The rate constants for nucleophilic reaction of nine substituted pyridines with methyl chloroformate gives a sharply curved Bronsted plot, the slope changing from p 0.93 to 0.1 5 with increasing reactivity. This contrasts with the straight line (p 0.93) observed with p-nitrophenyl acetate, and is shown to be quantitatively consistent with a change in rate-determining step. It is argued that this is from breakdown to formation of a zwitterionic tetrahedral intermediate which is only just stable enough to exist. The hydrolytic stabilities of some of the rnethoxycarbonylpyridinium ions produced by this reaction, and the nucleophilic reactivities towards methyl chloroformate of imidazole, of phenolate, p-nitrophenolate. and acetate anions, and of phosphate dianion are reported and discussed.

In a BRCA1 screening in familial breast cancer carried out in different centres in Spain, France, and United Kingdom, a missense mutation 330A>G which results in a Arg to Gly change at codon 71 (R71G) was independently identified in 6 families, all of them with Spanish ancestors. This residue coincides with the -2 position of the exon 5 donor splice site. We further investigated the effect of this base substitution on the splicing of BRCA1 mRNA. The sequence analysis of the cDNA indicated that 22 bp of exon 5 were deleted, creating with the first bases of exon 6 a termination codon at position 64, which results in a truncated protein. The BRCA1 haplotype of the R71G carrier patients and Spanish controls was analysed by use of six microsatellites located within or near BRCA1. Our results are consistent with the possibility that these families shared a common ancestry with BRCA1 R71G being a founder mutation of Spanish origin.

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A questionnaire was sent to veterinary surgeons who had diagnosed exocrine pancreatic insufficiency (EPI) by assay of low serum concentration of trypsin‐like immunoreactivity in 302 dogs. Two‐thirds of cases were German shepherd dogs, in which EPI was found equally in males and females. The disease was also diagnosed in 33 other breeds, most commonly in crossbreeds, spaniels, small terriers and collies, and was more common in females. Detailed replies on 160 cases were returned; 79 dogs were alive and 41 dead, with the remainder lost to long term follow‐up. The major reasons for death were euthanasia because of the cost, the prognosis, and failure to respond to treatment. An adequate response to treatment was obtained in 92 per cent of dogs. Uncoated preparations of pancreatic enzyme replacement were found to be more successful, and the use of dietary manipulation and antibiotics were frequently reported to be useful adjunctive therapies.

The rate constants for reaction of eight nitrogen and four oxygen bases with p-nifrophenyl methyl carbonate in water at 25 "C have been measured, and are closely similar to published values forp-nitrophenyl acetate. General acid catalysis is not observed in the methoxyaminolysis of the carbonate, unlike the acetate. Specific salt effects are shown to preclude conclusions regarding the extent of general base catalysis in these reactions. The rate constant for reactions of propylamine with the 1 -methoxycarbonyl-4-methylpyridinium ion has also been measured, and is compared with the published value for the 1 -acetyl compound.