Faculty Bibliography

BACKGROUND:Coronary artery disease (CAD) is the leading killer in the United States. Patients with severe CAD and ischemia have worse prognosis. Therefore expansion of biomarker research, to identify at-risk individuals and explain the complex biology between cardiovascular growth factors and atherosclerosis is needed. Neuregulin-1β (NRG-1β) is a myocardial stress activated growth and survival factor released from endocardial and endothelial cells. NRG-1β is essential for cardiovascular development and a regulator of angiogenesis. We postulated that plasma and serum levels of NRG-1β would vary in relation to CAD severity and the presence of stress-induced ischemia. METHODS:We measured serum and plasma levels of NRG-1β and vascular endothelial growth factor (VEGF) in 60 patients undergoing cardiac catheterization. CAD severity was calculated from angiographic results using a modified Duke jeopardy score. RESULTS:Serum NRG-1β (sNRG-1β), plasma NRG-1β (pNRG-1β), serum VEGF, and plasma VEGF were detectable in the majority of patients. The pNRG-1β levels were approximately two-fold higher than sNRG-1β. Both sNRG-1β and pNRG-1β correlated inversely with CAD severity. pNRG-1β levels were statistically higher in patients with stress-induced ischemia denoted by a positive myocardial perfusion imaging study that correlated with angiographic findings (P=0.02). CONCLUSION/CONCLUSIONS:Both sNRG-1β and pNRG-1β correlated inversely with angiographic severity of CAD. pNRG-1β levels were two-fold higher than serum and were higher in patients with stress-induced ischemia. Therefore we conclude that plasma is the optimal source for the further exploration of the biological significance of NRG-1β as a biomarker of CAD severity and ischemia.

OBJECTIVE: Pediatricians and orthopedists comprise the largest referral basis for knee MR examinations at our institution. In an era of cost optimization, the purpose of this study was to compare differences in pretest probability for an abnormal finding on knee MRI based on referral subspecialty. MATERIALS AND METHODS: A retrospective review of 501 consecutive knee MR examinations of pediatric patients (56% male; mean age, 14 years; age range, 1-18 years) referred by nononcology orthopedic surgeons and 93 consecutive knee MR examinations of patients (47% male; mean age, 14 years; age range, 2-18 years) referred by general pediatricians from 2005 to 2009 were reviewed. Two patient groups based on the MR report were established: patients with entirely normal MRI findings and those who had a clinically significant MRI finding or findings. The latter group included children with any internal derangement, a discoid meniscus, a neoplasm, or evidence of infection or inflammation. RESULTS: The incidence of an entirely normal knee MRI from pediatrician referral and orthopedic referral was 24% (22/93) and 17% (87/501) (p = 0.15), respectively. The respective incidence of selected specific injuries identified from pediatrician and orthopedic referral included any internal derangement, 39.8% and 48.3% (p = 0.13); neoplasm, 2.2% and 1.4% (p = 0.64); and inflammation, 6.5% and 2.0% (p = 0.03). CONCLUSION: Despite differences in subspecialty training, we found no significant differences in the proportion of normal knee MRI examinations and no statistical difference in the proportion of patients with internal derangement. Further investigation is necessary to determine whether these findings translate into overall cost-savings or differences in patient outcome.

To compare the relative effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in reducing cardiovascular mortality in chronic hemodialysis patients, we conducted an observational analysis of all patients initiated on ACEI or ARB therapy undergoing chronic hemodialysis at a large dialysis provider. Survival curves with mortality hazard ratios (HRs) were generated using the Kaplan-Meier method and Cox regression. Outcomes were compared using inverse probability of treatment weighting and propensity score matching. Over 6 years, 22,800 patients were newly initiated on an ACEI and 5828 on an ARB after at least 60 days of chronic hemodialysis. After adjustment for baseline cardiovascular risk factors, there was no significant difference in the risk of cardiovascular, all-cause, or cerebrovascular mortality in patients initiated on an ARB compared with an ACEI (HR of 0.96). A third of 28,628 patients, newly started on an ACEI or ARB, went on to another antihypertensive medication in succession. After adjustment for risk factors, 701 patients initiated on combined ACEI and ARB therapy (HR of 1.45) or 6866 patients on ACEI and non-ARB antihypertensive agent (HR of 1.27) were at increased risk of cardiovascular death compared with 1758 patients initiated on an ARB and non-ACEI antihypertensive therapy. Thus, an ARB, in combination with another antihypertensive medication (but not an ACEI), may have a beneficial effect on cardiovascular mortality. As observational studies may be confounded by indication, even when adjusted, randomized clinical trials are needed to confirm these findings.

RATIONALE AND OBJECTIVES: The aim of this study was to explore the reliability of osteopenia diagnosis based on digital radiographs of appendicular skeleton obtained as part of routine clinical practice as compared with dual-energy x-ray absorptiometry (DEXA) gold standard (Z-score <-1). MATERIALS AND METHODS: The study was an institutional review board-approved retrospective study of 58 children (mean age 12 years [4-18]). Digital radiographs of appendicular skeleton obtained within 6 months of DEXA scanning were presented in a blinded fashion to two musculoskeletal radiologists who were instructed to grade the level of mineralization. Sensitivity and specificity of each reviewer's osteopenia grading were calculated in comparison to lumbar DEXA Z-score values. Interobserver agreement was also calculated and significance evaluated with Bowker's test. RESULTS: The reviewers correctly identified 28% of all patients with severe osteopenia (Z-score -1) to 0 and 25% for mild and severe osteopenia respectively. CONCLUSIONS: Visual diagnosis of osteopenia based on digital radiographs of appendicular skeleton has poor sensitivity and interobserver agreement. Clinical features and risk factors of pediatric patients should therefore guide DEXA evaluation and treatment recommendations.

BACKGROUND: Although the abdominopelvic CT findings of abdominal trauma in children have been described, little has been written about the subset of children who are victims of abuse. OBJECTIVE: Our purpose is to describe abdominopelvic injuries in abused pre-school-age children as identified on CT. MATERIALS AND METHODS: An IRB-approved retrospective review of our institutional child abuse registry was performed. Searching a 14-year period, we identified 84 children </= 5 years of age with medically diagnosed abuse who underwent CT. We reviewed imaging studies, operative reports, autopsy findings and patient outcomes. Consensus review of the CT examinations was performed by CAQ-certified pediatric radiologists, and findings were categorized as normal or by injury types (solid organ versus bowel). The injuries were analyzed in light of existing literature on pediatric accidental and non-accidental injuries. RESULTS: Of the 84 children, 35 (41.7%) had abdominal injuries. Abdominal injuries included liver (15), bowel (13), mesentery (4), spleen (6), kidneys (7), pancreas (4) and adrenal glands (3). Of these children, 26% (9/35) required surgical intervention for bowel, mesenteric and pancreatic injuries. Another 9/35 children died, not as a result of abdominal injuries but as a direct result of inflicted intracranial injuries. CONCLUSION: Our data indicate that abdominal injuries in abused children present in a pattern similar to that of children with accidental abdominal trauma, underscoring the need for vigilance and correlative historical and clinical data to identify victims of abuse. Mortality in abused children with intra-abdominal injury was frequently related to concomitant head injury

BACKGROUND: Epiphyseal cartilage enhancement defects (ED) may occur in the setting of epiphyseal osteomyelitis (OM), and its significance is uncertain. OBJECTIVE: The aim of this study is to evaluate the incidence and clinical impact of epiphyseal cartilage ED in pediatric epiphyseal OM. MATERIALS AND METHODS: The 13 children involved in this retrospective review were younger than 6 years of age and diagnosed with OM. They underwent contrast-enhanced MRI and surgical exploration yielding 14 study epiphyses. Seventeen age-matched children without evidence of infection who underwent contrast-enhanced MRI in the same period yielded 28 control epiphyses. Images were reviewed for focal/global ED, correlated with cartilage abscesses and compared with surgical reports. RESULTS: Study and control ED were respectively present in 10/14 (71.4%-6 global, 4 focal) and 6/28 (21.4%-0 global, 6 focal), P = 0.0017. An analysis of ED patterns between study and control patients showed significant difference for global (P = 0.0006), but no difference for focal ED (P = 0.71). For the six study epiphyses with global ED, epiphyseal abscesses were present in two (33.3%). For the four study epiphyses with focal ED, epiphyseal abscesses were present in two (50%). For the controls, no abnormalities were found on follow-up of epiphyses with focal ED. CONCLUSION: ED are seen normally but more commonly in children with OM. ED should not be confused with epiphyseal abscesses

OBJECTIVE:To test the hypothesis that perioperative statin use reduces acute kidney injury (AKI) after cardiac surgery. DESIGN/METHODS:A retrospective analysis of prospectively collected data from an ongoing clinical trial. SETTING/METHODS:A quaternary-care university hospital. PARTICIPANTS/METHODS:Three hundred twenty-four adult elective cardiac surgery patients. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:The authors assessed the association of preoperative statin use, early postoperative statin use, and acute statin withdrawal with the incidence of AKI. Early postoperative statin use was defined as statin treatment within the first postoperative day. Statin withdrawal was defined as the discontinuation of preoperative statin treatment before surgery until at least postoperative day 2. Logistic regression and propensity score modeling were used to control for AKI risk factors. Sixty-eight of 324 patients (21.0%) developed AKI. AKI patients stayed in the hospital longer (p = 0.03) and were more likely to develop pneumonia (p = 0.002) or die (p = 0.001). A higher body mass index (p = 0.003), higher central venous pressure (p = 0.03), and statin withdrawal (27.4 v 14.7%, p = 0.046) were associated with a higher incidence of AKI, whereas early postoperative statin use was protective (12.5% v 23.8%, p = 0.03). Preoperative statin use did not affect the risk of AKI. In multivariate logistic regression, age (p = 0.03), male sex (p = 0.02), body mass index (p < 0.001), and early postoperative statin use (odds ratio = 0.32; 95% confidence interval, 0.14-0.72; p = 0.006) independently predicted AKI. Propensity score-adjusted risk assessment confirmed the association between early postoperative statin use and reduced AKI (odds ratio = 0.30; 95% confidence interval, 0.13-0.70; p = 0.005). CONCLUSIONS:Early postoperative statin use is associated with a lower incidence of AKI among both chronic statin users and statin-naive cardiac surgery patients.

