To date, risk factors for temporomandibular joint (TMJ) sounds are still not completely understood, and anatomical factors are suspected to influence their occurrence. This study aimed to evaluate the impact of body constitution on temporomandibular joint sounds of adolescents. 10- to 18-year-old participants of the LIFE Child Study were examined for TMJ sounds, and physical parameters such as body height, body weight, and general laxity of joints were measured. Odds ratios (OR) for associations of TMJ sounds and standard deviation scores (SDS) of body height and body weight were calculated by using binary logistic regression, including cofactors such as age and number of hypermobile joints. The OR for TMJ sounds and SDS of body height was 1.28 (95% confidence interval (CI) 1.06; 1.56) in females when the age-adjusted height value was above 0. SDS of body weight indicated significant ORs for TMJ sounds in males with values of 0.81 (95% CI 0.70; 0.94). No correlation was detected for SDS values and TMJ crepitus. Tall female adolescents seem to be more prone to TMJ clicking sounds, while their occurrence seems less likely in male adolescents with higher body weight.

O gene SHOX (short stature homeobox containing gene), expresso em altos níveis nas células osteogênicas, é fundamental para o desenvolvimento ósseo e para a determinação da altura. Haploinsuficiência do SHOX é responsável por vários fenótipos que envolvem a baixa estatura, como a síndrome de Turner, a discondrosteose de Léri-Weill e a baixa estatura idiopática. Cerca de dois terços das haploinsuficiências são causados por deleções. Neste trabalho, foi realizada uma comparação entre três técnicas para detecção de deleções do SHOX: a hibridação in situ com fluorescência (FISH), o estudo de microssatélites e o multiplex ligationdependent probe amplification (MLPA). Nos pacientes sem deleção do SHOX, foi realizado um rastreamento para identificação de mutações de ponto no gene que levassem à sua haploinsuficiência. Foram analisados seis pacientes com discondrosteose de Léri-Weill (DLW) e 20 com baixa estatura desproporcionada (BED). Na técnica de FISH, os cromossomos metafásicos obtidos a partir de cultura de linfócitos foram hibridados com o cosmídio LLNOYCO3M34F5. DNA genômico extraído a partir de leucócitos de sangue periférico foi submetido à análise de microssatélites e MLPA. Foram amplificados seis marcadores de microssatélites (repetições CA, DYS290, DXYS10093, DXYS10096, DXYS233 e DXYS234) e o MLPA foi realizado de acordo com as instruções dos kits SALSA MLPA P018-C1 e P018-D1 SHOX. Estes kits contêm oito sondas específicas para o gene SHOX e 13 para a área do SHOX, localizada a jusante do gene. O seqüenciamento direto da região codificadora do gene foi realizado nos pacientes sem deleção. Todos os pacientes com DLW apresentaram deleções envolvendo todo o gene. Entre os pacientes com BED, apenas um (5,0%) apresentou uma deleção intragênica envolvendo os exons 4, 5 e 6a. Os resultados das três metodologias foram concordantes na maioria dos casos, exceto em dois casos. No primeiro caso, inicialmente o FISH não identificou uma deleção envolvendo todos os éxons em um paciente com DLW. No segundo, uma deleção envolvendo os exons 4, 5 e 6a, identificada em uma paciente com BED, foi detectada apenas pelo MLPA. Ainda entre os pacientes com BED, três (15%) apresentaram deleção da região do marcador DXYS10096, a 3 do gene. Outros três (15%) pacientes apresentaram mutações de ponto identificadas pelo seqüenciamento direto: a mutação p.Tyr35X, que resulta na substituição de uma tirosina por um códon de parada prematuro; a