Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with Mucopolysaccharidosis type VII.

Mucopolysaccharidosis type VII (MPS7) is a lysosomal storage disorder (LSD) resulting from mutations in the ß-glucuronidase gene, leading to multiorgan dysfunction and fetal demise. While postnatal enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation have resulted in some phenotypic improvements, prenatal treatment might take advantage of a unique developmental window to penetrate the blood-brain barrier or induce tolerance to the missing protein, addressing two important shortcomings of postnatal therapy for multiple LSDs. We performed in utero ERT (IUERT) at E14.5 in MPS7 mice and improved survival of affected mice to birth. IUERT penetrated brain microglia, whereas postnatal administration did not, and neurological testing (after IUERT plus postnatal administration) showed decreased microglial inflammation and improved grip strength in treated mice. IUERT prevented antienzyme antibody development even after multiple repeated postnatal challenges. To test a more durable treatment strategy, we performed in utero hematopoietic stem cell transplantation (IUHCT) using congenic CX3C chemokine receptor 1-green fluorescent protein (CX3CR1-GFP) mice as donors, such that donor-derived microglia are identified by GFP expression. In wild-type recipients, hematopoietic chimerism resulted in microglial engraftment throughout the brain without irradiation or conditioning; the transcriptomes of donor and host microglia were similar. IUHCT in MPS7 mice enabled cross-correction of liver Kupffer cells and improved phenotype in multiple tissues. Engrafted microglia were seen in chimeric mice, with decreased inflammation near donor microglia. These results suggest that fetal therapy with IUERT and/or IUHCT could overcome the shortcomings of current treatment strategies to improve phenotype in MPS7 and other LSDs.

Molecular detection of inflammation in cell models using hyperpolarized 13C-pyruvate.

The detection and treatment monitoring of inflammatory states remain challenging in part due to the multifactorial mechanisms of immune activation and spectrum of clinical manifestations. Currently, diagnostic strategies tend to be subjective and limited quantitative tools exist to monitor optimal treatment strategies. Pro-inflammatory M1 polarized macrophages exhibit a distinct metabolic glycolytic phenotype compared to the continuum of M2 polarization states. In the present study, the distinct metabolic phenotypes of resting and activated macrophages were successfully characterized and quantified using hyperpolarized carbon-13 (13C) labeled pyruvate and its metabolic products, i.e. lactate, as a biomarker of resting, disease and treated states. Methods: Mouse macrophage J774A.1 cells were used as a model system in an NMR compatible bioreactor to facilitate dynamic hyperpolarized 13C measurements. The glycolytic metabolism of the cells in the quiescent or resting state were compared with macrophages stimulated by lipopolysaccharide, a classical M1 activator using hyperpolarized 13C labeled pyruvate. Additionally, the activated macrophages were also treated with a non-steroidal anti-inflammatory drug to assess the changes in hyperpolarized lactate signal. The hyperpolarized lactate signals were then correlated using biochemical and molecular assays. Results: We first validated our model system of inflammatory cells by the hallmarks of M1 polarization using steady state metabolic profiling with high resolution NMR in conjunction with nitric oxide Greiss assay, enzyme activity, and mRNA expression. Subsequently, we clearly showed that the cutting edge technology of hyperpolarized 13C NMR can be used to detect elevated lactate levels in M1 polarized macrophages in comparison to control and non-steroidal anti-inflammatory drug treated M2 states. Conclusion: Hyperpolarized 13C lactate has the potential to serve as a biomarker to non-invasively detect and quantify pro-inflammatory state of immune regulatory cells and its response to therapy.

Pediatric renal transplant biopsy with ultrasound guidance: the 'core' essentials.

This review provides a comprehensive and practical approach to pediatric percutaneous renal transplant biopsies, highlighting techniques and strategies to optimize adequate sample yield and ensure patient safety. In children with end-stage renal disease, transplantation is the preferred choice of therapy, providing for overall lower long-term morbidity and mortality compared with dialysis. In the ongoing management of renal transplant patients, core tissue sampling via a percutaneous renal biopsy remains the gold standard when transplant dysfunction is suspected. Indications for renal transplant biopsy and techniques/tools for adequate sample yield are discussed. Strategies for common challenges such as poor visualization and renal transplant mobility are addressed. We discuss the clinical signs, techniques and imaging findings for common complications including hematomas, arteriovenous fistulas and pseudoaneurysms. Although the percutaneous renal transplant biopsy procedure is generally safe with rare complications, care must be taken to ensure major complications are promptly recognized and treated. Adequate tissue samples obtained via renal biopsy are imperative to promptly identify transplant rejection to provide valuable information for patient diagnosis, treatment and outcomes. Radiologist and nephrologist attention to proper ultrasound techniques and optimal biopsy tools are critical to ensure tissue adequacy and minimize complications.

