A cladistic analysis of apolipoprotein B gene variation and plasma lipid and apolipoprotein B levels, using familial data

Any functionally important mutation is embedded in an evolutionary matrix of other mutations. Cladistic analysis, based on this, is a method of investigating gene effects using a haplotype phylogeny to define a set of tests which localize causal mutations to branches of the phylogeny. Previous implementations of cladistic analysis have not addressed the issue of analyzing data from related individuals, though in human studies, family data are usually needed to obtain unambiguous haplotypes. In this study, a method of cladistic analysis is described in which haplotype effects are parameterized in a linear model which accounts for familial correlations. The method was used to study the effect of apolipoprotein (Apo) B gene variation on total-, LDL-, and HDL-cholesterol, triglyceride, and Apo B levels in 121 French families. Five polymorphisms defined Apo B haplotypes: the signal peptide Insertion/deletion, Bsp 1286I, XbaI, MspI, and EcoRI. Eleven haplotypes were found, and a haplotype phylogeny was constructed and used to define a set of tests of haplotype effects on lipid and apo B levels.^ This new method of cladistic analysis, the parametric method, found significant effects for single haplotypes for all variables. For HDL-cholesterol, 3 clusters of evolutionarily-related haplotypes affecting levels were found. Haplotype effects accounted for about 10% of the genetic variance of triglyceride and HDL-cholesterol levels. The results of the parametric method were compared to those of a method of cladistic analysis based on permutational testing. The permutational method detected fewer haplotype effects, even when modified to account for correlations within families. Simulation studies exploring these differences found evidence of systematic errors in the permutational method due to the process by which haplotype groups were selected for testing.^ The applicability of cladistic analysis to human data was shown. The parametric method is suggested as an improvement over the permutational method. This study has identified candidate haplotypes for sequence comparisons in order to locate the functional mutations in the Apo B gene which may influence plasma lipid levels. ^

ASSESSMENT OF SKELETAL MUSCLE BLOOD FLOW AND GLUCOSE METABOLISM WITH POSITRON EMITTING RADIONUCLIDES

In order to evaluate factors regulating substrate metabolism in vivo positron emitting radionuclides were used for the assessment of skeletal muscle blood flow and glucose utilization. The potassium analog, Rb-82 was used to measure skeletal muscle blood flow and the glucose analog, 18-F-2-deoxy-2-fluoro-D-glucose (FDG) was used to examine the kinetics of skeletal muscle transport and phosphorylation.^ New Zealand white rabbits' blood flow ranged from 1.0-70 ml/min/100g with the lowest flows occurring under baseline conditions and the highest flows were measured immediately after exercise. Elevated plasma glucose had no effect on increasing blood flow, whereas high physiologic to pharmacologic levels of insulin doubled flow as measured by the radiolabeled microspheres, but a proportionate increase was not detected by Rb-82. The data suggest that skeletal muscle blood flow can be measured using the positron emitting K+ analog Rb-82 under low flow and high flow conditions but not when insulin levels in the plasma are elevated. This may be due to the fact that insulin induces an increase in the Na+/K+-ATPase activity of the cell indirectly through a direct increase in the Na+/H+pump activity. This suggests that the increased cation pump activity counteracts the normal decrease in extraction seen at higher flows resulting in an underestimation of flow as measured by rubidium-82.^ Glucose uptake as measured by FDG employed a three compartment mathematical model describing the rates of transport, countertransport and phosphorylation of hexose. The absolute values for the metabolic rate of FDG were found to be an order of magnitude higher than those reported by other investigators. Changes noted in the rate constant for transport (k1) were found to disagree with the a priori information on the effects of insulin on skeletal muscle hexose transport. Glucose metabolism was however, found to increase above control levels with administration of insulin and electrical stimulation. The data indicate that valid measurements of skeletal muscle glucose transport and phosphorylation using the positron emitting glucose analog FDG requires further model application and biochemical validation. (Abstract shortened with permission of author.) ^

Association of maternal sphinganine:sphingosine ratio and folate levels with neural tube defects along the South Texas border

Neural tube defects (NTDs) remain elevated in Hispanic women along the South Texas Border, despite folate supplementation and folate fortification of cereal products. Missmer et al. examined the relationships between fumonisins, a class of corn mycotoxin, and NTDs in Hispanic women who ate corn tortillas and found increased odds ratios with increasing exposure, as measured by serum sphinganine:sphingosine (sa:so) ratios. This study examined the interactions between categorized maternal serum folate levels and stratified sa:so ratios and the resultant odds ratios of NTDs, stratified by type (anencephaly and spina bifida). The hypothesis was that the above normal folate category would have lower odds ratios of NTDs at given sa:so ratio categories and that there would be a difference in odds ratio patterns for anencephaly and spina bifida. Methods. Data for 406 Hispanic women were obtained from the Missmer case-control study. Sa:so ratios were calculated and subjects were stratified into “below normal,” “normal,” and above normal range for folate. A logistic regression model was applied, controlling for BMI, serum B12, lab batch, and conception date. Results. While OR’s of NTDs increased for increasing sa:so ratios, OR’s for “above normal” folate were not decreased at any sa:so ratio and there was no statistically significant difference between OR’s of anencephaly and spina bifida. Conclusion. Folate does not appear to be protective against the potential teratogenic effect of fumonisins and did not differ in effect on OR’s of NTD by type. More research is necessary to determine the extent of fumonisin exposure in Hispanic women along the South Texas Border.^

