Evaluation of radiofrequency safety by high temperature resolution MR thermometry using a paramagnetic lanthanide complex.

PURPOSE: The current practice of calculating the specific absorption rate (SAR) relies on local temperature measurements made using temperature probes. For an accurate SAR measurement, a temperature imaging method that provides high temperature sensitivity is desirable, because acceptable levels of SAR produce small temperature changes. MR thermometry using paramagnetic lanthanide complexes can be used to obtain absolute temperature measurements with sub-degree temperature and sub-millimeter spatial resolution. The aim of this study was to develop and evaluate a high temperature resolution MR technique to determine SAR. METHODS: MR thermometry using a paramagnetic lanthanide complex thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis (methylene phosphonate) (TmDOTP(5-)), which has an almost 10(2) times stronger chemical shift temperature dependence than water, was used to develop a novel method for SAR measurement. Three-dimensional temperature and SAR images were calculated using MR images acquired with a conventional gradient recalled echo sequence and SAR-intensive T1ρ sequence. Effects of the presence of conducting wire and increasing T1ρ spin-lock pulse duration were also examined. RESULTS: SAR distribution could be visualized clearly and surges associated with conducting wires and increasing pulse duration were identified clearly in the computed high spatial resolution SAR images. CONCLUSION: A novel method with high temperature sensitivity is proposed as a tool to evaluate radiofrequency safety in MRI.

In vivo sodium MR imaging of the abdomen at 3T.

PURPOSE: Transmembrane sodium ((23)Na) gradient is critical for cell survival and viability and a target for the development of anti-cancer drugs and treatment as it serves as a signal transducer. The ability to integrate abdominal (23)Na MRI in clinical settings would be useful to non-invasively detect and diagnose a number of diseases in various organ systems. Our goal in this work was to enhance the quality of (23)Na MRI of the abdomen using a 3-Tesla MR scanner and a novel 8-channel phased-array dual-tuned (23)Na and (1)H transmit (Tx)/receive (Rx) coil specially designed to image a large abdomen region with relatively high SNR. METHODS: A modified GRE imaging sequence was optimized for (23)Na MRI to obtain the best possible combination of SNR, spatial resolution, and scan time in phantoms as well as volunteers. Tissue sodium concentration (TSC) of the whole abdomen was calculated from the inhomogeneity-corrected (23)Na MRI for absolute quantification. In addition, in vivo reproducibility and reliability of TSC measurements from (23)Na MRI was evaluated in normal volunteers. RESULTS: (23)Na axial images of the entire abdomen with a high spatial resolution (0.3 cm) and SNR (~20) in 15 min using the novel 8-channel dual-tuned (23)Na and (1)H transmit/receive coil were obtained. Quantitative analysis of the sodium images estimated a mean TSC of the liver to be 20.13 mM in healthy volunteers. CONCLUSION: Our results have shown that it is feasible to obtain high-resolution (23)Na images using a multi-channel surface coil with good SNR in clinically acceptable scan times in clinical practice for various body applications.

Variability of apoptosis and response in N1-S1 rodent hepatomas to benzamide riboside and correlation to early changes in water apparent diffusion coefficient and sodium MR imaging.

