Introdução O estudo dos efeitos da amamentação sobre o crescimento ou na proteção contra a obesidade na infância ainda comporta muitos resultados controversos ou inconclusivos. No Brasil existem poucos dados e análises sobre este assunto. Objetivo - Analisar a influência do aleitamento materno sobre o estado nutricional de crianças menores de 3 anos do Município de São Paulo. Métodos Foi utilizada a subamostra longitudinal com760 crianças de 0 a 36 meses do estudo de base domiciliar Saúde das Crianças de São Paulo II (1995-1997). As variáveis utilizadas como desfecho foram os índices antropométricos altura-para-idade (ZAI), IMC-para-idade (ZBI), e dobra cutânea triciptal-para-idade (ZDI), expressos em desvios-padrão (escores Z) da curva de referência apresentada pela Organização Mundial da Saúde em 2006. A associação entre o aleitamento materno predominante (AMP) e os desfechos antropométricos foi ajustada por: renda familiar per capita, escolaridade da mãe, peso ao nascer, ordem de nascimento da criança, idade da mãe, status do trabalho da mãe. Os efeitos fixos e aleatórios dos determinantes do crescimento infantil, nas 3 visitas realizadas, foram estimados utilizando-se a análise de painel. Resultados A duração do AMP mostrou-se negativamente associada a todos os índices antropométricos. O efeito médio mensal do AMP sobre os índices antropométricos foi de -0,068 Z no ZAI, de -0,044 Z no ZBI e de -0,065 Z no ZDI (p<0,05 em todos os casos). As médias dos índices nutricionais apresentaram efeito dose-resposta decrescente conforme o aumento na duração do AMP. O efeito do AMP sobre a situação nutricional infantil foi modificado pelo controle da sua interação com a escolaridade materna: filhos de mulheres com 8 ou mais anos de estudo apresentaram altura 0,075 Z acima da altura dos filhos de mães com até 3 anos de estudo (p<0,05); no caso do IMC a interação não foi estatisticamente significante. Conclusão O aleitamento materno mostrou-se negativamente associado aos índices nutricionais infantis, com efeito protetor contra o aumento médio do IMC e da gordura corporal em menores de 3 anos do município de São Paulo. / Introduction The study of the effects of breastfeeding over growth or in protection against infant obesity still have many controversy or inconclusive results. In Brazil there are feel data and analysis about this subject. Objective To analyze the breastfeeding influence on nutritional status of children under 3 years old of São Paulo City. Methods The longitudinal sub-sample with 760 children aged less than 36 months of a population-based study called The Health of São Paulo Children II was used. The outcome variables were the anthropometric indexes height-for-age index (ZAI), BMI-for-age index (ZBI) and triceps-skinfold-thickness-for-age index (ZDI), expressed in standard deviations (Z scores) of the World Health Organization reference standard (2006). The association between predominant breastfeeding (PBF) and the nutritional indexes was adjusted for: family income, years of maternal education, birth weight, birth order, maternal age and maternal work status. The fixed and random effects of the determinants of child growth, in 3 home visits, were estimated using panel analysis. Results The duration of PBF was negatively associated with all the anthropometric indexes. The mean effect of PBF on the indexes was of -0,068 Z on ZAI, -0,044 Z on ZBI and -0,065 Z on ZDI (p<0,05, all cases). The means of each index had decreasing dose-response effects according to the raise of the PBF duration. The PBF effect over children nutritional status was modified by controlling its interaction with maternal education: children of women with 8 or more years of study had mean height 0,075 Z higher than children of women with 3 or less years of study (p<0,05); for BMI, this interaction was not statistically significant. Conclusion Predominant breastfeeding was negatively associated to the children nutritional indexes, with a protection effect against high mean of BMI and body fat in children aged less then 3 years old in São Paulo City.