p.Arg147His localizada na região do homeodomínio e a NM_000451:c.1236 -10T>C que se encontra a 10 nucleotídeos antes do início do éxon 5. Em uma comparação das três metodologias, o FISH foi considerado a técnica mais trabalhosa e com menor sensibilidade, levando até oito dias para sua realização. A análise por microssatélites requer o estudo dos progenitores, além de um grande número de marcadores para a análise de regiões extensas. O MLPA detectou todas as deleções, sendo considerada a metodologia mais sensível. Ele apresentou também menor custo e tempo de execução, além de possibilitar a estimativa do tamanho da deleção. Desta forma, o MLPA foi considerado a melhor metodologia para investigação inicial dos pacientes com DLW e BED. / The SHOX gene (short stature homeobox containing gene), expressed at high levels in osteogenic cells, is essential for bone development and growth process. SHOX haploinsufficiency is responsible for several phenotypes involving short stature, such as Turner syndrome, Léri-Weill dyschondrosteosis (LWD) and idiopathic short stature. Deletions are responsible for 2/3 of SHOX haploinsufficiency. In this study, a comparison among three techniques for detection of SHOX deletions: fluorescence in situ hybridization (FISH), microsatellites analysis and multiplex ligationdependent probe amplification (MLPA) was performed. A screening for point mutations that could lead to haploinsufficiency was performed in patients without SHOX deletion. Six patients with Léri-Weill dyschondrosteosis (LWD) and 20 with disproportionate short stature (DSS) were analyzed. FISH analysis was performed using the cosmid LLNOYCO3\"M\"34F5 and metaphase spreads obtained from lymphocytes culture. Genomic DNA extracted from peripheral blood leukocytes was used to microsatellite and MLPA analysis. Six microsatellite markers (CA repeats, DYS290, DXYS10093, DXYS10096, DXYS233 and DXYS234) were amplified by PCR and MLPA was performed according to the manufacturers instructions for SALSA MLPA P018 and P018-C1-D1 SHOX kits. These kits contain 8 specific probes for SHOX gene and 13 for \"SHOX area, which is located downstream of the gene. The direct sequencing of entire encoding region was performed in patients with no SHOX deletions. All patients with LWD presented deletions involving the entire gene. One (5.0%) patient with DSS, presented an intragenic deletion involving exons 4, 5 and 6a. The results of the three methods were concordant in most cases, except in two cases. In the first case, a patient with DLW, the FISH did not identify a deletion involving all SHOX exons. In the second case, a deletion of exons 4, 5 and 6a in a patient with BED was identified only by MLPA. Other 3 (15%) DSS patients had deletion in SHOX area, in the DXYS10096 marker. Other three (15%) patients presented a point mutation identified by direct sequencing: p.Tyr35X, which replaces a tyrosine for a premature stop codon, p.Arg147His located in the homeodomain region and NM_000451: c.1236-10T> C which is 10 nucleotides before the exon 5. In a comparison of three methods, the FISH technique was considered the more laborious and less sensitive, taking until eight days to obtain the results. The microsatellite analysis requires the parents DNA study. In addition, several markers are essential for the analysis of extensive regions. The MLPA was considered the most sensitive methodology since it detected all deletions. It also presented lower cost and execution time, and allowed the estimation of the size of the deletion. Thus, the MLPA was considered the best approach for initial investigation of LWD and DSS patients.