PURPOSE: This pilot trial assesses variability of apoptosis and response 1 day after hepatic intraarterial (IA) benzamide riboside (BR) in rodent hepatomas and its correlation to water apparent diffusion coefficient (ADC) and single-quantum (SQ) and triple-quantum-filtered (TQF) sodium-23 ((23)Na) magnetic resonance (MR) imaging. MATERIALS AND METHODS: Sprague-Dawley rats (n = 8) were inoculated with 10(6) N1-S1 cells. IA BR (20 mg/kg) was infused after 14 days. Animals were killed 1 day (n = 4) or 21 days (n = 4) after therapy. Imaging was performed 1 day before and after treatment. Volume was assessed over 2 weeks. Percentage apoptosis was counted from terminal deoxynucleotidyl transferase dUTP nick-end labeling-stained slides at 400×magnification. Kruskal-Wallis tests were used to compare apoptosis, and Wilcoxon signed-rank tests were used to compare MR signal intensity (SI). RESULTS: Apoptosis was marginally greater in tumor than in nontumor (6.7% vs 1.3%; P = .08), varying from 2% to 10%. Before treatment, MR SI was greater in tumor than in nontumor (ADC, 1.18 vs 0.76 [P = .0078]; SQ, 1.20 vs 1.04 [P = .03]; TQF, 0.55 vs 0.34 [P = .03]). After treatment, tumors increased in volume (0.62 vs 0.33; P = .016) variably over 2 weeks. MR SI remained greater in tumor than in nontumor (ADC, 1.20 vs 0.77 [P = .0078]; SQ, 1.76 vs 1.15 [P = .016]; TQF, 0.84 vs 0.49 [P = .03]). SQ and TQF SI increased by 47% (P = .016) and 53% (P = .016) in tumors, whereas ADC did not change. CONCLUSIONS: Apoptosis was marginal and varied from 2% to 10%. Water ADC, SQ, and TQF MR imaging distinguished tumor from nontumor. Changes in water ADC and sodium MR imaging correlated to apoptosis and volume in select cases, but additional animals are needed to validate this trend against tumor growth.

Phosphorus liver MRSI at 3 T using a novel dual-tuned eight-channel ³¹P/¹H H coil.

Although phosphorus-31 (³¹P) magnetic resonance spectroscopy holds potential as noninvasive tool to monitor treatment response of liver malignancies, the lack of appropriate coils has so far restricted its use to liver lesions close to the surface. A novel eight-channel phased-array dual-tuned ³¹P/¹H coil that can assess ³¹P metabolism in deeper liver tissue as well is presented in this article. Analysis of its performance demonstrates that this coil can provide good sensitivity across a width of 20 cm, thereby enabling magnetic resonance spectroscopic imaging (MRSI) scans that can fully cover axial views of the abdomen in lean subjects. In vivo results and reproducibility of ³¹P MRSI at 3 T of axial slices covering the full depth of the liver are shown in healthy volunteers. To minimize intrasubject and intersubject data variability, spectra are corrected for coil sensitivities. Methods to maximize the reproducibility of coil placement and spectroscopic planning are discussed. The phosphomonoesters/phosphodiesters ratio calculated in healthy volunteers has an average intrasubject variation of 23% averaged over voxels selected from the entire liver. Finally, the feasibility of using the coil in the clinic is shown by preliminary ³¹P liver MRSI data obtained from a patient with hepatocellular carcinoma.

Effect of implantation site and growth of hepatocellular carcinoma on apparent diffusion coefficient of water and sodium MRI.

Hepatocellular carcinoma (HCC) and liver metastases are an increasing problem worldwide. Non-invasive methods for the early detection of HCC and understanding of the tumor growth mechanisms are highly desirable. Both the diffusion-weighted (1)H (DWI) and (23)Na MRI reflect alterations in tissue compartment volumes in tumors, as well as physiological and metabolic transformation in cells. Effects of untreated growth on apparent diffusion coefficient of water (ADC), single quantum (SQ) and triple quantum-filtered (TQF) (23)Na MRI were compared in intrahepatically and subcutaneously implanted HCCs in rats. Animals were examined weekly for 4 weeks after injection of N1S1 cells. ADC of intrahepatic HCC was 1.5-times higher compared to the nearby liver tissue, and with growth, the ADC did not increase. ADC of subcutaneous HCC was lower compared to intrahepatic HCC and it increased with growth. Untreated growth of both intrahepatic and subcutaneous HCCs was associated with an increase in SQ and TQF (23)Na signal intensity suggesting an increase in tissue Na(+) and intracellular Na(+) (Na(+)(i)), respectively, most likely due to an increase in relative extracellular space and Na(+)(i) concentration as a result of changes in tissue structure and cellular metabolism. Thus, SQ and TQF (23)Na MRI may be complementary to diffusion imaging in areas susceptible to motion for characterizing hepatic tumors and for other applications, such as, predicting and monitoring therapy response.

