TY - JOUR
AU - PhD, Yi Zhang, MD,
AB - Abstract Objective Correlation between radiologic structural abnormalities and clinical symptoms in low back pain patients is poor. There is an unmet clinical need to image inflammation in pain conditions to aid diagnosis and guide treatment. Ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle, is clinically used to treat iron deficiency anemia and showed promise in imaging tissue inflammation in human. We explored whether ferumoxytol can be used to identify tissue and nerve inflammation in pain conditions in animals and humans. Methods Complete Freud’s adjuvant (CFA) or saline was injected into mice hind paws to establish an inflammatory pain model. Ferumoxytol (20 mg/kg) was injected intravenously. Magnetic resonance imaging (MRI) was performed prior to injection and 72 hours postinjection. The changes in the transverse relaxation time (T2) before and after ferumoxytol injection were compared between mice that received CFA vs saline injection. In the human study, we administered ferumoxytol (4 mg/kg) to a human subject with clinical symptoms of lumbar radiculopathy and compared the patient with a healthy subject. Results Mice that received CFA exhibited tissue inflammation and pain behaviors. The changes in T2 before and after ferumoxytol injection were significantly higher in mice that received CFA vs saline (20.8 ± 3.6 vs 2.2 ± 2.5, P = 0.005). In the human study, ferumoxytol-enhanced MRI identified the nerve root corresponding to the patient’s symptoms, but the nerve root was not impinged by structural abnormalities, suggesting the potential superiority of this approach over conventional structural imaging techniques. Conclusions Ferumoxytol-enhanced MRI can identify tissue and nerve inflammation and may provide a promising diagnostic tool in assessing pain conditions in humans. Inflammation, Imaging, Pain, USPIO Introduction Inflammation underlies many common clinical pain conditions, such as joint pain in rheumatoid arthritis and low back pain in lumbar spondylosis and radiculopathy. However, diagnosing these pain conditions is challenging. Many radiologic abnormalities found in low back pain (LBP) patients are also present in asymptomatic individuals, and many patients with LBP and/or sciatica have no identifiable radiologic abnormalities. Furthermore, structural imaging does not capture functional biological processes leading to pain. Therefore, correlation between radiologic abnormalities and clinical symptoms remains poor [1, 2]. Thus, there is an unmet clinical need to image inflammation in pain conditions to aid in diagnosis and to guide treatment, especially for patients with sciatica. Macrophage and monocyte infiltration is a hallmark of tissue inflammation. These inflammatory cells are seen in joint arthritis and nerve root inflammation. Ferumoxytol is an iron product that has been approved by the US Food and Drug Administration to treat iron deficiency anemia. It is composed of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles that are taken up by the macrophage-monocyte system. Iron oxide nanoparticles can alter magnetic resonance imaging (MRI) signals by shortening the transverse relaxation times (T2) of protons, leading to signal changes quantifiable by MRI, even if the microscopic distribution is below the resolution threshold [3]. This property has been explored in experimental settings to track cells and image tumors. Ferumoxytol-labeled human neural progenitor cells can be tracked upon transplantation into the porcine spinal cord [4]. These cells can be identified with MRI for up to 105 days after transplantation. In a mouse model of human glioblastoma, MRI with ferumoxytol reveals monocyte infiltration into the tumor [5], a key prognostic factor in determining treatment response. In this report, we sought to examine whether ferumoxytol MRI can be used to image tissue and nerve inflammation in an experimental animal pain model and in humans with lumbar radicular pain. Methods Animals All procedures and animal use were approved by the Massachusetts General Hospital (MGH) Institutional Animal Care and Use Committee (IACUC) and were in accordance with the guidelines established by the National Institutes of Health and the International Association for the Study of Pain. Male C57BL/6 mice age five to seven weeks were purchased from Charles River Laboratories