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PURPOSE: This study comparted arterial occlusion pressure (AOP) of the superficial femoral artery (SFA) between the dominant and nondominant legs and the relationship between blood flow and occlusion pressure at rest and during muscle contractions in males and females. METHODS: The AOP of the SFA was measured using Doppler ultrasound in the dominant and nondominant legs of 35 (16 males, 19 females) apparently healthy, normotensive young adults. Blood flow in the SFA was measured in the resting state (REST) and during plantar flexion exercise (EXC) at occlusion pressures ranging from 0% to 100% of AOP. ANOVA was used to compare AOP between the dominant and nondominant legs and between males and females. Regression analysis was used to evaluate the influence of relevant variables on AOP. A mixed model was used to evaluate the relationship between blood flow and occlusion pressure at REST and during EXC. RESULTS: There was a significant difference in the AOP between the dominant and nondominant legs in males (230 ± 41 vs 209 ± 37 mmHg) and females (191 ± 27 vs 178 ± 21 mmHg), respectively. There was also a significant sex difference in the AOP in the dominant (230 ± 41 vs 191 ± 27 mmHg; p = 0.002) and nondominant (209 ± 37 vs 178 ± 21 mmHg; p = 0.004) legs, respectively. Regression analysis revealed that after accounting for leg circumference, age, sex, blood pressure, and skinfold thickness were not independent predictors of AOP. At REST and during EXC, there was a linear relationship between relative blood flow and occlusion pressure. CONCLUSIONS: Differences in leg circumference contribute to a portion of the differences in AOP between the dominant and nondominant legs and between sexes. The linear relationship between relative blood flow and occlusion pressure suggests that occlusion pressures during blood flow restriction exercise should be chosen carefully. A large variance in blood flow measurements at different occlusion pressures suggests the need for evaluating the reliability of blood flow measurements and standardization of methods.

Ovulatory follicle development and associated oocyte maturation involve complex coordinated molecular and cellular mechanisms not fully understood. This study addresses, for the first time in any species, the relationships among diameter, vascularization, follicular-fluid factors, and gene expression for follicle growth, steroidogenesis, angiogenesis and apoptosis in granulosa/cumulus cells and oocytes during different stages from the beginning of largest/ovulatory follicle to impending ovulation. Follicle dynamics was tracked and follicle-wall blood flow evaluated daily through transrectal ultrasonography in mares. The largest follicle of the ovulatory wave was distributed in six diameter groups (predeviation, deviation, postdeviation, early preovulatory, preovulatory, and impending ovulation) according to the targeted diameter for complete aspiration and cell harvesting. The most remarkable findings were (i) positive association between follicle development, blood flow, intrafollicular FSH, LH, estradiol, progesterone, and mRNA expression for FSHR and LHCGR in granulosa cells of largest/ovulatory follicle; (ii) plateau/decrease in follicle diameter, blood flow, and granulosa cell mRNA for FSHR, LHCGR, IGF1R, VEGFR2, CYP19A1, and CASP3 at the preovulatory stage; (iii) higher StAR and BCL2 and lower CASP3 mRNA in granulosa cells at impending ovulation; (iv) greater IGF1R mRNA in the granulosa cells at the predeviation stage; and (v) lower FSHR, LHCGR, IGF1R, and VEGFR2 mRNA in cumulus cells, and greater LHCGR and IGF1R mRNA in oocytes at the ovulatory stage. This study is a critical advance in the understanding of molecular mechanisms of follicle development and oocyte maturation and is expected to be vital for future studies targeting potential markers for follicle selection, development, and ovulation.

Indiana University-Purdue University Indianapolis (IUPUI) / Over 5 million older adults have Alzheimer's disease (AD) in the US, and this number is projected to double by 2050. Clinical trials of potential pharmacological treatments for AD have largely shown that once cognitive decline has occurred, targeting AD pathology in the brain does not improve cognition. Therefore, it is likely that the most effective treatments for AD will need to be administered before cognitive symptoms occur, necessitating a biomarker for the early, preclinical stages of AD. Cerebral blood flow (CBF) is a promising early biomarker for AD. CBF is decreased in individuals with AD compared to their normally aging counterparts, and it has been shown that CBF is altered in mild cognitive impairment (MCI) and earlier stages and may occur prior to amyloid or tau aggregation. In addition, CBF can be measured using arterial spin labeled (ASL) MRI, a noninvasive imaging technique that can be safely repeated over time to track prognosis or treatment efficacy. The complex temporal and spatial patterns of altered CBF over the course of AD, as well as the relationships between CBF and AD-specific and -nonspecific factors, will be critical to elucidate in order for CBF to be an effective early biomarker of AD. Here, we begin to characterize the relationships between CBF and risk factors, pathologies, and symptoms of AD. Chapter 1 is a systematic review of published literature that compares CBF in individuals with AD and MCI to CBF in cognitively normal (CN) controls and assesses the relationship between CBF and cognitive function. Chapter 2 reports our original research assessing the relationships between CBF, hypertension, and race/ethnicity in older adults without dementia from the the Indiana Alzheimer’s Disease Research Center (IADRC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI). Chapter 3 reports our original research assessing the relationships between CBF and amyloid beta and tau aggregation measured with PET, as well as whether hypertension or APOEε4 positivity affects these relationships, in older adults without dementia from the IADRC. Chapter 4 reports our original research assessing the relationship between the spatial distribution of tau and subjective memory concerns. / 2023-05-24

