Nancy E. Wang

Effectiveness of a Staged US and CT Protocol for the Diagnosis of Pediatric Appendicitis: Reducing Radiation Exposure in the Age of ALARA

PURPOSE To evaluate the effectiveness of a staged ultrasonography (US) and computed tomography (CT) imaging protocol for the accurate diagnosis of suspected appendicitis in children and the opportunity for reducing the number of CT examinations and associated radiation exposure. MATERIALS AND METHODS This retrospective study was compliant with HIPAA, and a waiver of informed consent was approved by the institutional review board. This study is a review of all imaging studies obtained in children suspected of having appendicitis between 2003 and 2008 at a suburban pediatric emergency department. A multidisciplinary staged US and CT imaging protocol for the diagnosis of appendicitis was implemented in 2003. In the staged protocol, US was performed first in patients suspected of having appendicitis; follow-up CT was recommended when US findings were equivocal. Of 1228 pediatric patients who presented to the emergency department for suspected appendicitis, 631 (287 boys, 344 girls; age range, 2 months to 18 years; median age, 10 years) were compliant with the imaging pathway. The sensitivity, specificity, negative appendectomy rate (number of appendectomies with normal pathologic findings divided by the number of surgeries performed for suspected appendicitis), missed appendicitis rate, and number of CT examinations avoided by using the staged protocol were analyzed. RESULTS The sensitivity and specificity of the staged protocol were 98.6% and 90.6%, respectively. The negative appendectomy rate was 8.1% (19 of 235 patients), and the missed appendicitis rate was less than 0.5% (one of 631 patients). CT was avoided in 333 of the 631 patients (53%) in whom the protocol was followed and in whom the US findings were definitive. CONCLUSION A staged US and CT imaging protocol in which US is performed first in children suspected of having acute appendicitis is highly accurate and offers the opportunity to substantially reduce radiation.

Biodistribution of Neural Stem Cells After Intravascular Therapy for Hypoxic–Ischemia

Background and Purpose— Intravascular transplantation of neural stem cells represents a minimally invasive therapeutic approach for the treatment of central nervous system diseases. The cellular biodistribution after intravascular injection needs to be analyzed to determine the ideal delivery modality. We studied the biodistribution and efficiency of targeted central nervous system delivery comparing intravenous and intra-arterial (IA) administration of neural stem cells after brain ischemia. Methods— Mouse neural stem cells were transduced with a firefly luciferase reporter gene for bioluminescence imaging (BLI). Hypoxic–ischemia was induced in adult mice and reporter neural stem cells were transplanted IA or intravenous at 24 hours after brain ischemia. In vivo BLI was used to track transplanted cells up to 2 weeks after transplantation and ex vivo BLI was used to determine single organ biodistribution. Results— Immediately after transplantation, BLI signal from the brain was 12 times higher in IA versus intravenous injected animals (P<0.0001). After IA injection, 69% of the total luciferase activity arose from the brain early after transplantation and 93% at 1 week. After intravenous injection, 94% of the BLI signal was detected in the lungs (P=0.004) followed by an overall 94% signal loss at 1 week, indicating lack of cell survival outside the brain. Ex vivo single organ analysis showed a significantly higher BLI signal in the brain than in the lungs, liver, and kidneys at 1 week (P<0.0001) and 2 weeks in IA (P=0.007). Conclusion— IA transplantation results in superior delivery and sustained presence of neural stem cells in the ischemic brain in comparison to intravenous infusion.

The CCR2/CCL2 Interaction Mediates the Transendothelial Recruitment of Intravascularly Delivered Neural Stem Cells to the Ischemic Brain

Background and Purpose— The inflammatory response is a critical component of ischemic stroke. In addition to its physiological role, the mechanisms behind transendothelial recruitment of immune cells also offer a unique therapeutic opportunity for translational stem cell therapies. Recent reports have demonstrated homing of neural stem cells (NSC) into the injured brain areas after intravascular delivery. However, the mechanisms underlying the process of transendothelial recruitment remain largely unknown. Here we describe the critical role of the chemokine CCL2 and its receptor CCR2 in targeted homing of NSC after ischemia. Methods— Twenty-four hours after induction of stroke using the hypoxia-ischemia model in mice CCR2+/+ and CCR2−/− reporter NSC were intra-arterially delivered. Histology and bioluminescence imaging were used to investigate NSC homing to the ischemic brain. Functional outcome was assessed with the horizontal ladder test. Results— Using NSC isolated from CCR2+/+ and CCR2−/− mice, we show that receptor deficiency significantly impaired transendothelial diapedesis specifically in response to CCL2. Accordingly, wild-type NSC injected into CCL2−/− mice exhibited significantly decreased homing. Bioluminescence imaging showed robust recruitment of CCR2+/+ cells within 6 hours after transplantation in contrast to CCR2−/− cells. Mice receiving CCR2+/+ grafts after ischemic injury showed a significantly improved recovery of neurological deficits as compared to animals with transplantation of CCR2−/− NSC. Conclusions— The CCL2/CCR2 interaction is critical for transendothelial recruitment of intravascularly delivered NSC in response to ischemic injury. This finding could have significant implications in advancing minimally invasive intravascular therapeutics for regenerative medicine or cell-based drug delivery systems for central nervous system diseases.

Intra-Arterial Injection of Neural Stem Cells using a Microneedle Technique does not Cause Microembolic Strokes

Intra-arterial (IA) injection represents an experimental avenue for minimally invasive delivery of stem cells to the injured brain. It has however been reported that IA injection of stem cells carries the risk of reduction in cerebral blood flow (CBF) and microstrokes. Here we evaluate the safety of IA neural progenitor cell (NPC) delivery to the brain. Cerebral blood flow of rats was monitored during IA injection of single cell suspensions of NPCs after stroke. Animals received 1×106 NPCs either injected via a microneedle (microneedle group) into the patent common carotid artery (CCA) or via a catheter into the proximally ligated CCA (catheter group). Controls included saline-only injections and cell injections into non-stroked sham animals. Cerebral blood flow in the microneedle group remained at baseline, whereas in the catheter group a persistent (15 minutes) decrease to 78% of baseline occurred (P < 0.001). In non-stroked controls, NPCs injected via the catheter method resulted in higher levels of Iba-1-positive inflammatory cells (P = 0.003), higher numbers of degenerating neurons as seen in Fluoro-Jade C staining (P < 0.0001) and ischemic changes on diffusion weighted imaging. With an appropriate technique, reduction in CBF and microstrokes do not occur with IA transplantation of NPCs.

Timing of Intra-Arterial Neural Stem Cell Transplantation After Hypoxia–Ischemia Influences Cell Engraftment, Survival, and Differentiation

Background and Purpose— Intra-arterial neural stem cell (NSC) transplantation shows promise as a minimally invasive therapeutic option for stroke. We assessed the effect of timing of transplantation on cell engraftment, survival, and differentiation. Methods— Mouse NSCs transduced with a green fluorescent protein and renilla luciferase reporter gene were transplanted into animals 6 and 24 hours and 3, 7, and 14 days after hypoxia–ischemia (HI). Bioluminescent imaging was used to assess cell survival at 6 hours and 4 and 7 days after transplantation. Immunohistochemistry was used to assess NSC survival and phenotypic differentiation 1 month after transplantation. NSC receptor expression and brain gene expression were evaluated using real-time reverse transcription–quantitative polymerase chain reaction to elucidate mechanisms of cell migration. Boyden chamber assays were used to assess cell migratory potential in vitro. Results— NSC transplantation 3 days after HI resulted in significantly higher cell engraftment and survival at 7 and 30 days compared with all other groups (P<0.05). Early transplantation at 6 and 24 hours after HI resulted in significantly higher expression of glial fibrillary acidic protein (P=0.0140), whereas late transplantation at 7 and 14 days after HI resulted in higher expression of &bgr;-tubulin (P<0.0001). Corroborating the high cell engraftment 3 days after HI was robust expression of vascular cell adhesion molecule-1, CCL2, and CXCL12 in brain homogenates 3 days after HI. Conclusion— Intra-arterial transplantation 3 days after HI results in the highest cell engraftment. Early transplantation of NSCs leads to greater differentiation into astrocytes, whereas transplantation at later time points leads to greater differentiation into neurons.

Interfacility transfer and mortality for patients with ruptured abdominal aortic aneurysm

