The rodent uterotrophic assay: Critical protocol features, studies with nonyl phenols, and comparison with a yeast estrogenicity assay

The major protocol features of the immature rat uterotrophic assay have been evaluated using a range of reference chemicals. The protocol variables considered include the selection of the test species and route of chemical administration, the age of the test animals, the maintenance diet used, and the specificity of the assay for estrogens. It is concluded that three daily oral administrations of test chemicals to 21- to 22-day-old rats, followed by determination of absolute uterus weights on the fourth day, provide a sensitive and toxicologically relevant in vivo estrogenicity assay. Rats are favored over mice for reasons of toxicological practice, but the choice of test species is probably not a critical protocol variable, as evidenced by the similar sensitivity of rats and mice to the uterotrophic activity of methoxychlor. Vaginal opening is shown to be a useful, but nondefinitive, adjunct to the uterotrophic assay. The ability of test chemicals to reduce or abolish the uterotrophic response of estradiol is suggested to provide a useful extension of the uterotrophic assay for the purpose of detecting antiestrogens. The results of a series of studies on the environmental estrogen nonyl phenol (NP), and its linear isomer n -nonyl phenol, confirm that branching of the aliphatic side chain is important for activity. 17beta-Desoxyestradiol is shown to be of similar activity to estradiol in the uterotrophic assay and is suggested to represent the "parent" estrogen of NP. Benzoylation of NP and 17-desoxyestradiol did not affect their uterotrophic activity, in contrast to the enhancing effect of benzoylation on estradiol. Selected chemicals shown to be active in the immature rat uterotrophic assay were also evaluated in an in vitro yeast human estrogen receptor transactivation assay. Most of the chemicals gave similar qualitative responses to those seen in the uterotrophic assay, and the detection of the estrogen methoxychlor by the yeast assay evidenced a degree of intrinsic metabolic competence. However, the assay had a reduced ability (compared to rodents) to hydrolyze the benzoate ester of estradiol, and the estrogenic benzoate derivative of NP was not active in the yeast assay. These last results indicate that current metabolic deficiencies of in vitro estrogenicity assays will limit the value of negative data for the immediate future. The results described illustrate the intrinsic complexity of evaluating chemicals for estrogenic activities and confirm the need for rigorous attention to experimental design and criteria for assessing estrogenic activity

Association between diabetes, diabetes treatment and risk of developing endometrial cancer.

BackgroundA growing body of evidence suggests that diabetes is a risk factor for endometrial cancer incidence. However, most of these studies used case-control study designs and did not adjust for obesity, an established risk factor for endometrial cancer. In addition, few epidemiological studies have examined the association between diabetes treatment and endometrial cancer risk. The objective of this study was to assess the relationships among diabetes, diabetes treatment and endometrial cancer risk in postmenopausal women participating in the Women's Health Initiative (WHI).MethodsA total of 88 107 postmenopausal women aged 50-79 years who were free of cancer and had no hysterectomy at baseline were followed until date of endometrial cancer diagnosis, death, hysterectomy or loss to follow-up, whichever came first. Endometrial cancers were confirmed by central medical record and pathology report review. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios (HRs) (95% confidence interval (CI)) for diagnosis of diabetes and metformin treatment as risk factors for endometrial cancer.ResultsOver a mean of 11 years of follow-up, 1241 endometrial cancers developed. In the primary analysis that focused on prevalent diabetes at enrolment, compared with women without diabetes, women with self-reported diabetes, and the subset of women with treated diabetes, had significantly higher risk of endometrial cancer without adjusting for BMI (HR=1.44, 95% CI: 1.13-1.85 for diabetes, HR=1.57, 95% CI: 1.19-2.07 for treated diabetes). However after adjusting for BMI, the associations between diabetes, diabetes treatment, diabetes duration and the risk of endometrial cancer became non-significant. Elevated risk was noted when considering combining diabetes diagnosed at baseline and during follow-up as time-dependent exposure (HR=1.31, 95% CI: 1.08-1.59) even after adjusting for BMI. No significant association was observed between metformin use and endometrial cancer risk.ConclusionsOur results suggest that the relationship observed in previous research between diabetes and endometrial cancer incidence may be largely confounded by body weight, although some modest independent elevated risk remains

A new family of phosphoinositide phosphatases in microorganisms: identification and biochemical analysis

<p>Abstract</p> <p>Background</p> <p>Phosphoinositide metabolism is essential to membrane dynamics and impinges on many cellular processes, including phagocytosis. Modulation of phosphoinositide metabolism is important for pathogenicity and virulence of many human pathogens, allowing them to survive and replicate in the host cells. Phosphoinositide phosphatases from bacterial pathogens are therefore key players in this modulation and constitute attractive targets for chemotherapy. MptpB, a virulence factor from <it>Mycobacterium tuberculosis</it>, has phosphoinositide phosphatase activity and a distinct active site P-loop signature HCXXGKDR that shares characteristics with eukaryotic lipid phosphatases and protein tyrosine phosphatases. We used this P-loop signature as a "diagnostic motif" to identify related putative phosphatases with phosphoinositide activity in other organisms.</p> <p>Results</p> <p>We found more than 200 uncharacterised putative phosphatase sequences with the conserved signature in bacteria, with some related examples in fungi and protozoa. Many of the sequences identified belong to recognised human pathogens. Interestingly, no homologues were found in any other organisms including Archaea, plants, or animals. Phylogenetic analysis revealed that these proteins are unrelated to classic eukaryotic lipid phosphatases. However, biochemical characterisation of those from <it>Listeria monocytogenes </it>and <it>Leishmania major</it>, demonstrated that, like MptpB, they have phosphatase activity towards phosphoinositides. Mutagenesis studies established that the conserved Asp and Lys in the P-loop signature (HCXXG<b>KD</b>R) are important in catalysis and substrate binding respectively. Furthermore, we provide experimental evidence that the number of basic residues in the P-loop is critical in determining activity towards poly-phosphoinositides.</p> <p>Conclusion</p> <p>This new family of enzymes in microorganisms shows distinct sequence and biochemical characteristics to classic eukaryotic lipid phosphatases and they have no homologues in humans. This study provides a foundation for examining the biological role of this new family of phosphatases and their potential as pharmaceutical targets against infectious diseases.</p

