Emory Childrens Center

Atlanta, GA, United States

Emory Childrens Center

Atlanta, GA, United States
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Novaira H.J.,Johns Hopkins University | Fadoju D.,Johns Hopkins University | Fadoju D.,Emory Childrens Center | Diaczok D.,Johns Hopkins University | Radovick S.,Johns Hopkins University
Journal of Neuroscience | Year: 2012

Kisspeptins (Kiss) have been shown to be key components in the regulation of gonadotropin-releasing hormone (GnRH) secretion. In vitro studies have demonstrated an increase in GnRH gene expression by Kiss suggesting regulation of GnRH at both the secretory and pretranslational levels. Here, we define genetic mechanisms that mediate Kiss action on target gene expression. In vitro, sequential deletions of the mouse GnRH (mGnRH) gene promoter fused to the luciferase (LUC) reporter gene localized at kisspeptin-response element (KsRE) between -3446 and -2806 bp of the mGnRH gene. In vivo, transgenic mice bearing sequential deletions of the mGnRH gene promoter linked to the LUC reporter localized an identical KsRE. To define the mechanism of regulation, Kiss was first shown to induce nucleosome-depleted DNA within the KsRE, and a potential binding site for the transcription factor, Otx-2, was revealed. Furthermore, increased Otx-2 mRNA, protein, and binding to the KsRE after Kiss treatment were demonstrated. In conclusion, this work identified elements in GnRH-neuronal cell lines and in transgenic mice that mediate positive regulation of GnRH by Kiss. In addition, we show for the first time that Otx-2 is regulated by Kiss, and plays a role in mediating the transcriptional response of mGnRH gene. © 2012 the authors.

Padilla-Parra S.,Emory Childrens Center | Padilla-Parra S.,University of Rennes 1 | Matos P.M.,University of Lisbon | Kondo N.,Emory Childrens Center | And 4 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2012

Diverse enveloped viruses enter host cells through endocytosis and fuse with endosomal membranes upon encountering acidic pH. Currently, the pH dynamics in virus-carrying endosomes and the relationship between acidification and viral fusion are poorly characterized. Here, we examined the entry of avian retrovirus that requires two sequential stimuli - binding to a cognate receptor and low pH - to undergo fusion. A genetically encoded sensor incorporated into the viral membrane was used to measure the pH in viruscarrying endosomes. Acid-induced virus fusion was visualized as the release of a fluorescent viral content marker into the cytosol. The pH values in early acidic endosomes transporting the virus ranged from 5.6 to 6.5 but were relatively stable over time for a given vesicle. Analysis of viralmotility and luminal pH showed that cells expressing the transmembrane isoform of the receptor (TVA950) preferentially sorted the virus into slowly trafficking, less acidic endosomes. In contrast, viruses internalized by cells expressing the GPI-anchored isoform (TVA800) were uniformly distributed between stationary and mobile compartments. We found that the lag times between acidification and fusion were significantly shorter and fusion pores were larger in dynamic endosomes than inmore stationary compartments. Despite the same average pH within mobile compartments of cells expressing alternative receptor isoforms, TVA950 supported faster fusion than TVA800 receptor. Collectively, our results suggest that fusion steps downstream of the low-pH trigger are modulated by properties of intracellular compartments harboring the virus.

Patel K.,Children's Hospital of Philadelphia | Kobrynski L.,Emory Childrens Center | Gathman B.,Albert Ludwigs University of Freiburg | Davis O.,United States Immunodeficiency Network Registry | Sullivan K.E.,Children's Hospital of Philadelphia
Journal of Pediatrics | Year: 2012

DiGeorge syndrome is associated with a T-lymphocyte immunodeficiency. The prevalence of hypogammaglobulinemia has not been reported. We found that 3% of patients with DiGeorge syndrome were receiving immunoglobulin replacement therapy and 6% of patients over the age of 3 years had hypogammaglobulinemia. We conclude that DiGeorge syndrome is associated with significant humoral immune deficiency. Copyright © 2012 Mosby Inc.

