Faculty Bibliography

The sympathetic nervous system regulates thermogenesis and energy homeostasis in humans. When activated it increases energy expenditure, particularly resting energy expenditure. Most human studies used acute infusion of β-blockers as a model to eliminate sympathetic stimulation and to examine the contribution of the sympathetic nervous system to energy metabolism and balance. Clinically, however, it is also important to assess the effect of chronic sympathetic attenuation on energy metabolism. In this context, we hypothesized that resting energy expenditure is decreased in patients with autonomic failure who, by definition, have low sympathetic tone. We measured 24-hour energy expenditure using whole-room indirect calorimeter in 10 adults with chronic autonomic failure (6 women; age, 64.9±9.1 years; body mass index, 25.2±4.4 kg/m(2)) and 15 sedentary healthy controls of similar age and body composition (8 women; age, 63.1±4.0 years; body mass index, 24.4±3.9 kg/m(2)). In 4 patients, we eliminated residual sympathetic activity with the ganglionic blocker trimethaphan. We found that, after adjusting for body composition, resting energy expenditure did not differ between patients with autonomic failure and healthy controls. However, resting energy expenditure significantly decreased when residual sympathetic activity was eliminated. Our findings suggest that sympathetic tonic support of resting energy expenditure is preserved, at least in part, in pathophysiological models of chronic sympathetic attenuation.

BACKGROUND:Studies in multiple organ systems have shown cross-talk between signaling through the bone morphogenetic protein receptor type 2 (BMPR2) and estrogen pathways. In humans, pulmonary arterial hypertension (PAH) has a female predominance, and is associated with decreased BMPR2 expression. The goal of this study was to determine if estrogens suppress BMPR2 expression. METHODS:A variety of techniques were utilized across several model platforms to evaluate the relationship between estrogens and BMPR2 gene expression. We used quantitative RT-PCR, gel mobility shift, and luciferase activity assays in human samples, live mice, and cell culture. RESULTS:BMPR2 expression is reduced in lymphocytes from female patients compared with male patients, and in whole lungs from female mice compared with male mice. There is an evolutionarily conserved estrogen receptor binding site in the BMPR2 promoter, which binds estrogen receptor by gel-shift assay. Increased exogenous estrogen decreases BMPR2 expression in cell culture, particularly when induced to proliferate. Transfection of increasing quantities of estrogen receptor alpha correlates strongly with decreasing expression of BMPR2. CONCLUSIONS:BMPR2 gene expression is reduced in females compared to males in live humans and in mice, likely through direct estrogen receptor alpha binding to the BMPR2 promoter. This reduced BMPR2 expression may contribute to the increased prevalence of PAH in females.

Biomarkers of oxidative stress and inflammation predict cardiovascular events in maintenance hemodialysis patients. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) reduce cardiovascular mortality in the general population, but their benefit in maintenance hemodialysis patients is not fully explored. To test whether ACE inhibitors and ARBs differentially affect markers of oxidative stress, inflammation, and fibrinolysis during hemodialysis, we conducted a randomized, double-blind, placebo-controlled 3×3 crossover study. We randomly assigned 15 participants undergoing hemodialysis to placebo, ramipril (5 mg/d), and valsartan (160 mg/d) for 7 days, with a washout period of 3 weeks in between the treatments. On the morning of the seventh day of drug treatment, participants underwent serial blood sampling during hemodialysis. Neither ramipril nor valsartan affected BP during hemodialysis. Ramipril increased IL-1β concentrations (P=0.02) and decreased IL-10 concentrations (P=0.04) compared with placebo. Valsartan and ramipril both lowered IL-6 levels during dialysis (P<0.01 for each compared with placebo). Valsartan increased F(2)-isoprostane levels, and ramipril suggested a similar trend (P=0.09). Valsartan and ramipril both lowered D-dimer levels (P<0.01 for both), whereas only ramipril seemed to prevent a rise in vWf levels (P=0.04). In summary, during hemodialysis, valsartan induces a greater anti-inflammatory effect compared with ramipril, although ramipril seems to prevent dialysis-induced endothelial dysfunction as measured by levels of vWf. A prospective clinical trial is necessary to determine whether ACE inhibitors and ARBs also differ with respect to their effects on cardiovascular mortality in this population.

PURPOSE: To determine the incidence and clinical and biomarker predictors of perioperative thrombosis in children with single ventricle physiology undergoing staged palliation. METHODS: Nineteen patients were enrolled and 16 completed the study. Serial ultrasounds of the central venous system were performed to evaluate for thrombus. Plasma antithrombin III, thrombin-antithrombin complex, protein C, protein S, tissue factor pathway inhibitor, plasminogen activator inhibitor-1, tissue plasminogen activator antigen, D-dimer, soluble CD40 ligand, and urinary thromboxane were measured serially before and after surgery. Cardiopulmonary bypass time, aortic cross clamp time, blood product administration, inotrope score, chest tube output, cardiac function by echocardiography, intensive care unit and hospital lengths of stay, and central venous catheter days were recorded. RESULTS: The incidence of perioperative thrombus was 31%. Patients who developed a thrombus had poorer preoperative ventricular function (p = 0.03) and longer cardiopulmonary bypass times (p = 0.03) than those who did not develop a thrombus. Preoperative plasma antithrombin III was lower (p = 0.01) and tissue plasminogen activator antigen concentrations were higher (p = 0.02) in patients with a thrombus compared with patients without a thrombus. When measured over time, antithrombin III remained lower (p = 0.002) and tissue plasminogen activator antigen higher (p = 0.005) in those who developed a thrombus compared with those who did not. There were no other statistically significant differences in biomarkers of coagulation between patients with and without thrombosis. CONCLUSION: One-third of patients undergoing palliative surgery for single ventricle physiology develop thrombosis. Decreased ventricular function, low antithrombin III, and increased tissue plasminogen activator may predict those most suitable for randomized clinical trials of anticoagulation.

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