Research Institute at Nationwide Childrens

Columbus, OH, United States

Research Institute at Nationwide Childrens

Columbus, OH, United States
Time filter
Source Type

Spencer J.D.,Ohio State University | Spencer J.D.,Research Institute at Nationwide Childrens | Jackson A.R.,Ohio State University | Li B.,Research Institute at Nationwide Childrens | And 8 more authors.
PLoS ONE | Year: 2015

Recent evidence indicates that antimicrobial peptides (AMPs) serve key roles in defending the urinary tract against invading uropathogens. To date, the individual contribution of AMPs to urinary tract host defense is not well defined. In this study, we identified Regenerating islet-derived 3 gamma (RegIIIγ) as the most transcriptionally up-regulated AMP in murine bladder transcriptomes following uropathogenic Escherichia coli (UPEC) infection. We confirmed induction of RegIIIγ mRNA during cystitis and pyelonephritis by quantitative RT-PCR. Immunoblotting demonstrates increased bladder and urinary RegIIIγ protein levels following UPEC infection. Immunostaining localizes RegIIIγ protein to urothelial cells of infected bladders and kidneys. Human patients with UTI have increased urine concentrations of the orthologous Hepatocarcinoma-Intestine-Pancreas / Pancreatitis Associated Protein (HIP/PAP) compared to healthy controls. Recombinant RegIIIγ protein does not demonstrate bactericidal activity toward UPEC in vitro, but does kill Staphylococcus saprophyticus in a dose-dependent manner. Kidney and bladder tissue from RegIIIγ knockout mice and wild-type mice contain comparable bacterial burden following UPEC and Grampositive UTI. Our results demonstrate that RegIIIγ and HIP/PAP expression is induced during human and murine UTI. However, their specific function in the urinary tract remains uncertain. © 2015 Spencer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Kerlin B.A.,Research Institute at Nationwide Childrens | Kerlin B.A.,Case Western Reserve University | Waller A.P.,Research Institute at Nationwide Childrens | Sharma R.,Research Institute at Nationwide Childrens | And 5 more authors.
Journal of the American Society of Nephrology | Year: 2015

Thrombotic disease, a major life-threatening complication of nephrotic syndrome, has been associated with proteinuria and hypoalbuminemia severity. However, it is not fully understood how disease severity correlates with severity of the acquired hypercoagulopathy of nephrotic syndrome. Without this knowledge, the utility of proteinuria and/or hypoalbuminemia as biomarkers of thrombotic risk remains limited. Here, we show that two well established ex vivo hypercoagulopathy assays, thrombin generation and rotational thromboelastometry, are highly correlated with proteinuria and hypoalbuminemia in the puromycin aminonucleoside and adriamycin rat models of nephrotic syndrome. Notably, in the puromycin aminonucleosidemodel, hyperfibrinogenemia and antithrombin deficiency were also correlated with proteinuria severity, consistentwith reports in human nephrotic syndrome. Importantly, although coagulation was not spontaneously activated in vivo with increasing proteinuria, vascular injury induced a more robust thrombotic response in nephrotic animals. In conclusion, hypercoagulopathy is highly correlated with nephrotic disease severity, but overt thrombosis may require an initiating insult, such as vascular injury. Our results suggest that proteinuria and/or hypoalbuminemia could be developed as clinicallymeaningful surrogate biomarkers of hypercoagulopathy to identify patients with nephrotic syndrome at highest risk for thrombotic disease and potentially target them for anticoagulant pharmacoprophylaxis. Copyright © 2015 by the American Society of Nephrology.

Kerlin B.A.,Research Institute at Nationwide Childrens | Kerlin B.A.,Ohio State University | Stephens J.A.,Ohio State University | Hogan M.J.,Ohio State University | And 4 more authors.
Pediatric Research | Year: 2015

Background:Pediatric venous thromboembolism (VTE) is an increasingly common, difficult to diagnose problem. Clinical probability tools (CPT) for adults estimate VTE likelihood, but are not available for children. We hypothesized that a pediatric-specific CPT is feasible.Methods:Radiology reports were utilized to identify children imaged for suspected VTE. Relevant signs, symptoms, and comorbidity variables, identified from published literature, were extracted from corresponding medical records. Variables associated with pediatric VTE were incorporated into a multivariate logistic regression to create a pilot CPT which was confirmed on a separate cohort.Results:A total of 389 subjects meeting inclusion criteria were identified: 91 with VTE and 298 without. Univariate analysis revealed male gender (odds ratio (OR) = 2.96; P < 0.001), asymmetric extremity (OR = 1.76; P = 0.033), central venous catheter utilization and/or dysfunction (OR = 2.51; P < 0.001), and cancer (OR = 2.35; P = 0.014) as VTE predictive variables. Documentation of an alternate diagnosis was inversely related to VTE (OR = 0.42; P = 0.004). Receiver operating characteristic analysis of the derived CPT demonstrated reasonable ability to discriminate VTE probability in the training cohort (area under the curve (AUC) = 0.73; P < 0.001) and moderate discrimination in a separate validation cohort of 149 children (AUC = 0.64; P = 0.011).Conclusion:A pediatric-specific VTE CPT is feasible, would facilitate early diagnosis, and could lead to improved outcomes. Copyright © 2015 International Pediatric Research Foundation, Inc.

