Iatrogenic Flexion-Related Classic Metaphyseal Lesion of the Distal Tibia: Three Cases.

BACKGROUND: Classic metaphyseal lesions (CMLs) should raise concern for nonaccidental trauma. However, iatrogenic causes for CMLs have increasingly been described and warrant close consideration. Increasing the clinical understanding of CML mechanics and their relation to often routine medical procedures will enhance provider awareness and expand the differential diagnosis when these otherwise highly concerning injuries are identified. CASE REPORTS: We describe three clinical cases where suspected iatrogenic dorsiflexion or plantar flexion resulted in an isolated distal tibia CML. Respectively, we present heel-stick testing and i.v. line placement as clinical correlates of these two mechanisms. Although prior reports have aimed to describe iatrogenic CML etiologies, they have not focused on dorsiflexion or plantar flexion as predominant mechanisms of injury. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians are critical to the surveillance and identification of nonaccidental trauma. Given that children oftentimes present to the emergency department with subtle yet concerning signs of maltreatment, an emergency physician must be aware of the potential causes of injury as well as the recommended response. Although avoiding missed cases of abuse and improving the detection of injuries is crucial for child health and well-being, failing to consider or recognize alternative explanations could also have serious implications for a child and their caregivers.

Targeting Glioblastoma Stem Cells with 2-Deoxy-D-Glucose (2-DG) Potentiates Radiation-Induced Unfolded Protein Response (UPR).

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, and despite optimized treatment options, median survival remains dismal. Contemporary evidence suggests disease recurrence results from expansion of a robustly radioresistant subset of GBM progenitor cells, termed GBM stem cells (GSCs). In this study, we utilized transmission electron microscopy to uncover ultrastructural effects on patient-derived GSC lines exposed to supratherapeutic radiotherapy levels. Elevated autophagosome formation and increased endoplasmic reticulum (ER) internal diameter, a surrogate for ER stress and activation of unfolded protein response (UPR), was uncovered. These observations were confirmed via protein expression through Western blot. Upon interrogating genomic data from an open-access GBM patient database, overexpression of UPR-related chaperone protein genes was inversely correlated with patient survival. This indicated controlled UPR may play a role in promoting radioresistance. To determine if potentiating UPR further can induce apoptosis, we exposed GSCs to radiation with an ER stress-inducing drug, 2-deoxy-D-glucose (2-DG), and found dose-dependent decreases in viability and increased apoptotic marker expression. Taken together, our results indicate GSC radioresistance is, in part, achieved by overexpression and overactivation of ER stress-related pathways, and this effect can be overcome via potentiation of UPR, leading to loss of GSC viability.

Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer.

Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter. Thus, blocking glutamate flux using riluzole (an amyotropic lateral sclerosis approved drug) can selectively kill CR cells in vitro and in vivo. However, we discovered here that glutathione suppression is not the primary pathway in eradicating the CR cells. Riluzole can lead to further decrease in NAD+ (nicotinamide adenine dinucleotide) and lactate dehydrogenase-A (LDHA) expressions which in turn further heightened oxidative stress in CR cells. LDHA knocked-down cells became hypersensitive to riluzole treatments and possessed increased levels of ROS. Addition of NAD+ re-stabilized LDHA and reversed riluzole induced cell death. Thus far, no drugs are available which could overcome cisplatin resistance or kill cisplatin resistant cells. CR cells possess high levels of ROS and undergo metabolic reprogramming. These metabolic adaptations can be exploited and targeted by riluzole. Riluzole may serve as a dual-targeting agent by suppression LDHA and blocking xCT antiporter. Repurposing of riluzole should be considered for future treatment of cisplatin resistant lung cancer patients.

Pediatric Chest CT Diagnostic Reference Ranges: Development and Application.

