Thesis (Ph. D.)--University of Michigan, 1994. / Includes bibliographical references (leaves 248-267).

Type II diabetes mellitus is currently on the rise and reaching epidemic proportions in the United States. In addition to this increase, the number of cases of diabetic complication such as kidney disease has increased. Currently diabetic kidney disease is the leading cause for end stage renal disease in the United States accounting for nearly half of all cases. Type II diabetes is the result of metabolic, hemodynamic and inflammatory alterations within the body. Currently there is a standard of care to treat both metabolic and hemodynamic perturbations by enforcing tight glycemic control and utilizing anti-hypertensive drugs, most notably RAS inhibitors. These therapeutic interventions however, are not sufficient as many patients with type II diabetes will still develop diabetic kidney disease therefore another treatment option is imperative. Currently there are no treatments available to counteract the adverse inflammatory responses associated with type II diabetes which are strong contributors to the progression of the diabetic kidney disease. Among the inflammatory parameters studied as potential targets for therapeutic intervention the inflammatory cytokine tumor necrosis factor-α (TNF-α) stands out among the rest for its multifaceted role in disease progression. TNF-α has been shown to both directly and indirectly involved in development and progression of diabetic kidney disease. The inflammatory cytokine itself is toxic to renal cells initially increasing the permeability of the glomerular filtration barrier and contributing to proteinuria which eventually causes cellular apoptosis. TNF-α also activates second messengers and up-regulates transcription factors that further contribute to the progression of diabetic kidney disease. Two TNF-α inhibitors, pentoxifylline and chrysin have stood out among the other investigational drugs which have been studied as potential therapeutic options to delay the progression of diabetic kidney disease. Pentoxifylline is a methyl-xanthine derivative that is currently used to treat peripheral vascular disease. It has shown good effect in clinical trials decreasing both urinary TNF-α concentrations as well as urinary protein excretion. Chrysin is a natural plant derivative belonging to the flavonoid family and is known for its anti-inflammatory and anti-oxidant properties. Currently chrysin has only been studied in animal models of diabetic kidney disease but has shown to not only decrease concentrations of inflammatory cytokines to control levels and improve renal functions but also prevented the histopathological changes associated with diabetic kidney disease suggesting that chrysin has the ability to not only slow the progression of disease and preserve renal function, it has the ability to prevent the disease from ever taking root. Diabetic kidney disease is a devastating disease affecting millions of people worldwide. It is important for further investigation with these investigational drugs to be performed in large scale clinical trials to produce safety and efficacy data with the end goal of becoming approved as new treatments for diabetic kidney disease.

Background: Type II diabetes, which is known as non-insulin dependent diabetes, has become an epidemic worldwide. In the United States, diabetes affects 25.8 million people which represent 8.3% of the population. Out of 25.8 million, 23.22 million people have Type II diabetes. According to the National Statistics Vital Report, Type II diabetes was the number seven cause of death in the USA and it can be prevented. The primary purpose of this study was to assess the overall knowledge and health beliefs about Type II diabetes among a sample of undergraduate students; the second purpose was to assess the relationship between the overall knowledge and health belief subscale. Methods: A cross-sectional and descriptive survey design was used. An existing knowledge and health belief instruments was adapted. In the 2014 spring semester, a non- random convenience sample of over 200 undergraduate students who enrolled in Foundation of Human Health 101- class were surveyed in order to assess knowledge and health belief about Type II diabetes. The Health Belief Model provided the theoretical framework for this study. Results: Overview of the participants in this study was provided through conducting a descriptive analysis. Majority of the participant were female, aged between eighteen and twenty, and Caucasian. Data analysis revealed that the overall knowledge about Type II diabetes among participants was low. For the individual health beliefs, perceived susceptibility, perceived severity, and perceived barriers to Type II diabetes were low; however, perceived benefits to engaging in healthy behaviors was high. Having other problems more important than worrying about diet and exercise, and not knowing the appropriate exercise to perform to reduce the risk of developing Type II diabetes were the major barriers among participants. A positive, weak, statistically significant correlation was found between overall knowledge and total belief of benefits to engaging in healthy actions. At the same time, a negative, weak, statistically significant correlation was found between overall knowledge and total belief of barriers to engaging in health lifestyles. Results from multiple regression revealed that knowledge was best predicted by race/ethnicity. Family history, stress level, and level of exercise were the best predictors of perceived susceptibility, perceived benefits, and perceived barriers, respectively. Perceived severity was not predicted by any of the independent variables.