and were kept in a specific pathogen-free environment with a 12-hour light (7:00 to 19:00) and 12-hour dark (19:00–7:00) cycle. Animals were supplied with food and water ad libitum. Human Subjects After institutional review board approval, we recruited two human subjects, including a healthy subject and a pain subject with a history of chronic right lower extremity radicular pain. The healthy subject is a 34-year-old male with no pain complaints. The pain subject is a 52-year-old male with a history of intermittent low back pain radiating to the left posterior thigh and leg for 15 years, which had subsided for three months at the time of imaging. He also has a four-year history of right groin and anteromedial thigh pain, which was his main pain complaint at the time of imaging. His right groin and anteromedial thigh pain had responded well to a previous right L3 transforaminal epidural steroid injection two and half years before but had recurred at the time of study. No further treatment was sought after due to his insurance issues. Medication Ferumoxytol injection was purchased from the manufacturer AMAG Pharmaceuticals (Waltham, MA, USA) via our institutional research pharmacy. Inflammatory Pain Model To induce long-term inflammation, a single 10-μL injection of 1-mg/mL complete Freud’s adjuvant (CFA; Sigma Aldrich, St. Louis, MO, USA) was injected into the plantar hind paw. Mice were anesthetized with isoflurane briefly for the injection. A single intraplantar injection of CFA in this location has been demonstrated to induce a rheumatoid arthritis–like pathology in the hind paw of C57BL/6 mice. Controls were injected in the same location with 10 μL of normal saline (Hospira, IL, USA). Hind Paw Thickness Measurements Hind paw thickness was measured using digital calipers (Neiko 01407 A, Neiko Tools, Shenyang, China). Mice were carefully handled, and hind paws were approached by digital caliper at the level of the metatarsal joint. The caliper was placed in contact with skin without pressure. Behavioral Testing Mechanical hind paw withdrawal thresholds were determined by the Up-Down method [6]. Habituation was performed prior to behavioral tests. Mice were brought to the testing room and placed on the testing platform for about 15 to 30 minutes two days prior to and one day prior to the testing day to ensure environmental familiarity and minimize anxiety-induced behavioral changes confounding mechanical withdrawal. Von Frey filaments were used to determine mechanical thresholds, and a threshold was established by at least two hind paw withdrawal responses out of five tests. Experimenters were blinded to the group assignments. Cell Isolation from Footpad Three days after CFA injection, mice were euthanized and then perfused with 40 mL of ice-cold normal saline solution through the left ventricle cannulation to minimize circulating red blood cell and white blood cell contamination. Total hind paw tissue following removal of the toes and bones was incubated at 37 °C for 90 minutes in 3 mL of Dulbecco's modified Eagle medium (DMEM) containing 160 μg/mL of Liberase TL purified enzyme blend (Roche Diagnostic Corp.). Following Liberase treatment, tissue was homogenized with 10 mL of RPMI medium containing 0.05% DNase (Stemcell Technologies), and the homogenate was filtered with a 50-μm-pore-size cell strainer. Cell pellets were made by centrifugation using 370 g × 7 min followed by resuspension in 5 mL of RPMI medium. A two-layer Percoll (Sigma-Aldrich) density gradients: 40% Percoll over 70% Percoll was used for leukocyte sedimentation at 2560 g for 11 minutes. Flow Cytometry Cells were washed with FACS buffer (PBS with 2% fetal calf serum and 0.1% NaN3), and cell surface stainings were performed at 4 °C for 30 minutes using the following antimouse antibodies from BioLegend: CD11b Pacific Blue (101223), F4/80 Alexa488 (246796), CD3 PE(100205). A Fc receptor block step with antimouse CD16/32 (BioLegend 101319) was performed to minimize nonspecific bindings of antibodies. Samples were acquired with LSR-II (BD) flow analyzer. Data were analyzed with FlowJo software (FlowJo). Mice MRI Imaging Mice were first imaged three days post-CFA. Following the baseline MRI, mice were administered 20 mg/kg of ferumoxytol intravenously. The second MRI was performed 72 hours after the ferumoxytol administration. Mice were anesthetized with 