The discovery of brown adipose tissue (BAT) in adult humans presents a new therapeutic target for metabolic disease; however, little is known about the regulation of human BAT. Chronic glucocorticoid ...excess causes obesity in humans, and glucocorticoids suppress BAT activation in rodents. We tested whether glucocorticoids regulate BAT activity in humans. In vivo, the glucocorticoid prednisolone acutely increased 18fluorodeoxyglucose uptake by BAT (measured using PET/CT) in lean healthy men during mild cold exposure (16°C–17°C). In addition, prednisolone increased supraclavicular skin temperature (measured using infrared thermography) and energy expenditure during cold, but not warm, exposure in lean subjects. In vitro, glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but substantially decreased isoprenaline-stimulated respiration and UCP-1 in primary murine brown and beige adipocytes. The highly species-specific regulation of BAT function by glucocorticoids may have important implications for the translation of novel treatments to activate BAT to improve metabolic health.
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•Glucocorticoids acutely increase but chronically suppress BAT activity in humans•Glucocorticoids increase UCP-1 and respiration in human brown adipocytes•Glucocorticoids decrease UCP-1 and respiration in murine brown and beige adipocytes•Species-specific differences exist in the regulation of BAT activation
The regulation of brown adipose tissue (BAT) in humans is not well understood. Ramage et al. show that glucocorticoids acutely increase BAT in vivo and in vitro in humans through increasing UCP-1. However, glucocorticoids decrease UCP-1 in murine beige/ brown adipocytes, identifying species-specific differences in the regulation of BAT function.
Human-wildlife conflict, in particular crop-foraging, challenges conservationists worldwide. Endangered golden monkeys (
Cercopithecus mitis kandti
) are frequent crop-foragers around Volcanoes ...National Park (VNP), Rwanda. To evaluate the impact of crop-foraging behaviour on monkeys and farmers, we interviewed 45 farmers near VNP using a structured questionnaire and organised a workshop for local and regional actors to discuss mitigation measures. To investigate differences in monkey behaviour when foraging inside versus outside VNP, and to inform mitigation strategies, we collected
ad libitum
behavioural data from one habituated golden monkey group for 11 weeks. We tested the feasibility of a taste aversion technique to deter monkeys, by placing chilli-laced potatoes in harvested potato fields adjacent to the study group’s home range but found that experimental aversion techniques were logistically challenging. Of 38 farmers, 95% experienced potato loss to monkeys and 36% of 44 farmers threw objects at/chased monkeys in the previous farming season. Farmers and workshop participants judged the most effective way to mitigate crop-foraging to be through improvement of existing crop-guarding. Behavioural observations indicated increased vigilance behaviour and decreased social behaviour when in farmland. Monkeys (N = 9) that visited the experimental area avoided chilli-laced potatoes but continued to forage on nearby crops. In conclusion, our results indicate that crop-foraging can negatively impact farmers' livelihoods and attitudes and can increase vigilance behaviour of monkeys. Our multi-faceted approach enabled the involvement of a wide range of stakeholders, highlighted the urgent need to improve existing management measures and explored alternatives to facilitate positive coexistence between monkeys and farmers.
The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We ...used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG).
In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent 18F-NaF and 18F-FDG PET-CT, and invasive coronary angiography. 18F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of 18F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction.
In 37 (93%) patients with myocardial infarction, the highest coronary 18F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 IQR 1·40–2·25 vs highest non-culprit 1·24 1·06–1·38, p<0·0001). By contrast, coronary 18F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 1·40–2·13 vs 1·58 1·28–2·01, p=0·34). Marked 18F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal 18F-NaF uptake (maximum tissue-to-background ratio 1·90 IQR 1·61–2·17) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 1·09–1·19 vs 1·01 0·94–1·06; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% 21–29 vs 18% 14–22, p=0·001).
18F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease.
Chief Scientist Office Scotland and British Heart Foundation.
Weaning marks an important milestone during life history in mammals indicating nutritional independence from the mother. Age at weaning is a key measure of maternal investment and care, affecting ...female reproductive rates, offspring survival, and, ultimately, the viability of a population. Factors explaining weaned age variation in the endangered mountain gorilla are not yet well understood. This study investigated the impact of group size; group type (one-male versus multimale); offspring sex; and maternal age, rank, and parity on weaned age variation in the Virunga mountain gorilla population. The status of nutritional independence was established in 69 offspring using long-term suckling observations. A Cox-regression with mixed effects was applied to model weaned age and its relationship with covariates. Findings indicate that offspring in one-male groups are more likely to be weaned earlier than offspring in multimale groups, which may reflect a female reproductive strategy to reduce higher risk of infanticide in one-male groups. Inferior milk production capacity and conflicting resource allocation between their own and offspring growth may explain later weaning in primiparous mothers compared to multiparous mothers. Sex-biased weaned age related to maternal condition defined by parity, rank, and maternal age will be discussed in the light of the Trivers-Willard hypothesis. Long-term demographic records revealed no disadvantage of early weaning for mother or offspring. Population growth and two peaks in weaned age within the Virunga population encourage future studies on the potential impact of bamboo shoots as a weaning food and other environmental factors on weaning.
Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured ...exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent 18fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by 133xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate.
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•Human BAT shows substantial glucose uptake and lactate release during warm conditions•Glycerol recycling occurs in human BAT, and cold exposure activates BAT lipolysis•BAT uses substrates other than just glucose or fatty acids during cold activation•Microdialysis is a novel technique to measure in vivo human BAT physiology
Weir et al., using microdialysis, have shown that human brown adipose tissue (BAT) is metabolically active in warm conditions, with higher glucose uptake and lactate release than white AT. Cold activation increased glucose and glutamate uptake and glycerol release by BAT, quantifying substrate utilization and hydrolysis of BAT triglycerides during thermogenesis.
Thrice-weekly hemodialysis (HD) is the most common treatment modality for kidney failure in the United States. We conducted a pilot study to assess the feasibility and safety of incremental-start HD ...in patients beginning maintenance HD.
Pilot study.
Adults with estimated glomerular filtration rate (eGFR) ≥5 mL/min/1.73 m2 and urine volume ≥500 mL/d beginning maintenance HD at 14 outpatient dialysis units.
Randomized allocation (1:1 ratio) to twice-weekly HD and adjuvant pharmacologic therapy for 6 weeks followed by thrice-weekly HD (incremental HD group) or thrice-weekly HD (conventional HD group).
The primary outcome was feasibility. Secondary outcomes included changes in urine volume and solute clearance.
Of 77 patients invited to participate, 51 consented to do so, representing 66% of eligible patients. We randomized 23 patients to the incremental HD group and 25 patients to the conventional HD group. Protocol-based loop diuretics, sodium bicarbonate, and patiromer were prescribed to 100%, 39%, and 17% of patients on twice-weekly HD, respectively. At a mean follow-up of 281.9 days, participant adherence was 96% to the HD schedule (22 of 23 and 24 of 25 in the incremental and conventional groups, respectively) and 100% in both groups to serial timed urine collection. The incidence rate ratio for all-cause hospitalization was 0.31 (95% CI, 0.08-1.17); and 7 deaths were recorded (1 in the incremental and 6 in the conventional group). At week 24, the incremental HD group had lower declines in urine volume (a difference of 51.0 95% CI, −0.7 to 102.8 percentage points) and in the averaged urea and creatinine clearances (a difference of 57.9 95% CI, −22.6 to 138.4 percentage points).
Small sample size, time-limited twice-weekly HD.
It is feasible to enroll patients beginning maintenance HD into a randomized study of incremental-start HD with adjuvant pharmacotherapy who adhere to the study protocol during follow-up. Larger multicenter clinical trials are indicated to determine the efficacy and safety of incremental HD with longer twice-weekly HD periods.
Funding was provided by Vifor Inc.
Registered at ClinicalTrials.gov, identifier NCT03740048.
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With combined positron emission tomography and computed tomography (CT), we investigated coronary arterial uptake of 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) as markers of ...active plaque calcification and inflammation, respectively.
The noninvasive assessment of coronary artery plaque biology would be a major advance particularly in the identification of vulnerable plaques, which are associated with specific pathological characteristics, including micro-calcification and inflammation.
