Browsing by Author "Department of Pediatrics, Indiana University School of Medicine"
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Item Adolescent Relationship Violence: Help-Seeking and Help-Giving Behaviors among Peers(Springer, Part of Springer Science+Business Media, 2014-04) Fry, Deborah A.; Messinger, Adam M.; Rickert, Vaughn I.; O’Connor, Meghan K.; Palmetto, Niki; Lessel, Harriet; Davidson, Leslie L.; Department of Pediatrics, Indiana University School of MedicineYoung people tend to disclose relationship violence experiences to their peers, if they disclose at all, yet little is known about the nature and frequency of adolescent help-seeking and help-giving behaviors. Conducted within a sample of 1,312 young people from four New York City high schools, this is the first paper to ask adolescent help-givers about the various forms of help they provide and among the first to examine how ethnicity and nativity impact help-seeking behaviors. Relationship violence victims who had ever disclosed (61 %) were more likely to choose their friends for informal support. Ethnicity was predictive of adolescent disclosure outlets, whereas gender and nativity were not. Latinos were significantly less likely than non-Latinos to ever disclose to only friends, as compared to disclosing to at least one adult. The likelihood of a young person giving help to their friend in a violent relationship is associated with gender, ethnicity, and nativity, with males being significantly less likely than females to give all forms of help to their friends (talking to their friends about the violence, suggesting options, and taking action). Foreign-born adolescents are less likely to talk or suggest options to friends in violent relationships. This study also found that Latinos were significantly more likely than non-Latinos to report taking action with or on behalf of a friend in a violent relationship. This research shows that adolescents often rely on each other to address relationship violence, underlining the importance of adolescents’ receipt of training and education on how to support their friends, including when to seek help from more formal services. To further understand the valuable role played by adolescent peers of victims, future research should explore both which forms of help are perceived by the victim to be most helpful and which are associated with more positive outcomes.Item Apurinic/Apyrimidinic Endonuclease/Redox Factor-1 (APE1/Ref-1) redox function negatively regulates NRF2(2015-01) Fishel, Melissa L.; Wu, Xue; Devlin, Cecilia M.; Logsdon, Derek P.; Jiang, Yanlin; Luo, Meihua; He, Ying; Yu, Zhangsheng; Tong, Yan; Lipking, Kelsey P.; Maitra, Anirban; Rajeshkumar, N. V.; Scandura, Glenda; Kelley, Mark R.; Ivan, Mircea; Department of Pediatrics, Indiana University School of MedicineApurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) (henceforth referred to as Ref-1) is a multifunctional protein that in addition to its base excision DNA repair activity exerts redox control of multiple transcription factors, including nuclear factor κ-light chain enhancer of activated B cells (NF-κB), STAT3, activator protein-1 (AP-1), hypoxia-inducible factor-1 (HIF-1), and tumor protein 53 (p53). In recent years, Ref-1 has emerged as a promising therapeutic target in cancer, particularly in pancreatic ductal carcinoma. Although a significant amount of research has centered on Ref-1, no wide-ranging approach had been performed on the effects of Ref-1 inhibition and transcription factor activity perturbation. Starting with a broader approach, we identified a previously unsuspected effect on the nuclear factor erythroid-related factor 2 (NRF2), a critical regulator of cellular defenses against oxidative stress. Based on genetic and small molecule inhibitor-based methodologies, we demonstrated that repression of Ref-1 potently activates NRF2 and its downstream targets in a dose-dependent fashion, and that the redox, rather than the DNA repair function of Ref-1 is critical for this effect. Intriguingly, our results also indicate that this pathway does not involve reactive oxygen species. The link between Ref-1 and NRF2 appears to be present in all cells tested in vitro, noncancerous and cancerous, including patient-derived tumor samples. In particular, we focused on understanding the implications of the novel interaction between these two pathways in primary pancreatic