Faculty Bibliography

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.

PURPOSE: To determine whether lack of visualization of the appendix on otherwise normal abdominopelvic computed tomographic (CT) images can help exclude appendicitis in the pediatric population. MATERIALS AND METHODS: The study was institutional review board approved and HIPAA compliant. One thousand one hundred thirty-nine children suspected of having appendicitis were referred for CT examination between July 2002 and December 2006. Exclusion criteria included CT diagnosis of appendicitis or other cause of symptoms and lack of clinical follow-up. Consensus review was performed by two pediatric radiologists to determine normal examinations, leaving a final study group (nonvisualized appendix) of 156 patients (mean age, 9.6 years; boys, 7.2 years; girls, 10.2 years) and a control group (visualized appendix) of 421 patients (mean age, 11.0 years; boys, 9.8 years; girls, 11.2 years). In the control group, there were 168 subjects with a partially visualized (PV) appendix and 253 with a fully visualized (FV) appendix. Pericecal fat was graded according to published criteria. Diagnosis was confirmed at surgery or clinical follow-up. Negative predictive values were calculated with 95% confidence intervals (CIs). RESULTS: There were three false-negative findings (study group, two; control group, one [FV]). The negative predictive value of a normal CT examination in pediatric patients with a nonvisualized appendix was 98.7% (95% CI: 95.5%, 99.8%); that with a visualized appendix, 99.8% (95% CI: 98.7%, 99.99%); that with a PV appendix, 100% (95% CI: 97.8%, 100%); and that with a FV appendix, 99.6% (95% CI: 97.8%, 99.99%). CONCLUSION: Pediatric abdominopelvic CT images with nonvisualized appendix have a high negative predictive value, without significant difference from cases with a PV or even FV appendix. The false-negative rate was similar to those reported in two adult series

OBJECTIVE: The purpose of our study was to evaluate the diagnostic efficacy and impact of emergent MRI after recent intervention in children with suspected osteomyelitis or septic arthritis. MATERIALS AND METHODS: This retrospective case-control study in children with suspected osteomyelitis or septic arthritis consisted of 34 study subjects (mean age, 5.3 years) who underwent MRI after intervention and 96 control subjects (mean age, 8.7 years) who underwent MRI without prior intervention. Final diagnosis and management were abstracted from medical records. Consensus MRI review of the study group was performed to evaluate whether objective MRI criteria of osteomyelitis can be applied to patients who have undergone prior intervention. RESULTS: For the study and control groups, no difference was seen in the final diagnosis of osteomyelitis (26.5% [9/34] and 29.2% [28/96], p = 0.76), osteomyelitis or septic arthritis (41.2% [14/34] and 37.5% [36/96], p = 0.70), cellulitis or pyomyositis (20.6% [7/34] and 34.4% [33/96], p = 0.13), and noninfectious conditions (23.5% [8/34] and 13.5% [13/96], p = 0.17). Objective MRI criteria for osteomyelitis were present in all nine patients with a final diagnosis of osteomyelitis and were not present in the remaining 25 who did not have a final diagnosis of osteomyelitis despite recent intervention. Repeat interventions were necessary in the study group at a rate not significantly different from single interventions in the control group (29.4% [10/34] and 27.1% [26/96], p = 0.79). CONCLUSION: Iatrogenic soft-tissue and bone edema related to recent intervention in children with suspected osteomyelitis or septic arthritis does not affect the diagnostic efficacy of MRI. Performing MRI before intervention adds efficacy to patient management, prevents unnecessary interventions, and guides surgical procedures when indicated

BACKGROUND:Postoperative atrial fibrillation (AF), a frequent complication after cardiac surgery, causes morbidity and prolongs hospitalization. Inotropic drugs are commonly used perioperatively to support ventricular function. This study tested the hypothesis that the use of inotropic drugs is associated with postoperative AF. METHODS AND RESULTS/RESULTS:We evaluated perioperative risk factors in 232 patients who underwent elective cardiac surgery. All patients were in sinus rhythm at surgery. Sixty-seven patients (28.9%) developed AF a mean of 2.9+/-2.1 days after surgery. Patients who developed AF stayed in the hospital longer (P<0.001) and were more likely to die (P=0.02). Milrinone use was associated with an increased risk of postoperative AF (58.2% versus 26.1% in nonusers; P<0.001). Older age (63.4+/-10.7 versus 56.7+/-12.3 years; P<0.001), hypertension (P=0.04), lower preoperative ejection fraction (P=0.03), mitral valve surgery (P=0.02), right ventricular dysfunction (P=0.03), and higher mean pulmonary artery pressure (27.1+/-9.3 versus 21.8+/-7.5 mm Hg; P=0.001) also were associated with postoperative AF. In multivariable logistic regression, age (P<0.001), ejection fraction (P=0.02), and milrinone use (odds ratio, 4.86; 95% confidence interval, 2.31 to 10.25; P<0.001) independently predicted postoperative AF. When only data from patients with pulmonary artery catheters were analyzed and pulmonary artery pressure was included in the model, age, milrinone use (odds ratio, 4.45; 95% confidence interval, 2.01 to 9.84; P<0.001), and higher pulmonary artery pressure (P=0.02) were associated with an increased risk of postoperative AF. Adding other potential confounders or stratifying analysis by mitral valve surgery did not change the association of milrinone use with postoperative AF. CONCLUSIONS:Milrinone use is an independent risk factor for postoperative AF after elective cardiac surgery.

