<p> Although historically treated as separate systems, there is considerable interaction between the immune system and brain. It has become increasingly clear that immunebrain communication is important to both health and disease. An immunogenic challenge given during the first postnatal week in rodents impacts the developing central nervous system (CNS) leading to long-term behavioural and molecular alterations reflective of enhanced stress-reactivity. Anxiety and depression are stress-related pathologies with a proposed neurodevelopmental origin suggesting that perturbation to neonatal immunebrain signalling may contribute to psychopathology. The current body of work examined the long-term impact of an early immune challenge on behavioural and molecular phenotypes associated with anxiety and depression. Mice were administered lipopolysaccharide (LPS) on postnatal days three and five. The emergence of anxietyrelated behaviour was characterized along the developmental trajectory of LPS-mice concurrent with changes to serotonergic neurocircuitry. Adult depressive-related behaviour was assessed in the forced swim test (FST) along with hippocampal neurogenesis as revealed by immunoreactivity for bromodeoxyuridine (BrdU) and doublecortin (DCX). The results demonstrated a sex-specific alteration in both the temporal emergence and phenotypic variant of anxiety-related behaviours displayed by LPS-mice. This was accompanied by changes to CNS serotonergic-related gene expression that coincided with a critical developmental time window essential to the establishment of emotionality. Adult LPS-mice exhibited hyperactivity during the FST that was accompanied by increased doublecortin immunoreactivity in the dorsal and ventral hippocampus, reflecting enhanced immature neuronal differentiation. The current results demonstrate that an early immune challenge impacts the developing CNS leading to enhanced emotional-reactivity. Altered serotonergic neurocircuitry and adult hippocampal neurogenesis may underlie behavioural abnormalities. The current body of work demonstrates a preeminent role for early-life immune disturbance in psychopathology and advances understanding of how immune-brain signalling impacts the developing CNS and confers risk for later disease. </p> / Thesis / Doctor of Philosophy (PhD)

Fluoxetine and escitalopram are the only antidepressants approved by the Food and Drug Administration of the United States of America (FDA) for treatment of major depression in children and adolescents. Both drugs are selective serotonin reuptake inhibitors (SSRIs). In recent years there has been a growing concern over the long-term developmental effects of early-life exposure to SSRIs. The current study employed male Flinders Sensitive Line (FSL) rats, a well described and validated translational model of depression, to investigate the long term effects of pre-pubertal fluoxetine exposure. First we examined the effect of such early-life exposure on the development of depressive-like behaviour, locomotor activity and anxiety-like behaviour as manifested in early adulthood. Next, the current study investigated the effect of pre-pubertal fluoxetine exposure on the acute monoaminergic stress response, as displayed later in life. Animals received either saline (vehicle control), or 10 mg/kg/day fluoxetine from postnatal day (ND+) 21 to ND+34 (pre-puberty). The treatment period was chosen to coincide with a developmental phase where the serotonergic system’s neurodevelopment had been completed, yet the noradrenergic and dopaminergic systems had not, a scenario comparable to neurodevelopment in human adolescents. Both behavioural and in vivo intra-cerebral microdialysis experiments were conducted after ND+60 (early adulthood). On ND+60 rats allocated to behavioural experiments were evaluated for depressive-like behaviour in the forced swim test (FST), locomotor activity in the open field test (OFT), and anxiety-like behaviour in the OFT. Corticosterone concentrations were shown to be significantly higher in male FSL rats exposed to a 10 minute forced swim stress when compared to male FSL rats not exposed to a forced swim stress on ND+60. In the microdialysis experiments the rats were exposed to an acute 10 minute forced swim stress and the concentrations of the monoamines and their metabolites were measured before, during, and after the acute stressor. Relative to saline-treated (control) rats, fluoxetine-treated FSL rats did not show long-term changes in immobility in the FST (i.e. no anti-depressant-like activity) on ND+60. Like-wise anxiety-like behaviour in the OFT did not change. However, a significant decrease in locomotor activity was observed in fluoxetine-treated FSL rats compared to