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Becknell B.,Research Institute at Nationwide Childrens Hospital | Schwaderer A.,Research Institute at Nationwide Childrens Hospital | Hains D.S.,Le Bonheur Childrens Hospital | Spencer J.D.,Research Institute at Nationwide Childrens Hospital
Nature Reviews Nephrology | Year: 2015

Urinary tract infections (UTIs), including pyelonephritis, are among the most common and serious infections encountered in nephrology practice. UTI risk is increased in selected patient populations with renal and urinary tract disorders. As the prevalence of antibiotic-resistant uropathogens increases, novel and alternative treatment options will be needed to reduce UTI-associated morbidity. Discoveries over the past decade demonstrate a fundamental role for the innate immune system in protecting the urothelium from bacterial challenge. Antimicrobial peptides, an integral component of this urothelial innate immune system, demonstrate potent bactericidal activity toward uropathogens and might represent a novel class of UTI therapeutics. The urothelium of the bladder and the renal epithelium secrete antimicrobial peptides into the urinary stream. In the kidney, intercalated cells - a cell-type involved in acid-base homeostasis - have been shown to be an important source of antimicrobial peptides. Intercalated cells have therefore become the focus of new investigations to explore their function during pyelonephritis and their role in maintaining urinary tract sterility. This Review provides an overview of UTI pathogenesis in the upper and lower urinary tract. We describe the role of intercalated cells and the innate immune response in preventing UTI, specifically highlighting the role of antimicrobial peptides in maintaining urinary tract sterility.


Mattoo T.K.,Wayne State University | Carpenter M.A.,University of North Carolina at Chapel Hill | Moxey-Mims M.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Chesney R.W.,Le Bonheur Childrens Hospital
Pediatric Nephrology | Year: 2015

Vesicoureteral reflux (VUR) increases the risk of urinary tract infection (UTI) and renal scarring. Many prospective studies have evaluated the role of antimicrobial prophylaxis in the prevention of recurrent UTI and renal scarring in children with VUR. Of these, the RIVUR trial was the largest, randomized, placebo-controlled, double blind, multicenter study, involving 607 children aged 2–72 months with grade I–IV VUR and a first or second symptomatic UTI. The median age of children in the RIVUR trial was 12 months, 92 % were female, 91 % were randomized after a first UTI, 86 % had a febrile index UTI, and 71 (56 %) of 126 toilet-trained children had bladder bowel dysfunction. Trimethoprim/sulfamethoxazole reduced the risk of UTI recurrences by 50 % (hazard ratio 0.50; 95 % confidence interval 0.34–0.74) as compared to placebo. No significant difference was seen in renal scarring between the two groups. However, this does not invalidate the role of prophylaxis in preventing renal scars because RIVUR and other recent prospective studies were not designed to address renal scarring as a primary study endpoint. In view of the RIVUR Trial and other studies that showed similar results, albeit in selected groups of patients, the debate on antimicrobial prophylaxis should shift from “no prophylaxis” to “selective prophylaxis” in children with VUR. © 2015, IPNA.


De Vincenzo J.P.,University of Tennessee Health Science Center | De Vincenzo J.P.,Le Bonheur Childrens Hospital
Antiviral Therapy | Year: 2012

