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Experimental Studies |
1 From the Institute of Diagnostic Radiology (A.M.L., K.G., B.M., D.W.) and Center for Experimental Rheumatology, Department of Rheumatology (C.S., R.E.G., B.A.M., S.G.), University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland; and Groupe Guerbet, Roissy-Charles-de-Gaulle, France (C.C.). Received August 31, 2003; revision requested November 11; revision received December 29; accepted January 30, 2004. Address correspondence to D.W. (e-mail: dominik.weishaupt@dmr.usz.ch).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Unilateral arthritis was induced by means of intraarticular injection of methylated bovine serum albumin in 10 knees of 10 rabbits that had been presensitized to the same antigen. The contralateral knees in these rabbits, as well as six knees in three other rabbits, served as controls. After onset of arthritis, all knees were imaged prior to and 24 hours after administration of USPIO. The magnetic resonance (MR) imaging protocol included T1-weighted spin-echo, T2-weighted fast spin-echo, T2*-weighted gradient-echo, and short inversion time inversion-recovery sequences. Images were analyzed quantitatively and qualitatively with regard to signal characteristics and pattern. MR findings were correlated with histopathologic findings. Wilcoxon signed rank test was used to compare results of signal-to-noise ratio calculations before and after USPIO administration.
RESULTS: All knees with intraarticular injection of antigen suspension developed unilateral arthritis, whereas no signs of arthritis occurred in the control knees. On USPIO-enhanced images obtained 24 hours after contrast agent administration, significant T1 (P = .03) and more predominantly T2* (P = .02) and T2 effects (P = .01) were evident in the synovium of all 10 arthritic knees, which reflected USPIO uptake by macrophages in the synovial tissue. To a lesser extent, T2* effects were present also within the joint effusion (P = .01). No significant changes in signal characteristics were detected in the 10 nonarthritic knees in the antigen-injected group or the six knees in the control group (P = .06–.91). Histologic examination confirmed uptake of iron in the macrophages of arthritic knees. Changes in MR signal characteristics within the arthritic synovium and synovial effusion were visually detectable after intravenous administration of USPIO.
CONCLUSION: MR imaging at 1.5 T can depict USPIO uptake in phagocytic-active macrophages in an antigen-induced arthritis animal model.
© RSNA, 2004
Index terms: Iron • Knee, arthritis, 45.71 • Knee, MR, 45.12143 • Magnetic resonance (MR), contrast media • Synovial membrane
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and interleukin-1ß, which are involved in the process of joint destruction by promoting the activation of synovial fibroblasts, as well as the production of matrix metalloproteinases in synovial fibroblasts (3–5). The cytokines tumor necrosis factor– and interleukin-1ß are also known to promote invasion and accumulation of lymphocytes and plasma cells within the synovial tissue. Moreover, in patients with rheumatoid arthritis, the number of CD14+ and CD68+ macrophages within the synovium correlates well with joint destruction and disease severity (6). The role of magnetic resonance (MR) imaging in the detection of macrophage activity is evolving. Findings of several in vitro and in vivo studies have shown the feasibility and clinical potential of macrophage-specific MR imaging following intravenous administration of iron oxide particles (7–19). Ultrasmall superparamagnetic iron oxide (USPIO) particles with a mean diameter of 18–30 nm are particularly suited for MR imaging of macrophage activity, and macrophage labeling with USPIO has been demonstrated in various inflammatory diseases including atherosclerosis, autoimmune encephalomyelitis, nephrotoxic nephritis, transplanted graft rejections, and bacterial soft-tissue infections (11–14,19,20).
For clinical purposes, the ability to visualize macrophage activity in arthritic joints by using MR imaging appears desirable in many respects. It might enable assessment of early stages of the disease before structural changes can be detected at conventional radiography or other imaging modalities. Moreover, a technique capable of in vivo detection of phagocytic-active macrophages by means of iron oxide–associated signal effects may be a useful tool for the surveillance of therapy response to drugs affecting the activity of macrophages in rheumatoid arthritis.
In a recent article, macrophage-specific MR imaging in a rat model of antigen-induced arthritis after intravenous administration of large particles of superparamagnetic iron oxide was reported (21). Experience with use of USPIO for MR imaging of macrophage activity in arthritis, however, is limited. To our knowledge, findings of only one study have shown a USPIO uptake in macrophages in arthritic knee joints of mice; however, this study was performed following intraarticular injection, rather than intravenous injection, of USPIO (22).