Introduction A group of 317 HIV-1 infected pregnant women and 53 postpartum HIV-negative women were recruited for a two-year prospective descriptive study of psychosocial and other determinants of antenatally planned and actual postnatal feeding, associations between maternal status and infant feeding practices, and health outcomes. Methods The subjects were interviewed periodically for 2 years using structured research instruments. Anthropometric measurements, biomarkers of nutritional status and measurements of pysychosocial wellbeing were obtained from the mothers. Data was collected on infant feeding and outcomes for the babies. Results At recruitment, 74% of mothers planned to formula-feed. Significant differences between these women and those who planned to breastfeed emerged. After delivery, 25% of the women who antenatally planned to formula-feed changed their minds and actually breastfed. Conversely, half of the women who antenatally planned to breastfeed actually formula-fed. Some significant reasons emerged for these feeding changes. Most mothers were well-nourished or overweight. Breastfeeding mothers lost little weight between six weeks and six months after delivery. At the end of follow-up, 65% were obese. While there were differences between HIV-infected and uninfected women in respect of micronutrients, no deficiencies were observed. Vitamin A and selenium concentrations were higher in the HIV-infected women than uninfected women at six weeks. There were no significant micronutrient changes over time. Most mothers maintained an adequate immune status with only slow deterioration of CD4 counts. At two years postpartum, 60% had a CD4 cell count greater than 500cells/mm³, and only about 8% less than 200/mm3. HIV transmission was 15% by 24 months of follow-up. Among the 65 ever breastfed children, 16 (24.6%) were HIV-infected compared to 12.8% of never breastfed children. Most children were growing normally, suggesting that, overall, maternal HIV status did not interfere with feeding ability. Eight mothers (3%) and 33 children (11%) died. Only 12 of 33 children who had died had a positive HIV-PCR. By 2 years, 78% surviving HIV-infected children had been initiated onto ARV therapy. Maternal adherence to HAART was poor. Conclusion HIV and infant feeding counselling is inadequate in the routine PMTCT programme, with stigma and lack of disclosure continuing as major barriers to appropriate care. Whilst maternal obesity was common, most children were growing normally. Weaknesses in routine PMTCT services were identified, and compliance with HAART was poor. / Thesis (PhD)--University of Pretoria, 2010. / Paediatrics and Child Health / unrestricted

<div>The first 1000 days of life, from conception until the child’s second birthday, constitute a critical window for child growth and development. During infancy and early childhood, significant and rapid physical changes occur, including increases in weight, height, and brain size and organ development accompanied by cognitive and psychomotor development. Adequate infant feeding, including breastfeeding and complementary feeding, that meets the infants’ energy and nutrient requirements can help protect against growth faltering, infant and child morbidity and mortality, and delayed mental and motor development. Adequate nutrition during this critical period can also protect against adverse health outcomes and chronic diseases later in life according to the hypothesis of developmental origins of health and disease.</div><div><br></div><div>A web of factors that are country- and culture- specific influence infant feeding practices and child growth. Further, the microbiome has been suggested as a strong potential player in the association between infant nutrition and child growth. Therefore, the overarching theme of the current dissertation is to investigate hypotheses that can provide evidence to inform the paradigm linking socio-demographic, maternal, and child determinants including prenatal intake to infant feeding, the breast milk and infant gut microbiome, and child growth within the first 1000 days of life. Specifically, aims one and two examine the socio-demographic, maternal, and child determinants of child growth and breastfeeding in a cross-sectional survey of mother-child dyads in Lebanon, a middle-income country undergoing nutrition transition in the Middle East. The third aim focuses on the CHILD cohort study, a multi-center longitudinal prospective birth cohort study, to examine the associations between prenatal diet and supplement intake and the breast milk microbiome. Finally, the fourth aim is to review the evidence for the potential of the infant gut microbiome as a promising target linking complementary feeding to child undernutrition in low- and middle- income countries (LMIC) with the highest burden of undernutrition.</div><div><br></div><div>The results for aim one revealed sex-specific determinants of child growth in Lebanon. The determinants examined through a hierarchical conceptual framework included: maternal and paternal education among boys and crowding index among girls at the distal sociodemographic level, and maternal obesity among girls at the intermediate maternal level. The proximal child determinants included birth length, number of children in the household and breastfeeding duration among girls, birthweight among boys and child’s age among boys and girls.</div><div><br></div><div>In the analysis for aim two, breastfeeding practices were suboptimal in Lebanon as less than half (41.5%) of the infants were exclusively breastfed during the 40-day rest period and 12.3% were exclusively breastfed during the 6-month duration recommended by the World Health Organization. Higher socioeconomic status, as reflected by a larger number of cars owned, and C-section delivery were consistently inversely associated with lower odds of exclusive breastfeeding for 40 days and 6 months. Belonging to a family with more children was associated with higher odds of exclusive breastfeeding for 40 days; while maternal overweight and obesity were associated with lower odds of exclusive breastfeeding for 6 months.</div><div><br></div><div>Findings from aim three suggested that prenatal supplement use, but not prenatal dietary quality and patterns, modulate the breast milk microbiota composition in the CHILD cohort in Canada. This project was exploratory and utilized one of the largest birth cohort studies with available breast milk microbiome data. Specifically, use of vitamin C and D supplements plus multivitamins during any trimester in pregnancy was consistently associated with milk microbial diversity and genus composition before and after adjustment for socio-demographic, maternal, and child covariates. Use of other supplements such as fish oil, folate, and calcium was less consistently associated with the breast milk microbiome.</div><div>The fourth aim of the review chapter focused on the infant gut microbiome. The effects of complementary feeding on the infant gut microbiome are less commonly studied than those of breastfeeding, with most research conducted in high-income countries but not LMIC. In contrast, associations between inadequate complementary feeding and undernutrition have been examined in LMIC where undernutrition is most prevalent. Further, a disrupted gut microbiota has been associated with child undernutrition. Indeed, animal studies have suggested a causal association although the direction of the causality is not clear and is potentially bi-directional depending on genetic and environmental conditions. In light of the current state of knowledge described in our review supporting the potential of the gut microbiota as a key player in the relation between complementary feeding and undernutrition, the development of microbiota-directed interventions during the complementary period offers a promising route for undernutrition management.</div><div><br></div><div>Findings from the studies presented in this dissertation highlight several culture-specific determinants of child growth and breastfeeding in Lebanon. The findings also highlight the need for future research using longitudinal prospective cohorts, intervention trails and animal models to provide evidence for the proposed links to enhance the understanding of the paradigm. Such a holistic view of the determinants of and pathways between infant feeding and child growth are of great public health significance to improve the health of children throughout their lives.</div>

