This thesis offers a broad approach in elucidating biological risk factors, as well as psychological and social functioning in schizophrenia. The aims are as follows: (I) investigate the association between birth characteristics and schizophrenia, (II) study the association between levels of neurotransmitter neuropeptide Y (NPY) in cerebrospinal fluid (CSF), social function and longitudinal outcome in schizophrenia, (III) compare social functioning of patients with schizophrenia with their biological siblings and (IV) explore how siblings to patients with schizophrenia perceive the sibling relationship and their role. Paper I was a cohort analysis of 11,360 same-sexed twins in which obstetric records were used. Low birth weight and small head circumference were associated with later development of schizophrenia. To some extent the results persisted in the within-pair analyses conducted on 82 pairs discordant for schizophrenia. Fifty-six patients with schizophrenia were included in paper II. Levels of NPY in CSF correlated to social competence at index admission. For each standard deviation increase in baseline NPY, there was a concomitant increased risk of being unemployed, having moderate or severe symptoms or recent hospitalization at the 3-year follow-up. In paper III, social functioning was investigated using the Swedish version of the videotaped test Assessment of Interpersonal Problem Solving Skills (AIPSS) in 70 participants (25 patients with schizophrenia, 20 siblings and 25 randomly selected controls). The patients presented severe deficits in social functioning. The siblings expressed subtle impairments in nonverbal language but did not generally differ from the controls. To explore the siblings’ perspective on schizophrenia a qualitative study was conducted with interviews of 16 siblings in paper IV. A unifying major theme was an emotional sibling bond. Siblings developed several coping patterns, including avoidance, isolation, normalization, care giving and grieving. A third major theme consisted of the fear of inheriting schizophrenia. In conclusion, fetal growth, altered levels of NPY in CSF and subtle impairments in nonverbal social behavior might be important risk factors in schizophrenia. Patients with schizophrenia revealed extensive impaired social functioning, and from the siblings’ perspective, a brother or sister’s diagnosis of schizophrenia seems to have a profound psychological impact on the siblings.

O Ferro (Fe) atua em vários processos metabólicos, principalmente do neurodesenvolvimento, cujo conteúdo corporal é ainda de difícil determinação, podendo sofrer influência de fatores como a prematuridade e o Crescimento Intrauterino Restrito (CIUR). Este estudo objetivou descrever a evolução hematológica e do conteúdo de Fe em Recém-Nascidos (RN) de Termo (T) e Pré-Termo Tardios (PT T), com e sem CIUR, em aleitamento materno exclusivo, durante os primeiros dois meses de vida, analisando a influência da prematuridade, presença de CIUR e evolução nutricional. Incluiu-se 95 RN: Grupo 1A, 25 RN PT T sem CIUR; Grupo 1B, 24 RN PT T com CIUR; Grupo 2A, 21 RN T sem CIUR e Grupo 2B, 25 RN T com CIUR. A presença de CIUR foi determinada pelo peso nascimento <P5 para a curva de Alexander. Determinou-se ao nascimento, com um e dois meses de idade: medidas antropométricas (peso, comprimento e perímetro cefálico) e Índice de Massa Corporal (IMC), Hemoglobina (Hb), Hematócrito (Ht), Reticulócitos (Ret), Volume Corpuscular Médio (VCM), Hemoglobina Corpuscular Média (HCM), Variação da Distribuição das Células Vermelhas (RDW), Capacidade de Ligação do Fe (CLFe), Saturação de Transferrina (SatTf), Fe sérico e Ferritina. As análises estatísticas basearam-se: Teste não paramétrico de Kolmogorov-Smirnov para testar normalidade. ANOVA One-Way ou Kruskall-Wallis para a análise das variáveis contínuas; Teste Exato de Fischer ou Qui-quadrado para comparação de proporções; Coeficiente de Pearson para análise de correlações. Odds Ratio e respectivos 95% Intervalos de Confiança para avaliação do risco de anemia. Significância de 5%. As medidas antropométricas