The objective of our study was to evaluate intravenously administered USPIO as a marker of phagocytic-active macrophages in an experimental rabbit model of antigen-induced arthritis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experiment Setup
Before the study was started, a statistician was consulted to determine the adequate number of animals according to the expected effects of the contrast agent on signal intensity.
After administration of general inhalation anesthetic (2.5% isoflurane in oxygen, Forene; Abbott Laboratories, Abbott Park, Ill) and an intramuscular injection of 0.4 mL of a mixture of fentanyl and fluanisone (Hypnorm; Janssen, Titusville, NJ), unilateral knee arthritis was induced (A.M.L., D.W.) in 10 rabbits according to the technique described by Dawson et al (23). The animal group in which unilateral knee arthritis was induced is hereafter referred to as the antigen-injected group. For the induction of knee arthritis, 0.5 mL of an antigen suspension (consisting of 4 mg methylated bovine serum albumin per milliliter homogenized in Freund incomplete adjuvant) was administered by means of intraarticular injection into the left knees of all 10 rabbits in the antigen-injected group. Intraarticular injection was achieved with use of fluoroscopic guidance. No intraarticular injection was performed in the right knees of the 10 animals in the antigen-injected group. These right knees served as internal controls (contralateral nonarthritic knees of the antigen-injected group). Three additional rabbits served as the control group. In the control group, the left knees of all three animals were injected intraarticularly with 0.5 mL of isotonic saline solution in a similar fashion as in the antigen-injected group. The right knees of the control group were not injected.
The day of the intraarticular injection of the knee (with antigen suspension or saline) was considered day 0 for all animals. Prior to intraarticular injections, all 13 animals were sensitized by means of intradermal injection of 2 mL of the same antigen suspension on day –28 (4 mg methylated bovine serum albumin per milliliter of Freund complete adjuvant) and on day –14 (4 mg methylated bovine serum albumin per milliliter of Freund incomplete adjuvant).
After intraarticular injection of the knee, all animals in both the antigen-injected group and the control group were kept in cages under standardized conditions and with free access to water and food for the next 9–29 days. As early as 1 day after induction of arthritis, the rabbits are known to develop knee arthritis, with swelling of the injected joint. Already in this early phase of arthritis development, the synovium is infiltrated by macrophages, granulocytes, and perivascular Ia-positive nonlymphoid cells (24). By using an antigen-induced arthritis model similar to the one used in our study, Pettipher and coworkers (25) showed that 17 days after induction of arthritis, up to 28% of the cells in the cellular composition of the synovial fluid belonged to the mononuclear cell system.
For each animal, the time between induction of arthritis and MR imaging had to be individually scheduled according to the animal’s clinical condition (mean, 18 days; range, 9–26 days). As soon as an animal experienced severe weight loss despite adequate pain medication, MR imaging was performed. In general, we aimed for the longest possible delay in each animal so that the arthritis could develop, with an accumulation of a sufficient number of macrophages within the synovial tissue of the affected joint. Animals in the control group underwent MR imaging after a mean delay of 24 days (range, 21–29 days) after the intraarticular injection of isotonic saline solution.
MR Imaging and Specimen Preparation
Two MR imaging sessions were performed in each animal group. The first session was performed as the baseline study before administration of the USPIO (precontrast MR study). The second MR imaging session was performed 24 hours after USPIO administration (postcontrast MR study). The 24-hour delay should allow clearance of all particles from the vascular space by means of macrophage activity (8,26,27).
In all animals, each MR imaging session was performed with the animal under general anesthesia (inhalation of 2.5% isoflurane in oxygen).
