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Mature locomotion involves modular spinal drives generating a set of fundamental patterns of motoneuron activation, each timed at a specific phase of locomotor cycles and associated with a stable muscle synergy. How locomotor modules develop and to what extent they depend on prior experience or intrinsic programs remains unclear. To address these issues, we herein leverage the presence at birth of two types of locomotor-like movements, spontaneous kicking and weight-bearing stepping. The former is expressed thousands of times in utero and postnatally, whereas the latter is elicited de novo by placing the newborn on the ground for the first time. We found that the neuromuscular modules of stepping and kicking differ substantially. Neonates kicked with an adult-like number of temporal activation patterns, which lacked a stable association with systematic muscle synergies across movements. However, on the ground neonates stepped with fewer temporal patterns but all structured in stable synergies. Since kicking and ground-stepping coexist at birth, switching between the two behaviors may depend on a dynamic reconfiguration of the underlying neural circuits as a function of sensory feedback from surface contact. We tracked the development of ground-stepping in 4- to 48-mo-old infants and found that, after the age of 6 mo, the number of temporal patterns increased progressively, reaching adult-like conformation only after independent walking was established. We surmise that mature locomotor modules may derive by combining the multiple patterns of repeated kicking, on the one hand, with synergies resulting from fractionation of those revealed by sporadic weight-bearing stepping, on the other hand.

Terrestrial locomotion requires coordinated bilateral activation of limb muscles, with left–right alternation in walking or running, and synchronous activation in hopping or skipping. The neural mechanisms involved in interlimb coordination at birth are well known in different mammalian species, but less so in humans. Here, 46 neonates (of either sex) performed bilateral and unilateral stepping with one leg blocked in different positions. By recording EMG activities of lower-limb muscles, we observed episodes of left–right alternating or synchronous coordination. In most cases, the frequency of EMG oscillations during sequences of consecutive steps was approximately similar between the two sides, but in some cases it was considerably different, with episodes of 2:1 interlimb coordination and episodes of activity deletions on the blocked side. Hip position of the blocked limb significantly affected ipsilateral, but not contralateral, muscle activities. Thus, hip extension backward engaged hip flexor muscle, and hip flexion engaged hip extensors. Moreover, the sudden release of the blocked limb in the posterior position elicited the immediate initiation of the swing phase of the limb, with hip flexion and a burst of an ankle flexor muscle. Extensor muscles showed load responses at midstance. The variable interlimb coordination and its incomplete sensory modulation suggest that the neonatal locomotor networks do not operate in the same manner as in mature locomotion, also because of the limited cortical control at birth. These neonatal mechanisms share many properties with spinal mammalian preparations (i.e., independent pattern generators for each limb, and for flexor and extensor muscles, load, and hip position feedback). SIGNIFICANCE STATEMENT Bilateral coupling and reciprocal activation of flexor and extensor burst generators represent the fundamental mechanisms used by mammalian limbed locomotion. Considerable progress has been made in deciphering the early development of the spinal networks and left–right coordination in different mammals, but less is known about human newborns. We compared bilateral and unilateral stepping in human neonates, where cortical control is still underdeveloped. We found neonatal mechanisms that share many properties with spinal mammalian preparations (i.e., independent pattern generators for each limb, the independent generators for flexor and extensor muscles, load, and hip-position feedback. The variable interlimb coordination and its incomplete sensory modulation suggest that the human neonatal locomotor networks do not operate in the same manner as in mature locomotion.

Human neonatal motoneurons show high synchronized discharge timings that modulate the generation of fast movements., Motoneurons of neonatal rodents show synchronous activity that modulates the development of the neuromuscular system. However, the characteristics of the activity of human neonatal motoneurons are largely unknown. Using a noninvasive neural interface, we identified the discharge timings of individual spinal motoneurons in human newborns. We found highly synchronized activities of motoneurons of the tibialis anterior muscle, which were associated with fast leg movements. Although neonates’ motor units exhibited discharge rates similar to those of adults, their synchronization was significantly greater than in adults. Moreover, neonatal motor units showed coherent oscillations in the delta band, which is directly translated into force generation. These results suggest that motoneuron synchronization in human neonates might be an important mechanism for controlling fast limb movements, such as those of primitive reflexes. In addition to help revealing mechanisms of development, the proposed neural interface might monitor children at risk of developing motor disorders.

