Parentage analysis with genetic markers in natural populations. I. The expected proportion of offspring with unambiguous paternity.

Recent studies indicate that polymorphic genetic markers are potentially helpful in resolving genealogical relationships among individuals in a natural population. Genetic data provide opportunities for paternity exclusion when genotypic incompatibilities are observed among individuals, and the present investigation examines the resolving power of genetic markers in unambiguous positive determination of paternity. Under the assumption that the mother for each offspring in a population is unambiguously known, an analytical expression for the fraction of males excluded from paternity is derived for the case where males and females may be derived from two different gene pools. This theoretical formulation can also be used to predict the fraction of births for each of which all but one male can be excluded from paternity. We show that even when the average probability of exclusion approaches unity, a substantial fraction of births yield equivocal mother-father-offspring determinations. The number of loci needed to increase the frequency of unambiguous determinations to a high level is beyond the scope of current electrophoretic studies in most species. Applications of this theory to electrophoretic data on Chamaelirium luteum (L.) shows that in 2255 offspring derived from 273 males and 70 females, only 57 triplets could be unequivocally determined with eight polymorphic protein loci, even though the average combined exclusionary power of these loci was 73%. The distribution of potentially compatible male parents, based on multilocus genotypes, was reasonably well predicted from the allele frequency data available for these loci. We demonstrate that genetic paternity analysis in natural populations cannot be reliably based on exclusionary principles alone. In order to measure the reproductive contributions of individuals in natural populations, more elaborate likelihood principles must be deployed.

An examination of the relationship between maternal and neighborhood-level characteristics and intrauterine growth retardation in Harris County, Texas, 1999--2001

The persistence of low birth weight and intrauterine growth retardation (IUGR) in the United States has puzzled researchers for decades. Much of the work that has been conducted on adverse birth outcomes has focused on low birth weight in general and not on IUGR. Studies that have examined IUGR specifically thus far have focused primarily on individual-level maternal risk factors. These risk factors have only been able to explain a small portion of the variance in IUGR. Therefore, recent work has begun to focus on community-level risk factors in addition to the individual-level maternal characteristics. This study uses Social Ecology to examine the relationship of individual and community-level risk factors and IUGR. Logistic regression was used to establish an individual-level model based on 155, 856 births recorded in Harris County, TX during 1999-2001. IUGR was characterized using a fetal growth ratio method with race/ethnic and sex specific mean birth weights calculated from national vital records. The spatial distributions of 114,460 birth records spatially located within the City of Houston were examined using choropleth, probability and density maps. Census tracts with higher than expected rates of IUGR and high levels of neighborhood disadvantage were highlighted. Neighborhood disadvantage was constructed using socioeconomic variables from the 2000 U.S. Census. Factor analysis was used to create a unified single measure. Lastly, a random coefficients model was used to examine the relationship between varying levels of community disadvantage, given the set of individual-level risk factors for 152,997 birth records spatially located within Harris County, TX. Neighborhood disadvantage was measured using three different indices adapted from previous work. The findings show that pregnancy-induced hypertension, previous preterm infant, tobacco use and insufficient weight gain have the highest association with IUGR. Neighborhood disadvantage only slightly further increases the risk of IUGR (OR 1.12 to 1.23). Although community level disadvantage only helped to explain a small proportion of the variance of IUGR, it did have a significant impact. This finding suggests that community level risk factors should be included in future work with IUGR and that more work needs to be conducted. ^

A review of effective weight loss and/or weight gain prevention for disadvantaged populations