Purpose To determine diagnostic reference ranges on the basis of the size of a pediatric patient's chest and to develop a method to estimate computed tomographic (CT) scanner-specific mean size-specific dose estimates (SSDEs) as a function of patient size and the radiation output of each CT scanner at a site. Materials and Methods The institutional review boards of each center approved this retrospective, HIPAA-compliant, multicenter study; informed consent was waived. CT dose indexes (SSDE, volume CT dose index, and dose length product) of 518 pediatric patients (mean age, 9.6 years; male patients, 277 [53%]) who underwent CT between July 1, 2012, and June 30, 2013, according to the guidelines of the Quality Improvement Registry in CT Scans in Children were retrieved from a national dose data registry. Diagnostic reference ranges were developed after analysis of image quality of a subset of 111 CT examinations to validate image quality at the lower bound. Pediatric dose reduction factors were calculated on the basis of SSDEs for pediatric patients divided by SSDEs for adult patients. Results Diagnostic reference ranges (SSDEs) were 1.8-3.9, 2.2-4.5, 2.7-5.1, 3.6-6.6, and 5.5-8.4 mGy for effective diameter ranges of less than 15 cm, 15-19 cm, 20-24 cm, 25-29 cm, and greater than or equal to 30 cm, respectively. The fractions of adult doses (pediatric dose reduction factors) used within the consortium for patients with lateral dimensions of 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, and 38 cm were 0.29, 0.33, 0.38, 0.44, 0.50, 0.58, 0.66, 0.76, 0.87, 1.0, and 1.15, respectively. Conclusion Diagnostic reference ranges developed in this study provided target ranges of pediatric dose indexes on the basis of patient size, while the pediatric dose reduction factors of this study allow calculation of unique reference dose indexes on the basis of patient size for each of a site's CT scanners. © RSNA, 2017 Online supplemental material is available for this article.

Novel "Superspreader" Bacteriophages Promote Horizontal Gene Transfer by Transformation.

Bacteriophages infect an estimated 1023 to 1025 bacterial cells each second, many of which carry physiologically relevant plasmids (e.g., those encoding antibiotic resistance). However, even though phage-plasmid interactions occur on a massive scale and have potentially significant evolutionary, ecological, and biomedical implications, plasmid fate upon phage infection and lysis has not been investigated to date. Here we show that a subset of the natural lytic phage population, which we dub "superspreaders," releases substantial amounts of intact, transformable plasmid DNA upon lysis, thereby promoting horizontal gene transfer by transformation. Two novel Escherichia coli phage superspreaders, SUSP1 and SUSP2, liberated four evolutionarily distinct plasmids with equal efficiency, including two close relatives of prominent antibiotic resistance vectors in natural environments. SUSP2 also mediated the extensive lateral transfer of antibiotic resistance in unbiased communities of soil bacteria from Maryland and Wyoming. Furthermore, the addition of SUSP2 to cocultures of kanamycin-resistant E. coli and kanamycin-sensitive Bacillus sp. bacteria resulted in roughly 1,000-fold more kanamycin-resistant Bacillus sp. bacteria than arose in phage-free controls. Unlike many other lytic phages, neither SUSP1 nor SUSP2 encodes homologs to known hydrolytic endonucleases, suggesting a simple potential mechanism underlying the superspreading phenotype. Consistent with this model, the deletion of endonuclease IV and the nucleoid-disrupting protein ndd from coliphage T4, a phage known to extensively degrade chromosomal DNA, significantly increased its ability to promote plasmid transformation. Taken together, our results suggest that phage superspreaders may play key roles in microbial evolution and ecology but should be avoided in phage therapy and other medical applications. IMPORTANCE: Bacteriophages (phages), viruses that infect bacteria, are the planet's most numerous biological entities and kill vast numbers of bacteria in natural environments. Many of these bacteria carry plasmids, extrachromosomal DNA elements that frequently encode antibiotic resistance. However, it is largely unknown whether plasmids are destroyed during phage infection or released intact upon phage lysis, whereupon their encoded resistance could be acquired and manifested by other bacteria (transformation). Because phages are being developed to combat antibiotic-resistant bacteria and because transformation is a principal form of horizontal gene transfer, this question has important implications for biomedicine and microbial evolution alike. Here we report the isolation and characterization of two novel Escherichia coli phages, dubbed "superspreaders," that promote extensive plasmid transformation and efficiently disperse antibiotic resistance genes. Our work suggests that phage superspreaders are not suitable for use in medicine but may help drive bacterial evolution in natural environments.

