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Technological advances for treatment of congenital heart disease (CHD) have led to decreases in mortality over the past thirty years. Persistent morbidity into adolescence and adulthood necessitates regular medical follow-up and the influence of ongoing physical health issues on the teens emotional health merits clinician and researcher attention. Employing interpretive description research methodology, 22 interviews with teens aged 13-17 years were analyzed to understand how adolescents with CHD describe everyday life and relate to questions about quality of life (QOL). Although the majority of these teens viewed themselves as normal, CHD was a part of their everyday life that they situated into the foreground or background of their lives, as it suited their needs. These teens spoke of QOL issues in a concrete manner focusing on physical activity limitations and their need to fit in. Further discussion of these issues must be undertaken as adolescents with CHD transition to adulthood.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 5 uppsatser.

Congenital Hyperinsulinism of Infancy (CHI) is a potentially lethal condition caused by excessive, unregulated insulin release from pancreatic β-cells. It is a complex clinical condition and the current understanding of this disease is still not completed. In this thesis, we investigated the disease islet pathobiology from 4 main perspectives; Using nucleomegaly as a novel diagnostic marker; Identifying the mosaic of immature delta-cells in atypical CHI (CHI-A); Assessing the insulin secretory profile at the ultrastructural level; Investigating endocrine cell turnover and the driving force/mechanism behind it. By quantifying the enlarged nuclei in the endocrine pancreas of patients with CHI, we discovered that the increased incidence of nucleomegaly is pathognomic for diffuse CHI (CHI-D). This finding potentially set a novel diagnostic hallmark for intraoperative diagnoses. A characteristic of CHI-A is a combination of active and quiescent islets. The maintained expression of NKX2.2 in somatostatin positive cells suggests an immature delta-cells phenotype in quiescent islets and this is potentially contributing to the pathobiology of CHI-A. By examining the insulin secretory profile at the ultrastructural level, as well as investigating the crucial exocytosis-related genes from both RNA and protein levels, our data suggested a greater secretory capacity in β-cells from focal CHI lesion compared to CHI-D. Despite seeing a maintained potential for proliferative (Ki67) in CHI samples, there was no significant increase in apoptosis rates (cleaved caspase-3) and whole cell mass compared to control samples. Alterations in the cellular localisation of cell cycle regulators are a plausible explanation for these abnormal disease dynamics. These data expanded our knowledge on understanding CHI, and provided us new clues for the phenotypical alterations and pathobiological mechanisms in patients with this disease. Meanwhile, they also provided new insights in the future management of CHI.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Congenital abnormalities of the diaphragm, specifically congenital diaphragmatic hernia (CDH), affect 1 in 3,000 live births and are associated with substantial morbidity and mortality. Evidence in humans and animal models support genetic causation. The etiology of most cases, however, remains unknown, though is likely polygenic in the majority. Another impediment to uncovering CDH etiology is that collection of human specimens at the onset of diaphragm development (4 weeks gestation) is not feasible. Identification of key transcriptional programs involved in normal diaphragm development is needed to gain a more comprehensive understanding of the genetic etiology of CDH. As an initial step, unique transcriptome-wide data sets are generated from laser-captured mouse embryonic diaphragms at three key time-points of diaphragm development. These data sets provide the first unbiased perspective on genes and signaling pathways active during early and late diaphragm morphogenesis. Moreover, using a curated list of known CDR-associated genes as "baits", the normal expression data sets are filtered for identification of biologically relevant CDH candidate genes. By this approach, 27 novel CDH candidate genes are described, among which, pre-B cell leukemia transcription factor 1 (Pbxl) is selected to validate the prioritization approach. Diaphragm defects resembling the human CDH phenotype, never previously appreciated, are observed among Pbxl mutant mice at E15.5. Secondly, a human family containing several affected individuals with CDH is used for gene discovery. A multiplatform analysis approach, coupled with external filtering with the normal diaphragm expression data, provide a mechanism for identification of candidate modifier loci. This integrative strategy, which identifies a FOG2 deletion and several potential modifiers of the CDH phenotype, is described. The design of a customized diagnostic/discovery capture array for next-generation sequencing of a large CDH patient cohort uses the set of CDR-candidate genes identified herein. / 2031-01-02

