'False, fleeting, perjured Clarence': pseudonymity and criminality in the writings of James Clarence Mangan

This article explores the significance of the adopted partial pseudonym “Clarence” to James Clarence Mangan (1803-1849), who is increasingly regarded as the most important Irish poet before W. B. Yeats. Tracing the literary history of “Clarence” from Shakespeare to Maria Edgeworth, this essay argues that the intriguing adoption exposes a preoccupation with themes of unlawful textual copying that is at the centre of Mangan’s imagination. These tropes assume singular significance when appreciated alongside Mangan’s profession as a scrivener. While literary criticism has separated Mangan the poet from Mangan the legal scribe, his hitherto under-explored assumption of “Clarence” provides a clue to their close and crucial connection. These themes of pseudonymity, copying, and criminality combine with particular resonance in his quasi-translation “The Man in the Cloak” (1838) to open up new perspectives on Mangan’s writing and its participation in wider European cultural contexts and concerns. The essay will conclude with a salient comparison of Mangan’s story with Nikolay Gogol’s seminal story “The Overcoat”, or, “The Cloak” (1842).

Prophylactic ranitidine treatment in critically ill children - a population pharmacokinetic study

Aims: To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods: Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results: A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P <0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1lh for total clearance and 285l for volume of distribution, both allometrically modelled for a 70kg adult. Final estimates for absorption rate constant and bioavailability were 1.31h and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions: Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Drug repositioning for Alzheimer's disease

Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.

Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk

We conducted a genome-wide association study of male breast cancer comprising 823 cases and 2,795 controls of European ancestry, with validation in independent sample sets totaling 438 cases and 474 controls. A SNP in RAD51B at 14q24.1 was significantly associated with male breast cancer risk (P = 3.02 × 10(-13); odds ratio (OR) = 1.57). We also refine association at 16q12.1 to a SNP within TOX3 (P = 3.87 × 10(-15); OR = 1.50).

Kingship by Descent or Kingship by Election? The Contested Title of James VI and I

Throughout the reign of Elizabeth I, a steady stream of tracts appeared in English print to vindicate the succession of the most prominent contenders, Mary and James Stuart of Scotland. This article offers a comprehensive account of the polemical battle between the supporters and opponents of the Stuarts, and further identifies various theories of English kingship, most notably the theory of corporate kingship, developed by the Stuart polemicists to defend the Scottish succession. James's accession to the English throne in March 1603 marked the protracted end of the debate over the succession. The article concludes by suggesting that, while powerfully renouncing the opposition to his succession, over the course of his attempt to unify his two kingdoms, James and his supporters ultimately departed from the polemic of corporate kingship, for a more assertive language of kingship by natural and divine law.

Seven new loci associated with age-related macular degeneration

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P <5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P <5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.