e IMC evoluíram com aumento ao longo do tempo (p<0,001). Os valores hematológicos reduziramse ao longo do tempo (p<0,001). A Hb foi maior nos grupos com CIUR ao nascimento e no T sem CIUR com dois meses (p<0,001). A variação relativa da Hb entre dois meses e nascimento foi maior no PT T com CIUR e menor no T sem CIUR (p<0,001). As reservas de Fe modificaram-se em todos os grupos. A CLFe foi maior no T sem CIUR ao nascimento (p<0,001) e com um mês vida (p=0,008). O Fe foi maior no T sem CIUR ao nascimento (p<0,001) e menor no PT T com CIUR que os grupos RN T com um mês de vida (p=0,007). A ferritina não apresentou diferenças entre os grupos. A Resumo _____________________________________________________________________________________________ xxxii SatTf foi maior no T sem CIUR ao nascimento (p<0,001) e a variação relativa da SatTf superior no PT T com CIUR (p=0,001). A Hb correlacionouse com o peso em todos os grupos (p<0,001) e a Ferritina nos PT T sem CIUR (r=-0,3250; p=0,0068) e com CIUR (r=-0,3280; p=0,0063). A anemia foi mais frequente nos grupos com CIUR (90,5% PT T com CIUR e 90% T com CIUR), sendo maior entre os RN de T com CIUR em relação aos sem CIUR (OR=16,500; p=0,0013) e nos PT T com CIUR em relação aos T sem CIUR (OR=17,417; p=0,0005). Provavelmente, as diferentes evoluções das reservas de Fe e a maior redução da hemoglobina no PT T com CIUR deveram-se à influência da prematuridade e do CIUR sobre seu crescimento. O CIUR parece ser o fator mais importante no desenvolvimento de anemia em RN em aleitamento materno exclusivo, pois somente os grupos com CIUR apresentaram risco de anemia aos dois meses de idade / Iron (Fe) acts in several metabolic processes, especially neurodevelopmental ones, which body content is still the difficult access and could be influenced by factors, such as, prematurity and Intrauterine Growth Restriction (IUGR). This study aimed at describing the hematological evolution and iron body content in Term (T) and Late Pre-Term (LPT) Newborns (NB), with and without IUGR, exclusive breastfeeding, during the first two months of life, and analyzing the prematurity influence, UGR presence and nutritional evolution. 95 NB were included: Group 1A, 25 LPTNB without IUGR, Group 1B, 24 LPTNB with IUGR, Group 2A, 21 TNB without IUGR and Group 2B, 25 TNB with IUGR. The presence of IUGR was determined by birth weight <P5 of Alexander Curve. At birth, one and two months of age were determined: anthropometric measures (weight, length, cephalic circumference) and Body Mass Index (BMI), Hemoglobin (Hb), Hematocrit (Ht), Reticulocytes, mean corpuscular volume, mean corpuscular hemoglobin, red blood cells distribution width, serum Fe, ferritin, Iron Binding Capacity (IBC) and Transferrin Saturation (TfSat). Statistical analysis was based on: Kolmogorov-Smirnov Test was used to verify normality. ANOVA One-Way or Kruskal-Wallis Test for continuous variables analysis, Fisher\'s Exact Test or Chi-Square Test for Comparison of proportions, Pearson Coefficient for correlations analysis, Odds Ratio and 95% Confidence Intervals for evaluation of anemia risk, Multiple Regression Stepwise Backward and Binary Logistic Regression for risk factors of Hb and anemia analysis at two months. Significance was set at 5%. The anthropometric measures and BMI increased along the time (p<0.001) and the hematological values decreased (p<0.001). The Hb was higher in groups with IUGR at birth and in T without IUGR at 2 months (p<0.001). The relative variation between 2 months and birth was higher in LPT with IUGR and lower in T without IUGR (p<0.001). The iron stores were modified in all the groups along the time. The IBC was higher in T without IUGR at birth (p<0,001) and 1 month of life (p=0.008). The serum iron was higher in T without IUGR at birth (p<0.001) and lower in LPT with IUGR than in the T NB groups at 1 month at life (p=0.007). Ferritin levels did not differ among the groups. The TfSat levels were higher in T without IUGR at birth (p<0.001) and the relative variation of TfSat was higher in LPT with IUGR (p=0.001). The Hb correlated with weight