Obesity Inhibits Alveolar Macrophage Responses to Pseudomonas aeruginosa Pneumonia via Upregulation of Prostaglandin E2 in Male, but Not Female, Mice.

Obesity is associated with increased morbidity and mortality during bacterial pneumonia. Cyclooxygenase-2 (COX-2) and PGE2 have been shown to be upregulated in patients who are obese. In this study, we investigated the role of obesity and PGE2 in bacterial pneumonia and how inhibition of PGE2 improves antibacterial functions of macrophages. C57BL/6J male and female mice were fed either a normal diet (ND) or high-fat diet (HFD) for 16 wk. After this time, animals were infected with Pseudomonas aeruginosa in the lung. In uninfected animals, alveolar macrophages were extracted for either RNA analysis or to be cultured ex vivo for functional analysis. HFD resulted in changes in immune cell numbers in both noninfected and infected animals. HFD animals had increased bacterial burden compared with ND animals; however, male HFD animals had higher bacterial burden compared with HFD females. Alveolar macrophages from HFD males had decreased ability to phagocytize and kill bacteria and were shown to have increased cyclooxygenase-2 and PGE2. Treating male, but not female, alveolar macrophages with PGE2 leads to increases in cAMP and decreased bacterial phagocytosis. Treatment with lumiracoxib-conjugated nanocarriers targeting alveolar macrophages improves bacterial phagocytosis and clearance in both ND and HFD male animals. Our study highlights that obesity leads to worse morbidity during bacterial pneumonia in male mice because of elevated PGE2. In addition, we uncover a sex difference in both obesity and infection, because females produce high basal PGE2 but because of a failure to signal via cAMP do not display impaired phagocytosis.

Modified calcium subtraction in dual-energy CT angiography of the lower extremity runoff: impact on diagnostic accuracy for stenosis detection.

OBJECTIVES: To investigate the diagnostic accuracy of a modified three-material decomposition calcium subtraction (CS) algorithm for the detection of arterial stenosis in dual-energy CT angiography (DE-CTA) of the lower extremity runoff compared to standard image reconstruction, using digital subtraction angiography (DSA) as the reference standard. METHODS: Eighty-eight patients (53 males; mean age, 65.9 ± 11 years) with suspected peripheral arterial disease (PAD) who had undergone a DE-CTA examination of the lower extremity runoff between May 2014 and May 2015 were included in this IRB-approved, HIPAA-compliant retrospective study. Standard linearly blended and CS images were reconstructed and vascular contrast-to-noise ratios (CNR) were calculated. Two independent observers assessed subjective image quality using a 5-point Likert scale. Diagnostic accuracy for ≥ 50% stenosis detection was analyzed in a subgroup of 45 patients who had undergone additional DSA. Diagnostic accuracy parameters were estimated with a random-effects logistic regression analysis and compared using generalized estimating equations. RESULTS: CS datasets showed higher CNR (15.3 ± 7.3) compared to standard reconstructions (13.5 ± 6.5, p < 0.001). Both reconstructions showed comparable qualitative image quality scores (CS, 4.64; standard, 4.57; p = 0.220). Diagnostic accuracy (sensitivity, specificity, positive and negative predictive values) for CS reconstructions was 96.5% (97.5%, 95.6%, 90.9%, 98.1) and 93.1% (98.8%, 90.4%, 82.3%, 99.1%) for standard images. CONCLUSIONS: A modified three-material decomposition CS algorithm provides increased vascular CNR, equivalent qualitative image quality, and greater diagnostic accuracy for the detection of significant arterial stenosis of the lower extremity runoff on DE-CTA compared with standard image reconstruction. KEY POINTS: • Calcified plaques may lead to overestimation of stenosis severity and false positive results, requiring additional invasive digital subtraction angiography (DSA). • A modified three-material decomposition algorithm for calcium subtraction provides greater diagnostic accuracy for the detection of significant arterial stenosis of the lower extremity runoff compared with standard image reconstruction. • The application of this algorithm in patients with heavily calcified vessels may be helpful to potentially reduce inconclusive CT angiography examinations and the need for subsequent invasive DSA.