SUMMARY Unequivocal apoptoses were seen by light microscopy in examples of leprosy, sarcoidosis, tuberculosis, Crohn's disease and foreign body granulomata. A limited electron microscopic investigation showed typical apoptotic bodies in both sarcoid and leprosy granulomata. The number of apoptoses and mitoses in granulomata were counted and their densities calculated. The wide variation in the results between individual lesions may reflect differences in disease activity.Current understanding of cell turnover in granulomata is based largely on studies of experimentally induced granulomata in animals by Dannenberg, Spector, and others.' These experiments established that mononuclear phagocytes in granulomata have a finite life span and that this varies with the eliciting agent. The eventual fate of mononuclear cells in granulomata is not clear, although evidence from some studies suggests that cell death has a major role.2 Cell necrosis is not readily apparent in noncaseating granulomata, however, and hence regression of differentiated mononuclear phagocytes to less mature forms with subsequent emigration from the lesion has been proposed as an alternative explanation.3Another possible mechanism for the loss of mononuclear phagocytes from granulomata is apoptosis, a morphologically distinctive form of cell death which affects isolated cells in living tissue.4 Apoptosis occurs in a wide range of physiological and pathological circumstances, including involution of the adrenal cortex,5 secretory endometrium,6 tadpole tails,7 and basal cell carcinoma.8 Cells undergoing apoptosis show condensation and fragmentation into a number of membrane bound eosinophilic fragments which are then endocytosed by surrounding cells, even if these are not normally phagocytic.9 In contrast with true necrosis, cells undergoing apoptosis do not provoke an inflammatory response. As the process lasts a matter of hours, detection of even small numbers of apoptotic bodies within tissues indicates appreciable cell loss.During a recent study of the histology of leprosy lesions, we observed apoptoses within both tuberculoid and lepromatous lesions.10 We now have ex-

V565 is an engineered TNFα-neutralising single domain antibody formulated into enteric coated mini-tablets to enable release in the intestine after oral administration as a possible oral treatment for inflammatory bowel disease (IBD). Following oral administration, ileal recovery of V565 was investigated in four patients with terminal ileostomy. Intestinal and systemic pharmacokinetics were measured in six patients with Crohn’s disease and evidence of target engagement assessed in five patients with ulcerative colitis. Following oral administration, V565 was detected at micromolar concentrations in ileal fluid from the ileostomy patients and in stools of the Crohn’s patients. In four of the five ulcerative colitis patients, biopsies taken after 7d dosing demonstrated V565 in the lamina propria with co-immunostaining on CD3+ T-lymphocytes and CD14+ macrophages. Phosphorylation of signalling proteins in biopsies taken after 7d oral dosing was decreased by approximately 50%. In conclusion, enteric coating of V565 mini-tablets provided protection in the stomach with gradual release in intestinal regions affected by IBD. Immunostaining revealed V565 tissue penetration and association with inflammatory cells, while decreased phosphoproteins after 7d oral dosing was consistent with V565-TNFα engagement and neutralising activity. Overall these results are encouraging for the clinical utility of V565 in the treatment of IBD.

SUMMARYBackground DDP733, a selective partial 5HT 3 receptor agonist, increases lower oesophageal sphincter pressure in experimental animal models. However, its effect on gastro-oesophageal reflux or lower oesophageal sphincter pressure in humans remains unknown.

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