C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection.

Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.

Association between Shame Aversion and Ruminative Retribution: Evidence for Moderation by Externalization of Blame and Control.

Shame aversion has been theorized to motivate aggression against the self or others as means of down-regulating shame. Additionally, the direction of aggression may depend on tendencies to attribute blame or causes internally or externally. Data from two separate samples were used to examine shame aversion and its interaction with causal or blame attributions in relation to aggression, controlling for shame-proneness, which is more commonly studied. Results indicated that shame aversion was positively associated with verbal, relational, and passive-rational aggression, as well as with ruminative retribution and non-suicidal self-injury, after accounting for shame-proneness. Most noteworthy, a significant two-way interaction indicated that the association between shame aversion and ruminative retribution (fantasizing about people getting their comeuppance) was particularly strong at high levels of externalization of blame. Findings therefore suggest that although shame-proneness may create situations in which shame regulation strategies are necessary, aggressive fantasies may be used as a regulation strategy when individuals have difficulty tolerating shame and blame others for their circumstances.

Asymmetric dimethylarginine and whole blood viscosity in renal failure.

BACKGROUND: Renal failure is a disease with accelerated atherosclerosis beginning with endothelial cell dysfunction. Factors affecting endothelial cell dysfunction include whole blood viscosity (WBV) and asymmetric dimethylarginine (ADMA). The relationship in controls and renal failure was determined. METHODS: 51 subjects, 20 controls, 11 renal transplant recipients, 10 chronic kidney disease and 10 end-stage renal disease patients had blood samples drawn for WBV, Hematocrit, and ADMA. WBV was measured at various shear rates from 10 s(-1) to 780 s(-1) at 37 °C. Hematocrit using CritSpin, and ADMA was assayed using an ELISA method. The significance between groups was compared by boxplots and analysis of variance. Linear relationships were shown by regression lines and correlation coefficients. RESULTS: ADMA was elevated in all groups with renal failure when compared to controls (p < 0.05). Control subjects showed a positive correlation between ADMA and WBV, while those who received a renal transplant had a negative correlation (p < 0.05). The difference in ADMA comparing pre-dialysis to post-dialysis conditions was positive (p < 0.05). CONCLUSIONS: The positive relationship between WBV and ADMA in controls is a novel finding and allows for comparison with other groups. This relationship is dramatically altered in renal failure.