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Alastair Forbes

Publications and source records attributed to Alastair Forbes.

11 recordsLinked to original sources
PubMed2003

Regulation of epithelial syndecan-1 expression by inflammatory cytokines.

Syndecan-1 is expressed on the basolateral surface of columnar epithelium and contributes to wound repair by facilitating increased growth factor binding. Inflammatory bowel disease (IBD) is associated with reduced syndecan-1 expression in areas of inflamed mucosa that is likely to impair mucosal healing. Reduced syndecan-1 expression in IBD may be related to the presence of increased inflammatory cytokines. To test this hypothesis, monolayers of HT29 and T84 colonic epithelial cells were stimulated with tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta or IL-6. Stimulation of HT29 cells with TNF-alpha and IL-1beta resulted in reversible down-regulation of syndecan-1 at both protein and mRNA levels but little effect was observed with IL-6. Loss of syndecan-1 expression was caused by shedding of the ectodomain as revealed by increased levels of soluble syndecan-1 measured in the conditioned medium of stimulated cells. No increase in cytoplasmic staining accompanied the loss of cell surface syndecan-1 expression. TNF-alpha and IL-1beta are capable of down-regulating syndecan-1 expression and may account in part for the reduced expression of syndecan-1 seen in IBD.

Cells, Cultured↗
PubMed2003

Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease.

A common haplotype spanning 250 kb in the cytokine gene cluster on chromosome 5q31 has recently been reported to be strongly associated with Crohn disease (CD) in Canadian families. We have replicated this finding by both the transmission-disequilibrium test (TDT) (P=.016) and in a case-control association study (P=.008) in a large European cohort of patients with CD, although the increase in disease risk was small (odds ratio 1.49 for homozygotes, 95% CI 1.11-2.0). No association was detected in families or individuals with ulcerative colitis (UC). Stratification of offspring with CD in the TDT sample by mutation status in the CD susceptibility gene CARD15 showed that the association with the 5q31 risk haplotype was present only in offspring with at least one of the known CARD15 disease susceptibility alleles (P=.044). The 5q31 risk haplotype frequency was 53.1% in unrelated individuals with CD who had one or two CARD15 mutations versus 43.7% in control subjects (P=.0001) but was not significantly elevated in individuals with CD who had no CARD15 mutations (45.4%, P=.41). Kaplan-Meier survival analysis of age at disease onset showed a significantly earlier onset in homozygotes for the 5q31 risk haplotype (P=.0019). These findings suggest that genetic variants at the 5q31 (IBD5) locus may hasten the onset of Crohn disease and cooperate with CARD15 in disease causation.

Aging↗
PubMed2003

Alternative immunomodulators.

There is now a large number of potential immunomodulatory agents that may be of value in inflammatory bowel disease. The newer immunosuppressants, such as tacrolimus and mycophenolate, probably offer little more than providing comparable alternatives to more established agents, and fish oil and other eicosanoid modulators are probably not especially potent if effective. The biological agents, however, bring a more novel and potentially powerful approach. Natalizumab, and targeted mucosal delivery of interleukin-10 already show considerable promise.

Humans↗
PubMed2002

Potential therapeutic role for cytokine or adhesion molecule manipulation in Crohn's disease: in the shadow of infliximab?

BACKGROUND: Inappropriate activation of the intestinal immune system leading to a persistent inflammatory response is implicated in the pathogenesis of both Crohn's disease and ulcerative colitis. Various cytokines and cell surface molecules expressed by immunologically active cells are involved and are potential targets for intervention. To date the most effective biological agent has proved to be infliximab, but many other possibilities are being considered actively. STUDIES CONSIDERED: Use of the immunoregulatory cytokines IL-10 and IL-11, and of antagonists to IL-12, IL-15 and IL-18, to integrins, and to ICAM-1 are considered. RESULTS AND CONCLUSION: IL-10 and the anti-integrin natalizumab are currently best evaluated. Both are effective, but neither is yet a direct competitor for infliximab in Crohn's disease, and there is no strong evidence in ulcerative colitis. These agents have considerable potential which, in combination with new delivery systems (perhaps taking into account some form of genetic engineering), hold great promise.

Animals↗
PubMed2002

Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6.

