Pain and heart rate variability in neonates receiving dexmedetomidine.

INTRODUCTION: Neonates in a NICU experience pain. Based on the cardiovascular and nociceptive systems link, a Newborn Infant Parasympathetic Evaluation (NIPE) monitor was designed to assess pain. The use of α2-agonists as analgesic-sedative drugs has increased in neonates. Given their effect on the autonomic system, we hypothesized that their use may alter NIPE's measurement capacity. METHODS: Data were prospectively collected. The included patients were evaluated using combined pain assessment systems. RESULTS: Sixteen newborns requiring sedoanalgesia underwent a total of 84 pain assessments. A good correlation was found between the NIPE-index and the COMFORT-neo and the crSO2 (cerebral regional oxygen saturation). No correlation was found in premature infants. By sedation group, the correlation remained in those receiving α2-agonist. CONCLUSION: NIPE is a reliable tool for pain assessment. Further studies in premature infants are needed. The use of α2-agonist does not alter the measuring capacity of NIPE. The correlation between NIPE-index and crSO2 was also demonstrated.

Implementing palliative care, based on family-centered care, in a highly complex neonatal unit

Abstract Objective: To describe the causes and circumstances of neonatal mortality and determine whether the implementation of a palliative care protocol has improved the quality of end-of-life care. Methods: A retrospective observational study including all patient mortalities between January 2009 and December 2019. Cause of death and characteristics of support during the dying process were collected. Two periods, before and after the implementation of a palliative care protocol, were compared. Results: There were 344 deaths. Congenital malformations were the most frequent cause of death (45.6 %). Most patients died after the transition to palliative care (74.4 %). The most frequently cited criteria for initiating transition of care was poor neurocognitive prognosis (47.2 %). Parents accompanied their children in the dying process in 72 % of cases. Twenty-three percent of patients died outside the Neonatal Intensive Care Unit after being transferred to a private room to enhance family intimacy. After the addition of the palliative care protocol, statistically significant differences were observed in the support and patient experience during the dying process. Conclusions: The most frequent causes of death were severe congenital malformations. Most patients died accompanied by their parents after the transition to palliative care. The implementation of a palliative care protocol helped to improve the family-centered end-of-life care.

Pediatric Animal Model of Extracorporeal Cardiopulmonary Resuscitation after Prolonged Circulatory Arrest.

Congenital heart disease (CHD) is the most prevalent congenital malformation, with about one million births impacted worldwide per year. Comprehensive investigation of this disease requires appropriate and validated animal models. Piglets are commonly used for translational research due to their analogous anatomy and physiology. This work aimed to describe and validate a neonatal piglet model of cardiopulmonary bypass (CPB) with circulatory and cardiac arrest (CA) as a tool for studying severe brain damage and other complications of cardiac surgery. In addition to including a list of materials, this work provides a roadmap for other investigators to plan and execute this protocol. After experienced practitioners performed several trials, the representative results of the model demonstrated a 92% success rate, with failures attributed to small piglet size and variant vessel anatomy. Furthermore, the model allowed practitioners to select from a wide variety of experimental conditions, including varying times in CA, temperature alterations, and pharmacologic interventions. In summary, this method uses materials readily available in most hospital settings, is reliable and reproducible, and can be widely employed to enhance translational research in children undergoing heart surgery.

Do FETO CDH survivors need the same follow-up program as non-FETO patients?