Koontz C.S.,University of Tennessee at Chattanooga | Ricketts R.R.,Emory Childrens Center
American Surgeon | Year: 2010

The aim of this study is to compare liver function and cholangitis episodes during the first year postoperatively between patients who undergo hepatic portocholecystostomy (HPC) and patients who undergo hepatic portoenterostomy (HPE). Records of six patients who underwent HPC for biliary atresia (BA) and 27 patients who underwent HPE for BA were reviewed retrospectively. Comparison was done of the patient's total bilirubin, albumin, and international normalized ratio values preoperatively and at 3 months, 6 months, and 1 year postoperatively. Comparison was also done of the occurrence of ascending cholangitis during the first year postoperatively and in rates of transplant and mortality during long-term follow-up. Preoperative laboratory values between the two groups were not significantly different. At 6 months, the patients who underwent HPC had significantly lower total bilirubin levels compared with those who underwent HPE (HPC 0.8 ± 0.96, n = 4; HPE 4.93 ± 7.73, n = 21; P < 0.05). No other laboratory values or rates of ascending cholangitis, transplant, or mortality showed a significant difference. Those patients who underwent HPC had significantly lower total bilirubin levels at 6 months postoperatively. This may suggest that HPC may be a superior operative technique for patients who are candidates for the operation.

Srisuma S.,University of Rochester | Srisuma S.,Mahidol University | Srisuma S.,Harvard University | Bhattacharya S.,University of Rochester | And 8 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: The mechanisms contributing to alveolar formation are poorly understood. A better understanding of these processes will improve efforts to ameliorate lung disease of the newborn and promote alveolar repair in the adult. Previous studies have identified impaired alveogenesis in mice bearing compound mutations of fibroblast growth factor (FGF) receptors (FGFRs) 3 and 4, indicating that these receptors cooperatively promote postnatal alveolar formation. Objectives: To determine the molecular and cellular mechanisms of FGF-mediated alveolar formation. Methods: Compound FGFR3/FGFR4-deficient mice were assessed for temporal changes in lung growth, airspace morphometry, and genome-wide expression. Observed gene expression changes were validated using quantitative real-time RT-PCR, tissue biochemistry, histochemistry, and ELISA. Autocrine and paracrine regulatory mechanisms were investigated using isolated lung mesenchymal cells and type II pneumocytes. Measurements and Main Results: Quantitative analysis of airspace ontogeny confirmed a failure of secondary crest elongation in compound mutant mice. Genome-wide expression profiling identified molecular alterations in these mice involving aberrant expression of numerous extracellular matrix molecules. Biochemical and histochemical analysis confirmed changes in elastic fiber gene expression resulted in temporal increases in elastin deposition with the loss of typical spatial restriction. No abnormalities in elastic fiber gene expression were observed in isolated mesenchymal cells, indicating that abnormal elastogenesis in compound mutant mice is not cell autonomous. Increased expression of paracrine factors, including insulin-like growth factor21, in freshly-isolated type II pneumocytes indicated that these cells contribute to the observed pathology. Conclusions: Epithelial/mesenchymal signaling mechanisms appear to contribute to FGFR-dependent alveolar elastogenesis and proper airspace formation.

Caidi H.,Centers for Disease Control and Prevention | Harcourt J.L.,Centers for Disease Control and Prevention | Tripp R.A.,University of Georgia | Anderson L.J.,Emory Childrens Center | Haynes L.M.,Centers for Disease Control and Prevention
PLoS ONE | Year: 2012

Therapeutic options to control respiratory syncytial virus (RSV) are limited, thus development of new therapeutics is high priority. Previous studies with a monoclonal antibody (mAb) reactive to an epitope proximal to the central conserved region (CCR) of RSV G protein (mAb 131-2G) showed therapeutic efficacy for reducing pulmonary inflammation RSV infection in BALB/c mice. Here, we show a protective effect in RSV-infected mice therapeutically treated with a mAb (130-6D) reactive to an epitope within the CCR of G protein, while treatment with a mAb specific for a carboxyl G protein epitope had no effect. Combined treatment with mAbs 130-6D and 131-2G significantly decreased RSV-associated pulmonary inflammation compared to either antibody alone. The results suggest that anti-RSV G protein mAbs that react at or near the CCR and can block RSV G protein-mediated activities are effective at preventing RSV disease and may be an effective strategy for RSV therapeutic treatment.

Harring T.R.,Baylor College of Medicine | Nguyen N.T.T.,Baylor College of Medicine | Liu H.,Baylor College of Medicine | Karpen S.J.,Emory Childrens Center | And 2 more authors.
Pediatric Transplantation | Year: 2013

CF affects one of 2000 Caucasians, and approximately 25% are found to have CFLD for which OLT may be indicated. Timing of transplantation, contraindications, and survival are still widely debated. We report the outcomes of OLT for pediatric patients with CFLD from the largest children's hospital in the United States. Our records since September 1998 were analyzed for all patients undergoing OLT for CFLD. Nine patients were then compared to similar patients in the UNOS/OPTN database (n = 155). Survivals were calculated with the Kaplan-Meier method and compared using the log-rank test. All statistics were performed in SPSS 15.0. We performed OLT on nine pediatric patients with CFLD, with age ranging from nine to 17 yr at the time of transplant. Mean survival was 69.2 months; patient and allograft survivals at one and five yr were 88.9%, with one death at day 21 due to Aspergillus fumigatus sepsis. Two patients underwent concurrent multi-organ transplantation. One patient required double lung transplantation four yr after isolated OLT. Comparison to the UNOS/OPTN database revealed a trend toward improved survival. Patients with CF can achieve favorable outcomes after OLT, as we report excellent survivals for pediatric patients with CFLD. © 2013 John Wiley & Sons A/S.

