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Background & Rationale: Heart rate variability analysis has provided scholars and clinicians with a powerful non-invasive tool for the assessment of cardiac autonomic function in health and disease. However, the interpretation of the information provided by this technique would be greatly facilitated by a more precise definition of 'normality'. The purpose of this investigation was to examine the alterations in cardiac autonomic function across a broad spectrum of ages in healthy males and females. Methods: Heart rate variability data during 20 min supine rest and orthostatic stress (10 min free standing) as well as 24-hour ambulatory Holter ECG recordings were obtained on 123 healthy volunteers (72 female/51 male). Subjects were arbitrarily classified into five categories: pediatric (PED; 5-12 yrs, n=22, 12 female:10 male), adolescent (ADO; 13-17 yrs, n=21, 13 female:8 male), adult (ADU; 18-30 yrs, n=26, 13 female:13 male), middle aged (MDA; 31-60 yrs, n=24, 15 female:9 male) and elderly (ELD; 61+ yrs, n=30, 19 female:11 male) age groups. Power spectral analysis (autoregressive) was determined from supine and standing acute data sets as well as six evenly spaced one hour periods during the Holter recording. Time domain variables (pNN50, R-MSSD, SDNN, SDANN & SDNN index) were derived from the 24-hour data sets. Results: Heart rate in the supine position declined progressively from age 5 years to 30 years but showed no further changes thereafter. In contrast, power spectral measures remained relatively stable in the younger age groups but subsequently exhibited a significant shift toward a higher LF:HF area signifying sympathetic dominance (or vagal withdrawal) in the MDA and ELD subjects. The heart rate and spectral response to orthostasis was most dramatic in the ADO subjects and exhibited a progressive decline in the three older age groups. With respect to the time domain variables, those parameters characterizing short term variability (pNN5O & R-MSSD) were stable in the PED, ADO and ADU subjects but significantly diminished in the two older age groups. In contrast, time domain variables encompassing long term (SDNN & SDANN) and intermediate (SDNN index) oscillations exhibited age-related increases reaching peak values in the ADU subjects and declining progressively thereafter. Power spectral analysis of the six evenly spaced one hour periods of the 24-hour holter recording revealed a diminished circadian rhythm for the majority of the frequency domain indices in the two oldest age groups. Conclusions: The present investigation revealed substantial evidence supporting the existence of an age dependent change in cardiac autonomic function. However, this process appeared to act homogeneously across gender. The similarity of these age dependent changes to those previously observed in pathological conditions commonly associated with autonomic neuropathy serves to emphasize the importance of HRV research aimed at the establishment of reference standards in healthy populations and a more precise definition of 'normal' autonomic neurocardiac function. / Thesis / Master of Science (MSc)

Typescript (photocopy). / Digitized by Kansas Correctional Industries

An in vitro system has been developed to study N-acetyltransferase (NAT) activity using human liver slices in dynamic organ culture. Acetylation of para-aminobenzoic acid (PABA) and sulfamethazine (SMZ) in the presence of human liver slices was monitored by measuring the disappearance of the parent amine from the incubation medium using the colorimetric procedure of Bratton & Marshall. Presence of the acetyl conjugate was confirmed using HPLC. PABA acetylation rates varied from 0.72-2.52 nmoles/hr/mg protein (n = 8). This small variation (4 fold) is consistent with the classification of PABA as a monomorphic substrate. The variation in the rate of SMZ acetylation was greater than 20 fold (0.144-3.68 nmoles/hr/mg protein; n = 9). This larger variation is characteristic of SMZ as a polymorphic substrate. The results obtained indicate that human liver slices in dynamic organ culture can be used for the determination of hepatic NAT activity and acetylator status of individual human livers.

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published_or_final_version / Mathematics / Master / Master of Philosophy

published_or_final_version / Mathematics / Master / Master of Philosophy

Molecular dynamics (MD) provides an atomically detailed description of the dynamics of a system of atoms. It is a useful tool to understand how protein function arises from the dynamics of the atoms of the protein and of its environment. When the MD model is accurate, analyzing a MD trajectory unveils features of the proteins that are not available from a single snapshot or a static structure. When the sampling of the accessible configurations is accurate, we can employ statistical mechanics (SM) to connect the trajectory generated by MD to experimentally measurable kinetic and thermodynamic quantities that are related to function. In this dissertation I describe three applications of MD and SM in the field of biochemistry. First, I discuss the theory of alchemical methods to compute free energy differences. In these methods a fragment of a system is computationally modified by removing its interactions with the environment and creating the interactions of the environment with the new species. This theory provides a numerical scheme to efficiently compute protein-ligand affinity, solvation free energies, and the effect of mutations on protein structure. I investigated the theory and stability of the numerical algorithm. The second research topic that I discuss considers a model of the dynamics of a set of coarse variables. The dynamics in coarse space is modeled by the Smoluchowski equation. To employ this description it is necessary to have the correct potential of mean force and diffusion tensor in the space of coarse variables. I describe a new method that I developed to extract the diffusion tensor from a MD simulation. Finally, I employed MD simulations to explain at a microscopic level the stereospecificity of the enzyme ketoreductase. To do so, I ran multiple simulations of the enzyme bound with the correct ligand and its enantiomer in a reactive configuration. The simulations showed that the enzyme retained the correct stereoisomer closer to the reactive configuration, and highlighted which interactions are responsible for the specificity. These weak physical interactions enhance binding with the correct ligand even prior to the steps of chemical modification. / text

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