Insights provided by the study of the small intestine in the child and the foetus.
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Biomedical subjects
Publications and source records attributed to J Walker-Smith.
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Over a 10 year period a total of 102 teenage patients with coeliac disease were assessed on transfer from paediatric hospitals to an adult clinic. Fifty seven patients said they were on a strict gluten free diet; 36 were semistrict, and nine admitted to eating a normal diet. Jejunal mucosal abnormalities, however, suggested that many patients on the 'strict' diet were actually consuming gluten. All patients were well with biochemical parameters within the normal range. Height percentiles were not significantly different from the normal population but patients, as a group, were significantly lighter.
We have investigated DNA polymorphism of the class II alpha chain genes in HLA typed patients with insulin dependent diabetes mellitus (IDDM; n = 79), celiac disease (CD; n = 46), dermatitis herpetiformis (DH; n = 53), and controls (n = 86). Preferential allelic associations of HLA genes and gene products have thus been constructed for susceptibility to these diseases. DR alpha and DQ alpha gene polymorphisms indicated heterogeneity of HLA DR3, DRw6, and DR7, and HLA DR2 and DRw6, respectively. In DR7 positive CD patients a 3.8-kilobase (kb) DR alpha fragment, which correlated with DQw3, was found in only 11% of patients compared with 45% of corresponding controls (P less than 0.05). An increased frequency of a DX alpha genotype UU in all three diseases was found (IDDM 59%, DH 45%, CD 48%, compared to 21% in controls, P less than 0.001), which is not explained solely by the increased frequencies of DR3-DX alpha U. We therefore conclude part of the genetic susceptibility for these three conditions is encoded by genes within the DQ-DX subregion.
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A male infant, aged 1 year 3 months, was admitted to the hospital with protracted diarrhoea, vomiting, and weight loss. The diarrhoea and vomiting coincided with an outbreak of acute diarrhoea and vomiting affecting other family members. Biopsy showed a flat small intestinal mucosa which did not respond to a diet free of gluten, cow's milk, and eggs, or during 8 weeks of intravenous alimentation. Steroids were given, and courses of nalcrom and later cimetidine, but these did not produce any significant improvement. A rare IgG autoantibody specific for gut epithelium was found, which, when present, was associated with a cytological abnormality of crypt enteroblasts. The autoantibody disappeared after treatment with cyclophosphamide, and the cytological abnormality subsequently diminished. However, the mucosa remained severely abnormal and has been so for 23 months. It is possible that an autoimmune reaction against the patient's small intestinal mucosa has led to persistence of the enteropathy.
Six healthy children, born in the UK, travelled to their parental homeland and developed a severe form of traveller's diarrhoea. This was characterised by rapid loss of weight and chronic diarrhoea. On return to this country, investigation in 5 of them showed an abnormal, small intestinal mucosa. There was a high incidence of pathogens and potential pathogens found in stools and duodenal juice. Immunodeficiency was found in 2 of them. Small intestinal mucosal damage related to gut infection in previously well children appears to be of cardinal importance in the interaction between chronic diarrhoea and malnutrition. This observation may point the way to future research into the primary role of gut infection in the initiation of the cycle of malnutrition and chronic diarrhoea in developing communities.
Although impaired growth hormone secretion in response to pharmacological stimuli occurs in some growth retarded children with Crohn's disease, its relationship to past and future th is uncertain. We have therefore determined the growth hormone and gonadotrophin response to the physiological stimulus of sleep by continuous venous sampling in five severely gonadotrophin profiles, the mean plasma hormone concentrations during the first five hours of sleep were determined. In three of the five patients, five hour mean growth hormone levels were reduced (3.8, 5.0, and 8.5 mU/l) compared with levels reported previously in normal short children (10-43 mU/l), although the pulsatile pattern of growth hormone secretion was preserved in all. Nocturnal growth hormone secretion was unrelated to the growth velocities of these children during both pre- and post-treatment assessment periods but a significant correlation was found between growth hormone concentration and a disease activity score (r = 0.79, P less than 0.05), suggesting that growth hormone release by the pituitary was influenced by the severity of the disease. Nocturnal growth hormone secretion was also correlated with gonadotrophin secretion (luteinising hormones, r = 0.99, and follicle stimulating hormone, r = 0.96; p less than 0.01) indicating more extensive hypothalamic-pituitary disturbance. These findings suggest that hypothalamic-pituitary function is depressed in growth retarded children with Crohn's disease, but that abnormalities of growth hormone secretion are unlikely to be directly involved in the growth retardation seen in this condition.
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Serial small intestinal biopsies related to withdrawal and challenge with cows' milk are described in 5 infants with cows' milk protein intolerenace. On the basis of these serial observations the existence of a cows' milk-sensitive enteropathy in infancy is clearly established. The cows' milk-sensitive mucosal lesion varied in its severity ranging from a partly flat mucosa to a mild degree of partial villous atrophy. Intraepithelial lymphocyte counts rose after a positive milk challenge, but on only one occasion to a level outside the normal range. The technique of serial biopsies related to dietary milk enables a firm diagnosis of cows' milk intolerance to be made upon the basis of a single milk challenge. Clinically this appears to be a temporary condition which disappears by the age of 2 years.
Case history is reported of an infant who was changed from breast to bottle feeding at fourth day of life, who on ninth day developed bilious vomiting and bloody diarrhoea. Later gas was found in colonic wall on X-ray. Necrotizing enterocolitis was diagnosed and infant managed with total intravenous alimentation. On recovery although she tolerated breast milk, return to cow's milk formula lead to return of bloody diarrhoea. Subsequently she thrived on a cow's milk-free diet based on chicken meat formula. At four months after total of 15 ml cow's milk she had an acute anaphylactic reaction. She recovered and is well on milk-free diet. Thus, this infant has recovered from necrotizing enterocolitis but has evidence of persistent cow's milk protein intolerance. The hypothesis is put forward that in this child cow's milk protein played a major role in the pathogenesis of necrotizing enterocolitis.
Although perianal ulceration is common in Crohn's disease, extensive perineal ulceration particularly in children is rare. The case history is presented of a child who developed progressive hypertrophy of the vulva and ulceration of the groins at the age of 11 years but diagnosis of Crohn' s disease was delayed for 21 months. Treatment with steroids and azathioprine has induced a successful remission but difficulty has been experienced in reducing the steroid dosage.
The pH of the stool and the amount of reducing substances present were observed in 51 normal neonates aged 5 to 8 days. A stool pH of 5 or less was found in 6, 4 of whom were exclusively breast fed. Reducing substances, 0-5% or more, were found in the stools of 16. Stool chromatography in 13 showed lactose, glucose, galactose, or a variable combination of these sugars--that is, a pattern consistent with lactose malabsorption. The stools of 3 infants contained oligosaccharides or maltose only. Chromatography of urine from 60 normal neonates showed detectable sugars in 11 but only 3 had levels above 50 mg/100 ml.
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