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Item Advanced Modeling of Longitudinal Spectroscopy Data(2014) Kundu, Madan Gopal; Harezlak, Jaroslaw; Randolph, Timothy W.; Sarkar, Jyotirmoy; Steele, Gregory K.; Yiannoutsos, Constantin T.Magnetic resonance (MR) spectroscopy is a neuroimaging technique. It is widely used to quantify the concentration of important metabolites in a brain tissue. Imbalance in concentration of brain metabolites has been found to be associated with development of neurological impairment. There has been increasing trend of using MR spectroscopy as a diagnosis tool for neurological disorders. We established statistical methodology to analyze data obtained from the MR spectroscopy in the context of the HIV associated neurological disorder. First, we have developed novel methodology to study the association of marker of neurological disorder with MR spectrum from brain and how this association evolves with time. The entire problem fits into the framework of scalar-on-function regression model with individual spectrum being the functional predictor. We have extended one of the existing cross-sectional scalar-on-function regression techniques to longitudinal set-up. Advantage of proposed method includes: 1) ability to model flexible time-varying association between response and functional predictor and (2) ability to incorporate prior information. Second part of research attempts to study the influence of the clinical and demographic factors on the progression of brain metabolites over time. In order to understand the influence of these factors in fully non-parametric way, we proposed LongCART algorithm to construct regression tree with longitudinal data. Such a regression tree helps to identify smaller subpopulations (characterized by baseline factors) with differential longitudinal profile and hence helps us to identify influence of baseline factors. Advantage of LongCART algorithm includes: (1) it maintains of type-I error in determining best split, (2) substantially reduces computation time and (2) applicable even observations are taken at subject-specific time-points. Finally, we carried out an in-depth analysis of longitudinal changes in the brain metabolite concentrations in three brain regions, namely, white matter, gray matter and basal ganglia in chronically infected HIV patients enrolled in HIV Neuroimaging Consortium study. We studied the influence of important baseline factors (clinical and demographic) on these longitudinal profiles of brain metabolites using LongCART algorithm in order to identify subgroup of patients at higher risk of neurological impairment.Item The effects of acute ethanol on cholinergic activity in the hippocampus and nucleus accumbens of rat brain(1992) Gongwer, Cameron R.Item Effects of choline kinase activity on phospholipid metabolism and malignant phenotype of prostate cancer cells(2010-10) Bansal, Aditya; DeGrado, Timothy R.; Harris, Robert A. (Robert Allison), 1939-; Bosron, William F.; Klaunig, James E.High choline uptake and increased choline kinase activity have been reported in many cancers. This has motivated the use of choline as a biomarker for tumor imaging. Tumors in general are heterogeneous in nature with respect to oxygen tension. There are regions of hypoxia and normoxia that are expected to have different metabolism but regulation of choline metabolism under hypoxia is poorly understood. It is important to clarify the status of choline metabolism in hypoxic microenvironment as it will have an impact on potential of choline as a cancer biomarker. The primary goal was to determine the status of choline phosphorylation in hypoxic cancer cells and its effect on uptake of choline. This was examined by tracer studies in cancer cells exposed to hypoxia. It was observed that hypoxia universally inhibits choline uptake /phosphorylation in cancer cells. Decreased choline phosphorylation resulted in transient uptake of choline radiotracers in cultured cancer cells and 9L tumors suggesting potential problem in using choline as a biomarker for cancers in hypoxic microenvironment. To investigate the mechanism behind decrease in choline phosphorylation, steady state levels of