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..

Ketogenic diet for infants with epilepsy: A literature review.

The ketogenic diet (KD) is an established, nonpharmacological treatment for drug-resistant epilepsy (DRE). Actually, KD and its variants have been shown to be elective and resolute for patients with glucose transporter type 1 (GLUT1) deficiency. The aim of this review was to study the use of KD and its variants in infancy, including the neonatal age, and demonstrate the safety and efficacy of this treatment in patients with the age of 0-23 months affected by DRE already subjected to pharmacological approach attempts. A literature search was conducted using PubMed as the medical database source. We used the age limit of 0-23 months, and we considered only articles published between the years 2015 and 2018, in light of increasing interest worldwide in the use of KD and its variants to manage DRE. We included 52 publications: 1 Cochrane study, 22 retrospective studies, 9 prospective studies, 4 randomized controlled trials (RCTs), 12 clinical cases, and 4 clinical reviews. Literature data showed that KD and its variants are safe and useful in patients with the age of 0-23 months with DRE. Classical KD is of first choice in the treatment of GLUT1 deficiency. Earlier introduction of KD in GLUT1 promises a better outcome and a decrease in seizure frequency in these patients.

High mobility group box 1 and markers of oxidative stress in human cord blood.

BACKGROUND: Parturition induces considerable oxidative stress and many inflammatory mediators, such as high mobility group box 1 (HMGB1), are involved from the beginning of the pregnancy to birth. The aim of the present study was to evaluate serum cord blood concentration of diacron-reactive oxygen metabolites (d-ROM), biological antioxidant potential (BAP), and HMGB1 to investigate the perinatal oxidative status of neonates and correlation with mode of delivery, as well as the influence of labor. METHODS: The subjects consisted of 214 neonates delivered at University Hospital "G. Martino", Messina, in a 6 months period. Venous blood samples were collected from the umbilical cord after cord separation. RESULTS: Umbilical cord venous blood HMGB1 was significantly higher in the spontaneous vaginal delivery (SVD) group than in the elective or emergency cesarean section (CS) group (P = 0.018). Regarding labor, there was no significant difference in HMGB1 concentration in umbilical vein blood between the spontaneous and induced labor groups (P = 0.250). Furthermore, d-ROM was significantly different between the SVD group and the elective or emergency CS group (P = 0.044). BAP concentration, however, was not significantly different, not even with regard to mode of labor. CONCLUSION: Oxidation is higher in newborns delivered by SVD than in those delivered by CS, and HMGB1 may be involved in the mechanisms of birth, and responsible for decidual modifications that lead to birth.

Outbreak of Brucella melitensis infection in Eastern Sicily: risk factors, clinical characteristics and complication rate.

Brucellosis is one of the most common zoonoses in the world, especially in Southern Italy, where many cases are still recorded every year. 128 cases of brucellosis were observed in Messina (Sicily) in 2016, representing a tenfold increase in the number of cases of brucellosis expected. The aim of this multicenter retrospective study was to analyze clinical and microbiological aspects of a brucellosis outbreak in the province of Messina in 2016, the incidence of its complications and the treatment combinations applied. The principal transmission route was through the ingestion of unpasteurized fresh cheese. The mean latency period between the onset of the symptoms and diagnosis was 35.58±42.75 days. A late diagnosis increases the risk of developing complications. Drug-resistant strains of B. melitensis to Trimethoprim/ Sulfamethoxazole and Ciprofloxacin were found in blood cultures of 58.4% patients. Brucellosis is still present in Sicily. A diagnostic delay predisposes to complications requiring prolonged therapies. The finding of Brucella melitensis strains resistant to the most widespread treatments is worrisome and needs further investigation. Moreover, the use of alternative combination antibiotic therapy is recommended.

Outbreak of Brucella melitensis infection in Eastern Sicily: risk factors, clinical characteristics and complication rate.

