Ultrasound evaluation of brain parenchyma in preterm infants with prenatal opioid exposure.

OBJECTIVE: To evaluate whether preterm infants with prenatal opioid exposure had differences in brain size on head ultrasounds (HUS) in comparison to non-exposed infants. STUDY DESIGN: Preterm infants ≤34 weeks with prenatal opioid exposure (n = 47) and matched non-exposed infants (n = 62) with early HUSs were examined. Fifteen brain measurements were made and linear regression models performed to evaluate differences. RESULTS: Brain measurements were smaller in the right ventricular index [ß = -0.18 mm (95% CI -0.32, -0.03]), left ventricular index [ß = -0.04 mm (95% CI -0.08, -0.003)], left basal ganglia insula [ß = -0.10 mm (95% CI -0.15, -0.04)], right basal ganglia insula [ß = -0.08 mm (95% CI -0.14, -0.03)], corpus callosum fastigium length [ß = -0.16 mm (95% CI -0.25, -0.06)], intracranial height index [ß = -0.31 mm (95% CI -0.44, -0.18)], and transcerebellar measurements [ß = -0.13 (95% CI -0.25, -0.02)] in the opioid-exposed group. CONCLUSIONS: Preterm infants with prenatal opioid exposure have smaller brain sizes compared to non-exposed infants, potentially increasing their risk for neurodevelopmental abnormalities.

Utilization of a two-material decomposition from a single-source, dual-energy CT in acute traumatic vertebral fractures.

Purpose: The purpose of this study is to utilize a two-material decomposition to quantify bone marrow edema on a dual-energy computed tomography (DECT) scanner at the cervical, thoracic, and lumbar spine acute fractures in correlation with short tau inversion recovery (STIR) hyperintensity on magnetic resonance imaging (MRI) in comparison with the normal bone marrow. Materials and methods: This retrospective institutional review board-approved study gathered patients over 18 years old who had acute cervical, thoracic, or lumbar spinal fractures scanned on a DECT scanner. Those who had a spinal MRI done with bone marrow STIR hyperintensity within 3 weeks of the DECT were included. The water (calcium) and fat (calcium) density (mg/cm3) measurements of the region of interest of the bone marrow were obtained at a normal anatomic equivalent site and at the fracture site where STIR hyperintensity was noted on MRI. A statistical analysis was performed using the paired t-test and Wilcoxon signed rank test (p > 0.05). Results: A total of 20 patients met the inclusion criteria (males n = 17 males, females n = 3). A total of 32 fractures were analyzed: 19 cervical and 13 thoracolumbar. There were statistically significant differences in the water (43 ± 24 mg/cm3) and fat (36 ± 31 mg/cm3) density (mg/cm3) at the acute thoracic and lumbar spine fractures in correlation with edema on STIR images (both paired t-test <0.001, both Wilcoxon signed ranked test p < 0.01). There were no significant differences in the water (-10 ± 46 mg/cm3) or fat (+7 ± 50 mg/cm3) density (mg/cm3) at the cervical spine fractures. Conclusion: The DECT two-material decomposition using water (calcium) and fat (calcium) analyses has the ability to quantify a bone marrow edema at the acute fracture site in the thoracic and lumbar spine.

Percutaneous nephrostomy placement in pregnant patients: a retrospective single center experience.

PURPOSE: Literature on percutaneous nephrostomy (PCN) placement in pregnant patients is limited. The purpose of this case series of 20 pregnant patients was to report short term maternal and fetal outcomes in this population. MATERIALS AND METHODS: A 12-year retrospective study was performed on pregnant patients undergoing PCN. Clinical indications, technical success, maternal outcome, fetal outcome, and complications were obtained from the electronic medical record. RESULTS: Indications for PCN placement included urolithiasis (40%), congenital ureteral dysfunction in the setting of prior ureteral repair (30%), obstruction associated pain (15%), infection (10%), and ureteral injury in the setting of surgery for ovarian torsion (5%). Catheter insertion was successful in all patients (n = 20), with one major complication (urosepsis). Follow up data was available in 19 patients (95%). Catheters were in situ for a median of 82 days. All patients had clinical and symptomatic improvement. Emergency C-sections were required in two cases. Radiation exposure data were available in 15 of 19 patients and revealed a median fluoroscopy time of 2.8 min, median cumulative dose of 43 mGy, and median dose area product of 635 µGy × m2. No adverse fetal outcomes were recorded at time of delivery. CONCLUSION: PCN placement has good clinical results as a treatment option for ureteral obstruction in a pregnant cohort.

Single center experience with ultrasound guided axillary vein port placement.

