Exposure to the parents' speech is positively associated with preterm infant's face preference.

BACKGROUND: The parents' presence and involvement in neonatal care is a promising approach to improve preterm infants' neurodevelopmental outcomes. We examined whether exposure to the parents' speech is associated with the preterm infant's social-cognitive development. METHODS: The study included infants born before 32 gestational weeks in two neonatal units. Each infant's language environment was assessed from 16-hour recordings using Language Environment Analysis (LENA®). Parental presence was assessed with Closeness Diary for 14 days during the hospital stay. Attention to faces and non-face patterns was measured at the corrected age of seven months using an eye-tracking disengagement test. RESULTS: A total of 63 preterm infants were included. Infants were less likely to disengage their attention from faces (M = 0.55, SD = 0.26) than non-face patterns (M = 0.24, SD = 0.22), p < 0.001, d = 0.84. Exposure to the parents' speech during the neonatal period was positively correlated with the preference for faces over non-face patterns (rs = 0.34, p = 0.009) and with the preference for parents over unfamiliar faces (rs = 0.28, p = 0.034). CONCLUSION: The exposure to the parents' speech during neonatal hospital care is a potential early marker for later social development in preterm infants. IMPACT: The exposure to the parents' speech during neonatal intensive care is a potential early marker for optimal social-cognitive development in preterm infants. This is the first study to show an association between parental vocal contact during neonatal intensive care and early social development (i.e., face preference), measured at seven months of corrected age. Our findings suggest that we should pay attention to the parents' vocal contact with their child in the neonatal intensive care unit and identify need for tailored support for face-to-face and vocal contact.

Evaluation of a community health worker home visit intervention to improve child development in South Africa: A cluster-randomized controlled trial.

BACKGROUND: Effective integration of home visit interventions focused on early childhood development into existing service platforms is important for expanding access in low- and middle-income countries (LMICs). We designed and evaluated a home visit intervention integrated into community health worker (CHW) operations in South Africa. METHODS AND FINDINGS: We conducted a cluster-randomized controlled trial in Limpopo Province, South Africa. CHWs operating in ward-based outreach teams (WBOTs; clusters) and caregiver-child dyads they served were randomized to the intervention or control group. Group assignment was masked from all data collectors. Dyads were eligible if they resided within a participating CHW catchment area, the caregiver was at least 18 years old, and the child was born after December 15, 2017. Intervention CHWs were trained on a job aid that included content on child health, nutrition, developmental milestones, and encouragement to engage in developmentally appropriate play-based activities, for use during regular monthly home visits with caregivers of children under 2 years of age. Control CHWs provided the local standard of care. Household surveys were administered to the full study sample at baseline and endline. Data were collected on household demographics and assets; caregiver engagement; and child diet, anthropometry, and development scores. In a subsample of children, electroencephalography (EEG) and eye-tracking measures of neural function were assessed at a lab concurrent with endline and at 2 interim time points. Primary outcomes were as follows: height-for-age z-scores (HAZs) and stunting; child development scores measured using the Malawi Developmental Assessment Tool (MDAT); EEG absolute gamma and total power; relative EEG gamma power; and saccadic reaction time (SRT)-an eye-tracking measure of visual processing speed. In the main analysis, unadjusted and adjusted impacts were estimated using intention-to-treat analysis. Adjusted models included a set of demographic covariates measured at baseline. On September 1, 2017, we randomly assigned 51 clusters to intervention (26 clusters, 607 caregiver-child dyads) or control (25 clusters, 488 caregiver-child dyads). At endline (last assessment June 11, 2021), 432 dyads (71%) in 26 clusters remained in the intervention group, and 332 dyads (68%) in 25 clusters remained in the control group. In total, 316 dyads attended the first lab visit, 316 dyads the second lab visit, and 284 dyads the third lab visit. In adjusted models, the intervention had no significant impact on HAZ (adjusted mean difference (aMD) 0.11 [95% confidence interval (CI): -0.07, 0.30]; p = 0.220) or stunting (adjusted odds ratio (aOR) 0.63 [0.32, 1.25]; p = 0.184), nor did the intervention significantly impact gross motor skills (aMD 0.04 [-0.15, 0.24]; p = 0.656), fine motor skills (aMD -0.04 [-0.19, 0.11]; p = 0.610), language skills (aMD -0.02 [-0.18, 0.14]; p = 0.820), or social-emotional skills (aMD -0.02 [-0.20, 0.16]; p = 0.816). In the lab subsample, the intervention had a significant impact on SRT (aMD -7.13 [-12.69, -1.58]; p = 0.012), absolute EEG gamma power (aMD -0.14 [-0.24, -0.04]; p = 0.005), and total EEG power (aMD -0.15 [-0.23, -0.08]; p < 0.001), and no significant impact on relative gamma power (aMD 0.02 [-0.78, 0.83]; p = 0.959). While the effect on SRT was observed at the first 2 lab visits, it was no longer present at the third visit, which coincided with the overall endline assessment. At the end of the first year of the intervention period, 43% of CHWs adhered to monthly home visits. Due to the COVID-19 pandemic, we were not able to assess outcomes until 1 year after the end of the intervention period. CONCLUSIONS: While the home visit intervention did not significantly impact linear growth or skills, we found significant improvement in SRT. This study contributes to a growing literature documenting the positive effects of home visit interventions on child development in LMICs. This study also demonstrates the feasibility of collecting markers of neural function like EEG power and SRT in low-resource settings. TRIAL REGISTRATION: PACTR 201710002683810; https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=2683; South African Clinical Trials Registry, SANCTR 4407.