saline-treated (control) rats. These data suggest that a long-lasting anti-depressant-like effect of fluoxetine may be masked by the effect on locomotor activity. With measurements from the microdialysis experiments a significant attenuation of the noradrenergic stress response was observed in fluoxetine-treated rats compared to saline controls. A similar picture was observed for 5-hydroxyindole-3-acetic acid (5-HIAA), a metabolite of serotonin (5-HT), although the latter was not statistically significant. At baseline, before the stressor, significant increase in dopamine (DA) levels were observed in fluoxetine treated rats when compared to saline controls, suggesting that enhanced dopamine neurotransmission may comprise a long-term effect of pre-pubertal fluoxetine treatment. There were no discernible differences in homovanilllic acid (HVA) concentrations between fluoxetine-treated rats and saline controls. In conclusion significant developmental effects of pre-pubertal fluoxetine exposure were observed later in life and these findings warrant further investigation. / MPharm (Pharmacology), North-West University, Potchefstroom Campus, 2015

Fluoxetine and escitalopram are the only antidepressants approved by the Food and Drug Administration of the United States of America (FDA) for treatment of major depression in children and adolescents. Both drugs are selective serotonin reuptake inhibitors (SSRIs). In recent years there has been a growing concern over the long-term developmental effects of early-life exposure to SSRIs. The current study employed male Flinders Sensitive Line (FSL) rats, a well described and validated translational model of depression, to investigate the long term effects of pre-pubertal fluoxetine exposure. First we examined the effect of such early-life exposure on the development of depressive-like behaviour, locomotor activity and anxiety-like behaviour as manifested in early adulthood. Next, the current study investigated the effect of pre-pubertal fluoxetine exposure on the acute monoaminergic stress response, as displayed later in life. Animals received either saline (vehicle control), or 10 mg/kg/day fluoxetine from postnatal day (ND+) 21 to ND+34 (pre-puberty). The treatment period was chosen to coincide with a developmental phase where the serotonergic system’s neurodevelopment had been completed, yet the noradrenergic and dopaminergic systems had not, a scenario comparable to neurodevelopment in human adolescents. Both behavioural and in vivo intra-cerebral microdialysis experiments were conducted after ND+60 (early adulthood). On ND+60 rats allocated to behavioural experiments were evaluated for depressive-like behaviour in the forced swim test (FST), locomotor activity in the open field test (OFT), and anxiety-like behaviour in the OFT. Corticosterone concentrations were shown to be significantly higher in male FSL rats exposed to a 10 minute forced swim stress when compared to male FSL rats not exposed to a forced swim stress on ND+60. In the microdialysis experiments the rats were exposed to an acute 10 minute forced swim stress and the concentrations of the monoamines and their metabolites were measured before, during, and after the acute stressor. Relative to saline-treated (control) rats, fluoxetine-treated FSL rats did not show long-term changes in immobility in the FST (i.e. no anti-depressant-like activity) on ND+60. Like-wise anxiety-like behaviour in the OFT did not change. However, a significant decrease in locomotor activity was observed in fluoxetine-treated FSL rats compared to saline-treated (control) rats. These data suggest that a long-lasting anti-depressant-like effect of fluoxetine may be masked by the effect on locomotor activity. With measurements from the microdialysis experiments a significant attenuation of the noradrenergic stress response was observed in fluoxetine-treated rats compared to saline controls. A similar picture was observed for 5-hydroxyindole-3-acetic acid (5-HIAA), a metabolite of serotonin (5-HT), although the latter was not statistically significant. At baseline, before the stressor, significant increase in dopamine (DA) levels were observed in fluoxetine treated rats when compared to saline controls, suggesting that enhanced dopamine neurotransmission may comprise a long-term effect of pre-pubertal fluoxetine treatment. There were no discernible differences in homovanilllic acid (HVA) concentrations between fluoxetine-treated rats and saline controls. In conclusion significant developmental effects of pre-pubertal fluoxetine exposure were observed later in life and these findings warrant further investigation. / MPharm (Pharmacology), North-West University, Potchefstroom Campus, 2015

