Finnish children who needed long-term home respiratory support had severe sleep-disordered breathing and complex medical backgrounds.

AIM: No studies have described long-term paediatric home respiratory support in Nordic countries. We examined the clinical characteristics and long-term outcomes of paediatric patients who received continuous positive airway pressure, non-invasive-positive-pressure ventilation and invasive ventilation from a multidisciplinary home respiratory support team. METHODS: Retrospective tertiary-level data were collected between 1 January 2010 and 31 December 2020 in Tampere University Hospital. These comprised patient demographics, treatment course and polysomnography-confirmed sleep-disordered breathing (SDB). RESULTS: There were 93 patients (63.4% boys). The median age at treatment initiation was 8.4 (range 0.11-16.9) years. The patients had: neuromuscular disease (16.1%), central nervous system disease (14.0%), developmental disabilities and congenital syndrome (29.0%), lung-airway conditions (11.8%), craniofacial syndrome (15.1%) and severe obesity (14.0%). More than two-thirds had severe SDB (66.7%) and the most common one was obstructive sleep apnoea in 66.7%. We found that 92.5% received long-term therapy for more than 3 months and the mean treatment duration was 3.3 ± 2.7 years. A non-invasive mask interface was used in 94.7% of cases and 5.3% needed tracheostomy ventilation. More than a quarter (26.7%) achieved disease resolution during the study period. CONCLUSION: Most children who needed long-term home respiratory support had complex conditions and severe, persistent SDB.

Paternal perinatal stress is associated with children's emotional problems at 2 years.

BACKGROUND: Paternal mental health in pregnancy and postpartum has been increasingly highlighted as important both in its own right, but also as crucial for the development of children. Rates of help-seeking among fathers is low, possibly due to conceptualising their own difficulties as stress rather than problems with mood. The relationship between paternal stress and child outcomes has not been investigated. METHODS: This study used data from the Finnish CHILD-SLEEP birth cohort. Data were available for 901 fathers and 939 mothers who completed questionnaires on demographics, stress, anxiety and depression at 32 weeks gestation, 3 months, 8 months and 24 months postpartum. Parental report of child emotional and behavioural problems was collected at 24 months. RESULTS: Around 7% of fathers experienced high stress (over 90% percentile) at each timepoint measured in the perinatal period, rising to 10% at 2 years postpartum. Paternal stress measured antenatally, at 3 and 24 months was associated with child total problems at 24 months, while paternal depression and anxiety were not related to child outcomes when in the same model. After adjusting for concurrent maternal depression, anxiety and stress, an association remained between paternal stress at each timepoint and child total problem scores at 24 months. The strongest association was with paternal stress at 3 months (OR 3.17; 95% CI 1.63-6.16). There were stronger relationships between paternal stress and boys' rather than girls' total problem scores, although the interactions were not statistically significant. CONCLUSIONS: Paternal stress is an important manifestation of perinatal distress and is related to child mental health, particularly when present in the early postpartum months. Paternal stress should therefore be assessed in the perinatal period, which presents opportunities for early intervention and prevention of difficulties for both father and child.

Sleep disturbances and depressive and anxiety symptoms during pregnancy: associations with delivery and newborn health.

