<p>Leptin, an adipose derived hormone, has emerged as a regulator of bone metabolism. Recent findings support a role of leptin in the process of fetal bone remodeling during pregnancy; however, the link between maternal leptin during pregnancy and offspring bone status is undocumented. Evidence exists that the intrauterine environment plays a role in programming peak bone mass that is achieved in late adolescence and thus osteoporosis risk later in life. We investigated the association between maternal leptin during the third trimester and offspring bone mass at 3 years of age.</p> <p><strong>Method:</strong> Based on a sub-sample of a prospective birth cohort study, we conducted analysis on 425 mothers from whom maternal blood samples in pregnancy were analyzed for leptin and 25- hydroxyvitamin D, and whole body bone mass by dual energy x-ray absorptiometry were available for both mother and child at 3 years. Data were collected for maternal prepregnancy body mass index (BMI), lifestyle, and nutrition during pregnancy, as well as the child’s nutrition and physical activity at 3 years.</p> <p><strong>Results:</strong> Women obese on entering pregnancy have a two-fold greater circulating leptin during pregnancy than women with normal weight BMIs. Maternal age and skinfold thickness were positively associated with maternal leptin status. However, maternal leptin status was not a significant predictor of offspring BMC z-score at 3 years of age, when adjusted for relevant maternal and child variables. Maternal vitamin D status was also not a predictor of offspring bone status. Rather the key predictors of child BMC z-score were maternal bone mineral density z-score and child’s weight and vitamin D intake at 3 years.</p> <p><strong>Conclusion:</strong> While maternal leptin status during pregnancy is highly variable among women of different BMI categories, in utero exposure to leptin is not a significant factor that influences child bone status at 3 years of age when adjusted for other relevant variables.</p> / Master of Science (MSc)

Thesis (M.A.)-- University of Texas Southwestern Medical Center at Dallas, 2006. / Vita. Bibliography: p. 158-163

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Wnt proteins are crucial for development/homeostasis by controlling cell fate including apoptosis (Moon RT et al. 1997). Three humanWnt13 isoforms were identified: the secreted Wnt13A, mitochondrial Wnt13B, and nuclear Wnt13C forms; and nuclear Wnt13 had an increased sensitivity to LPS/TNF-induced apoptosis in primary endothelial cells (EC); both Wnt13B and C mRNA contain two start codons (AUG+1 and +74), but the same protein encoded from AUG+74 by Wnt13C was expressed lower than Wnt13B (Struewing IT et al.2006). We hypothesize that during EC apoptosis, the nuclear Wnt13C expression is regulated translationally; nuclear Wnt13 favors apoptosis through regulating the activity/expression of apoptosis-related factors; Wnt13 isoforms may have differential effects on EC apoptosis and apoptosis-related factors. 1. The protein levels, but not the mRNA levels of Wnt13C were induced by apoptosis-inducers. And the Myc-tag insertion at the AUG+1 in Wnt13C mRNA inhibited its expression, indicating the RNA sequences/structures are critical. Therefore, nuclear Wnt13C is regulated during apoptosis at translational levels. 2. Nuclear Wnt13 increased caspase-3/7 expression with/without LPS, followed by an increase in LPS-induced caspase-3/7 cleavage; and nuclear Wnt13 upregulated the pro-apoptotic Bcl-2 family member Bim expression, suggesting that nuclear Wnt13 increased caspase activation through upregulating caspase and Bim expression. Wnt13 isoforms increased EC apoptosis with different strengths: nuclear > mitochondrial > secreted forms. 3. Both caspase-3 and Bim are FOXO target genes; and nuclear Wnt13 increased the nuclear localization of FOXOs, suggesting increased FOXO activity. Nuclear Wnt13 also upregulated SOD2, another FOXO target gene related to oxidative stress-resistance. Nuclear Wnt13 did not increase FOXO activity at the SOD2 promoter, but increased the SOD2-intron 2 element luciferase activity upon LPS, where a novel putative FOXO site was found, implying intron 2 may be responsible for enhanced SOD2 transcription by nuclear Wnt13. Altogether, our results pinpoint the interplay between the expression and functions of Wnt13 forms during EC apoptosis, forming a positive cycle further facilitating the apoptotic program completion, which is important for EC homeostasis.

