Fentanyl dosage for preterm infants suggested by a pharmacokinetic, -dynamic, and -genetic model.

BACKGROUND: Fentanyl is commonly administered for procedural pain management in preterm infants, but target concentrations have not yet been defined. METHODS: To investigate pharmacokinetics (PK), -dynamics (PD), and -genetics (PG), 25 infants (gestational age 23.3-34.1 weeks) received a fentanyl dose before a skin-breaking procedure (0.5 µg/kg) or tracheal intubation (2 µg/kg). Four pain scales were used as a PD endpoint to evaluate efficacy. The impact of polymorphism in genes encoding enzymes (UGT2B7, CYP3A7, CYP3A4, COMT, CYP2D6, KCNJ6), transporters (SLC22A1, ABCC1, ABCC3) and receptor (OPRM1) on PK parameters was explored. RESULTS: A two-compartment PK model adequately described the fentanyl concentration. The effects of weight and maturity on the clearance were included as covariates in the model. One genetic variant encoding the ABCC1 transporter (rs111517339 T/TA) and two encoding the ABCC3 transporter (rs11079921 T/C and rs8077268 C/T) had a significant effect on fentanyl elimination that explained 15% of the interindividual variability on the clearance. A proportional odds PK/PD model was used to describe the concentration-effect relationship of fentanyl using the Échelle de douleur et d'inconfort du nouveau-né (EDIN) pain score. CONCLUSION: The simulations suggest that an intravenous dose of 2 µg/kg would be appropriate in preterm infants for a clearly painful procedure, such as an intubation. IMPACT: Design of personalized analgesia with fentanyl for newborn infants should consider maturation and genetic variants of opioid transporters affecting drug elimination. The results indicate that an intravenous dose of 2 µg/kg fentanyl would be suitable before a clearly painful procedure in preterm infants. Genetic variants encoding ABCC1 and ABCC3 transporters increase the clearance of fentanyl, which is a novel finding.

Hypothermic treatment for neonatal asphyxia in low-resource settings using phase-changing material-An easy to use and low-cost method.

AIM: To evaluate whether phase-changing material can be used for therapeutic hypothermia of asphyxiated newborns in low-resource settings. METHODS: Prospective interventional study of asphyxiated term infants fulfilling criteria for hypothermia treatment at Vietnam National Children's Hospital from September 2014 to September 2016. Hypothermia was induced within 6 hours after birth and maintained for 72 hours by a phase-changing material mattress with melting point of 32°C. Rectal temperature was continuously measured, and deviations from target temperature range 33.5-34.5°C were recorded. RESULTS: In total 52 infants (mean gestational age 39.3 ± 1.1 weeks) included and cooled, the median temperature at initiation of cooling was 35.3 (IQR 34.5-35.9)°C. The median time to reach target temperature was 2.5 (IQR 2-3) hours. The mean temperature during the cooling phase was 33.95 ± 0.2°C. Throughout the cooling phase, the target temperature range (33.5-34.5°C) was maintained more than 80% of the time. Rate of rewarming was 0.5 ± 0.14°C/hour. CONCLUSION: Phase-changing material can be used as an effective cooling method. Though not a servo-controlled system, it is easy to induce hypothermia, maintain target temperature and rewarm infants in a slow and controlled manner without need for frequent changes and minimum risk of skin injury.

Making of the mind.

The essence of the mind is consciousness. It emerged early during evolution and ontogeny appears to follow the same process as phylogeny. Consciousness comes from multiple sources, including visual, auditory, sensorimotor and proprioceptive senses. These gradually combine during development to build a unified consciousness, due to the constant interactions between the brain, body, and environment. In the human the emergence of consciousness depends on the activation of the cortex by thalamocortical connections around 24 weeks after conception. Then, the human foetus can be potentially conscious, as it is aware of its body and reacts to touch, smell and sound and shows social expressions in response to external stimuli. However, it is mainly asleep and probably not aware of itself and its environment. In contrast, the newborn infant is awake after its first breaths of air and can be aware of its own self and others, express emotions and share feelings. The development of consciousness is a progressive, stepwise, structural and functional evolution of multiple intricate components. The infant fulfils some of the more basic criteria for consciousness. However, there are some important missing pieces at this stage, as it cannot remember the past and anticipate the future.

Cortical Responses to Alien Odors in Newborns: An fNIRS Study.

Very preterm (VPT) infants are exposed to odors released by healthcare products, triggering the trigeminal and olfactory subsystems. Irritation of the nasal mucosa induces pain in adults. We examined whether preterm and full-term (FT) newborns perceived trigeminal odors at different cortical levels, whether these odors elicit pain, and if oral glucose modulates this pain. We performed 44 recording sessions in newborn (15 VPT infants, 12 VPT infants at term-equivalent age, and 17 FT infants) following exposure to trigeminal/olfactory stimuli from the hospital environment. We repeated the exposure after oral glucose administration. We recorded cortical activation in the olfactory, frontal, and somatosensory cortices by functional near-infrared spectroscopy, and analyzed pain behaviors from videotaped recordings. Newborns integrated trigeminal/olfactory stimuli in trigeminal/olfactory and nociceptive processing areas beginning at 31 weeks postmenstrual age, and also exhibited pain behaviors. Pain scores were positively associated with the level of cortical activation. Oral glucose inhibited pain behaviors and cortical activation. There were developmental differences in cortical integration related to brain maturation and duration of the extra-uterine experience. In conclusion, VPT and FT infants showed trigeminal sensitivity after exposure to alien odors that induce pain, potentially affecting the wiring of the neuronal circuits of the newborn brain.

