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Wierzba T.F.,Korean International Vaccine Institute | Kar S.K.,Regional Medical Research Center | Mogasale V.V.,Korean International Vaccine Institute | Kerketta A.S.,Regional Medical Research Center | And 9 more authors.
Vaccine | Year: 2015

Background: A clinical trial conducted in India suggests that the oral cholera vaccine, Shanchol, provides 65% protection over five years against clinically-significant cholera. Although the vaccine is efficacious when tested in an experimental setting, policymakers are more likely to use this vaccine after receiving evidence demonstrating protection when delivered to communities using local health department staff, cold chain equipment, and logistics. Methods: We used a test-negative, case-control design to evaluate the effectiveness of a vaccination campaign using Shanchol and validated the results using a cohort approach that addressed disparities in healthcare seeking behavior. The campaign was conducted by the local health department using existing resources in a cholera-endemic area of Puri District, Odisha State, India. All non-pregnant residents one year of age and older were offered vaccine. Over the next two years, residents seeking care for diarrhea at one of five health facilities were asked to enroll following informed consent. Cases were patients seeking treatment for laboratory-confirmed V. cholera-associated diarrhea. Controls were patients seeking treatment for V. cholerae negative diarrhea. Results: Of 51,488 eligible residents, 31,552 individuals received one dose and 23,751 residents received two vaccine doses. We identified 44 V. cholerae O1-associated cases and 366 non V. cholerae diarrhea controls. The adjusted protective effectiveness for persons receiving two doses was 69.0% (95% CI: 14.5% to 88.8%), which is similar to the adjusted estimates obtained from the cohort approach. A statistical trend test suggested a single dose provided a modicum of protection (33%, test for trend, p = 0.0091). Conclusion: This vaccine was found to be as efficacious as the results reported from a clinical trial when administered to a rural population using local health personnel and resources. This study provides evidence that this vaccine should be widely deployed by public health departments in cholera endemic areas. © 2015 The Authors.


PubMed | George Washington University and Center for Translational Research
Type: | Journal: Hospital pediatrics | Year: 2016

Health care disparities have been described for children of limited English-proficient (LEP) families compared with children of English-proficient (EP) families. Poor communication with the medical team may contribute to these worse health outcomes. Previous studies exploring communication in the PICU have excluded LEP families. We aimed to understand communication experiences and preferences in the 3 primary communication settings in the PICU. We also explored LEP families views on interpreter use in the PICU.EP and Spanish-speaking LEP families of children admitted to the PICU of a large tertiary pediatric hospital completed surveys between 24 hours and 7 days of admission.A total of 161 of 184 families were surveyed (88% response rate); 52 were LEP and 109 EP. LEP families were less likely to understand the material discussed on rounds (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.11-0.90), to report that PICU nurses spent enough time speaking with them (OR 0.15, 95% CI 0.05-0.41), and to report they could rely on their nurses for medical updates (OR 0.07, 95% CI 0.02-0.25) controlling for covariates, such as education, insurance type, presence of a chronic condition, PICU length of stay, and mortality index. LEP families reported 53% of physicians and 41% of nurses used an interpreter often.Physician and nurse communication with LEP families is suboptimal. Communication with LEP families may be improved with regular use of interpreters and an increased awareness of the added barrier of language proficiency.


Sharma. A.,U.S. National Institute on Aging | Berga-Bolanos. R.,Center for Translational Research | Sen J.M.,U.S. National Institute on Aging | Alberola-Ila J.,Oklahoma Medical Research Foundation
PLoS ONE | Year: 2014

Natural killer T (NKT) cells are a component of innate and adaptive immune systems implicated in immune, autoimmune responses and in the control of obesity and cancer. NKT cells develop from common CD4+ CD8+ double positive (DP) thymocyte precursors after the rearrangement and expression of T cell receptor (TCR) Vα14-Jα18 gene. Temporal regulation and late appearance of Vα14-Jα18 rearrangement in immature DP thymocytes has been demonstrated. However, the precise control of lifetime of DP thymocytes in vivo that enables distal rearrangements remains incompletely defined. Here we demonstrate that T cell factor (TCF)-1, encoded by the Tcf7 gene, is critical for the extended lifetime of DP thymocytes. TCF-1-deficient DP thymocytes fail to undergo TCR Vα14-Jα18 rearrangement and produce significantly fewer NKT cells. Ectopic expression of Bcl-xL permits Va14-Ja18 rearrangement and rescues NKT cell development. We report that TCF-1 regulates expression of RORγt, which regulates DP thymocyte survival by controlling expression of Bcl-xL. We posit that TCF-1 along with its cofactors controls the lifetime of DP thymocytes in vivo.