Eye tracking: empirical foundations for a minimal reporting guideline.

In this paper, we present a review of how the various aspects of any study using an eye tracker (such as the instrument, methodology, environment, participant, etc.) affect the quality of the recorded eye-tracking data and the obtained eye-movement and gaze measures. We take this review to represent the empirical foundation for reporting guidelines of any study involving an eye tracker. We compare this empirical foundation to five existing reporting guidelines and to a database of 207 published eye-tracking studies. We find that reporting guidelines vary substantially and do not match with actual reporting practices. We end by deriving a minimal, flexible reporting guideline based on empirical research (Section "An empirically based minimal reporting guideline").

Maternal stress and development of infant attention to threat-related facial expressions.

Attentional biases to threat-related stimuli, such as fearful and angry facial expressions, are important to survival and emerge early in development. Infants demonstrate an attentional bias to fearful facial expressions by 5-7 months of age and an attentional bias toward anger by 3 years of age that are modulated by experiential factors. In a longitudinal study of 87 mother-infant dyads from families predominantly experiencing low income, we examined whether maternal stress and depressive symptoms were associated with trajectories of attentional biases to threat, assessed during an attention disengagement eye-tracking task when infants were 6-, 9-, and 12-month old. By 9 months, infants demonstrated a generalized bias toward threat (both fearful and angry facial expressions). Maternal perceived stress was associated with the trajectory of the bias toward angry facial expressions between 6 and 12 months. Specifically, infants of mothers with higher perceived stress exhibited a greater bias toward angry facial expressions at 6 months that decreased across the next 6 months, compared to infants of mothers with lower perceived stress who displayed an increased bias to angry facial expressions over this age range. Maternal depressive symptoms and stressful life events were not associated with trajectories of infant attentional bias to anger or fear. These findings highlight the role of maternal perceptions of stress in shaping developmental trajectories of threat-alerting systems.

Converging neural and behavioral evidence for a rapid, generalized response to threat-related facial expressions in 3-year-old children.

