Low birthweight is now known to be associated with increased rates of CHD and the related disorders, stroke, hypertension and type 2 diabetes. Associations between low birthweight and later disease have been extensively replicated in studies in different countries. They extend across the normal range of birthweight and depend on lower birthweights in relation to the duration of gestation rather than the effects of premature birth. The associations are thought to be consequences of developmental plasticity, the phenomenon by which one genotype can give rise to a range of different physiological or morphological states in response to different environmental conditions during development. Recent observations have shown that impaired growth in infancy and rapid childhood weight gain exacerbate the effects of impaired prenatal growth. CHD and the disorders related to it arise through a series of interactions between environmental influences and the pathways of growth and development that precede them.
Environmental Influences on the Development of the Immune System: Consequences for Disease Outcome
Bengt Björkstén, Sweden
Early T cell responses to external antigens and autoantigens are subject to a variety of regulatory mechanisms. An unifying link between the increase in both Th1-dependent autoimmune disease and Th2-linked atopic allergy would be a disturbed immune regulation involving T regulatory cells.
There is a strong global correlation between childhood wheezing and diabetes. It is increasingly recognised that microbial colonisation of the gastrointestinal tract, linked with lifestyle and/or geographic factors, may be important determinants of the heterogeneity in disease prevalence throughout the world. These suggestions are supported by observations that germ free mice do not develop tolerance in the absence of a gut flora.
The potential effects of environmental stimuli on immune function is greatest in early life including foetal life, when systems and responses are developing and the maternal influences during foetal life could be particularly important for the development of immune regulation and tolerance induction.
In recent years, focus has switched from searching environmental risk factors towards an interest in factors that could induce and maintain immune regulation and tolerance to allergens and autoantigens. Currently evaluated strategies include the use of immunomodulatory factors, such as probiotics, prebiotics, and dietary nutrients although data are still insufficient evidence to make specific recommendations.
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Growth and Bone Development
Cyrus Cooper
Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most effort in fracture prevention has been directed at retarding the rate of age-related bone loss, and reducing the frequency and severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterised in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone mineral content, but not volumetric bone density, than girls. Furthermore, there is a dissociation between the peak velocities for height gain and bone mineral accrual, in both genders. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites. Many factors influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet, physical activity, endocrine status, and sporadic risk factors such as cigarette smoking. In addition to these modifiable factors during childhood, evidence has also accrued that fracture risk might be programmed during intrauterine life. Epidemiological studies have demonstrated a relationship between birthweight, weight in infancy, and adult bone mass. This appears to be mediated through modulation of the set-point for basal activity of pituitary-dependent endocrine systems such as the HPA and GH/IGF-1 axes. Maternal smoking, diet (particularly vitamin D deficiency), and physical activity also appear to modulate bone mineral acquisition during intrauterine life; furthermore, both low birth size and poor childhood growth, are directly linked to the later risk of hip fracture. The optimisation of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.
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The Role of Genes in Growth and Later Health
Johan Eriksson
Genetic factors are of importance for the development of the metabolic syndrome
and type 2 diabetes, but despite extensive research the identification of the underlying genes have not been fruitful. This report focuses upon interactions between intrauterine growth and genes in relation to adult health outcomes based upon findings from the Helsinki Birth Cohort Study. Candidate genes for type 2 diabetes and the metabolic syndrome have been focused upon and we report on interactions between polymorphisms of the PPAR?2, PC-1 and the glucocorticoid receptor (GR) gene and prenatal growth in relation to adult health outcomes. In elderly individuals the effects of the Pro12Pro/Pro12Ala polymorphisms of the PPAR?2 gene depended on their body size at birth. Individuals, who had a small body size at birth, and were carriers of the Ala allele seemed to be protected against insulin resistance and type 2 diabetes in later life. Similar gene environment interactions will be described in relation to the PC-1 and the GR gene. We propose that these findings reflect gene-early environment interactions and can be attributed to the phenomenon of developmental plasticity.
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Growth and Nutrition the First 6 Months
Lars A. Hanson, Sweden
Today we are using WHO Growth Chart Standards based on the growth of breastfed infants. These growth curves solve the problem of the deviating observations for breastfed infants compared to non-breastfed using previous growth charts.
Presently it is not clear as to how the mother’s diet, especially the fat intake, may influence the growth of the offspring. Animal experiments indicate that low intake of n-3 polyunsaturated fatty acids via the milk may have short and long term negative consequences. There is limited information in man.
It is suggested that the mammary glands phylogenetically may have originated from glands providing innate immunity, later developing capacities for providing nutrition. This would agree with the fact that human milk contains so many major components, which do not primarily function as nutrients, but seem to protect nutrition and growth. Lactoferrin, oligosacharides, glycoproteins, secretory IgA antibodies, ?-lactalbumin and the anti-secretory factor have such functions.