Introduction Melatonin has been studied and used for several years as a sleep-wake cycle modulator in patients with sleep disorders. Experimental evidence has demonstrated the multiple neuroprotective benefits of this indoleamine secreted by the pineal gland. Melatonin is also used in neurological investigations, for its ability to induce sleep in children. In fact, it favors falling asleep during electroencephalogram, Magnetic Resonance Imaging (MRI), and during brainstem auditory evoked potentials. Previous studies are focused on infants and children. No investigation have been performed in neonates, before or during instrumental assessments. Material and methods One hundred ten newborns (term and preterm) undergoing brain MRI were enrolled in the study. Thirty minutes before the planned time for the examination, we administered a single dose solution of melatonin- tryptophan-vitamin B6. Twenty minutes after the initial administration of 2 mg, a second dose of 1 mg was administered, if the baby was still awake. If after further 15 min the baby was still not sleeping, an additional dose of 1 mg was administered. Results In 106 patients we obtained adequate sedation without adverse events, allowing us to perform an adequate quality MRI, with a median time of 25 min to reach sleeping. Only in three patients MRI could not be performed. In patients having a large weight, higher doses of melatonin were necessary to reach sleeping. Considering the pro kg dose of melatonin, the average dose that induced sleepiness in neonates was 0,64 ± 0.16 mg/Kg. Conclusion A solution based on Melatonin- tryptophan-vitamin B6 can be a helpful sedative to administer to neonates undergoing brain MRI, avoiding the use of anesthetics and achieving adequate assessments.

Objective This report discusses the neurological involvement in respiratory syncytial virus (RSV) infection in neonates. Study Design We present a case report of a 2-month-old infant affected by a bronchiolitis RSV-positive, with syndrome of inappropriate antidiuretic hormone secretion (SIADH) correlated seizure and encephalopathy. Results RSV infection can be associated as a serious disease in newborns involving the central nervous system (CNS) and causing seizures or acute encephalopathy. RSV may be also responsible for SIADH and seizures associated with hyponatremia. The RSV related encephalopathy could be caused by different mechanisms, such as direct viral invasion of the CNS or by indirect mechanism mediated by inflammatory cytokines. In addition, it can be favored by severe hyponatremia and SIADH that can cause cerebral edema. Some studies highlight that this virus-related encephalopathy lead to sudden infant death syndrome. Conclusion In presence of neurological involvement during RSV-infection must be taken in consideration to performing instrumental test to detect cerebral edema. In addiction could be useful to dose inflammatory cytokines, and to consider the immune-modulatory therapy.

Objective: To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit. Study design: This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants. Results: Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants. Conclusion: Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage. Trial registration: isrctn.org: ISRCTN53107700.

Lutein (LT) is a naturally occurring xanthophyll carotenoid most predominant in the central nervous system (CNS), but its neurotrophic role is still debated. We therefore investigated whether cord blood concentrations correlated with a well-established neurobiomarker, namely activin A.We conducted a prospective study on the distribution of LT and activin A in arterial cord blood of healthy preterm (n=50) and term (n=82) newborns according to weeks of gestational age (wGA) and gender.LT and activin A showed a pattern of concentration characterized by higher levels (P0.01, for all) at 33-36 wGA followed by a progressive decrease (P0.01, for all) from 37 onwards with a dip at term. Both LT and activin A were gender-dependent with significantly (P0.01, for all) higher levels in all recruited females and after sub-grouping for preterm and term births. LT (R=0.33; P0.001) correlated with wGA at sampling. There were significant positive correlations between lutein and activin A in male (R=0.93; P0.001) and female (R=0.89; P0.001) groups.The present data showing a correlation between LT and activin A support the notion of a neurotrophic role gender-dependent for LT and open the way to further investigations correlating LT with well-established biochemical markers of CNS development/damage.

[Accessibilty and safety of drugs in pediatrics] Many of pediatric drugs have not been tested and evaluate in children. The risks associated with the off-label use of drugs without pediatric indications include adverse effects, inefficacy, and improper formulation. Furthermore the use of magistral or officinal formulations to treat the pediatric population may be of poor quality. The objectives of EU Regulation 1901/2006 on medicinal products for pediatric are to improve the health of children by facilitating the development and availability of medicines for children, ensuring that medicines for use in children are of high quality, ethically researched and authorised appropriately, and improving the availability of information on the use of medicines for children. Peyona (caffeine citrate) is authorised for the treatment of primary apnea of premature newborns and it’s a good example of drug tested and evaluate in children.