in all the groups (p<0.001) and the Ferritin in LPT without IUGR (r=-0.3250; p=0.0068) and with IUGR (r=-0.3280; p=0.0063). The anemia was more frequent in IUGR groups (90.5% in LPT with IUGR and 90% in T with IUGR). The anemia risk was hugher in T with IUGR than in without IUGR (OR=12.37, p=0.0022) and in LPT with IUGR in relation to T without IUGR (OR=13.06, p=0.0019). The different evolutions of the iron stores and the higher reduction of Hb in LPT with IUGR could be an effect of prematurity and IUGR influence on their growth. The IUGR must be the most important anemia development factor in exclusive breastfeeding NB, because only groups with IUGR showed risk for anemia at two months of age

Orientadores: Ricardo Barini, Lourenço Sbragia Neto / Tese (doutorado) - Universidade Estadual de Campinas. Faculdade de Ciencias Medicas / Made available in DSpace on 2018-11-27T12:29:22Z (GMT). No. of bitstreams: 1 Bueno_MarciaPereira_D.pdf: 2898828 bytes, checksum: 2c6dcaa4a20ec185bea4b47114c30a0e (MD5) Previous issue date: 2010 / Resumo: A restrição do crescimento intrauterino (RCIU) limita o desenvolvimento fetal adequado aumentando a morbidade e mortalidades perinatais. Os mecanismos fetais adaptativos na RCIU podem desencadear alterações endócrinas e metabólicas que explicariam a ocorrência de doenças na idade adulta. O objetivo do estudo foi avaliar na RCIU experimental pela ligadura da artéria uterina se existem alterações na morfometria e histologia do fígado, intesti no e rins e se existem diferenças na expressão dos receptores de insulina, IR-(3, IRS-1, IRS-2, IGF-IR(3 no grupo de fetos submetidos à RCIU. O presente experimento foi submetido ao Comitê de Ética e Experimentação Animal da Universidade Estadual de Campinas (CEEA-UNICAMP) e aprovado como projeto de pesquisa N° 1644-1. Para realização do estudo utilizamos fetos de ratas Sprague Dawley divididos em 3 grupos. Grupo I (RCIU) - 40 fetos submetidos à ligadura da artéria uterina unilateral com 18,5 dias de gestação, Grupo II (Controle-RCIU) - 40 fetos do corno oposto ao da ligadura da artéria uterina e Grupo III (Controle Externo) - 40 fetos sem procedimento cirúrgico ou alimentar. Os resultados mostraram no modelo experimental de RCIU uma diminuição do peso corporal (PC), hepático (PH) e intestinal (PI) (p<0,01) no grupo RCIU, as relações entre PH/PC, PI/PC, PR/PC foram mantidas, fetos RC IU tem diminuição das camadas submucosas e mucosas intestinais (p<0,05); diminuição da camada cortical renal e do número de glomérulos, com aumento do volume glomerular (p<0,05). Na RCIU encontramos menor expressão hepática do IR-(3, IRS-1 e IRS-2, menor expressão do IRS-2 no intestino e rins e maior expressão do IGF-IR(3 em todos os tecidos. O modelo experimental estudado causou uma RCIU simétrica com alterações morfométricas e do metabolismo da glicose que poderiam justificar no futuro um maior risco de doenças metabólicas / Abstract: Intrauterine growth restriction (IUGR) limits appropriate fetal development increasing morbidity and perinatal mortality. Adaptive mechanisms in fetal IUGR may leave to endocrine and metabolic alterations that could explain the occurrence of diseases in adulthood. The aim of this study was to evaluate whether experimental IUGR by uterine artery ligation causes changes in morphology and histology of the liver, intestines and kidneys. We also evaluated if there were differences in the expression of insulin receptors, IR-(3, IRS-1, IRS-2, IGF-IR(3 of fetuses subjected to IUGR. This experiment was submitted to the Ethics and Animal Experimentation of the Campinas State University (UNICAMP CEEA) and was approved as a research project No. 1644-1. The study used fetuses Sprague-Dawley rats divided into 3 groups. Group I (IUGR) - 40 fetuses who underwent uterine artery ligation sided with 18.5 days of pregnancy Group II (Control-IUGR) - 40 fetuses of the horn opposite to the uterine artery ligation, and Group III (External Control) - 40 fetuses without surgery or food The results showed the experimental model of IUGR, a reduction in body weight (BW), liver (PH) and intestine (PI) (p <0.01) in IUGR, the relationship between PH/PC, PI/PC, PR/PC have been retai ned, IUGR fetuses have reduced layers of the intestinal mucosa and submucosa (p<0,05), decreased renal cortical layer and the glomerular number and increased volume rate (p<0,05). In IUGR found lower hepatic expression of IR-(3, IRS-1 and IRS-2, reduced expression of IRS-2 in the intestine and kidney and increased expression of IGF-IR(3 in all tissues. The experimental model studied caused a symmetrical IUGR with histological changes and glucose metabolism that could justify a greater risk of metabolic diseasesin the future / Doutorado / Ciencias Biomedicas / Doutor em Tocoginecologia

O Ferro (Fe) atua em vários processos metabólicos, principalmente do neurodesenvolvimento, cujo conteúdo corporal é ainda de difícil determinação, podendo sofrer influência de fatores como a prematuridade e o Crescimento Intrauterino Restrito (CIUR). Este estudo objetivou descrever a evolução hematológica e do conteúdo de Fe em Recém-Nascidos (RN) de Termo (T) e Pré-Termo Tardios (PT T), com e sem CIUR, em aleitamento materno exclusivo, durante os primeiros dois meses de vida, analisando a influência da prematuridade, presença de CIUR e evolução nutricional. Incluiu-se 95 RN: Grupo 1A, 25 RN PT T sem CIUR; Grupo 1B, 24 RN PT T com CIUR; Grupo 2A, 21 RN T sem CIUR e Grupo 2B, 25 RN T com CIUR. A presença de CIUR foi determinada pelo peso nascimento <P5 para a curva de Alexander. Determinou-se ao nascimento, com um e dois meses de idade: medidas antropométricas (peso, comprimento e perímetro cefálico) e Índice de Massa Corporal (IMC), Hemoglobina (Hb), Hematócrito (Ht), Reticulócitos (Ret), Volume Corpuscular Médio (VCM), Hemoglobina Corpuscular Média (HCM), Variação da Distribuição das Células Vermelhas (RDW), Capacidade de Ligação do Fe (CLFe), Saturação de Transferrina (SatTf), Fe sérico e Ferritina. As análises estatísticas basearam-se: Teste não paramétrico de Kolmogorov-Smirnov para testar normalidade. ANOVA One-Way ou Kruskall-Wallis para a análise das variáveis contínuas; Teste Exato de Fischer ou Qui-quadrado para comparação de proporções; Coeficiente de Pearson para análise de correlações. Odds Ratio e respectivos 95% Intervalos de Confiança para avaliação do risco de anemia. Significância de 5%. As medidas antropométricas e IMC evoluíram com aumento ao longo do tempo (p<0,001). Os valores hematológicos reduziramse ao longo do tempo (p<0,001). A Hb foi maior nos grupos com CIUR ao nascimento e no T sem CIUR com dois meses (p<0,001). A variação relativa da Hb entre dois meses e nascimento foi maior no PT T com CIUR e menor no T sem CIUR (p<0,001). As reservas de Fe modificaram-se em todos os grupos. A CLFe foi maior no T sem CIUR ao nascimento (p<0,001) e com um mês vida (p=0,008). O Fe foi maior no T sem CIUR ao nascimento (p<0,001) e menor no PT T com CIUR que os grupos RN T com um mês de vida (p=0,007). A ferritina não apresentou diferenças entre os grupos. A Resumo _____________________________________________________________________________________________ xxxii SatTf foi maior no T sem CIUR ao nascimento (p<0,001) e a variação relativa da SatTf superior no PT T com CIUR (p=0,001). A Hb correlacionouse com o peso em todos os grupos (p<0,001) e a Ferritina nos PT T sem CIUR (r=-0,3250; p=0,0068) e com CIUR (r=-0,3280; p=0,0063). A anemia foi mais frequente nos grupos com CIUR (90,5% PT T com CIUR e 90% T com CIUR), sendo maior entre os RN de T com CIUR em relação aos sem CIUR (OR=16,500; p=0,0013) e nos PT T com CIUR em relação aos T sem CIUR (OR=17,417; p=0,0005). Provavelmente, as diferentes evoluções das reservas de Fe e a maior redução da hemoglobina no PT T com CIUR deveram-se à influência da prematuridade e do CIUR sobre seu crescimento. O CIUR parece ser o fator mais importante no desenvolvimento de anemia em RN em aleitamento materno exclusivo, pois somente os grupos com CIUR apresentaram risco de anemia aos dois meses de idade / Iron (Fe) acts in several metabolic processes, especially neurodevelopmental ones, which body content is still the difficult access and could be influenced by factors, such as, prematurity and Intrauterine Growth Restriction (IUGR). This study aimed at describing the hematological evolution and iron body content in Term (T) and Late Pre-Term (LPT) Newborns (NB), with and without IUGR, exclusive breastfeeding, during the first two months of life, and analyzing the prematurity influence, UGR presence and nutritional evolution. 