Molecular mechanisms of oxidative stress-related neonatal jaundice.

Oxidative stress is a pathological condition characterized by an overload of oxidant products, named free radicals, which are not well counteracted by antioxidant systems. Free radicals induce oxidative damage to many body organs and systems. In neonatal red blood cells, free-radical mediated-oxidative stress leads to eryptosis, a suicidal death process of erythrocytes consequent to alteration of cell integrity. Neonatal red blood cells are targets and at the same time generators of free radicals through the Fenton and Haber-Weiss reactions. Enhanced eryptosis in case of oxidative stress damage may cause anemia if the increased loss of erythrocytes is not enough compensated by enhanced new erythrocytes synthesis. The oxidative disruption of the red cells may cause unconjugated idiopathic hyperbilirubinemia in neonates. High levels of bilirubin are recognized to be dangerous for the central nervous system in newborns, however, many studies have highlighted the antioxidant function of bilirubin. Recently, it has been suggested that physiologic concentration of bilirubin correlates with higher antioxidant status while high pathological bilirubin levels are associated with pro-oxidants effects. The aim of this educational review is to provide an updated understanding of the molecular mechanisms underlying erythrocyte oxidant injury and its reversal in neonatal idiopathic hyperbilirubinemia.

Melatonin Administration from 2000 to 2020 to Human Newborns with Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is the main cause of long-term neurodevelopmental morbidity in term born infants worldwide. Melatonin is a hormone with antioxidant and anti-inflammatory effects that make it a promising molecule for the treatment of perinatal asphyxia. Probably, the synergistic use of hypothermia associated with melatonin treatment may improve the neurological outcome in infants with HIE. In the past 20 years, the efficacy of melatonin in reducing oxidative stress has been demonstrated in animals; however, clinical trials with sufficient sample size of newborns are lacking to date. Since in 2000 we were among the first to study the neuroprotective properties of melatonin on infants, in this review, we want to summarize the advantages and limitations of the investigations conducted to date. KEY POINTS: · HIE is the main cause of morbidity in term born infants worldwide.. · Melatonin is a promising molecule for the treatment of perinatal asphyxia.. · This review summarizes advantages and limitations of the investigations conducted on melatonin..

Pediatric Multisystem Syndrome Associated with SARS-CoV-2 (MIS-C): The Interplay of Oxidative Stress and Inflammation.

Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (MIS-C) is characterized by persistent fever and evidence of single or multiorgan dysfunction, and laboratory evidence of inflammation, elevated neutrophils, reduced lymphocytes, and low albumin. The pathophysiological mechanisms of MIS-C are still unknown. Proinflammatory mediators, including reactive oxygen species and decreased antioxidant enzymes, seems to play a central role. Virus entry activates NOXs and inhibits Nrf-2 antioxidant response inducing free radicals. The biological functions of nonphagocytic NOXs are still under study and appear to include: defense of epithelia, intracellular signaling mechanisms for growth regulation and cell differentiation, and post-translational modifications of proteins. This educational review has the aim of analyzing the newest evidence on the role of oxidative stress (OS) in MIS-C. Only by relating inflammatory mediators to OS evaluation in children following SARS-CoV-2 infection will it be possible to achieve a better understanding of these mechanisms and to reduce long-term morbidity. The link between inflammation and OS is key to developing effective prevention strategies with antioxidants to protect children.

Potential benefits of melatonin to control pain in ventilated preterm newborns: An updated review.

Infants admitted to neonatal intensive care units are repeatedly stimulated by painful events, especially if intubated. Preterm infants are known to have greater pain perception than full term infants due to immaturity of descending inhibitory circuits and poor noxious inhibitory modulation. Newborns exposed to repetitive painful stimuli are at high risk of impairments in brain development and cognition. Chronic pain is induced and supported by proinflammatory cytokines, free radicals, and reactive oxygen species creating a self- sustaining vicious circle. Melatonin is a neurohormone secreted by the pineal gland with antioxidant and anti-inflammatory functions. This review describes the in-depth beneficial effects of melatonin for pain control in ventilated preterm newborns. As yet, a minimal amount of literature has been undertaken to consider all its promising bioactivities. The rationale behind the use of melatonin for pain control has also been taken into account in this review. Besides, this review addresses safety concerns and dosages. The potential benefits of melatonin have been assessed against neurological disorders, respiratory distress, microbial infections, and as analgesic adjuvant during ventilation. Additionally, a possible approach for the use of melatonin in ventilated newborns will be discussed.

