Comparative analysis of clinical outcomes after allogeneic bone marrow transplantation versus peripheral blood stem cell transplantation from a related donor in Japanese patients

A reduced incidence of graft versus host disease (GvHD) has been documented among Japanese allogeneic bone marrow transplantation (BMT) patients, as the Japanese are genetically more homogeneous than western populations. To clarify whether this ethnic difference affects the results of allogeneic peripheral blood stem cell transplantation (PBSCT), we conducted a nationwide survey to compare clinical outcomes of allogeneic PBSCT (n = 214) and BMT (n = 295) from a human leucocyte antigen-identical-related donor in Japanese patients. The cumulative incidence of grades II-IV acute GvHD was 37.4% for PBSCT and 32.0% for BMT. The cumulative incidence of extensive chronic GvHD at 1 year was significantly higher after PBSCT than BMT (42% vs. 27%; P < 0.01). The organ involvement patterns of GvHD were different between the two groups. By multivariate analyses, the incidence of chronic GvHD was significantly increased in PBSCT, whereas the stem cell source did not affect the incidence of acute GvHD, transplant-related mortality, relapse or survival. We concluded that Japanese PBSCT patients have an increased risk of chronic GvHD compared with BMT patients, but the incidence of acute GvHD was still lower than in western populations. Thus, the choice of haematopoietic stem cell source should be considered based on data for individual ethnic populations.     

Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese Acute Coronary Syndrome Study)

Serum uric acid (UA) levels reflect circulating xanthine oxidase activity and oxidative stress production. Hyperuricemia has been identified in patients who have congestive heart failure and is a marker of poor prognosis in such patients. We investigated the relation between serum UA levels and Killip's classification suggestive of the severity of heart failure and whether hyperuricemia influences mortality of patients who have acute myocardial infarction (AMI). Using the Japanese Acute Coronary Syndrome Study database, we evaluated 1,124 consecutive patients who were hospitalized within 48 hours of onset of symptoms of AMI from January to December 2002. There was a close relation between serum UA concentration and Killip's classification. Patients who developed short-term adverse events had high UA concentrations. Serum UA levels, Killip's class, age, and peak creatine phosphokinase level were significant predictors of long-term mortality. The hazard ratio for patients in the highest quartile of UA was 3.7 compared with those in the lowest quartile for death after AMI after adjustment for independent factors that were related to mortality. The combination of the best UA cutoff (447 micromol/L) for predicting survival based on receiver-operating characteristics analysis and Killip's class significantly predicted the prognosis of acute and long-term AMI-related complications. In conclusion, our results suggest that hyperuricemia after AMI is associated with the development of heart failure. Serum UA level is a suitable marker for predicting AMI-related future adverse events, and the combination of Killip's class and serum UA level after AMI is a good predictor of mortality in patients who have AMI.     

Novel percutaneous catheter thrombectomy in acute massive pulmonary embolism: rotational bidirectional thrombectomy (ROBOT).

BACKGROUND: Although thrombolysis is a standard therapy in cases of pulmonary embolism (PE), fatal outcome is often observed. We designed and investigated the efficacy of a novel percutaneous catheter therapy, rotational bidirectional thrombectomy (ROBOT), for PE. METHODS AND RESULTS: Eighteen patients with acute massive PE (Miller score > or = 20) were included in this study. We separated them into two groups [group A (n = 10), thrombolysis; group B (n = 8): thrombolysis and ROBOT or ROBOT alone]. There was no difference in the hemodynamic indices between the groups at diagnosis. ROBOT was designed to fragment emboli by rotating a regular pigtail catheter. Three deaths occurred in group A because of hemodynamic impairment, but there was no death in group B. One day after treatment, systolic pulmonary artery pressure had decreased from 53 +/- 8 to 30 +/- 8 mm Hg (P < 0.05) in group B and from 54 +/- 5 to 42 +/- 19 mm Hg (NS) in group A. The hospitalization period in group B was shorter than that in group A (17 +/- 6 vs. 27 +/- 10 days, P < 0.05). CONCLUSION: ROBOT therapy results in a significant, rapid improvement in the hemodynamic situation and in a better outcome than conventional therapy in patients with acute massive pulmonary embolism.     