Background Transcutaneous bilirubin (TcB) measurement is widely used as screening for neonatal hyperbilirubinaemia. Aims To prospectively validate TcB measurement using hour-specific nomogram in identifying newborn infants not at risk for severe hyperbilirubinaemia. Study design prospective, observational, multicenter. Subjects 2167 term and late preterm infants born in 5 neonatal units in the Lazio region of Italy. Methods All neonates had simultaneous TcB and total serum bilirubin (TSB) measurements, when jaundice appeared and/or before hospital discharge. TcB and TSB values were plotted on a percentile-based hour-specific transcutaneous nomogram previously developed, to identify the safe percentile able to predict subsequent significant hyperbilirubinaemia defined as serum bilirubin > 17 mg/dL or need for phototherapy. Results Fifty-five babies (2.5%) developed significant hyperbilirubinaemia. The 50th percentile of our nomogram was able to identify all babies who were at risk of significant hyperbilirubinaemia, but with a high false positive rate. Using the 75th percentile, two false negatives reduced sensitivity in the first 48 hours but we were able to detect all babies at risk after the 48th hour of age. Conclusions: This study demonstrates that the 75th percentile of our TcB nomogram is able to exclude any subsequent severe hyperbilirubinaemia from 48 h of life ahead.

Respiratory Syncytial Virus infections are one of the leading causes of severe respiratory diseases that require hospitalization and, in some cases, intensive care. Once resolved, there may be respiratory sequelae of varying severity. The lack of effective treatments for bronchiolitis and the lack of vaccines for RSV accentuate the role of prevention in decreasing the impact of this disease. Prevention of bronchiolitis strongly relies on the adoption of environment and the hygienic behavior measures; an additional prophylactic effect may be offered, in selected cases, by Palivizumab, a humanized monoclonal antibody produced by recombinant DNA technology, able to prevent RSV infection by blocking viral replication. After many years the Italian Society of Neonatology, on the basis of the most recent scientific knowledge, has decided to revise recommendations for the use of palivizumab in the prevention of RSV infection.

Background Late preterm (LP) infants [gestational age (GA): 3436 weeks] are at increased risk of neonatal acute respiratory morbidity compared with term infants (GA: 3741) [1,2]. The observed rate of acute respiratory morbidity, in a population of about 20,000 LP infants, was 10-12% vs 1.4% of term infants [1]. Transient tachypnea of the newborn (TTN) and respiratory distress syndrome (RDS) are the most common diagnosis, with RDS rate reaching 10.5% in infants born at 34 weeks of GA [1,2]. Major causes of respiratory morbidity in LP are: prematurity and birth by Cesarean Section (CS) [1,3]. Material and methods We retrospectively studied 830 LP and moderate preterm (MP) infants (GA: 33-36 weeks) admitted to our unit from June 2009 to December 2013. Infants were classified according to GA: 33 weeks (n = 129), 34 weeks (n = 176), 35 weeks (n = 225), 36 weeks (n = 300). Clinical charts for each patient were reviewed and main diagnosis recorded.

BackgroundEarly discharge of healthy late preterm and full term newborn infants has become common practice because of the current social and economic necessities. Severe jaundice, and even kernicterus, has developed in some term infants discharged early. This study was designed to elaborate a percentile-based hour specific total serum bilirubin (TSB) nomogram and to assess its ability to predict the absence of risk for subsequent non physiologic severe hyperbilirubinaemia before discharge.MethodsA percentile-based hour-specific nomogram for TSB values was performed using TSB data of 1708 healthy full term neonates. The nomogram's predictive ability was then prospectively assessed in five different first level neonatal units, using a single TSB value determined before discharge.ResultsThe 75thpercentile of hour specific TSB nomogram allows to predict newborn babies without significant hyperbilirubinemia only after the first 72 hours of life. In the first 48 hours of life the observation of false negative results did not permit a safe discharge from the hospital.ConclusionThe hour-specific TSB nomogram is able to predict all neonates without risk of non physiologic hyperbilirubinemia only after 48 to 72 hours of life. The combination of TSB determination and risk factors for hyperbilirubinemia could facilitate a safe discharge from the hospital and a targeted intervention and follow-up.

Apnea of prematurity is a developmental disorder that frequently affects preterm infants, especially those with lower gestational age. Even if apnea of prematurity is by definition a self-limiting condition, it can cause serious problems during the hospital stay and can potentially have long-term neurological and cognitive consequences depending on the severity and inten- sity of the episodes. The diagnosis of apnea of prematurity can be made only after excluding a number of diseases of the preterm infant in which apnea may be an epiphenomenon. Etiological diagnosis is essential for selection of appropriate treatment, which may be nonpharmacological or involve use of drugs.

