Biomedical subjects
Publications and source records attributed to S H Murch.
Simple routine blood tests (full blood count, platelet count, erythrocyte sedimentation rate, C reactive protein, and serum albumin) may select children with chronic gastrointestinal symptoms who require endoscopic assessment and are thus an important aid in the prediction of endoscopic status. When all of the results are normal then chronic inflammatory bowel disease is an unlikely diagnosis.
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BACKGROUND/AIMS: Cytokines are thought to be important in mediating tissue damage in inflammatory bowel disease (IBD). Many of the in vivo activities of tumor necrosis factor alpha (TNF-alpha) match the changes found in IBD, but its importance is controversial. METHODS: A sensitive, reverse hemolytic plaque assay was used to determine the frequency of TNF-alpha secreting cells isolated from mucosal biopsy specimens of children with Crohn's disease or ulcerative colitis (UC) and non-IBD controls before and after medical treatment. RESULTS: Frequency of TNF-alpha secreting cells was significantly increased in biopsy specimens from children with mild, nonspecific inflammation compared with those with histologically normal intestine. Frequency did not increase in UC compared with children with nonspecific inflammation but was significantly greater in Crohn's disease than in UC. After treatment, the frequency of TNF-alpha secreting cells was reduced in patients receiving cyclosporin A, not reduced in patients with steroids or enteral nutrition, and not changed with treatment in UC. CONCLUSIONS: TNF-alpha secreting cells are increased in the mucosa of inflamed intestine, regardless of pathogenesis. In patients with IBD, higher levels are seen in Crohn's disease than in UC, probably reflecting the extensive T-cell activation in Crohn's disease. No relation existed between histological healing and the frequency of TNF-alpha-secreting cells.
While Crohn's disease and ulcerative colitis are both conditions characterized by intestinal inflammation, with some overlap in their clinical and histological features, they are essentially different in pathogenesis. Crohn's disease appears to be primarily a condition of chronic T-lymphocyte activation, with tissue damage induced by secondary macrophage activation. What activates the T-cells is unknown. In this chapter we look at the evidence for and against cell-wall deficient mycobacteria species, viral infection of vascular endothelium and luminal contents as potential mechanisms of chronic activation. In ulcerative colitis, by contrast, there is no strong evidence for T-cell activation, and humoral mechanisms predominate. While the finding of atypical anti-neutrophil cytoplasmic antibodies (P-ANCAs) may be useful in screening, the only novel pathogenetic discovery is the co-localization of a 40 kD colonic autoantibody with immunoglobulins and complement on the apical enterocyte surface. Despite the fundamental differences in initiating mechanisms, the two conditions have many 'downstream' inflammatory processes in common. We discuss the evidence for local production of cytokines, arachidonic acid metabolites and reactive oxygen and nitrogen radicals, highlighting the potential adverse consequences for intestinal vascular integrity.
In the absence of a definitive cure for Crohn's disease and ulcerative colitis, the aim of therapy must be to induce and maintain clinical remission at acceptable cost to the patient in terms of adverse effects. Despite the differences in their pathogenesis, the first-line treatments for Crohn's disease and ulcerative colitis are still based upon combinations of amino-salicylic acid derivatives and corticosteroids, although the use of enteral nutrition regimes is becoming increasingly widespread in Crohn's disease. In this chapter we attempt to provide reasonably didactic guidance for the management of most cases of chronic inflammatory bowel disease. However, we have tried to go beyond this brief, motivated by the recent explosion in knowledge of inflammatory mechanisms, to suggest a rational approach to the choice of newer and less well tested therapeutic approaches in the affected child who is not responding effectively. The relative failure of cyclosporine therapy in Crohn's disease has been particularly disappointing in view of its ideal theoretical suitability. However, the encouraging early reports of treatment with anti-CD4 and anti-TNF alpha monoclonals suggest that the shift from broad spectrum immunomodulation to the targeting of critical components of the inflammatory cascade may yet field important dividends.
