Cardiovascular MRI with ferumoxytol.

The practice of contrast-enhanced magnetic resonance angiography (CEMRA) has changed significantly in the span of a decade. Concerns regarding gadolinium (Gd)-associated nephrogenic systemic fibrosis in those with severely impaired renal function spurred developments in low-dose CEMRA and non-contrast MRA as well as efforts to seek alternative MR contrast agents. Originally developed for MR imaging use, ferumoxytol (an ultra-small superparamagnetic iron oxide nanoparticle), is currently approved by the US Food and Drug Administration for the treatment of iron deficiency anaemia in adults with renal disease. Since its clinical availability in 2009, there has been rising interest in the scientific and clinical use of ferumoxytol as an MR contrast agent. The unique physicochemical and pharmacokinetic properties of ferumoxytol, including its long intravascular half-life and high r1 relaxivity, support a spectrum of MRI applications beyond the scope of Gd-based contrast agents. Moreover, whereas Gd is not found in biological systems, iron is essential for normal metabolism, and nutritional iron deficiency poses major public health challenges worldwide. Once the carbohydrate shell of ferumoxytol is degraded, the elemental iron at its core is incorporated into the reticuloendothelial system. These considerations position ferumoxytol as a potential game changer in the field of CEMRA and MRI. In this paper, we aim to summarise our experience with the cardiovascular applications of ferumoxytol and provide a brief synopsis of ongoing investigations on ferumoxytol-enhanced MR applications.

Contrast-enhanced MR angiography at 3T in the evaluation of intracranial aneurysms: a comparison with time-of-flight MR angiography.

The combination of 3T and parallel-acquisition techniques holds promise for improved performance of contrast-enhanced MR angiography (MRA), in terms of speed, spatial resolution, and coverage. We present a comparison of 2 MRA techniques, including time-of-flight (TOF) and contrast-enhanced MRA, for detection and evaluation of intracranial aneurysms. Our results show that contrast-enhanced MRA with highly accelerated parallel acquisition at 3T does not have the known drawbacks of TOF-MRA techniques, including prolonged acquisition time, spin saturation, and flow-related artifacts, with comparable aneurysm characterization.

[Cardiac MR tagging: optimization of sequence parameters and comparison at 1.5 T and 3.0 T in a volunteer study]. / Kardiales MR-Tagging: Parameteroptimierung und Sequenzvergleich bei 1.5 T und 3.0 T an einem Probandenkollektiv.

PURPOSE: The aim of this study was the optimization of a gradient echo (GRE) MR tagging sequence at 3.0 T in comparison to 1.5 T in order to obtain the best image contrast between the myocardium, tag lines and blood signal. Theoretically expected improvements of signal-to-noise (SNR) and contrast-to-noise ratios (CNR) were also calculated. MATERIALS AND METHODS: 14 healthy volunteers (8 male, 6 female; mean age 43.4 +/- 10.3 years) were scanned using a 3.0 T as well as a 1.5 T whole-body system. A GRE flash-2 D tagging sequence was evaluated (midventricular short axis view) by varying the flip angle (8 - 16 degrees ), slice thickness (4 - 8 mm; fixed flip angle 1.5/3.0 T: 12 degrees /8 degrees , tag size 8 mm) and tag size (4 - 8 mm, fixed flip angle 1.5/3.0 T: 12 degrees /8 degrees , slice thickness 6 mm). The field of view, acquisition time and temporal resolution (45 ms) were kept constant. Qualitative and quantitative image analysis was performed by calculating the SNR, CNR (tag) as well as the relative contrast between the myocardium and tag lines (RCMT). RESULTS: Based on individual comparison, the best imaging protocol was found at a slice thickness of 6 mm, tag size of 8 mm, optimized flip angle of 8 degrees (3.0 T) and 12 degrees (1.5 T), respectively. Compared to 1.5 T, a significantly higher overall image score was determined (mean +/- sd; 3.2 +/- 0.2 vs. 2.7 +/- 0.4) and a strong correlation between the CNR (tag) and RCMT for flip angle alpha and the slice thickness was found. A higher field strength resulted in an 80 % increase in the CNR (tag) compared to 1.5 T (mean 10.7/6.1). Furthermore, the SNR was improved by 35 % (mean 20.6/15.3) and the RCMT by 35 % (mean 0.47/0.35). CONCLUSION: Myocardial tagging at 3.0 T has shown superior image quality in comparison to 1.5 T due to a higher baseline SNR and an improved CNR as well as RCMT. The suppressed fading of the tags enables the accessibility to the diastolic phase of the cardiac cycle.

Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function.

BACKGROUND: Contrast MRI enhancement patterns in several pathophysiologies resulting from ischemic myocardial injury are controversial or have not been investigated. We compared contrast enhancement in acute infarction (AI), after severe but reversible ischemic injury (RII), and in chronic infarction. METHODS AND RESULTS: In dogs, a large coronary artery was occluded to study AI and/or chronic infarction (n = 18), and a second coronary artery was chronically instrumented with a reversible hydraulic occluder and Doppler flowmeter to study RII (n = 8). At 3 days after surgery, cine MRI revealed reduced wall thickening in AI (5+/-6% versus 33+/-6% in normal, P<0.001). In RII, wall thickening before, during, and after inflation of the occluder for 15 minutes was 35+/-5%, 1+/-8%, and 21+/-10% and Doppler flow was 19.8+/-5.3, 0.2+/-0.5, and 56.3+/-17.7 (peak hyperemia) cm/s, respectively, confirming occlusion, transient ischemia, and reperfusion. Gd-DTPA-enhanced MR images acquired 30 minutes after contrast revealed hyperenhancement of AI (294+/-96% of normal, P<0.001) but not of RII (98+/-6% of normal, P = NS). Eight weeks later, the chronically infarcted region again hyperenhanced (253+/-54% of normal, n = 8, P<0.001). High-resolution (0.5 x 0.5 x 0.5 mm) ex vivo MRI demonstrated that the spatial extent of hyperenhancement was the same as the spatial extent of myocyte necrosis with and without reperfusion at 1 day (R = 0.99, P<0.001) and 3 days (R = 0.99, P<0.001) and collagenous scar at 8 weeks (R = 0.97, P<0.001). CONCLUSIONS: In the pathophysiologies investigated, contrast MRI distinguishes between reversible and irreversible ischemic injury independent of wall motion and infarct age.

The feasibility of spatial high-resolution magnetic resonance angiography (MRA) of the renal arteries at 3.0 T.

PURPOSE: To evaluate the feasibility of high-spatial resolution magnetic resonance angiography (MRA) of the renal arteries at 3.0 T. MATERIAL AND METHODS: Twelve healthy volunteers (mean age, 38.8 years) underwent renal MRA at 3.0 T. The application of parallel imaging with an acceleration factor of 3 allowed obtaining MR angiographic data with a voxel size of 0.9 x 0.8 x 0.9 mm in scan time of only 16 s. A dose of 0.2 mmol/kg body weight of 0.5-molar gadodiamide was administered at a flow rate of 2 ml/s. For image analysis, image quality, presence of artifacts, venous contamination and level of noise were rated by two radiologists in consensus. RESULTS: All examinations were of diagnostic quality. The image quality was rated good or very good in 91 % (11/12) of cases. Due to the high parallel imaging factor the level of noise was slightly increased without diagnostic impairment. Mild venous enhancement was found in 75 % (9/12) of the examinations. CONCLUSION: Renal MRA at 3.0 T is feasible with high spatial resolution and a short acquisition time.

Immunolocalization of the mitogen-activated protein kinases p42MAPK and JNK1, and their regulatory kinases MEK1 and MEK4, in adult rat central nervous system.