Aryl Hydrocarbon Receptor (AhR) is a ligand-actviated receptor known as the dioxin receptor. Environmental pollutants called dioxin-like toxicants are found in food, cigarette smoke, automobile exhaust and air. Therefore, they could chronically amplify the pathology of numerous chronic inflammatory diseases. AhR is a well known target of these environmental chemicals that disrupt endocrine signaling. By the year 2020, the number of people older than 60 years is expected to top 1 billion. The burden of treating chronic disease is significant both in dollars spent and in lost productivity. The need to identify risk factors for chronic diseases must be evaluated along with diet and lifestyle factors that will promote healthy aging. The studies presented in this dissertation tested the hypothesis that habitual exposure to dioxin-like contaminants contributes to chronic inflammatory disease states through activation of AhR pathway. Due to their lipophilicity, dioxin like toxicants (like PCB 77) accumulated in mice' visceral adipose tissue and induced adipocytes maturation and ectopic fat deposition. Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCB 77) can cause endothelial cells activation and inflammation by inducing pro-inflammatory signaling pathways. In our studies, PCB 77 had cumulative effects in Angiotensin II - induced Abdominal Aortic Aneurysm (AAA) by exacerbating inflammation in and around the aortic wall. More, PCB 77 increased mortality in mice that developed AAA. In order to appreciate the AhR involvement in inflammation we used a mouse model of Inflammatory Bowel Disease(IBD). Mice that had a reduced Ahr Receptor expression developed a less severe colitis and had a decreased general inflammatory status. These data provide evidence that exposure to environmental toxicants could augment inflammation and contribute to the social burden of obesity and obesity related chronic inflammatory diseases.

This study investigated whether a salicylate-restricted diet (eliminating foods containing artificial additives and natural salicylates) could effectively reduce hyperactivity in children more so than a diet not restricting salicylates (ostensibly restricting foods containing refined sugar). Ten hyperactive children, nine boys and one girl, were matched on their pre-treatment activity rates and assigned to either a salicylate-restricted diet (Group I) or a diet not restricting salicylates (Group II). After approximately nine weeks, post-treatment activity rates were obtained, and a significant difference in favor of the salicylate-restricted diet group was found with this diet group exhibiting a significantly lower mean post-treatment activity rate in comparison to the group placed on a diet not restricting salicylates (p<.05). Implications for diagnosis and treatment of hyperactivity in children were discussed.

This study involves data from the Cache County Study, which began in 1994 with joined efforts by Duke University, Utah State University, and Johns Hopkins University. It consisted of 5,092 participants from Cache County, Utah, located in the northern part of the state. Characteristics of the population include high participation rates (~ 90%), a majority of participants are members of The Church of Jesus Christ of Latter-day Saints, longer life expectancy than the general US population, a greater than 80% rate of at least a high school education, and low rates of migration. Subjects cognitive status was screened using the Modified Mini-Mental State Examination or rated by knowledgeable informants using an Informant Questionnaire for Cognitive Decline. Low scoring subjects were examined using the Dementia Questionnaire, an inventory of cognitive symptoms, functional impairments, and medical conditions relevant to dementia. The clinical data were reviewed by a geropsychiatrist and neuropsychologist. Those suspected of dementia underwent further testing and final dementia diagnoses were decided by a consensus conference of experts. Clinical assessment at the baseline interview identified 368 individuals out of the original 5,092 subjects as having dementia. These individuals were removed from the present analysis. Prevalent cases of dementia were excluded in our analyses of risk associated with incident AD. Dietary data were collected using a food frequency questionnaire at baseline in 1995. A list of 142 foods was provided and participants noted frequency they consume the food or food group. To calculate intake of a specific nutrient, the nutrient content of each food is multiplied by the frequency of consumption for each food. This number is summed over all food items. Cox Proportional hazards modeling was used to assess risk of incident AD in relationship to folate and B-vitamin intake over eleven subsequent years of data collection. Cox modeling assists in analysis of censored cases (drop-outs and deaths). No relationship was found between folate from food, supplement, or combined sources with dementia or with AD. Similar results were observed for B-12 and B-6.

