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

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

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 3 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 4 uppsatser.

Thesis (M.N.)--Memorial University of Newfoundland, 2004. / Typescript. Bibliography: leaves 141-150.

abstract: Type 1 Diabetes Mellitus (T1DM) is a chronic disease that requires maintaining tight metabolic control through complex behavioral and pharmaceutical regimens. Subtle cognitive impairments and stress response dysregulation may partially account for problems negotiating life changes and maintaining treatment adherence among emerging adults. The current study examined whether young adults with T1DM physiologically respond to psychological stress in a dysregulated manner compared to non-diabetic peers, and if such individuals also demonstrated greater cognitive declines following psychological stress. Participants included 23 young adults with T1DM and 52 non-diabetic controls yoked to T1DM participants based on age, gender, ethnicity, participant education, and maternal education. Participants completed a laboratory-based social stressor, pre- and post-stressor neurocognitive testing, provided fingerstick blood spots (for glucose levels) and salivary samples (for cortisol levels) at five points across the protocol, and completed psychosocial questionnaires. Related measures ANOVAs were conducted to assess differences between T1DM participants and the average of yoked controls on cortisol and cognitive outcomes. Results demonstrated that differences in cortisol reactivity were dependent on T1DM participants' use of insulin pump therapy (IPT). T1DM participants not using IPT demonstrated elevated cortisol reactivity compared to matched controls. There was no difference in cortisol reactivity between the T1DM participants on IPT and matched controls. On the Stroop task, performance patterns did not differ between participants with T1DM not on IPT and matched controls. The performance of participants with T1DM on IPT slightly improved following the stressor and matched controls slightly worsened. On the Trail Making Test, the performance of participants with T1DM was not different following the stressor whereas participants without T1DM demonstrated a decline following the stressor. Participants with and without T1DM did not differ in patterns of performance on the Rey Verbal Learning Task, Sustained Attention Allocation Task, Controlled Oral Word Association Task, or overall cortisol output across participation. The results of this study are suggestive of an exaggerated cortisol response to psychological stress in T1DM and indicate potential direct and indirect protective influences of IPT. / Dissertation/Thesis / Ph.D. Psychology 2013

O adequado manejo do DM Tipo 1 tem se tornado um desafio, principalmente para as próprias crianças, em virtude da presença de comportamentos, habilidades e conhecimentos inadequados que colaboram para a não adesão ao tratamento e para aumento de complicações em longo prazo. Estudos têm demonstrado que compreender as experiências de vida das crianças nos seus diversos espaços, valorizando-as e buscando maior aproximação com as mesmas, pode contribuir para a partilha do conhecimento sobre o manejo do diabetes e para o maior envolvimento da criança no cuidado. O objetivo deste trabalho foi compreender, na perspectiva de crianças com DM Tipo 1, os fatores que interferem no manejo da doença. Trata-se de uma pesquisa qualitativa, de natureza exploratória. Participaram do estudo 19 crianças. Utilizamos a entrevista semiestruturada e, como recurso facilitador da comunicação com a criança, os fantoches. Esses brinquedos foram confeccionados pelas próprias crianças e criou-se, também, um cenário que ilustrou e complementou a utilização dos fantoches no dia da entrevista. A análise dos dados empíricos foi feita por meio da análise de conteúdo. Os resultados evidenciaram a compreensão do que é ser criança com diabetes e dos fatores relacionados à sua existência, como seus sentimentos e percepções. A compreensão da interação da criança com os conhecimentos que possui sobre a sua doença, sua inserção no processo do autocuidado, as habilidades desenvolvidas e os recursos disponíveis para lidar com as demandas da doença constituem fatores que interferem de forma positiva ou negativa no manejo da doença e merecem ser foco de atenção dos profissionais de saúde. Todos esses elementos atuam dinamicamente nos espaços do cotidiano da criança, tais como o familiar, o escolar, o de amizades, o de lazer e o dos serviços de saúde, atuando como fatores que fragilizam ou potencializam o manejo da doença. O apoio de familiares, amigos, professores e profissionais de saúde que compartilham as experiências de ser uma criança com diabetes mostrou-se essencial para o alcance do adequado manejo. Além disso, o conhecimento adquirido por estes atores e pela própria criança interfere diretamente no manejo do DM Tipo 1. Os resultados deste estudo evidenciam ações que visam a fortalecer o trabalho da