1–2% isoflurane gas in oxygen throughout the scan with respiratory monitoring. Mice were imaged on a Bruker 4.7 Tesla MRI scanner. T2-mapping images were acquired using the multislice multi-echo (MSME) sequence with a TR = 2316 ms, four averages, 128 × 128 × 16 matrix size, 0.313 × 0.313 × 0.6 mm voxel size sequence with 16 echos with 8.68-ms echo spacing. In addition, T2-weighted images were obtained using the rapid acquisition with refocused echoes (RARE) sequence, with TE = 18.26 ms, TR = 2000 ms, rare factor 8, and eight averages on a 256 × 256 × 16 image matrix and 0.216 × 0.156 × 1.0 mm voxels. T2 values were computed from the MSME sequences by performing nonlinear least squares fit to an exponential decay equation M(t) = M0*exp(-t/T2) using a house-built plugin in the Osirix software environment (www.osirix-viewer.com). Human MR Imaging Each subject underwent two lumbar spine MRI sessions: one at baseline and one 48 hours after ferumoxytol administration. We elected to perform the postferumoxytol MR scan at 48 hours after administration based on a recent human study showing optimal imaging at this time point after ferumoxytol administration [7]. Lumbar MRI was acquired on a 1.5T scanner (GE) using an eight-channel CTL spine coil. Sagittal T2-weighted 3D images (CUBE) were acquired with the following parameters: TR = 1500 ms, TE = 101 ms, field of view (FOV) = 24 cm, matrix size = 224 × 224 × 144. The CUBE images were subsequently reconstructed to obtain axial and coronal images. Axial and sagittal T2 mapping experiments were conducted using TR = 1000 ms, TE = 5.3, 10.6, 15.9, 21.2, 26.5, 31.8, 37.1, 42.4 ms, FOV = 21 cm, matrix size = 256 × 192. T2 mapping images were then curve-fitted to an exponential decay equation to obtain T2 maps. T2*-weighted imaging was performed with a 3D gradient echo sequence with the following parameters: TR = 43, TE = 12, flip angle = 5, FOV = 18 cm, matrix size = 256 × 128 × 128. Following the baseline MRI session, ferumoxytol at a dose of 4 mg/kg diluted in 250 mL of normal saline was infused intravenously over 30 minutes under MD supervision. Forty-eight hours after ferumoxytol administration, the subjects underwent MR imaging with the same sequences. Image Interpretation Human MR images were interpreted by two board-certified neuroradiologists blinded to subjects’ clinical conditions (healthy or pain subject, pain symptoms). Mouse MR images were interpreted by investigators blinded to the group assignment of the mice. Statistics Animal behavior data and paw thickness were analyzed using one-way analysis of variance with repeated measures. Monocyte and macrophage comparison was analyzed with the Student’s t test. Animal MRI T2 values were analyzed using the Student’s t test. Results Inflammatory Pain Model We randomized C57BL/6 mice into a CFA group and a saline (control) group. We examined the hind paw mechanical withdrawal thresholds at different time points after the injection. While the two groups did not exhibit differences in their baseline mechanical withdrawal thresholds, mice in the CFA group displayed significantly lower mechanical withdrawal thresholds than mice in saline group at each of the time points postinjection (Figure 1A). The lower mechanical withdrawal thresholds indicate the development of pain behavior secondary to CFA injection. We also compared the hind paw thicknesses between mice in the CFA with those in the saline group. Mice in the CFA group were noted to have significant hind paw and ankle swelling after injection, and their hind paws were significantly thicker than those of mice in the saline group (Figure 1B). Therefore, CFA group mice displayed increased hind paw tissue swelling as measured by paw thickness, and pain behavior as indicated by significantly reduced mechanical withdrawal thresholds. These results are consistent with previous reports that CFA hind paw injection elicits tissue inflammation and inflammatory pain [8, 9]. Figure 1 View largeDownload slide Complete Freud’s adjuvant (CFA) induces inflammatory pain. (A, B) Mice were given CFA (N = 6) or saline control (N = 6) injection in the hind paws. (A) Hind paw mechanical withdrawal threshold was determined at indicated time points postinjection. CFA injection group exhibited significant mechanical pain, as suggested by decrease of withdrawal threshold. *P < 0.05. (B) Hind paw thickness was examined