A l'interface de la génétique et de l'environnement, l'épigénétique contribue à la diversité phénotypique. Déterminer l'impact de la variation épigénétique sur les caractères quantitatifs (QT) est un nouveau défi. La croissance staturale fournit l’opportunité d’étudier la variabilité de plusieurs traits phénotypiques liés entre eux : des QT cliniques (la taille, l’accélération de la vitesse de croissance en réponse à l'hormone de croissance, GH) et des QT biologiques tels que la concentration d’IGF1 et la réponse de cette concentration à la GH. L’ « Insulin-like Growth Factor 1 » (IGF1) contrôle la croissance postnatale chez les mammifères, y compris l'homme. Nous l’avons choisi comme locus candidat pour nos études épigénétiques. Nous avons quantifié la méthylation des deux promoteurs P1 et P2 de ce gène, qui régulent son expression. Notre objectif était d’évaluer la contribution de la méthylation d’ADN de ces promoteurs i) à la taille des enfants en croissance, ii) à l’IGF1 circulant, iii) et à la réponse de ces paramètres à un traitement par la GH. Taille et IGF1 circulant. La relation entre la méthylation des promoteurs d’IGF1 et la taille a été étudiée au sein de deux cohortes du service d'endocrinologie pédiatrique, totalisant 216 enfants prépubères de différentes statures. Nous avons montré que la méthylation d'un groupe de six CGs situés dans la partie proximale du promoteur P2 du gène IGF1 présentait une corrélation inverse avec la croissance et l'IGF1 circulant. Les enfants les plus grands sont ainsi moins méthylés sur ces CGs que les enfants de petite taille. La contribution de la méthylation à la variance de la taille a été évaluée à environ 13%, et à 10% pour la variance de l'IGF1 sérique. Pour montrer que l’association observée reflète une causalité biologique, nous avons étudié le lien entre la méthylation des promoteurs P1 et P2 et l'activité transcriptionnelle du gène IGF1 in vivo et in vitro. Nous avons montré que les quantités de transcrits de classe II, issus du promoteur P2, sont inversement corrélés à la méthylation du promoteur P2 dans les cellules sanguines mononucléées. In vitro, nous avons cloné le promoteur P2 déméthylé ou méthylé dans un plasmide rapporteur (luciferase) transfecté dans la lignée HEK293 : le promoteur déméthylé s’est révélé nettement plus actif (+57%). Finalement, nous suggérons que l’hyperméthylation de certains CGs du P1 et du P2 d’IGF1 pourrait être un des nombreux mécanismes moléculaires responsables d’une moindre expression du gène et d’un phénotype de petite taille. La réponse au traitement par la GH. Une fraction des enfants de petite taille est traitée par l'hormone de croissance (GH) pour accélérer sa croissance, mais l’efficacité du traitement est très variable entre les individus. Les causes de cette variabilité sont partiellement comprises : la génétique joue un rôle, mais il reste une place possible pour la variabilité épigénétique. Dans ce but, nous avons étudié l'effet direct de la variabilité épigénétique sur la transcription du gène IGF1 et l’IGF1 circulant, dans un test aigu d’administration de GH, puis sur la réponse thérapeutique à un traitement d’un an par la GH. Après une injection de GH, nous avons constaté une augmentation variable du nombre de transcrits d’IGF1 chez les enfants étudiés. L'augmentation des transcrits de la classe II était inversement corrélée à la méthylation des CGs du P2. La variabilité de méthylation au CG-137 contribuait pour 20% à 67% de l’expression d’IGF1 en réponse à la GH. Chez 136 enfants de petite taille, nous avons montré que la méthylation de l'ADN du promoteur P2 était associée à la réponse au traitement par la GH au cours de la première année. Cette association est observée pour l'augmentation de la vitesse de croissance et pour les taux d’IGF1. (...) / At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits (QT), an emerging challenge in humans. Growth provides a handset of quantitative traits to epigenetic studies. We studied the variability of several inter-related QTs: clinical QTs (height, height reponse to growth hormone and biological QT (serum IGF1 and serum IGF1 response to GH). Since insulin-like growth factor 1 (IGF1) controls postnatal growth in mammals including human, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene could be a epigenetic contributor to the individual variation i) in circulating IGF1 and stature in growing children. ii) on response of these parameters to treatment with (GH). Child height and circulating IGF1. To explore the relation between IGF1 promoter methylation and height, we studied two cohorts of pedriatric endocrinology department, totalling 216 prepubertal children with various statures. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. These correlations were observed in two cohorts of growing children. Tall children show lower levels of methylation in several CGs in P2 and P1 promoters of IGF1 gene than short children with idiopathic short stature. CG methylation contributed 13% to the variance of height and 10% to the variance of serum IGF1. To test if the found association reflected biological causality, we tested if methylation at the P2 promoter affects the transcriptional activity of the IGF1 gene. The transcriptional activity of the P2 promoter was inversely correlated with the CG methylation in mononuclear blood cells. We established that high levels of CG methylation at the two promoters of IGF1 contributed to the many molecular mechanisms responsible for “idiopathic” short stature. Response to treatment with (GH). Short children using growth hormone (GH) to accelerate their growth respond to this treatment with a variable efficacy. The causes of this individual variability are partially understood and could involve epigenetics. In this aim, we investigated the contribution of DNA methylation to the response to GH at two levels: direct effect of GH on transcription of IGF1 gene, on circulating IGF1 and on the growth response to GH. Following a GH injection, we found a variable increase in IGF1 transcripts across the studied children. The increase in P2-driven transcripts showed a strong inverse correlation with 4/8 of P2 CGs. Among the CGs of P1 promoter, only CG-611 showed an inverse correlation with P1-driven transcripts. Variability of DNA methylation in these CGs contributes with 27% to 67% of increase in transcripts. In 136 children with idiopatic short stature, we showed that DNA methylation of the P2 promoter is associated with growth response to GH during the first year of GH administration, for both increment in growth rate and circulating IGF1. CG-137 methylation of P2 promoter contributes 25% to variance of growth response to GH. The link between DNA methylation and the response to a treatment in humans illustrating the role of epigenetic marks as potent contributors to conclusion « pharmacoepigenetics». Our work can find application in growth physiology and therapeutics, as well as for studies in aging, longevity or cancer where IGF1 has a prominent role.