equipe multidisciplinar no cuidado da criança com diabetes e apontam cenários de atuação que podem ser incrementados pelos profissionais de saúde. O enfermeiro ocupa posição privilegiada para identificar e operacionalizar ações apropriadas ao estágio de desenvolvimento da criança e às suas necessidades, em todos os espaços em que vive, atuando, assim, em consonância com todos os envolvidos em prol do sucesso do manejo da doença. / The adequate handling of Type 1 DM has become a challenge, mainly for the children themselves, due to the presence of inadequate behaviors, skills and knowledge that contribute to non-adherence to treatment and increased complications in the long term. Research has demonstrated that understanding children\'s life experiences in their different spaces, valuing them and seeking greater approximation, can contribute to knowledge sharing on diabetes management and to the children\'s greater involvement in care. This research aimed to understand, from the perspective of children with Type 1 DM, the factors that interfere in the management of this disease. This is a qualitative and exploratory research. Study participants were 19 children. Semi-structured interviews were used and, to facilitate communication with the child, puppets, which the children made themselves. A scenario was also created to illustrate and complement the use of puppets on the day of the interview. Content analysis was used for empirical data analysis. Results evidenced the understanding of what it means to be a child with diabetes and the factors related to his/her existence, such as feelings and perceptions. Understanding of these children\'s interaction with their knowledge about their disease, their insertion in the self-care process, developed skills and resources available to deal with the demands of the disease constitute factors that interfere positively or negatively in disease management and deserve further attention from health professionals. All of these elements act dynamically in the child\'s daily spaces, such as the family, school, friendships, leisure and health services, as factors that weaken or strengthen disease management. Support from relatives, friends, teachers and health professionals who share the experiences of being a child with diabetes showed to be essential to achieve adequate management. Moreover, the knowledge these actors and the children themselves acquire interferes directly in Type 1 DM management. These study results evidence actions aimed at strengthening the work of the multidisciplinary team in care delivery to children with diabetes and indicate activity scenarios which health professionals can build upon. Nurses play a privileged role to identify and put in practice actions that are appropriate for the children\'s development stage and needs, in all spaces they live in. Thus, they act in line with all parties involved with a view to successful disease management.

Introdução: Diabetes tipo 1A(DM1A) é uma doença causada pela destruição autoimune das células beta. Em adição aos linfócitos T helper 1(Th1) e Th2, um subtipo específico de células T helper recentemente descrito, Th17, caracterizado pela produção da interleucina 17(IL-17A), IL-17F e IL-22, está também envolvido na imunidade adaptativa e autoimunidade, incluindo DM1A. A IL-23 tem função fundamental na expansão e sobrevivência das células Th17. A mesma é composta por 2 subunidades: a p19-específica (IL-23A) e a p40. Variantes dos genes IL-23A e de seu receptor (IL-23R) ou o aumento das concentrações séricas da IL-23 estão associados a várias doenças autoimunes, mas seus efeitos no DM1A não estão definidos. Com o intuito de avaliar a importância da IL-23 na patogênese do DM1A, as variantes dos genes IL23A e IL23R foram analisadas. Metodologia: A região codificadora e os regiões intrônicas proximais do gene IL23A, incluindo a região 5 proximal foram sequenciadas. Duas variantes do gene IL23A (rs2066808 e rs11171806) e duas do gene IL-23R (rs11209026 e rs10889677) foram também genotipadas. A amostra contou com 370 pacientes com DM1A e 314 indivíduos controles saudáveis. As medidas das concentrações séricas da IL-23 e os autoanticorpos pancreáticos e extra-pancreáticos foram determinados. Resultados: Nós observamos somente uma das seis variantes da IL-23 descritas nos bancos de dados (rs11171806 G>A localizada no exon 3) e descrevemos uma nova variante no gene IL-23A, que consistiu na substituição da citosina por timina na posição c.