PURPOSE: To retrospectively review a single institution experience of ultrasound guided axillary vein port placement. METHODS: In this retrospective study, a patient list was generated after searching our internal database from 1/1/2012 to 10/1/2018. Patients who had undergone axillary vein port placement were included. Chart review was performed to confirm approach, laterality and to gather demographic data, clinical indications, technical outcomes, and complications. Descriptive statistics were used to analyze this cohort. Chi-square statistics were used to compare outcomes by laterality. RESULTS: Three hundred seven patients (51% female) with an average age of 58 years were included. The port was placed via the right axillary vein in 85% (261/307), predominantly for the indication of chemotherapy access (296/307). Technical success was achieved in all 307 cases. Peri procedural complications occurred in 1% (4/307) of cases and included port malpositioning requiring replacement and a case of port pocket hematoma. Post procedural complications including deep vein thrombosis and port malfunction occurred in 17% (52/307) of cases and port removal as a result of complication occurred in 9% (29/307) of cases. CONCLUSIONS: Ultrasound guided placement of an axillary port is a safe procedure to perform and demonstrates good clinical outcomes.

Pediatric Congenital Lung Malformations: Imaging Guidelines and Recommendations.

Congenital lung malformations are a spectrum of developmental anomalies comprised of malformations of the lung parenchyma, airways, and vasculature. Imaging assessment plays a pivotal role in the initial diagnosis, management, and follow-up evaluation of congenital lung malformations in the pediatric population. However, there is currently a lack of practical imaging guidelines and recommendations for the diagnostic imaging assessment of congenital lung malformations in infants and children. This article reviews the current evidence regarding the imaging evaluation of congenital lung malformations and provides up-to-date imaging recommendations for pediatric congenital lung malformations.

Thoracic CTA in infants and young children: Image quality of dual-source CT (DSCT) with high-pitch spiral scan mode (turbo flash spiral mode) with or without general anesthesia with free-breathing technique.

PURPOSE: To determine whether diagnostic quality thoracic computed tomography angiography (CTA) studies can be obtained without general anesthesia (GA) in infants and young children using dual-source computed tomography (DSCT) with turbo flash spiral mode (TFSM) and free-breathing technique. MATERIALS AND METHODS: All consecutive infants and young children (≤ 6 years old) who underwent thoracic CTA studies from January 2018 to October 2020 for suspected congenital thoracic disorders were categorized into two groups: with GA (Group 1) and without GA (Group 2). All thoracic CTA studies were performed on a DSCT scanner using TFSM and free-breathing technique. Two pediatric thoracic radiologists independently evaluated motion artifact in three lung zones (upper, mid, and lower). Degree of motion artifact was graded 0-3 (0, none; 1, mild; 2, moderate; and 3, severe). Logistic models adjusted for age and gender were used to compare the degree of motion artifact between lung zones. Interobserver agreement between reviewers was evaluated with kappa statistics. RESULTS: There were a total of 73 pediatric patients (43 males (59%) and 30 females (41%); mean age, 1.4 years; range, 0-5.9 years). Among these 73 patients, 42 patients (58%) underwent thoracic CTA studies with GA (Group 1) and the remaining 31 patients (42%) underwent thoracic CTA studies without GA (Group 2). Overall, the degree of motion artifact was higher for Group 2 (without GA). However, only a very small minority (1/31, 3%) of Group 2 (without GA) thoracic CTA studies had severe motion artifact. There was no significant difference between the two groups with respect to the presence of severe motion artifact (odds ratio [OR] = 6, p = .222). When two groups were compared with respect to the presence of motion artifact for individual lung zones, motion artifact was significantly higher in the upper lung zone for Group 2 (without GA) (OR = 20, p = .043). Interobserver agreement for motion artifact was high, the average Kappa being 0.81 for Group 1 and 0.95 for Group 2. CONCLUSION: Although the degree of motion artifact was higher in the group without GA, only a small minority (3%) of thoracic CTA studies performed without GA had severe motion artifact, rendering the study nondiagnostic. Therefore, the results of this study support the use of thoracic CTA without GA using DSCT with TFSM and free-breathing in infants and young children. In addition, given that motion artifact was significantly higher in the upper lung zone without GA, increased stabilization in the upper chest and extremities should be considered.

Choledochal Cyst or Benign Biliary Dilation: Is Resection Always Necessary?