Targeting mitogen-activated protein kinase kinase with the inhibitor PD0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems.

Hepatocellular carcinoma (HCC) is a common cause of death from solid organ malignancy worldwide. Extracellular signal-regulated/mitogen-activated protein kinase kinase (MEK) signaling is a critical growth regulatory pathway in HCC. Targeting MEK with a novel small molecule inhibitor, PD0325901, may inhibit HCC tumorigenesis. PD0325901 (0.01-100 nM) inhibited growth and MEK activity in vitro in immortalized murine transforming growth factor alpha (TGF-alpha) transgenic hepatocyte (TAMH) cells, derived from the livers of TGF-alpha transgenic mice. Treatment of athymic mice bearing TAMH flank tumors with vehicle or PD0325901 (20 mg/kg) revealed a significant reduction of MEK activity ex vivo 24 hours after a single PD0325901 dose. The growth rate of TAMH flank tumors over 16 days was reduced threefold in the treatment arm (1113 +/- 269% versus 3077 +/- 483%, P < 0.01). PD0325901 exhibited similar inhibitory effects in HepG2 and Hep3B human HCC cells in vitro and in Hep3B flank tumors in vivo. To confirm this in a developmental model, MT-42 (CD-1) TGF-alpha mice were treated with vehicle or PD0325901 (20 mg/kg) for 5 weeks. Gross HCC was detected in 47% and 13.3% of the control and treatment mice, respectively. Tumor growth suppression by PD0325901 relative to vehicle was also shown by magnetic resonance imaging. These studies provide compelling preclinical evidence that targeting MEK in human clinical trials may be promising for the treatment of HCC.

Controlled radio-frequency hyperthermia using an MR scanner and simultaneous monitoring of temperature and therapy response by (1)H, (23)Na and (31)P magnetic resonance spectroscopy in subcutaneously implanted 9L-gliosarcoma.

A magnetic resonance (MR) technique is developed to produce controlled radio-frequency (RF) hyperthermia (HT) in subcutaneously-implanted 9L-gliosarcoma in Fisher rats using an MR scanner and its components; the scanner is also simultaneously used to monitor the tumour temperature and the metabolic response of the tumour to the therapy. The method uses the (1)H chemical shift of thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (TmDOTA(-)) to monitor temperature. The desired HT temperature is achieved and maintained using a feedback loop mechanism that uses a proportional-integral-derivative controller. The RF HT technique was able to heat the tumour from 33 degrees to 45 degrees C in approximately 10 min and was able to maintain the tumour temperature within +/-0.2 degrees C of the target temperature (45 degrees C). Simultaneous monitoring of the metabolic changes with RF HT showed increases in total tissue and intracellular Na(+) as measured by single-quantum and triple-quantum filtered (23)Na MR spectroscopy (MRS), respectively, and decreases in intra- and extracellular pH and cellular bioenergetics as measured by (31)P MRS. Monitoring of metabolic response in addition to the tumour temperature measurements may serve as a more reliable and early indicator of therapy response. In addition, such measurements during HT treatment will enhance our understanding of the tumour response mechanisms during HT, which may prove valuable in designing methods to improve therapeutic efficiency.

Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice.

Increased iron levels and iron-mediated oxidative stress play an important role in the pathogenesis of many neurodegenerative diseases. The finding that mutations in the ferritin light polypeptide (FTL) gene cause a neurodegenerative disease known as neuroferritinopathy or hereditary ferritinopathy (HF) provided a direct connection between abnormal brain iron storage and neurodegeneration. HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic ferritin inclusion bodies in glia and neurons throughout the CNS and in tissues of multiple organ systems. Here we report that the expression in transgenic mice of a human FTL cDNA carrying a thymidine and cytidine insertion at position 498 (FTL498-499InsTC) leads to the formation of nuclear and cytoplasmic ferritin inclusion bodies. As in HF, ferritin inclusions are seen in glia and neurons throughout the CNS as well as in cells of other organ systems. Our studies show histological, immunohistochemical, and biochemical similarities between ferritin inclusion bodies found in transgenic mice and in individuals with HF. Expression of the transgene in mice leads to a significant decrease in motor performance and a shorter life span, formation of ferritin inclusion bodies, misregulation of iron metabolism, accumulation of ubiquitinated proteins, and incorporation of elements of the proteasome into inclusions. This new transgenic mouse represents a relevant model of HF in which to study the pathways that lead to neurodegeneration in HF, to evaluate the role of iron mismanagement in neurodegenerative disorders, and to evaluate potential therapies for HF and related neurodegenerative diseases.