Lysophosphatidylcholine induces urokinase-type plasminogen activator and its receptor in human macrophages partly through redox-sensitive pathway

Urokinase-type plasminogen activator (uPA) and its cell surface receptor (uPAR) have been shown to be expressed in macrophages in atherosclerotic arterial walls, but the regulatory mechanisms of their expression remain unclear. The present study was performed to examine the effects of lysophosphatidylcholine (lysoPC), an important atherogenic lipid, on the expression of uPA and uPAR in human monocyte-derived macrophages. LysoPC upregulated the mRNA expression of uPA and uPAR, and it increased the protein expression of uPA in the culture medium and bound to the cell surface and of uPAR in the particulate fraction of the cells. LysoPC significantly increased the binding of the amino-terminal fragment of uPA to the treated cells and the cell-associated plasminogen activator activity. LysoPC stimulated superoxide anion production and increased intracellular oxidant levels in the cells. The combined incubation with reduced glutathione diethyl ester or N-acetylcysteine, antioxidants, suppressed the upregulation of uPA and uPAR mRNA and the increase in plasminogen activator activity by lysoPC. uPA and uPAR mRNA expression was also induced by the incubation with xanthine and xanthine oxidase, a superoxide anion-generating system. The results suggest that lysoPC increased the expression of uPA and uPAR and their functional activities in human monocyte-derived macrophages, at least in part through a redox-sensitive mechanism. This coordinate increase in the expression of uPA and uPAR in human macrophages by lysoPC could play an important role in plaque formation and disruption, arterial remodeling, and angiogenesis in atherosclerotic arterial walls.     

Risk factors of thrombotic recurrence and major bleeding in patients with intermediate-risk for recurrence of venous thromboembolism

Journal of Thrombosis and Thrombolysis - Prolonged anticoagulation therapy is recommended for patients with intermediate-risk for recurrence of venous thromboembolism (VTE). The current study aimed...     

Increased plasma antigen levels of monocyte chemoattractant protein-1 in patients with restenosis after percutaneous transluminal coronary angioplasty

Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the progression of atherosclerosis in coronary arteries. To examine whether or not plasma antigen levels of MCP-1 are related to restenosis after percutaneous transluminal coronary angioplasty (PTCA), the plasma antigen levels of MCP-1 were measured by enzyme-linked immunosorbent assay (pg/ml) before, 24 and 48 h, and 3 months after elective PTCA for stable exertional angina performed between June 1997 and March 1998. Restenosis was defined as recurrence of stenosis greater than 50% of the diameter in the dilated segment at 3-month follow-up angiography. There were no differences in plasma MCP-1 antigen levels before and at 24 h after PTCA between restenosis (R; n=27) and no-restenosis (N; n=43) groups (R vs N: 633+/-35 vs 589+/-34, and 669+/-41 vs 575+/-36 pg/ml before and at 24 h after PTCA, respectively), but plasma MCP-1 antigen levels were higher at 48 h and 3 months after PTCA in the R than in N group (R vs N: 678+/-41 vs 558+/-35, and 735+/-35 vs 571+/-32 pg/ml at 48 h and 3 months after PTCA, respectively). These data suggest that the MCP-1 production and macrophage accumulation in the balloon-injured site is partially associated with restenosis after PTCA.     

Liver with hypoechoic nodular pattern as a risk factor for hepatocellular carcinoma

Ultrasonography should be used for screening of hepatocellular carcinoma, but there are few reports on the relationship between liver ultrasonographic findings and the development of hepatocellular carcinoma (HCC). Using prospective follow-up studies, we examined the role of liver with a hypoechoic nodular pattern as a high-risk factor in HCC. The study was performed by follow-up on 593 patients with chronic liver disease recorded at our hospital. The ultrasonographic pattern of the liver parenchyma was classified either as a small or large hypoechoic nodular pattern or as a nonnodular pattern. Patients were followed up from the time of initial ultrasonographic examination (1985–1987) until January 1, 1991. During the follow-up period (average, 4.2 years, range, 0.3–6.0 years), 62 patients were found to have HCC (12%). Patients whose livers showed small or large hypoechoic nodular pattern had a significantly higher risk of HCC than did patients whose livers showed a nonnodular pattern (rate ratios were 14.0 and 20.0, respectively, adjusted for age, sex, hepatitis virus markers, ICG R15, α-fetoprotein concentration, and ultrasonographic pattern of the liver). Liver showing a hypoechoic nodular pattern is a major risk factor in HCC.     

