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Purpose: Hyperpolarized [1‐13C]pyruvate MRS can measure cardiac metabolism in vivo. We investigated whether [1‐13C]pyruvate MRS could predict left ventricular remodeling following myocardial infarction (MI), long‐term left ventricular effects of heart failure medication, and could identify responders to treatment. Methods: Thirty‐five rats were scanned with hyperpolarized [1‐13C]pyruvate MRS 3 days after MI or sham surgery. The animals were re‐examined after 30 days of therapy with β‐blockers and ACE‐inhibitors (active group, n = 12), placebo treatment (placebo group, n = 13) or no treatment (sham group, n = 10). Furthermore, heart tissue mitochondrial respiratory capacity was assessed by high‐resolution respirometry. Metabolic results were compared between groups, over time and correlated to functional MR data at each time point. Results: At 30 ± 0.5 days post MI, left ventricular ejection fraction (LVEF) differed between groups (sham, 77% ± 1%; placebo, 52% ± 3%; active, 63% ± 2%, P <.001). Cardiac metabolism, measured by both hyperpolarized [1‐13C]pyruvate MRS and respirometry, neither differed between groups nor between baseline and follow‐up. Three days post MI, low bicarbonate + CO2/pyruvate ratio was associated with low LVEF. At follow‐up, in the active group, a poor recovery of LVEF was associated with high bicarbonate + CO2/pyruvate ratio, as measured by hyperpolarized MRS. Conclusion: In a rat model of moderate heart failure, medical treatment improved function, but did not on average influence [1‐13C]pyruvate flux as measured by MRS; however, responders to heart failure medication had reduced capacity for carbohydrate metabolism. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Is it possible to combine the hyperpolarized magnetic resonance technique and the hyperinsulinaemic clamp method in order to evaluate skeletal muscle metabolism in a large animal model?What is the main finding and its importance?The logistical set‐up is possible, and we found substantial increments in glucose infusion rates representing skeletal muscle glucose uptake but no differences in ratios of [1‐13C]lactate to [1‐13C]pyruvate, [1‐13C]alanine to [1‐13C]pyruvate, and 13C‐bicarbonate to [1‐13C]pyruvate, implying that the hyperpolarization technique might not be optimal for detecting effects of insulin in skeletal muscle of anaesthetized animals, which is of significance for future studies. In skeletal muscle, glucose metabolism is tightly regulated by the reciprocal relationship between insulin and adrenaline, with pyruvate being at the intersection of both pathways. Hyperpolarized magnetic resonance (hMR) is a new approach to gain insights into these pathways, and human trials involving hMR and skeletal muscle metabolism are imminent. We aimed to combine the hyperinsulinaemic clamp technique and hMR in a large animal model resembling human physiology. Fifteen anaesthetized pigs were randomized to saline (control group), hyperinsulinaemic euglycaemic clamp technique (HE group) or hyperinsulinaemic hypoglycaemic clamp technique (HH group). Skeletal muscle metabolism was evaluated by hyperpolarized [1‐13C]pyruvate injection and hMR at baseline and after intervention. The glucose infusion rate per kilogram increased by a statistically significant amount in the HE and HH groups (P < 0.001). Hyperpolarized magnetic resonance showed no statistically significant changes in metabolite ratios: [1‐13C]lactate to [1‐13C]pyruvate in the HH group versus control group (P = 0.19); and 13C‐bicarbonate to [1‐13C]pyruvate ratio in the HE group versus the control group (P = 0.12). We found evidence of profound increments in glucose infusion rates representing skeletal muscle glucose uptake, but interestingly, no signs of significant changes in aerobic and anaerobic metabolism using hMR. These results imply that hyperpolarized [1‐13C]pyruvate might not be optimally suited to detect effects of insulin in anaesthetized resting skeletal muscle, which is of significance for future studies. [ABSTRACT FROM AUTHOR]

