published_or_final_version / abstract / Mathematics / Master / Master of Philosophy

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Faculty of Health Sciencs School of physiology 0010633J bnkeh@uycdc.uninet.m / Blood pressure (BP) is a heritable trait. However, the loci responsible and the mechanisms by which these genes determine BP are uncertain. Based on widely published data regarding frequent phenotypic characteristics that exemplify essential hypertension (EHT) in persons of African ancestry, in the present thesis I explored the role of gene candidates most likely to contribute to BP in this group. In this regard a high frequency of persons of African descent experience increases in BP in response to an enhanced salt intake (salt-sensitive hypertension). In addition, many patients of African origin with EHT fail to respond to inhibition of angiotensin-converting enzyme (ACE) with an appropriate decrease in BP, a factor that cannot be explained entirely on the basis of reduced plasma renin levels in this group. Thus, I evaluated the role of several gene variants that could influence either renal salt handling or the activity and effects of the renin-angiotensin system on BP in subjects of African ancestry. Although the angiotensinogen (AGT) gene has at least 3 variants in the promoter region that influence angiotensinogen expression and which occur with a remarkably high frequency in populations of African ancestry, their role in this group is still controversial. To-date, interactions between these variants have not been considered. Using a casecontrol study design in a sample of 1325 subjects, as well as association analysis with 24 hour ambulatory BP (ABP) values in 626 hypertensives, I confirmed that an independent effect of functional AGT gene variants on the risk for EHT or 24 hour ABP was weak at best. Importantly, however, interactions between the -20A C and -217G A variants were noted to strongly impact on the risk for EHT as well as ABP. Furthermore, interactions between the -20A C and -217G A variants played a major role in iii contributing toward the variability of ABP responses to ACE inhibitors, but not calcium channel blockers in this population group, with genotype determining whether or not ACE inhibitor responses occurred. Although the 825C T polymorphism of the guanosine triphosphate (G) protein 3 subunit (GNB3) gene influences the activity of a substance that modifies renal salt handling, namely the Na+/H+ exchanger, its impact in hypertensives of African descent is controversial. In the present thesis I confirmed in a large sample that the GNB3 variant was not associated with the risk for EHT or ABP values in subjects of African ancestry. However, because the activity of the exchanger is enhanced in obesity I hypothesised that the GNB3 gene variant could mediate a clinically relevant BP effect by modifying the impact of body size on BP (type I or II genetic effect). Indeed, GNB3 genotype proved to be a strong determinant of the impact of body size on systolic BP values, with genotype determining whether or not the effect occurred. The epithelial sodium channel (ENaC) and atrial natriuretic peptide (ANP) have an important influence on renal salt handling. The T594M polymorphism of the -subunit of the ENaC gene only exists with a relatively high frequency in subjects of African ancestry. Previous studies conducted in this population group in relatively small samples have indicated that the ENaC and ANP gene variants determine BP in subjects of African descent. In a larger sample of subjects of African descent I demonstrated that the T594M polymorphism of the ENaC gene has no impact on BP in this population group. However, my results suggest that the ANP gene may be a candidate worthy of further study. In conclusion, the results described in this thesis provide evidence that lends some clarity to the role of likely gene candidates for BP control in people of African descent. iv Importantly, data from this thesis suggest that interactions between functional variants of specific loci (e.g the AGT gene), and clinically relevant type I or II genetic effects (no independent actions, but modifier gene effects, e.g, GNB3) should be considered before excluding loci as playing an important role in BP control. Moreover, this thesis provides the first substantial data to indicate that gene variants determine the variability of BP responses to pharmacological agents in hypertension in this population group.

Thesis (M. Phil.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

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Performance and stability of many iterative algorithms such as stochastic gradient descent largely depend on a fixed and scalar step-size parameter. Use of a fixed and scalar step-size value may lead to limited performance in many problems. We study several existing step-size adaptation algorithms in nonstationary, supervised learning problems using simulated and real-world data. We discover that effectiveness of the existing step-size adaptation algorithms requires tuning of a meta parameter across problems. We introduce a new algorithm - Autostep - by combining several new techniques with an existing algorithm, and demonstrate that it can effectively adapt a vector step-size parameter on all of our training and test problems without tuning its meta parameter across them. Autostep is the first step-size adaptation algorithm that can be used in widely different problems with the same setting of all of its parameters.