Congenital diaphragmatic hernia (CDH) survivors are at risk of developing significant chronic health conditions and disabilities. The main purpose of this study was to compare the outcomes of CDH infants at 2 years of age (2y) according to whether the infants had undergone fetoscopic tracheal occlusion (FETO) during the prenatal period and characterize the relationship between morbidity at 2y and perinatal characteristics. Retrospective cohort single center study. Eleven years of clinical follow-up data (from 2006 to 2017) were collected. Prenatal and neonatal factors as well as growth, respiratory, and neurological evaluations at 2y were analyzed. One hundred and fourteen CDH survivors were evaluated. Failure to thrive (FTT) was present in 24.6% of patients, gastroesophageal reflux disease (GERD) in 22.8%, 28.9% developed respiratory problems, and 22% had neurodevelopment disabilities. Prematurity and birth weight < 2500 g were related to FTT and respiratory morbidity. Time to reach full enteral nutrition and prenatal severity markers seemed to influence all outcomes, but FETO therapy itself only had an effect on respiratory morbidity. Some variables related to postnatal severity (ECMO, patch closure, days on mechanic ventilation, and vasodilator treatment) were associated with almost all outcomes.  Conclusion: CDH patients have specific morbidities at 2y, most of them related to lung hypoplasia severity. Only respiratory problems were related to FETO therapy itself. The implementation of a specific multidisciplinary follow-up program for CDH patients is essential to provide them the best standard of care, but, more severe patients, regardless of whether they received prenatal therapy, need a more intensive follow-up. What is Known: • Antenatal fetoscopic endoluminal tracheal occlusion (FETO) increases survival in more severe congenital diaphragmatic hernia patients. • Congenital diaphragmatic hernia survivors are at risk of developing significant chronic health conditions and disabilities. Very limited data are available about the follow-up in patients with congenital diaphragmatic hernia and FETO therapy. What is New: • CDH patients have specific morbidities at 2 years of age, most of them related to lung hypoplasia severity. • FETO patients present more respiratory problems at 2 years of age but they don't have an increased incidence of other morbidities. More severe patients, regardless of whether they received prenatal therapy, need a more intensive follow-up.

Cardiac function in bronchiolitis: Not only a right ventricle matter.

OBJECTIVES: Extrapulmonary manifestations of bronchiolitis have been previously studied, with some identifying right ventricle (RV) diastolic/systolic dysfunction. We hypothesized that severe cases of bronchiolitis would have cardiac dysfunction resulting an increase in N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) values and worse outcomes. Therefore, the objective was to evaluate the existence of cardiac dysfunction and to determine its association with severe bronchiolitis. METHODS: This prospective cohort study included children hospitalized for bronchiolitis under 1-year old between January 2019 and March 2020. At admission, an echocardiography was performed and plasma levels of NT-proBNP were measured. To analyze outcomes, the cohort was divided into two groups based on the need for positive pressure respiratory support (PPRS), and both were compared to healthy infants. STATISTICS: bivariant analysis, significant differences p < 0.05. RESULTS: One hundred eighty-one patients were included; median age was 2 months. Seventy-three patients required PPRS. Compared to controls, patients requiring PPRS showed worse RV systolic function, with lower tricuspid annular-plane systolic excursion (p = 0.002) and parameters of worse right and left diastolic function (trans-tricuspid E and A wave [p = 0.004 and p = 0.04, respectively] and tricuspid tissue doppler imaging [TDI] e' [p = 0.003], trans-mitral E and mitral TDI a' [p = 0.02 and p = 0.005, respectively]). An NT-ProBNP greater than 3582 pg/dl predicts the need for longer necessity of PPRS in patients younger than 2 months. CONCLUSIONS: In addition to the expected RV systolic dysfunction, patients with severe bronchiolitis have parameters of global diastolic worse function possibly secondary to intrinsic myocardial involvement. NT-ProBNP values at admission had strong discriminatory power to predict worse outcomes.

Oxidative Stress and Indicators of Brain Damage Following Pediatric Heart Surgery.