Knockdown of macrophage migration inhibitory factor disrupts adipogenesis in 3T3-L1 cells

Obesity is a condition in which adipose tissue mass is expanded. Increases in both adipocyte size and number contribute to enlargement of adipose tissue. The increase in cell number is thought to be caused by proliferation and differentiation of preadipocytes. Macrophage migration inhibitory factor (MIF) is expressed in adipocytes, and intracellular MIF content is increased during adipogenesis. Therefore, we hypothesized that MIF is associated with adipocyte biology during adipogenesis and focused on the influence of MIF on adipogenesis. To examine the effects of MIF on adipocytes, MIF expression in 3T3-L1 preadipocytes was inhibited by RNA interference, and cell differentiation was induced by standard procedures. The triglyceride content of MIF small interfering RNA (siRNA)-transfected 3T3-L1 cells was smaller than that of nonspecific siRNA-transfected cells. In addition, MIF knockdown apparently abrogated increases in adiponectin mRNA levels during differentiation. Gene expression of peroxisome proliferator-activated receptor (PPAR)gamma, CCAAT/enhancer binding protein (C/EBP)alpha, and C/EBPdelta decreased with MIF siRNA transfection, but C/EBPbeta expression increased. Cell number and incorporation of 5-bromo-2-deoxyuridine into cells decreased from 1-3 d and from 14-20 h, respectively, after induction of differentiation in MIF siRNA-transfected cells, thus suggesting that MIF siRNA inhibits mitotic clonal expansion. Taken together, these results indicated that MIF regulates differentiation of 3T3-L1 preadipocytes, at least partially, through inhibition of mitotic clonal expansion and/or C/EBPdelta expression.     

Transgenic expression of mutant peroxisome proliferator-activated receptor gamma in liver precipitates fasting-induced steatosis but protects against high-fat diet-induced steatosis in mice

Steatosis is one of the most common liver diseases and is associated with the metabolic syndrome. A line of evidence suggests that peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma are involved in its pathogenesis. Hepatic overexpression of PPARgamma1 in mice provokes steatosis, whereas liver-specific PPARgamma disruption ameliorates steatosis in ob/ob mice, suggesting that hepatic PPARgamma functions as an aggravator of steatosis. In contrast, PPARalpha-null mice are susceptible to steatosis because of reduced hepatic fatty acid oxidation. PPARgamma with mutations in its C-terminal ligand-binding domain (L468A/E471A mutant PPARgamma1) have been reported as a constitutive repressor of both PPARalpha and PPARgamma activities in vitro. To elucidate the effect of co-suppression of PPARalpha and PPARgamma on steatosis, we generated mutant PPARgamma transgenic mice (Liver mt PPARgamma Tg) under the control of liver-specific human serum amyloid P component promoter. In the liver of transgenic mice, PPARalpha and PPARgamma agonist-induced augmentation of the expression of downstream target genes of PPARalpha and PPARgamma, respectively, was significantly attenuated, suggesting PPARalpha and PPARgamma co-suppression in vivo. Suppression of PPARalpha and PPARgamma target genes was also observed in the fasted and high-fat-fed conditions. Liver mt PPARgamma Tg were susceptible to fasting-induced steatosis while being protected against high-fat diet-induced steatosis. The opposite hepatic outcomes in Liver mt PPARgamma Tg as a result of fasting and high-fat feeding may indicate distinct roles of PPARalpha and PPARgamma in 2 different types of nutritionally provoked steatosis.     

Is admission hyperglycaemia in non-diabetic patients with acute myocardial infarction a surrogate for previously undiagnosed abnormal glucose tolerance?

AIMS: To investigate whether admission hyperglycaemia in non-diabetic patients with acute myocardial infarction (AMI) is a surrogate for previously undiagnosed abnormal glucose tolerance. METHODS AND RESULTS: Two hundred non-diabetic patients with AMI were divided into three groups: 81 patients with admission glucose < 7.8 mmol/L (group 1), 83 patients with admission glucose > or = 7.8 mmol/L and < 11.1 mmol/L (group 2), and 36 patients with admission glucose > or = 11.1 mmol/L (group 3). Abnormal glucose tolerance, diabetes, or impaired glucose tolerance (IGT) was diagnosed by oral glucose tolerance test (OGTT). OGTT identified diabetes in 53 patients (27%) and IGT in 78 patients (39%). When the fasting glucose criteria were applied, however, only 14 patients (7%) were diagnosed as having diabetes. The prevalence of abnormal glucose tolerance was similar among the three groups: 67% in group 1, 63% in group 2, and 69% in group 3 (P = 0.74). The relation of fasting glucose (r2 = 0.50, P < 0.001) and HbA1c (r2 = 0.34, P < 0.001) to 2-h post-load glucose was significant, but the relation of admission glucose to 2-h post-load glucose was not significant (r2 = 0.02, P = 0.08). Multivariable analysis showed that fasting glucose and HbA1c were independent predictors of abnormal glucose tolerance, but admission glucose was not. CONCLUSION: Admission hyperglycaemia in non-diabetic patients with AMI does not represent previously undiagnosed abnormal glucose tolerance. Fasting glucose and HbA1c, rather than admission glucose, may be useful to predict abnormal glucose tolerance. However, these parameters lacked sensitivity. OGTT should be considered in all non-diabetic patients with AMI.