Baker J.N.,St Jude Childrens Research Hospital | Levine D.R.,St Jude Childrens Research Hospital | Hinds P.S.,Center for Translational Research | Weaver M.S.,St Jude Childrens Research Hospital | And 11 more authors.
Journal of Pediatrics | Year: 2015

Objective To synthesize the perspectives of a broad range of pediatric palliative care (PPC) clinicians and parents, to formulate a consensus on prioritization of the PPC research agenda. Study design A 4-round modified Delphi online survey was administered to PPC experts and to parents of children who had received PPC. In round 1, research priorities were generated spontaneously. Rounds 2 and 3 then served as convergence rounds to synthesize priorities. In round 4, participants were asked to rank the research priorities that had reached at least 80% consensus. Results A total of 3093 concepts were spontaneously generated by 170 experts and 72 parents in round 1 (65.8% response rate [RR]). These concepts were thematically organized into 78 priorities and recirculated for round 2 ratings (n = 130; 53.7% RR). Round 3 achieved response stability, with 31 consensus priorities oscillating within 10% of the mode (n = 98; 75.4% RR). Round 4 resulted in consensus recognition of 20 research priorities, which were thematically grouped as decision making, care coordination, symptom management, quality improvement, and education. Conclusions This modified Delphi survey used professional and parental consensus to identify preeminent PPC research priorities. Attentiveness to these priorities may help direct resources and efforts toward building a formative evidence base. Investigating PPC implementation approaches and outcomes can help improve the quality of care services for children and families. © 2015 Elsevier Inc.


PubMed | Akron Children’s Hospital, University of Texas at Austin, Mercy Hospital Center and Clinics, Dana-Farber Cancer Institute and 5 more.
Type: Journal Article | Journal: The Journal of pediatrics | Year: 2015

To synthesize the perspectives of a broad range of pediatric palliative care (PPC) clinicians and parents, to formulate a consensus on prioritization of the PPC research agenda.A 4-round modified Delphi online survey was administered to PPC experts and to parents of children who had received PPC. In round 1, research priorities were generated spontaneously. Rounds 2 and 3 then served as convergence rounds to synthesize priorities. In round 4, participants were asked to rank the research priorities that had reached at least 80% consensus.A total of 3093 concepts were spontaneously generated by 170 experts and 72 parents in round 1 (65.8% response rate [RR]). These concepts were thematically organized into 78 priorities and recirculated for round 2 ratings (n = 130; 53.7% RR). Round 3 achieved response stability, with 31 consensus priorities oscillating within 10% of the mode (n = 98; 75.4% RR). Round 4 resulted in consensus recognition of 20 research priorities, which were thematically grouped as decision making, care coordination, symptom management, quality improvement, and education.This modified Delphi survey used professional and parental consensus to identify preeminent PPC research priorities. Attentiveness to these priorities may help direct resources and efforts toward building a formative evidence base. Investigating PPC implementation approaches and outcomes can help improve the quality of care services for children and families.


Marino N.,U.S. National Cancer Institute | Marshall J.-C.,U.S. National Cancer Institute | Marshall J.-C.,Center for Translational Research | Collins J.W.,U.S. National Cancer Institute | And 4 more authors.
Cancer Research | Year: 2013

Nm23-H1 has been identified as a metastasis suppressor gene, but its protein interactions have yet to be understood with any mechanistic clarity. In this study, we evaluated the proteomic spectrum of interactions made by Nm23-H1 in 4T1 murine breast cancer cells derived from tissue culture, primary mammary tumors, and pulmonary metastases. By this approach, we identified the actin-severing protein Gelsolin as binding partner for Nm23-H1, verifying their interaction by coimmunoprecipitation in 4T1 cells as well as in human MCF7, MDA-MB-231T, and MDA-MB-435 breast cancer cells. In Gelsolin-transfected cells, coexpression of Nm23-H1 abrogated the actin-severing activity of Gelsolin. Conversely, actin severing by Gelsolin was abrogated by RNA interference- mediated silencing of endogenous Nm23-H1. Tumor cell motility was negatively affected in parallel with Gelsolin activity, suggesting that Nm23-H1 binding inactivated the actin-depolymerizing function of Gelsolin to inhibit cell motility. Using indirect immunoflourescence to monitor complexes formed by Gelsolin and Nm23-H1 in living cells, we observed their colocalization in a perinuclear cytoplasmic compartment that was associated with the presence of disrupted actin stress fibers. In vivo analyses revealed that Gelsolin overexpression increased the metastasis of orthotopically implanted 4T1 or tail vein-injected MDA-MB-231T cells (P = 0.001 and 0.04, respectively), along with the proportion of mice with diffuse liver metastases, an effect ablated by coexpression of Nm23-H1. We observed no variation in proliferation among lung metastases. Our findings suggest a new actin-based mechanism that can suppress tumor metastasis. © 2013 American Association for Cancer Research.


Tully C.,Center for Translational Research | Aronow L.,Center for Translational Research | Mackey E.,Center for Translational Research | Mackey E.,George Washington University | And 2 more authors.
Current Diabetes Reports | Year: 2016

Youth with type 1 diabetes are at risk for developing cardiovascular disease, and regular physical activity is strongly recommended as one strategy for prevention, as well as for good glycemic control. Despite recommendations, families in this pediatric population face unique barriers to physical activity, including fear of hypoglycemia. Moreover, families are not routinely counseled in the specific health and psychosocial benefits of following physical activity recommendations for youth with type 1 diabetes. To bridge this gap, the recent literature regarding physical activity in children with type 1 diabetes is reviewed with particular focus on young children. A discussion of the limitations of the current body of research, and recommendations for objectively measured physical activity are provided. Specific recommendations for clinical practice are given, including provider endorsements for regular physical activity for longer than 60 minutes, at least three times a week. © 2016, Springer Science+Business Media New York.


