Association analysis of toll-like receptor 4 polymorphisms in Japanese primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts that often result in liver failure. Toll-like receptor (TLR) 4 recognizes lipopolysaccharides of Gram-negative bacteria. Infectious agents have been suspected to play a crucial role in PBC pathogenesis since TLR4 expression was found in bile duct epithelial cells and periportal hepatocytes in liver tissues of PBC. To assess the potential contribution of TLR4 SNPs to the development of this disease, we genotyped five SNPs in TLR4 in 261 PBC patients and 359 controls using a TaqMan assay. No significant positive associations with either PBC susceptibility or progression were uncovered. These results indicate that TLR4 polymorphisms do not play a prominent role in the development of PBC in Japanese patients.     

Emetic Potentials of Newly Identified Staphylococcal Enterotoxin-Like Toxins

Staphylococcal enterotoxins (SEs) are a common causative agent of food poisoning. Recently, many new SE-like (SEl) toxins have been reported, although the role of SEls in food poisoning remains unclear. In this study, the emetic potentials of SElK, SElL, SElM, SElN, SElO, SElP, and SElQ were assessed using a monkey-feeding assay. All the SEls that were tested induced emetic reactions in monkeys at a dose of 100 μg/kg, although the numbers of affected monkeys were significantly smaller than the numbers that were affected after consuming SEA or SEB. This result suggests that these new SEs may play some role in staphylococcal food poisoning.     

Impact of statin therapy on late target lesion revascularization after sirolimus-eluting stent implantation (from the CREDO-Kyoto Registry Cohort-2)

Therapeutic strategies preventing late target lesion revascularization (TLR) after drug-eluting stent implantation have not been yet adequately investigated. In 13,087 consecutive patients undergoing first percutaneous coronary intervention in the CREDO-Kyoto Registry Cohort-2, we identified 10,221 patients who were discharged alive after implantation of sirolimus-eluting stents (SESs) only (SES stratum 5,029) or bare-metal stents (BMSs) only (BMS stratum 5,192). Impact of statin therapy at time of discharge from the index hospitalization on early (within the first year) and late (1 year to 4 years) TLR, was assessed in the SES stratum (statin group 2,735; nonstatin group 2,294) and in the BMS stratum (statin group 2,576; nonstatin group 2,616). Despite a significantly lower incidence of early TLR (7.8% vs 22.2%, p <0.0001), SES use compared to BMS use was associated with a significantly higher incidence of late TLR (7.7% vs 3.0%, p <0.0001). In the SES and BMS strata, the incidence of early TLR was similar regardless of statin use. In the SES stratum, the incidence of late TLR was significantly lower in the statin group than in the nonstatin group (6.1% vs 9.6%, p = 0.002), whereas no significant difference was found in the BMS stratum (2.6% vs 3.3%, p = 0.38). After adjusting confounders, risk for late TLR significantly favored statin use in the SES stratum (hazard ratio 0.73, 95% confidence interval 0.54 to 0.98, p = 0.04), whereas the risk decrease was not significant in the BMS stratum (hazard ratio 0.74, 95% confidence interval 0.46 to 1.20, p = 0.23). In conclusion, statin therapy at hospital discharge was associated with a significantly lower risk for late TLR after SES implantation.     

Limited value of the international staging system for predicting long-term outcome of transplant-ineligible,newly diagnosed,symptomatic multiple myeloma in the era of novel agents

We retrospectively investigated clinical outcomes and prognostic factors of 131 patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) who received melphalan and prednisolone (MP) as first-line therapy from 2006 to 2013. Eighty-one patients received salvage therapies incorporating bortezomib, lenalidomide, and/or thalidomide. The overall response rate to MP was 54.2 %, including 9.2 % of better than very good partial response. With a median follow-up period of 30.2 months, median overall survival (OS) and median time to next treatment (TNT) were 54.4 and 19.0 months, respectively. Univariate analysis revealed that performance status and serum calcium level significantly associated with both OS and TNT, and multivariate analysis revealed that the higher serum calcium level had a significantly unfavorable impact on OS and TNT. Importantly, staging informed by the international staging system (ISS) was not predictive for OS or TNT in the analyzed cohort. Our study revealed that, in the context of first-line MP therapy for NDMM, the salvage therapy incorporating novel agents produced a survival period of >30 months after the initiation of second-line therapy, suggesting that the predictive value of ISS for OS and TNT may be limited in the era of novel agents.     

Early dynamics of hepatitis B virus in chimeric mice carrying human hepatocytes monoinfected or coinfected with genotype G

Of the 8 genotypes of HBV (genotypes A-H), genotype G is unique in that it has an insertion in the core gene and two stop codons in the precore region preventing the synthesis of hepatitis B e antigen. Most individuals with genotype G are coinfected with other genotypes, typically genotype A. Mice with severe combined immunodeficiency disease carrying human hepatocytes were infected with HBV particles propagated in Huh7 cells in culture. Mice monoinfected with genotype G did not raise detectable HBV DNA in serum, although products of the core gene emerged 4 to 8 weeks after inoculation. When they were superinfected with genotype A at week 10, however, HBV DNA of genotype A developed, which was replaced almost completely by that of genotype G within 10 weeks. Such a rapid takeover was also observed in mice initially infected with genotype A or C and superinfected with genotype G. Similar viral dynamics occurred in mice simultaneously coinfected with genotypes G and A. Takeover was markedly enhanced in mice inoculated with a serum passage containing genotype G with a trace of genotype A. Coinfection of mice with genotypes G and A induced abundant cellular steatosis along with increased fibrosis in the liver, which was not detected in mice monoinfected with genotype A or G. CONCLUSION: Genotype G can monoinfect chimeric mice at very low levels, and its replication increases maredly when coinfected with other genotypes. Coinfection with genotype G could enhance fibrosis under immunocompromised states.     

Specific cellular immune responses to pancreatic antigen in chronic pancreatitis and Sjögren's syndrome

The specific cellular immune response to the partially purified pancreatic antigen was studied by the peripheral blood lymphocyte proliferation assay in patients with chronic pancreatitis, Sjögren's syndrome, and primary biliary cirrhosis. A significant positive result (stimulation index >2.0) was observed in 7 of 21 patients with idiopathic chronic pancreatitis (33%;P<0.05), 6 of 7 patients with Sjögren's syndrome-associated chronic pancreatitis (86%;P<0.0005), and 6 of 11 patients with Sjögren's syndrome (55%;P<0.01), compared to normal controls whose stimulation index was 0.94±0.28 (mean ± SD;n=14; range, 0.56–1.60). On the other hand, patients with alcoholic chronic pancreatitis (17%;n=12), stone-related chronic pancreatitis (0%;n=7), primary biliary cirrhosis-associated chronic pancreatitis (33%;n=3), primary biliary cirrhosis (0%;n=4), systemic lupus erythematosus (17%;n=6), and autoimmune thyroiditis (0%;n=6) showed no significant difference from normal controls. Furthermore, in patients with idiopathic chronic pancreatitis who had positive results, a lymphocyte proliferative response to the pancreatic antigen was observed in T cells, especially in the CD4⁺ T cell subpopulation. These results suggest that the pancreatic antigen plays a role in the pathogenesis of a part of idiopathic chronic pancreatitis and Sjögren's syndrome in association with T cell responses and, also, suggest that autoimmunity may be a possible etiological factor in chronic pancreatitis.