Early monitoring of acute tubular necrosis in the rat kidney by 23Na-MRI.

Reabsorption of water and other molecules is dependent on the corticomedullary sodium concentration gradient in the kidney. During the early course of acute tubular necrosis (ATN), this gradient is altered. Therefore, 23Na magnetic resonance imaging (MRI) was used to study the alterations in renal sodium distribution in the rat kidney during ischemia and reperfusion (IR) injury, which induces ATN. In-magnet ischemia was induced for 0 (control), 10, 20, 30 or 50 min in Wistar rats. 23Na images were collected every 10 min during baseline, ischemia, and 60-min reperfusion periods. T1 and T2 relaxation times were measured by both 23Na-MRI and -MRS on a separate cohort of animals during ischemia and reperfusion for correction of relaxation-related tissue sodium concentration (TSC). A marked decrease was observed in the medulla and cortex 23Na-MRI signal intensity (SI) during the early evolution of ATN caused by IR injury, with the sodium reabsorption function of the kidney being irreversibly damaged after 50 min of ischemia. Sodium relaxation time characteristics were similar in the medulla and cortex of normal kidney, but significantly decreased with IR. The changes in relaxation times in both compartments were identical; thus the medulla-to-cortex sodium SI ratio represents the TSC ratio of both compartments. The extent of IR damage observed with histological examination correlated with the 23Na-MRI data. 23Na-MRI has great potential for noninvasive, clinical diagnosis of evolving ATN in the setup of acute renal failure and in differentiating ATN from other causes of renal failure where tubular function is maintained.

Absolute temperature MR imaging with thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetic acid (TmDOTMA-).

MR thermometry based on the water (1)H signal provides high temporal and spatial resolution, but it has low temperature sensitivity (approximately 0.01 ppm/degrees C) and requires monitoring of another weaker signal for absolute temperature measurements. The use of the paramagnetic lanthanide complex, thulium 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetate (TmDOTMA(-)), which is approximately 60 times more sensitive to temperature than the water (1)H signal, is advanced to image absolute temperatures in vivo using water signal as a reference. The temperature imaging technique was developed using gradient echo and asymmetric spin echo imaging sequences on 9.4 Tesla (T) horizontal and vertical MR scanners. A comparison of regional temperatures measured with TmDOTMA(-) and fiber-optic probes showed that the accuracy of imaging temperature is <0.3 degrees C. The temperature imaging technique was found to be insensitive to inhomogeneities in the main magnetic field. The feasibility of imaging temperature of intact rats at approximately 1.4 mmol/kg dose with approximately 1-mm spatial resolution in only 3 min is demonstrated. TmDOTMA(-) should prove useful for imaging absolute temperatures in deep-seated organs in numerous biomedical applications.

Nonalcoholic fatty liver disease.

OBJECTIVE: The inflammatory subtype of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, is becoming one of the most important causes of chronic liver disease. In this article, we discuss the epidemiology, pathogenesis, and clinical and radiologic diagnosis of the subtypes of nonalcoholic fatty liver disease. CONCLUSION: We discuss the current and evolving imaging tests in the evaluation of hepatic fatty content, inflammation, and fibrosis.

Monitoring chemotherapeutic response in RIF-1 tumors by single-quantum and triple-quantum-filtered (23)Na MRI, (1)H diffusion-weighted MRI and PET imaging.

