Current Pediatric Reviews (v.5, #1)

Editorial by Anne Greenough (1-1).
Gentamicin is a frequently used antibiotic for neonates, yet there remains debate as to the most appropriate dose and the dosing intervals. In this issue, Dr. Pacifici reports a search of the literature to compare peak and trough concentrations following schedules of gentamicin 2.5 mg/kg twice daily, 4 mg/kg once daily and extended interval dosing (5 ml/kg every 48 hours). The literature search highlighted little was known about the peak and trough concentrations of extended interval dosing. Cystic fibrosis is estimated to affect 60,000 individuals worldwide. The gene responsive (CF Transmembrane Conductance Regulator), was discovered in 1989. In this issue, Conese and colleagues review studies of gene therapy vectors and strategies for delivering them more safely and efficiently. In addition, the results of novel interventions to improve mucociliary clearance including hypertonic saline mannitol and ENaC inhibitors are discussed. Deconinck and Stojkovic have described the typical clinical and biochemical findings of the collagenopathies - Ullrich congenital muscular dystrophy and Bethlem myopathy, to facilitate paediatricians identifying the collagenopathies within the complex diagnostic group of congenital dystrophies. In addition, they have outlined the current understanding of the pathogenesis, management and potential therapeutic avenues. Many chronic paediatric diseases arise from early life immune insults and postnatal immune dysfunction. As a consequence, to further improve the understanding of the nature of the immune dysfunction and the reported associated health risks, Dietert and Zelikoff have described paediatric immune dysfunctions produced by well studied immunotoxicants and provide a matrix of health risks which appear to be linked together via underlying paediatric immune dysfunction. Gisser and colleagues describe a rare case of upper gastrointestinal bleeding that is a Schwannoma, which is a rare gastrointestinal mesenchymal tumour occurring most commonly in the stomach as a nodular mass in the muscularis propria. They highlight that they are benign tumours with a good prognosis, even when treated with enucleation. Idopathic nephrotic syndrome has a reported incidence of between two and seven cases per 100,000 children. There are two distinct histological variants: minimal change nephrotic syndrome and focal segmental glomerulosclerosis. Kaneko in this issue discusses the pathogenesis of idiopathic nephrotic syndrome both by reviewing the literature and experimental data.

Background: Sepsis is common in neonates and is a major cause of morbidity and mortality. 60and#x25; of preterm neonates receive at least one antibiotic and 43and#x25; of the antibiotics administered to these neonates are aminoglycosides. Gentamicin is an aminoglycoside which is largely used. Dosing of gentamicin gives rise to two concentrations, the peak concentration which is measured soon after dosing, and the trough concentration which is measured before the next administration. There has been a long debate about the appropriate dose of gentamicin to administer to neonates and the interval between doses. The ideal dosing of gentamicin should yield a peak concentration of 10and#956;g/ml and a trough concentration of 1and#956;g/ml. Objectives: The aim of this work is to compare the peak and trough concentrations of gentamicin in the neonate after twice-daily dosing, once-daily dosing and extended interval dosing to establish the safest one for neonates. Another aim of this note is to provide a critical analysis of the literature that can be a useful tool in the hands of physicians. Methods: The bibliographic search was performed electronically using PubMed, as the search engine, until January 14th 2008. Medline searches were performed with the following keywords and#x201C;twice-daily dosing of gentamicin in neonatesand#x201D; with the limit of and#x201C;humanand#x201D;; and#x201C;once-daily dosing of gentamicin in neonatesand#x201D;; and#x201C;extended interval dosing of gentamicin in neonatesand#x201D;; and#x201C;pharmacokinetics of gentamicin in neonatesand#x201D;. In addition, the book Neofax: a Manual of Drugs Used in the Neonatal Care by Young and Mangum [2007] was consulted. Results: The peak and trough concentrations were compared after the following dosing schedules of gentamicin 2.5 mg/kg twice-daily dosing, 4 mg/kg once-daily dosing and 5 mg/kg every 48 h defined and#x201C;extended interval dosingand#x201D;. Twice-daily dosing was associated with the lowest peak gentamicin concentration and with the highest trough concentration. The lowest trough concentration was associated with the extended interval dosing of gentamicin. Gentamicin is mainly eliminated through glomerular filtration whose rate increases with the growth of the infant. The trough concentration was negatively correlated with the body weight indicating that in better developed neonates gentamicin was more rapidly eliminated. Conclusions: The dosing schedule contributes to determining the peak and trough concentrations of gentamicin in the neonate. There are numerous articles comparing the peak and trough concentrations after twice-daily dosing and oncedaily dosing of gentamicin. In contrast, little is known about the peak and trough concentration of extended interval dosing of gentamicin. More studies are required to better highlight the peak and trough concentrations of extended interval dosing of gentamicin at different gestational age.

