mitochondria would lead to the destruction of the projection neurons in the cerebral cortex with consequent neurocognitive impairment. Finally, the increase in modified protein belonging to the family of sulfoxide compounds and hexoses, acting as inhibitors of the IV and V mitochondria complex, could result in direct ROS overproduction. Neuroinflammation in DGS individuals could be directly related to the development of the syndrome’s characteristic psychiatric and cognitive disorders. In patients with psychotic disorders, the most frequent psychiatric manifestation in DGS, Th-17, Th-1 and Th-2 cells are increased with consequent elevation of proinflammatory cytokine IL-6 and IL1β. In patients with anxiety disorders, both CD3 and CD4 are increased. Some patients with autism spectrum disorders (ASDs) have an augmented level of proinflammatory cytokines IL-12, IL-6 and IL-1β, while IFNγ and the anti-inflammatory cytokine IL-10 seem to be reduced. Other data proposed that altered synaptic plasticity could be directly involved in DGS cognitive disorders. In conclusion, the use of antioxidants for restoring mitochondrial functionality in DGS could be a useful tool to protect cortical connectivity and cognitive behavior.

Both physiological and pathological aging processes induce brain alterations especially affecting the speed of processing, working memory, conceptual reasoning and executive functions. Many therapeutic approaches to reduce the impact of brain aging on cognitive functioning have been tested; unfortunately, there are no satisfactory results as a single therapy. As aging is partly contributed by free radical reactions, it has been proposed that exogenous antioxidants could have a positive impact on both aging and its associated manifestations. The aim of this report is to provide a summary and a subsequent review of the literature evidence on the role of antioxidants in preventing and improving cognition in the aging brain. Manipulation of endogenous cellular defense mechanisms through nutritional antioxidants or pharmacological compounds represents an innovative approach to therapeutic intervention in diseases causing brain tissue damage, such as neurodegeneration. Coherently with this notion, antioxidants, especially those derived from the Mediterranean diet such as hydroxytyrosol and resveratrol, seem to be able to delay and modulate the cognitive brain aging processes and decrease the occurrence of its effects on the brain. The potential preventive activity of antioxidants should be evaluated in long-term exposure clinical trials, using preparations with high bioavailability, able to bypass the blood-brain barrier limitation, and that are well standardized.

Infertility is a worldwide health issue defined by the World Health Organization (WHO) as the inability to establish a pregnancy after 12 months or more of regular and unprotected sexual intercourse. Male infertility etiology can be related to either congenital or acquired factors. The therapeutical approach to male infertility depends on the underlying causes and includes medical and surgical treatments. In recent studies, the potential role of nerve growth factor (NGF) in male reproductive physiology has been proposed. It has been hypothesized that neurotrophins might be involved in testis morphogenesis and regulation of several aspects of spermatogenesis. Moreover, it has been shown that NGF exerts its role on gonadotropin-releasing hormone (GnRH) neurons through the activation of the PKC/p–ERK1/2/p–CREB cascade, which leads to the activation of hypothalamic cells and the consequent activation of hypothalamus–pituitary–gonadal axis (HPG) with the secretion of GnRH. Lastly, it has been shown that the physiology of mature sperm is affected by both exogenous and endogenous NGF. The NGF impact on the HPG axis and its effect on GnRH neurons might be exploited in the therapy of male hypogonadism or used as a protective strategy against gonadal dysfunction related to chemotherapeutic agents. Moreover, the improving effect of NGF on sperm motility and vitality could be useful to enhance assisted reproduction outcomes. NGF could be supplemented to cryopreserved sperm samples to counteract the oxidative stress induced by the frozen and thawing processes. Indeed, the potential clinical applications of NGF in male infertility treatment have been discussed.

Oxidative stress is a condition determined by an imbalance between antioxidant and oxidative factors. Oxidative stress can have serious consequences on our organism. Indeed, it causes both necrosis and cell apoptosis, determining cellular aging, increased carcinogenesis, vascular stiffening, increased autoimmune diseases, and muscle decay. In the context of pediatric syndromes, oxidative stress could play a role in the first order. In fact, our review of the literature showed that in some pathologies, such as fetal alcohol spectrum disorders, oxidative stress related to the intake of ethanol during pregnancy is a main etiological factor determining the associated clinical syndrome. On the contrary, in Williams syndrome, Down syndrome, Marfan syndrome, Gaucher syndrome, ataxia-telangiectasia, autistic spectrum disorder, Fanconi’s anemia, and primitive immunodeficiencies, the increase in oxidative stress is directly associated with the genetic alterations that cause the same pathologies. Although further studies are needed to better understand the relationship between oxidative stress and pediatric diseases, a better knowledge of this crucial issue encourages future therapeutic strategies.