95 NB were included: Group 1A, 25 LPTNB without IUGR, Group 1B, 24 LPTNB with IUGR, Group 2A, 21 TNB without IUGR and Group 2B, 25 TNB with IUGR. The presence of IUGR was determined by birth weight <P5 of Alexander Curve. At birth, one and two months of age were determined: anthropometric measures (weight, length, cephalic circumference) and Body Mass Index (BMI), Hemoglobin (Hb), Hematocrit (Ht), Reticulocytes, mean corpuscular volume, mean corpuscular hemoglobin, red blood cells distribution width, serum Fe, ferritin, Iron Binding Capacity (IBC) and Transferrin Saturation (TfSat). Statistical analysis was based on: Kolmogorov-Smirnov Test was used to verify normality. ANOVA One-Way or Kruskal-Wallis Test for continuous variables analysis, Fisher\'s Exact Test or Chi-Square Test for Comparison of proportions, Pearson Coefficient for correlations analysis, Odds Ratio and 95% Confidence Intervals for evaluation of anemia risk, Multiple Regression Stepwise Backward and Binary Logistic Regression for risk factors of Hb and anemia analysis at two months. Significance was set at 5%. The anthropometric measures and BMI increased along the time (p<0.001) and the hematological values decreased (p<0.001). The Hb was higher in groups with IUGR at birth and in T without IUGR at 2 months (p<0.001). The relative variation between 2 months and birth was higher in LPT with IUGR and lower in T without IUGR (p<0.001). The iron stores were modified in all the groups along the time. The IBC was higher in T without IUGR at birth (p<0,001) and 1 month of life (p=0.008). The serum iron was higher in T without IUGR at birth (p<0.001) and lower in LPT with IUGR than in the T NB groups at 1 month at life (p=0.007). Ferritin levels did not differ among the groups. The TfSat levels were higher in T without IUGR at birth (p<0.001) and the relative variation of TfSat was higher in LPT with IUGR (p=0.001). The Hb correlated with weight in all the groups (p<0.001) and the Ferritin in LPT without IUGR (r=-0.3250; p=0.0068) and with IUGR (r=-0.3280; p=0.0063). The anemia was more frequent in IUGR groups (90.5% in LPT with IUGR and 90% in T with IUGR). The anemia risk was hugher in T with IUGR than in without IUGR (OR=12.37, p=0.0022) and in LPT with IUGR in relation to T without IUGR (OR=13.06, p=0.0019). The different evolutions of the iron stores and the higher reduction of Hb in LPT with IUGR could be an effect of prematurity and IUGR influence on their growth. The IUGR must be the most important anemia development factor in exclusive breastfeeding NB, because only groups with IUGR showed risk for anemia at two months of age

Abstract not available

BACKGROUND: Fetal growth is a complex process which depends on nutrient and oxygen availability and transport from the mother to the fetus across the placenta. This involves hormones and growth factors as well as maternal and fetal genes. The failure of the fetus to reach his or her full potential for growth is called Intrauterine Growth Restriction (IUGR) and implies risks for adverse short‐ and long‐ term outcomes. Imprinted genes are a specific subset of genes that display, in mammals and flowering plants, monoallelic expression depending on the parental origin of the allele. The regulation of imprinted expression depends on epigenetic mechanisms, a subset of heritable marks that have the ability to regulate DNA functions without altering its sequence. Imprinted genes tend to cluster in the genome due to coordinated regulation through Imprinting Control Centers, usually in the form of Differentially Methylated Regions between the paternally and maternally inherited alleles. Studies in both animals and humans as well as imprinting syndromes have