Hirschsprung’s (HSCR) disease is a congenital disorder in which some enteric ganglion cells are absent in the colon due to incomplete colonization of neural crest cells (NCCs) in the hindgut, causing chronic constipation. A significant number of HSCR patients also clinically present with other NC- associated disorders, such as ventricular and atrial septal defects (VSD/ASD). A hypomorphic allele or SNP of a major gene, RET, causes or imparts susceptibility to HSCR. In particular, SNP (rs2435357) residing in the intron 1 of RET gene was found to be highly associated with HSCR and lead to reduced RET expression. However, the molecular basis of syndromic HSCR with VSD/ASD is largely unclear. In our project, with the use of the induced pluripotent stem cell (iPSC) technology, we aim to establish a patient-specific model unravel the etiology of HSCR and the associated disorders. To this end, 3 iPSC clones from a syndromic HSCR patient with VSD/ASD, carrying the RET risk allele in rs2435357 were generated. We attempted to use different protocols to directly differentiate iPSCs into NCCs with unique HOX expression patterns, corresponding to anterior cranial/vagal or posterior vagal/trunk NCCs. Consistently, the patient iPSCs displayed similar capacities in generating NCCs at all axial levels, marked by HNK-1 and 〖p75〗^NTR. Nevertheless, the patient NCCs and their derivatives exhibited severe migration and/ or differentiation defects in making neurons and smooth muscle cells. In particular, HNK-1+〖p75〗^NTR+ HOX+ (vagal/trunk) NCCs derived from patient-iPSCs were less migratory compared to the control NCCs, while no obvious migration defect was observed in their cranial counterpart, indicating that the migration defect was only restricted to the more posterior NCCs. In addition, these patient NCCs were less capable in generating neurons and readily biased toward generating glial cells. Intriguingly, the neural differentiation defects were restricted to NC lineage. The capacity of patient iPSCs to make various types of CNS progenitors and neurons was comparable to that of the control iPSCs, nicely recapitulating the patient’s phenotype where only enteric neurons, but not CNS progenitors were affected. Subsequent expression analysis revealed that patient NCCs express lower level of RET which is known to be regulating enteric NCC migration and differentiation. Whole transcriptome RNA sequencing analysis also revealed an enhanced expression of genes associated with gliogenesis and a reduced expression in genes associated with neurogenesis and migration. Moreover, the expression of a new candidate gene ALDH3B1 was shown to be significantly reduced in the HSCR-iPSC-derived NCCs that might contribute to the disease pathogenesis. In summary, these data suggests that reduced RET expression in HSCR patient NCCs may at least partly account for the disease phenotypes. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Alzheimer’s disease (AD) has been defined as a type of dementia that causes problems with memory, thinking, and behavior. AD is characterized by tau tangles and Aβ plaques in and around neurons, respectively. The impact this disease has on its victims’ health, both physically and mentally, is unimaginable and the rate of progression is not expected to decrease any time soon. This threat to our minds encourages the importance of understanding AD. Amongst the theories as to what bio mechanisms cause the brain to intertwine is the amyloid cascade hypothesis. The purpose of this thesis is to review the amyloid cascade hypothesis and discuss treatments which utilize this model. We also wish to examine social aspects such as loneliness and socioeconomic factors which are associated with the progression of AD. Research presented provides evidence that targeting the accumulation of Aβ in the brain will prevent further biochemical responses to form neurodegenerative pathology. From the collected data, we observe that therapies targeting the amyloidogenic pathway have received positive feedback in the medical community. Amongst them, an Aβ synthetic peptide vaccine which made history in vaccine development due to their responder rate. The impact of social factors such as loneliness in the advancement of AD is also supported by research. While it is acknowledged that any neurodegenerative disease is far too complex to narrow its cause specifically, this thesis provides an association with multiple aspects that can be understood and applied to future research in this field. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

An altered small intestinal permeability has been proposed as an important aetiological factor in the pathogenesis of inflammatory bowel disease. The relevant literature was reviewed. Intestinal permeability to Polyethylene glycol 400 in patients with Crohn' s disease, their relatives and healthy controls was examined and the data compared with studies of small bowel permeability to other similar sized probes. A new technique of analysis of urinary Polythylene Glycol 400 by High Performance Liquid Chromatography was described and compared with a previously established HPLC method. No evidence of an altered bowel permeability could be found using Polyethylene glycol 400, but the possibility that this may have been related to probe size and characteristics can not be excluded .