Cell survival, death, and stress signals are transduced from the cell surface to the cytoplasm and nucleus via a cascade of phosphorylation events involving the mitogen-activated protein kinase (MAPK) family. We compared the distribution of p42 mitogen-activated protein kinase (p42MAPK) and its activator MAPK or ERK kinase (MEK1; involved in transduction of growth and differentiation signals), with c-Jun N-terminal kinase (JNK1) and its activator MEK4 (involved in transduction of stress and death signals) in the adult rat central nervous system. All four kinases were present in the cytoplasm, dendrites, and axons of neurons. The presence of p42MAPK and JNK1 in dendrites and axons, as well as in cell bodies, suggests a role for these kinases in phosphorylation and regulation of cytoplasmic targets. A high degree of correspondence was found between the regional distribution of MEK1 and p42MAPK. Immunostaining for MEK1 and p42MAPK was intense in olfactory structures, neocortex, hippocampus, striatum, midline, and interlaminar thalamic nuclei, hypothalamus, brainstem, Purkinje cells, and spinal cord. In addition to neurons, p42MAPK was also present in oligodendrocytes. Whereas MEK4 was ubiquitously distributed, JNK1 was more selective. Immunostaining for MEK4 and JNK1 was intense in the olfactory bulb, lower cortical layers, the cholinergic basal forebrain, most nuclei of the thalamus, medial habenula, and cranial motor nuclei. The distribution of MEK1 and p42MAPK proteins only partially overlapped with that of MEK4 and JNK1. This suggests that the growth/differentiation and death/stress pathways affected by these kinases may not necessarily act to counterbalance each other in response to extracellular stimuli. The differential distribution of these kinases may control the specificity of neuronal function to extracellular signals.

Use of magnetic resonance angiography in the pretransplant evaluation of portal vein pathology.

The assessment of portal vein patency in patients selected as candidates for orthotopic liver transplantation should be accomplished noninvasively and with great accuracy. Magnetic resonance angiography (MRA) is a new technique that is completely noninvasive and is capable of graphically assessing portal vein anatomy and blood flow. In an attempt to establish the accuracy of portal venous MRA, 74 patients with established cirrhosis underwent abdominal MRA prior to liver transplantation. MRA findings were correlated with surgical findings at the time of transplantation in all patients, and were shown to be extremely accurate. The three-dimensional images generated by MRA and computer postprocessing allowed for correct identification of portal venous anatomy in all of the patients examined. We conclude that MRA is an extremely useful method of determining portal venous anatomy in potential liver transplant patients, and potentially offers greater definition and clarify compared with other non-invasive methods.

Magnetic resonance angiography of the central chest veins. A new gold standard?

PURPOSE: The systemic chest veins may be difficult to show comprehensively by contrast venography, especially if there is limited venous access or contraindications to intravenous contrast. As an alternative, can magnetic resonance angiography (MRA) reliably detect occluded chest veins and predict suitable sites for central venous access? PATIENTS AND METHODS: Eighty-four patients were examined using breath-hold time-of-flight MRA and three-dimensional image reconstruction. Thirty-three were evaluated to identify possible central venous access. Fifty-seven patients were examined to diagnose and stage central venous occlusion. RESULTS: The associated diagnoses were malignancy 46, parenteral nutrition 21, hemodialysis 6, chemotherapy 4, and other long-term venous access 7. Of the 28 patients in whom MRA predicted a patent site for central venous access, satisfactory access was achieved. In two patients, cannulation of veins shown to be occluded on MRA was attempted unsuccessfully. Correlation with contrast venography was available in 17. There was agreement with MRA concerning the level of occluded veins in all cases. Contrast venography did not show all patent veins, including some accessed during surgical line placement. CONCLUSION: Compared with surgical line placement or contrast venography, MRA of the systemic chest veins is accurate. Patent and occluded chest veins are reliably defined, including potential sites for central line placement, in a way that is not possible with other techniques. MRA may be the new "gold standard" for defining systemic venous anatomy in the chest.

Measurement of visceral blood flow with magnetic resonance imaging.

With the increasing application of magnetic resonance imaging (MRI) and MR angiography in parenchymal liver disease, methods are becoming more widely available for noninvasive measurement of visceral blood flow. Amplitude-based (time-of-flight) and phase-based techniques have proved effective for measurement of portal blood flow, and phase-sensitive methods are applicable to arterial flow measurements. Because respiratory motion degrades the quality of examinations in the abdomen, it is desirable to use methods that can generate flow information in a breath-hold period. Although substantial technical difficulties persist for quantitative arterial flow measurements in the abdomen, the technical requirements for venous flow are less stringent, and important clinical information can be derived using straightforward techniques. The authors describe the principles of flow measurement using time-of-flight and phase methods in visceral arteries and veins, and discuss their practical implementation. Clinical applications are discussed, based on the experience of the authors and others working in the field.

First-pass evaluation of myocardial output during dipyridamole stress using turbo-FLASH magnetic resonance imaging.

