CAREGIVER SENSITIVITY AND CONSISTENCY AND CHILDREN'S PRIOR FAMILY EXPERIENCE AS CONTEXTS FOR EARLY DEVELOPMENT WITHIN INSTITUTIONS.

The current study addressed whether two institution-wide interventions in St. Petersburg, Russian Federation, that increased caregiver sensitivity (Training Only: TO) or both caregiver sensitivity and consistency (Training plus Structural Changes: T+SC) promoted better socioemotional and cognitive development than did a No Intervention (NoI) institution during the first year of life for children who were placed soon after birth. It also assessed whether having spent less than 9 versus 9 to 36 months with a family prior to institutionalization was related to children's subsequent socioemotional and cognitive development within these three institutions. The Battelle Developmental Inventory (J. Newborg, J.R. Stock, L. Wnek, J. Guidubaldi, & J. Svinicki, 1988) was used to assess the socioemotional and cognitive functioning of children in NoI (n = 95), TO (n = 104), and T+SC (n = 86) at two to three time points during their first 6 to 12 months of residency. Results suggest that improving caregiver sensitivity can improve the cognitive development of infants in the first year of institutionalization whereas improving caregiver consistency in addition to sensitivity is more beneficial for socioemotional development than is sensitivity alone. Similarly, for children in T+SC, longer time with a family prior to institutionalization (consistent caregiver, unknown sensitivity) was associated with better socioemotional, but not cognitive, baseline scores and more rapid cognitive than socioemotional development during institutionalization. These results suggest caregiver sensitivity is more highly related to cognitive development whereas caregiver consistency is more related to socioemotional development in the first years of life.

The Effect of a Social-Emotional Intervention on the Development of Preterm Infants in Institutions.

This study examined the effect of a social-emotional intervention implemented in one St. Petersburg (Russian Federation) institution (called a Baby Home, BH) on the general behavioral development of preterm children (gestational ages of 30-36 weeks) during their first two years of life. The intervention consisted of training caregivers and implementing structural changes to create a more family-like environment. The study included preterm (N = 56) and full-term (N = 93) children from one BH that implemented the intervention and from another BH with no intervention. Children were assessed at 3, 6, 9, 12, 18 and 24 months of age with the Battelle Development Inventory (LINC Associates, 1988). The results showed that the intervention positively influenced the general behavioral development of BH preterm children throughout their first two years of life compared to preterms from the no-intervention BH. Also, results indicated that the intervention effect was developmentally similar for preterm and for full-term children, but preterm children consistently scored lower than full-terms during their first two years living in the BH. In general, our research emphasizes the crucial role of warm, sensitive, and responsive interactions with a constant and emotionally available caregiver for healthy child development for both term and preterm children.

CAREGIVER-CHILD INTERACTION, CAREGIVER TRANSITIONS, AND GROUP SIZE AS MEDIATORS BETWEEN INTERVENTION CONDITION AND ATTACHMENT AND PHYSICAL GROWTH OUTCOMES IN INSTITUTIONALIZED CHILDREN.

This report describes a secondary analysis of data from a comprehensive intervention project which included training and structural changes in three Baby Homes in St. Petersburg, Russian Federation. Multiple mediator models were tested according to the R.M. Baron and D.A. Kenny () causal-steps approach to examine whether caregiver-child interaction quality, number of caregiver transitions, and group size mediated the effects of the intervention on children's attachment behaviors and physical growth. The study utilized a subsample of 163 children from the original Russian Baby Home project, who were between 11 and 19 months at the time of assessment. Results from comparisons of the training and structural changes versus no intervention conditions are presented. Caregiver-child interaction quality and number of caregiver transitions fully mediated the association between intervention condition and attachment behavior. No other mediation was found. Results suggest that the quality of interaction between caregivers and children in institutional care is of primary importance to children's development, but relationship context may play a less direct mediational role, supporting caregiver-child interactions.

The development of postinstitutionalized versus parent-reared Russian children as a function of age at placement and family type.

A total of 149 children, who spent an average of 13.8 months in Russian institutions, were transferred to Russian families of relatives and nonrelatives at an average age of 24.7 months. After residing in these families for at least 1 year (average = 43.2 months), parents reported on their attachment, indiscriminately friendly behavior, social-emotional competencies, problem behaviors, and effortful control when they were 1.5-10.7 years of age. They were compared to a sample of 83 Russian parents of noninstitutionalized children, whom they had reared from birth. Generally, institutionalized children were rated similarly to parent-reared children on most measures, consistent with substantial catch-up growth typically displayed by children after transitioning to families. However, institutionalized children were rated more poorly than parent-reared children on certain competencies in early childhood and some attentional skills. There were relatively few systematic differences associated with age at family placement or whether the families were relatives or nonrelatives. Russian parent-reared children were rated as having more problem behaviors than the US standardization sample, which raises cautions about using standards cross-culturally.