Introduction. The prevalence of overweight and obesity has increased sharply for both adults and children, particularity in disadvantaged populations. Changes in dietary habits are small; however applying behavior-change principles has been associated with weight loss and preventing weight gain. This article will review studies targeting economically disadvantaged and/or communities of color incorporating the Transtheoretical Model of Change (TTM).^ Methods. Inclusion criteria were established. Descriptions of characteristics of the reviewed study interventions are included.^ Results. The search yielded a total of 23 articles identified through the electronic database PubMed that included Transtheoretical Model of Change (TTM) interventions regarding diet and/or nutrition, physical activity and/or exercise in disadvantaged populations. Thirteen study interventions centered solely on diet modification, five focused only on physical activity, and five concentrated on a combination of both. The preponderance of studies targeted WIC and urban recipients.^ Discussion/Conclusion. Although the majority of intervention studies supported the use of the Transtheoretical Model of Change (TTM) for weight loss and preventing weight gain, researchers noted that challenges still exist and further interventions are needed.^

Adult weight gain and risk of colon cancer in men

Previous research supports the hypothesis that a "rich" diet (i.e., high in fat and low in fiber) increases the risk of colon cancer. Previous research also supports the hypothesis that physical inactivity increases the risk of colon cancer, perhaps because physical inactivity decreases gut motility, thereby increasing tee time that carcinogens are in contact with the intestinal mucosa. Habitual physical inactivity, combined with rich diet, ordinarily results in chronic energy imbalance and gain in weight, except when energy balance is modified by disease or factors such as cigarette smoking. Cigarette smokers typically stay lean because of effects of smoking on the resting metabolic rate as well as on efficiency of caloric intake and storage. Therefore, if physical inactivity and rich diet do increase the risk of colon cancer, then weight gain during young adulthood should be positively associated with incidence of colon cancer during later life, especially in nonsmokers.^ This hypothesis was investigated in a cohort of 2,059 randomly selected middle-aged men who were employed at the Western Electric Company in Chicago and were free of clinically diagnosed cancer at initial examination in 1958. Body mass index (BMI) in middle age was calculated from measured height and weight at the initial examination. BMI at age 20 was estimated from weight at age 20 as recalled at the initial examination and height as measured at the initial examination. Change in BMI between age 20 and middle age was estimated by subtracting the BMI at 20 from the BMI in middle age. Forty-nine incident cases of colon cancer were detected during 25 years (43,326 person-years) at risk. When stratified by level of change in BMI from age 20 to middle age ($\le$1.9, 2.0-3.9, 4.0-5.9, $\ge$6.0 kg/m$\sp2$), age-adjusted relative hazards of colon cancer in never-smokers were 1.00, 1.22, 2.31, and 5.01, respectively (p for trend = 0.008); corresponding values in ever-smokers were 1.00, 0.95, 0.77, and 0.87, These associations did not change appreciably after further adjustment for BMI at age 20, subscapular-triceps skinfold ratio, cigarette smoking, consumption of alcohol, energy, fat, and calcium.^ We also investigated the hypothesis that the risk of colon cancer was higher in men who were lean at age 20 and became fat by middle age (lean-to-fat) than in men who were fat at age 20 and stayed fat in middle-age (fat-to-fat). "Lean" was defined as BMI $<$24 kg/m$\sp2$ at age 20 and as BMI $<$27.0 kg/m$\sp2$ in middle age. Among never-smokers, in comparison to men who were lean at age 20 and in middle age (lean-to-lean), the age-adjusted relative hazard of colon cancer was 1.43 in the fat-to-fat group (95% confidence interval (CI) 0.37-5.52) and 3.36 in the lean-to-fat group (95% CI 1.21-9.37). This investigation provides new results on the magnitude of risk of colon cancer associated with weight gain during adulthood (from age 20 to middle age). This relation was obscured or underestimated in previous studies due to effect-modification by cigarette smoking. Finally, the result supports the idea that a life-style characterized by chronic energy imbalance during young adulthood increases risk of colon cancer. ^