Cervical spine imaging in hospitalized children with traumatic brain injury.

OBJECTIVES: The purposes of this study, in children with traumatic brain injury (TBI), to describe cervical spine imaging practice, to assess for recent changes in imaging practice, and to determine whether cervical spine computed tomography (CT) is being used in children at low risk for cervical spine injury. METHODS: The setting was children's hospitals participating in the Pediatric Health Information System database, from January 2001 to June 2011. Participants were children (younger than 18 y) with TBI who were evaluated in the emergency department, admitted to the hospital, and received a head CT scan on the day of admission. The primary outcome measures were cervical spine imaging studies. This study was exempted from institutional review board assessment. RESULTS: A total of 30,112 children met study criteria. Overall, 52% (15,687/30,112) received cervical spine imaging. The use of cervical spine radiographs alone decreased between 2001 (47%) and 2011 (23%), with an annual decrease of 2.2% (95% confidence interval [CI], 1.1%-3.3%), and was largely replaced by an increased use of CT, with or without radiographs (8.6% in 2001 and 19.5% in 2011, with an annual increase of 0.9%; 95% CI, 0.1%-1.8%). A total of 2545 children received cervical spine CT despite being discharged alive from the hospital in less than 72 hours, and 1655 of those had a low-risk mechanism of injury. CONCLUSIONS: The adoption of CT clearance of the cervical spine in adults seems to have influenced the care of children with TBI, despite concerns about radiation exposure.

The role of focused abdominal sonography for trauma (FAST) in pediatric trauma evaluation.

PURPOSE: With increasing concerns about radiation exposure, we questioned whether a structured program of FAST might decrease CT use. METHODS: All pediatric trauma surgeons in our level 1 pediatric trauma center underwent formal FAST training. Children with potential abdominal trauma and no prior imaging were prospectively evaluated from 10/2/09 to 7/31/11. After physical exam and FAST, the surgeon declared whether the CT could be eliminated. RESULTS: Of 536 children who arrived without imaging, 183 had potential abdominal trauma. FAST was performed in 128 cases and recorded completely in 88. In 48% (42/88) the surgeon would have elected to cancel the CT based on the FAST and physical exam. One of the 42 cases had a positive FAST and required emergent laparotomy; the others were negative. The sensitivity of FAST for injuries requiring operation or blood transfusion was 87.5%. The sensitivity, specificity, PPV, and NPV in detecting pathologic free fluid were 50%, 85%, 53.8%, and 87.9%. CONCLUSIONS: True positive FAST exams are uncommon and would rarely direct management. While the negative FAST would have potentially reduced CT use due to practitioner reassurance, this reassurance may be unwarranted given the test's sensitivity.

Diagnostic reference ranges for pediatric abdominal CT.

PURPOSE: To develop diagnostic reference ranges (DRRs) and a method for an individual practice to calculate site-specific reference doses for computed tomographic (CT) scans of the abdomen or abdomen and pelvis in children on the basis of body width (BW). MATERIALS AND METHODS: This HIPAA-compliant multicenter retrospective study was approved by institutional review boards of participating institutions; informed consent was waived. In 939 pediatric patients, CT doses were reviewed in 499 (53%) male and 440 (47%) female patients (mean age, 10 years). Doses were from 954 scans obtained from September 1 to December 1, 2009, through Quality Improvement Registry for CT Scans in Children within the National Radiology Data Registry, American College of Radiology. Size-specific dose estimate (SSDE), a dose estimate based on BW, CT dose index, dose-length product, and effective dose were analyzed. BW measurement was obtained with electronic calipers from the axial image at the splenic vein level after completion of the CT scan. An adult-sized patient was defined as a patient with BW of 34 cm. An appropriate dose range for each DRR was developed by reviewing image quality on a subset of CT scans through comparison with a five-point visual reference scale with increments of added simulated quantum mottle and by determining DRR to establish lower and upper bounds for each range. RESULTS: For 954 scans, DRRs (SSDEs) were 5.8-12.0, 7.3-12.2, 7.6-13.4, 9.8-16.4, and 13.1-19.0 mGy for BWs less than 15, 15-19, 20-24, 25-29, and 30 cm or greater, respectively. The fractions of adult doses, adult SSDEs, used within the consortium for patients with BWs of 10, 14, 18, 22, 26, and 30 cm were 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively. CONCLUSION: The concept of DRRs addresses the balance between the patient's risk (radiation dose) and benefit (diagnostic image quality). Calculation of reference doses as a function of BW for an individual practice provides a tool to help develop site-specific CT protocols that help manage pediatric patient radiation doses.