We have studied the distribution and nature of sulphated glycosaminoglycans (GAGs) within normal and inflamed intestine. There is increasing evidence that these negatively charged polysaccharides, which both regulate the ability of albumin to leave the vasculature and inhibit thrombosis, may be affected by inflammatory cells and their products. We obtained samples of freshly resected intestinal tissue from eight controls, eleven patients with Crohn's disease, and six with ulcerative colitis. Sulphated GAGs were detected by means of a gold-conjugated poly-L-lysine probe, and the tissue density of anionic sites was assessed semiquantitatively by means of a Lennox graticule. In normal intestine there was staining in the vascular endothelium and the subepithelial basal lamina and throughout the extracellular matrix of the lamina propria and submucosa. Tissue from the patients with inflammatory bowel disease showed inflammation macroscopically and on histology. There were profound abnormalities of extracellular matrix GAGs, limited to the mucosa in ulcerative colitis and greatest in the submucosa in Crohn's disease. There was also substantial loss of GAGs from the subepithelial basal lamina in both disorders and from the vascular endothelium in submucosa in Crohn's disease. The extent of local GAG disruption was associated with the distribution of macrophages immunoreactive for tumour necrosis factor alpha and the activation marker RM 3/1. We suggest that inflammatory disruption of vascular and connective tissue GAGs may be an important pathogenetic mechanism, contributing to the leakage of protein and fluid, thrombosis, and tissue remodelling seen in inflammatory bowel disease.
Staphylococcus aureus enterotoxin B (SEB) was added to explants of fetal human intestine in organ culture or administered into the lumen of fetal small intestine prior to culture. Both routes produced a massive increase in lamina propria T cells expressing V beta 3, and to a lesser extent, those expressing V beta 5 and V beta 12. SEB-activated lamina propria T cells produced interleukin-2 and interferon-gamma and T cell activation was accompanied by tissue damage, which was inhibited by FK506.
BACKGROUND: T-cell hypersensitivity is implicated in the tissue damage in a variety of gastrointestinal diseases. The aim of this study was to characterize the spectrum of pathological changes induced by T-cell activation in explants of fetal human small intestine, to modulate the pathology by immunological intervention, and to define the cellular pathways in intestinal damage. METHODS: Explants of fetal human small intestine were cultured with pokeweed mitogen in the presence or absence of dexamethasone or FK506. Pathological changes were then assessed by morphology or on frozen sections. RESULTS: Activation of lamina propria T cells produced variable mucosal damage that could be classified into two main types. Some explants showed villous atrophy and crypt hyperplasia whereas in others there was almost total mucosal destruction. This latter appearance predominated in explants from older specimens. Explants that were destroyed contained high numbers of T cells and activated macrophages. FK506 could completely inhibit mucosal damage, especially in younger specimens, whereas dexamethasone, even at high doses, prevented mucosal destruction, but individual explants continued to show villus atrophy and crypt hyperplasia. CONCLUSIONS: These results indicate that there is a quantitative relationship between mucosal cell-mediated immunity and the pathological outcome and that large numbers of activated macrophages in the mucosa can result in tissue destruction.
In the intestine large numbers of bacteria and their products are separated by a single epithelial layer from resident inflammatory cells (macrophages and lymphocytes). Many of these bacterial products, such as lipopolysaccharides and peptidoglycans, are potent stimulators of free radical and inflammatory cytokine production by macrophages. This can occur in vivo in response to mucosal invasion by enteropathogenic bacteria or because of inappropriate activation of these cells, as in chronic inflammatory bowel disease. In this review we present evidence for production of cytokines in normal intestine and in intestinal inflammatory conditions. The adverse effects of cytokine production upon intestinal homeostasis, in particular disruption of epithelial integrity and prothrombotic changes in the vascular endothelium, are also discussed.