Becknell B.,Nationwide Childrens Hospital | Becknell B.,Ohio State University | Becknell B.,Research Institute at Nationwide Childrens | Mohamed A.Z.,University of Louisville | And 5 more authors.
PLoS ONE | Year: 2015

Purpose Urinary stasis is a risk factor for recurrent urinary tract infection (UTI). Homozygous mutant Megabladder (Mgb-/-) mice exhibit incomplete bladder emptying as a consequence of congenital detrusor aplasia. We hypothesize that this predisposes Mgb-/- mice to spontaneous and experimental UTI. Methods Mgb-/-, Mgb+/-, and wild-type female mice underwent serial ultrasound and urine cultures at 4, 6, and 8 weeks to detect spontaneous UTI. Urine bacterial isolates were analyzed by Gram stain and speciated. Bladder stones were analyzed by x-ray diffractometry. Bladders and kidneys were subject to histologic analysis. The pathogenicity of coagulase-negative Staphylococcus (CONS) isolated from Mgb-/- urine was tested by transurethral administration to culture-negative Mgb-/- or wild-type animals. The contribution of urinary stasis to CONS susceptibility was evaluated by cutaneous vesicostomy in Mgb-/- mice. Results Mgb-/- mice develop spontaneous bacteriuria (42%) and struvite bladder stones (31%) by 8 weeks, findings absent in Mgb+/- and wild-type controls. CONS was cultured as a solitary isolate from Mgb-/- bladder stones. Bladders and kidneys from mice with struvite stones exhibit mucosal injury, inflammation, and fibrosis. These pathologic features of cystitis and pyelonephritis are replicated by transurethral inoculation of CONS in culture-negative Mgb-/- females, whereas wild-type animals are less susceptible to CONS colonization and organ injury. Cutaneous vesicostomy prior to CONS inoculation significantly reduces the quantity of CONS recovered from Mgb-/- urine, bladders, and kidneys. © 2015 Becknell et al.

Korbel L.,Ohio State University | Spencer J.D.,Research Institute at Nationwide Childrens
Journal of Diabetes and its Complications | Year: 2015

Aims The objective of this study is to evaluate the number of diabetics that seek medical treatment in emergency departments or require hospitalization for infection management in the United States. This study also assesses the socioeconomic impact of inpatient infection management among diabetics. Methods We accessed the Healthcare Cost and Utilization Project's Nationwide Emergency Department Sample database and the Nationwide Inpatient Sample database to perform a retrospective analysis on diabetics presenting to the emergency department or hospitalized for infection management from 2006 to 2011. Results Emergency Department: Since 2006, nearly 10 million diabetics were annually evaluated in the emergency department. Infection was the primary reason for presentation in 10% of these visits. Among those visits, urinary tract infection was the most common infection, accounting for over 30% of emergency department encounters for infections. Other common infections included sepsis, skin and soft tissue infections, and pneumonia. Diabetics were more than twice as likely to be hospitalized for infection management than patients without diabetes. Hospitalization: Since 2006, nearly 6 million diabetics were annually hospitalized. 8-12% of these patients were hospitalized for infection management. In 2011, the inpatient care provided to patients with DM, and infection was responsible for over $48 billion dollars in aggregate hospital charges. Conclusions Diabetics commonly present to the emergency department and require hospitalization for infection management. The care provided to diabetics for infection management has a large economic impact on the United States healthcare system. More efforts are needed to develop cost-effective strategies for the prevention of infection in patients with diabetes. © 2015 Elsevier Inc. All rights reserved.

Kerlin B.A.,Ohio State University | Kerlin B.A.,Research Institute at Nationwide Childrens | Kerlin B.A.,Nationwide Childrens Hospital | Haworth K.,Nationwide Childrens Hospital | And 3 more authors.
Pediatric Nephrology | Year: 2014

Childhood nephrotic syndrome (NS) is one of the most common pediatric kidney diseases, with an incidence of 2-7 per 100,000. Venous thromboembolism (VTE) is associated with significant morbidity and mortality, and occurs in ∼3 % of children with NS, though incidence approaches 25 % in high-risk groups. VTE etiology is multifactorial, with disease-associated coagulopathy thought to be a significant contributor. Other risks include age, disease severity, and treatment-related hazards, such as the presence of central venous catheters. Non-pharmacologic preventive measures such as ambulation and compression stockings are recommended for patients with identified VTE risks. Central venous catheters should be avoided whenever possible. Symptoms of VTE include venous catheter dysfunction, unilateral extremity symptoms, respiratory compromise, flank pain, and gross hematuria. When VTE is suspected, confirmatory imaging studies should be obtained, followed by appropriate laboratory evaluation and treatment. Therapeutic goals include limiting thrombus growth, extension, and embolization by early institution of anticoagulant therapy. Anticoagulation is recommended for a minimum of 3 months, but should be continued until NS remission is achieved. Further studies are necessary to identify VTE-risk biomarkers and optimal therapeutic regimens. Observational cohort studies are needed to identify VTE-risk groups who may benefit from thromboprophylaxis and to define disease-specific treatment algorithms. © 2013 IPNA.

Loading Research Institute at Nationwide Childrens collaborators
Loading Research Institute at Nationwide Childrens collaborators