uncovered a role for this group of genes in prenatal growth. Two imprinted genes (PLAGL1 and HYMAI) have been described in the 6q24 locus. Genetic and epigenetic defects in this region relate to the Transient Neonatal Diabetes Mellitus 1 phenotype, including severe growth restriction. We aimed to study the involvement of this region in non‐syndromic IUGR. PARTICIPANTS AND METHODS: One hundred placental samples from a cohort of healthy term singletons, fetal tissues from fifty‐four first trimester terminations and one hundred placental samples from healthy and complicated pregnancies of different gestational ages were used to analyze the role of the 6q24 region in normal fetal growth and IUGR, respectively. Relevant clinical data was obtained after informed consent. The methylation status of the 6q24 CpG islands was studied by array technology and bisulfite sequencing in normal term placenta and in first trimester fetal tissues. Methylation levels in the PLAGL1 DMR in healthy and IUGR placentas were compared by pyrosequencing. Allelic origin of expression was assessed by heterozygous DNA/cDNA SNP analysis. Levels of expression of imprinted transcripts were analyzed by qRT‐PCR. RESULTS: PLAGL1 P1, HYMAI and two newly described PLAGL1 isoforms (P3 and P4) were the only transcripts subjected to genomic imprinting in the investigated 6q24 region. Correspondingly, the CpG island associated to the P1 promoter was the only differentially methylated region. There was no correlation between PLAGL1 expression in the placenta and fetal size in uneventful pregnancies. In placentas from IUGR gestations, expression of HYMAI was significantly higher than in those from normally grown fetuses. Levels of expression of PLAGL1 were lower in IUGR and correlated positively and significantly with the presence of IUGR in placentas from girls, but not boys. These changes in expression were not mediated by Loss of Imprinting or abnormalities in the levels of methylation of the promoter‐associated DMR, but possibly by a change in regulatory posttranscriptional mechanisms, as suggested by the loss of correlation of PLAGL1 P1 and HYMAI expression in IUGR. CONCLUSIONS: Imprinted expression in the 6q24 region is limited to the PLAGL1/HYMAI locus, maybe due to demarcation of this region by CTCF boundaries. Intrauterine Growth Restriction is associated to abnormalities in expression of PLAGL1 and HYMAI in the placenta, which are not due to LOI or methylation changes.

Objective. Most biomarker studies of maternal smoking have been based on a single blood or urinary cotinine value, which is inadequate in capturing maternal tobacco exposure over the entire pregnancy. This thesis used maternal hair biomarkers to investigate the association between maternal active and passive smoking, and birthweight for gestational age (BW for GA). / Methods. Subjects were 444 term controls drawn from 5,337 participants of a multi-centre nested case-control study of preterm birth in Montreal. Maternal hair, collected after delivery, was measured for average nicotine and cotinine concentration across the pregnancy, assuming hair growth of 1 cm/month. The BW for GA z-score used Canadian population-based standards. Multiple linear regression was used to assess effects on the z-score, after controlling for potential confounders. / Results. In regression models for maternal active smoking analysis, the addition of hair nicotine to models containing either self-report or hair cotinine or both self-report and cotinine explained significantly more variance in the BW for GA z-score (p=0.009, p=0.017, and p=0.033, respectively). In maternal passive smoking analysis, no significant effect of ETS on BW for GA was found using hair biomarkers. / Conclusion. These results indicate that hair biomarkers are sensitive tools capable of predicting reductions in birthweight for maternal active smoking. The stronger results obtained for nicotine are reflective of the fact that hair nicotine is a better measure of maternal smoking, but it could also suggest that nicotine plays an aetiologic role in affecting foetal growth.