MR imaging was performed by using a 1.5-T system (Signa CV/i; GE Medical Systems, Milwaukee, Wis). To maximize signal-to-noise ratio (SNR), animals were placed with their knees centrally in a dedicated phased-array knee coil. This coil was chosen because the design provides an optimal SNR. Imaging protocol for both precontrast and postcontrast studies included the following sequences: T1-weighted spin echo (SE) (repetition time msec/echo time msec, 300/14; field of view, 14 x 14 cm; matrix, 512 x 192), T2-weighted fast SE (3820/107; echo train length, 14; field of view, 14 x 14 cm; matrix, 512 x 192), T2*-weighted fast gradient echo (1000/15; field of view, 14 x 14 cm; matrix, 512 x 192; flip angle, 25°), and short inversion time inversion-recovery (repetition time msec/echo time msec/inversion time msec, 5020/35/150; field of view, 14 x 14 cm; matrix, 512 x 192). MR imaging was performed in the transverse, sagittal, and coronal planes for all sequences. Section thickness was 3 mm without an intersection gap for all acquired sequences, which led to a voxel size of 0.27 x 0.73 x 3.0 mm for T1- and T2*-weighted sequences, 0.55 x 0.55 x 3.0 mm for T2-weighted fast SE sequences, and 0.23 x 0.63 x 3.0 mm for short inversion time inversion-recovery sequences.
Immediately after the second MR imaging session (postcontrast MR study), the animals were sacrificed by using an overdose of pentobarbital (Vetanarcol; Veterinaria, Zurich, Switzerland). The arthritic knee joints and contralateral nonarthritic knees in the antigen-injected group and both knee joints in the control group were dissected and fixed in 4% formalin for histologic evaluation.
Contrast Agent
The USPIOs used in this study are nanoparticles that consist of a core of iron oxide crystals that measure 4–6 nm in diameter and are coated with anionic dextran (AMI-7228, ferumoxytol; Guerbet, Aulnay-sous-Bois, France, and Advanced Magnetics, Boston, Mass). The overall mean particle diameter is approximately 30 nm, and the blood half-life of AMI-7228 in rats is about 67 minutes at a dose of 40 µmol of iron per kilogram of body weight (according to manufacturer’s data). The relaxivities R1 and R2 are 17.9 mmol · L–1 · sec–1 and 97 mmol · L–1 · sec–1, respectively (measured at 21°C and a magnetic field strength of 1.5 T, according to manufacturer’s data). This relatively long half-life allows uptake of iron particles into non–organ-based macrophages outside of the organs of the mononuclear phagocyte system (7,28,29). AMI-7228 is currently undergoing phase II clinical trials.
The USPIO contrast agent was administered intravenously through an ear vein immediately after completing the precontrast imaging session. A dose of 150 µmol of iron per kilogram of body weight (corresponding to a dose of 0.28 mL of AMI-7228 per kilogram of body weight) was intravenously administered to each animal.
Histopathologic Preparation
After fixation in 4% formalin, all knee joints were cut in either transverse or sagittal slices (according to the imaging planes) of 2–3 mm thickness for histologic staining. After decalcification and embedding of the selected slices in paraffin, Perls Prussian blue stain and Turnbull blue reaction (30) were used to detect presence of iron at light microscopy with magnifications from x100 to x400 (C.S., 4 years of experience in pathology). In addition, hematoxylin-eosin-saffron stain was used (C.S.) to determine the amount and distribution of macrophages within the synovium and the surrounding tissues.
Data Analysis
Both qualitative visual analysis and quantitative measurements of signal intensity were performed. MR images of all sequences were transferred to a commercially available workstation (Advantage Windowing; GE Medical Systems, Buc, France).
Qualitative image analysis was performed by two radiologists working in consensus (A.M.L. and D.W., 3 and 10 years of experience in musculoskeletal radiology, respectively). The readers were blinded to the animal groups; however, during reading sessions, the images obtained before and after USPIO administration were available. The readers evaluated the precontrast images with regard to thickening of the synovium and the amount of synovial effusion as typical early signs of chronic inflammatory joint disorders (31). Because the joint capsule and the synovium (including synovial lining and subsynovium) were not consistently visible as separate anatomic structures on MR images, the synovium and the joint capsule were considered a single structure for image analysis. The amount of joint fluid was assessed as follows: grade 1, physiologic with a thin liquid film in the suprapatellar recess or popliteal joint space; grade 2, moderate effusion defined as suprapatellar recess or popliteal joint space with a sagittal diameter on the midline (at the level of the suprapatellar tendon) of less than or equal to 4 mm; and grade 3, large effusion when the sagittal aspect of the suprapatellar recess or popliteal joint space is more than 4 mm. Images obtained with short inversion time inversion-recovery were used for quantification of the joint effusion. In both knees of both animal groups, changes in signal characteristics of the synovium and the synovial fluid between pre- and postcontrast T1-, T2-, and T2*-weighted images were evaluated semiquantitatively according to the following three-point Likert scale: On T1-weighted images, T1 effects were rated as 0, no signal enhancement; 1, slight enhancement; and 2, distinct enhancement. On T2-weighted images, T2 effects were rated as 0, no signal loss; 1, slight signal loss; and 2, distinct signal loss. Finally, on T2*-weighted images, T2* or susceptibility effects were rated as 0, no susceptibility effect; 1, slight susceptibility effect; and 2, distinct susceptibility effect.