Advances in the understanding of RNA biological processing and control are leading to new concepts in human therapeutics with practical implications for many human diseases, including antiviral therapy of respiratory viruses. So-called 'non-coding RNA' exerts specific and profound functional control on regulation of protein production and indeed controls the expression of all genes through processes collectively known as RNA interference (RNAi). RNAi is a naturally occurring intracellular process that regulates gene expression through the silencing of specific messenger RNAs (mRNAs). Methods are being developed that allow the catalytic degradation of targeted mRNAs using specifically designed complementary small interfering RNAs (siRNA). siRNAs are now being chemically modified and packaged into advanced delivery systems so as to acquire drug-like properties and the ability to deliver their effects systemically. Recent in vivo studies have provided proofs of the concept that RNAi may be useful therapeutically. Much of the design of these siRNAs can be accomplished bioinformatically, thus potentially expediting drug discovery and opening new avenues of therapy for many uncommon, orphan, or emerging diseases. Theoretically, any disease that can be ameliorated through knockdown of any endogenous or exogenous protein is a potential therapeutic target for RNAi-based therapeutics. Lung diseases in general are attractive targets for RNAi therapeutics, since the location of affected cells increases their accessibility to topical administration of siRNA, and respiratory viral infections are particularly attractive targets for RNAi-based drug discovery and development. RNAi therapeutics have been shown to exert potent antiviral effects against respiratory syncytial virus (RSV), parainfluenza, influenza, coronaviruses, measles and human metapneumoviruses in vitro and in vivo. Recently, a double-blind placebo-controlled clinical trial of an RNAi-based therapeutic against RSV demonstrated that this technology has therapeutic activity, representing the first proof-of-concept test of efficacy for RNAi's therapeutic effect in humans. This review discusses the science behind RNAi and the potential practical issues in applying this technology to various respiratory viral diseases. © 2012 International Medical Press.


We evaluate the clinical performance of the Luminex xTAG gastrointestinal (GI) pathogen in vitro diagnostic (IVD) assay in a comparison between clinical and public health laboratories. The site reproducibility study showed 98.7% sensitivity with high positive and negative agreement values (96.2% and 99.8%, respectively), while assay performance against confirmatory methods resulted in 96.4% sensitivity with similar positive and negative agreement values (90.1% and 99.5%, respectively). High-throughput detection of multiple GI pathogens improved turnaround time, consolidated laboratory workflow, and simplified stool culture practices, thus reducing the overall cost and number of specimens processed. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


DeVincenzo J.P.,University of Memphis | DeVincenzo J.P.,Le Bonheur Childrens Hospital | Whitley R.J.,University of Alabama at Birmingham | Mackman R.L.,Gilead Sciences | And 14 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists. METHODS: We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores. RESULTS: Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] x hours per milliliter; P<0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P = 0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 x hours; P = 0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806. CONCLUSIONS: Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. Copyright © 2014 Massachusetts Medical Society.


Parvaneh N.,Tehran University of Medical Sciences | Casanova J.-L.,Rockefeller University | Casanova J.-L.,University of Paris Descartes | Notarangelo L.D.,Harvard University | And 2 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

The characterization of primary immunodeficiencies (PIDs) in human subjects is crucial for a better understanding of the biology of the immune response. New achievements in this field have been possible in light of collaborative studies; attention paid to new phenotypes, infectious and otherwise; improved immunologic techniques; and use of exome sequencing technology. The International Union of Immunological Societies Expert Committee on PIDs recently reported on the updated classification of PIDs. However, new PIDs are being discovered at an ever-increasing rate. A series of 19 novel primary defects of immunity that have been discovered after release of the International Union of Immunological Societies report are discussed here. These new findings highlight the molecular pathways that are associated with clinical phenotypes and suggest potential therapies for affected patients. © 2013 American Academy of Allergy, Asthma & Immunology.


Khazaee A.,Babol Noshirvani University of Technology | Ebrahimzadeh A.,Babol Noshirvani University of Technology | Babajani-Feremi A.,University of Tennessee Health Science Center | Babajani-Feremi A.,Le Bonheur Childrens Hospital
Clinical Neurophysiology | Year: 2015