MEASURING THE EFFECT OF ILLNESS ON THE EXPECTED REMAINING SERVICE TIME FOR THE ACTIVE DUTY ARMY: A LIFE TABLE APPROACH

A life table methodology was developed which estimates the expected remaining Army service time and the expected remaining Army sick time by years of service for the United States Army population. A measure of illness impact was defined as the ratio of expected remaining Army sick time to the expected remaining Army service time. The variances of the resulting estimators were developed on the basis of current data. The theory of partial and complete competing risks was considered for each type of decrement (death, administrative separation, and medical separation) and for the causes of sick time.^ The methodology was applied to world-wide U.S. Army data for calendar year 1978. A total of 669,493 enlisted personnel and 97,704 officers were reported on active duty as of 30 September 1978. During calendar year 1978, the Army Medical Department reported 114,647 inpatient discharges and 1,767,146 sick days. Although the methodology is completely general with respect to the definition of sick time, only sick time associated with an inpatient episode was considered in this study.^ Since the temporal measure was years of Army service, an age-adjusting process was applied to the life tables for comparative purposes. Analyses were conducted by rank (enlisted and officer), race and sex, and were based on the ratio of expected remaining Army sick time to expected remaining Army service time. Seventeen major diagnostic groups, classified by the Eighth Revision, International Classification of Diseases, Adapted for Use In The United States, were ranked according to their cumulative (across years of service) contribution to expected remaining sick time.^ The study results indicated that enlisted personnel tend to have more expected hospital-associated sick time relative to their expected Army service time than officers. Non-white officers generally have more expected sick time relative to their expected Army service time than white officers. This racial differential was not supported within the enlisted population. Females tend to have more expected sick time relative to their expected Army service time than males. This tendency remained after diagnostic groups 580-629 (Genitourinary System) and 630-678 (Pregnancy and Childbirth) were removed. Problems associated with the circulatory system, digestive system and musculoskeletal system were among the three leading causes of cumulative sick time across years of service. ^

SOCIAL AND BIOLOGICAL DETERMINANTS OF SHORT-TERM GROWTH VELOCITY AMONG PRESCHOOLERS OF RURAL GUATEMALA: A PATH ANALYSIS APPROACH (WEIGHT-GAIN, IRON DEFICIENCY, GASTROINTESTINAL SYMPTOMS)

This dissertation develops and tests through path analysis a theoretical model to explain how socioeconomic, socioenvironmental, and biologic risk factors simultaneously influence each other to further produce short-term, depressed growth in preschoolers. Three areas of risk factors were identified: child's proximal environment, maturational stage, and biological vulnerability. The theoretical model represented both the conceptual framework and the nature and direction of the hypotheses. Original research completed in 1978-80 and in 1982 provided the background data. It was analyzed first by nested-analysis of variance, followed by path analysis. The study provided evidence of mild iron deficiency and gastrointestinal symptomatology in the etiology of depressed, short-term weight gain. Also, there was evidence suggesting that family resources for material and social survival significantly contribute to the variability of short-term, age-adjusted growth velocity. These results challenge current views of unifocal intervention, whether for prevention or control. For policy formulations, though, the mechanisms underlying any set of interlaced relationships must be decoded. Theoretical formulations here proposed should be reassessed under a more extensive research design. It is suggested that studies should be undertaken where social changes are actually in progress; otherwise, nutritional epidemiology in developing countries operates somewhere between social reality and research concepts, with little grasp of its real potential. The study stresses that there is a connection between substantive theory, empirical observation, and policy issues. ^

A Pre-Clinical Assessment of Minocycline for Treatment of Chronic Neuropathic Pain after Spinal Cord Injury