BACKGROUND: Sleep disturbances and mood symptoms are common in late pregnancy; according to the literature, they can affect delivery and newborn outcomes. This study evaluated the effect of sleep and mood symptoms on delivery and newborn health, because there are insufficient and partly contradictory studies on the topic. METHODS: A cohort of 1414 mothers in their third trimester was enrolled in this prospective cross-sectional questionnaire study. Validated questionnaires were assessed for the measurement of sleep disturbances and depressive and anxiety symptoms. The data on delivery and newborn outcomes were obtained from hospital medical records. RESULTS: Sleep disturbances were very common. A higher insomnia score (ß = - 0.06, p = 0.047) and longer sleep need (ß = 0.07, p = 0.047) were related to delivery at a lower gestational age. In addition, a higher insomnia score (ß = - 28.30, p = 0.010) and lower general sleep quality (ß = - 62.15, p = 0.025) were associated with lower birth weight, but longer sleep duration and longer sleep need with a higher birth weight (ß = 28.06, p = 0.019; ß = 27.61, p = 0.028, respectively). However, the findings regarding birth weight lost their significance when the birth weight was standardized by gestational weeks. Concerning Apgar scores and umbilical artery pH, no associations were found. Snoring was associated with a shorter duration of the first phase of delivery (ß = - 78.71, p = 0.015) and total duration of delivery (ß = - 79.85, p = 0.016). Mothers with higher insomnia, depressive, or anxiety symptoms were more often treated with oxytocin (OR 1.54 95% CI 1.00-2.38, p = 0.049, OR 1.76, 95% CI 1.02-3.04, p = 0.049 and OR 1.91, CI 95% 1.28-2.84, p < 0.001, respectively) and those with higher depressive and anxiety symptoms were delivered more often with elective cesarean section (OR 4.67, 95% CI 2.04-12.68, p < 0.001 and OR 2.22, 95% CI 1.03-4.79, p = 0.042). CONCLUSIONS: Maternal sleep disturbances and mood symptoms during pregnancy are associated with delivery and newborn health. However, nearly, all the outcomes fell within a normal range, implying that the actual risks are low.

Finnish children who experienced narcolepsy after receiving the Pandemrix vaccine during the 2009-2010 H1N1 pandemic demonstrated high level of psychosocial problems.

AIM: We assessed psychosocial burdens in children who developed narcolepsy after receiving the Pandemrix H1N1 vaccine during the 2009-2010 pandemic. Parental quality of life was also assessed. METHODS: This multicentre study covered four of the five Finnish University Hospital Districts, which dealt with about 90% of the paediatric narcolepsy cases after the Pandemrix vaccination. The medical records of children diagnosed from 2010 to 2014 were reviewed. The questionnaires included the Youth Self-Report (YSR), Children's Depression Inventory (CDI), the Child Behaviour Checklist (CBCL) and questions on parental resources, stress and quality of life. RESULTS: We obtained the medical records of 94 children who were aged 5-17 years at the time of their narcolepsy diagnosis and questionnaire data for 73 of those children. Most children had strong narcolepsy symptoms, and 25% had CDI scores that suggested depression. In addition, 41% had total CBCL problem scores above the clinically significant limit and 48% were anxious, withdrawn and had somatic complaints. Sleep latency was weakly associated with the CBCL total problem score. Half of the children needed psychiatric interventions and parental stress was common. CONCLUSION: Depression and behavioural problems were common in children with narcolepsy after the Pandemrix vaccination and their parents frequently reported feeling stressed.

Exposure to electronic media was negatively associated with speech and language development at 18 and 24 months.

AIM: This study evaluated early speech and language development at 18 and 24 months, and associated factors, based on parental reports. METHOD: We followed up the CHILD-SLEEP birth cohort of 1667 Finnish-speaking families, who were randomly recruited in 2011-2013 during routine visits to maternity clinics in the Pirkanmaa Hospital District of Finland. The women were approximately 32 weeks' pregnant at enrolment. Parents reported the size of their child's expressive vocabulary, word combinations, intelligibility, finger-pointing and adherence to instructions. A subsample was studied using the Expressive Language subscale of the Bayley Scales of Infant and Toddler Development, Third Edition. RESULTS: The children's vocabulary was smaller than previously reported. At 18 months of age, 68.8% of the 997 children had a vocabulary of 20 words or less and 35.7% used about five words at most. At 24 months, 32.4% of the 822 children had a vocabulary of 50 words or less and 18.4% used about 20 words at most. Longer child and parental exposure to electronic media was negatively associated with the size of the child's expressive vocabulary. CONCLUSION: Vocabulary size at 18 and 24 months was smaller than previously reported and negatively associated with exposure to electronic media.

Snoring toddlers with and without obstructive sleep apnoea differed with regard to snoring time, adenoid size and mouth breathing.