Parkinson‟s disease (PD) is the most common neurodegenerative movement disorder. It is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Although the etiology of PD remains incompletely understood, emerging evidence suggests that iron homeostasis dysregulation may be involved. A pathological hallmark of PD is the formation of Lewy bodies, intra-cytoplasmic inclusions that are major composed of α-synuclein (α-syn). α-synuclein is encoded by the SNCA gene. It is generally believed that α-synuclein aggregation is a main pathogenic feature and the cause of PD. Previous in vitro studies have provided direct evidence showing that iron could interact with α-synuclein and facilitate its aggregation. Nevertheless, the exact role of iron in the pathogenesis of PD is still inconclusive, and so far no studies have proved the interaction between iron and α-synuclein in vivo. / Here, based on a Drosophila model, we tested the hypothesis that the interaction between iron and α-synuclein accumulation accelerates the pathogenesis of PD, and that restoring brain iron homeostasis provides neuroprotective effects against PD. In our present studies, two groups of Drosophila, including w¹¹¹⁸ control and mutant α-synuclein A53T Drosophila were cultured under normal- (normal medium) and high-iron diet (medium added with 30mM ferric ammonium citrate (FAC)) for up to 30 days. During chronic iron treatment, startle-induced negative geotaxis assay was conducted every ten days to test the locomotor ability in the flies. After that, whole-mount immunostaining was used to assess dopaminergic neuronal survival. These flies were also collected and subjected to the quantification of brain iron content for the characterization of the brain iron content status. Furthermore, quantitative real-time PCR and western-blot analysis were conducted to investigate the amount of various α-synuclein conformations. / In the first part, we observed that α-synuclein A53T fly exhibited age-related increase of brain iron content compared with age-matched control. These were accompanied by shorter life-span, locomotor dysfunction, and TH-positive neuronal loss in PPM1/2 and PPM3 cluster. Meanwhile, we have demonstrated that neuronal toxicity and motor deficits were associated with increased proteinase K resistant, insoluble α-synuclein rather than the total amount of protein level. The insoluble α-synuclein was regarded as α-synuclein aggregation. / In the second part, we found that in α-synuclein A53T fly, excessive iron uptake aggravated locomotion defects and led to specific TH positive neuronal loss in cluster PPM3 after 30 days of iron treatment. Moreover, the excessive iron-induced neurological toxicity and motor dysfunction were also associated with increased α-synuclein aggregation. Overall, these two sets of results suggest that abnormal up-regulation of brain iron content may be associated with α-synuclein, and contribute to the pathogenesis of PD through α-synuclein aggregation-dependent mechanisms. / In the third part, we further explored the potential neuroprotective effect of restoring brain iron homeostasis in PD. We made use of genetic modification to manipulate iron-transport protein DMT1 expression, in turn to identify the protective effect of decreasing brain iron content in α-synuclein Drosophila model. Our present results proved that inactivation of Malvolio in α-synuclein A53T fly can suppress the increase of brain iron contents, and can also prolong life span, partially ameliorate locomotion deficits, and attenuate TH positive neuronal loss in α-synuclein A53T fly. In addition, these beneficial effects