Inflammatory bowel disease (IBD) is a multifactorial disorder, with both genetic and environmental factors contributing to the two clinical phenotypes of Crohn's disease (CD) and ulcerative colitis (UC). The underlying genetic model is thought to involve multiple genes with complex interactions between disease loci, and the NOD2 gene on chromosome 16 has recently been identified as a CD susceptibility locus. Several genome-wide linkage studies have identified candidate regions, but there has been little replication across studies. Here we investigate the role of sex-specific loci in susceptibility to IBD. Linkage data from our previously reported genome search and follow-up study were stratified by the sex of the affected sib pair. Non-parametric linkage analysis was performed using Genehunter Plus. Simulation studies were used to assess the significance of differences in LOD scores between male and female families for each chromosome. Several regions of sex-specific linkage were identified, including existing and novel candidate loci. The major histocompatibility region on chromosome 6p, referred to as IBD3, showed evidence of male-specific linkage with a maximum LOD score of 5.9 in both CD and UC male-affected families. Regions on chromosomes 11, 14 and 18 showed strong evidence of linkage in male-affected families but not in female-affected families. No evidence of sex-specific linkage was found in the IBD1 or IBD2 candidate regions of chromosomes 16 and 12. The existence of sex-specific linkage is further evidence of the complex mechanisms involved in IBD and will facilitate future studies to identify susceptibility genes.

Chromosome Mapping↗
PubMed2002

Review article: Immunosuppressants in distal ulcerative colitis.

BACKGROUND: Distal ulcerative colitis may prove to be resistant to steroids and aminosalicylates, but total colectomy is more difficult to justify than in severe extensive colitis. Immunosuppression is of established benefit in generalized colitis, but there are no data available specific to distal disease. AIM: To determine whether the protocol-driven use of immunosuppressants in resistant distal ulcerative colitis is of similar efficacy and safety to that in extensive disease. METHODS: Two hundred and twenty-eight patients with distal ulcerative colitis seen in a 5-year period were identified from a prospective database. Details of 52 who had received immunosuppression were analysed. RESULTS: The 52 patients received 68 courses of therapy (53 azathioprine, five mercaptopurine, 10 ciclosporin). The thiopurines yielded clinically valuable responses in only 43% of courses, with failure of response in 16% and toxicity in 34%. Ciclosporin was helpful on only two of 10 occasions. Eight patients required total colectomy. Adverse events were typical of those normally associated with immunosuppressants, with potential risk to life in seven patients; treatment was discontinued because of toxicity on a total of 31% of occasions. CONCLUSIONS: Immunosuppression appears to be of lower efficacy and higher toxicity in resistant distal colitis than when used in more extensive colitis.

Adult↗
PubMed2002

The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease.

BACKGROUND & AIMS: Mutations in the NOD2 gene are strongly associated with susceptibility to Crohn's disease (CD). We analyzed a large cohort of European patients with inflammatory bowel disease to determine which mutations confer susceptibility, the degree of risk conferred, their prevalence in familial and sporadic forms of the disease, and whether they are associated with site of disease. METHODS: Individuals were genotyped for 4 NOD2 mutations: P268S, R702W, G908R, and 3020insC. Allelic transmission distortion to 531 CD- and 337 ulcerative colitis-affected offspring was assessed by the transmission disequilibrium test. Association was also tested in an independent cohort of 995 patients with inflammatory bowel disease and 290 controls. Cases were stratified by disease site and compared across NOD2 genotypes. RESULTS: R702W, G908R, and 3020insC were strongly associated with CD but not with ulcerative colitis. Linkage disequilibrium was observed between P268S and the other mutations, forming 3 independent disease haplotypes. Genotype relative risks were 3.0 for mutation heterozygotes and 23.4 for homozygotes or compound heterozygotes. The frequency of NOD2 mutations was higher in cases from families affected only with CD and was significantly increased in ileal-specific disease cases compared with colon-specific disease (26.9% vs. 12.7%, P = 0.0004). CONCLUSIONS: The R702W, G908R, and 3020insC mutations are strong independent risk factors for CD and are associated particularly with ileal disease.

Carrier Proteins↗
PubMed2002

Microscopic colitis: the tip of the iceberg?