Pediatric cardiac surgery induces an increased oxidative stress (OS) response. Increased OS is associated with poor neurologic outcomes in neonatal populations with similar patterns of brain injury. We investigated OS and brain injury in infants undergoing heart surgery. Patients 6 months or younger, undergoing cardiac surgery with or without cardiopulmonary bypass (CPB), were included in this prospective, observational study. Patients were divided into infant (30 days−6 months) and neonatal (<30 days) groups for analysis. Urine OS biomarker 8-iso-prostaglandin F2α (8-iso-PGF2α) was quantified pre-surgery and at 0 and 24 h post-surgery. A serum brain damage biomarker S100B protein was also measured pre-surgery and at 0 and 72 h post-surgery. Amplitude-integrated electroencephalography during surgery was analyzed. Neuropsychological evaluation using the Bayley III or Vineland test was performed in all patients at 24 months of age. Sixty-two patients were included, 44 of whom underwent follow-up neurologic evaluation. 8-iso-PGF2α and S100B levels were increased after surgery. Postoperative levels of S100B were positively correlated with 8-iso-PGF2α levels 24 h after surgery (rho = 0.5224; p = 0.0261). There was also a correlation between immediate post-surgery levels of 8-iso-PGF2α and intra-surgery seizure burden (rho = 0.4285, p = 0.0205). Patients with an abnormal neurological evaluation had increased levels of S100B 72 h after surgery (p = 0.048). 8-iso-PGF2α levels 24 h after surgery were also related to abnormal neurologic outcomes. Levels of 8-iso-PGF2α following pediatric cardiac surgery are associated with several indicators of brain injury including brain damage biomarkers, intra-operative seizures, and abnormal neurological evaluation at follow-up, suggesting the importance of oxidative stress response in the origin of brain damage in this population.

Brain Oxygen Perfusion and Oxidative Stress Biomarkers in Fetuses with Congenital Heart Disease-A Retrospective, Case-Control Pilot Study.

Fetuses with congenital heart disease (CHD) have circulatory changes that may lead to predictable blood flow disturbances that may affect normal brain development. Hypoxemia and hypoperfusion may alter the redox balance leading to oxidative stress (OS), that can be assessed measuring stable end-products. OS biomarkers (OSB) were measured in amniotic fluid in fetuses with (n = 41) and without CHD (n = 44) and analyzed according to aortic flow, expected cyanosis after birth, and a CHD classification derived from this. Birth head circumference (HC) was used as a neurodevelopment biomarker. CHD fetuses had higher levels of ortho-Tyrosine (o-Tyr) than controls (p = 0.0003). There were no differences in o-Tyr levels considering aortic flow obstruction (p = 0.617). Fetuses with expected extreme cyanosis presented the highest levels of o-Tyr (p = 0.003). Among groups of CHD, fetuses without aortic obstruction and extreme cyanosis had the highest levels of o-Tyr (p = 0.005). CHD patients had lower HC than controls (p = 0.023), without correlation with OSB. Patients with HC < 10th percentile, presented high levels of o-Tyr (p = 0.024). Fetuses with CHD showed increased OSB and lower HC when compared to controls, especially those with expected extreme cyanosis. Our results suggest that increased levels of OSB are more influenced by the effect of low oxygenation than by aortic flow obstruction. Future studies with larger sample size are needed to further investigate the role of OSB as an early predictor of neurodevelopmental problems in CHD survivors.

A UPLC-MS/MS method for the determination of oxidative stress biomarkers in amniotic fluid.

Oxidative stress in the fetal period is associated with preterm birth as well as short and long-term adverse clinical outcomes. Here, an Ultra-Performance Liquid Chromatography-tandem Mass Spectrometry (UPLC-MS/MS) method for the simultaneous quantification of biomarkers of oxidative stress-derived damage to proteins and DNA in amniotic fluid (AF) samples is presented. Appropriate accuracy and precision levels, as well as sensitivity with limits of detection in the low nanomolar (<2 nM) range were achieved. The analytical method was applied to a set of AF samples and reference ranges of the biomarker panel are presented. Median concentrations of biomarkers of protein oxidation (ortho-, 3-chloro-, and 3-nitrotyrosine) and their precursors (para-tyrosine and phenylalanine) ranged between 0.6 and 3 nM and 23 and 30 µM, respectively, while levels of a biomarker of DNA-oxidation (8-hydroxydeoxyguanosine, 8OHdG) and its precursor (2'-deoxyguanosine) were found to be 0.18 and 3 nM, respectively. Detection frequencies of all metabolites were 100% with exception of 3-chlorotyrosine (3Cl-Tyr) and 8OHdG, that were only detected in 8% of samples. The developed method may be applied in research studies focusing on oxidative stress-related complications during pregnancy.

Mid-regional pro-adrenomedullin for diagnosing evolution after cardiac surgery in newborns: the PRONEW study.

