Environmental and genetic factors contribute to the development of schizophrenia. For example, epidemiological evidence has linked infections during pregnancy with increased incidence of schizophrenia in the adult offspring. At the same time mutation to DISC1, a protein involved in neurone migration and synaptic plasticity, is an important genetic risk for the disorder. Accordingly, the aim of this project was to determine if these environmental and genetic influences converge along a common pathogenic pathway leading to schizophrenia. Using a model of prenatal infection by bacterial endotoxin in rodents, we demonstrated a 50% reduction in DISC1 protein expression in the hippocampus and cortex of juvenile offspring. In addition, we found a significant induction of prostaglandins (final mediators of the inflammatory process) in the fetal brain while many cytokines remained unaltered. Taken together our results identify prostaglandins as potential mediators of the teratogenic effects of prenatal infection and show that prenatal infection itself can affect systems related to genetic risk factors for schizophrenia, in this case DISC1.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--West Virginia University, 1999. / Title from document title page. Document formatted into pages; contains xiv, 223 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 187-220).

Made available in DSpace on 2015-07-22T20:49:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-22 / Objetivo: Avaliar as alterações orais tardias em pacientes não operados de cabeça e pescoço, submetidos a radioterapia (RT) com ou sem quimioterapia (QT). Material e Métodos: Foram revisados 515 prontuários de pacientes tratados para tumores de cabeça e pescoço, entre 2005 e 2009, sendo que 41 pacientes preencheram os critérios de inclusão. Os efeitos tardios foram graduados através do sistema do Common Toxicity Criteria (CTC) - Radiotherapy and Oncology Group /European Organization for Research and Treatment of Cancer (RTOG/EORTC) – Escala de graduação de morbidade tardia da radiação. A função salivar foi verificada através da sialometria e de um método de avaliação simplificado. Os dados foram submetidos a análise estatística. Resultados: O tempo médio de seguimento foi de 17,1 meses e houve a predominância de complicações tardias leves para as complicações estudadas. Entre as alterações classificadas como graus 2 ou 3, as mais freqüentes ocorreram em glândulas salivares, mucosa oral e alterações no paladar. Foi verificada uma correlação estatística significante entre os níveis de fluxo de saliva não estimulada/estimulada e a graduação, segundo o CTC – RTOG/EORTC, para a mucosa oral. O nível baixo de fluxo salivar (<0,03 mL/min e <0,09 mL/min) foi identificado como fator de risco independente para a toxicidade em mucosa oral (graus ≥ 2) (valor de p = variou de 0,001 a 0,032); (odds ratio [OR] = variou de 7,14 a 30; risco relativo [RR] = variou de 4,3 a 8,3). Verificou-se também, relação significante entre o sistema de graduação de xerostomia (objetivo) e a graduação, segundo o CTC – RTOG/EORTC, para glândulas salivares (p = 0,001). Oitenta e cinco por cento dos pacientes apresentavam hipossalivação e 58,7% consideravam a xerostomia como o efeito tardio mias debilitante. Conclusão: A maioria dos pacientes apresentou graduações tardias leves (0 e 1), segundo os critérios do CTC – RTOG/EORTC; as variáveis demográficas, do tumor e do tratamento não se apresentaram como fatores estatisticamente significantes para o desenvolvimento e severidade das complicações orais tardias; a hipofunção salivar aumentou de 4,3 a 8,3 vezes o RR para o ocorrência de reações tardias severas em mucosa; a xerostomia foi considerada o fator mais debilitante após o tratamento. Os resultados mostram a importância da avaliação do hipofluxo salivar como um fator preditivo independente para a severidade de efeitos tardios em mucosa oral. / Purpose: To assess the late oral complications (LOC) in non surgical head and neck cancer (HNC) patients, submitted to radiotherapy (RT) with or without chemotherapy (chemo). Materials and Methods: The average follow-up for HNC patients was 17.1 months. Five hundred fifteen charts from patients treated for HNC between 2005 and 2009 were reviewed and 41 non surgical HNC patients met the inclusion criteria. Salivary glands function was assessed using a simplified new grading system (NGSX) (Esibruch et al. 2003) and sialometry. Late effects were assessed using the Common Toxicity Criteria (CTC) - Radiotherapy and Oncology Group /European Organization for Research and Treatment of Cancer (RTOG/EORTC) - Late Radiation Morbidity Scale. Data were submitted to statistical analysis. Results: There was a predominance of mild LOC complications among the variables studied. A statistical correlation was found for both unstimulated/stimulated salivary flow rates and the average CTC – RTOG/EORTC grades for the mucous membrane. The low salivary flow rates (<0.03 mL/min e <0.09 mL/min) were identified as a potential risk factor (p <0.005) and an independent predictor for mucous membrane toxicity (for ≥2 grades). A significant correlation was also found between objective NGSX scores (p = 0.001) and CTC – RTOG/EORTC grades for salivary glands. Eighty five percent of the patients were classified as suffered from hyposalivation as well as 58,7% considered the dryness in the mouth the most debilitating complication. Conclusions: Considering the late effects assessed, the majority of patients presented mild graduation (0 and 1) according to CTC – RTOG/EORTC criteria; the demographic, tumor and treatment variables were not statistically significant for the development and severity of late oral complication; the salivary hipofunction increased from 4.3 to 8.3 times the RR for the occurrence of severe late mucosal reaction; xerostomia was considered the most debilitating complication after treatment. Data show the role of salivary hypofunction as an independet predictor for the severity of late mucous membrane complication. / TEDE / BV UNIFESP: Teses e dissertações