OBJECTIVES: The aims were to determine whether a wide variation exists between hospitals in the diagnosis of microscopic colitis and to assimilate clinical data. DESIGN: Retrospective study of 90 patients with microscopic colitis aged between 16 and 92 years from 11 hospitals in south-east England. METHODS: A questionnaire was designed to collect relevant data from all patients in whom a new diagnosis of microscopic colitis had been made at the source hospital between January 1990 and December 1996. The inclusion criteria were presentation with watery diarrhoea, a normal endoscopy and a histological report of microscopic colitis. Histology slides were then requested and reviewed. Clinical data were analysed with reference to the confirmed diagnosis. RESULTS: The number of patients diagnosed at each hospital ranged between zero and 30, with a median of six. Sixty-eight patients had histological slides reviewed. The numbers of patients with a final reviewed diagnosis of collagenous colitis, lymphocytic colitis and microscopic colitis, type undesignated, were 37, 18 and seven respectively. In thirty-one patients (34%) there was a recent history of the use of non-steroidal anti-inflammatory drugs. CONCLUSIONS: These data confirm that there is wide hospital variation in the diagnosis of microscopic colitis. Furthermore, the small group with the undesignated type may be associated with the use of non-steroidal anti-inflammatory drugs.

Adolescent↗
PubMed2002

Pharmacogenomics of response to anti-tumor necrosis factor therapy in patients with Crohn's disease.

The relatively recent development of genetically engineered agents has the potential to alter the treatment of Crohn's disease radically, and drugs that inhibit tumor necrosis factor-alpha (TNFalpha) have been introduced as a new therapeutic class with high efficacy, rapid onset of action, prolonged effect, and improved tolerance. However these agents are expensive and at least one-third of the eligible patients fail to show any useful response. Finding a means to predict those who will respond, and to anticipate relapse are, therefore, of obvious importance. T helper-type 1 (Th1) lymphocytes orchestrate much of the inflammation in Crohn's disease mainly via production of TNFalpha, which appears to play a pivotal role as a pro-inflammatory cytokine. It exerts its effects through its own family of receptors (TNFR1 and TNFR2), the end results of which include apoptosis, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activation and NF-kappaB activation. Activated NF-kappaB enters the nucleus and induces transcription of genes associated with inflammation, host defense and cell survival. The promoter region of the TNF gene lies between nucleotides -1 and -1300, and encompasses numerous polymorphic sites associated with potential binding sites for various transcription factors. Carriers of the TNF allele 2 (TNF2), which contains a single base-pair polymorphism at the -308 promoter position, produce slightly more TNFalpha in their intestinal mucosa than non-TNF2 carriers. TNF polymorphisms also appear to influence the nature and frequency of extraintestinal manifestations of inflammatory bowel disease (IBD). A number of routes of inhibition of TNF are being investigated. Most extensively evaluated is the use of monoclonal antibodies against TNFalpha (e.g. infliximab). Several large controlled trials indicate that infliximab has a role in treating patients with moderate to severely active Crohn's disease and in fistulating Crohn's disease. Although it would be useful to genetically differentiate 'responders' from 'non-responders,' currently there are few published data on TNF polymorphisms in IBD, and often only selected polymorphisms are genotyped. Small studies have shown possible associations between poor response to infliximab and increasing mucosal levels of activated NF-kappaB, homozygosity for the polymorphism in exon 6 of TNFR2 (genotype Arg196Arg), positivity for perinuclear antineutrophil cytoplasmic antibodies (ANCA), and with the presence of increased numbers of activated lamina propia mononuclear cells producing interferon-gamma and TNFalpha. This is a rapidly changing field, and more information of greater direct clinical benefit can be expected soon.

Animals↗
PubMed2001

Intravenous nutrition in critical illness.

Our understanding of the effects of total parenteral nutrition in critical illness has been refined over the past year. The importance of not overfeeding patients has been highlighted. The effects of lipid emulsions containing medium-chain triglycerides, compared with standard ones, have been investigated and show, in particular, changes in platelet membrane fatty acid composition. Although data on clinical end-points are lacking, this is likely to be a fruitful area of further research. The importance of providing enteral support, if at all possible, has been further underlined by its beneficial effects on bile composition in the intensive care setting. Finally, critical illness has been shown to be, in general, a contraindication to growth hormone therapy.

Journal Article↗