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PURPOSE: Deranged metabolism is now recognized as a key causal factor in a variety of heart diseases, and is being studied extensively. However, invasive methods may alter metabolism, and conventional imaging techniques measure tracer uptake but not downstream metabolism. These challenges may be overcome by hyperpolarized MR, a noninvasive technique currently crossing the threshold into human trials. The aim of this study was to image metabolic changes in the heart in response to endogastric glucose bolus and to acute hypertension.METHODS: Five postprandial pigs were scanned with hyperpolarized [1-13C]pyruvate cardiac MR at baseline, after oral glucose bolus, and after infusion of angiotensin-II.RESULTS: No effect of glucose bolus was seen using hyperpolarized [1-13C]pyruvate MR despite changes in circulating substrates. During angiotensin-II infusion, blood pressure increased 179% (P = 0.008) and ejection fraction decreased from 54 ± 2% to 47 ± 6% (P = 0.03) The hemodynamic changes were accompanied by increases in the hyperpolarized [1-13C]pyruvate MR derived ratios of lactate/alanine (from 0.58 ± 0.13 to 0.78 ± 0.06, P = 0.03) and bicarbonate/alanine (from 0.55 ± 0.12 to 0.91 ± 0.14, P = 0.007).CONCLUSION: Glucose loading did not alter cardiac metabolism, but during acute hypertensive stress, cardiac aerobic, carbohydrate metabolism, and pyruvate-lactate exchange was altered. Hyperpolarized MR allows noninvasive evaluation of acute changes in cardiac metabolism. However, hemodynamics must be taken into account when interpreting the results.

Magnetic resonance imaging (MRI) is increasingly the method of choice for rapid stroke assessment in patients and for guiding patient selection in clinical trials. The underlying metabolic status during stroke and following treatment is recognized as an important prognostic factor; thus, new methods are required to monitor local biochemistry following cerebral infarction, rapidly and in vivo. Hyperpolarized MRI with the tracer [1-13C]pyruvate enables rapid detection of localized [1-13C]lactate production, which has recently been shown in patients, supporting its translation to assess clinical stroke. Here we show the ability of hyperpolarized 13C MRI to detect the metabolic alterations characteristic of endothelin-1-induced ischemic stroke in rodents. In the region of penumbra, determined via T2-weighted 1H MRI, both [1-13C]pyruvate delivery and [1-13C]pyruvate cellular uptake independently increased. Furthermore, we observed a 33% increase in absolute [1-13C]lactate signal in the penumbra, and we determined that half of this increase was due to increased intracellular [1-13C]pyruvate supply and half was mediated by enhanced lactate dehydrogenase-mediated [1-13C]lactate production. Future work to characterize the kinetics of delivery, uptake, and enzymatic conversions of hyperpolarized tracers following ischemic stroke could position hyperpolarized 13C MRI as an ideal technology for rapid assessment of the penumbra during the critical time window following ischemic stroke in patients.

PURPOSE: The aim of this work was to investigate whether hyperpolarized (13) C,(15) N2 -urea can be used as an imaging marker of renal injury in renal unilateral ischemic reperfusion injury (IRI), given that urea is correlated with the renal osmotic gradient, which describes the renal function.METHODS: Hyperpolarized three-dimensional balanced steady-state (13) C magnetic resonance imaging (MRI) experiments alongside kidney function parameters and quantitative polymerase chain reaction measurements were performed in rats subjected to unilateral renal ischemia for 60-minute and 24-hour reperfusion.RESULTS: We revealed a significant reduction in the intrarenal gradient in the ischemic kidney in agreement with cortical injury markers neutrophil gelatinase-associated lipocalin and kidney injury molecule 1, as well as functional kidney parameters.CONCLUSION: Hyperpolarized functional (13) C,(15) N2 urea MRI can be used to successfully detect changes in the intrarenal urea gradient post-IRI, thereby enabling in vivo monitoring of the intrarenal functional status in the rat kidney. Magn Reson Med 76:1524-1530, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

PURPOSE: A decline in cortico-medullary osmolality gradient of the kidney may serve as an early indicator of pathological disruption of the tubular reabsorption process. The purpose of this study was to investigate the feasibility of hyperpolarized (13) C,(15) N2 -urea MRI as a biomarker of renal function in healthy porcine kidneys resembling the human physiology.METHODS: Five healthy female Danish domestic pigs (weight 30 kg) were scanned at 3 Tesla (T) using a (13) C 3D balanced steady-state MR pulse sequence following injection of hyperpolarized (13) C,(15) N2 -urea via a femoral vein catheter. Images were acquired at different time points after urea injection, and following treatment with furosemide.RESULTS: A gradient in cortico-medullary urea was observed with an intramedullary accumulation 75 s after injection of hyperpolarized (13) C,(15) N2 -urea, whereas images acquired at earlier time points postinjection were dominated by cortical perfusion. Furosemide treatment resulted in an increased urea accumulation in the cortical space, leading to a reduction of the medullary-to-cortical signal ratio of 49%.CONCLUSION: This study demonstrates that hyperpolarized (13) C,(15) N2 -urea MRI is capable of identifying the intrarenal accumulation of urea and can differentiate acute renal functional states in multipapillary kidneys, highlighting the potential for human translation. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

