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Biomedical subjects

David C Wilson

Publications and source records attributed to David C Wilson.

10 recordsLinked to original sources
PubMed2007

Genetics of the innate immune response in inflammatory bowel disease.

The discovery of nucleotide-binding oligomerization domain 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15) as the first susceptibility gene in Crohn's disease (CD) has shifted the focus of research into the pathogenesis of inflammatory bowel disease (IBD) firmly to the innate immune response and the integrity of the epithelial barrier. The subsequent implication in IBD of variant alleles of OCTN, DLG5, MDR1, and TLRs has provided further support for a new, more complex model of innate immunity function in the gastrointestinal tract. In this review, we examine the recent advances in our understanding of the influence of genetics of the innate immune response on IBD. We will focus on germline variation of genes encoding pathogen-recognition receptors, proteins involved in epithelial homeostasis and secreted antimicrobial proteins.

Genetic Predisposition to Disease↗
PubMed2006

Follistatin-like protein-1 is a novel proinflammatory molecule.

While analyzing gene expression in collagen-induced arthritis, we discovered that a poorly characterized gene, follistatin-like protein 1 (FSTL-1), is highly overexpressed in mouse paws during early arthritis, especially at the interface of synovial pannus and eroding bone. In this study, we show that FSTL-1 is a novel proinflammatory molecule with a previously unrecognized role in inflammation. Transfection of FSTL-1 into macrophages and fibroblasts leads to up-regulation of proinflammatory cytokines, including IL-1beta, TNF-alpha, and IL-6. Overexpression of FSTL-1 in mouse paws by gene transfer results in severe paw swelling and arthritis.

Animals↗
PubMed2006

A prospective randomized clinical trial of 0.1% tacrolimus ointment in a model of chronic allergic contact dermatitis.

OBJECTIVE: Tolerability and safety of 0.1% tacrolimus ointment in treating nickel-induced allergic contact dermatitis (ACD) were evaluated. METHODS: Patients allergic to nickel applied nickel patches to each upper inner aspect of the arm for 4 to 8 hours daily. Tacrolimus was applied to patch site on one arm and vehicle to patch site on the other, twice daily. Physician's Global Assessment, signs and symptoms of ACD, pruritus scores, and adverse events were evaluated. RESULTS: After 8 weeks, dermatitis in 45% of patients was clear or almost clear (Physician's Global Assessment) with tacrolimus; and 1% with vehicle (P < .001). Significant results were achieved as early as day 8. Tacrolimus was superior in ACD signs and symptoms improvement and pruritus reduction (P < .001). Adverse events were similar between treatments. LIMITATIONS: This model, involving one agent, may not be generalizable for other agents. CONCLUSIONS: Tacrolimus ointment 0.1% is well tolerated and significantly more effective than vehicle in treating chronically exposed, nickel-induced ACD.

Adolescent↗
PubMed2006

Adapalene gel 0.3% for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial.

BACKGROUND: A new 0.3% gel formulation of adapalene has been developed. OBJECTIVE: We sought to provide evidence of the superiority of adapalene gel 0.3% over adapalene gel 0.1% and gel vehicle in the treatment of acne. METHODS: A total of 653 patients were randomized to receive adapalene gel 0.3%, adapalene gel 0.1%, or vehicle once daily for 12 weeks (2:2:1 randomization). Analysis for efficacy was conducted on correlated repeated measurements at weeks 8 and 12 using Generalized Estimating Equation methodology. RESULTS: Adapalene gel 0.3% was significantly superior to adapalene gel 0.1% and vehicle in success rate, total lesion count, and inflammatory lesion count. A consistent, dose-dependent effect was demonstrated for all efficacy measures. Signs and symptoms were mostly mild to moderate and transient in nature. LIMITATIONS: Adjunctive topical or oral agents and their impact on acne were not studied in this trial. CONCLUSIONS: Adapalene gel 0.3% was effective and well tolerated in the treatment of acne.

Acne Vulgaris↗
PubMed2006

6-Thioguanine-related chronic hepatotoxicity and variceal haemorrhage in children treated for acute lymphoblastic leukaemia--a dual-centre experience.

BACKGROUND: 6-Thioguanine treatment in childhood acute lymphoblastic leukaemia (ALL) has been shown to cause hepatic veno-occlusive disease, but this usually resolved with drug withdrawal. Recent reports suggested that treatment of ALL with 6-thioguanine can lead to chronic hepatotoxicity and portal hypertension. We describe our experience from 2 UK centres of chronic hepatotoxicity in children receiving maintenance 6-thioguanine for ALL in the national leukaemia protocol ALL 97/99. METHODS: Retrospective review of children who were referred with liver disease secondary to 6-thioguanine treatment of ALL was performed. A paediatric pathologist blinded to the clinical features reviewed liver histology slides. RESULTS: Ten of 75 children (13%) treated with 6-thioguanine in both centres were referred at a median of 6 months (range, 2-29) after discontinuation of chemotherapy. In 8 cases, referral was due to persistent thrombocytopenia and splenomegaly. Two children presented with acute variceal bleeding. All had thrombocytopenia at referral, and ultrasonography showed coarse hepatic echo texture and splenomegaly in all. Endoscopy showed oesophageal varices in 7 and gastric varices in 1. Nine underwent liver biopsy that showed features compatible with nodular regenerative hyperplasia in 5 cases. After a median follow-up of 36 months, a further child has had a variceal haemorrhage and all but 2 children remain thrombocytopenic. CONCLUSIONS: 6-Thioguanine-induced chronic hepatotoxicity is a significant complication in children treated with this agent for ALL. Children may present several months to years after discontinuation of 6-thioguanine. All children given maintenance treatment of ALL with this agent should be screened, and affected children require long-term surveillance.