Growth impairment of undefined aetiology occurs in approximately 30% of children with chronic inflammatory bowel disease. We measured urinary growth hormone concentrations in 36 children with chronic inflammatory bowel disease and 51 normal controls. The median urinary concentration of growth hormone in the stunted children with chronic inflammatory bowel disease was 15.8 ng/g creatinine (range 4.3-32.6), compared with 11.7 ng/g creatinine (range 4.1-35.9) in those with normal growth. The difference was statistically not significant (p = 0.15). Moreover, there was no significant difference between the patients and the control group. One stunted patient had a urinary growth hormone (UGH) concentration below the normal range, whereas four patients with normal height were also below the normal range. Four of these five patients (80%) were on corticosteroid treatment at the time of urinary collection, whereas only 26% of the patients with normal UGH were also on corticosteroid treatment. We conclude that growth retardation in children with chronic inflammatory bowel disease is probably not related to growth hormone deficiency but must involve other mechanisms.
This study determined the location and tissue density of cells immunoreactive for tumour necrosis factor alpha (TNF alpha) in intestinal specimens from 24 patients with chronic inflammatory bowel disease (15 with Crohn's disease, nine with ulcerative colitis) and 11 controls. There was significantly increased density of TNF alpha immunoreactive cells in the lamina propria of both ulcerative colitis and Crohn's disease specimens, although the distribution of these cells differed in the two conditions. In ulcerative colitis most of the TNF alpha immunoreactivity was seen in the subepithelial macrophages, with comparatively less in the deep lamina propria, while in Crohn's disease immunoreactive cells were distributed evenly throughout the lamina propria. Increased submucosal immunoreactivity was found only in Crohn's disease, in which TNF alpha positive macrophages tended to cluster around arterioles and venules, often infiltrating and disrupting vascular endothelium. It is suggested that this degree of TNF alpha production probably contributes significantly to the pathogenesis of both Crohn's disease and ulcerative colitis, by impairing the integrity of epithelial and endothelial membranes, increasing inflammatory cell recruitment, and by prothrombotic effects on the vascular endothelium.
Both immunological hypersensitivity and vascular abnormalities have been implicated in the pathogenesis of inflammatory bowel disease. In an attempt to link the two hypotheses, we sought evidence of local production of endothelin-1, a potent vasoconstrictor, in patients with Crohn's disease and ulcerative colitis. An immunohistochemical method was used to detect endothelin-1 in tissue samples from sixteen Crohn's disease patients, nine ulcerative colitis patients, and thirteen controls. In the controls, positively staining cells were infrequent in both lamina propria (mean 0.9% of total cells, 95% confidence interval 0.1-1.7%) and submucosa (2.3%, 0.4-4.1%). The percentage of endothelin-immunoreactive cells was significantly higher in the two disease groups than in the controls. Among the Crohn's disease patients, there were more immunoreactive cells in the submucosa than in the lamina propria (19.1%, 15.2-22.1% vs 12.3%, 8.1-16.5%; p less than 0.001), whereas the converse was true for the ulcerative colitis group (8.6%, 1.1-16.1% vs 24.4%, 14.1-34.6%; p less than 0.001). Immunoreactive macrophage aggregates around submucosal blood vessels were common in samples from Crohn's disease patients. Endothelin concentrations, measured by radioimmunoassay, in supernatants of homogenised tissue samples were significantly higher in Crohn's disease and ulcerative colitis than in controls. We suggest that local endothelin production by inflammatory cells may contribute to vasculitis in chronic inflammatory bowel disease by inducing intestinal ischaemia through vasoconstriction.
Measurement of disease activity in patients with inflammatory bowel disease is difficult. The best available methods are complex and time consuming, but it may be possible to use tumour necrosis factor alpha (TNF alpha) concentration in stool as a marker of disease activity. We measured TNF alpha concentrations in stool samples from normal children, infants with diarrhoea, and children with inflammatory bowel disease in active and inactive phases of the disease. In 10 normal children and 14 children with diarrhoea, median stool TNF alpha concentrations were 58 and 45 pg/g stool, respectively. Compared with diarrhoeal controls, stool TNF alpha concentrations were significantly increased in children with active Crohn's disease (n = 13, median 994 pg/g, p less than 0.0002) and active ulcerative colitis (n = 4, range 276-5982 pg/g, p less than 0.003). In patients with inactive disease, either as a result of surgery or treatment with steroids, the concentration of stool TNF alpha fell to those of controls. Measurement of stool TNF alpha concentrations may provide a simple way to monitor disease activity in inflammatory bowel disease.
