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Individuals with the short variant of the serotonin transporter linked polymorphic region gene are more susceptible than individuals homozygous for the long allele to the effects of stressful life events on risk for internalizing and externalizing problems. We tested whether individual differences in coping style explained this increased risk for problem behavior among youth who were at both genetic and environmental risk. Participants included 279 children, ages 8-11, from the Children's Experiences and Development Study. Caregivers and teachers reported on children's internalizing and externalizing symptoms, and caregivers and children on children's exposure to harsh parenting and parental warmth in middle childhood, and traumatic events. Children reported how frequently they used various coping strategies. Results revealed that short/short homozygotes had higher levels of internalizing problems compared with long allele carriers and that short allele carriers had higher levels of externalizing problems compared with long/long homozygotes under conditions of high cumulative risk. Moreover, among children who were homozygous for the short allele, those who had more cumulative risk indicators less frequently used distraction coping strategies, which partly explained why they had higher levels of internalizing problems. Coping strategies did not significantly mediate Gene × Environment effects on externalizing symptoms.

BackgroundGiven mixed findings as to whether stressful experiences and relationships are associated with increases or decreases in children's cortisol reactivity, we tested whether a child's developmental history of risk exposure explained variation in cortisol reactivity to an experimentally induced task. We also tested whether the relationship between cortisol reactivity and children's internalizing and externalizing problems varied as a function of their developmental history of stressful experiences and relationships.MethodParticipants included 400 children (M = 9.99 years, SD = 0.74 years) from the Children's Experiences and Development Study. Early risk exposure was measured by children's experiences of harsh, nonresponsive parenting at 3 years. Recent risk exposure was measured by children's exposure to traumatic events in the past year. Children's cortisol reactivity was measured in response to a social provocation task and parents and teachers described children's internalizing and externalizing problems.ResultsThe effect of recent exposure to traumatic events was partially dependent upon a child's early experiences of harsh, nonresponsive parenting: the more traumatic events children had recently experienced, the greater their cortisol reactivity if they had experienced lower (but not higher) levels of harsh, nonresponsive parenting at age 3. The lowest levels of cortisol reactivity were observed among children who had experienced the most traumatic events in the past year and higher (vs. lower) levels of harsh, nonresponsive parenting in early childhood. Among youth who experienced harsh, nonresponsive parent-child relationships in early childhood and later traumatic events, lower levels of cortisol reactivity were associated with higher levels of internalizing and externalizing problems.ConclusionsHypothalamic-pituitary-adrenal (HPA) axis reactivity to psychological stressors and the relationship between HPA axis reactivity and children's internalizing and externalizing problems vary as a function of a child's developmental history of exposure to stressful relationships and experiences.

Background: A common polymorphism in the serotonin transporter gene (SLC6A4, 5HTT) has been repeatedly shown to moderate the influence of childhood adversity and stressful life events on the development of psychopathology. Using data from the English and Romanian Adoptee Study, a prospective-longitudinal study of individuals (n = 125) exposed to severe early institutional deprivation (ID), we tested whether the effect of ID on adolescent emotional problems is moderated by 5HTT genotype and stressful life events in adolescence. Methods: Emotional problems were assessed using questionnaire data (age 11), and on the basis of the CAPA diagnostic interview (age 15). Additionally, the number of stressful life events was measured. Results: There was a significant effect for genotype (p = 0.003) and a gene x environment interaction (p = 0.008) that was independent of age at testing. Carriers of the s/l and s/s genotype who experienced severe ID showed the highest emotional problem scores, while l/l homozygotes in the severe ID group showed the lowest overall levels. Furthermore, s/s carriers in the severe ID group who experienced a high number of stressful life events between 11 and 15 years had the largest increases in emotional problem scores, while a low number of stressful life events was associated with the largest decrease (4-way interaction: p = 0.05). Conclusions: The effects of severe early ID on emotional problems in adolescence are moderated by 5HTT genotype, and influenced by stressful life events in adolescence.

Throughout this monograph, there has been frequent reference to levels of risk, inference of causation, testing for mediating variables, and the need to consider possible moderating influences. In this chapter, the authors review what is meant by these concepts, and then seek to pull together the findings from the English and Romanian Adoptee (ERA) studies that were relevant for these issues. (Contains 6 tables and 3 figures.)