For the quantitative analysis, signal intensities were measured by two radiologists (A.M.L. and D.W.), working independently, in defined regions of interest on both pre- and postcontrast T1-, T2-, and T2*-weighted images. Regions of interest were set in comparable locations within the synovial tissue and within the synovial joint fluid (as far as joint fluid was present) of all knee joints. A total of three regions of interest, each with a diameter between 2 and 5 mm2, were placed within the synovial tissue. Three regions of interest were also set within the synovial fluid, as far as sufficient volume of synovial fluid was present. The mean values of the three regions of interest were calculated for further analysis. In addition, the background noise was measured within three regions of interest placed within the air adjacent to either knee.
For calculation of the relative SNR changes within the synovial tissue and fluid, the SNR values were calculated by dividing the mean of the measured signal intensity of these locations by the standard deviation of the background noise. Then, the relative SNR changes were quantified by using the following equation: SNR change = [(SNRPOST – SNRPRE)/SNRPRE] x 100, where SNRPRE and SNRPOST are the SNRs of the pre- and postcontrast images, respectively. Positive values meant an increase in SNR for sequences after USPIO administration, and negative values meant a decrease in SNR from the precontrast to the postcontrast MR images. The thickness of the synovium was measured in all animals by using unenhanced T2-weighted sequences.
Statistical Analysis
Statistical analysis was performed by using the software StatView (version 5.0.1; SAS Institute, Cary, NC). Results of signal intensity measurements are given as mean ± standard deviation. Wilcoxon signed rank test was used to compare the results of SNR calculations before and after USPIO administration. P 
.05 was considered to indicate a statistically significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Synovial Thickening and Joint Fluid
Extensive synovial thickening was present in all left knees in the antigen-injected group on images from all MR sequences. Synovial thickening did not occur in the nonarthritic contralateral knees in the antigen-injected animal group or in any of the knees in the control group. The mean thickness of the arthritic synovium, as measured on T2-weighted images, was 2.8 mm ± 1 (± standard deviation; range, 1.6–4.5 mm). Thickness of the synovium in the nonarthritic knees of the antigen-injected group and in both knees in the control group was, in general, below 1 mm in diameter. Moderate to large amounts of joint effusion could be appreciated on images obtained with T2- and T2*-weighted and short inversion time inversion-recovery sequences in the arthritic left knees of eight animals in the antigen-injected group (Fig 1). In all nonarthritic knees (both groups), either no joint fluid or only a small amount of joint fluid was present.
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Histopathologic Evaluation
At histopathologic evaluation, cellular infiltrates containing monocytes, lymphocytes, and macrophages were noted within the hyperplastic synovium of the arthritic knees. Histopathologic analysis showed a marked uptake of iron particles in the macropages embedded in the cellular infiltrates of all arthritic knees. These iron-positive macrophages containing blue iron-loaded vesicles in their cytoplasm were detected within the hyperplastic synovium of all arthritic knees (Fig 2) of the antigen-injected group but were not detected in the normal synovium of the contralateral knees of the antigen-injected group or in the knees of the control group (Fig 2). Iron-loaded macrophages were found at histologic evaluation in the same synovial areas where signal attenuation or susceptibility effects were detected at MR imaging. Also, iron-positive macrophages were present in the bone marrow of the osseous structures of all knees, as well as in popliteal lymph nodes. No iron was detected in extracellular locations in any of the examined knees. Also, no iron vesicles were detected in granulocytes or lymphocytes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The role of MR imaging for assessment of joint damage in rheumatoid arthritis is evolving (31,35–38). The ability of MR imaging to provide both high-spatial-resolution and high soft-tissue contrast images in multiple planes makes it a very valuable technique for imaging bone and soft-tissue abnormalities in patients with rheumatoid arthritis. With the application of gadolinium-based contrast agents, the sensitivity of MR imaging to depict joint disease can be even more improved (31,35–37). Extracellular gadolinium-based contrast agents enable effusions within joints or tendon sheaths to be distinguished from synovial hyperplasia (31,36). Moreover, gadolinium-based contrast agents in combination with dynamic gradient-echo sequences allow quantification of synovitis in rheumatoid arthritis by enabling measurement of signal changes of the contrast agent over time (37), or they may help, to a certain extent, in discriminating active from inactive disease (38). Nevertheless, tissue enhancement caused by extracellular gadolinium-based contrast agents merely indicates increased capillary permeability of the inflamed tissue, with contrast agent accumulation within the extracellular space. Hence, this technique does not reflect a tissue- or cell-specific labeling with the contrast agent.
