Simvastatin Improves Outcomes of Endotoxin-induced Coagulopathy by Regulating Intestinal Microenvironment.

OBJECTIVE: The systemic inflammatory response is regarded as the major cause of endotoxin-induced coagulopathy, which is a strong predictor of mortality in patients with severe sepsis. Simvastatin plays an important role in reducing inflammation. In addition, the gut has long been hypothesized to be the "motor" of critical illness, driving or aggravating sepsis by the increased intestinal permeability and bacterial translocation. Whether simvastatin plays a role in severe endotoxin-induced coagulopathy through the gut is unclear. METHODS: In this study, mice were administered 20 mg/kg simvastatin by gavage for 2 weeks and then intraperitoneally injected with 50 mg/kg endotoxin. Twelve h later, cytokine release, coagulation dysfunction, organ damage, and survival were assessed. Besides, the intestinal barrier, permeability, bacteria abundance, and translocation were evaluated. RESULTS: We found that the severity of endotoxin-induced coagulopathy was significantly improved in simvastatin-pretreated mice, who showed attenuated depletion of coagulation factors and platelets, decreased plasminogen activator inhibitor-1 (PAI-1) expression, reduced organ fibrin deposition, and improved survival time. Also, simvastatin reduced epithelial apoptosis and improved intestinal barrier function by upregulating antimicrobial peptides, lysozyme, and mucins. Simvastatin increased Lactobacillales counts, while the lipopolysaccharide group showed increased Desulfovibrio and Mucispirillum, which can produce harmful toxins. Finally, the decreased intestinal permeability in the simvastatin group caused reduced bacterial translocation in the organs and blood, both in terms of quantity and species. CONCLUSION: Simvastatin improves the prognosis of severe endotoxemia, and the intestinal microenvironment participates in this process.

Evaluation of different scoring systems and gene mutations for the prognosis of myelodysplastic syndrome (MDS) in Chinese population.

MDS is a heterogeneous disease with diverse clinical manifestations, and an effective prognostic evaluation tool for MDS patients is needed. To achieve more accurate prognosis assessment for Chinese MDS patients, here we examined several scoring systems and explored the implications of gene mutations. The prognostic conditions were stratified against three different score systems (International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS), and Revised International Prognostic Scoring System (IPSS-R)) were retrospectively applied to 110 de novo MDS patients in study cohort in our hospital and the prognostic conditions were stratified respectively. IPSS-R out-performed the others, since it had less overlaps in survival curve, especially in the relatively low-risk group. Furthermore, genetic mutations were identified in 84 out of 110 patients and their association with overall survival (OS) were determined. Among them, sixty-three percent patients had at least one-point mutation, including thirty-five patients with normal karyotypes. The presence of TP53 mutations, but not TET2, DNMT3A or ASXL1 mutations was significantly correlated with shorter OS. A new model incorporating IPSS-R and TP53 mutations into survival analysis was proposed, and the prognostic value of this model was validated to be predominant in a 190-primary MDS patient independent cohort. Our data suggested that IPSS-R was more suitable for Chinese population. Attentions should be paid to the unfavourable mutations that might exert impact on the survival, especially in patients with relatively low risk.