Intravoxel incoherent motion analysis of renal allograft diffusion with clinical and histopathological correlation in pediatric kidney transplant patients: A preliminary cross-sectional observational study.

The purpose of this study was to compare IVIM values in pediatric renal transplants with histopathology and clinical management change. Fifteen pediatric renal transplant recipients (mean 15.7±2.9 years) were prospectively scanned on a 3T MR scanner with multi-b DTI, prior to same-day transplant biopsy. IVIM maps from 14 subjects were analyzed (one excluded due to motion). Mean values were computed from cortical ROIs and medullary ROIs corresponding to the biopsy site. Subjects were also grouped according to whether or not the biopsy resulted in a change in clinical management. Cortico-medullary IVIM estimates and histopathologic Banff scores were correlated with KT. Cortico-medullary IVIM differences between the "change" and "no change" groups was compared with Mann-Whitney U test. Cortical Dp showed significant moderate negative correlation with Banff t and ci scores (KT=-0.497, P=.035 and KT=-0.46, P=.046) and moderate positive correlation with Banff i score (KT=0.527, P=.028). Cortical Pf showed significant moderate correlation with ci and ct scores (KT=0.489, P=.035 and KT=0.457, P=.043). Tissue diffusivity, Dt , estimated with IVIM was significantly different between the "change" and "no change" groups in medullary ROIs (U=6, P=.021). IVIM analysis has potential as a noninvasive biomarker in assessment of pediatric renal allograft pathology.

Pilot Study of Renal Diffusion Tensor Imaging as a Correlate to Histopathology in Pediatric Renal Allografts.

OBJECTIVE: Fractional anisotropy (FA) is a measure of molecular motion obtained from diffusion tensor imaging (DTI). The objective of this study was to assess the use of FA as a noninvasive correlate of renal allograft histopathology. SUBJECTS AND METHODS: Sixteen pediatric renal allograft recipients were imaged using DTI in a prospective study, between October 2014 and January 2016, before a same-day renal allograft biopsy. The Kendall tau correlation coefficient was used to assess the relationship between cortical and medullary FA values and several clinically important Banff renal allograft histopathology scores. The Mann-Whitney U test was also used to compare cortical and medullary FA values in the region of biopsy in patients whose biopsy results did and in those whose biopsy results did not change clinical management. RESULTS: Medullary FA values had direct inverse correlation with several histopathology scores: tubulitis (designated "t" score in Banff pathologic classification, p < 0.04), interstitial inflammation (i score, p < 0.005), tubular atrophy (ct score, p < 0.002), and interstitial fibrosis (ci score, p < 0.007). Cortical FA values inversely correlated with peritubular capillaritis (ptc score, p < 0.02). Neither medullary nor cortical FA values correlated with glomerulitis (g score). At a b value of 800 s/mm2, medullary FA values of pediatric renal allograft recipients whose renal biopsies prompted a change in clinical management (mean ± SD at a b value of 800 s/mm2 = 0.262 ± 0.07; n = 9) were statistically different compared with the group whose biopsy results did not change clinical management (mean ± SD at a b value of 800 s/mm2 = 0.333 ± 0.06; n = 7) (p < 0.006). CONCLUSION: FA is a noninvasive correlate of several important renal allograft histopathology scores and a potential noninvasive method of assessing renal allograft health in pediatric allograft recipients.

Pediatric chest CT at chest radiograph doses: when is the ultralow-dose chest CT clinically appropriate?

