Antenatal Glucocorticoid Treatment is Associated with Diurnal Cortisol Regulation in Term-Born Children

Due to the rapid developmental changes that occur during the fetal period, prenatal influences can affect the developing central nervous system with lifelong consequences for physical and mental health. Glucocorticoids are one of the proposed mechanisms by which fetal programing occurs. Glucocorticoids pass through the blood-brain barrier and target receptors throughout the central nervous system. Unlike endogenous glucocorticoids, synthetic glucocorticoids readily pass through the placental barrier to reach the developing fetus. The synthetic glucocorticoid, betamethasone, is routinely given prenatally to mothers at risk for preterm delivery. Over 25% of the fetuses exposed to betamethasone will be born at term. Few studies have examined the lasting consequences of antenatal treatment of betamethasone on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The purpose of this study is to examine whether antenatal exposure to betamethasone alters circadian cortisol regulation in children who were born full term. School-aged children prenatally treated with betamethasone and born at term (n=19, mean (SD) = 8.1 (1.2) years old) were compared to children not treated with antenatal glucocorticoids (n=61, mean (SD) = 8.2 (1.4) years old). To measure the circadian release of cortisol, saliva samples were collected at awakening; 30, 45, and 60 minutes after awakening; and in the evening. Comparison children showed a typical diurnal cortisol pattern that peaked in the morning (the cortisol awakening response) and gradually decreased throughout the day. In contrast, children exposed to antenatal betamethasone lacked a cortisol awakening response and had a flatter diurnal slope (p’

Unpredictable Maternal Behavior Is Associated with a Blunted Infant Cortisol Response

Background Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with poor physical and mental health. Early-life adversity may dysregulate cortisol response to subsequent stress. This study examines the association between patterns of maternal behavior and infant stress response to a challenge. Specifically, we test whether infant exposure to unpredictable maternal sensory signals is related to the cortisol response to a painful stressor. Method Participants were 102 mothers and their children enrolled in a longitudinal study. Patterns of maternal sensory signals were evaluated at 6 and 12 months during a 10-min mother–infant play episode. Entropy rate was calculated as a quantitative measure of the degree of unpredictability of maternal sensory signals (visual, auditory, and tactile) exhibited during the play episode. Infant saliva samples were collected for cortisol analysis before and after inoculation at 12 months. Results Unpredictable patterns of maternal sensory signals were associated with a blunted infant cortisol response to a painful stressor. This relation persisted after evaluation of covariates including maternal sensitivity and maternal psychological distress. Conclusions This study provides evidence that unpredictable patterns of maternal sensory signals are one process through which caregiving affects the function of infant stress response systems

Salivary biomarkers of HPA axis and autonomic activity in adults with intellectual disability with and without stereotyped and self-injurious behavior disorders

Salivary levels of biomarkers for the hypothalamic–pituitary–adrenal axis (HPA; cortisol) and sympatho-adreno-medullary system (SAM; α-amylase) were measured in 51 adults (57% male) with neurodevelopmental disorders associated with intellectual disability (i.e., mental retardation) and chronic self-injurious behavior (SIB) and compared with matched controls without SIB. Cortisol levels differed significantly (p < 0.01) between the SIB and control group (SIB > control). Within-group analyses showed significant differences (p < 0.05) in levels of salivary α-amylase between individuals with SIB and those with SIB meeting criteria for stereotyped movement disorder (SMD; SIB + SMD > SIB). Salivary α-amylase was significantly correlated with frequency of stereotypy among the SIB group (r = 0.36, p < 0.05). These preliminary findings warrant further exploration into the role of the SAM system in the pathophysiology of SIB and related repetitive behaviors among individuals with neurodevelopmental disorders associated with intellectual disability

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate &lt;0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P &lt; 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood

The PDZ domain of the SpoIVB serine peptidase facilitates multiple functions

During spore formation in Bacillus subtilis, the SpoIVB protein is a critical component of the sigma (K) regulatory checkpoint. SpoIVB has been shown to be a serine peptidase that is synthesized in the spore chamber and which self-cleaves, releasing active forms. These forms can signal proteolytic processing of the transcription factor sigma (K) in the outer mother cell chamber of the sporulating cell. This forms the basis of the sigma (K) checkpoint and ensures accurate sigma (K)-controlled gene expression. SpoIVB has also been shown to activate a second distinct process, termed the second function, which is essential for the formation of heat-resistant spores. In addition to the serine peptidase domain, SpoIVB contains a PDZ domain. We have altered a number of conserved residues in the PDZ domain by site-directed mutagenesis and assayed the sporulation phenotype and signaling properties of mutant SpoIVB proteins. Our work has revealed that the SpoIVB PDZ domain could be used for up to four distinct processes, (i) targeting of itself for trans proteolysis, (11) binding to the protease inhibitor BofC, (iii) signaling of pro-sigma (K) processing, and (iv) signaling of the second function of SpoIVB

Single-subject analysis of N400 event-related potential component with five different methods