Purpose: The article compares physeal recovery after insertion of autologous cartilage and a conventional fat graft in a standardized porcine physeal gap model. Presence of a bone bridge was the primary outcome. Methods: Ten porcines in two groups of five were included in a paired design. A standardized physeal gap in the distal femur was made in all animals. One group (n = 5) was randomized for deposition of autologous cartilage and a Tisseel® or Tisseel® alone. The autologous cartilage was harvested from the femoral articular surface. The other group was randomized for fat grafting or no grafts at all. All animals were housed for 14 weeks. Magnetic resonance imaging (MRI) was performed at 14 weeks prior to euthanasia. The physis was harvested for histology. Results: MRI - Three bone bridges were seen in the fat grafted gaps. All empty gaps formed a bone bridge. No gaps filled with autologous cartilage and Tisseel® resulted in bone bridges. One gap filled with Tisseel® only caused a bone bridge. Histology - The cartilage grafted gaps recovered with physeal-like cartilaginous tissue in histological analysis. Conclusions: Fat grafts seems ineffective in preventing bone bridges. The use of autologous cartilage may be superior to the current treatment. However, donor site complications were not investigated. The study serves as a proof of concept study and requires further investigation. [ABSTRACT FROM AUTHOR]

Metabolic sex differences have recently been shown to be particularly important in tailoring treatment strategies. Sex has a major effect on fat turnover rates and plasma lipid delivery in the body. Differences in kidney structure and transporters between male and female animals have been found. Here we investigated sexspecific renal pyruvate metabolic flux and whole-kidney functional status in age-matched healthy Wistar rats. Blood oxygenation level-dependent and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) were used to assess functional status. Hyperpolarized [1-13C]pyruvate was used to assess the metabolic differences between male and female rats. Female rats had a 41% 6 3% and 41% 6 5% lower absolute body and kidney weight, respectively, than age-matched male rats. No difference was seen between agematched male and female rats in the kidney-to-body weight ratio. A 56% 6 11% lower lactate production per mL/100 mL/min was found in female rats than in age-matched male rats measured by hyperpolarized magnetic resonance and DCE MRI. Female rats had a 33% 6 11% higher glomerular filtration rate than age-matched male rats measured by DCE MRI. A similar renal oxygen tension (T2*) was found between agematched male and female rats as shown by blood oxygenation level-dependent MRI. The results were largely independent of the pyruvate volume and the difference in body weight. This study shows an existing metabolic difference between kidneys in age-matched male and female rats, which indicates that sex differences need to be considered when performing animal experiments. [ABSTRACT FROM AUTHOR]

Key points: This is the first long‐term human clinical trial to report on effects of nicotinamide riboside (NR) on skeletal muscle mitochondrial function, content and morphology.NR supplementation decreases nicotinamide phosphoribosyltransferase (NAMPT) protein abundance in skeletal muscle.NR supplementation does not affect NAD metabolite concentrations in skeletal muscle.Respiration, distribution and quantity of muscle mitochondria are unaffected by NR.NAMPT in skeletal muscle correlates positively with oxidative phosphorylation Complex I, sirtuin 3 and succinate dehydrogenase. Preclinical evidence suggests that the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) boosts NAD+ levels and improves diseases associated with mitochondrial dysfunction. We aimed to determine if dietary NR supplementation in middle‐aged, obese, insulin‐resistant men affects mitochondrial respiration, content and morphology in skeletal muscle. In a randomized, placebo‐controlled clinical trial, 40 participants received 1000 mg NR or placebo twice daily for 12 weeks. Skeletal muscle biopsies were collected before and after the intervention. Mitochondrial respiratory capacity was determined by high‐resolution respirometry on single muscle fibres. Protein abundance and mRNA expression were measured by Western blot and quantitative PCR analyses, respectively, and in a subset of the participants (placebo n = 8; NR n = 8) we quantified mitochondrial fractional area and mitochondrial morphology by laser scanning confocal microscopy. Protein levels of nicotinamide phosphoribosyltransferase (NAMPT), an essential NAD+ biosynthetic enzyme in skeletal muscle, decreased by 14% with NR. However, steady‐state NAD+ levels as well as gene expression and protein abundance of other NAD+ biosynthetic enzymes remained unchanged. Neither respiratory capacity of skeletal muscle mitochondria nor abundance of mitochondrial associated proteins were affected by NR. Moreover, no changes in mitochondrial fractional area or network morphology were observed. Our data do not support the hypothesis that dietary NR supplementation has significant impact on skeletal muscle mitochondria in obese and insulin‐resistant men. Future studies on the effects of NR on human skeletal muscle may include both sexes and potentially provide comparisons between young and older people. Key points: This is the first long‐term human clinical trial to report on effects of nicotinamide riboside (NR) on skeletal muscle mitochondrial function, content and morphology.NR supplementation decreases nicotinamide phosphoribosyltransferase (NAMPT) protein abundance in skeletal muscle.NR supplementation does not affect NAD metabolite concentrations in skeletal muscle.Respiration, distribution and quantity of muscle mitochondria are unaffected by NR.NAMPT in skeletal muscle correlates positively with oxidative phosphorylation Complex I, sirtuin 3 and succinate dehydrogenase. [ABSTRACT FROM AUTHOR]