PURPOSE: Computed tomography (CT) use in emergency departments represents a significant contribution to pediatric patients' exposure to ionizing radiation. Here, we evaluate whether ultralow-dose chest CT can be diagnostically adequate for other diagnoses and whether model-based iterative reconstruction (MBIR) can improve diagnostic adequacy compared to adaptive statistical iterative reconstruction (ASIR) at ultralow doses. METHODS: Twenty children underwent chest CTs: 10 standard-dose reconstructed with ASIR and 10 ultralow-dose reconstructed with ASIR and MBIR. Four radiologists assessed images for their adequacy to exclude five hypothetical diagnoses: foreign body, fracture, lung metastasis, pulmonary infection, and interstitial lung disease. Additionally, pairwise comparison for subjective image quality was used to compare ultralow-dose chest CT with ASIR and MBIR. Radiation dose and objective image noise measures were obtained. RESULTS: For exclusion of an airway foreign body, the adequacy of ultralow-dose CT was comparable to standard-dose (p = 0.6). For the remaining diagnoses, ultralow-dose CT was inferior to standard-dose (p = 0.03-<0.001). MBIR partially recovered the adequacy of ultralow-dose CT to exclude pulmonary infection (p = 0.017), but was suboptimal for the other diagnoses. Image noise was significantly lower with MBIR compared to ASIR in ultralow-dose CT (p < 0.001), although subjective preference showed only a slight advantage of MBIR (58 versus 42%). CONCLUSIONS: Ultralow-dose chest CT may be adequate for airway assessment, but suboptimal for the evaluation parenchymal lung disease. Although MBIR improves objective and subjective image quality, it does not completely restore the diagnostic adequacy of ultralow-dose CT when compared to standard-dose CT.

Ultrasound elastography: is there a shear wave speed cutoff for pediatric liver fibrosis and inflammation?

OBJECTIVE: The objective was to identify a shear wave speed (SWS) cutoff in pediatric liver disease to detect fibrosis and inflammation. METHODS: We performed an institutional-review-board-approved prospective study of liver SWS in 41 children undergoing liver biopsy. RESULTS: In patients without inflammation, SWS was higher when fibrosis was present compared to when fibrosis was not present (average SWS 1.8 vs. 1.4 m/s, respectively, P=.02). A SWS cutoff of 1.7 m/s had 100% positive predictive value and 24% negative predictive value for detecting fibrosis or inflammation. CONCLUSION: Point shear wave elastography is an insufficient stand-alone screening tool for liver fibrosis and inflammation in a heterogeneous patient population.

Detection of bowel inflammation with fused DWI/T2 images versus contrast-enhanced images in pediatric MR enterography with histopathologic correlation.

PURPOSE: To evaluate the fused, colorized diffusion weighted imaging (DWI) and anatomic T2 images compared to routine contrast-enhanced T1 images at pediatric magnetic resonance enterography (MRE). METHODS: Fused, colorized DWI/T2 images were created from patients with magnetic resonance enterography (MRE) and colonoscopy/biopsy. Radiologists noted inflammation in five bowel segments (terminal ileum-rectosigmoid colon) on postcontrast images and DWI/T2 images. Test characteristics and agreement were calculated. RESULTS: For 20 patients, sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) were 0.53/0.90/0.77/0.76 for DWI/T2 and 0.45/0.90/0.72/0.73 for postcontrast images. Intraobserver agreement was Ò¡=0.45-0.73. Interobserver agreement was Ò¡=0.53 for DWI/T2 and Ò¡=0.63 for postcontrast images. CONCLUSION: DWI/T2 images are similar in sensitivity/specificity to contrast-enhanced images and with moderate intra/interobserver reliability.

Premature physeal closure following 13-cis-retinoic acid and prolonged fenretinide administration in neuroblastoma.

Retinoid therapy has contributed to improved outcomes in neuroblastoma. Clinical trials of fenretinide report favorable toxicity and disease stabilization in patients with high risk (HR) neuroblastoma. Skeletal effects have been described with other retinoids, but not with fenretinide to date. Two patients with HR, metastatic, refractory neuroblastoma received protracted courses of oral fenretinide for more than 5 years' duration. Both developed premature long bone physeal closure, causing limb length discrepancies; their neuroblastoma remains in remission. The radiographic and clinical findings reported suggest these skeletal abnormalities may be a consequence of treatment with 13-cis-retinoic acid (13cisRA) followed by prolonged oral fenretinide exposure.

How Much Does Lead Shielding during Fluoroscopy Reduce Radiation Dose to Out-of-Field Body Parts?

