The role of cathepsin C in Papillon-Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis

We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon Lefevre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early,onset, severe periodontitis. Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations. The possible role of CTSC variants in more common types of non-mendelian, early-onset, severe periodontitis ("aggressive periodontitis") has not been investigated. In this study, we have investigated the role of CTSC in all three conditions. We demonstrate that PLS is genetically homogeneous and the mutation spectrum that includes three novel mutations (c.386T>A/p. V129E, c.935A>G/p.Q312R, and c.1235A>G/p.Y412C) in 21 PLS families (including eight from our previous study) provides an insight into structure-function relationships of CTSC. Our data also suggest that a complete loss-of-function appears to be necessary for the manifestation of the phenotype, making it unlikely that weak CTSC mutations are a cause of aggressive periodontitis. This was confirmed by analyses of the CTSC activity in 30 subjects with aggressive periodontitis and age-sex matched controls, which demonstrated that there was no significant difference between these two groups (1,728.7 +/- SD 576.8 mu moles/mg/min vs. 1,678.7 +/- SD 527.2 mu moles/mg/min, respectively, p = 0.73). CTSC mutations were detected in only one of two families with prepubertal periodontitis; these did not form a separate functional class with respect to those observed in classical PLS. The affected individuals in the other prepubertal periodontitis family not only lacked CTSC mutations, but in addition did not share the haplotypes at the CTSC locus. These data suggest that prepubertal periodontitis is a genetically heterogeneous disease that, in some families, just represents a partially penetrant PLS. (C) 2004 Wiley-Liss, Inc.

Famine and land in Ireland and India 1845-1880: James Caird and the political economy of hunger

The perception of Ireland and India as ‘zones of famine’ led many nineteenth-century observers to draw analogies between these two troublesome parts of the British empire. This article investigates this parallel through the career of James Caird (1816–92), and specifically his interventions in the latter stages of both the Great Irish Famine of 1845–50, and the Indian famines of 1876–9. Caird is best remembered as the joint author of the controversial dissenting minute in the Indian famine commission report of 1880; this article locates the roots of his stance in his previous engagements with Irish policy. Caird's interventions are used to track the trajectory of an evolving ‘Peelite’ position on famine relief, agricultural reconstruction, and land reform between the 1840s and 1880s. Despite some divergences, strong continuities exist between the two interventions – not least concern for the promotion of agricultural entrepreneurship, for actively assisting economic development in ‘backward’ economies, and an acknowledgement of state responsibility for preserving life as an end in itself. Above all in both cases it involved a critique of a laissez-faire dogmatism – whether manifest in the ‘Trevelyanism’ of 1846–50 or the Lytton–Temple system of 1876–9.