The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Summary. The effects of orally-administered myo-inositol have been compared with those of an aldose reductase inhibitor on acute neurological defects in experimentally diabetic rats. Three groups of streptozotocin-treated diabetic rats (50 mg/kg, IP) together with three groups of age-matched controls (saline, IP) were compared. One pair of groups (control and diabetic) were untreated for 3 weeks, another pair of groups received daily oral myo-inositol (667 mg/kg) and the third pair received an aldose reductase inhibitor (IC1105 552; 50mg.kg-l.day -1, orally). The untreated diabetic group showed statistically significant deficits in accumulation, proximal to 24h sciatic nerve constrictions, of choline acetyltransferase activity by comparison with untreated controls (2.8 _+ 0.4 versus 5.1 + 0.4 nmol acetylcholine, h-~. nerve-~ ; p<0.001). The untreated diabetic rats also showed a fall in motor nerve conduction velocity of 6.2 + 0.7 m/s which was statistically significant (p<0.001). Treatment of the diabetic group with myo-inositol prevented the development of both defects of axonal transport and conduction velocity; both measurements were similar to those of the myo-inositol treated control rats. Likewise the diabetic rats which received aldose reductase inhibitor showed prevention of both defects. Nerves from untreated diabetic rats showed marked sorbitol accumulation and a statistically significant reduction in myoinositol content by comparison with the untreated controls (sorbitol, 1.56 + 0.22 versus 0.8___ 0.01 and myo-inositol, 1.47 _+ 0.10 versus 2.3 _+ 0.10 nmol/mg; p < 0.001). Treatment of the diabetic rats with myo-inositol elevated the myo-inositol levels in nerve (3.05 + 0.22 nmol/mg) without affecting nerve sorbitol levels. Treatment of diabetic rats with aldose reductase inhibitor also normalised nerve myo-inositol (2.75 + 0.20 nmol/mg) and reduced nerve sorbitol (0.08 + 0.01 nmol/mg). These findings are consistent with the suggestion that both treatments prevent the development of the two functional defects by normalising the nerve myo-inositol content.Key words: Diabetic neuropathy, axonal transport, nerve conduction, nerve crush, myo-inositol, aldose reductase.Investigation into the causes of diabetic neuropathy has stimulated interest in three areas of study. Firstly, there have been a number of demonstrations of disordered axonal transport in the nerves of experimentally diabetic rats [17]. Secondly, several groups of workers have shown that inhibitors of the enzyme aldose reductase prevent or ameliorate some of the acute neurological defects seen in diabetic animals [20,25] and patients [4,11]. Thirdly, there has been the discovery that administration of myo-inositol to diabetic rats reverses the reduction in nerve myo-inositol content associated with diabetes and attenuates or abolishes nerve conduction velocity defects [8,9]. We have sought to examine possible links between these phenomena. In a preliminary study we found that administration of an inhibitor of aldose reductase, over the first ...

This investigation was designed to determine whether the aldose reductase inhibitor Sorbinil prevented the development of or reversed defects of nerve conduction and axonal transport in streptozotocin-diabetic rats. Untreated diabetes of either 3 or 6 wk duration caused a fall in sciatic motor nerve conduction velocity (MNCV) of 6-9 m/s (P less than 0.001) and significantly reduced the accumulation of axonally transported choline acetyltransferase activity against a 24-h sciatic nerve crush. These functional defects were associated with accumulation of sorbitol and depletion of myo-inositol in the sciatic nerve. Treatment with Sorbinil (25 mg/kg/day, p.o.) throughout the period of diabetes prevented the development of all these abnormalities in both 3- and 6-wk diabetic groups. In a second study, three groups of rats were subject to 3 wk untreated diabetes followed by Sorbinil treatment (as above) for 1, 2, or 3 wk to determine whether the abnormalities expected from 3 wk of untreated diabetes could be reversed. One week of treatment significantly elevated both MNCV and choline acetyltransferase accumulation (P less than 0.05). The longer treatments progressively ameliorated these defects such that the group that received Sorbinil for the second 3 wk of a 6-wk diabetic period gave values that were similar to controls and to diabetic rats that had been given Sorbinil throughout their diabetes. Sorbitol accumulation was markedly reduced by only 1 wk of Sorbinil treatment, but the normalization of myo-inositol levels required 2 wk of treatment. These findings indicate that Sorbinil treatment in diabetic rats prevented and reversed both Sorbitol accumulation and depletion of nerve myo-inositol in the sciatic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

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