Long-term cardiometabolic outcome in patients with pituitary adenoma diagnosed in chilhood and adolescence.

PURPOSE: Pituitary adenomas (PAs) rarely occur in childhood and adolescence. Management of PAs in this critical age can be particularly challenging considering the auxological sequelae and potential long-term cardiometabolic consequences. We aimed to describe the clinical characteristics of patients with PA aged < 18years at diagnosis and during long-term follow-up, focusing on the prevalence of cardio-metabolic comorbidities and the impact of different therapeutic strategies. METHODS: Clinical data at diagnosis and at last follow-up visit (mean 10.3 ± 9.2 years) of 101 patients aged < 18 years with PA, referred to our University Hospital from 1990 to 2017, were retrospectively evaluated. RESULTS: At diagnosis, 11.9% of patients presented with pituitary hormone deficiencies, whose number was positively correlated with pituitary tumor diameter (p < 0.001). At diagnosis, 26.7% of patients were overweight and 15.8% were obese. In patients with hypercortisolism or GH excess the prevalence of obesity was more than 2-fold greater than in general population. No correlation was found between pituitary tumor size and BMI. At baseline, the greater the number of pituitary hormone deficits, the higher BMI (p = 0.039). In prolactinoma patients still on medical therapy at last visit, BMI was higher than at baseline. CONCLUSION: We found an increased prevalence of overweight/obesity only in pediatric and adolescent patients with GH- or ACTH-secreting PA. Regarding cardio-metabolic comorbidities other than obesity/overweight, we have not found anything worth of mention. The remission of hypercortisolism positively impacted on BMI, while medical therapy in patients with prolactinoma seemed unable to avoid weight gain, suggesting a careful metabolic management of these patients.

Spinal cord compression as tumor onset: an unusual case report of Hodgkin lymphoma in a teenager.

BACKGROUND: Spinal cord compression (SCC) is an uncommon, severe complication of Hodgkin lymphoma (HL), occurring in 0.2% of cases at the onset and in 6% during disease progression. We present a teenager with SCC with clinical onset of HL; her pre-existing neurological abnormalities covered the presence of an epidural mass, which could have misled us. CASE PRESENTATION: A 13-year-old girl presented with a three-month history of lower back pain and degrading ability to walk. She suffered from a chronic gait disorder due to her preterm birth. A magnetic resonance imaging of the spine revealed an epidural mass causing collapse of twelfth thoracic vertebra and thus compression and displacement of the spinal cord. Histological examination with immunohistochemical analysis of the epidural mass demonstrated a classic-type Hodgkin lymphoma. Early pathology-specific treatment allowed to avoid urgent surgery, achieve survival and restore of neurological function. CONCLUSIONS: Children and adolescents with back pain and neurological abnormalities should be prioritized to avoid diagnostic delay resulting in potential loss of neurological function. SCC requires a prompt radiological assessment and an expert multidisciplinary management.

Oxidative Stress and Respiratory Diseases in Preterm Newborns.

Premature infants are exposed to increased generation of reactive oxygen species, and on the other hand, they have a deficient antioxidant defense system. Oxidative insult is a salient part of lung injury that begins as acute inflammatory injury in respiratory distress disease and then evolves into chronic and structural scarring leading to bronchopulmonary dysplasia. Oxidative stress is also involved in the pathogenesis of pulmonary hypertension in newborns through the modulation of the vascular tone and the response to pulmonary vasodilators, with consequent decrease in the density of the pulmonary vessels and thickening of the pulmonary arteriolar walls. Oxidative stress has been recognized as both a trigger and an endpoint for several events, including inflammation, hypoxia, hyperoxia, drugs, transfusions, and mechanical ventilation, with impairment of pulmonary function and prolonged lung damage. Redoxomics is the most fascinating new measure to address lung damage due to oxidative stress. The new challenge is to use omics data to discover a set of biomarkers useful in diagnosis, prognosis, and formulating optimal and individualized neonatal care. The aim of this review was to examine the most recent evidence on the relationship between oxidative stress and lung diseases in preterm newborns. What is currently known regarding oxidative stress-related lung injury pathogenesis and the available preventive and therapeutic strategies are also discussed.

Brain-Oriented Strategies for Neuroprotection of Asphyxiated Newborns in the First Hours of Life.