The Development of Children Placed into Different Types of Russian Families Following an Institutional Intervention.

This study examined whether interventions in Russian Baby Homes promoting warm, sensitive, and responsive caregiver-child interactions and relationships would be associated with advantages in those children's behavior years after they transitioned to family care. Children (N = 135) who had resided for at least 3 months (M = 13.8 months) in one of three intervention institutions were subsequently placed in Russian families (relatives or non-relatives) for at least 1 year (M = 33.5 months). When children were 1.5-10.8 years of age, parents provided ratings of attachment, indiscriminate friendliness, executive functioning, social-emotional development, and behavior problems. Despite very substantial differences in the developmental status of children at departure from the three institutions, there were fewer than expected significant differences between children from the three institutions at follow-up or as a function of being placed with relatives or non-relatives. Specifically, children reared in the most improved institution displayed less indiscriminate friendliness, were less aggressive/defiant, and had less externalizing behavior. Children from all three institutions who were placed into families at older ages tended to be rated more poorly on some measures. These results suggest that previously institutionalized children adjust well to family life, but improved institutional caregiving can have some persistent benefits over several years in children transitioned to families.

CAPON modulates neuronal calcium handling and cardiac sympathetic neurotransmission during dysautonomia in hypertension.

Genome-wide association studies implicate a variant in the neuronal nitric oxide synthase adaptor protein (CAPON) in electrocardiographic QT variation and sudden cardiac death. Interestingly, nitric oxide generated by neuronal NO synthase-1 reduces norepinephrine release; however, this pathway is downregulated in animal models of cardiovascular disease. Because sympathetic hyperactivity can trigger arrhythmia, is this neural phenotype linked to CAPON dysregulation? We hypothesized that CAPON resides in cardiac sympathetic neurons and is a part of the prediseased neuronal phenotype that modulates calcium handling and neurotransmission in dysautonomia. CAPON expression was significantly reduced in the stellate ganglia of spontaneously hypertensive rats before the development of hypertension compared with age-matched Wistar-Kyoto rats. The neuronal calcium current (ICa; n=8) and intracellular calcium transient ([Ca(2+)]i; n=16) were significantly larger in the spontaneously hypertensive rat than in Wistar-Kyoto rat (P<0.05). A novel noradrenergic specific vector (Ad.PRSx8-mCherry/CAPON) significantly upregulated CAPON expression, NO synthase-1 activity, and cGMP in spontaneously hypertensive rat neurons without altering NO synthase-1 levels. Neuronal ICa and [Ca(2+)]i were significantly reduced after CAPON transduction compared with the empty vector. In addition, Ad.PRSx8-mCherry/CAPON also reduced (3)H-norepinephrine release from spontaneously hypertensive rat atria (n=7). NO synthase-1 inhibition (AAAN, 10 µmol/L; n=6) reversed these effects compared with the empty virus alone. In conclusion, targeted upregulation of CAPON decreases cardiac sympathetic hyperactivity. Moreover, dysregulation of this adaptor protein in sympathetic neurons might further amplify the negative cardiac electrophysiological properties seen with CAPON mutations.

Behavior problems in children transferred from a socioemotionally depriving institution to St. Petersburg (Russian Federation) families.

Behavior problems were studied in fifty 5- to 8-year-old children transferred from a socioemotionally depriving Russian institution to domestic families. Results indicated that the postinstitutional (PI) sample as a whole had higher clinical/borderline behavior problem rates on the parent-reported Child Behavior Checklist for Ages 6-18 (T.M. Achenbach & L.A. Rescorla, 2001) aggressive and lower rates on the withdrawn/depressed and internalizing problems scales than did non-institutionalized (non-I) children reared in Russian families. Compared with the U.S. standardization sample, PI children had significantly higher rates for aggressive, externalizing, and social problems; the non-I children had higher rates for withdrawn/depressed and internalizing problems; and both groups had higher rates for rule-breaking behavioral problems. PI children placed in domestic families at 18 months or older had higher rates of problems than did the U.S. non-I standardization sample, but children placed at younger ages did not. PI children transferred to nonbiological families had lower rates of problems compared to U.S. norms than did children transferred to biological families. Thus, prolonged early socioemotional deprivation was associated with a higher percentage of behavior problems in children placed in domestic families, especially if transferred to biological families.

Maintaining a social-emotional intervention and its benefits for institutionalized children.

