Continuing mortality of vultures in India associated with illegal veterinary use of diclofenac and a potential threat from nimesulide

AbstractThe collapse of South Asia's Gyps vulture populations is attributable to the veterinary use of the non-steroidal anti-inflammatory drug (NSAID) diclofenac. Vultures died after feeding on carcasses of recently-medicated animals. The governments of India, Nepal and Pakistan banned the veterinary use of diclofenac in 2006. We analysed results of 62 necropsies and 48 NSAID assays of liver and/or kidney for vultures of five species found dead in India between 2000 and 2012. Visceral gout and diclofenac were detected in vultures from nine states and three species: Gyps bengalensis, Gyps indicus and Gyps himalayensis. Visceral gout was found in every vulture carcass in which a measurable level of diclofenac was detected. Meloxicam, an NSAID of low toxicity to vultures, was found in two vultures and nimesulide in five vultures. Nimesulide at elevated tissue concentrations was associated with visceral gout in four of these cases, always without diclofenac, suggesting that nimesulide may have similar toxic effects to those of diclofenac. Residues of meloxicam on its own were never associated with visceral gout. The proportion of Gyps vultures found dead in the wild in India with measurable levels of diclofenac in their tissues showed a modest and non-significant decline since the ban on the veterinary use of diclofenac. The prevalence of visceral gout declined less, probably because some cases of visceral gout from 2008 onwards were associated with nimesulide rather than diclofenac. Veterinary use of nimesulide is a potential threat to the recovery of vulture populations.Financial support and assistance for the project from the Director, Indian Veterinary Research Institute (IVRI), the UK Government’s Darwin Initiative and the Royal Society for the Protection of Birds is gratefully acknowledged.This is the accepted manuscript. The final version is available from Cambridge University Press via http://dx.doi.org/10.1017/S003060531500037

Recent changes in populations of Critically Endangered Gyps vultures in India

SummaryPopulations of the White-rumped VultureGyps bengalensis, Indian VultureG. indicusand Slender-billed VultureG. tenuirostrisdeclined rapidly during the mid-1990s all over their ranges in the Indian subcontinent because of poisoning due to veterinary use of the non-steroidal anti-inflammatory drug diclofenac. This paper reports results from the latest in a series of road transect surveys conducted across northern, central, western and north-eastern India since the early 1990s. Results from the seven comparable surveys now available were analysed to estimate recent population trends. Populations of all three species of vulture remained at a low level. The previously rapid decline of White-rumped Vulture has slowed and may have reversed since the ban on veterinary use of diclofenac in India in 2006. A few thousand of this species, possibly up to the low tens of thousands, remained in India in 2015. The population of Indian Vulture continued to decline, though probably at a much slower rate than in the 1990s. This remains the most numerous of the three species in India with about 12,000 individuals in 2015 and a confidence interval ranging from a few thousands to a few tens of thousands. The trend in the rarest species, Slender-billed Vulture, which probably numbers not much more than 1,000 individuals in India, cannot be determined reliably.</jats:p

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. // Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. // Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. // Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe