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Background and Aims: Peroxisome proliferator-activated receptor α (PPARα) is crucial for regulating cardiac β-oxidation in the heart, liver, and kidney. Ageing can induce cardiac metabolic alterations, but the role of PPARα has not been extensively characterised. The aim of this research was to investigate the role of PPARα in the aged heart., Methods: Hyperpolarized [1- 13 C]pyruvate was used to evaluate in vivo cardiac carbohydrate metabolism in fed and fasted young (3 months) and old (20-22 months) PPARα knockout (KO) mice versus controls. Cine MRI assessed cardiac structural and functional changes. Cardiac tissue analysis included qRT-PCR and Western blotting for Pparα, medium chain acyl-CoA dehydrenase (MCAD), uncoupling protein (UCP) 3, glucose transporter (GLUT) 4 and PDH kinase (PDK) 1,2, and 4 expression., Results: PPARα-KO hearts from both young and old mice showed significantly reduced Pparα mRNA and a 58-59 % decrease in MCAD protein levels compared to controls. Cardiac PDH flux was similar in young control and PPARα-KO mice but 96 % higher in old PPARα-KO mice. Differences between genotypes were consistent in fed and fasted states, with reduced PDH flux when fasted. Increased PDH flux was accompanied by a 179 % rise in myocardial GLUT4 protein. No differences in PDK 1, 2, or 4 protein levels were observed between fed groups, indicating the increased PDH flux in aged PPARα-KO mice was not due to changes in PDH phosphorylation., Conclusions: Aged PPARα-KO mice demonstrated higher cardiac PDH flux compared to controls, facilitated by increased myocardial GLUT4 protein levels, leading to enhanced glucose uptake and glycolysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13 C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13 C MRI in 2011, preclinical studies involving [1- 13 C]pyruvate as well a number of other 13 C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1- 13 C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13 C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine if hyperpolarized [1,4- 13 C 2 ]malate imaging could measure cardiomyocyte necrosis after myocardial infarction (MI)., Background: MI is defined by an acute burst of cellular necrosis and the subsequent cascade of structural and functional adaptations. Quantifying necrosis in the clinic after MI remains challenging. Magnetic resonance-based detection of the conversion of hyperpolarized [1,4- 13 C 2 ]fumarate to [1,4- 13 C 2 ]malate, enabled by disrupted cell membrane integrity, has measured cellular necrosis in vivo in other tissue types. Our aim was to determine whether hyperpolarized [1,4- 13 C 2 ]malate imaging could measure necrosis after MI., Methods: Isolated perfused hearts were given hyperpolarized [1,4- 13 C 2 ]fumarate at baseline, immediately after 20 min of ischemia, and after 45 min of reperfusion. Magnetic resonance spectroscopy measured conversion into [1,4- 13 C 2 ]malate. Left ventricular function and energetics were monitored throughout the protocol, buffer samples were collected and hearts were preserved for further analyses. For in vivo studies, magnetic resonance spectroscopy and a novel spatial-spectral magnetic resonance imaging sequence were implemented to assess cardiomyocyte necrosis in rats, 1 day and 1 week after cryo-induced MI., Results: In isolated hearts, [1,4- 13 C 2 ]malate production became apparent after 45 min of reperfusion, and increased 2.7-fold compared with baseline. Expression of dicarboxylic acid transporter genes were negligible in healthy and reperfused hearts, and lactate dehydrogenase release and infarct size were significantly increased in reperfused hearts. Nonlinear regression revealed that [1,4- 13 C 2 ]malate production was induced when adenosine triphosphate was depleted by >50%, below 5.3 mmol/l (R 2  = 0.904). In vivo, the quantity of [1,4- 13 C 2 ]malate visible increased 82-fold over controls 1 day after infarction, maintaining a 31-fold increase 7 days post-infarct. [1,4- 13 C 2 ]Malate could be resolved using hyperpolarized magnetic resonance imaging in the infarct region one day after MI; [1,4- 13 C 2 ]malate was not visible in control hearts., Conclusions: Malate production in the infarcted heart appears to provide a specific probe of necrosis acutely after MI, and for at least 1 week afterward. This technique could offer an alternative noninvasive method to measure cellular necrosis in heart disease, and warrants further investigation in patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiovascular disease is the leading cause of death world-wide. It is increasingly recognised that cardiac pathologies show, or may even be caused by, changes in metabolism, leading to impaired cardiac energetics. The heart turns over 15 times its own weight in ATP every day and thus relies heavily on the availability of substrates and on efficient oxidation to generate this ATP. A number of old and emerging drugs that target different aspects of metabolism are showing promising results with regard to improved cardiac outcomes in patients. A non-invasive imaging technique that could assess the role of different aspects of metabolism in heart disease, as well as measure changes in cardiac energetics due to treatment, would be valuable in the routine clinical care of cardiac patients. Hyperpolarised magnetic resonance spectroscopy and imaging have revolutionised metabolic imaging, allowing real-time metabolic flux assessment in vivo for the first time. In this review we summarise metabolism in the healthy and diseased heart, give an introduction to the hyperpolarisation technique, 'dynamic nuclear polarisation' (DNP), and review the preclinical studies that have thus far explored healthy cardiac metabolism and different models of human heart disease. We furthermore show what advances have been made to translate this technique into the clinic, what technical challenges still remain and what unmet clinical needs and unexplored metabolic substrates still need to be assessed by researchers in this exciting and fast-moving field., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The stability and longevity of recordings obtained from intracortical microelectrodes continues to remain an area of concern for neural interfacing applications. The limited longevity of microelectrode performance has been associated with the integrity of the blood brain barrier (BBB) and the neuroinflammatory response to the microelectrode. Here, we report the investigation of an additive approach that targets both mechanical and chemical factors believed to contribute to chronic BBB instability and the neuroinflammatory response associated with implanted intracortical microelectrodes. The implants investigated were based on a mechanically adaptive, compliant nanocomposite (NC), which reduces the tissue response and tissue strain. This material was doped with various concentrations of the antioxidant resveratrol with the objective of local and rapid delivery. In vitro analysis of resveratrol release, antioxidant activity, and cytotoxicity suggested that a resveratrol content of 0.01% was optimal for in vivo assessment. Thus, probes made from the neat NC reference and probes containing resveratrol (NC Res) were implanted into the cortical tissue of rats for up to sixteen weeks. Histochemical analysis suggested that at three days post-implantation, neither materials nor therapeutic approaches (independently or in combination) could alter the initial wound healing response. However, at two weeks post-implantation, the NC Res implant showed a reduction in activated microglia/macrophages and improvement in neuron density at the tissue-implant interface when compared to the neat NC reference. However, sixteen weeks post-implantation, when the antioxidant was exhausted, NC Res and the neat NC reference exhibited similar tissue responses. The data show that NC Res provides short-term, short-lived benefits due to the antioxidant release, and a long-term reduction in neuroinflammation on account of is mechanical adaptive, compliant nature. Together, these results demonstrate that local delivery of resveratrol can provide an additive advantage by providing a consistent reduction in the tissue response., (Published by Elsevier Ltd.)