O presente trabalho avaliou a associação entre duas condições clínicas de grande importância no contexto atual da pediatria: o Transtorno de Déficit de Atenção e Hiperatividade (TDAH) e a obesidade. O projeto foi desenvolvido com pacientes acompanhados no Instituto da Criança do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP) e dividido em 2 braços. No primeiro, realizamos uma análise retrospectiva dos prontuários dos pacientes seguidos no ambulatório de Distúrbios de Aprendizagem com o intuito de estimar a prevalência de sobrepeso/obesidade em pacientes com diagnóstico de TDAH e comparamos tal prevalência com a de um grupo controle. Em seguida, avaliamos a influência do tratamento medicamentoso do TDAH (metilfenidato) no estado nutricional e estatura dos indivíduos. No segundo braço do estudo, avaliamos os pacientes seguidos no ambulatório de Obesidade a fim de estimar a prevalência de TDAH. A primeira etapa dessa avaliação, ocorreu por meio da aplicação do questionário SNAP-IV. Pacientes que tiveram uma triagem inicial positiva, foram encaminhados para a segunda etapa de avaliação, que consistiu em anamnese clínica e aplicação das seguintes ferramentas: Escala Wechsler de Inteligência para Crianças (WISC-IV), Escala Multidimensional de Ansiedade para Crianças (MASC) e Patient Health Questionnaire (PHQ-9). As análises estatísticas foram realizadas através dos testes \"qui-quadrado\" e teste \"T de Student pareado\". Ao final das coletas de dados, 93 pacientes com diagnóstico de TDAH foram incluídos no \"braço 1\" cujos resultados evidenciaram prevalência de sobrepeso/obesidade estatisticamente superior à observada no grupo controle (com p < 0,05). Na segunda etapa da avaliação, observamos que após o tratamento com metilfenidato (tempo médio de 2,6 anos) houve uma diminuição estatisticamente significativa (p < 0,01) no Z-score do IMC dos indivíduos, porém não foi observada influência estatisticamente significativa na estatura dos mesmos (p=0,30). Além disso, observamos que 42,1% dos indivíduos que estavam inicialmente nas faixas de sobrepeso/obesidade evoluíram com \"melhora\" do estado nutricional ao final do tratamento. No \"braço 2\" do estudo foram avaliados 103 pacientes, dos quais 37 (35,9%) apresentaram triagem inicial positiva para TDAH sendo convocados para a segunda etapa de avaliação. Desses, 26 participaram da segunda etapa, sendo 2 excluídos pois apresentaram déficit cognitivo. Em 15 pacientes foi confirmado o diagnóstico de TDAH (16,67%). As principais conclusões do trabalho são: (1) a prevalência de sobrepeso/obesidade em portadores de TDAH foi estatisticamente superior à observada na população geral; (2) o tratamento medicamentoso do TDAH não teve influência no crescimento estatural dos pacientes, independentemente do tempo de tratamento, mas promoveu uma redução no z-score de IMC dos indivíduos; (3) a prevalência de TDAH observada na amostra de pacientes portadores de obesidade foi estatisticamente superior à observada na população geral (16,7% - 95% IC 8,97-24,37% vs 5,29% - 95% CI=5,01-5,56%); (4) a presença de outras afecções como transtorno depressivo, transtorno de ansiedade e distúrbios do sono não foi significativa a ponto de explicar a associação entre TDAH e obesidade; (5) a ocorrência de ronco é bastante frequente em indivíduos obesos, tanto portadores quanto não portadores de TDAH. As principais limitações do estudo foram: (1) desenho retrospectivo do \"braço 1\"; (2) No \"braço 2\", 11 dos 37 pacientes que tiveram a triagem inicial positiva para TDAH não participaram da segunda etapa de avaliação. Além disso, seria interessante avaliar mais profundamente a ocorrência de distúrbios do sono (através da realização de polissonografia) e de alterações do processamento auditivo / The present study evaluated the association between attention deficit hyperactivity disorder (ADHD) and obesity, two clinical conditions currently of great importance in the field of pediatrics. The project included patients at the Children Institute of the HC-FMUSP (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo), and were divided into two arms. In the first arm, we retrospectively analyzed the medical records of the ADHD patients at the learning disorder clinic to estimate the prevalence of overweight/obesity and compared this prevalence with that of a control group. Next, we