It has come to be generally accepted that the psychopathological effects of psychosocial stress and adversity are diagnostically nonspecific. There is a good deal of supporting evidence in support of this assumption, even though it may be that the nonspecificity has been exaggerated through a failure to take account of comorbidity. This chapter presents findings on the designation of deprivation-specific psychological patterns (DSPs). These included an early onset (at least by age 6 years, the earliest age at which data were available for the whole sample) and persistence to 11 years of age. The persistence to 11-year requirement was introduced particularly because minor manifestations of DA were so frequent at age 6 years in the pooled comparison group. Without the persistence criterion, the association of DSPs with institutional deprivation would be much weakened. (Contains 5 tables and 8 figures.)

In chapter IV, the authors focused on their findings on the developmental course of deprivation-specific psychological patterns (DSPs). The authors rediscussed the syndrome concept in the light of two main considerations. First, the findings indicated substantial overlap among the four postulated DSPs at 15 years including CI and I/O before requiring cooccurrence with Q-A or DA. Second, they realized that, ordinarily, syndromes are defined on the basis of a unifying pathophysiology rather than a mere clustering together of symptoms. Although they have not identified the nature of such pathophysiology, the strong continuing association with institutional deprivation extending up to at least 6 months of age, plus the findings from the pilot brain imaging study points to the likelihood that there is a unifying pathophysiology. Accordingly, they conclude that, on balance, a coherent syndrome remains a strong possibility. (Contains 6 tables.)

This monograph is concerned with the mid adolescent follow-up of a group of adoptees from Romania and from within the United Kingdom who were first assessed at the age of 4 years (or 6 years in the case of the oldest children). Chapter I provides the background as it applied at the time that the study began, and then goes on to outline the overall research strategy and the measures relevant for the first assessment at age 4 years. It then goes on to summarize, briefly, some of the key findings from the follow-ups undertaken up to the age of 11 years. In the authors' published papers on the age 4-, 6-, and 11-year assessments, they mainly dealt with findings in relation to key outcome variables. In this monograph, they have adopted a different strategy that capitalizes on the unique features of their study. Their study is the only investigation with detailed interview and observation measures, together with psychometric assessments, spanning a 10-year follow-up period. Most especially, their study is unique in having systematic, standardized measurements of key behavioral patterns that seem to be specific to institutional deprivation. Accordingly, the authors have been able to focus on the crucial issue of the extent to which these patterns account for the deficits and problems that have persisted to age 15 years. In order to do that, it was first necessary both to determine which patterns met criteria for specificity to institutional deprivation and to determine their boundaries. This topic is tackled in Chapter III, after outlining the methods and measures in Chapter II. Chapter IV builds on the authors' prospective data over the course of a decade in order to describe the developmental course of the deprivation-specific psychological patterns (DSPs) defined in Chapter III. To facilitate this, the several apparently DSPs are pooled, having noted the major overlap among them. Chapter V considers disturbances of emotion, conduct and peer relations--that is, the three major domains of psychopathology that, up to age 11 years, appeared "not" to follow a DSPs. Chapter VI takes as its starting point the major catch-up found in cognitive functioning following adoption and goes on to ask how far cognitive findings vary according to specific cognitive function and how far cognitive gains up to age 11 have been translated into meaningful educational attainments at age 15-16 years. Chapter VII reevaluates these findings in the light of the age 15 results and examines the physical growth and maturational effects of institutional deprivation. It considers how far the findings differ according to the presence/absence of institutional deprivation-specific features. Chapter VIII reexamines the issue of possible postadoption environmental mediators, paying attention to key methodological challenges. Throughout their study, there has been abundant evidence of heterogeneity in outcome. Chapter IX seeks to pull together the relevant findings with respect to possible biological moderators and mediators. There is reexamination of the apparently protective role of minimal language skills, of genetic influences on environmental susceptibility, of possible effects of social cognitive features, of the role of subnutrition, and of impaired head growth. Finally, Chapter X provides an overview of the findings at age 15, together with the theoretical and practical implications of these findings. (Contains 48 tables and 21 figures.)

