Atrazine and Rat Mammary Gland Development

The herbicide atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine, ATR) is used to control growth of broadleaf and grassy weeds. It has been registered with the United States Environmental Protection Agency and is monitored to prevent unsafe levels of this possible endocrine disrupting compound from reaching human and animal populations via contaminated surface or ground water. Life-time feeding studies on ATR have shown an increased incidence and decreased time to tumors in mammary glands (MG) of rats, via its long-term effects on the brain and altered estrous cyclicity. This thesis focuses on changes observed in developing MG of female Long Evans rats (offspring and dam) exposed during late gestation to ATR. It also explores possible confounders of observed effects including body weights, pubertal timing, and serum hormone concentrations. Dams were gavage dosed with 100 mg/kg ATR during late gestation corresponding to fetal mammary bud development and outgrowth. That exposure caused a delay in puberty and mammary development in female offspring. From cross-fostered litters, it was determined that nursing from an ATR-treated dam delayed both puberty and mammary development. However, a brief transplacental exposure to ATR caused delays only in MG development that persist into adulthood. MG development was most delayed in offspring exposed during fetal mammary epithelial cell proliferation (GD17-19), but it was also delayed in offspring exposed only by nursing from dams treated during that same time. These results suggested that ATR may reprogram fetal and neonatal MG development. These findings suggested changes in dam MG development or lactation. MG from ATR-exposed dams were developmentally different from those of controls at early timepoints. ATR and its metabolites were detected in the urine, amniotic fluid, and serum of treated dams at several timepoints post exposure suggesting that ATR metabolites may be available to the developing offspring until at least PND11 when abnormal MG development has been detected in female pups. These studies taken together suggest that ATR can have long-term effects on the MG of female offspring and dams without association of confounders. The effects of this brief exposure are persistent, extending into adulthood and affecting weight gain of future generations via the lactational effects

Beyond winning : party goals and campaign strategy in Australian elections

Discussions of election campaigning and strategy often focus on winning. Researchers and practitioners alike aim to tease out the campaign tools and methods that help parties pull in votes, while positing a desire to win as the rationale behind almost every campaign decision. But is winning the only goal that parties hold when embarking on an election campaign? Drawing on qualitative interviews with more than 50 representatives from 13 Australian parties, this research finds that parties actually articulate a broader range of goals, including taking (or retaining) majority government, preserving a viable parliamentary presence, maximising their influence over the political process and advocating for specific policy issues. These objectives are discussed in the context of existing research on party goals, as we seek to incorporate the voices and views of real campaign practitioners into an academic space where they have often been more noticeable by their absence. Building from the understanding that parties hold different goals, this research then explores the relationship between these goals and the strategies adopted by the parties contesting five case study state elections between 2010 and 2013. Informed by content analysis of campaign materials and observation of party activities, we find that parties with different goals make different strategic choices in a range of key areas, including their choice of target audiences, their selection of key messages and themes, and their preferredcommunication tools and channels. Importantly however, we find that a party's goals are not the only factor driving decisions about campaign strategies, withinstitutional, organisational and environmental features also playing an influential role. In exploring the interaction between party goals and campaign strategies in Australian elections, this research contributes a different perspective on party behaviour to the international discussion about electioneering. It also helps to broaden our understanding of the Australian political landscape both by analysing the campaigns of major and minor parties from across the political spectrum, and by including the direct perspectives of local campaigners. As someone who has been fortunate enough to work in and around politics for several years, it was surprising to discover that the voices of those who practice this on a daily basis have not often been included in academic studies. This project therefore represents an attempt to bring those voices into the conversation, while also demonstrating to other researchers that there is value and benefit in doing so

Calling time: How to remove fossil fuel sponsorships from sports, arts & events

Sports, arts and major events are deeply embedded in the Australian way of life. Weekend matches, concerts and festivals bring us together - to cheer, to share pride and excitement, to feel connected to each other and to keep building our national story. When we barrack for our beloved teams, discover the work of a new local artist or laugh until our cheeks hurt at a comedy show, we are taking part in a ritual that has shaped social and cultural life in Australia for generations. Climate change – driven by burning coal, oil and gas – is putting all of this at risk. From flooded festivals, to concerts cancelled by bushfire threats and unsafe heat disrupting play at the tennis, footy and more, climate change is wreaking havoc on the activities and events we love..