In contrast to the extracellular gadolinium-based contrast agents, iron oxide particles with a long plasma circulation time are (after a certain time delay) phagocytosed by macrophages; to a lesser extent, the iron oxide particles can also be taken up by other phagocytosing cells (7–9). Among the iron oxide particles, USPIO particles (mean particle diameter, 18–30 nm) are particularly well suited for in vivo macrophage-specific MR imaging. USPIO particles are small enough to extravasate through the tight capillary pores of the cells that measure between 5 and 100 nm in diameter (8,39). This capillary permeability may give USPIO particles a major advantage over their larger progenitor particles, the superparamagnetic iron oxides, which most commonly have mean particles sizes of up to 150 nm. After intravenous administration, superparamagnetic iron oxide particles are nearly entirely ingested by the cells of the mononuclear phagocyte system in the bone marrow, liver, and spleen (8,40). Only a very small amount of the injected superparamagnetic iron oxide particles is taken up by macrophages and other phagocytosing cells outside of organs of the mononuclear phagocyte system (40). Intravenously injected USPIO particles, on the other hand, are considerably taken up by migrating macrophages and other phagocytosing cells that are mobilized by an inflammatory disease process in other parts of the body (7,14,26).
The site of USPIO uptake by macrophages in inflammatory diseases is still debatable. Most authorities agree that the iron particles permeate through capillary walls into the interstitial spaces at sites of inflammation, where the particles are phagocytosed by phagocytic-active macrophages of the inflamed tissues (absorbtive endocytosis) (8,41,42). In addition, the duration of USPIO intravascular residency is long enough to allow phagocytosis of the particles already within the vascular space by macrophages, which are attracted by the inflammatory process (43).
Beckmann et al (21) have shown the feasibility of MR imaging to depict macrophage infiltration in arthritic knees in an antigen-induced arthritis rat model. In that study, large superparamagnetic iron oxide particles (mean particle size, 150 nm) were injected intravenously at a relative high dose of 468 µmol of iron per kilogram of body weight, and imaging was performed 24 hours after contrast agent administration by using an ultra-high-field-strength MR imager of 4.7 T. In comparison, in our study in which USPIO particles and a clinical 1.5-T MR imager were used, less than one-third of the iron dose was applied; this resulted in significantly detectable SNR changes within the synovium and, to a lesser extent, within the joint effusion. Hence, it may be concluded that USPIO is probably better suited for detecting macrophage activity in arthritic joints than is superparamagnetic iron oxide.
The results of this preliminary animal study indicate that USPIOs are phagocytosed by macrophages contained within the inflamed synovial tissue in an experimental model of antigen-induced arthritis. The implications of this observation are potentially vast, because they may profoundly affect future strategies for the diagnosis and therapy of rheumatoid arthritis. Instead of defining the morphologic makeup of the arthritic joint, a functional strategy is pursued. On the basis of the assumption that inflamed synovial tissues harbor macrophages, the technique relies on intravenous administration of ultrasmall iron particles with a long intravascular half-life. After 24 hours, the concentration of USPIO within the macrophages is high enough to induce predominantly T2 and T2* effects, and to a lesser degree, T1 effects, which are detectable by using a clinical MR imager. These USPIO-induced changes in tissue signal characteristics resulted in visible effects at a blinded analysis by different observers. The visual impressions are reflected by the quantitative analysis, which showed a dramatic decrease of signal intensity in the synovial tissue on USPIO-enhanced T2- and T2*-weighted images, and, to a lesser degree, a signal increase on T1-weighted images.