Newborns are the most vulnerable patients after cardiac surgery. Although mortality risk scores before surgery may help predict the risk of poor outcome, new tools are required, and biomarkers could add objective data to these tools. The aim of this study was to assess the ability of mid-regional pro-adrenomedullin (pro-ADM) and pro-atrial natriuretic peptide (pro-ANP) to predict poor outcome after cardiac surgery. This is a pilot diagnostic accuracy study that includes newborns and infants under 2 months admitted to an intensive care unit after cardiac surgery. Pro-ADM and pro-ANP were determined immediately upon admission. Poor outcome was defined as mortality, cardiac arrest, requiring extracorporeal support, requiring renal replacement therapy, or neurological injury. Forty-four patients were included. Twenty-six (59%) had a STAT category of ≥ 4. Ten patients (22.7%) presented a poor outcome, four of whom (9.1%) died. Pro-ADM was higher in patients with poor outcome (p = 0.024) and death (p = 0.012). Pro-ADM showed the best area under curve (AUC) for predicting poor outcome (0.735) and mortality alone (0.869). A pro-ADM of 2 nmol/L had a Sn of 75% and a Sp of 85% for predicting mortality. Pro-ADM > 2 nmol/L was independently associated with poor outcome (OR 5.8) and mortality (OR 14.1). Although higher pro-ANP values were associated with poor outcomes, no cut-off point were found. The combination of STAT ≥ 4 and the biomarkers did not enhance predictive power for poor outcome or mortality.Conclusion: Pro-ADM and pro-ANP determined immediately after surgery could be helpful for stratifying risk of poor outcome and mortality in newborns. What is Known: • Some congenital heart diseases must be corrected/palliated during the first days of life. A useful tool to predict the risk of severe complications has not been proposed. • Most unstable newborns would have higher values of biomarkers such as pro-ADM and pro-ANP related to shock and compensatory actions. What is New: • Pro-ADM and pro-ANP seem to be good biomarkers to predict poor outcome after cardiac surgery. A pro-ADM < 2 nmol/L would imply a low likelihood of a poor outcome. • Deepening the analysis of biomarkers can help in making decisions to prevent/treat complications.

Effects of Hypothermia and Allopurinol on Oxidative Status in a Rat Model of Hypoxic Ischemic Encephalopathy.

Hypoxic ischemic encephalopathy (HIE) is one of the main causes of morbidity and mortality during the neonatal period, despite treatment with hypothermia. There is evidence that oxidative damage plays an important role in the pathophysiology of hypoxic-ischemic (HI) brain injury. Our aim was to investigate whether postnatal allopurinol administration in combination with hypothermia would reduce oxidative stress (OS) biomarkers in an animal model of HIE. Postnatal 10-day rat pups underwent unilateral HI of moderate severity. Pups were randomized into: Sham operated, hypoxic-ischemic (HI), HI + allopurinol (HIA), HI + hypothermia (HIH), and HI + hypothermia + allopurinol (HIHA). Biomarkers of OS and antioxidants were evaluated: GSH/GSSG ratio and carbonyl groups were tested in plasma. Total antioxidant capacity (TAC) was analyzed in plasma and cerebrospinal fluid, and 8-iso-prostaglandin F2α was measured in brain tissue. Plasma 2,2'-azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) levels were preserved in those groups that received allopurinol and dual therapy. In cerebrospinal fluid, only the HIA group presented normal ferric reducing ability of plasma (FRAP) levels. Protein oxidation and lipid peroxidation were significantly reduced in all groups treated with hypothermia and allopurinol, thus enhancing neuroprotection in HIE.

Oxidative stress response in children undergoing cardiac surgery: Utility of the clearance of isoprostanes.

