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Cincinnati, OH, United States

Sengupta A.,Heart Institute | Kalinichenko V.V.,Cincinnati Childrens Medical Center | Yutzey K.E.,Heart Institute
Circulation Research

Rationale: In the mammalian heart, cardiomyocytes withdraw from the cell cycle and initiate hypertrophic growth soon after birth, but the transcriptional regulatory mechanisms that control these neonatal transitions are not well-defined. Objective: Forkhead family transcription factors have been implicated as positive (forkhead box [Fox] transcription factor M1) and negative (FoxO1 and FoxO3) regulators of cardiomyocyte proliferation prenatally, but their regulatory interactions and functions in neonatal cell-cycle withdrawal have not been reported previously. Potential regulators of Fox activity, including the metabolic indicator AMP-activated protein kinase (AMPK), and Fox transcriptional targets (p21, p27, insulin-like growth factor 1 [IGF1]) also were examined. Methods and Results: In cultured neonatal rat cardiomyocytes, AMPK activates FoxOs, and AMPK inhibition is sufficient to induce cell proliferation. In vivo, combined loss of FoxO1 and FoxO3 specifically in cardiomyocytes leads to delayed cell-cycle withdrawal and increased expression of IGF1 and FoxM1. Conversely, cardiomyocyte-specific loss of FoxM1 results in decreased neonatal cardiomyocyte cell proliferation, decreased expression of IGF1, and increased expression of cell-cycle inhibitors p21 and p27. IGF1 is a direct downstream target of cardiac Fox transcription factors, which is negatively regulated by FoxOs and positively regulated by FoxM1, dependent on AMPK activation status. Conclusions: These data support a regulatory mechanism whereby the balance of FoxO and FoxM1 transcription factors integrates metabolic status, mediated by AMPK, and cell-cycle regulation, through competitive regulation of target genes, including IGF1, in neonatal cardiomyocytes. © 2012 American Heart Association, Inc. Source

Sinner D.I.,Cincinnati Childrens Medical Center | Kim G.J.,Rutgers University | Kim G.J.,Clarassance | Henderson G.C.,Rutgers University | Igal R.A.,Rutgers University

Recent studies have demonstrated that human stearoylCoA desaturase-1 (SCD1), a Δ9-desaturase that converts saturated fatty acids (SFA) into monounsaturated fatty acids, controls the rate of lipogenesis, cell proliferation and tumorigenic capacity in cancer cells. However, the biological function of stearoylCoA desaturase-5 (SCD5), a second isoform of human SCD that is highly expressed in brain, as well as its potential role in human disease, remains unknown. In this study we report that the constitutive overexpression of human SCD5 in mouse Neuro2a cells, a widely used cell model of neuronal growth and differentiation, displayed a greater n-7 MUFA-to-SFA ratio in cell lipids compared to empty-vector transfected cells (controls). De novo synthesis of phosphatidylcholine and cholesterolesters was increased whereas phosphatidylethanolamine and triacylglycerol formation was reduced in SCD5-expressing cells with respect to their controls, suggesting a differential use of SCD5 products for lipogenic reactions. We also observed that SCD5 expression markedly accelerated the rate of cell proliferation and suppressed the induction of neurite outgrowth, a typical marker of neuronal differentiation, by retinoic acid indicating that the desaturase plays a key role in the mechanisms of cell division and differentiation. Critical signal transduction pathways that are known to modulate these processes, such epidermal growth factor receptor (EGFR)Akt/ERK and Wnt, were affected by SCD5 expression. Epidermal growth factor-induced phosphorylation of EGFR, Akt and ERK was markedly blunted in SCD5-expressing cells. Furthermore, the activity of canonical Wnt was reduced whereas the non-canonical Wnt was increased by the presence of SCD5 activity. Finally, SCD5 expression increased the secretion of recombinant Wnt5a, a non-canonical Wnt, whereas it reduced the cellular and secreted levels of canonical Wnt7b. Our data suggest that, by a coordinated modulation of key lipogenic pathways and transduction signaling cascades, SCD5 participates in the regulation of neuronal cell growth and differentiation. © 2012 Sinner et al. Source

Eghtesady P.,Cincinnati Childrens Medical Center | Brar A.,Cincinnati Childrens Hospital | Hall M.,Child Health Corporation of America
Journal of Thoracic and Cardiovascular Surgery

