Thesis (M.S.)--University of Michigan, 1964.

Orientador: Emilio Carlos Elias Baracat / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-10T19:56:13Z (GMT). No. of bitstreams: 1 Souza_TathianaGhiside_M.pdf: 2695580 bytes, checksum: b0307c601001a0729b775051fc783c4c (MD5) Previous issue date: 2008 / Resumo: Recém-nascidos prematuros correspondem de 7 a 10% de todos os nascimentos, mas concentram aproximadamente 85% de todas as complicações perinatais, com alto risco para o desenvolvimento de lesões pulmonares, principalmente a displasia broncopulmonar (DBP), e do sistema nervoso central. O objetivo deste estudo foi descrever e comparar a avaliação neurológica de recém-nascidos pré-termo (RNPT) com e sem DBP. Recém-nascidos pré-termo com peso de nascimento inferior a 1.500g e idade gestacional menor de 32 semanas foram avaliados com 40 semanas de idade gestacional corrigida, no Centro de Atenção Integral a Saúde da Mulher (CAISM) da UNICAMP. Foi utilizada a Avaliação Neurológica de Dubowitz, composta integralmente por 34 itens, dos quais 29 foram avaliados, divididos em 6 categorias: tônus, padrões de tônus, reflexos, movimentos, sinais anormais e comportamento. O estado de consciência do RN no momento do exame foi graduado utilizando-se os 6 graus definidos por BRAZELTON (1973). No período de janeiro de 2005 a setembro de 2007, vinte e quatro recém-nascidos, 12 com DBP e 12 controles sem a doença foram avaliados. A idade média de nascimento foi de 28 semanas (+- 1,38) no grupo com DBP e 31 semanas (+- 1,44) no grupo controle; peso médio no grupo de estudo de 884g (+- 202g) e no grupo controle de 1.156g (+- 216g). Dezoito dos 29 itens avaliados foram homogêneos entre os grupos (p = 1,00) e a pontuação geral dos dois grupos não apresentou diferença (p = 0,30). Na análise dos dados descritivos, observou-se um percentual maior de anormalidade no grupo com DBP em oito itens. A avaliação neurológica de RNPTs com e sem Displasia Broncopulmonar, pelo método Dubowitz, não apresenta diferença às 40 semanas de idade gestacional corrigida / Abstract: Preterm newborns corresponds to 7 to 10% of all births, but concentrates approximately 85% of all perinatal complications, with high risk of pulmonary injuries development, mainly bronchopulmonary dysplasia (BPD), and in the central nervous system. This study objective describes and compares preterm newborns neurological assessment with and without BPD. Preterm newborns with birth weight less than 1.500g and gestational age less than 32 weeks were evaluated by Dubowitz Method, with 40 weeks corrected gestational age, at Centro de Atenção Integral a Saúde da Mulher (CAISM) - UNICAMP. Dubowitz Neurological Assessment was used, consisting of 34 items, which 29 were evaluated, grouped in 6 categories: tone, tone patterns, reflexes, movements, abnormal signs and behavior. Newborn behavioral state was graded in 6 degrees defined by BRAZELTON (1973). From January 2005 to September 2007, twenty four newborns with average birth age of 28 weeks (+- 1,38) from BPD group and 31 weeks (+- 1,44) from control group were evaluated; Study¿s group mean weight was 884g (+- 202g) and control¿s group was 1.156g (+- 216g). Eighteen from 29 checked items were classified as homogeneous among groups (p = 1.00) and general score on two groups were not significantly different (p = 0.30). When analyzed in descriptive manner, the data showed greater abnormality percentage on the BPD group in eight items. The neurological assessment using Dubowitz Neurological method on preterm newborns with and without BPD does not show differences from 40 weeks corrected gestational age / Mestrado / Saude da Criança e do Adolescente / Mestre em Saude da Criança e do Adolescente