Theory of Mind (ToM) and Executive Function (EF) have been associated with autism and with attention-deficit hyperactivity disorder (ADHD), and hence might play a role in similar syndromes found following profound early institutional deprivation. In order to examine this possibility the current study included a group of 165 Romanian adoptees, of whom 144 were adopted into the UK from deprived institutional settings before 43 months of age, and a group of 52 within-UK adoptees, all adopted before 6 months of age. Both groups were assessed at 6 and 11 years. The Strange Stories task was used to assess ToM and the Stroop task was used to assess EF, both at age 11. The Romanian adoptees displayed deficits in both ToM and EF compared with the within-UK adoptee group. The degree of deficit was greater for children who had experienced more than 6 months of institutional deprivation. Deficits in both domains (ToM and EF) were associated with each of the three apparently deprivation-specific problems, namely quasi-autism, disinhibited attachment and inattention/overactivity. Statistical analyses indicated a mediating role for both ToM and EF with respect to quasi-autism; possibly a partial mediating role for EF with respect to inattention/overactivity; and probably no mediating role for either ToM or EF in the case of disinhibited attachment. In conclusion, there is evidence for a possible mediating role for ToM and EF in the development of some apparently deprivation-specific difficulties in institution-reared Romanian adoptees, but neither accounts for the overall pattern of deprivation-related difficulties.

The current study examined the persistence and phenotypic presentation of inattention/overactivity (I/O) into early adolescence, in a sample of institution reared (IR) children adopted from Romania before the age of 43 months. Total sample comprised 144 IR and 21 non-IR Romanian adoptees, and a comparison group of 52 within-UK adoptees, assessed at ages 6 and 11 years. I/O was rated using Rutter Scales completed by parents and teachers. I/O continued to be strongly associated with institutional deprivation, with continuities between ages 6 and 11 outcomes. There were higher rates of deprivation-related I/O in boys than girls, and I/O was strongly associated with conduct problems, disinhibited attachment and executive function but not IQ more generally, independently of gender. Deprivation-related I/O shares many common features with ADHD, despite its different etiology and putative developmental mechanisms. I/O is a persistent domain of impairment following early institutional deprivation of 6 months or more, suggesting there may be a possible pathway to impairment through some form of neuro-developmental programming during critical periods of early development.

The relationship between severe early institutional deprivation and scholastic attainment at age 11 in 127 children (68 girls and 59 boys) adopted from institutions in Romania was compared to the attainment of 49 children (17 girls and 32 boys) adopted within the UK from a non-institutional background. Overall, children adopted from Romania had significantly lower attainment scores than those adopted within the UK; the children within the Romanian sample who had spent 6 months or more in an institution had significantly lower attainment scores than those who had spent less than 6 months in an institution, but there was no additional risk of low attainment associated with longer institutional care after 6 months. The lower scholastic attainment in the children adopted from Romanian institutions, as compared with domestic adoptees, was mediated by IQ, and to a lesser degree, inattention/overactivity. When these factors were taken into account, only small between-group differences in attainment remained.

Longitudinal analyses on normal versus impaired functioning across 7 domains were conducted in children who had experienced profound institutional deprivation up to the age of 42 months and were adopted from Romania into U.K. families. Comparisons were made with noninstitutionalized children adopted from Romania and with nondeprived within-U.K. adoptees placed before the age of 6 months. Specifically, the validity of the assessment, the degree of continuity and change in levels of functioning from 6 to 11 years, and the factors in the pre- and postadoption environment accounting for heterogeneity in outcome were examined. Pervasive impairment was significantly raised in children experiencing institutional deprivation for =6 months of life, with a minority within this group showing no impairment. There was no additional significant effect of duration of deprivation beyond the 6-month cutoff, and few other predictors explained outcome. The pattern of normality/impairment was mainly established by 6 years of age, with considerable continuity at the individual level between 6 and 11 years. The findings are discussed in terms of the possibility of a sensitive period for development.

Background: Disinhibited attachment is an important sequel of an institutional rearing, but questions remain regarding its measurement, its persistence, the specificity of the association with institutional rearing and on whether or not it constitutes a meaningful disorder. Method: Children initially reared in profoundly depriving institutions in Romania and subsequently adopted into UK families were compared with respect to findings at 11 years with children who had not experienced institutional deprivation and who had been adopted within the UK before the age of 6 months. Measures included parental reports, a Strange Situation procedure modified for use in the home and systematic standardised investigator ratings of the children's behaviour. Results: Disinhibited attachment, as reported by parents, showed a high degree of persistence from 6 to 11, but also a reduction over time in its frequency. Investigator ratings validated the parental reports but suggested that much of the fall in rate of disinhibited attachment was a function of the parental measure being less developmentally appropriate at 11 than it had been at 6. Disinhibited attachment was strongly associated with institutional rearing but there was not a significant increase in relation to duration of institutional deprivation beyond the age of 6 months. Mild, but not marked, disinhibited attachment was quite frequent in non-institutionalised adopted children but both the course and correlates indicated that its meaning was probably quite different. In the institution-reared children, disinhibited attachment was associated with a marked increase in service usage and associations with other forms of psychopathology. Conclusions: Disinhibited attachment constitutes a valid, and handicapping, clinical pattern that is strongly associated with an institutional rearing.