-403 (C>T) na região 5 proximal deste gene (encontrada em heterozigose em apenas uma paciente com DM1A, do sexo feminino, com 28 anos ao diagnóstico).Os alelos G dessas duas variantes estiveram em forte desequilíbrio de ligação (D\' = -0,825 para controles, p<2,0X10-6 e D\' = -0,902, p<2,0X10-17 para pacientes). Em consequência, a análise dos haplótipos destas variantes foi realizada. O haplótipo GG foi mais frequente nos controles (16.7%) do que nos pacientes com DM1A (9.5%), conferindo proteção à doença (pc = 0,0009, OR = 0,53) . A presença do haplótipo GG diferiu de acordo com a etnia no conjunto de pacientes e controles, sendo menor naqueles de etnia caucasóide (18%) em relação aos outros grupos (39%); p<0.0001. Entretanto, o efeito protetor da haplótipo GG foi independente da etnia. As duas variantes do gene IL23R (rs10889677 e rs11209026) tinham frequência alélica e genotípica semelhante entre pacientes com DM1A e controles. Não foi observada diferença significante nas concentrações da IL-23 entre 135 pacientes com DM1A (5,65 ± 14,0 pg/mL) e 112 indivíduos controles (9,06 ± 23,7pg/mL) (p =0,18). , mesmo quando analisamos apenas o pacientes com duração do diabetes inferior a dois anos, nos quais a resposta imune contra as células beta ainda está presente, (4.65 ± 6.94 pg/mL e 9.07 ± 23.62 pg/mL, p = 0.076). Não foi encontrada associação entre as variantes do gene IL23A com a idade diagnóstica, presença do peptídeo C residual e auto-anticorpo anti-descarboxilase do ácido glutâmico em pacientes com diagnóstico recente de DM1A. Estas variantes também não influenciaram na freqüência dos auto anticorpos extrapancreáticos: anti-tireoglobulina, anti-peroxidase, anti-21 hidroxilase, fator anti-núcleo, fator reumatóide e anti-citoplasma de neutrófilos. Conclusões: O haplótipo GG das variantes do gene lL23A (rs11171806 e rs2066808) foi associado a proteção ao DM1A. As variantes do gene IL23R (rs11209026 e rs10889677) não foram associadas ao DM1A. As concentrações séricas da IL-23 foram semelhantes entre os grupos. / Introduction: Type 1 diabetes mellitus (T1D) is a disorder caused by the immune-mediated destruction of insulin-secreting pancreatic beta cells. In addition to T helper 1 (Th1) and Th2 cells, a recently discovered subset of T helper cells, Th17, characterized by the production of interleukin 17 A (IL-17A), IL-17F, and IL-22 is also involved in adaptive immunity and autoimmunity, including T1D. The Interleukin IL-23 has a central role in the expansion and survival of Th 17 cells. It is composed of two subunits: p19-specific (IL-23A) and p40. Single nucleotide polymorphisms (SNPs) of IL-23A and IL-23 receptor (IL-23R) genes or increased IL-23 serum concentrations were associated with several autoimmune diseases, but their role in T1D has not been defined. We therefore searched for variants of IL-23A and IL-23R genes that could predispose to T1D. Methods:The coding regions and boundary intron sequences of IL-23A gene, including the 5 proximal region were sequenced. Two variants (rs2066808 and rs 11171806) of IL-23A and two of IL-23R (rs11209026 and rs10889677) genes were also genotyped. IL-23 serum levels and pancreatic and extra-pancreatic auto-antibodies were also determined. The cohort involved 370 patients with T1D and 314 healthy control subjects.Results: We observed only 1 out of 6 IL-23A coding variants (rs11171806 G>A localized in exon 3) described in a database repository . A new allelic variant of the IL-23A gene, consisting of the substitution of a cytosine by a thymine at position c.-403 (C>T) in the 5 proximal region of the IL-23A gene (found in heterozygosis in only 1 female patient with T1D) was described. The G alleles of rs11171806 and rs2066808 variants of IL-23A gene were in strong linkage disequilibrium (D\' = -0,825 for controls, p<2,0X10-6 and D\' = -0,902, p<2,0X10-17 for patients). So, further analyses were performed with the haplotypes instead of separated SNPs. The GG haplotype was more frequent in controls (16,7%) than in T1D patients (9,5%), conferring a protection to the disease (pc= 0,0009, OR = 0.53). The presence of haplotype GG was also different according to the ethnic group in the overall sample (patients+controls), when we pooled the Caucasians (18%) against the other groups (39%); p<0.0001. However, the lower susceptibility to T1D conferred by GG haplotype was independent of the ethnic group. Two IL-23R gene variants (rs10889677 and rs11209026) were also analyzed. The allelic and genotypic frequency of the variants did not differ between patients with T1D and control subjects. No significant differences were observed between the plasma IL-23 concentrations of 135 T1D patients (5.65 ± 14.0) and 112 control subjects (9.06 ± 23.7) (p = 0.18), even when we only the patients with less than 2 years disease duration (n = 43), when the immune attack to beta cells is still present, were included (4.65 ± 6.94 pg/mL and 9.07 ± 23.62 pg/mL, p = 0.076). No association was found between IL-23A variants with age at diagnosis of diabetes, presence of residual C-peptide levels or frequency of glutamic acid anti-decarboxilase antibody in patients with recent-onset T1D. Furthermore, these variants were not related to the presence of the extrapancreatic autoantibodies such as thyroid peroxidase (TPO) Ab, thyroglobulin (TG) Ab, 21-Hydroxilase (21OH) Ab, Anti nuclear factor (ANA) Ab, rheumatoid factor (FR) Ab and Neutrophil cytoplasmic (ANCA) Ab. Conclusions : The GG haplotype of lL23A gene variants( rs11171806 and rs2066808) was protective against T1D. The IL23R variants (rs11209026 and rs10889677) were not associated with susceptibility toT1D . IL-23 serum concentrations did not differ between T1D patients and controls.

