Pivotal findings for a high-sensitivity cardiac troponin assay: Results of the HIGH-US study.

BACKGROUND: Cardiac troponin (cTn) is the keystone for diagnosis of acute myocardial infarction (AMI). We examined the analytical and diagnostic accuracy of the Atellica IM TnIH assay to determine high-sensitivity performance and appropriate diagnostic performance for clinical use. METHODS: Sex-specific 99th percentile upper reference limits (URLs) were determined for a healthy cohort of 1007 women and 1000 men using non-parametric statistics. High-sensitivity performance was assessed by examining if imprecision was ≤10% at sex-specific URLs and if ≥50% of cTnI values for each sex exceeded the assay's limit of detection (LoD) with the AACC Universal Sample Bank. Precision, high-dose hook effect, endogenous/exogenous interferences were examined with CLSI guidance. Clinical characterization was with 2494 suspected AMI subjects presenting to emergency departments across the United States. AMI was adjudicated by expert cardiologists and emergency medicine physicians. There were no comorbidity exclusions. RESULTS: 99th percentile URLs were 34 ng/L, 53 ng/L and 45 ng/L for the female, male and overall populations, respectively. Total imprecision was <5% from 12 ng/L to 16,000 ng/L; ≥55% of cTnI values for each sex exceeded the LoD. No high-dose hook or endogenous/exogenous interferences were identified. After 2.5-3.5 h post presentation the sensitivity and specificity were >90%; negative and positive predictive value were ≥98% and >60%, respectively. Non-AMI subjects with comorbidities and values exceeding 99th percentile URLs had absolute and percent change at 2-4 h that were lower than AMI patients with comorbidities (p = 0.001). CONCLUSION: The Atellica IM TnIH assay is a high-sensitivity method and demonstrates clinical performance appropriate for AMI diagnosis.

Cytokine dependent inverse regulation of CD54 (ICAM1) and major histocompatibility complex class I antigens by nuclear factor kappaB in HEp2 tumor cell line: effect on the function of natural killer cells.

The aim of this study is to investigate the mechanisms by which elevated nuclear factor kappaB (NFkappaB) activity in HEp2 cells can modulate the function and survival of immune effector cells. Inhibition of NFkappaB functional activity by stable expression of IkappaB super-repressor rendered HEp2 cells (HEp2-IkappaB((S32AS36A))) susceptible to natural killer (NK) cell mediated cytotoxicity. Increase in surface ICAM1 expression was greater on HEp2-IkappaB((S32AS36A)) cells than on the surface of vector alone transfected HEp2 cells when these cells were treated with IFN-gamma. In contrast, tumor necrosis factor alpha (TNF-alpha) treatment augmented ICAM-1 expression on the surface of vector-alone transfected HEp2 cells and not on the HEp2-IkappaB((S32AS36A)) cells. Moreover, synergistic augmentation of ICAM-1 by a combination of TNF-alpha and interferon-gamma (IFN-gamma) treatment was completely abrogated on the surface of HEp2-IkappaB((S32AS36A)) cells. The addition of blocking antibody to ICAM-1 surface antigen partially inhibited the increased cytotxicity mediated by interleukin-2 treated NK cells against HEp2-IkappaB((S32AS36A)) cells. In contrast to ICAM-1, the expression of major histocompatibility complex (MHC) class I antigens were downregulated when the function of nuclear NFkappaB was inhibited in HEp2 cells. The addition of IFN-gamma to HEp2-kappaB((S32AS36A)) cells increased the expression of MHC class I antigen and rendered these cells less susceptible to NK cell mediated cytotoxicity. Secretion of IFN-gamma and granulocyte macrophage-colony-stimulating factor (GM-CSF) by NK cells was also significantly increased in the presence of HEp2-IkappaB((S32AS36A)) cells, and the treatment of these tumor cells with IFN-gamma prior to their addition to the cultures of NK cells decreased the released IFN-gamma and GM-CSF by NK cells. However, the levels of NK cell mediated cytotoxicity and IFN-gamma secretion remained significantly higher in the presence of both untreated and IFN-gamma treated HEp2-IkappaB((S32AS36A)) cells when compared with vector-alone transfected HEp2 cells. Thus, NFkappaB regulates inversely the expression of ICAM-1 and MHC class I antigens on HEp2 tumor cells and this may contribute to the resistance of these cells to NK cell mediated cytotoxicity.