Hyperpolarized [1-13C]pyruvate magnetic resonance (MR) spectroscopy has the unique ability to detect real-time metabolic changes in vivo owing to its high sensitivity compared with thermal MR and high specificity compared with othe r metabolic imaging methods. The aim of this study was to explore the potential of hyperpolarized MR spectroscopy for quantification of liver pyruvate metabolism dur ing a hyperinsulinemic- isoglycemic clamp in mice. Hyperpolarized [1-13C]pyruvate was used for in vivo MR spectroscopy of liver pyruvate metabolism in mice. Mice were divided into two groups: (i) non-stimulated 5-h fasted mice and (ii) hyperinsulinemic-isoglycemic clamped mice. During clamp conditions, insulin and donor blood were administered at a constant rate, whereas glucose was infused to maintain isoglycemia. When steady state was reached, insulin-stimulated mice were rapidly infused with hyperpolarized [1-13C]pyruvate for real-time tracking of the dynamic distribution of metabolic derivatives from pyruvate, such as [1-13C]lactate, [1-13C]alanine and [13C]bicarbonate. Isotopomer analysis of plasma glucose confirmed 13C-incorporation from [1-13C]pyruvate into glucose was increased in fasted mice compared with insulin-stimulated mice, demonstrating an increased gluconeogenesis in fasted mice. The AUC ratios for [1-13C]alanine/ [1-13C]pyruvate (38.2%), [1-13C]lactate/[1-13C]pyruvate (41.8%) and [13C]bicarbonate/ [1-13C]pyruvate (169%) all increased significantly during insulin sti mulation. Hyperpolarized [1-13C]pyruvate can be used for in vivo MR spectroscopy of liver pyruvate metabolism during hyperinsulinemic-isoglycemic clamp conditions. Under these conditions, insulin decreased gluconeogenesis and increased [1-13C]alanine, [1-13C]lactate and [13C]bicarbonate after a [1-13C]pyruvate bolus. This application of in vivo spectroscopy has the potential to identify impairments in spec ific metabolic pathways in the liver associated with obesity, insulin resistance and nonalcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Introduction: The majority of young women use oral contraceptives (OCs). Use of OCs has been associated with lower myofibrillar protein and tendon collagen synthesis rates, but it is unknown whether OCs will limit the adaptive response of myotendinous tissue to resistance training. Design and Methods: Fourteen healthy untrained young regular OC users (24 ± 1 years, fat% 32 ± 1, 35 ± 2 ml⋅min-1⋅kg-1) and 14 NOC users (non-OC, controls) (24 ± 1 years, fat% 32 ± 2, 34 ± 2 ml⋅min-1⋅kg-1) performed a 10-week supervised lower extremity progressive resistance training program. Before and after the intervention biopsies from the vastus lateralis muscle and the patellar tendon were obtained. Muscle (quadriceps) and tendon cross-sectional area (CSA) was determined by magnetic resonance imaging (MRI) scans, and muscle fiber CSA was determined by histochemistry. Maximal isometric knee extension strength was assessed by dynamometry while 1 repetition maximum (RM) was determined during knee extension. Results: Training enhanced CSA in both muscle (p < 0.001) and tendon (p < 0.01). A trend toward a greater increase in muscle CSA was observed for OC (11%) compared to NOC (8%) (interaction p = 0.06). Analysis of mean muscle fiber type CSA showed a trend toward an increase in type II muscle fiber area in both groups (p = 0.11, interaction p = 0.98), whereas type I muscle fiber CSA increased in the OC group (n = 9, 3821 ± 197 to 4490 ± 313 mm2, p < 0.05), but not in NOC (n = 7, 4020 ± 348 to 3777 ± 354 mm2, p = 0.40) (interaction p < 0.05). Post hoc analyses indicated that the effect of OCs on muscle mass increase was induced by the OC-users (n = 7), who used OCs containing 30 μg ethinyl estradiol (EE), whereas the response in users taking OCs with 20 μg EE (n = 7) did not differ from NOC. Both the OC and NOC group experienced an increase in maximal knee strength (p < 0.001) and 1RM leg extension (p < 0.001) after the training period with no difference between groups. Conclusion: Use of OCs during a 10-week supervised progressive resistance training program was associated with a trend toward a greater increase in muscle mass and a significantly greater increase in type I muscle fiber area compared to controls. Yet, use of OCs did not influence the overall increase in muscle strength related to training. [ABSTRACT FROM AUTHOR]

Purpose: Owing to its noninvasive nature, hyperpolarized MRI may improve delineation of myocardial metabolic derangement in heart disease. However, consistency may depend on the changeable nature of cardiac metabolism in relation to whole‐body metabolic state. This study investigates the impact of feeding status on cardiac hyperpolarized MRI in a large animal model resembling human physiology. Methods: Thirteen 30‐kg pigs were subjected to an overnight fast, and 5 pigs were fed a carbohydrate‐rich meal on the morning of the experiments. Vital parameters and blood samples were registered. All pigs were then scanned by hyperpolarized [1‐13C]pyruvate cardiac MRI, and results were compared between the 2 groups and correlated with circulating substrates and hormones. Results: The fed group had higher blood glucose concentration and mean arterial pressure than the fasted group. Plasma concentrations of free fatty acids (FFAs) were decreased in the fed group, whereas plasma insulin concentrations were similar between groups. Hyperpolarized MRI showed that fed animals had increased lactate/pyruvate, alanine/pyruvate, and bicarbonate/pyruvate ratios. Metabolic ratios correlated negatively with FFA levels. Conclusion: Hyperpolarized MR can identify the effects of different metabolic states on cardiac metabolism in a large animal model. Unlike previous rodent studies, all metabolic derivatives of pyruvate increased in the myocardium of fed pigs. Carbohydrate‐rich feeding seems to be a feasible model for standardized, large animal hyperpolarized MRI studies of myocardial carbohydrate metabolism. [ABSTRACT FROM AUTHOR]

Level of Evidence: 5 Technical Efficacy Stage: 1 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Anesthesia is necessary for most animal studies requiring invasive procedures. It is well documented that various types of anesthesia modulate a wide variety of important metabolic and functional processes in the body, and as such, represent a potential limitation in the study design. In the present study, we aimed to investigate the renal functional and metabolic consequences of 3 typical rodent anesthetics used in preclinical MRI: sevoflurane, inaction, and a mixture of fentanyl, fluanisone, and midazolam (FFM). Methods: The renal effects of 3 different classes of anesthetics (inactin, servoflurane, and FFM) were investigated using functional and metabolic MRI. The renal glucose metabolism and hemodynamics was characterized with hyperpolarized [1‐13C]pyruvate MRI and by DCE imaging. Results: Rats receiving sevoflurane or FFM had blood glucose levels that were 1.3‐fold to 1.4‐fold higher than rats receiving inactin. A 2.9‐fold and 4.8‐fold increased 13C‐lactate/13C‐pyruvate ratio was found in the FFM mixture anesthetized group compared with the sevoflurane and the inactin anesthetized groups. The FFM anesthesia resulted in a 50% lower renal plasma flow compared with the sevoflurane and the inactin anesthetized groups. Conclusion: This study demonstrates different renal metabolic and hemodynamic changes under 3 different anesthetics, using hyperpolarized MR in rats. Inactin and sevoflurane were found to affect the renal hemodynamic and metabolic status to a lesser degree than FFM. Sevoflurane anesthesia is particularly easy to induce and maintain during the whole anesthesia procedure, and as such, represents a good alternative to inaction, although it alters the blood glucose level. [ABSTRACT FROM AUTHOR]

