Branched-chain amino acids (BCAA) are a group of essential amino acids consisting of leucine, isoleucine, and valine. Leucine, in particular, has signaling functions affecting protein and energy metabolism. Plasma leucine concentration is positively correlated with obesity and associated metabolic disorders. We set out to test the hypothesis that metabolic dysfunction from high fat diets precedes dysfunctional BCAA metabolism. First, BCAA were supplemented to neonatal pigs for 4 weeks to evaluate whether the anabolic signaling function of leucine could increase muscle growth when fed for a longer duration than in previous studies. Neither normal pigs nor low birth weight pigs, which have naturally impaired muscle growth, grew better in response to BCAA supplementation, despite low birth weight pigs expressing less of the leucine sensing protein Sestrin2 in skeletal muscle. Furthermore, high plasma BCAA concentrations caused by the experimental diets had no effect on adiposity, liver fat accumulation, or expression of genes related to fatty acid synthesis, mitochondrial biogenesis, or energy expenditure in the pigs' livers. Having produced strong evidence that long term BCAA supplementation neither improves lean growth nor causes abnormal fat metabolism, we then tested whether fat supplementation changes BCAA metabolism. Pigs were fed milk replacer formula with either low energy (Control), or high energy from long-chain fatty acids (LCFA) or medium-chain fatty acids (MCFA) for 22 days. Although high fat diets did not increase plasma BCAA concentrations, the MCFA diet in particular caused metabolic changes which could lead to fatty liver disease and decreased oxidative BCAA disposal. Expression of fatty acid synthesizing genes were increased in the livers of pigs fed MCFA formula compared to Control and LCFA formula. Oxidation of α-ketoisocaproic acid was decreased in liver homogenate of pigs fed MCFA and LCFA formulas compared to Control. Additionally, hepatic oxidation of α-ketoisovalerate was decreased, and plasma concentration of α-ketoisovalerate was consequently increased, in pigs fed MCFA formula compared to Control, with LCFA formula causing intermediate results. In future research, it would be valuable to feed high MCFA formula for a longer period of time to determine whether nonalcoholic fatty liver disease will develop, and whether plasma BCAA concentrations will increase due to decreased oxidation. Overall, these studies concluded that long term BCAA supplementation does not increase muscle growth in neonatal pigs, but there is also no indication that they cause obesity or dysfunctional fat metabolism. On the other hand, high fat diets cause impairments in BCAA catabolism which may precede elevated plasma BCAA concentrations. / Doctor of Philosophy / Branched-chain amino acids (BCAA) are essential amino acids which are abundant in plant and animal proteins. In addition, the BCAA leucine has functions in protein and energy metabolism. Leucine consumption induces a signal to build new muscle protein. However, leucine concentration is also higher in blood plasma of obese individuals than in non-obese individuals, which has caused uncertainty regarding the safety of leucine consumption. In order to demonstrate that leucine does not cause obesity, we set out to test the hypothesis that high fat diets cause decreased breakdown of BCAA. In the first study, we tested whether one month of BCAA supplementation could increase muscle growth in neonatal pigs. Neither normal pigs nor low birth weight pigs, which have naturally impaired muscle growth, grew better in response to BCAA supplementation, despite low birth weight pigs expressing less of a leucine sensing protein in skeletal muscle. Furthermore, BCAA supplementation caused higher BCAA concentrations in blood plasma, but did not cause pigs to gain more fat, or cause any changes in liver fat metabolism. Having produced strong evidence that BCAA supplementation neither improves lean growth nor causes abnormal fat metabolism, we then tested whether fat supplementation changes BCAA metabolism. Pigs were fed milk replacer formula which was either low calorie (Control), or high calorie from animal fat, which is rich in long-chain fatty acids (LCFA) or high calorie from coconut oil, which is rich in medium-chain fatty acids (MCFA). Although high fat diets did not increase blood plasma BCAA concentrations, the MCFA formula in particular caused changes which could lead to fatty liver disease and decreased breakdown of BCAA. Genes which synthesize new fatty acids were increased in the livers of pigs fed MCFA formula compared to those fed LCFA and Control formulas. Furthermore, liver samples taken from pigs fed the MCFA and LCFA formulas were less able to fully break down metabolites of leucine compared to pigs fed the Control formula. In addition, liver samples from MCFA fed pigs were less able to fully break down metabolites of the BCAA valine, which led to higher concentrations of that metabolite in the blood plasma of pigs fed MCFA formula compared to pigs fed LCFA or Control formula. In the future, it would be valuable to feed a high MCFA formula for a longer period of time to determine whether nonalcoholic fatty liver disease will develop, and whether blood plasma BCAA concentrations will increase due to decreased breakdown. Overall, these studies concluded that long term BCAA supplementation does not increase muscle growth in neonatal pigs, but there is also no indication that they cause obesity or dysfunctional fat metabolism. On the other hand, high fat diets cause impairments in BCAA breakdown which may lead to elevated BCAA concentrations in blood plasma.