might occur through the inhibition of α-synuclein aggregation in α-synuclein A53T fly. Consequently, this result implicates that reducing brain iron by inactivation of iron up-take protein DMT1 can inhibit α-synuclein aggregation and provide beneficial effect on DA neuronal survival in PD model. / In conclusion, we demonstrated that : (1) abnormal up-regulation of brain iron content may be associated with α-synuclein and contributes to the pathogenesis of PD through α-synuclein aggregation-dependent mechanisms; (2) iron uptake protein DMT1 may serve as a potential therapeutic target for alleviating aberrant iron accumulation and retards the progression of neurodegeneration in PD. / 帕金森氏病（PD）是最常見的神經退行性疾病之一，其病理學特徵是黑質緻密部（SNpc）的多巴胺能神經元退行性變性。和，其中α-突觸核蛋白（α-synuclein）是Lewy小體的主要成分。雖然帕金森氏病的發病機制仍不十分清楚，隨著研究的進展，越來越多的證據表明鐵穩態失調可能是其中一個重要的致病因素。細胞內Lewy小體聚集物的形成是帕金森病的一個病理標誌物，其主要的成分是α-synuclein蛋白。α-synuclein是由SNCA基因編碼的蛋白。其聚集通常被認為是帕金森病的一個主要的病理特徵，同時也是導致帕金森病的一個原因。之前的研究證據表明，在體外實驗中，鐵能夠與α-synuclein相互作用並促進α-synuclein的聚集。然而，鐵和α-synuclein的相互關係在帕金森病的發病機制中的確切作用仍不十分確定。 / 我們的課題是基於果蠅模型來驗證腦鐵增加導致的α-synuclein聚集加速了帕金森病的病理進程，且恢復腦鐵平衡可以保護帕金森病人多巴胺能神經元的假說。在我們目前的研究中使用了兩組不同基因型的果蠅，其中包括w¹¹¹⁸對照組和突變體α-synA53T果蠅。兩組果蠅分別同時餵養正常食物（正常培養基）和高鐵食物（30mM檸檬酸鐵銨（FAC））。經過30天的慢性鐵處理，分別收集不同組的果蠅並測定其腦鐵含量用於對不同組果蠅的腦鐵含量進行定量分析。在進行鐵處理的30天期間，每隔10天進行一次趨地性行為學實驗用於評價不同組果蠅的運動能力。行為學實驗過後，可使用整腦免疫染色法來觀察果蠅多巴胺能神經元的存活情況。此外，還运用实时定量PCR和蛋白免疫印跡分析法來檢測不同組果蠅體內α-synuclein mRNA和蛋白的表達情況。 / 在第一部分的實驗中我们發現，與年齡相當的對照組相比，α-synA53T果蠅表現為明顯增高的腦鐵含量，並伴隨著壽命短，運動功能障礙以及PPM1/2和PPM3多巴胺能神經元簇的TH-陽性神經元丟失。同時我們發現，α-synA53T果蠅的神經元的毒性和運動障礙與α-synuclein的蛋白總量無關，而可能與在蛋白酶K中穩定的不溶性α-synuclein蛋白的增加相關，這部分α-synuclein的增加被認為與α-synuclein聚集有關。 / 此外在第二部分實驗中我們還發現，α-synA53T果蠅經過30天鐵處理後會加劇其運動功能障礙，並導致更嚴重的PPM3多巴胺能神經元簇的TH-陽性神經元丟失。並且這種由腦鐵含量增加而導致的神經毒性和運動功能障礙也與α-synuclein聚集增加有關。這兩部分的實驗結果表明，腦鐵含量異常增加調節α-synuclein聚集可能與帕金森病的發病機制有關。 / 在第三部分實驗中，我們進一步探討維持腦鐵穩態在PD中潛在的神經元保護作用。我們利用遺傳學手段調節鐵轉運蛋白DMT1的表達來研究腦鐵含量減少對α-synuclein果蠅的保護作用。目前的結果表明，降低α-synA53T果蠅中DMT1同源基因-Malvolio的表達可以抑制隨著年齡增加而顯著增加的腦鐵含量，並且可以延長果蠅的壽命，部分改善α-synA53T果蠅的運動功能障礙，以及完全減輕了TH陽性神經元的丟失。這些保護作用可能是由於抑制了α-synA53T果蠅中α-synuclein的聚集。因此，這些結果顯示，通過降低DMT1的表達來減少腦鐵含量DMT1可以抑制α-synuclein蛋白聚集並對神經元有保護作用。 / 綜上所述，我們的實驗結果證明了：（1）腦鐵含量異常增加調節α-synuclein聚集可能與帕金森病的發病機制有關; （2）鐵攝取蛋白DMT1可作為一個潛在的選擇性鐵螯合劑治療靶標來減緩帕金森病神經退行性進程。 / Zhu, Zhoujing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 155-181). / Abstracts also in Chinese. / Title from PDF title page (viewed on 03, October, 2016). / Zhu, Zhoujing. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Background: Normative values of VO2max have been developed or updated based on the estimated VO2max, but measured normative values of VO2max have not been developed yet. VO2max has been reported to relate to coronary heart disease (CHD) risk factors, yet most of the studies have used estimated VO2max to compare CHD risk factors. Therefore, the purpose of this study was to develop norms for VO2max from the Ball State University (BSU) Adult Physical Fitness Program cohort that represented percentiles based on the measured VO2max. In addition, this study evaluated the relationship between measured VO2max and six coronary heart disease (CHD) risk factors, which include Body Bass Index (BMI), high density lipoprotein cholesterol (HDL-C), glucose, triglyceride (TG), total cholesterol (TC) and resting blood pressure (BP).Methods: Subjects were healthy men (N=1,867) and women (N=1,253), ranging in age from 19 to 75 years, who completed the standard BSU Adult Physical Fitness Program quiet and exercise testing sessions between 1971 and 2000, with the graded exercise testing (GXT) conducted with one of the following protocols including modified walking, running, Balke, Bruce, and