Assessment of the "Weekend Effect" in Lower Extremity Vascular Trauma.

BACKGROUND: Studies suggest that patients admitted on weekends may have worse outcomes as compared with those admitted on weekdays. Lower extremity vascular trauma (LEVT) often requires emergent surgical intervention and might be particularly sensitive to this "weekend effect." The objective of this study was to determine if a weekend effect exists for LEVT. METHODS: The National and Nationwide Inpatient Sample Database (2005-2014) was queried to identify all adult patients who were admitted with an LEVT diagnosis. Patient and hospital characteristics were recorded or calculated and outcomes including in-hospital mortality, amputation, length of stay (LOS), and discharge disposition were assessed. Independent predictors of outcomes were identified using multivariable regression models. RESULTS: There were 9,282 patients admitted with LEVT (2,866 weekend admissions vs. 6,416 weekday admissions). Patients admitted on weekends were likely to be younger than 45 years (68% weekend vs. 55% weekday, P < 0.001), male (81% weekend vs. 75% weekday, P < 0.001), and uninsured (22% weekend vs. 17% weekday, P < 0.001) as compared with patients admitted on weekdays. There were no statistically significant differences in mortality (3.8% weekend vs. 3.3% weekday, P = 0.209), amputation (7.2% weekend vs. 6.6% weekday, P = 0.258), or discharge home (57.4% weekend vs. 56.1% weekday, P = 0.271). There was no clinically significant difference in LOS (median 7 days weekend vs. 7 days weekday), P = 0.009. On multivariable regression analyses, there were no statistically significant outcome differences between the groups. CONCLUSIONS: This study did not identify a weekend effect in LEVT patients in the United States. This suggests that factors other than the day of admission may be important in influencing outcomes after LEVT.

It Is Not Just Folklore: The Aqueous Extract of Mung Bean Coat Is Protective against Sepsis.

Mung bean (Vigna Radiata) has been traditionally used in China both as nutritional food and herbal medicine against a number of inflammatory conditions since the 1050s. A nucleosomal protein, HMGB1, has recently been established as a late mediator of lethal systemic inflammation with a relatively wider therapeutic window for pharmacological interventions. Here we explored the HMGB1-inhibiting capacity and therapeutic potential of mung bean coat (MBC) extract in vitro and in vivo. We found that MBC extract dose-dependently attenuated LPS-induced release of HMGB1 and several chemokines in macrophage cultures. Oral administration of MBC extract significantly increased animal survival rates from 29.4% (in saline group, N = 17 mice) to 70% (in experimental MBC extract group, N = 17 mice, P < 0.05). In vitro, MBC extract stimulated HMGB1 protein aggregation and facilitated both the formation of microtubule-associatedprotein-1-light-chain-3-(LC3-)containing cytoplasmic vesicles, and the production of LC3-II in macrophage cultures. Consequently, MBC extract treatment led to reduction of cellular HMGB1 levels in macrophage cultures, which was impaired by coaddition of two autophagy inhibitors (bafilomycin A1 and 3-methyladenine). Conclusion. MBC extract is protective against lethal sepsis possibly by stimulating autophagic HMGB1 degradation.

Tanshinone IIA sodium sulfonate facilitates endocytic HMGB1 uptake.

Our seminal discovery of high mobility group box 1 (HMGB1) as a late mediator of lethal systemic inflammation has prompted a new field of investigation for the development of experimental therapeutics. We previously reported that a major Danshen ingredient, tanshinone IIA sodium sulfonate (TSN-SS), selectively inhibited endotoxin-induced HMGB1 release and conferred protection against lethal endotoxemia and sepsis. To investigate the underlying mechanisms by which TSN-SS effectively inhibits HMGB1 release, we examined whether TSN-SS stimulates HMGB1 uptake by macrophages and whether genetic depletion of HMGB1 receptors [e.g., toll-like receptors (TLR)2, TLR4, or the receptor for advanced glycation end product (RAGE)] or pharmacological inhibition of endocytosis impairs TSN-SS-facilitated HMGB1 cellular uptake. TSN-SS stimulated internalization of exogenous HMGB1 protein into macrophage cytoplasmic vesicles that subsequently co-localized with microtubule-associated protein light chain 3 (LC3)-positive punctate structures (likely amphisomes). Meanwhile, it time-dependently elevated cellular levels of internalized HMGB1, leading to elevated LC3-II production and aggregation. Although genetic depletion of TLR2, TLR4, and/or RAGE did not impair TSN-SS-mediated HMGB1 uptake, specific inhibitors of the clathrin- and caveolin-dependent endocytosis significantly impaired TSN-SS-mediated HMGB1 uptake. Co-treatment with a lysosomal inhibitor, bafilomycin A1, led to enhanced accumulation of endogenous LC3-II and internalized exogenous HMGB1 in TSN-SS/rHMGB1-treated macrophages. Taken together, these findings suggest that TSN-SS may facilitate HMGB1 endocytic uptake, and subsequently delivered it to LC3-positive vacuoles (possibly amphisomes) for degradation via a lysosome-dependent pathway.

EGCG stimulates autophagy and reduces cytoplasmic HMGB1 levels in endotoxin-stimulated macrophages.

Historically, consumption of Green tea (Camellia sinensis) has been associated with health benefits against multiple diseases including cancer, atherosclerosis and cardiovascular disorders. Emerging evidence has suggested a pathogenic role for HMGB1, a newly identified "late" mediator of lethal systemic inflammation, in the aforementioned diseases. Here we demonstrated that a major ingredient of Green tea, EGCG, was internalized into HMGB1-containing LC3-positive cytoplasmic vesicles (likely autophagosomes) in macrophages, and induced HMGB1 aggregation in a time-dependent manner. Furthermore, EGCG stimulated LC3-II production and autophagosome formation, and inhibited LPS-induced HMGB1 up-regulation and extracellular release. The EGCG-mediated HMGB1 inhibitory effects were diminished by inhibition of class III phosphatidylinositol-3 kinase (with 3-methyladenine) or knockdown of an essential autophagy-regulating protein, beclin-1. Moreover, the EGCG-mediated protection against lethal sepsis was partly impaired by co-administration of an autophagy inhibitor, chloroquine. Taken together, the present study has suggested a possibility that EGCG inhibits HMGB1 release by stimulating its autophagic degradation.