This article reports the maintenance of one of the largest interventions conducted in St. Petersburg (Russian Federation) orphanages for children birth to 4 years using regular caregiving staff. One orphanage received training plus structural changes, another training only, and a third business as usual. The intervention produced substantial differences between these institutions on the Home Observation for Measurement of the Environment (HOME) Inventory and on the Battelle Developmental Inventory scores for children. These institutional differences in HOME scores (N = 298) and Battelle scores for children (N = 357) departing the institutions for families in St. Petersburg and the United States were maintained for at least 6 years after the intervention project. This result may be associated with certain features of the intervention and activities conducted during the follow-up interval.

Targeted neuronal nitric oxide synthase transgene delivery into stellate neurons reverses impaired intracellular calcium transients in prehypertensive rats.

Hypertension is associated with the early onset of cardiac sympathetic hyperresponsiveness and enhanced intracellular Ca(2+) concentration [Ca(2+)](i) in sympathetic neurons from both prehypertensive and hypertensive, spontaneously hypertensive rats (SHRs). Oxidative stress is a hallmark of hypertension, therefore, we tested the hypothesis that the inhibitory action of the nitric oxide-cGMP pathway on [Ca(2+)](i) transients is impaired in cardiac sympathetic neurons from the SHR. Stellate ganglia were isolated from young prehypertensive SHRs and age-matched normotensive Wistar-Kyoto rats. [Ca(2+)](i) was measured by ratiometric fluorescence imaging. Neurons from the prehypertensive SHR ganglia had a significantly higher depolarization evoked [Ca(2+)](i) transient that was also associated with decreased expression of neuronal nitric oxide synthase (nNOS), ß1 subunit of soluble guanylate cyclase and cGMP when compared with the Wistar-Kyoto rat ganglia. Soluble guanylate cyclase inhibition or nNOS inhibition increased [Ca(2+)](i) in the Wistar-Kyoto rats but had no effect in SHR neurons. A nitric oxide donor decreased [Ca(2+)](i) in both sets of neurons, although this was markedly less in the SHR. A novel noradrenergic cell specific vector (Ad.PRSx8-nNOS/Cherry) or its control vector (Ad.PRSx8-Cherry) was expressed in sympathetic neurons. In the SHR, Ad.PRSx8-nNOS/Cherry-treated neurons had a significantly reduced peak [Ca(2+)](i) transient that was associated with increased tissue levels of nNOS protein and cGMP concentration compared with gene transfer of Ad.PRSx8-Cherry alone. nNOS inhibition significantly increased [Ca(2+)](i) after Ad.PRSx8-nNOS/Cherry expression. We conclude that artificial upregulation of stellate sympathetic nNOS via targeted gene transfer can directly attenuate intracellular Ca(2+) and may provide a novel method for decreasing enhanced cardiac sympathetic neurotransmission.

The role of transitions to new age groups in the development of institutionalized children.

Children in two institutions in St. Petersburg (Russian Federation) experienced ward transitions, one in which caregivers were trained to provide sensitive, responsive caregiving and one that conducted business as usual. A third institution eliminated transitions, received the same training, and implemented a variety of structural and employment changes designed to promote improved caregiver-child interactions and relationships. While the no-transition comprehensive intervention group of children steadily improved in Battelle Developmental Inventory (LINC Associates, 1988) scores across all age intervals, the children in the institution who encouraged some positive caregiver-child interactions improved before and after, but not during, an age period that involved a transition. In contrast, the no-treatment group displayed no developmental changes across any age period with or without a transition. These results suggest that the common institutional practice of ward transitions to new peers and caregivers is potentially disruptive to infants' and toddlers' general development, but primarily in a context in which some degree of caregiver-child sensitive and responsive interactions are encouraged.

D-amino acid oxidase knockdown in the mouse cerebellum reduces NR2A mRNA.

Virus mediated RNA-interference (RNAi) is a powerful approach to study genes in vivo. Here we report a method using lentivirus-delivered RNAi to knockdown the glial enzyme, D-amino acid oxidase (DAO), in the mouse cerebellum. After initial characterisation in vitro, we achieved a 40-50% reduction of DAO mRNA in the cerebellum 7 and 28 days after a single injection of lentivirus encoding a DAO-specific, short-hairpin RNA. Injections also decreased DAO immunoreactivity (-33%). The major substrate for DAO is D-serine, an N-methyl-D-aspartate receptor (NMDAR) co-agonist. Thus, we also measured whether DAO knockdown impacted on d-serine, or expression of NMDAR subunits, and found that DAO RNAi led to increased cerebellar D-serine levels (+77%), and decreased NMDAR subunit NR2A mRNA (-22%), but did not affect NR1 or NR2C mRNAs. These data demonstrate the utility of lentiviruses to deliver RNAi to glial cells within the cerebellum, and confirm the role of DAO in D-serine metabolism. They also provide a tool to investigate DAO, an enzyme currently of considerable interest in the pathophysiology and therapy of schizophrenia.

