Hyperammonemia, bane of the brain.

Ammonia, normally produced from catabolism of amino acids, is a deadly neurotoxin. As such, the concentration of free ammonia in the blood is very tightly regulated and is exceeded by two orders of magnitude by its physiologic derivative, urea. The normal capacity for urea production far exceeds the rate of free ammonia production by protein catabolism under normal circumstances, such that any increase in free blood ammonia concentration is a reflection of either biochemical or pharmacologic impairment of urea cycle function or fairly extensive hepatic damage.

Altered terminal glycosylation and the pathophysiology of CF lung disease.

Altered terminal glycosylation, with increased fucosylation and decreased sialylation, is a hallmark of the cystic fibrosis (CF) glycosylation phenotype. The glycosylation phenotype of CF airway epithelial cells has been modulated by the expression of wtCFTR. Understanding the effects of mutant CFTR on glycosylation may provide further insight into the regulation of glycoconjugate processing as well as new approaches to the therapy of CF.

Congenital hyperinsulinism: intraoperative biopsy interpretation can direct the extent of pancreatectomy.

Most cases of congenital hyperinsulinism (HI) manifest as either a diffuse or focal form. Diffuse HI is characterized by the presence of enlarged islet cell nuclei, defined as those occupying an area 3 times larger than the surrounding nuclei, throughout the pancreas, and usually requires near total pancreatectomy. Focal HI contains, within an otherwise normal pancreas with islet cell nuclei of normal size, a focus of adenomatous hyperplasia characterized by endocrine cell overgrowth occupying more than 40% of a given area.

Myopathies resulting from mutations in sarcomeric proteins.

Purpose Of Review: The past decade has seen the discovery of the major role that mutations in the protein components of the sarcomere plays as a cause of human muscle disease. An overview of the more precise molecular definitions of these diseases is timely.

Recent Findings: Recent findings include: the beginnings of an understanding of the role of the sarcomere in controlling muscle gene expression; the theoretical analysis of the increasing number of mutations identified in the skeletal muscle actin gene; the identification of mutations in myosin causing hereditary inclusion body myopathy and hyaline body myopathy and the identification of mutations in myotilin in myofibrillar myopathy.

Nocturnal enuresis: behavioral treatments.

Nocturnal enuresis is a common problem. Physiologic and environmental factors are thought to have a role in the etiology and treatment of this condition. This article discusses the association between enuresis and behavioral or emotional problems.

Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms.

Atypical teratoid/rhabdoid tumor (AT/RT) may be misdiagnosed as primitive neuroectodermal tumor/medulloblastoma (PNET) and occasionally as other tumors. Molecular genetic analysis of AT/RT demonstrates deletion and mutation of the hSNF5/INI1 gene in most cases, with decreased or absent expression at the RNA or protein level. Immunohistochemistry with an antibody to INI1 was performed to determine whether this would be a sensitive and specific means of assessing INI1 loss in pediatric brain tumors.

The congenital and limb-girdle muscular dystrophies: sharpening the focus, blurring the boundaries.

During the past decade, outstanding progress in the areas of congenital and limb-girdle muscular dystrophies has led to staggering clinical and genetic complexity. With the identification of an increasing number of genetic defects, individual entities have come into sharper focus and new pathogenic mechanisms for muscular dystrophies, like defects of posttranslational O-linked glycosylation, have been discovered. At the same time, this progress blurs the traditional boundaries between the categories of congenital and limb-girdle muscular dystrophies, as well as between limb-girdle muscular dystrophies and other clinical entities, as mutations in genes such as fukutin-related protein, dysferlin, caveolin-3 and lamin A/C can cause a striking variety of phenotypes.

Streptococcal intertrigo: an underrecognized condition in children.

Group A beta-hemolytic streptococci have been implicated in a variety of common childhood cutaneous infections. Infants and young children may be particularly susceptible to a form of streptococcal intertrigo that has heretofore been underrecognized in this population. Manifesting as intense, fiery-red erythema and maceration in the intertriginous folds of the neck, axillae, or inguinal spaces, the condition is characterized by a distinctive foul odor and an absence of satellite lesions.

NKX2.5 mutations in patients with congenital heart disease.

Objectives: The purpose of this study was to estimate the frequency of NKX2.5 mutations in specific cardiovascular anomalies and investigate genotype-phenotype correlations in individuals with NKX2.5 mutations.

Treatment of Gastrointestinal Problems in Cystic Fibrosis.

The gastrointestinal (GI) manifestations of cystic fibrosis (CF) are varied and include pancreatic insufficiency, meconium ileus, distal intestinal obstruction syndrome (DIOS), liver disease, and other less common manifestations. Treatment of pancreatic insufficiency consists of providing appropriate pancreatic enzyme replacement therapy and may include raising duodenal pH to allow for optimal action of these enzymes. Despite a number of pancreatic enzyme replacement products, malabsorption cannot be normalized.

Pancreatic-derived factor (FAM3B), a novel islet cytokine, induces apoptosis of insulin-secreting beta-cells.

PANDER (PANcreatic DERived factor, FAM3B), a newly discovered secreted cytokine, is specifically expressed at high levels in the islets of Langerhans of the endocrine pancreas. To evaluate the role of PANDER in beta-cell function, we investigated the effects of PANDER on rat, mouse, and human pancreatic islets; the beta-TC3 cell line; and the alpha-TC cell line. PANDER protein was present in alpha- and beta-cells of pancreatic islets, insulin-secreting beta-TC3 cells, and glucagon-secreting alpha-TC cells.