Electrophysiological studies on adults suggest that humans are efficient at detecting threat from facial information and tend to grant these signals a priority in access to attention, awareness, and action. The developmental origins of this bias are poorly understood, partly because few studies have examined the emergence of a generalized neural and behavioral response to distinct categories of threat in early childhood. We used event-related potential (ERP) and eye-tracking measures to examine children's early visual responses and overt attentional biases towards multiple exemplars of angry and fearful vs. other (e.g., happy and neutral) faces. A large group of children was assessed longitudinally in infancy (5, 7, or 12 months) and at 3 years of age. The final ERP dataset included 148 infants and 132 3-year-old children; and the final eye-tracking dataset included 272 infants and 334 3-year-olds. We demonstrate that 1) neural and behavioral responses to facial expressions converge on an enhanced response to fearful and angry faces at 3 years of age, with no differentiation between or bias towards one or the other of these expressions, and 2) a support vector machine learning model using data on the early-stage neural responses to threat reliably predicts the duration of overt attentional dwell time for threat-related faces at 3 years. However, we found little within-subject correlation between threat-bias attention in infancy and at 3 years of age. These results provide unique evidence for the early development of a rapid, unified response to two distinct categories of facial expressions with different physical characteristics, but shared threat-related meaning.

Pupillary and Attentional Responses to Infant Facial Expressions in Mothers Across Socioeconomic Variations.

Maternal responses to infant facial expressions were examined in two socioeconomically diverse samples of South African mothers (Study I, N = 111; and Study II, N = 214; age: 17-44 years) using pupil and gaze tracking. Study I showed increased pupil response to infant distress expressions in groups recruited from private as compared to public maternity clinics, possibly reflecting underlying differences in socioeconomic status (SES) across the groups. Study II, sampling uniformly low-SES neighborhoods, found increased pupil dilation and faster orientation to expressions of infant distress, but only in the highest income group. These results are consistent with maternal physiological and attentional sensitivity to infant distress cues but challenge the universality of this sensitivity across socioeconomic diversity.

Prodrug Approach for Posterior Eye Drug Delivery: Synthesis of Novel Ganciclovir Prodrugs and in Vitro Screening with Cassette Dosing.

Because of poor ocular drug bioavailability, intravitreal injections have become the gold standard for drug delivery to the posterior eye. The prodrug approach can be used for optimizing the biopharmaceutical properties of intravitreal drugs. The preclinical screening of prodrugs' properties, such as hydrolysis and bioconversion, should be conducted in a resource-efficient way for an extensive set of synthesized compounds with validated methods. Our objective was to explore cassette dosing in in vitro prodrug hydrolysis and bioconversion studies in buffer, vitreous, and retinal pigment epithelium (RPE) homogenate for rapid medium-throughput screening. Moreover, our aim was to correlate the prodrug structure with hydrolytic behavior. We synthesized 18 novel ganciclovir prodrugs and first studied their hydrolysis in aqueous buffer and porcine vitreous in vitro with cassette dosing for 35 h. A method for vitreous homogenate pH equilibration to a physiological level by using buffer and incubation under 5% carbon dioxide was validated. The hydrolysis of the prodrugs was evaluated in porcine RPE homogenate in vitro with cassette dosing, and five prodrugs were assayed individually to examine their bioconversion into ganciclovir in RPE after 2 h. Lastly, the prodrugs' binding to melanin was studied in vitro. The prodrugs showed a wide spectrum of hydrolysis rates, ranging from a few percentages to 100% in the vitreous and RPE; in general, hydrolysis in RPE was faster than in vitreous. Prodrugs with long carbon chains and disubstitution showed lability in the tissue homogenates, whereas prodrugs with branched carbon chains and aromatic groups were stable. All five prodrugs chosen for the bioconversion study in RPE were hydrolyzed into ganciclovir, and their hydrolytic behavior matched results from the cassette mix experiment, supporting the cassette mix approach for hydrolysis and bioconversion studies. None of the prodrugs bound highly to melanin (<50% bound). In conclusion, cassette dosing proved useful for the rapid screening of prodrug hydrolysis and bioconversion properties. Analyzing several compounds simultaneously can complicate the analytics, and thus, choosing the compounds of the cassette mix should be done carefully to avoid mutual interference of the compounds with the results. The methodology and results of the work are applicable in ocular drug research and prodrug design.