<p>The aim of this thesis was to explore the impact of physical, sexual and emotional violence against women of reproductive age and the level of controlling behaviour in marriage on child health and survival in two different cultural settings: Bangladesh and Nicaragua. </p><p>Data were acquired from four quantitative community-based studies. In two studies, a cohort including a prospective two year follow-up of 3164 mother-infant pairs in rural Bangladesh was investigated. A third study was a case-referent study in Nicaragua including mothers of 110 cases of under-five deaths and 203 referents, and in a forth study an other cohort of 1048 rural Bangladeshi women and their 2691 children was followed until 5 years of age. </p><p>Maternal exposure to any form of violence, including physical, sexual, emotional, and controlling behaviour was independently associated with lower body size at birth, increased risk of stunting and under-weight at 24 months of age, slower growth velocity during the first two years of life and a higher incidence of diarrhoeal episodes and respiratory tract infections. In the Nicaraguan setting, the children of women who experienced any history of physical violence had a two-fold increase in risk of death before the age of 5 years, and those whose mothers experienced both physical and sexual violence had a six-fold increase in risk of death. In Bangladesh, an association between violence against women and under-five mortality was found among daughters of educated mothers who were exposed to severe physical violence or a high level of controlling behaviour in marriage. In all four studies, lifetime violence experience among participating mothers was high (37-69%), and the timing was less relevant than the exposure to violence <i>per se</i>. </p><p>In conclusion, this investigation revealed that violence against women severely affects child health and survival. The findings are especially relevant in a context of high level of child under-nutrition, morbidity and under-five mortality. Efforts for protecting women from all forms of violence are needed as part of the interventions for improved child health.</p>

A l'interface de la génétique et de l'environnement, l'épigénétique contribue à la diversité phénotypique. Déterminer l'impact de la variation épigénétique sur les caractères quantitatifs (QT) est un nouveau défi. La croissance staturale fournit l’opportunité d’étudier la variabilité de plusieurs traits phénotypiques liés entre eux : des QT cliniques (la taille, l’accélération de la vitesse de croissance en réponse à l'hormone de croissance, GH) et des QT biologiques tels que la concentration d’IGF1 et la réponse de cette concentration à la GH. L’ « Insulin-like Growth Factor 1 » (IGF1) contrôle la croissance postnatale chez les mammifères, y compris l'homme. Nous l’avons choisi comme locus candidat pour nos études épigénétiques. Nous avons quantifié la méthylation des deux promoteurs P1 et P2 de ce gène, qui régulent son expression. Notre objectif était d’évaluer la contribution de la méthylation d’ADN de ces promoteurs i) à la taille des enfants en croissance, ii) à l’IGF1 circulant, iii) et à la réponse de ces paramètres à un traitement par la GH. Taille et IGF1 circulant. La relation entre la méthylation des promoteurs d’IGF1 et la taille a été étudiée au sein de deux cohortes du service d'endocrinologie pédiatrique, totalisant 216 enfants prépubères de différentes statures. Nous avons montré que la méthylation d'un groupe de six CGs situés dans la partie proximale du promoteur P2 du gène IGF1 présentait une corrélation inverse avec la croissance et l'IGF1 circulant. Les enfants les plus grands sont ainsi moins méthylés sur ces CGs que les enfants de petite taille. La contribution de la méthylation à la variance de la taille a été évaluée à environ 13%, et à 10% pour la variance de l'IGF1 sérique. Pour montrer que l’association observée reflète une causalité biologique, nous avons étudié le lien entre la méthylation des promoteurs P1 et P2 et l'activité transcriptionnelle du gène IGF1 in vivo et in vitro. Nous avons montré que les quantités de transcrits de classe II, issus du promoteur P2, sont inversement corrélés à la méthylation du promoteur P2 dans les cellules sanguines mononucléées. In vitro, nous avons cloné le promoteur P2 déméthylé ou méthylé dans un plasmide rapporteur (luciferase) transfecté dans la lignée HEK293 : le promoteur déméthylé s’est révélé nettement plus actif (+57%). Finalement, nous suggérons que l’hyperméthylation de certains CGs du P1 et du P2 d’IGF1 pourrait être un des nombreux mécanismes moléculaires responsables d’une moindre expression du gène et d’un phénotype de petite taille. La réponse au traitement par la GH. Une fraction des enfants de petite taille est traitée par l'hormone de croissance (GH) pour accélérer sa croissance, mais l’efficacité du traitement est très variable entre les individus. Les causes de cette variabilité sont partiellement comprises : la génétique joue un rôle, mais il reste une place possible pour la variabilité épigénétique. Dans ce but, nous avons étudié l'effet direct de la variabilité épigénétique sur la transcription du gène IGF1 et l’IGF1 circulant, dans un test aigu d’administration de GH, puis sur la réponse thérapeutique à un traitement d’un an par la GH. Après une injection de GH, nous avons constaté une augmentation variable du nombre de transcrits d’IGF1 chez les enfants étudiés. L'augmentation des transcrits de la classe II était inversement corrélée à la méthylation des CGs du P2. La variabilité de méthylation au CG-137 contribuait pour 20% à 67% de l’expression d’IGF1 en réponse à la GH. Chez 136 enfants de petite taille, nous avons montré que la méthylation de l'ADN du promoteur P2 était associée à la réponse au traitement par la GH au cours de la première année. Cette association est observée pour l'augmentation de la vitesse de croissance et pour les taux d’IGF1. (...) / At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits (QT), an emerging challenge in humans. Growth provides a handset of quantitative traits to epigenetic studies. We studied the variability of several inter-related QTs: clinical QTs (height, height reponse to growth hormone and biological QT (serum IGF1 and serum IGF1 response to GH). Since insulin-like growth factor 1 (IGF1) controls postnatal growth in mammals including human, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene could be a epigenetic contributor to the individual variation i) in circulating IGF1 and stature in growing children. ii) on response of these parameters to treatment with (GH). Child height and circulating IGF1. To explore the relation between IGF1 promoter methylation and height, we studied two cohorts of pedriatric endocrinology department, totalling 216 prepubertal children with various statures. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. These correlations were observed in two cohorts of growing children. Tall children show lower levels of methylation in several CGs in P2 and P1 promoters of IGF1 gene than short children with idiopathic short stature. CG methylation contributed 13% to the variance of height and 10% to the variance of serum IGF1. To test if the found association reflected biological causality, we tested if methylation at the P2 promoter affects the transcriptional activity of the IGF1 gene. The transcriptional activity of the P2 promoter was inversely correlated with the CG methylation in mononuclear blood cells. We established that high levels of CG methylation at the two promoters of IGF1 contributed to the many molecular mechanisms responsible for “idiopathic” short stature. Response to treatment with (GH). Short children using growth hormone (GH) to accelerate their growth respond to this treatment with a variable efficacy. The causes of this individual variability are partially understood and could involve epigenetics. In this aim, we investigated the contribution of DNA methylation to the response to GH at two levels: direct effect of GH on transcription of IGF1 gene, on circulating IGF1 and on the growth response to GH. Following a GH injection, we found a variable increase in IGF1 transcripts across the studied children. The increase in P2-driven transcripts showed a strong inverse correlation with 4/8 of P2 CGs. Among the CGs of P1 promoter, only CG-611 showed an inverse correlation with P1-driven transcripts. Variability of DNA methylation in these CGs contributes with 27% to 67% of increase in transcripts. In 136 children with idiopatic short stature, we showed that DNA methylation of the P2 promoter is associated with growth response to GH during the first year of GH administration, for both increment in growth rate and circulating IGF1. CG-137 methylation of P2 promoter contributes 25% to variance of growth response to GH. The link between DNA methylation and the response to a treatment in humans illustrating the role of epigenetic marks as potent contributors to conclusion « pharmacoepigenetics». Our work can find application in growth physiology and therapeutics, as well as for studies in aging, longevity or cancer where IGF1 has a prominent role.

O propósito deste estudo foi contribuir para a análise da epidemiologia da oclusão dentária na infância e discutir a implicação para os sistemas de saúde, examinando dados de prevalência de uma amostra probabilística (n=985) da população de 5 e 12 anos de idade na cidade de São Paulo, Brasil (1996); e estudos epidemiológicos transversais publicados nos últimos 70 anos. A prevalência na cidade, cresceu de 49,0 ± 4,5 por cento na dentição decídua para 71,3 ± 3,9 por cento na dentição permanente (p<0,001), sendo que a chance de ocorrência de oclusopatia moderada/severa foi quase duas vezes maior na segunda dentição (OR=1,87; IC95 por cento =1,43-2,45; p<O,OOO). O ataque de cárie acima das metas da OMS para o ano 2000 mostrou associação positiva com a severidade do dano (OR=1,51; IC95s por cento =1,15-1,99; p<0,003). Análise de regressão logística múltipla mostrou que o risco estimado da população portadora de dentição permanente e com experiência de cárie acima dessas metas apresentar oclusopatia moderada/severa se elevou de 22 por cento para 50 por cento . Sexo, tipo de escola (pública e privada) e diferenças étnicas entre brancos e pardos não influenciaram essa distribuição. O exame da literatura através de meta-análise indicou que a prevalência dos problemas oclusais foi duas vezes maior na dentição permanente quando comparada às dentições decídua/mista. Tanto a realização de estudos longitudinais quanto de levantamentos e triagens para a identificação e o tratamento dos casos mais severos, não apenas no período da dentição permanente, mas também nas dentições decídua/mista, combinado à introdução de ações de proteção específica em programas materno-infantis direcionadas ao desenvolvimento oro-facial dos zero aos 6 anos são medidas que devem ser consideradas no planejamento estratégico e normativo dos sistemas de saúde. Métodos de intervenção em saúde pública devem ser pesquisados e implementados o mais precocemente possível para aumentar a proporção da população com oclusão normal e reduzir o percentual de oclusopatia moderada/severa. / The purpose of this study was to analyze some epidemiological aspects of dental occlusal problems at childhood and to discuss their implications for health systems. It were used prevalence data of a probabilistic sample (n=985) of five and twelve years old schoolchildren in São Paulo City, Brazil (1996); and cross-sectional data of studies published in the last 70 years. The results showed that the proportion of these problems in the city increased from 49.0 ± 4.5 per cent at deciduous dentition to 71.3 ± 3.9 per cent at permanent dentition (p<O,OO1), and the risk to severe/moderate malocclusion was closely twice higher at second dentition (OR= 1.87; CI95 per cent = 1.43-2.45; p<O,OOO). Caries experience above OMS goals for the year 2000 indicated positive association with severity of injury (OR= 1.51; CI95 per cent = 1.15-1.99; p<0,003). Multiple logistic regression analysis pointed out