AIM: The difficulty of assessing the likelihood of obstructive sleep apnoea (OSA) in children who snore without full-night polysomnography is widely recognised. Our aim was to identify features that were characteristic of two-year-old children with OSA and evaluate whether this information could be used to assess the likelihood of OSA. METHODS: The study was carried out as part of the Child-Sleep Project, a longitudinal birth cohort study of children born at Tampere University Hospital, Finland. This part of the study focused on the children in the cohort who snored and was carried out between 2013 and 2015. The primary outcomes were measured using parental questionnaires, polysomnography and clinical examinations. RESULTS: In total, 52 children participated at a mean age of 27 months (range 23-34). Of these, 32 (44% male) snorers and 20 (70% male) controls. The most significant findings were that children who had OSA demonstrated longer snoring time (P = .003), a greater tendency for mouth breathing (P = .007) and bigger adenoid size (P = .008) than snorers without OSA. CONCLUSION: Snoring time, adenoid tissue size and mouth breathing were important features that identified the likelihood of OSA in snoring toddlers.

Prenatal and Postnatal Predictive Factors for Children's Inattentive and Hyperactive Symptoms at 5 Years of Age: The Role of Early Family-related Factors.

We examined several parent-reported prenatal and postnatal factors as potential risk factors for attention-deficit and hyperactivity disorder (ADHD) symptomatology in 5-year-old children. Our study is based on the CHILD-SLEEP birth cohort. Several parental questionnaires were collected prenatally (32nd pregnancy week) and postnatally (i.e. child aged 3, 8, and 24 months and at 5 years). At 5 years of age, ADHD symptoms were assessed using questionnaires. Our main results showed that being a boy, parental depressive symptoms, more negative family atmosphere or a child's shorter sleep duration, and maternal authoritarian parenting style predicted inattentive/hyperactive symptoms. Maternal and paternal authoritative parenting style predicted less inattentive/hyperactive symptoms. Children with several risk factors together had the highest risk for inattentive/hyperactive symptoms. Our findings emphasise the need for early screening and treatment of parental mental health, and early evidence-based targeted parental support, to enable early intervention in those children at a risk of developing ADHD.

Maternal and paternal depressive symptoms and children's emotional problems at the age of 2 and 5 years: a longitudinal study.

BACKGROUND: Maternal and paternal depressive symptoms are related to children's emotional problems, but their combined effect remains unclear. Here, we constructed four parental longitudinal depressive symptom trajectory groups and studied their associations with children's emotional problems at the age of 2 and 5 years. METHODS: We did an assessment of maternal and paternal depressive symptoms (gestational week 32, as well as 3, 8 and 24 months postnatally) and children's emotional problems at ages two (N = 939) and five (N = 700) in the CHILD-SLEEP cohort. Three separate maternal and paternal depressive symptom trajectories based on latent profile analysis were combined to form four parental depressive symptom trajectory groups. We compared groups with a general linear model, with children's emotional (total, internalizing and externalizing) - problem scores serving as the dependent variables. RESULTS: At both ages, combined parental depressive symptom trajectories were associated with children's emotional problems: effect sizes were medium for total and small for other domains. According to post hoc comparisons, children whose mothers or both parents had persistent depressive symptoms had significantly more total, externalizing and internalizing problems than did children who had neither parent nor only the father showing depressive symptoms. A higher (and persistent) level of maternal depressive symptoms was related to a higher level of these children's emotional problems, a pattern not evident with paternal depressive symptoms. In all analyses, the interaction effect was nonsignificant between parental trajectories and child gender. CONCLUSIONS: Findings suggest that an absence of depressive symptoms in their fathers cannot compensate for the adverse effects of maternal depressive symptoms upon their children. Moreover, paternal depressive symptoms alone do not lead to increased risk for emotional problems in these 2- and 5-year-old children. In contrast, even subclinical levels of maternal depressive symptoms in late pregnancy are associated with increased risk for their children's experiencing internalizing and externalizing emotional problems.

Development of sleep-wake rhythms during the first year of age.

