A world-wide series of epidemiological studies has demonstrated that there is an association between being born small and the risk of visceral obesity, a more central deposition of subcutaneous fat and insulin resistance in adult life. In the lamb, intrauterine growth restriction (IUGR) results in a low birth weight and an increased visceral fat mass by 45d of postnatal life. In this thesis I have investigated the effect of IUGR on adipose tissue development and function during fetal and early postnatal life in the sheep. IUGR was induced by removal of the majority of endometrial caruncles in non pregnant ewes prior to mating which resulted in the subsequent placental restriction of fetal growth (PR). Fetal blood samples were collected from 116d gestation and visceral perirenal adipose tissue (PAT) collected from PR and control fetuses at 145d. In lambs IUGR was defined as a birth weight less than 2 standard deviations below the mean of a cohort of singleton Merino lambs. Blood samples were collected throughout the first 3 weeks of life and PAT and subcutaneous adipose tissue (SAT) was collected at 21 d. It was determined whether IUGR alters the expression of genes which regulate adipogenesis (IGF1, IGFR1, IGF2, IGFR2, PPARy, and RXRα), adipocyte metabolism (LPL, G3PDH, GAPDH) and adipokine signalling (leptin, adiponectin) in adipose tissue depots before and after birth using qRT-PCR. PR fetuses were hypoglycaemic, hypoinsulinaemic, hypoxic, and had a lower body weight than Control fetuses. The expression of both IGF1 and leptin mRNA in PAT, the major fetal adipose depot, was lower in the PR fetuses, although there was no difference in the expression of other adipokine or adipogenic genes in PAT between PR and control fetuses. Thus restriction of placental and hence fetal substrate supply results in decreased IGF1 and leptin expression in fetal visceral adipose tissue which may alter the functional development of the perirenal fat depot and contribute to altered leptin signalling in the growth restricted newborn and the subsequent emergence of an increased visceral adiposity. At 21d of postnatal life there was no increase in the relative mass of perirenal or subcutaneous fat in IUGR lambs compared with controls. Thus, this study has investigated the effect of IUGR on the development of adipose tissue prior to the development of an obese phenotype. At 21d of life there was a sex specific effect of IUGR on the expression of PPARy and leptin mRNA in perirenal visceral fat such that PPARy and leptin mRNA expression was decreased in male IUGR lambs, but not females. Interestingly PAT mass was greater in females than males, independent of birth weight. Plasma insulin concentrations during the first 24h after birth predicted the size of the adipocytes and expression of adiponectin in visceral adipose tissue in both males and females at 21d. Thus, the nutritional environment before, and immediately after birth, may program adipocyte growth and gene expression in visceral adipose tissue. The differential effect of sex and birth weight on PPARy and leptin expression in visceral fat may be important in the subsequent development of visceral obesity and the insulin resistant phenotype in later life. At 21d of life there was no difference between Control and IUGR lambs in the relative mass of subcutaneous fat, or the expression of PPARy, RXRα, leptin, adiponectin, LPL, G3PDH, and GAPDH in subcutaneous fat at 21d of life. We have shown that the growth of the subcutaneous fat depot is related to plasma glucose, insulin and leptin concentrations, and to the development of perirenal fat. Thus, in contrast to perirenal adipose tissue, the postnatal, but not the fetal nutritional environment, programs subcutaneous adipocyte growth and gene expression. This thesis speculates that there may be a factor secreted from visceral fat that influences the development of the subcutaneous fat depot. At 21d of life there was also an effect of sex, but not IUGR, on the expression of IGF mRNA in adipose tissue. Male lambs had a higher expression of IGF1 mRNA in both PAT and SAT, and a higher expression of IGF1R and IGF2R in SAT compared with female lambs. It is likely that these differences in IGF mRNA levels reflect sexual dimorphism of the GH-IGF axis. When male and female lambs were combined there was a higher expression of IGF1 mRNA in SAT compared with PAT, and a higher expression of IGF2, IGF1R and IGF2R mRNA in PAT compared with SAT. These differences in IGF mRNA expression provide a potential mechanism to explain the sex and depot specific variations in mitogenic potency of IGF1 and proliferative capacities of preadipocytes, the regional variation in adipocyte metabolism, and the difference in incidence of visceral obesity between men and women in adult life. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1347421 / Thesis (Ph.D.) - University of Adelaide, School of Molecular and Biomedical Science, 2008