The effects of 5-fluorouracil (5FU, 150 mg/kg, ip) on subcutaneously implanted radiation-induced fibrosarcoma (RIF-1) tumors were monitored by in vivo (1)H MRI to evaluate the water apparent diffusion coefficient (ADC), by single-quantum (SQ) and triple-quantum-filtered (TQF) (23)Na MRI to evaluate compartmental Na(+) content and by positron emission tomography (PET) to evaluate 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG) uptake in the tumor. The MRI experiments were performed on untreated control and treated mice once before and then daily for 3 days after treatment. The PET experiments were performed on separate groups of age- and tumor-volume-matched animals once before and then 3 days after treatment. Tumor volumes significantly decreased in treated animals 2 and 3 days posttreatment. At the same time points, in vivo MRI measurements showed an increase in both total tissue SQ (23)Na signal intensity (SI) and water ADC in treated tumors while control tumors showed no change in these parameters. TQF (23)Na SI and FDG uptake were significantly lower in treated tumors compared with control tumors 3 days after 5FU treatment. The correlated increases in total tissue (23)Na SI and water ADC following chemotherapy reflect an increase in extracellular space, while the lower TQF (23)Na SI and FDG uptake in treated tumors compared with control tumors suggest a shift in tumor metabolism from glycolysis to oxidation and/or a decrease in cell density.

Cyclophosphamide treatment modifies tumor oxygenation and glycolytic rates of RIF-1 tumors: 13C magnetic resonance spectroscopy, Eppendorf electrode, and redox scanning.

The effect of cyclophosphamide (Cp) on the glycolytic rate of radiation-induced fibrosarcomas (RIF-1) was measured in vivo in C3H mice by following the production of [3-(13)C]lactate after tail vein infusion of labeled [1-(13)C]glucose. Cp administered i.p. at a dose of 300 mg/kg caused a significant drop in glycolytic rate 24 h after treatment (P < 0.01). This drop was accompanied by an increase in [C-3]/[C-4] glutamate ratio in perchloric acid extracts of the tumors, indicating an increase in the Kreb's cycle activity. Treatment with Cp led to a significant decrease (P < 0.01) in tissue pO(2), measured in vivo with an oxygen Eppendorf electrode. Increases in NADH levels were also observed in rapidly frozen excised tumors examined by three-dimensional optical redox scanning. A significant decrease in tumor pO(2) and an increase in the NADH levels are suggestive of an increase in oxygen consumption by these tumors after Cp treatment. Overall, these data indicate that the reduction in glycolytic rate of Cp-treated RIF-1 tumors is due to an increase in aerobic metabolism.

Application of 23Na MRI to monitor chemotherapeutic response in RIF-1 tumors.

Effects of an alkylating anticancer drug, cyclophosphamide (Cp), on 23Na signal intensity (23Na SI) and water apparent diffusion coefficient (ADC) were examined in subcutaneously-implanted radiation-induced fibrosarcoma (RIF-1) tumors by 23Na and 1H magnetic resonance imaging (MRI). MRI experiments were performed on untreated control (n = 5) and Cp-treated (n = 6) C3H mice, once before Cp injection (300 mg/kg) then daily for 3 days after treatment. Tumor volumes were significantly lower in treated animals 2 and 3 days posttreatment. At the same time points, in vivo MRI experiments showed an increase in both 23Na SI and water ADC in treated tumors, whereas control tumors did not show any significant changes. The correlation between 23Na SI and water ADC changes was dramatically increased in the Cp-treated group, suggesting that the observed increases in 23Na SI and water ADC were caused by the same mechanism. Histologic sections showed decreased cell density in the regions of increased 23Na and water ADC SI. Destructive chemical analysis showed that Cp treatment increased the relative extracellular space and tumor [Na+]. We conclude that the changes in water ADC and 23Na SI were largely due to an increase in extracellular space. 23Na MRI and 1H water ADC measurements may provide valuable noninvasive techniques for monitoring chemotherapeutic responses.

Influence of ischemic preconditioning on intracellular sodium, pH, and cellular energy status in isolated perfused heart.