Aim: The aim of this study was to investigate the differences between older and younger adults in the attenuation of impact during descent from a step. Strategies that have been implicated in reducing either the magnitude of vertical ground reaction force (vertical GRF) or the time taken to reach the maximum vertical GRF in the stepping leg were explored. Study Design: The study was an experimental, laboratory based, repeated measures design. Participants: Twenty participants took part in this exploratory study. Ten in the older group of 60-80 years, mean 65.3 (SD 5) years and ten in the younger age group of 20-30 years, mean 22.8 (SD 2.5) years. Main Measures: The vertical GRF and the time taken to reach maximum vertical GRF were measured to ascertain impact during step descent. Electromyography and kinematic variables were measured to determine the effect they may have on the impact. The variables measured were the maximum joint range of motion of the hip and knee during early stance in step descent. Surface electromyography from four lower limb muscles was recorded to ascertain the magnitude of muscle activity at impact. The relationship in an antero-posterior direction of the upper body and stepping leg at initial contact (IC) was also investigated. Results: There was a significant difference in both the amount of knee flexion and the amount of activity of the vastus lateralis muscle during impact between older and younger adults. Older adults had significantly less knee flexion during a step descent activity than younger adults (F(1,18)=5.48; p=.031).Older adults had significantly more vastus lateralis activity during a step descent activity than younger adults (F(1,18)=5.21; p=.035). Conclusions: Older and younger adults use different strategies in both muscle activation and joint range of motion around the knee of the leading leg during the step descent. Older adults used more vastus lateralis activity perhaps to increase stiffness in the knee, leading to a reduction in range of motion at impact. Although no change in vertical GRF was detected in this study, both of these strategies have the potential to increase the impact of a step and therefore cause jarring and possible damage. This study recruited healthy active older adults and differences in impact may be observed in an older or less active population, or in those with joint pathology such as osteoarthritis.

Aim: The aim of this study was to investigate the differences between older and younger adults in the attenuation of impact during descent from a step. Strategies that have been implicated in reducing either the magnitude of vertical ground reaction force (vertical GRF) or the time taken to reach the maximum vertical GRF in the stepping leg were explored. Study Design: The study was an experimental, laboratory based, repeated measures design. Participants: Twenty participants took part in this exploratory study. Ten in the older group of 60-80 years, mean 65.3 (SD 5) years and ten in the younger age group of 20-30 years, mean 22.8 (SD 2.5) years. Main Measures: The vertical GRF and the time taken to reach maximum vertical GRF were measured to ascertain impact during step descent. Electromyography and kinematic variables were measured to determine the effect they may have on the impact. The variables measured were the maximum joint range of motion of the hip and knee during early stance in step descent. Surface electromyography from four lower limb muscles was recorded to ascertain the magnitude of muscle activity at impact. The relationship in an antero-posterior direction of the upper body and stepping leg at initial contact (IC) was also investigated. Results: There was a significant difference in both the amount of knee flexion and the amount of activity of the vastus lateralis muscle during impact between older and younger adults. Older adults had significantly less knee flexion during a step descent activity than younger adults (F(1,18)=5.48; p=.031).Older adults had significantly more vastus lateralis activity during a step descent activity than younger adults (F(1,18)=5.21; p=.035). Conclusions: Older and younger adults use different strategies in both muscle activation and joint range of motion around the knee of the leading leg during the step descent. Older adults used more vastus lateralis activity perhaps to increase stiffness in the knee, leading to a reduction in range of motion at impact. Although no change in vertical GRF was detected in this study, both of these strategies have the potential to increase the impact of a step and therefore cause jarring and possible damage. This study recruited healthy active older adults and differences in impact may be observed in an older or less active population, or in those with joint pathology such as osteoarthritis.

Thesis (M. Phil.)--University of Hong Kong, 2006. / Also available online.