Circadian rhythms refer to biological rhythms that have an endogenous period length of approximately 24 hr. However, not much is known about the variance in the development of the sleep-wake rhythm. The study objectives were (a) to describe the normative variation in the development of a sleep-wake rhythm in infancy, (b) to assess whether slower development is related to sleep quality and (c) to evaluate factors that are related to the slower development of a sleep-wake rhythm. The study is based on a representative birth cohort. Questionnaires at the ages of 3 (n = 1,427) and 8 months (n = 1,302) and actigraph measurement at 8 months (n = 372) were available. Infants with significant developmental delays (n = 11) were excluded. The results are based on statistical testing and multivariate modelling. We found that the average percentage of daytime sleep was 36.3% (standard deviation [SD], 8.5%) at 3 months and 25.6% (SD, 6.6%) at 8 months. At both time-points, infants with slower sleep-wake rhythm development slept more hours per day, had a later sleep-wake rhythm, more difficulties in settling to sleep and longer sleep-onset latency; they also spent a longer time awake during the night. According to actigraph registrations, we found that the infants with slow development of a sleep-wake rhythm slept less and had a later start and end to night-time sleep than the other infants. Infants' sleep-wake rhythm development is highly variable and is related to parent-reported and objectively measured sleep quality and quantity. Interventions to improve the sleep-wake rhythm might improve sleep quality in these infants.

Variation near MTNR1A associates with early development and interacts with seasons.

Melatonin is a circadian regulatory hormone with neuroprotective properties. We have previously demonstrated the association of the genetic variant rs12506228 near the melatonin receptor 1A gene (MTNR1A) with intolerance to shift-work. Furthermore, this variant has been connected to Alzheimer's disease. Because of the previously suggested role of melatonin signalling in foetal neurocognitive and sleep development, we studied here the association of rs12506228 with early development. The study sample comprised 8-month-old infants from the Finnish CHILD-SLEEP birth cohort (n = 1,301). Parental questionnaires assessed socioemotional, communication and motor development, as well as sleep length and night awakenings. The A allele of rs12506228 showed an association with slower socioemotional (p = .025) and communication (p = .0098) development, but no direct association with sleep. However, the association of the Finnish seasons with infant sleep length interacted with rs12506228. Taken together, rs12506228 near MTNR1A, which has been previously linked to adult and elderly traits, is shown here to associate with slower early cognitive development. In addition, these results suggest that the darker seasons associate with longer infant sleep time, but only in the absence of the rs12506228 AA genotype. Because the risk allele has been connected to fewer brain MT1 melatonin receptors, these associations may reflect the influence of decreased melatonin signalling in early development.

Night Awakening and Its Association With Executive Functioning Across the First Two Years of Life.

Longitudinal associations between signaled night awakening and executive functioning (EF) at 8 and 24 months in children with (≥ 3 awakenings, n = 77) and without parent-rated fragmented sleep (≤ 1 awakening, n = 69) were studied. EF was assessed with the Switch task at 8 and 24 months. At 24 months, behavioral tasks and parental ratings of EF (Behavior Rating Inventory of Executive Function-Preschool version) were also used. In the Switch task, children with fragmented sleep were less able to learn stimulus sequences and inhibit previously learned responses than children without fragmented sleep. The groups differed only marginally in parental ratings of EF, and no differences were found in behavioral EF tasks. These results suggest that eye movement-based measures may reveal associations between sleep and EF already in infancy and toddlerhood.

Short Sleep Duration and Later Overweight in Infants.

OBJECTIVE: To provide further knowledge about the longitudinal association between sleep duration and overweight in infants. STUDY DESIGN: The data for this study are from the CHILD-SLEEP birth cohort (n = 1679). The sleep data are based on parent-reported total sleep duration collected at 3, 8, 18, and 24 months. For a subgroup of 8-month old participants (n = 350), an actigraph recording was also made. Growth data were derived from the child health clinic records. A logistic regression model was used to study the association between sleep duration and later weight development. RESULTS: Shorter sleep duration in 3-month-old infants was cross-sectionally associated with lower weight-for-length/height (all P values ≤ .026) and body mass index (all P values ≤ .038). Moreover, short sleep duration at the age of 3 months was associated with greater weight-for-length/height z score at the age of 24 months (aOR 1.56; 95% CI 1.02-2.38) as well as with a predisposition to gain excess weight between 3 and 24 months of age (aOR 2.61; 95% CI 1.75-3.91). No significant associations were found between sleep duration at 8, 18, or 24 months and concurrent or later weight status. Actigraph-measured short night-time sleep duration at the age of 8 months was associated with greater weight-for-length at the age of 24 months (aOR 1.51; 95% CI 1.02-2.23). CONCLUSIONS: Short total sleep duration at the age of 3 months and short night-time sleep duration at the age of 8 months are associated with the risk of gaining excess weight at 24 months of age.

