Three-dimensional MRI of coronary arteries using an intravascular contrast agent

OBJECTIVE: To clarify the influence of interindividual difference in the level of aldose reductase on the polyol pathway-related metabolism in diabetic patients. RESEARCH DESIGN AND METHODS: The enzyme protein content was determined by a two-site enzyme-linked immunosorbent assay using monoclonal and polyclonal antibodies to recombinant human aldose reductase in erythrocytes from 35 diabetic patients and 11 healthy volunteers. Patients were stratified into two groups by the median of aldose reductase content, and the erythrocyte sorbitol level, the fructose level, and the lactate-to-pyruvate ratio were compared between the two groups. We also examined the correlation of the enzyme content with these metabolic parameters. RESULTS: The group of patients whose enzyme content was above the median showed a significant increase in the levels of sorbitol (34.7 +/- 4.9 vs. 20.4 +/- 2.0 nmol/g Hb, P < 0.05) and fructose (99.8 +/- 17.2 vs. 45.9 +/- 4.6 nmol/g Hb, P < 0.05), along with an elevated lactate-to-pyruvate ratio (28.6 +/- 6.1 vs. 11.7 +/- 1.2, P < 0.05), compared with patients with low enzyme levels. The aldose reductase content in erythrocytes was well correlated with its activity, and there was a significant correlation between the enzyme content and the erythrocyte sorbitol (r = 0.58, P < 0.001) or fructose (r = 0.57, P < 0.001) levels as well as between the enzyme level and the lactate-to-pyruvate ratio (r = 0.38, P < 0.05). CONCLUSIONS: These results suggest that the interindividual variability of aldose reductase content may contribute tangibly to the polyol-pathway flux and cytoplasmic redox alteration in diabetic patients.     

Intestinal and peritoneal bleeding: detection with an intravascular contrast agent and fast three-dimensional MR imaging--preliminary experience from an experimental study

We investigated transcobalamin II (TC) isoelectrofocusing (IEF) phenotype and codon 259 polymorphism, in Caco-2 and HT-29 cells and in blood drawn from 39 healthy Caucasians. Caco-2 cells expressed a single TC variant (259-Arg), while HT-29 cells expressed TC with either Arg or Pro at codon 259 and exhibited two isoproteins in IEF with urea, but only one in IEF without urea. Among the Caucasians, 7 subjects expressed the TC 259-Arg variant, 10 the 259-Pro variant, and 22 were heterozygous. The TC 259-Pro isoprotein issued from HT-29 cells and heterozygous caucasian sera, was, respectively, 2. 4-fold and 1.6-fold higher than the TC 259-Arg isoprotein. Apo-TC and vitamin B12 serum concentrations in 259-Pro homozygotes were, respectively, 1.7 and 1.4-fold higher than those in 259-Arg homozygotes (p<0.005 and p=0.05). In conclusion, the 259-Arg/Pro polymorphism yields two TC variants only titratable in denaturing conditions and affects the blood level of both Apo-TC and vitamin B12.     

Use of three-dimensional segmented FLASH sequence with magnetization transfer contrast to improve Gd-DTPA-enhanced intrahepatic MR portography

Twenty healthy volunteers underwent gadopentetate dimeglumine (gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA))-enhanced MR angiography (MRA) using three-dimensional-segmented fast low angle shot images (FLASH) with magnetization transfer contrast (MTC) pulses. MRA was obtained at 75 seconds (early phase) and 135 seconds (late phase) after bolus injection of Gd-DTPA (MTC+ group) during one period of breath-holding. Within 1 week. MRA without MTC was performed under the same scanning conditions. Visualization of intrahepatic portal branches with these methods was compared in both phases. Portal vein-liver contrast-to-noise ratios were significantly higher in the MTC+ group in both phases. For third- and fourth-order portal branches, visualization was significantly better in the MTC+ group in both phases. Use of three-dimensional-segmented FLASH shortened acquisition time and facilitated imaging during breath-holding and also reduced whole-body average specific absorption rate values. Visualization of intrahepatic portal vein branches was improved by MTC pulses, and effective imaging time was prolonged.     