choline metabolites were measured and choline kinase catalyzed choline phosphorylation step was found to be rate-limiting in PC-3 cells. This suggested that modulation in choline kinase levels can alter choline metabolism in hypoxic cancer cells. Expression and activity assays for choline kinase revealed that choline kinase expression is down-regulated in hypoxia. This regulation involved transcriptional level mediation by HIF1 at the conserved HRE7 site in choline kinase promoter. To further understand the importance of down-regulation of choline kinase in hypoxia, stable prostate cancer cell lines over-expressing choline kinase were generated. Effect of over-expression of choline kinase in hypoxia was evaluated in terms of malignant phenotypes like proliferation rate, anchorage independent growth and invasion potential. Both over-expression of choline kinase and hypoxia had a pronounced effect on malignant phenotypes of prostate cancer cells. Further study showed that increased choline kinase activity and hypoxic tumor microenvironment are important for progression of early-stage, androgen-dependent LNCaP prostate cancer cells but confer little survival advantage in undifferentiated, androgen-independent PC-3 prostate cancer cells.Item Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD(Wolters Kluwer, 2021) Vilar-Gomez, Eduardo; Pirola, Carlos Jose; Sookoian, Silvia; Wilson, Laura A.; Belt, Patricia; Liang, Tiebing; Liu, Wanqing; Chalasani, Naga; Medicine, School of MedicineIntroduction: This study explored the relationship between patatin-like phospholipase domain-containing 3 gene (PNPLA3 rs738409), nutrient intake, and liver histology severity in patients with nonalcoholic fatty liver disease (NAFLD). Methods: PNPLA3-rs738409 variant was genotyped in 452 non-Hispanic whites with histologically confirmed NAFLD who completed Food Frequency Questionnaire within 6 months of their liver biopsy. The fibrosis severity on liver histology was the outcome of interest. Results: The distribution of PNPLA3 genotypes was CC: 28%, CG: 46%, and GG: 25%. High-carbohydrate (% of energy/d) intake was positively associated (adjusted [Adj] odds ratio [OR]: 1.03, P < 0.01), whereas higher n-3 polyunsaturated fatty acids (n-3 PUFAs) (g/d) (Adj. OR: 0.17, P < 0.01), isoflavones (mg/d) (Adj. OR: 0.74, P = 0.049), methionine (mg/d) (Adj. OR: 0.32, P < 0.01), and choline (mg/d) (Adj. OR: 0.32, P < 0.01) intakes were inversely associated with increased risk of significant fibrosis (stage of fibrosis ≥2). By using an additive model of inheritance, our moderation analysis showed that PNPLA3 rs738409 significantly modulates the relationship between carbohydrate (%), n-3 PUFAs, total isoflavones, methionine, and choline intakes and fibrosis severity in a dose-dependent, genotype manner. These dietary factors tended to have a larger and significant effect on fibrosis severity among rs738409 G-allele carriers. Associations between significant fibrosis and carbohydrates (Adj. OR: 1.04, P = 0.019), n-3 PUFAs (Adj. OR: 0.16, P < 0.01), isoflavones (Adj. OR: 0.65, P = 0.025), methionine (Adj. OR: 0.30, P < 0.01), and total choline (Adj. OR: 0.29, P < 0.01) intakes remained significant only among rs738409 G-allele carriers. Discussion: This gene-diet interaction study suggests that PNPLA3 rs738409 G-allele might modulate the effect of specific dietary nutrients on risk of fibrosis in patients with NAFLD.Item Maternal choline supplementation in a sheep model of first trimester binge alcohol fails to protect against brain volume reductions in peripubertal lambs(Elsevier, 2016-09) Birch, Sharla M.; Lenox, Mark W.; Kornegay, Joe N.; Paniagua, Beatriz; Styner, Martin A.; Goodlett, Charles R.; Cudd, Tim A.; Washburn, Shannon E.; Psychology, School of ScienceFetal alcohol spectrum disorder (FASD) is a leading potentially preventable birth defect. Poor nutrition may contribute to adverse developmental outcomes of prenatal alcohol exposure, and supplementation of essential micronutrients such as choline has shown benefit in rodent models. The sheep model of first-trimester binge alcohol exposure was used in this study to model the dose of maternal choline supplementation used in an