Dysbiosis in Snoring Children: An Interlink to Comorbidities?

BACKGROUND AND OBJECTIVES: Early microbial colonization has a key impact on infant health through nutritional, immunological, and metabolic programming. The origin of child snoring is multifactorial and complex, and may thereby also generate long-term health problems. The link between child snoring and gut microbes remains unclear, although indirect evidence exists regarding this relationship. This study aimed to characterize the connection between gut microbiota and child snoring. METHODS: In a prospective, observational CHILD-SLEEP birth cohort study, gut microbiota in a subcohort of 43 of these children at 2 years of life was profiled with 16S ribosomal RNA gene amplicon sequencing. RESULTS: A higher abundance of the Proteobacteria phylum, the Enterobacteriaceae family, and Erysipelotrichaceae family, as well as a higher ratio of Firmicutes to Bacteroidetes were detected in snorers as compared to controls. Furthermore, snorers showed significantly lower microbial diversity and richness than non-snorers. CONCLUSIONS: The snoring children manifest different gut microbiota as compared with healthy children. Considering that snoring and sleep disorders can be a source of long-term consequences, including cardiovascular, metabolic, immunological, neurocognitive and behavioral consequences, our results proposes early microbiota as a new treatment target.

Sleeping problems during pregnancy-a risk factor for postnatal depressiveness.

In the general population, sleeping problems can precede an episode of depression. We hypothesized that sleeping problems during pregnancy, including insomnia symptoms, shortened sleep, and daytime tiredness, are related to maternal postnatal depressiveness. We conducted a prospective study evaluating sleep and depressive symptoms, both prenatally (around gestational week 32) and postnatally (around 3 months after delivery) in the longitudinal CHILD-SLEEP birth cohort in Finland. Prenatally, 1667 women returned the questionnaire, of which 1398 women participated also at the postnatal follow-up. Sleep was measured with the Basic Nordic Sleep Questionnaire (BNSQ) and depressive symptoms with a 10-item version of the Center for Epidemiological Studies Depression Scale (CES-D). Altogether, 10.3% of the women had postnatal depressiveness (CES-D ≥ 10 points). After adjusting for main background characteristics and prenatal depressiveness (CES-D ≥ 10), poor general sleep quality (AOR 1.87, 95% CI 1.21-2.88), tiredness during the day (AOR 2.19, 95% CI 1.41-3.38), short sleep ≤ 6 and ≤ 7 h, sleep latency > 20 min, and sleep loss ≥ 2 h were associated with postnatal depressiveness (all p < .050). Postnatally, after the adjustment for background characteristics, virtually all sleeping problems (i.e., difficulty falling asleep (AOR 7.93, 95% CI 4.76-13.20)), except frequent night awakenings per week or severe sleepiness during the day, were related to concurrent postnatal depressiveness. Thus, several prenatal and postnatal sleeping problems are associated with increased depressive symptoms 3 months postnatally. Screening of maternal prenatal sleeping problems, even without depressive symptoms during pregnancy or lifetime, would help to identify women at an increased risk for postnatal depressiveness.

Parental reports showed that snoring in infants at three and eight months associated with snoring parents and smoking mothers.

AIM: This prospective study examined the prevalence of snoring during infancy and the prenatal and postnatal risk factors for this condition. METHODS: The study population comprised 1388 infants from the CHILD-SLEEP birth cohort, who were recruited in the Pirkanmaa Hospital District, Finland, between 2011 and 2013. Sleep and background factor questionnaires were filled out prenatally by parents and when the infant was three and eight months old. RESULTS: The prevalence of habitual snoring was 3.2% at the age of three months and 3.0% at eight months, and snoring infants had more sleeping difficulties at those ages, with odds ratios (ORs) of 3.11 and 4.63, respectively. At three months, snoring infants slept for a shorter length of time (p = 0.001) and their sleep was more restless (p = 0.004). In ordinal logistic regression models, parental snoring (adjusted OR = 1.65 and 2.60) and maternal smoking (adjusted OR = 2.21 and 2.17) were significantly associated with infant snoring at three and eight months, while formula feeding and dummy use (adjusted OR = 1.48 and 1.56) were only associated with infant snoring at three months. CONCLUSION: Parental snoring and maternal smoking increased the risk of snoring. Infants who snored also seemed to suffer more from other sleep difficulties.

