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De Leon D.D.,Childrens Hospital of Philadelphia | De Leon D.D.,University of Pennsylvania | De Leon D.D.,Abramson Research Center | Stanley C.A.,Childrens Hospital of Philadelphia | Stanley C.A.,University of Pennsylvania
Best Practice and Research: Clinical Endocrinology and Metabolism

Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. The diagnosis of hyperinsulinemic hypoglycemia relies on the evaluation of the biochemical profile at the time of hypoglycemia, however, contrary to common perception, plasma insulin is not always elevated. Thus, the diagnosis must often be based on the examination of other physiologic manifestations of excessive insulin secretion, such as suppression of glycogenolysis, lipolysis and ketogenesis, which can be inferred by the finding of a glycemic response to glucagon, and the suppression of plasma free fatty acids and beta-hydroxybutyrate concentrations during hypoglycemia. © 2013 Elsevier Ltd. All rights reserved. Source

Tsai J.,Childrens Hospital of Philadelphia | Sulkowski J.,Childrens Hospital of Philadelphia | Adzick N.S.,Childrens Hospital of Philadelphia | Hedrick H.L.,Childrens Hospital of Philadelphia | And 2 more authors.
Journal of Pediatric Surgery

Background: Large congenital diaphragmatic hernia (CDH) defects often require the use of synthetic patches for tension-free repair. Although high rates of recurrence and other morbidities have been previously reported, our favorable perception of patch repair prompted this review. Methods: A single-center retrospective chart review of CDH cases repaired between January 1, 1999, and October 1, 2010. Patch repairs were performed by multiple surgeons with an effort to construct a tension-free dome-shaped patch. Results: One hundred eighty-four children underwent CDH repair of whom 99 (53.8%) required a patch. Seventy-four (74.7%) of the 99 patients who underwent patch repair survived to discharge and were compared with 75 primary repair survivors. Of those undergoing patch repair, 88% were prenatally diagnosed, 55% had liver herniation, and 22 (29.9%) were repaired on extracorporeal membrane oxygenation. Two patients experienced a recurrence after a patch repair and 3 after a primary repair for a rate of 5.4% and 4.0%, respectively (P = 1.0). Conclusions: These results demonstrate that synthetic patch repair for CDH can be performed with a very low rate of recurrence challenging the need for alternative approaches to diaphragmatic replacement. High rates of recurrence reported for patch repair may be technical rather than intrinsic to the patch. © 2012 Elsevier Inc. Source

Cho G.,Childrens Hospital of Philadelphia | Nasrallah M.P.,University of Pennsylvania | Lim Y.,University of Pennsylvania | Golden J.A.,Childrens Hospital of Philadelphia | And 2 more authors.

Mutations in the Aristaless-related homeobox gene (ARX) are associated with a wide variety of neurologic disorders including lissencephaly, hydrocephaly, West syndrome, Partington syndrome, and X-linked intellectual disability with or without epilepsy. A genotype - phenotype correlation exists for ARX mutations; however, the molecular basis for this association has not been investigated. To begin understanding the molecular basis for ARX mutations, we tested the DNA binding sequence preference and transcriptional repression activity for Arx, deletion mutants and mutants associated with various neurologic disorders. We found DNA binding preferences of Arx are influenced by the amino acid sequences adjacent to the homeodomain. Mutations in the homeodomain show a loss of DNA binding activity, while the T333N and P353R homeodomain mutants still possess DNA binding activities, although less than the wild type. Transcription repression activity, the primary function of ARX, is reduced in all mutants except the L343Q, which has no DNA binding activity and does not functionally repress Arx targets. These data indicate that mutations in the homeodomain result in not only a loss of DNA binding activity but also loss of transcriptional repression activity. Our results provide novel insights into the pathogenesis of ARX-related disorders and possible directions to pursue potential therapeutic interventions. © Springer-Verlag 2012. Source

Schrenk S.,Kaiserslautern University of Applied Sciences | Schuster A.,Kaiserslautern University of Applied Sciences | Klotz M.,Kaiserslautern University of Applied Sciences | Schleser F.,Kaiserslautern University of Applied Sciences | And 7 more authors.
Histochemistry and Cell Biology

Enteric neurons and blood vessels form intricate networks throughout the gastrointestinal tract. To support the hypothesis of a possible interaction of both networks, we investigated whether primary mesenteric vascular cells (MVCs) and enteric nervous system (ENS)-derived cells (ENSc) depend on each other using two- and three-dimensional in vitro assays. In a confrontation assay, both cell types migrated in a target-oriented manner towards each other. The migration of MVCs was significantly increased when cultured in ENSc-conditioned medium. Co-cultures of ENSc with MVCs resulted in an improved ENSc proliferation and differentiation. Moreover, we analysed the formation of the vascular and nervous system in developing mice guts. It was found that the patterning of newly formed microvessels and neural stem cells, as confirmed by nestin and SOX2 stainings, is highly correlated in all parts of the developing gut. In particular in the distal colon, nestin/SOX2-positive cells were found in the tissues adjacent to the capillaries and in the capillaries themselves. Finally, in order to provide evidences for a mutual interaction between endothelial and neural cells, the vascular patterns of a RET(−/−) knockout mouse model as well as human Hirschsprung’s cases were analysed. In the distal colon of postnatal RET(−/−) knockout mice, the vascular and neural networks were similarly disrupted. In aganglionic zones of Hirschsprung’s patients, the microvascular density was significantly increased compared with the ganglionic zone within the submucosa. Taken together, these findings indicate a strong interaction between the enteric nervous and vascular system. © 2014, Springer-Verlag Berlin Heidelberg. Source

Cho G.,Childrens Hospital of Philadelphia | Lim Y.,University of Pennsylvania | Golden J.A.,Childrens Hospital of Philadelphia | Golden J.A.,Abramson Research Center
Gene Expression Patterns

Sizn1 (Zcchc12) is a transcriptional co-activator that positively modulates bone morphogenic protein (BMP) signaling through its interaction with Smad family members and CBP. We have demonstrated a role for Sizn1 in basal forebrain cholinergic neuron specific gene expression. Furthermore, mutations in SIZN1 have been associated with X-linked mental retardation. Given the defined role of SIZN1 in mental retardation, knowing its complete forebrain expression pattern is essential to further elucidating its role in cognition. To better define the dynamic expression pattern of Sizn1 during forebrain development, we investigated its expression in mouse brain development from embryonic day 8.0 (E8.0) to adult. We found that Sizn1 is primarily restricted to the ventral forebrain including the medial ganglionic eminence, the septum, amygdala, and striatum. In addition, Sizn1 expression is detected in the cortical hem and pallial-subpallial boundary (PSB; anti-hem); both sources of Cajal-Retzius cells. Sizn1 expression in the dorsal forebrain is restricted to a subset of cells in the marginal zone that also express Reln, indicative of Cajal-Retzius cells. These data provide novel information on brain regions and cell types that express Sizn1, facilitating further investigations into the function of Sizn1 in both development and the pathogenesis of mental retardation. © 2010 Elsevier B.V. All rights reserved. Source

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