New Genetic and Pharmacological Treatments for Cystic Fibrosis by Massimo Conese, Mario Romano, Maria Furnari, Elena Copreni, Ida De Fino, Francesca Pardo, Luis Galietta (8-27).
Cystic Fibrosis (CF) is a still life-treathening disease, although therapies have augmented the life span of CF individuals. Isolation of the CF gene, named CFTR (CF Transmembrane Conductance Regulator), led to the discovery that it encodes for a protein kinase A-regulated chloride channel, expressed by epithelial cells mainly in mucosal tissues. Mutated or absent CFTR brings about altered muco-ciliary clearance, by a yet disputed mechanism (likely involving overfunction of the epithelial sodium channel [ENaC]), and ultimately to colonization and infection of the airways by a few opportunistic bacteria species, including Pseudomonas aeruginosa (P.a.). An exuberant and persistent acute inflammatory reaction is commonly observed in the lung from CF patients, representing a key pathogenetic event of lung damage and respiratory insufficiency. Lung disease is the chief cause of morbidity and mortality in CF patients and current therapies are aimed at controlling the respiratory symptoms by antibiotic and anti-inflammatory treatments. Major improvements in the strategy to fight pulmonary P.a. infection are based on treatment of first colonization with P.a., of chronic infection and of multidrug resistant bacteria. Controlling inflammation is a challenging, however crucial, task in CF therapy. Since classical steroidal and non-steroidal anti-inflammatory drugs are endowed with serious side-effects, alternative antiinflammatory strategies are being developed, including drugs which modulate cytokine expression, nitric oxide production and the oxidation unbalance in the CF airways. Soon after gene identification, gene transfer vectors to replace the defective gene were developed and underwent a number of human trials which have not yet produced a viable clinical gene therapy strategy. Novel gene therapy vectors and strategies for delivering them more efficiently and safely to the lung are being studied. In the last few years various in vitro studies have demonstrated the possibility of pharmacological intervention to correct the primary defect in CF. This may be obtained by directly addressing the CFTR protein (by means of so-called correctors and potentiators) or by modulating the activity of other types of ion transport in epithelial cells (such as with Moli1901 or denufosol). Novel interventions aimed to improve the mucociliary clearance, including hypertonic saline, mannitol and ENaC inhibitors, will be finally discussed.

Ullrich congenital muscular dystrophy (UCMD) is a genetically and clinically heterogeneous muscle disorder causing severe muscle weakness with proximal joint contractures and distal hyperlaxity linked to collagen VI deficiency. It was initially described within the wider group of muscular congenital dystrophies. Collagen VI is an extracellular matrix protein forming a microfibrillar network. The protein is composed of three different and#945;-chains encoded by separate genes named COL6A1, COL6A2, and COL6A3 in humans. Mutations of collagen VI gene are also responsible for Bethlem myopathy (BM), a relatively mild dominantly inherited disorder characterised by proximal weakness and distal joint contractures that was previously believed to be a completely separate entity. The pathogenesis of both diseases is still poorly understood. However, some recent data, obtained from experiments mouse models and from human myoblast cultures provide valuable insights into the pathogenesis of UCMD. A potential mitochondrial involvement may become the focus of specific therapeutic approaches. In this review we emphasise the typical clinical and biochemical findings that will help the paediatrician to identify collagenopathies within the complex diagnostic group of congenital muscular dystrophies, and outline the current understanding of UCMD pathogenesis, management, and potential therapeutic avenues.

