Asthma prevalence is increasing worldwide and the causes of this increase are largely unknown. There is increasing recognition of the importance of early environmental exposures in childhood asthma development. Outdoor air pollution has been shown to trigger asthma symptoms but its role in incident disease remains controversial. To address these questions, I investigated the effect of in utero and first year of life exposure to ambient air pollution on risk of asthma diagnosis in a nested case-control study. All children born in Southwestern British Columbia in 1999 and 2000 (N=37,401) were assessed for incidence of asthma diagnosis at age 3 - 4 years using hospitalization and primary physician records. Exposure to ambient air pollution was estimated for the gestational period and first year of life using high-resolution pollution surfaces derived from government monitoring station data as well as land use regression models adjusted for temporal variation. Conditional logistic regression analyses were used to estimate effects of CO, NO, NO₂, PM₁₀, PM₂.₅, O₃, SO₂, black carbon, wood smoke and proximity to roads and point sources on asthma diagnosis. Elevated risks of asthma diagnosis were observed with increased early life exposure to CO, NO, NO₂, PM₁₀, SO₂, black carbon and proximity to point sources. Effects were generally larger for first year exposures than in utero exposures, and larger for girls than boys. The results indicate that early life exposure to air pollution is associated with increased risk of asthma diagnosis in early childhood. Although the effect sizes are small, air pollution exposure in urban areas is ubiquitous so may have significant effects at the population level. These results should be confirmed when children are older and asthma diagnosis is more robust. / Medicine, Faculty of / Population and Public Health (SPPH), School of / Graduate

Yes / Objectives: Recent developments in incremental dentine analysis allowing increased temporal resolution for tissues formed during the first 1000 days of life have cast doubt on the veracity of weaning studies using bone collagen carbon (δ13C) and nitrogen (δ15N) isotope ratio data from infants. Here we compare published bone data from the well-preserved Anglo-Saxon site of Raunds Furnells, England, with co-forming dentine from the same individuals, and investigate the relationship of these with juvenile stature. The high resolution isotope data recorded in dentine allow us to investigate the relationship of diet with juvenile stature during this critical period of life. Materials and methods: We compare incremental dentine collagen δ13C and δ15N data to published bone collagen data for 18 juveniles and 5 female adults from Anglo Saxon Raunds Furnells alongside new data for juvenile skeletal and dental age. An improvement in the method by sampling the first 0.5mm of the sub-cuspal or sub-incisal dentine allows the isotopic measurement of dentine formed in utero. Results and Discussion: δ13C profiles for both dentine and bone are similar and more robust than δ15N for estimating the age at which weaning foods are introduced. Our results suggest δ15N values from dentine can be used to evaluate the maternal/in utero diet and physiology during pregnancy, and that infant dentine profiles may reflect diet PLUS an element of physiological stress. In particular, bone collagen fails to record the same range of δ15N as coforming dentine, especially where growth is stunted, suggesting that infant bone collagen is unreliable for weaning studies. / Funded in part by the NERC standard grant NE/F018096/2; University of Bradford.

Orientador: Ana Paula Girol / Coorientador: Sonia Maria Oliani / Banca: Ayder Anselmo Gomes Vivi / Banca: Cristiane Damas Gil / Resumo: As lesões uterinas são causas importantes de desconforto, infertilidade e óbito entre as mulheres no Brasil e no mundo. O câncer de endométrio é um tumor maligno frequente e sua incidência vem aumentando nas últimas décadas. Enquanto, o tumor uterino benigno mais comum, o leiomioma, acomete cerca de 40% das mulheres na idade reprodutiva, sendo relacionado à menorragia, dismenorreia e infertilidade. Investigações indicam que o microambiente tumoral é crucial para o avanço do câncer, sendo caracterizado, principalmente, pela composição alterada da matriz extracelular, alta densidade de microvasos e abundância de células inflamatórias, como mastócitos (MCs). MCs desgranulados liberam fatores quimiotáticos e proteases, como triptase e quimase, para o meio extracelular, contribuindo na degradação da matriz extracelular, promoção da angiogênese, propiciando ambiente favorável para invasão tumoral e remodelação tecidual por meio de proteólises seletivas na matriz e ativação de metaloproteinases. Outro aspecto importante no crescimento tumoral é a proteína anti-inflamatória Anexina A1 (ANXA1), relacionada à regulação dos processos de crescimento e migração/invasão celular, sendo seus efeitos mediados por receptores para peptídeos formilados (FPRs), especialmente FPR1 e FPR2. Diante da importância dos MCs e da ANXA1/FPR no desenvolvimento tumoral, o objetivo desta investigação foi analisar a heterogeneidade dos MCs e a expressão das proteínas ANXA1, FPR1 e FPR2 em biópsias humanas da... / Abstract: Uterine lesions are important causes of discomfort, infertility and death among women in Brazil and in the world. Endometrial cancer is a frequent malignant tumor and its incidence has been increasing in the last decades. Besides, the most common benign uterine tumor, leiomyoma, affects about 40% of women at reproductive age, being related to menorrhagia, dysmenorrhea and infertility. Investigations indicate that the tumor microenvironment is crucial for the advancement of cancer, being characterized mainly by the altered composition of the extracellular matrix, high microvessel density and abundance of inflammatory cells, such as mast cells (MCs). Degranulated MCs release chemotactic and protease factors, such as tryptase and chymase, to the extracellular medium, contributing to the degradation of the extracellular matrix, promoting angiogenesis, providing a favorable environment for tumor invasion and tissue remodeling through selective proteolysis in the matrix and activation of metalloproteinases. Another important aspect of tumor growth is the anti-inflammatory protein Annexin A1 (ANXA1), related to the regulation of growth and migration / invasion processes, and its effects mediated by receptors for formylated peptides (FPRs), especially FPR1 and FPR2. The objective of this investigation was to analyze the heterogeneity of the MCs and the expression of the ANXA1, FPR1 and FPR2 proteins in human biopsies of clinical-pathological variables of normal uterus: simple endometrial hyperplasia (HES), adenomyosis, leiomyomas and endometrial adenocarcinoma (ADC) of grades I and II. MCs were quantified according to their state of activation and expression of tryptase and chymase proteases. Expression of ANXA1 and its FPR1 and FPR2 receptors in the MCs and uterine tissues were analyzed in the different biopsies studied. Our results showed intact and degranulated MCs in the normal ... / Mestre

Publicación a texto completo no autorizada por el autor / Determina el nivel de conocimiento sobre factores de riesgo y medidas preventivas del cáncer de cuello uterino en los estudiantes del colegio Nº 6066 del distrito de Villa El Salvador del año 2014. El propósito está orientado en reforzar el conocimiento y garantizar la prevención del cáncer de cuello uterino en los estudiantes. El presente estudio es nivel aplicativo de tipo cuantitativo, el método descriptivo de corte transversal, el estudio se realiza en una institución educativa. El instrumento que se utiliza es, para la recolección de datos, el cuestionario y la técnica es la encuesta, el cual es aplicado a una muestra de 60 estudiantes de colegio. Concluyendo que el nivel de conocimientos que tienen los estudiantes del colegio I.E. Nº 6066 sobre factores de riesgo y medidas preventivas del cáncer de cuello uterino, en su mayoría es alto y medio. / Trabajo académico

MSc, Paediatrics and Child Health, Faculty of Health Sciences,University of the Witwatersrand / Background To investigate whether in-utero exposure to highly active antiretroviral treatment (HAART) is associated with low birth weight and/or preterm birth in a population of South African women with advanced HIV infection. Methods A retrospective observational study was performed on women with CD4 cell counts ≤250 cells/mm3 attending antenatal antiretroviral clinics at two clinics in Johannesburg between October 2004 and March 2007. Low birth weight (<2.5kg) and preterm birth rates (<37 weeks) were compared in those exposed versus unexposed to HAART during pregnancy. Effects of different HAART regimen and duration (<28 weeks or ≥ 28 weeks) were assessed. Results Among HAART-unexposed infants 27% (60/224) were low birth weight (LBW) compared to 23% (90/388) of early HAART-exposed and 19% (76/407) of late HAART-exposed infants (P=0.05). In the early HAART group, older maternal age was associated with LBW and higher CD4 cell count protective against LBW (AOR 1.06, 95% CI 1.00- 1.12 and AOR 0.58, 95% CI 0.46-0.73, P<0.001, respectively). HAART-exposed infants had an increased risk of preterm birth vii (<37 weeks) (15% [138/946] versus 5% [7/147], p=0.001), with early (<28 weeks) nevirapine and efavirenz having the strongest associations with preterm birth (AOR 5.4, 95%CI 2.1-13.7, P<0.001 and AOR 5.6, 95%CI 2.1-15.2, P=0.001, respectively). Conclusion Among infants born to women with CD4 cell counts <250 cells/mm3, HAART exposure was associated with preterm birth, but not with low birth weight. More advanced immunosuppression was a significant risk factor for both LBW and preterm birth, highlighting the importance of earlier HAART initiation in pregnant women, both to optimize maternal health and to improve infant outcomes

