The role of P2 receptors in controlling infections by intracellular pathogens

A growing number of studies have demonstrated the importance of ATPe-signalling via P2 receptors as an important component of the inflammatory response to infection. More recent studies have shown that ATPe can also have a direct effect on infection by intracellular pathogens, by modulating membrane trafficking in cells that contain vacuoles that harbour intracellular pathogens, such as mycobacteria and chlamydiae. A conserved mechanism appears to be involved in controlling infection by both of these pathogens, as a role for phospholipase D in inducing fusion between lysosomes and the vacuoles has been demonstrated. Other P2-dependent mechanisms are most likely operative in the cases of pathogens, such as Leishmania, which survive in an acidic phagolysosomal-like compartment. ATPe may function as a ‘danger signal–that alerts the immune system to the presence of intracellular pathogens that damage the host cell, while different intracellular pathogens have evolved enzymes or other mechanisms to inhibit ATPe-mediated signalling, which should, thus, be viewed as virulence factors for these pathogens

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

North American montane red foxes: expansion, fragmentation, and the origin of the Sacramento Valley red fox

Most native red foxes (Vulpes vulpes) in the western contiguous United States appear to be climatically restricted to colder regions in the major mountain ranges and, in some areas, have suffered precipitous declines in abundance that may be linked to warming trends. However, another population of unknown origin has occurred in arid habitats in the Sacramento Valley of California well outside this narrow bioclimatic niche since at least 1880. If native, this population would be ecologically distinct among indigenous North American red foxes. We used mitochondrial and microsatellite markers from historical and modern samples (modes: 1910–1930 and 2000–2008, respectively) obtained throughout the western United States to determine the origins of the Sacramento Valley red fox, and assess the historical and modern connectivity and genetic effective population sizes of Sacramento Valley and montane red foxes. We found clear and consistent evidence supporting the indigenous origin of the Sacramento Valley population, including the phylogenetic positioning of the dominant, endemic mtDNA clade and microsatellite clustering of the Sacramento Valley population with the nearest montane population. Based on both mitochondrial and microsatellite AMOVAs, connectivity among Western populations of red foxes declined substantially between historical and modern time periods. Estimates based on temporal losses in gene diversity for both marker types suggest that both the Sierra Nevada (including the Southern Cascades population) and the Sacramento Valley populations have small genetic effective population sizes. Significant heterozygote excesses also indicate the occurrence of recent bottlenecks in these populations. Both substitutions distinguishing the 2 endemic Sacramento Valley haplotypes from the dominant montane haplotype were in the coding region and nonsynonymous, consistent with adaptive differences. These findings along with previously reported body size distinctions between Sacramento Valley and montane red foxes argue for distinct subspecific status for the Sacramento Valley red fox, for which we propose the designation V. v. patwin n. subsp. The small genetic effective population size estimates for the Sierra Nevada red fox and Sacramento Valley red fox are cause for concern, as is the possibility of genetic introgression into the latter population from an adjacent, recently established nonnative population