Perinatal asphyxia represents the first cause of severe neurological disabilities and the second cause of neonatal death in term-born babies. Currently, no treatment can prevent immediate cell death from necrosis, but some therapeutic interventions, such as therapeutic hypothermia (TH), can reduce delayed cell death from apoptosis. TH significantly improves the combined outcome of mortality or major neurodevelopmental disability, but the number of patients to be treated is 7 to get 1 child with no adverse neurological outcome. The aim of this educational review is to analyze the other care strategies to be implemented to improve the neurological outcome of children with hypoxic ischemic encephalopathy (HIE). Hypocapnia, hypoglycemia, pain control, and functional brain monitoring are recognized as appropriate approaches to improve outcome in critically ill infants with HIE. Pharmacologic neuroprotective adjuncts are currently under investigation. New drugs such as allopurinol and melatonin seem to provide positive effects although more randomized controlled trials are required to establish the effective therapeutic scheme. In the meantime, sustaining the respiratory, metabolic, and cardiovascular system during TH can be a valuable aid in managing and treating the patient with HIE in an optimal way.

Global incidence and prevalence of differentiated thyroid cancer in childhood: systematic review and meta-analysis.

Objective: Differentiated thyroid cancer (DTC) is rare in childhood and adolescence although it represents the most frequent endocrine malignancy in this population. DTC includes both papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). Most pediatric DTCs are PTCs, while FTCs are rare. To date, no systematic reviews on the global epidemiology of pediatric and adolescent DTC have been published. This systematic review and meta-analysis aims to estimate the overall incidence and prevalence of DTCs in patients aged 0-19 years. Methods: The systematic research was conducted from January 2000 to December 2021 through MEDLINE via PubMed, Cochrane Library, and Embase databases. Two separate meta-analyses were performed for PTC and FTC. Results: After the selection phase, a total of 15 studies (3,332 screened) met the inclusion criteria and are reported in the present systematic review. Five studies were conducted in Europe, five in North America, two in South America, one in Asia, one reported data for 49 countries and territories across the five continents, and one from both the USA and Africa. Most of the studies (n = 14) reported data obtained from national registries, and only one provided information collected from hospital medical records. Beyond the actual trend over time, our study reported a pooled global incidence rate (IR) of PTC and FTC in the pediatric age of 0.46 (95% CI: 0.33-0.59) and 0.07 (95% CI: 0.02-0.12) per 100,000 person-years, respectively. The highest IRs were recorded among Caucasian girls, and the lowest in black or other races/ethnicities. Conclusion: Our data confirm that DTC in the pediatric population is a rare condition. The pooled IRs of the studies included in this meta-analysis are ~0.5 for PTC, which is the most common histological type when both genders and all age groups are considered. The implementation of a prospective international registry on pediatric DTC, as part of the wider European Registries for Rare Endocrine Conditions, has been recently proposed. In addition to providing relevant information on the clinical behavior of this rare disease, standardization of data collection will be pivotal to fill current gaps and allow an accurate estimation of the real incidence and risk factors of DTC.

Antioxidant Effect of Melatonin in Preterm Newborns.

INTRODUCTION: Preterm infants are at risk of free radical-mediated diseases from oxidative stress (OS) injury. Increased free radical generation has been demonstrated in preterm infants during the first seven days of life. Melatonin (MEL) is a powerful antioxidant and scavenger of free radicals. In preterm neonates, melatonin deficiency has been reported. Exogenous melatonin administration appears a promising strategy in the treatment of neonatal morbidities in which OS has a leading role. OBJECTIVE: The aim was to evaluate plasma MEL concentrations and OS biomarkers in preterm newborns after early administration of melatonin. METHODS: A prospective, randomized double-blind placebo-controlled pilot study was conducted from January 2019 to September 2020. Thirty-six preterm newborns were enrolled. Starting from the first day of life, 21 received a single dose of oral melatonin 0.5 mg/kg once a day, in the morning (MEL group); 15 newborns received an equivalent dose of placebo (placebo group). Samples of 0.2 mL of plasma were collected at 24 and 48 hours after MEL administration. Plasma concentrations of melatonin, non-protein-bound iron (NPBI), advanced oxidation protein products (AOPP), and F2-isoprostanes (F2-Isopr) were measured. Babies were clinically followed until discharge. RESULTS: At 24 and 48 hours after MEL administration, the MEL concentrations were significantly higher in the MEL group than in the placebo group (52759.30 ± 63529.09 vs. 28.57 ± 46.24 pg/mL and 279397.6 ± 516344.2 vs. 38.50 ± 44.01 pg/mL, respectively). NPBI and AOPP did not show any statistically significant differences between the groups both at 24 and 48 hours. At 48 hours, the mean blood concentrations of F2-Isopr were significantly lower in the MEL group than in the placebo group (36.48 ± 33.85 pg/mL vs.89.97 ± 52.01 pg/mL). CONCLUSIONS: Early melatonin administration in preterm newborns reduces lipid peroxidation in the first days of life showing a potential role to protect high-risk newborns. Trial Registration. This trial is registered with NCT04785183, Early Supplementation of Melatonin in Preterm Newborns: the Effects on Oxidative Stress.

