Changes in serum lipids with change and fluctuation in body mass index and body fat distribution in Mexican Americans with type 2 diabetes

This dissertation was written in the format of three journal articles. Paper 1 examined the influence of change and fluctuation in body mass index (BMI) over an eleven-year period, on changes in serum lipid levels (total, HDL, and LDL cholesterol, triglyceride) in a population of Mexican Americans with type 2 diabetes. Linear regression models containing initial lipid value, BMI and age, BMI change (slope of BMI), and BMI fluctuation (root mean square error) were used to investigate associations of these variables with change in lipids over time. Increasing BMI over time was associated with gains in total and LDL cholesterol and triglyceride levels in women. Fluctuation of BMI was not associated with detrimental lipid profiles. These effects were independent of age and were not statistically significant in men. In Mexican-American women with type 2 diabetes, weight reduction is likely to result in more favorable levels of total and LDL cholesterol and triglyceride, without concern for possible detrimental effects of weight fluctuation. Weight reduction may not be as effective in men, but does not appear to be harmful either. ^ Paper 2 examined the associations of upper and total body fat with total cholesterol, HDL and LDL cholesterol, and triglyceride levels in the same population. Multilevel analysis was used to predict serum lipid levels from total body fat (BMI and triceps skinfold) and upper body fat (subscapular skinfold), while controlling for the effects of sex, age and self-correlations across time. Body fat was not strikingly associated with trends in serum lipid levels. However, upper body fat was strongly associated with triglyceride levels. This suggests that loss of upper body fat may be more important than weight loss in management of the hypertriglyceridemia commonly seen in type 2 diabetes. ^ Paper 3 was a review of the literature reporting associations between weight fluctuation and lipid levels. Few studies have reported associations between weight fluctuation and total, LDL, and HDL cholesterol and triglyceride levels. The body of evidence to date suggests that weight fluctuation does not strongly influence levels of total, LDL and HDL cholesterol and triglyceride. ^

MATHEMATICAL STUDIES ON THE EVOLUTIONARY CHANGE OF DNA SEQUENCES

With the aim of understanding the mechanism of molecular evolution, mathematical problems on the evolutionary change of DNA sequences are studied. The problems studied and the results obtained are as follows: (1) Estimation of evolutionary distance between nucleotide sequences. Studying the pattern of nucleotide substitution for the case of unequal substitution rates, a new mathematical formula for estimating the average number of nucleotide substitutions per site between two homologous DNA sequences is developed. It is shown that this formula has a wider applicability than currently available formulae. A statistical method for estimating the number of nucleotide changes due to deletion and insertion is also developed. (2) Biases of the estimates of nucleotide substitutions obtained by the restriction enzyme method. The deviation of the estimate of nucleotide substitutions obtained by the restriction enzyme method from the true value is investigated theoretically. It is shown that the amount of the deviation depends on the nucleotides in the recognition sequence of the restriction enzyme used, unequal rates of substitution among different nucleotides, and nucleotide frequences, but the primary factor is the unequal rates of nucleotide substitution. When many different kinds of enzymes are used, however, the amount of average deviation is generally small. (3) Distribution of restriction fragment lengths. To see the effect of undetectable restriction fragments and fragment differences on the estimate of nucleotide differences, the theoretical distribution of fragment lengths is studied. This distribution depends on the type of restriction enzymes used as well as on the relative frequencies of four nucleotides. It is shown that undetectability of small fragments or fragment differences gives a serious underestimate of nucleotide substitutions when the length-difference method of estimation is used, but the extent of underestimation is small when the site-difference method is used. (4) Evolutionary relationships of DNA sequences in finite populations. A mathematical theory on the expected evolutionary relationships among DNA sequences (nucleons) randomly chosen from the same or different populations is developed under the assumption that the evolutionary change of nucleons is determined solely by mutation and random genetic drift. . . . (Author's abstract exceeds stipulated maximum length. Discontinued here with permission of author). UMI ^

Growth and development of body fat distribution from skinfold measurements: Longitudinal principal components

Longitudinal principal components analyses on a combination of four subcutaneous skinfolds (biceps, triceps, subscapular and suprailiac) were performed using data from the London Longitudinal Growth Study. The main objectives were to discover at what age during growth sex differences in body fat distribution occur and to see if there is continuity in body fatness and body fat distribution from childhood into the adult status (18 years). The analyses were done for four age sectors (3mon-3yrs, 3yrs-8yrs, 8yrs-18yrs and 3yrs-18yrs). Longitudinal principal component one (LPC1) for each age interval in both sexes represents the population mean fat curve. Component two (LPC2) is a velocity of fatness component. Component three (LPC3) in the 3mon-3yrs age sector represents infant fat wave in both sexes. In the next two age sectors component three in males represents peaks and shifts in fat growth (change in velocity), while in females it represents body fat distribution. Component four (LPC4) in the same two age sectors is a reversal in the sexes of the patterns seen for component three, i.e., in males it is body fat distribution and in females velocity shifts. Components five and above represent more complicated patterns of change (multiple increases and decreases across the age interval). In both sexes there is strong tracking in fatness from middle childhood to adolescence. In males only there is also a low to moderate tracking of infant fat with middle to late childhood fat. These data are strongly supported in the literature. Several factors are known to predict adult fatness among the most important being previous levels of fatness (at earlier ages) and the age at rebound. In addition we found that the velocity of fat change in middle childhood was highly predictive of later fatness (r $\approx -$0.7), even more so than age at rebound (r $\approx -$0.5). In contrast to fatness (LPC1), body fat distribution (LPC3-LPC4) did not track well even though significant components of body fat distribution occur at each age. Tracking of body fat distribution was higher in females than males. Sex differences in body fat distribution are non existent. Some sex differences are evident with the peripheral-to-central ratios after age 14 years. ^

