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Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturer-recommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft-Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 10-40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine-based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.

Objective To test the hypothesis that high-fat (HF) diet-induced obesity increases pro-inflammatory cytokine expression, macrophage infiltration and M1 polarization in the infrapatellar fat pad (IFP) prior to knee cartilage degeneration. Methods We characterized the effect of HF feeding on knee OA pathology, body adiposity, and glucose intolerance in male C57BL/6J mice and identified a diet duration that induces metabolic dysfunction prior to cartilage degeneration. Magnetic resonance imaging and histomorphology were used to quantify changes in epididymal, subcutaneous, and infrapatellar fat pads and adipocyte sizes. Finally, we utilized targeted gene expression and protein arrays, immunohistochemsitry, and flow cytometry to quantify differences in fat pad inflammatory markers and immune cell populations. Results 20 weeks of HF diet treatment induced marked obesity, glucose intolerance, and early osteoarthritis (OA), including osteophytes and cartilage tidemark duplication. This duration of HF feeding increased IFP volume. However, it did not increase IFP inflammation, macrophage infiltration, or M1 macrophage polarization as observed in epididymal fat. Furthermore, leptin protein was reduced. This protection from obesity-induced inflammation corresponded with increased IFP fibrosis and the absence of adipocyte hypertrophy. Conclusion The IFP does not recapitulate classical abdominal adipose tissue inflammation during the early stages of knee OA in a high-fat diet-induced model of obesity. Consequently, these findings do not support the hypothesis that IFP inflammation is an initiating factor of obesity-induced knee OA. Furthermore, the pro-fibrotic and anti-hypertrophic responses of IFP adipocytes to high-fat feeding suggest that intra-articular adipocytes are subject to distinct spatial-temporal structural and metabolic regulation among fat pads.

Objective To quantify functional age-related changes in the cartilage antioxidant network to discover novel mediators of cartilage oxidative stress and osteoarthritis (OA) pathophysiology. Methods We evaluated knee OA histopathology in 10, 20, and 30-month old male F344BN rats and analyzed cartilage oxidation by the ratio of reduced:oxidized glutathione. Antioxidant gene expression and protein abundance were analyzed by qRT-PCR and selected reaction-monitoring mass spectrometry, respectively. Superoxide dismutase 2 (SOD2) activity and acetylation were analyzed by colorimetric enzyme assays and Western blotting, respectively. We examined human OA cartilage to evaluate the clinical relevance of SOD2 acetylation, and we tested age-related changes in the mitochondrial deacetylase, sirtuin 3 (SIRT3), in rats and mice. Results Cartilage oxidation and OA severity increased with age and were associated with an increase in SOD2 expression and protein abundance. However, SOD2 specific activity decreased with age due to elevated post-translational lysine acetylation. Consistent with these findings, SIRT3 decreased substantially with age, and treatment with SIRT3 increased SOD2 activity in an age-dependent manner. SOD2 was also acetylated in human OA cartilage, and activity was increased with SIRT3 treatment. Moreover, in C57BL6 mice, cartilage SIRT3 expression decreased with age and whole-body deletion of SIRT3 accelerated the development of knee OA. Conclusion Our results show that SIRT3 mediates age-related changes in cartilage redox regulation and protects against early-stage OA. These findings suggest that mitochondrial acetylation promotes OA and that restoration of SIRT3 in aging cartilage may improve cartilage resistance to oxidative stress by rescuing acetylation-dependent inhibition of SOD2 activity.