Urtasun R.,Mount Sinai School of Medicine | Urtasun R.,Center for Translational Research | Cubero F.J.,Mount Sinai School of Medicine | Cubero F.J.,RWTH Aachen | Nieto N.,Mount Sinai School of Medicine
Alcoholism: Clinical and Experimental Research | Year: 2012

Background: Induction of reactive oxygen species (ROS) is a central mechanism in alcohol hepatotoxicity. Krüppel-like factor 6 (KLF6), a transcription factor and a tumor-suppressor gene, is an early-responsive gene to injury; however, the effect of ROS and alcohol on KLF6 induction is unknown. The aim of this study is to investigate the contribution of 2 sources of ROS, cytochrome P450 2E1 (CYP2E1), NAD(P)H quinone oxidoreductase (NQO1), and alcohol on the modulation of KLF6Full expression, splicing to KLF6_V1 and KLF6_V2, and the effect on TNFα, a downstream target. Methods and Results: Endogenous ROS production in CYP2E1-expressing HepG2 cells induced mRNA and protein expression of KLF6Full and its splice variants compared to control cells. Incubation with pro-oxidants such as arachidonic acid (AA), β-naphtoflavone, and H2O2 further enhanced KLF6Full and its splice variants. The AA effects on KLF6Full and its splice forms were blocked by vitamin E-which prevents lipid peroxidation-and by diallylsulfide-a CYP2E1 inhibitor. Menadione and paraquat, 2 pro-oxidants metabolized via NQO1, induced KLF6Full mRNA in a thiol-dependent manner. Antioxidants and an NQO1 inhibitor suppressed the menadione-dependent increase in KLF6Full and its splice variants mRNA. Furthermore, primary hepatocytes and livers from chronic alcohol-fed rats, with elevated lipid peroxidation, H2O2 and CYP2E1 but with low GSH, showed a ~2-fold increase in KLF6Full mRNA compared to controls. Inhibition of p38 phosphorylation further up-regulated the CYP2E1 and the AA effects on KLF6Full mRNA, whereas inhibition JNK and ERK1/2 phosphorylation decreased both. KLF6_V1 but not KLF6Full ablation markedly increased TNFα levels in macrophages; thus, TNFα emerges as a downstream target of KLF6_V1. Conclusions: The novel effect of ROS on modulating KLF6Full expression and its splice variants could play a relevant role in liver injury and in TNFα regulation. © 2012 by the Research Society on Alcoholism.


Duan L.,Rush University Medical Center | Danzer B.,Rush University Medical Center | Levenson V.V.,Rush University Medical Center | Levenson V.V.,Center for Translational Research | Maki C.G.,Rush University Medical Center
Cancer Letters | Year: 2014

Autophagy is a mechanism of tamoxifen (TAM) resistance in ER-positive (ER+) breast cancer cells. In this study, we showed in ER+ MCF7 cells that 4-hydroxytamoxifen (4OHTAM) induced cellular nitric oxide (NO) that negatively regulates cellular superoxide (O2-) and cytotoxicity. 4OHTAM stimulated LC3 lipidation and formation of monodansylcadaverine (MDC)-labeled autophagic vesicles dependent on O2-. Depletion of NO increased O2- and LC3 lipidation, yet reduced formation of MDC-labeled autophagic vesicles. Instead, NO-depleted cells formed remarkably large vacuoles with rims decorated by LC3. The vacuoles were not labeled by MDC or the acidic lysosome-specific fluorescence dye acridine orange (AO). The vacuoles were increased by the late stage autophagy inhibitor chloroquine, which also increased LC3 lipidation. These results suggest NO is required for proper autophagic vesicle formation or maturation at a step after LC3 lipidation. In addition, 4OHTAM induced O2--dependent activation of ERK, inhibition of which destabilized lysosomes/autolysosomes upon 4OHTAM treatment and together with depletion of NO led to necrotic cell death. These results suggest an essential role for endogenous NO and ERK activation in the completion of pro-survival autophagy. © 2014 Elsevier Ireland Ltd.


PubMed | Center for Translational Research
Type: Review | Journal: Current neurology and neuroscience reports | Year: 2016

Increasing knowledge on genetic etiology of pediatric neurologic disorders is affecting the practice of the specialty. I reviewed here the history of pediatric neurologic disorder classification and the role of genetics in the process. I also discussed the concept of clinical neurogenetics, with its role in clinical practice, education, and research. Finally, I propose a flexible model for clinical neurogenetics in child neurology in the twenty-first century. In combination with disorder-specific clinical programs, clinical neurogenetics can become a home for complex clinical issues, repository of genetic diagnostic advances, educational resource, and research engine in child neurology.

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