PURPOSE: In the current study, we investigated hyperpolarized urea as a possible imaging biomarker of the renal function by means of the intrarenal osmolality gradient.METHODS: Hyperpolarized three-dimensional balanced steady state (13) C MRI experiments alongside kidney function parameters and quantitative polymerase chain reaction measurements was performed on two groups of rats, a streptozotocin type 1 diabetic group and a healthy control group.RESULTS: A significant decline in intrarenal steepness of the urea gradient was found after 4 weeks of untreated insulinopenic diabetes in agreement with an increased urea transport transcription.CONCLUSION: MRI and hyperpolarized [(13) C,(15) N]urea can monitor the changes in the corticomedullary urea concentration gradients in diabetic and healthy control rats. Magn Reson Med, 2016. © 2016 Wiley Periodicals, Inc.

Hyponatraemia is common clinically, and if it develops rapidly, brain oedema evolves, and severe morbidity and even death may occur. Experimentally, acute hyponatraemia is most frequently studied in small animal models in which the hyponatraemia is produced by intraperitoneal instillation of hypotonic fluids (IP-model). This hyponatraemia model is described as "dilutional" or "syndrome of inappropriate ADH (SIADH)", but seminal studies contradict this interpretation. To confront this issue, we developed an IP-model in a large animal (pig) and studied water and electrolyte responses in brain, muscle, plasma and urine. We hypothesised that hyponatraemia was induced by simple water dilution, with no change in organ sodium content. Moderate hypotonic hyponatraemia was induced by a single IV dose of desmopressin and intraperitoneal instillation of 2.5% glucose. All animals were anaesthetised and intensively monitored. In vivo brain and muscle water was determined by magnetic resonance imaging and related to plasma sodium concentration. Muscle water content increased less than expected due to pure dilution, and muscle sodium content decreased significantly (28%). Sodium was redistributed to the peritoneal fluid, resulting in a significantly reduced plasma volume. This shows that the IP-model induces hypovolaemic hyponatraemia and not dilutional/SIADH hyponatraemia. Brain oedema evolved, but brain sodium content decreased significantly (21%). To conclude, the IP-model induces hypovolaemic hyponatraemia due to sodium redistribution and not water dilution. The large reduction in brain sodium is probably due to the specific mechanism that causes the hyponatraemia. This is not accounted for in the current understanding of the brain response to acute hyponatraemia. This article is protected by copyright. All rights reserved.

Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers. The lack of effect disagrees with persuasive data obtained from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders.

BACKGROUND: The spin-lattice relaxation in the rotating frame (T1ρ) is proposed as an attractive alternative parameter to probe biochemical changes in cartilage. The early stage of osteoarthritis is primarily associated with proteoglycan loss and little change in collagen. OBJECTIVE: To evaluate changes in the T1ρ relaxation time from porcine patellar articular cartilages with or without trypsin digestion in vitro by means of T1ρ imaging and relaxation time map quantitative analysis. DESIGN, TIME AND SETTING: Self-control study was carried out at the Orthopaedic Research Laboratory and MRI Research Center, Aarhus University Hospital, Denmark between February 2007 and January 2008. MATERIALS: Ten Danish female Landrace were involved, totally 20 patella. METHODS: The porcine patellar cartilage samples (n = 20) were assigned to 2 groups. Ten right patellar samples were immersed in PBS for 4 hours to serve as self-control group. Ten left patellar samples were immersed in PBS with trypsin for 4 hours as treated group. T1ρ weighted images of articular cartilage were collected with a spin-echo sequence pre-encoded with a spin-lock pulse cluster and a spin-echo sequence on a 7.0T scanner. T1ρ relaxation time map was reconstructed to determine the T1ρ value of articular cartilage. Both left and right patellar cartilage was stained with Safranin O/fast green for the histological observation. MAIN OUTCOME MEASURES: Circled digit one Quantitative analysis of T1ρ relaxation time map; Circled digit two Histological results of cartilage samples in two groups. RESULTS: Following trypsin digestion, the T1ρ weighted image of patellar cartilage exhibited clear outcomes, good layer and contrast without any abnormal shadow. General observation showed local signals of T1ρ weighted image changed abnormally in two groups of articular cartilage. Reconstructed T1ρ relaxation time map quantitative analysis revealed that, T1ρ relaxation in superficial layers increased significantly in samples after 4 hours trypsin digestion compared with control group (P < 0.05). However, T1ρ relaxation showed no difference on full, deep and calcified layers in the control groups (P > 0.05). CONCLUSION: The T1ρ relaxation time changes at the articular cartilage following trypsin digestion, especially at the superficial layer, indicating T1ρ relaxation time is a sensitive and specific determination index, thus, T1ρ measurements could be used as non-invasive early evaluation method for cartilage disease.