Accuracy of magnetic resonance imaging for measuring maturing cartilage: A phantom study

OBJECTIVES: To evaluate the accuracy of magnetic resonance imaging measurements of cartilage tissue-mimicking phantoms and to determine a combination of magnetic resonance imaging parameters to optimize accuracy while minimizing scan time. METHOD: Edge dimensions from 4 rectangular agar phantoms ranging from 10.5 to 14.5 mm in length and 1.25 to 5.5 mm in width were independently measured by two readers using a steel ruler. Coronal T1 spin echo (T1 SE), fast spoiled gradient-recalled echo (FSPGR) and multiplanar gradient-recalled echo (GRE MPGR) sequences were used to obtain phantom images on a 1.5-T scanner. RESULTS: Inter- and intra-reader reliability were high for both direct measurements and for magnetic resonance imaging measurements of phantoms. Statistically significant differences were noted between the mean direct measurements and the mean magnetic resonance imaging measurements for phantom 1 when using a GRE MPGR sequence (512x512 pixels, 1.5-mm slice thickness, 5:49 min scan time), while borderline differences were noted for T1 SE sequences with the following parameters: 320x320 pixels, 1.5-mm slice thickness, 6:11 min scan time; 320x320 pixels, 4-mm slice thickness, 6:11 min scan time; and 512x512 pixels, 1.5-mm slice thickness, 9:48 min scan time. Borderline differences were also noted when using a FSPGR sequence with 512x512 pixels, a 1.5-mm slice thickness and a 3:36 min scan time. CONCLUSIONS: FSPGR sequences, regardless of the magnetic resonance imaging parameter combination used, provided accurate measurements. The GRE MPGR sequence using 512x512 pixels, a 1.5-mm slice thickness and a 5:49 min scan time and, to a lesser degree, all tested T1 SE sequences produced suboptimal accuracy when measuring the widest phantom

Data-Driven Decision Support Tool Co-Development with a Primary Health Care Practice Based Learning Network

Background: The Alliance for Healthier Communities is a learning health system that supports Community Health Centres (CHCs) across Ontario, Canada to provide team-based primary health care to people who otherwise experience barriers to care. This case study describes the ongoing process and lessons learned from the first Alliance for Healthier Communities’ Practice Based Learning Network (PBLN) data-driven decision support tool co-development project. Methods: We employ an iterative approach to problem identification and methods development for the decision support tool, moving between discussion sessions and case studies with CHC electronic health record (EHR) data. We summarize our work to date in terms of six stages: population-level descriptive-exploratory study, PBLN team engagement, decision support tool problem selection, sandbox case study 1: individual-level risk predictions, sandbox case study 2: population-level planning predictions, project recap and next steps decision. Results: The population-level study provided an initial point of engagement to consider how clients are (not) represented in EHR data and to inform problem selection and methodological decisions thereafter. We identified three meaningful types of decision support, with initial target application areas: risk prediction/screening, triaging specialized program referrals, and identifying care access needs. Based on feasibility and expected impact, we started with the goal to support earlier identification of mental health decline after diabetes diagnosis. As discussions deepened around clinical use cases associated with example prediction task set ups, the target problem evolved towards supporting the upstream task of organizational planning and advocacy for adequate mental health care service capacity to meet incoming needs. Conclusions: This case study contributes towards a tool to support diabetes and mental health care, as well as lays groundwork for future CHC decision support tool initiatives. We share lessons learned and reflections from our process that other primary health care organizations may use to inform their own co-development initiatives

