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Item 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 MedicineHigh-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.Item Alcohol Use Trajectories after High School Graduation among Emerging Adults with Type 1 Diabetes(Elsevier, 2014-08) Hanna, Kathleen M.; Stupiansky, Nathan W.; Weaver, Michael T.; Slaven, James E.; Stump, Timothy E.; IU School of NursingObjective Explore alcohol involvement trajectories and associated factors during the year post-high school (HS) graduation among emerging adults with type 1 diabetes. Methods Youth (N=181) self-reported alcohol use at baseline and every 3 months for 1 year post-HS graduation. Data were also collected on parent-youth conflict, diabetes self-efficacy, major life events, living and educational situations, diabetes management, marijuana use, cigarette smoking, and glycemic control. Trajectories of alcohol use were modeled using latent class growth analysis. Associations between trajectory class and specific salient variables were examined using analysis of variance, chi square, or generalized linear mixed model, as appropriate. Results Identified alcohol involvement trajectory classes were labeled as: 1) Consistent Involvement Group (n=25, 13.8%) with stable, high use relative to other groups over the 12 months; 2) Growing Involvement Group (n=55, 30.4%) with increasing use throughout the 12 months; and 3) Minimal Involvement Group (n=101, 55.8%) with essentially no involvement until month nine. Those with minimal involvement had the best diabetes management and better diabetes self-efficacy than those with consistent involvement. In comparison to those minimally involved, those with growing involvement were more likely to live independently of parents; those consistently involved had more major life events; and both the growing and consistent involvement groups were more likely to have tried marijuana and cigarettes. Conclusions This sample of emerging adults with type 1 diabetes has 3 unique patterns of alcohol use during the first year after high school. Implication and Contribution Among youth with type 1 diabetes in the year post-HS graduation, alcohol involvement knowledge was extended by identifying patterns of such use. Further research of alcohol use patterns is needed to guide health care professionals in their assessments and researchers in testing interventions that target unique patterns.Item Atomoxetine improved attention in children and adolescents with attention-deficit/hyperactivity disorder and dyslexia in a 16 week, acute, randomized, double-blind trial(Mary Ann Liebert, 2013-11) Wietecha, Linda; Williams, David; Shaywitz, Sally; Shaywitz, Bennett; Hooper, Stephen R.; Wigal, Sharon B.; Dunn, David; McBurnett, Keith; Pediatrics, School of MedicineOBJECTIVE: The purpose of this study was to evaluate atomoxetine treatment effects in attention-deficit/hyperactivity disorder (ADHD-only), attention-deficit/hyperactivity disorder with comorbid dyslexia (ADHD+D), or dyslexia only on ADHD core symptoms and on sluggish cognitive tempo (SCT), working memory, life performance, and self-concept. METHODS: Children and adolescents (10-16 years of age) with ADHD+D (n=124), dyslexia-only (n=58), or ADHD-only (n=27) received atomoxetine (1.0-1.4 mg/kg/day) or placebo (ADHD-only subjects received atomoxetine) in a 16 week, acute, randomized, double-blind trial with a 16 week, open-label extension phase (atomoxetine treatment only). Changes from baseline were assessed to weeks 16 and 32 in ADHD Rating Scale-IV-Parent-Version:Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv); ADHD Rating Scale-IV-Teacher-Version (ADHDRS-IV-Teacher-Version); Life Participation Scale-Child- or Parent-Rated Version (LPS); Kiddie-Sluggish Cognitive Tempo (K-SCT) Interview; Multidimensional Self Concept Scale (MSCS); and Working Memory Test Battery for Children (WMTB-C). RESULTS: At week 16, atomoxetine treatment resulted in significant (p<0.05) improvement from baseline in subjects with ADHD+D versus placebo on ADHDRS-IV-Parent:Inv Total (primary outcome) and subscales, ADHDRS-IV-Teacher-Version Inattentive subscale, K-SCT Interview Parent and Teacher subscales, and WMTB-C Central Executive component scores; in subjects with Dyslexia-only, atomoxetine versus placebo significantly improved K-SCT Youth subscale scores from baseline. At Week 32, atomoxetine-treated ADHD+D subjects significantly improved from baseline on all measures except MSCS Family subscale and WMTB-C Central Executive and Visuo-spatial Sketchpad component scores. The atomoxetine-treated dyslexia-only subjects significantly improved from baseline to week 32 on ADHDRS-IV-Parent:Inv Inattentive subscale, K-SCT Parent and Teacher subscales, and WMTB-C Phonological Loop and Central Executive component scores. The atomoxetine-treated ADHD-only subjects significantly improved from baseline to Week 32 on ADHDRS-Parent:Inv Total and subscales, ADHDRS-IV-Teacher-Version Hyperactive/Impulsive subscale, LPS Self-Control and Total, all K-SCT subscales, and MSCS Academic and Competence subscale scores. CONCLUSIONS: Atomoxetine treatment improved ADHD symptoms in subjects with ADHD+D and ADHD-only, but not in subjects with dyslexia-only without ADHD. This is the first study to report significant effects of any medication on SCT.Item Azithromycin efficacy in asymptomatic rectal chlamydial infection in MSM: A more definitive answer soon?