The possible relationships between intracellular Na(+) (Na(i)(+)), bioenergetic status and intracellular pH (pH(i)) in the mechanism for ischemic preconditioning were studied using (23)Na and (31)P magnetic resonance spectroscopy in isolated Langendorff perfused rat heart. The ischemic preconditioning (three 5-min ischemic episodes followed by two 5-min and one 10-min period of reperfusion) prior to prolonged ischemia (20 min stop-flow) resulted in a decrease in ischemic acidosis and faster and complete recovery of cardiac function (ventricular developed pressure and heart rate) after 30 min of reperfusion. The response of Na(i) during ischemia in the preconditioned hearts was characterized by an increase in Na(i)(+) at the end of preconditioning and an accelerated decrease during the first few minutes of reperfusion. During post-ischemic reperfusion, bioenergetic parameters (PCr/P(i) and betaATP/P(i) ratios) were partly recovered without any significant difference between control and preconditioned hearts. The reduced acidosis during prolonged ischemia and the accelerated decrease in Na(i)(+) during reperfusion in the preconditioned hearts suggest activation of Na(+)/H(+) exchanger and other ion transport systems during preconditioning, which may protect the heart from intracellular acidosis during prolonged ischemia, and result in better recovery of mechanical function (LVDP and heart rate) during post-ischemic reperfusion.

Tumor response and apoptosis of N1-S1 rodent hepatomas in response to intra-arterial and intravenous benzamide riboside.

PURPOSE: Benzamide riboside (BR) induces tumor apoptosis in multiple cell lines and animals. This pilot study compares apoptosis and tumor response in rat hepatomas treated with hepatic arterial BR (IA) or intravenous (IV) BR. METHODS: A total of 10(6) N1-S1 cells were placed in the left hepatic lobes of 15 Sprague-Dawley rats. After 2 weeks, BR (20 mg/kg) was infused IA (n=5) or IV (n=5). One animal in each group was excluded for technical factors, which prevented a full dose administration (1 IA and 1 IV). Five rats received saline (3 IA and 2 IV). Animals were killed after 3 weeks. Tumor volumes after IA and IV treatments were analyzed by Wilcoxon rank sum test. The percentage of tumor and normal liver apoptosis was counted by using 10 fields of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-stained slides at 40× magnification. The percentage of apoptosis was compared between IV and IA administrations and with saline sham-treated rats by the Wilcoxon rank sum test. RESULTS: Tumors were smaller after IA treatment, but this did not reach statistical significance (0.14 IA vs. 0.57 IV; P=0.138). There was much variability in percentage of apoptosis and no significant difference between IA and IV BR (44.49 vs. 1.52%; P=0.18); IA BR and saline (44.49 vs. 33.83%; P=0.66); or IV BR and saline (1.52 vs. 193%; P=0.18). CONCLUSIONS: Although differences in tumor volumes did not reach statistical significance, there was a trend toward smaller tumors after IA BR than IV BR in this small pilot study. Comparisons of these treatment methods will require a larger sample size and repeat experimentation.

Predicting response to benzamide riboside chemotherapy in hepatocellular carcinoma using apparent diffusion coefficient of water.

AIM: To monitor the effects of the apoptotic agent benzamide riboside (BR) on tumor volume and water apparent diffusion coefficient (ADC) in rat hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Water ADC of the tumors and nearby liver tissue was measured using diffusion-weighted 1H MRI (DWI). The two groups of BR-treated animals, which differed in their sensitivity to the treatment, were identified as responsive (RBR) and non-responsive (NRBR). RESULTS: Tumor growth in the RBR group was arrested and the mean tumor volume in this group was 1/6th and 1/16th compared to that of the NRBR group on days 7 and 14 after treatment, respectively. Water ADC of HCC was higher than in nearby normal liver tissue. Before BR treatment, the mean water ADC was significantly higher in the RBR group compared to the NRBR group. BR therapy did not change the water ADC value regardless of tumor sensitivity. CONCLUSION: Although the water ADC did not change after chemotherapy by BR, DWI has great potential for detecting and predicting response to chemotherapy in HCC.

