Trichloroethylene and trichloroethanol-induced formic aciduria and renal injury in male F-344 rats following 12 weeks exposure

Trichloroethylene (TCE) is widely used as a cleaning and decreasing agent and has been shown to cause liver tumours in rodents and a small incidence of renal tubule tumours in male rats. The basis for the renal tubule injury is believed to be related to metabolism of TCE via glutathione conjugation to yield the cysteine conjugate that can be activated by the enzyme cysteine conjugate β-lyase in the kidney. More recently TCE and its major metabolite trichloroethanol (TCE-OH) have been shown to cause formic aciduria which can cause renal injury after chronic exposure in rats. In this study we have compared the renal toxicity of TCE and TCE-OH in rats to try and ascertain whether the glutathione pathway or formic aciduria can account for the toxicity. Male rats were given TCE (500 mg/kg/day) or TCE-OH at (100 mg/kg/day) for 12 weeks and the extent of renal injury measured at several time points using biomarkers of nephrotoxicity and prior to termination assessing renal tubule cell proliferation. The extent of formic aciduria was also determined at several time points, while renal pathology and plasma urea and creatinine were determined at the end of the study. TCE produced a very mild increase in biomarkers of renal injury, total protein, and glucose over the first two weeks of exposure and increased Kim-1 and NAG in urine after 1 and 5 weeks exposure, while TCE-OH did not produce a consistent increase in these biomarkers in urine. However, both chemicals produced a marked and sustained increase in the excretion of formic acid in urine to a very similar extent. The activity of methionine synthase in the liver of TCE and TCE-OH treated rats was inhibited by about 50% indicative of a block in folate synthesis. Both renal pathology and renal tubule cell proliferation were reduced after TCE and TCE-OH treatment compared to controls. Our findings do not clearly identify the pathway which is responsible for the renal toxicity of TCE but do provide some support for metabolism via glutathione conjugation

Ecological knowledge, leadership, and the evolution of menopause in killer whales

This is the final version of the article. Available from Elsevier via the DOI in this record.There is another record in ORE for this publication: http://hdl.handle.net/10871/16488Classic life-history theory predicts that menopause should not occur because there should be no selection for survival after the cessation of reproduction [1]. Yet, human females routinely live 30 years after they have stopped reproducing [2]. Only two other species-killer whales (Orcinus orca) and short-finned pilot whales (Globicephala macrorhynchus) [3, 4]-have comparable postreproductive lifespans. In theory, menopause can evolve via inclusive fitness benefits [5, 6], but the mechanisms by which postreproductive females help their kin remain enigmatic. One hypothesis is that postreproductive females act as repositories of ecological knowledge and thereby buffer kin against environmental hardships [7, 8]. We provide the first test of this hypothesis using a unique long-term dataset on wild resident killer whales. We show three key results. First, postreproductively aged females lead groups during collective movement in salmon foraging grounds. Second, leadership by postreproductively aged females is especially prominent in difficult years when salmon abundance is low. This finding is critical because salmon abundance drives both mortality and reproductive success in resident killer whales [9, 10]. Third, females are more likely to lead their sons than they are to lead their daughters, supporting predictions of recent models [5] of the evolution of menopause based on kinship dynamics. Our results show that postreproductive females may boost the fitness of kin through the transfer of ecological knowledge. The value gained from the wisdom of elders can help explain why female resident killer whales and humans continue to live long after they have stopped reproducing.This research was funded by a Natural Environment Research Council grant (NE/K01286X/1) to D.P.C., D.W.F., and M.A.C

Factors associated with medication adherence in school-aged children with asthma

Adherence to preventive asthma treatment is poor, particularly in children, yet the factors associated with adherence in this age group are not well understood. Adherence was monitored electronically over 6 months in school-aged children who attended a regional emergency department in New Zealand for an asthma exacerbation and were prescribed twice-daily inhaled corticosteroids. Participants completed questionnaires including assessment of family demographics, asthma responsibility and learning style. Multivariable analysis of factors associated with adherence was conducted. 101 children (mean (range) age 8.9 (6-15) years, 51% male) participated. Median (interquartile range) preventer adherence was 30% (17-48%) of prescribed. Four explanatory factors were identified: female sex (+12% adherence), Asian ethnicity (+19% adherence), living in a smaller household (-3.0% adherence per person in the household), and younger age at diagnosis (+2.7% for every younger year of diagnosis) (all p<0.02). In school-aged children attending the emergency department for asthma, males and non-Asian ethnic groups were at high risk for poor inhaled corticosteroid adherence and may benefit most from intervention. Four factors explained a small proportion of adherence behaviour indicating the difficulty in identifying adherence barriers. Further research is recommended in other similar populations