Ventilation, oxidative stress and risk of brain injury in preterm newborn.

Preterm infants have an increased risk of cognitive and behavioral deficits and cerebral palsy compared to term born babies. Especially before 32 weeks of gestation, infants may require respiratory support, but at the same time, ventilation is known to induce oxidative stress, increasing the risk of brain injury. Ventilation may cause brain damage through two pathways: localized cerebral inflammatory response and hemodynamic instability. During ventilation, the most important causes of pro-inflammatory cytokine release are oxygen toxicity, barotrauma and volutrauma. The purpose of this review was to analyze the mechanism of ventilation-induced lung injury (VILI) and the relationship between brain injury and VILI in order to provide the safest possible respiratory support to a premature baby. As gentle ventilation from the delivery room is needed to reduce VILI, it is recommended to start ventilation with 21-30% oxygen, prefer a non-invasive respiratory approach and, if mechanical ventilation is required, prefer low Positive End-Expiratory Pressure and tidal volume.

Efficacy of Intravenous Hydrocortisone Treatment in Refractory Neonatal Seizures: A Report on Three Cases.

Neonatal seizures are the most common neurological emergency, and neonatal status epilepticus (NSE) remains a controversial entity, with no general consensus about its definition and treatment. Here, we report on three newborns with NSE refractory to first- and second-line antiepileptic drugs successfully treated with intravenous (IV) hydrocortisone. The patients had previously failed therapy with levetiracetam, phenobarbital and midazolam, showing persistent clinical and electrical seizures. Modulation of brain inflammation triggered during prolonged epileptic activity has been thought to potentially explain the beneficial effects of anti-inflammatory treatment.

Surgery-Related Quality of Life of Pediatric Patients With Crohn's Disease.

Objective: Up to 30% of pediatric patients with Crohn's disease (CD) require surgery. The aim of the study was to evaluate long-term health-related quality of life (HRQoL) outcome in children with CD who have had ileocolonic resection. Materials and methods: This was a retrospective cross-sectional study on all pediatric patients who had undergone surgery for CD between January 2015 and December 2017 in the Pediatric Surgery and Gastroenterology Units of the University Hospital of Messina. Surgical treatment was represented by laparoscopic ileocecal resection with latero-lateral anastomosis. Patients were asked to fill in a modified version of the IMPACT III questionnaire made up of 15 closed questions before and after surgery. The questionnaire was scored on a five-point scale with 5 reporting "not a problem" and 1 "a very severe problem." The total score ranged from 15 (worst HRQoL) to 75 (best HRQoL). Frequency of relapses, reoperations, complications during follow-up, and postoperative bowel function were also studied. Results: Data were obtained in 10 patients (9 males), who underwent surgery at a median age of 13.5 years (range 13-18), after a median post-diagnosis period of 2.5 years (range 0-8). Preoperative scores were low in all 4 domains of the questionnaire. Postoperatively, HRQoL measures improved significantly (p < 0.05) about symptoms, school attendance, social and emotional functioning. Overall, nearly all patients were completely satisfied with the surgical outcome. Conclusions: HRQoL is low in CD children referred for possible operation, and surgery may positively affect the overall HRQoL. Collecting HRQoL data provides insight into the impact of treatment on children health status.

Differentiated thyroid carcinoma presentation may be more aggressive in children and adolescents than in young adults.