The present study (NCT01446276, ClinicalTrials.gov) assessed long‐term effects of high‐dose Resveratrol (RSV) on basal and insulin‐mediated very low‐density lipoprotein triglyceride (VLDL‐TG), palmitate and glucose kinetics, and liver fat content in men with nonalcoholic fatty liver disease (NAFLD). Participants (n = 16) were non‐diabetic, upper‐body obese (BMI > 28 kg/m2, WHR > 0.9) men with NAFLD who were randomized (1:1) in a double‐blinded, placebo‐controlled clinical trial to either RSV or placebo (500 mg 3 times daily) for 6 months. Magnetic resonance (MR) spectroscopy, dual‐X‐ray absorptiometry and MR imaging assessed liver fat content and body composition, respectively. 14C‐labeled VLDL‐TG and 3H‐labeled glucose and palmitate tracers, in combination with indirect calorimetry and breath samples, were used to assess kinetics and substrate oxidations during basal and hyperinsulinaemic euglycaemic clamp conditions. RSV did not improve either basal or insulin‐mediated VLDL‐TG secretion, oxidation or clearance rates, nor did it affect palmitate or glucose turnover. Likewise, no changes in body composition or liver fat content occurred following RSV compared with placebo treatment. Therefore, RSV cannot be recommended for treatment of metabolic abnormalities in NAFLD. [ABSTRACT FROM AUTHOR]

Since coffee may help to prevent the development of metabolic syndrome (MetS), we aimed to evaluate the short- and long-term effects of a coffee-based supplement on different features of diet-induced MetS. In this study, 24 Sprague Dawley rats were divided into control or nutraceuticals groups to receive a high-fat/high-fructose diet with or without a mixture of caffeic acid (30 mg/day), trigonelline (20 mg/day), and cafestol (1 mg/day) for 12 weeks. An additional 11 rats were assigned to an acute crossover study. In the chronic experiment, nutraceuticals did not alter body weight or glycemic control, but improved fed hyperinsulinemia (mean difference = 30.80 mU/L, p = 0.044) and homeostatic model assessment-insulin resistance (HOMA-IR) (mean difference = 15.29, p = 0.033), and plasma adiponectin levels (mean difference = -0.99 µg/mL, p = 0.048). The impact of nutraceuticals on post-prandial glycemia tended to be more pronounced after acute administration than at the end of the chronic study. Circulating (mean difference = 4.75 U/L, p = 0.014) and intrahepatocellular alanine transaminase activity was assessed by hyperpolarized-13C nuclear magnetic resonance NMR spectroscopy and found to be reduced by coffee nutraceuticals at endpoint. There was also a tendency towards lower liver triglyceride content and histological steatosis score in the intervention group. In conclusion, a mixture of coffee nutraceuticals improved insulin sensitivity and exhibited hepatoprotective effects in a rat model of MetS. Higher dosages with or without caffeine deserve to be studied in the future. [ABSTRACT FROM AUTHOR]