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

Submitted by LUIZA TAVARES CARNEIRO SANTIAGO null (luiza_tcs@hotmail.com) on 2016-05-23T14:20:11Z No. of bitstreams: 1 Dissertação Mestrado - Luiza Tavares Carneiro Santiago.pdf: 1233741 bytes, checksum: bb457286bd0f32f04ccc8f34ad966dc1 (MD5) / Approved for entry into archive by Felipe Augusto Arakaki (arakaki@reitoria.unesp.br) on 2016-05-24T12:46:40Z (GMT) No. of bitstreams: 1 santiago_ltc_me_bot.pdf: 1233741 bytes, checksum: bb457286bd0f32f04ccc8f34ad966dc1 (MD5) / Made available in DSpace on 2016-05-24T12:46:40Z (GMT). No. of bitstreams: 1 santiago_ltc_me_bot.pdf: 1233741 bytes, checksum: bb457286bd0f32f04ccc8f34ad966dc1 (MD5) Previous issue date: 2016-02-29 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / INTRODUÇÃO: O efeito da idade gestacional e do crescimento fetal nos imunocomponentes do leite materno ainda é pouco conhecido. OBJETIVO: Determinar a quantidade de citocinas no colostro em função da idade gestacional e do crescimento fetal. MÉTODO: Estudo transversal, envolvendo mães de recém-nascidos prematuros (PT) e de termo (T), nascidos na Maternidade da Faculdade de Medicina de Botucatu – UNESP, em 2014-2015. Critério de inclusão: gestação única; ausência de diabetes materno, ou uso de medicações/drogas ilícitas, sorologias negativas; recém-nascido com peso adequado (AIG) ou pequeno para idade gestacional (PIG) e sem malformação. Excluídos: não obtenção do colostro, mastite, uso de medicamento pela puérpera. Foram estudados 4 grupos: PT-PIG (n=18), PT-AIG (n=42), T-PIG (n=45), T-AIG (controle, n=42). No colostro coletado entre 24-72 horas pós-nascimento, foram dosadas as citocinas (IL-1β, IL-6, IL-8, IL-10, IL-12 e TNF-α) por citometria de fluxo. Na comparação entre grupos utilizou-se o Qui-quadrado ou teste Exato de Fisher, ANOVA, e Correlação de Pearson. RESULTADOS: As características maternas foram semelhantes nos 4 grupos. A idade gestacional média foi 34 semanas nos prematuros e 39 semanas nos termos. Os níveis de citocinas do colostro não diferiram entre os grupos de termo e pretermo. O grupo T-PIG apresentou maior quantidade de citocinas comparado aos demais. Nos 4 grupos houve correlação entre as citocinas, especialmente nos T-PIG. CONCLUSÃO: A quantidade de citocinas no colostro foi influenciada pelo crescimento fetal e não pela idade gestacional. / INTRODUCTION: The effect of gestational age and foetal growth in the imunno componentes of human milk is not well stablished. OBJECTIVE: To determine cytokines levels in colostrum according to gestational age and foetal growth. METHOD: Cross-sectional study with mothers of term (T) and preterm (PT) infants, with birth weight appropriate-for-gestational age (AGA) and small-for-gestational age (SGA), born at the Maternity of Botucatu School of Medicine- UNESP, during 2014 -2015. Inclusion criteria were: single gestation; absence of diabetes mellitus; no maternal use of medications or illicit drugs; negative maternal serology; and newborn without malformation. Mothers with mastitis, or use of medication, or failure to obtain colostrum, were excluded. Four groups were studied: PT-SGA (n=18), PT-AGA (n=42), T-SGA (n=45), and T-AGA (control, n=42). Colostrum was collected between 24-72 hours after birth, and cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12 and TNF-α) were measured by flow cytometry. Chi-square or Fisher's exact test, ANOVA and Pearson's correlation were used to evaluate differences among the groups. RESULTS: Maternal characteristics did not differ between groups. The mean gestational age was 34 and 39 weeks for preterm and term groups. Cytokines levels in the colostrum were not different between term and preterm groups. However cytokines levels were significantly higher in colostrum from mothers of T-SGA. A positive correlation between cytokines was found in all groups, especially in T-SGA. CONCLUSION: Cytokines levels in colostrum was influenced by foetal growth, while the correlation between cytokines varied according to gestational age and foetal growth. / FAPESP: 2014/12784-9