BACKGROUND: Choledochal cysts (CC) are often diagnosed during the first few decades of life, when, due to the risk of malignancy, resection is advised. With an increasing number of patients undergoing abdominal imaging, many older patients have recently been radiographically diagnosed with biliary duct enlargement that meets the criteria of choledochal cysts. The management in these patients is less well defined, but resection is often recommended as it is for younger patients. We sought to better understand the significance of these biliary duct anomalies in adults. METHODS: We retrospectively reviewed all patients 18 years and older at our institution, who were given a radiographic diagnosis of choledochal cyst during the interval 2006-2019. Demographics, comorbidities, complications, readmissions, and follow-up imaging were evaluated. RESULTS: We identified 22 patients, of whom 40.9% (n = 9) underwent an operation. The remainder was observed. Median duct size was 15 mm (range 2-25 mm). There were no significant differences in demographics between the two cohorts. Of those who underwent resection, none had evidence of high-grade dysplasia or invasive carcinoma upon final pathology. However, 33.3% (n = 3) had subsequent readmissions for complications, including post-operative nausea and vomiting, cholangitis, and anastomotic stenoses that required stenting. In the observation group, there was no obvious growth of the cysts or development of worrisome features to suggest malignant degeneration (median follow-up = 68 months). CONCLUSION: A radiographic diagnosis of choledochal cyst in older adults is likely a different entity than those diagnosed in childhood. Close surveillance of these biliary duct anomalies in older adults may be a better option than resection and reconstruction with the associated risks of long-term morbidity.

Imaging for Pulmonary Embolism in Sickle Cell Disease: A 17-Year Experience.

Sickle cell disease, a complex disorder with known pulmonary complications, has the potential to confound the diagnosis of pulmonary embolism. We hypothesized that when the choice of imaging is guided by chest radiographic results, CT pulmonary angiography (CTPA) and ventilation-perfusion (V/Q) scintigraphy have comparable diagnostic performance in sickle cell disease. Methods: A retrospective cohort of adults with sickle cell disease who were imaged for suspected pulmonary embolism with either CTPA or V/Q, from 2000 to 2016 at our institution, was established. To reduce radiation exposure, our practice recommends V/Q for stable patients with normal chest radiographs. Results of index pulmonary embolism imaging, 90-d follow-up, and results of chest radiography were recorded. Results: Two hundred forty-five adults with sickle cell disease comprised the cohort. The mean age (±SD) was 33 ± 10.5 y, and 58% (141) were men. Index imaging was V/Q in 62.9% (n = 154) and CTPA in 37.1% (n = 91). Chest radiographs, performed in 96.3% (n = 236), were normal in 72.9% (n = 172). Imaging results for pulmonary embolism were negative in 88.2% (n = 216), positive in 4.1% (n = 10), and indeterminate in 7.8% (n = 19) with no difference between V/Q and CTPA (P = 0.63). Reimaging within 90 d occurred in 9.8% (n = 24), 14.7% (20/136) after initial V/Q, and 5% (4/109) after initial CTPA (P = 0.08). Reimaging revealed a pulmonary embolism diagnosis after negative/indeterminate results in 0.7% (1/149) of V/Qs and 1.2% of (1/86) CTPAs (P = 0.69). Over the 17-y study period, 47% (114/245) underwent repeated imaging, and 11% (27/245) were diagnosed with pulmonary embolism at least once. Conclusion: In sickle cell disease patients with suspected pulmonary embolism, positive imaging rates were low for any given clinical presentation, but 11% of the cohort was diagnosed with pulmonary embolism over the 17-y study period. CTPA and V/Q performed comparably for pulmonary embolism diagnosis when the choice of imaging was guided by results of chest radiography. Hence, V/Q is a reasonable first choice for sickle cell disease patients with normal chest radiographs.

Epigenetically Aberrant Stroma in MDS Propagates Disease via Wnt/ß-Catenin Activation.

The bone marrow microenvironment influences malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. In addition, the role of the bone marrow stroma in regulating clinical responses to DNA methyltransferase inhibitors (DNMTi) is also poorly understood. In this study, we conducted a DNA methylome analysis of bone marrow-derived stromal cells from myelodysplastic syndrome (MDS) patients and observed widespread aberrant cytosine hypermethylation occurring preferentially outside CpG islands. Stroma derived from 5-azacytidine-treated patients lacked aberrant methylation and DNMTi treatment of primary MDS stroma enhanced its ability to support erythroid differentiation. An integrative expression analysis revealed that the WNT pathway antagonist FRZB was aberrantly hypermethylated and underexpressed in MDS stroma. This result was confirmed in an independent set of sorted, primary MDS-derived mesenchymal cells. We documented a WNT/ß-catenin activation signature in CD34+ cells from advanced cases of MDS, where it associated with adverse prognosis. Constitutive activation of ß-catenin in hematopoietic cells yielded lethal myeloid disease in a NUP98-HOXD13 mouse model of MDS, confirming its role in disease progression. Our results define novel epigenetic changes in the bone marrow microenvironment, which lead to ß-catenin activation and disease progression of MDS. Cancer Res; 77(18); 4846-57. ©2017 AACR.

Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells.

The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis. Gene expression profiling of SYNCRIP-depleted cells demonstrated a loss of the MLL and HOXA9 leukemia stem cell program. SYNCRIP and MSI2 interact indirectly though shared mRNA targets. SYNCRIP maintains HOXA9 translation, and MSI2 or HOXA9 overexpression rescued the effects of SYNCRIP depletion. Altogether, our data identify SYNCRIP as a new RBP that controls the myeloid leukemia stem cell program. We propose that targeting these RBP complexes might provide a novel therapeutic strategy in leukemia.

MSI2 is required for maintaining activated myelodysplastic syndrome stem cells.

Myelodysplastic syndromes (MDS) are driven by complex genetic and epigenetic alterations. The MSI2 RNA-binding protein has been demonstrated to have a role in acute myeloid leukaemia and stem cell function, but its role in MDS is unknown. Here, we demonstrate that elevated MSI2 expression correlates with poor survival in MDS. Conditional deletion of Msi2 in a mouse model of MDS results in a rapid loss of MDS haematopoietic stem and progenitor cells (HSPCs) and reverses the clinical features of MDS. Inversely, inducible overexpression of MSI2 drives myeloid disease progression. The MDS HSPCs remain dependent on MSI2 expression after disease initiation. Furthermore, MSI2 expression expands and maintains a more activated (G1) MDS HSPC. Gene expression profiling of HSPCs from the MSI2 MDS mice identifies a signature that correlates with poor survival in MDS patients. Overall, we identify a role for MSI2 in MDS representing a therapeutic target in this disease.

Interactions of the Metalloregulatory Protein SloR from Streptococcus mutans with Its Metal Ion Effectors and DNA Binding Site.

UNLABELLED: Streptococcus mutans is the causative agent of dental caries, a significant concern for human health, and therefore an attractive target for therapeutics development. Previous work in our laboratory has identified a homodimeric, manganese-dependent repressor protein, SloR, as an important regulator of cariogenesis and has used site-directed mutagenesis to map functions to specific regions of the protein. Here we extend those studies to better understand the structural interaction between SloR and its operator and its effector metal ions. The results of DNase I assays indicate that SloR protects a 42-bp region of DNA that overlaps the sloABC promoter on the S. mutans UA159 chromosome, while electrophoretic mobility shift and solution binding assays indicate that each of two SloR dimers binds to this region. Real-time semiquantitative reverse transcriptase PCR (real-time semi-qRT-PCR) experiments were used to determine the individual base pairs that contribute to SloR-DNA binding specificity. Solution studies indicate that Mn(2+) is better than Zn(2+) at specifically activating SloR to bind DNA, and yet the 2.8-Å resolved crystal structure of SloR bound to Zn(2+) provides insight into the means by which selective activation by Mn(2+) may be achieved and into how SloR may form specific interactions with its operator. Taken together, these experimental observations are significant because they can inform rational drug design aimed at alleviating and/or preventing S. mutans-induced caries formation. IMPORTANCE: This report focuses on investigating the SloR protein as a regulator of essential metal ion transport and virulence gene expression in the oral pathogen Streptococcus mutans and on revealing the details of SloR binding to its metal ion effectors and binding to DNA that together facilitate this expression. We used molecular and biochemical approaches to characterize the interaction of SloR with Mn(2+) and with its SloR recognition element to gain a clearer picture of the regulatory networks that optimize SloR-mediated metal ion homeostasis and virulence gene expression in S. mutans. These experiments can have a significant impact on caries treatment and/or prevention by revealing the S. mutans SloR-DNA binding interface as an appropriate target for the development of novel therapeutic interventions.

Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program.

Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia.

Musashi-2 controls cell fate, lineage bias, and TGF-ß signaling in HSCs.

Hematopoietic stem cells (HSCs) are maintained through the regulation of symmetric and asymmetric cell division. We report that conditional ablation of the RNA-binding protein Msi2 results in a failure of HSC maintenance and engraftment caused by a loss of quiescence and increased commitment divisions. Contrary to previous studies, we found that these phenotypes were independent of Numb. Global transcriptome profiling and RNA target analysis uncovered Msi2 interactions at multiple nodes within pathways that govern RNA translation, stem cell function, and TGF-ß signaling. Msi2-null HSCs are insensitive to TGF-ß-mediated expansion and have decreased signaling output, resulting in a loss of myeloid-restricted HSCs and myeloid reconstitution. Thus, Msi2 is an important regulator of the HSC translatome and balances HSC homeostasis and lineage bias.