Improving MR quantification of regional blood volume with intravascular T1 contrast agents: accuracy, precision, and water exchange

The goal of this work was to develop a comprehensive understanding of the relationship between vascular proton exchange rates and the accuracy and precision of tissue blood volume estimates using intravascular T1 contrast agents. Using computer simulations, the effects of vascular proton exchange and experimental pulse sequence parameters on measurement accuracy were quantified. T1 and signal measurements made in a rat model implanted with R3230 mammary adenocarcinoma tumors demonstrated that the theoretical findings are biologically relevant; data demonstrated that over-simplified exchange models may result in measures of tumor, muscle, and liver blood volume fractions that depend on experimental parameters such as the vascular contrast concentration. As a solution to the measurement of blood volume in tissues with exchange that is unknown, methods that minimize exchange rate dependence were examined. Simulations that estimated both the accuracy and precision of such methods indicated that both the inversion recovery and the transverse-spoiled gradient echo methods using a "no-exchange" model provide the best trade-off between accuracy and precision.     

Small vessels in the human brain: MR venography with deoxyhemoglobin as an intrinsic contrast agent

To assess a magnetic resonance (MR) imaging method for depicting small veins in the brain, a three-dimensional, long echo time, gradient-echo sequence that depended on the paramagnetic property of deoxyhemoglobin was used. Veins with diameters smaller than a pixel were depicted. This MR imaging method is easy to implement and may prove helpful in the evaluation of venous diseases.     

Ultrasmall superparamagnetic iron oxide particles (AMI 227) as a blood pool contrast agent for MR angiography: experimental study in rabbits

We report a case of successful surgical management of a potentially life-threatening complication of aortoiliac stent placement. A 59-year-old man who had Leriche syndrome underwent bilateral iliac artery and infrarenal aortic stent placement at another institution. His history was significant for retroperitoneal lymph node dissection at 19 years of age for testicular cancer. One week after stent placement, the patient was readmitted with abdominal pain, poor oral intake, and diffuse intermittent tenderness. Evaluation with computed tomographic scanning and endoscopy was unremarkable, and the patient was discharged. He was admitted to our institution 1 week later with persistent abdominal pain. A computed tomographic scan of the abdomen revealed a large pseudoaneurysm of the abdominal aorta. The patient underwent urgent exploration, and exclusion of his infrarenal aorta was achieved with aortobifemoral bypass grafting. After the operation, the patient's course was complicated by a large paraduodenal hematoma, which resulted in a gastric outlet obstruction, which was managed without operation. This case illustrates a potential life-threatening complication of extensive stent placement for aortoiliac occlusive disease. Injury to the abdominal aorta must be considered in a symptomatic patient after the placement of stents in the aortoiliac region, beyond the immediate periprocedural period.     

Perflubron as a gastrointestinal MR imaging contrast agent in the pediatric population

A microplate enzyme immunoassay (EIA) for the detection of lysergic acid diethylamide (LSD) in human urine was developed. The assay kit is designed around an LSD derivative coated on the wall of microplate wells with preservatives and stabilizers. Sample and rabbit anti-LSD are added to the microplate well. The immobilized LSD and LSD present in specimens compete for the opportunity to bind to the anti-LSD antibodies. An anti-rabbit antibody labeled with horseradish peroxidase is used to provide the assay signal, which is inversely proportional to the concentration of LSD in the sample. The assay requires a 25-microL urine sample and three consecutive incubation periods of 60, 30, and 30 min at room temperature. The assay was tested with a variety of drugs, including ergot alkaloids spiked into drug-free urine at up to 100,000 ng/mL without cross-reaction. Nor-LSD was shown to cross-react between 16% and 28%, depending on its concentration. Of the other compounds tested, only ergonovine demonstrated slight cross-reactivity at approximately 0.0008%. The assay is designed to be used with a qualitative cutoff of 0.5 ng/mL. Precision testing at 0.5 ng/mL gave a coefficient of variation (CV) of 6% based on 20 replicates. The CV at 0.375 ng/mL (cutoff, -25%) was 5.2% and at 0.625 ng/mL was 6.6%. Precision at other concentrations within the range of the calibration curve gave similar results both intra- and interassay. Clinical performance of the assay was compared with that of a commercial radioimmunoassay (RIA). Comparable performance was observed with both methods, each screening a total of 458 samples as negative and 17 samples as positive relative to a 0.5 ng/mL cutoff. The EIA found an additional three positive samples that were negative by RIA. The EIA is suitable for the screening of urine samples for the presence of LSD. Preliminary indications are that the assay is also suitable for use with whole blood specimens. The assay can be performed manually or be fully automated and without the need for radioactivity; it can be used in any laboratory.     