BSU/Bruce ramp. To be included, subjects had to achieve respiratory exchange ratio (RER) >1.0 during their exercise test.Results: All subjects were classified into ten group determined by deciles of VO2max for each decade of age for males and females respectively. A linear regression showed that VO2max decreased 10.1% per decade (0.44 mi.kg'•min'•yr') for men and 9.7% per decade (0.32 ml•kg-l.min-l.yr') for women. There was no significant difference in the rate of agerelated decline in VO2max per decade between men and women or between deciles of VO2max. Also, the percent of subjects with an exercise history code >5 (regularly participate in exercise at least 3 days per week) was higher in the higher VO2max deciles. In addition, five positive CHD risk factors were inversely related to VO2max, and one negative CHD risk factor was directly related to VO2max. As expected, the higher CRF groups had a more favorable CHD risk factor profile. Also, the mean of VO2max decreased with the greater number of CHD risk factors.Conclusion: This study developed normative values of the VO2max based on measured VO2max. VO2max was significantly correlated to CHD risk factors. / School of Physical Education, Sport, and Exercise Science

Made available in DSpace on 2014-06-11T19:33:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2005-02-16Bitstream added on 2014-06-13T20:45:00Z : No. of bitstreams: 1 traversomartinez_ae_dr_arafo.pdf: 265959 bytes, checksum: 4d4ed4b0dacd2d55f96b02084a0d8a78 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / O estudo teve como objetivo avaliar em mulheres menopáusicas, com e sem reposição hormonal, possíveis diferenças na resposta inicial ao tratamento periodontal básico, assim como determinar se a reposição hormonal com estrógeno influencia na estabilidade das condições clínicas periodontais após tratamento periodontal e terapia de manutenção. Foram selecionadas 38 mulheres na fase da menopausa com periodontites crônica, sendo divididas em dois grupos segundo seus níveis plasmáticos de estrógeno: 18 mulheres no grupo estrógeno-suficiente (>40 pg/ml) e 20 mulheres no grupo estrógeno-deficiente (<30 pg/ml). Todas as pacientes fizeram exame de sangue para avaliar os níveis plasmáticos de 17-beta estradiol, no início e no final do estudo, também foi feito o exame dos níveis de FSH só no início do estudo, para comprovação da menopausa. Os parâmetros clínicos de avaliação foram: índice de placa visível, índice de sangramento marginal, sangramento à sondagem, profundidade de sondagem e nível de inserção clínico. Um operador calibrado (Kappa 0.711) e cego para os grupos experimentais realizou todas as avaliações. Todos os parâmetros clínicos foram avaliados em 6 momentos: inicial, reavaliação (após 40 dias do tratamento básico), avaliações sucessivas a cada 3, 6 , 9, e 12 meses do final do tratamento. O tratamento periodontal básico foi realizado por dois pesquisadores segundo a necessidade individual de cada paciente. O grupo estrógeno-suficiente apresentou maior proporção de sítios com placa visível em todos os períodos de avaliação. Após sessão inicial houve reduções significativas dos níveis de placa visível tanto para o grupo estrógeno-deficiente como para o grupo estrógeno-suficiente. Em relação ao sangramento (marginal e a sondagem) ambos os grupos apresentaram uma tendência de redução dos níveis de sangramento... . / The aim of the present study was investigated if estrogen replacement therapy influences the response to the active periodontal therapy (scaling and root planning), or stability of clinical periodontal conditions in women during