Association between snoring and deciduous dental development and soft tissue profile in 3-year-old children.

INTRODUCTION: The aim was to study the association between snoring and development of occlusion, maxillary dental arch, and soft tissue profile in children with newly completed deciduous dentition. METHODS: Thirty-two (18 female, 14 male) parent-reported snorers (snoring ≥3 nights/week) and 19 (14 female, 6 male) nonsnorers were recruited. Breathing preference (nose or mouth) was assessed at the mean age of 27 months by otorhinolaryngologist. At the mean age of 33 months, an orthodontic examination was performed, including sagittal relationship of second deciduous molars, overjet, overbite, and occurrence of crowding and lateral crossbite. Bite index was obtained to measure maxillary dental arch dimensions (intercanine and intermolar width, arch length). A profile photograph was obtained to measure facial convexity. RESULTS: No significant differences were found between nonsnorers and snorers in any of the studied occlusal characteristics or in measurements of maxillary dental arch dimensions. Snorers were found to have a more convex profile than nonsnorers. Occurrence of mouth breathing was more common among snorers. CONCLUSIONS: Parent-reported snoring (≥3 nights/week) does not seem to be associated with an adverse effect on the early development of deciduous dentition, but snoring children seem to have more convex profile than nonsnorers. Snoring is a mild sign of sleep-disordered breathing, and in the present study its short time lapse may not have had adequate functional impact on occlusion.

Craniofacial and occlusal development in 2.5-year-old children with obstructive sleep apnoea syndrome.

OBJECTIVES: Paediatric obstructive sleep apnoea syndrome (OSAS) is associated with a range of changes in craniofacial and occlusal development. There is, however, little knowledge of how early in life these changes can be found. The aim of the present study was to determine whether changes in dental arch morphology, occlusion, facial profile, tonsil size, breathing habit or body mass index (BMI) can already be found among 2.5-year-old children with OSAS. MATERIALS AND METHODS: Fifty-two children were recruited to the study. Of these, OSAS was diagnosed in 9 children and 18 children did not snore in polysomnography. These two groups were subsequently compared when evaluating polysomnographic, otorhinolaryngological and dental variables. RESULTS: Children with OSAS had narrower inter canine width than non-snoring children (P = 0.032). Furthermore, children with OSAS had larger adenoid size with respect to the nasopharyngeal volume (P = 0.020) and more tendency to mouth breathing (P = 0.002). No statistically significant differences were found when comparing palatine tonsil size, occlusal characteristics, soft tissue profile measurements or BMI. LIMITATIONS: The limitation of the study is the small sample size. CONCLUSION: Children with OSAS had narrower upper inter canine width than non-snoring children at the age of 2.5 years. Larger adenoid size and mouth breathing tendency were also more common among children with OSAS. Further studies with larger sample sizes are needed to determine if other changes in craniofacial and occlusal development can be found in this age group.

The effects of maternal risk factors during pregnancy on the onset of sleep difficulties in infants at 3 months old.

Sleep problems in young children are among the most common concerns reported to paediatricians. Sleep is thought to have important regulatory functions, and sleep difficulties in early childhood are linked to several psychosocial and physiological problems. Moreover, several prenatal factors have been found to influence infants' sleep. Among them, most of the studies have been focused on maternal prenatal depression and/or anxiety as potential risk factors for sleep problems in childhood, whereas other relevant psychological factors during pregnancy have not received as much attention. Therefore, we aimed to examine the effect of several psychiatric maternal risk factors during pregnancy (i.e. symptoms of anxiety, depression, insomnia, alcohol use, seasonality, attention deficit and hyperactivity disorder and/or stressful life events) on the onset of some sleep problems related to sleep quality and sleep practices in 3-month-old infants. We examined 1,221 cases from a population-based birth cohort, with subjective measures during pregnancy in mothers, and at 3 months after birth in the infants. The findings showed that all the maternal risk factors during pregnancy, except for symptoms of alcoholism and sleepiness, were related to sleep difficulties in infants. Interestingly, attention deficit and hyperactivity disorder symptomatology in mothers during pregnancy was the only variable that predicted more than two sleeping difficulties (i.e. long sleep-onset latency, co-sleeping with parents and irregular sleeping routines) at 3 months old. Our results highlight the relevance of maternal risk factors during pregnancy, and not only prenatal depression and/or anxiety, as variables to be considered when examining sleep difficulties in infants.