Histologic analysis confirmed the intracellular presence of iron particles in macrophages. Areas of focal signal loss on T2-weighted fast SE or susceptibility effects on T2*-weighted images corresponded to foci of iron staining at histologic examination. Thanks to results of various in vitro and in vivo studies, there is now clear evidence that once the USPIO particles are ingested by macrophages, the particles are dissolved within the lysosomes of cells by separating the coating and the iron oxide core (8,19,26).
The feasibility of USPIO-enhanced imaging in antigen-induced arthritis has also been investigated in an experimental murine model of autoimmune arthritis induced by means of two intradermal injections of bovine collagen (22). In that study, USPIOs were administered either intravenously or intraarticularly into the knees of mice with autoimmune arthritis. MR imaging of the murine knees was performed 24 hours after intravenous or intraarticular injection with an ultra-high-field-strength MR imager at 3 T. In a comparison with knees of nonarthritic control animals, Dardzinski et al (22) reported that there was signal loss within the synovium of the arthritic knees after intraarticular injection of USPIO on T1-weighted gradient-echo MR images. In that study, however, after intravenous USPIO administration susceptibility effects were noted only in the soft tissue posterior to the joint capsule. It may be hypothesized that the MR parameters or the USPIO dose chosen in that study (22) was not optimally sensitive for detecting T2* effects. Contrary to the results of the study by Dardzinski et al (22), our results have shown that changes in MR signal characteristics within the arthritic synovium, as well as within the joint effusion, are visually evident even after intravenous USPIO administration. This is an important finding with regard to potential implementation of this technique in clinical practice, since intravenous injection of the contrast agent is much more practicable in a clinical setting than is an intraarticular injection.
Since neither MR signal changes nor iron-containing macrophages were detected histologically within the synovium of contralateral nonarthritic knees of the antigen-injected group or the knees of control animals, our study has demonstrated that USPIO-enhanced MR imaging can be used for labeling of macrophages within synovial tissue of arthritic knees.
Although the results of this study are very promising (since the macrophages in the synovial tissue of arthritic joints may be visualized selectively by using MR imaging), two possible limitations of the study have to be addressed as follows: First, the study was performed with rabbits. Although we chose an animal model that is considered to closely reflect rheumatoid arthritis in humans (23), it is unclear whether the results in this study will be entirely applicable to humans. Before the technique can be applied to human patients with rheumatoid arthritis, the kinetics of USPIO uptake in macrophages has to be studied in detail. Second, we did not quantify the uptake of USPIO into synovial macrophages. The possibility of quantifying USPIO uptake, however, might be the basis for the evaluation of drug effects on the activity of macrophages in rheumatoid arthritis. Therefore, findings of future studies should show whether the uptake of USPIO in synovial macrophages can be quantified.
In conclusion, our study has demonstrated that MR imaging can enable visualization of USPIO uptake in phagocytic-active macrophages in an antigen-induced arthritis model and can thereby help in the evaluation of synovial activity.
Practical application: Because macrophages play a central role in the pathogenesis of rheumatoid arthritis and are known to be abundantly present within the synovial structures of affected joints, there is a high clinical potential in visualizing macrophage activity in arthritic joints at USPIO-enhanced MR imaging. In rheumatoid arthritis, this functional imaging strategy might enable assessment of early stages of arthritis before structural changes can be detected at either conventional radiography or other imaging modalities. Moreover, USPIO-enhanced MR imaging may be a useful tool for the surveillance of therapy response to novel drugs affecting the macrophage activity.
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FOOTNOTES |
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See also Science to Practice in this issue.
Author contributions: Guarantors of integrity of entire study, A.M.L., D.W.; study concepts, C.C., A.M.L., K.G., C.S., R.E.G., S.G., D.W., B.A.M.; study design, A.M.L., B.M., D.W.; literature research, C.C., K.G., A.M.L., C.S., S.G.; experimental studies, A.M.L., K.G., C.S.; data acquisition, A.M.L., K.G., C.S., D.W.; data analysis/interpretation, A.M.L., C.S., D.W., R.E.G., S.G., B.A.M.; statistical analysis, A.M.L.; manuscript preparation, A.M.L., D.W., C.S., R.E.G., C.C.; manuscript definition of intellectual content, A.M.L., D.W., C.S., S.G., B.M., B.A.M.; manuscript editing, A.M.L., K.G.; manuscript revision/review, all authors; manuscript final version approval, B.M., S.G., D.W.
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