In Vivo Assessment of Oxygen Consumption via Deuterium Magnetic Resonance

We present a novel approach to simultaneously measure, in vivo, non-invasively, glucose and oxygen consumption via Deuterium Magnetic Resonance (DMR). Mice are administered deuteriated glucose by intravenous injection. The rate of formation of nascent (deuteriated) mitochondrial water is then measured via DMR. The rate of glucose metabolism and oxygen utilization is assessed by tracking their separate peaks in DMR spectra during dynamic scanning. Further studies will aim to validate these results by comparison with in vivo O-17-MRI (mitochondrial function), C-13-MRI and (19)FDG-PET (glucose metabolism) and ex vivo H-1- and H-2-MR, as well as mass spectrometry.(1

Normalized T1 Magnetic Resonance Imaging for Assessment of Regional Lung Function in Adult Cystic Fibrosis Patients - A Cross-Sectional Study

Background: Cystic fibrosis (CF) patients would benefit from a safe and effective tool to detect early-stage, regional lung disease to allow for early intervention. Magnetic Resonance Imaging (MRI) is a safe, non-invasive procedure capable of providing quantitative assessments of disease without ionizing radiation. We developed a rapid normalized T1 MRI technique to detect regional lung disease in early-stage CF patients. Materials and Methods: Conventional multislice, pulmonary T1 relaxation time maps were obtained for 10 adult CF patients with normal spirometry and 5 healthy non-CF control subjects using a rapid Look-Locker MRI acquisition (5 seconds/imaging slice). Each lung absolute T1 map was separated into six regions of interest (ROI) by manually selecting upper, central, and lower lung regions in the left and right lungs. In order to reduce the effects of subject-to-subject variation, normalized T1 maps were calculated by dividing each pixel in the absolute T1 maps by the mean T1 time in the central lung region. The primary outcome was the differences in mean normalized T1 values in the upper lung regions between CF patients with normal spirometry and healthy volunteers. Results: Normalized T1 (nT1) maps showed visibly reduced subject-to-subject variation in comparison to conventional absolute T1 maps for healthy volunteers. An ROI analysis showed that the variation in the nT1 values in all regions was <= 2% of the mean. The primary outcome, the mean (SD) of the normalized T1 values in the upper right lung regions, was significantly lower in the CF subjects [.914 (.037)] compared to the upper right lung regions of the healthy subjects [.983 (.003)] [difference of .069 (95% confidence interval .032-.105); p=.001). Similar results were seen in the upper left lung region. Conclusion: Rapid normalized T1 MRI relaxometry obtained in 5 seconds/imaging slice may be used to detect regional early-stage lung disease in CF patients

Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is associated with caspase activation. However, a role for pro-inflammatory caspases or inflammasomes has not been explored in diet-induced liver injury. Our aims were to examine the role of caspase-1 in high fat-induced NASH. C57BL/6 wild-type and caspase 1-knockout (Casp1(-/-)) mice were placed on a 12-week high fat diet. Wild-type mice on the high fat diet increased hepatic expression of pro-caspase-1 and IL-1β. Both wild-type and Casp1(-/-) mice on the high fat diet gained more weight than mice on a control diet. Hepatic steatosis and TG levels were increased in wild-type mice on high fat diet, but were attenuated in the absence of caspase-1. Plasma cholesterol and free fatty acids were elevated in wild-type, but not Casp1(-/-) mice, on high fat diet. ALT levels were elevated in both wild-type and Casp1(-/-) mice on high fat diet compared to control. Hepatic mRNA expression for genes associated with lipogenesis was lower in Casp1(-/-) mice on high fat diet compared to wild-type mice on high fat diet, while genes associated with fatty acid oxidation were not affected by diet or genotype. Hepatic Tnfα and Mcp-1 mRNA expression was increased in wild-type mice on high fat diet, but not in Casp1(-/-) mice on high fat diet. αSMA positive cells, Sirius red staining, and Col1α1 mRNA were increased in wild-type mice on high fat diet compared to control. Deficiency of caspase-1 prevented those increases. In summary, the absence of caspase-1 ameliorates the injurious effects of high fat diet-induced obesity on the liver. Specifically, mice deficient in caspase-1 are protected from high fat-induced hepatic steatosis, inflammation and early fibrogenesis. These data point to the inflammasome as an important therapeutic target for NASH

