Browsing by Author "Department of Pediatrics, IU School of Medicine"

Now showing 1 - 10 of 382
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    12-Lipoxygenase Promotes Obesity-Induced Oxidative Stress in Pancreatic Islets
    (American Society for Microbiology (ASM), 2014-10) Tersey, Sarah A.; Maier, Bernhard; Nishiki, Yurika; Maganti, Aarthi V.; Nadler, Jerry L.; Mirmira, Raghavendra G.; Department of Pediatrics, IU School of Medicine
    High-fat diets lead to obesity, inflammation, and dysglycemia. 12-Lipoxygenase (12-LO) is activated by high-fat diets and catalyzes the oxygenation of cellular arachidonic acid to form proinflammatory intermediates. We hypothesized that 12-LO in the pancreatic islet is sufficient to cause dysglycemia in the setting of high-fat feeding. To test this, we generated pancreas-specific 12-LO knockout mice and studied their metabolic and molecular adaptations to high-fat diets. Whereas knockout mice and control littermates displayed identical weight gain, body fat distribution, and macrophage infiltration into fat, knockout mice exhibited greater adaptive islet hyperplasia, improved insulin secretion, and complete protection from dysglycemia. At the molecular level, 12-LO deletion resulted in increases in islet antioxidant enzymes Sod1 and Gpx1 in response to high-fat feeding. The absence or inhibition of 12-LO led to increases in nuclear Nrf2, a transcription factor responsible for activation of genes encoding antioxidant enzymes. Our data reveal a novel pathway in which islet 12-LO suppresses antioxidant enzymes and prevents the adaptive islet responses in the setting of high-fat diets.
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    Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer
    (SpringerNature, 2016-12-15) Li, J.; Gu, D.; Lee, SS-Y.; Song, B.; Bandyopadhyay, S.; Chen, S.; Konieczny, SF.; Ratliff, TL.; Liu, X.; Xie, J.; Cheng, J-X.; Department of Pediatrics, IU School of Medicine
    Cancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.
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    An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion
    (The Endocrine Society, 2015-07) Priyadarshini, Medha; Villa, Stephanie R.; Fuller, Miles; Wicksteed, Barton; Mackay, Charles R.; Alquier, Thierry; Poitout, Vincent; Mancebo, Helena; Mirmira, Raghavendra G.; Gilchrist, Annette; Layden, Brian T.; Department of Pediatrics, IU School of Medicine
    G protein-coupled receptors have been well described to contribute to the regulation of glucose-stimulated insulin secretion (GSIS). The short-chain fatty acid-sensing G protein-coupled receptor, free fatty acid receptor 2 (FFAR2), is expressed in pancreatic β-cells, and in rodents, its expression is altered during insulin resistance. Thus, we explored the role of FFAR2 in regulating GSIS. First, assessing the phenotype of wild-type and Ffar2(-/-) mice in vivo, we observed no differences with regard to glucose homeostasis on normal or high-fat diet, with a marginally significant defect in insulin secretion in Ffar2(-/-) mice during hyperglycemic clamps. In ex vivo insulin secretion studies, we observed diminished GSIS from Ffar2(-/-) islets relative to wild-type islets under high-glucose conditions. Further, in the presence of acetate, the primary endogenous ligand for FFAR2, we observed FFAR2-dependent potentiation of GSIS, whereas FFAR2-specific agonists resulted in either potentiation or inhibition of GSIS, which we found to result from selective signaling through either Gαq/11 or Gαi/o, respectively. Lastly, in ex vivo insulin secretion studies of human islets, we observed that acetate and FFAR2 agonists elicited different signaling properties at human FFAR2 than at mouse FFAR2. Taken together, our studies reveal that FFAR2 signaling occurs by divergent G protein pathways that can selectively potentiate or inhibit GSIS in mouse islets. Further, we have identified important differences in the response of mouse and human FFAR2 to selective agonists, and we suggest that these differences warrant consideration in the continued investigation of FFAR2 as a novel type 2 diabetes target.