(Wolters Kluwer, 2017-07) Batteiger, Byron E.; Medicine, School of MedicineItem Characterization of a novel deep-intronic variant in DYNC2H1 identified by whole-exome sequencing in a patient with a lethal form of a short-rib thoracic dysplasia type III(Cold Spring Harbor Laboratory, 2022-12-28) Buchh, Muqsit; Gillespie, Patrick J.; Treat, Kayla; Abreu, Marco A.; Schwantes-An, Tae-Hwi Linus; Helm, Benjamin M.; Fang, Fang; Xuei, Xiaoling; Mantcheva, Lili; Suhrie, Kristen R.; Graham, Brett H.; Conboy, Erin; Vetrini, Francesco; Medical and Molecular Genetics, School of MedicineBiallelic pathogenic variants in DYNC2H1 are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the DYNC2H1 gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in DYNC2H1 was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited DYNC2H1 deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of DYNCH2H1 mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.Item Clinical features of young children referred for impairing temper outbursts(Mary Ann Liebert, 2013-11) Roy, Amy K.; Klein, Rachel G.; Angelosante, Aleta; Bar-Haim, Yair; Leibenluft, Ellen; Hulvershorn, Leslie; Dixon, Erica; Dodds, Alice; Spindel, Carrie; Psychiatry, School of MedicineOBJECTIVE: In light of the current controversy about whether severe temper outbursts are diagnostic of mania in young children, we conducted a study to characterize such children, focusing on mania and other mood disorders, emotion regulation, and parental psychiatric history. METHODS: Study participants included 51 5-9-year-old children with frequent, impairing outbursts (probands) and 24 non-referred controls without outbursts. Parents completed a lifetime clinical interview about their child, and rated their child's current mood and behavior. Teachers completed a behavior rating scale. To assess emotion regulation, children were administered the Balloons Game, which assesses emotion expressivity in response to frustration, under demands of high and low regulation. Parental lifetime diagnoses were ascertained in blind clinical interviews. RESULTS: No child had bipolar disorder, bipolar disorder not otherwise specified (NOS), or major depression (MDD). The most prevalent disorder was oppositional defiant disorder (88.2%), followed by attention-deficit/hyperactivity disorder (74.5%), anxiety disorders (49.0%), and non-MDD depressive disorders (33.3%). Eleven probands (21.6%) met criteria for severe mood dysregulation. During the Balloons Game, when there were no demands for self-regulation, children with severe outbursts showed reduced positive expressivity, and also showed significant deficits in controlling negative facial expressions when asked to do so. Anxiety disorders were the only diagnoses significantly elevated in probands' mothers. CONCLUSIONS: Overall, young children with severe temper outbursts do not present with bipolar disorder. Rather, disruptive behavior disorders with anxiety and depressive mood are common. In children with severe outbursts, deficits in regulating emotional facial expressions may reflect deficits controlling negative affect. This work represents a first step towards elucidating mechanisms underlying severe outbursts in young children.Item Community Engagement and Venue-Based Sampling in Adolescent Male Sexually Transmitted Infection Prevention Research(Elsevier, 2018-03) Ott, Mary A.; Moon, Julianne; Imburgia, Teresa M.; Yang, Ziyi; Tu, Wanzhu; Auerswald, Colette L.; Pediatrics, School of MedicineOBJECTIVES: Middle adolescent males are a difficult group to recruit for community sexually transmitted infection (STI) prevention research. We describe a process of community engagement, and venue-based sampling of 14-17-year-old adolescent males, and compare rates of STIs and STI risk behaviors by venue. METHODS: Community engagement consisted of (1) informational meetings with organizations; (2) participation in community meetings and events; (3) hiring community members as study personnel; and (4) an adolescent advisory board recruited from the community. Venues were identified and assessed at different times of the day and days of the week using a structured tool. At selected venues, males ages 14-17 years were invited to participate in a brief survey and provide a urine sample and an optional anal swab for DNA-based STI testing. RESULTS: Venues were assessed (n = 249), and 31 were selected for recruitment, including parks, apartment complexes, community events, entertainment venues, a community school, and community programs for LGBT (gay, lesbian, bisexual, transgender) and adjudicated youth. We enrolled 667 participants, average age 15.7 years. Participants reported high rates of sexual and STI risk behaviors, but had low rates of STIs. These rates differed by venue, with more structured venues recruiting youth reporting fewer STI risk behaviors and less structured venues within the highest STI prevalence zip code recruiting youth reporting more STI risk behaviors. CONCLUSION: Venue-based sampling is a feasible mechanism to target recruitment and enrollment adolescent males with high STI risk behaviors in community settings, with risk profiles varying by setting.Item A Comparison Study of Temporomandibular Joint Symptoms in Patients Following Mandibular Advancement by Bilateral Sagittal Split Osteotomies: Rigid Fixation Versus Nonrigid Fixation(1989) Flynn, Brent Cameron; Roberts, W. Eugene; Brown, David T.; Nelson, Charles L.; Shanks, James C.; Hennon, David K.Primary consideration must be given to the temporomandibular joint when planning and performing orthognathic surgical procedures. It has long been understood that the status of the temporomandibular joint can easily and unintentionally be altered during orthognathic surgery, regardless of the method of fixation used. With the advent of modern fixation techniques, many clinicians and investigators have questioned the effects of rigid fixation on the temporomandibular joint. To investigate this, a clinical study of 40 patients treated with mandibular advancement for retrognathism was performed. Twenty patients were treated with rigid fixation while another 20 patients had inferior border wires placed with anterior skeletal fixation. All patients were asked questions regarding the history of their temporomandibular joints. In addition, all patients received a clinical postoperative temporomandibular joints. In addition, all patients received a clinical postoperative temporomandibular joint evaluation. The results were statistically analyzed with the Chi-square analysis and Standard T test. It was determined that the Null Hypothesis could not be rejected for any of the symptoms evaluated in this study. The results support the belief that rigid fixation is no different when compared to wire osteosynthesis in terms of prevalence of temporomandibular joint symptoms.Item Decline in vaccine-type human papillomavirus prevalence in young men from a Midwest metropolitan area of the United States over the six years after vaccine introduction(Elsevier, 2019-09-30) Widdice, Lea E.; Bernstein, David I.; Franco, Eduardo L.; Ding, Lili; Brown, Darron R.; Ermel, Aaron C.; Higgins, Lisa; Kahn, Jessica A.; Medicine, School of MedicinePurpose: The aim of this study was to determine changes in human papillomavirus (HPV) prevalence among young men from a Midwest metropolitan area over the six years after vaccine introduction, including HPV prevalence in men overall, in vaccinated men to examine vaccine impact and in unvaccinated men to examine herd protection. An exploratory aim was to examine associations between number of vaccine doses and HPV prevalence. Methods: Men aged 14–26 years reporting male-female and/or male-male sexual contact were recruited from a primary care clinic, sexually transmitted disease clinic, and community setting during two waves of data collection: 2013–2014 (N = 400) and 2016–2017 (N = 347). Participants completed a questionnaire and were tested for penile, scrotal and anal HPV. Changes in prevalence of any (≥1 type) and vaccine-type HPV (HPV6, 11, 16, and/or 18) were examined using propensity score weighted logistic regression. Associations between number of doses and HPV infection were determined using chi-square tests and logistic regression. Results: The proportion of men with a history of ≥1 HPV vaccine doses increased from 23% to 44% (p < 0.001) from waves 1 to 2. After propensity score weighting, infection with ≥1 vaccine-type HPV significantly decreased among all men (29% to 20%; 31% decrease; odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.44–0.88) and unvaccinated men (32% to 21%; 36% decrease; OR = 0.56, 95%CI = 0.34–0.86); there was a non-significant decrease (21%) among vaccinated men. Associations between number of doses and HPV prevalence were not statistically significant. Conclusions: Prevalence of vaccine-type HPV decreased among all, vaccinated, and unvaccinated men six years after HPV vaccine recommendation, supporting vaccine impact and herd protection. Decreases in vaccine-type HPV in all men appear to be due to decreases in unvaccinated men, suggesting that the full impact of vaccination has yet to be realized. Continued monitoring and efforts to vaccinate men prior to sexual initiation are warranted.Item Endoscopic Treatment of Acute Biliary Diseases: Have We Optimized the Value of Inpatient Endoscopic Retrograde Cholangiopancreatography?(Elsevier B.V., 2014-07) Coté, Gregory A.; Department of Medicine, IU School of Medicine
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