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Impact of Fetal and Neonatal viral (and Parasitic) Infections on Later Development and Diseases Outcome
Yvonne A. Maldonado, USA
It is estimated that there are 4 million neonatal deaths and an equal number of stillbirths annually, the majority in the developing world. Neonatal deaths account for one-third of deaths in children less than 5 years of age, and at least one-third of neonatal deaths are related to infections. Infections also account for 80 percent of deaths in the postneonatal period through 5 years of age. There are several viral and parasitic infections which produce fetal and neonatal morbidity and mortality.
Neonatal infections occur during one or more perinatal periods: in utero (congenital), intrapartum (during labor and delivery), and early or late postpartum. Here the term perinatal refers to all of these stages of fetal or neonatal infections. The mechanisms of perinatal viral and parasitic infections vary depending on the specific pathogen, however, all begin with maternal infection. Following maternal infection, organisms may produce indirect placental infection with or without fetal infection, direct fetal or neonatal infection, or primary maternal infection and subsequent perinatal sequelae without either placental or fetal infection. Some pathogens may produce infections by more than one mechanism.
This brief report will provide an overview of the pathogenesis, general outcomes, and known pathogens associated with perinatal viral and parasitic infections.
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Effects of Early Environment on Mucosal Immunologic Homeostasis,
Subsequent Immune Responses and Disease Outcome
Pearay L. Ogra, USA
During the neonatal period, the mammalian neonate is for the first time exposed through mucosal surfaces to a plethora of environmental macromolecules and microbial agents. The neonatal mucosa is endowed with all major elements of innate and adaptive immunologic repertoire. Rudimentary Peyer’s Patches and mucosal lymphoid follicles expressing HLA-DR+ and CD4+ cells can be observed as early as 10 -11 weeks of gestation. CD5+ and IgA+B cells can be detected in Peyer’s Patches by 16-18 weeks .CD7+ CD3+ T lymphocytes have been observed in fetal Peyer’s Patches, epithelial surfaces as well as in the lamina propria, .Interestingly however , the early neonatal period is also characterized by a relative deficiency of antigen- presenting cell functions , altered cell -mediated immune responses , and a relative increase in apoptosis and eosinophilic responses . After birth, each human being may be colonized by over 100 trillion bacteria, representing over 500 bacterial species. The ratio of Bacterial to Human cells in a normal adult may exceed 10:1.The nature and the species of micro flora acquired in the first few months of life is determined by many factors including, external environmental micro flora, introduction of cow’s milk, use of antibiotics and immunomodulatory agents, and use of breast feeding. Recent Investigations have shown that the nature of mucosal micro flora acquired in early infancy determines the outcome of mucosal inflammation and subsequent development of mucosal disease, autoimmunity and allergic disorders later in life. It appears that altered mucosal micro flora in early childhood alters signaling reactions which determine T cell differentiation and or induction of tolerance. Reduced Th1 and increased Th2 cytokine expression in the respiratory tract associated with increased allergic disease has been correlated with reduced exposure to microbial agents associated with Th1 responses. In contrast, reduced exposure to helminthes in the gut associated with reduced Th2 expression appears to correlate well with dominant Th1 cytokine expression and inflammatory bowel disease. These observations suggest that the nature of interaction between external environment and the mucosal tissues in early neonatal period and infancy may be critical in directing and controlling the expression of disease specific responses in later life.
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The Diabetic Pregnancy, Macrosomia, and Perinatal Nutritional Programming
Andreas Plagemann, Germany
Health and diseases are generally perceived to be caused genetically. It is meanwhile accepted, however, that alterations of the intrauterine and early postnatal nutritional, metabolic, and hormonal environment may also predispose for disorders and diseases throughout later life. Studies in offspring of diabetic mothers (ODM) have decisively contributed to this perception and our understanding of causal mechanisms.
It is long known that hormones are environment-dependent organizers of the developing ‘neuro-endocrine-immune network‘, which regulates all fundamental processes of life. When present in non-physiological concentrations during ‘critical periods‘ of development, induced by altered intrauterine and/or neonatal environment, hormones can therefore also act as ‘endogenous functional teratogens‘.
Fetal and neonatal hyperinsulinism is the pathognomic feature in ODM. Epidemiological, clinical, as well as experimental data obtained by our group indicate that insulin itself, when occurring in elevated concentrations during perinatal life, may ‘program‘ the development of obesity and diabetes. Similar may occur due to maternal overweight accompanied by increased fetal food supply, and neonatal overfeeding.
From a clinical point of view, general screening and therapy of all types of diabetes during pregnancy as well as avoidance of early postnatal overfeeding are therefore recommended. These measures might serve as causal approaches to a genuine primary prevention.