Orthostatic hypotension affects patients with autonomic failure producing considerable disability because of presyncopal symptoms. Severely affected patients may have residual sympathetic tone that can be engaged to increase blood pressure (BP) with the α-2 adrenergic antagonist yohimbine. This medication activates sympathetic outflow centrally and unrestrains norepinephrine release from noradrenergic neurons. Alternatively, the acetylcholinesterase inhibitor, pyridostigmine, can increase sympathetic tone by improving ganglionic cholinergic neurotransmission. Our purpose was to compare these complementary approaches and to explore whether the combination would lead to synergistic increases in BP. We compared the effects of 60 mg of pyridostigmine and 5.4 mg of yohimbine in a single-blind, randomized, placebo-controlled, crossover fashion. In a subset of patients we tested the combination of pyridostigmine and yohimbine. Our primary outcome was the change in standing diastolic BP 60 minutes after drug administration from baseline. We studied a total of 31 patients with severe autonomic failure. Yohimbine significantly improved standing diastolic BP as compared with placebo (11±3 mm Hg [95% CI: 6 to 16 mm Hg]; P<0.001). On the contrary, pyridostigmine did not increase the standing diastolic BP (0.6±3 mm Hg [95% CI: -5 to 5 mm Hg]; P=0.823). Only yohimbine showed a significant improvement in presyncopal symptoms. Sixteen patients received the combination of pyridostigmine and yohimbine, but no evidence of synergistic pressor effect was found. Engaging residual sympathetic tone with yohimbine is a more effective approach to improve orthostatic hypotension as compared with pyridostigmine in patients with severe orthostatic hypotension.

BACKGROUND:Immunosuppressants decrease circulating dipeptidyl peptidase IV (DPPIV) activity in transplant patients, and decreased DPPIV activity has been associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. One study has reported an increased incidence of ACE inhibitor-associated angioedema among transplant patients compared to published rates, while several case series report angioedema in patients taking specific immunosuppressant agents. OBJECTIVE:To test the hypothesis that transplant patients are at increased risk of ACE inhibitor-associated angioedema. METHODS:We assessed the proportion of transplant patients in 145 cases with ACE inhibitor-associated angioedema and 280 ACE inhibitor-exposed controls. We measured the relationship between case-control status, transplant status, and immunosuppressant use and circulating DPPIV activity. We also assessed the incidence of angioedema among consecutive patients who underwent renal or cardiac transplant and were treated with an ACE inhibitor. RESULTS:Transplant patients were significantly overrepresented among ACE inhibitor-associated angioedema cases compared to controls (odds ratio 18.5, 95% CI 2.3-147.2, P = 0.0004). Immunosuppressant use, chronic renal failure, seasonal allergies and smoking were also associated with ACE inhibitor-associated angioedema in univariate analysis. The association of transplant status with ACE inhibitor-associated angioedema was no longer significant after inclusion of immunosuppressant therapy in a multivariate analysis. Dipeptidyl peptidase IV activity was significantly decreased in sera from cases compared to ACE inhibitor-exposed controls, as well as in individuals taking immunosuppressants. Two of 47 ACE inhibitor-treated renal transplant patients and one of 36 ACE inhibitor-treated cardiac transplant patients developed angioedema. CONCLUSION/CONCLUSIONS:Transplant patients are at increased risk of ACE inhibitor-associated angioedema possibly because of the effects of immunosuppressants on the activity of DPPIV.

RATIONALE AND OBJECTIVES: Abdominopelvic computed tomography (APCT) is often performed in patients with skeletal Ewing sarcoma family of tumors during initial staging and for subsequent clinical indications, such as metastasis surveillance; however, its clinical impact is unknown. The purpose of this study was to evaluate whether these computed tomographic examinations alter oncologic management and therefore patient outcomes. MATERIALS AND METHODS: One hundred eight consecutive patients with skeletal Ewing sarcoma family of tumors seen from 1985 to 2008 were retrospectively reviewed to identify imaging workup, pathology, primary site, evidence of metastatic disease, and patient outcomes. Data were analyzed using Wilcoxon's rank sum tests. RESULTS: Sixty-five of the 108 patients (60%) underwent 342 abdominopelvic computed tomographic examinations during a mean follow-up period of 8.9 years. During this time period, only one of the 65 patients (1.5%) who underwent APCT was discovered to have abdominal metastatic disease. There was no significant difference in the incidence of metastatic disease to the skeleton or chest between the groups without and with APCT (P = .10). There were 26 pelvic and lumbosacral primaries (24%) and 82 limb primaries (76%). Subgroup analysis performed on the 82 patients with limb primaries without (n = 36) and with (n = 46) APCT showed no significant differences in metastatic incidence to the skeleton or chest (P = .14). CONCLUSIONS: This study indicates that APCT, associated with increased radiation exposure and health expenditure, has a limited role in initial staging and follow-up in patients with skeletal Ewing sarcoma, particularly in patients with limb primaries