Human Cytomegalovirus (HCMV) is the most common cause of viral congenital infection in the world. Around 5-10% of HCMV infected children are symptomatic at birth, and 50-90% of these develop severe manifestations with a 30% mortality rate. Among the asymptomatic children at birth, 10-15% develop late sequelae. The major cell entry glycoproteins of HCMV form three complexes: gC-I containing gB; gC-II containing gM &amp; gN; and gC-III containing gH, gL, and gO (or UL128-131). These entry glycoproteins are polymorphic, producing different glycoprotein genotypes. The polymorphic nature of the glycoproteins as well as their ability to elicit neutralizing antibodies made them of interest in correlating them with the severity and outcome of the disease. This study aimed to develop a robust system to identify clusters of glycoprotein genotypes and to correlate them with disease manifestation. PCR assays of high sensitivity were used to identify all six glycoproteins. The PCR products were digested using restriction enzymes (RFLP) to identify the glycoprotein genotypes. Available laboratory strains (AD169, Towne, Davis, Toledo, and Merlin) as well as 112 clinical samples were amplified and genotyped using the assay, and their glycoprotein genotype profile was determined. A reliable sensitive assay was successfully developed to identify all glycoprotein genotypes including a novel gM assay using PCR/RFLP. The clinical samples were grouped according to disease manifestation (Group 1: congenital/postnatal patients (subgroup 1A: confirmed congenital patients &amp; subgroup 1B: patients with either congenital or postnatal infection), Group 2: immunocompetent patients, Group 3: immunocompromised patients (subgroup 3A: immunocompromised patients with primary infection, subgroup 3B: immunocompromised patients with recurrent infection &amp; subgroup 3C: immunocompromised patients with unconfirmed primary or recurrent infection)). Genotype gB1 was found predominantly prevalent in congenital/postnatal and immunocompromised patients, while gB3 was the most common genotype in immunocompetent patients. This result along with the phylogenetic analysis performed in this study suggest a relationship between gB genotypes and the immune response of the patients, where gB3 may be positively selected by host immune pressure. The novel gM assay genotyped the highly conserved gene (UL100) into three distinct genotypes; gM3 genotype associated with the congenital/postnatal group; which may provide an insight into understanding viral attachment and spread into the host cell. In congenital/postnatal infection, gH1 (72.7%) and gL4 (65.1%) were the most prevalent genotypes (gH1= 32/44, gL4= 28/43; P=0.000). In immunocompetent patients, mixed gH and mixed gL genotypes significantly correlated with the group, and in the immunocompromised group gH2 and mixed gL genotype were the most common genotypes (51.1% and 46.9% respectively). Glycoproteins gO, gH and gL are components of gC-III complex and gO1 was found to be the most prevalent gO genotype in all infection types (Group 1= 32.1%, Group 2= 85.7%, Group 3= 18.8%; P < 0.05). Also, in congenital/postnatal infection gN and gO were found to significantly link with each other and this is expected since both glycoproteins are highly polymorphic and are located on adjacent gene loci in HCMV genome (gN1+gO1a (P=0.000), gN3a+gO4 (P= 0.000)). The specific gN-gO linkages found here could be potential indicators for congenital/postnatal infection. In congenital/postnatal infection group, gH had significant linkages to gN and gO (gH1+gN1 (P=0.023, gH1+gO1a (P=0.013)) suggesting that interlinked selection of glycoprotein genotypes in the gC-II and gC-III complexes is involved in the development of congenital infection. High viral loads were found trending with immunocompromised patients, while low viral loads were significantly associated with mixed infected patients. This study has shown significant associations between a number of glycoproteins and congenital infection. Previously ignored glycoproteins gM and gL have been shown to be potentially of significant interest in this study and a larger study to confirm this is needed. In most cases the pattern of glycoprotein genotypes in congenital infection is more similar to that of immunocompromised than immunocompetent patients and it is possible that immune pressure is selecting for or against particular glycoprotein genotypes. The relationship between mixed infection and sample type may offer opportunities for development of prognostic biomarkers for congenital disease and further work is warranted.