Determina el nivel de conocimiento sobre prevención de cáncer de cérvix y mama de las mujeres del asentamiento humano San Carlos. El estudio es de nivel aplicativo, de tipo cuantitativo, método descriptivo y de corte transversal. La población consta de 30 mujeres. La técnica es la entrevista y el instrumento un cuestionario sometido a juicio de expertos, a la prueba correlación de Pearson para determinar la validez y a la prueba de Kuder – Richardson para determinar su confiabilidad. Encuentra que del 100% (30) de las mujeres, el 60% (18) presentan un nivel de conocimiento medio, el 27% (8) muestra un nivel de conocimiento alto y el 13% (4) tiene un nivel de conocimiento bajo. Concluye que la mayoría de mujeres del asentamiento humano San Carlos tiene un nivel de conocimientos medio sobre prevención de cáncer de cérvix y mama. / Trabajo académico

Lacking a healthy attachment to a caregiver and having in-utero methamphetamine exposure have been linked to a variety of cognitive delays, developmental delays, and mental health issues throughout a person's lifespan. It is unknown if there is a relationship between in-utero methamphetamine exposure and the ability to build a healthy attachment to a caregiver. The purpose of this generic qualitative study was to improve understanding of the perceptions of caregivers about attachment efforts for foster children under the age of 3, who have had in-utero methamphetamine exposure. This study was guided by attachment theory. Purposeful sampling was used to select 7 participants who had provided care to foster children with in-utero methamphetamine exposure within the last year. Data were collected through the use of semistructured interviews, which were conducted in-person, audiotaped, and then transcribed. Data was analyzed through text searches of themes, axial coding, and repetitive words. Trustworthiness was obtained through member checking and generating a rich description of the participants' experiences. The findings revealed that many of the participants feel that these children do not respond to their efforts to build a healthy attachment to them. They also felt that the foster children did not process stimuli, such as touch, in the same way as other children; that the foster children found such interactions to be aversive. The findings of this study have the potential to impact social change by assisting therapists, caseworkers, and foster parents better understand the needs of foster children and to create a foundation for interventions to better serve foster children with in-utero methamphetamine exposure.

Cerebral cortex development is a complex process that integrates both extrinsic and intrinsic mechanisms. The surrounding cellular environment triggers receptor activation, which in turn initiates components of different signalling cascades and subsequently gene transcription, influencing cell survival, proliferation, and differentiation. Genetic mutations causing a loss-of-function or gain-of-function of signalling pathways elements can lead to cortical abnormalities and result in cognitive dysfunctions. In this thesis, I examined the receptor tyrosine kinase (RTK) TrkB and TrkC, the small GTPase Ras, and the C/EBP family of transcription factors, investigating their roles during cerebral cortex development. First, I looked at the role of C/EBPs during cortical cell fate determination. I determined that inhibition of C/EBPs decrease neurogenesis, keeping precursors in an undifferentiated state and later promoting their differentiation into astrocytes, while expression of an activated form of C/EBP promoted neurogenesis and reduced astrogenesis. Moreover, the inhibition of MEK, a mediator of C/EBPβ phosphorylation, also caused a decrease in neurogenesis. Thus, activation of the MEK-C/EBP pathway biases precursor cells to become neurons rather than astrocytes, thereby acting as a differentiation switch. Second, I examined the involvement of Trk signalling during cortical development. I showed that genetic knockdown using shRNA, or inhibition using dominant negative of TrkB and TrkC lead to a decrease in proliferation and later to postnatal precursor cells depletion. Moreover, it caused a reduction in number of neurons combined with mislocalization of the generated neurons to the different cortical layers. Thus, Trk signalling plays an essential role in the regulation of cortical precursor cell proliferation and differentiation during embryonic development. Third, I elucidated the effect of Costello syndrome H-Ras mutations during cerebral cortex formation. I determined that these mutations promoted cell proliferation and astrogenesis, while reducing neurogenesis. Together, these data support a model where proper Trks/Ras/MEK/C/EBP signalling is essential for normal genesis of neurons and astrocytes and show that cortical development perturbations can ultimately lead to cognitive dysfunction as seen in Costello syndrome patients.