The neonatal period in mammals is characterized by high growth rates and is dominated by skeletal muscle hypertrophy. Low birth weight (LBWT) neonates experience restricted growth and development of skeletal muscle, leading to metabolic perturbations later in life. The overall hypothesis of this dissertation was that in utero disturbances in glucose metabolism and increased energy requirements predisposes LBWT neonatal pigs to metabolic disturbances after birth. We sought to increase growth of skeletal muscle and improve glucose production through increasing dietary energy and to determine the changes in glucose catabolism and metabolic flexibility in different skeletal muscle fiber types in LBWT neonates. Piglets were considered normal birth weight (NBWT) and LBWT when birth weight was within 0.5 SD and below 2 SD of the litter average, respectively. Increasing dietary energy increased lean deposition in the longissimus dorsi (LD) in both NBWT and LBWT neonates. Although glucose rate of appearance was greater in LBWT compared to their NBWT sibling, glucose concentrations were reduced in LBWT compared to NBWT pigs, regardless of diet fed. Postprandial glucose concentrations were lower in LBWT compared to NBWT pigs, regardless of diet fed, although rate of appearance did not differ between them. This would suggest that glucose is being absorbed in the peripheral tissues to be utilized. However, expression of enzymes related to glycolysis were downregulated in both the soleus and LD of LBWT compared to NBWT neonatal pigs. In addition, expression of enzymes related to the catabolism of glucose in the serine biosynthetic pathway were decreased in both the soleus and LD muscles of LBWT compared to NBWT neonatal pigs. Expression of the pentose phosphate pathway was slightly increased in LBWT compared to NBWT siblings in both muscle types. Increased expression of pyruvate dehydrogenase 4 was exhibited in both the soleus and LD of LBWT pigs compared to NBWT siblings. This would indicate a switch in fuel utilization to more fatty acid oxidation. By contrast, CO2 production from the oxidation of palmitate was reduced in LBWT compared with NBWT pigs along with reduced oxidation of glucose and pyruvate. In conclusion, lipid supplementation increased growth at the expense of fat deposition in the liver of NBWT and LBWT pigs. However, supplementing with fat did not increase glucose production due to the contribution of glycerol remaining constant. Hypoglycemia cannot be attributed to greater catabolism in skeletal muscle due to decreased expression of glycolytic genes and the addition of fatty acids did not spare glucose oxidation in skeletal muscle of LBWT pigs. / PHD / During the neonatal period animals display the fastest growth rates, especially pertaining to muscle growth. Muscle development in low birth weight (LBWT) is restricted, leading not only to impaired postnatal growth but increases the risk for developing metabolic diseases later in life such as obesity and type 2 diabetes. LBWT is also characterized by decreased glucose concentrations and decreased body fat content at birth. In the present studies we sought to increase growth and improve glucose production by supplementing with a high energy diet and to compare the changes in glucose catabolism in different skeletal muscle fiber types along with analyzing the ability to switch fuel substrates in LBWT and NBWT neonatal pigs. Increasing dietary energy increased longissimus dorsi (LD) weight as a percentage of bodyweight, regardless of growth status. In addition, during fasting glucose production was higher in LBWT compared to their NBWT siblings, regardless of diet. However, glucose concentration in LBWT were lower compared to NBWT neonatal pigs. Although