RATIONALE AND OBJECTIVES: This study evaluated the value of dynamically enhanced fast low-angle shot (FLASH) magnetic resonance (MR) imaging in measuring cardiac output with and without dipyridamole pharmacological stress. METHODS: Ten subjects underwent rest and stress MR imaging. Rest images were acquired using electrocardiogram gated MR (turbo-FLASH: repetition time = 6 mseconds; echo time = 12 mseconds; flip angle = 12 degrees, inversion time = 100) 10 to 45 seconds after intravenous bolus of 0.04 mmol/kg gadolinium (Gd)-DTPA using a Siemens 1.0-tesla Magnetom SP. Stress was induced within the MR imaging scanner with 0.56 mg/kg dipyridamole over 4 minutes with stress MR images obtained after a second bolus of Gd-DTPA in exactly the same position and time intervals. Cardiac output was calculated with a least squares error analysis before and after dipyridamole stress for the left and right ventricles in all 10 patients, and comparison was made with cardiac output by Fick dilution technique during cardiac catheterization in seven patients. RESULTS: This MR analysis methodology shows reasonable correlation (r = 0.953) between left ventricular and right ventricular cardiac output with no effect on cardiac output during immediate dipyridamole stress. Fick dilution studies demonstrated a correlation of 0.96. CONCLUSIONS: Turbo-FLASH MR can demonstrate time-activity curves and cardiac output calculations consistent with theoretical predictions.

Hemifacial spasm in infancy.

Three infants presented with the onset of hemifacial spasm after birth and at the age of 10 months. One patient was found to have occlusion of the straight sinus and large collateral veins at the base of the brain, presumably due to venous sinus thrombosis, supporting the concept of vascular compression of the facial nerve at its exit from the brain stem as a mechanism for the production of hemifacial spasm. The other patients each had an intrinsic mass compressing the fourth ventricle, located in the lower pons and extending into the cerebellar vermis and right cerebellar peduncle in one; in the other patient, the mass involved the cerebellar vermis and right middle cerebellar peduncle alone. These patients widen the etiologic spectrum of the syndrome and show that serious intracranial diseases may underlie hemifacial spasm in infancy.

A molecular analysis of vesicular amine transport.

To package classical neurotransmitters into vesicles so that their release can be regulated by activity, neuronal cells express a set of specific vesicular transport proteins. We have used selection in MPP+ to clone the cDNAs encoding two vesicular monoamine transporters, the first members of this novel gene family that now also includes the vesicular transporter for acetylcholine. The sequences show similarity to several bacterial antibiotic resistance proteins, further supporting a role in detoxification and possibly Parkinson's disease. The two vesicular amine transporters show differences in their affinity for substrates, their turnover number and their pharmacology. In particular, the proteins differ in their interactions with the potent inhibitor tetrabenazine and with amphetamines, accounting for several classic pharmacological observations. Since the subcellular localization of the transport proteins determines the site of monoamine storage and the site of monoamine storage appears to differ from other classical transmitters, we have also raised polyclonal antibodies to the transporters and used these to demonstrate localization in dense core vesicles rather than synaptic vesicles. In addition to the implications for monoamine release, these observations also indicate a vesicular amine transporter as the first integral membrane protein restricted to the regulated secretory pathway.

Impact of vessel distortion on transcranial Doppler velocity measurements: correlation with magnetic resonance imaging.

Because transcranial Doppler ultrasound is a blind procedure, it is not possible to routinely correct for insonation angle errors, which are presumed to be small. In anatomically normal brains this is a valid assumption; however, in some patients with distorted vascular anatomy (as in hydrocephalus) a small insonation angle cannot be assumed, and measurements of flow velocity may be misleadingly low. The orientation of the middle cerebral arteries was studied on magnetic resonance images of 17 control patients and three patients with hydrocephalus, and estimates of insonation angle errors in velocity measurements were made. When asymmetrical vessel distortion is present, relative flow to each hemisphere may not be accurately reflected in the measured velocities. Under these circumstances, the resistivity index may be a more reliable hemodynamic parameter.

Contrast-enhanced magnetic resonance angiography of the carotid circulation.