BACKGROUND: Fluoroscopy technologists routinely place a lead shield between the x-ray table and the patient's gonads, even if the gonads are not directly in the x-ray field. Internal scatter radiation is the greatest source of radiation to out-of-field body parts, but a shield placed between the patient and the x-ray source will not block internal scatter. Prior nonfluoroscopy research has shown that there is a small reduction in radiation dose when shielding the leakage radiation that penetrates through the collimator shutters. The goal of this in vitro study was to determine if there was any radiation dose reduction when shielding leakage radiation during fluoroscopy. METHODS: This was an in vitro comparison study of radiation doses using different collimation and shielding strategies during fluoroscopy. Ionization chamber measurements were obtained during fluoroscopy of an acrylic block with and without collimation and shielding. Ionization chamber readings were taken in-field at 0 cm and out-of-field at 7.5, 10, and 12.5 cm from beam center. RESULTS: Collimation reduced 87% of the out-of-field radiation dose, and the remaining measurable dose was because of internal scatter. The radiation dose contribution from leakage radiation was negligible, as there was not any measurable radiation dose difference when shielding leakage radiation, with P value of .48. CONCLUSION: These results call into question the clinical utility of routinely shielding out-of-field body parts during fluoroscopy.

Nonanesthesia magnetic resonance enterography in young children: feasibility, technique, and performance.

OBJECTIVES: The aim of the present study was to demonstrate the effectiveness and cost savings of a nonanesthesia approach to magnetic resonance enterography (MRE) in 14 young pediatric patients (age 4-7 years) with clinically suspected early-onset inflammatory bowel disease using an MRE protocol. METHODS: MRE was performed using a combination of an abbreviated imaging protocol, magnetic resonance imaging video goggles, and Child Life Services support. MRE results were correlated with both colonoscopy and pathology results using Pearson correlation coefficient. Sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: MRE was performed successfully in 13 of 14 patients (age range 4 years 0 months to 7 years 6 months). MRE findings matched with results in 12 of 13 patients in whom colonoscopy was successfully performed. Both MRE and colonoscopy demonstrated a high specificity (100%) and a positive predictive value (100%), but a low sensitivity (43%) and a negative predictive value (50%). CONCLUSIONS: MRE can be successfully performed in children ages 4 to 7 years using this approach. In addition to decreased risks to the child, the lack of anesthesia also offers a potential overall cost reduction.

Scrotal swelling in the neonate.

Discovery of scrotal swelling in a neonate can be a source of anxiety for parents, clinicians, and sonologists alike. This pictorial essay provides a focused review of commonly encountered scrotal masses and mimics specific to the neonatal setting. Although malignancy is a concern, it is very uncommon, as most neonatal scrotal masses are benign. Key discriminating features and management options are highlighted to improve the radiologist's ability to diagnose neonatal scrotal conditions and guide treatment decisions. Neonatal scrotal processes ranging from common to uncommon will be discussed.

Magnetic resonance imaging findings in juvenile spondyloarthropathy and effects of treatment observed on subsequent imaging.

BACKGROUND: Magnetic resonance imaging (MRI) is often used to diagnose and monitor treatment effects of juvenile spondyloarthropathy (SpA). Our objective was to describe MRI findings in juvenile SpA and determine predictors of active sacroiliitis and response to treatment. METHODS: Children who had MRI of the sacroiliac (SI) joints and were referred to the pediatric rheumatology clinic from 2009 to 2012 were retrospectively studied. The clinical parameters, laboratory studies and findings on MRI were collected and a composite score ratio (CR) was calculated for both SI joints on each MRI study based on a semi-quantitative scale that included evaluation of bone marrow edema (BME), synovial enhancement (SE), and erosions (ER). The findings on MRI were correlated with clinical and laboratory values. RESULTS: 50 subjects who underwent 76 MRI for suspected or known SpA were included in the study. Sacroiliitis was seen in 48 MRIs in 32 subjects. Of the subjects with sacroiliitis, mean age ± standard deviation was 13.7 ± 2.6 years, 71% were male and 41% were HLA B27 positive. SE without BME was seen in 31% cases of sacroiliitis. In subjects with sacroiliitis, 79% also had hip arthritis and 41% had enthesitis of the pelvic region on MRI. In 38% of subjects with sacroiliitis, physical exam was not indicative of sacroiliitis or hip arthritis. Longitudinal data were available for 13 subjects. Sacroiliitis on MRI improved in 9 subjects with the greatest improvement in MRI composite score ratio after initiation of etanercept therapy. CR improvement was due to improvement of BME and SE components, while the ER score remained the same or worsened in all but 1 subject. CONCLUSION: History, physical exam or laboratory data may not predict sacroiliitis in children. Magnetic resonance imaging plays a valuable role in the initial evaluation and later treatment monitoring of children with spondyloarthropathy. Synovial enhancement is significantly reduced after treatment, and unlike adults, synovial enhancement may be detected without accompanying bone marrow edema, which suggests gadolinium contrast may be an important component in the assessment of children with spondyloarthropathy.

Intra-abdominal inverted umblical cord in gastroschisis: a unique ultrasound finding.

