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Jadcherla S.R.,Ohio State University | Jadcherla S.R.,Nationwide Childrens Hospital Research Institute | Wang M.,Nationwide Childrens Hospital Research Institute | Vijayapal A.S.,Medical College of Wisconsin | Leuthner S.R.,Medical College of Wisconsin
Journal of Perinatology | Year: 2010

Objective: Feeding problems are an important area of neonatal morbidity that requires attention. We defined the feeding milestones related to transition to per oral feeding among premature infants based on gestational (GA) and postmenstrual ages (PMA), and elucidated the co-morbidity variables affecting with these skills. Study Design: Feeding progress was tracked during the first hospitalization in a retrospective study involving 186 infants. We measured the age at acquisition of first feedings, maximum gavage feedings and maximum oral feedings. Resource usage measures included the total length of hospital stay (LOS), duration of gavage tube and duration of respiratory support. Effects of perinatal and co-morbidity factors on the acquisition of feeding milestones were evaluated. ANOVA, t-test, Wilcoxon rank sum test, χ2 test, univariate and multivariate analysis, stepwise linear regression analysis and logistic regression analysis were applied as appropriate. Data were presented as mean±s.d., or as stated. P<0.05 was considered significant. Result: We stratified the data into three groups based on GA at birth: <28.0 weeks (group-1), 28.0 to 32.0 weeks (group-2) and 32.0 to 35.0 weeks (group-3). Compared with group-3, group-1 needed four-fold more ventilation and five-fold more continuous positive airway pressure (CPAP) duration (all P<0.001); whereas group-2 needed two-fold more CPAP duration. Age at first feed correlated with age at full gavage feedings and age at full oral feedings (r=0.53 and r=0.71, both P<0.0001). Age at full gavage feedings correlated with age at full oral feedings (r=0.81, P<0.0001). Univariate analysis was significant for GA age, hypotension, the effects of gastroesophageal reflux, and duration of ventilation and CPAP on the PMA at maximal oral feedings (all P<0.05); multivariate analysis for these variables was also significant (R 2=0.58, P<0.0001). The success rate for oral feedings at discharge accelerated with GA maturation and caffeine use; on the other hand, the need for respiratory support and management of positive blood culture were associated with failure rates (P<0.05). Conclusion: Infants < 28 weeks GA have significant feeding delays with respect to initiation and progression to maximal gavage and oral feedings, as well as prolonged LOS. Infants >28 weeks GA attained successful feeding milestones by similar PMA. Specific aero-digestive co-morbidities significantly affected maximal oral feeding milestone. Delays in achieving maximum gavage and maximum oral feeding milestones suggest delays with the development of control and regulation of foregut motility. © 2010 Nature Publishing Group All rights reserved.


Miranda C.J.,Nationwide Childrens Hospital Research Institute | Braun L.,Nationwide Childrens Hospital Research Institute | Jiang Y.,Nationwide Childrens Hospital Research Institute | Hester M.E.,Nationwide Childrens Hospital Research Institute | And 7 more authors.
Aging Cell | Year: 2012

Accumulating evidence suggests that adult hippocampal neurogenesis relies on the controlled and continued proliferation of neural progenitor cells (NPCs). With age, neurogenesis decreases through mechanisms that remain unclear but are believed to involve changes in the NPC microenvironment. Here, we provide evidence that NPC proliferation in the adult brain is in part regulated by astrocytes via Wnt signaling and that this cellular cross-talk is modified in the aging brain, leading to decreased proliferation of NPCs. Furthermore, we show that astrocytes regulate the NPC cell cycle by acting on the expression levels of survivin, a known mitotic regulator. Among cell cycle genes found down-regulated in aged NPCs, survivin was the only one that restored NPC proliferation in the aged brain. Our results provide a mechanism for the gradual loss of neurogenesis in the brain associated with aging and suggest that targeted modulation of survivin expression directly or through Wnt signaling could be used to stimulate adult neurogenesis. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.