INTRODUCTION: Cardiac surgery (CS) in pediatric patients induces an overt oxidative stress (OS) response. Children are particularly vulnerable to OS related injury. The immaturity of their organs and antioxidant systems as well as the induction of OS in cardio-pulmonary bypass (CPB) surgery may have an important impact on outcomes. The purpose of this study was to describe the OS response, measured by urinary free 8-iso-PGF2α, in infants undergoing CS and to evaluate the relationship between OS response and post-operative clinical outcomes. METHODS: Infants with congenital heart disease undergoing CS with or without CPB were eligible for enrollment. Children were classified as neonates (<30 days) or infants (30 days-6 months) based on the age at surgery. Perioperative continuous non-invasive neuromonitoring included amplitude-integrated electroencephalogram and cerebral regional oxygen saturation measured with near-infrared spectroscopy. Urine 8-iso-PGF2α levels were measured before, immediately post-, and 24-hours post-surgery, and the 8-iso-PGF2 clearance was calculated. RESULTS: Sixty-two patients (60% neonates) were included. Urine 8-iso-PGF2α levels 24 hours after surgery (8.04 [6.4-10.3] ng/mg Cr) were higher than pre-operative levels (5.7 [4.65-7.58] ng/mg Cr) (p<0.001). Those patients with a severe degree of cyanosis caused by Transposition of the Great Arteries (TGA) had the highest post-operative 8-iso-PGF2α levels. Patients with intra-operative seizures had higher post-operative 8-iso-PGF2α levels. 8-iso-PGF2α clearance at 24 hours post-surgery was different between newborns and infant patients, and it was inversely correlated with days of mechanical ventilation (p = 0.05), ICU LOS (p = 0.05) and VIS score at 24 hours (p = 0.036). CONCLUSIONS: Children undergoing CS, particularly neonatal patients, experience a significant post-operative OS response that might play an important role in postoperative morbidity. TGA patients undergoing arterial switch operations demonstrate the highest post-operative OS response. Rapid clearance of isoprostanes, which occurs more frequently in older patients with more mature antioxidant systems, might be associated with better clinical outcomes.

Blind Endotracheal Intubation in Neonatal Rabbits.

The newborn rabbit is a useful animal model for various pathologies and procedures. Airway management of the rabbit is complex due to its anatomical characteristics, which is further complicated in the case of the newborn. Of the different methods of advanced airway management, endotracheal intubation is less aggressive than tracheostomy, and is more feasible than supraglottic management given the lack of supraglottic devices of such a small size. As direct glottis visualization is very difficult in animals this size, this blind intubation model is presented as an effective alternative, especially for experiments requiring prolonged anesthesia. Using this method, we performed blind intubations with a 90% success rate.

Lung ultrasound in the follow-up of primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is an airways ciliary defect, making them unable to beat normally. Hence, there is an increase in the incidence of respiratory recurrent infections leading to multiple atelectasis from different lung lobes during the first months of life repeat chest X-ray (CXR) controls with increase of radiation exposure in this younger population. We report the lung ultrasound follow-up of two newborn diagnosed with PCD. The illness in these cases was suspected during the first days of life due to worsening of respiratory distress on previous healthy newborns. Both patients cases show the ability of bedside lung ultrasound (LUS) to confirm clinical suspicion of atelectasis or pneumonia. Using LUS for the diagnosis and follow-up may help in avoiding routine CXR, thus reducing the huge amount of ionizing radiation in these patients.

Estimated dead space fraction and the ventilatory ratio are associated with mortality in early ARDS.

BACKGROUND: Indirect indices for measuring impaired ventilation, such as the estimated dead space fraction and the ventilatory ratio, have been shown to be independently associated with an increased risk of mortality. This study aimed to compare various methods for dead space estimation and the ventilatory ratio in patients with acute respiratory distress syndrome (ARDS) and to determine their independent values for predicting death at day 30. The present study is a post hoc analysis of a prospective observational cohort study of ICUs of two tertiary care hospitals in the Netherlands. RESULTS: Individual patient data from 940 ARDS patients were analyzed. Estimated dead space fraction and the ventilatory ratio at days 1 and 2 were significantly higher among non-survivors (p < 0.01). Dead space fraction calculation using the estimate from physiological variables [VD/VT phys] and the ventilatory ratio at day 2 showed independent association with mortality at 30 days (odds ratio 1.28 [95% CI 1.02-1.61], p < 0.03 and 1.20 [95% CI, 1.01-1.40], p < 0.03, respectively); whereas, the Harris-Benedict [VD/VT HB] and Penn State [VD/VT PS] estimations were not associated with mortality. The predicted validity of the estimated dead space fraction and the ventilatory ratio improved the baseline model based on PEEP, PaO2/FiO2, driving pressure and compliance of the respiratory system at day 2 (AUROCC 0.72 vs. 0.69, p < 0.05). CONCLUSIONS: Estimated methods for dead space calculation and the ventilatory ratio during the early course of ARDS are associated with mortality at day 30 and add statistically significant but limited improvement in the predictive accuracy to indices of oxygenation and respiratory system mechanics at the second day of mechanical ventilation.