ongoing prospective clinical trial involving pregnancies at risk for FASD. Primary outcome measures included volumetrics of the whole brain, cerebellum, and pituitary derived from magnetic resonance imaging (MRI) in 6-month-old lambs, testing the hypothesis that alcohol-exposed lambs would have brain volume reductions that would be ameliorated by maternal choline supplementation. Pregnant sheep were randomly assigned to one of five groups – heavy binge alcohol (HBA; 2.5 g/kg/treatment ethanol), heavy binge alcohol plus choline supplementation (HBC; 2.5 g/kg/treatment ethanol and 10 mg/kg/day choline), saline control (SC), saline control plus choline supplementation (SCC; 10 mg/kg/day choline), and normal control (NC). Ewes were given intravenous alcohol (HBA, HBC; mean peak BACs of ~280 mg/dL) or saline (SC, SCC) on three consecutive days per week from gestation day (GD) 4–41; choline was administered on GD 4–148. MRI scans of lamb brains were performed postnatally on day 182. Lambs from both alcohol groups (with or without choline) showed significant reductions in total brain volume; cerebellar and pituitary volumes were not significantly affected. This is the first report of MRI-derived volumetric brain reductions in a sheep model of FASD following binge-like alcohol exposure during the first trimester. These results also indicate that maternal choline supplementation comparable to doses in human studies fails to prevent brain volume reductions typically induced by first-trimester binge alcohol exposure. Future analyses will assess behavioral outcomes along with regional brain and neurohistological measures.Item Persistent Changes in Stress-Regulatory Genes in Pregnant Women or Children Exposed Prenatally to Alcohol(Wiley, 2019-07-22) Sarkar, Dipak K.; Gangisetty, Omkaram; Wozniak, Jeffrey R.; Eckerle, Judith K.; Georgieff, Michael K.; Foroud, Tatiana M.; Wetherill, Leah; Wertelecki, Wladimir; Chambers, Christina D.; Riley, Edward; Zymak-Zakutnya, Natalya; Yevtushok, Lyubov; Medical and Molecular Genetics, School of MedicineBackground: We have recently shown that binge or heavy levels of alcohol drinking increases DNA methylation and reduces gene expression of POMC and PER2 in adult human subjects (Gangisetty et al., 2019). One hypothesis would be that methylation of these two genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of PAE. Results of the present study provided some support for this hypothesis. Methods: We conducted a series of studies to determine DNA methylation changes in stress regulatory genes proopiomelanocortin (POMC) and period 2 (PER2) using biological samples from three separate cohorts of patients i) pregnant women who consumed moderate to high levels of alcohol or low/unexposed controls, ii) children with PAE and non-alcohol exposed controls, and iii) children with PAE treated with or without choline. Results: We found pregnant women who consumed moderate to high levels of alcohol and gave birth to PAE children had higher DNA methylation of POMC and PER2. PAE children also had increased methylation of POMC and PER2. The differences in the gene methylation of PER2 and POMC between PAE and controls did not differ by maternal smoking status. PAE children had increased levels of stress hormone cortisol and adrenocorticotropic hormone (ACTH). Choline supplementation reduced DNA hypermethylation and increased expression of POMC and PER2 in children with PAE. Conclusions: These data suggest that PAE significantly elevates DNA methylation of POMC and PER2 and increases levels of stress hormones. Furthermore, these results suggest the possibility that measuring DNA methylation levels of PER2 and POMC in biological samples from pregnant women or from children may be useful for identification of a woman or a child with PAE.Item Rat strain differences in brain structure and neurochemistry in response to binge alcohol(Springer, 2014-01) Zahr, Natalie M.; Mayer, Dirk; Rohlfing, Torsten; Hsu, Oliver; Vinco, Shara; Orduna, Juan; Luong, Richard; Bell, Richard L.; Sullivan, Edith V.; Pfefferbaum, Adolf; Psychiatry, School of MedicineRATIONALE: Ventricular enlargement is a robust phenotype of the chronically dependent alcoholic human