The subplate layer of the cerebral cortex is comprised of a heterogeneous population of cells and contains some of the earliest-generated neurons. Subplate plays a fundamental role in cortical development. In the embryonic brain, subplate cells contribute to the guidance and areal targeting of corticofugal and thalamic axons. At later stages, these cells are involved in the maturation and plasticity of the cortical circuitry and the establishment of functional modules. In my thesis, I aimed to further characterize the embryonic murine subplate by establishing a gene expression profile of this population at embryonic day 15.5 (E15.5) using laser capture microdissection combined with microarrays. I found over 250 transcripts with presumed higher expression in the subplate at E15.5. Using quantitative RT-PCR, in situ hybridization and immunohistochemistry, I have confirmed specific expression in the E15.5 subplate for 13 selected genes which have not been previously associated with this compartment. In the reeler mutant, the expression pattern of a majority of these genes was shifted in accordance with the altered position of subplate cells. These genes belong to several functional groups and likely contribute to the maturation and electrophysiological properties of subplate cells and to axonal growth and guidance. The roles of two selected genes - cadherin 10 (Cdh10) and Unc5 homologue c (Unc5c) - were explored in more detail. Preliminary results suggest an involvement of Cdh10 in subplate layer organization while Unc5c could mediate the waiting period of subplate corticothalamic axons in the internal capsule. Finally, I compared the expression of a selection of subplate-specific genes (subplate markers) between mouse and rat and found some surprising species differences. Confirmed subplate markers were used to monitor subplate injury in a rat model of preterm hypoxiaischemia and it appeared that deep cortical layers including subplate showed an increased vulnerability over upper layers. Further characterization of subplate-specific genes will allow us to broaden our understanding of molecular mechanisms underlying subplate properties and functions in normal and pathological development.

L’objectif de cette thèse est l’étude du développement de l’attention auditive et des capacités de discrimination langagière chez l’enfant né prématurément ou à terme. Les derniers mois de grossesse sont particulièrement importants pour le développement cérébral de l’enfant et les conséquences d’une naissance prématurée sur le développement peuvent être considérables. Les enfants nés prématurément sont plus à risque de développer une variété de troubles neurodéveloppementaux que les enfants nés à terme. Même en l’absence de dommages cérébraux visibles, de nombreux enfants nés avant terme sont à risque de présenter des troubles tels que des retards langagiers ou des difficultés attentionnelles. Dans cette thèse, nous proposons donc une méthode d’investigation des processus préattentionnels auditifs et de discrimination langagière, à l’aide de l’électrophysiologie à haute densité et des potentiels évoqués auditifs (PEAs). Deux études ont été réalisées. La première visait à mettre sur pied un protocole d’évaluation de l’attention auditive et de la discrimination langagière chez l’enfant en santé, couvrant différents stades de développement (3 à 7 ans, 8 à 13 ans, adultes ; N = 40). Pour ce faire, nous avons analysé la composante de Mismatch Negativity (MMN) évoquée par la présentation de sons verbaux (syllabes /Ba/ et /Da/) et non verbaux (tons synthétisés, Ba : 1578 Hz/2800 Hz ; Da : 1788 Hz/2932 Hz). Les résultats ont révélé des patrons d’activation distincts en fonction de l’âge et du type de stimulus présenté. Chez tous les groupes d’âge, la présentation des stimuli non verbaux a évoqué une MMN de plus grande amplitude et de latence plus rapide que la présentation des stimuli verbaux. De plus, en réponse aux stimuli verbaux, les deux groupes d’enfants (3 à 7 ans, 8 à 13 ans) ont démontré une MMN de latence plus tardive que celle mesurée dans le groupe d’adultes. En revanche, en réponse aux stimuli non verbaux, seulement le groupe d’enfants de 3 à 7 ans a démontré une MMN de latence plus tardive que le groupe d’adulte. Les processus de discrimination verbaux semblent donc se développer plus tardivement dans l’enfance que les processus de discrimination non verbaux. Dans la deuxième étude, nous visions à d’identifier les marqueurs prédictifs de déficits attentionnels et langagiers pouvant découler d’une naissance prématurée à l’aide des PEAs et de la MMN. Nous avons utilisé le même protocole auprès de 74 enfants âgés de 3, 12 et 36 mois, nés prématurément (avant 34 semaines de gestation) ou nés