Faculty Bibliography

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

The acetylcholinesterase inhibitor donepezil hydrochloride improves cognitive function in patients with Alzheimer's disease and vascular dementia. Given acetylcholine's important actions on the heart, we undertook a retrospective cohort investigation to assess whether donepezil usage affects cardiovascular mortality. In patients treated with donepezil, hazard ratios for total and cardiovascular mortality were 0.68 (P = 0.045, 95% confidence interval 0.46-0.99) and 0.54 (P = 0.042, 95% confidence interval 0.30-0.98), respectively. The apparent survival benefit in donepezil-treated patients should not be overinterpreted. Prospective clinical trials are warranted.

BACKGROUND: Chest CT after pediatric trauma is frequently performed but its clinical impact, particularly with respect to surgical intervention, has not been adequately evaluated. OBJECTIVE: To assess the impact of chest CT compared with chest radiography on pediatric trauma management. MATERIALS AND METHODS: Two hundred thirty-five consecutive pediatric trauma patients who had both chest CT and radiography were identified. Images were reviewed and findings were categorized and correlated with subsequent chest interventions, blinded to final outcome and management. RESULTS: Of the 235 children, 38.3% (90/235) had an abnormal chest radiograph and 63.8% (150/235) had an abnormal chest CT (P < 0.0001). Chest interventions followed in 4.7% (11/235); of these, the findings could be made 1 cm above the dome of the liver in 91% (10/11). Findings requiring chest intervention included pneumothorax (PTX) and vertebral fractures. PTX was found on 2.1% (5/235) of chest radiographs and 20.0% (47/235) of chest CTs (P < 0.0001); 1.7% (4/235) of the children received a chest tube for PTX, 0.85% (2/235) seen on chest CT only. Vertebral fractures were present in 3.8% of the children (9/235) and 66.7% (6/9) of those cases were treated with spinal fusion or brace. There were no instances of mediastinal vascular injury. CONCLUSION: Most intrathoracic findings requiring surgical management in our population were identified in the lower chest and would be included in routine abdominopelvic CT exams; this information needs to be taken into consideration in the diagnostic algorithm of pediatric trauma patients

BACKGROUND:Previous studies of children with homozygous sickle cell anemia (SCA) show impaired growth and maturation. The correlation of this suboptimal growth with metabolic and hematological factors during puberty is poorly understood. PROCEDURE/METHODS:We studied a group of pre-adolescent children with SCA (19 males, 14 females) and healthy controls (16 males, 15 females) matched for race, sex, body size, and pubertal development. Height, weight, body mass index (BMI), and body composition changes were longitudinally assessed over a 2-year period and compared between the groups and with Z scores based on US growth charts. These changes were correlated with hemoglobin (Hgb) concentration and with energy expenditure (EE) measured using indirect whole-room calorimetry. RESULTS:Children with SCA progressed through puberty slower than control children. While, after 2 years, pubertal males with SCA were shorter, their annual increases in weight were not different from controls. The mean fat free mass (FFM) increments were significantly less in males and females with SCA than in control children. In males with SCA, growth in height declined over time and was significantly slower than in matched controls (P < 0.05). CONCLUSION/CONCLUSIONS:Growth delays were present during puberty in children with SCA. Decreased growth velocity in children with SCA was independently associated with decreased Hgb concentration and increased total EE.

BACKGROUND:Autosomal dominant inheritance of germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for pulmonary arterial hypertension (PAH). While previous studies demonstrated a difference in severity between BMPR2 mutation carriers and noncarriers, it is likely disease severity is not equal among BMPR2 mutations. We hypothesized that patients with missense BMPR2 mutations have more severe disease than those with truncating mutations. METHODS:Testing for BMPR2 mutations was performed in 169 patients with PAH (125 with a family history of PAH and 44 with sporadic disease). Of the 106 patients with a detectable BMPR2 mutation, lymphocytes were available in 96 to functionally assess the nonsense-mediated decay pathway of RNA surveillance. Phenotypic characteristics were compared between BMPR2 mutation carriers and noncarriers, as well as between those carriers with a missense versus truncating mutation. RESULTS:While there was a statistically significant difference in age at diagnosis between carriers and noncarriers, subgroup analysis revealed this to be the case only for females. Among carriers, there was no difference in age at diagnosis, death, or survival according to exonic location of the BMPR2 mutation. However, patients with missense mutations had statistically significant younger ages at diagnosis and death, as well as shorter survival from diagnosis to death or lung transplantation than those with truncating mutations. Consistent with this data, the majority of missense mutations were penetrant prior to age 36 years, while the majority of truncating mutations were penetrant after age 36 years. CONCLUSION/CONCLUSIONS:In this cohort, BMPR2 mutation carriers have more severe PAH disease than noncarriers, but this is only the case for females. Among carriers, patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations. These findings suggest that treatment and prevention strategies directed specifically at BMPR2 pathway defects may need to vary according to the type of mutation.

Testing Hardy-Weinberg equilibrium (HWE) in the control group is commonly used to detect genotyping errors in genetic association studies. We propose a likelihood ratio test for testing HWE in the study population using both case and control samples. This test incorporates underlying association models. Another feature is that, when we infer the disease-genotype association, we explicitly incorporate HWE or a possible departure from Hardy-Weinberg equilibrium (DHWE) into the model. Our unified framework enables us to infer the disease-genotype association when a detected DHWE needs to be part of the model after causes for the DHWE are explored. Real data sets are used to illustrate the application of the methodology and its implication in genetic association studies. Our analysis and interpretation touch on issues such as genotyping errors, population selection, population stratification, or the study sampling plan, that all could be the cause of DHWE.