evaluated the effect of ADHD drug treatment (methylphenidate) on nutritional status and height of the patients. In the second arm of the study, we examined the patients at the obesity clinic to estimate the prevalence of ADHD. The first evaluation step involved the use of the SNAP-IV questionnaire. Patients considered to have ADHD on initial screening were included in the second evaluation step, which comprised clinical history examination and the use of the Wechsler Intelligence Scale for Children, Multidimensional Anxiety Scale for Children, and Patient Health Questionnaire. Statistical analyses were performed using the chi-square and paired Student t tests. After data collection, 93 ADHD patients were included in arm 1; these patients showed a statistically higher prevalence of overweight/obesity than the control group (p < 0.05). During the second evaluation step, we found a statistically significant decrease (p < 0.01) in the BMI z-score of the individuals after methylphenidate treatment (mean duration of 2.6 years). However, there was no statistically significant effect on height (p=0,30). In addition, we found that 42.1% of patients who were initially overweight/obese evolved with improved nutritional status at the end of treatment. A total of 103 patients were evaluated in arm 2 of the study, among whom 37 (35.9%) found to have ADHD on initial screening were invited for the second evaluation step. Of these patients, 26 consented to participate in the second step. Two patients were excluded because they had cognitive impairment. ADHD was confirmed in 15 patients (16.67%). The main conclusions of the study were as follows: (1) prevalence of overweight/obesity among ADHD patients was statistically higher than that in the general population; (2) ADHD drug treatment did not affect the height of the patients, regardless of treatment duration, but caused a decrease in BMI z-score ; (3) prevalence of ADHD observed in the obese patient sample was statistically higher than that observed in the general population (16.7-95% CI 8.97-24.37% vs. 5.29- 95% CI=5.01-5.56%); (4) presence of other disorders such as depressive, anxiety, and sleep disorders was not sufficient to explain the association between ADHD and obesity; and (5) snoring is common in obese patients, both those with and without ADHD. The limitations of the study were as follows: (1) retrospective design of arm 1; (2) 11 of 37 patients in arm 2 diagnosed with ADHD on initial screening did not participate in the second evaluation step. Additionally, it would be interesting to further evaluate the occurrence of sleep disorders (using polysomnography) and auditory processing disorders

O presente trabalho avaliou a associação entre duas condições clínicas de grande importância no contexto atual da pediatria: o Transtorno de Déficit de Atenção e Hiperatividade (TDAH) e a obesidade. O projeto foi desenvolvido com pacientes acompanhados no Instituto da Criança do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP) e dividido em 2 braços. No primeiro, realizamos uma análise retrospectiva dos prontuários dos pacientes seguidos no ambulatório de Distúrbios de Aprendizagem com o intuito de estimar a prevalência de sobrepeso/obesidade em pacientes com diagnóstico de TDAH e comparamos tal prevalência com a de um grupo controle. Em seguida, avaliamos a influência do tratamento medicamentoso do TDAH (metilfenidato) no estado nutricional e estatura dos indivíduos. No segundo braço do estudo, avaliamos os pacientes seguidos no ambulatório de Obesidade a fim de estimar a prevalência de TDAH. A primeira etapa dessa avaliação, ocorreu por meio da aplicação do questionário SNAP-IV. Pacientes que tiveram uma triagem inicial positiva, foram encaminhados para a segunda etapa de avaliação, que consistiu em anamnese clínica e aplicação das seguintes ferramentas: Escala Wechsler de Inteligência para Crianças (WISC-IV), Escala Multidimensional de Ansiedade para Crianças (MASC) e Patient Health Questionnaire (PHQ-9). As análises estatísticas foram realizadas através dos testes \"qui-quadrado\" e teste \"T de Student pareado\". Ao final das coletas de dados, 93 pacientes com diagnóstico de TDAH foram incluídos no \"braço 1\" cujos resultados evidenciaram prevalência de sobrepeso/obesidade estatisticamente superior à observada no grupo controle (com