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Growth and Host-Pathogen Interactions
Andrew Prentice, UK
Differing trajectories of infant and child growth are associated with different patterns of disease and mortality in adulthood. Since post-natal growth patterns are partially modifiable by diet these associations raise fresh questions about what constitutes an optimal growth rate. We use data from contemporary societies that still suffer poor nutrition and high burdens of infectious disease to illustrate early growth patterns that have likely been typical of our evolutionary past. Pathogenic assault is a major suppressor of growth; populations frequently average –1.0 to -1.5 Z-scores (standard deviations relative to standard growth curves) for height, and –2.0 to –2.5 Z-scores for weight, body mass index and head circumference. Many infections are symptomatic (eg diarrhoea, malaria, pneumonia, HIV), but others are sub-clinical (eg hepatitis B, cytomegalovirus, Epstein-Barr virus, herpes, Helicobacter pylori). The great majority of young children become infected by multiple pathogens which initiate a downward cycle of infection > suppressed appetite and malabsorption > reduced growth > lowered immunity > repeated infection. Examination of the evolutionary ‘norm’ for early growth, and of the external environmental factors that influenced it, may provide clues towards identifying the current day optimum for growth.
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Maternal Nutrition Before and During Pregnancy
Theresa O. Scholl, USA
In humans, the link between the maternal diet and the outcome of pregnancy is best illustrated by the classic study of war-time famine in Holland. During the famine it is likely that a low food intake reduced the glucose stream from mother to fetus and gave rise to smaller size at birth. Maternal glucose production also is influenced by the type of carbohydrate in the diet. Even when famine and starvation are not issues, a low dietary glycemic index can alter maternal blood glucose production and the area under the glucose curve, and give rise to reductions in fetal growth and infant weight at birth.
Reduced food intake in famine areas would also reduce the concentration of micronutrients in the maternal diet. Two micronutrients (iron, folate) have effects on pregnancy outcome that have been shown with some consistency in pregnant women. Emerging evidence now suggests that use of micronutrient containing prenatal vitamins before and during pregnancy is associated with reductions in the risk of congenital defects, preterm delivery, low infant birth weight, and pre-eclampsia.
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The Role of Growth in Heart Development
Kent L. Thornburg, USA
While it is established that the quality of the perinatal environment is critical in sculpting the developing individual, the mechanisms by which this occurs remains poorly defined. The growing fetus is dependent on the nutrients (including oxygen) it receives from the mother, via the placenta. When this supply line is compromised, heart growth patterns can be altered. In addition, hormones and other circulating factors, and the hemodynamic environment in which the fetus develops are important in determining outcomes for organ structure and function. Numerous studies in sheep have demonstrated that heart development can be modified in a number of ways, and the nature of the change differs between types and gestational timings of insults. Embolization of the placenta leads to the cessation of proliferation and maturation of cardiomyocytes; this may be due in part to changes in circulating insulin-like growth factor-1 levels. Such insults may be the underlying cause of cardiovascular disease in adults. Insults that modify the maturational timeline, final myocyte number, vascularity and endothelial responsiveness in the heart can have effects that persist long after the insult is ameliorated.
Neonatal Microbial Flora and Disease Outcome
Allan Walker, USA
The now outdated perception of microorganisms of the gastrointestinal tract as pathogens or at best commensals continues to undergo remodeling. It is now clear that the microbiome of the gut participates in many activities including: digestion, ecologic protection from pathogens, and an increasingly appreciated immunoregulatory role in vertebrates. Studies of the complex interactions of microbes and hosts point to a convergence of two well-supported (though imperfect) hypotheses: the “Hygiene Hypothesis” and the “fetal programming hypothesis” proposed by Strachnan [reviewed in 1] and Barker respectively [2]. Our current understanding is one in which factors that exist pre-conception, during gestation, occur perinatally and infant in the milieu, in addition to exposures to nutrients and microbes have the potential for long-term effects in the development of healthy offspring and adults. Epidemiology, basic science and clinical research in such previously diverse areas of study such as microbiology, allergy, gastroenterology, endocrinology, immunology, rheumatology, infectious disease, perinatology, and nutrition are providing evidence that appropriate development and tendency towards the development of certain diseases are directly affected by intestinal microbe-host interactions. It appears likely that perinatal colonization of the gastrointestinal tract is a particularly pivotal process in which microbe-host programming occurs. Intestinal microbes and hosts have co-evolved, that when in appropriate balance, they produce and propagate a life-long mutualism.
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Induction of Antigen-specific Immunity in Human Neonates and Infants
Christopher B. Wilson, USA
The first months of life represent a period of heightened susceptibility to infection, but the immunological differences involved are as yet incompletely understood. T cell-independent B cell (antibody) responses are markedly compromised in the first year of life. T cell-dependent antibody responses mature much earlier, but neonates and infants may require multiple immunizations to achieve or sustain titers comparable to those in older individuals. Neonates can mount effective antigen-specific T cell responses, but CD4 T cell responses are often slower to develop, less readily sustained, and in general more easily biased towards a Th2 type response. The last observation likely reflects in part the less efficient capacity of neonatal dendritic cells to establish a milieu that favors a Th1 CD4 T cell response, but this limitation can be overcome given appropriate stimuli, as occurs in neonates immunized with BCG. We currently lack a clear mechanistic understanding of the molecular basis for these immunological differences between adults and neonates. The goal of ongoing and future studies is to generate the mechanistic insights needed to enable the rational design of vaccines and adjuvants for use in neonates and young infants, and thereby reduce the morbidity and mortality of infections early in life.