glucose concentrations were lower in LBWT compared to NBWT pigs after a meal, glucose production rate was unchanged among LBWT and NBWT siblings fed either a high or low energy diet. This suggests that glucose uptake is increased in peripheral tissues of LBWT pigs. However, enzymes related to glycolysis in the LD and soleus of LBWT pigs had lower expression than their NBWT sibling. In addition, the enzyme responsible for the shift in fuel selection, pyruvate dehydrogenase kinase 4 (PDK4) was highly expressed in LBWT compared to NBWT neonatal pigs in both the LD and soleus. This would suggest a switch in glucose oxidation to fatty acid oxidation in the skeletal muscle of LBWT neonatal pigs. However, oxidation of fatty acids in both the soleus and LD of LBWT was reduced compared to NBWT neonatal pigs. In conclusion, lipid supplementation increased growth at the expense of lipid deposition in the liver and did not increase glucose production. Reduced glucose concentrations are not due to greater catabolism in skeletal muscle due to decreased expression of glycolytic genes and the addition of fatty acids did not spare glucose oxidation in the skeletal muscle of LBWT pigs.

The neonatal period in mammals is characterized by high rates of growth, attributed to rapid myonuclear accretion and protein deposition in muscle. Low-birth-weight (LBWT) neonates experience restricted muscle development, which leads to impaired postnatal growth and metabolic disorders later in life. The overall hypothesis of this dissertation was that dysfunction of myogenic satellite cells and aberrant regulation of protein synthesis and degradation signaling predispose LBWT neonatal pigs to slower postnatal growth. We sought to determine the proliferation and differentiation of satellite cells (SCs) derived from skeletal muscle of LBWT neonatal pigs and to elucidate the cellular mechanisms that regulate protein synthesis and degradation in LBWT pig muscles. Newborn pigs were considered as normal-birth-weight (NBWT) or LBWT when weight at birth was within 0.5 SD and below 2 SD of litter average respectively. SCs isolated from longissimus dorsi (LD) muscle of NBWT and LBWT neonatal pigs displayed similar proliferation rates. Fusion was modestly diminished in SCs from muscle of LBWT pigs compared with their NBWT siblings, suggesting SCs were not intrinsically different between the two groups and were unlikely a major contributor to the impaired muscle growth of LBWT pigs. Plasma and muscle insulin-like growth factor (IGF)-I was diminished in LBWT compared with NBWT pigs. In addition, reduced activation of key components of IGF-I downstream signaling pathway in LBWT pigs muscle may lead to diminished translation initiation signaling and thus decreased protein synthesis in these animals. However, IGF-I receptor expression and myostatin signaling inversely correlated to LBWT, indicating they may participate in compensatory responses for the reduction in protein synthesis signaling. Expression of eukaryotic initiation factor (eIF) 4F complex subunits, eIF4E, eIF4G, and eIF4A was reduced in LBWT compared with NBWT pigs. This would suggest that diminished translation initiation signaling in skeletal muscle of LBWT pigs is the main factor that predisposes LBWT pigs to slower growth rates in the neonatal period. In contrast, changes in protein degradation signaling do not appear to affect protein turnover in LBWT neonatal pigs. / PHD