Follow-up skeletal surveys for nonaccidental trauma: can a more limited survey be performed?

BACKGROUND: Studies have demonstrated the value of the follow-up skeletal survey in identifying additional fractures, clarifying indeterminate findings, and improving dating of skeletal injuries in victims of physical abuse. OBJECTIVE: To determine whether a more limited follow-up survey could yield the same radiologic data as a full follow-up survey. MATERIALS AND METHODS: The study cohort comprised 101 children who had follow-up surveys that met our inclusion criteria. Consensus readings of both original and follow-up surveys were performed by two pediatric radiologists. These results were compared to determine additional findings from the follow-up surveys. Limited skeletal survey protocols were evaluated to determine whether they would detect the same fractures seen with a complete osseous survey. RESULTS: In the 101 children 244 fractures were identified on the initial osseous survey. Follow-up surveys demonstrated new information in 38 children (37.6%). A 15-view limited follow-up survey identified all additional information seen on the complete follow-up survey. CONCLUSION: Our data demonstrate that a 15-view limited follow-up skeletal survey could be performed without missing clinically significant new fractures and still allow proper identification of confirmed fractures or normal findings. A limited survey would decrease radiation dose in children.

Oblique chest views as a routine part of skeletal surveys performed for possible physical abuse--is this practice worthwhile?

OBJECTIVE: To evaluate the utility of oblique chest views in the diagnosis of rib fractures when used as a routine part of the skeletal survey performed for possible physical abuse. METHODS: Oblique chest views have been part of the routine skeletal survey protocol at Primary Children's Medical Center since October 2002. Dictated radiology reports since that time were reviewed, and all cases with rib fractures documented were chosen for study. For each chosen case two pediatric radiologists identified and recorded rib fractures using only the PA and lateral chest radiographs (standard two-view chest series) from the skeletal survey for each case. In a separate session they identified and recorded rib fractures using the PA, lateral, right oblique, and left oblique radiographs (four-view chest series) from the skeletal survey for each case. The results were compared. RESULTS: Twenty-two cases with rib fractures were identified. Interpretation of the four-view chest series was different than interpretation of the two-view chest series in 12 of the 22 cases (54%). Overall, the four-view chest series differed significantly in the number of rib fractures diagnosed compared with the two-view chest series (p=.02, Wilcoxon matched-pairs signed-rank test) adding 19 rib fractures and excluding 6 rib fractures. CONCLUSIONS: The results indicate that use of the four-view chest series adds information to that obtained from the two-view chest series and increases the accuracy of diagnosing rib fractures in cases of possible physical abuse. Addition of oblique chest views to the routine protocol for skeletal surveys performed for possible physical abuse is recommended.

MRI of anterior cruciate ligament injuries and associated findings in the pediatric knee: changes with skeletal maturation.

OBJECTIVE: The objective of our study was to evaluate the MRI characteristics of anterior cruciate ligament (ACL) injuries and associated findings relative to skeletal maturity. We also contrast the frequency of findings in this younger population to adult data. MATERIALS AND METHODS: Eighty-two consecutive knees with an MRI report diagnosis of ACL injury (partial tear, sprain, or complete tear) or tibial spine avulsion fracture imaged over 4 years were retrospectively reviewed. Patients were grouped by degree of skeletal maturity as determined from the MR images. The examinations were reviewed for the type of ACL injury, secondary imaging findings, and associated knee injuries. Findings were correlated to skeletal maturity, and frequencies were compared with adult data. RESULTS: ACL injuries were more common in boys in the skeletally immature group, but more common in girls in the skeletally mature group (p = 0.03). Tibial spine avulsion fractures were most common in skeletally immature patients (p < 0.01), whereas complete tears of the ACL were most common in skeletally mature patients. Associated injuries were less common in the skeletally immature group, but this trend did not reach statistical significance. Most secondary signs of ACL injuries occurred at similar rates in all groups with frequencies similar to those reported in adults. CONCLUSION: ACL injuries in skeletally immature patients are seen more often in boys. Tibial avulsion fractures and partial tears are more common in younger, less rigid skeletons that may absorb the forces of trauma. As children mature, complete ACL tears and associated injuries occur in frequencies approaching those patterns seen in adults. Similarly, skeletally mature girls are affected more often than mature boys.