Background:Targeting tumor vasculature with vascular disrupting agents (VDAs) results in substantial cell death that precede tumor shrinkage. Here, we investigate the potential of hyperpolarized magnetic resonance spectroscopy (HPMRS) to monitor early metabolic changes associated with VDA treatment. Methods:Mice bearing C3H mammary carcinomas were treated with the VDAs combretastatin-A4-phosphate (CA4P) or the analog OXi4503, and HPMRS was performed following [1-13C]pyruvate administration. Similarly, treated mice were positron emission tomography (PET) scanned following administration of the glucose analog FDG. Finally, metabolic imaging parameters were compared to tumor regrowth delay and measures of vascular damage, derived from dynamic contrast-agent enhanced magnetic resonance imaging (DCE-MRI) and histology. Results:VDA-treatment impaired tumor perfusion (histology and DCE-MRI), reduced FDG uptake, increased necrosis, and slowed tumor growth. HPMRS, revealed that the [1-13C]pyruvate-to-[1-13C]lactate conversion remained unaltered, whereas [1-13C]lactate-to-[13C]bicarbonate (originating from respiratory CO2) ratios increased significantly following treatment. Conclusions:DCE-MRI and FDG-PET revealed loss of vessel functionality, impaired glucose delivery and reduced metabolic activity prior to cell death. [1-13C]lactate-to-[13C]bicarbonate ratios increased significantly during treatment, indicating a decline in respiratory activity driven by the onset of hypoxia. HPMRS is promising for early detection of metabolic stress inflicted by VDAs, which cannot easily be inferred based on blood flow measurements. [ABSTRACT FROM AUTHOR]

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 13C 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 [13C,15N]urea can monitor the changes in the corticomedullary urea concentration gradients in diabetic and healthy control rats. Magn Reson Med 77:1650-1655, 2017. © 2016 International Society for Magnetic Resonance in Medicine [ABSTRACT FROM AUTHOR]

Renal ischemia-reperfusion injury is the state of which a tissue experiences injury after a phase of restrictive blood supply and recirculation. Ischemia-reperfusion injury (I/R-I) is a leading cause of acute kidney injury (AKI) in several disease states, including kidney transplantation, sepsis, and hypovolemic shock. The most common methods to evaluate AKI are creatinine clearance, plasma creatinine, blood urea nitrogen, or renal histology. However, currently, there are no precise methods to directly assess renal injury state noninvasively. Hyperpolarized 13C-pyruvate MRI enables noninvasive accurate quantification of the in vivo conversion of pyruvate to lactate, alanine, and bicarbonate. In the present study, we investigated the in situ alterations of metabolic conversion of pyruvate to lactate, alanine, and bicarbonate in a unilateral I/R-I rat model with 30 min and 60 min of ischemia followed by 24 h of reperfusion. The pyruvate conversion was unaltered compared with sham in the 30 min I/R-I group, while a significant reduced metabolic conversion was found in the postischemic kidney after 60 min of ischemia. This indicates that after 30 min of ischemia, the kidney maintains normal metabolic function in spite of decreased kidney function, whereas the postischemic kidney after 60 min of ischemia show a generally reduced metabolic enzyme activity concomitant with a reduced kidney function. We have confidence that these findings can have a high prognostic value in prediction of kidney injury and the outcome of renal injury. [ABSTRACT FROM AUTHOR]

The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-13C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned 13C/1 H-volume rat coil. The rats received intravenous hyperpolarized [1-13C]pyruvate and were imaged using a slice-selective 13C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [13C]alanine levels, indicating an intact glucose-alanine cycle, or [13C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes. [ABSTRACT FROM AUTHOR]

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 13C,15N2-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 13C 3D balanced steady-state MR pulse sequence following injection of hyperpolarized 13C,15N2-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 13C,15N2-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 13C,15N2-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 76:1895-1899, 2016. © 2016 International Society for Magnetic Resonance in Medicine. [ABSTRACT FROM AUTHOR]

Purpose The aim of this work was to investigate whether hyperpolarized 13C,15N2-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 13C 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 13C,15N2 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 [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? The brain response to acute hyponatraemia is usually studied in rodents by intraperitoneal instillation of hypotonic fluids ( i.p. model). The i.p. model is described as 'dilutional' and 'syndrome of inappropriate ADH (SIADH)', but the mechanism has not been explored systematically and might affect the brain response. Therefore, in vivo brain and muscle response were studied in pigs., What is the main finding and its importance? The i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution, not dilution. A large reduction in brain sodium is observed, probably because of the specific mechanism causing the hyponatraemia. This is not accounted for in current understanding of the brain response to acute hyponatraemia., 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 ( i.p. 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 i.p. model in a large animal (the pig) and studied water and electrolyte responses in brain, muscle, plasma and urine. We hypothesized that hyponatraemia was induced by simple water dilution, with no change in organ sodium content. Moderate hypotonic hyponatraemia was induced by a single i.v. dose of desmopressin and intraperitoneal instillation of 2.5% glucose. All animals were anaesthetized and intensively monitored. In vivo brain and muscle water was determined by magnetic resonance imaging and related to the plasma sodium concentration. Muscle water content increased less than expected as a result of pure dilution, and muscle sodium content decreased significantly (by 28%). Sodium was redistributed to the peritoneal fluid, resulting in a significantly reduced plasma volume. This shows that the i.p. model induces hypovolaemic hyponatraemia and not dilutional/SIADH hyponatraemia. Brain oedema evolved, but brain sodium content decreased significantly (by 21%). To conclude, the i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution and not water dilution. The large reduction in brain sodium is probably attributable to the specific mechanism that causes the hyponatraemia. This is not accounted for in the current understanding of the brain response to acute hyponatraemia. [ABSTRACT FROM AUTHOR]