Male infertility represents about 50% of the causes of infertility in couples. The diagnosis process represents an important procedure for defining, when possible, the causes and approaching treatments (pharmacological, surgical) aimed at overcoming the problem. Several scientific studies have set out to discover early and indicative markers capable of providing information on the biological origin of infertility and increase current knowledge in the context of new potential therapeutic approaches. The prokineticin system (PROK) consists of the prokineticin 1 (PROK1) and prokineticin 2 (PROK2) proteins. Through the activation of two G-protein receptors (PROKR1 and PROKR2) regulate a wide range of biological functions, including gastrointestinal motility, circadian rhythm regulation, neurogenesis, angiogenesis, pain perception, and mood regulation. Several studies have highlighted the crucial role of the PROK system in the development and maturation of both male and female human reproductive organs. Particularly in men, the PROK system represents a new system useful to clarify some aspects of testicular pathophysiology and provide new potential hypotheses for therapeutic intervention. This narrative review aims to illustrate the state of the art regarding, in particular, the role of PROK2 in male infertility.

COVID-19 (COronaVIrus Disease 19) is an infectious disease also known as an acute respiratory syndrome caused by the SARS-CoV-2. Although in children and adolescents SARS-CoV-2 infection produces mostly mild or moderate symptoms, in a certain percentage of recovered young people a condition of malaise, defined as long-COVID-19, remains. To date, the risk factors for the development of long-COVID-19 are not completely elucidated. Neurotrophins such as NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor) are known to regulate not only neuronal growth, survival and plasticity, but also to influence cardiovascular, immune, and endocrine systems in physiological and/or pathological conditions; to date only a few papers have discussed their potential role in COVID-19. In the present pilot study, we aimed to identify NGF and BDNF changes in the serum of a small cohort of male and female adolescents that contracted the infection during the second wave of the pandemic (between September and October 2020), notably in the absence of available vaccines. Blood withdrawal was carried out when the recruited adolescents tested negative for the SARS-CoV-2 (“post-infected COVID-19”), 30 to 35 days after the last molecular test. According to their COVID-19 related outcomes, the recruited individuals were divided into three groups: asymptomatics, acute symptomatics and symptomatics that over time developed long-COVID-19 symptoms (“future long-COVID-19”). As a control group, we analyzed the serum of age-matched healthy controls that did not contract the infection. Inflammatory biomarkers (TNF-α, TGF-β), MCP-1, IL-1α, IL-2, IL-6, IL-10, IL-12) were also analyzed with the free oxygen radicals’ presence as an oxidative stress index. We showed that NGF serum content was lower in post-infected-COVID-19 individuals when compared to healthy controls; BDNF levels were found to be higher compared to healthy individuals only in post-infected-COVID-19 symptomatic and future long-COVID-19 girls, leaving the BDNF levels unchanged in asymptomatic individuals if compared to controls. Oxidative stress and inflammatory biomarkers were unchanged in male and female adolescents, except for TGF-β that, similarly to BDNF, was higher in post-infected-COVID-19 symptomatic and future long-COVID-19 girls. We predicted that NGF and/or BDNF could be used as early biomarkers of COVID-19 morbidity in adolescents.

Polyphenols are antioxidants contained in plants as olive and grape. As part of the Mediterranean diet, they may decrease the risk of cancer, of chronic and neurodegenerative diseases. Alcohol consumption plays a detrimental effect on health, causing tissue damage and disrupting the metabolism of Neurotrophins (NTs). NTs are crucial proteins for the life cycle of neuronal and non-neuronal cells. Alcohol abuse elicits changes in NTs levels in the brain and in other target organs, however, it was observed minor damage in animals early exposed to red wine, probably due to the antioxidant effects of polyphenols. Indeed, data show that resveratrol or other polyphenols extracted from the olive can effectively counteract serum free radicals’ formation caused by chronic alcohol intake, contrasting also alcohol-induced NTs liver elevation. The aim of the present review is to update pieces of evidences about the antioxidant properties of polyphenols and their role in counteracting alcohol-induced damage.