menopause. Thirty-eight menopausal women with chronic periodontitis were recruited and divided in two groups according serum estrogen levels: 1) estrogen-sufficient (> 40 pg/ml, n = 18) or 2) estrogen-deficient (< 30 pg/ml, n = 20). At the beginning and at the end of the study the women suffer blood exam to evaluate the serum levels of 17-ß-estradiol, and at the beginning of the study the FSH levels was examined to prove the menopausal period. Clinical measurements for evaluation were: visible plaque, marginal bleeding, bleeding on probing, probing depths and clinical attachment level. An examiner (Kappa 0.711), blind to the experimental groups, made the evaluations. Clinical measurements were taken in 6 times: initial, reevaluation (40 days after the basic treatment) and successive evaluations in each 3, 6, 9 and 12 months from the final treatment. The active periodontal therapy was made for two researchers according to the individual needs of each patient. The estrogen-sufficient group presented bigger proportions of supragingival plaque in all periods of evaluation. After the first section there was significant reduction of supragingival plaque for both estrogen-sufficient and estrogen-deficient groups. Concern about the bleeding (marginal or on probing) both groups presented a tendency to reductions on bleeding levels after the periodontal treatment, however the estrogen-deficient group presented greater percentiles of visible plaque sites in all periods after initial evaluation. The clinical attachment level was different between the groups... (Complete abstract, click electronic address below).

Self-administration of 1-methyl-4-pheny]-1,2,3,6-tetrahydropyridine (MPTP) has resulted in irreversible symptoms of Parkinson's disease in several young drug abusers. It was found that this neurotoxicant selectively destroys neuronal cells in the substantia nigra of humans and other primates. Although the mechanism of action of MPTP is not fully understood, it is now generally believed that the crucial species for MPTP neurotoxicity is not MPTP itself, but rather some of its metabolites. MPDP⁺, an intermediate in the metabolism of the neurotoxin MPTP, was found to generate superoxide radical (⋅O₂⁻) during its autoxidation process. The generation of ⋅O₂⁻ was detected by their ability to reduce ferricytochrome c. Superoxide dismutase (SOD) inhibited this reduction in a dosedependent manner. The rate of reduction of ferricytochrome c was dependent not only on the concentration of MPDP⁺, but also on the pH of the system. Thus, the rate of autoxidation of MPDP⁺ and the sensitivity of this autoxidation to superoxide dismutase inhibitable ferricytochrome c reduction were both augmented as the pH was raised from 7.0 to 10.5. The rate constant (k_c) for the reaction of superoxide radical with ferricytochrome c to form ferrocytochrome c was found to be 3.48 x 10⁵ M⁻¹S⁻¹. The rate constant (k_MPDP⁺) for the reaction of MPDP⁺ with ferricytochrome c was found to be 4.86 M⁻¹S⁻¹. The generation of ⋅O₂⁻ was further confirmed by spin-trapping in combination with EPR techniques using 5, 5-dimethyl-1-pyrrolonine-N-oxide (DMPO) as the spin trapping agent. The rate of formation of spin adduct (DMPO-O₂⁻) was dependent not only on the concentrations of MPDP⁺ and oxygen but also on the pH of the system. Superoxide dismutase inhibited the spin adduct formation in a dose-dependent manner. The ability of DMPO to trap superoxide radicals, generated during the autoxidation of MPDP⁺, and of SOD to effectively compete with this reaction for the available ⋅O₂⁻, was used as a convenient competition reaction to