p < 0,05). Na segunda etapa da avaliação, observamos que após o tratamento com metilfenidato (tempo médio de 2,6 anos) houve uma diminuição estatisticamente significativa (p < 0,01) no Z-score do IMC dos indivíduos, porém não foi observada influência estatisticamente significativa na estatura dos mesmos (p=0,30). Além disso, observamos que 42,1% dos indivíduos que estavam inicialmente nas faixas de sobrepeso/obesidade evoluíram com \"melhora\" do estado nutricional ao final do tratamento. No \"braço 2\" do estudo foram avaliados 103 pacientes, dos quais 37 (35,9%) apresentaram triagem inicial positiva para TDAH sendo convocados para a segunda etapa de avaliação. Desses, 26 participaram da segunda etapa, sendo 2 excluídos pois apresentaram déficit cognitivo. Em 15 pacientes foi confirmado o diagnóstico de TDAH (16,67%). As principais conclusões do trabalho são: (1) a prevalência de sobrepeso/obesidade em portadores de TDAH foi estatisticamente superior à observada na população geral; (2) o tratamento medicamentoso do TDAH não teve influência no crescimento estatural dos pacientes, independentemente do tempo de tratamento, mas promoveu uma redução no z-score de IMC dos indivíduos; (3) a prevalência de TDAH observada na amostra de pacientes portadores de obesidade foi estatisticamente superior à observada na população geral (16,7% - 95% IC 8,97-24,37% vs 5,29% - 95% CI=5,01-5,56%); (4) a presença de outras afecções como transtorno depressivo, transtorno de ansiedade e distúrbios do sono não foi significativa a ponto de explicar a associação entre TDAH e obesidade; (5) a ocorrência de ronco é bastante frequente em indivíduos obesos, tanto portadores quanto não portadores de TDAH. As principais limitações do estudo foram: (1) desenho retrospectivo do \"braço 1\"; (2) No \"braço 2\", 11 dos 37 pacientes que tiveram a triagem inicial positiva para TDAH não participaram da segunda etapa de avaliação. Além disso, seria interessante avaliar mais profundamente a ocorrência de distúrbios do sono (através da realização de polissonografia) e de alterações do processamento auditivo / The present study evaluated the association between attention deficit hyperactivity disorder (ADHD) and obesity, two clinical conditions currently of great importance in the field of pediatrics. The project included patients at the Children Institute of the HC-FMUSP (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo), and were divided into two arms. In the first arm, we retrospectively analyzed the medical records of the ADHD patients at the learning disorder clinic to estimate the prevalence of overweight/obesity and compared this prevalence with that of a control group. Next, we evaluated the effect of ADHD drug treatment (methylphenidate) on nutritional status and height of the patients. In the second arm of the study, we examined the patients at the obesity clinic to estimate the prevalence of ADHD. The first evaluation step involved the use of the SNAP-IV questionnaire. Patients considered to have ADHD on initial screening were included in the second evaluation step, which comprised clinical history examination and the use of the Wechsler Intelligence Scale for Children, Multidimensional Anxiety Scale for Children, and Patient Health Questionnaire. Statistical analyses were performed using the chi-square and paired Student t tests. After data collection, 93 ADHD patients were included in arm 1; these patients showed a statistically higher prevalence of overweight/obesity than the control group (p < 0.05). During the second evaluation step, we found a statistically significant decrease (p < 0.01) in the BMI z-score of the individuals after methylphenidate treatment (mean duration of 2.6 years). However, there was no statistically significant effect on height (p=0,30). In addition, we found that 42.1% of patients who were initially overweight/obese evolved with improved nutritional status at the end of treatment. A total of 103 patients were evaluated in arm 2 of the study, among whom 37 (35.9%) found to have ADHD on initial screening were invited for the second evaluation step. Of these patients, 26 consented to participate in the second step. Two patients were excluded because they had cognitive impairment. ADHD was confirmed in 15 patients (16.67%). The main conclusions of the study were as follows: (1) prevalence