that risk estimative related to population carrier of permanent dentition and caries experience above these goals to present severe/moderate malocclusion growed up from 22 per cent to 50 per cent . Sex, kind of school (public and private) and ethnics diferences between whites and african-brazilians did not affect this distribution. The examination of literature through metanalysis showed that prevalence was twice higher at permanent dentition than deciduous/mixed. The realization of longitudinal studies as much as surveys and screenings to identify and care people with severe occlusal problems not only at permanent dentition but also at deciduous dentition, allied to especific protection measures on maternal-childhood programmes directed to orofacial development from O to 6 years old are aspects to be considering at estrategic and normative planning of health systems. Public health methods must be researched and introduced as earlier as possible in order to increase the proportion of population with normal occlusion and reduce the amount of severe/moderate malocclusion.

A l'interface de la génétique et de l'environnement, l'épigénétique contribue à la diversité phénotypique. Déterminer l'impact de la variation épigénétique sur les caractères quantitatifs (QT) est un nouveau défi. La croissance staturale fournit l’opportunité d’étudier la variabilité de plusieurs traits phénotypiques liés entre eux : des QT cliniques (la taille, l’accélération de la vitesse de croissance en réponse à l'hormone de croissance, GH) et des QT biologiques tels que la concentration d’IGF1 et la réponse de cette concentration à la GH. L’ « Insulin-like Growth Factor 1 » (IGF1) contrôle la croissance postnatale chez les mammifères, y compris l'homme. Nous l’avons choisi comme locus candidat pour nos études épigénétiques. Nous avons quantifié la méthylation des deux promoteurs P1 et P2 de ce gène, qui régulent son expression. Notre objectif était d’évaluer la contribution de la méthylation d’ADN de ces promoteurs i) à la taille des enfants en croissance, ii) à l’IGF1 circulant, iii) et à la réponse de ces paramètres à un traitement par la GH. Taille et IGF1 circulant. La relation entre la méthylation des promoteurs d’IGF1 et la taille a été étudiée au sein de deux cohortes du service d'endocrinologie pédiatrique, totalisant 216 enfants prépubères de différentes statures. Nous avons montré que la méthylation d'un groupe de six CGs situés dans la partie proximale du promoteur P2 du gène IGF1 présentait une corrélation inverse avec la croissance et l'IGF1 circulant. Les enfants les plus grands sont ainsi moins méthylés sur ces CGs que les enfants de petite taille. La contribution de la méthylation à la variance de la taille a été évaluée à environ 13%, et à 10% pour la variance de l'IGF1 sérique. Pour montrer que l’association observée reflète une causalité biologique, nous avons étudié le lien entre la méthylation des promoteurs P1 et P2 et l'activité transcriptionnelle du gène IGF1 in vivo et in vitro. Nous avons montré que les quantités de transcrits de classe II, issus du promoteur P2, sont inversement corrélés à la méthylation du promoteur P2 dans les cellules sanguines mononucléées. In vitro, nous avons cloné le promoteur P2 déméthylé ou méthylé dans un plasmide rapporteur (luciferase) transfecté dans la lignée HEK293 : le promoteur déméthylé s’est révélé nettement plus actif (+57%). Finalement, nous suggérons que l’hyperméthylation de certains CGs du P1 et du P2 d’IGF1 pourrait être un des nombreux mécanismes moléculaires responsables d’une moindre expression du gène et d’un phénotype de petite taille. La réponse au traitement par la GH. Une fraction des enfants de petite taille est traitée par l'hormone de croissance (GH) pour accélérer sa croissance, mais l’efficacité du traitement est très variable entre les individus. Les causes de cette variabilité sont partiellement comprises : la génétique joue un rôle, mais il reste une place possible pour la variabilité épigénétique. Dans ce but, nous avons étudié l'effet direct de la variabilité épigénétique sur la transcription du gène IGF1 et l’IGF1 circulant, dans un test aigu d’administration de GH, puis sur la réponse thérapeutique à un traitement d’un an par la GH. Après une injection de GH, nous avons constaté une augmentation variable du nombre de transcrits d’IGF1 chez les enfants étudiés. L'augmentation des transcrits de la classe II était inversement corrélée à la méthylation des CGs du P2. La variabilité de méthylation au CG-137 contribuait pour 20% à 67% de l’expression d’IGF1 en réponse à la GH. Chez 136 enfants de petite taille, nous avons montré que la méthylation de l'ADN du promoteur P2 était associée à la réponse au traitement par la GH au cours de la première année. Cette association est observée pour l'augmentation de la vitesse de croissance et pour les taux d’IGF1. (...) / At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits (QT), an emerging challenge in humans. Growth provides a handset of quantitative traits to epigenetic studies. We studied the variability of several inter-related QTs: clinical QTs (height, height reponse to growth hormone and biological QT (serum IGF1 and serum IGF1 response to GH). Since insulin-like growth factor 1 (IGF1) controls postnatal growth in mammals including human, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene could be a epigenetic contributor to the individual variation i) in circulating IGF1 and stature in growing children. ii) on response of these parameters to treatment with (GH). Child height and circulating IGF1. To explore the relation between IGF1 promoter methylation and height, we studied two cohorts of pedriatric endocrinology department, totalling 216 prepubertal children with various statures. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. These correlations were observed in two cohorts of growing children. Tall children show lower levels of methylation in several CGs in P2 and P1 promoters of IGF1 gene than short children with idiopathic short stature. CG methylation contributed 13% to the variance of height and 10% to the variance of serum IGF1. To test if the found association reflected biological causality, we tested if methylation at the P2 promoter affects the transcriptional activity of the IGF1 gene. The transcriptional activity of the P2 promoter was inversely correlated with the CG methylation in mononuclear blood cells. We established that high levels of CG methylation at the two promoters of IGF1 contributed to the many molecular mechanisms responsible for “idiopathic” short stature. Response to treatment with (GH). Short children using growth hormone (GH) to accelerate their growth respond to this treatment with a variable efficacy. The causes of this individual variability are partially understood and could involve epigenetics. In this aim, we investigated the contribution of DNA methylation to the response to GH at two levels: direct effect of GH on transcription of IGF1 gene, on circulating IGF1 and on the growth response to GH. Following a GH injection, we found a variable increase in IGF1 transcripts across the studied children. The increase in P2-driven transcripts showed a strong inverse correlation with 4/8 of P2 CGs. Among the CGs of P1 promoter, only CG-611 showed an inverse correlation with P1-driven transcripts. Variability of DNA methylation in these CGs contributes with 27% to 67% of increase in transcripts. In 136 children with idiopatic short stature, we showed that DNA methylation of the P2 promoter is associated with growth response to GH during the first year of GH administration, for both increment in growth rate and circulating IGF1. CG-137 methylation of P2 promoter contributes 25% to variance of growth response to GH. The link between DNA methylation and the response to a treatment in humans illustrating the role of epigenetic marks as potent contributors to conclusion « pharmacoepigenetics». Our work can find application in growth physiology and therapeutics, as well as for studies in aging, longevity or cancer where IGF1 has a prominent role.

O propósito deste estudo foi contribuir para a análise da epidemiologia da oclusão dentária na infância e discutir a implicação para os sistemas de saúde, examinando dados de prevalência de uma amostra probabilística (n=985) da população de 5 e 12 anos de idade na cidade de São Paulo, Brasil (1996); e estudos epidemiológicos transversais publicados nos últimos 70 anos. A prevalência na cidade, cresceu de 49,0 ± 4,5 por cento na dentição decídua para 71,3 ± 3,9 por cento na dentição permanente (p<0,001), sendo que a chance de ocorrência de oclusopatia moderada/severa foi quase duas vezes maior na segunda dentição (OR=1,87; IC95 por cento =1,43-2,45; p<O,OOO). O ataque de cárie acima das metas da OMS para o ano 2000 mostrou associação positiva com a severidade do dano (OR=1,51; IC95s por cento =1,15-1,99; p<0,003). Análise de regressão logística múltipla mostrou que o risco estimado da população portadora de dentição permanente e com experiência de cárie acima dessas metas apresentar oclusopatia moderada/severa se elevou de 22 por cento para 50 por cento . Sexo, tipo de escola (pública e privada) e diferenças étnicas entre brancos e pardos não influenciaram essa distribuição. O exame da literatura através de meta-análise indicou que a prevalência dos problemas oclusais foi duas vezes maior na dentição permanente quando comparada às dentições decídua/mista. Tanto a realização de estudos longitudinais quanto de levantamentos e triagens para a identificação e o tratamento dos casos mais severos, não apenas no período da dentição permanente, mas também nas dentições decídua/mista, combinado à introdução de ações de proteção específica em programas materno-infantis direcionadas ao desenvolvimento oro-facial dos zero aos 6 anos são medidas que devem ser consideradas no planejamento estratégico e normativo dos sistemas de saúde. Métodos de intervenção em saúde pública devem ser pesquisados e implementados o mais precocemente possível para aumentar a proporção da população com oclusão normal e reduzir o percentual de oclusopatia moderada/severa. / The purpose of this study was to analyze some epidemiological aspects of dental occlusal problems at childhood and to discuss their implications for health systems. It were used prevalence data of a probabilistic sample (n=985) of five and twelve years old schoolchildren in São Paulo City, Brazil (1996); and cross-sectional data of studies published in the last 70 years. The results showed that the proportion of these problems in the city increased from 49.0 ± 4.5 per cent at deciduous dentition to 71.3 ± 3.9 per cent at permanent dentition (p<O,OO1), and the risk to severe/moderate malocclusion was closely twice higher at second dentition (OR= 1.87; CI95 per cent = 1.43-2.45; p<O,OOO). Caries experience above OMS goals for the year 2000 indicated positive association with severity of injury (OR= 1.51; CI95 per cent = 1.15-1.99; p<0,003). Multiple logistic regression analysis pointed out that risk estimative related to population carrier of permanent dentition and caries experience above these goals to present severe/moderate malocclusion growed up from 22 per cent to 50 per cent . Sex, kind of school (public and private) and ethnics diferences between whites and african-brazilians did not affect this distribution. The examination of literature through metanalysis showed that prevalence was twice higher at permanent dentition than deciduous/mixed. The realization of longitudinal studies as much as surveys and screenings to identify and care people with severe occlusal problems not only at permanent dentition but also at deciduous dentition, allied to especific protection measures on maternal-childhood programmes directed to orofacial development from O to 6 years old are aspects to be considering at estrategic and normative planning of health systems. Public health methods must be researched and introduced as earlier as possible in order to increase the proportion of population with normal occlusion and reduce the amount of severe/moderate malocclusion.