Patients living with a spinal cord injury (SCI) often develop chronic neuropathic pain (CNP). Unfortunately, the clinically approved, current standard of treatment, gabapentin, only provides temporary pain relief. This treatment can cause numerous adverse side effects that negatively affect the daily lives of SCI patients. There is a great need for alternative, effective treatments for SCI-dependent CNP. Minocycline, an FDA-approved antibiotic, has been widely prescribed for the treatment of acne for several decades. However, recent studies demonstrate that minocycline has neuroprotective properties in several pre-clinical rodent models of CNS trauma and disease. Pre-clinical studies also show that short-term minocycline treatment can prevent the onset of CNP when delivered during the acute stage of SCI and can also transiently attenuate established CNP when delivered briefly during the chronic stage of SCI. However, the potential to abolish or attenuate CNP via long-term administration of minocycline after SCI is unknown. The purpose of this study was to investigate the potential efficacy and safety of long-term administration of minocycline to abolish or attenuate CNP following SCI. A severe spinal contusion injury was administered on adult, male, Sprague-Dawley rats. At day 29 post-injury, I initiated a three-week treatment regimen of daily administration with minocycline (50 mg/kg), gabapentin (50 mg/kg) or saline. The minocycline treatment group demonstrated a significant reduction in below-level mechanical allodynia and above- level hyperalgesia while on their treatment regimen. After a ten-day washout period of minocycline, the animals continued to demonstrate a significant reduction in below-level mechanical allodynia and above-level hyperalgesia. However, minocycline-treated animals exhibited abnormal weight gain and hepatotoxicity compared to gapabentin-treated or vehicle-treated subjects.The results support previous findings that minocycline can attenuate CNP after SCI and suggested that minocycline can also attenuate CNP via long-term delivery of minocycline after SCI (36). The data also suggested that minocycline had a lasting effect at reducing pain symptoms. However, the adverse side effects of long-term use of minocycline should not be ignored in the rodent model. Gabapentin treatment caused a significant decrease in below-level mechanical allodynia and below-level hyperalgesia during the treatment regimen. Because gabapentin treatment has an analgesic effect at the concentration I administered, the results were expected. However, I also found that gabapentin-treated animals demonstrated a sustained reduction in pain ten days after treatment withdrawal. This result was unexpected because gabapentin has a short half-life of 1.7 hours in rodents and previous studies have demonstrated that pre-drug pain levels return shortly after withdrawal of treatment. Additionally, the gabapentin-treated animals demonstrated a significant and sustained increase in rearing events compared with all other treatment groups which suggested that gabapentin treatment was not only capable of reducing pain long-term but may also significantly improve trunk stability or improve motor function recovery.

Comparing Campus Discipline Rates: A Multivariate Approach for Identifying Schools with Significantly Different than Expected Exclusionary Discipline Rates

Campus behavior management is important for ensuring classroom order and promoting positive academic outcomes. Previous studies have shown the importance of individual student and campus personnel characteristics and campus context for explaining campus discipline rates (e.g., rates of suspension and expulsion). Assessing campus discipline rates, while controlling for these individual and campus characteristics, is important for the monitoring, evaluation, and intervention role of policymakers as well as state and federal level education agencies. Systems or metrics exist that measure other student outcomes (i.e., academic performance) with controls for individual and campus characteristics, but none exist that monitor these differences for discipline rates across campuses. In this paper, we use a multivariate model to analyze a longitudinal, statewide dataset for all secondary students in Texas from 2000 to 2008 in order to examine how campus discipline rates differ across schools with statistically similar students, teachers, and campus characteristics. The findings are important for understanding that some schools with similar characteristics have significantly different exclusionary discipline rates, and they are important for informing policy and agency level decision-making. The methodology described can easily be used by monitoring agencies as well as local school districts.

Role of obesity, weight gain, physical activity, and polymorphisms in the mTOR pathway and the risk of renal cell carcinoma