à terme (au moins 37 semaines de gestation). Les résultats ont révélé que les enfants nés prématurément de tous les âges démontraient un délai significatif dans la latence de la réponse MMN et de la P150 par rapport aux enfants nés à terme lors de la présentation des sons verbaux. De plus, les latences plus tardives de la MMN et de la P150 étaient également corrélées à des performances langagières plus faibles lors d’une évaluation neurodéveloppementale. Toutefois, aucune différence n’a été observée entre les enfants nés à terme ou prématurément lors de la discrimination des stimuli non verbaux, suggérant des capacités préattentionnelles auditives préservées chez les enfants prématurés. Dans l’ensemble, les résultats de cette thèse indiquent que les processus préattentionnels auditifs se développent plus tôt dans l'enfance que ceux associés à la discrimination langagière. Les réseaux neuronaux impliqués dans la discrimination verbale sont encore immatures à la fin de l'enfance. De plus, ceux-ci semblent être particulièrement vulnérables aux impacts physiologiques liés à la prématurité. L’utilisation des PEAs et de la MMN en réponse aux stimuli verbaux en bas âge peut fournir des marqueurs prédictifs des difficultés langagières fréquemment observées chez l’enfant prématuré. / The aim of this thesis is to investigate early auditory attention and language development in full-term and preterm children. The last months of pregnancy are particularly important for the child’s cerebral development, and the impacts of a premature birth on his/her neurodevelopment can be substantial. Prematurely born children are at higher risk of developing a variety of neurodevelopmental disorders compared to full-terms. Even without visible brain injury, many premature children are at risk of presenting disorders such as language delays and attentional difficulties. In this thesis, we suggest an approach to investigate pre-attentional processes and early language discrimination abilities in infants using high-density electrophysiology and auditory event-related potentials (AERPs). We conducted two studies. The first one aimed at establishing a paradigm to evaluate auditory attention and language discrimination development in healthy full-term children, over different developmental stages (3 to 7 years, 8 to 13 years, adults; N = 40). To do so, we analyzed the Mismatch Negativity (MMN) component in response to speech (spoken syllables /Ba/ and /Da/) and non-speech stimuli (frequency-synthesized tones, Ba: 1578 Hz/2800 Hz; Da: 1788 Hz/2932 Hz). Distinct patterns of activation were revealed according to stimulus type and age. In all groups, non-speech stimuli elicited an MMN of larger amplitude and earlier latency than did the presentation of speech stimuli. Moreover, in response to speech stimuli, both children groups (3 to 7 years, 8 to 13 years) showed a significantly delayed MMN response compared to the adults group. In contrast, in response to non-speech stimuli, only the youngest group (3 to 7 years) showed a significantly delayed MMN compared to the adults. Age-related differences for tone discrimination therefore appear to occur earlier in children’s development than do the discriminative processes for speech sounds. In the second study, we aimed at identifying the electrophysiological markers of auditory attention and language deficits often incurred by a premature birth. We thus presented this paradigm to 74 infants born preterm (before 34 gestational weeks) or full-term (at least 37 gestational weeks), aged 3, 12 and 36 months old. Our results indicated that preterm children of all age groups showed a significantly delayed MMN and P150 responses to speech stimuli compared to full-terms. Moreover, significant correlations were found between the delayed MMN and P150 responses to speech sounds and lower language scores on a neurodevelopmental assessment. However, no significant differences were found between full-term and preterm children for the MMN in response to non-speech stimuli, suggesting preserved pre-attentional auditory discrimination abilities in these children. Altogether, the findings from this thesis indicate that the neurodevelopmental processes associated with auditory pre-attentional skills occur earlier in childhood compared to language discrimination processes. Cerebral networks involved in speech discrimination are still immature in late childhood. Furthermore, neural networks involved in speech discrimination and language development also appear to be particularly vulnerable to the impacts of prematurity. The use of AERPs and the MMN response to speech stimuli in infancy can thus provide predictive markers of language difficulties commonly seen in premature infants.