Contrast-enhanced 3D-TOF MRA of peripheral vessels: intravascular versus extracellular MR contrast media

MR contrast media have been used to improve MR angiography (MRA). Their effect has been particularly beneficial for extracranial MRA. This study evaluated the efficacy of a new formulation of ultrasmall superparamagnetic iron oxide particles (USPIO) on three-dimensional (3D) time of flight (TOF) MRA in the pelvis and lower limb circulation. Each of six dogs received 3 mg/kg of USPIO and .2 mmol/kg of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) bis-methylamide (BMA) by intravenous infusion on separate examinations. Precontrast and postcontrast 3D-TOF MRA images of the lower extremities were acquired over the course of 45 minutes postinjection. Signal intensity (SI) was measured on axial views along the external iliac, femoral, and popliteal arteries. USPIO provided clear demarcation of the major primary, secondary, and tertiary vessels and the improved contrast-to-noise ratio (CNR) was maintained for 45 minutes. Gd-DTPA-BMA provided less signal enhancement than USPIO. The increase in CNR with this agent had significantly declined by 15 minutes after injection. The major vessels could no longer be visualized at 30 and 45 minutes after injection of Gd-DTPA-BMA This study demonstrates the efficacy of USPIO as a contrast medium for 3D-TOF MRA. It was concluded that USPIO provided effective and persistent enhancement of the peripheral vessels.     

Measurement of brain activity with bolus administration of contrast agent and gradient-echo MR imaging

This study was performed to measure changes in cerebral blood volume (CBV) associated with visual activation by use of bolus administration of contrast agent and conventional, clinically configured magnetic resonance (MR) hardware and software. Fast gradient-recalled acquisition in the steady state technique was used to study five healthy subjects during visual activation and a control dark state. MR images were obtained every 2.048 seconds for 2 minutes. A bolus of gadopentetate dimeglumine was injected during visual stimulation and darkness. Cine images produced from the series of rapid images clearly depicted arterial, capillary, and venous phases. Analysis of serial concentration maps derived from the rapid images revealed expected differences between the relative CBV of gray matter and that of white matter, as well as significantly increased relative CBV in calcarine cortex during visual activation versus the control state (mean increase, 15.24%; range, 6.41%-27.78%; P < .05). These results confirm those reported in echo-planar imaging studies and demonstrate that brain function can be assessed with the bolus method by means of MR imaging hardware and software with conventional clinical configurations.     

Quantification of intravascular and extravascular contributions to BOLD effects induced by alteration in oxygenation or intravascular contrast agents

A simple model is presented that allows quantitative separation of the contributions of signals from water in blood and extravascular parenchyma due to changes in blood oxygenation, induced either by brain activation or by alteration of inspired oxygen. The separation is based on the progressive attenuation of the signals in the vasculature of different levels when bipolar field gradient pulses are applied. Diffusion-weighted spin-echo echo-planar imaging sequences were used to measure signal changes under various conditions in both animals and human volunteers. Normoxic-hyperoxic episodes were induced in rats before and after injection of a superparamagnetic iron oxide contrast agent. Signal changes produced by visual stimulation were measured in human volunteers, and in volunteers subject to alternating normoxic-hyperoxic episodes, and with administration of Gd-DTPA. Analysis of the results with our simple model suggests that the apparent diffusion coefficient increases and R2 (= 1/T2) decreases upon brain activation, with a large component from extravascular water related to the decrease in the blood deoxyhemoglobin concentration. Furthermore, this study suggests that apparent diffusion coefficient of the extravascular component alone may provide localization of neuronal activation.     

T1 effects in sequential dynamic susceptibility contrast experiments

Benign osteoblastoma is an uncommon bone tumor accounting for approximately 1% of all bone tumors. There are only 35 cases of skull osteoblastoma reported in the literature. We describe the case of a 23 year old male with a giant osteoblastoma of temporal bone submitted to a total removal of the tumor after an effective embolization of all external carotid branches. The authors discuss diagnostic and management aspects of this uncommon skull tumor.     

Synthesis and preliminary evaluation of MP-2269: a novel, nonaromatic small-molecule blood-pool MR contrast agent

A nonaromatic, small-molecule, gadolinium(3+)-chelate code named MP-2269 was synthesized and evaluated in animals as a potential MR contrast agent for blood pool. The ligand of MP-2269 was prepared by conjugating a lipophilic, albumin-binding moiety, 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid, to an amino-functionalized DTPA derivative by means of a diaspartic acid linker. Proton relaxometry studies in vitro yielded spin-lattice relaxivities (R1) for MP-2269 of 6.2, 20.0 and 26.1 mM(-1)sec(-1) in water, rabbit blood, and human blood, respectively. The enhanced relaxivities in blood indicate significant binding of the agent to blood proteins. At a dose of 45 micromol/kg, MP-2269 showed a biphasic rabbit blood clearance profile with half-lives of 4.7 and 142 minutes, respectively, for the fast and slow components. In rats, the agent is cleared predominantly through the hepatobiliary pathway (approximately 70% in 24 h by this mode). The LD50 value of MP-2269 is approximately 3.0 mmol/kg in mice. Preliminary MR angiograms obtained in the rabbit showed excellent enhancement of blood vessels. Hence, MP-2269 has potential for future exploitation as a contrast agent for MR angiography.     

