During the last decade, a revolution has taken place among clinical and developmental psychologists. Whereas the emphasis was formerly on continuity and stability over time, with earlier experiences uniformly shaping developmental trajectories, many researchers have come to recognise that individuals are not uniformly plastic, so that some are more susceptible than others to influence. In perhaps the most widely cited demonstration of this, Caspi and colleagues showed in a retrospective study in New Zealand that individual differences in a specific genetic allele determined which children would be adversely affected by depriving early life experiences, whereas children without this allele emerged apparently unscathed from similarly debilitating experiences. The clarity of this finding quickly made believers of many researchers who had hitherto viewed with scepticism decades of scholarship on risk and vulnerability by such researchers as Rutter, Gottesman, and Masten, but empirical demonstration of the nature, extent, and limits of susceptibility to influence (both vulnerability and its obverse, strength in the face of adversity) has been limited. The goal of the proposed research is to examine multiple possible sources (both genetic and environmental) of these individual differences and an array of developmental outcomes using a large, representative, and rich data set collected by the ALSPAC team.

For many years (and with differing degrees of emphasis at different times on either side of the Atlantic) students of child development have recognised that psychological and behavioural development are neither predetermined nor infinitely malleable, although infants appear to be born with marked congenital individual differences. Child psychiatrists such as Thomas and Chess devoted their careers to illustrating the impact of such inborn temperamental attributes on children's developmental trajectories, whereas psychologists such as Rothbart have sought to understood the physiological bases of the major dimensions of temperament that have been identified (Rothbart & Bates, 2006). Students of temperament and behaviour genetics have thus emphasized the importance of biogenetic predispositions and have sought to unpack the ways in which experience might, in combination with congenital individual differences, shape children's development, by promoting stability over time (i.e., 'the child is father to the man'), leading some children to develop more poorly than anticipated, or ensuring that some children prosper, doing better than originally expected. To some extent, progress has been impeded by measurement difficulties, particularly by the challenge of making sense of differences between temperamental appraisals provided by parents (reflecting their subjective perceptions of the child) and those obtained through more objective and systematic observational and physiological means.

In addition, the focus has largely been on the temperamental factors that place some children at greater risk of developing behaviour problems, including serious psychological disturbances-especially because they are "difficult" or "irritable"-- and upon the stability of individual differences, that is, the degree to which children remain difficult across infancy, childhood and adolescence. By contrast, considerably less attention has been paid to such positive characteristics as cheerfulness, perseverance, the capacity to love and be loved, or resilience that might presage positive outcomes; and even less empirical work has focused upon the extent to which-and the reasons why-children's characteristics change. Even though developmental psychologists have shown more interest in the positive side of life than have clinical psychologists, investigating such topics as the origins of empathy, prosocial behaviour, and social skills, few researchers have explored why some children change from negative to positive developmental trajectories and vice versa.

Although it is seductive to assume that those most positively or negatively disposed early in life remain that way as they age, new findings reported by Sharp, Croudace, and Goodyer (2007) caution against such potentially simplistic reasoning. Not only were optimistic 7- to 11-year-olds more likely to change their orientations than peers who had an initial 'neutral' orientation, but those who initially scored highest on optimism scored highest on psychopathology two years later. Clearly, one cannot presume that continuity always characterises the process of human development, including positive development.

Attachment theory has played a particularly important role in shaping understanding of the ways in which early experiences (notably, the quality of parental behaviour and of infant-parent interaction) influence the quality of the close, emotional relationships that infants form to each of their attachment figures and which, in turn, help shape children's later social relationships and approaches to other challenging tasks and experiences. Over the last 40 years, and especially since Ainsworth developed the Strange Situation Procedure (SSP) to assess the security of infants' emotional ties ('attachments') to their mothers, fathers and other caregivers, developmental psychologists have made considerable progress in illuminating the origins and predictive implications of individual differences in child development, even those measured very early in life.

No outline received

The aim of the pilot work is to support an application for the proposed 17+ clinic. The following data are required for preliminary analyses:

1. Hearing threshold and hearing questionnaire data collected at the Focus11+ clinic.

2. Sex of child

3. Social status of child

The following analyses will be performed:

1. Comparison of the frequency distribution of hearing threshold at 11 years with the data currently being collected at age 15 years.

2. Comparison of the frequency distributions at age 11 and 15 with similar data from the 1958 cohort study

3. Estimation of the percentage of children with a permanent hearing loss at age 11 years

4. Effect of sex and social status on hearing thresholds at age 11

The results of these analyses will be used as part of a grant application, and may also be written up for publication.

Objectives/aims:

1. To establish whether markers of adverse psychosocial environment (such as adverse socioeconomic circumstances and stressful life events) are associated with biochemical markers of cortisol metabolism (fasting cortisol levels and urinary excretion of total cortisol metabolites at age 8), central fat patterning (by waist circumference and DXA), and earlier timing of thelarche and menarche (by questionnaire).
2. To establish whether these associations are modified by level of physical activity and energy intake.