quantitatively determine various kinetic parameters. Using this technique, the rate constant for scavenging of superoxide radicals by superoxide dismutase was found to be 7.56 x 10⁹ M⁻¹S⁻¹. The maximum rate of superoxide generation at a fixed spin trap concentration using different amounts of MPDP⁺ was found to be 4.48 x 10⁻¹⁰ M⋅S⁻¹. The rate constant (k₁) for MPDP⁺ making superoxide radical was found to be 3.97 x 10⁻⁶ Sec⁻¹. The second order rate constant (k_DMPO) for DMPO trapping superoxide radicals was found to be 10.2 M⁻¹S⁻¹. The life time of superoxide radical at pH 10.0 was calculated to be 1.25 seconds. These data indicate that superoxide radicals are produced during spontaneous oxidation of MPDP⁺ and that EPR spin trapping techniques can be used to determine the rate constants and life time of free radicals generated in aqueous solution. Monoamine oxidase type B (MAO-B), an enzyme present in mitochondrial membranes, is known to metabolize MPTP to MPDP⁺, which then spontaneously oxidizes to MPP⁺. In the studies of MAO-B catalyzed oxidation of MPTP, the neurotoxicant was found to generate reactive oxygen species during its interaction with the enzyme. The kinetic parameters, K_m and V_max, for MAO-B catalyzed oxidation of MPTP to the corresponding species MPDP⁺ were found to be 0.194 mM and 0.335 µM/min, respectively. The generation of ⋅O₂⁻ and hydroxyl (⋅OH) radicals was detected as the DMPO spin adduct by spin trapping in combination with EPR techniques. Addition of Fe²⁺ (10 µM) to this system caused a 5-fold enhancement in EPR signal intensity of the DMPO-OH adduct. Catalase, a scavenger of hydrogen peroxide (H₂O₂), inhibited the DMPO-OH spin adduct formation in a dose-dependent manner, indicating that H₂O₂ is produced in the MAO-B catalyzed oxidation of MPTP. Ethanol, a well known scavenger of hydroxy] radical, rapidly produced an alpha-hydroxyethyl radical signal. SOD inhibited the formation of DMPO-O₂⁻ and DMPO-OH spin adducts in a dose-dependent fashion. These data suggest that ⋅O₂⁻ are produced during the oxidation of MPTP by MAO-B and that the generation of H₂O₂ and ⋅OH was secondary to the production of ⋅O₂⁻. MPTP and its metabolites, MPDP⁺ and MPP⁺, were found to inhibit the activity of acetylcholinesterase (AChE). The kinetic parameter, K_m for the substrate (acetylthiocholine), was found to be 0.216 mM and K_i values for MPTP, MPDP⁺ and MPP⁺ to inactivate AChE were found to be 2.14, 0.265 and 0.197 mM, respectively. The inactivation of AChE by these neurotoxicants was found to be dose-dependent. It was found that MPTP, MPDP⁺ and MPP⁺ are neither substrates of AChE nor the time-dependent inactivators. The studies of reaction kinetics indicate that the inactivation of ACHE by these inactivators is via a mixed-type inhibition. The dilution of the enzyme-inhibitor complex completely reversed the MPTP inhibition but only partially reversed the MPDP+ and MPP+ inhibition. These data indicate that MPTP and its metabolites can inactivate AChE and thereby increase ACh level in the basal ganglia of the brain, leading to potential cell dysfunction. These results suggest that once MPTP enters the basal ganglia of the brain, it can be catalyzed by MAO-B to generate a series of reactive species, including ⋅O₂⁻, H₂O₂ and ⋅OH, which are known to destroy cell membranes, enzymes and other important biological molecules. The nigrostriatal toxicity by MPTP leading to Parkinson's disease-like syndrome may largely be due to the reactivity of these reactive oxygen species in combination with the inactivation of the AChE enzyme in the brain, leading to potential cell dysfunction. / Ph. D.