We prospectively recruited 119 volunteers (72 ± 8 years of age, 68% men) with and without aortic valve disease and measured their coronary calcium score and 18F-NaF and 18F-FDG uptake. Patients with a calcium score of 0 were used as control subjects and compared with those with calcific atherosclerosis (calcium score >0).
Inter-observer repeatability of coronary 18F-NaF uptake measurements (maximum tissue/background ratio) was excellent (intra-class coefficient 0.99). Activity was higher in patients with coronary atherosclerosis (n = 106) versus control subjects (1.64 ± 0.49 vs. 1.23 ± 0.24; p = 0.003) and correlated with the calcium score (r = 0.652, p < 0.001), although 40% of those with scores >1,000 displayed normal uptake. Patients with increased coronary 18F-NaF activity (n = 40) had higher rates of prior cardiovascular events (p = 0.016) and angina (p = 0.023) and higher Framingham risk scores (p = 0.011). Quantification of coronary 18F-FDG uptake was hampered by myocardial activity and was not increased in patients with atherosclerosis versus control subjects (p = 0.498).
18F-NaF is a promising new approach for the assessment of coronary artery plaque biology. Prospective studies with clinical outcomes are now needed to assess whether coronary 18F-NaF uptake represents a novel marker of plaque vulnerability, recent plaque rupture, and future cardiovascular risk. (An Observational PET/CT Study Examining the Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis; NCT01358513).
Bioprosthetic aortic valve degeneration is increasingly common, often unheralded, and can have catastrophic consequences.
The authors sought to assess whether 18F-fluoride positron emission ...tomography (PET)-computed tomography (CT) can detect bioprosthetic aortic valve degeneration and predict valve dysfunction.
Explanted degenerate bioprosthetic valves were examined ex vivo. Patients with bioprosthetic aortic valves were recruited into 2 cohorts with and without prosthetic valve dysfunction and underwent in vivo contrast-enhanced CT angiography, 18F-fluoride PET, and serial echocardiography during 2 years of follow-up.
All ex vivo, degenerate bioprosthetic valves displayed 18F-fluoride PET uptake that colocalized with tissue degeneration on histology. In 71 patients without known bioprosthesis dysfunction, 14 had abnormal leaflet pathology on CT, and 24 demonstrated 18F-fluoride PET uptake (target-to-background ratio 1.55 interquartile range (IQR): 1.44 to 1.88). Patients with increased 18F-fluoride uptake exhibited more rapid deterioration in valve function compared with those without (annualized change in peak transvalvular velocity 0.30 IQR: 0.13 to 0.61 vs. 0.01 IQR: −0.05 to 0.16 ms−1/year; p < 0.001). Indeed 18F-fluoride uptake correlated with deterioration in all the conventional echocardiographic measures of valve function assessed (e.g., change in peak velocity, r = 0.72; p < 0.001). Each of the 10 patients who developed new overt bioprosthesis dysfunction during follow-up had evidence of 18F-fluoride uptake at baseline (target-to-background ratio 1.89 IQR: 1.46 to 2.59). On multivariable analysis, 18F-fluoride uptake was the only independent predictor of future bioprosthetic dysfunction.
18F-fluoride PET-CT identifies subclinical bioprosthetic valve degeneration, providing powerful prediction of subsequent valvular dysfunction and highlighting patients at risk of valve failure. This technique holds major promise in the diagnosis of valvular degeneration and the surveillance of patients with bioprosthetic valves. (18F-Fluoride Assessment of Aortic Bioprosthesis Durability and Outcome 18F-FAABULOUS; NCT02304276)
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ObjectivesIntraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvβ3) integrin pathway. We investigated the applicability of the ...αvβ3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis.MethodsVascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217–237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring.Results18F-Fluciclatide uptake co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02).ConclusionsIn vivo expression of αvβ3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvβ3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis.
The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown.
Patients with aortic ...sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate, and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r(2)=0.540, P<0.001), with a more modest increase observed for 18F-FDG (r(2)=0.218, P<0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (>1.97), and 35% had increased 18F-FDG uptake (>1.63). A weak correlation between the activities of these tracers was observed (r(2)=0.174, P<0.001).
Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF.
http://www.clinicaltrials.gov. Unique identifier: NCT01358513.
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