Saffron Walden Community Hospital

1. The anatomical arrangements of the submucosal layer at the pylorus have been examined and the attachment of mucosa to muscle at the pylorus has been emphasised. 2. It is argued that because of this attachment, contracttion of the muscularis mucosae will pull up mucous membrane into the pyloric ring to form a plug which occludes the lumen. This plug can be seen in a proportion of gastrectomy specimens, where it forms a watertight seal. Movements of the mucosa without affecting the muscularis propria can be shown to “open” and “close” the pylorus. 3. A hypothesis of closure of the pylorus by this plug is advanced, and reasons given that although it is a low-pressure closure, it is sufficient to obstruct the low pressure emptying of the stomach and hence explain some radio-logical observations. 4. Closure of the whole pyloric canal by the fan-shaped muscle is described and this produces high intra-luminal pressure with an action like a mechanical press, squirting fluid forwards and backwards out of the canal. 5. It is believed that the pylorus also closes at high pressure during duodenal cap contraction as a barrier to reflux into the stomach.

The role of complement regulation at the cell surface is reviewed and the desirability of being able to design exogenous therapeutic agents that function in this way is considered. An analysis of naturally occurring membrane proteins suggested that one particular type of membrane-localization mechanism (the myristoyl-electrostatic peptide switch) could be mimicked by minimization of the key molecular features involved and incorporation into relatively simple synthetic protein modification agents that could be attached to soluble proteins with retention of water solubility. This approach amounts to reconstruction of a membrane protein by substitution of the natural anchor by a more chemically tractable structure. It allows solution of a number of practical problems associated with production of recombinant membrane-interactive proteins and has permitted the development of one such protein (APT070, Mirococept) as a pharmaceutical agent. The membrane-binding properties of APT070 make it not only a potent regulator of complement activation but also permit it to be used in experimental and therapeutic situations where conventional soluble biopharmaceuticals are of limited use. Two such clinical applications of APT070 and the scope for application of other complement regulators such as CD59 in these reconstructed forms are also outlined.