Cerebral cortex development is a complex process that integrates both extrinsic and intrinsic mechanisms. The surrounding cellular environment triggers receptor activation, which in turn initiates components of different signalling cascades and subsequently gene transcription, influencing cell survival, proliferation, and differentiation. Genetic mutations causing a loss-of-function or gain-of-function of signalling pathways elements can lead to cortical abnormalities and result in cognitive dysfunctions. In this thesis, I examined the receptor tyrosine kinase (RTK) TrkB and TrkC, the small GTPase Ras, and the C/EBP family of transcription factors, investigating their roles during cerebral cortex development. First, I looked at the role of C/EBPs during cortical cell fate determination. I determined that inhibition of C/EBPs decrease neurogenesis, keeping precursors in an undifferentiated state and later promoting their differentiation into astrocytes, while expression of an activated form of C/EBP promoted neurogenesis and reduced astrogenesis. Moreover, the inhibition of MEK, a mediator of C/EBPβ phosphorylation, also caused a decrease in neurogenesis. Thus, activation of the MEK-C/EBP pathway biases precursor cells to become neurons rather than astrocytes, thereby acting as a differentiation switch. Second, I examined the involvement of Trk signalling during cortical development. I showed that genetic knockdown using shRNA, or inhibition using dominant negative of TrkB and TrkC lead to a decrease in proliferation and later to postnatal precursor cells depletion. Moreover, it caused a reduction in number of neurons combined with mislocalization of the generated neurons to the different cortical layers. Thus, Trk signalling plays an essential role in the regulation of cortical precursor cell proliferation and differentiation during embryonic development. Third, I elucidated the effect of Costello syndrome H-Ras mutations during cerebral cortex formation. I determined that these mutations promoted cell proliferation and astrogenesis, while reducing neurogenesis. Together, these data support a model where proper Trks/Ras/MEK/C/EBP signalling is essential for normal genesis of neurons and astrocytes and show that cortical development perturbations can ultimately lead to cognitive dysfunction as seen in Costello syndrome patients.

Benzene is an ubiquitous pollutant and industrial solvent that has been identified as a human leukemogen. Early exposure to environmental carcinogens such as benzene has been postulated to play a role in the etiology of childhood leukemia, however the association remains controversial. Genotoxic agents such as benzene can cause an increase in the frequency of DNA double-strand breaks, which may remain unrepaired or result in the initiation of DNA recombinational repair mechanisms. The first objective was to investigate the induction of DNA double-strand breaks following in utero treatment to 200 mg/kg and 400 mg/kg benzene i.p. using the phosphorylated histone γ-H2A.X as a marker. Using immunoblotting, treatment with benzene did not increase the formation of γ-H2A.X in bone marrow cells of adult C57Bl/6N male mice and in maternal bone marrow, fetal liver, and post-natal bone marrow cells following in utero exposure to 200 mg/kg or 400 mg/kg benzene throughout gestational days 7 to 15. Secondly, the study investigated the induction of micronuclei following in utero exposure to benzene. Acute exposure to 400 mg/kg benzene resulted in a statistically significant increase in the percentage of micronucleated cells in adult male bone marrow cells. In utero exposure to 400 mg/kg benzene throughout gestational days 7 to 15 also caused a statistically significant increase in the percentage of micronucleated cells in maternal bone marrow and post-natal bone marrow cells. Fetal liver cells also demonstrated a statistically significant increase in the percentage of micronucleated cells following 200 mg/kg and 400 mg/kg benzene. The third objective was to investigate the initiation of DNA recombination following in utero exposure to benzene using the pKZ1 mutagenesis mouse model as a surrogate marker for non-homologous end joining activity. Adult pKZ1 mouse tissue yielded no recombination events; however, post-natal bone marrow cells did contain detectable recombination frequencies. iii In utero benzene exposure did cause an increasing trend in recombination events, and upon analysis of only the samples containing detectable levels of recombination, in utero exposure to 400 mg/kg of benzene caused a statistically significant increase in recombination frequency within this group. These results demonstrate that benzene does not increase the formation of γ-H2A.X after acute and in utero exposure, however, the induction of micronuclei following acute and in utero benzene exposure confirmed that benzene is a genotoxic agent causing chromosomal breaks. In utero benzene exposure increased the frequency of DNA recombination in bone marrow from post-natal day 9 pups exhibiting detectable levels of recombination. Further investigations into different types of DNA damage and repair pathways are warranted to fully elucidate the role of genotoxic mechanisms in the etiology of benzene-induced childhood leukemias. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2008-08-22 11:07:49.162