Orientador: Franciele Marques Vanderlei / Resumo: Estudos sobre o treinamento resistido de baixa intensidade associado à restrição de fluxo sanguíneo (RFS) atualmente tem ganhado destaque, porém ainda existem lacunas que podem ser exploradas em relação aos seus efeitos fisiológicos quando associado a treinamentos excêntricos, principalmente na força e hipertrofia muscular. Objetivo: Realizar uma revisão sistemática com metanálise e um estudo aleatorizado controlado a fim de esclarecer os reais efeitos do TRBI associado à RFS nos desfechos de força, hipertrofia muscular e desempenho funcional, e se a RFS quando associada a treinamentos excêntricos de baixa e alta intensidade é capaz de aumentar as respostas desses desfechos dos extensores de joelho em homens adultos saudáveis. Métodos: A revisão sistemática foi registrada no PROSPERO (número do registro #CRD42018104065). Os estudos foram selecionados por meio de sete bases de dados. Todos os estudos incluídos foram avaliados quanto à qualidade metodológica, utilizando a Escala PEDro, bem como foi avaliada a qualidade da evidência. Somente ensaios clínicos randomizados que avaliaram a eficácia do treinamento com RFS na força e hipertrofia muscular dos músculos extensores de joelho em adultos do sexo masculino, saudáveis e/ou fisicamente ativos, com idade de 18 a 35 anos, contra algum grupo de intervenção foram considerados elegíveis. Todas as metanálises foram conduzidas por meio do software Review Manager – RevMan e descritos como diferenças médias padronizadas (standardized ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Studies on low intensity resistance training associated with blood flow restriction (RFS) are currently gaining prominence, however there are still gaps that can be explored in relation to their physiological effects when associated with eccentric training, especially in muscle strength and hypertrophy. Objective: To carry out a systematic review with meta-analysis and a randomized controlled study in order to clarify the real effects of TRBI associated with RFS on the outcomes of strength, muscle hypertrophy and functional performance, and whether RFS when associated with low and high intensity eccentric training is able to increase the responses of these knee extensor outcomes in healthy adult men. Methods: The systematic review was registered in PROSPERO (registration number # CRD42018104065). The studies were selected through seven databases. All included studies were assessed for methodological quality, using the PEDro Scale, as well as the quality of evidence was assessed. Only randomized controlled trials that assessed the effectiveness of RFS training on muscle strength and hypertrophy of knee extensor muscles in healthy, male and / or physically active adults, aged 18 to 35, against any intervention group were considered eligible. All meta-analyzes were conducted using the Review Manager - RevMan software and described as standardized mean differences (SMD) or mean differences (mean difference - MD) with 95% confidence intervals (CI). The randomized controlled study ... (Complete abstract click electronic access below) / Mestre

Indiana University-Purdue University Indianapolis (IUPUI) / Glaucoma is a multifactorial ocular disease progressively leading to irreversible blindness. There is clear evidence of correlations between alterations in ocular hemodynamics and glaucoma; however, the mechanisms giving rise to these correlations are still elusive. The objective of this thesis is to develop mathematical models and methods to help elucidate these mechanisms. First, we develop a mathematical model that describes the deformation of ocular structures and ocular blood flow using a reduced-order fluid-structure interaction model. This model is used to investigate the relevance of mechanical and vascular factors in glaucoma. As a first step in expanding this model to higher dimensions, we propose a novel energy-based technique for coupling partial and ordinary differential equations in blood flow, using operator splitting. Next, we combine clinical data and model predictions to propose possible explanations for the increase in venous oxygen saturation in advanced glaucoma patients. We develop a computer-aided manipulation process of color Doppler images to extract novel waveform parameters to distinguish between healthy and glaucomatous individuals. The results obtained in this work suggest that: 1) the increase in resistance of the retinal microcirculation contributes to the influence of intraocular pressure on retinal hemodynamics; 2) the influence of cerebrospinal fluid pressure on retinal hemodynamics is mediated by associated changes in blood pressure; 3) the increase in venous oxygen saturation levels observed among advanced glaucoma patients depends on the value of the patients’ intraocular pressure; 4) the normalized distance between the ascending and descending limb of the ophthalmic artery velocity profile is significantly higher in glaucoma patients than in healthy individuals.