Background: There is uncertainty about the extent to which language skills are part of general intelligence and even more uncertainty on whether deprivation has differential effects on language and non-language skills. Methods: Language and cognitive outcomes at 6 and 11 years of age were compared between a sample of 132 institution-reared Romanian children adopted into UK families under the age of 42 months, and a sample of 49 children adopted within the UK under the age of 6 months who had not experienced either institutional rearing or profound deprivation. Results: The effects of institutional deprivation were basically similar for language and cognitive outcomes at age 6; in both there were few negative effects of deprivation if it ended before the age of 6 months and there was no linear association with duration of deprivation within the 6 to 42 month range. For the children over 18 months on arrival (range 18-42 months), the presence of even very minimal language skills (imitation of speech sounds) at the time of arrival was a strong beneficial prognostic factor for language and cognitive outcomes, but not for social/emotional/behavioural outcomes. Individual variations in adoptive parent characteristics were unrelated to differences in language or cognitive outcomes, possibly as a consequence of the limited variability in the adoptive family group. Conclusions: Minimal language probably indexes some form of cognitive reserve that, in turn, indexes the degree of institutional deprivation.

Cognitive outcomes at age 11 of 131 Romanian adoptees from institutions were compared with 50 U.K. adopted children. Key findings were of both continuity and change: (1) marked adverse effects persisted at age 11 for many of the children who were over 6 months on arrival; (2) there was some catch-up between ages 6 and 11 for the bottom 15%; (3) there was a decrease of 15 points for those over 6 months on arrival, but no differentiation within the 6-42-month range; (4) there was marked heterogeneity of outcome but this was not associated with the educational background of the adoptive families. The findings draw attention to the psychological as well as physical risks of institutional deprivation.

Parents of 165 children adopted from Romania and 52 children adopted from within the United Kingdom rated the success of the adoptions when the children were 11 years old. As was the case at two earlier study waves, satisfaction was found to be extremely high. Both positive and negative assessments were generally stable between ages 6 and 11, although for the children who had more problems there was an increase in negative evaluation, albeit within an overall positive picture. Parents' evaluations were somewhat more negative for this group of children; however, parents reported that having the child as part of their family was very rewarding. Negative evaluation was not directly related to age at placement, but appeared to be a reflection of the later-placed children's higher rates of problem behavior. As found at earlier assessment waves, child factors, in particular conduct problems and inattention or overactivity, were key in predicting parental evaluations at age 11, as were four domains closely associated with institutional deprivation, namely cognitive impairment, quasi-autistic patterns, inattention or overactivity, and disinhibited attachment. The findings emphasize the need for early intervention for children in severely deprived conditions, and for access to postadoption services that target the particular problem behaviors the children may exhibit. Keywords: Romania, adoption, outcome, risk factors DOI: 10.1037/a0017262

Longitudinal analyses on normal versus impaired functioning across 7 domains were conducted in children who had experienced profound institutional deprivation up to the age of 42 months and were adopted from Romania into U.K. families. Comparisons were made with noninstitutionalized children adopted from Romania and with nondeprived within-U.K. adoptees placed before the age of 6 months. Specifically, the validity of the assessment, the degree of continuity and change in levels of functioning from 6 to 11 years, and the factors in the pre- and postadoption environment accounting for heterogeneity in outcome were examined. Pervasive impairment was significantly raised in children experiencing institutional deprivation for [greater than or equal to] 6 months of life, with a minority within this group showing no impairment. There was no additional significant effect of duration of deprivation beyond the 6-month cutoff, and few other predictors explained outcome. The pattern of normality/impairment was mainly established by 6 years of age, with considerable continuity at the individual level between 6 and 11 years. The findings are discussed in terms of the possibility of a sensitive period for development. Keywords: early deprivation, sensitive period, psychological functioning

Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]

Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect *OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 [+ or -] 0.11 ng/ml) compared with the sham-operated animals (0.26 [+ or -] 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial *OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metaholites to exert their neurotoxic effects. oxidative stress; microdialysis; tyrosine hydroxylase; norepinephrine; ceramide.