Objective: Study of brain network on the basis of resting-state functional magnetic resonance imaging (fMRI) has provided promising results to investigate changes in connectivity among different brain regions because of diseases. Graph theory can efficiently characterize different aspects of the brain network by calculating measures of integration and segregation. Method: In this study, we combine graph theoretical approaches with advanced machine learning methods to study functional brain network alteration in patients with Alzheimer's disease (AD). Support vector machine (SVM) was used to explore the ability of graph measures in diagnosis of AD. We applied our method on the resting-state fMRI data of twenty patients with AD and twenty age and gender matched healthy subjects. The data were preprocessed and each subject's graph was constructed by parcellation of the whole brain into 90 distinct regions using the automated anatomical labeling (AAL) atlas. The graph measures were then calculated and used as the discriminating features. Extracted network-based features were fed to different feature selection algorithms to choose most significant features. In addition to the machine learning approach, statistical analysis was performed on connectivity matrices to find altered connectivity patterns in patients with AD. Results: Using the selected features, we were able to accurately classify patients with AD from healthy subjects with accuracy of 100%. Conclusion: Results of this study show that pattern recognition and graph of brain network, on the basis of the resting state fMRI data, can efficiently assist in the diagnosis of AD. Significance: Classification based on the resting-state fMRI can be used as a non-invasive and automatic tool to diagnosis of Alzheimer's disease. © 2015 International Federation of Clinical Neurophysiology.


Jacobs J.D.,University of Tennessee Health Science Center | Jacobs J.D.,Le Bonheur Childrens Hospital | Foster M.,University of Tennessee Health Science Center | Wan J.,University of Tennessee Health Science Center | And 2 more authors.
Pediatrics | Year: 2014

BACKGROUND: Research suggests that hypertonic saline (HS) may improve mucous flow in infants with acute bronchiolitis. Data suggest a trend favoring reduced length of hospital stay and improved pulmonary scores with increasing concentration of nebulized solution to 3% and 5% saline as compared with 0.9% saline mixed with epinephrine. To our knowledge, 7% HS has not been previously investigated. METHODS: We conducted a prospective, double-blind, randomized controlled trial in 101 infants presenting with moderate to severe acute bronchiolitis. Subjects received either 7% saline or 0.9% saline, both with epinephrine. Our primary outcome was a change in bronchiolitis severity score (BSS), obtained before and after treatment, and at the time of disposition from the emergency department (ED). Secondary outcomes measured were hospitalization rate, proportion of admitted patients discharged at 23 hours, and ED and inpatient length of stay. RESULTS: At baseline, study groups were similar in demographic and clinical characteristics. The decrease in mean BSS was not statistically significant between groups (2.6 vs 2.4 for HS and control groups, respectively). The difference between the groups in proportion of admitted patients (42% in HS versus 49% in normal saline), ED or inpatient length of stay, and proportion of admitted patients discharged at 23 hours was not statistically significant. CONCLUSIONS: In moderate to severe acute bronchiolitis, inhalation of 7% HS with epinephrine does not appear to confer any clinically significant decrease in BSS when compared with 0.9% saline with epinephrine. Copyright © 2014 by the American Academy of Pediatrics.


Bridges D.,University of Tennessee Health Science Center | Bridges D.,Le Bonheur Childrens Hospital | Saltiel A.R.,University of Michigan
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2015

Abstract Phosphoinositides are key players in many trafficking and signaling pathways. Recent advances regarding the synthesis, location and functions of these lipids have dramatically improved our understanding of how and when these lipids are generated and what their roles are in animal physiology. In particular, phosphoinositides play a central role in insulin signaling, and manipulation of PtdIns(3,4,5)P3 levels in particular, may be an important potential therapeutic target for the alleviation of insulin resistance associated with obesity and the metabolic syndrome. In this article we review the metabolism, regulation and functional roles of phosphoinositides in insulin signaling and the regulation of energy metabolism. This article is part of a Special Issue entitled Phosphoinositides. © 2014 Elsevier B.V. All rights reserved.


Hoberman A.,University of Pittsburgh | Greenfield S.P.,Children's Hospital of Buffalo | Mattoo T.K.,Wayne State University | Keren R.,Children's Hospital of Philadelphia | And 7 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial. METHODS: In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim-sulfamethoxazole prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance. RESULTS: Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. CONCLUSIONS: Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring. Copyright © 2014 Massachusetts Medical Society.

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