O presente estudo investigou a prevalência e a validade de construto das experiências psicóticas (EPs) na gestação e os fatores de risco associados em uma amostra comunitária do município de São Paulo. Foram investigados fatores de risco sociodemográficos, ambientais, transtornos psiquiátricos no presente e ao longo da vida, violência doméstica, capacidade intelectual e histórico familiar de transtornos psiquiátricos. Foram também avaliados desfechos da gestação e do parto. Trata-se de um estudo prospectivo, com início no 3º trimestre de gestação. As entrevistas de avaliação foram realizadas por psicólogos treinados. Para a avaliação das EPs, foi utilizado o instrumento de entrevista diagnóstica padronizada breve - Mini International Neuropsyquiatric Interview (M.I.N.I), validado para a realidade brasileira. Para os fatores de risco sociodemográficos, foram aplicados: questionário socioeconômico (QSE), densidade demográfica (DM) e utilizado o critério de classificação econômica do Brasil CCEB, pela Associação Brasileira de Empresas de Pesquisa (ABEP) e World Health Organization - WHO para violência doméstica. Foi realizada a avaliação da capacidade intelectual através da Escala de Inteligência Wechsler para adultos, terceira versão (WAISS-III) e investigado o histórico familiar para transtornos mentais através do The Family History Screen (FHS). Os resultados apontaram uma prevalência de 19,22% das EPs na gestação e compartilhando os fatores de risco presentes na esquizofrenia, como: urbanicidade, gestantes jovens, o uso de drogas e álcool, desvantagem socioeconômica, baixo nível de escolaridade, exposição à situações de violência, a presença dos transtornos psiquiátricos como depressão e ansiedade, e histórico familiar para qualquer condição psiquiátrica. Este estudo, realizado em uma região urbana da cidade de São Paulo, com altos índices de vulnerabilidade social, indica que a prevalência de EPs em gestantes é alta, afetando cerca de 1 em 6 mulheres. A presença de EPs associa-se fortemente com psicopatologia geral e com amplos fatores de risco. Neste sentido, a presença de EPs pode se constituir em um importante indicador de risco a ser avaliado em ambientes clínicos durante a gestação. Estudos futuros que possam investigar a sua utilidade para indicação de intervenções são necessários, assim como estudos que investiguem o curso de EPs apos o período gestacional e a sua associação com desfechos de saúde nas mulheres e em seus filhos / This research investigated the prevalence and construct validity of psychotic experiences (PEs) during pregnancy and the risk factors in a community sample in the city of São Paulo. Sociodemographic and environmental risk factors, psychiatric disorders, domestic violence, intellectual capacity and family history of psychiatric disorders in the present and throughout life were the investigated elements. Pregnancy and delivery outcomes were also evaluated. This is a prospective research, starting in the 3rd trimester of pregnancy. The evaluation interviews were conducted by trained psychologists. For the evaluation of PEs, the brief standardized diagnostic interview tool was used - Mini International Neuropsyquiatric Interview (M.I.N.I), validated for the Brazilian reality. For the sociodemographic risk factors, both socioeconomic questionnaire (SEQ) and population density (PD) were applied and the criterion of economic classification in Brazil (CECB) was used by the Brazilian Association of Research Companies (BARC) and World Health Organization - WHO for domestic violence. The intellectual capacity evaluation was carried out, using the Wechsler Intelligence Scale for Adults, third version (Waiss-III), and the family history of mental disorders was investigated through The Family History Screen (FHS). The results indicated a prevalence of 19.22% of PEs during pregnancy and sharing the risk factors present in schizophrenia, such as urbanicity, young pregnant women, use of drugs and alcohol, socioeconomically disadvantaged, low educational level, exposure to situations of violence, the presence of psychiatric disorders such as depression and anxiety, and family history of any psychiatric condition. This research, conducted in an urban area of the city of São Paulo, with high social vulnerability, indicates that the prevalence of PEs in pregnant women is high, affecting about 1 in 6 of them. The presence of PEs is strongly associated with general psychopathology and broad risk factors. In this sense, the presence of PEs may constitute an important risk factor to be evaluated in clinical environments during pregnancy. Future researches intending to look into its usefulness for indication of interventions are needed, as well as studies to search into the course of PEs after pregnancy and its association with health outcomes for women and their children