In addition to providing a test of our proposed stress-body fat-puberty model, the proposed study also has the potential to inform the scientific basis of targeted interventions to reverse the childhood obesity epidemic .

No outline received

Project outline:

The recent swathe of genomewide analyses, which are essentially acephalous scientific experiments testing all available genetic variants for association with common disease traits, has thrown up a series of apparently novel pathways for further analysis. One of these is that of the FTO locus of chromosome 16 which has been shown now to have a association with T2D driven entirely by its robust associaion with fat mass (Zeginni et al Science 2007, Frayling et al Science 2007). As yet, neither the driving force behind this association, nor its biological foundation have been elucidated.

Returning to the work of Remy & Michnick (Molecular and Cellular Biology) and personal experience alongside Pof Jeremy Tavare, Prof Holly recalled that the adjacent locus to FTO, AKTIP (seen below)fundamentally involved in the insulin signalling pathway. This protein has been observed to enhance the PKB mediated recruitment of GLUT4 to the cell surface and hence the action of IGF1, IGF2, and consequent responsiveness to insulin.

Whilst not the actual site of association

Observed by Zeginni and Frayling, the

protein (FT1) encoded by AKTIP

may well lie in the 5' promoter of the

FTO locus, possibly having an impact on

the expression pattern and profile of the

locus concentrated on by these new

reports.

In efforts to verify this, a simple

experiment can be performed which can

enable one to assess the relative

abundance of this protein (FT1) in the

lysate of spent samples (here derived from

the ALSPAC cohort. With genotypes

already collected for this cohort, one simply

requires samples of cell pellets for examination via the use of FT1 antibody which has already been developed and delivered to Bristol (and lab in question here) by Remy and Michnick. This experiment will employ simple western blotting approaches for the examination of FT1 protein levels (measured in a semi-quantitative manner) in individuals organised by their respective FTO genotype. Under the hypothesis that the FTO locus is exerting its observed metabolic association through its interaction with the FT1 locus, one may anticipate a genotype specific difference in the yield of FT1 by this approach.

Fish and seafood are regarded healthy components of a varied diet, particularly important for pregnant women so that they can pass on essential nutrients needed for fetal development of the brain and other organs1. On the other hand, fish may contain environmental pollutants, such as methylmercury, that can put fetal brain development at risk2. A balance has been sought by state and federal agencies in advising the public 3, but certain subpopulations (i.e. pregnant women or women of childbearing age) generally eat less fish than desirable in order to obtain the beneficial effects of fish 1. At the same time, U.S.EPA reports that over 300,000 children born every year exceed the Reference Dose (RfD) for methylmercury and may therefore be at risk at developing adverse effects4.

Tragic pollution episodes have clearly documented that the fetal brain is particularly susceptible to methylmercury toxicity; the adverse effects on the nervous system appear to be irreversible and are much more widespread and serious in children than in adults, especially when exposures have occurred prenatally5,6. While the existence of adverse effects at low exposure levels has been affirmed by national and international regulatory agencies,7-10 certain scientific questions remain unanswered. They relate to the possible occurrence of neurotoxic effects close to the U.S.EPA Reference Dose, the persistence of the cognitive deficits through adolescence, and the possible compensation of adverse effects by essential nutrients present in fish and seafood. The proposed research aims at developing new and more definite information on the benefits and risks associated with seafood intakes at levels relevant to the US general population.

This proposal builds upon the extensive data already collected on a cohort of 14,138 children born between April 1st 1991 and December 31st 1992 in Avon, England, as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) study11. The focus was to identify features of the environment that affect the health and development of children. Detailed information and biological samples were collected at the time of birth and continue to be collected during the course of follow-up11. A10% sample randomly selected was seen at 4, 8 and every 6 months until age 5 years with data including motor and intellectual development. From age 7 years, all children were invited annually for neurobehavioral assessment (including IQ). A pilot project was carried out to measure cord-mercury wet-weight concentrations12, and frozen cords are available from 7,500 subjects to link to the outcome parameters already available.

Because cord tissue has been collected from over half of the children, and because the mercury concentration in the umbilical cord is an excellent biomarker of prenatal exposure levels13, the opportunity exists to assess the developmental mercury exposure level to determine its possible impact on highly relevant neurodevelopmental functions, and the possible interaction with beneficial effects of maternal fish intake.

The specific aims of this project are therefore: to determine if methylmercury-associated cognitive deficits are present at low-level prenatal methylmercury exposures and remain detectable through to adolescence;

• to examine whether intake of fish containing beneficial nutrients affect the same outcomes and counterbalance the methylmercury-associated deficits; and
• to identify other behavioral outcomes that are linked to prenatal methylmercury exposure for possible consideration in future research.

No outline received

No outline received