Intravenous polyethylene glycol successfully treats severe acceleration-induced brain injury in rats as assessed by magnetic resonance imaging.

OBJECTIVE: Polyethylene glycol (PEG) is a nontoxic molecule with known efficacy as a cell membrane sealant, improving histological and behavioral outcomes in trauma models. Diffusion-weighted (DW) magnetic resonance imaging (MRI) is the most sensitive method of detecting in vivo diffuse axonal injury (DAI), where a decreased apparent diffusion coefficient (ADC) of water reflects cytotoxic edema. We use DW-MRI to assess severe DAI in rats treated with a single acute postinjury injection of PEG. METHODS: Rats were divided into uninjured, injured saline-treated, and injured PEG-treated groups. Injury groups received a severe brain injury using an impact-acceleration weight-drop model. Saline or PEG was administered acutely as a single intravenous dose to injured saline-treated and injured PEG-treated groups, respectively. DW-MRI analysis was performed at postinjury day 7 with a 9.4-T magnet. ADC was calculated for cortex, corpus callosum/hippocampus, and thalamus in each group. RESULTS: An expected decrease in ADC, representing cytotoxic edema, was observed in the injured saline-treated group. The injured PEG-treated group demonstrated no decrease in ADC relative to the uninjured rats, and the difference between ADC in saline and PEG-treated groups reached significance for all 3 zones of assessed brain. Differences were seen grossly between injured saline-treated and injured PEG-treated groups on representative color-mapped ADC images. CONCLUSION: A single intravenous dose of PEG dramatically limits sequelae of severe acceleration-induced brain injury--in this case, assessed by cytotoxic edema on DW-MRI--by intervening at the primary injury level of neuronal membrane disruption. This outcome is unprecedented, as no prior treatments for DAI have demonstrated similar efficacy. DAI treatment with intravenous PEG may have future clinical relevance and warrants further investigation.

Fat and water 1H MRI to investigate effects of leptin in obese mice.

Leptin is known to be associated with regulation of body weight and fat content. The effects of exogenous leptin on abdominal visceral (VS) and subcutaneous (SC) fat volume and hepatic fat-to-water ratio in leptin-deficient obese mice were investigated by (1)H magnetic resonance imaging (MRI). Chemical shift-selected fat and water (1)H MRI of control and leptin-treated mice were obtained 1 day before treatment and after 7 days of treatment (0.3 mg/kg/day). Hepatic fat-to-water ratio and VS fat volume decreased significantly with treatment, whereas SC fat volume did not change. Noninvasive measurement of fat and water content in different body regions using MRI should prove useful for evaluating new drugs for the treatment of obesity and other metabolic disorders.

Evaluation of extra- and intracellular apparent diffusion coefficient of sodium in rat skeletal muscle: effects of prolonged ischemia.

The mechanism of water and sodium apparent diffusion coefficient (ADC) changes in rat skeletal muscle during global ischemia was examined by in vivo 1H and 23Na magnetic resonance spectroscopy (MRS). The ADCs of Na+ and water are expected to have similar characteristics because sodium is present as an aqua-cation in tissue. The shift reagent, TmDOTP5(-), was used to separate intra- and extracellular sodium (Na+i and Na+e, respectively) signals. Water, total tissue sodium (Na+t), Na+i, and Na+e ADCs were measured before and 1, 2, 3, and 4 hr after ischemia. Contrary to the general perception, Na+i and Na+e ADCs were identical before ischemia. Thus, ischemia-induced changes in Na+e ADC cannot be explained by a simple change in the size of relative intracellular or extracellular space. Na+t and Na+e ADCs decreased after 2-4 hr of ischemia, while water and Na+i ADC remained unchanged. The correlation between Na+t and Na+e ADCs was observed because of high Na+e concentration. Similarly, the correlation between water and Na+i ADCs was observed because cells occupy 80% of the tissue space in the skeletal muscle. Ischemia also caused an increase in the Na+i and an equal decrease in Na+e signal intensity due to cessation of Na+/K+-ATPase function.