Globally, the prevalence of Type 2 diabetes is rising. The most affected populations are those that have undergone recent and rapid transition towards a Western lifestyle, characterised by energy-dense diets and physical inactivity.¶ Two major hypotheses have attempted to explain the variation in diabetes prevalence, both between and within populations, beyond the contributions made by adult lifestyle. The thrifty genotype hypothesis proposes that some populations are genetically well adapted to surviving in a subsistence environment, and are predisposed to develop diabetes when the dietary environment changes to one that is fat and carbohydrate rich. The programming hypothesis focuses on the developmental environment, particularly on prenatal and early postnatal conditions: nutritional deprivation in utero and early postnatal life, measured by low birthweight and disrupted child growth, is proposed to alter metabolism permanently so that risk of diabetes is increased with subsequent exposure to an energy-dense diet. Both hypotheses emphasise discord between adaptation (genetic or developmental) and current environment, and both now put forward insulin resistance as a likely mechanism for predisposition.¶ Diabetes contributes significantly to morbidity and mortality among Australia’s Indigenous population. Indigenous babies are more likely to be low birthweight, and typical patterns of child growth include periods of faltering and rapid catch-up. Although there have been numerous studies in other populations, the programming hypothesis has not previously been tested in an Australian Indigenous community. The framework of the programming hypothesis is thus expanded to consider exposure of whole populations to adverse prenatal and postnatal environments, and the influence this may have on diabetes prevalence.¶ The present study took place in Cherbourg, a large Aboriginal community in southeast Queensland with a high prevalence of diabetes. Study participants were adults with diagnosed diabetes and a random sample of adults who had never been diagnosed with diabetes. Data were collected on five current risk factors for diabetes (general and central obesity, blood pressure, age and family history), in addition to fasting blood glucose levels. A lifestyle survey was also conducted. Participants’ medical records detailing weight growth from birth to five years were analysed with regard to adult diabetes risk to determine whether childhood weight and rate of weight gain were associated with subsequent diabetes. Adult lifestyle factors were xiialso explored to determine whether variation in nutrition and physical activity was related to level of diabetes risk.¶ Approximately 20% of adults in Cherbourg have diagnosed diabetes. Prevalence may be as high as 38.5% in females and 42% in males if those who are high-risk (abnormal fasting glucose and three additional factors) are included. Among those over 40 years, total prevalence is estimated to be 51% for females and 59% for males.¶ Patterns of early childhood growth may contribute to risk of diabetes among adults. In particular, relatively rapid weight growth to five years is associated with both general and central obesity among adult women. This lends some qualified support to the programming hypothesis as catch-up growth has previously been incorporated into the model; however, although the most consistent association was found among those who gained weight more rapidly, it was also found that risk is increased among children who are heavier at any age.¶ No consistent associations were found between intrauterine growth retardation (as determined by lower than median birthweight and higher than median weight growth velocity to one and three months) and diabetes risk among women or men. A larger study sample with greater statistical power may have yielded less ambiguous results.¶ Among adults, levels of physical activity may be more important than nutritional intake in moderating diabetes risk, although features of diet, such as high intake of simple carbohydrates, may contribute to risk in the community overall, especially in the context of physical inactivity. A genetic component is not ruled out. Two additional areas which require further investigation include stress and high rates of infection, both of which are highly relevant to the study community, and may contribute to the insulin resistance syndrome.¶ Some accepted thresholds indicating increased diabetes risk may not be appropriate in this population. Given the relationship between waist circumference and other diabetes risk factors and the propensity for central fat deposition among women even with low body mass index (BMI), it is recommended that the threshold where BMI is considered a risk be lowered by 5kg/m2 for women, while no such recommendation is made for men.¶ There are a number of social barriers to better community health, including attitudes to exercise and obesity, patterns of alcohol and tobacco use and consumption of fresh foods. Some of these barriers are exacerbated by gender roles and expectations.¶