Batisky D.L.,Emory University | Batisky D.L.,Children's Healthcare Of Atlanta | Batisky D.L.,Emory Childrens Center
Current Hypertension Reports | Year: 2012

There has been an evolution in the understanding of the treatment of hypertension in children and adolescents over the past decade. This has been fueled in part by the increased attention paid to the clinical problem, given the increasing numbers of children and adolescents being diagnosed with this condition. There has also been a growing number of clinical trials performed and completed that demonstrate the blood pressure (BP)-lowering effects of antihypertensives and the side effect profiles of these medications, and that has led to FDA-labeling of many antihypertensive medications for use in children and adolescents. However, none of these trials has provided definitive data on the optimal first line agent for this patient population. Clinical experience and other approaches discussed in this review are still necessary to guide treatment of hypertension in the young. The quest for the optimal antihypertensive agent is just beginning, and it is going to take some extraordinary effort to reach that goal. © Springer Science+Business Media, LLC 2012.

Kobrynski L.J.,Emory Childrens Center | Mayer L.,Mount Sinai Medical Center
Clinical Immunology | Year: 2011

An estimated 250,000 individuals in the Unites States have been diagnosed with a primary immunodeficiency disease (PIDD). Early diagnosis and treatment of PIDD are critical to minimizing morbidity and improving quality of life. Patients with certain subtypes of PIDD may present with gastrointestinal complaints such as chronic or acute diarrhea, malabsorption, gastrointestinal pain, and inflammatory bowel diseases. Therefore, gastroenterologists are well positioned to help identify patients with PIDD. The hallmarks of PIDD include recurrent or persistent infections, infections due to microorganisms that rarely cause significant disease in immunocompetent people, unusually severe or life-threatening infections, and either low or persistently high white blood cell counts. An assessment for PIDD involves detailed patient and family histories, a physical examination, and diagnostic screening tests. Immunoglobulin replacement therapy is the cornerstone of treatment for most subtypes of PIDD. © 2011 Elsevier Inc.

Kondo N.,Emory Childrens Center | Melikyan G.B.,Emory Childrens Center | Melikyan G.B.,Children's Healthcare Of Atlanta
PLoS ONE | Year: 2012

Incorporation of intercellular adhesion molecule 1 (ICAM-1) into HIV-1 particles is known to markedly enhance the virus binding and infection of cells expressing lymphocyte function-associated antigen-1 (LFA-1). At the same time, ICAM-1 has been reported to exert a less pronounced effect on HIV-1 fusion with lymphoid cells. Here we examined the role of ICAM-1/LFA-1 interactions in productive HIV-1 entry into lymphoid cells using a direct virus-cell fusion assay. ICAM-1 promoted HIV-1 attachment to cells in a temperature-dependent manner. It exerted a marginal effect on virus binding in the cold, but enhanced binding up to 4-fold at physiological temperature. ICAM-1-independent attachment in the cold was readily reversible upon subsequent incubation at elevated temperature, whereas ICAM-1-bearing particles were largely retained by cells. The better virus retention resulted in a proportional increase in HIV-1 internalization and fusion, suggesting that ICAM-1 did not specifically accelerate endocytosis or fusion steps. We also measured the rates of CD4 engagement, productive endocytosis and HIV-endosome fusion using specific fusion inhibitors. These rates were virtually independent of the presence of ICAM-1 in viral particles. Importantly, irrespective of the presence of ICAM-1, HIV-1 escaped from the low temperature block, which stopped virus endocytosis and fusion, much later than from a membrane-impermeant fusion inhibitor targeting surface-accessible particles. This result, along with the complete inhibition of HIV-1 fusion by a small molecule dynamin inhibitor, implies this virus enters lymphoid cells used in this study via endocytosis and that this pathway is not altered by the viral ICAM-1. Our data highlight the role of ICAM-1 in stabilizing the HIV-1 attachment to LFA-1 expressing cells, which leads to a proportional enhancement of the receptor-mediated uptake and fusion with endosomes. © 2012 Kondo, Melikyan.

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