1 Caspases play a critical role in apoptosis, and are considered to be key targets for the design of cytoprotective drugs. As part of our antiapoptotic drug-discovery effort, we have synthesized and characterized Z-VD-fmk, MX1013, as a potent, irreversible dipeptide caspase inhibitor. 2 MX1013 inhibits caspases 1, 3, 6, 7, 8, and 9, with IC 50 values ranging from 5 to 20 nm. MX1013 is selective for caspases, and is a poor inhibitor of noncaspase proteases, such as cathepsin B, calpain I, or Factor Xa (IC 50 values 410 mm). 3 In several cell culture models of apoptosis, including caspase 3 processing, PARP cleavage, and DNA fragmentation, MX1013 is more active than tetrapeptide-and tripeptide-based caspase inhibitors, and blocked apoptosis at concentrations as low as 0.5 mm. 4 MX1013 is more aqueous soluble than tripeptide-based caspase inhibitors such as Z-VAD-fmk. 5 At a dose of 1 mg kg À1 i.v., MX1013 prevented liver damage and the lethality caused by Fas death receptor activation in the anti-Fas mouse-liver apoptosis model, a widely used model of liver failure. 6 At a dose of 20 mg kg À1 (i.v. bolus) followed by i.v. infusion for 6 or 12 h, MX1013 reduced cortical damage by approximately 50% in a model of brain ischemia/reperfusion injury. 7 At a dose of 20 mg kg À1 (i.v. bolus) followed by i.v. infusion for 12 h, MX1013 reduced heart damage by approximately 50% in a model of acute myocardial infarction. 8 Based on these studies, we conclude that MX1013, a dipeptide pan-caspase inhibitor, has a good combination of in vitro and in vivo properties. It has the ability to protect cells from a variety of apoptotic insults, and is systemically active in three animal models of apoptosis, including brain ischemia.

BackgroundTo evaluate the meaning of serum CRP, ESR, and D-Dimer in the diagnosis of prosthetic joint infection.MethodsIn a retrospective study, 101 patients presented with osteoarthritis, PJI, and aseptic loosening were divided into three groups according to the type of operation they received in our department from June 2016 to December 2018: group A, 44 patients treated with primary arthroplasty; group B, 31 PJI patients treated with resection arthroplasty and spacer insertion surgery; group C, 26 aseptic loosening patients treated with revision arthroplasty. Data such as gender, age, preoperative serum CRP, ESR, and D-Dimer level were compared among the three different groups.ResultsThere are no statistically significant differences when comparing general data such as gender and age in patients from the three different groups. However, Serum CRP level in group B (43.49 ± 10.00 mg/L) is significantly higher than in group A (2.97 ± 0.75 mg/L) and C (4.80 ± 1.26 mg/L). Serum ESR level in group B (49.84 ± 5.48 μg/L) is significantly higher than those in group A (15.28 ± 2.63 μg/L) and C (22.50 ± 3.47 μg/L). Serum D-Dimer level in group B (1.58 ± 0.17 μg/L) is significantly higher than that in group A (0.51 ± 0.50 μg/L), but similar with group C (1.22 ± 0.29 μg/L). There are no statistically significant differences when compared with sensitivity and specificity of CRP, ESR, and D-Dimer in the diagnosis of PJI among patients from the three different groups when D-Dimer > 0.85 μg/L was set as the optimal threshold value for the diagnosis of PJI.ConclusionD-Dimer is not a parameter to distinguish between aseptic loosening and PJI.

Recently, accumulating evidence has suggested that gut microbiota may be involved in the occurrence and development of ankylosing spondylitis (AS). It has been suggested that rifaximin have the ability to modulate the gut bacterial communities, prevent inflammatory response, and modulate gut barrier function. The goal of this work is to evaluate the protective effects of rifaximin in fighting AS and to elucidate the potential underlying mechanism. Rifaximin were administered to the proteoglycan (PG)-induced AS mice for 4 consecutive weeks. The disease severity was measured with the clinical and histological of arthritis and spondylitis. Intestinal histopathological, pro-inflammatory cytokine levels and the intestinal mucosal barrier were evaluated. Then, western blot was performed to explore the toll-like receptor 4 (TLR-4) signal transducer and NF-κB expression. Stool samples were collected to analyze the differences in the gut microbiota via next-generation sequencing of 16S rDNA. We found that rifaximin significantly reduced the severity of AS and resulted in down-regulation of inflammatory factors, such as TNF-α, IL-6, IL-17A, and IL-23. Meanwhile, rifaximin prevented ileum histological alterations, restored intestinal barrier function and inhibited TLR-4/NF-κB signaling pathway activation. Rifaximin also changed the gut microbiota composition with increased Bacteroidetes/Firmicutes phylum ratio, as well as selectively promoting some probiotic populations, including Lactobacillales . Our results suggest that rifaximin suppressed progression of AS and regulated gut microbiota in AS mice. Rifaximin might be useful as a novel treatment for AS.