Kerlin B.A.,Nationwide Childrens Hospital | Kerlin B.A.,Ohio State University | Kerlin B.A.,Nationwide Childrens Hospital Research Institute
American Journal of Hematology | Year: 2012

Venous thromboembolism (VTE) is an increasingly common complication encountered in tertiary care pediatric settings. The purpose of this review is to summarize the epidemiology, current and emerging pharmacotherapeutic options, and management of this disease. Over 70% of VTE occur in children with chronic diseases. Although they are seen in children of all ages, adolescents are at greatest risk. Pediatric VTE is associated with an increased risk of in-hospital mortality; recurrent VTE and post-thrombotic syndrome are commonly seen in survivors. In recent years, anticoagulation with low molecular weight heparin has emerged as the mainstay of therapy, but compliance is limited by its onerous subcutaneous administration route. New anticoagulants either already approved for use in adults or in the pipeline offer the possibility of improved dose stability and oral routes of administration. Current recommended anticoagulation course durations are derived from very limited case series and cohort data, or extrapolations from adult literature. However, the pathophysiologic underpinnings of pediatric VTE are dissimilar from those seen in adults and are often variable within groups of pediatric patients. Clinical studies and trials in pediatric VTE are underway which will hopefully improve the quality of evidence from which therapeutic guidelines are derived. © 2012 Wiley Periodicals, Inc.


Armstrong K.R.,Ohio State University | Armstrong K.R.,Nationwide Childrens Hospital Research Institute | Chamberlin H.M.,Ohio State University
Molecular Genetics and Genomics | Year: 2010

Excretory renal organs are critical in animals for osmoregulation and the elimination of waste. Renal organs across a range of species exhibit cellular and molecular similarities. For example, class III POU-homeodomain transcription factors are expressed in the renal organs of many invertebrates and vertebrates. However, the functional role for these factors is not well characterized. To better understand the role of class III POU-homeodomain proteins in animal excretory systems, we have characterized a set of genes expressed in the Caenorhabditis elegans excretory cell, and determined their regulation by the POU-III transcription factor CEH-6. Our molecular and biochemical studies show that CEH-6 regulates a subset of genes expressed in the excretory cell. Additionally, we find that the CEH-6-dependent genes share two molecular features: They contain at least one octamer regulatory element and they encode for transport and channel proteins. This work suggests that a role for POU-III factors in renal organs is to coordinate the expression of a set of functionally related genes. © 2009 Springer-Verlag.


Jadcherla S.R.,Ohio State University | Jadcherla S.R.,Nationwide Childrens Hospital Research Institute | Chan C.Y.,Nationwide Childrens Hospital Research Institute | Moore R.,Nationwide Childrens Hospital Research Institute | And 4 more authors.
Journal of Parenteral and Enteral Nutrition | Year: 2012

Background. Feeding difficulties and gastroesophageal reflux (GER) are common problems in neonates. The authors hypothesize that GER could be influenced by feeding mechanics by evaluating the effects of feeding volumes, feeding durations, feeding flow rates, and caloric density on the chemical composition and clearance of GER in dysphagic neonates. Methods: Symptomatic dysphagic neonates (n = 35) underwent evaluation for suspected GER using pH-impedance methods. Results: The proportions of acid and nonacid GER were different during the first, second, and third postprandial hours (P <.0001). Prolonged feeding duration was significantly associated with decreased total, nonacid GER and BCT (P <.03). Significant positive correlations (P <.05) were detected between feeding flow rate vs frequency of total, nonacid GER and BCT. Significant positive correlation (P =.002) was noted between feeding volume and BCT. BCT decreased with each hourly interval (analysis of variance [ANOVA] P <.05); however, ACT increased with each hourly interval (ANOVA P =.05). Comparison between BCT and ACT at each postprandial hour is remarkable for longer ACT during the second and third hours after the initiation of feed (P ≤.001). No significant correlation was noted between the milk types (breast milk or formula) or caloric density with regard to the GER characteristics. Oral-fed infants had more GER events than gavage-fed infants. Conclusions: Prolonged feeding durations and slower flow rates are associated with decreased frequency of GER. Modification of feeding duration and flow rate can be a useful adjunct to ameliorate GER in dysphagic neonates. © 2012 American Society for Parenteral and Enteral Nutrition.