Poor Brain Growth in Extremely Preterm Neonates Long Before the Onset of Autism Spectrum Disorder Symptoms.

Preterm infants face an increased risk of autism spectrum disorder (ASD). The relationship between autism during childhood and early brain development remains unexplored. We studied 84 preterm children born at <27 weeks of gestation, who underwent neonatal magnetic resonance imaging (MRI) at term and were screened for ASD at 6.5 years. Full-scale intelligence quotient was measured and neonatal morbidities were recorded. Structural brain morphometric studies were performed in 33 infants with high-quality MRI and no evidence of focal brain lesions. Twenty-three (27.4%) of the children tested ASD positive and 61 (72.6%) tested ASD negative. The ASD-positive group had a significantly higher frequency of neonatal complications than the ASD-negative group. In the subgroup of 33 children, the ASD infants had reduced volumes in the temporal, occipital, insular, and limbic regions and in the brain areas involved in social/behavior and salience integration. This study shows that the neonatal MRI scans of extremely preterm children, subsequently diagnosed with ASD at 6.5 years, showed brain structural alterations, localized in the regions that play a key role in the core features of autism. Early detection of these structural alterations may allow the early identification and intervention of children at risk of ASD.

Intrinsic Functional Connectivity in Preterm Infants with Fetal Growth Restriction Evaluated at 12 Months Corrected Age.

Fetal growth restriction (FGR) affects brain development in preterm infants, but little is known about its effects on resting-state functional connectivity. We compared 20 preterm infants, born at <34 weeks of gestation with abnormal antenatal Doppler measurements and birth weights <10th percentile, with 20 appropriate for gestational age preterm infants of similar gestational age and 20 term infants. They were scanned without sedation at 12 months of age and screened for autistic traits at 26 months. Resting functional connectivity was assessed using group independent component analysis and seed-based correlation analysis. The groups showed 10 common resting-state networks involving cortical, subcortical regions, and the cerebellum. Only infants with FGR showed patterns of increased connectivity in the visual network and decreased connectivity in the auditory/language and dorsal attention networks. No significant differences between groups were found using seed-based correlation analysis. FGR infants displayed a higher frequency of early autism features, related to decreased connectivity involving the salience network, than term infants. These data suggest that FGR is an independent risk factor for disrupted intrinsic functional connectivity in preterm infants when they are 1-year old and provide more clues about the neurodevelopmental abnormalities reported in this population.

Long-term cardiovascular reprogramming by short-term perinatal exposure to nicotine's main metabolite cotinine.

AIM: Gather 'proof-of-concept' evidence of the adverse developmental potential of cotinine (a seemingly benign biomarker of recent nicotine/tobacco smoke exposure). METHODS: Pregnant C57 mice drank nicotine- or cotinine-laced water for 6 wks from conception (NPRE = 2% saccharin + 100 µg nicotine/mL; CPRE = 2% saccharin + 10 µg cotinine/mL) or 3 wks after birth (CPOST = 2% saccharin + 30 µg cotinine/mL). Controls drank 2% saccharin (CTRL). At 17 ± 1 weeks (male pups; CTRL n = 6; CPOST n = 6; CPRE n = 8; NPRE n = 9), we assessed (i) cardiovascular control during sleep; (ii) arterial reactivity ex vivo; and (iii) expression of genes involved in arterial constriction/dilation. RESULTS: Blood cotinine levels recapitulated those of passive smoker mothers' infants. Pups exposed to cotinine exhibited (i) mild bradycardia - hypotension at rest (p < 0.001); (ii) attenuated (CPRE , p < 0.0001) or reverse (CPOST ; p < 0.0001) BP stress reactivity; (iii) adrenergic hypocontractility (p < 0.0003), low protein kinase C (p < 0.001) and elevated adrenergic receptor mRNA (p < 0.05; all drug-treated arteries); and (iv) endothelial dysfunction (NPRE only). CONCLUSION: Cotinine has subtle, enduring developmental consequences. Some cardiovascular effects of nicotine can plausibly arise via conversion into cotinine. Low-level exposure to this metabolite may pose unrecognised perinatal risks. Adults must avoid inadvertently exposing a foetus or infant to cotinine as well as nicotine.

Extremely Preterm-Born Infants Demonstrate Different Facial Recognition Processes at 6-10 Months of Corrected Age.