Axonal protein synthesis is rapidly regulated by extrinsic cues during neural wiring but the full landscape of proteomic changes and their translational control mechanisms remain unknown. The ability to investigate the nascent proteome on subcellular compartments has been hampered by the low sensitivity of existing methodology on quantity-limited samples combined with the difficulty of obtaining sufficient amounts of pure material. By combining pulsed Stable Isotope Labelling by Amino acids in Cell culture (pSILAC) with Single-Pot Solid-Phase-enhanced Sample Preparation (SP3), I have established an approach to characterize the nascent proteome from quantity-limited somaless retinal axons (~2μg) on an unparalleled rapid time-scale (5 min). The results show that a surprisingly large number of proteins (>350) is translated constitutively in axons, many of which are linked to neurological disease. Axons stimulated by different cues (Netrin-1, BDNF, Sema3A) each show a signature set of up/down newly synthesised protein (NSP) changes (>100) within 5 min. Remarkably, conversion of Netrin-1-induced responses from repulsion to attraction triggers opposite translational regulation for 73% of a common subset corresponding to >100 NSPs. Further, I show that pharmacological increase in cAMP, known to induce chemoattractive response, also leads to rapid and wide-scale remodelling of the nascent axonal proteome (~100 NSP changes). I find that the cAMP-elicited NSP changes underlie the attractive turning but are distinct from those induced by the physiological chemoattractant Netrin-1, suggesting that the same type of chemotropic response can be mediated by different protein synthesis-dependent mechanisms. Finally, I show that Sema3A, but not Slit1, triggers a physiological and non-canonical PERK-eIF2α-eIF2B signalling pathway required in neural wiring to elicit the rapid (< 15 min) local translation control of a specific subset of NSPs. Collectively my findings lead to the general conclusion that guidance molecules rapidly induce cue-specific remodelling of the nascent axonal proteome via distinct regulatory mechanisms.

O presente estudo investigou a prevalência e a validade de construto das experiências psicóticas (EPs) na gestação e os fatores de risco associados em uma amostra comunitária do município de São Paulo. Foram investigados fatores de risco sociodemográficos, ambientais, transtornos psiquiátricos no presente e ao longo da vida, violência doméstica, capacidade intelectual e histórico familiar de transtornos psiquiátricos. Foram também avaliados desfechos da gestação e do parto. Trata-se de um estudo prospectivo, com início no 3º trimestre de gestação. As entrevistas de avaliação foram realizadas por psicólogos treinados. Para a avaliação das EPs, foi utilizado o instrumento de entrevista diagnóstica padronizada breve - Mini International Neuropsyquiatric Interview (M.I.N.I), validado para a realidade brasileira. Para os fatores de risco sociodemográficos, foram aplicados: questionário socioeconômico (QSE), densidade demográfica (DM) e utilizado o critério de classificação econômica do Brasil CCEB, pela Associação Brasileira de Empresas de Pesquisa (ABEP) e World Health Organization - WHO para violência doméstica. Foi realizada a avaliação da capacidade intelectual através da Escala de Inteligência Wechsler para adultos, terceira versão (WAISS-III) e investigado o histórico familiar para transtornos mentais através do The Family History Screen (FHS). Os resultados apontaram uma prevalência de 19,22% das EPs na gestação e compartilhando os fatores de risco presentes na esquizofrenia, como: urbanicidade, gestantes jovens, o uso de drogas e álcool, desvantagem socioeconômica, baixo nível de escolaridade, exposição à situações de violência, a presença dos transtornos psiquiátricos como depressão e ansiedade, e histórico familiar para qualquer condição psiquiátrica. Este estudo, realizado em uma região urbana da cidade de São Paulo, com altos índices de vulnerabilidade social, indica que a prevalência de EPs em gestantes é alta, afetando cerca de 1 em 6 mulheres. A presença de EPs associa-se fortemente com psicopatologia geral e com amplos fatores de risco. Neste sentido, a presença de EPs pode se constituir em um importante indicador de risco a ser avaliado em ambientes clínicos durante a gestação. Estudos futuros que possam investigar a sua utilidade para indicação de intervenções são necessários, assim como estudos que investiguem o curso de EPs apos o período gestacional e a sua associação com desfechos de saúde nas mulheres e em seus filhos / This research investigated the prevalence and construct validity of psychotic experiences (PEs) during pregnancy and the risk factors in a community sample in the city of São Paulo. Sociodemographic and environmental risk factors, psychiatric