at indicated time points postinjection. CFA injection group exhibited significant paw swelling. *P < 0.05. (C, D) Inflammatory cell infiltration into hind paw. At day 3 after CFA or saline injection, hind paw tissues from six mice of each group were processed to isolate infiltrating cells, followed by flow cytometry staining on these cells. (C) Cells were stained with F4/80 and CD11b antibodies. Dot plots were gated on live cells based on forward and side scatter parameters. Each plot represents six stainings. (D) Cell counts for each group of animals. Numbers of CD11b+ F4/80+ macrophages and CD11b+ F4/80− monocytes were compared between CFA group and saline control group. CFA group had significantly higher numbers of macrophage and monocyte infiltration. CFA = complete Freud’s adjuvant. Figure 1 View largeDownload slide Complete Freud’s adjuvant (CFA) induces inflammatory pain. (A, B) Mice were given CFA (N = 6) or saline control (N = 6) injection in the hind paws. (A) Hind paw mechanical withdrawal threshold was determined at indicated time points postinjection. CFA injection group exhibited significant mechanical pain, as suggested by decrease of withdrawal threshold. *P < 0.05. (B) Hind paw thickness was examined at indicated time points postinjection. CFA injection group exhibited significant paw swelling. *P < 0.05. (C, D) Inflammatory cell infiltration into hind paw. At day 3 after CFA or saline injection, hind paw tissues from six mice of each group were processed to isolate infiltrating cells, followed by flow cytometry staining on these cells. (C) Cells were stained with F4/80 and CD11b antibodies. Dot plots were gated on live cells based on forward and side scatter parameters. Each plot represents six stainings. (D) Cell counts for each group of animals. Numbers of CD11b+ F4/80+ macrophages and CD11b+ F4/80− monocytes were compared between CFA group and saline control group. CFA group had significantly higher numbers of macrophage and monocyte infiltration. CFA = complete Freud’s adjuvant. We next examined whether there is an influx of macrophages and monocytes during the development of hind paw inflammatory pain. Hind paw tissue from mice in both CFA and saline groups was digested; infiltrating cells were isolated and stained for cell surface markers (Figure 1C). Numbers of both F4/80+ CD11b+ macrophages and F4/80- CD11b+ monocytes were significantly higher in the CFA group than in the saline group (Figure 1D). Ferumoxytol MRI Reports Inflammation Related to Pain Seventy-two hours after ferumoxytol injection, mice injected with CFA demonstrated marked signal loss on T2-weighted imaging (Figure 2A) compared with control mice injected with saline. Moreover, the T2 mapping experiment in these mice showed that in mice with CFA-induced pain, T2 change was significantly higher than that in control mice without CFA (20.8 ±3.6 vs 2.2 ± 2.5, mean ± SE, P = 0.005) (Figure 2B), confirming that ferumoxytol accumulated in the CFA-inflamed tissue but not in the uninflamed tissue. Figure 2 View largeDownload slide Ferumoxytol-contrasted magnetic resonance imaging (MRI) in inflammatory pain. (A, B) Mice were given complete Freud’s adjuvant (CFA; N = 4) or saline control (N = 4) injection in the hind paws. (A) Noncontrast MRI was performed at day 3 post–CFA and saline injection. Immediately after the MRI, ferumoxytol was administered to these mice, followed by MRI at 48 hours after ferumoxytol administration. MRI images represent four mice from each group. (B) Changes in T2 before and after ferumoxytol were calculated. CFA group showed significantly higher changes in T2 than saline group. Figure 2 View largeDownload slide Ferumoxytol-contrasted magnetic resonance imaging (MRI) in inflammatory pain. (A, B) Mice were given complete Freud’s adjuvant (CFA; N = 4) or saline control (N = 4) injection in the hind paws. (A) Noncontrast MRI was performed at day 3 post–CFA and saline injection. Immediately after the MRI, ferumoxytol was administered to these mice, followed by MRI at 48 hours after ferumoxytol administration. MRI images represent four mice from each group. (B) Changes in T2 before and after ferumoxytol were calculated. CFA group showed significantly higher changes in T2 than saline group. Human Imaging on Neuroinflammation In the pain subject, the T2-weighted signal showed a substantial change after ferumoxytol administration