Down Syndrome (DS) is the most common chromosomal disorder. Although DS individuals are mostly perceived as characterized by some distinct physical features, cognitive disabilities, and cardiac defects, they also show important dysregulations of immune functions. While critical information is available for adults with DS, little literature is available on the neuroinflammation in prepubertal DS children. We aimed to evaluate in prepubertal DS children the serum levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), oxidative stress as free oxygen radicals defense (FORD), free oxygen radicals test (FORT), and cytokines playing key roles in neuroinflammation and oxidative processes as TNF-α, TGF-β, MCP-1, IL-1α, IL-2, IL-6, IL-10, and IL-12. No differences were found in NGF between DS children and controls. However, BDNF was higher in DS subjects compared to controls. We also did not reveal changes in FORD and FORT. Quite interestingly, the serum of DS children disclosed a marked decrease in all analyzed cytokines with evident differences in serum cytokine presence between male and female DS children. In conclusion, the present study evidences in DS prepubertal children a disruption in the neurotrophins and immune system pathways.

Head and neck cancer (HNC) concerns more than 890,000 patients worldwide annually and is associated with the advanced stage at presentation and heavy outcomes. Alcohol drinking, together with tobacco smoking, and human papillomavirus infection are the main recognized risk factors. The tumorigenesis of HNC represents an intricate sequential process that implicates a gradual acquisition of genetic and epigenetics alterations targeting crucial pathways regulating cell growth, motility, and stromal interactions. Tumor microenvironment and growth factors also play a major role in HNC. Alcohol toxicity is caused both directly by ethanol and indirectly by its metabolic products, with the involvement of the oral microbiota and oxidative stress; alcohol might enhance the exposure of epithelial cells to carcinogens, causing epigenetic modifications, DNA damage, and inaccurate DNA repair with the formation of DNA adducts. Long-term markers of alcohol consumption, especially those detected in the hair, may provide crucial information on the real alcohol drinking of HNC patients. Strategies for prevention could include food supplements as polyphenols, and alkylating drugs as therapy that play a key role in HNC management. Indeed, polyphenols throughout their antioxidant and anti-inflammatory actions may counteract or limit the toxic effect of alcohol whereas alkylating agents inhibiting cancer cells’ growth could reduce the carcinogenic damage induced by alcohol. Despite the established association between alcohol and HNC, a concerning pattern of alcohol consumption in survivors of HNC has been shown. It is of primary importance to increase the awareness of cancer risks associated with alcohol consumption, both in oncologic patients and the general population, to provide advice for reducing HNC prevalence and complications.

Background. COVID-19 is a severe acute respiratory disease caused by SARS-CoV-2, a virus belonging to the Coronaviridae family. This disease has spread rapidly around the world and soon became an international public health emergency leading to an unpredicted pressure on the hospital emergency units. Early routine blood biomarkers could be key predicting factors of COVID-19 morbidity and mortality as suggested for C-reactive protein (CRP), IL-6, prothrombin and D-dimer. This study aims to identify other early routine blood biomarkers for COVID-19 severity prediction disclosed directly into the emergency section. Methods. Our research was conducted on 156 COVID-19 patients hospitalized at the Sapienza University Hospital “Policlinico Umberto I” of Rome, Italy, between March 2020 and April 2020 during the paroxysm’s initial phase of the pandemic. In this retrospective study, patients were divided into three groups according to their outcome: (1) emergency group (patients who entered the emergency room and were discharged shortly after because they did not show severe symptoms); (2) intensive care unit (ICU) group (patients who attended the ICU after admission to the emergency unit); (3) the deceased group (patients with a fatal outcome who attended the emergency and, afterward, the ICU units). Routine laboratory tests from medical records were collected when patients were admitted to the emergency unit. We focused on Aspartate transaminase (AST), Alanine transaminase (ALT), Lactate dehydrogenase (LDH), Creatine kinase (CK), Myoglobin (MGB), Ferritin, CRP, and D-dimer. Results. As expected, ANOVA data show an age morbidity increase in both ICU and deceased groups compared with the emergency group. A main effect of morbidity was revealed by ANOVA for all the analyzed parameters with an elevation between the emergency group and the deceased group. Furthermore, a significant increase in LDH, Ferritin, CRP, and D-dimer was also observed between the ICU group and the emergency group and between the deceased group and ICU group. Receiver operating characteristic (ROC) analyses confirmed and extended these findings. Conclusions. This study suggests that the contemporaneous presence of high levels of LDH, Ferritin, and as expected, CRP, and D-dimer could be considered as potential predictors of COVID-19 severity and death.

