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.
Belshe R.B.,Saint Louis University |
Frey S.E.,Saint Louis University |
Graham I.L.,Saint Louis University |
Anderson E.L.,Saint Louis University |
And 15 more authors.
JAMA - Journal of the American Medical Association | Year: 2014
DESIGN, SETTING, AND PARTICIPANTS Multicenter US randomized clinical trial beginning in June 2010 with follow-up continuing through October 2011 enrolling 72 healthy adults who were vaccinated 1 year previously with the Vietnam vaccine and 565 vaccine-naive adults.INTERVENTIONS Participants who were previously vaccinated with 90 μg of unadjuvanted Vietnam vaccine were randomly assigned to receive 3.75 μg of avian influenza Anhui vaccine with or without MF59 adjuvant, stratified by 1 vs 2 previous doses (1 dose: n = 18 with MF59 and n = 17 without; 2 doses: n = 19 with MF59 and n = 18 without). Vaccine-naive individuals were randomly assigned to receive Ahnui vaccine with or without MF59 adjuvant in 1 of 5 doses (3.75 μg [n = 55 with MF59 and n = 59 without], 7.5 μg [n = 51 with MF59 and n = 57 without], 15 μg [n = 48 with MF59 and n = 44 without], 45 μg [n = 47 with MF59 and n = 47 without], or 90 μg [n = 57 without adjuvant]) or placebo (n = 100) given at days 0 and 28.MAIN OUTCOMES AND MEASURES The primary immunogenicity outcomewas hemagglutination inhibition assay (HAI) titer against each vaccine antigen 1 month (day 28) and 6 months (day 180) after last vaccination. The primary safety outcomes were local and systemic adverse events on days 0 to 7 after each vaccination and serious adverse events.CONCLUSIONS AND RELEVANCE Previous receipt of a single dose of influenza A(H5N1) Vietnam vaccine was associated with sufficient immunologic priming to facilitate antibody response to a different H5N1 antigen using low-dose Anhui (booster) vaccine. In participants who had not previously received H5 vaccine, low-dose Anhui vaccine plus adjuvant was more immunogenic compared with higher doses of unadjuvanted vaccine. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00680069.RESULTS Previously vaccinated participants manifested secondary antibody responses after receipt of low-dose Anhui vaccine ("boosting"); by day 28, 21% to 50% developed HAI responses of 1:40 or greater. Use of adjuvant was not associated with increased HAI responses. Among vaccine-naive participants (n = 565), the optimum dose was 7.5 μg of antigen with adjuvant (geometric mean titer [GMT], 63.3; 95%CI, 43.0-93.1). The greatest response to unadjuvanted antigen was seen at the highest dose, 90 μg (GMT, 28.5; 95%CI, 19.7-41.2). Local or systemic reactions occurred, respectively, in 40 (78%) and 25 (49%) of 51 participants who received 7.5 μg plus adjuvant vs 50 (88%) and 29 (51%) of 57 who received 90 μg of unadjuvanted vaccine. In general, antibodies were short-lived, and by day 180, HAI titers had decreased to less than 1:20 in all treatment groups.IMPORTANCE The need to respond quickly to potential influenza pandemics is important. Immunologic priming (initial presentation of an antigen to allow antibody responses on revaccination) with vaccine directed toward an older avian influenza H5 strain might lead to secondary antibody responses to a single dose of more current H5 avian influenza vaccine.OBJECTIVES To assess priming with the older avian influenza A/Vietnam/1203/2004(H5N1) (Vietnam) vaccine and to conduct dose-response studies with vaccine directed against the more contemporary H5N1 avian influenza virus, influenza A/Anhui/01/2005 (Anhui). © 2014 American Medical Association. All rights reserved.
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.
Turner D.,Shaare Zedek Medical Center |
Mack D.,Childrens Hospital of Eastern Ontario |
Leleiko N.,Brown University |
Walters T.D.,The Hospital for Sick Children |
And 12 more authors.
Gastroenterology | Year: 2010
Background & Aims: In a prospective study of children with severe ulcerative colitis (UC), we aimed to assess outcomes and to identify predictors of nonresponse to intravenous corticosteroids. Methods: A total of 128 children (47% males; 12.9 ± 3.9 y) hospitalized for severe UC were enrolled from 10 pediatric centers. Clinical and laboratory data and the Pediatric UC Activity Index (PUCAI) were recorded throughout the admission. Patients were followed up for 1 year postdischarge. Results: Thirty-seven (29%; 95% confidence interval [CI], 22%-37%) children failed intravenous corticosteroids and received, within 10.5 ± 6.4 days, cyclosporine (n = 1; 3%), colectomy (n = 3; 8%), or infliximab (n = 33; 89%). Several predictors were associated with intravenous corticosteroids failure, but the best model included number of stools, amount of blood, age, and new-onset disease (odds ratio [OR], 1.9; 95% CI, 1.1-3.5; OR, 2.5; 95% CI, 1.3-4.6; OR, 1.2; 95% CI, 1.04-1.36; and OR, 0.27; 95% CI, 0.1-0.7, respectively). The PUCAI, followed closely by the Travis rule, strongly predicted response when compared with other measures (Seo and Lindgren indices, C-reactive protein level, and fecal calprotectin level) (P < .001). Aiming for sensitivity on day 3, a PUCAI greater than 45 screened for patients likely to fail intravenous corticosteroids (negative predictive value, 94%; positive predictive value, 43%; P < .001). Aiming for specificity on day 5, a PUCAI score greater than 70 optimally guided implementation of salvage therapy (positive predictive value, 100%; negative predictive value, 79%; P < .001). Twenty-five of 33 children treated with infliximab responded. The overall cumulative colectomy rate was 9% and 19% by discharge and 1-year, respectively. The day 3 PUCAI score predicted response up to 1 year postdischarge (P < .001; time to salvage therapy). Conclusions: The PUCAI, calculated on days 3 and 5 of steroid therapy, can identify patients requiring salvage therapy. Infliximab is an effective therapy in steroid-refractory pediatric UC. © 2010 AGA Institute.
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.