Montreal Children's Hospital

About: Montreal Children's Hospital is a healthcare organization based out in Montreal, Quebec, Canada. It is known for research contribution in the topics: Population & Poison control. The organization has 3842 authors who have published 4816 publications receiving 200198 citations.

How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression.

Abstract: Mutations in the human PAH gene, which encodes phenylalanine hydroxylase are associated with varying degrees of hyperphenylalaninemia (HPA). The more severe of these manifest as a classic metabolic disease--phenylketonuria (PKU). In vitro expression analysis of PAH mutations has three major applications: 1) to confirm that a disease-associated mutation is genuinely pathogenic, 2) to assess the severity of a mutation's impact, and 3) to examine how a mutation exerts its deleterious effects on the PAH enzyme, that is, to elucidate the molecular mechanisms involved. Data on expression analysis of 81 PAH mutations in multiple in vitro systems is summarized in tabular form online at www.pahdb.mcgill.ca. A review of these findings points in particular to a prevalent general mechanism that appears to play a major role in the pathogenicity of many PAH mutations. Amino acid substitutions promote misfolding of the PAH protein monomer and/or oppose the correct assembly of monomers into the native tetrameric enzyme. The resulting structural aberrations trigger cellular defenses, provoking accelerated degradation of the abnormal protein. The intracellular steady-state levels of the mutant PAH enzyme are therefore reduced, leading to an overall decrease in phenylalanine hydroxylation within cells and thus to hyperphenylalaninemia. There is considerable scope for modulation of the enzymic and metabolic phenotypes by modification of the cellular handling--folding, assembly, and degradation--of the mutant PAH protein. This has major implications, both for our understanding of genotype-phenotype correlations and for the development of novel therapeutic approaches.

Disorders of Renal Tubular Phosphate Transport

Abstract: The kidney plays a major role in the maintenance of inorganic phosphate (Pi) homeostasis and, as such, ensures that an adequate supply of this ubiquitous anion is available for proper cellular function and skeletal mineralization. Physiologic studies have revealed that the bulk of filtered Pi is

Reflections on measuring pain in infants: dissociation in responsive systems and “honest signalling”

Abstract: Consider the following scenario: Robert Smith R Barr is head nurse at a neonatal intensive care unit at a major teaching hospital; Joanne Johnston is the clinical director of the neonatology service. Both have been following closely the changing attitudes and published data on pain and stress in infants.1 They believe that the formerly widely held assumptions that infants do not experience pain and do not benefit from analgesia are wrong. They now believe that premature infants not only have the neurological capability to experience pain, but that they may be hypersensitive to nociceptive stimuli,2 3 and may remember pain experiences.4 They are aware of the classic study by Anand and colleagues5 and others since6 7supporting the idea that infants undergoing major painful operations will have better outcomes if given analgesics during surgery. Indeed, they have been active in a campaign to educate their colleagues that infants experience pain the way adults do. Many of their colleagues do not subscribe to this belief, which may partly explain why infants and children receive less analgesia for the same procedures than do adults.8-13 Finally, they have instituted measures for “individualised, developmentally focused intensive care,” where nursery routines and practices are organised to be as consistent as possible with the developmental strengths and vulnerabilities of premature infants.14 In pursuit of these aims, however, they have been trying to address the following question. What should be taken as evidence that the infant is in pain or stressed? This applies to premature infants undergoing repeated minor procedures some of which are painful and many of which are stressful, who are often recovering from major surgical procedures, and who may have chronic indwelling catheters, intravenous lines, etc. They recognise this poses a dilemma for several reasons. First, infants …

Economic impact of juvenile idiopathic arthritis

Abstract: Objective Juvenile idiopathic arthritis (JIA) is a potentially devastating chronic pediatric disease. Although high costs have been well described in adult arthritis, little is known about the economic impact of JIA. Our objective was to describe direct medical costs for children with JIA compared with controls. Methods Consecutive clinic attendees (n = 155) with JIA were enrolled from 2 tertiary referral pediatric centers. Outpatient clinic controls without JIA (n = 181) were recruited at the respective centers. Data on direct medical costs were obtained at 3-month intervals. Average annualized direct medical costs were calculated, expressed in 2005 Canadian dollars. Results The total difference in annualized average direct medical costs for children with JIA versus controls was $1,686 (95% confidence interval $875, $2,500). JIA subjects had substantially higher costs concerning medication use, visits to specialists and allied health care professionals, and diagnostic tests. Multiple linear regression models for the JIA sample revealed that higher active joint count was independently associated with greater total direct medical costs. Also, JIA type was a predictor of greater direct costs, with higher costs for patients with polyarthritis (rheumatoid factor positive or negative) or systemic JIA. Conclusion The economic impact of JIA is substantial, and higher active joint count is independently associated with greater costs. This may be of particular significance given the emergence of new, costly medications for use in JIA. Insights into the relationship between disease activity and cost in JIA should assist policy makers regarding resource allocation in the setting of competing demands. Ultimately, decisions regarding access to therapies should be considered in terms of overall cost-benefit ratios.