Mammary Gland Development as a Sensitive End Point after Acute Prenatal Exposure to an Atrazine Metabolite Mixture in Female Long-Evans Rats

BACKGROUND: Atrazine (ATR), a widely used chlorotriazine herbicide, inhibits a number of endocrine-dependent processes, including gonadotrophin surges and mammary gland development in rats. Chlorotriazine herbicides are rapidly metabolized in plants and animals to form a group of metabolites that are detected both in the environment and in exposed animals. The extent to which these metabolites are responsible directly for the observed health effects is not understood. OBJECTIVES: Our goal was to determine if a mixture of ATR metabolites, in proportions found in the environment, might produce developmental effects in Long-Evans rats following exposure late in pregnancy. METHODS: We administered an ATR metabolite mixture (AMM) containing ATR, hydroxyatrazine, diaminochlorotriazine, deethylatrazine, and deisopropylatrazine orally to pregnant Long-Evans rats at 0.09, 0.87, or 8.73 mg/kg body weight (bw)/day, on gestation days 15–19, using 0 and 100 mg ATR/kg bw/day as negative and positive controls, respectively. RESULTS: We observed no significant effect of acute AMM exposure on body weight gain in dams during the dosing period, weight loss in pups on postnatal day (PND)4, or pubertal timing, as is seen with ATR alone. However, as with ATR, we detected delayed mammary gland development, evaluated by whole mount analysis, as early as PND4 in all treatment groups. CONCLUSIONS: Our data suggest that acute exposure to AMM at levels as low as 0.09 mg/kg bw during late pregnancy causes persistent alterations in mammary gland development of female offspring, and that these effects do not appear to be related to bw or associated with pubertal timing

Long-term dietary nitrate supplementation does not reduce renal cyst growth in experimental autosomal dominant polycystic kidney disease

Augmentation of endogenous nitric oxide (NO) synthesis, either by the classical L-arginine-NO synthase pathway, or the recently discovered entero-salivary nitrate-nitrite-NO system, may slow the progression of autosomal dominant polycystic kidney disease (ADPKD). To test this hypothesis, the expression of NO in human ADPKD cell lines (WT 9-7, WT 9-12), and the effect of L-arginine on an in vitro model of three-dimensional cyst growth using MDCK cells, was examined. In addition, groups of homozygous Pkd1RC/RC mice (a hypomorphic genetic ortholog of ADPKD) received either low, moderate or high dose sodium nitrate (0.1, 1 or 10 mmol/kg/day), or sodium chloride (vehicle; 10 mmol/kg/day), supplemented drinking water from postnatal month 1 to 9 (n = 12 per group). In vitro, intracellular NO, as assessed by DAF-2/DA fluorescence, was reduced by >70% in human ADPKD cell lines, and L-arginine and the NO donor, sodium nitroprusside, both attenuated in vitro cyst growth by up to 18%. In contrast, in Pkd1RC/RC mice, sodium nitrate supplementation increased serum nitrate/nitrite levels by ~25-fold in the high dose group (P<0.001), but kidney enlargement and percentage cyst area was not altered, regardless of dose. In conclusion, L-arginine has mild direct efficacy on reducing renal cyst growth in vitro, whereas long-term sodium nitrate supplementation was ineffective in vivo. These data suggest that the bioconversion of dietary nitrate to NO by the entero-salivary pathway may not be sufficient to influence the progression of renal cyst growth in ADPKD

Nonadherence in hemodialysis: Associations with mortality, hospitalization, and practice patterns in the DOPPS