Objective: Hypoplastic left heart syndrome is a major congenital heart defect and is associated with significant morbidity and mortality. Its etiology remains unknown although genetic studies imply complex inheritance. Anecdotal reports of cluster presentations suggest the possible involvement of an environmental component, although previous epidemiologic studies have been of limited scope. The objective of this study was to examine seasonal and temporal patterns of hypoplastic left heart syndrome births compared with other left-sided heart defects in the United States. Methods: We conducted a retrospective analysis of the Pediatric Health Information System inpatient database from pediatric hospitals across the country from 1996 to 2006. Population and index case patterns were analyzed for each diagnostic category. An epidemiologic survey was performed through time-series analyses using Fisher's Kappa test and the Bartlett Kolmogorov-Smirnov test. The existence and strength of seasonality for the left-sided heart defects was quantified by the autoregression R2. Results: A seasonal occurrence was found in hypoplastic left heart syndrome but not other left-sided heart diseases. Significant seasonal differences occurred each year, with peaks in summer months and troughs in winter months. The seasonality inversely correlated with the incidence of chromosomal and extracardiac anomalies; such anomalies were highest in interrupted aortic arch, which had a random pattern of presentation. Conclusions: There is a significant seasonal pattern in the presentation of hypoplastic left heart syndrome, with preponderance in summer months, in contrast to the random pattern in other left-sided heart diseases. Further studies are warranted to identify the influence of potential environmental factor(s) in hypoplastic left heart syndrome, as seen in diseases with seasonal patterns. Copyright © 2011 by The American Association for Thoracic Surgery. Source

Gupta A.A.,University of Toronto | Anderson J.R.,University of Nebraska Medical Center | Pappo A.S.,St Jude Childrens Research Hospital | Spunt S.L.,St Jude Childrens Research Hospital | And 3 more authors.

Background: Patients aged >10 years with rhabdomyosarcoma have an inferior outcome compared with patients ages 1 to 9 years, which may be explained by toxicities (adverse events [AEs]) that result in chemotherapy dose reductions. Methods: AEs observed during 1 of 3 randomized chemotherapy regimens (vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide [VAI]; or vincristine, ifosfamide, and etoposide [VIE]) in the Fourth Intergroup Rhabdomyosarcoma Study were recorded. The incidence of toxicities by age and treatment regimen was determined. The odds of developing AEs in a particular age group (ages 5-9 years, 10-14 years, and 15-20 years) were compared with the odds in the control group of patients ages 1 to 4 years. Results: In total, 657 patients were eligible for analysis. The estimated 5-year event-free survival rates were 78%, 83%, 67%, and 58% for the groups ages 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 20 years, respectively. Patients ages 15 to 20 years experienced less neutropenia (odds ratio [OR], 0.43; P <.0001), thrombocytopenia (OR, 0.41; P <.0001), anemia (OR, 0.34; P <.0001), and infection (OR, 0.41; P <.0001) compared with younger patients, although they received similar amounts of chemotherapy. In contrast, peripheral nervous system toxicity was higher in adolescents aged >10 years (OR, 4.18; P <.0001). Females experienced more neutropenia (OR, 1.28; P =.05) and thrombocytopenia (OR, 1.26; P =.06) compared with males. Conclusions: Adolescents who received treatment for rhabdomyosarcoma experienced significantly less hematologic toxicity and more peripheral nervous system toxicity compared with younger children despite receiving similar amounts of chemotherapy. Although outcomes were inferior in adolescents, it was unclear whether the differences in toxicity observed in the current study had an impact on outcome. The authors concluded that future studies examining the age-related and sex-related differences in pharmacokinetics of chemotherapy are necessary. © 2011 American Cancer Society. Source

Nanda M.K.,Asthma and Immunology | Elenburg S.,University of Tennessee Health Science Center | Bernstein J.A.,University of Cincinnati | Assa'ad A.H.,Cincinnati Childrens Medical Center
Journal of Allergy and Clinical Immunology: In Practice

Background: There is a paucity of data that describe the clinical course of hereditary angioedema (HAE) in children. Objective: The purpose of this study was to examine the clinical features of children with HAE. Methods: Electronic medical records from the past 10 years at Cincinnati Children's Hospital Medical Center and an outpatient allergy community practice were searched for ICD-9 code 277.6 (Other deficiencies of circulating enzyme). Exclusion criteria included laboratory data not supportive of type I or II HAE diagnosis or age at diagnosis greater than 18 years. Chart review was performed and missing data were collected by telephone interviews with patient families. Descriptive statistics were performed using SAS version 9.4. Results: Twenty-one children were identified. The median age was 13.2 years (interquartile range [IQR], 9.1-18.8), 71% were male, 86% had an HAE family history, and 95% were Caucasian. The median age of symptom onset and diagnosis was 5.7 (IQR, 5-9 years) and 5.0 (IQR, 4-8 years), respectively. Five children diagnosed were asymptomatic. Three children without a family history had a 6.0-year delay in diagnosis. The most common angioedema attack sites were abdominal, peripheral, and laryngeal, which occurred at least once in 93%, 73%, and 27%, respectively. Of the 15 children with onset of symptoms, only 6 children received on-demand therapy for an acute attack, whereas 13 children were administered either short-term or long-term prophylaxis therapy. Conclusions: In this pediatric HAE population, symptom onset and diagnosis occurred at a median age of 5 years with a delay in diagnosis in those without a family history. Abdominal attacks were more common than peripheral attacks in this population. © 2015 American Academy of Allergy, Asthma & Immunology. Source

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