A meningite bacteriana no período neonatal é uma doença grave, associada à mortalidade elevada e seqüelas em cerca de 12 a 29% dos sobreviventes. Nos recém-nascidos com peso ao nascimento < 2500 g, o risco de adquirir meningite é três vezes superior àqueles com peso >= 2500 g e, entre neonatos de muito baixo peso (< 1500 g), o risco é 17 vezes maior. Objetivo: Geral: descrever o quadro clínico e as complicações da meningite bacteriana em dois grupos de recém-nascidos, considerados de acordo com o peso de nascimento (= 2500 g). Específico: descrever e comparar os agentes etiológicos, a freqüência de sinais e sintomas neurológicos e de complicações, a mortalidade e a duração do tratamento nos dois grupos. Métodos: Estudo observacional de 87 recém-nascidos com meningite bacteriana, admitidos na Unidade de Cuidados Intensivos Neonatais do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de 11 anos (janeiro de 1994 a dezembro de 2004). Os dados foram obtidos através da análise de prontuários. Na análise estatística foram utilizados o teste exato de Fisher e teste não paramétrico de Mann Whitney. Resultados: Foram identificadas bactérias no líquor em 39% dos pacientes, sendo 50% bactérias Gram-positivas e 50% Gram-negativas. A maioria dos neonatos apresentou sinais e sintomas inespecíficos: febre (63,2%), irritabilidade (31%), letargia (26,4%). Os achados neurológicos ocorreram em 35,3% dos casos. As complicações ocorreram em 48,2% dos neonatos, principalmente convulsões (23%), hemorragia intracraniana (14,9%) e hidrocefalia (13,8%) com mortalidade de 11,5 %. Na comparação entre evolução clínica e peso de nascimento observou-se associação entre peso >= 2500 g e convulsão (p=0,047), peso >= 2500 g e fontanela abaulada (p=0,019), bactéria no LCR e complicações (p=0,008) e bactéria no LCR e óbitos (p=0,043). Conclusões: Os agentes etiológicos mais freqüentemente identificados no LCR foram as enterobactérias (41%), seguidas de Streptococcus B (17,5%), Streptococcus não B (17,5%), Staphylococcus aureus (11,7%), Neisseria meningitidis (8,8%) e Enterococcus faecalis (3,0%), não havendo diferença entre tipo de bactérias e peso de nascimento. Os sinais e sintomas predominantes foram inespecíficos, com achados neurológicos em 35% dos casos. A freqüência maior de sintomas neurológicos nos recém-nascidos com peso >= 2500 g, sugere maior grau de maturidade do sistema nervoso central nestas crianças. Embora a mortalidade tenha sido inferior à observada em estudos anteriores no mesmo Serviço, a freqüência de complicações foi alta, independentemente do peso de nascimento. A presença de bactéria no LCR associou-se à maior freqüência de convulsões e mortalidade. A necessidade de manutenção do tratamento por tempo mais prolongado nos recém-nascidos de baixo peso sugere maior gravidade da doença neste grupo de neonatos. / Bacterial meningitis in the neonatal period is a severe disease, associated to elevated mortality and sequelae in around 12 to 29% of the survivors. Newborns whose birth weight is < 2,500g have a 3-fold increase in the risk of acquiring meningitis when compared to those whose weight is >= 2,500; among those with very low birth weight (< 1,500g), the risk increases 17-fold. Objectives: General: to describe the clinical picture and the complications of bacterial meningitis in two groups of newborns, considered according to birth weight (< 2,500g or >= 2,500g). Specific: to describe and compare the etiological agents, the frequency of neurological signs and symptoms and complications, mortality rate and duration of treatment in both groups. Methods: Observational study of 87 newborns with bacterial meningitis, admitted at the Neonatal Intensive Care Unit (NICU) of Instituto da Criança of Hospital das Clínicas of the University of São Paulo School of Medicine, during an 11-year period (January 1994 to December 2004). The data were obtained through the analysis of hospital files. Statistical analysis was carried out with Fisher\'s exact test and the non-parametric Mann Whitney test. Results: Bacteria were identified in the