1 Characterization of allelic variants of the TPMT gene (TPMT) responsible for changes in TPMT activity, and elucidation of the mechanism by which these alleles act, are required because of the clinical importance of this polymorphism for patients receiving thiopurine drugs. 2 We de®ned the mutational and allelic spectrum of TPMT in a group of 191 Europeans. Using PCR ± SSCP, we screened for mutation the entire coding sequence, the exon-intron boundaries, the promoter region and the 3'-¯anking region of the gene. Six mutations were detected throughout the ten exons and seven TPMT alleles were characterized. Four of them, TPMT*2, *3A, *3C and *7, harbouring the known mutations, G238C, G460A, A719G or T681G, were nonfunctional and accounted for 0.5, 5.7, 0.8 and 0.3% of the allele totality, respectively. 3 Within the promoter region, six alleles corresponding to a variable number of tandem repeats (VNTR), were identi®ed. VNTR*V4 and *V5a which harbour four or ®ve repeats of a 17 ± 18 bp unit, were the most frequent (55% and 34%, respectively). The other VNTR alleles, having from ®ve to eight repeats, were rarer. 4 The TPMT phenotype was correctly predicted by genotyping for 87% of individuals. A clear negative correlation between the total number of repeats from both alleles and the TPMT activity level was observed, indicating that VNTRs contribute to interindividual variations of TPMT activity. Therefore, additional analysis of the promoter region of TPMT can improve the phenotype prediction rate by genotyping.

No abstract

A low dose (0.5 mg/kg) of lipopolysaccharide (LPS), administered 72 hours before 60-minute middle cerebral artery occlusion, induced a delayed neuroprotection proven by the significant decrease (-35%) of brain infarct volume in comparison with control, whereas infarct volumes remained unchanged in rats treated 12, 24, or 168 hours before ischemia. This delayed neuroprotective effect of LPS was induced only with low doses (0.25 to 1 mg/kg), whereas this effect disappeared with a higher dose (2 mg/kg). The delayed neuroprotection of LPS was induced in the cortical part of the infarcted zone, not in the subcortical part. The beneficial effect of LPS on consequences of middle cerebral artery occlusion was suppressed by dexamethasone (3 mg/kg) and indomethacin (3 mg/ kg) administered 1 hour before LPS, whereas both drugs had no direct effect on infarct volume by themselves, suggesting that activation of inflammatory pathway is involved in the development of LPS-induced brain ischemic tolerance. Preadministration of cycloheximide, an inhibitor of protein synthesis, also blocked LPS-induced brain ischemic tolerance suggesting that a protein synthesis is also necessary as a mediating mechanism. Superoxide dismutase (SOD) could be one of the synthesized proteins because lipopolysaccharide increased SOD brain activity 72 hours, but not 12 hours, after its administration, which paralleled the development of brain ischemic tolerance. In contrast, catalase brain activity remained unchanged after LPS administration. The LPS-induced delayed increase in SOD brain content was suppressed by a previous administration of indomethacin. These data suggest that the delayed neuroprotective effect of low doses of LPS is mediated by an increased synthesis of brain SOD that could be triggered by activation of inflammatory pathway.

No abstract

Human respiratory mucins consist of a family of glycoproteins with different peptides in which glycosylation, the major post-translational phenomenon, is responsible for about 70 to 80% of the weight of these molecules. This glycosylation generates a remarkable diversity of O-glycosidically linked carbohydrate chains, which are expressed as several hundreds of different chains in a single person. These chains, which can vary from one to about 20 sugars, may be neutral, sialylated, or sulfated. They bear multiple epitopes. Some antigenic determinants such as ABO, Leb antigens in secretor individuals, Lea, or X or Y antigens have been identified. There is increasing evidence that, among other functions, this diversity of chains allows many interactions with microorganisms and may be an important factor in maintaining the sterility of the respiratory tree. In certain pathologic situations such as cystic fibrosis, which is associated with colonization by Pseudomonas aeruginosa, the hypothesis of an alteration of this interaction is open.