Increase of Parkin and ATG5 plasmatic levels following perinatal hypoxic‐ischemic encephalopathy

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

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: Study protocol for a randomized controlled trial

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. Methods/design: In this study, 206 spontaneously breathing infants born at 24+0-27+6 weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. Trial registration: ClinicalTrials.gov identifier: NCT02482766. Registered on 1 June 2015

Use of Ketamine in a Newborn With Refractory Status Epilepticus: A Case Report

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

Universal Head Ultrasound Screening in Full-term Neonates: A Retrospective Analysis of 6771 Infants

Background Full-term neonates may have asymptomatic cranial injuries at birth and head ultrasound screening 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 head ultrasound screening in these infants. Methods Head ultrasound screening 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 (6771) born at our hospital underwent head ultrasound screening. One hundred fourteen of 6771 (1.7%) presented ultrasound abnormalities, whereas 6657 were normal or exhibited insignificant findings. In 101 of 114 (88.6%), abnormalities were minor, and only 13 infants had major abnormalities (0.19% of all full-term newborns). All neonates with major abnormalities presented with either microcephaly or abnormal neurological evaluations. Only one individual with major abnormalities was detected exclusively by ultrasound. Conclusions The number of significant anomalies detected by head ultrasound screening in asymptomatic full-term neonates born during the study period was low. Therefore, there is no indication for routine general head ultrasound screening in these patients. However, even if low, in neonates who have neurological abnormalities, risk factors or suspected brain malformations, head ultrasound screening may play an important role in the early diagnosis of intracranial anomalies

Il riconoscimento del dolore nel neonato a termine e pretermine

L’identificazione e il trattamento del dolore neonatale sono ancora oggi problematici, sebbene sia stato dimostrato che il neonato è in grado di percepire il dolore e che esperienze dolorose precoci possono avere ripercussioni sulla futura elaborazione degli stimoli nocicettivi. Allo scopo di condividere queste recenti acquisizioni, nel corso della rassegna verranno presentate le tappe cruciali che hanno portato al riconoscimento del dolore nel neonato, verranno descritte le fasi dello sviluppo anatomo-funzionale delle strutture nocicettive, nonché i problemi relativamente agli effetti a breve e a lungo termine, alla valutazione e al trattamento del dolore neonatale

Two Mutations in Surfactant Protein C Gene Associated with Neonatal Respiratory Distress

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

Universal Cranial Ultrasound Screening in Preterm Infants With Gestational Age 33-36 Weeks. A Retrospective Analysis of 724 Newborns

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

Double Interstitial Deletion of the Long Arm of Chromosome 6 in a Patient with Pierre Robin Sequence, Dysmorphisms, and Severe Developmental Delay

Reported here is the case of a 1.8-year-old boy with a 9.6-Mb deletion in 6q13q14.1 and an 11.2-Mb deletion in 6q21q22.31, ascertained through array CGH, as the result of a complex de novo chromosome rearrangement. The clinical picture of this patient is characterized by severe psychomotor delay, dysmorphic features, and some congenital defects. Although, as reported in the literature, phenotypes associated with 6q deletions may vary, an attempt was made to associate the patient's symptoms to either deletion, comparing them to previously reported cases. Only a limited specific correlation was found, probably due to the prevalence of very common symptoms

Expanding the clinical spectrum of recessive truncating mutations of KLHL7 to a Bohring-Opitz-like phenotype

Background 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 ofASXL1. However, several typical patients with BOS have no molecular diagnosis, suggesting clinical and genetic heterogeneity. Objectives To expand the phenotypical spectrum of autosomal recessive variants of KLHL7, reported as causing Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like syndrome. Methods 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. Results 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 KLHL7 gene. KLHL7 encodes a BTB-kelch protein implicated in the cell cycle and in protein degradation by the ubiquitin-proteasome pathway. Recently, biallelic mutations in the KLHL7 gene were reported in four families and associated with CS/CISS1, characterised by clinical features overlapping with our patients. Conclusion We have expanded the clinical spectrum of KLHL7 autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS