“Every land / carves a people, marks them heavy like an / accent,” writes Gavin Lambert in his poem, “In Summer We Move Slowly,” and Lambert’s collection explores the connective tissue of that very ...relationship—the one between a land and its people. On the dirt roads and highways that take us along the continuum from geography to identity (part drunken road trip, part afternoon stroll, part shambling hike, part not-so reliable history tour) he takes us on a journey through a strange and familiar landscape where “Every place is sacred / or near a sacred place.”
•Chronic stress enhances cancer progression including metastasis in mouse models of breast cancer.•Splanchnic nerve lesioning eliminates epinephrine release from the adrenal medulla.•Circulating ...epinephrine does not affect stress-enhanced cancer progression.
Signaling through β-adrenergic receptors drives cancer progression and β-blockers are being evaluated as a novel therapeutic strategy to prevent metastasis. Orthotopic mouse models of breast cancer show that β-adrenergic signaling induced by chronic stress accelerates metastasis, and that β2-adrenergic receptors on tumor cells are critical for this. Endogenous catecholamines are released during chronic stress: norepinephrine from the adrenal medulla and sympathetic nerves, and epinephrine from the adrenal medulla. β2-adrenergic receptors are much more sensitive to epinephrine than to norepinephrine. To determine if epinephrine is necessary in the effects of stress on cancer progression, we used a denervation strategy to eliminate circulating epinephrine, and quantified the effect on metastasis. Using both human xenograft and immune-intact murine models of breast cancer, we show that circulating epinephrine is dispensable for the effects of chronic stress on cancer progression. Measured levels of circulating norepinephrine were sufficiently low that they were unlikely to influence β2-adrenergic signaling, suggesting a possible role for norepinephrine release from sympathetic nerve terminals.
Accurate diagnosis of power transformers is critical for the reliable and cost-effective operation of the power grid. Presently there are a range of methods and analytical models for transformer ...fault diagnosis based on dissolved gas analysis. However, these methods give conflicting results and they are not able to generate uncertainty information associated with the diagnostics outcome. In this situation it is not always clear which model is the most accurate. This paper presents a novel multiclass probabilistic diagnosis framework for dissolved gas analysis based on Bayesian networks and hypothesis testing. Bayesian network models embed expert knowledge, learn patterns from data and infer the uncertainty associated with the diagnostics outcome, and hypothesis testing aids in the data selection process. The effectiveness of the proposed framework is validated using the IEC TC 10 dataset and is shown to have a maximum diagnosis accuracy of 88.9%.
Patients with diabetic hypertensive nephropathy have accelerated disease progression. Diabetes and hypertension have both been associated with changes in renal catecholamines and reactive oxygen ...species. With a specific focus on renal catecholamines and oxidative stress we examined a combined model of hypertension and diabetes using normotensive BPN/3J and hypertensive BPH/2J Schlager mice. Induction of diabetes (5 × 55 mg/kg streptozotocin i.p.) did not change the hypertensive status of BPH/2J mice (telemetric 24 h avg. MAP, non-diabetic 131 ± 2 vs. diabetic 129 ± 1 mmHg, n.s at 9 weeks of study). Diabetes-associated albuminuria was higher in BPH/2J vs. diabetic BPN/3J (1205 + 196/-169 versus 496 + 67/-59 μg/24 h,
= 0.008). HPLC measurement of renal cortical norepinephrine and dopamine showed significantly greater levels in hypertensive mice whilst diabetes was associated with significantly lower catecholamine levels. Diabetic BPH/2J also had greater renal catecholamine levels than diabetic BPN/3J (diabetic: norepinephrine BPN/3J 40 ± 4, BPH/2J 91 ± 5,
= 0.010; dopamine: BPN/3J 2 ± 1; BPH/2J 3 ± 1 ng/mg total protein,
< 0.001 after 10 weeks of study). Diabetic BPH/2J showed greater cortical tubular immunostaining for monoamine oxidase A and cortical mitochondrial hydrogen peroxide formation was greater in both diabetic and non-diabetic BPH/2J. While cytosolic catalase activity was greater in non-diabetic BPH/2J it was significantly lower in diabetic BPH/2J (cytosolic: BPH/2J 127 ± 12 vs. 63 ± 6 nmol/min/ml,
< 0.001). We conclude that greater levels of renal norepinephrine and dopamine associated with hypertension, together with diabetes-associated compromised anti-oxidant systems, contribute to increased renal oxidative stress in diabetes and hypertension. Elevations in renal cortical catecholamines and reactive oxygen species have important therapeutic implications for hypertensive diabetic patients.
Aims/hypothesis
Brown adipose tissue (BAT) activation increases energy expenditure and may have therapeutic potential to combat obesity. The primary activating and adaptive signal for BAT is via ...β-adrenergic signalling. We previously demonstrated that human BAT is acutely responsive to oral administration of the sympathomimetic, ephedrine. Here we aimed to determine whether adaptive thermogenesis can be induced via chronic treatment with ephedrine.
Methods
Twenty-three healthy young men, recruited from the general public in Melbourne, Australia, who were non-smokers, physically inactive and non-medicated with no prior history of cardiovascular disease or diabetes were recruited for this study. They were assigned to receive either 1.5 mg kg
−1
day
−1
ephedrine (‘active’ group;
n
= 12, age 23 ± 1 years, BMI 24 ± 1 kg/m
2
) or placebo (
n
= 11; 22 ± 2 years, 23 ± 2 kg/m
2
) for 28 days in a randomised (computer-generated random order sequence), placebo-controlled, parallel-group trial. Participants and all investigators were blinded to treatments. Body composition was measured before and after the intervention by dual energy X-ray absorptiometry. BAT activity, measured via
18
F-fluorodeoxyglucose positron emission tomography-computed tomography, in response to a single dose of 2.5 mg/kg ephedrine, was the primary outcome measure to be determined before and after the 28 day treatment period.
Results
Twenty-eight individuals were randomised and consented to the study. Twenty-three completed the trial and only these participants were included in the final analyses. After 28 days of treatment, the active group lost a significant amount of total body fat (placebo 1.1 ± 0.3 kg, ephedrine −0.9 ± 0.5 kg;
p
< 0.01) and visceral fat (placebo 6.4 ± 19.1 g, ephedrine −134 ± 43 g;
p
< 0.01), with no change in lean mass or bone mineral content compared with the placebo group. In response to acute ephedrine, BAT activity (change in mean standardised uptake value: placebo −3 ± 7%, ephedrine −22 ± 6%) and the increase in systolic blood pressure were significantly reduced (
p
< 0.05) in the active group compared with placebo.
Conclusions/interpretation
Chronic ephedrine treatment reduced body fat content, but this was not associated with an increase in BAT activity. Rather, chronic ephedrine suppressed BAT glucose disposal, suggesting that chronic ephedrine treatment decreased, rather than increased, BAT activity.
Trial registration
: ClinicalTrials.gov NCT02236962
Funding
: This study was funded by the National Health and Medical Research Council of Australia Program Grant (1036352) and the OIS scheme from the Victorian State Government.
Aims/hypothesis
Increasing brown adipose tissue (BAT) activity is a possible therapeutic strategy to increase energy expenditure and glucose and lipid clearance to ameliorate obesity and associated ...comorbidities. The thiazolidinedione (TZD) class of glucose-lowering drugs increase BAT browning in preclinical experimental models but whether these actions extend to humans in vivo is unknown. The aim of this study was to determine the effect of pioglitazone treatment on adipocyte browning and adaptive thermogenesis in humans.
Methods
We first examined whether pioglitazone treatment of cultured human primary subacromioclavicular-derived adipocytes induced browning. Then, in a blinded, placebo-controlled, parallel trial, conducted within the Baker Institute clinical research laboratories, 14 lean male participants who were free of cardiometabolic disease were randomised to receive either placebo (lactose;
n
= 7, age 22 ± 1 years) or pioglitazone (45 mg/day,
n
= 7, age 21 ± 1 years) for 28 days. Participants were allocated to treatments by Alfred Hospital staff independent from the study via electronic generation of a random number sequence. Researchers conducting trials and analysing data were blind to treatment allocation. The change in cold-stimulated BAT activity, assessed before and after the intervention by
18
Ffluorodeoxyglucose uptake via positron emission tomography/computed tomography in upper thoracic and cervical adipose tissue, was the primary outcome measure. Energy expenditure, cardiovascular responses, core temperature, blood metabolites and hormones were measured in response to acute cold exposure along with body composition before and after the intervention.
Results
Pioglitazone significantly increased in vitro browning and adipogenesis of adipocytes. In the clinical trial, cold-induced BAT maximum standardised uptake value was significantly reduced after pioglitazone compared with placebo (−57 ± 6% vs −12 ± 18%, respectively;
p
< 0.05). BAT total glucose uptake followed a similar but non-significant trend (−50 ± 10% vs −6 ± 24%, respectively;
p
= 0.097). Pioglitazone increased total and lean body mass compared with placebo (
p
< 0.05). No other changes between groups were detected.