Collagen crosslinking and cell density have distinct effects on fibroblast-mediated contraction of collagen gels.

Background/purpose: Fibroblasts are actively and dynamically involved in wound healing (dermal regeneration, wound contraction, and scar contracture) and fibrosis. Fibroblast-seeded collagen gels provide an in vitro model for these processes. Over time, fibroblasts will contract the gels, but the mechanisms are not completely understood.

Genotyping on a thermal gradient DNA chip.

Silicon-based chips with discrete, independently temperature-controlled islands have been developed for use in DNA microarray hybridization studies. Each island, containing a heater made of a diffusion layer and a temperature sensor based on a p-n junction, is created on a silicon dioxide/nitride surface by anisotropic etching. Different reactive groups are subsequently added to the surface of the islands, and allele-specific oligonucleotide probes are attached to discrete spots on the chip.

Formation of a tissue-specific histone acetylation pattern by the hematopoietic transcription factor GATA-1.

One function of lineage-restricted transcription factors may be to control the formation of tissue-specific chromatin domains. In erythroid cells, the beta-globin gene cluster undergoes developmentally regulated hyperacetylation of histones at the active globin genes and the locus control region (LCR). However, it is unknown which transcription factor(s) governs the establishment of this erythroid-specific chromatin domain.

Insulin receptor substrate 1 regulation of sarco-endoplasmic reticulum calcium ATPase 3 in insulin-secreting beta-cells.

We have previously characterized an insulin receptor substrate 1 (IRS-1)-overexpressing beta-cell line. These beta-cells demonstrated elevated fractional insulin secretion and elevated cytosolic Ca(2+) levels compared with wild-type and vector controls. This effect of IRS-1 may be mediated via an interaction with the sarco-endoplasmic reticulum calcium ATPase (SERCA).

Filamin C accumulation is a strong but nonspecific immunohistochemical marker of core formation in muscle.

Filamin C is the muscle isoform of a group of large actin-crosslinking proteins. On the one hand, filamin C is associated with the Z-disk of the myofibrillar apparatus and binds to myotilin; on the other hand, it interacts with the sarcoglycan complex at the sarcolemma. Filamin C may be involved in reorganizing the cytoskeleton in response to signalling events and in muscle it may, in addition, fulfill structural functions at the Z-disk.

Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome.

Background: Cardiovascular anomalies are among the most common features of Alagille syndrome (AGS). Mutations of JAG1 are found in most individuals with AGS. This study was undertaken to determine the spectrum of cardiovascular phenotypes associated with a JAG1 mutation and/or AGS, investigate potential genotype-phenotype correlations, and begin to correlate clinical outcome with genetic pathogenesis.

Barriers to booster seat use and strategies to increase their use.

Objective: Children who have outgrown child safety seats and been placed in adult seat belts are at increased risk for injury. Pediatricians and other advocates have been called on to encourage booster seat use in these children. The objective of this study was to identify barriers to booster seat use and strategies to increase their use.

Outcomes after the Fontan procedure.

Over the past two decades, advances in congenital heart surgery, pediatric cardiology, and intensive care medicine have dramatically increased the survival of infants with critical congenital heart disease. The group of patients that has perhaps benefited the most from this progress has been the single-ventricle population. Staged palliation culminating in the Fontan procedure has resulted in a decreasing mortality rate and an increase in the number of single-ventricle survivors.

Racial differences in the evaluation of pediatric fractures for physical abuse.

Context: Child maltreatment is a significant problem within US society, and minority children have higher rates of substantiated maltreatment than do white children. However, it is unclear whether minority children are abused more frequently than whites or whether their cases are more likely to be reported.

Objectives: To determine whether there are racial differences in the evaluation and Child Protective Services (CPS) reporting of young children hospitalized for fractures.

Monozygotic twins with a severe form of Alagille syndrome and phenotypic discordance.

Alagille syndrome is an autosomal dominant disorder affecting multiple organ systems, predominantly the liver, heart, skeleton, eye, face, and kidney. The phenotype in Alagille syndrome is highly variable both within and between families. We report monozygotic twins with Alagille syndrome concordant for a mutation in Jagged1 but discordant for clinical phenotype.

Supernumerary digital flexion creases: an additional clinical manifestation of Alagille syndrome.

Alagille syndrome (AGS; OMIM 118450) is a complex dominantly inherited multisystem disorder involving the liver, heart, eyes, facies, skeleton, and other systems. Criteria for the clinical diagnosis have been established as the presence of bile duct paucity on liver biopsy in association with three of five major clinical findings (cholestasis, butterfly vertebrae, posterior embryotoxon, congenital heart disease, and facial features). Jagged1 has been identified as the AGS disease gene.

Facial features in Alagille syndrome: specific or cholestasis facies?

Alagille syndrome is a complex multisystem disorder characterized by bile duct paucity, cholestasis, cardiac defects, vertebral anomalies, ophthalmologic changes, and facial dysmorphism. Although the facial features are highly conserved in affected individuals both within and between families, the possibility has been raised that cholestasis is the causative factor for the facies. In this study, the diagnostic specificity of the facies in Alagille syndrome has been evaluated by asking clinical dysmorphologists to examine a photographic panel of 18 pediatric and adult individuals with Alagille syndrome and other forms of congenital intrahepatic cholestasis.