Role of beta-2-microglobulin as a biomarker in very preterm and extremely preterm infants with CNS inflammation.

BACKGROUND: Premature infants are at risk for severe sepsis and meningitis, both infections associated with high mortality and morbidity. Cerebro-spinal fluid (CSF) culture is the gold standard method for meningitis diagnosis, but interpretation of biochemical parameters of CSF is essential at the moment of the analysis in order to start the appropriate treatment. The main objective of this study was to determine whether levels of CSF beta-2-microglobulin (B2M) were elevated in preterm infants with CNS infections or other inflammatory processes, and to establish if there were differences in B2M concentrations amongst various inflammatory settings (sepsis, meningitis, and progressive post-hemorrhagic ventricular dilatation (PHVD)). METHODS: This is a retrospective study of all very preterm and extremely preterm infants (< 32 weeks of gestation) admitted to our NICU between 2012 and 2017. All those who underwent a lumbar puncture during their stay as part of a sepsis work-up or PHVD were considered for inclusion. CSF biochemical parameters and B2M were tested in all of the patients. RESULTS: Fifty-nine patients were included in the study. In patients with CNS infections, the median value of B2M was 8.69 mg/L (3.92-18.5). B2M levels above 3.92 mg/L showed greater sensitivity and specificity than leukocyte levels in discriminating between patients with CNS infections or other inflammatory processes and those without CNS inflammation. CONCLUSIONS: In this population, CSF B2M proved to be an effective biomarker to discriminate between patients with CNS infections and other inflammatory processes and those without CNS inflammation.

Acute Neurologic Injury in Children Admitted to the Cardiac Intensive Care Unit.

BACKGROUND: Children with acquired and congenital heart disease both have low mortality but an increased risk of neurologic morbidity that is multifactorial. Our hypothesis was that acute neurologic injuries contribute to mortality in such children and are an important cause of death. METHODS: All admissions to the pediatric cardiac intensive care unit (CICU) from January 2011 through January 2015 were retrospectively reviewed. Patients were assessed for any acute neurologic events (ANEs) during admission, as defined by radiologic findings or seizures documented on an electroencephalogram. RESULTS: Of the 1,573 children admitted to the CICU, the incidence of ANEs was 8.6%. Mortality of the ANE group was 16.3% compared with 1.5% for those who did not have an ANE. The odds ratio for death with ANEs was 8.55 (95% confidence interval, 4.56 to 16.03). Patients with ANEs had a longer hospital length of stay than those without ANEs (41.4 ± 4 vs 14.2 ± 0.6 days; p < 0.001). Need for extracorporeal membrane oxygenation, previous cardiac arrest, and prematurity were independently associated with the presence of an ANE. CONCLUSIONS: Neurologic injuries are common in pediatric CICUs and are associated with an increase in mortality and hospital length of stay. Children admitted to the CICU are likely to benefit from improved surveillance and neuroprotective strategies to prevent neurologic death.

Study protocol for a randomised controlled trial: treatment of early intrauterine growth restriction with low molecular weight heparin (TRACIP).

