There is growing evidence that sepsis-related complications in neonates are crucially mediated by the action of proinflammatory cytokines. It has previously been demonstrated that elevated IL-6 and IL-8 levels can predict brain damage and chronic lung disease in preterm infants. However, it is the current view that neonates have a reduced capability to produce proinflammatory cytokines. To clarify this issue, we analyzed the inflammatory response in term and preterm infants directly at the single cell level by flow cytometry. Endotoxin challenge was performed under defined conditions on monocytes obtained from 50 healthy adults and 119 neonates, which consist of 45 term infants, 63 preterm infants (26.1-36.7 wk of gestational age), and 11 preterm infants with proven infection (24.6 -29.9 wk). Our results challenge the existing view of an immature inflammatory response by demonstrating that term infants and preterm infants display a higher percentage of IL-6 -and IL-8 -positive cells than adults. After preincubation with dexamethasone the number of cytokine-positive cells decreased in all groups, but the number of IL-8 -positive cells remained higher in term and preterm infants Ͼ32 wk compared with adults. These observations demonstrate not only a well-developed but also an enhanced inflammatory response in term and preterm infants. Under consideration of several detrimental effects of IL-6 and IL-8, our data may have major implications on the pathophysiology of inflammatorytriggered neonatal diseases. Neonatal bacterial sepsis remains a critical determinant of outcome in infants of very low birth weight despite the availability of antibiotics (1-3). The immaturity of the neonatal immune system, especially a reduced cytokine-producing capacity, was assumed to be responsible for the high susceptibility to infections (4 -11). Particularly, the high prevalence of complications secondary to infections represents a major determinant of neonatal mortality and morbidity (3). Although older children and adults are usually able to restrict bacterial infections, neonates often develop a severe systemic inflammatory response with detrimental effects. There is growing evidence that this process is crucially mediated by the action of distinct inflammatory cytokines (12, 13). It has previously been demonstrated that elevated IL-6 and IL-8 levels in cord blood and lung lavage can predict neonatal brain damage and chronic lung disease in preterm infants (14 -16). Furthermore, proinflammatory cytokines could be demonstrated in high amounts in brain white matter lesions of preterm infants (17). These observations strongly suggest a key role of proinflammatory cytokines in the pathogenesis of several neonatal diseases. Although a variety of studies have been performed on inflammatory mediators in neonates during infection, these data can be misleading because of the evolving immunoparalysis occurring in progressing sepsis (18,19). To better characterize the inflammatory response in neonates we performed an ex vivo model of sepsis, ...
Intracytoplasmic detection of cytokines by flow cytometry has become a powerful tool in the characterization of cytokine-producing cells. However, it is not known to what extent specimen age and the use of various negative controls may influence the amount of cytokine-positive cells. We therefore compared different times of storage and the use of several negative controls in the determination of intracytoplasmic levels of cytokines. There was a substantial decline of interleukin-2-and gamma interferon-positive lymphocytes after 20 h and especially after 48 h of storage. The precision of intracytoplasmic interleukin-6 determination decreases after long-term storage compared to 2 h of storage, whereas the amount of interleukin-8-positive monocytes remained rather stable. Therefore, we recommend performing the analysis as fast as possible after the blood sample is drawn. Under consideration of isotype-matched antibodies and nonstimulated cells as negative controls instead of the purified antibody-blocking control, strikingly higher amounts of interleukin-2-, gamma interferon, interleukin-6-, and interleukin-8-positive cells were found. For a meaningful interpretation of data these differences have to be kept in mind. Further studies should evaluate the exact specificity of these controls.
Background: The aim is to compare the machine learning-based coronary-computed tomography fractional flow reserve (CT-FFRML) and coronary-computed tomographic morphological plaque characteristics with the resting full-cycle ratio (RFRTM) as a novel invasive resting pressure-wire index for detecting hemodynamically significant coronary artery stenosis. Methods: In our single center study, patients with coronary artery disease (CAD) who had a clinically indicated coronary computed tomography angiography (cCTA) and subsequent invasive coronary angiography (ICA) with pressure wire-measurement were included. On-site prototype CT-FFRML software and on-site CT-plaque software were used to calculate the hemodynamic relevance of coronary stenosis. Results: We enrolled 33 patients (70% male, mean age 68 ± 12 years). On a per-lesion basis, the area under the receiver operating characteristic curve (AUC) of CT-FFRML (0.90) was higher than the AUCs of the morphological plaque characteristics length/minimal luminal diameter4 (LL/MLD4; 0.80), minimal luminal diameter (MLD; 0.77), remodeling index (RI; 0.76), degree of luminal diameter stenosis (0.75), and minimal luminal area (MLA; 0.75). Conclusion: CT-FFRML and morphological plaque characteristics show a significant correlation to detected hemodynamically significant coronary stenosis. Whole CT-FFRML had the best discriminatory power, using RFRTM as the reference standard.
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