Previous epidemiological evidence from a number of studies supports the hypothesis that the risk of essential hypertension, coronary heart disease and non-insulin dependent diabetes is, in part, programmed by intrauterine nutritional status. An increasing number of human studies indicate that the developing kidney is particularly vulnerable to the adverse effects of fetal growth retarding influences. In animals growth retarding diets or other insults, which have an impact on the development of cardiovascular functions, also appear to impact upon nephron number. In this study, the feeding of a 9% casein diet to pregnant rats, a mild protein restriction, reduced nephron number in the offspring, which progressively declined with age compared to those exposed to an 1 8% control diet. At weaning low-protein exposed offspring had hypertension and evedence of renal insufficiency. On natural death, the kidneys from aged male rats exposed to both low-protein and control maternal diets had a higher incidence glornerulosclerosis and renal disruption than females. Supplementing the maternal 9% casein diet with 3% glycine, 1.5% urea and 3% alanine in the rat normalised nephron number in the offspring. Only the addition of glycinc in the maternal low- protein diet prevented the appearance of high blood pressure in the offspring. In this study it has been demonstrated that in humans, those of a low birth weight or ponderal index, a marker of fetal undernutrition, had evidence of increased glomerular permeability, but not elevated blood pressure at age 10. This association was not evident at age 12 or in a separate cohort of young adults. It is possible that hypertension and a reduced nephron reserve are not causally associated. The evidence from this thesis suggest that prenatal undernutrition may programme renal structure in later life, but that renal programming is not one of the primary mechanisms leading to hypertension

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Prediction for future coronary artery disease (CAD) from high-density lipoprotein (HDL) and triglyceride (TG) measurements are based off of a single measurement that has been shown to be variable. To better determine risk for CAD based on blood lipids, studies in the postprandial state are warranted. To assess the reproducibility of TG clearance, 10 men underwent three trials of a 70g oral fat loading test with blood samples collected every two hours for eight hours. These trials were all scheduled at least one week apart. Men who had fasting TG concentrations > 250 mg - dL -' were excluded from the study. Each subject presented to the laboratory having abstained from exercise for 24 hours and alcohol 72 hours prior to the upcoming trial. Each subject was also provided with a standardized frozen dinner to eat the night before at a time which allowed the subject to be 12 hours fasted for the next days' trial. To specifically assess postprandial lipemia, TG concentrations were plotted against bi-hourly collection times to form a curve. The area under this curve was then calculated to determine PPL area. Itwas found that there was no significant difference in area under the TG curve (p = 0.25) for any of the three trials (1096 ± 168, 948 ± 105, and 995 ± 127 mg - dL -' - 8 • hr-' respectively for trials one, two, and three). Pearson correlations between trials were 0.79 for trials one and two, 0.82 for trials two and three, and 0.90 for trials one and three. Also, there was no significant difference in peak TG (p = 0.34) on each of the three trial days (167 ± 27, 150 ± 16, and 151 ± 19 mg • dL -1 in peak TG for trials one, two, and three respectively). Time taken to reach peak TG concentrations (p = 0.20) or time to return to baseline TG (p = 0.27) were not significantly different across three trial days. The men in this study reached peak TG concentrations in this study in 3.2 ± 0.5, 4.0 ± 0.4, 4.0 ± 0.3 hours respectively for trials one, two, and three. Time to return to baseline was 6.8 ± 0.6, 7.4 ± 0.4, 7.8 ± 0.4 hours for trials one through three respectively. Correlations between trials and the lack of a difference between trials using repeated measures ANOVA in regards to PPL area gives some preliminary evidence that some postprandial measures such as PPL area and can be reproduced across trials. However, the intra-individual variation was 19 ± 4% which provides no additional support for reproducibility of PPL. Additionally, results from this study, as well as all others pertaining to the study of reproducibility of PPL are specific to the protocol used and the method of interpretation. / School of Physical Education