Elizabeth A. Williamson

Anaphylaxis fatalities and admissions in Australia.

BACKGROUND Detailed data on fatal anaphylaxis are limited, with national anaphylaxis fatality data for the United Kingdom and food-induced anaphylaxis fatality data for the United States. Time trends for anaphylaxis fatalities are not available. OBJECTIVE We examined causes, demographics, and time trends for anaphylaxis fatalities in Australia between January 1997 and December 2005 and compared these with findings for anaphylaxis admissions. METHODS Data on anaphylaxis deaths and hospital admissions were extracted from a national database. Death certificate codes were analyzed to determine the likely cause and associated comorbidities. RESULTS There were 112 anaphylaxis fatalities in Australia over 9 years. Causes were as follows: food, 7 (6%); drugs, 22 (20%); probable drugs, 42 (38%); insect stings, 20 (18%); undetermined, 15 (13%); and other, 6 (5%). All food-induced anaphylaxis fatalities occurred between 8 and 35 years of age with female preponderance, despite the majority of food-induced anaphylaxis admissions occurring in children less than 5 years of age. Most insect sting-induced anaphylaxis deaths occurred between 35 and 84 years almost exclusively in male subjects, although bee sting-induced admissions peak between 5 and 9 years of age with a male/female ratio of 2.7. However, most drug-induced anaphylaxis deaths occurred between 55 and 85 years with equal sex distribution similar to drug-induced anaphylaxis admissions. There was no evidence of an increase in death rates for food-induced anaphylaxis, despite food-induced anaphylaxis admissions increasing approximately 350%. In contrast, drug-induced anaphylaxis deaths increased approximately 300% compared with an approximately 150% increase in drug-induced anaphylaxis admissions. CONCLUSION The demographics for anaphylaxis deaths are different to those for anaphylaxis presentations. Anaphylaxis mortality rates remain low and stable, despite increasing anaphylaxis prevalence, with the exception of drug-induced anaphylaxis deaths, which have increased.

Gorilla diet in the Lope Reserve, Gabon: A nutritional analysis

SummaryThe results of an analysis of gorilla diet in the Lopé Reserve, Gabon are presented. Samples were assayed for nutrients and plant secondary compounds (total phenols, condensed tannins and alkaloids) in an attempt to explain gorilla food choice. The diet is the most diverse so far analysed for gorillas; it seems to be a balance between sugary fruit, proteinaceous leaves, and relatively fibrous stems. Most fruits and herbaceous stems are succulent, but some drier, fibrous fruit and bark is also consumed. Seeds are another component of the diet, including unripe ones. Fruit, seeds, leaves and bark may all contain very high levels of total phenols and condensed tannins; but all herbaceous stems assayed contain low levels of these compounds. Alkaloids are not apparently a significant component of gorilla foods, and may be avoided. Gorillas at Lopé tend to avoid fatty fruit, and select leaves which are high in protein and low in fibre compared to the general vegetation. When fruit and preferred young leaves are scarce, proteinaceous barks and mature leaves, and sugary pith, are important sources of nutrients. We conclude that gorillas exploit the broad frugivore niche in West African lowland forests, and are part of the frugivore community there. What distinguishes them is their ability to eat large fibrous fruit, mature leaves and stems, and to overcome high levels of phenolics (we use “phenolics” as an umbrella term for both total phenols and condensed tannins). Gorilla diet at Lopé overlaps greatly with that of sympatric, frugivorous, primates, and resembles more closely that of chimpanzees than it does gorilla diet studied elsewhere in Africa.

Devastating Decline of Forest Elephants in Central Africa

African forest elephants– taxonomically and functionally unique–are being poached at accelerating rates, but we lack range-wide information on the repercussions. Analysis of the largest survey dataset ever assembled for forest elephants (80 foot-surveys; covering 13,000 km; 91,600 person-days of fieldwork) revealed that population size declined by ca. 62% between 2002–2011, and the taxon lost 30% of its geographical range. The population is now less than 10% of its potential size, occupying less than 25% of its potential range. High human population density, hunting intensity, absence of law enforcement, poor governance, and proximity to expanding infrastructure are the strongest predictors of decline. To save the remaining African forest elephants, illegal poaching for ivory and encroachment into core elephant habitat must be stopped. In addition, the international demand for ivory, which fuels illegal trade, must be dramatically reduced.

Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining

Given its significant role in the maintenance of genomic stability, histone methylation has been postulated to regulate DNA repair. Histone methylation mediates localization of 53BP1 to a DNA double-strand break (DSB) during homologous recombination repair, but a role in DSB repair by nonhomologous end-joining (NHEJ) has not been defined. By screening for histone methylation after DSB induction by ionizing radiation we found that generation of dimethyl histone H3 lysine 36 (H3K36me2) was the major event. Using a novel human cell system that rapidly generates a single defined DSB in the vast majority of cells, we found that the DNA repair protein Metnase (also SETMAR), which has a SET histone methylase domain, localized to an induced DSB and directly mediated the formation of H3K36me2 near the induced DSB. This dimethylation of H3K36 improved the association of early DNA repair components, including NBS1 and Ku70, with the induced DSB, and enhanced DSB repair. In addition, expression of JHDM1a (an H3K36me2 demethylase) or histone H3 in which K36 was mutated to A36 or R36 to prevent H3K36me2 formation decreased the association of early NHEJ repair components with an induced DSB and decreased DSB repair. Thus, these experiments define a histone methylation event that enhances DNA DSB repair by NHEJ.

Propensity scores: from naive enthusiasm to intuitive understanding.

Estimation of the effect of a binary exposure on an outcome in the presence of confounding is often carried out via outcome regression modelling. An alternative approach is to use propensity score methodology. The propensity score is the conditional probability of receiving the exposure given the observed covariates and can be used, under the assumption of no unmeasured confounders, to estimate the causal effect of the exposure. In this article, we provide a non-technical and intuitive discussion of propensity score methodology, motivating the use of the propensity score approach by analogy with randomised studies, and describe the four main ways in which this methodology can be implemented. We carefully describe the population parameters being estimated — an issue that is frequently overlooked in the medical literature. We illustrate these four methods using data from a study investigating the association between maternal choice to provide breast milk and the infants subsequent neurodevelopment. We outline useful extensions of propensity score methodology and discuss directions for future research. Propensity score methods remain controversial and there is no consensus as to when, if ever, they should be used in place of traditional outcome regression models. We therefore end with a discussion of the relative advantages and disadvantages of each.

Gorillas in the crossfire: population dynamics of the Virunga mountain gorillas over the past three decades

Small populations are particularly susceptible to disturbance. Routine censusing to monitor changes is important for understanding both population dynamics and the effectiveness of conservation strategies. Mountain gorillas Gorilla beringei beringei in the Virunga Volcanoes region of Rwanda, Uganda and the Democratic Republic of Congo have been censused five times since 1970. However, due to war and political unrest in the region since 1990, no census had been conducted since 1989, when the population was thought to number 324 gorillas. In 2000 we estimated population size using repeated observations of 17 habituated groups and information on 15 unhabituated groups obtained during patrols. The minimum population was 359 gorillas, and a best-case scenario correcting for groups that might not have been counted was 395. Using the minimum population and best-case scenario respectively, this represents a 0.9% or 1.8% annual growth rate over the last decade and 1.0% or 1.3% annual growth rate since 1972. This is lower than growth estimates made in several population viability analyses, but approximately 5% of the 1989 population is known to have died due to military activity over the last decade. Different subsets of the population exhibited different responses to disturbance caused by war. We discuss conservation strategies that are likely to have contributed to an increase in the gorilla population during this time of turmoil. While the population has grown, the results should be viewed with caution, not only because all known growth during the last decade can be attributed to one subset of the population, but also because the region is still plagued by political unrest.