INTRODUCTION: The incidence of intrauterine growth restriction (IUGR) is estimated at about 3% of pregnancies, and it is associated with 30% of all perinatal mortality and severe morbidity with adverse neurodevelopmental and cardiovascular health consequences in adult life. Early onset IUGR represents 20%-30% of all cases and is highly associated with severe placental insufficiency. The existing evidence suggests that low molecular weight heparin (LMWH) has effects beyond its antithrombotic action, improving placental microvessel structure and function of pregnant women with vascular obstetric complications by normalising proangiogenic and antiapoptotic protein levels, cytokines and inflammatory factors. The objective of our study is to demonstrate the effectiveness of LMWH in prolonging gestation in pregnancies with early-onset IUGR. METHODS AND ANALYSIS: This is a multicentre, triple-blind, parallel-arm randomised clinical trial. Singleton pregnancies qualifying for early (20-32 weeks at diagnosis) placental IUGR (according to Delphi criteria) will be randomised to subcutaneous treatment with bemiparin 3500 IU/0.2 mL/day or placebo from inclusion at diagnosis to the time of delivery. Analyses will be based on originally assigned groups (intention-to-treat). The primary objective will be analysed by comparing gestational age and prolongation of pregnancy (days) in each group with Student's t-tests for independent samples and by comparing Kaplan-Maier survival curves (from inclusion to delivery, log-rank test). A linear regression model for gestational age at birth will consider the following covariates: gestational age at inclusion (continuous) and pre-eclampsia (binary). ETHICS AND DISSEMINATION: The study will be conducted in accordance with the principles of Good Clinical Practice. This study was approved by the Clinical Research Ethics Committee (CEIC) of Sant Joan de Déu Hospital, on 13 July 2017. The trial is registered in the public registry www.clinicaltrial.gov. according to Science Law 14/2011, and the results will be published in an open access journal. TRIAL REGISTRATION NUMBER: NCT03324139; Pre-results.

Deficiency of Parkinson's disease-related gene Fbxo7 is associated with impaired mitochondrial metabolism by PARP activation.

This corrects the article DOI: 10.1038/cdd.2016.104.

Neuroprotection with hypothermia and allopurinol in an animal model of hypoxic-ischemic injury: Is it a gender question?

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of neonatal brain injury. Therapeutic hypothermia (TH) is the standard treatment for term newborns after perinatal hypoxic ischemic injury (HI). Despite this, TH does not provide complete neuroprotection. Allopurinol seems to be a good neuroprotector in several animal studies, but it has never been tested in combination with hypothermia. Clinical findings show that male infants with (HI) fare more poorly than matched females in cognitive outcomes. However, there are few studies about neuroprotection taking gender into account in the results. The aim of the present study was to evaluate the potential additive neuroprotective effect of allopurinol when administrated in association with TH in a rodent model of moderate HI. Gender differences in neuroprotection were also evaluated. METHODS: P10 male and female rat pups were subjected to HI (Vannucci model) and randomized into five groups: sham intervention (Control), no treatment (HI), hypothermia (HIH), allopurinol (HIA), and dual therapy (hypothermia and allopurinol) (HIHA). To evaluate a treatment's neuroprotective efficiency, 24 hours after the HI event caspase3 activation was measured. Damaged area and hippocampal volume were also measured 72 hours after the HI event. Negative geotaxis test was performed to evaluate early neurobehavioral reflexes. Learning and spatial memory were assessed via Morris Water Maze (MWM) test at 25 days of life. RESULTS: Damaged area and hippocampal volume were different among treatment groups (p = 0.001). The largest tissue lesion was observed in the HI group, followed by HIA. There were no differences between control, HIH, and HIHA. When learning process was analyzed, no differences were found. Females from the HIA group had similar results to the HIH and HIHA groups. Cleaved caspase 3 expression was increased in both HI and HIA. Despite this, in females cleaved caspase-3 was only differently increased in the HI group. All treated animals present an improvement in short-term (Negative geotaxis) and long-term (WMT) functional tests. Despite this, treated females present better long-term outcome. In short-term outcome no sex differences were observed. CONCLUSIONS: Our results suggest that dual therapy confers great neuroprotection after an HI event. There were functional, histological, and molecular improvements in all treated groups. These differences were more important in females than in males. No statistically significant differences were found between HIHA and HIH; both of them present a great improvement. Our results support the idea of different regulation mechanisms and pathways of cell death, depending on gender.