Brucellosis is one of the most common zoonoses in the world, especially in Southern Italy, where many cases are still recorded every year. 128 cases of brucellosis were observed in Messina (Sicily) in 2016, representing a tenfold increase in the number of cases of brucellosis expected. The aim of this multicenter retrospective study was to analyze clinical and microbiological aspects of a brucellosis outbreak in the province of Messina in 2016, the incidence of its complications and the treatment combinations applied. The principal transmission route was through the ingestion of unpasteurized fresh cheese. The mean latency period between the onset of the symptoms and diagnosis was 35.58 ± 42.75 days. A late diagnosis increases the risk of developing complications. Drug-resistant strains of B. melitensis to Trimethoprim/Sulfamethoxazole and Ciprofloxacin were found in blood cultures of 58.4% patients. Brucellosis is still present in Sicily. A diagnostic delay predisposes to complications requiring prolonged therapies. The finding of Brucella melitensis strains resistant to the most widespread treatments is worrisome and needs further investigation. Moreover, the use of alternative combination antibiotic therapy is recommended.

Association between Allergies and Hypercholesterolemia: A Systematic Review.

BACKGROUND: There is controversy in the literature regarding the potential relationship between atopic predisposition (AP) and serum cholesterol levels. To this purpose, we reviewed human studies that investigated this possible link. METHODS: Following PRISMA guidelines, a literature search of PubMed and Science Direct for peer-reviewed journal articles in English from January 2003, with updates through to August 2016, was conducted. Relevant publications were reviewed that included pediatric and adult populations. Information on the study design, sample, intervention, comparators, outcome, time frame, and risk of bias were abstracted for each article. RESULTS: Of 601 reviewed reports, 18 were included in this systematic review. Fifteen studies assessed the relationship between AP and serum cholesterol levels. Due to the lack both of observational and cross-sectional studies from the literature search at this time (only 8 studies also analyzed confounding factors) there is a high possibility of confounding variables (familial and genetic predisposition, age, gender, BMI, comorbidity, and medication status) that could not be ruled out. CONCLUSION: Existing studies are heterogeneous, making it difficult to draw broad conclusions. Future studies and more detailed analyses, considering confounding variables and including a larger and homogeneous population, are needed to strengthen the argument for a link between lipid metabolism and atopy.

Premedication with melatonin vs midazolam: efficacy on anxiety and compliance in paediatric surgical patients.

Preoperative anxiety is a major problem in paediatric surgical patients. Melatonin has been used as a premedicant agent and data regarding effectiveness are controversial. The primary outcome of this randomized clinical trial was to evaluate the effectiveness of oral melatonin premedication, in comparison to midazolam, in reducing preoperative anxiety in children undergoing elective surgery. As secondary outcome, compliance to intravenous induction anaesthesia was assessed. There were 80 children undergoing surgery randomly assigned, 40 per group, to receive oral midazolam (0.5 mg/kg, max 20 mg) or oral melatonin (0.5 mg/kg, max 20 mg). Trait anxiety of children and their mothers (State-Trait Anxiety Inventory) at admission, preoperative anxiety and during anaesthesia induction (Modified Yale Pre-operative Anxiety Scale), and children's compliance with anaesthesia induction (Induction Compliance Checklist) were all assessed. Children premedicated with melatonin and midazolam did not show significant differences in preoperative anxiety levels, either in the preoperative room or during anaesthesia induction. Moreover, compliance during anaesthesia induction was similar in both groups. CONCLUSIONS: This study adds new encouraging data, further supporting the potential use of melatonin premedication in reducing anxiety and improving compliance to induction of anaesthesia in children undergoing surgery. Nevertheless, further larger controlled clinical trials are needed to confirm the real effectiveness of melatonin as a premedicant agent in paediatric population. What is Known: • Although midazolam represents the preferred treatment as a premedication for children before induction of anaesthesia, it has several side effects. • Melatonin has been successfully used as a premedicant agent in adults, while data regarding effectiveness in children are controversial. What is New: • In this study, melatonin was as effective as midazolam in reducing children's anxiety in both preoperative room and at induction of anaesthesia.

Neonatal stridor and laryngeal cyst: Which comes first?

Neonatal stridor is a rare condition usually caused by laryngomalacia. Congenital laryngeal cyst represents an uncommon cause of stridor in the neonatal population and may be misinterpreted as laryngomalacia, leading to serious morbidity and mortality if diagnosis and treatment are delayed. Herein we report the case of a full-term infant with stridor, feeding problems and failure to thrive. Initially, direct laryngoscopy diagnosed only laryngomalacia. As stridor worsened, however, and respiratory distress appeared, repeat laryngoscopy showed vallecular laryngeal cyst, visible macroscopically. The patient was successfully treated with endoscopic marsupialization. There was no evidence of recurrence at follow up after 3 months. This case highlights the importance of laryngoscopic assessment for suspected laryngeal abnormalities in infants with stridor. If symptoms worsen, endoscopy should be repeated, because congenital laryngeal cysts may not be immediately visible macroscopically.

Melatonin Secretion Is Increased in Children with Severe Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Oxidative stress plays a significant role in brain damage and melatonin exhibits both direct and indirect antioxidant effects. The primary aim of the present study was to evaluate serum melatonin levels in children with severe TBI in comparison to critically ill children admitted to the Pediatric Intensive Care Unit for conditions other than TBI. METHODS: Twenty-four children were evaluated, equally divided into severe TBI and no-TBI. Blood samples for serum melatonin analysis were collected at 22:00, 01:00, 03:00, 05:00, 08:00, and 12:00. RESULTS: Mean serum melatonin peaks in children of the TBI group were higher compared to the values of no-TBI critically ill children (495 ± 102 vs. 294 ± 119 pg/mL, p = 0.0002). Furthermore, the difference was even more significant in comparison to values reported in literature for healthy age-matched children (495 ± 102 vs. 197 ± 71 pg/mL, p < 0.0001). CONCLUSION: This study has shown that endogenous serum melatonin levels dramatically increase in children after severe TBI. This elevation is likely to represent a response to oxidative stress and/or inflammation due to severe head injury.

Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates.

Melatonin possesses potential efficacy in perinatal brain injuries, and has been proposed as adjunctive pharmacological therapy in combination with hypothermia in the clinical setting. However, the pharmacokinetics of melatonin in preterm and term newborns is still unknown. The aim of this study was to analyze the pharmacokinetics of melatonin after intragastric administration in preterm infants. Preterm newborns were enrolled 24-72 h after birth, and randomly assigned to three groups receiving a single bolus of 0.5 mg·kg-1 melatonin, or 3 boluses of 1 or 5 mg·kg-1 of melatonin at 24-h intervals. Blood samples were collected before and at selective times after melatonin administration. The half-life of melatonin in plasma ranged from 7.98 to 10.94 h, and the area under the curve (AUC) from 10.48 to 118.17 µg·mL-1·h-1. Our results indicate a different pharmacokinetic profile in premature newborns, compared to adults and experimental animals. The high peak plasma concentrations and the long half-life indicate that in the neonatal clinical setting, it is possible to obtain and maintain high serum concentrations using a single administration of melatonin repeated every 12/24 h.

Visfatin: New marker of oxidative stress in preterm newborns.

BACKGROUND: Oxidative stress is involved in several neonatal conditions characterized by an upregulation in the production of oxidative or nitrative free radicals and a concomitant decrease in the availability of antioxidant species. Oxygen, which is obviously vital to survival, can be highly damaging to neonatal tissue which is known to be poorly equipped to neutralize toxic derivatives. Thus, exposure of the newborn infant to high oxygen concentrations during resuscitation at birth increases oxidative damage. Visfatin is an adipocytokine involved in oxidative stress and an important mediator of inflammation that induces dose-dependent production of both pro-inflammatory and anti-inflammatory cytokines. To our knowledge, the diagnostic value of visfatin as a marker of oxidative stress in preterm newborns has not been investigated. OBJECTIVE: The aim of this study was to evaluate visfatin levels in preterm neonates resuscitated with different concentrations of oxygen in the delivery room. PATIENTS: Fifty-two preterm newborns with gestational age less than 32 weeks, resuscitated randomly with different oxygen concentrations (40%, 60%, or 100%) were enrolled at the University Hospital of Messina, over a 12-month period to evaluate serum visfatin levels at T0 (within 1 h after birth), T24 h, T72 h, and T168 h of life. RESULTS: At T72 h and T168 h, higher serum visfatin values in the high-oxygen group compared to the low- and mild-oxygen subjects (P=0.002 and P<0.001, respectively) were noted. CONCLUSION: The results of this study suggest that visfatin could be a new marker of oxidative stress in preterm newborns.