Hasenstab K.A.,Nationwide Childrens Hospital Research Institute | Jadcherla S.R.,Nationwide Childrens Hospital Research Institute | Jadcherla S.R.,Ohio State University
Journal of Pediatrics | Year: 2014

Objective To test the hypothesis that proximal aerodigestive clearance mechanisms mediated by pharyngoesophageal motility during spontaneous respiratory events (SREs) are distinct in infants with apparent life threatening events (ALTEs). Study design Twenty infants (10 with proven ALTE, 10 healthy controls) had pharyngoesophageal manometry to investigate motility changes concurrent with respiratory events detected by respiratory inductance plethysmography and nasal thermistor methods. We measured changes in resting upper esophageal and lower esophageal sphincter pressures, esophageal peristalsis characteristics, and gastroesophageal reflux. Statistical analysis included mixed models; data presented as mean ± SD, median (range), or percentage. Results Infants with ALTE (vs controls) had: (1) delays in restoring aerodigestive normalcy as indicated by more frequent (P =.03) and prolonged SREs (P <.01); (2) a lower magnitude of protective upper esophageal sphincter contractile reflexes (P =.01); (3) swallowing as the most frequent esophageal event associated with SREs (84%), with primary peristalsis as the most prominent aerodigestive clearance mechanism (64% vs 38%, P <.01); (4) a higher proportion of failed esophageal propagation (10% vs 0%, P =.02); and (5) more frequent mixed apneic mechanisms (P <.01) and more gasping breaths (P =.04). Conclusions In infants with ALTE, prolonged SREs are associated with ineffective esophageal motility characterized by frequent primary peristalsis and significant propagation failure, thus suggestive of dysfunctional regulation of swallow-respiratory junction interactions. Hence, treatment should not target gastroesophageal reflux, but rather the proximal aerodigestive tract. Copyright © 2014 Elsevier Inc. All rights reserved.


Setty B.A.,Nationwide Childrens Hospital | Setty B.A.,Ohio State University | O'Brien S.H.,Nationwide Childrens Hospital | O'Brien S.H.,Ohio State University | And 4 more authors.
Pediatric Blood and Cancer | Year: 2012

Background: Pediatric venous thromboembolism (VTE) is an increasingly common problem. We hypothesized that VTE occurs most commonly in tertiary care settings and that the pattern of associated illnesses may have changed from earlier reports. Methods: The Kids' Inpatient Database 2006 was utilized to identify children ≤18 years old with in-hospital VTE. Children were identified by the presence of thrombosis specific ICD-9-CM diagnosis or procedure codes. Remaining ICD-9-CM codes were utilized to categorize patients by acute or chronic illness. The incidence of in-hospital VTE by hospital type, age, gender, race, and disposition were estimated. Results: Over 4,500 children met the inclusion criteria (188/100,000 discharges). Most VTE discharges (67.5%) were from children's hospitals (RR 5.09; 95% CI 4.76; 5.44). Underlying chronic illnesses were associated with most VTE (76.2%), most commonly: cardiovascular (18.4%), malignancy (15.7%), and neuromuscular disease (9.9%). VTE not associated with chronic illness were most often idiopathic (12.6%), followed by infections (9.5%), and trauma (9.1%). The greatest proportions of children with VTE were infants (23.1%) and adolescents (37.8%). However, when standardized against the entire database of discharges, infants were least likely to develop VTE (RR 0.48; 95% CI 0.43; 0.52), while adolescents were at highest risk (RR 1.89; 95% CI 1.73; 2.07). Hospitalizations ending with death were more likely to include VTE (RR 6.16; 95% CI 5.32; 7.13). Conclusions: Pediatric VTE is most commonly seen in tertiary care. Adolescents are at greatest risk to develop in-hospital VTE. Patients whose hospitalization ended with death are at much greater risk to develop VTE. © 2011 Wiley Periodicals, Inc..