Congenital leukemia is a very rare severe condition and leukemia cutis may represent the presenting sign of this malignancy, sometimes preceding hematological findings of weeks. Typical clinical features include multiple red to purple papules, macules and nodules due to direct infiltration of the skin by malignant cells. We illustrate these cutaneous findings in a patient with congenital leukemia and tetralogy of Fallot.

Background The increased number of childbearing women with autoimmune diseases leads to a growing interest in studying relationship among maternal disease, therapy, pregnancy and off-spring. The aim of this study was to determine the impact of autoimmune disease on pregnancy and on neonatal outcome, taking into account the maternal treatment and the transplacental autoantibodies passage. Methods We studied 70 infants born to 70 pregnant women with autoimmune disease attended in Fondazione IRCCS Policlinico San Matteo, Pavia, Italy from June 2005 to June 2012. Maternal and neonatal characteristics were collected and relevant clinical, laboratory, therapeutics, sonographic and electrocardiographic investigations were recorded and analyzed. Results We observed a high rate of spontaneous abortions in medical history, 29 %, and 18.6 % of preterm births and 22.9 % of low birth weight (< 2500 g). Transplacental autoantibodies passage wasn’t related to maternal or obstetrical complication, but anti-Ro/SSA positive pregnancies correlated with abnormal fetal heart rate (P = 0.01). Pregnant women on therapy showed an higher incidence of maternal (p = 0.002), obstetric (p = 0.007) complications and an increased rate of intrauterine growth restriction (p = 0.01) than the untreated ones. Conclusions Autoimmune diseases in pregnancy require to be carefully monitored to ensure the best possible management of mothers, fetuses and newborns due to the high rate of morbidity specially in case of maternal polytherapy and/or anti-Ro/SSA positivity.

An appropriate stabilization before transport is essential to reduce adverse events [1-5]. The aim of this study was to describe the characteristics of a cohort of newborns transported and to evaluate the association between stabilization time and change of Transport Risk Index of Physiologic Stability (TRIPS score)[6].

Cortisol production by the human fetal adrenal cortex has been shown to be not adequate at early gestation. This is due to an inefficient expression of 3β-hydroxysteroid dehydrogenase, the enzyme that catalyzes the synthesis of progesterone from pregnenolone, before about 23 weeks of gestation. Whereas, the fetal adrenal cortex it is able to produce dehydroepiandrosterone sulphate for placental estrogen synthesis and to convert placental progesterone to cortisol [1,2]. During the last trimester of pregnancy the fetal adrenal gland undergoes significant anatomical and functional maturation for adaptation to extra-uterine life and cortisol production increases greatly in the last two months of gestation. Cortisol increases synthesis of surfactant, enhances the reabsorption of lung fluid, promotes the conversion of T4 to T3, favors the closure of the ductus arteriosus and maturation of liver and intestinal enzymes [2]. Adrenal insufficiency can be caused by rare conditions such as adrenocortical hypoplasia or congenital enzymatic deficiencies of steroidogenesis, with clinical variables depending on the hormone involved. In preterm infants, the developmental immaturity, combined with increased demands in critical illness, may result in insufficient cortisol production to maintain homeostasis in the face of acute stress or illness, despite apparently normal cortisol levels. This condition is known as “transient or relative adrenal insufficiency” (TAI) [3,4]. TAI usually appears in the first week of life and normalizes in the second week. Infants with TAI can exhibit refractory hypotension (hypotension not responsive to volume expanders and inotropic drugs, but responsive to corticosteroids), respiratory distress, patent ductus arteriosus and bronchopulmonary dysplasia (BPD) [2,3]. Diagnosis of TAI is not easy because many other conditions can cause hypotension in VLBW infants: hypovolemia, myocardial dysfunction, deficient vascular tone, hyaline membrane disease, infection or a combinations of these factors. In addition, normal basal cortisol levels are extremely variable in preterms and to date there is no consensus on the diagnosis of adrenal insufficiency based on tests with adrenocorticotropic hormone (ACTH) [5-8]. Appropriate dose and duration of steroid therapy have not been established yet. On the other hand refractory and persistent hypotension is associated with intraventricular hemorrhage, periventricular leukomalacia, increased mortality and neurological disability [9]. Poor adrenal response has been shown to be associated with later development of BPD and with death [10,11]. For these reasons further studies are needed to evaluate the efficacy and safety of glucocorticoids in the treatment of cardiovascular failure due to TAI in ill preterm and term infants [12,13].