Maternal Depressive Symptoms During the Pre- and Postnatal Periods and Infant Attention to Emotional Faces.

We examined how infants' attentional disengagement from happy, fearful, neutral, and phase-scrambled faces at 8 months, as assessed by eye tracking, is associated with trajectories of maternal depressive symptoms from early pregnancy to 6 months postpartum (decreasing n = 48, increasing n = 34, and consistently low symptom levels n = 280). The sample (mother-infant dyads belonging to a larger FinnBrain Birth Cohort Study) was collected between 5/2013-6/2016. The overall disengagement probability from faces to distractors was not related to maternal depressive symptoms, but fear bias was heightened in infants whose mothers reported decreasing or increasing depressive symptoms. Exacerbated attention to fearful faces in infants of mothers with depressive symptoms may be independent of the timing of the symptoms in the pre- and postnatal stages.

Tyrosine-Chlorambucil Conjugates Facilitate Cellular Uptake through L-Type Amino Acid Transporter 1 (LAT1) in Human Breast Cancer Cell Line MCF-7.

l-type amino acid transporter 1 (LAT1) is an amino acid transporter that is overexpressed in several types of cancer and, thus, it can be a potential target for chemotherapy. The objectives of this study were to (a) synthesize LAT1-targeted chlorambucil derivatives and (b) evaluate their LAT1-mediated cellular uptake as well as antiproliferative activity in vitro in the human breast cancer MCF-7 cell line. Chlorambucil was conjugated to l-tyrosine-an endogenous LAT1 substrate-via either ester or amide linkage (compounds 1 and 2, respectively). While chlorambucil itself did not bind to LAT1, its derivatives 1 and 2 bound to LAT1 with a similar affinity as with l-tyrosine and their respective cellular uptake was significantly higher than that of chlorambucil in MCF-7. The results of our cellular uptake study are indicative of antiproliferative activity, as a higher intracellular uptake of chlorambucil derivatives resulted in greater cytotoxicity than chlorambucil by itself. LAT1 thus contributes to intracellular uptake of chlorambucil derivatives and, therefore, increases antiproliferative activity. The understanding gained from our research can be used in the development of LAT1-targeted anticancer drugs and prodrugs for site-selective and enhanced chemotherapeutic activity.

Perinatal suicidality: Risk factors in South African women with mental illness.

Background: Maternal Mortality is a global health concern. The lack of suicide data, particularly in low and middle income countries, is concerning and needs to be addressed. Aim: This study assessed suicidality and associated factors during pregnancy and the postpartum period amongst women with known psychiatric diagnoses. Setting: The study sample included pregnant South African women over the age of 18 years with a psychiatric disorder who presented at two maternal mental health clinics. Method: Suicidality was assessed by means of psychiatric interviews - the Mini International Neuropsychiatric Interview and the Montgomery Asberg Depression Rating Scale. Results: The results revealed that women were at a higher risk of experiencing suicidality if they had attempted suicide before, presented at a later gestation for psychiatric care or were employed. It was also clear that multiple assessments, carried out by means of clinical interviews and various scales, were necessary to screen suicidality successfully in pregnant women diagnosed with psychiatric illness. Conclusion: The results confirmed the view of the World Health Organization that in order to promote mental health and well-being, women's health should be viewed contextually, not in isolation. Screening for and treatment of perinatal mental illness, including suicidality, are essential if we hope to meet the maternal morbidity and mortality targets of the United Nations by 2030.

Early development of visual attention in infants in rural Malawi.