BACKGROUND: Polyphenols from olive are known to possess antioxidant and anti-inflammatory properties. AIM: The aim of this study was to study whether or not 10 consecutive days i.p. administration of a blend of olive (Olea europaea L.) polyphenols (10 mg/kg) containing mostly hydroxytyrosol could have an effect on cytokines playing important roles in inflammatory processes as TNF-α and IL-10. MATERIALS AND METHODS: Inflammation was induced in the mouse paw by 2 carrageenan injections (50 5l vol, 5 mg/kg each). TNF-α and IL-10 were measured by enzyme-linked immunosorbent assay. RESULTS: Carrageenan decreased IL-10 in the paws, however, this reduction appeared to be less evident in mice treated with carrageenan but administered with polyphenols. As for TNF-α, our findings did not reveal differences between groups but an increase in the polyphenol and carrageenan group if compared to the carrageenan only group. As for antioxidant polyphenols' properties, no differences between groups in the serum glutathione were found. CONCLUSIONS: Altogether, this investigation shows that olive polyphenols in the mouse may modulate the levels of cytokines having a role in the process of inflammation as TNF-α and IL-10.

In this study we explored metaphor and idiom competencies in two clinical populations, children with autistic spectrum disorder (ASD) and children with Klinefelter syndrome (KS), (age range: 9–12), compared to typically developing (TD) children of the same age. These three groups were tested with two multiple-choice tests assessing idiom comprehension through iconic and verbal alternatives and a metaphor comprehension test composed of novel, physical-psychological metaphors, requesting verbal explanations. To these instruments, another test was added, assessing basic sentence comprehension. Performances on the different linguistic tasks were examined by means of discriminant analysis which showed that idiom comprehension had a very small weight in distinguishing children with ASD from TD controls, whereas metaphor explanation did distinguish them. This study suggests that figurative language comprehension is not a “core deficit” per se in individuals with ASD. Only when the task requires to explicitly construct and explain a semantic mapping between the two terms of a metaphor does the performance of children with ASD significantly deviate from the typical population. These results are interpreted in terms of a difficulty in children with ASD and KS with complex cognitive and linguistic processes and also in relation with clinical assessment.

Literature on children with Klinefelter Syndrome (KS) points to general linguistic difficulties in both comprehension and production among other cognitive functions, and in the majority of cases, these coexist with an intellectual level within the norms. In these conditions, children having language delay generally engage in language therapy and are systematically monitored across ages. In this article, we present the profiles of two children with KS (47, XXY), aged 9.1 (Child S) and 13 (Child D), whose language development was assessed as adequate at age 3, and for this reason, did not receive any language treatment. At the present stage, their IQ, as measured by Wechsler Scales (Child S: 92; Child D: 101), is within the norm, but they both present marked weaknesses in pragmatic skills such as figurative language comprehension. The analysis of these two cases points to the need to go beyond global indexes of verbal abilities, as the same global index may mask a wide diversification of individual profiles. In addition, this study underlines the importance of monitoring the developmental trajectories of children like Child D and Child S, because weaknesses in pragmatic skills that are relevant for both academic achievement and social adaptation could emerge at later stages.

Chiari type I malformation (CMI) is a congenital hindbrain anomaly characterized by downward displacement of the cerebellar tonsils through the foramen magnum. Chiari type I malformation often presents with a complex clinical picture and can be sporadic or linked to a variety of genetic conditions. We report on a girl in whom Chiari type I malformation was associated with hypoglycemia, headache, vertigo, syncope and hepatic steatosis. We hypothesize that these symptoms are primarily a consequence of Chiari type I malformation.