disorders, domestic violence, intellectual capacity and family history of psychiatric disorders in the present and throughout life were the investigated elements. Pregnancy and delivery outcomes were also evaluated. This is a prospective research, starting in the 3rd trimester of pregnancy. The evaluation interviews were conducted by trained psychologists. For the evaluation of PEs, the brief standardized diagnostic interview tool was used - Mini International Neuropsyquiatric Interview (M.I.N.I), validated for the Brazilian reality. For the sociodemographic risk factors, both socioeconomic questionnaire (SEQ) and population density (PD) were applied and the criterion of economic classification in Brazil (CECB) was used by the Brazilian Association of Research Companies (BARC) and World Health Organization - WHO for domestic violence. The intellectual capacity evaluation was carried out, using the Wechsler Intelligence Scale for Adults, third version (Waiss-III), and the family history of mental disorders was investigated through The Family History Screen (FHS). The results indicated a prevalence of 19.22% of PEs during pregnancy and sharing the risk factors present in schizophrenia, such as urbanicity, young pregnant women, use of drugs and alcohol, socioeconomically disadvantaged, low educational level, exposure to situations of violence, the presence of psychiatric disorders such as depression and anxiety, and family history of any psychiatric condition. This research, conducted in an urban area of the city of São Paulo, with high social vulnerability, indicates that the prevalence of PEs in pregnant women is high, affecting about 1 in 6 of them. The presence of PEs is strongly associated with general psychopathology and broad risk factors. In this sense, the presence of PEs may constitute an important risk factor to be evaluated in clinical environments during pregnancy. Future researches intending to look into its usefulness for indication of interventions are needed, as well as studies to search into the course of PEs after pregnancy and its association with health outcomes for women and their children

Background Due to small iron stores and rapid growth during the first months of life, infants with low birth weight (LBW) are at risk of iron deficiency (ID). ID in infancy is associated with irreversible impaired neurodevelopment. Preventive iron supplementation may reduce the risk of ID and benefit neurodevelopment, but there is also a possible risk of adverse effects. More than 50% of all LBW infants are born with marginally LBW (MLBW, 2000-2500g), and it is not known if they benefit from iron supplementation. Methods We randomized 285 healthy, Swedish, MLBW infants to receive 3 different doses of oral iron supplements; 0 (Placebo), 1, and 2 mg/kg/day from six weeks to six months of age. Iron status, during and after the intervention was assessed and so was the prevalence of ID and ID anemia (IDA), growth, morbidity and the interplay with iron and the erythropoetic hormones hepcidin and erythropoietin (EPO). As a proxy for conduction speed in the developing brain, auditory brainstem response (ABR) was analyzed at six months. In a follow up at 3.5 years of age, the children were assessed with a cognitive test (WPPSI-III) and a validated parental checklist of behavioral problems (CBCL), and compared to a matched reference group of 95 children born with normal birth weight. Results At six months of age, the prevalence of ID and IDA was significantly higher in the placebo group compared to the iron supplemented infants. 36% had ID in the placebo group, compared to 8% and 4 % in the 1 and 2mg/kg/day-groups, respectively. The prevalence of IDA was 10%, 3% and 0%, respectively. ABR-latencies did not correlate with the iron intake and was not increased in infants with ID or IDA. ABR wave V latencies were similar in all three groups. Hepcidin correlated to ferritin and increased in supplemented infants while EPO, which was negatively correlated to iron status indicators, decreased. At follow up there were no differences in cognitive scores between the groups but the prevalence of behavioral problems was significantly higher in the placebo group compared to those supplemented and to controls. The relative risk increase of CBCL-scores above a validated cutoff was 4.5 (1.4 – 14.2) in the placebo-group compared to supplemented children. There was no detected difference in growth or morbidity at any age. Conclusion MLBW infants are at risk of ID in infancy and behavioral problems at 3 years of age. Iron supplementation at a dose of 1-2 mg/kg/day from six weeks to six months of age reduces the risks with no adverse effects, suggesting both short and long term benefit. MLBW infants should be included in general iron supplementation programs during their first six months of life.