Ventilation strategies for preventing oxidative stress-induced injury in preterm infants with respiratory disease: an update.

Reactive oxygen and nitrogen species are produced by several inflammatory and structural cells of the airways. The lungs of preterm newborns are susceptible to oxidative injury induced by both reactive oxygen and nitrogen species. Increased oxidative stress and imbalance in antioxidant enzymes may play a role in the pathogenesis of inflammatory pulmonary diseases. Preterm infants are frequently exposed to high oxygen concentrations, infections or inflammation; they have reduced antioxidant defense and high free iron levels which enhance toxic radical generation. Multiple ventilation strategies have been studied to reduce injury and improve outcomes in preterm infants. Using lung protective strategies, there is the need to reach a compromise between satisfaction of gas exchange and potential toxicities related to over-distension, derecruitment of lung units and high oxygen concentrations. In this review, the authors summarize scientific evidence concerning oxidative stress as it relates to resuscitation in the delivery room and to the strategies of ventilation.

Melatonin versus midazolam premedication in children undergoing surgery: A pilot study.

AIM: Melatonin has been proposed as a premedication alternative to midazolam, preceding anaesthesia induction. However, to our knowledge, data concerning interaction between melatonin and intravenous anaesthetic drugs in children are not available. The aim of this prospective, randomized, double-blind pilot study was to investigate the possible effect of melatonin premedication, in comparison to midazolam, on the required infusion of propofol in children undergoing surgery. As a secondary outcome, the effect of oral melatonin on the preoperative sedation level and on the post anaesthesia recovery score was evaluated. METHODS: Children between the age of 5 and 14 years, scheduled for elective surgery, were prospectively enrolled between January 2012 and December 2013, and randomly assigned to two groups based on whether they received oral melatonin (0.5 mg/kg) or oral midazolam (0.5 mg/kg) premedication before induction of anaesthesia with propofol. Degree of sedation before and after anaesthesia was also evaluated. RESULTS: Ninety-two patients were studied, 46 for each group. We found that oral administration of melatonin significantly reduced doses of propofol required for induction of anaesthesia in paediatric patients, more than midazolam (P < 0.001). No statistically significant differences were found in the pre- and post-anaesthesia sedation score (P = 0.387 and P = 0.525, respectively) between the two groups. CONCLUSIONS: The present study demonstrates that melatonin enhances the potency of propofol also in paediatric patients. Moreover, considering the paediatric level of sedation, melatonin was equally as effective as midazolam. These data support the use of melatonin as a premedicant in paediatric surgical patients.

Fibrodysplasia ossificans progressiva in a newborn with cardiac involvement.

Fibrodysplasia ossificans progressiva is a rare genetic disease that manifests in early life with malformed big toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. Mutation c.617G>A in the activin A receptor type I gene is reported in all patients with fibrodysplasia ossificans progressiva. No cases of cardiac involvement have been described in children. We report the case of a child with halluces valgi at birth, along with two tender, firm, immovable masses located on the right and left parietal-occipital region, a transitory subluxation of the right hip and an unusual ventricular septal hypertrophy. We hypothesize that the ventricular septal hypertrophy could be the result of a thickening of the fibrous portion of the septum, and a possible new element of the phenotype, probably resulting from the mechanical stimuli secondary to the significant hemodynamic changes occurring at birth.

Oxidative Stress-Mediated Damage in Newborns with Necrotizing Enterocolitis: A Possible Role of Melatonin.