Respiratory sinus arrhythmia moderates the impact of maternal prenatal anxiety on infant negative affectivity.

Maternal prenatal anxiety is associated with infants' temperamental negative affectivity (NA), but it is unclear to what extent children vary in their susceptibility to prenatal influences. We tested a hypothesis that infants' respiratory sinus arrhythmia (RSA), an index of parasympathetic vagal tone and a potential marker of differential susceptibility to environmental influences, moderates the effects of maternal prenatal anxiety on the development of infant NA. Prenatal anxiety was assessed during the last trimester of pregnancy in a low-risk community sample. Infant NA, baseline RSA, and maternal postnatal anxiety were assessed at 8-10 months of infant age. Regression analyses were performed to predict infant NA on the basis of prenatal anxiety, infant baseline RSA, and their interaction (N = 173). Maternal prenatal anxiety and infant RSA interactively predicted infant NA at 8-10 months. Among infants with high RSA, a significant positive association between prenatal anxiety and infant NA was observed, whereas prenatal anxiety did not predict infant NA among infants with low RSA. Vagal tone, as indexed by baseline RSA, may provide a promising marker of differential susceptibility to the long-term effects of varying intrauterine conditions.

Integrins are not essential for entry of coxsackievirus A9 into SW480 human colon adenocarcinoma cells.

BACKGROUND: Coxsackievirus A9 (CV-A9) is a pathogenic enterovirus type within the family Picornaviridae. CV-A9 infects A549 human epithelial lung carcinoma cells by attaching to the αVß6 integrin receptor through a highly conserved Arg-Gly-Asp (RGD) motif, which is located at the exposed carboxy-terminus of the capsid protein VP1 detected in all studied clinical isolates. However, genetically-modified CV-A9 that lacks the RGD motif (CV-A9-RGDdel) has been shown to be infectious in some cell lines but not in A549, suggesting that RGD-mediated integrin binding is not always essential for efficient entry of CV-A9. METHODS: Two cell lines, A549 and SW480, were used in the study. SW480 was the study object for the integrin-independent entry and A549 was used as the control for integrin-dependent entry. Receptor levels were quantitated by cell sorting and quantitative PCR. Antibody blocking assay and siRNA silencing of receptor-encoding genes were used to block virus infection. Peptide phage display library was used to identify peptide binders to CV-A9. Immunofluorescence and confocal microscopy were used to visualize the virus infection in the cells. RESULTS: We investigated the receptor use and early stages of CV-A9 internalization to SW480 human epithelial colon adenocarcinoma cells. Contrary to A549 infection, we showed that both CV-A9 and CV-A9-RGDdel internalized into SW480 cells and that function-blocking anti-αV integrin antibodies had no effect on the binding and entry of CV-A9. Whereas siRNA silencing of ß6 integrin subunit had no influence on virus infection in SW480, silencing of ß2-microglobulin (ß2M) inhibited the virus infection in both cell lines. By using a peptide phage display screening, the virus-binding peptide identical to the N-terminal sequence of HSPA5 protein was identified and shown to block the virus infection in both A549 and SW480 cell lines. HSPA5 was also found to co-localize with CV-A9 at the SW480 cell periphery during the early stages of infection by confocal microscopy. CONCLUSIONS: The data suggest that while αVß6 integrin is essential for CV-A9 in A549 cell line, it is not required in SW480 cell line in which ß2M and HSPA5 alone are sufficient for CV-A9 infection. This suggests that the choice of CV-A9 receptor(s) is dependent on the tissue/cellular environment.