Dynamic MR imaging of the breast combined with analysis of contrast agent kinetics in the differentiation of primary breast tumours

OBJECTIVE: To assess dynamic Gd-DTPA-enhanced magnetic resonance (MR) imaging in the diagnosis of primary breast pathology, and to test the hypothesis that analysis of contrast agent kinetics increases specificity. METHODS: Forty-seven women underwent breast MR imaging using three-dimensional and dynamic spoiled gradient-recalled sequences. Image interpretation was based on the evaluation of lesion conspicuity, signal intensity, contour and enhancement pattern from the static acquisitions. Assessment of contrast kinetics was based on pixel-by-pixel analysis of the dynamic data. A two-compartment model described by three parameters (amplitude of uptake, exchange rate and washout rate), and a three-compartment model described by two parameters (permeability and exchange rate) were used. Regions of interest were drawn for all lesions found in the dynamic sections. Mean regional pixel values were calculated for each parameter and tested for diagnostic efficacy. RESULTS: Twenty-two malignant and 36 benign lesions were examined. Fibroadenomas accounted for 86% of the benign tumours. Image interpretation had a sensitivity of 0.95 and specificity of 0.86. The fat-suppressed post-contrast images permitted good visualization of the contour and matrix characteristics of fibroadenomas, but all non-fibroadenomatous benign lesions were classified as indeterminate or suspicious. Significant differences were found between benign and malignant lesions in the amplitude of uptake (P = 0.0008) and exchange rate (P < 0.00005) of the two-compartment model, and permeability (P=0.0001) and exchange rate (P < 0.00005) of the three-compartment model. However, image interpretation was superior to the isolated use of quantitative indices (P=0.02). The most discriminating parameters were the exchange rates of both models, with no significant difference between them. CONCLUSION: Assessment of lesion morphology is essential and probably sufficient for the differentiation of fibroadenomas from malignant tumours. However, specificity of conventional MR imaging may be much lower for other types of primary benign breast pathology. Analysis of Gd-DTPA kinetics improves the specificity obtained using simple enhancement measurements and can be used to produce parametric images that provide information about lesion heterogeneity, permeability and vascularity.     

Use of contrast-enhanced MR imaging to detect sacroiliitis in children

PURPOSE: To verify the diagnostic value of contrast-enhanced MR imaging compared with conventional radiography in the diagnosis of sacroiliitis in children. DESIGN AND PATIENTS: Radiography and MR imaging of the sacroiliac joints were performed in 185 children subdivided into the following groups according to the modified European Spondyloarthropathy (SpA) Study Group (ESSG) criteria: group 1, undifferentiated spondyloarthropathy (uSpA) (n=53, 94.5% HLA-B27+); group 2, differentiated SpA (n=45, 93.3% HLA-B27+); group 3, patients with no signs of SpA other than oligoarthritis (n=39, 92.3% HLA-B27+); group 4, HLA-B27+ controls with various other non-SpA diagnoses (n=22); and group 5, HLA-B27-controls with various other non-SpA diagnoses (n=26). Radiographs were evaluated on the basis of the modified New York criteria independently by three experienced radiologists masked to the clinical data. In a second step, the same radiologists independently evaluated the MR images without knowledge of the clinical data and radiographic findings using the recently published criteria developed by our group. These criteria allow differentiation of acute and chronic inflammatory changes. RESULTS: Radiography demonstrated sacroiliitis in 18 patients: 4 of 53 in group 1 (7.5%), 14 of 45 in group 2 (31%), but none in groups 3, 4 and 5. In contrast, MR imaging demonstrated acute and/or chronic sacroiliitis in 44 patients: 18 of 53 in group 1 (34%), 21 of 45 in group 2 (46.7%) and 5 of 39 in group 3 (12.8%), but none in groups 4 and 5. The percentage of sacroiliitis detected by MR imaging was significantly higher than that detected by radiography (P<0.001). CONCLUSION: Contrast-enhanced MR imaging is a useful method for detecting sacroiliitis in children. Advantages of contrast-enhanced MR imaging compared with conventional radiography are a higher sensitivity due to the ability to document early and acute changes and the absence of radiation exposure.     