Additional tools to analyze follicle development would be highly advantageous because current methods require sacrifice of animals at specific times and time-consuming sectioning of tissues for histologic analysis. Magnetic resonance imaging (MRI) may provide a less involved, faster and more cost-effective method to analyze follicles in whole ovaries. Fixed ovaries were collected at different stages of the estrus cycle and after stimulation with gonadotrophins (24 and 48 h post pregnant mares serum (PMSG), and 10 and 24 h post human chorionic gonadotrophin (hCG)) with or without administration of the contrast agent gadodiamide. The MR images were generated using a vertical-bore, 11.7 Tesla MR system. Analysis of the MR images revealed large antral follicles in fixed ovaries with the oocyte and cumulus mass identifiable within preovulatory follicles. The use of gadodiamide had no impact on the quality of MR images obtained. The fixed ovaries were paraffin embedded, sectioned, and hematoxylin stained. Follicles were counted using the MR images and the histology sections. Preovulatory follicle numbers determined using MR images were comparable to those using histology; however counts of smaller follicles were inconsistent. MRI of gonadotrophin-stimulated ovaries in situ did not reveal discernable ovarian structures. Therefore, MRI is a useful tool for studying whole fixed ovaries leaving the ovary intact for additional analyses or for selection of samples based on morphology. The MRI is also useful for identifying preovulatory follicles, although analysis of smaller follicles is not possible, and thus the potential exists for cyst analysis in mouse models of polycystic ovarian syndrome (PCOS)., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: High-fat, low-carbohydrate diets are widely used for weight reduction, but they may also have detrimental effects via increased circulating free fatty acid concentrations., Objective: We tested whether raising plasma free fatty acids by using a high-fat, low-carbohydrate diet results in alterations in heart and brain in healthy subjects., Design: Men (n = 16) aged 22 ± 1 y (mean ± SE) were randomly assigned to 5 d of a high-fat, low-carbohydrate diet containing 75 ± 1% of calorie intake through fat consumption or to an isocaloric standard diet providing 23 ± 1% of calorie intake as fat. In a crossover design, subjects undertook the alternate diet after a 2-wk washout period, with results compared after the diet periods. Cardiac (31)P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, and computerized cognitive tests were used to assess cardiac phosphocreatine (PCr)/ATP, cardiac function, and cognitive function, respectively., Results: Compared with the standard diet, subjects who consumed the high-fat, low-carbohydrate diet had 44% higher plasma free fatty acids (P < 0.05), 9% lower cardiac PCr/ATP (P < 0.01), and no change in cardiac function. Cognitive tests showed impaired attention (P < 0.01), speed (P < 0.001), and mood (P < 0.01) after the high-fat, low-carbohydrate diet., Conclusion: Raising plasma free fatty acids decreased myocardial PCr/ATP and reduced cognition, which suggests that a high-fat diet is detrimental to heart and brain in healthy subjects.