ductal adenocarcinoma tumor cells and provide the first evidence that this mechanism has implications for overcoming the resistance against experimental drugs targeting Ref-1 activity, with clear translational implications.Item Bmi1 promotes erythroid development through regulating ribosome biogenesis(Wiley, 2015-03) Gao, Rui; Chen, Sisi; Kobayashi, Michihiro; Yu, Hao; Zhang, Yingchi; Wan, Yang; Young, Sara K.; Soltis, Anthony; Yu, Ming; Vemula, Sasidhar; Fraenkel, Ernest; Cantor, Alan; Antipin, Yevgeniy; Xu, Yang; Yoder, Mervin C.; Wek, Ronald C.; Ellis, Steven R.; Kapur, Reuben; Zhu, Xiaofan; Liu, Yan; Department of Pediatrics, Indiana University School of MedicineWhile Polycomb group protein Bmi1 is important for stem cell maintenance, its role in lineage commitment is largely unknown. We have identified Bmi1 as a novel regulator of erythroid development. Bmi1 is highly expressed in mouse erythroid progenitor cells and its deficiency impairs erythroid differentiation. BMI1 is also important for human erythroid development. Furthermore, we discovered that loss of Bmi1 in erythroid progenitor cells results in decreased transcription of multiple ribosomal protein genes and impaired ribosome biogenesis. Bmi1 deficiency stabilizes p53 protein, leading to upregulation of p21 expression and subsequent G0/G1 cell cycle arrest. Genetic inhibition of p53 activity rescues the erythroid defects seen in the Bmi1 null mice, demonstrating that a p53-dependent mechanism underlies the pathophysiology of the anemia. Mechanistically, Bmi1 is associated with multiple ribosomal protein genes and may positively regulate their expression in erythroid progenitor cells. Thus, Bmi1 promotes erythroid development, at least in part through regulating ribosome biogenesis. Ribosomopathies are human disorders of ribosome dysfunction, including Diamond-Blackfan anemia (DBA) and 5q- syndrome, in which genetic abnormalities cause impaired ribosome biogenesis, resulting in specific clinical phenotypes. We observed that BMI1 expression in human hematopoietic stem and progenitor cells from patients with DBA is correlated with the expression of some ribosomal protein genes, suggesting that BMI1 deficiency may play a pathological role in DBA and other ribosomopathies.Item Bone Density in Children with Single Ventricle Physiology(Springer, 2015-04) Bendaly, Edgard A.; DiMeglio, Linda A.; Fadel, William F.; Hurwitz, Roger A.; Department of Pediatrics, Indiana University School of MedicineBackground Children with chronic diseases are at risk for low bone mineral density (BMD). There are no studies of BMD in children with congenital heart disease and particularly SV. Children with this defect are often treated with warfarin, suspected to negatively impact BMD in adults. We assessed BMD in patients with single ventricle (SV) physiology and compared the BMD of subjects taking warfarin to those who were not. Methods Subjects 5-12 years with SV were included. BMD z-scores by dual-energy X-ray absorptiometry (DXA) of the spine and total body less head (TBLH) were obtained. Calcium intake, activity level, height, and Tanner stage were assessed. Linear regression models and t-tests were used to investigate differences between participants and normative data as well as between subjects' subgroups. Results Twenty six subjects were included; 16 took warfarin. Mean BMD z-score at the spine was significantly lower than expected at -1.0±0.2 (p<0.0001), as was the BMD z-score for TBLH at - 0.8±0.2 (p<0.0001). Those results remained significant after adjusting for height. Subjects who were on warfarin tended to have lower BMD at both the spine and TBLH than those who were not, with a z-score difference of 0.6±0.46 at the spine (p=0.106) and a difference of 0.4±0.34 at TBLH (p=0.132). Conclusions BMD is significantly reduced in children with SV. Warfarin appears to lower BMD but the effect is less conclusive. Continued evaluation is recommended for these patients at risk for reduced bone density. Evaluation of other cardiac patients on warfarin therapy should also be considered.Item CD4 T cells but not Th17 cells are Required for Mouse Lung Transplant Obliterative Bronchiolitis(Wiley, 2015-07) Wu, Qiang; Gupta, Pawan Kumar; Suzuki, Hidemi; Wagner, Sarah R.; Zhang, Chen; Cummings, Oscar W.; Fan, Lin; Kaplan, Mark H.; Wilkes, David S.; Shilling, Rebecca A.; Department of Pediatrics, Indiana University School