Diabetes mellitus (DM) is not just a simple metabolic disorder, however, it is considered to be a cardiovascular disease of a metabolic origin. This is apparent especially when speaking about type 2 diabetes (DM II). Patients with DM have a high occurrence of vegetative nervous system (VNS) disorders that manifest themselves as an increased activity of the sympathetic nervous system that correlates with peripheral autonomic neuropathy and is considered to be the major pathophysiological mechanism for the development of DM II. The objective of our study was to determine whether a comprehensive spa treatment (ST) may affect the level of the sympathetic tone of patients suffering from DM II. As an indicator of the sympathetic tone, selected electrocardiographic parameters derived from the HRV, microvolt T-wave alternans, and microvolt R-wave alternans were evaluated. The electrophysiological examination of patients was performed before and after a three-week spa treatment using the KARDiVAR system. The method is used to examine the current state of the autonomic nervous system and carry out an analysis of risk factors and adaptive capabilities of the organism. The results showed favorable changes in DM II patients after the ST, primarily in terms of reduced sympathetic adrenal system activity,...

Orientadores: Denise Pontes Cavalcanti, Luciana Cardoso Bonadia / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T20:03:03Z (GMT). No. of bitstreams: 1 Silveira_KarinadaCosta_M.pdf: 2998560 bytes, checksum: 286fe3d0377e879226faf2cb88d92569 (MD5) Previous issue date: 2014 / Resumo: As displasias esqueléticas ou osteocondrodisplasias são doenças genéticas que afetam o crescimento e o desenvolvimento do tecido ósseo e cartilaginoso produzindo, em geral, baixa estatura. Mutações em heterozigose no gene COL2A1 são responsáveis por uma série de displasias esqueléticas conhecidas como colagenopatias do tipo II que geralmente apresentam um padrão espondiloepifisário típico. Apesar das mutações no COL2A1 serem, em geral, "privadas", o estudo molecular desse gene em pacientes com fenótipos sugestivos de colagenopatia do tipo II pode contribuir seja para um melhor entendimento das colagenopatias do tipo II seja para refinar, quando possível, a correlação genótipo-fenótipo. O objetivo desse estudo foi investigar o gene COL2A1 numa coorte de pacientes com fenótipo de colagenopatia do tipo II de modo a melhorar o conhecimento sobre essas colagenopatias. Foram estudados 33 pacientes com fenótipo de colagenopatia do tipo II. A análise molecular foi feita por sequenciamento automático bidirecional direto do gene COL2A1, começando pelos domínios relacionados a cada fenótipo seguido de sequenciamento completo das regiões codificantes do gene quando as primeiras foram negativas. Foram identificadas alterações potencialmente deletérias em heterozigose em 23 dos 33 pacientes (69,7%): 18 alterações do tipo missense (11 inéditas, 7 descritas), 4 alterações que alteram sítio de splice (2 inéditas, 2 descritas) e uma deleção inédita. Das mutações do tipo missense encontradas, duas foram recorrentes em 5 pacientes: p.G594E e p.R989C. Ambas as mutações recorrentes foram associadas a fenótipos graves: a p.R989C foi observada em displasia espondiloepifisária congênita (SEDC) grave enquanto que a p.G594E foi associadaa 2 recém-nascidos com fenótipo de SEDC-letal. Para todas as mutações novas, a análise in silico, estudo em controles e/ou dos pais confirmaram a patogenicidade de todas elas. Concluindo, os resultados deste estudo permitiram a identificação de 14 mutações novas no gene COL2A1 e um melhor refinamento da correlação genótipo-fenótipo / Abstract: Skeletal dysplasias are genetic disorders that affect the growth and development of the bone and cartilage tissues producing, in general, short stature. Heterozygous mutations in the COL2A1 gene are responsible for a number of skeletal dysplasias that usually exhibit a pattern spondyloepiphyseal and are called type II collagenopathies. Although the mutations in COL2A1 are usually privates, molecular studies of this gene in patients with suggestive phenotypes can contribute to a better understanding of the type II collagenopathies. The aim of this study was to sequence the COL2A1 in a cohort of patients with type II collagenopathy phenotypes in order to refine the knowledge regarding the genotype-phenotype correlation. Thus, 33 patients with suggestive phenotype were studied. The molecular analysis was performed by automated Sanger bidirectional sequencing of the COL2A1 gene, starting with the domains related to each phenotype followed by whole sequencing of the gene coding regions when the first ones were negative. Potentially deleterious changes in heterozygosity were identified in 23 of 33 patients (69.7 %): 18 missense changes (11 undescribed), 4 changes that modify the splice site (2 undescribed) and a new deletion. The pathogenicity of the undescribed changes were confirmed by in silico analysis, study of control individuals and/or of the respective parents. Among the found missense mutations, two were recurrent and associated with severe phenotypes. These mutations, p.G594E and p.R989C, were found in five patients. The R989C change was observed in three children presenting a phenotype of spondyloepiphyseal dysplasia congenita (SEDC), which follow up showed a pattern of severe SEDC featured by severe disproportioned short stature with coxa vara and kyphoscoliosis. The G594E change was associated with two newborns presenting also a SEDC phenotype, however with lethal evolution. In conclusion, the results of this study allowed the identification of 14 new mutations in COL2A1 gene and a better refinement of the genotype-phenotype correlation / Mestrado / Ciencias Biomedicas / Mestra em Ciências Médicas