brain, yet the mechanism of ventriculomegaly is unestablished. Heterogeneous stock Wistar rats administered binge EtOH (3 g/kg intragastrically every 8 h for 4 days to average blood alcohol levels (BALs) of 250 mg/dL) demonstrate profound but reversible ventricular enlargement and changes in brain metabolites (e.g., N-acetylaspartate (NAA) and choline-containing compounds (Cho)). OBJECTIVES: Here, alcohol-preferring (P) and alcohol-nonpreferring (NP) rats systematically bred from heterogeneous stock Wistar rats for differential alcohol drinking behavior were compared with Wistar rats to determine whether genetic divergence and consequent morphological and neurochemical variation affect the brain's response to binge EtOH treatment. METHODS: The three rat lines were dosed equivalently and approached similar BALs. Magnetic resonance imaging and spectroscopy evaluated the effects of binge EtOH on brain. RESULTS: As observed in Wistar rats, P and NP rats showed decreases in NAA. Neither P nor NP rats, however, responded to EtOH intoxication with ventricular expansion or increases in Cho levels as previously noted in Wistar rats. Increases in ventricular volume correlated with increases in Cho in Wistar rats. CONCLUSIONS: The latter finding suggests that ventricular volume expansion is related to adaptive changes in brain cell membranes in response to binge EtOH. That P and NP rats responded differently to EtOH argues for intrinsic differences in their brain cell membrane composition. Further, differential metabolite responses to EtOH administration by rat strain implicate selective genetic variation as underlying heterogeneous effects of chronic alcoholism in the human condition.Item The effects of gestational choline supplementation on cerebellar Purkinje cell number in the sheep model of binge alcohol exposure during the first trimester-equivalent(Elsevier, 2022) Carugati, Megan; Goodlett, Charles R.; Cudd, Timothy A.; Washburn, Shannon E.; Psychology, School of ScienceIndividuals with fetal alcohol spectrum disorders (FASD) incur enduring brain damage and neurodevelopmental impairments from prenatal alcohol exposure (PAE). Preclinical rodent models have demonstrated that choline supplementation during development can reduce the severity of adverse neurodevelopmental consequences of PAE. This study used the sheep model to evaluate dietary choline supplementation during pregnancy as a therapeutic intervention, testing the hypothesis that choline can ameliorate alcohol-induced cerebellar Purkinje cell loss. Pregnant ewes were randomly assigned either to a normal control [NC] group (n = 8), or to groups given intravenous infusions of alcohol (or saline) from gestational days 4-41 (the first trimester-equivalent). A weekly binge-drinking pattern was modeled, with three consecutive days of infusions of saline [SAL], 1.75 g/kg/day alcohol [1.75ALC], or 2.5 g/kg/day alcohol [2.5ALC] followed by four days off. Infused ewes were randomly assigned to receive dietary supplements throughout pregnancy of choline (10 mg/kg/day) or placebo (n = 8 per group). Mean blood alcohol concentrations (BAC) were significantly higher in the 2.5ALC groups (287 mg/dL) than the 1.75ALC groups (197 mg/dL). Lamb cerebella were harvested on postnatal day 180 and processed for stereological counts of Purkinje cells. Both alcohol doses caused significant reductions in Purkinje number relative to NC and SAL-Placebo groups, confirming previous findings. Effects of choline supplementation depended on infusion group: it significantly protected against Purkinje cell loss in the 2.5ALC group, had no effect in the 1.75ALC group, and significantly reduced numbers in the SAL-Choline group (though neither the SAL-Choline nor the SAL-Placebo group differed from the NC group). The protection by choline evident only in the 2.5ALC group suggests that multiple, BAC-dependent mechanisms of cerebellar damage may be activated with alcohol exposure in the first trimester, and that choline may protect against pathogenic mechanisms that emerge at higher BACs. These outcomes extend the evidence that early choline supplementation can mitigate some neurodevelopmental defects resulting from binge-like PAE.