OBJECTIVE Patients receiving interfacility transfer to a higher level of medical care for ruptured abdominal aortic aneurysms (rAAAs) are an important minority that are not well characterized and are typically omitted from outcomes and quality indicator studies. Our objective was to compare patients transferred for treatment of rAAAs with those treated without transfer, with particular emphasis on mortality and resource utilization. METHODS We linked longitudinal data from 2005 to 2010 Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases and Emergency Department Databases from California, Florida, and New York. Patients were identified using International Classification of Diseases-Ninth Revision-Clinical Modification codes. Our main outcome variables were mortality, length of stay, and cost. Data included discharge information on the transfer-out and transfer-in hospital. We used univariate and multivariate analysis to identify variables independently associated with transfer and in-hospital mortality. RESULTS Of 4439 rAAA patients identified with intent to treat, 847 (19.1%) were transferred before receiving operative repair. Of those transferred, 141 (17%) died without undergoing AAA repair. By multivariate analysis, increasing age in years (odds ratio [OR] 0.98; 95% confidence interval [CI], 0.97-0.99; P < .001), private insurance vs Medicare (OR, 0.62; 95% CI, 0.47-0.80; P < .001), and increasing comorbidities as measured by the Elixhauser Comorbidity Index (OR, 0.90; 95% CI, 0.86-0.95; P < .001) were negatively associated with transfer. Weekend presentation (OR, 1.23; 95% CI, 1.02-1.47; P = .03) was positively associated with transfer. Transfer was associated with a lower operative mortality (adjusted OR, 0.81; 95% CI, 0.68-0.97; P < .02) but an increased overall mortality when including transferred patients who died without surgery (OR, 1.30; 95% CI, 1.05-1.60; P = .01). Among the transferred patients, there was no significant difference in travel distance between those who survived and those who died (median, 28.7 vs 25.8 miles; P = .07). Length of stay (median, 10 vs 9 days; P = .008), and hospital costs (

BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery After Transplantation in Hypoxic-Ischemic Stroke.

161,000 vs

Clinical correlation needed: What do emergency physicians do after an equivocal ultrasound for pediatric acute appendicitis?

146,000; P = .02) were higher for those transferred. CONCLUSIONS The survival advantage for patients transferred who received treatment was eclipsed by increased mortality of the transfer process. Including 17% of transferred patients who died without receiving definitive repair, mortality was increased for patients transferred for rAAA repair compared with those not transferred after adjusting for demographic, clinical, and hospital factors. Transferred patients used significantly more hospital resources. Improving systems and guidelines for interfacility transfer may further improve the outcomes for these patients and decrease associated hospital resource utilization.

Improved management of acute asthma among pregnant women presenting to the ED

Intra-arterial neural stem cell (NSC) therapy has the potential to improve long-term outcomes after stroke. Here we evaluate if pretreatment of NSCs with brain-derived neurotrophic factor (BDNF) prior to transplantation improves cell engraftment and functional recovery following hypoxic–ischemic (HI) stroke. Human embryonic-derived NSCs with or without BDNF pretreatment (1 h, 100 ng/ml) were transplanted 3 days after HI stroke. Functional recovery was assessed using the horizontal ladder test. Cell engraftment was evaluated using bioluminescence imaging (BLI) and histological counts of SC121+ cells. Fluoro-Jade C (FJC) and NeuN stains were used to evaluate neuroprotection. The effect of BDNF on NSCs was analyzed using a migration assay, immunocytochemistry, Luminex proteomic assay, and RT-qPCR.BLI analysis demonstrated significantly higher photon flux in the BDNF-treated NSC group compared to untreated NSC (p = 0.049) and control groups (p = 0.0021) at 1 week after transplantation. Immunohistochemistry confirmed increased transplanted cell survival in the cortex (p = 0.0126) and hippocampus (p = 0.0098) of animals injected with BDNF-treated NSCs compared to untreated NSCs. Behavioral testing revealed that the BDNF-treated NSC group demonstrated increased sensorimotor recovery compared to the untreated NSC and control groups (p < 0.001) over the 1-month period (p < 0.001) following transplantation. A significant improvement in performance was found in the BDNF-treated NSC group compared to the control group at 14, 21, and 28 (p < 0.05) days after transplantation. The cortex and hippocampus of the BDNF-treated NSC group had significantly more SC121+ NSCs (p = 0.0125, p = 0.0098), fewer FJC+ neurons (p = 0.0370, p = 0.0285), and a higher percentage of NeuN+ expression (p= 0.0354) in the cortex compared to the untreated NSC group. BDNF treatment of NSCs resulted in significantly greater migration to SDF-1, secretion of M-CSF, VEGF, and expression of CXCR4, VCAM-1, Thrombospondins 1 and 2, and BDNF. BDNF pretreatment of NSCs results in higher initial NSC engraftment and survival, increased neuroprotection, and greater functional recovery when compared to untreated NSCs.

From 9-1-1 call to death: evaluating traumatic deaths in seven regions for early recognition of high-risk patients.

Although follow‐up CT is recommended for pediatric appendicitis if initial ultrasound (US) is equivocal, many physicians observe the patient at home. There are limited data to understand currently how common or safe this practice is. Our objectives are to assess prevalence of acute appendicitis and outcomes in patients with equivocal US with and without follow‐up CT and to identify variables associated with ordering a follow‐up CT.