>Magister Scientiae - MSc / Diabetes, a worldwide disease, is classified into two types, type 1 or insulin-dependent and type 2 or noninsulin-dependent. Based on reports published by the International Diabetes Federation, the total number of those suffering from diabetes is growing every year. Statistics predict that type 2 diabetes, currently affecting about 8% of the adult population, would spread at such a pace that by 2030, more than 40 million cases of diabetes would be found throughout the world. On the other hand, studies revealed that patients with type 2 diabetes mellitus (T2DM) have a lower incidence of tumour development than healthy controls and that patients diagnosed with cancer have a lower risk of mortality when treated with metformin. However, the frequent use of metformin with low oral bioavailability ranging between 40-60% in the intestinal environment leads to large accumulation on the enterocytes. / 2024-02-24

OBJECTIVE: Prolonged elevation of blood glucose levels in Type 2 Diabetes is related to a host of medical complications, most of which are mediated by micro and macro vascular damage. Importantly, diabetes is associated with accelerated cognitive decline and compromised brain health as the cerebral vasculature undergoes negative changes stemming from hyperglycemia. It is hypothesized that participants in the Look Ahead Brain study with higher HbA1c levels will exhibit worse performance on the cognitive measures, specifically on tasks assessing executive function. METHODS: Data on participants from the Look Ahead study who also participated in the Look Ahead Brain ancillary study (n = 113) were analyzed. This included HbA1c levels at year 10 (the year that participants were administered the cognitive assessment), mean HbA1c, and change in HbA1c from baseline to year. In order to assess executive function the results on two cognitive tests, the Modified Stroop Color and Word Test and the Trail Making Test, were analyzed. Then, relationships between HbA1c and performance on each of these cognitive tasks were analyzed using two approaches. First, the cohort was split into two group based on HbA1c (HbA1c ≤ 7% vs HbA1c > 7%). The latter of the two groups represented participants will poorer glycemic control. Second, linear correlations were assessed using the full range of HbA1c values as a continuous variable. RESULTS: There were no significant differences between HbA1c groups and performance on either of the cognitive tests. Interestingly, although not statistically significant, those with higher HbA1c levels performed slightly better on cognitive tasks. Correlation analyses revealed further trends in the direction opposite than expected, such that higher HbA1c levels were associated with better scores on both tests. CONCLUSION: The surprising results of this study are evidence of the fact that a great deal has yet to be learned about the effects of T2DM and cognitive decline. There are many potential future directions for the Look Ahead Brain data, and further analyses might provide clarifications to the results of this study.