Use of iohexol as a gastrointestinal contrast agent in three dogs, five cats, and one bird

Barium sulfate suspension is routinely used as contrast medium for upper gastrointestinal procedures. It has been contraindicated for use in cases of suspected perforation. In such instances, water-soluble iodides are recommended for use. Most of the water-soluble iodides available for use in veterinary medicine at this time are hyperosmolar. This results in in transit dilution of the contrast column. The dilution of the contrast agent within the intestines may prevent visualization of a perforation, especially if the perforation is in the distal portion of the small intestine. Iohexol a nonionic water-soluble iodide of low osmolality, is currently used in veterinary medicine for myelography. We have used it as the contrast agent for upper gastrointestinal studies in cases of suspected obstruction or perforation, with good results, and no adverse effects have been associated with its use. Opacity of the contrast column was adequate, and segmentation or flocculation of the column was not apparent.     

Use of tissue culture to examine neurotoxicity of contrast media

The effect of small concentrations of diatrizoate, ioglycamate, and iopanoate salts on cultured sympathetic ganglia was studied. Biliary contrast media in clinical blood concentrations caused severe degeneration of cultured neurons, but similar concentrations of diatrizoate caused no effect. This technique may be used to measure the direct neurotoxicity or general cytotoxicity of contrast media.     

Optimized visualization of vessels in contrast enhanced intracranial MR angiography

Agonist-induced desensitization has been described for the A1, A2A, and A3 adenosine receptor subtypes of the G protein-coupled receptor superfamily. Desensitization of the fourth adenosine receptor subtype, the A2B adenosine receptor (A(2B)R), has not been studied extensively. We sought to determine whether the A(2B)R is subject to agonist-induced desensitization. COS 7 cells, which exhibit endogenous expression of the A(2B)R, and transfected CHO cells, which stably express a modified rat A(2B)R bearing a 5' FLAG epitope tag, were studied. Cyclic AMP (cAMP) responsiveness to an acute challenge was measured after pretreating (desensitizing) cells with the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA). Incubation with NECA resulted in hyporesponsiveness to acute agonist challenge in both COS 7 and transfected CHO cells. Desensitized cells exhibited restoration of cAMP responses after recovery for 24 hr in growth medium. Choleratoxin-induced cAMP responses were preserved in desensitized cells, and high concentrations of NECA were unable to overcome the desensitization. Membrane levels of the epitope-tagged A(2B)R were assessed by western blot in transiently transfected COS 7 cells. The expression of epitope-tagged A(2B)Rs was not different between control and desensitized cells. In northern blot analysis, levels of endogenous A(2B)R mRNA were similar in control and desensitized COS 7 cells. We conclude that the A(2B)R is subject to agonist-induced desensitization with preserved expression of A(2B)R mRNA and protein. Uncoupling of the A2B adenosine receptor from the G protein complex may contribute to the mechanism of desensitization.     

Pharmacokinetics of the liver-specific contrast agent Gd-EOB-DTPA in relation to contrast-enhanced liver imaging in humans

This study was performed to evaluate the effect of dose on the pharmacokinetics and efficacy of the gadolinium-based contrast medium gadoxetic acid, disodium, [gadolinium (4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6, 9-triazaundecandioic acid-disodium salt] (Gd-EOB-DTPA) as a liver-specific hepatobiliary contrast medium for computed tomography. Pharmacokinetics in serum and the pattern of elimination were investigated in 18 healthy volunteers up to 6 days after a 10-minute infusion of 0.2 mmol, 0.35 mmol, and 0.5 mmol of gadolinium per kilogram of body weight. Pharmacokinetic behavior was compared with the compute tomographic attenuation data in the liver parenchyma after the same doses in patients. Urinary and fecal excretion accounted for approximately equal portions of the administered dose. The degree of renal elimination increased with increasing doses, whereas renal clearance and half-life from urine data were not affected by dose. Dose-normalized area under the concentration-time curve was significantly increased with increasing doses indicating saturation in liver uptake for the highest dose. This finding was in agreement with the measured net increase in liver attenuation by computed tomography. Hepatic disposition revealed slight saturation phenomena for the highest dose (0.5 mmol gadolinium/kg). Nevertheless, this dose resulted in sufficient uptake by human liver, allowing for computed tomographic imaging.