BACKGROUND: Necrotizing enterocolitis is a gastrointestinal surgical emergency in premature neonates. Free radicals have been linked to the development of the disease in infants. Ischemia, hypoxia-reperfusion, infection, and inflammation produce elevated levels of reactive oxygen species, impairing the redox balance and shifting cells into a state of oxidative stress. Melatonin, an effective direct free-radical scavenger and indirect antioxidant agent, exerts pleiotropic action on the human body. Several studies have tested the efficacy of melatonin in counteracting oxidative injury in diseases of newborns. Melatonin has been widely used in newborns including cases of asphyxia, respiratory distress syndrome, and sepsis, and no significant toxicity or treatment-related side effects with long-term melatonin therapy have been reported. CONCLUSION: Therefore, melatonin, besides standard therapies, could be considered as a potentially safe approach to prevent and treat necrotizing enterocolitis in premature infants. This review summarizes what is known about the role of oxidative stress, and potentially beneficial effects of antioxidants, such as melatonin, in necrotizing enterocolitis.

Analgesic, anxiolytic and anaesthetic effects of melatonin: new potential uses in pediatrics.

Exogenous melatonin is used in a number of situations, first and foremost in the treatment of sleep disorders and jet leg. However, the hypnotic, antinociceptive, and anticonvulsant properties of melatonin endow this neurohormone with the profile of a drug that modulates effects of anesthetic agents, supporting its potential use at different stages during anesthetic procedures, in both adults and children. In light of these properties, melatonin has been administered to children undergoing diagnostic procedures requiring sedation or general anesthesia, such as magnetic resonance imaging, auditory brainstem response tests and electroencephalogram. Controversial data support the use of melatonin as anxiolytic and antinociceptive agents in pediatric patients undergoing surgery. The aim of this review was to evaluate available evidence relating to efficacy and safety of melatonin as an analgesic and as a sedative agent in children. Melatonin and its analogs may have a role in antinociceptive therapies and as an alternative to midazolam in premedication of adults and children, although its effectiveness is still controversial and available data are clearly incomplete.

Melatonin and atopy: role in atopic dermatitis and asthma.

Melatonin may have important immunostimulatory actions in allergic diseases, in addition to its well-known antioxidant and cytoprotective effects in several inflammatory conditions. The activation of the immune system leads to free radical production associated with decreased melatonin levels and depressed antioxidant enzyme activities in several inflammatory diseases. Many skin disorders, including atopic dermatitis, are accompanied by infiltration and activation of mast cells, which release vasoactive and proinflammatory mediators. Experimental data suggest that melatonin inhibits development of atopic eczema and reduces serum total IgE and IL-4. Allergic asthma is a condition characterized by bronchial hyperresponsiveness and the presence of IgE antibodies in response to inhaled allergens; often there is also enhanced total serum IgE levels. Melatonin regulates smooth muscle tone and influences the immune response. Melatonin may, however, act as a pro-inflammatory agent in asthma leading to bronchial constriction. The safety of melatonin as a sleep-inducing agent has been confirmed in asthmatic subjects, but its routine use is not recommended in bronchial asthma. This review summarizes what is known about the role of melatonin as an immunomodulatory agent in asthma and atopic eczema.

Oxidative stress in obesity: a critical component in human diseases.

Obesity, a social problem worldwide, is characterized by an increase in body weight that results in excessive fat accumulation. Obesity is a major cause of morbidity and mortality and leads to several diseases, including metabolic syndrome, diabetes mellitus, cardiovascular, fatty liver diseases, and cancer. Growing evidence allows us to understand the critical role of adipose tissue in controlling the physic-pathological mechanisms of obesity and related comorbidities. Recently, adipose tissue, especially in the visceral compartment, has been considered not only as a simple energy depository tissue, but also as an active endocrine organ releasing a variety of biologically active molecules known as adipocytokines or adipokines. Based on the complex interplay between adipokines, obesity is also characterized by chronic low grade inflammation with permanently increased oxidative stress (OS). Over-expression of oxidative stress damages cellular structures together with under-production of anti-oxidant mechanisms, leading to the development of obesity-related complications. The aim of this review is to summarize what is known in the relationship between OS in obesity and obesity-related diseases.