Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including ...high cell permeability, the ability to easily cross both the blood-brain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care.
Brain injury at birth is an important cause of neurological and behavioral disorders. Hypoxic-ischemic encephalopathy (HIE) is a critical cerebral event occurring acutely or chronically at birth with ...high mortality and morbidity in newborns. Therapeutic strategies for the prevention of brain damage are still unknown, and the only medical intervention for newborns with moderate-to-severe HIE is therapeutic hypothermia (TH). Although the neurological outcome depends on the severity of the initial insult, emerging evidence suggests that infants with mild HIE who are not treated with TH have an increased risk for neurodevelopmental impairment; in the current clinical setting, there are no specific or validated biomarkers that can be used to both correlate the severity of the hypoxic insult at birth and monitor the trend in the insult over time. The aim of this work was to examine the presence of autophagic and mitophagic proteins in bodily fluids, to increase knowledge of what, early at birth, can inform therapeutic strategies in the first hours of life. This is a prospective multicentric study carried out from April 2019 to April 2020 in eight third-level neonatal intensive care units. All participants have been subjected to the plasma levels quantification of both Parkin (a protein involved in mitophagy) and ATG5 (involved in autophagy). These findings show that Parkin and ATG5 levels are related to hypoxic-ischemic insult and are reliable also at birth. These observations suggest a great potential diagnostic value for Parkin evaluation in the first 6 h of life.
Abstract Background Cranial ultrasonography is a useful tool to detect intracranial lesions in premature neonates at risk. Our primary aim was to determine the number of patients with abnormal ...cranial ultrasonography. Secondary aims were to evaluate the usefulness of universal cranial ultrasonography screening in moderately preterm infants. Methods All infants born from 2007 to 2012 at the University Hospital of Ferrara (Italy), with gestational age of 33-36 weeks, were included in the study. Cranial ultrasonography findings were retrospectively classified into nonsignificant and significant. Results All the 724 babies born were screened. Intracranial lesions were in 13% of neonates (3.7% at 36 weeks to 27.1% at 33 weeks of gestational age). Babies born at 33-34 weeks of gestational age were four times more likely to have an abnormal cranial ultrasonography than those at 35-36 weeks. Statistical analysis revealed no association between cranial ultrasonography abnormalities and being small for gestational age or mode of delivery. A significant association was present between the presence of head circumference less than the third percentile, the need for ventilation or surfactant, low Apgar index at fifth minute, and neurological abnormalities. The presence of at least one considered risk factor increases the probability of cranial ultrasonography abnormalities twice in infants born at 33-34 weeks and 15 times in born at 35-36 weeks. Conclusions A considerable number of infants born between 33 and 36 weeks have cranial ultrasonography abnormalities. We suggest that screening should be performed or at least that a uniform protocol should be developed for the early detection of all significant cranial ultrasonography abnormalities.
Abstract Background Brain malformations represent a major cause of refractory seizures. Standardized protocols to treat status epilepticus of newborn are not available in the literature. Patient We ...present a case report of use of ketamine administered to a late preterm with Pierre Robin sequence, lissencephaly, polymicrogyria, and severe epilepsy. Results The infusion of ketamine permitted resolution of status epilepticus, cardiorespiratory stabilization, and improved parental care for 15 days. No significant side effects were noted. Conclusion In the literature there are few studies regarding the use of ketamine for refractory status epilepticus, and only in nine of these described the use of, ketamine in children (2 months-18 years). This is the first report to document the effective use of ketamine in the newborn with status epilepticus.
Multiple mutations of surfactant genes causing surfactant dysfunction have been described. Surfactant protein C (SP-C) deficiency is associated with variable clinical manifestations ranging from ...neonatal respiratory distress syndrome to lethal lung disease. We present an extremely low birth weight male infant with an unusual course of respiratory distress syndrome associated with two mutations in the SFTPC gene: C43-7G>A and 12T>A. He required mechanical ventilation for 26 days and was treated with 5 subsequent doses of surfactant with temporary and short-term efficacy. He was discharged at 37 weeks of postconceptional age without any respiratory support. During the first 16 months of life he developed five respiratory infections that did not require hospitalization. Conclusion. This mild course in our patient with two mutations is peculiar because the outcome in patients with a single SFTPC mutation is usually poor.
Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine ...(ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.
Abstract Background Full-term neonates may have asymptomatic cranial injuries at birth and HUS could be useful for early diagnosis. The aim of this study was to assess the prevalence and type of ...intracranial abnormalities and the usefulness of HUS in these infants. Methods A HUS was performed on all full-term neonates (gestational age between 37 and 42 weeks), born at Sant’Anna University Hospital of Ferrara, Italy, from June 1, 2008 through May 31, 2013. Ultrasound findings were categorized into three groups: normal, minor and major anomalies. Results All full-term neonates (6,771) born at our hospital underwent HUS. 114/6771 (1.7%) presented ultrasound abnormalities, while 6,657 were normal (or insignificant). In 101/114 (88.6%), abnormalities were minor and only 13 infants were affected by major abnormalities (0.19% of all full-term newborns). All neonates with major abnormalities presented with either microcephaly or abnormal neurological evaluations. Only one case of major abnormalities was detected exclusively by ultrasound. Conclusions The number of significant anomalies detected by HUS in asymptomatic full-term neonates born during the study period was low. Therefore, according to data collected in this study, we believe that there is no indication for routine general HUS in these patients. However, even if low, in neonates who have neurological abnormalities, risk factors or suspected brain malformations, HUS may play an important role in the early diagnosis of intracranial anomalies.
The importance of lung recruitment before surfactant administration has been shown in animal studies. Well designed trials in preterm infants are absent. We aimed to examine whether the application ...of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (intubate-recruit-surfactant-extubate IN-REC-SUR-E), decreased the need for mechanical ventilation during the first 72 h of life compared with no recruitment manoeuvre (ie, intubate-surfactant-extubate IN-SUR-E).
We did a randomised, unblinded, controlled trial in 35 tertiary neonatal intensive care units in Italy. Spontaneously breathing extremely preterm neonates (24 + 0 to 27 + 6 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 h of life were randomly assigned (1:1) with a minimisation algorithm to IN-REC-SUR-E or IN-SUR-E using an interactive web-based electronic system, stratified by clinical site and gestational age. The primary outcome was the need for mechanical ventilation in the first 72 h of life. Analyses were done in intention-to-treat and per-protocol populations, with a log-binomial regression model correcting for stratification factors to estimate adjusted relative risk (RR). This study is registered with ClinicalTrials.gov, NCT02482766.
Of 556 infants assessed for eligibility, 218 infants were recruited from Nov 12, 2015, to Sept 23, 2018, and included in the intention-to-treat analysis. The requirement for mechanical ventilation during the first 72 h of life was reduced in the IN-REC-SUR-E group (43 40% of 107) compared with the IN-SUR-E group (60 54% of 111; adjusted RR 0·75, 95% CI 0·57-0·98; p=0·037), with a number needed to treat of 7·2 (95% CI 3·7-135·0). The addition of the recruitment manoeuvre did not adversely affect the safety outcomes of in-hospital mortality (19 19% of 101 in the IN-REC-SUR-E group vs 37 33% of 111 in the IN-SUR-E group), pneumothorax (four 4% of 101 vs seven 6% of 111), or grade 3 or worse intraventricular haemorrhage (12 12% of 101 vs 17 15% of 111).
A lung recruitment manoeuvre just before surfactant administration improved the efficacy of surfactant treatment in extremely preterm neonates compared with the standard IN-SUR-E technique, without increasing the risk of adverse neonatal outcomes. The reduced need for mechanical ventilation during the first 72 h of life might facilitate implementation of a non-invasive respiratory support strategy.
None.
Bohring-Opitz syndrome (BOS) is a rare genetic disorder characterised by a recognisable craniofacial appearance and a typical 'BOS' posture. BOS is caused by sporadic mutations of
. However, several ...typical patients with BOS have no molecular diagnosis, suggesting clinical and genetic heterogeneity.
To expand the phenotypical spectrum of autosomal recessive variants of
, reported as causing Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like syndrome.
We performed whole-exome sequencing in two families with a suspected recessive mode of inheritance. We used the Matchmaker Exchange initiative to identify additional patients.
Here, we report six patients with microcephaly, facial dysmorphism, including exophthalmos, nevus flammeus of the glabella and joint contractures with a suspected BOS posture in five out of six patients. We identified autosomal recessive truncating mutations in the
gene.
encodes a BTB-kelch protein implicated in the cell cycle and in protein degradation by the ubiquitin-proteasome pathway. Recently, biallelic mutations in the
gene were reported in four families and associated with CS/CISS1, characterised by clinical features overlapping with our patients.
We have expanded the clinical spectrum of
autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS.
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