Nonadherence in hemodialysis: Associations with mortality, hospitalization, and practice patterns in the DOPPS.BackgroundNonadherence among hemodialysis patients compromises dialysis delivery, which could influence patient morbidity and mortality. The Dialysis Outcomes and Practice Patterns Study (DOPPS) provides a unique opportunity to review this problem and its determinants on a global level.MethodsNonadherence was studied using data from the DOPPS, an international, observational, prospective hemodialysis study. Patients were considered nonadherent if they skipped one or more sessions per month, shortened one or more sessions by more than 10 minutes per month, had a serum potassium level openface>6.0mEq/L, a serum phosphate level openface>7.5mg/dL (>2.4mmol/L), or interdialytic weight gain (IDWG)>5.7% of body weight. Predictors of nonadherence were identified using logistic regression. Survival analysis used the Cox proportional hazards model adjusting for case-mix.ResultsSkipping treatment was associated with increased mortality [relative risk (RR) = 1.30, P = 0.01], as were excessive IDWG (RR = 1.12, P = 0.047) and high phosphate levels (RR = 1.17, P = 0.001). Skipping also was associated with increased hospitalization (RR = 1.13, P = 0.04), as were high phosphate levels (RR = 1.07, P = 0.05). Larger facility size (per 10 patients) was associated with higher odds ratios (OR) of skipping (OR = 1.03, P = 0.06), shortening (OR = 1.03, P = 0.05), and IDWG (OR = 1.02, P = 0.07). An increased percentage of highly trained staff hours was associated with lower OR of skipping (OR = 0.84 per 10%, P = 0.02); presence of a dietitian was associated with lower OR of excessive IDWG (OR = 0.75, P = 0.08).ConclusionNonadherence was associated with increased mortality risk (skipping treatment, excessive IDWG, and high phosphate) and with hospitalization risk (skipping, high phosphate). Certain patient/facility characteristics also were associated with nonadherence

Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats

The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long Evans rats were treated by gavage with 0.09, 0.87, or 8.73 mg AMM/kg body weight (BW), vehicle, or 100 mg ATR/kg BW positive control, on gestation days 15-19. Preputial separation was significantly delayed in 0.87 mg and 8.73 mg AMM-exposed males. AMM-exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose-dependent increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear

Cardiac Energetics in Patients With Aortic Stenosis and Preserved Versus Reduced Ejection Fraction.

BACKGROUND: Why some but not all patients with severe aortic stenosis (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and flux is associated with this transition. METHODS: We recruited 102 participants to 5 groups: moderate aortic stenosis (ModAS) (n=13), SevAS, left ventricular (LV) ejection fraction ≥55% (SevAS-preserved ejection fraction, n=37), SevAS, LV ejection fraction 0.99). Accompanying the fall in CK flux, total CK and citrate synthase activities and the absolute activities of mitochondrial-type CK and CK-MM isoforms were also lower (P<0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity (r=0.86, P=0.003). CONCLUSIONS: Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS and suggest that a fall in CK flux is not by itself a necessary cause of transition to systolic failure. However, because ATP demands increase with AS severity, this could increase susceptibility to systolic failure. As such, targeting CK capacity and flux may be a therapeutic strategy to prevent and treat systolic failure in AS.This study was principally funded by a British Heart Foundation Clinical Training Research Fellowship FS/15/80/31803 (to Dr Peterzan) with support from a British Heart Foundation Program Grant (RG/18/12/34040). Drs Neubauer and Rider acknowledge support from British Heart Foundation Center of Research Excellence. Dr Neubauer acknowledges support from the National Institute of Health Research Oxford Biomedical Research Center. Dr Rodgers receives funding from the Wellcome Trust and the Royal Society (grant no. 098436/Z/12/B) and supported by the National Institute of Health Research Cambridge Biomedical Research Center. Dr Rider is funded by the British Heart Foundation FS/16/70/32157. Dr Miller was supported by a Novo Nordisk Postdoctoral Fellowship run in conjunction with the University of Oxford. The Biotechnology and Biological Sciences Research Council provided Advanced Life Sciences Research Technology Initiative 13 funding for serial block-face scanning electron microscopy through grant BB/C014122/1 (to Prof Chris Hawes, Oxford Brookes University)