Faculty Bibliography

Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular permeability and cause tissue edema in animals. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor-associated angioedema. This case-control study tested the hypothesis that dipeptidyl peptidase IV activity and antigen are decreased in sera of patients with a history of angiotensin-converting enzyme inhibitor-associated angioedema. Fifty subjects with a history of angiotensin-converting enzyme inhibitor-associated angioedema and 176 angiotensin-converting enzyme inhibitor-exposed control subjects were ascertained. Sera were assayed for angiotensin-converting enzyme activity, aminopeptidase P activity, aminopeptidase N activity, dipeptidyl peptidase IV activity, and antigen and the ex vivo degradation half-lives of bradykinin, des-Arg(9)-bradykinin, and substance P in a subset. The prevalence of smoking was increased and of diabetes decreased in case versus control subjects. Overall, dipeptidyl peptidase IV activity (26.6+/-7.8 versus 29.6+/-7.3 nmol/mL per minute; P=0.026) and antigen (465.8+/-260.8 versus 563.1+/-208.6 ng/mL; P=0.017) were decreased in sera from individuals with angiotensin-converting enzyme inhibitor-associated angioedema compared with angiotensin-converting enzyme inhibitor-exposed control subjects without angioedema. Dipeptidyl peptidase IV activity (21.5+/-4.9 versus 29.8+/-6.7 nmol/mL per minute; P=0.001) and antigen (354.4+/-124.7 versus 559.8+/-163.2 ng/mL; P=0.003) were decreased in sera from cases collected during angiotensin-converting enzyme inhibition but not in the absence of angiotensin-converting enzyme inhibition. The degradation half-life of substance P correlated inversely with dipeptidyl peptidase IV antigen during angiotensin-converting enzyme inhibition. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema.

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.

BACKGROUND:National guidelines recommend targeted tuberculin testing and treatment of latent tuberculosis infection (LTBI) among high-risk groups but discourage testing low-risk persons. METHODS:We determined the LTBI prevalence (tuberculin skin test [TST] reaction > or = 10 mm) among adults with and without TB exposure risk factors screened in Tennessee from 1/2/2002 to 4/19/2005. We then quantified LTBI risk among groups at high-risk for TB using multivariate analysis. RESULTS:Of 53,061 adults tested, the LTBI prevalence was 34% among foreign-born persons, compared with 3.2% among nonforeign-born persons (prevalence odds ratio [POR] 15.7, 95% confidence interval [CI] 14.5-16.8). Among nonforeign-born adults, Asian race (POR 11.7, 95% CI 5.9-23.4), and Hispanic ethnicity (POR 11.7, 95% CI 9.0-15.2) were most strongly associated with LTBI. Only 2.4% of low-risk persons had LTBI. CONCLUSIONS:Risk-based screening can effectively distinguish persons who will benefit from LTBI testing and treatment. Targeted testing programs should prioritize foreign-born persons. Testing of low-risk persons is unnecessary.

We describe new families of discrete distributions that are used to model sums of exchangeable Bernoulli random variables. These discrete distributions can be parameterized in terms of their range, mean, variance, and shape parameters. These models are fitted to an example involving mortality rates for children in a survey of families in Brazil. The methods illustrate that mortality rates in this survey increase with family size and that the correlation of within-family mortality status also depends on the family size. These methods are also applied to a laboratory study of birth defects in mice.

We examined the effect of -58 C/T and BE1 +9/-9 polymorphisms in the bradykinin B2 receptor gene on forearm vascular resistance (FVR) before and during intrabrachial artery infusion of the B2 receptor-, endothelium-dependent agonist bradykinin and the endothelium-independent agonist sodium nitroprusside in 228 normotensive subjects. In 166 white Americans, systolic blood pressure (SBP) and pulse pressure were highest in the BE1 +9/+9 group (118+/-2 and 51+/-2 mm Hg, respectively; P<0.05 versus -9/-9 for either), intermediate in the +9/-9 group (114+/-1 and 49+/-1 mm Hg, P<0.05 versus -9/-9 for pulse pressure), and lowest in the -9/-9 group (110+/-2 and 44+/-2 mm Hg). In 62 black Americans, FVR was 25% higher in the BE1 +9/+9 group compared with the BE1 +9/-9 and -9/-9 groups at baseline (P=0.038) or during bradykinin (P=0.03). Increased SBP or vascular resistance may contribute to increased left ventricular mass reported previously in individuals with the BE1+9/+9 genotype.

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.

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown etiology characterized by extrapyramidal, pyramidal, cerebellar, and autonomic dysfunction in any combination. We report a patient with a 4-year history of MSA who developed dementia associated with sporadic Creutzfeldt-Jakob disease (CJD). Our proband was MM homozygous for the M129V polymorphism within the prion protein gene (PRNP), a known risk factor for CJD. We conducted a case-control study to test the hypothesis that homozygosity for the M129V polymorphism of PRNP occurs more frequently in MSA in comparison to Parkinson's disease and healthy volunteers. A total of 63 patients with MSA, 54 age-, race- and gendermatched controls with Parkinson's disease, and 126 matched healthy volunteers were studied. The genotype analysis revealed no significant difference in the codon 129 genotype distribution in MSA as compared to controls. Nonetheless, the frequencies of the MM and VV genotypes were higher in MSA than in Parkinson's disease. Thus, homozygosity, particularly VV homozygosity, at codon 129 of PRNP is associated with MSA compared to a clinically related but pathophysiologically distinct alpha-synucleinopathy. Considering the possibility that the prion protein contributes to the pathogenesis of MSA would require confirmation of these findings in an independent patient population.

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

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

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