BACKGROUND: The available studies concerning the influence of age on the phenotypical expression of differentiated thyroid carcinoma (DTC) have hitherto compared DTC presentation either between pre-pubertal and pubertal children or between pediatric patients and aged adults; aim of this study was to ascertain for the first time whether presentation of DTC may significantly vary according to age, even within a peculiar study population covering only young patients aged less than 30 years. METHODS: The main clinical, biochemical and pathologic data at DTC diagnosis were retrospectively recorded in 2 selected cohorts including, respectively, 18 children and adolescents aged less than 18 years (Group A) or 45 young adults aged between 20 and 29.8 years (Group B). RESULTS: The statistical distribution of DTC cases in the different age ranges was found to progressively increase with increasing age; furthermore, the patients of Group A exhibited at diagnosis a more severe clinical involvement and a higher rate of extra-regional metastases; finally, also the association with both autoimmune thyroid diseases (AITDs) and a biochemical hypothyroid pattern was more common in Group A patients. CONCLUSIONS: In a study population younger than 30 years: a) the risk of developing DTC increases with age, achieving its zenith during the 3rd decade of life; b) clinical presentation is more severe in children and adolescents younger than 18 years than in the patients aged between 20 and 30; c) in the cohort of children and adolescents DTC is more often associated with AITDs, which might play some role in conditioning the more aggressive phenotypical presentation of DTC in this patient group.

A child with severe iron-deficiency anemia and a complex TMPRSS6 genotype.

OBJECTIVES: We report a case of a 7-year-old girl with severe hypochromic microcytic anemia, who was unresponsive to classical iron supplements. We suspected IRIDA, iron-refractory iron-deficiency anemia, a genetic iron metabolism disorder, caused by TMPRSS6 variations. TMPRSS6 encodes matriptase-2, a negative regulator of hepcidin, and its pathological variants are related to normal to high levels of hepcidin. We analyzed the TMPRSS6 gene and we improved clinical management of the patient, selecting the appropriate supplementation therapy. Intervention & Technique: The parenteral iron therapy was started, but the patient was only partially responsive and the anemia persisted. To confirm the diagnosis, the TMPRSS6 gene sequence was analyzed by DNA sequencing and other relevant biochemical parameters were evaluated. RESULTS: The TMPRSS6 sequence analysis showed a complex genotype with a rare heterozygous missense variant, in addition to other common polymorphisms. The serum hepcidin value was normal. We unexpectedly observed a normalization of patient's hemoglobin (Hb) levels only after liposomal iron treatment. DISCUSSION AND CONCLUSION: The proband was symptomatic for IRIDA during a critical phase of growth and development, but we did not find a clearly causative genotype. A long-term result, improving stably patient's Hb levels, was obtained only after liposomal iron supplementation. Children may be at greater risk for iron deficiency and the degree of anemia as well as the response to the iron supplements varies markedly patient to patient. Here, we show the importance of comprehensive study of these patients in order to collect useful information about genotype-phenotype association of genes involved in iron metabolism.

Visceral adiposity index as an indicator of cardiometabolic risk in patients treated for craniopharyngioma.

PURPOSE: Craniopharyngioma is associated with metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index has been proposed as a marker of visceral adipose tissue dysfunction and of the related cardiometabolic risk. The role of the visceral adiposity index has never been explored in craniopharyngioma patients. We assessed the cardiometabolic risk on the basis of the visceral adiposity index in craniopharyngioma patients. METHODS: We evaluated data of 24 patients treated for craniopharyngioma in a single-centre. We investigated the relationship among patients' clinical and biochemical features, cardiovascular risk -assessed by the Framingham and the atherosclerotic cardiovascular disease risk scores-, visceral adiposity index and adipose tissue dysfunction severity. RESULTS: Increased visceral adiposity index was found in 8 patients (33%). Adipose tissue dysfunction resulted to be severe, moderate or mild in 5, 2 and 1 cases. Increased visceral adiposity index significantly correlated with the occurrence of metabolic syndrome (p 0.027), IRI (p 0.001), triglycerides (p < 0.001), HOMA-IR (p < 0.001) and with lower ISI-Matsuda (p 0.005) and HDL-cholesterol (p < 0.001). Higher degree of adipose tissue dysfunction associated with increased insulin resistance. No gender difference was found for visceral adiposity index, adipose tissue dysfunction severity, and cardiovascular risk scores. Patients with adulthood onset craniopharyngioma showed higher Framingham risk score (p 0.004), atherosclerotic cardiovascular disease 10-year (p < 0.001) and lifetime (p 0.018) risk scores than those with childhood onset disease. CONCLUSIONS: Visceral adiposity index is increased in one third of our patients with craniopharyngioma, even if metabolic syndrome does not occur. Increased visceral adiposity index and adipose tissue dysfunction severity correlate with insulin sensitivity parameters, do not correlate with Framingham or atherosclerotic cardiovascular disease risk scores, and are not influenced by gender and age of disease onset.