Dose-dependent artificial prolongation of prothrombin time by interaction between daptomycin and test reagents in patients receiving warfarin: a prospective in vivo clinical study.

Background: Daptomycin has been reported to cause artificial prolongation of prothrombin time (PT) by interacting with some test reagents of PT. This prolongation was particularly prominent with high concentrations of daptomycin in vitro. However, whether this prolongation is important in clinical settings and the optimal timing to assess PT remain unclear.

Inverse correlations between serum ADAMTS13 levels and systolic blood pressure, pulse pressure, and serum C-reactive protein levels observed at a general health examination in a Japanese population: a cross-sectional study.

Background: Although a defect in ADAMTS13 activity is known to cause platelet thrombosis resulting in thrombotic thrombocytopenic purpura (TTP), recent evidence has revealed that low plasma ADAMTS13 concentrations may increase the risk of ischemic vascular diseases. Furthermore, reduced plasma ADAMTS13 activity has been reported in acute systemic inflammation or sepsis. These findings prompted us to examine whether ADAMTS13 may play a role in more diverse diseases, not limited to TTP.

Prediction of hepatocellular carcinoma development by plasma ADAMTS13 in chronic hepatitis B and C.

Background: Chronic liver injury evokes a wound healing response, promoting fibrosis and finally hepatocellular carcinoma (HCC), in which hepatic stellate cells play an important role. Although a blood marker of hepatic stellate cells is not known, those cells importantly contribute to the regulation of plasma a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) activity, a defect of which causes thrombotic thrombocytopenic purpura.

Methods: Plasma ADAMTS13 was evaluated in chronic hepatitis B or C patients with or without HCC.

Specific increase in serum autotaxin activity in patients with pancreatic cancer.

Objectives: To evaluate the potential clinical significance of serum autotaxin (ATX) level in patients with cancers of the digestive system.

Design And Methods: Serum ATX activity was measured as the lysophospholipase D activity in patients with cancer of the esophagus (n=8), stomach (n=18), colorectum (n=21), biliary tract (n=19), or pancreas (n=103) and in patients with benign pancreatic diseases (n=73).

Results: Among patients with various cancers of digestive system, increased serum ATX activity was predominantly observed among pancreatic cancer patients.

Autotaxin as a novel serum marker of liver fibrosis.

Background: The clinical significance of autotaxin (ATX), a key enzyme for the production of the bioactive lysophospholipid lysophosphatidic acid remains unknown. Serum ATX enzymatic activity reportedly increases in parallel with liver fibrosis and exhibits a gender difference.

Methods: Serum ATX antigen level, measured easier than the activity, was evaluated as a marker of liver fibrosis in 2 cohorts of chronic liver disease caused by hepatitis C virus.

AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopathological variables of HCC.

Background: Alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxy prothrombin (DCP), and Golgi protein-73 (GP73) have been used or proposed as tumor markers for hepatocellular carcinoma (HCC).

Methods: They were measured in 96 patients undergoing hepatectomy for HCC to investigate their treatment response and association with variables linked with tumor invasiveness and/or prognosis. Values at 1 month post-surgery in the 77 patients without recurrence within 6 postoperative months were adopted as those after surgery.

Thrombocytopenia is more severe in patients with advanced chronic hepatitis C than B with the same grade of liver stiffness and splenomegaly.

Background And Aim: The mechanism responsible for thrombocytopenia in chronic liver diseases (CLD) is not yet fully understood. The prevalence of thrombocytopenia has been reported to be higher in patients with hepatitis C virus-related hepatocellular carcinoma (CLD-C) than in those with hepatitis B virus-related hepatocellular carcinoma (CDC-B). We have examined the potential difference in thrombocytopenia between patients with CLD-B and those with CLD-C in terms of liver fibrosis adjustment and splenomegaly.

Plasma concentration of bioactive lipid mediator sphingosine 1-phosphate is reduced in patients with chronic hepatitis C.

Background: Bioactive lipid mediator S1P has been suggested to play pathophysiological roles in various fields of clinical science as a circulating paracrine mediator. We previously established a reliable method of measuring plasma S1P concentration, and reported that the one in healthy subjects has a gender difference and a correlation with red blood cell (RBC)-parameters, however, the reports of S1P measurements in the blood in patients with a specific disease have been scarce. Because our previous evidence suggests that S1P is involved in liver pathophysiology, we examined plasma S1P concentration in chronic hepatitis C patients.

Increased production of ADAMTS13 in hepatic stellate cells contributes to enhanced plasma ADAMTS13 activity in rat models of cholestasis and steatohepatitis.