A world-wide series of epidemiological studies has demonstrated that there is an association between being born small and the risk of visceral obesity, a more central deposition of subcutaneous fat and insulin resistance in adult life. In the lamb, intrauterine growth restriction (IUGR) results in a low birth weight and an increased visceral fat mass by 45d of postnatal life. In this thesis I have investigated the effect of IUGR on adipose tissue development and function during fetal and early postnatal life in the sheep. IUGR was induced by removal of the majority of endometrial caruncles in non pregnant ewes prior to mating which resulted in the subsequent placental restriction of fetal growth (PR). Fetal blood samples were collected from 116d gestation and visceral perirenal adipose tissue (PAT) collected from PR and control fetuses at 145d. In lambs IUGR was defined as a birth weight less than 2 standard deviations below the mean of a cohort of singleton Merino lambs. Blood samples were collected throughout the first 3 weeks of life and PAT and subcutaneous adipose tissue (SAT) was collected at 21 d. It was determined whether IUGR alters the expression of genes which regulate adipogenesis (IGF1, IGFR1, IGF2, IGFR2, PPARy, and RXRα), adipocyte metabolism (LPL, G3PDH, GAPDH) and adipokine signalling (leptin, adiponectin) in adipose tissue depots before and after birth using qRT-PCR. PR fetuses were hypoglycaemic, hypoinsulinaemic, hypoxic, and had a lower body weight than Control fetuses. The expression of both IGF1 and leptin mRNA in PAT, the major fetal adipose depot, was lower in the PR fetuses, although there was no difference in the expression of other adipokine or adipogenic genes in PAT between PR and control fetuses. Thus restriction of placental and hence fetal substrate supply results in decreased IGF1 and leptin expression in fetal visceral adipose tissue which may alter the functional development of the perirenal fat depot and contribute to altered leptin signalling in the growth restricted newborn and the subsequent emergence of an increased visceral adiposity. At 21d of postnatal life there was no increase in the relative mass of perirenal or subcutaneous fat in IUGR lambs compared with controls. Thus, this study has investigated the effect of IUGR on the development of adipose tissue prior to the development of an obese phenotype. At 21d of life there was a sex specific effect of IUGR on the expression of PPARy and leptin mRNA in perirenal visceral fat such that PPARy and leptin mRNA expression was decreased in male IUGR lambs, but not females. Interestingly PAT mass was greater in females than males, independent of birth weight. Plasma insulin concentrations during the first 24h after birth predicted the size of the adipocytes and expression of adiponectin in visceral adipose tissue in both males and females at 21d. Thus, the nutritional environment before, and immediately after birth, may program adipocyte growth and gene expression in visceral adipose tissue. The differential effect of sex and birth weight on PPARy and leptin expression in visceral fat may be important in the subsequent development of visceral obesity and the insulin resistant phenotype in later life. At 21d of life there was no difference between Control and IUGR lambs in the relative mass of subcutaneous fat, or the expression of PPARy, RXRα, leptin, adiponectin, LPL, G3PDH, and GAPDH in subcutaneous fat at 21d of life. We have shown that the growth of the subcutaneous fat depot is related to plasma glucose, insulin and leptin concentrations, and to the development of perirenal fat. Thus, in contrast to perirenal adipose tissue, the postnatal, but not the fetal nutritional environment, programs subcutaneous adipocyte growth and gene expression. This thesis speculates that there may be a factor secreted from visceral fat that influences the development of the subcutaneous fat depot. At 21d of life there was also an effect of sex, but not IUGR, on the expression of IGF mRNA in adipose tissue. Male lambs had a higher expression of IGF1 mRNA in both PAT and SAT, and a higher expression of IGF1R and IGF2R in SAT compared with female lambs. It is likely that these differences in IGF mRNA levels reflect sexual dimorphism of the GH-IGF axis. When male and female lambs were combined there was a higher expression of IGF1 mRNA in SAT compared with PAT, and a higher expression of IGF2, IGF1R and IGF2R mRNA in PAT compared with SAT. These differences in IGF mRNA expression provide a potential mechanism to explain the sex and depot specific variations in mitogenic potency of IGF1 and proliferative capacities of preadipocytes, the regional variation in adipocyte metabolism, and the difference in incidence of visceral obesity between men and women in adult life. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1347421 / Thesis (Ph.D.) - University of Adelaide, School of Molecular and Biomedical Science, 2008

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 5 uppsatser.

Thesis (M.P.H.M. (Primary Health Care Management))--Mahidol University, 2008. / LICL has E-Thesis 0038 ; please contact computer services.

Thesis (M.S.)--University of Michigan, 1989.

Thesis (M.Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 1999. / Typescript. Bibliography: leaves 204-215.

Thesis (M.S.)--University of Michigan, 1989.