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    Actionable recommendations in the Bright Futures child health supervision guidelines
    (Schattauer, 2014) Finnell, S.M.E.; Stanton, J.L.; Downs, S.M.; Department of Pediatrics, IU School of Medicine
    BACKGROUND: With the growing use of electronic health record systems, there is a demand for an electronic version of the leading American pediatric preventive care guideline, Bright Futures. As computer implementation requires actionable recommendations, it is important to assess to what degree Bright Futures meets criteria for actionability. OBJECTIVES: We aimed to 1) determine the number of actionable recommendations in the current edition of Bright Futures and 2) to recommend a specific format for representing an important class of guidelines in a way that better facilitates computer implementation. METHODS: We consolidated all action statements in Bright Futures into recommendations. We then used two dimensions (decidability and executability) in the Guideline Implementability Appraisal v 2.0 (GLIA) to determine the actionability of the recommendations. Decidability means the recommendation states precisely under what conditions to perform those actions. Executability means actions are stated specifically, unambiguously and in sufficient detail. The results were presented in a figure titled Service Interval Diagram (SID), describing actionable recommendations, age intervals during which they are applicable, and how frequently they should occur in that interval. RESULTS: We consolidated 2161 action items into 245 recommendations and identified 52 that were actionable (21%). Almost exclusively, these recommendations addressed screening, such as newborn metabolic screening, or child safety, such as car seat use. A limited number (n=13) of recommendations for other areas of anticipatory guidance were also actionable. No recommendations on child discipline, family function or mental health met our criteria for actionability. The SID representing these recommendations is presented in a figure. CONCLUSION: Only a portion of the Bright Futures Guidelines meets criteria for actionability. Substantial work lies ahead to develop most recommendations for anticipatory guidance into a computer implementable format.
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    Acute Methylenedioxypyrovalerone Toxicity
    (Springer-Verlag, 2015-06) Froberg, Blake A.; Levine, Michael; Beuhler, Michael C.; Judge, Bryan S.; Moore, Philip W.; Engebretsen, Kristin M.; Mckeown, Nathanael J.; Rosenbaum, Christopher D.; Young, Amy C.; Rusyniak, Daniel E.; ACMT Toxicology Investigators Consortium (ToxIC); Department of Pediatrics, IU School of Medicine
    The objective of this study was to characterize the acute clinical effects, laboratory findings, complications, and disposition of patients presenting to the hospital after abusing synthetic cathinone. We conducted a retrospective multicenter case series of patients with synthetic cathinone abuse by searching for the terms bath salts, MDPV, methylenedioxypyrovalerone, mephedrone, methcathinone, methylone, methedrone, and cathinone within the "agent" field of a national clinical toxicology database (ToxIC). The medical records of these patients were obtained and abstracted by investigators at each study site. Patients with confirmatory testing that identified a synthetic cathinone in either blood or urine were included in the series. Patients who had either an undetectable synthetic cathinone test or no confirmatory testing were excluded. A data abstraction sheet was used to obtain information on each patient. We entered data into an Excel spreadsheet and calculated descriptive statistics. We identified 23 patients with confirmed synthetic cathinone exposure--all were positive for methylenedioxyprovalerone (MDPV). Eighty-three percent were male and 74 % had recreational intent. The most common reported clinical effects were tachycardia (74 %), agitation (65 %), and sympathomimetic syndrome (65 %). Acidosis was the most common laboratory abnormality (43 %). Seventy-eight percent of patients were treated with benzodiazepines and 30 % were intubated. Ninety-six percent of patients were hospitalized and 87 % were admitted to the ICU. The majority (61 %) of patients was discharged home but 30 % required inpatient psychiatric care. There was one death in our series. The majority of patients presenting to the hospital after abusing MDPV have severe sympathomimetic findings requiring hospitalization. A number of these patients require inpatient psychiatric care after their acute presentation.
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    Adherence to pediatric diabetic ketoacidosis guidelines by community emergency departments' providers
    (Springer, 2017-12) Zee-Cheng, Janine E.; Webber, Emily C.; Abu-Sultaneh, Samer; Department of Pediatrics, IU School of Medicine
    Background: Diabetic ketoacidosis (DKA) is a common presentation of type I diabetes mellitus to the emergency departments. Most children with DKA are initially managed in community emergency departments where providers may not have easy access to educational resources or pediatric-specific guidelines and protocols that are readily available at pediatric academic medical centers. The aim of this study is to evaluate adherence of community emergency departments in the state of Indiana to the pediatric DKA guidelines. Methods: We performed a retrospective chart review of patients, age 18 years of age or under, admitted to the pediatric intensive care unit with a diagnosis of DKA. Results: A total of 100 patients were included in the analysis. Thirty-seven percent of patients with DKA were managed according to all six guideline parameters. Only 39% of patients received the recommended hourly blood glucose checks. Thirty percent of patients received intravenous insulin bolus, which is not recommended. Conclusions: Non-adherence to pediatric DKA guidelines still exists in the state of Indiana. Further, larger studies are needed to reveal the etiology of non-adherence to pediatric DKA guidelines and strategies to improve that adherence.