Contrast-enhanced MR angiography (CE MR angiography) is rapidly becoming the investigation of first choice for evaluating disease of the vascular system. It is particularly applicable to the carotid circulation and has replaced more traditional time-of-flight imaging because of shorter acquisition times and fewer artifacts. With recent advances in gradient hardware, shorter repetition times allow high spatial resolution imaging of the entire carotid circulation form the aortic arch to the circle of Willis in less than 20 seconds. Additional acquisitions can be utilized as part of the same study to accurately time the arrival of contrast in the arterial system and overcome the problem of early venous enhancement. A number of techniques have been developed recently that allow CE MR angiography to be implemented with high temporal resolution. Both atherosclerotic and nonatherosclerotic carotid artery disease can be comprehensively assessed with CE MR angiography, preventing the need for conventional diagnostic angiography.

Body magnetic resonance angiography and its effect on the use of alternative imaging--experience in 1026 patients.

Time-of-flight magnetic resonance (MR) angiography has been described for numerous applications but the number of patients described in published reports is usually relatively small. There is little information concerning the general utility of MR angiography in the body, outside the cranial circulation, or its effect on use of other imaging studies. Utilization of two-dimensional (2D) time-of-flight MR angiography over a 3 year period was reviewed to determine its accuracy and impact on other imaging modalities. Cranial and cardiac studies were excluded. Correlation was made with alternative imaging and surgical findings. Between January 1990 and December 1992 2D time-of-flight MR angiography was used to examine 1026 patients. MR angiography was used most frequently to examine the venous system. There was a slight reduction in the use of alternative imaging with two exceptions. When chest MR venography was performed, alternative imaging was completely abolished. Also, contrast portal venography was virtually eliminated. Five errors (0.2% of total MR angiography examinations) were recorded. Time-of-flight MR angiography, especially MR venography, is accurate and can replace contrast venography for abdominal and thoracic applications. Cost and limited availability means that other imaging, usually ultrasound, often precedes MR angiography.

Sedation in children scanned with high-field magnetic resonance; the experience at the Hospital for Sick Children, Great Ormond Street.

Patient movement is the most common cause of image degradation when performing magnetic resonance scans in children. This is a particular problem scanning at high field, as noise levels of up to 90 dB may be reached. Movement can be reduced by adequate sedation. We present the results of two sedation protocols when scanning with a 1.5T Magnetom scanner. Optimal scan quality can be achieved in up to 85% of scans using Pethco combined with triclofos in children aged 1 month-2 years, and trimeprazine combined with papaveretum in children over 2 years. When heavy sedation is used, patient selection must be cautious, and there is a minimum acceptable level of monitoring including close physical observation, electrocardiographic and apnoea monitoring.

Clinical comparison of a new technetium 99m DTPA aerosol delivery system with krypton 81m.

We compared the clinical performance of a new 99Tcm DTPA aerosol delivery system with steady-state 81Krm gas in the diagnosis of pulmonary embolic disease. Forty patients had aerosol and 81Krm ventilation imaging followed by perfusion scintigraphy. The combined aerosol/perfusion images were compared with 81Krm/perfusion images for diagnostic equivalence. Aerosol image quality was also compared directly with 81Krm. Three-quarters of the patients who had segmental ventilation-perfusion (V/Q) mismatch on 81Krm/perfusion images also had mismatch on aerosol/perfusion images. Of those who had no mismatch on Kr/perfusion images, it was possible to rule out mismatch on aerosol/perfusion images in 80% of cases. Fifteen per cent of aerosol images were uninterpretable due to excess deposition in large airways. This problem was significantly more frequent in smokers than in non-smokers. The average delivery efficiency of the system was 2%, in terms of the proportion of loaded activity retained in the lungs. We conclude that the new device gives accurate clinical information in most cases, but is of less value for smokers.

Magnetic resonance angiography in transjugular intrahepatic portosystemic stenting: comparison with contrast hepatic and portal venography.

In order to highlight the role of magnetic resonance angiography [MRA] in the assessment of patients pre-transjugular intrahepatic portosystemic shunt (TIPS) stenting, the MRA images of portal and hepatic veins of 21 patients were compared with the images from contrast portal and hepatic venograms performed on the same patients at the time of TIPS stenting (20 patients). MRA enabled accurate, non-invasive, multiplanar imaging of portal and systemic venous anatomy in each of the patients studied. MRA facilitated accurate determination of vessel patency and flow direction, images correlating exactly with contrast venograms of hepatic and portal veins in each case. In one patient, identification of occult hepatocellular carcinoma extending to the portal vein lead to the postponement of the TIPS procedure.