of overweight/obesity among ADHD patients was statistically higher than that in the general population; (2) ADHD drug treatment did not affect the height of the patients, regardless of treatment duration, but caused a decrease in BMI z-score ; (3) prevalence of ADHD observed in the obese patient sample was statistically higher than that observed in the general population (16.7-95% CI 8.97-24.37% vs. 5.29- 95% CI=5.01-5.56%); (4) presence of other disorders such as depressive, anxiety, and sleep disorders was not sufficient to explain the association between ADHD and obesity; and (5) snoring is common in obese patients, both those with and without ADHD. The limitations of the study were as follows: (1) retrospective design of arm 1; (2) 11 of 37 patients in arm 2 diagnosed with ADHD on initial screening did not participate in the second evaluation step. Additionally, it would be interesting to further evaluate the occurrence of sleep disorders (using polysomnography) and auditory processing disorders

Objetivos: Diversos trabalhos documentaram a associação entre o fumo ativo na gestação e a redução no peso,comprimento e perímetro cefálico dos recémnascidos. Porém, existem controvérsias quanto aos efeitos do fumo passivo. Esse estudo buscou colaborar na elucidação sobre os efeitos da exposição da gestante ao fumo nas medidas antropométricas do recém-nascido. Métodos: Estudo transversal, que incluiu 200 parturientes, identificando a intensidade da exposição das mesmas ao fumo através da mensuração da cotinina urinária e do auto-relato sobre seu hábito tabágico e de seus familiares,o que possibilitou categorizá-las em não fumantes, fumantes passivas e fumantes ativas e posterior comparação com as medidas antropométricas dos recémnascidos. Resultados: Encontramos uma diferença estatisticamente significativa no peso,quando comparamos as fumantes passivas às não fumantes, -152g (IC95%: -285 a -18;P=0,026) e a diferença encontrada nas fumantes ativas foi de - 159g (IC95%: -301 a -16; P=0,029), em relação às não fumantes. Na medida do comprimento, observou-se uma diferença significativa entre as fumantes passivas, -0,8cm (IC95%: -1,4 a -0,2;P=0,012) em relação às não fumantes, e entre as fumantes ativas a diferença foi de -1,0cm (IC95%: -1,6 a -0,3;P=0,003), quando comparado às não fumantes. Quanto à medida do perímetro cefálico, não foram observadas diferenças significativas quando os grupos, das fumantes passivas e fumantes ativas, foram comparados ao grupo das não fumantes. Conclusões: Os resultados sugerem que o fumo passivo durante a gestação pode apresentar efeitos semelhantes aos do fumo ativo nas medidas antropométricas dos recém-nascidos. / Objectives: Several studies have documented the association between active smoking during pregnancy to weight, height and head circumference reduction on newborns. However, there are controversies about the passive smoking. The present study sough the elucidation of the effects of tobacco exposition of pregnant women on anthropometric measurements of newborns. Methods: Cross-sectional study, including 200 in labor women, identifying the intensity of their exposition to tobacco through the measurement of urine cotinine and the self reported information about the smoking habit of their relatives and themselves, what allowed us to classify them as non-smokers, passive smokers and active smokers and later the comparison with the anthropometric measurements of newborns. Results: We found a statistically significant difference in weight when comparing passive smokers to non-smokers, -152g (CI 95%: -285 to –18; P=0.026) and the difference found on active smokers was - 159g (CI 95%: -301 to 16; P=0.029) when compared to non-smokers. On the height measurements, a significant difference was found within the group of passive smokers, -0,8 cm (CI 95%: -1,4 to -0.2; P=0.012) comparing to the non-smokers group, within the smokers group the difference was -1,0 cm (CI 95%: -1,6 to -0.3; P=0.003) when compared to nonsmokers. About the measurements of head circumference, no was found a significant difference when the passive smokers and active smokers group was compared to non-smokers group. Conclusions: The results suggest that the passive smoking during pregnancy may present similar effects as the active smoking on the anthropometric measurements of newborns.