Eye tracking research has shown that infants develop a repertoire of attentional capacities during the first year. The majority of studies examining the early development of attention comes from Western, high-resource countries. We examined visual attention in a heterogeneous sample of infants in rural Malawi (N = 312-376, depending on analysis). Infants were assessed with eye-tracking-based tests that targeted visual orienting, anticipatory looking, and attention to faces at 7 and 9 months. Consistent with prior research, infants exhibited active visual search for salient visual targets, anticipatory saccades to predictable events, and a robust attentional bias for happy and fearful faces. Individual variations in these processes had low to moderate odd-even split-half and test-retest reliability. There were no consistent associations between attention measures and gestational age, nutritional status, or characteristics of the rearing environment (i.e., maternal cognition, psychosocial well-being, socioeconomic status, and care practices). The results replicate infants' early attentional biases in a large, unique sample, and suggest that some of these biases (e.g., bias for faces) are pronounced in low-resource settings. The results provided no evidence that the initial manifestation of infants' attentional capacities is associated with risk factors that are common in low-resource environments.

Maternal and infant characteristics connected to shared pleasure in dyadic interaction.

The aim of the study was to analyze which maternal factors (depressive symptoms, effect of life events, maternal sensitivity and structuring) and infant characteristics (temperament, social withdrawal symptoms, interactive behavior, genotype, gender) contribute to shared pleasure (SP) in parent-infant interaction. Participants were 113 mother-infant dyads. The mothers filled in the Edinburgh Postnatal Depression Scale, the Infant Behavior Questionnaire, and the Life Events Questionnaire. The dyads were videotaped in a free-play situation, and the videos were analyzed using the Alarm Distress Baby Scale and the Emotional Availability Scales. The infants were genotyped for four genes involved in emotion regulation. The occurrence and duration of SP (SP-MD) in mother-infant interactions were analyzed from the videotapes. Higher maternal sensitivity and depressive symptoms, better infant responsiveness, and the infant having the GG variant of the gene tryptophan hydroxylase isoform 2 (TPH2) -307 were associated with the occurrence of SP. Lower level depressive symptoms, better maternal structuring, and greater infant involvement were associated with the longer duration of SP. Those dyads where the mother and infant were best able to read each other's positive cues and to respond to them were more likely to experience mutual positive affect, as seen in SP.

El propósito de este estudio fue analizar cuáles factores maternos (síntomas depresivos, efectos de eventos vividos, sensibilidad y estructuración maternas) y características del infante (temperamento, síntomas de despego social, comportamiento interactivo, genotipo, género sexual) contribuyen al placer compartido (SP) en la interacción progenitor-infante. En el estudio participaron 113 díadas madre-infante. Las madres completaron la Escala de Depresión Postnatal de Edimburgo, el Cuestionario de Comportamiento del Infante y el Cuestionario de Eventos de Vida. A las díadas se les grabó en video durante una sesión de juego libre y los videos se analizaron usando la Escala de Alarma de la Angustia del Bebé y las Escalas de Disponibilidad Emocional. A los infantes se les determinó el genotipo en el caso de cuatro genes que tienen que ver con la regulación emocional. Con base en las videograbaciones, se analizó la incidencia y duración de SP (SP-MD) en las interacciones madre-infante. Una más alta sensibilidad materna y síntomas depresivos, mejor sensibilidad por parte del infante, y el hecho de que el infante tenía la variante GG del gen TPH2 -307 se asociaron con la incidencia de SP. Síntomas depresivos de bajo nivel, una mejor estructuración materna y una mayor participación del infante se asociaron con una más larga duración de SP. Aquellas díadas en que la madre y el infante eran más capaces de comprender las señales positivas de cada uno y de responder a las mismas, estaban en mejor condición de experimentar un mutuo afecto positivo, como el que se ve en SP.