Design and analysis of multiple choice feeding preference data.

Traditional analyses of feeding experiments that test consumer preference for an array of foods suffer from several defects. We have modified the experimental design to incorporate into a multivariate analysis the variance due to autogenic change in control replicates. Our design allows the multiple foods to be physically paired with their control counterparts. This physical proximity of the multiple food choices in control/experimental pairs ensures that the variance attributable to external environmental factors jointly affects all combinations within each replicate. Our variance term, therefore, is not a contrived estimate as is the case for the random pairing strategy proposed by previous studies. The statistical analysis then proceeds using standard multivariate statistical tests. We conducted a multiple choice feeding experiment using our experimental design and utilized a Monte Carlo analysis to compare our results with those obtained from an experimental design that employed the random pairing strategy. Our experimental design allowed detection of moderate differences among feeding means when the random design did not.

Ceftriaxone-associated nephrolithiasis and biliary pseudolithiasis in a child.

Ceftriaxone is a widely used third-generation cephalosporin. It is generally very safe, but complications of biliary pseudolithiasis and, rarely, nephrolithiasis have been reported in children. These complications generally resolve spontaneously with cessation of the ceftriaxone therapy; however, they may symptomatically mimic more serious clinical problems, such as cholecystitis. We report a case of both ceftriaxone-induced biliary pseudolithiasis and nephrolithiasis.

Nonneoplastic lesions of the tracheobronchial wall: radiologic findings with bronchoscopic correlation.

Nonneoplastic diseases of the central airways are uncommon but can be categorized as either focal or diffuse, although there is some overlap. Focal diseases include postintubation stenosis, postinfectious stenosis, posttransplantation stenosis, and various systemic diseases that may involve the airways and lead to focal stenosis (eg, Crohn disease, sarcoidosis, Behçet syndrome). Diffuse diseases of the central airways include Wegener granulomatosis, relapsing polychondritis, tracheobronchopathia osteochondroplastica, amyloidosis, papillomatosis, and rhinoscleroma. Conventional radiography is often the first step in the evaluation of suspected central airway disease and may be adequate in itself to identify the abnormality. However, computed tomography (CT) improves both the detection and characterization of central airway disease. Bronchoscopy remains the primary procedure for the diagnostic work-up of these disease entities. Nevertheless, a thorough radiologic evaluation with radiography and CT may demonstrate specific imaging findings (eg, calcification) that can help narrow the differential diagnosis and aid in the planning of bronchoscopy or therapeutic intervention.

Normal cross-sectional dimensions of the thyroid gland on routine chest CT scans.

PURPOSE: The purpose of this work was to determine the range of normal measurements for the thyroid gland on chest CT scans and relate it to the dimensions of the trachea. METHOD: Chest CT scans in 118 patients were examined prospectively for visibility of the thyroid gland and its relationship to the trachea. The greatest transverse dimensions of the lobes and the transverse tracheal diameter were measured. A thyroid/trachea ratio was determined. RESULTS: The mean value for the transverse diameter of the thyroid gland was 28.79 mm (SD 6.57 mm). The right lobe averaged 15.05 mm (SD 3.51 mm). The left lobe averaged 13.74 mm (SD 3.91 mm). Measurements for the trachea showed a mean value of 19.97 mm (SD 2.37 mm). A thyroid/trachea index was calculated with a mean value of 1.46 (SD 0.39). CONCLUSION: Our investigation provides initial values for assessing the thyroid gland on CT scans, defining the limits of normal and the border zones of abnormal size.