Iron deficiency (ID) is especially common in pregnant women and may even persist following childbirth. This is of concern in light of reports demonstrating that ID may be sufficient to produce homeostatic dysregulation of other metals, including manganese (Mn). These results are particularly important considering the potential introduction of the Mn-containing gas additive, methyl cyclopentadienyl manganese tricarbonyl (MMT), in various countries around the world. In order to model this potentially vulnerable population, we fed female rats fed either control (35 mg Fe/kg chow; 10 mg Mn/kg chow) or low iron/high-manganese (IDMn; 3.5 mg Fe/kg chow; 100 mg Mn/kg chow) diet, and examined whether these changes had any long-term behavioral effects on the animals' spatial abilities, as tested by the Morris water maze (MWM). We also analyzed behavioral performance on auditory sensorimotor gating utilizing prepulse inhibition (PPI), which may be related to overall cognitive performance. Furthermore, brain and blood metal levels were assessed, as well as regional brain isoprostane production. We found that treated animals were slightly ID, with statistically significant increases in both iron (Fe) and Mn in the hippocampus, but statistically significantly less Fe in the cerebellum. Additionally, isoprostane levels, markers of oxidative stress, were increased in the brain stem of IDMn animals. Although treated animals were indistinguishable from controls in the PPI experiments, they performed less well than controls in the MWM. Taken together, our data suggest that vulnerable ID populations exposed to high levels of Mn may indeed be at risk of potentially dangerous alterations in brain metal levels which could also lead to behavioral deficits.

Maternal obesity has significant consequences on the lifelong health of the developing child and rising global incidences make it one of the most common comorbidities during pregnancy. Offspring of obese mothers are at an increased risk of hospitalization for respiratory infections throughout childhood, which predispose these children to non-communicable respiratory diseases in later life. Animal models of maternal high fat diet (mHFD) feeding have observed common inflammatory outcomes with obesogenic models, but the effect on offspring varies with timing of the nutritional challenge and diet composition across studies. These studies demonstrate significant alterations to circulating and lung specific immune cells but the sequence of events that link maternal diet to these fetal outcomes are unclear, nor have they been tested in the context of a bacterial respiratory infection. Streptococcus pneumonaie is the most common causative pathogen of bacterial pneumonia and meningitis, making it of high clinical relevance. We aimed to investigate the effect of a mHFD (45% kcal from fat) during gestation and lactation, on offspring outcome and recovery from Streptococcus pneumoniae infection. Immunophenotyping, both before and after infection, revealed a hypo-inflammatory phenotype in circulating monocytes of the mHFD offspring with a decreased capacity to both initiate and terminate inflammatory responses. These offspring had significantly higher bacterial counts in lung tissues during infection and sustained cellular inflammation in survivors. In this thesis, we present foundational work on the detrimental influence of excess maternal nutrition on offspring immune function and infection outcomes, which may be involved in susceptibility to inflammatory and chronic disease in later life. A better understanding of this deep and lasting influence of the maternal environment will allow us to target preconception health as a form of harm reduction, informing stake holders and institutions to direct efforts towards DOHaD knowledge translation. / Thesis / Master of Science (MSc)

No description available.