cerebrospinal fluid (CSF) of 39% of the patients, with 50% of them being Gram-positive and 50%, Gram-negative. Most neonates presented unspecific signs and symptoms: fever (63.2%), irritability (31%), and lethargy (26.4%). The neurological findings occurred in 35.3% of the cases. Complications occurred in 48.2% of the neonates, and were mainly seizures (23%), intracranial hemorrhage (14.9%) and hydrocephalus (13.8%) with a mortality rate of 11.5%. At the comparison between clinical evolution and birth weight, associations between weight >= 2,500g and seizures (p=0.047), weight >= 2,500g and concave fontanel (p=0.019), bacteria in the CSF and complications (p=0.008) and bacteria in the CSF and death (p=0.043) were observed. Conclusions: The etiological agents most often identified in the CSF were enterobacteria (41%), followed by B Streptococcus (17.5%), non-B Streptococcus (17.5%), Staphylococcus aureus (11.7%), Neisseria meningitidis (8.8%) and Enterococcus faecalis(3.0%), with no statistical difference between the type of bacteria and birth weight. The predominant signs and symptoms were unspecific, with neurological findings in 35% of the cases. The higher frequency of neurological signs and symptoms in newborns with birth weight >= 2,500g suggest a higher degree of central nervous system maturity in these infants. Although the mortality was lower than that observed in previous studies at the same Service, the frequency of complications was high, regardless of birth weight. The presence of bacteria in the CSF was associated to a higher frequency of seizures and mortality. The need for prolonged treatment in newborns with low birth weight suggests higher disease severity in this group of neonates.

A meningite bacteriana no período neonatal é uma doença grave, associada à mortalidade elevada e seqüelas em cerca de 12 a 29% dos sobreviventes. Nos recém-nascidos com peso ao nascimento < 2500 g, o risco de adquirir meningite é três vezes superior àqueles com peso >= 2500 g e, entre neonatos de muito baixo peso (< 1500 g), o risco é 17 vezes maior. Objetivo: Geral: descrever o quadro clínico e as complicações da meningite bacteriana em dois grupos de recém-nascidos, considerados de acordo com o peso de nascimento (= 2500 g). Específico: descrever e comparar os agentes etiológicos, a freqüência de sinais e sintomas neurológicos e de complicações, a mortalidade e a duração do tratamento nos dois grupos. Métodos: Estudo observacional de 87 recém-nascidos com meningite bacteriana, admitidos na Unidade de Cuidados Intensivos Neonatais do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de 11 anos (janeiro de 1994 a dezembro de 2004). Os dados foram obtidos através da análise de prontuários. Na análise estatística foram utilizados o teste exato de Fisher e teste não paramétrico de Mann Whitney. Resultados: Foram identificadas bactérias no líquor em 39% dos pacientes, sendo 50% bactérias Gram-positivas e 50% Gram-negativas. A maioria dos neonatos apresentou sinais e sintomas inespecíficos: febre (63,2%), irritabilidade (31%), letargia (26,4%). Os achados neurológicos ocorreram em 35,3% dos casos. As complicações ocorreram em 48,2% dos neonatos, principalmente convulsões (23%), hemorragia intracraniana (14,9%) e hidrocefalia (13,8%) com mortalidade de 11,5 %. Na comparação entre evolução clínica e peso de nascimento observou-se associação entre peso >= 2500 g e convulsão (p=0,047), peso >= 2500 g e fontanela abaulada (p=0,019), bactéria no LCR e complicações (p=0,008) e bactéria no LCR e óbitos (p=0,043). Conclusões: Os agentes etiológicos mais freqüentemente identificados no LCR foram as enterobactérias (41%), seguidas de Streptococcus B (17,5%), Streptococcus não B (17,5%), Staphylococcus aureus (11,7%), Neisseria