<p>Most human traits and common diseases have a complex genetic makeup involving more than one gene. The work presented in this thesis investigates standing body height and the common disease type 2 diabetes mellitus (T2DM). In study I we analyzed two single nucleotide polymorphisms (SNPs) in the TCF7L2 gene that had been shown to be associated with T2DM. Analysis was performed in the ULSAM population cohort of ~1500 males. We were able to replicate the association to type 2 diabetes and in addition to that we made a novel find, showing association between the risk alleles and increased proinsulin levels. In study II we analyzed four genes identified to be associated with T2DM in a genome-wide association study. We analyzed SNPs in these genes in the ULSAM population cohort and found an association between SNPs in the HHEX gene and insulin responses and insulin levels. </p><p>The aim of studies III-V was to identify genes affecting normal variation in standing body height. Using a candidate gene approach in study III, 17 genes were screened in the ULSAM population cohort using SNPs. A suggestive association of the ESR1 gene with height was found and confirmed as significant in males from the PIVUS population cohort. In study IV, as a part of the GenomEUtwin project, we performed genetic fine mapping of a linked locus for body height on the X-chromosome. By analyzing 1377 SNPs in 780 Finnish twins, we mapped a region spanning 65kb of this locus with linkage to body height in males. This region contains the GPC3 and PHF6 genes that have known connections to syndromes were standing body height is affected. In study V significant linkage and association to standing body height in males was found for the COL1A11 gene, using population cohorts from Finland and Iceland. </p>

Most human traits and common diseases have a complex genetic makeup involving more than one gene. The work presented in this thesis investigates standing body height and the common disease type 2 diabetes mellitus (T2DM). In study I we analyzed two single nucleotide polymorphisms (SNPs) in the TCF7L2 gene that had been shown to be associated with T2DM. Analysis was performed in the ULSAM population cohort of ~1500 males. We were able to replicate the association to type 2 diabetes and in addition to that we made a novel find, showing association between the risk alleles and increased proinsulin levels. In study II we analyzed four genes identified to be associated with T2DM in a genome-wide association study. We analyzed SNPs in these genes in the ULSAM population cohort and found an association between SNPs in the HHEX gene and insulin responses and insulin levels. The aim of studies III-V was to identify genes affecting normal variation in standing body height. Using a candidate gene approach in study III, 17 genes were screened in the ULSAM population cohort using SNPs. A suggestive association of the ESR1 gene with height was found and confirmed as significant in males from the PIVUS population cohort. In study IV, as a part of the GenomEUtwin project, we performed genetic fine mapping of a linked locus for body height on the X-chromosome. By analyzing 1377 SNPs in 780 Finnish twins, we mapped a region spanning 65kb of this locus with linkage to body height in males. This region contains the GPC3 and PHF6 genes that have known connections to syndromes were standing body height is affected. In study V significant linkage and association to standing body height in males was found for the COL1A11 gene, using population cohorts from Finland and Iceland.

Thesis--University of Oklahoma. / Includes bibliographical references (leaves 75-79).

Placental function is central for normal pregnancy and in many of the major pregnancy disorders. We used magnetic resonance imaging techniques to investigate placental function in normal pregnancy, in early and late preeclampsia and in intrauterine growth restriction. We also investigated maternal body mass index and height, as risk factors for preeclampsia. A high body mass index and a short maternal stature increase the risk of preeclampsia, of all severities. The association seems especially strong between short stature and early preeclampsia, and a high body mass index and late preeclampsia. (Study I) Using diffusion-weighted magnetic resonance imaging, we found that the placental perfusion fraction decreases with increasing gestational age in normal pregnancy. Also, the placental perfusion fraction is smaller in early preeclampsia, and larger in late preeclampsia, compared with normal pregnancies. That these differences are in opposite directions, suggests that there are differences in the underlying pathophysiology of early and late preeclampsia. (Study II) Using magnetic resonance spectroscopy, we found that the phosphodiester spectral intensity fraction and the phosphodiester/phosphomonoester spectral intensity ratio increases with increasing gestational age. Also, we found that the phosphodiester spectral intensity fraction and the phosphodiester/phosphomonoester spectral intensity ratio are higher in early preeclampsia, compared with early normal pregnancy. These findings indicate increased apoptosis with increasing gestational age in normal pregnancy, and increased apoptosis in early preeclampsia. (Study III) The placental perfusion fraction is smaller in intrauterine growth restriction than in normal pregnancy. Fetal growth, Doppler blood flow in maternal and fetal vessels, infant birth weight and plasma markers of placental function are all correlated to the placental perfusion fraction. The placental perfusion fraction examination seems therefore to offer a fast, direct estimate of the degree of placental dysfunction. (Study IV) In conclusion: Our findings in studies I-III all support the hypothesis of partly different pathophysiology between early and late preeclampsia, and suggest a strong link between early preeclampsia and placental dysfunction. Study IV shows that the placental perfusion fraction has potential to contribute to the clinical assessment of placental dysfunction.