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    Adolescent decision making about participation in a hypothetical HIV vaccine trial
    (Elsevier, 2015-03-10) Alexander, Andreia B.; Ott, Mary A.; Lally, Michelle A.; Sniecinski, Kevin; Baker, Alyne; Zimet, Gregory D.; Department of Pediatrics, IU School of Medicine
    Purpose The purpose of this study was to examine the process of adolescent decision-making about participation in an HIV vaccine clinical trial, comparing it to adult models of informed consent with attention to developmental differences. Methods As part of a larger study of preventive misconception in adolescent HIV vaccine trials, we interviewed 33 male and female 16–19-year-olds who have sex with men. Participants underwent a simulated HIV vaccine trial consent process, and then completed a semistructured interview about their decision making process when deciding whether or not to enroll in and HIV vaccine trial. An ethnographic content analysis approach was utilized. Results Twelve concepts related to adolescents' decision-making about participation in an HIV vaccine trial were identified and mapped onto Appelbaum and Grisso's four components of decision making capacity including understanding of vaccines and how they work, the purpose of the study, trial procedures, and perceived trial risks and benefits, an appreciation of their own situation, the discussion and weighing of risks and benefits, discussing the need to consult with others about participation, motivations for participation, and their choice to participate. Conclusion The results of this study suggest that most adolescents at high risk for HIV demonstrate the key abilities needed to make meaningful decisions about HIV vaccine clinical trial participation.
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    Adolescent relationship violence and acculturation among NYC Latinos
    (Springer-Verlag, 2015-07) DuPont-Reyes, Melissa; Fry, Deborah; Rickert, Vaughn; Davidson, Leslie L.; Department of Pediatrics, IU School of Medicine
    Acculturation has been shown to positively and negatively affect Latino health. Little research investigates the overlap between acculturation and the different types of relationship violence among Latino youth and most research in this area predominantly involves Mexican-American samples. The current study examined associations between indices of acculturation (language use at home, chosen survey language, and nativity) and relationship physical violence and sexual coercion, both received and delivered, among predominantly Dominican and Puerto Rican adolescents from New York City. From 2006 to 2007, 1,454 adolescents aged 13-21 years in New York City completed an anonymous survey that included the Conflict in Adolescent Relationships Inventory which estimates experiences of physical violence and sexual coercion, both received and delivered, in the previous year. This analysis includes bivariate and multivariate methods to test the associations between language use at home, chosen survey language, and nativity with the different types of relationship violence. Among females, there is a significant association between language use at home and overall level of acculturation with delivering and receiving relationship physical violence; however, we did not find this association in delivering and receiving relationship sexual coercion. We found no association between acculturation and any type of relationship violence among males. Among Latina females, language spoken at home is an indicator of other protective factors of physical relationship violence. Future research in this area should explore the potential protective factors surrounding relationship violence among Latina females of various subgroups using comprehensive measures of acculturation, household composition and family engagement.
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    Adolescent women's daily academic behaviors, sexual behaviors, and sexually related emotions
    (Elsevier, 2014-12) Hensel, Devon J.; Sorge, Brandon H.; Department of Pediatrics, IU School of Medicine
    PURPOSE: Emerging literature suggests that the emotional and behavioral experience in young women's romantic/sexual relationships may link to their academic success. However, existing studies' reliance on retrospective and/or global measures prevents detailed understanding of how and when specific academic experiences link to specific relationship experiences and whether these associations could vary over different school days. METHODS: Adolescent women (N = 387; 14-17 years at enrollment) were recruited from primary care adolescent clinics for a longitudinal cohort study of sexual relationships and sexual behavior. Participants provided daily diary information on academic behaviors, sexual emotions, and sexual behaviors. Chi-square and generalized estimating equation ordinal logistic or linear regression, respectively, assessed prevalence of sexual behaviors or differences in sexual emotions when academic behaviors did and did not occur. RESULTS: Young women's weekday reports of skipping school or failing a test were significantly linked to more frequent vaginal sex, less frequent condom use, and different levels of sexual emotions, on that same day. CONCLUSIONS: Our findings provide evidence that the emotional and behavioral experiences in young women's romantic/sexual relationships may impact young women's reaction to academic events.
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    Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus
    (Ovid Technologies Wolters Kluwer -American Heart Association, 2014-03-18) Patel, Kunjal; Wang, Jiajia; Jacobson, Denise L.; Lipshultz, Steven E.; Landy, David C.; Geffner, Mitchell E.; DiMeglio, Linda A.; Seage, George R.; Williams, Paige L.; Van Dyke, Russell B.; Siberry, George K.; Shearer, William T.; Young, Luciana; Scott, Gwendolyn B.; Wilkinson, James D.; Fisher, Stacy D.; Starc, Thomas J.; Miller, Tracie L.; Department of Pediatrics, IU School of Medicine
    BACKGROUND: Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. METHODS AND RESULTS: Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. CONCLUSIONS: A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.