Temper outbursts in Lowe syndrome:Characteristics, sequence, environmental context and comparison to Prader–Willi syndrome

Background: There is limited research into the nature and aetiology of temper outbursts in people with intellectual disabilities. In this study, we describe the phenomenology and environmental context of temper outbursts in Lowe syndrome, a rare genetic syndrome in which outbursts are purportedly frequent. Method: A temper outburst interview (TOI) was conducted with caregivers of seventeen individuals with Lowe syndrome to generate an account of the behavioural sequence, common antecedents and consequences of temper outbursts, and to enable comparisons with similar work on Prader–Willi syndrome. Results: Outbursts in Lowe syndrome were frequently triggered by thwarted goaldirected behaviour and were associated with high levels of physical aggression and property destruction. Conclusions: Form and sequence of outbursts showed similarities to Prader–Willi syndrome and to behaviours reported in literature on typically developing children. The results highlight the importance of considering shared aetiology as well as syndrome‐specific pathways in the development of outbursts

Measured Sensitivity of the First Mark II Phased Array Feed on an ASKAP Antenna

This paper presents the measured sensitivity of CSIRO's first Mk. II phased array feed (PAF) on an ASKAP antenna. The Mk. II achieves a minimum system-temperature-over-efficiency $T_\mathrm{sys}/\eta$ of 78 K at 1.23 GHz and is 95 K or better from 835 MHz to 1.8 GHz. This PAF was designed for the Australian SKA Pathfinder telescope to demonstrate fast astronomical surveys with a wide field of view for the Square Kilometre Array (SKA).Comment: 5 pages, 2 figures, accepted for publication in Electromagnetics in Advanced applications (ICEAA), 2015 International Conference o

Staying in touch in the digital era: New social work practice

The findings of a small-scale empirical study are drawn upon to explore the concept of social presence and the way in which it can contribute to meeting service users’ expectations of relationship-based social work. Findings from the study highlight the role of mobile communication technologies in establishing social presence with service users and an argument is made for the proactive use of mobile devices as a component of direct practice. However, such emerging digital social work practices will require practitioners, and social work organisations, to respond positively to new ethical and organisational challenges

Influence of Enterococci and Thermophilic Starter Bacteria on Cheddar Cheese Flavour

End of Project ReportThis project set out to identify suitable enterococci and thermophilic starter strains which could be added to the cheese during manufacture (as starter adjuncts) with the specific aims of enhancing flavour during ripening as well as facilitating flavour diversity - a trait sought by many commercial Cheddar companies. This project confirmed the potential of thermophilic lactic acid strains to affect flavour when used as starter adjuncts in Cheddar cheese manufacture. Their use can also lead to the development of novel flavours. Many adjunct cultures proposed to-date to enhance Cheddar flavour are composed of strains of lactococcal starter, selected for their flavouring capacity. However, application of such strains in industry would lead to increased probability of phage attack on the primary starter. On the other hand, thermophilic lactic acid strains are phage unrelated to conventional starter and thus would not lead to the introduction of starter specific phage into the cheese plant. A thermophilic strain from the Moorepark collection (DPC 4571) was shown to have major commercial potential as a flavour enhancer.Department of Agriculture, Food and the Marin

Spatial datasets of radionuclide contamination in the Ukrainian Chernobyl Exclusion Zone

The dataset “Spatial datasets of radionuclide contamination in the Ukrainian Chernobyl Exclusion Zone” was developed to enable data collected between May 1986 (immediately after Chernobyl) and 2014 by the Ukrainian Institute of Agricultural Radiology (UIAR) after the Chernobyl accident to be made publicly available. The dataset includes results from comprehensive soil sampling across the Chernobyl Exclusion Zone (CEZ). Analyses include radiocaesium (134Cs and 134Cs) 90Sr, 154Eu and soil property data; plutonium isotope activity concentrations in soil (including distribution in the soil profile); analyses of “hot” (or fuel) particles from the CEZ (data from Poland and across Europe are also included); and results of monitoring in the Ivankov district, a region adjacent to the exclusion zone. The purpose of this paper is to describe the available data and methodology used to obtain them. The data will be valuable to those conducting studies within the CEZ in a number of ways, for instance (i) for helping to perform robust exposure estimates to wildlife, (ii) for predicting comparative activity concentrations of different key radionuclides, (iii) for providing a baseline against which future surveys in the CEZ can be compared, (iv) as a source of information on the behaviour of fuel particles (FPs), (v) for performing retrospective dose assessments and (vi) for assessing natural background dose rates in the CEZ. The CEZ has been proposed as a “radioecological observatory” (i.e. a radioactively contaminated site that will provide a focus for long-term, radioecological collaborative international research). Key to the future success of this concept is open access to data for the CEZ. The data presented here are a first step in this process. The data and supporting documentation are freely available from the Environmental Information Data Centre (EIDC) under the terms and conditions of the Open Government Licence: https://doi.org/10.5285/782ec845-2135-4698-8881-b38823e533bf