Functional MRI (fMRI) represents experiments with experimental design in the time domain, and yields a very high number of response variables. In this paper an fMRI data set is analyzed for temporal response delays relative to the design, and for spatial response patterns. Two families of two-block PLS are compared, namely PLS Regression (PLSR) and a method developed by F.L. Bookstein, here called Bookstein PLS (BPLS). In BPLS, all components are found simultaneously, making the deflation of X and/or y superfluous. When reformulated as a regression method y = f(X), the BPLS performs badly compared with PLSR in the case of only one dependent variable, y, because only one component can be calculated. Contrary to the asymmetrical PLSR, the symmetrical BPLS lacks a predictive direction from X to y, and is therefore difficult to assess, e.g. by cross-validation. A new PLS method, here called bridge-PLS regression, is presented. It combines elements from both PLSR (predictive asymmetry) and BPLS (all components determined by one single eigen-decomposition).

The rate of conversion of D-[1-(13)C]glucose into [3-(13)C]lactate (apparent glycolytic rate) has been determined in C3H murine mammary carcinomas in vivo using tumor-selective (13)C nuclear magnetic resonance spectroscopy with (1)H-(13)C cross-polarization. Under conditions of acute hypoxia induced by breathing carbon monoxide at 660 ppm, the apparent glycolytic rate was 0.0239 +/- 0.0019 min(-1). The proportion of (13)C label incorporated into [4-(13)C]glutamate (measured in tumor extracts) was 25-fold lower than that incorporated into [3-(13)C]lactate, reflecting a very limited oxidative metabolism during this hypoxic episode. For animals breathing air or carbogen (95% O(2) + 5% CO(2)), the calculated glycolytic rates were correspondingly lower (0.0160 +/- 0.0021 min(-1) and 0.0050 +/- 0.0011 min(-1), respectively). Although (13)C labeling of glutamate at C4 was still an order of magnitude lower than that for lactate at C3 (11-fold for air and 9-fold for carbogen), these ratios did show a greater degree of oxidative metabolism than that seen in animals breathing carbon monoxide at 660 ppm. The marked difference in apparent glycolytic rate for this tumor model between well-oxygenated and hypoxic conditions demonstrates a substantial Pasteur effect (inhibition of glycolysis by oxygen). Dynamic (13)C nuclear magnetic resonance spectroscopy provides a noninvasive estimate of tumor glycolysis that can be used to evaluate the relationship between oxygenation and energy metabolism, and this has potential consequences for the sensitivity of hypoxic cells to treatment and their ability to promote angiogenesis.

Combretastatins are a new class of compounds that appear to have anti-tumour activity as a result of specifically targeting the vasculature of tumours. The aim of this study was to investigate the potential of combretastatin A-4 disodium phosphate (CA4DP) to induce vascular effects in a C3H mouse mammary carcinoma, and to see if the anti-tumour response could be improved by combining the drug with conventional anti-cancer therapies. It was found that CA4DP (250 mg/kg) significantly decreased tumour perfusion within 30 minutes after injection and maintained this decrease for several hours, although there was a return to normal by 24 hours. Similar changes were seen in the tumours bioenergetic and oxygenation status. The drug also significantly increased tumour necrosis and had a small inhibitory effect on tumour growth. It was also able to enhance the tumour response to radiation and hyperthermia, when given at the same time or 30 minutes after the radiation and hyperthermia, respectively. Giving the drug 1 hour after cisplatin injection only resulted in a tumour response that was no greater than additive. These results confirm the anti-vascular effects of CA4DP and demonstrate its potential to enhance the anti-tumour activity of conventional therapy.

Single voxel 1H localized spectroscopy (PRESS at 300 MHz) was used to monitor physiological and biochemical changes induced by hydralazine (5 mg/kg, i.p.) in murine C3H mammary tumours. In addition to a significant increase (by 52%, maximal at 30 min) in the intensity of the 1.32 ppm signal (predominantly from lactate, consistent with a selective reduction in tumour blood supply by hydralazine), downfield shifts in the resonance frequencies of 1H signals were observed. In particular, the signal initially at 3.24 ppm (total choline, tCho) shifted by 0.050 ppm (maximal at 13 min), whereas water shifted by 0.086 ppm. Lactate intensity and water and tCho resonance frequencies returned to control values at approximately 100 min after treatment. No significant changes in the resonance frequencies of water or tCho were observed over this time period in the tumours of mice given saline. In vitro studies showed that, while the resonance frequency of water was temperature dependent, the main components of the tCho signal (choline, phosphorylcholine and glycerophosphorylcholine) were more than 30-fold less sensitive to temperature. It was concluded that the shift in the water resonance frequency was due to the combined effects of tumour temperature reduction and a paramagnetic shift from increased deoxyhaemoglobin levels, whereas the tCho signal was only affected by the paramagnetic shifts.