Mechanisms and Impacts of Earth System Tipping Elements

Tipping elements are components of the Earth system which may respond nonlinearly to anthropogenic climate change by transitioning toward substantially different long-term states upon passing key thresholds or “tipping points.” In some cases, such changes could produce additional greenhouse gas emissions or radiative forcing that could compound global warming. Improved understanding of tipping elements is important for predicting future climate risks and their impacts. Here we review mechanisms, predictions, impacts, and knowledge gaps associated with 10 notable Earth system components proposed to be tipping elements. We evaluate which tipping elements are approaching critical thresholds and whether shifts may manifest rapidly or over longer timescales. Some tipping elements have a higher risk of crossing tipping points under middle-of-the-road emissions pathways and will possibly affect major ecosystems, climate patterns, and/or carbon cycling within the 21st century. However, literature assessing different emissions scenarios indicates a strong potential to reduce impacts associated with many tipping elements through climate change mitigation. The studies synthesized in our review suggest most tipping elements do not possess the potential for abrupt future change within years, and some proposed tipping elements may not exhibit tipping behavior, rather responding more predictably and directly to the magnitude of forcing. Nevertheless, uncertainties remain associated with many tipping elements, highlighting an acute need for further research and modeling to better constrain risks

Electronic adherence monitoring device performance and patient acceptability: a randomized control trial

BACKGROUND: To investigate the performance and patient acceptability of an inhaler electronic monitoring device in a real-world childhood asthma population. METHODS: Children 6 to 15 years presenting with asthma to the hospital emergency department and prescribed inhaled corticosteroids were included. Participants were randomized to receive a device with reminder features enabled or disabled for use with their preventer. Device quality control tests were conducted. Questionnaires on device acceptability, utility and ergonomics were completed at six months. RESULTS: A total of 1306 quality control tests were conducted; 84% passed pre-issue and 87% return testing. The most common failure reason was actuation under-recording. Acceptability scores were high, with higher scores in the reminder than non-reminder group (median, 5th-95th percentile: 4.1, 3.1–5.0 versus 3.7, 2.3–4.8; p 90%) rated the device easy to use. Feedback was positive across five themes: device acceptability, ringtone acceptability, suggestions for improvement, effect on medication use, and effect on asthma control. CONCLUSIONS: This study investigates electronic monitoring device performance and acceptability in children using quantitative and qualitative measures. Results indicate satisfactory reliability, although failure rates of 13–16% indicate the importance of quality control. Favorable acceptability ratings support the use of these devices in children

Effect of correlations on network controllability

A dynamical system is controllable if by imposing appropriate external signals on a subset of its nodes, it can be driven from any initial state to any desired state in finite time. Here we study the impact of various network characteristics on the minimal number of driver nodes required to control a network. We find that clustering and modularity have no discernible impact, but the symmetries of the underlying matching problem can produce linear, quadratic or no dependence on degree correlation coefficients, depending on the nature of the underlying correlations. The results are supported by numerical simulations and help narrow the observed gap between the predicted and the observed number of driver nodes in real networks

Variations of training load, monotony, and strain and dose-response relationships with maximal aerobic speed, maximal oxygen uptake, and isokinetic strength in professional soccer players

This study aimed to identify variations in weekly training load, training monotony, and training strain across a 10-week period (during both, pre- and in-season phases); and to analyze the dose-response relationships between training markers and maximal aerobic speed (MAS), maximal oxygen uptake, and isokinetic strength. Twenty-seven professional soccer players (24.9±3.5 years old) were monitored across the 10-week period using global positioning system units. Players were also tested for maximal aerobic speed, maximal oxygen uptake, and isokinetic strength before and after 10 weeks of training. Large positive correlations were found between sum of training load and extension peak torque in the right lower limb (r = 0.57, 90%CI[0.15;0.82]) and the ratio agonist/antagonist in the right lower limb (r = 0.51, [0.06;0.78]). It was observed that loading measures fluctuated across the period of the study and that the load was meaningfully associated with changes in the fitness status of players. However, those magnitudes of correlations were small-to-large, suggesting that variations in fitness level cannot be exclusively explained by the accumulated load and loading profile