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Summary In this study, we report on the distribution of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) mRNA expression in human normal colorectal mucosa, adenomas and adenocarcinomas. Northern blot analysis showed five TIMP-3 mRNA transcripts to be present in normal mucosal epithelium and in moderately and poorly differentiated carcinoma. Adenomas and well-differentiated carcinomas were not examined in this part of the investigation. In situ hybridization studies showed no detectable TIMP-3 mRNA in normal and adenomatous tissue. In contrast, TIMP-3 mRNA is localized to stromal fibroblast-like cells in colorectal carcinomas, with an increased incidence in moderately and poorly differentiated groups compared with well-differentiated carcinomas. Expression in both the moderately and the poorly differentiated tumour groups was strongest at the tumour invasive edge; none of the poorly differentiated carcinomas showed mRNA expression in regions ahead of the invasive edge, compared with 3 of 12 of the moderate group. To our knowledge, this is the first detailed report on the regional localization of TIMP-3 mRNA in colorectal tumours. We suggest that the lack of TIMP-3 mRNA expression in host stromal tissues ahead of poorly differentiated carcinomas may contribute to their increased invasiveness.

Background-Basic fibroblast growth factor (bFGF) promotes angiogenesis and healing of gastric ulcers in rats, and bFGF expression is up regulated in such ulcers. However, little is known about expression of bFGF in human gastric mucosa. Aims-To investigate bFGF expression in intact human gastric mucosa and gastric ulcers and to determine whether low bFGF content or altered binding by mucosa is associated with ulceration. Subjects-Endoscopy outpatients, gastrectomy patients, and organ donors. Methods-bFGF was isolated by heparin aYnity chromatography and characterised by western blotting and endothelial cell bioassay. bFGF was measured by immunoassay and its distribution defined by immunohistochemistry and in situ hybridisation. Binding of bFGF by heparan sulphate proteoglycans was investigated by sodium chloride and heparin extraction. Results-Bioactive bFGF (19 kDa) was detected in normal mucosa but bFGF mRNA was not found. bFGF expression was up regulated in granulation tissue endothelial cells, mononuclear cells, and epithelial cells at the ulcer rim. Gastric ulcer patients had constitutively low bFGF concentrations in intact antral mucosa which were not explained by changes in binding to heparan sulphate proteoglycans. Conclusions-bFGF expression is up regulated in human gastric ulcers. Low intact mucosal bFGF content is associated with gastric ulceration. (Gut 1998;43:525-536)

DNA probes for specific integrase genes were used to study 122 R plasmids encoding the predominant trimethoprim-insusceptible type Ia dihydrofolate reductase (DHFR) found in clinical isolates of Escherichia coli. The predominance of the type Ia DHFR was thought to result from the location of its gene on transposon Tn7, but of trimethoprim R plasmids carrying this gene that were collected between 1978 and 1983, between 1987 and 1988, and during 1992, only 49/60 (81.6%), 30/43 (69.8%) and 9/19 (47.4%) respectively hybridized with a probe for the Tn7 integrase gene. It has been suggested that novel genetic elements termed 'integrons' may play an important role in the dissemination of antibiotic resistance genes. Known integrons encode an integrase similar to that encoded by transposon Tn21, and 28 Tn7-negative plasmids (10/60 from 1978-83, 10/43 from 1987-8 and 8/19 from 1992) showed homology with a probe specific for the Tn21 integrase gene. Six plasmids were negative with both probes. It is concluded that Tn7 has played an important role in the dissemination of the gene encoding the type Ia DHFR amongst clinical isolates of E. coli in the Nottingham region of the UK, but that other genetic structures, some of which seem to have an integrase function similar to that of known integrons, may be playing an increasingly significant role.