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.

Cathepsin S expression: An independent prognostic factor in glioblastoma tumours - A pilot Study

Cysteine proteinases have been implicated in astrocytoma invasion. We recently demonstrated that cathepsin S (CatS) expression is up-regulated in astrocytomas and provided evidence for a potential role in astrocytoma invasion (Flannery et al., Am J Path 2003;163(1):175–82). We aimed to evaluate the significance of CatS in human astrocytoma progression and as a prognostic marker. Frozen tissue homogenates from 71 patients with astrocytomas and 3 normal brain specimens were subjected to ELISA analyses. Immunohistochemical analysis of CatS expression was performed on 126 paraffin-embedded tumour samples. Fifty-one astrocytoma cases were suitable for both frozen tissue and paraffin tissue analysis. ELISA revealed minimal expression of CatS in normal brain homogenates. CatS expression was increased in grade IV tumours whereas astrocytoma grades I–III exhibited lower values. Immunohistochemical analysis revealed a similar pattern of expression. Moreover, high-CatS immunohistochemical scores in glioblastomas were associated with significantly shorter survival (10 vs. 5 months, p = 0.014). With forced inclusion of patient age, radiation dose and Karnofsky score in the Cox multivariate model, CatS score was found to be an independent predictor of survival. CatS expression in astrocytomas is associated with tumour progression and poor outcome in glioblastomas. CatS may serve as a useful prognostic indicator and potential target for anti-invasive therapy.

Deep sampling and testing in soft stratified clay

A 37-m thick layer of stratified clay encountered during a site investigation at Swann's Bridge, near the sea-coast at Limavady, Northern Ireland, is one of the deepest and thickest layers of this type of material recorded in Ireland. A study of the relevant literature and stratigraphic evidence obtained from the site investigation showed that despite being close to the current shoreline, the clay was deposited in a fresh-water glacial lake formed approximately 13 000 BP. The 37-m layer of clay can be divided into two separate zones. The lower zone was deposited as a series of laminated layers of sand, silt, and clay, whereas the upper zone was deposited as a largely homogeneous mixture. A comprehensive series of tests was carried out on carefully selected samples from the full thickness of the deposit. The results obtained from these tests were complex and confusing, particularly the results of tests done on samples from the lower zone. The results of one-dimensional compression tests, unconsolidated undrained triaxial tests, and consolidated undrained triaxial compression tests showed that despite careful sampling, all of the specimens from the lower zone exhibited behaviour similar to that of reconstituted clays. It was immediately clear that the results needed explanation. This paper studies possible causes of the results from tests carried out on the lower Limavady clay. It suggests a possible mechanism based on anisotropic elasticity, yielding, and destructuring that provides an understanding of the observed behaviour.Key words: clay, laminations, disturbance, yielding, destructuring, reconstituted.