The heart challenge: The effect of regular aerobic exercise on body fat distribution in third and fourth grade school children: A randomized clinical trial

The pattern of body fat distribution known as "centralized", and characterized by a predominance of subcutaneous fat on the trunk and a "pot belly", has been associated with an increased risk of chronic disease. These patterns of fat distribution, as well as the lifestyle habit variables associated with adult fatness and chronic morbidity clearly begin to develop during childhood, indicating the need for intervention and primary prevention of obesity, particularly the centralized form, during childhood or adolescence. The purpose of this study was to determine whether regular aerobic exercise could beneficially alter the distribution of body fat in 8 and 9 year old children. One hundred and eighty-eight participants were randomized into either a regular aerobic exercise treatment group or a standard physical education program control group. A variety of aerobic activities was used for intervention 5 days per week during physical education class for a period of 12 weeks. Fat distribution was measured by a number of the most commonly used indices, including ratios of body circumferences and skinfolds and indices derived from a principal components analysis. Change over time in average pulse rate was used to determine if intervention actually occurred. Approximately 10% of the students were remeasured, allowing the calculation of intra- and interexaminer measurement reliability estimates for all indices.^ This study group was comparable to the U.S. population, though the study children were slightly larger for certain measures. No effect of the exercise intervention was found. The most likely explanation for this was inadequacy of the intervention, as indicated by the lack of any change in average pulse rate with treatment. The results of the measurement reliability analysis are reported and indicate that body circumference ratios are more precise than skinfold ratios, particularly when multiple observers are used. Reliability estimates for the principal component indices were also high.^ It remains unclear whether the distribution of body fat can be altered with exercise. It is likely that this issue will remain undecided until one highly reliable, valid, and sensitive measure of fat distribution can be found. ^

Comparison of Tumor Shrinkage and Cumulative Dose Distribution for Lung Cancers

Background: The physical characteristic of protons is that they deliver most of their radiation dose to the target volume and deliver no dose to the normal tissue distal to the tumor. Previously, numerous studies have shown unique advantages of proton therapy over intensity-modulated radiation therapy (IMRT) in conforming dose to the tumor and sparing dose to the surrounding normal tissues and the critical structures in many clinical sites. However, proton therapy is known to be more sensitive to treatment uncertainties such as inter- and intra-fractional variations in patient anatomy. To date, no study has clearly demonstrated the effectiveness of proton therapy compared with the conventional IMRT under the consideration of both respiratory motion and tumor shrinkage in non-small cell lung cancer (NSCLC) patients. Purpose: This thesis investigated two questions for establishing a clinically relevant comparison of the two different modalities (IMRT and proton therapy). The first question was whether or not there are any differences in tumor shrinkage between patients randomized to IMRT versus passively scattered proton therapy (PSPT). Tumor shrinkage is considered a standard measure of radiation therapy response that has been widely used to gauge a short-term progression of radiation therapy. The second question was whether or not there are any differences between the planned dose and 5D dose under the influence of inter- and intra-fractional variations in the patient anatomy for both modalities. Methods: A total of 45 patients (25 IMRT patients and 20 PSPT patients) were used to quantify the tumor shrinkage in terms of the change of the primary gross tumor volume (GTVp). All patients were randomized to receive either IMRT or PSPT for NSCLC. Treatment planning goals were identical for both groups. All patients received 5 to 8 weekly repeated 4-dimensional computed tomography (4DCT) scans during the course of radiation treatments. The original GTVp contours were propagated to T50 of weekly 4DCT images using deformable image registration and their absolute volumes were measured. Statistical analysis was performed to compare the distribution of tumor shrinkage between the two population groups. In order to investigate the difference between the planned dose and the 5D dose with consideration of both breathing motion and anatomical change, we re-calculated new dose distributions at every phase of the breathing cycle for all available weekly 4DCT data sets which resulted 50 to 80 individual dose calculations for each of the 7 patients presented in this thesis. The newly calculated dose distributions were then deformed and accumulated to T50 of the planning 4DCT for comparison with the planned dose distribution. Results: At the end of the treatment, both IMRT and PSPT groups showed mean tumor volume reductions of 23.6% ( 19.2%) and 20.9% ( 17.0 %) respectively. Moreover, the mean difference in tumor shrinkage between two groups is 3% along with the corresponding 95% confidence interval, [-8%, 14%]. The rate of tumor shrinkage was highly correlated with the initial tumor volume size. For the planning dose and 5D dose comparison study, all 7 patients showed a mean difference of 1 % in terms of target coverage for both IMRT and PSPT treatment plans. Conclusions: The results of the tumor shrinkage investigation showed no statistically significant difference in tumor shrinkage between the IMRT and PSPT patients, and the tumor shrinkage between the two modalities is similar based on the 95% confidence interval. From the pilot study of comparing the planned dose with the 5D dose, we found the difference to be only 1%. Overall impression of the two modalities in terms of treatment response as measured by the tumor shrinkage and 5D dose under the influence of anatomical change that were designed under the same protocol (i.e. randomized trial) showed similar result.