Adolescent↗
PubMed2006

Hyaluronic acid predicts hepatic fibrosis in children with hepatic disease.

BACKGROUND: Hyaluronic acid (HA) is removed by the liver via sinusoidal cell adhesion molecules. This is impeded in fibrosis, leading to a rise in serum HA. As a noninvasive marker of fibrosis, HA may obviate the need for liver biopsy. OBJECTIVE: To evaluate HA as a marker of hepatic fibrosis, in unselected children undergoing liver biopsy. METHODS: Ninety-three unselected consecutive children (median age, 7.5 years; range, 0.07-19 years) undergoing a liver biopsy between April 2003 and March 2004 were prospectively recruited. Liver biopsy and fasting HA levels were taken simultaneously. The Ishak score was used to stage fibrosis. Scores of 3 or greater were regarded as significant fibrosis. Hyaluronic acid levels were measured using an enzyme-linked binding protein assay (2002 Corgenix, Inc) (adult reference range, 0-75 ng/mL; pediatric reference range, 0-30 ng/mL). RESULTS: Twenty-three (25%) of 93 biopsies had significant fibrosis, and HA levels in this group were significantly higher than those with mild fibrosis (Ishak score, <3), (median level, 72 ng/mL vs 30 ng/mL; Mann-Whitney U test; P < 0.005). Hyaluronic acid level of 50 ng/mL had a positive predictive value 40% and negative predictive value 86% for significant fibrosis. An HA level 200 ng/mL has a sensitivity of 26% and specificity of 90%. CONCLUSIONS: Hyaluronic Acid is a valid noninvasive predictor of hepatic fibrosis in unselected children with liver disease. An HA level of 200 ng/mL strongly suggests significant fibrosis. Hyaluronic acid level of less than 50 ng/mL accurately identifies those who do not have significant fibrosis.

Adolescent↗
PubMed2005

Changes in response to insulin and the effects of varying glucose tolerance on whole-body protein metabolism in patients with cystic fibrosis.

BACKGROUND: Diabetes mellitus has been reported to increase whole-body protein breakdown and thus loss of lean body mass. Cystic fibrosis-related diabetes (CFRD) is associated with undernutrition and increased mortality. OBJECTIVE: We hypothesized that CFRD is associated with increased whole-body protein breakdown, which results in negative protein balance, and that correction of the glucose intolerance with insulin therapy would normalize whole-body protein metabolism. DESIGN: Rates of whole-body protein turnover and protein balance were measured in 28 adults with cystic fibrosis (17 M, 11 F). Subjects were assessed with a modified oral-glucose-tolerance test and categorized as having normal glucose tolerance, impaired glucose tolerance, or CFRD with and without fasting hyperglycemia; then they were compared with previously diagnosed CFRD adults already receiving insulin therapy. Indexes of protein turnover were calculated from [15N]glycine and 15N in urinary urea. RESULTS: Analysis of variance for the 28 subjects showed that whole-body protein breakdown was highest (P<0.05) in patients with CFRD. Whole-body protein synthesis was not significantly affected by impaired glucose tolerance. Significant (P<0.05) improvement in net protein synthesis occurred in the CFRD group 3 mo after insulin therapy was administered. Follow-up studies of 3 subjects with CFRD showed significant improvement in net protein synthesis after insulin therapy. Monitoring of the protein homeostasis of the impaired glucose tolerance group gave clues to the progression of their metabolic homeostasis. CONCLUSION: CFRD has an adverse effect on protein homeostasis by increasing net protein synthesis.

Adult↗
PubMed2005

Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.

INTRODUCTION: The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population. PATIENTS AND METHODS: 906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case-control analysis and detailed genotype-phenotype analysis were performed. RESULTS: The Leu1007finsC variant was associated with susceptibility to CD by case-control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5-14.7]). CONCLUSIONS: These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.

Adolescent↗
PubMed2003

Glucose intolerance in children with cystic fibrosis.

OBJECTIVE: To evaluate the relations among glucose intolerance, genotype, and exocrine pancreatic status in patients with cystic fibrosis (CF). STUDY DESIGN: Data on 335 patients <18 years of age were from the Toronto CF database. A modified oral glucose tolerance test was given to 94 patients 10 to 18 years of age without recognized CF-related diabetes. CF transmembrane conductance regulator mutations and exocrine pancreatic status were determined for all patients. RESULTS: CF-related diabetes was clinically recognized in 9 of 335 (2.7%) patients <18 years of age, all of whom were pancreatic insufficient, and 8 of 9 had severe (classes I through III) mutations on both alleles. The ninth patient had unidentified mutations. Although all patients given the oral glucose tolerance test were asymptomatic and had normal fasting blood glucose, 16 of 94 (17%) had impaired glucose tolerance and 4 of 94 (4.3%) had CF-related diabetes without fasting hyperglycemia. Abnormal glucose tolerance was associated exclusively with severe mutations and exocrine pancreatic insufficiency. Glycosylated hemoglobin (HbA(1)C) levels did not correlate with glucose tolerance results. CONCLUSIONS: Screening of pancreatic-insufficient, adolescent patients with CF identified more with abnormal oral glucose tolerance than was suspected clinically and is recommended as a routine practice. HbA(1)C was not useful in screening for CF-related glucose intolerance.

Adolescent↗