Citations

Abstract Eosinophils are multifunctional leukocytes involved in various inflammatory processes, as well as tissue remodeling and immunoregulation. During inflammation and infection, injured cells and damaged tissues release uric acid and monosodium urate (MSU) crystals as important endogenous danger signals. Uric acid is also implicated in the immunogenic effects of an authentic Th2 adjuvant, aluminum hydroxide. Eosinophils often localize at sites of Th2-type chronic inflammation; therefore, we hypothesized that eosinophils may react to endogenous danger signals. We found that human eosinophils migrate toward soluble uric acid and MSU crystals in a gradient-dependent manner. Eosinophils incubated with MSU crystals, but not those incubated with uric acid solution, produced elevated levels of IL-6 and IL-8/CXCL8. Other cytokines and chemokines, including IL-1β, IL-10, IL-17, IFN-γ, CCL2, CCL3, CCL4, TNF-α, G-CSF, GM-CSF, fibroblast growth factor, vascular endothelial growth factor, and TGF-β, were also produced by eosinophils incubated with MSU crystals. Eosinophils exposed to MSU crystals rapidly (i.e., within 1 min of exposure) released ATP into the extracellular milieu. Importantly, this autocrine ATP was necessary for eosinophils to produce cytokines in response to MSU crystals, and P2 nucleotide receptors, in particular P2Y2, are likely involved in this positive feedback loop. Finally, at higher concentrations, MSU crystals promoted P2R-dependent release of a granule protein (eosinophil-derived neurotoxin) and cell death. Thus, human eosinophils may respond to particulate damage-associated endogenous danger signals. These responses by eosinophils to tissue damage may explain the self-perpetuating nature of chronic inflammation in certain human diseases, such as asthma.

Evidence has emerged that the clinical benefit of tamoxifen is related to the functional status of the hepatic metabolizing enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6 is the key enzyme responsible for the generation of the potent tamoxifen metabolite, endoxifen. Multiple studies have examined the relationship of CYP2D6 status to breast cancer outcomes in tamoxifen-treated women; the majority of studies demonstrated that women with impaired CYP2D6 metabolism have lower endoxifen concentrations and a greater risk of breast cancer recurrence. As a result, practitioners must be aware that some of the most commonly prescribed medications coadministered with tamoxifen interfere with CYP2D6 function, thereby reducing endoxifen concentrations and potentially increasing the risk of breast cancer recurrence. After reviewing the published data regarding tamoxifen metabolism and the evidence relating CYP2D6 status to breast cancer outcomes in tamoxifen-treated patients, we are providing a guide for the use of medications that inhibit CYP2D6 in patients administered tamoxifen.

Purpose Multiple studies have found an association between the prompt initiation of empirically-appropriate antimicrobial therapy and improved patient outcomes. Such empiric-antimicrobial therapy is often broad; however, once the patient's infectious syndrome, microbiology, and susceptibilities are more defined, it is important to refine antimicrobial therapy. Despite the potential benefits of an “antimicrobial de-escalation” approach, it may be difficult to enforce in clinical practice. Mayo Clinic's Computer-Based Antimicrobial Monitoring System (CBAM) is a medical-informatics tool that was used to assist in this endeavor. This study evaluates the hypothesis that CBAM can enhance the de-escalation of vancomycin and broad-spectrum combination antimicrobial therapy. Methods Hospitalized patients at the Mayo Clinic were screened from January through June 2006 using rule-based algorithms incorporated by CBAM. Interventions were performed by physicians and pharmacists as pertinent. These patients were compared with a historical group of patients obtained by CBAM reporting capabilities. De-escalation rates and mean duration of antimicrobial therapy were compared between groups. Results Vancomycin de-escalation rates significantly improved from 33% to 68% with intervention ( P = 0.001). In addition, the average duration of therapy was decreased from 10.4 ± 7.3 days to 7.7 ± 2.4 days among patients who underwent vancomycin de-escalation per recommendation ( P = 0.014). Conclusions Utilizing the Mayo Clinic's CBAM system to identify potential patients for de-escalation is a unique approach and was successful at improving adherence to vancomycin de-escalation.

There is little information available at present regarding the mechanisms of failure of modern metallic radial head implants. Between 1998 and 2008, 44 consecutive patients (47 elbows) underwent removal of a failed metallic radial head replacement. In 13 patients (13 elbows) the initial operation had been undertaken within one week of a fracture of the radial head, at one to six weeks in seven patients (seven elbows) and more than six weeks (mean of 2.5 years (2 to 65 months)) in 22 patients (25 elbows). In the remaining two elbows the replacement was inserted for non-traumatic reasons. The most common indication for further surgery was painful loosening (31 elbows). Revision was undertaken for stiffness in 18 elbows, instability in nine, and deep infection in two. There were signs of over-lengthening of the radius in 11 elbows. Degenerative changes were found in all but one. Only three loose implants had been fixed with cement. Instability was not identified in any of the bipolar implants.