Lipid elimination with an echo‐shifting N/2‐ghost acquisition (LEENA) MRI

Purpose The Dixon techniques provide uniform water‐fat separation but require multiple image sets, which extend the overall acquisition time. Here, an alternative rapid single acquisition method, lipid elimination with an echo‐shifting N/2‐ghost acquisition (LEENA), was introduced. Methods The LEENA method utilized a fast imaging with steady‐state free precession sequence to obtain a single k‐space dataset in which successive k‐space lines are acquired to allow the fat magnetization to precess 180°. The LEENA data were then unghosted using either image‐domain (LEENA‐S) or k‐space domain (LEENA‐G) parallel imaging techniques to reconstruct water‐only and fat‐only images. An off‐resonance correction technique was incorporated to improve the uniformity of the water‐fat separation. Results Uniform water‐fat separation was achieved for both the LEENA‐S and LEENA‐G methods for phantom and human body and leg imaging applications at 1.5T and 3T. The resultant water and fat images were qualitatively similar to conventional 2‐point Dixon and fat‐suppressed images. Conclusion The LEENA‐S and LEENA‐G methods provide uniform water and fat images from a single MRI acquisition. These straightforward methods can be adapted to 1.5T and 3T clinical MRI scanners and provide comparable fat/water separation with conventional 2‐point Dixon and fat‐suppression techniques. Magn Reson Med 73:711–717, 2015. © 2014 Wiley Periodicals, Inc

A low-glycemic diet lifestyle intervention improves fat utilization during exercise in older obese humans

OBJECTIVE: To determine the influence of dietary glycemic index on exercise training-induced adaptations in substrate oxidation in obesity. DESIGN AND METHODS: Twenty older, obese individuals undertook 3-months of fully-supervised aerobic exercise and were randomised to low (LoGIX) or high glycemic (HiGIX) diets. Changes in indirect calorimetry (VO(2); VCO(2)) were assessed at rest, during a hyperinsulinemic-euglycemic clamp, and during submaximal exercise (walking: 65% VO(2)max, 200 kcal energy expenditure). Intramyocellular lipid (IMCL) was measured by (1)H-magnetic resonance spectroscopy. RESULTS: Weight loss (−8.6±1.1%) and improvements (P<0.05) in VO(2)max, glycemic control, fasting lipemia, and metabolic flexibility were similar for both LoGIX and HiGIX groups. During submaximal exercise, energy expenditure was higher following the intervention (P<0.01) in both groups. Respiratory exchange ratio (RER) during exercise was unchanged in the LoGIX group but increased in the HiGIX group (P<0.05). However, fat oxidation during exercise expressed relative to changes in body weight was increased in the LoGIX group (+10.6±3.6%; P<0.05). Fasting IMLC was unchanged, however extramyocellular lipid was reduced (P<0.05) after LoGIX. CONCLUSIONS: A low glycemic diet/exercise weight-loss intervention increases fat utilization during exercise independent of changes in energy expenditure. This highlights the potential therapeutic value of low glycemic foods for reversing metabolic defects in obesity

Nanosensors for the Chemical Imaging of Acetylcholine Using Magnetic Resonance Imaging

A suite of imaging tools for detecting specific chemicals in the central nervous system could accelerate the understanding of neural signaling events critical to brain function and disease. Here, we introduce a class of nanoparticle sensors for the highly specific detection of acetylcholine in the living brain using magnetic resonance imaging. The nanosensor is composed of acetylcholine-catalyzing enzymes and pH-sensitive gadolinium contrast agents co-localized onto the surface of polymer nanoparticles, which leads to changes in <i>T</i>₁ relaxation rate (1/<i>T</i>₁). The mechanism of the sensor involves the enzymatic hydrolysis of acetylcholine leading to a localized decrease in pH which is detected by the pH-sensitive gadolinium chelate. The concomitant change in 1/<i>T</i>₁ <i>in vitro</i> measured a 20% increase from 0 to 10 μM acetylcholine concentration. The applicability of the nanosensors <i>in vivo</i> was demonstrated in the rat medial prefrontal cortex showing distinct changes in 1/<i>T</i>₁ induced by pharmacological stimuli. The highly specific acetylcholine nanosensor we present here offers a promising strategy for detection of cholinergic neurotransmission and will facilitate our understanding of brain function through chemical imaging

EB1089, a vitamin D receptor agonist, reduces proliferation and decreases tumor growth rate in a mouse model of hormone-induced mammary cancer

1,25-Dihydroxyvitamin D 3 and several of its analogs, such as EB1089, induce growth arrest and apoptosis of breast cancer cells in culture. EB1089 has also been shown to limit growth of xenografts in nude mice and carcinogen-induced mammary tumors in rats. Coupled with the fact that the vitamin D receptor is highly expressed in a large proportion of breast tumors, these data suggest that it may be a broad spectrum therapeutic target. We utilized a transgenic model of hormone-induced mammary cancer, the LH-overexpressing mouse, to assess, for the first time, the efficacy of EB1089 in a spontaneous tumor model. Similar to human breast cancers, the pre-neoplastic mammary glands and mammary tumors in these mice express high levels of vitamin D receptor. Treatment with EB1089 decreased proliferation of mammary epithelial cells in pre-neoplastic glands by 35%. Moreover, half of hormone-induced mammary tumors treated with EB1089 demonstrated a decreased rate of growth, with a subset of these tumors even regressing, suggesting that 1,25-dihydroxyvitamin D 3 analogs may be effective chemopreventive and chemotherapeutic agents for breast cancer