There are several different approaches to analyze event-related potentials (ERPs) at single-subject level, and the aim of the current study is to provide information for choosing a method based on its ability to detect ERP effects and factors influencing the results. We used data from 79 healthy participants with EEG referenced to mastoid average and investigated the detection rate of auditory N400 effect in single-subject analysis using five methods: visual inspection of participant-wise averaged ERPs, analysis of variance (ANOVA) for amplitude averages in a time window, cluster-based non-parametric testing, a novel Bayesian approach and Studentized continuous wavelet transform (t-CWT). Visual inspection by three independent raters yielded N400 effect detection in 85% of the participants in at least one paradigm (active responding or passive listening), whereas ANOVA identified the effect in 68%, the cluster-method in 59%, the Bayesian method in 89%, and different versions of t-CWT in 22–59% of the participants. Thus, the Bayesian method was the most liberal and also showed the greatest concordance between the experimental paradigms (active/passive). ANOVA detected significant effect only in cases with converging evidence from other methods. The t-CWT and cluster-based method were the most conservative methods. As we show in the current study, different analysis methods provide results that do not completely overlap. The method of choice for determining the presence of an ERP component at single-subject level thus remains unresolved. Relying on a single statistical method may not be sufficient for drawing conclusions on single-subject ERPs.</p

Pandemic dreams: network analysis of dream content during the COVID-19 lockdown

We used crowdsourcing (CS) to examine how COVID-19 lockdown affects the content of dreams and nightmares. The CS took place on the 6th week of the lockdown. Over the course of one week, 4275 respondents (mean age 43, SD=14 years) assessed their sleep and 811 reported their dream content. Overall, respondents slept substantially more (54.2%) but reported an average increase of awakenings (28.6%) and nightmares (26%) from the pre-pandemic situation. We transcribed the content of the dreams into word lists and performed unsupervised computational network and cluster analysis of word associations, which suggested 33 dream clusters including 20 bad dream clusters, of which 55% were pandemic specific (e.g. Disease Management, Disregard of Distancing, Elderly in Trouble). The dream association networks were more accentuated for those who reported an increase in perceived stress. This CS survey on dream-association networks and pandemic stress introduces novel, collectively shared COVID-19 bad dream contents. </p

Pediatric Microdose Study of [14C]Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept

Results: Ten infants (aged 0.1–83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [14C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (Cmax) [14C]AAP 1.68 (0.75–4.76) ng/L, [14C]AAP-Glu 0.88 (0.34–1.55) ng/L, and [14C]AAP-4Sul 0.81 (0.29–2.10) ng/L. Dose-normalized oral [14C]AAP Cmax approached median intravenous average concentrations (Cav): 8.41 mg/L (3.75–23.78 mg/L) and 8.87 mg/L (3.45–12.9 mg/L), respectively.Conclusions: We demonstrate the feasibility of using a [14C]labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children.Background: Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons.Methods: In an open-label microdose pharmacokinetic pilot study, infants (0–6 years of age) received a single oral [14C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg intravenous every 6 h). Blood samples were taken from an indwelling catheter. AAP blood concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and [14C]AAP and metabolites ([14C]AAP-Glu and [14C]AAP-4Sul) were measured by accelerator mass spectrometry.Objective: The objective of this study was to present pilot data of an oral [14C]paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children

Spoken words are processed during dexmedetomidine-induced unresponsiveness

Background: Studying the effects of anaesthetic drugs on the processing of semantic stimuli could yield insights into how brain functions change in the transition from wakefulness to unresponsiveness. Here, we explored the N400 event-related potential during dexmedetomidine- and propofol-induced unresponsiveness. Methods: Forty-seven healthy subjects were randomised to receive either dexmedetomidine (n = 23) or propofol (n = 24) in this open-label parallel-group study. Loss of responsiveness was achieved by stepwise increments of pseudo-steady-state plasma concentrations, and presumed loss of consciousness was induced using 1.5 times the concentration required for loss of responsiveness. Pre-recorded spoken sentences ending either with an expected (congruous) or an unexpected (incongruous) word were presented during unresponsiveness. The resulting electroencephalogram data were analysed for the presence of the N400 component, and for the N400 effect defined as the difference between the N400 components elicited by congruous and incongruous stimuli, in the time window 300-600 ms post-stimulus. Recognition of the presented stimuli was tested after recovery of responsiveness. Results: The N400 effect was not observed during dexmedetomidine- or propofol-induced unresponsiveness. The N400 component, however, persisted during dexmedetomidine administration. The N400 component elicited by congruous stimuli during unresponsiveness in the dexmedetomidine group resembled the large component evoked by incongruous stimuli at the awake baseline. After recovery, no recognition of the stimuli heard during unresponsiveness occurred. Conclusions: Dexmedetomidine and propofol disrupt the discrimination of congruous and incongruous spoken sentences, and recognition memory at loss of responsiveness. However, the processing of words is partially preserved during dexmedetomidine-induced unresponsiveness.</p