around the right L3 nerve root as it exits the neural foramen (Figure 3A, only T2-weighted images shown; T2*-weighted images had susceptibility artifact in this location) and as it descends within the spinal canal (Figure 3B, T2*-weighted images shown.), indicating inflammation around the nerve root. This change in T2*-weighted signals after ferumoxytol was not present on the left side, where the subject has no pain symptoms (Figure 3A). Interestingly, even though there were structural abnormalities interpreted by the neuroradiologists in this subject, such as a small disc protrusion touching on the exiting right L4 nerve root and narrowing of the subarticular zone touching on the right descending L5 nerve roots at the L4/5 level, there was no noticeable T2* signal change after ferumoxytol administration at these levels (Figure 3C). Importantly, the presence of reduced T2* signals around the right L3 nerve root, suggesting an inflammatory process, is concordant with the subject’s clinical presentation of right-sided groin and anteromedial thigh pain symptoms. Therefore, ferumoxytol MRI was able to differentiate the “culprit” nerve root from other nerve roots. As expected, in the healthy subject with no pain symptoms, no signal changes around any spinal nerve roots were identified (Figure 4). Figure 3 View largeDownload slide Ferumoxytol-contrasted magnetic resonance imaging (MRI) in clinical radicular pain secondary to intervertebral disc protrusion. (A) T2-weighted MR images of a human pain subject with clinical diagnosis of right L3 radiculitis before and after ferumoxytol administration. Upper panels were MR images. Middle panels were heat map–coded MR images; white arrow: right L3 nerve root; black arrow: left L3 nerve root. Lower panels were the right L3 nerve root. T2-weighted signal strength was reduced on the right side, but not on the left side, after ferumoxytol. (B) T2*-weighted MR images of the same subject. Images showing right L3 nerve root (white arrow) as it descends in the spinal canal. Upper pannels were MR images. Lower pannels were heat map–coded MR images. (C) MR image of the same subject at L4/5 level. Upper pannels were MR images. Lower pannels were heat map–coded MR images. Arrow indicates a small disc protrusion touching on the exiting right L4 nerve root and narrowing of the bilateral subarticular zone touching on the right descending L5 nerve roots at the L4/5 level. Figure 3 View largeDownload slide Ferumoxytol-contrasted magnetic resonance imaging (MRI) in clinical radicular pain secondary to intervertebral disc protrusion. (A) T2-weighted MR images of a human pain subject with clinical diagnosis of right L3 radiculitis before and after ferumoxytol administration. Upper panels were MR images. Middle panels were heat map–coded MR images; white arrow: right L3 nerve root; black arrow: left L3 nerve root. Lower panels were the right L3 nerve root. T2-weighted signal strength was reduced on the right side, but not on the left side, after ferumoxytol. (B) T2*-weighted MR images of the same subject. Images showing right L3 nerve root (white arrow) as it descends in the spinal canal. Upper pannels were MR images. Lower pannels were heat map–coded MR images. (C) MR image of the same subject at L4/5 level. Upper pannels were MR images. Lower pannels were heat map–coded MR images. Arrow indicates a small disc protrusion touching on the exiting right L4 nerve root and narrowing of the bilateral subarticular zone touching on the right descending L5 nerve roots at the L4/5 level. Figure 4 View largeDownload slide Ferumoxytol-contrasted magnetic resonance imaging (MRI) in a healthy subject. A subject without any pain symptoms underwent MR imaging study using the same protocol as pain subject. Upper panels were MR images; lower panels were heat map–coded MR images. There were no significant disc protrusions identified by conventional MR images. Heat map–coded MR images did not reveal signal strength changes around nerve roots before and after ferumoxytol administration. Figure 4 View largeDownload slide Ferumoxytol-contrasted magnetic resonance imaging (MRI) in a healthy subject. A subject without any pain symptoms underwent MR imaging study using the same protocol as pain subject. Upper panels were MR images; lower panels were heat map–coded MR images. There were no significant disc protrusions identified