Objetivo: Avaliar a prevalência de retinopatia da prematuridade (ROP) e os fatores de risco em recém-nascidos de muito baixo peso internados em uma Unidade de Tratamento Intensivo Neonatal. Métodos: Estudo transversal incluindo todos os recém-nascidos com peso ao nascimento ≤ 1500g e/ou idade gestacional ≤ 32 semanas, admitidos na UTI Neonatal do Hospital de Clínicas de Porto Alegre, entre outubro de 2002 e março de 2004. Os pacientes foram submetidos a exame de fundo de olho sob oftalmoscopia binocular indireta na 6ª semana de vida. Foi realizado tratamento a laser nos que atingiram a doença limiar. Resultados: Foram estudados 114 recém-nascidos. Em oitenta e três pacientes não se diagnosticou retinopatia da prematuridade, dezoito apresentaram retinopatia da premauridade 1, sete retinopatia da prematuridade 2, seis ROP em doença limiar. A prevalência de ROP foi de 27,2% (IC 95%: 19,28 – 36,32) afetando 31 recém-nascidos, e a prevalência de retinopatia da prematuridade que atingiu doença limiar foi de 5,26% (IC 95%: 1,96 – 11,10) afetando 6 pacientes. Verificou-se retinopatia da prematuridade em 50% dos pacientes com peso inferior a 1000g e em 71,5% dos recém-nascidos com idade gestacional inferior a 28 semanas. A idade gestacional e o peso de nascimento foram significativamente menores nos pacientes com ROP em comparação aos normais. Conclusões: Embora os resultados deste estudo mostrem que a prevalência encontrada foi semelhante a encontrada na literatura, a ocorrência de retinopatia da prematuridade ainda é alta nos recém-nascidos de muito baixo peso. O desenvolvimento da retinopatia da prematuridade foi inversamente proporcional ao peso e a idade gestacional ao nascimento. / Objective: To evaluate the prevalence of retinopathy of prematurity (ROP) and risk factors in very low birth weight infants admitted to a Neonatal Intensive Care Unit. Methods: A cross sectional study investigating all newborn infants with birth weights ≤ 1,500g and/or gestational ages ≤ 32 weeks, admitted to Neonatal Intensive Care Unit of Hospital de Clínicas de Porto Alegre, from October 2002 to March 2004. Patients underwent indirect binocular ophthalmoscopy of the fundus at six weeks postpartum. Infants who progressed to threshold disease were given laser therapy. Results: One hundred and fourteen patients were studied. Eighty-three patients were not diagnosed with retinopathy of prematurity, 18 had stage I retinopathy of prematurity, 7 stage II retinopathy of prematurity and 6 patients had threshold retinopathy of prematurity. The prevalence of retinopathy of prematurity was 27.2% (CI 95%:19.28-36.32) affecting 31 newborn infants, and the prevalence of retinopathy of prematurity progressing to threshold disease was 5.26% (CI 95%: 1.96-11.10) affecting six patients. Retinopathy of prematurity was confirmed in 50% of the patients with weights below 1.000g and 71,5% of newborn infants born of gestational ages less than 28 weeks. Gestational age and birth weight were significantly lower among patients with retinopathy of prematurity than among those without. Conclusions: Although the results of this study demonstrate that the observed prevalence was similar to described in literature, this ROP frequency remains elevated among very low birth weight infants. The development of retinopathy of prematurity was inversely proportional to birth weight and gestational age at birth.