Islet transplantation has proved to be a useful treatment for Type 1 diabetes mellitus, but inadequate supplies of transplantable donor tissue have intensified the need to find a renewable source of β-cells. Human embryonic stem cells (HESC) are pluripotent and may offer a viable alternative to donor islets, but their targeted differentiation to a more specific β-cell phenotype is proving challenging. One strategy to restore β-cell mass is through activation of progenitor cells present in the pancreas. The aim of this study was to isolate and characterise progenitor cells from pancreatic tissue obtained from patients with Congenital Hyperinsulinism of Infancy (CHI). An enzymatic digestion was used to isolate islets from four patients with CHI and CHI-derived cell lines (NES139, NES140, NES140 and NES144) were subsequently derived that had the potential to proliferate in vitro. The previously-described cell line NES2Y was utlised as a control cell line for comparison. Using RT-PCR, exon array, qPCR, immunocytochemistry and Ca2+ microfluorimetry techniques this thesis examines both the molecular and physiological characteristics of these four CHI-derived cell lines to establish their potential as populations of pancreatic progenitor cells. Genotyping revealed that all of the patients carried mutations in the SUR1 gene, ABCC8. Pancreatic endocrine progenitor markers (e.g. PDX1, SOX9 and HLBX9) as well as islet precursor markers (e.g. NKX2.2, NKX6.1, NEUROD1, PAX6 and FOXA2) were identified and their expression was stable over continuous cell culture. However, each of the cell lines failed to express other markers, specifically NGN3, PAX4, and ISLET1. Cell lines developed from each patient then underwent a fibroblast to epithelial-like morphological transition. High-throughput exon array analysis revealed a significant down regulation of ACTA2, VIM and upregulation of CDH1 (q value < 0.05), a gene expression pattern associated with a mesenchymal-to-epithelial transition. Analysis at the mRNA level identified that CHI-derived cell lines expressed those channels and transporters associated with the β-cell function of glucose-stimulated insulin secretion (GSIS). Yet, when expression of all five endocrine hormones was investigated, mRNA expression was undetectable in three CHI-derived cell lines, except for the expression of insulin in NES143. Protein level assessment, however, failed to detect any expression of insulin. Functional studies examining whole cellular calcium dynamics and those underlying GSIS revealed that, whilst ATP (0.1 mM) and histamine (0.1 mM) readily raised intracellular Ca2+, each of the cell lines failed consistently to respond to tolbutamide (0.1 mM), glucose (20 mM), diazoxide (0.1 mM) and KCl (40 mM), except for NES140 which responded to applications of acetylcholine (0.1 mM). Given the display of cellular plasticity, molecular and physiological characteristics, the data show CHI-derived cell lines mimic pancreatic progenitor cell populations. More importantly, they represent islet precursor cells of the secondary transition phase of pancreatic development. Future studies should concentrate on the inductive potential of these cells to produce mature insulin-secreting β-cells.

Made available in DSpace on 2014-06-11T19:29:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-07-22Bitstream added on 2014-06-13T19:25:49Z : No. of bitstreams: 1 magalhaes_dms_me_botfm.pdf: 206735 bytes, checksum: aa519bde82357abc38ac12018ce6a987 (MD5) / Fundação de Ensino e Pesquisa em Ciências da Saúde (FEPECS) / A sífilis na gestação é um grave problema de saúde pública, responsável por altos índices de morbimortalidade intrauterina. Estima-se que leve, em pelo menos 50% das gestações acometidas, a desfechos perinatais adversos. Esses dados remetem à falta de controle das doenças sexualmente transmissíveis (DST) e à deficiência na assistência pré-natal. O objetivo deste estudo transversal foi conhecer o perfil sócio-demográfico e os antecedentes obstétricos das gestantes com VDRL reagentes no DF no ano de 2010. Verificou-se o percentual de gestantes que tiveram acesso ao pré-natal e foram inadequadamente tratadas de acordo com as recomendações do MS. Foram entrevistadas 67 gestantes/ puérparas notificadas no SINAN, em cinco maternidades públicas do DF e consultadas as informações do prontuário e cartão da gestante quando disponível. Foram avaliados dados sóciodemográficos, obstétricos, informações relacionadas ao diagnóstico e tratamento da gestante/puérpara e parceiro. Apenas 41,8% gestantes foram adequadamente tratadas e o principal motivo para a inadequação do tratamento foi a falta (83,6%) ou inadequação do tratamento do parceiro (88,1%). Foi constatada a necessidade de novo tratamento da gestante na maternidade por falta de documentação do tratamento realizado no pré-natal. Os dados demonstram que a qualidade do pré-natal recebido pela gestante não é suficiente para garantir o controle da sífilis congênita e o atingimento da meta de controle da doença / Syphilis during pregnancy is a serious public health problem responsible for high rates of intrauterine mortality. It is estimated that in at least 50% of pregnancies affected, adverse perinatal outcomes happen. These findings reflect the lack of control of sexually transmitted diseases (STDs) and disability in prenatal care. The goal of this survey was to understand the epidemiological profile of women with VDRL reagents in the Federal District in 2010. The study verified the percentage of pregnant women who had access to prenatal care and were inadequately treated in accordance with the recommendations of the Ministry of Health. We interviewed 67 pregnant and postpartum women who reported to the SINAN, users of five public hospitals of the DF and consulted information from medical records and from prenatal care charts, when available. Data were collected on sociodemographic, obstetric, information related to diagnosis and treatment of pregnant and puerperal women and their partners. Only 28 (41.8%) patients were adequately treated and the main reason for inadequacy was the lack of treatment (83.6%) or inadequate treatment of the partner (88.1%). The study demonstrated the need for new treatment of the mother at the hospital for lack of documentation of the treatment in prenatal care. Our data demonstrates that the quality of prenatal care received by pregnant women is not sufficient to ensure control of congenital syphilis and reaching the goal of controlling the disease

No description available.