by conventional MR images. Heat map–coded MR images did not reveal signal strength changes around nerve roots before and after ferumoxytol administration. Discussion In this report, using an inflammatory pain animal model, we demonstrate that ferumoxytol MRI reveals tissue inflammation, which is not feasible with conventional MRI. In addition, proof-of-concept human study indicate that ferumoxytol MRI can identify the symptomatic neuronal tissue inflammation in lumbar radiculopathy. Pain has traditionally been categorized into neuropathic pain and inflammatory pain [10]. Neuropathic pain and inflammatory pain respond to treatment differently. Many pain conditions, including lumbar radiculopathy secondary to intervertebral disc protrusion, can have prominent inflammatory component [11, 12]. Epidural steroid injections (ESIs), delivering potent anti-inflammatory steroid medications to the epidural space where spinal nerve roots are located, are widely used to treat radicular pain, with varying degrees of success and also potential complications [13–16]. However, not all radicular pain responds to ESIs. Patients with radicular pain who do not benefit from epidural steroid injections may respond to neuropathic pain medications, suggesting inflammation may not be the only process leading to radicular pain. Thus it would be extremely valuable to determine whether inflammation is present in radicular pain before proceeding with ESIs. The ability to detect nerve root inflammation in vivo can provide crucial guidance to the treatment pathway selection. Ferumoxytol is clinically used to treat iron deficiency anemia. Off-label use of ferumoxytol as an MRI contrast agent has been reported as an alternative to gadolinium-based contrast agent [17]. For example, for patients with end-stage renal disease, ferumoxytol is used because it does not cause nephrogenic systemic fibrosis. Unlike gadolinium-based agents, which are nonspecific and do not reliably report tissue inflammation, ferumoxytol has been found to label infiltrating monocytes and macrophages in mouse glioblastoma [18], a critical prognostic factor for chemotherapy treatment response. In type 1 diabetes, the activation of mononuclear phagocytes is a critical factor in disease onset and progression. Nanoparticle-based MRI technology has provided major technological advancement in imaging pancreatic inflammation. Gaglia et al. recently showed that ferumoxytol MRI enables imaging of macrophage infiltration in the pancreas and leads to high-resolution mapping of pancreatic inflammation in type 1 diabetes patients [7, 19]. In this report, we took advantage of the uptake of USPIO by the macrophage-monocyte system and the subsequent signal loss effect on T2-weighted MR images to identify tissue inflammation. In an animal model of inflammatory pain caused by joint arthritis after CFA injection, we demonstrated that ferumoxytol-contrasted MRI can show significant changes in T2, consistent with inflammatory macrophage and monocyte infiltration in the tissue and the uptake of ferumoxytol by these cells. In this proof-of-concept human MRI study, we demonstrated that ferumoxytol MRI showed a loss of T2-weighted signal in a spinal nerve root that is concordant with the subject’s pain symptoms and clinical diagnosis, whereas structural abnormalities identified by conventional MRI had no correlation. Taken together, this study suggests that USPIO, such as ferumoxytol, may be able to detect pain-inducing inflammation in humans in vivo. This imaging approach may be superior to conventional structural MRI in identifying the anatomical source of pain caused by inflammation and providing guidance to interventional treatments. While results from this pilot animal study and single-patient clinical study are encouraging, future studies with more human subjects are warranted to examine the utility of ferumoxytol MRI in diagnosing different pain conditions in a large patient cohort. References 1 Jarvik JJ, Hollingworth W, Heagerty P, Haynor DR, Deyo RA. The Longitudinal Assessment of Imaging and Disability of the Back (LAIDBack) Study: Baseline data. Spine (Phila Pa 1976)  2001; 26 10: 1158– 66. http://dx.doi.org/10.1097/00007632-200105150-00014 Google Scholar CrossRef Search ADS PubMed  2 el Barzouhi A, Vleggeert-Lankamp CL, Lycklama à Nijeholt GJet al.  , Magnetic resonance imaging in follow-up assessment of sciatica. N Engl J Med  2013; 368 11: 999– 1007. Google Scholar CrossRef Search ADS PubMed  3 Neuwelt A, Sidhu N, Hu CAet al.  , Iron-based superparamagnetic nanoparticle contrast agents for MRI of infection and inflammation. AJR Am J Roentgenol  2015; 204 3: W302– 13. Google Scholar CrossRef Search ADS PubMed  4 Lamanna JJ, Gutierrez J, Urquia LNet al.  , Ferumoxytol labeling of human neural progenitor cells for diagnostic cellular tracking in the porcine spinal cord with magnetic resonance imaging. Stem Cells Transl Med  6 1: 139– 50. CrossRef Search ADS PubMed  5 Yang R, Sarkar S, Korchinski DJet al.  , MRI monitoring of monocytes to detect immune stimulating treatment response in brain tumor. Neuro Oncol  19 3: 364– 71. PubMed  6 Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods  1994; 53 1: 55– 63. http://dx.doi.org/10.1016/0165-0270(94)90144-9 Google Scholar CrossRef Search ADS PubMed  7 Gaglia JL, Harisinghani M, Aganj Iet al.  , Noninvasive mapping of pancreatic inflammation in recent-onset type-1 diabetes patients. Proc Natl Acad Sci U S A  2015; 112 7: 2139– 44. http://dx.doi.org/10.1073/pnas.1424993112 Google Scholar CrossRef Search ADS PubMed  8 Segond von Banchet G, Boettger MK, Fischer Net al.  , Experimental arthritis causes tumor necrosis factor-alpha-dependent infiltration of macrophages into rat dorsal root ganglia which correlates with pain-related behavior. Pain  2009; 145 1: 151– 9. http://dx.doi.org/10.1016/j.pain.2009.06.002 Google Scholar CrossRef Search ADS PubMed  9 Inglis JJ, Nissim A, Lees DMet al.  , The differential contribution of tumour necrosis factor to thermal and mechanical hyperalgesia during chronic inflammation. Arthritis Res Ther  2005; 7 4: R807– 16. Google Scholar CrossRef Search ADS PubMed  10 Backonja MM. Defining neuropathic pain. Anesth Analg  2003; 97 3: 785– 90. Google Scholar CrossRef Search ADS PubMed  11 Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci  2005; 6 7: 521– 32. http://dx.doi.org/10.1038/nrn1700 Google Scholar CrossRef Search ADS PubMed  12 Moalem G, Xu K, Yu L. T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience  2004; 129 3: 767– 77. http://dx.doi.org/10.1016/j.neuroscience.2004.08.035 Google Scholar CrossRef Search ADS PubMed  13 Bicket MC, Gupta A, Brown CHt, Cohen SP. Epidural injections for spinal pain: A systematic review and meta-analysis evaluating the “control” injections in randomized controlled trials. Anesthesiology  2013; 119 4: 907– 31. Google Scholar CrossRef Search ADS PubMed  14 Koes BW, Scholten RJPM, Mens JMA, Bouter LM. Efficacy of epidural steroid injections for low-back pain and sciatica: A systematic review of randomized clinical trials. Pain  1995; 63 3: 279– 88. http://dx.doi.org/10.1016/0304-3959(95)00124-7 Google Scholar CrossRef Search ADS PubMed  15 Armon C, Argoff CE, Samuels Jet al.  , Assessment: Use of epidural steroid injections to treat radicular lumbosacral pain: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology  2007; 68 10: 723– 9. http://dx.doi.org/10.1212/01.wnl.0000256734.34238.e7 Google Scholar CrossRef Search ADS PubMed  16 Abdi S, Datta S, Trescot AMet al.  , Epidural steroids in the management of chronic spinal pain: A systematic review. Pain Physician  2007; 10 1: 185– 212. Google Scholar PubMed  17 Neuwelt EA, Hamilton BE, Varallyay CGet al.  , Ultrasmall superparamagnetic iron oxides (USPIOs): A future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int  2009; 75 5: 465– 74. Google Scholar CrossRef Search ADS PubMed  18 Deng L, Stafford JH, Liu S-Cet al.  , SDF-1 blockade enhances anti-VEGF therapy of glioblastoma and can be monitored by MRI. Neoplasia  2017; 19 1: 1– 7. http://dx.doi.org/10.1016/j.neo.2016.11.010 Google Scholar CrossRef Search ADS PubMed  19 Gaglia JL, Guimaraes AR, Harisinghani Met al.  , Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients. J Clin Invest  2011; 121 1: 442– 5. http://dx.doi.org/10.1172/JCI44339 Google Scholar CrossRef Search ADS PubMed  © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
TI - Ultrasmall Superparamagnetic Iron Oxide Imaging Identifies Tissue and Nerve Inflammation in Pain Conditions
JF - Pain Medicine
DO - 10.1093/pm/pnx267
DA - 2018-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/ultrasmall-superparamagnetic-iron-oxide-imaging-identifies-tissue-and-AkYvmdm7mf
SP - 686
EP - 692
VL - 19
IS - 4
DP - DeepDyve
ER -