No description available.

Diversos estudos observaram uma correlação entre doenças na idade adulta e o ambiente durante a vida fetal. O estudo realizado por Barker e colaboradores foi um dos primeiros a relatar a hipótese de um possível envolvimento do ambiente intra-uterino com o desenvolvimento de doenças cardiovasculares, mas os mecanismos responsáveis por esta associação ainda não são totalmente conhecidos. Estudos demonstraram uma associação entre baixo peso ao nascimento com resistência à insulina e intolerância à glicose na vida adulta. Recentemente, verificamos que o consumo de dieta hipossódica, conhecido modelo de resistência à insulina, durante a gestação e lactação está vinculado a menor sensibilidade à insulina na prole adulta. Visto que a presença de resistência à insulina durante a gestação leva a diversas alterações metabólicas na prole adulta, pode-se supor que a sobrecarga de sacarose, um modelo de resistência à insulina, durante a gestação e lactação influencie no desenvolvimento da prole. Assim, o objetivo do presente estudo foi verificar a repercussão da resistência à insulina, durante a gestação sobre a prole adulta. Para tanto, ratas Wistar foram alimentadas com dieta hipo (HO) ou normossódica (NR) suplementadas ou não com sacarose (NR+SAC - 20g/dL) ou maltodextrina (NR+MALTO - 20g/dL) desde a oitava semana de vida até o final da gestação e amamentação. Na prole resultante destes animais foi observado menor peso ao nascimento nos grupos HO, NR+SAC e NR+MALTO. Esta alteração resultou no desenvolvimento de maior insulinemia, pressão arterial e maior captação de glicose na prole de fêmeas das mães do grupo NR+SAC. Os machos apresentaram menor índice de adiposidade e maior expressão gênica renal dos componentes do sistema renina-angiotensina. Tais resultados nos permitem concluir que a sobrecarga de carboidratos durante a gestação e lactação está associada a alterações no peso ao nascimento e no metabolismo da insulina na idade adulta. É possível que a ativação do sistema renina-angiotensina materno induzido pela sobrecarga de carboidrato esteja associada a alterações deste mesmo sistema observado na prole adulta. / Many studies observed a correlation between diseases in adult subjects and the environment during the fetal life. Barker and coworkers hypothesized that there is a possible intrauterine enviroment association with cardiovascular diseases in adulthood. The mechanisms responsible for this association are still not very well known. Recently, we have verified that low-salt diet consumption, a well-known model of insulin resistance, during pregnancy and lactation is associated with a lower insulin sensitivity in the adult offspring. Since insulin resistance during pregnancy leads to many metabolic alterations in the adult offspring, we suppose that sucrose overload during pregnancy and lactation could influence the offspring development. The aim of this study was to verify the effects on adult offspring of insulin resistance during pregnancy and lactation. Female Wistar rats were fed low (LSD) and normal-salt diet (NSD) supplemented or not with sucrose (SUC - 20 g/dL) or maltodextrin (MALTO - 20 g/dL) until the end of pregnancy and lactation. Lower birth weight was observed in offspring of LSD, SUC and MALTO groups. Higher plasma insulin level, blood pressure and glucose uptake was detected in the adult SUC female offspring. SUC male offspring had lower adiposity index and higher gene expression of the renal renin-angiotensin components. These results show that carbohydrate overload during pregnancy and lactation is associated with alterations in birth weight and in insulin metabolism at adult life. It is possible that the maternal renin-angiotensin system activation by the carbohydrate overload is associated with alterations in the same system observed in the adult offspring.