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Mutation of staphylococcal accessory regulator (sarA) results in increased production of extracellular proteases in Staphylococcus aureus, which has been correlated with decreased biofilm formation and decreased accumulation of extracellular toxins. We used murine models of implant-associated biofilm infection and S. aureus bacteremia (SAB) to compare virulence of USA300 strain LAC, its isogenic sarA mutant, and derivatives of each of these strains with mutations in all 10 of the genes encoding recognized extracellular proteases. The sarA mutant was attenuated in both models, and this was reversed by eliminating production of extracellular proteases. To examine the mechanistic basis, we identified proteins impacted by sarA in a protease-dependent manner. We identified 253 proteins where accumulation was reduced in the sarA mutant compared to the parent strain, and was restored in the sarA/protease mutant. Additionally, in SAB, the LAC protease mutant exhibited a hypervirulent phenotype by comparison to the isogenic parent strain, demonstrating that sarA also positively regulates production of virulence factors, some of which are subject to protease-mediated degradation. We propose a model in which attenuation of sarA mutants is defined by their inability to produce critical factors and simultaneously repress production of extracellular proteases that would otherwise limit accumulation of virulence factors.

Multiple markers of ER stress are activated in human adipose with obesity, particularly for protective chaperones downstream of activating transcription factor 6alpha.

Objective To assess the determinants of patients’ (PTGL) and physicians’ (MDGL) global assessment of rheumatoid arthritis (RA) activity and factors associated with discordance among them. Methods A total of 7,028 patients in the Quantitative Standard Monitoring of Patients with RA study had PTGL and MDGL assessed at the same clinic visit on a 0–10-cm visual analog scale (VAS). Three patient groups were defined: concordant rating group (PTGL and MDGL within ±2 cm), higher patient rating group (PTGL exceeding MDGL by >2 cm), and lower patient rating group (PTGL less than MDGL by >2 cm). Multivariable regression analysis was used to identify determinants of PTGL and MDGL and their discordance. Results The mean ± SD VAS scores for PTGL and MDGL were 4.01 ± 2.70 and 2.91 ± 2.37, respectively. Pain was overwhelmingly the single most important determinant of PTGL, followed by fatigue. In contrast, MDGL was most influenced by swollen joint count (SJC), followed by erythrocyte sedimentation rate (ESR) and tender joint count (TJC). A total of 4,454 (63.4%), 2,106 (30%), and 468 (6.6%) patients were in the concordant, higher, and lower patient rating groups, respectively. Odds of higher patient rating increased with higher pain, fatigue, psychological distress, age, and morning stiffness, and decreased with higher SJC, TJC, and ESR. Lower patient rating odds increased with higher SJC, TJC, and ESR, and decreased with lower fatigue levels. Conclusion Nearly 36% of patients had discordance in RA activity assessment from their physicians. Sensitivity to the “disease experience” of patients, particularly pain and fatigue, is warranted for effective care of RA.

Context:Retinol binding protein 4 (RBP4) was recently found to be expressed and secreted by adipose tissue, and was strongly associated with insulin resistance. Objective:The aim was to determine the relationship between RBP4 and obesity, insulin resistance, and other markers of insulin resistance in humans.Design and Patients: RBP4 mRNA levels in adipose tissue and muscle of nondiabetic human subjects with either normal or impaired glucose tolerance (IGT) were studied, along with plasma RBP4. RBP4 gene expression was also measured in adipose tissue fractions, and from visceral and sc adipose tissue (SAT) from surgical patients. Setting:The study was conducted at University Hospital and General Clinical Research Center.Intervention: Insulin sensitivity (S I ) was measured, and fat and muscle biopsies were performed. In IGT subjects, these procedures were performed before and after treatment with metformin or pioglitazone. Main Outcome Measures:The relationship between RBP4 expression and obesity, S I , adipose tissue inflammation, and intramyocellular lipid level, and response to insulin sensitizers was measured.Results: RBP4 was expressed predominantly from the adipocyte fraction of SAT. Although SAT RBP4 expression and the plasma RBP4 level demonstrated no significant relationship with body mass index or S I , there was a strong positive correlation between RBP4 mRNA and adipose inflammation (monocyte chemoattractant protein-1 and CD68), and glucose transporter 4 mRNA. Treatment of IGT subjects with pioglitazone resulted in an increase in S I and an increase in RBP4 gene expression in both adipose tissue and muscle, but not in plasma RBP4 level, and the in vitro treatment of cultured adipocytes with pioglitazone yielded a similar increase in RBP4 mRNA. Conclusions