Le but de cette étude était d'analyser quels facteurs maternels (symptômes dépressifs, effet d'événements de la vie, sensibilité maternelle et structuration maternelle) et quelles caractéristiques du nourrisson (tempérament, symptômes de retrait social, comportement interactif, génotype, genre) contribuent au plaisir partagé (abrégé ici en français PP) dans l'interaction parent-nourrisson. Les participants ont consisté en 113 dyades mère-nourrisson. Les mères ont rempli l'Echelle de Dépression Postnatale d'Edinbourg, le Questionnaire du Comportement du Nourrisson, et le Questionnaire d'Evénements de la Vie. Les dyades ont été filmées à la vidéo pendant une situation de jeu libre et les vidéos ont été analysées en utilisant l'Echelle d'Alarme de Détresse du Bébé et les Echelles de Disponibilité Emotionnelle. Les nourrissons ont été génotypés pour quatre gènes impliqués dans la régulation de l'émotion. L'apparition et la durée du PP (en anglais SP-MD) dans les interactions mère-nourrisson ont été analysées à partir des vidéos. Une sensibilité maternelle plus élevée et des symptômes dépressifs, une meilleure réaction du nourrisson, le nourrisson ayant la variante GG du gène TPH2 -307 étaient liés à l'apparition du PP. Des niveaux plus bas de symptômes dépressifs, une meilleure structuration maternelle et un engagement plus important du nourrisson étaient liés à une durée plus longue du PP. Les dyades où la mère et le nourrisson étaient le plus capables de lire leurs signaux positifs réciproques et d'y répondre étaient moins à même de faire l'expérience d'une affect positif mutuel, comme on le voit dans le PP.

Infants' attention bias to faces as an early marker of social development.

Infants have a strong tendency to look at faces. We examined individual variations in this attentional bias in 7-month-old infants by using a face-distractor competition paradigm and tested in a longitudinal sample whether these variations were associated with outcomes reflecting social behavior at 24 and 48 months of age (i.e., spontaneous helping, emotion understanding, mentalizing, and callous-unemotional traits; N = 100-138). The results showed a robust and distinct attention bias to faces at 7 months, particularly when faces were displaying a fearful expression. This bias declined between 7 and 24 months and there were no significant correlations in attention dwell times between 7 and 24 months of age. Variations in attention to faces at 7 months were not associated with emotion understanding or mentalizing abilities at 48 months of age, but increased attention to faces at 7 months (regardless of facial expression) was related to more frequent helping responses at 24 months and reduced callous-unemotional traits at 48 months of age. Thus, while the results fail to associate infants' face bias with later-emerging emotion understanding and mentalizing capacities, they are consistent with a model whereby increased attention to faces in infancy is linked with the development of affective empathy and responsivity to others' needs.

Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase.

Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (±)-22. The latter showed remarkable (> 0.5 mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD7.4 of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC50 4.99 ±â€¯0.18 nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain.

Risk factors for unplanned pregnancy in women with mental illness living in a developing country.

Pregnant women in general are at an increased risk of experiencing symptoms of mental illness, and those living in a developing country are even more vulnerable. Research points towards a causal relationship between unplanned pregnancy and perinatal mental illness and suggests that pregnancy planning can aid in reducing the negative impact of mental illness on a woman, her unborn baby, and the rest of the family. In this quantitative, descriptive study, we investigated both socio-demographic factors and variables relating to mental illness itself that may place women at an increased risk of experiencing unplanned pregnancy. Data was gathered at two maternal mental health clinics in Cape Town by means of semi-structured interviews. Univariate analyses of the data revealed five independent key risk factors for unplanned pregnancy: lower levels of education, unmarried status, belonging to the Colored ethnic population, substance use, and having a history of two or more suicide attempts. Some of these factors overlap with findings of similar studies, but others are unique to the specific population (women with mental illness within a developing country). Screening of women based on these risk predictors may pave the way for early interventions and reduce the incidence of unplanned pregnancy and the negative consequences thereof in the South African population.

Mothers' pupillary responses to infant facial expressions.