Background: Oruro is a mining city in the Bolivian highlands. Most of its citizens are exposed to polymetalic cocktails. This study aims to determine whether the neuropsychological development of one year-old children can be associated with 1) polymetalic exposures and/or 2) growth patterns. Methods: The thesis builds from data collected by the ToxBol multidisciplinary project. The health task was centred on the follow-up of a birth-cohort that set to evaluate child development. Children were examined at 11 and 12 months of age using the Bayley Scale of Infant Development (BSID). Results: 1) Analyses revealed no high concentrations of metals in the blood of pregnant women. 2) No neuropsychological anomalies were observed in association with metal concentrations or growth patterns. 3) A positive association was observed between low lead values in blood and the neuropsychological development of children. 4) During the first 6 months of life, growth rate was negatively associated with weight at birth and positively associated with the BMI at 12 months of age. Conclusion: Although heavy metallic pollution was demonstrated by environmental studies, unexpected low levels of exposure were registered from pregnant women. Neither the level of exposure to metals nor the growth patterns appear to have an impact on child neuropsychological development. We argue that the positive effect that was observed in association to lead might be caused by factors such as diet. / Antecedentes: Oruro es una ciudad minera del altiplano boliviano. Muchos de sus habitantes están expuestos a un cóctel polimetálico. El objetivo principal es el de determinar si existe una asociación entre desarrollo neuropsicológico de los niños de un año y 1) la exposición polimetálica y/o 2) los patrones de crecimiento. Métodos: Esta tesis está basada en los datos recogidos del Proyecto multidisciplinario ToxBol. Se realizó el seguimiento de una cohorte de niños para evaluar su desarrollo. Para evaluar el desarrollo neuropsicológico de los niños se utilizaron las escalas de Bayley de desarrollo infantil (BSID). Resultados: 1) No se observaron altas concentraciones de metales en sangre de las mujeres embarazadas. 2) No se observaron anormalidades neuropsicológicas en relación con concentraciones de metales o patrones de crecimiento. 3) Se observó una asociación positiva entre exposiciones bajas de plomo y el desarrollo neuropsicológico del niño al año de vida. 4) La velocidad de crecimiento, desde el nacimiento hasta los 6 meses, se asoció negativamente con el peso al nacer y positivamente con el BMI a los 12 meses. Conclusión: A diferencia de lo demostrado en otros estudios epidemiológicos, se observó una inesperada baja exposición. No se observó una relación entre el grado de exposición a metales- o los patrones de crecimiento -y el desarrollo neuropsicológico del niño. El efecto positivo del plomo creemos que se debe a otros factores como la dieta. / Antecedents: Oruro es una ciutat minera del altiplà Bolivià. La població es troba es contacte amb fonts de contaminación polimetàlica. L’objectiu principal es el de determinar si existeix una associació entre el desenvolupament neuropsicològic dels nens d’un any i 1) la exposició polimetálica i/o 2) patrons de creixement. Mètodes: Esta tesi està basada en dades del Projecte multidisciplinari ToxBol. La tasca de salut es va centrar en el seguiment del desenvolupament d’una cohort de nens. El desenvolupament neuropsicològic infantil es va avaluar amb les escales de Baley de Desenvolupament infantil (BSID). Resultats: 1) No es van observar concentracions altes de metalls en sang de les dones embarassades. 2) No es va observar anormalitats neuropsicològiques en realció amb les concentracions de metalls o patrons de creixement. 3) Es va observar una associació positiva entre concentracions baixes de plom en sang i el desenvolupament neuropsicològic dels nens d’un any. 4) La velocitat de creixement, des del naixement fins els 6 mesos, es va associar negativament amb el pes al néixer i positivament amb el BMI als 12 mesos. Conclusió: A diferencia del que esperàvem, es van registrar baixes concentracions de metalls a les dones embarassades. Tampoc s’observa una relació entre el grau d’exposició a metalls, o patrons de creixement, i el desenvolupament neuropsicològic del nens. El efecte positiu que observem del plom, pensem que es deu a altres factors com la dieta.