Abstract Type 1 diabetes mellitus (T1DM) among children is of a particular importance in Finland, where its incidence is the highest in the world and still increasing. However, the aetiology of T1DM is not fully known. According to current knowledge, both genetic and environmental factors operate together, leading to an attack by the immune system on the insulin-producing beta cells. The purpose of this study was to investigate the geographical variation in the incidence of T1DM among children aged up to 14 years in Finland. Geographical Information Systems (GIS) and Bayesian spatial statistics were applied in a search for unusual spatial patterns and risk factor associations. The incidence of T1DM among children aged up to 14 years showed clear geographical variations in Finland. Living in a rural environment increased the risk for T1DM, and the risk was particularly high among children living in rural heartland areas. There was no association between the variation in T1DM incidence and the zinc and nitrate concentrations of drinking water. A male excess in the incidence of T1DM was seen in the low-incidence areas. The geographical variation in the risk of T1DM was marked only among children aged up to 9 years. Because genetics is a necessary but not a sufficient cause of T1DM, it could be hypothesized that there are some thus far unknown environmental risk factors affecting particularly younger children in Finland. Some of those factors may be related to a rural environment. The geographical variation in the M/F ratio of T1DM was a challenging observation and warrants more analytical study.

Orientador: Maria Luiza Silveira Mello / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-22T06:29:06Z (GMT). No. of bitstreams: 1 Ghiraldini_FlaviaGerelli_D.pdf: 75704253 bytes, checksum: 9d1afc3cebcffd05000b5efb25d3996d (MD5) Previous issue date: 2013 / Resumo: O diabetes mellitus do tipo I (DM1) caracteriza-se pela ocorrência de insulite com consequente hiperglicemia e poliuria. Alterações celulares estruturais e metabólicas decorrentes do aumento da glicemia podem provocar fenótipos de envelhecimento precoce. O envelhecimento celular e resultado de fatores intrínsecos e extrínsecos, que alteram a estrutura e a organização da cromatina e que, consequentemente, afetam a expressão gênica. As sirtuinas, deacetilases NAD+-dependentes, estão envolvidas na transcrição gênica, reparo de DNA, transcrição do rDNA, regulação metabólica e remodelação cromatinica. As sirtuinas nucleares, especialmente Sirt1 e Sirt6 estão envolvidas com o envelhecimento precoce, no metabolismo de glicose e na resposta a inflamação. O presente trabalho teve como objetivo geral comparar os processos de remodelação cromatinica em hepatocitos sob o efeito da hiperglicemia e do envelhecimento, usando-se modelo animal (camundongos). Um modelo de cultura celular (HepG2) foi também utilizado para estudo de efeitos da hiperglicemia, utilizando-se como metodologias analisem morfológicas e moleculares. Foi observado um aumento em conteúdo de DNA e em acessibilidade da cromatina a MNase mais acentuado em hepatocitos de animais DM1 do que de idosos. O aumento na abundancia de Sirt1 em animais hiperglicêmicos não refletiu em sua maior atividade, enquanto em idosos houve um decréscimo generalizado nesses parâmetros e aumento da aceptilação de sítios histónicos. Em animais DM1, Sirt6 apresentou abundancia semelhante à de Sirt1, possivelmente devido à alta fragmentação de DNA observada nesses animais, diferente do ocorrido em idosos. Ambos os animais DM1 e idosos apresentaram baixa relação área AgNOR+/área nuclear. Em animais diabéticos isto foi devido ao aumento na área nuclear, enquanto nos idosos, foi devido à diminuição na área AgNOR+ e aumento na área nuclear. O aumento na metilação de rDNA na porção 18S e a baixa abundancia de Sirt7 confirmam diminuição no metabolismo celular no envelhecimento. Em hepatocitos de camundongos DM1 e idosos foi observado genes diferencialmente expressos relacionados à inflamação. Admite-se que no primeiro caso este achado seja devido à natureza auto-imune da doença, enquanto no segundo possa ser um indício de inflamação naturalmente encontrada em processos de envelhecimento. Em animais DM1, a expressão diferenciada de genes envolvidos com metabolismo de lipídios poderia contribuir para com a peroxidação lipídica e produção de ROS levando a esteatose hepática. Nas células HepG2, alterações na expressão dos