of MedicineLung transplant survival is limited by obliterative bronchiolitis (OB), but the mechanisms of OB development are unknown. Previous studies in a mouse model of orthotopic lung transplantation suggested a requirement for IL-17. We have used this orthotopic mouse model to investigate the source of IL-17A and the requirement for T cells producing IL-17A. The major sources of IL-17A were CD4+ T cells and γδ T cells. Depletion of CD4+ T cells led to a significantly decreased frequency and number of IL-17A+ lymphocytes and was sufficient to prevent acute rejection and OB. However, mice with STAT3-deficient T cells, which are unable to differentiate into Th17 cells, rejected lung allografts and developed OB similar to control mice. The frequency of IL-17A+ cells was not decreased in mice with STAT3-deficient T cells due mainly to the presence of IL-17A+ γδ T cells. Deficiency of γδ T cells also did not affect the development of airway fibrosis. Our data suggest that CD4+ T cells are required for OB development and expansion of IL-17A responses in the lung, while Th17 and γδ T cells are not absolutely required and may compensate for each other.Item Central Precocious Puberty: Update on Diagnosis and Treatment(Springer, 2015-08) Chen, Melinda; Eugster, Erica A.; Department of Pediatrics, Indiana University School of MedicineCentral precocious puberty (CPP) is characterized by the same biochemical and physical features as normally timed puberty but occurs at an abnormally early age. Most cases of CPP are seen in girls, in whom it is usually idiopathic. In contrast, ~50 % of boys with CPP have an identifiable cause. The diagnosis of CPP relies on clinical, biochemical, and radiographic features. Untreated, CPP has the potential to result in early epiphyseal fusion and a significant compromise in adult height. Thus, the main goal of therapy is preservation of height potential. The gold-standard treatment for CPP is gonadotropin-releasing hormone (GnRH) analogs (GnRHa). Numerous preparations with a range of delivery systems and durations of action are commercially available. While the outcomes of patients treated for CPP have generally been favorable, more research about the psychological aspects, optimal monitoring, and long-term effects of all forms of GnRHa treatment is needed. Several potential therapeutic alternatives to GnRHa exist and await additional investigation.Item Cinacalcet Administration by Gastrostomy Tube in a Child Receiving Peritoneal Dialysis(Pediatric Pharmacy Advocacy Group and Allen Press Publishing Services, 2014-07) Nichols, Kristen R.; Knoderer, Chad A.; Johnston, Bethanne; Wilson, Amy C.; Department of Pediatrics, Indiana University School of MedicineA 2-year-old male with chronic kidney disease with secondary hyperparathyroidism developed hypercal - cemia while receiving calcitriol, without achieving a serum parathyroid hormone concentration within the goal range. Cinacalcet 15 mg (1.2 mg/kg), crushed and administered via gastrostomy tube, was added to the patient’s therapy. This therapy was effective in achieving targeted laboratory parameters in our patient despite instructions in the prescribing information that cinacalcet should always be taken whole.Item Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic encephalopathy(Spandidos, 2015-07) Rong, Zhihui; Pan, Rui; Chang, Liwen; Lee, Weihua; Department of Pediatrics, Indiana University School of MedicineNeonatal hypoxic-ischemic (HI) brain injury causes severe brain damage in newborns. Following HI injury, rapidly accumulating oxidants injure neurons and interrupt ongoing developmental processes. The antioxidant, sodium pyruvate, has been shown to reduce neuronal injury in neonatal rats under conditions of oxygen glucose deprivation (OGD) and HI injury. In this study, we evaluated the effects of ethyl pyruvate (EP) and insulin‑like growth factor‑I (IGF‑I) alone or in combination in a similar setting. For this purpose, we used an in vitro model involving primary neonatal rat cortical neurons subjected to OGD for 2.5 h and an in vivo model involving unilateral carotid ligation in rats on post-natal day 7 with exposure to 8% hypoxia for 2.5 h. The cultured neurons were examined by lactate dehydrogenase (LDH) and cell viability assays. For the in vivo experiments, behavioral development was evaluated by the foot fault test at 4 weeks of recovery. 