meningitidis (8,8%) e Enterococcus faecalis (3,0%), não havendo diferença entre tipo de bactérias e peso de nascimento. Os sinais e sintomas predominantes foram inespecíficos, com achados neurológicos em 35% dos casos. A freqüência maior de sintomas neurológicos nos recém-nascidos com peso >= 2500 g, sugere maior grau de maturidade do sistema nervoso central nestas crianças. Embora a mortalidade tenha sido inferior à observada em estudos anteriores no mesmo Serviço, a freqüência de complicações foi alta, independentemente do peso de nascimento. A presença de bactéria no LCR associou-se à maior freqüência de convulsões e mortalidade. A necessidade de manutenção do tratamento por tempo mais prolongado nos recém-nascidos de baixo peso sugere maior gravidade da doença neste grupo de neonatos. / Bacterial meningitis in the neonatal period is a severe disease, associated to elevated mortality and sequelae in around 12 to 29% of the survivors. Newborns whose birth weight is < 2,500g have a 3-fold increase in the risk of acquiring meningitis when compared to those whose weight is >= 2,500; among those with very low birth weight (< 1,500g), the risk increases 17-fold. Objectives: General: to describe the clinical picture and the complications of bacterial meningitis in two groups of newborns, considered according to birth weight (< 2,500g or >= 2,500g). Specific: to describe and compare the etiological agents, the frequency of neurological signs and symptoms and complications, mortality rate and duration of treatment in both groups. Methods: Observational study of 87 newborns with bacterial meningitis, admitted at the Neonatal Intensive Care Unit (NICU) of Instituto da Criança of Hospital das Clínicas of the University of São Paulo School of Medicine, during an 11-year period (January 1994 to December 2004). The data were obtained through the analysis of hospital files. Statistical analysis was carried out with Fisher\'s exact test and the non-parametric Mann Whitney test. Results: Bacteria were identified in the cerebrospinal fluid (CSF) of 39% of the patients, with 50% of them being Gram-positive and 50%, Gram-negative. Most neonates presented unspecific signs and symptoms: fever (63.2%), irritability (31%), and lethargy (26.4%). The neurological findings occurred in 35.3% of the cases. Complications occurred in 48.2% of the neonates, and were mainly seizures (23%), intracranial hemorrhage (14.9%) and hydrocephalus (13.8%) with a mortality rate of 11.5%. At the comparison between clinical evolution and birth weight, associations between weight >= 2,500g and seizures (p=0.047), weight >= 2,500g and concave fontanel (p=0.019), bacteria in the CSF and complications (p=0.008) and bacteria in the CSF and death (p=0.043) were observed. Conclusions: The etiological agents most often identified in the CSF were enterobacteria (41%), followed by B Streptococcus (17.5%), non-B Streptococcus (17.5%), Staphylococcus aureus (11.7%), Neisseria meningitidis (8.8%) and Enterococcus faecalis(3.0%), with no statistical difference between the type of bacteria and birth weight. The predominant signs and symptoms were unspecific, with neurological findings in 35% of the cases. The higher frequency of neurological signs and symptoms in newborns with birth weight >= 2,500g suggest a higher degree of central nervous system maturity in these infants. Although the mortality was lower than that observed in previous studies at the same Service, the frequency of complications was high, regardless of birth weight. The presence of bacteria in the CSF was associated to a higher frequency of seizures and mortality. The need for prolonged treatment in newborns with low birth weight suggests higher disease severity in this group of neonates.