BACKGROUND: Due to high rates of resistance and a limited number of efficacious antimicrobials for vancomycin‐resistant Enterococcus (VRE), appropriate antibiotic selection is vital to treatment success. The purpose of this study was to assess clinical and microbiologic outcomes associated with the use of linezolid or daptomycin in the treatment of VRE bacteremia. METHODS: A retrospective analysis of adult patients with VRE bacteremia between January 2004 and July 2009 was conducted at a tertiary care hospital in the United States. Clinical and microbiologic outcomes for both therapies were evaluated using multiple criteria. RESULTS: Of the 361 patients with VRE bacteremia identified, 201 were included in the study (linezolid group, n = 138; daptomycin group, n = 63). More patients in the daptomycin group had hematologic malignancies (33% vs 14%) or received liver transplants (13% vs 4%). There was no difference in clinical or microbiologic cure between the linezolid and daptomycin groups (74% vs 75% and 94% vs 94%, respectively). Recurrence was documented in 3% of linezolid patients vs 12% of daptomycin patients (P = 0.0321). Reinfection was noted in 1% of patients in the linezolid group vs 6% of patients in the daptomycin group (P not significant). The average length of stay (LOS) was 37 days for the linezolid group vs 40 days for the daptomycin group (P not significant). Overall mortality was 20%, occurring in 25/138 linezolid patients vs 15/63 daptomycin patients (P not significant). CONCLUSIONS: No differences in clinical or microbiologic cure rates, LOS, or mortality were identified between the groups. Various factors may have contributed to the significantly higher recurrence of VRE bacteremia in daptomycin patients. This study suggests that linezolid and daptomycin appear equally efficacious in the treatment of VRE bacteremia. Journal of Hospital Medicine 2011;. © 2011 Society of Hospital Medicine.

Hyperkalemia is a common electrolyte abnormality identified in the emergency department (ED) and potentially fatal. However, there is no consensus over the potassium threshold that warrants intervention or its treatment algorithm. Commonly used medications are at best temporizing measures, and the roles of binders are unclear in the emergent setting. As the prevalence of comorbid conditions altering potassium homeostasis rises, hyperkalemia becomes more common, and hence there is a need to standardize management. A panel was assembled to synthesize the available evidence and identify gaps in knowledge in hyperkalemia treatment in the ED. The panel was composed of 7 medical practitioners, including 5 physicians, a nurse, and a clinical pharmacist with collective expertise in the areas of emergency medicine, nephrology, and hospital medicine. This panel was sponsored by the American College of Emergency Physicians with a goal to create a consensus document for managing acute hyperkalemia. The panel evaluated the evidence on calcium for myocyte stabilization and potassium shifting and excretion. This article summarizes information on available therapies for hyperkalemia and proposes a hyperkalemia treatment algorithm for the ED practitioner based on the currently available literature and highlights diagnostic pitfalls and evidence gaps.

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Objective We evaluated the effect of a reduction in the systemic ratio of n-6:n-3 polyunsaturated fatty acids (PUFAs) on changes in inflammation, glucose metabolism, and the idiopathic development of knee osteoarthritis (OA) in mice. We hypothesized that a lower ratio of n-6:n-3 PUFAs would protect against OA markers in cartilage and synovium, but not bone. Design Male and female fat-1 transgenic mice (Fat-1), which convert dietary n-6 to n-3 PUFAs endogenously, and their wild-type (WT) littermates were fed an n-6 PUFA enriched diet for 9-14 months. The effect of gender and genotype on serum PUFAs, IL-6, TNF-α, and glucose tolerance was tested by 2-factor analysis of variance. Cortical and trabecular subchondral bone changes were documented by micro-focal computed tomography, and knee OA was assessed by semi-quantitative histomorphometry grading. Results The n-6:n-3 ratio was reduced 12-fold and 7-fold in male and female Fat-1 mice, respectively, compared to WT littermates. IL-6 and TNF-α levels were reduced modestly in Fat-1 mice. However, these systemic changes did not reduce osteophyte development, synovial hyperplasia, or cartilage degeneration. Also the fat-1 transgene did not alter subchondral cortical or trabecular bone morphology or bone mineral density. Conclusions Reducing the systemic n-6:n-3 ratio does not slow idiopathic changes in cartilage, synovium, or bone associated with early-stage knee OA in mice. The anti-inflammatory and anti-catabolic effects of n-3 PUFAs previously reported for cartilage may be more evident at later stages of disease or in post-traumatic and other inflammatory models of OA.