Osteoarthritis of the hip frequently occurs in the absence of osteoarthritis in other large joints, suggesting that local factors are important in its pathogenesis. Hip morphology has been recognised as a potential local biomechanical risk factor for the development of hip osteoarthritis. There are no adequate studies examining osteoarthritis development in the hip. Historical cohorts are either limited by a short follow up or by small numbers. This thesis explores the natural history of hip osteoarthritis in a large population cohort with particular attention to hip morphology as a predictor of osteoarthritis development. Software was developed which allows objective measurements of hip morphology in a reproducible manner. Hip morphology was then measured in a 1000 subject cohort. A detailed description of hip morphology is presented in this thesis, with interesting observations of wide variation and a bimodal distribution for alpha angle (a measure of cam-type femoroacetabular impingement). This is suggestive of a discrete pathological entity, which was associated with osteoarthritis in the cross-sectional analysis. No significant changes exist in terms of morphology during the course of the study and no significant relationship exists between age and hip morphology. Longitudinal analysis of hip morphology with radiographic osteoarthritis and total hip replacement revealed a significant association between cam-type femoroacetabular impingement and acetabular dysplasia with both outcome measures. Measurements of hip morphology were independently predictive of outcome when controlling for baseline age, BMI and joint space width, and significantly increased our ability to predict osteoarthritis and total hip replacement. Similar associations were seen when considering hip pain and symptomatic osteoarthritis as the outcome measures of interest. Pincer-type femoroacetabular impingement was not significantly associated with any of the outcome measures of interest and pain remains relatively poorly explained by both hip morphology and/or radiographic change. The understanding of hip morphology and its role in the natural history of osteoarthritis is significantly improved by this research. Further research is now required to determine whether these morphological abnormalities represent modifiable risk factors for osteoarthritis progression.

Bronchopulmonary dysplasia (BPD) is diagnosed in approximately 40% of extremely preterm infants, those born before 28 weeks’ gestational age, and affects roughly 10,000 to 15,000 infants annually in the United States alone. Current treatment of BPD aims to not only aid in the survival of the infant but to also minimize further lung damage and promote physiologic growth to enhance lung development and repair. As the pathogenesis of the disease is multifactorial, including pre-, peri-, and postnatal factors, treatment and prevention approaches to BPD are diverse and include both medical treatment and ventilation strategies. Late postnatal steroids (> 7 days of life) have been proven to facilitate extubation and reduce the incidence of BPD in preterm infants. However, there is evidence that the use of steroids may contribute to increased rates of neurological impairment, including increased incidence of cerebral palsy. Given these findings, the American Academy of Pediatrics (AAP) guidelines recommend against the routine use of systemic steroids in the prevention of BPD and instead argues its use should be limited to infants who are considered extremely high-risk. The aim of this study is to determine whether the use of postnatal dexamethasone decreases the risk of developing BPD in a subset of high-risk infants, those with a concomitant diagnosis of necrotizing enterocolitis or late onset sepsis. A sample size of 200 extremely preterm infants with either necrotizing enterocolitis (NEC) and/or sepsis will be enrolled in a multi-center double-blinded randomized controlled trial comparing a low-dose dexamethasone taper and saline placebo. Infants will be evaluated for the development of BPD based on respiratory support and supplemental oxygen requirement at 36 weeks’ post-menstrual age (PMA). Infants will also be evaluated for presence of neurodevelopmental outcomes at 18- to 22-months follow-up. The results of this proposed study will build the evidence base for the safety and efficacy of postnatal steroids in the prevention of BPD in a subset of high risk, extremely preterm infants. This will help to establish a more detailed characterization of infants for which the benefits of steroids outweigh the risks. The results will enable clinicians to make more informed decisions regarding the medical care of extremely preterm infants and more accurately counsel parents on the incidence of subsequent BPD development, as well as long-term morbidities.