This diploma thesis should sketch quantitative research of early enteral nutrition at newborns with low birth weight under 1500 grams at specialized department - neonatology in České Budějovice. Research in this diploma thesis is focused on evaluating of implemetation level according to current recommendations neonatology for the start of early enteral nutrition at premature babies. In the theoretical part of the diploma thesis we try to describe all things that include the issue of premature babies care. Next chapters deal with differences of premature baby in relation to nutrition. The nutrition of the newborn with very low birth weight is provided immediately after parenteral delivery. Quantitative research definately prefers the start of enteral nutrition in the first few hours after delivery. Goal of this strategy is to completely replace the parenteral nutrition as soon as possible. Goal of this diploma thesis is to descibe quantitative research with implementing of the enteral nutrition at newborns with birth weight under 1500 grams at specialized neonatology departments and to identify the most important differences from current recommendations for this field of care. Considering the set goal there was used the quantitative research for this diploma thesis. To get the data to create the research, secundar analysis of the data from nursing documentation of our research team was used. Through the quantitative research we try to demonstrate lack of starts with early enteral nutrition at premature babies with birth weight under 1500 grams in the 2012 and 2013. Secundar analysis of the date was made during my working experience at neonatology department in České Budějovice. Data needed for this research were systematically written into prepared chart created in Microsoft Excel. After entering all necessary data in the table, they were subsequently created graphs that reflect the real situation examined issues. After identifying the most significant differences from the current recommendations for this area of care deficiencies are subsequently provided to the department of neonatology in the České Budějovice for future improvement strategy early initiation of enteral nutrition in premature infants in this weight category, was written Decalogue of practical recommendations for optimization of enteral nutrition for preterm infants nurses working in the neonatal intensive care. The research file was created by 139 respondents (newborns with low birth weight under 1500 grams). This file is created by newborns born from 1 January 2012 to 31 December 2013 which means during two years.

Stockholm Neonatal Project is a longitudinal population-based study of children born prematurely in 1988-93, with a very low birth weight (&lt;1500 g), who have been followed prospectively from birth through adolescence. A matched control group was recruited at age 5 ½ years. The overall aim was to investigate long-term developmental outcome, paying particular attention to executive functions (EF) in relation to degree of prematurity, birth weight and medical risks. Study I showed a disadvantage in visuo-motor development at 5 ½ years, especially among the preterm boys. Visuo-motor skills were highly related to IQ, and also to EF. In Study II, neuropsychological profiles typical of preterm children and term born children, respectively, were identified through cluster analysis. The general level of performance corresponded well with IQ, motor functions and parental education in both groups, but preterm children had overall lower results and exhibited greater variability across domains. Study III showed that extremely preterm birth (w. 23-27) per se poses a risk for cognitive outcome at age 18, particularly for EF, and that perinatal medical complications add to the risk. By contrast, adolescents born very preterm (w. 28-31) performed just as well as term-born controls in all cognitive domains. However, adolescents born moderately preterm (w. 32-36) and small for gestational age showed general cognitive deficits. Study IV found that cognitive development was stable over time, with parental education and EF at 5 ½ years as significant predictors for cognitive outcome at age 18. Among preterm children, perinatal medical risks and being small for gestational age had a continued negative impact on cognitive development from 5 ½ to 18 years. Study V demonstrated that neuropsychological scoring of Bender drawings, developed in study I, predicted cognitive outcome in adolescence, indicating that the method  may be useful in developmental screening around school entry. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Submitted.</p>

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.