BACKGROUND: Tumour necrosis factor alpha may contribute to the lung damage that occurs in the adult respiratory distress syndrome. Whether it occurs in the lungs of preterm infants with respiratory distress syndrome is unknown. METHODS: Tumour necrosis factor alpha concentrations in the bronchopulmonary secretions of 28 ventilated preterm infants were determined by the enzyme linked immunosorbent assay. RESULTS: Concentrations were low in the first three days of life, being undetectable in nine of the 20 infants whose bronchopulmonary secretions were sampled. From day 4 concentrations were increased and detectable in all but two of 14 infants. Similar concentrations were found in samples taken on days 8-20 and 21-40. Greater mean concentrations occurred in those infants requiring oxygen for a long time. In six infants who received dexamethasone treatment for prolonged ventilator dependency treatment was associated with a reduction in tumour necrosis factor alpha concentrations. CONCLUSIONS: Tumour necrosis factor may contribute to the neonatal respiratory distress syndrome, as suggested for the adult respiratory distress syndrome. The therapeutic effects of dexamethasone treatment in neonatal respiratory distress syndrome may be mediated, at least in part, by reduced production of pulmonary tumour necrosis factor.
An 8-year-old girl presenting in hypoglycaemic coma was shown to have isolated deficiency of adrenocorticotrophic hormone (ACTH) secretion. Failure to secrete ACTH in response to intravenous administration of synthetic ovine corticotrophin-releasing factor (CRF-41) suggests that this disorder was due to a primary pituitary defect, rather than of hypothalamic origin.
Serum tumour necrosis factor alpha (TNF alpha) concentrations were measured by enzyme linked immunoadsorbent assay in 31 normal children and during 65 episodes of clinical remission and 54 episodes of relapse in 92 children with chronic inflammatory bowel disease. An appreciable rise in TNF alpha was found only in children in relapse of ulcerative colitis and colonic Crohn's disease. The group of children with small bowel Crohn's disease in relapse did not show increases of TNF alpha above control concentrations, despite an equivalent rise in disease indices. Height velocity was depressed in children with relapse of large bowel Crohn's disease and ulcerative colitis compared with the equivalent condition in remission. The impairment of growth velocity was significantly greater in relapse of large bowel Crohn's disease and ulcerative colitis than in small bowel Crohn's disease alone, although for the subgroups in stage 1 puberty (prepubertal) the differences were not significant. Inadequate growth in chronic inflammatory bowel disease is currently ascribed to inadequate nutrition and TNF alpha may contribute to this through its cachexia inducing effects. It may, in addition, diminish pituitary growth hormone release. These results suggest that production of TNF alpha may be associated with growth failure in relapse of colonic inflammatory bowel disease.
Kawasaki disease (mucocutaneous lymph node syndrome) is an acute vasculitis of childhood carrying a 1-2 per cent mortality from cardiovascular complications. Despite the extensive literature on Kawasaki disease in paediatric journals, there has been a paucity of documentation in the otolaryngology literature. This is despite the fact that Kawasaki disease may present as an otolaryngological emergency before the diagnosis is established. We describe three cases of Kawasaki disease, all of which presented to the ENT department of this hospital within a period of two months. These cases illustrate the slow evolution characteristic of the disease and highlight the difficulties of diagnosis in the initial febrile stage. We emphasize the importance of considering the diagnosis when treating a young child with a pyrexia resistant to antibiotics, as prompt introduction of therapy may decrease the risk of fatal coronary artery or cardiac involvement.
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