A multicenter trial in the United Kingdom is conducted for comparing rescue percutaneous coronary intervention (PCI) with repeated thrombolysis. Event-free survival after failed thrombolytic therapy is significantly higher with rescue PCI than with repeated thrombolysis or conservative treatment.

Right heart failure (RHF) is characterized by chamber-specific reductions of myocardial norepinephrine (NE) reuptake, [beta]-receptor density, and profiles of cardiac sympathetic nerve ending neurotransmitters. To study the functional linkage between NE uptake and the pre- and postsynaptic changes, we administered desipramine (225 mg/day), a NE uptake inhibitor, to dogs with RHF produced by tricuspid avulsion and progressive pulmonary constriction or sham-operated dogs for 6 wk. Animals receiving no desipramine were studied as controls. We measured myocardial NE uptake activity using [sup.3H]NE, [beta]-receptor density by [sup.125.I]iodocyanopindolol, inotropic responses to dobutamine, and noradrenergic terminal neurotransmitter profiles by glyoxylic acid-induced histofluorescence for catecholamines, and immunocytochemical staining for tyrosine hydroxylase and neuropeptide Y. Desipramine decreased myocardial NE uptake activity and had no effect on the resting hemodynamics in both RHF and sham animals but decreased myocardial [beta]-adrenoceptor density and [beta]-adrenergic inotropic responses in both ventricles of the RHF animals. However, desipramine treatment prevented the reduction of sympathetic neurotransmitter profiles in the failing heart. Our results indicate that NE uptake inhibition facilitates the reduction of myocardial [beta]-adrenoceptor density and [beta]-adrenergic subsensitivity in RHF, probably by increasing interstitial NE concentrations, but protects the cardiac noradrenergic nerve endings from damage, probably via blockade of NE-derived neurotoxic metabolites into the nerve endings. congestive heart failure; neuronal norepinephrine uptake; tyrosine hydroxylase; neuropeptide Y

Loss of cardiac sympathetic neurotransmitters in heart failure and NE infusion is associated with reduced NGF. Am J Physiol Heart Circ Physiol 282: H363-H371, 2002. First published September 27, 2001, 10.1152/ajpheart.00319.2001.--Sympathetic neurotransmitters are diminished in cardiac efferent nerve endings in congestive heart failure (CHF). Similar changes occur after exogenous norepinephrine (NE) infusion. Since NE reduces nerve growth factor (NGF) in cultured cardiomyocytes, we proposed to determine whether the loss of noradrenergic transmitters in the failing heart is caused by the NE-mediated reduction of NGF or its neurotrophic receptor tyrosine kinase A (TrKA). Dogs were assigned to receive either rapid ventricular pacing (225 beats/min) or NE infusion (0.5 [micro]g/kg/ min) for 8 wk. Control animals received either cardiac pacing of 100 beats/min or saline infusion. We measured NGF and TrKA proteins by Western blot and immunocytochemistry and measured NGF and TrKA mRNAs by reverse transcription polymerase chain reaction, neuronal catecholaminergic histofluorescence, tyrosine hydroxylase-immunostained profiles, and plasma NE. Rapid ventricular pacing produced CHF with increased plasma NE, decreased myocardial NGF protein (0.61 [+ or -] 0.07 vs. 1.04 [+ or -] 0.04, P < 0.05), TrKA protein (0.75 [+ or -] 0.08 vs. 0.98 [+ or -] 0.06, P < 0.05), NGF and TrKA mRNAs and reduced catecholaminergic histofluorescence (197 [+ or -] 23 vs. 485 [+ or -] 43, P < 0.05), and tyrosine hydroxylase profiles (360 [+ or -] 51 vs. 773 [+ or -] 36, P < 0.05). Decreases in tissue NGF and TrKA protein were also noted by immunocytochemistry. Similar changes occurred in NE-treated animals. Tissue NGF and TrKA levels correlated closely with the noradrenergic transmitter profiles. We conclude that cardiac NGF and TrKA are reduced by rapid ventricular pacing and NE infusion, and that these changes correlate with decreases of cardiac catecholaminergic and tyrosine hydroxylase profiles. Findings indicate that decrease of cardiac sympathetic transmitters in heart failure is associated with NE-mediated reduction of NGF and TrKA. nerve growth factor; norepinephrine; sympathetic efferent nerve fibers