No description available.

We investigate the nonequilibrium steady state of driven magnetic flux lines in type-II superconductors subject to strong point or columnar pinning centers and the aging dynamics of nonequilibrium relaxation process in the presence of weak point pinning centers. We employ a three-dimensional elastic line model and Metropolis Monte Carlo simulations. For the first part, we characterize the system by means of the force-velocity / current-voltage curve, static structure factor, mean vortex radius of gyration, number of double-kink and half-loop excitations, and velocity / voltage noise features. We compare the results for the above quantities for randomly distributed point and columnar defects. Most of both numerical works have been done in two-dimensional systems such as thin film in which the structure of flux lines is treated as a point-like particle. Our main point of investigation in this paper is to demonstrate that the vortex structure and its other transport properties may exhibit a remarkable variety of complex phenomena in three-dimensional or bulk superconductors. The second part devotes to the study of aging phenomena in the absence of a driving force in disordered superconductors with much weaker point disorder. By investigating the density autocorrelation function, we observe all three crucial properties of the aging phenomena; slow power-law relaxation, breaking of time-translation invariance, and the presence of the dynamical scaling. We measure the dynamical exponents b and lambda_c/z and compare to other work. We find exponent values increase for increasing pinning strength, smaller interaction range, lower temperature, and denser defect density while the exponents measured in other approach tend to decrease. / Ph. D.

Neurofibromatosis Type II (NF2) is a neurological disorder arising from mutations in the rif2 gene. NF2 is characterized by formation of bilateral vestibular schwannomas. These tumors arise from Schwann cells, the myelin-forming glia in nerves. Schwannoma cells lose the characteristic bipolar, spindle morphology and assume a round fibroblast-like phenotype. Phenotypic de-differentiation of schwannomas has been attributed to increased levels of Cdc42/Rac-GTP and activation of downstream pathways. The n/2 gene encodes the tumor suppressor called merlin. It is targeted to the plasma membrane by direct binding to paxillin at paxillin-binding domain 1, encoded by exon 2 of the nj2 gene. At the plasma membrane, merlin associates with B1-integrin and erbB2/3 receptors and actin regulating proteins. We hypothesize that merlin modulates actin polymerization, and thus cell shape, by controlling the activity of actin filament regulating proteins. We developed an in vitro model ofNF2 using ad-ere ( ad-Cre) viral mediated deletion of nj2 exon 2 in primary mouse Schwann cells. Within 5 days of ad-Cre infection, merlin levels fall to 40% of normal levels in Schwann cells. Moreover, the expressed merlin protein has the expected lower molecular weight and does not target to the plasma membrane. Schwann cells expressing this mutant merlin lose their characteristic bipolar shape. We tested the activation levels of2 candidate Cdc42/Rac dependent-actin regulating proteins in these cells. Using immunofluorescence, we found that the activity of these proteins increased dramatically within 4 days of n/2 inactivation. This increase in activity was then confirmed with western blotting. We conclude that the function of these actin-filament regulating proteins could contribute to changes in morphology associated with schwannoma formation in NF2.