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Summary The importance of breastfeeding in low-income and middle-income countries is well recognised, but less consensus exists about its importance in high-income countries. In low-income and middle-income countries, only 37% of children younger than 6 months of age are exclusively breastfed. With few exceptions, breastfeeding duration is shorter in high-income countries than in those that are resource-poor. Our meta-analyses indicate protection against child infections and malocclusion, increases in intelligence, and probable reductions in overweight and diabetes. We did not find associations with allergic disorders such as asthma or with blood pressure or cholesterol, and we noted an increase in tooth decay with longer periods of breastfeeding. For nursing women, breastfeeding gave protection against breast cancer and it improved birth spacing, and it might also protect against ovarian cancer and type 2 diabetes. The scaling up of breastfeeding to a near universal level could prevent 823 000 annual deaths in children younger than 5 years and 20 000 annual deaths from breast cancer. Recent epidemiological and biological findings from during the past decade expand on the known benefits of breastfeeding for women and children, whether they are rich or poor.

Summary There have been real advances in understanding the pathogenesis of autoimmune enteropathy, including determination of specific autoantigens. The most important clinical association is with IPEX (X-linked immune polyendocrinopathy) syndrome, which is due to mutation in the Foxp3 transcription factor, a molecule critical in generation of regulatory T cells. Association of non-IPEX autoimmune enteropathy with T cell activation defects further point to impairment of T cell tolerance mechanisms as the primary underlying cause of autoimmune enteropathy. This also explains the frequency of other autoimmune manifestations. The centrality of T cell responses in autoimmune enteropathy, rather than B cell autoantibody production, as previously thought, is further suggested by the finding of late-onset gut autoimmunity in APS-1 (autoimmune polyglandular syndrome-1), a condition where negative selection of T cells within the thymus is disrupted due to mutation in the Aire (autoimmune regulator) gene. However, this form of autoimmune enteropathy is milder because the immune target is within entero-endocrine cells rather than absorptive enterocytes. There have also been important changes in management, with introduction of more potent immunoregulatory therapy, and more recently the use of bone marrow transplantation, which may theoretically offer hope of a cure in what frequently used to be a fatal condition.

Protein-losing enteropathy (PLE), the loss of plasma proteins through the intestine, is a symptom in ostensibly unrelated diseases. Emerging commonalities indicate that genetic insufficiencies predispose for PLE and environmental insults, e.g. viral infections and inflammation, trigger PLE onset. The specific loss of heparan sulfate (HS) from the basolateral surface of intestinal epithelial cells only during episodes of PLE suggests a possible mechanistic link. In the first tissue culture model of PLE using a monolayer of intestinal epithelial HT29 cells, we proved that HS loss directly causes protein leakage and amplifies the effects of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha). Here, we extend our in vitro model to assess the individual and combined effects of HS loss, interferon gamma (IFNgamma), TNFalpha, and increased pressure, and find that HS plays a central role in the patho-mechanisms underlying PLE. Increased pressure, mimicking venous hypertension seen in post-Fontan PLE patients, substantially increased protein leakage, but HS loss, IFNgamma, or TNFalpha alone had only minor effects. However, IFNgamma up-regulated TNFR1 expression and amplified TNFalpha-induced protein leakage. IFNgamma and TNFalpha compromised the integrity of the HT29 monolayer and made it more susceptible to increased pressure. HS loss itself compromises the integrity of the monolayer, amplifying the effects of pressure, but also amplifies the effects of both cytokines. In the absence of HS a combination of increased pressure, IFNgamma, and TNFalpha caused maximum protein leakage. Soluble heparin fully compensated for HS loss, providing a reasonable explanation for patient favorable response to heparin therapy.

Objective Although immunoglobulin (Ig)E-mediated allergies are readily identifiable, non-IgE-mediated allergies present more diagnostic difficulty. We performed a formal retrospective analysis to determine whether there is a recognizable clinical pattern in children. Methods We studied 121 children (mean age, 17.3 months) with multiple food allergies who were recruited on the basis of adequate immunological assessment by using case notes and parental questionnaire. Results Group 1 (n=44) had rapid reactions to dietary antigens, of whom 41 also showed delayed reactions. Group 2 (n=77) had delayed reactions only. Mean IgE was increased in group 1 but both groups otherwise shared a pattern of increased IgG1, decreased IgG2/4, and low-normal IgA. Lymphocyte subsets were skewed, with an increased percentage of CD4 and CD19 and decreased CD8 and natural killer cells. Gastroesophageal reflux, esophagitis, subtle enteropathy, and constipation were frequent in both groups. Of 55 exclusively breast-fed infants, 44 sensitized before weaning. Twenty-one of the mothers suffered from autoimmunity. Conclusions There appears to be a recognizable pattern of immune deviation and minor enteropathy in children with multiple food allergy, irrespective of the speed of reactions. Disturbed gut motility is particularly common, as is a maternal history of autoimmunity.

Intestinal biopsy in a boy with gastroenteritis-induced protein-losing enteropathy (PLE) showed loss of heparan sulfate (HS. and syndecan-1 core protein from the basolateral surface of the enterocytes, which improved after PLE subsided. Isoelectric focusing analysis of serum transferrin indicated a congenital disorder of glycosylation (CDG) and subsequent analysis showed three point mutations in the ALG6 gene encoding an α1,3-glucosyltransferase needed for the addition of the first glucose to the dolichol-linked oligosaccharide. The maternal mutation, C998T, causing an A333V substitution, has been shown to cause CDG-Ic, whereas the two paternal mutations, T391C (Y131H) and C924A (S308R) have not previously been reported. The mutations were tested for their ability to rescue faulty N -linked glycosylation of carboxypeptidase Y in an ALG6 -deficient Saccharomyces cerevisiae strain. Normal human ALG6 rescues glycosylation and A333V partially rescues, whereas the combined paternal mutations (Y131H and S308R) are ineffective. Underglycosylation resulting from each of these mutations is much more severe in rapidly dividing yeast. Similarly, incomplete protein glycosylation in the patient is most severe in rapidly dividing enterocytes during gastroenteritis-induced stress. Incomplete N -linked glycosylation of an HS core protein and/or other biosynthetic enzymes may explain the selective localized loss of HS and PLE.

Summary 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 twoconditions 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.

Summary 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 aminosalicylic 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-TNFα monoclonals suggest that the shift from broad spectrum immunomodulation to the targeting of critical components of the inflammatory cascade may yet field important dividends.

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.

This statement refers to the Early Report “Ileal-lymphoidnodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children”, published in The Lancet in 1998. It is made by 10 of the 12 original authors who could be contacted. It should be noted that this statement does not necessarily reflect the views of the other co-authors. The main thrust of this paper was the first description of an unexpected intestinal lesion in the children reported. Further evidence has been forthcoming in studies from the Royal Free Centre for Paediatric Gastroenterology and other groups to support and extend these findings. While much uncertainty remains about the nature of these changes, we believe it important that such work continues, as autistic children can potentially be helped by recognition and treatment of gastrointestinal problems. We wish to make it clear that in this paper no causal link was established between MMR vaccine and autism as the data were insufficient. However, the possibility of such a link was raised and consequent events have had major implications for public health. In view of this, we consider now is the appropriate time that we should together formally retract the interpretation placed upon these findings in the paper, according to precedent. We were unable to contact John Linnell.