Newer biological treatment strategies have been developed in the last decade with some promising outcomes. Their safety, however, has been questioned lately with multiple reports of increased risk for malignancies and infectious complications. These reports render their use suboptimal. We report a 44-year-old woman receiving adalimumab (Humira®) for advanced juvenile rheumatoid arthritis who then developed acute myelogenic leukemia.

Craniometaphyseal dysplasia (CMD) is a rare genetic skeletal disorder, whose biological understanding is not very well known. The disease manifests itself through bony hypertrophy of the skull base, craniofacial bones, and abnormal morphology of the long bones, present in the carrier of the disease. CMD has been previously determined through genetic analysis to be a result of one of 15 (to date) discovered mutations. Fourteen of those mutations are inherited in an autosomal dominant fashion, via mutations in the ANKH gene. One mutation has been discovered to result in CMD through autosomal recessive inheritance, via a locus found in the connexin 43 gene, coding for gap junction protein alpha-1. As the genetic foundation of CMD has become more clearly understood over time, there has been a lack of similar progress in understanding the clinical manifestations of CMD. To improve our understanding of the clinical characteristics of CMD, we propose a natural history of disease study to be conducted. This study serves as a pilot for this larger scale study, by using a smaller patient population comprised of CMD patient database at the Reichenberger Lab at University of Connecticut Health (UCH), and CMD patients reported in the literature, to understand what is currently known about the clinical manifestations of CMD, and what should be evaluated for further research. In this study, the existing literature on CMD has been compiled and sorted into distinct groups – created to guide those unfamiliar to the disease through the available information. Secondly, a set of 76 patient cases compiled at the Reichenberger lab at UCH were analyzed to determine what clinical information on CMD has already been collected. Lastly, from an in depth analysis of two specific case files from the Reichenberger Lab CMD patient database it was discovered that blood chemistry levels are an important parameter for analysis in future studies. From abnormalities in blood chemistry within both cases were found. . In both patients it was found that elevations in serum alkaline phosphatase were present congenitally, and persisted throughout the early childhood years. Specific attention to changing serum alkaline phosphatase concentrations over early childhood development is recommended. Additionally, from data present in patient case 2, blood urea nitrogen (BUN/creatinine) was found to be highly elevated through early childhood, though eventually slowly decreasing to the upwards bounds of the normal physiological reference range, by the time the patient grew from ages 1 to 12. No BUN/Creatinine data was provided by the first case. Lastly, from an analysis of the literature, the patient case files at the Reichenberger lab at UCH and an in depth study of two specific patient cases a list of clinical parameters useful for investigation in a full-scale natural history of disease study of CMD is presented.