OBJECTIVES: To compare cortical hemodynamic responses to known and unknown facial stimuli between infants born extremely preterm and term-born infants, and to correlate the responses of the extremely preterm-born infants to regional cortical volumes at term-equivalent age. STUDY DESIGN: We compared 27 infants born extremely preterm (<28 gestational weeks) with 26 term-born infants. Corrected age and chronological age at testing were between 6 and 10 months, respectively. Both groups were exposed to a gray background, their mother's face, and an unknown face. Cerebral regional concentrations of oxygenated and deoxygenated hemoglobin were measured with near-infrared spectroscopy. In the preterm group, we also performed structural brain magnetic resonance imaging and correlated regional cortical volumes to hemodynamic responses. RESULTS: The preterm-born infants demonstrated different cortical face recognition processes than the term-born infants. They had a significantly smaller hemodynamic response in the right frontotemporal areas while watching their mother's face (0.13 µmol/L vs 0.63 µmol/L; P < .001). We also found a negative correlation between the magnitude of the oxygenated hemoglobin increase in the right frontotemporal cortex and regional gray matter volume in the left fusiform gyrus and amygdala (voxels, 25; r = 0.86; P < .005). CONCLUSION: At 6-10 months corrected age, the preterm-born infants demonstrated a different pattern in the maturation of their cortical face recognition process compared with term-born infants.

Planar cell polarity gene expression correlates with tumor cell viability and prognostic outcome in neuroblastoma.

BACKGROUND: The non-canonical Wnt/Planar cell polarity (PCP) signaling pathway is a major player in cell migration during embryonal development and has recently been implicated in tumorigenesis. METHODS: Transfections with cDNA plasmids or siRNA were used to increase and suppress Prickle1 and Vangl2 expression in neuroblastoma cells and in non-tumorigenic cells. Cell viability was measured by trypan blue exclusion and protein expression was determined with western blotting. Transcriptional activity was studied with luciferase reporter assay and mRNA expression with real-time RT-PCR. Immunofluorescence stainings were used to study the effects of Vangl2 overexpression in non-tumorigenic embryonic cells. Statistical significance was tested with t-test or one-way ANOVA. RESULTS: Here we show that high expression of the PCP core genes Prickle1 and Vangl2 is associated with low-risk neuroblastoma, suppression of neuroblastoma cell growth and decreased Wnt/ß-catenin signaling. Inhibition of Rho-associated kinases (ROCKs) that are important in mediating non-canonical Wnt signaling resulted in increased expression of Prickle1 and inhibition of ß-catenin activity in neuroblastoma cells. In contrast, overexpression of Vangl2 in MYC immortalized neural stem cells induced accumulation of active ß-catenin and decreased the neural differentiation marker Tuj1. Similarly, genetically modified mice with forced overexpression of Vangl2 in nestin-positive cells showed decreased Tuj1 differentiation marker during embryonal development. CONCLUSIONS: Our experimental data demonstrate that high expression of Prickle1 and Vangl2 reduce the growth of neuroblastoma cells and indicate different roles of PCP proteins in tumorigenic cells compared to normal cells. These results suggest that the activity of the non-canonical Wnt/PCP signaling pathway is important for neuroblastoma development and that manipulation of the Wnt/PCP pathway provides a possible therapy for neuroblastoma.

Brain Growth Gains and Losses in Extremely Preterm Infants at Term.

Premature exposure to the extrauterine environment negatively affects the brains' developmental trajectory. Our aim was to determine whether extremely preterm (EPT) infants, with no evidence of focal brain lesions, show morphological brain differences when compared with term-born infants. Additionally, we investigated associations between perinatal factors and neuroanatomical alterations. Conventional magnetic resonance imaging was acquired at term-equivalent age (TEA) from 47 EPT infants born before 27 weeks of gestation, and 15 healthy, term-born controls. Automatic segmentation and voxel-based morphometry-Diffeomorphic Anatomical Registration through Exponentiated Lie algebra (DARTEL) were used. Compared with controls, EPT infants displayed global reductions in cortical and subcortical gray matter, brainstem, and an increased cerebrospinal fluid volume. Regionally, they showed decreased volumes of all brain tissues, in particular cortical gray matter. Increased volumes of cortical gray and white matter were observed in regions involved in visual processing. Increasing prematurity, intraventricular hemorrhage grade I-II, and patent ductus arteriosus ligation were associated with decreased volumes and had a particular effect on the cerebellum. Concluding, EPT infants without focal brain lesions had an altered brain growth at TEA that particularly affected the gray matter, and varied when it came to the presence of perinatal risk factors. Brain growth gains in EPT infants may be related to a longer extrauterine experience.

Connecting the brain of the child from synapses to screen-based activity.

The connectome of the brain is constructed during foetal life by neurogenesis, arborisation of the neurons and synaptogenesis. The optimal neuronal connections are selected by endogenous spontaneous neuronal activity and sensory input from the external world, particularly after birth. The development of the social brain depends on interaction, particularly with the parents. Infants start to imitate adults from birth and soon learn to recognise faces. They also absorb phonemes like magnets, particularly if they are sitting on their mother's lap and she is speaking motherese. External coupling of the brain to TV, DVDs, iPads and smartphones cannot replace this direct multisensory interaction and does not seem to have the same advantageous effects for children under two years of age that it may have for older children.