BACKGROUND: Human parental care relies heavily on the ability to monitor and respond to a child's affective states. The current study examined pupil diameter as a potential physiological index of mothers' affective response to infant facial expressions. METHODS: Pupillary time-series were measured from 86 mothers of young infants in response to an array of photographic infant faces falling into four emotive categories based on valence (positive vs. negative) and arousal (mild vs. strong). RESULTS: Pupil dilation was highly sensitive to the valence of facial expressions, being larger for negative vs. positive facial expressions. A separate control experiment with luminance-matched non-face stimuli indicated that the valence effect was specific to facial expressions and cannot be explained by luminance confounds. Pupil response was not sensitive to the arousal level of facial expressions. CONCLUSIONS: The results show the feasibility of using pupil diameter as a marker of mothers' affective responses to ecologically valid infant stimuli and point to a particularly prompt maternal response to infant distress cues.

Amino Acid Promoieties Alter Valproic Acid Pharmacokinetics and Enable Extended Brain Exposure.

Valproic acid (VPA) has been used to treat epileptic seizures for decades, but it may also possess therapeutic potential in other nervous system diseases. However, VPA is extensively bound to plasma proteins, asymmetrically transported across the blood-brain barrier and metabolized to toxic species in the liver, which all contribute to its severe off-target adverse effects and possible drug-drug interactions. In this study, we evaluated seven amino acid prodrugs of VPA that were targeted to utilize L-type amino acid transporter 1 (LAT1), if they could alter the brain uptake mechanism and systemic pharmacokinetics of VPA. All prodrugs had affinity for LAT1 studied as competitive inhibition of [14C]-L-leucine in human breast cancer (MCF-7) cell line. However, since the ester prodrugs were unstable they were not studied further, instead the corresponding amide prodrugs were used to evaluate their systemic pharmacokinetics in rats and the uptake mechanism via LAT1 into the rat brain. All amide prodrugs were bound to a lesser extent to plasma proteins than VPA and this being independent of the prodrug concentration. Amide prodrugs were also delivered into the brain after intravenous bolus injection. One of the prodrug showed greater brain uptake and high selectivity for LAT1 and it was able to release VPA slowly within the brain. Therefore, it was concluded that the VPA brain concentrations can be stabilized as well as the problematic pharmacokinetic profile can be altered by a LAT1-selective prodrug.

Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs.

INTRODUCTION: Prenatal antiepileptic drug (AED) exposure is associated with an increased risk of cognitive impairment and autism spectrum disorders detected mainly at the age of two to six years. We examined whether the developmental aberrations associated with prenatal AED exposure could be detected already in infancy and whether effects on visual attention can be observed at this early age. MATERIAL AND METHODS: We compared a prospective cohort of infants with in utero exposure to AED (n=56) with infants without drug exposures (n=62). The assessments performed at the age of seven months included standardized neurodevelopmental scores (Griffiths Mental Developmental Scale and Hammersmith Infant Neurological Examination) as well as a novel eye-tracking-based test for visual attention and orienting to faces. Background information included prospective collection of AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, and information on maternal epilepsy type. RESULTS: Carbamazepine, oxcarbazepine, and valproate, but not lamotrigine or levetiracetam, were associated with impaired early language abilities at the age of seven months. The general speed of visuospatial orienting or attentional bias for faces measured by eye-tracker-based tests did not differ between AED-exposed and control infants. DISCUSSION: Our findings support the idea that prenatal AED exposure may impair verbal abilities, and this effect may be detected already in infancy. In contrast, the early development of attention to faces was spared after in utero AED exposure.

Attention to Faces Expressing Negative Emotion at 7 Months Predicts Attachment Security at 14 Months.

To investigate potential infant-related antecedents characterizing later attachment security, this study tested whether attention to facial expressions, assessed with an eye-tracking paradigm at 7 months of age (N = 73), predicted infant-mother attachment in the Strange Situation Procedure at 14 months. Attention to fearful faces at 7 months predicted attachment security, with a smaller attentional bias to fearful expressions associated with insecure attachment. Attachment disorganization in particular was linked to an absence of the age-typical attentional bias to fear. These data provide the first evidence linking infants' attentional bias to negative facial expressions with attachment formation and suggest reduced sensitivity to facial expressions of negative emotion as a testable trait that could link attachment disorganization with later behavioral outcomes.