The neuron-derived orphan receptor 1 (NOR1) belongs to the NR4A nuclear receptor subfamily. As an immediate early response gene, NOR1 is rapidly induced by a broad spectrum of physiological and pathological signals. Functional studies demonstrate NOR1 as a constitutively active ligand-independent nuclear receptor whose transcriptional activity is dependent on both expression level and posttranslational modifications. To date, an increasing number of studies have demonstrated a pivotal role of NOR1 in the transcriptional control of metabolism and the development of cardiovascular diseases. In this dissertation, we demonstrate NOR1 expression in endothelial cells and sub-endothelial cells of human atherosclerotic lesions. In response to inflammatory stimuli, NOR1 expression is rapidly induced in endothelial cells through an NF-κB-dependent signaling pathway. Functional studies reveal that NOR1 increases monocyte adhesion by inducing the expression of adhesion molecules VCAM-1 and ICAM-1 in endothelial cells. Transient transfection and chromatin immunoprecipitation assays identify VCAM-1 as a bona fide NOR1 target gene in endothelial cells. Finally, we demonstrate that NOR1-deficiency reduces hypercholesterolemia-induced atherosclerosis formation in apoE-/- mice by decreasing the macrophage content of the lesion. In smooth muscle cells (SMC), NOR1 was previously established as a cAMP response element binding protein (CREB) target gene in response to platelet-derived growth factor (PDGF) stimulation. CREB phosphorylation and subsequent binding of phosphorylated CREB to the NOR1 promoter play a critical role in inducing NOR1 expression. In this dissertation, we further demonstrate that histone deacetylase (HDAC) inhibition potentiates and sustains PDGF-induced NOR1 mRNA and protein expression in SMC. This augmented NOR1 expression is associated with increased phosphorylation of CREB, recruitment of phosphorylated CREB to the NOR1 promoter, and trans-activation of the NOR1 promoter. Additionally, HDAC inhibition also increases NOR1 protein half-life in SMC. Collectively, these findings identify a novel pathway in endothelial cells underlying monocyte adhesion and expand our knowledge of the epigenetic mechanisms orchestrating NOR1 expression in SMC. Finally, we establish a previously unrecognized atherogenic role of NOR1 in positively regulating monocyte recruitment to the vascular wall.

Background. Premature infants are at risk for many complications. Among these, growth failure and intermittent hypoxia (IH) can independently impact the outcomes of other comorbidities. Recent data suggest that IH may directly affect postnatal growth. Our study aims to evaluate the impact of IH on growth velocity in preterm infants. Methods. This prospective cohort study utilized inpatient oximetry, nutrition, and growth data to evaluate the relationship between IH and growth velocity. Enrolled infants were dichotomized by high- versus low-exposure to IH. This relationship was explored in both unadjusted analyses and generalized linear models with repeated measures. Results. The study population included 19 preterm infants, with average birth gestational age of 29 weeks, each contributing one or more measures of weekly data. Infants in the high-exposure cohort had lower birth weight, higher rates of bronchopulmonary dysplasia, and longer duration of respiratory support and caffeine treatment. The unadjusted analysis revealed a marginally significant trend towards higher IH rates during weeks of slower growth. The logistic regression with repeated measures analysis also supported increased odds of slower growth associated with higher IH rates, but this relationship was also only marginally significant. Conclusion. Our study suggests a relationship between exposure to IH and slower growth velocity in preterm infants. The prospectively collected data allowed for accurate measures of IH, growth, and nutrition, but the small sample size likely contributed to the lack of significance of our results.

The purpose of this study was to determine if post-operative serum albumin and percentage of weight loss improved in patients who received formalized pre-operative nutrition counseling. Nutrition intervention was measured quantitatively. A retrospective review of records was conducted on 77 RYGB patients (68 female subjects and 9 male subjects), ages 21-64, during January 2001 through January 2006. The results indicated that patients who received pre-operative nutrition intervention had better clinical outcomes of serum albumin than those with no nutrition intervention from a registered dietitian. However, outcomes regarding percentage of weight loss varied. Both pre-operatively and at the 3 month post-operative visit the weight of subjects who received nutrition intervention seemed to be increasing by the 6 month post-operative visit the subjects with no nutrition intervention had lost more weight.