A case study of a plant-animal relationship: Cola lizae and lowland gorillas in the Lope Reserve, Gabon

The fiuits of Cola lizae, an endemic tree with a limited geographical distribution, have been a major food source for lowland gorillas in the Lope Reserve during part of each year over a six-year period. Faecal analysis indicated that 11,000-18,000 Cola seeds km-2 were deposited by gorillas during the 4-month season in 1989. Gorillas are the only important dispersers of this species: other primates consume the succulent mesocarp, but do not swallow the large seed; elephants do not eat Cola fruits. Observations of Cola seeds in gorilla faeces showed a very high germination rate and, despite initial high mortality, 18%/ of seedlings still survived six months after deposition. Survival of seedlings was significantly better in faeces left at nest-sites than in other areas of the forest: 40% of seedlings were viable at nest-sites six months after deposition. This suggests that the open areas of forest, preferred by gorillas as nest-sites, are advantageous to the propagation of this species.

FOXA1: Growth inhibitor and a favorable prognostic factor in human breast cancer

The transcription factor Forkhead‐box A1 (Foxa1), a member of the FOX class of transcription factors, has been implicated in the pathogenesis of lung, esophageal and prostate cancers. We have recently identified transcriptional activation of p27 by FOXA1. In this study, we analyzed the activities and expression pattern of FOXA1 in breast cancer. Forced expression of FOXA1 inhibited clonal growth of breast cancer cell lines, and FOXA1 levels inversely correlated with growth stimuli. In the estrogen receptor (ER)‐positive MCF‐7 cells, FOXA1 increased p27 promoter activity and inhibited the ER pathway activity. Analysis of FOXA1 expression in breast tissue arrays revealed significantly higher expression in pure ductal carcinomas in situ compared to invasive ductal carcinomas (IDC); and in IDC, high expression of FOXA1 was associated with favorable prognostic factors. Yet, FOXA1 expression was noted in a subset of the ER‐negative tumors. Taken together, our findings suggest a growth inhibitory role for FOXA1, and identify it as a novel, potential prognostic factor in breast cancer.

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

KRAS-mutated carcinomas comprise 35–40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O6-methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wild-type carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; P<0.001), demonstrated mucinous differentiation (46 vs 31%; P=0.001) and were associated with different MSI status (P<0.001) and with MGMT methylation (47 vs 21%; P=0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P=0.001), mucinous differentiation (46 vs 25%; P<0.001), presence of a contiguous polyp (38 vs 22%; P<0.001), MGMT methylation (47 vs 26%; P=0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P=0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal–distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P=0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.

Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer

A pharmacological-based global screen for epigenetically silenced tumor suppressor genes was performed in MCF-7 and MDA-MB-231 breast cancer cells. Eighty-one genes in MCF-7 cells and 131 in MDA-MB-231 cells were identified, that had low basal expression and were significantly upregulated following treatment. Eighteen genes were studied for methylation and/or expression in breast cancer; PTCH, the receptor for the hedgehog (Hh) pathway and a known tumor suppressor gene, was selected for further analysis. Methylation of the PTCH promoter was found in MCF-7 cells and in breast cancer samples, and correlated with low PTCH expression. Immunohistochemical analysis of breast tissue arrays revealed high expression of PTCH in normal breast compared to ductal carcinomas in situ (DCIS) and invasive ductal carcinomas; furthermore, association was found between PTCH expression and favorable prognostic factors. PTCH is an inhibitor of the Hh pathway, and its silencing activates the pathway and promotes growth. Indeed, high activity of the Hh pathway was identified in MCF-7 cells and overexpression of PTCH inhibited the pathway. Moreover, treatment with cyclopamine, an inhibitor of the pathway, reduced cell growth and slowed the cell cycle in these cells. Thus, unmasking of epigenetic silencing in breast cancer enabled us to discover a large number of candidate tumor suppressor genes. Further analysis suggested a role of one of these genes, PTCH, in breast cancer tumorigenesis.