Retrograde viral vector-mediated inhibition of pontospinal noradrenergic neurons causes hyperalgesia in rats.

Pontospinal noradrenergic neurons form a component of an endogenous analgesic system and represent a potential therapeutic target. We tested the principle that genetic manipulation of their excitability can alter nociception using an adenoviral vector (AVV-PRS-hKir(2.1)) containing a catecholaminergic-selective promoter (PRS) to retrogradely transduce and inhibit the noradrenergic neurons projecting to the lumbar dorsal horn through the expression of a potassium channel (hKir(2.1)). Expression of hKir(2.1) in catecholaminergic PC12 cells hyperpolarized the membrane potential and produced a barium-sensitive inward rectification. LC neurons transduced by AVV-PRS-hKir(2.1) in slice cultures also showed barium-sensitive inward rectification and reduced spontaneous firing rate (median 0.2 Hz; n = 19 vs control 1.0 Hz; n = 18, p < 0.05). Pontospinal noradrenergic neurons were retrogradely transduced in vivo by injection of AVV into the lumbar dorsal horn (L4-5). Rats transduced with AVV-PRS-hKir(2.1) showed thermal but not mechanical hyperalgesia. Similar selective augmentation of thermal hyperalgesia was seen in the CFA-inflammatory pain model after AVV-PRS-hKir(2.1). In the formalin test, rats transduced with hKir(2.1) showed enhanced nocifensive behaviors (both Phase I and II, p < 0.05, n = 11/group) and increased c-Fos-positive cells in the lumbar dorsal horn. Transduction with AVV-PRS-hKir(2.1) before spared nerve injury produced no change in tactile or cold allodynia. Thus, the selective genetic inhibition of approximately 150 pontospinal noradrenergic neurons produces a modality-specific thermal hyperalgesia, increased nocifensive behaviors, and spinal c-Fos expression in the formalin test, but not in the spared nerve injury model of neuropathic pain, indicating that these neurons exert a selective tonic restraining influence on in vivo nociception.

Improvements in early care in Russian orphanages and their relationship to observed behaviors.

This article describes a unique study that attempts to promote positive social-emotional relationships and attachment between caregivers and children in orphanages in St. Petersburg, Russia. The children who reside in these orphanages are typically between birth and 48 months of age; approximately 50% are diagnosed with disabilities, and approximately 60% leave through foreign adoption. Initially, their orphanage caregivers showed a high level of current anxiety and depression and were detached from and communicated little with the children. Likewise, during baseline observations, the children demonstrated poor attachment behaviors such as indiscriminant friendliness, lack of eye contact with adults, aggression, and impulsive behavior. Two interventions were used in a quasiexperimental design: (a) training of caregivers to promote warm, responsive caregiving and (b) staffing and structural alterations to support relationship building, especially increasing the consistency of caregivers. The methodology required that both the training and staffing interventions be provided to one orphanage, only the training to a second, and neither to a third. (At any one time, ns = 80-120 in each condition.) Initial informal observations reveal positive behaviors for both the caregivers and the children, such as increased two-way conversations, animated and enthusiastic emotional responses, and positive social and language interactions. Early data analyses show an increase in the consistency and stability of caregivers and increased scores for caregivers on every subscale of the HOME Scales. Children showed improvements in physical growth, cognition, language, motor, personal-social, and affect, with children having severe disabilities improving the most. The implications of these findings suggest that training staff with modest educational backgrounds and structural changes are effective, can increase socially responsive caregiving behaviors, and improves social interactions of children, at least temporarily. ©2005 Michigan Association for Infant Mental Health.

Induction of alternatively spliced spermidine/spermine N1-acetyltransferase mRNA in the human kidney cells infected by venezuelan equine encephalitis and tick-borne encephalitis viruses.

293 and RH cells derived from human embryo kidney were infected by Venezuelan equine encephalitis and tick-borne encephalitis viruses and cDNA libraries representing cellular mRNAs induced or suppressed due to the infection were prepared using suppressive subtractive hybridization. Among the up-regulated clones the RT-PCR and Northern analyses revealed an unusual transcript of the spermidine/spermine N1-acetyltransferase (SSAT) gene that was shown to be an alternatively spliced form containing an additional 110-bp exon. The alternatively spliced transcript is polyadenylated and can be expected to yield only a truncated 71 amino acid polypeptide. This first evidence of the host gene alternatively spliced mRNA induction by RNA viruses raises the questions of its biological role, regulation mechanisms of alternative splicing, and significance for the virus life cycle.