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M.Sc. Thesis Dissertation, August 2019, McMaster University / Renal dysplasia, defined as the abnormal development of kidney tissue, is the leading cause of kidney disease in children. While there are numerous causes of renal dysplasia (i.e. genetic, environmental and epigenetic factors), there is no cure to this abnormal defect. Kidney development occurs by two main processes: branching morphogenesis, which forms the collecting duct system, and nephrogenesis, which generates the nephrons, the functional units of the kidney. Our previous studies have demonstrated that β-catenin, a dual-function protein involved in cell adhesion and gene transcription, regulates branching morphogenesis and nephrogenesis. Furthermore, we discovered that nuclear β-catenin levels are increased in kidneys from patients with renal dysplasia, suggesting β-catenin can be a potential therapeutic target to modulate kidney development and renal dysplasia. Quercetin is a flavonoid that reduces β-catenin levels and inhibits its transcriptional activity, leading to improved outcomes in cancer and in kidney fibrosis. The role of quercetin in kidney development and in abnormal defects that arise during kidney development is yet to be examined. Using embryonic mouse kidney organ culture, I found that quercetin treatment resulted in a dose-dependent disruption in branching morphogenesis and nephrogenesis. In addition, quantitative reverse-transcriptase PCR revealed a decreased expression of β-catenin target genes essential for kidney development (i.e. Pax2, Six2 and GDNF). Immunohistochemistry for β-catenin demonstrated that quercetin reduced nuclear β-catenin expression and increased cytoplasmic and membrane-bound expression in a dose-dependent manner. These results were confirmed by Western blot analysis. These novel findings demonstrate that quercetin treatment resulted in decreased levels of nuclear β-catenin, resulting in a decrease in its transcriptional activity which manifested in alterations in kidney developmental processes, suggesting quercetin is effective at reducing nuclear β-catenin in wild-type embryonic kidneys. Next, to determine whether quercetin has any effects on renal dysplasia, I utilized transgenic mice models that overexpress β-catenin in select cells of the embryonic kidney. These models recapitulate the defects observed in human renal dysplasia, including disorganized branching morphogenesis and disrupted nephrogenesis. Quercetin treatment of embryonic dysplastic kidneys resulted in a partial rescue of renal dysplasia which was evident in marked improvements in branching morphogenesis and nephrogenesis, as well as an increase in the number of properly-developing nephrons in the kidney tissue. Analysis of β-catenin expression in quercetin-treated dysplastic kidneys revealed a decrease in nuclear levels and an increase in cytoplasmic and membrane-bound levels, resulting in a reduced expression of target genes (Pax2, Six2, and GDNF). Finally, this partial rescue of renal dysplasia was associated with an improved and organized E-cadherin expression in quercetin-treated dysplastic kidneys, suggesting a possible molecular mechanism of quercetin action in resolving abnormal kidney development. Overall, my findings demonstrate, for the first time, that quercetin reduces β-catenin transcriptional activity in normal and dysplastic kidneys and reduces the severity of defects in renal dysplasia. / Thesis / Master of Science in Medical Sciences (MSMS)

Ectodermal dysplasia with immunodeficiency (ED-ID) is a rare primary immunodeficiency syndrome characterized by defects in ectodermal tissues (skin, hair and sweat glands), recurrent infections, impaired response to Toll-like receptor ligands, hypogammaglobulinemia and deficient antibody production. It is caused by defective \(NF\kappa B\) signaling. The most common form of ED-ID is X-linked. It is caused by hypomorphic mutations in the \(NF\kappa B\) essential modifier gene NEMO, which is an important regulatory component in the \(NF\kappa B\) signaling pathway. We report the first case of ED-ID caused by insufficient expression of a NEMO protein of normal sequence, due to a mutation in the 5’ untranslated region of the NEMO gene. Autosomal dominant ED-ID, a rare form of ED-ID, has been reported to be caused by a heterozygous S32I mutation in the \(I \kappa B \alpha\). This mutation prevents IκBα phosphorylation and inhibits its degradation. The mutant sequesters \(NF\kappa B\) in the cytoplasm and acts as a dominant negative. We report the first ED-ID patient with a heterozygous mutation (W11X) that causes N-terminal truncation of \(I \kappa B \alpha\) and results in functional haploinsufficiency. We have constructed a knock-in mouse model of ED-ID caused by a heterozygous S32I mutation in \(I \kappa B \alpha\). The mutant mice had ED, increased mortality, complete lack of lymph nodes and Peyer’s patches, and disorganized spleens that lacked follicles, marginal zone B cells and follicular dendritic cells. T cell proliferation and cytokine production was normal in vitro, but in vivo contact hypersensitivity was severely impaired, B cell function in vitro and specific antibody response to antigens were severely reduced. All immune defects, except those that affected B cell function, were absent in \(I \kappa B \alpha\) S32I mutant \(Rag2^{-/- }\) bone marrow chimeras, indicating that defects in non-lymphiod cells play a major role in the immunodeficiency of patients with ED-ID due to mutations in \(I \kappa B \alpha\). This has important clinical implications, as bone marrow transplant may not be able to correct immune function in such patients. The lessons learned in these chapters may be applicable to other mutations that impair \(NF\kappa B\) signaling and have important implications for the treatment of patients who carry these mutations.