Objective“The obesity epidemic” has led to an increase in obesity-related conditions including non-alcoholic fatty liver disease (NAFLD), for which effective treatments are in demand. The polyphenol resveratrol prevents the development of experimental NAFLD through modulation of cellular pathways involved in calorie restriction. We aimed to test the hypothesis that resveratrol alleviates NAFLD in a randomised, clinical trial.Materials and methodsA total of 28 overweight patients with transaminasemia and histological NAFLD were randomised 1:1 to placebo or resveratrol 1.5 g daily for 6 months. Twenty-six participants completed the trial and underwent repeated clinical investigation, blood work, MR spectroscopy; and 19 participants agreed to a repeat liver biopsy.ResultsResveratrol treatment was generally not superior to placebo in improving plasma markers of liver injury (primary outcome: alanine transaminase,p = 0.51). Resveratrol-treated patients showed a 3.8% decrease in liver lipid content (p = 0.03), with no difference between the two treatment arms (p = 0.38) and no improvement of histological features. Resveratrol treatment was not associated with improvements in insulin sensitivity or markers of the metabolic syndrome, except for a transient decrease in systolic BP. Microarray analysis and qRT-PCR revealed no major changes in expression profile. Also, we report a serious adverse event in a patient who developed fever and bicytopenia.ConclusionsIn this placebo-controlled, high-dose and long-term study, resveratrol treatment had no consistent therapeutic effect in alleviating clinical or histological NAFLD, though there may be a small ameliorating effect on liver function tests and liver fat accumulation. [ABSTRACT FROM PUBLISHER]

Early diabetic nephropathy is largely undetectable before substantial functional changes have occurred. In the present study, we investigated the distribution of electrolytes and urea in the early diabetic kidney in order to explore whether pathophysiological and metabolic changes appear concomitantly with a decreased sodium and urea gradient. By using hyperpolarized 13C urea it was possible to measure the essential intrarenal electrolyte gradients and the acute changes following furosemide treatment. No differences in either intrarenal urea or sodium gradients were observed in early diabetes compared to healthy controls. These results indicate that the early metabolic and hypertrophic changes occurring in the diabetic kidney prelude the later functional alterations in diabetic kidney function, thus driving the increased metabolic demand commonly occurring in the diabetic kidney. [ABSTRACT FROM AUTHOR]

Purpose Our aim was to assess a novel 13C radial fast spin echo golden ratio single shot method for interrogating early renal changes in the diabetic kidney, using hyperpolarized (HP) [13C,15N2]urea as a T2 relaxation based contrast bio-probe. Methods A novel HP 13C MR contrast experiment was conducted in a group of streptozotocin type-1 diabetic rat model and age matched controls. Results A significantly different relaxation time ( P = 0.004) was found in the diabetic kidney (0.49 ± 0.03 s) compared with the controls (0.64 ± 0.02 s) and secondly, a strong correlation between the blood oxygen saturation level and the relaxation times were observed in the healthy controls. Conclusion HP [13C,15N2]urea apparent T2 mapping may be a useful for interrogating local renal pO2 status and renal tissue alterations. Magn Reson Med, 2015. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Magn Reson Med 75:515-518, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. [ABSTRACT FROM AUTHOR]