The interplay between obesity, physical activity, weight gain and genetic variants in mTOR pathway have not been studied in renal cell carcinoma (RCC). We examined the associations between obesity, weight gain, physical activity and RCC risk. We also analyzed whether genetic variants in the mTOR pathway could modify the association. Incident renal cell carcinoma cases and healthy controls were recruited from the University of Texas MD Anderson Cancer Center in Houston, Texas. Cases and controls were frequency-matched by age (±5 years), ethnicity, sex, and county of residence. Epidemiologic data were collected via in-person interview. A total of 577 cases and 593 healthy controls (all white) were included. One hundred ninety-two (192) SNPs from 22 genes were available and their genotyping data were extracted from previous genome-wide association studies. Logistic regression and regression spline were performed to obtain odds ratios. Obesity at age 20, 40, and 3 years prior to diagnosis/recruitment, and moderate and large weight gain from age 20 to 40 were each significantly associated with increased RCC risk. Low physical activity was associated with a 4.08-fold (95% CI: 2.92-5.70) increased risk. Five single nucleotide polymorphisms (SNPs) were significantly associated with RCC risk and their cumulative effect increased the risk by up to 72% (95% CI: 1.20-2.46). Strata specific effects for weight change and genotyping cumulative groups were observed. However, no interaction was suggested by our study. In conclusion, energy balance related risk factors and genetic variants in the mTOR pathway may jointly influence susceptibility to RCC. ^

Association between sugar-sweetened beverages and both gestational weight gain and gestational diabetes

This cross-sectional study aimed at evaluating the association between sugar sweetened beverage (SSB) consumption and both excessive gestational weight gain (EGWG) and gestational diabetes mellitus (GDM). The study was conducted in the postpartum units of Memorial Hermann Hospital, Lyndon Baines Johnson General Hospital, the University of Texas Medical Branch at Galveston General Hospital, and the University of Texas at Brownsville Hospital. Between June 2009 and September 2010, women between the ages of 18 and 49 years with singleton pregnancies who delivered an infant born at 37 weeks of gestation or later were approached. Descriptive, univariate and multivariate analysis were employed in our study using the Statistical Analysis System (SAS) software version 9.1 (SAS Institute Inc. Cary, North Carolina). Our investigation did not find statistically significant associations between SSBs and EGWG. Our study reported no evidence of an association between SSBs and GDM except for sports drinks. However, the estimate of this association was deemed very imprecise. In conclusion, our study did not find strong provide strong support for the hypothesis that high consumption of SSBs increases the risk of EGWG or GDM. ^

Gain-of-function of the p53R172H mutation in a mouse model of Li -Fraumeni syndrome

Missense mutations in the p53 tumor-suppressor gene are the most common alterations of p53 in somatic tumors and in patients with Li-Fraumeni syndrome. p53 missense mutations occur in the DNA binding region and disrupt the ability of p53 to activate transcription. In vitro studies have shown that some p53 missense mutants have a gain-of-function or dominant-negative activity. ^ The p53 175 Arg-to-His (p53 R175H) mutation in humans has been shown to have dominant-negative and gain-of-function properties in vitro. This mutation is observed in the germline of individuals with Li-Fraumeni syndrome. To accurately model Li-Fraumeni syndrome and to examine the mechanistic nature of a gain-of-function missense mutation on in vivo tumorigenesis, we generated and characterized a mouse with the corresponding mutation, p53 R172H. p53R172H homozygous and heterozygous mice developed similar tumor spectra and survival curves as p53 −/− and p53+/− mice, respectively. However, tumors in p53+/R172H mice metastasized to various organs with high frequency, suggesting a gain-of-function phenotype by p53R172H in vivo. Mouse embryonic fibroblasts (MEFs) from p53R172H mice also showed gain-of-function phenotypes in cell proliferation, DNA synthesis, and transformation potential, while cells from p53+/− and p53−/− mice did not. ^ To mechanistically characterize the gain-of-function phenotype of the p53R172H mutant, the role of p53 family members, p63 and p73, was analyzed. Disruption of p63 and p73 by siRNAs in p53 −/− MEFs increased transformation potential and reinitiated DNA synthesis to levels observed in p53R172H/R172H cells. Additionally, p63 and p73 were bound and functionally inactivated by p53R172H in metastatic p53 R172H tumor-derived cell lines, indicating a role for the p53 family members in the gain-of-function phenotype. This study provides in vivo evidence for the gain-of-function effect of p53 missense mutations and more accurately models the Li-Fraumeni syndrome. ^