Although hepatic stellate cells, endothelial cells, glomerular podocytes and plateles were reported to be a source of ADAMTS13, it is not clarified which source is involved in the regulation of plasma ADAMTS13 activity. It was demonstrated previously that selective hepatic stellate cell damage in rats caused decreased plasma ADAMTS13 activity. To further elucidate the potential contribution of hepatic stellate cells to the regulation of plasma ADAMTS13 activity, this study examined plasma ADAMTS13 activity when hepatic stellate cells proliferate during the process of liver fibrosis by employing rat models of liver fibrosis due to cholestasis, bile duct ligation, and steatohepatitis, a choline-deficient L-amino acid-defined-diet.

[Significance of serum autotaxin activity in gastrointestinal disease].

Autotaxin (ATX), discovered in human melanoma cells, has been gaining attention because it could be involved in cancer invasion and metastasis as an autocrine motility factor. Recent evidence has indicated that ATX is a key enzyme in the synthesis of lysophosphatidic acid, a lipid mediator with a wide range of biological actions including the stimulation of proliferation and contraction in hepatic stellate cells, a pivotal player in hepatic fibrosis. Serum ATX activity was found to be enhanced in relation to hepatic fibrosis in chronic liver disease due to hepatitis virus C infection, and the possible contribution of ATX to the pathogenesis of hepatic fibrosis should be further clarified.

Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2.

Sphingosine 1-phosphate (S1P), a bioactive lipid mediator, stimulates proliferation and contractility in hepatic stellate cells, the principal matrix-producing cells in the liver, and inhibits proliferation via S1P receptor 2 (S1P(2)) in hepatocytes in rats in vitro. A potential role of S1P and S1P(2) in liver regeneration and fibrosis was examined in S1P(2)-deficient mice. Nuclear 5-bromo-2'-deoxy-uridine labeling, proliferating cell nuclear antigen (PCNA) staining in hepatocytes, and the ratio of liver weight to body weight were enhanced at 48 h in S1P(2)-deficient mice after a single carbon tetrachloride (CCl(4)) injection.

Plasma lysophosphatidic acid level and serum autotaxin activity are increased in liver injury in rats in relation to its severity.

Lysophosphatidic acid (LPA) is a lipid mediator with multiple biological actions. We have reported that LPA stimulates hepatic stellate cell proliferation and inhibits DNA synthesis in hepatocytes, suggesting that LPA might play some role in the liver. We have found that plasma LPA level and serum autotaxin (ATX) activity were increased in patients with chronic hepatitis C.

Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats.

A protective effect of Rho-kinase inhibitor on various organ injuries is gaining attention. Regarding liver injury, Rho-kinase inhibitor is reported to prevent carbon tetrachloride (CCl4)- or dimethylnitrosamine-induced liver fibrosis and hepatic ischemia-reperfusion injury in rats. Because Rho-kinase inhibitor not only improved liver fibrosis but also reduced serum alanine aminotransferase (ALT) level in CCl4-induced liver fibrosis, we wondered whether Rho-kinase inhibitor might exert a direct hepatocyte-protective effect.

Both plasma lysophosphatidic acid and serum autotaxin levels are increased in chronic hepatitis C.

Objectives: Recent accumulating evidence indicates that lysophosphatidic acid (LPA) is a lipid mediator, abundantly present in blood, with a wide range of biologic actions including the regulation of proliferation and contraction in liver cells. Although it is speculated that LPA might play a role in pathophysiologic processes in vivo, not only its role but also even a possible alteration in its blood concentration under specific diseases is essentially unknown. Autotaxin (ATX), originally purified as an autocrine motility factor for melanoma cells, was revealed to be a key enzyme in LPA synthesis.

Hepatic stellate cell damage may lead to decreased plasma ADAMTS13 activity in rats.

ADAMTS13 is gaining attention, because its deficiency causes thrombotic thrombocytopenic purpura. Although its regulatory mechanism is not fully understood, we wondered if hepatic stellate cells (HSCs) play a role, because ADAMTS13 mRNA is exclusively expressed in the liver and primarily in HSCs. Plasma ADAMTS13 activity was markedly reduced in dimethylnitrosamine-treated rats, where HSC apoptosis is an essential event, but not in carbon tetrachloride- or thioacetamide-treated rats without HSC apoptosis.

The herbal medicine inchin-ko-to (TJ-135) induces apoptosis in cultured rat hepatic stellate cells.

Use of herbal remedies in the treatment of various diseases has a long tradition in Eastern medicine and the liver diseases are not an exception. In their use, lack of elucidation of mechanism(s) as well as randomized, placebo-controlled clinical trials has been a problem. Recently, we and others reported that inchin-ko-to (TJ-135), one of herbal remedies, suppressed hepatic fibrosis in animal models.