PURPOSE: To assess the incremental value of the left-side-down decubitus view in radiographic evaluation of ileocolic intussusception. MATERIALS AND METHODS: The institutional review board approved this retrospective investigation with waiver of informed consent. Between February 24, 2002, and January 25, 2007, 304 studies (300 patients; mean age, 1.3 years; range, 0.1-3.9 years) met the following inclusion criteria: kidney ureter bladder (KUB) and decubitus views obtained, with subsequent proof of diagnosis. Using a consensus approach, two pediatric radiologists evaluated KUB and decubitus views for four variables: (a) discrete mass and (b) small-bowel obstruction (positive criteria); (c) air or stool in ascending colon and (d) cecal air or stool (negative criteria). On the basis of these criteria, each study was graded as negative, positive, or indeterminate for intussusception. Diagnostically determinate studies and the ability to visualize or exclude intussusception were calculated to determine sensitivity and specificity. The difference between proportions was calculated, along with 95% confidence intervals. Agreement between the supine KUB view and supine KUB plus left-side-down decubitus views was tested with the McNemar test. RESULTS: Intussusception was present in 58 of 304 studies (19%). Adding the decubitus view to the KUB view increased the number of determinate studies from 110 of 304 (36.2%) to 205 of 304 (67.4%) (difference, 31.2 percentage points; P < .001). Intussusception was correctly identified with KUB view alone in 35 of 58 studies (60.3%); this value increased to 43 of 58 (74.1%) with KUB plus decubitus views (P = .0215). Intussusception was correctly excluded with the KUB view alone in 63 of 246 studies (25.6%); this increased to 143 of 246 studies (58.1%) with addition of the decubitus view (P < .0001). CONCLUSION: The addition of decubitus views increased the number of diagnostically determinate studies and increased the ability to diagnose or exclude intussusception. The authors believe that a left-side-down decubitus view should be included in the initial evaluation of patients suspected of having intussusception, particularly when the supine view is diagnostically indeterminate

CYP4A11 arachidonic acid monooxygenase oxidizes endogenous arachidonic acid to 20-hydroxyeicosatetraenoic acid, a renal vasoconstrictor and natriuretic. Cyp4a deficiency causes hypertension in male mice, and a loss-of-function variant (T8590C) of CYP4A11 is associated with hypertension in white individuals. Hypertension and hypertensive renal disease are more common among black than white individuals, but the relationship between genetic variation at CYP4A11 and hypertension in black individuals is not known. This study tested the hypothesis that the CYP4A11 T8590C polymorphism is associated with higher BP or clinical outcomes in 732 black Americans with hypertensive renal disease participating in the African American Study of Kidney Disease (AASK). Men with the 8590CC genotype had significantly higher systolic BP (CC 156.5 +/- 22.6 versus 148.4 +/- 24.3 mmHg in CT and TT combined; P = 0.04) and pulse pressure (P = 0.04) at baseline; this association was not observed among women. In addition, this genotype was associated with higher systolic and diastolic BP at 36-mo follow-up among those randomly assigned to the lower BP arm of the AASK. Among all participants (or men but not women) with proteinuria, the 8590CC genotype was associated with an increased cumulative incidence of ESRD or death, controlling for randomization and clinical characteristics. In summary, the CYP4A11 8590CC genotype is associated with increased BP in black men with hypertensive nephrosclerosis and is associated with adverse clinical outcomes in those with baseline proteinuria. These data support a role for renal monooxygenases and 20-hydroxyeicosatetraenoic acid in the regulation of BP and renal function in men.

AIM: To determine reliable magnetic resonance imaging (MRI) features differentiating three paediatric intra-articular congenital or neoplastic synovial lesions that contain blood products, from post-traumatic or haemorrhagic inflammatory processes. MATERIALS AND METHODS: This was a retrospective review of MRI findings of 22 paediatric intra-articular congenital or neoplastic synovial lesions, including venous malformation (VM) (n=12), pigmented villonodular synovitis (PVNS; n=8), and synovial sarcoma (SS; n=2). These MRI features were compared with 22 paediatric post-traumatic or inflammatory intra-articular processes containing blood products and producing mass effect. The following imaging features were assessed: presence of a discrete mass, extension, extra-articular oedema, susceptibility, joint effusion, and size. Fisher's exact test was used and results were considered statistically significant when p<0.05. RESULTS: The three intra-articular synovial lesions, compared with controls, were more likely to directly invade osseous structures when a discrete mass was present (13/16, 81.3% versus 1/9, 11.1%; p<0.002) and extend into extra-articular soft tissues (13/21, 61.9% versus 2/17, 11.8%; p<0.003), but were less likely to show extra-articular oedema (3/22, 13.6% versus 13/22, 59.1%; p<0.004), a joint effusion (10/22,45.5% versus 19/22, 86.4%, p<0.01), susceptibility within a joint effusion (0/22, 0% versus 11/22, 40.9%; p=0.00), osseous oedema (3/16, 18.8% versus 7/9, 77.8%; p<0.009), and synovial enhancement (8/21, 38.1% versus 14/16, 87.5%; p<0.003). VMs had characteristic tubular vessels with internal fluid-fluid levels (11/12) that extended into bone (10/12) and extracapsular soft tissues (11/12). CONCLUSION: Our study indicates that, despite the overlapping presence of haemorrhagic products, intra-articular VM, PVNS, and SS show MRI features that permit distinction from acquired post-traumatic and haemorrhagic inflammatory lesions