Behavioral decision making and the levels of change: An application of the transtheoretical model to prenatal smoking in low -income women

Despite continued research and public health efforts to reduce smoking during pregnancy, prenatal cessation rates in the United States have decreased and the incidence of low birth weight has increased from 1985 to 1991. Lower socioeconomic status women who are at increased risk for poor pregnancy outcomes may be resistant to current intervention efforts during pregnancy. The purpose of this dissertation was to investigate the determinants of continued smoking and quitting among low-income pregnant women.^ Using data from cross-sectional surveys of 323 low-income pregnant smokers, the first study developed and tested measures of the pros and cons of smoking during pregnancy. The original decisional balance measure for smoking was compared with a new measure that added items thought to be more salient to the target population. Confirmatory factor analysis using structural equation modeling showed neither the original nor new measure fit the data adequately. Using behavioral science theory, content from interviews with the population, and statistical evidence, two 7-item scales representing the pros and cons were developed from a portion (n = 215) of the sample and successfully cross-validated on the remainder of the sample (n = 108). Logistic regression found only pros were significantly associated with continued smoking. In a discriminant function analysis, stage of change was significantly associated with pros and cons of smoking.^ The second study examined the structural relationships between psychosocial constructs representing some of the levels of and the pros and cons of smoking. The cross-sectional design mandates that statements made regarding prediction do not prove causation or directionality from the data or methods analysis. Structural equation modeling found the following: more stressors and family criticism were significantly more predictive of negative affect than social support; a bi-directional relationship was found between negative affect and current nicotine addiction; and negative affect, addiction, stressors, and family criticism were significant predictors of pros of smoking.^ The findings imply reversing the trend of decreasing smoking cessation during pregnancy may require supplementing current interventions for this population of pregnant smokers with programs addressing nicotine addiction, negative affect, and other psychosocial factors such as family functioning and stressors. ^

Evaluation of a wellness program at a large private sector petrochemical company in Texas

The study purpose was to analyze the effects Integrated Health Solutions (IHS), an employee wellness program that has been implemented for one year on the corporate campus of a major private sector petrochemical company in Houston, TX, has on employee health. ^ Chronic diseases are the leading causes of morbidity and mortality in the United States and are the most preventable of all health problems. The costs of chronic diseases in the working-age adult population include not only health problems and a decrease in quality of life, but also an increase the cost of health care and costs to businesses and employers, both directly and indirectly. These emerging costs to employers as well as the fact that adults now spend the majority of waking hours at the office have increased the interest in worksite health promotion programs that address many of the behavioral factors that lead to chronic conditions. Therefore, implementing and evaluating programs that are aimed at promoting health and decreasing the prevalence of chronic diseases at worksites is very important. ^ Data came from existing data that were collected by IHS staff during employee biometric screenings at the company in 2010 and 2011. Data from employees who participated in screenings in both 2010 and 2011 were grouped into a cohort by IHS staff. ^ One-tailed t-tests were conducted to determine if there were significant improvements in the biometric measures of body fat percentage, BMI, waist circumference, systolic and diastolic blood pressures, total, HDL, and LDL cholesterol levels, triglycerides, blood glucose levels, and cardiac risk ratios. Sensitivity analysis was conducted to determine if there were differences in program outcomes when stratified by age, gender, job type, and time between screenings. ^ Mean differences for the variables from 2010 to 2011 were small and not always in the desired direction for health improvement indicators. Through conducting t-tests, it was found that there were significant improvements in HDL, cardiac risk ratio, and glucose levels. There were significant increases in cholesterol, LDL, and diastolic blood pressures. For the IHS program, it appears that gender, job type, and time between screenings were possible modifiers of program effectiveness. When program outcome measures were stratified by these factors, results suggest that corporate employees had better outcomes than field employees, males had better outcomes overall than females, and more positive program effects were seen for employees with less time between their two screenings. ^ Recommendations for the program based on the results include ensuring validity of instruments and initial and periodic training of measurement procedures and equipment handling, using normative data or benchmarks to decrease chances for biased estimates of program effectiveness, measuring behaviors as well as biometric and physiologic statuses and changes, and collecting level of engagement data.^

Sources of familial aggregation and co-aggregation of fasting blood glucose and nutritional factors among Mexican -Americans in Starr County, Texas

The purpose of this study was to determine the effects of nutrient intake, genetic factors and common household environmental factors on the aggregation of fasting blood glucose among Mexican-Americans in Starr County, Texas. This study was designed to determine: (a) the proportion of variation of fasting blood glucose concentration explained by unmeasured genetic and common household environmental effects; (b) the degree of familial aggregation of measures of nutrient intake; and (c) the extent to which the familial aggregation of fasting blood glucose is explained by nutrient intake and its aggregation. The method of path analysis was employed to determine these various effects.^ Genes play an important role in fasting blood glucose: Genetic variation was found to explain about 40% of the total variation in fasting blood glucose. Common household environmental effects, on the other hand, explained less than 3% of the variation in fasting blood glucose levels among individuals. Common household effects, however, did have significant effects on measures of nutrient intake, though it explained only about 10% of the total variance in nutrient intake. Finally, there was significant familial aggregation of nutrient intake measures, but their aggregation did not contribute significantly to the familial aggregation of fasting blood glucose. These results imply that similarities among relatives for fasting blood glucose are not due to similarities in nutrient intake among relatives. ^