Kelly L.E.,Nationwide Childrens Hospital Research Institute | El-Hodiri H.M.,Nationwide Childrens Hospital Research Institute | El-Hodiri H.M.,Ohio State University
Development Genes and Evolution | Year: 2016

Nkx5 family members are homeobox transcription factors important for sensory organ development. Several members of the Nkx5 family are expressed in the eye, brain, developing ear, and lateral line. Members of this family have been previously identified in medaka, chick, and mouse. Here, we characterize two members of the Nkx5 family, Nkx5.3 and SOHo, in Xenopus laevis. We verify the identity of X. laevis Nkx5.3 and SOHo by phylogenetic comparison to chicken, medaka, and zebrafish orthologs. Both Nkx5.3 and SOHo are expressed in the developing eye, ear, lateral line system, and cranial neurons as determined by in situ hybridization. © 2016 Springer-Verlag Berlin Heidelberg


Arango J.I.,Barrow Neurological Institute | Deibert C.P.,University of Pittsburgh | Brown D.,Barrow Neurological Institute | Bell M.,University of Pittsburgh | And 2 more authors.
Child's Nervous System | Year: 2012

Purpose Traumatic brain injury (TBI) remains a leading cause of childhood death and disability worldwide. Seizures are a common complication of TBI and they are particularly common in pediatric populations. The proper management of children sustaining severe TBI is still controversial. Our study aims to share our experience contributing to build evidence for better care Methods Retrospective chart review was performed on individuals ages 0 to <18 who presented to a level 1 trauma center during a 10-year period with the diagnosis of severe TBI. Data analyzed included patient's demographics, event information, clinical and radiological presentation, management, and midterm follow-up. Presence of seizures was tracked through EEG monitoring, staff witnessing, or guardian referral. Results The incidence of early posttraumatic seizures (EPTS) observed in our population (19%) exceeds those previously reported. Such findings likely reflect the importance of close monitoring including EEG. An association between the presence of EPTS and the development of late posttraumatic seizures (LPTS) was evidenced (p00.001; 95% CI 2.2, 16.5), while this association should not be assumed as a measure of causality, it should be considered for the management of patients presenting EPTS. Nonaccidental trauma and young age were identified as independent predictors for the development of seizures. Conclusions Seizures are a common complication of severe TBI among children aged 0-3 years. Given the detrimental effects that seizures produce on the injured brain, close observation and appropriate monitoring with EEG are essential for the management of children sustaining severe TBI. © Springer-Verlag 2012.


Rocco K.A.,Yale University | Maxfield M.W.,Yale University | Best C.A.,Nationwide Childrens Hospital Research Institute | Dean E.W.,Yale University | Breuer C.K.,Nationwide Childrens Hospital Research Institute
Tissue Engineering - Part B: Reviews | Year: 2014

There is great clinical demand for synthetic vascular grafts with improved long-term efficacy. The ideal vascular conduit is easily implanted, nonthrombogenic, biocompatible, resists aneurysmal dilatation, and ultimately degrades or is assimilated as the patient remodels the graft into tissue resembling native vessel. The field of vascular tissue engineering offers an opportunity to design the ideal synthetic graft, and researchers have evaluated a variety of methods and materials for use in graft construction. Electrospinning is one method that has received considerable attention within tissue engineering for constructing so-called tissue scaffolds. Tissue scaffolds are temporary, porous structures which are commonly composed of bioresorbable polymers that promote native tissue ingrowth and have degradation kinetics compatible with a patient's rate of extracellular matrix production in order to successfully transit from synthetic conduits into neovessels. In this review, we summarize the history of tissue-engineered vascular grafts (TEVG), focusing on scaffolds generated by the electrospinning process, and discuss in vivo applications. We review the materials commonly employed in this approach and the preliminary results after implantation in animal models in order to gauge clinical viability of the electrospinning process for TEVG construction. Scientists have studied electrospinning technology for decades, but only recently has it been orthotopically evaluated in animal models such as TEVG. Advantages of electrospun TEVG include ease of construction, favorable cellular interactions, control of scaffold features such as fiber diameter and pore size, and the ability to choose from a variety of polymers possessing a range of mechanical and chemical properties and degradation kinetics. Given its advantages, electrospinning technology merits investigation for use in TEVG, but an emphasis on long-term in vivo evaluation is required before its role in clinical vascular tissue engineering can be realized. © 2014, Mary Ann Liebert, Inc.

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