Objetivos: Diversos trabalhos documentaram a associação entre o fumo ativo na gestação e a redução no peso,comprimento e perímetro cefálico dos recémnascidos. Porém, existem controvérsias quanto aos efeitos do fumo passivo. Esse estudo buscou colaborar na elucidação sobre os efeitos da exposição da gestante ao fumo nas medidas antropométricas do recém-nascido. Métodos: Estudo transversal, que incluiu 200 parturientes, identificando a intensidade da exposição das mesmas ao fumo através da mensuração da cotinina urinária e do auto-relato sobre seu hábito tabágico e de seus familiares,o que possibilitou categorizá-las em não fumantes, fumantes passivas e fumantes ativas e posterior comparação com as medidas antropométricas dos recémnascidos. Resultados: Encontramos uma diferença estatisticamente significativa no peso,quando comparamos as fumantes passivas às não fumantes, -152g (IC95%: -285 a -18;P=0,026) e a diferença encontrada nas fumantes ativas foi de - 159g (IC95%: -301 a -16; P=0,029), em relação às não fumantes. Na medida do comprimento, observou-se uma diferença significativa entre as fumantes passivas, -0,8cm (IC95%: -1,4 a -0,2;P=0,012) em relação às não fumantes, e entre as fumantes ativas a diferença foi de -1,0cm (IC95%: -1,6 a -0,3;P=0,003), quando comparado às não fumantes. Quanto à medida do perímetro cefálico, não foram observadas diferenças significativas quando os grupos, das fumantes passivas e fumantes ativas, foram comparados ao grupo das não fumantes. Conclusões: Os resultados sugerem que o fumo passivo durante a gestação pode apresentar efeitos semelhantes aos do fumo ativo nas medidas antropométricas dos recém-nascidos. / Objectives: Several studies have documented the association between active smoking during pregnancy to weight, height and head circumference reduction on newborns. However, there are controversies about the passive smoking. The present study sough the elucidation of the effects of tobacco exposition of pregnant women on anthropometric measurements of newborns. Methods: Cross-sectional study, including 200 in labor women, identifying the intensity of their exposition to tobacco through the measurement of urine cotinine and the self reported information about the smoking habit of their relatives and themselves, what allowed us to classify them as non-smokers, passive smokers and active smokers and later the comparison with the anthropometric measurements of newborns. Results: We found a statistically significant difference in weight when comparing passive smokers to non-smokers, -152g (CI 95%: -285 to –18; P=0.026) and the difference found on active smokers was - 159g (CI 95%: -301 to 16; P=0.029) when compared to non-smokers. On the height measurements, a significant difference was found within the group of passive smokers, -0,8 cm (CI 95%: -1,4 to -0.2; P=0.012) comparing to the non-smokers group, within the smokers group the difference was -1,0 cm (CI 95%: -1,6 to -0.3; P=0.003) when compared to nonsmokers. About the measurements of head circumference, no was found a significant difference when the passive smokers and active smokers group was compared to non-smokers group. Conclusions: The results suggest that the passive smoking during pregnancy may present similar effects as the active smoking on the anthropometric measurements of newborns.