genes Apoe, Igfbp1 e Foxo1, ocorridas em meio de cultura hiperglicêmicas, tornaram-se revertidas quando as células foram retornadas a normoglicemia. Contudo, as abundancias das marcações epigenéticas nos promotores desses genes decresceram progressivamente, indicação de uma memória hiperglicêmica, dado não observado em modelo animal. A análise do fenótipo nuclear dessas células indicou possível indução da proliferação celular quando retornadas a normoglicemia. A inibição de sirtuinas aumentou o conteúdo Feulgen-DNA e o contraste entre cromatina condensada e não-condensada, indicativo de atuação na proliferação celular e na remodelação cromatinica. DM1 e envelhecimento, portanto, não podem ser considerados fenômenos idênticos, pois enquanto no primeiro ha um mecanismo compensatório que promove alterações genéticas, epigenéticas e remodelação cromatinica, no segundo ha um decréscimo generalizado no metabolismo celular levando a modificações diferentes nos mesmos parâmetros / Abstract: Diabetes mellitus type I (DM1) is characterized by insulitis and consequent hyperglycemia and polyuria. Structural and metabolic changes in the cell caused by hyperglycemia might induce an early-ageing phenotype. Both intrinsic and extrinsic agents might contribute to cellular ageing thus leading to chromatin structural changes and differential gene expression. Sirtuins, NAD+-dependent deacetilases, play a role in cell metabolism, transcription, DNA repair and chromatin remodeling. Sirt1 and Sirt6, especially, are nuclear proteins related to early-ageing, glucose metabolism and inflammatory response. The general purpose of the present work was to compare processes of chromatin remodeling in hepatocytes under the effects of hyperglycemia and aging, using mouse models. A model using cells in culture (HepG2) was also used to study the effects caused by hyperglycemia. The methodology used involved morphological and molecular analysis. An increase in DNA content and chromatin accessibility to MNAse was found more pronounced in hepatocytes from DM1 than from aged mice. Despite the high abundance of Sirt1 in DM1 animals, its activity was not proportionally high, whereas in old animals there was a reduction in these parameters, increasing the acetylation of Sirt1-histonic sites. In DM1 mice, Sirt6 presented similar abundance as Sirt1, possibly due to the high DNA fragmentation, different to what was found in aged animals. Both DM1 and normoglycemic old mice presented a decrease in AgNOR+ area/nuclear area ratio. While in DM1 animals it was a result from the increase in nuclear area, in old animals it was a combination of increased nuclear areas and decreased AgNOR+ areas. The DNA methylation increase in the 18S rDNA region and the decrease in Sirt7 abundance in the hepatocytes from old mice support the hypothesis of diminished cellular metabolism. Differential expression analysis for DM1 and old mouse hepatocytes presented a high number of genes involved in the inflammatory response. While in the former it could be an autoimmune characteristic of the disease, in the latter it might be an evidence of inflammatory state naturally associated with aging. Moreover, DM1 mice also presented differential gene expression related to lipid metabolism, which could contribute to increase lipid peroxidation and ROS production leading to hepatic steatosis. HepG2 cells showed changes in Apoe, Igfbp1 and Foxo1 expression in hyperglycemic medium and they were reverted when the cells returned to normoglycemic medium. The epigenetic marks, however, presented a progressive decrease in abundance, indicative of a hyperglycemic memory, which was not observed in DM1 animals. The nuclear phenotype in HepG2 cells under these same experimental conditions indicated a possible induction in cellular proliferation when the cells were returned to the normoglycemic medium. Inhibition of sirtuins increased the contrast between condensed and non-condensed chromatin and the Feulgen-DNA content, indicating a role in cell division and chromatin remodeling. Therefore, DM1 and ageing cannot be considered as identical processes, because while in DM1 there is a compensatory mechanism that induces changes in epigenetic marks, chromatin remodeling and differential gene expression, there is a general decrease in cell metabolism under aging that leads to different changes in the same parameters / Doutorado / Biologia Celular / Doutor em Biologia Celular e Estrutural