A relatively new surgical technique allows for sutureless closure of a gastroschisis defect. Immediately after birth, a long umbilical cord stump is temporarily inverted into the abdominal cavity and later retracted and used to close the abdominal wall defect. Knowledge of this entity is important since the inverted umbilical cord simulates an intra-abdominal mass on cross-sectional imaging. While this procedure is well described in the surgical literature, the imaging features of inverted umbilical cord have yet to be reported. The case presented here highlights the sonographic imaging findings of the umbilical cord during the intestinal decompression phase of sutureless repair of gastroschisis.

Radiation dose reduction in pediatric CT-guided musculoskeletal procedures.

BACKGROUND: Computed-tomography-guided interventions are attractive for tissue sampling of pediatric bone lesions; however, it comes with exposure to ionizing radiation, inherent to CT and magnified by multiple passes during needle localization. OBJECTIVE: We evaluate a method of CT-guided bone biopsy that minimizes ionizing radiation exposure by lowering CT scanner tube current (mAs) and voltage (kVp) during each localization scan. MATERIALS AND METHODS: We retrospectively reviewed all CT-guided bone biopsies (n = 13) over a 1-year period in 12 children. Three blinded readers identified the needle tip on the reduced-dose CT images (mAs = 50, kVp = 80) during the final localization scan at biopsy and rated the image quality as high, moderate or low. RESULTS: The image quality of the reduced-dose scans during biopsy was rated as either high or moderate, with needle tip visualized in 12 out of 13 biopsies. Twelve of 13 biopsies also returned sufficient sample for a pathological diagnosis. The average savings in exposure using the dose-reduction technique was 87%. CONCLUSION: Our results suggest that a low mAs and kVp strategy for needle localization during CT-guided bone biopsy yields a large dose reduction and produces acceptable image quality without sacrificing yield for biopsy diagnosis.

Ureteral fibroepithelial polyp causing urinary obstruction.

Ureteral polyps are rare causes of ureteropelvic junction (UPJ) obstruction, particularly in children. We report a nine year-old boy with UPJ obstruction initially suggestive of an obstructive urinary stone. CT showed intraureteral calcification at the UPJ and hydronephrosis. A retrograde pyelogram showed narrowing at the UPJ and partial obstruction that was found to be a ureteral polyp. This case illustrates a rare cause of UPJ obstruction that should be considered when the imaging findings and presentation are atypical for more common etiologies of ureteral obstruction.

Primary mixed malignant tumor of bone in an 18-year-old male: Report of a case with radiologic-pathologic correlation.

We report a case of primary malignant mixed tumor (MMT) of bone in an 18-year-old boy with X-ray, CT, MR, scintigraphic, FDG PET, and pathologic correlation. Primary MMT of bone is a highly aggressive tumor and presents both a diagnostic and clinical treatment challenge. This tumor is extremely rare and to the best of our knowledge, this is the first report of the diagnostic imaging findings for primary MMT arising from bone in a patient of this age group.

Scapular stress fracture initially masquerading as tumor or infection.

We present a case of a scapular stress fracture in a 17-year-old athletic male that was initially thought to be a neoplasm. Radiographs showed a lesion at the neck of the glenoid with aggressive features. A subsequent MRI and bone scan supported a diagnosis of either tumor or infection. However, before a scheduled bone biopsy, a screening chest CT for pulmonary metastases revealed features of a healing stress fracture. The patient ceased intense athletic activity and four weeks later experienced a continued decrease in shoulder symptoms. A followup shoulder CT confirmed a healing fracture. This case illustrates how a stress fracture at an uncommon location may mimic a neoplasm. CT provides complementary information to radiography and MRI and helps establish a definitive diagnosis.

MRI of HAGL lesions: four arthroscopically confirmed cases of false-positive diagnosis.

OBJECTIVE: The purpose of this article is to present the cases of four consecutive patients with preoperative MR diagnosis of humeral avulsion of the glenohumeral ligament (HAGL) who had no evidence of HAGL at arthroscopy. CONCLUSION: These four cases suggest that the diagnosis of HAGL should be reserved for arthroscopy and illustrate the difficulty in distinguishing HAGL from other abnormalities of the inferior glenohumeral ligament complex with MRI. Thus, MRI findings classically associated with HAGL should be more broadly described as defects of the inferior glenohumeral ligament complex. This terminology more accurately describes the abnormalities of the inferior glenohumeral ligament complex that may be depicted by MRI.