Conclusions/interpretation
The disparity in the actions of pioglitazone on BAT between preclinical experimental models and our in vivo human trial highlight the imperative to conduct human proof-of-concept studies as early as possible in BAT research programmes aimed at therapeutic development. Our clinical trial findings suggest that reduced BAT activity may contribute to weight gain associated with pioglitazone and other TZDs.
Trial registration
ClinicalTrials.gov
NCT02236962
Funding
This work was supported by the Diabetes Australia Research Program and OIS scheme from the Victorian State Government.
Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS ...era provides an opportunity for cross-phenotype analyses between different complex phenotypes.
To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach.
Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017.
The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases.
Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes.
The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.
The eastern paralysis tick, Ixodes holocyclus, is a tick of much veterinary importance in Australia. Each year, thousands of dogs and cats present to veterinary clinics and hospitals with signs of ...tick paralysis. In a previous paper, we constructed two models to explain prevalence and temporal distributions of tick paralysis cases presenting to emergency veterinary hospitals in South East Queensland (2009–2020) and the Northern Beaches of Sydney (1999–2017). The first model accounted for the intensity of the clinical burden of tick paralysis based on the prevalence of cases of tick paralysis in the tick paralysis season whereas the second model accounted for the start of the tick paralysis season. In the present paper, we test our models further, with much additional data from 2021 to 2023 (South East Queensland) and from 2018 to 2023 (Northern Beaches of Sydney). During the defined tick paralysis season in these locations, 10.3 % (3207 of 31,217) of veterinary-consultations were for tick paralysis. On average, predictions for the prevalence of cases of tick paralysis were 1.3 % (0.013) away from the actual prevalence whereas predictions for the start of the tick paralysis season were 1.7 weeks away from the actual start of the season. The prediction of the prevalence of tick paralysis cases was most accurate for Brisbane and least accurate for the Northern Beaches of Sydney whereas, curiously, the prediction for the start of the tick paralysis season was most accurate for the Northern Beaches of Sydney and least accurate for Brisbane. We re-fitted the models with the new data. We predict that about 10 % (Sunshine Coast), 5 % (Brisbane), 7 % (Gold Coast) and 12 % (Northern Beaches of Sydney) of veterinary-consultations in the tick paralysis season of 2024 will be cases of tick paralysis, resulting in a tick paralysis clinical burden intensity of similar magnitude to previous years. Such predictions allow for timely public education campaigns around the importance of prevention and appropriate resource planning for veterinary clinics.
Display omitted
•The weather determined how ‘hot’ the tick paralysis season was in eastern Australia: 2018–2024.•The weather in summer predicted the prevalence of tick paralysis with an error of 1.3 %.•The weather in winter predicted the start of the tick paralysis season with an error of 1.7 weeks.•Predictions for the tick paralysis season of 2024 were made.
IntroductionPregnant women and infants are at risk of severe influenza and pertussis infection. Inactivated influenza vaccine (IIV) and diphtheria-tetanus-acellular pertussis vaccine (dTpa) are ...recommended during pregnancy to protect both mothers and infants. In Australia, uptake is not routinely monitored but coverage appears sub-optimal. Evidence on the safety of combined antenatal IIV and dTpa is fragmented or deficient, and there remain knowledge gaps of population-level vaccine effectiveness. We aim to establish a large, population-based, multi-jurisdictional cohort of mother-infant pairs to measure the uptake, safety and effectiveness of antenatal IIV and dTpa vaccines in three Australian jurisdictions. This is a first step toward assessing the impact of antenatal vaccination programmes in Australia, which can then inform government policy with respect to future strategies in national vaccination programmes.Methods and analysis‘Links2HealthierBubs’ is an observational, population-based, retrospective cohort study established through probabilistic record linkage of administrative health data. The cohort includes births between 2012 and 2017 (~607 605 mother-infant pairs) in jurisdictions with population-level antenatal vaccination and health outcome data (Western Australia, Queensland and the Northern Territory). Perinatal data will be the reference frame to identify the cohort. Jurisdictional vaccination registers will identify antenatal vaccination status and the gestational timing of vaccination. Information on maternal, fetal and child health outcomes will be obtained from hospitalisation and emergency department records, notifiable diseases databases, developmental anomalies databases, birth and mortality registers.Ethics and disseminationEthical approval was obtained from the Western Australian Department of Health, Curtin University, the Menzies School of Health Research, the Royal Brisbane and Women’s Hospital, and the West Australian Aboriginal Health Ethics Committees. Research findings will be disseminated in peer-reviewed journals, at scientific meetings, and may be incorporated into communication materials for public health agencies and the public.
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