Methods for making rapid and accurate measurements and maps of the transverse relaxation time from a single free induction decay (FID) are proposed. The methods use a multi-echo sequence in combination with B1 insensitive (hyperbolic secant or BIREF2b) refocusing pulses and rapid echo-planar imaging techniques. The results were calibrated against a single spin echo echo-planar imaging sequence using a phantom containing a range of CuSO4 concentrations. The mean percentage absolute difference between the multi-echo and single-echo results was 3% for the multi-echo sequence using the hyperbolic secant refocusing pulse, and 7% for the multi-echo sequence using the BIREF2b refocusing pulse, compared to 13% for a multi-echo sequence using a nonselective sinc refocusing pulse. The use of the sequences in vivo has been demonstrated in studies of gastric function, i.e., the measurement of gastric dilution and monitoring of formation of a raft of alginate polysaccharide within the stomach.

Magnetic resonance imaging provides a non-invasive method for investigating functional changes in the human placenta in vivo. In this study, we combine a magnetic resonance imaging technique called magnetization transfer with established stereological methods in order to analyse and compare placentae from normal (16-36 weeks of gestation) and complicated (pre-eclampsia, intrauterine growth restriction) pregnancies. Magnetization transfer provided an in vivo measure of the ratio of bound protons:total protons and stereological analysis of histological sections was used to estimate a residual:total volume ratio (the ratio of non-vascular volume to total placental volume). Statistical comparisons were drawn using tests for related samples (longitudinal data) or one-way analysis of variance (cross-sectional data). We found no significant differences in magnetization transfer between gestational age groups or between uncomplicated pregnancies and pregnancies complicated by pre-eclampsia or intrauterine growth restriction. In comparable groups of different subjects, stereological analyses also failed to demonstrate significant differences in residual:total volume ratios. We conclude that [a] the ratio of non-vascular volume:total placental volume does not alter between 16 and 36 weeks of normal gestation, and [b] this integrated response is also conserved in pre-eclampsia and intrauterine growth restriction.

This paper presents a novel method of measuring the droplet size in oil-in-water emulsions. It is based on changes in the NMR transverse relaxation rate due to the effect of microscopic magnetic susceptibility differences between fat droplets and the surrounding water. The longitudinal and transverse relaxation rates of a series of emulsions with constant oil volume fraction and five different mean droplet sizes, in the range 0.4-20.9 microm, were measured in vitro at 37 degrees C using EPI. While the longitudinal relaxation rate 1/T(1) did not change significantly, 1/T(2) was observed to increase with mean droplet size. The measured changes in 1/T(2) were found to be in good agreement with results predicted from proton random walk simulations, and were also consistent with analytical solutions based on an outer sphere relaxation model. Measurements of 1/T(2) on emulsions with a higher oil volume fraction, and on emulsions of a fixed size where the water phase was doped with gadolinium to modulate the susceptibility difference between the phases, also showed the predicted behavior. As part of this study the susceptibility difference between olive oil and water was measured to be 1.55 ppm., (Copyright 2001 Academic Press.)

The aim of this study was to measure and portray blood movement in the placenta in vivo in normal and growth restricted pregnancies, using Intra Voxel Incoherent Motion (IVIM) magnetic resonance imaging. Thirteen patients with apparently normal healthy pregnancies were scanned at 31+/-7 (mean+/-s.d.) weeks gestation and seven patients with intrauterine growth restriction (IUGR) were scanned at 31+/-4 weeks. A region of interest (ROI) was defined encompassing the placenta between the decidual and chorionic plates. The volume of moving blood within each imaging voxel of the ROI was then calculated as a percentage of the total voxel volume (f per cent). This information was colour coded to produce maps of moving blood volume. The placenta was segmented length ways into two zones of approximately equal area, termed inner and outer, the latter being adjacent to the uterine wall. f was fitted for the average in the outer zone (f(out)) and inner zone (f(in)). The parameter (f(out)-f(in)) was then calculated for each subject. This was positive in 12/13 of the normal cases and zero for one case (+10 per cent+10, mean+/-s.d.). For pregnancy affected by IUGR this value was negative in all cases (-4 per cent+/-3). Perfusion fraction mapping identified differences in function within the normal placenta in vivo, and between the placentae of normal and IUGR pregnancies. The technique has potential applications in managing, and investigating the aetiology of, pregnancy compromise., (Copyright 2000 Harcourt Publishers Ltd.)