Chronic pediatric diseases arising from early-life immune insult and postnatal immune dysfunction are among the most prevalent health challenges for children. Diseases such as childhood asthma and allergies, chronic otitis media, type 1 diabetes, childhood leukemia and pediatric celiac disease all feature dysfunctional immune responses and/or inappropriately skewed immune capacities. Additionally, these disorders have been increasing in incidence in recent years with previously identified risk factors unable to fully account for the change. Still, some treatment approaches target the initial health complaint and its symptoms without fully addressing either the underlying immune dysfunction of the initial disease or the likelihood for additional associated health risks in later life. Therefore, it is useful to understand both the nature of the immune dysfunction as well as the reported associated health risks. This review characterizes those pediatric immune dysfunctions produced by well-studied immunotoxicants and provides a matrix of those health risks that appear to be linked together via the underlying pediatric immune dysfunction. This information could lead to: 1) improved identification and treatment of underlying immune dysfunction, 2) long-term approaches to health management, and 3) improved prenatal and neonatal prevention strategies to avoid environmentally-induced immune insult and developmental immunotoxicity.

A Rare Cause of Upper Gastrointestinal Bleeding in Children: Gastric Schwannoma by Jonathan Gisser, Samra Blanchard, Robert Parry, Raymond Redline, Gisela Chelimsky (52-55).
A 16-year old female presented with a pre-syncopal event and one episode of melena. Her stool was positive for occult blood and her hemoglobin was 6.1g/dl. A mass in the greater curvature of the stomach was noted on endoscopy, and endoscopic ultrasound confirmed the presence of a heterogeneous gastric mass arising from the submucosa. Laparoscopic visualization followed by partial gastrectomy and biopsies revealed a 7.5 cm centrally-ulcerated antral mass arising from the muscularis with multiple areas of ischemic necrosis and hyalinization. Focal nuclear enlargement and hyperchromasia were also noted. Immunohistochemically, the tumor was negative for CD117, CD34 and desmin, but positive for S-100, consistent with the diagnosis of Schwannoma. Schwannomas are rare gastrointestinal mesenchymal tumors that occur most commonly in the stomach as a nodular mass in the muscularis propria. As such, they are sometimes misdiagnosed as neurofibromas and Gastrointestinal Stromal Tumors. Histologically, they have prominent peripheral lymphocytic aggregates with or without a germinal center. They are mainly composed of spindle cells, but epithelioid and rare plexiform variants have also been described. Immunohistochemically, they stain positive for vimentin and S-100 protein, but negative for CD117. Gastrointestinal Schwannomas are benign tumors and have a good prognosis even when treated with enucleation.

Idiopathic nephrotic syndrome in children was proposed to be a disorder of T-cell dysfunction. Though the mechanism by which T-cells increase glomerular permeability has remained elusive, cytokines released from activated Tcells have been considered to be candidates as vascular permeability factor(s). Therefore, efforts have been made to identify the pathogenetic cytokines as well as to understand the mechanism(s) for the increased release of these factors. In addition, free radicals, such as reactive oxygen species and reactive nitrogen species other than cytokines are also considered to be involved in the pathogenesis of idiopathic nephrotic syndrome. Meanwhile, recent clinical experience of remission induced by rituximab, monoclonal antibodies against B-cells (CD 20 positive cells), in refractory idiopathic nephrotic syndrome has changed our mind and B-cells have come under the spotlight as another key player. Furthermore, it is suggested that polymorphisms in the genes encoding the slit-diaphragm proteins of the glomerular barrier are contributed to the phenotype of idiopathic nephrotic syndrome. This review critically analyzes the available published data in combination with our experimental data and the emerging concept of pathogenesis in childhood idiopathic nephrotic syndrome.