O baixo peso ao nascer (BPN) possui grande impacto na mortalidade neonatal, assim como no desenvolvimento de complicações futuras, como obesidade, hipertensão arterial sistêmica e resistência insulínica, condições relacionadas à doença cardiovascular aterosclerótica, principal causa de morbimortalidade no mundo. O objetivo desta pesquisa foi estudar o perfil clínico, metabólico, hormonal e inflamatório relacionado à doença cardiovascular em crianças pré-púberes de BPN, bem como avaliar a influência do BPN, prematuridade e restrição do crescimento intrauterino nas variáveis de interesse. Realizou-se estudo transversal com 58 crianças de dois a sete anos de BPN, sendo 32 prematuros adequados para idade gestacional (AIG), 17 prematuros pequenos para idade gestacional (PIG), 9 a termo PIG e 38 crianças de peso ao nascer adequado, nascidas no Hospital Universitário Pedro Ernesto da Universidade do Estado do Rio de janeiro, oriundas do Ambulatório de Pediatria Geral deste mesmo hospital. Frequências de perfil lipídico alterado, assim como medianas das variações no Z escore de peso e estatura do nascimento até o momento do estudo, do Z escore de índice de massa corporal (ZIMC), da circunferência da cintura, da pressão arterial sistólica e diastólica, do colesterol total, da lipoproteína de baixa densidade, da lipoproteína de baixa densidade, do triglicerídeo, da glicose, insulina, do Homeostasis Assessment for Insulin Resistance (HOMA-IR), da leptina, da adiponectina, da interleucina 6 e da proteína C reativa foram comparadas entre os dois grupos. No grupo de BPN, avaliou-se a correlação entre estas mesmas variáveis e peso de nascimento, idade gestacional, Z escores de peso e comprimento de nascimento e variações no Z escore de peso e comprimento até o primeiro ano, e até o momento do estudo, com ajuste para idade e sexo. O grupo de BPN apresentou maiores variações nos Z escore de peso (p-valor 0,0002) e estatura (p-valor 0,003) até o momento do estudo e menores níveis de adiponectina (p-valor 0,027). Não houve correlação entre as variáveis associadas ao risco cardiovascular e o grau de baixo peso, prematuridade ou crescimento intrauterino retardado. Os níveis de ZIMC (p-valor 0,0001), circunferência da cintura (p-valor 0,0008), pressão arterial diastólica (p-valor 0,046), insulina (p-valor 0,02), HOMA-IR (p-valor 0,016) e leptina (p-valor= 0,0008) se correlacionaram com a variação no Z escore de peso no primeiro ano. O ZIMC (p-valor 0,042) também se correlacionou com a variação do Z escore de comprimento no primeiro ano. Houve ainda correlação entre o ZIMC (p-valor 0,0001), circunferência da cintura (p-valor 0,0001), pressão arterial sistólica (p-valor 0,022), pressão arterial diastólica (p-valor 0,003), insulina (p-valor 0,007), HOMA-IR (p-valor 0,005) e leptina (p-valor 0,0001) com a variação no Z escore de peso até o momento do estudo. Os achados mostram que este grupo de crianças pré-púberes com BPN ainda não diferem do grupo de crianças nascidas com peso adequado exceto pelos níveis de adiponectina, sabidamente um protetor cardiovascular. Em relação às análises de correlação, nem o peso ao nascer, tampouco a prematuridade ou CIUR, influenciaram as variáveis de interesse. No entanto, fatores pós-natais como o ganho pondero-estatural se correlacionaram com o ZIMC, circunferência da cintura, pressão arterial sistólica e diastólica, insulina, HOMA-IR e leptina. Mais estudos são necessários para avaliar se os achados configuram risco cardiovascular aumentado neste grupo de pacientes. / Low birth weight (LBW) has been associated with increased neonatal mortality and long-term risks for central obesity, hypertension, insulin resistance, conditions related to cardiovascular disease, the leading cause of morbidity and mortality worldwide. The objective of this study was to evaluate clinical, metabolic, hormonal and inflammatory profile associated with cardiovascular risk in prepubertal LBW and to determine the influence of birth weight, prematurity and fetal growth restriction on this variables of interest. A cross-sectional study of 58 LBW children, between 2-7 years, including 32 preterm appropriate for gestational age (AGA), 17 preterm small for gestational age (SGA), 9 term SGA and 38 term AGA children born at the Pedro Ernesto University Hospital of the State University of Rio de Janeiro, derived from pediatric outpatient clinics of the same hospital. Frequency of altered lipid profile, as well as the median of change in weight and height SD score (SDS) between birth and the time of the study, body mass index SDS (BMI SDS), waist circumference, systolic and diastolic blood pressure, total cholesterol, low density lipoprotein, low density lipoprotein, triglyceride, glucose, insulin, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), leptin, adiponectin, interleukin-6 and C-reactive protein were compared between these two groups. In the LBW group, the correlation between these same variables and birth weight, gestational age, birth weight and length SDS and change in weight and length SDS between birth and the first year, and up to the time of the study, were evaluated after adjustment for age and sex. The LBW group showed greater variation in weight (p-value = 0.0002) and height SDS (p = 0.003) up to the time of the study and lower levels of adiponectin (p-value = 0.027). There were no correlation between the variables associated with cardiovascular risk and the degree of LBW, prematurity or fetal growth restriction. BMI SDS levels (p-value = 0.0001), waist circumference (p-value = 0.0008), diastolic blood pressure (p = 0.046), insulin (p = 0.02), HOMA -IR (p = 0.016) and leptin (p-value = 0.0008) correlated with the change in weight SDS in the first year. The BMI SDS (p-value = 0.042) also correlated with the change in length SDS in the first year. There was correlation between BMI SDS (p-value = 0.0001), waist circumference (p-value = 0.0001), systolic blood pressure (p = 0.022), diastolic blood pressure (p = 0.003), insulin (p = 0.007), HOMA-IR (p = 0.005) and leptin (p-value = 0.0001) with the change in weight SDS until the time of the study. These findings shows that prepubertal LBW children, do not differ from the group of children born with adequate weight, except for the levels of adiponectin, a known cardiovascular protective adipocitocin. Regarding the correlation analysis, neither birth weight, prematurity or fetal growth restriction influenced the variables of interest. However, postnatal factors, such as weight and height gain correlated with variables related to cardiovascular risk. Further studies are necessary to assess whether these findings constitute increased cardiovascular risk in this group of patients.