Neurotoxicity studies on sucralose and its hydrolysis products with special reference to histopathologic and ultrastructural changes.

Comparative neuropathological studies of 1,6-dichloro-1, 6-dideoxy-beta-D-fructofuranosyl-4-chloro-4-deoxy-alpha-D-galactopyra noside (sucralose), an equimolar mixture of 1,6-dichloro-1, 6-dideoxyfructose (1,6-DCF) and 4-chloro-4-deoxygalactose (4-CG), the hydrolysis products of sucralose, and 6-chloro-6-deoxyglucose (6-CG) were conducted in male and female mice and male marmoset monkeys, focusing on morphological changes in the central nervous system. 6-Chloro-6-deoxyglucose, previously reported to produce neurotoxic effects, served as the positive control and was administered by gavage at a daily dose of 500mg/kg. Sucralose and the sucralose hydrolysis products (sucralose-HP) were similarly administered to mice and marmosets at doses of up to 1000mg/kg for 21 and 28 days, respectively. No changes were detected in the central nervous system by light or electron microscopy in either of the species that received sucralose or its hydrolysis products. 6-Chloro-6-deoxyglucose, in contrast, induced symmetrical lesions in the deep nuclei of the cerebellum, brain stem and spinal cord with definitive neurological signs of CNS involvement.

A combined chronic toxicity/carcinogenicity study of sucralose in Sprague-Dawley rats.

The chronic toxicity and potential carcinogenicity of sucralose was evaluated by exposing Sprague-Dawley rats to dietary concentrations of this low-calorie sweetener both in utero and for up to 104 weeks following parturition. The rats assigned to the toxicity phase of this investigation were administered diets containing either 0% (control), 0.3% (3000 ppm), 1.0% (10,000 ppm) or 3.0% (30,000 ppm) sucralose. Each treatment group comprised 30 male and 30 female rats, of which 15 males and 15 females were sacrificed after 52 weeks of treatment. The surviving rats were killed following 78 weeks of sucralose administration. In the carcinogenicity phase of this investigation, groups of 50 male and 50 female rats were administered dietary sucralose at concentrations of 0% (control 1), 0% (control 2), 0.3%, 1.0% or 3.0% for 104 weeks. Evaluation of the data obtained from the two phases of this study showed that sucralose was not carcinogenic. Sucralose did not adversely affect the survival or clinical condition of the rats, and there were no toxicologically significant findings. Group mean body weight gain and food consumption were significantly decreased in a dose-dependent manner in sucralose-treated rats throughout the treatment period as compared to the controls. The primary effect of sucralose on food consumption, and secondarily on body weight gain, was established in later studies to be due to the fact that diets containing high concentrations of sucralose are unpalatable to rats. These subsequent studies established that the reduction of body weight gain seen in previous rat studies using sucralose in the diet at concentrations of 1% and below resulted from reduced food intake as a direct consequence of the unpalatable nature of sucralose. Similarly, at concentrations of 3% in the diet, it was shown that approximately 95% of the effect on body weight gain could be attributed to the reduction in food intake due to the reduced palatability of the diet, the remainder apparently due to a physiologic response to the high concentrations of non-digestible sucralose in the rats' diet. Complete toxicological evaluations of gavage studies with histopathological evaluations demonstrated that even at the 3% dietary level, toxicity was not responsible for the small body weight gain decrement. Gross and histopathologic examinations revealed that the administration of sucralose affected neither the types nor incidence of the tumours observed. The incidences of some non-neoplastic findings were statistically significantly increased in the sucralose treated groups relative to the controls. These included: renal pelvic epithelial hyperplasia in all female treatment groups, renal pelvic mineralization in females administered the intermediate or highest dietary concentrations of sucralose, adrenal cortical haemorrhagic degeneration in high-dose group female rats, and the histopathologic incidence of cataracts at necropsy in high-dose group male rats. The non-neoplastic findings that occurred were of no toxicological significance since they were either spontaneous findings commonly observed in aged rats of this strain or the physiological response to high dietary levels of a poorly absorbed compound.