Background: Health policies that seek to improve pregnancy outcomes focus on increasing the availability and access to prenatal care (PNC) services based on studies that support an association between insufficient PNC and adverse birth outcomes. These studies employ PNC utilization indices that measure the adequacy of PNC use, but these indices fail to account for the content or specific components of PNC. Objectives: The purpose of this study was to utilize PRAMS and birth certificate data to evaluate the content and quality of PNC in Virginia, and its impact on preterm birth and maternal postpartum health behaviors. Methods: Data was from the 2007 Virginia Pregnancy Risk Assessment Monitoring System (PRAMS). This population-based data is representative of all Virginia women who have had a live birth recently and included 1,236 female participants. Results: Inadequate PNC was associated with nearly a three-fold increase in risk of low birth weight (OR = 2.8, 95% CI = 1.5, 5.2), but not preterm birth. Women with adequate plus PNC were more likely to deliver infants who were preterm (OR = 10.2, 95% CI = 4.3, 24.4) and low birth weight (OR = 6.3, 95% CI = 4.2, 9.4). After adjusting for method of payment, income, and reported problems during pregnancy, women with lower income and no private insurance were more likely to have inadequate PNC (OR = 1.4, 95% CI = 0.5, 4.1) and (OR = 8.8, 95% CI = 1.3, 59.8), respectively. Provider discussions were not different based on adequacy of PNC. In addition, among women who received adequate PNC, those whose providers discussed postpartum birth control use were 4.5 times more likely to use birth control after delivery compared to women who did not receive education (95% CI=1.7, 11.8). Conclusion: The lack of strong associations between adequacy of PNC and birth outcomes indicate that there are other factors (intergenerational, stress, cultural) that may play a more prominent role in predicting maternal and infant health.

Introdução: A poluição atmosférica é um problema de saúde pública em todo o mundo. Os efeitos adversos produzidos pelos poluentes do ar estão fortemente associados com as doenças respiratórias e cardiovasculares e, com magnitude inferior, aos desfechos da gestação. Objetivo: estimar a relação entre os poluentes PM10 e O3 e o baixo peso ao nascer em crianças nascidas na cidade de Santo André. Casuística e métodos: este é um estudo de coorte histórica. Foram incluídos todos os bebês nascidos de mães que vivem no município de Santo André - São Paulo Brasil, entre 2000 e 2006 com declarações de nascimento de vivos concluído. A Companhia de Tecnologia de Saneamento Ambiental Cetesb forneceu dados diários do material particulado (PM10), ozônio (O3), temperatura e umidade. Foram realizadas análises descritivas e de regressão logística. Resultados: Dos 58.114 nascimentos ocorridos entre 2000 e 2006, 5,91 % dos bebês apresentaram baixo peso ao nascer. Houve uma relação dosedependente entre as concentrações de PM10 e o baixo peso ao nascer. Concentrações de PM10 no quarto quartil no terceiro trimestre aumentaram o risco de baixo peso ao nascer em 32% (Razão de Chance: 1,32; IC95%: 1,15 1,50) quando comparado com os valores do primeiro quartil. Comportamentos semelhantes foram observados nos demais trimestres. Não foram observados riscos para o O3. Conclusão: o aumento na concentração de PM10, na cidade de Santo André, no período estudado, produziu um aumento na chance de ocorrência de baixo peso ao nascer Este efeito foi observado mesmo não ocorrendo ultrapassagem dos padrões de qualidade do ar / Introduction: The atmospheric pollution is a public health problem worldwide. The adverse effects related to air pollutants are robustly associated with respiratory and cardiovascular diseases and, in a lesser extent, with pregnancy adverse outcomes. Objective: estimating the relationship between air pollutants PM10 and O3 and low birth weight of children were borne in the city of Santo André, São Paulo. Casuistic and methods: This is a crossectional study. We included in the study all newborns of mothers that were inhabitants of Santo André, São Paulo, Brazil, and that were born from 2000 to 2006. The São Paulo State Environmental Agency (CETESB) provided daily records of particulate matter (PM10), temperature, and humidity. We performed descriptive analysis and logistic regressions. Results: Among the 58,114 newborns it was observed a low birth weight rate of 5.9%. There was a dose-response relationship between PM10 concentrations and low birth weight. Particles concentrations in the highest quartile in the third trimester of pregnancy increased the risk of low birth weight in 32% ((Odds Ratio: 1,32; 95% CI: 1,15 1,50) when compared with the first quartile. The same pattern of effect was observed in the other trimesters. For the O3 not were detected risks. Conclusion: The increase in PM10 concentrations, in Santo André, during the studied period, lead to an increase in the odds of low birth weight. This effect was observed even though there was no surpassing of air quality standards