Indiana University-Purdue University Indianapolis (IUPUI) / Glaucoma is a multi-factorial ocular disease associated with death of retinal ganglion cells and irreversible vision loss. Many risk factors contribute to glaucomatous damage, including elevated intraocular pressure (IOP), age, genetics, and other diseases such as diabetes and systemic hypertension. Interestingly, alterations in retinal hemodynamics have also been associated with glaucoma. A better understanding of the factors that contribute to these hemodynamic alterations could lead to improved and more appropriate clinical approaches to manage and hopefully treat glaucoma patients. In this thesis, we develop several mathematical models aimed at describing ocular hemodynamics and oxygenation in health and disease. Precisely we describe: (i) a time-dependent mathematical model for the retinal circulation that includes macrocirculation, microcirculation, phenomenological vascular regulation, and the mechanical effect of IOP on the retinal vasculature; (ii) a steady-state mathematical model for the retinal circulation that includes macrocirculation, microcirculation, mechanistic vascular regulation, the effect of IOP on the central retinal artery and central retinal vein, and the transport of oxygen in the retinal tissue using a Krogh cylinder type model; (iii) a steady-state mathematical model for the transport of oxygen in the retinal microcirculation and tissue based on a realistic retinal anatomy; and (iv) a steady-state mathematical model for the production and drainage of aqueous humor (AH). The main objective of this work is to study the relationship between IOP, systemic blood pressure, and the functionality of vascular autoregulation; the transport and exchange of oxygen in the retinal vasculature and tissue; and the production and drainage of AH, that contributes to the level of IOP. The models developed in this thesis predict that (i) the autoregulation plateau occurs for different values of IOP in hypertensive and normotensive patients. Thus, the level of blood pressure and functionality of autoregulation affect the changes in retinal hemodynamics caused by IOP and might explain the inconsistent outcomes of clinical studies; (ii) the metabolic and carbon dioxide mechanisms play a major role in the vascular regulation of the retina. Thus, the impairment of either of these mechanisms could cause ischemic damage to the retinal tissue; (iii) the multi-layer description of transport of oxygen in the retinal tissue accounts for the effect of the inner and outer retina, thereby improving the predictive ability of the model; (iv) a greater reduction in IOP is obtained if topical medications target AH production rather that AH drainage and if IOP-lowering medications are administrated to patients that exhibit a high initial level of IOP. Thus, the effectiveness of IOP-lowering medications depend on a patient’s value of IOP. In conclusion, the results of this thesis demonstrate that the insight provided by mathematical modeling alongside clinical studies can improve the understanding of diseases and potentially contribute to the clinical development of new treatments.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21449号 / 医博第4416号 / 新制||医||1032(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 松原 和夫, 教授 川上 浩司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Cardiovascular diseases, including heart failure, are a global health concern, necessitating advancements in non-invasive diagnostic tools and treatments. Computational modeling offers an invaluable approach to simulate and understand the intricacies of cardiac flow dynamics. This study aims to identify critical blood flow properties in the left atrium, a crucial component of the heart responsible for receiving oxygenated blood from the lungs and pumping it into the left ventricle. Building on previous work, this project implemented an idealized model of the left atrium using Finite Element Method (FEM) and simulated various properties related to its geometry, revealing crucial aspects of fluid dynamics. Specifically, analysis revealed a U-shaped inflow profile, pressure variations due to flow jets and presence of vortices, asymmetrical outflow due to differences in pulmonary vein geometry, and the presence of longitudinal vortex structures within the atrium. These properties can provide valuable insights about the blood flow in a healthy heart. This research presents a foundation for future work aiming to integrate models of the left ventricle and left atrium, offering a more comprehensive understanding of the left heart's functionality and potential pathologies. Further studies should focus on in-depth analysis, extension and validation of these properties using real patient data to enhance their diagnostic potential.