2,3,5‑Triphenyltetrazolium chloride monohydrate and cresyl violet staining were used to evaluate HI injury. The injured neurons were Fluoro‑Jade B-labeled, new neuroprecursors were double labeled with bromodeoxyuridine (BrdU) and doublecortin, new mature neurons were BrdU-labeled and neuronal nuclei were labeled by immunofluorescence. Under conditions of OGD, the LDH levels increased and neuronal viability decreased. Treatment with 0.5 mM EP or 25 ng/ml IGF‑I protected the neurons (P<0.05), exerting additive effects. Similarly, either the early administration of EP or delayed treatment with IGF‑I protected the neonatal rat brains against HI injury and improved neurological performance and these effects were also additive. This effect may be the result of reduced neuronal injury, and enhanced neurogenesis and maturation. On the whole, our findings demonstrate that the combination of the early administration of EP with delayed treatment with IGF‑I exerts neuroprotective effects against HI injury in neonatal rat brains.Item Computer decision support changes physician practice but not knowledge regarding autism spectrum disorders(Schattauer, 2015) Bauer, Nerissa S.; Carroll, Aaron E.; Saha, Chandan K.; Downs, Stephen M.; Department of Pediatrics, Indiana University School of MedicineObjective: To examine whether adding an autism module promoting adherence to clinical guidelines to an existing computer decision support system (CDSS) changed physician knowledge and self-reported clinical practice. Methods: The CHICA (Child Health Improvement through Computer Automation) system, a CDSS, was enhanced with a module to improve management of autism in 2 of the 4 community pediatric clinics using the system. We examined the knowledge and beliefs of pediatric users using cross-sectional surveys administered at 3 time points (baseline, 12 months and 24 months post-implementation) between November 2010 and January 2013. Surveys measured knowledge, beliefs and self-reported practice patterns related to autism. Results: A total of 45, 39, and 42 pediatricians responded at each time point, respectively, a 95-100% response rate. Respondents’ knowledge of autism and perception of role for diagnosis did not vary between control and intervention groups either at baseline or any of the two post-intervention time points. At baseline, there was no difference between these groups in rates in the routine use of parent-rated screening instruments for autism. However, by 12 and 24 months post-implementation there was a significant difference between intervention and control clinics in terms of the intervention clinics consistently screening eligible patients with a validated autism tool. Physicians at all clinics reported ongoing challenges to community resources for further work-up and treatment related to autism. Conclusions: A CDSS module to improve primary care management of ASD in pediatric practice led to significant improvements in physician-reported use of validated screening tools to screen for ASDs. However it did not lead to corresponding changes in physician knowledge or attitudes.Item Consensus of German Transplant Centers on Hematopoietic Stem Cell Transplantation in Fanconi Anemia(Thieme, 2015) Chao, M. M.; Ebell, W.; Bader, P.; Beier, R.; Burkhardt, B.; Feuchtinger, T.; Handgretinger, R.; Hanenberg, H.; Koehl, U.; Kratz, C.; Kremens, B.; Lang, P.; Meisel, R.; Mueller, I.; Roessig, C.; Sauer, M.; Schlegel, P. G.; Schulz, A.; Strahm, B.; Thol, F.; Sykora, K. W.; Department of Pediatrics, Indiana University School of MedicineAllogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative therapy for the severe hematopoietic complications associated with Fanconi anemia (FA). In Germany, it is estimated that 10–15 transplants are performed annually for FA. However, because FA is a DNA repair disorder, standard conditioning regimens confer a high risk of excessive regimen-related toxicities and mortality, and reduced intensity regimens are linked with graft failure in some FA patients. Moreover, development of graft-versus-host disease is a major contributing factor for secondary solid tumors. The relative rarity of the disorder limits HSCT experience at any single center. Consensus meetings were convened to develop a national approach for HSCT in FA. This manuscript outlines current experience and knowledge about HSCT in FA and, based on this analysis, general recommendations reached at these meetings.