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Background: Flow-mediated dilation (FMD) and reactive hyperemia-peripheral arterial tonometry (RH-PAT) are both established modalities to assess vascular endothelial function. However, clinical significance of FMD and RH-PAT may be different because these methods measure vascular function in different vessels (conduit arteries and resistance vessels). Methods: To elucidate differences in the clinical significance of FMD and RH-PAT, a simultaneous determination of FMD was performed and reactive hyperemia index (RHI) measured by RH-PAT in 131 consecutive patients who underwent coronary angiography for suspicion of coronary artery disease (CAD). Results: There was no significant correlation between FMD and RHI in patients overall. When patients were divided into four groups: FMD ≥ 6%/RHI ≥ 1.67 group, FMD ≥ 6%/RHI < 1.67 group, FMD < 6%/RHI ≥ 1.67 group and FMD < 6%/RHI < 1.67 group, the highest incidence of multivessel CAD was seen in the FMD < 6%/RHI < 1.67 group (52%). Multiple logistic regression analysis showed that a prevalence of both FMD < 6% and RHI < 1.67 was an independent predictor of multivessel CAD (odds ratio: 4.160, 95% confidence interval: 1.505–11.500, p = 0.006). RHI was negatively correlated with the baseline vessel diameter (R = –0.268, p = 0.0065) and maximum vessel diameter (R = –0.266, p = 0.0069) in patients with FMD < 6%, whereas these correlations were absent in patients with FMD ≥ 6%. Conclusions: Present results suggest that noninvasive assessment of vascular endothelial functions provide pathophysiological information on both conduit arteries and resistance vessels in patients with CAD.

We herein report the case of a 72-year-old man with endocarditis of the aortic valve who underwent urgent aortic valve replacement 36 hours after admission due to an aggravation of aortic valve regurgitation. Postoperative cultures of the blood and site of valve vegetation identified Candida parapsilosis as a pathogen. Antifungal therapy with amphotericin B and fluconazole was initiated after surgical treatment. Thereafter, the patient displayed a favorable clinical course. Candida parapsilosis endocarditis involving the native valves is extremely rare and associated with a very high mortality rate. Prompt surgical treatment and the aggressive use of antifungal agents are required to save the patient's life.

We herein report the case of a 72-year-old man with endocarditis of the aortic valve who underwent urgent aortic valve replacement 36 hours after admission due to an aggravation of aortic valve regurgitation. Postoperative cultures of the blood and site of valve vegetation identified Candida parapsilosis as a pathogen. Antifungal therapy with amphotericin B and fluconazole was initiated after surgical treatment. Thereafter, the patient displayed a favorable clinical course. Candida parapsilosis endocarditis involving the native valves is extremely rare and associated with a very high mortality rate. Prompt surgical treatment and the aggressive use of antifungal agents are required to save the patient's life.

Vascular endothelial growth factor (VEGF) and its associated molecule, placenta growth factor (PlGF) are now known to support normal hematopoiesis, and leukemia cell growth. In this study, expression of VEGF and PlGF in acute lymphoblastic leukemia (ALL) cells was examined by real time reverse transcription-polymerase chain reaction in 20 patient samples. Expression of PlGF was more intense in Philadelphia chromosome positive (Ph(+)) ALL than in Ph(-) ALL cases. On the other hand, expression level of VEGF was not different between Ph(+) and Ph(-) cases. Then, PlGF was added to the two ALL cell lines, CRL1929 (Ph(+)), and Nalm6 (Ph(-)). The PlGF stimulated the growth of CRL1929 in time- and dose-dependent manners, although the growth of Nalm6 was not affected by PlGF. The growth stimulation of CRL1929 by PlGF was confirmed by the increase of S phase cells. And the growth promoting effect of PlGF on CRL1929 was cancelled by simultaneous addition of VEGFR1/Fc (which binds to PlGF and abrogates its function), but was not cancelled by VEGFR2/Fc (which does not bind to PlGF). Then, addition of VEGFR1/Fc to the simple culture of CRL1929 demonstrated growth inhibitory effect. These observations demonstrated that PlGF stimulates the growth of Ph(+) ALL cells by both autocrine and paracrine pathways. Finally, PlGF-VEGFR1 loop might be a therapeutic target to improve the prognosis of Ph(+) ALL.

ARK5, AMP-activated protein kinase (AMPK)-related protein kinase mediating Akt signals, is closely involved in tumor progression, and its stage-associated expression was observed in colorectal cancer. In this study, we found ARK5 expression in multiple myeloma cell lines expressing c-MAF and MAFB. In addition, gene expression profiling of 351 clinical specimens revealed ARK5 expression in primary myelomas expressing c-MAF and MAFB, suggesting that ARK5 may be a transcriptional target of the Large-MAF family. Sequence analysis of the ARK5 gene promoter revealed that it contains two putative MAF-recognition element (MARE) sequences. In support of this hypothesis, ARK5 was induced when an MAFB or c-MAF expression vector was introduced into non-ARK5-expressing colon cancer cells. Furthermore, ARK5 promoter activity was dramatically decreased by mutation or deletion of MARE sequences. Chromatin immunoprecipitation assays revealed an interaction between the Large-MAF family proteins and MARE sequences in the ARK5 promoter. Moreover, in ARK5 mRNA-expressing multiple myeloma lines, but not in ARK5-negative lines, insulin-like growth factor (IGF)-1 increased invasion activity. IGF-1-induced invasion was reproduced when ARK5 was overexpressed in Burkitt's lymphoma and plasmacytoma lines. Based on results, we conclude that ARK5 is a transcriptional target of the Large-MAF family through MARE sequence and that ARK5 may in part mediate the aggressive phenotype associated with c-MAF- and MAFB-expressing myelomas.

We report a case of acute promyelocytic leukemia (APL) with drug-induced hypersensitivity syndrome associated with Epstein-Barr virus (EBV) infection. A 33-year-old woman was admitted because of APL. After complete remission was obtained with the use of all-trans retinoic acid (ATRA), intensive chemotherapy was administered. She developed high grade fever and severe systemic erythematous eruptions followed by cervical lymphoadenopathy, hepatosplenomegaly, hepatitis and hypotension in a state of myelosuppression during consolidation chemotherapy. Systemic corticosteroids alleviated the symptoms. Since an anti-EB VCA IgM antibody titer was continuously positive, persistent infection of EBV was suspected. In this case, EBV infection may have contributed to the development of drug-induced hypersensitivity syndrome.

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients.

22歳,男性.発熱出現,急性肝炎(A, B, C, D, G陰性)と診断され補液により肝機能改善. HSV, CMV, EBV,パルボウイルス,風疹,麻疹抗体価の上昇認めず. WBC 1,400/μl, Hb 12.1g/dl, Plt 22,000/μlと汎血球減少悪化. methylprednisolone (m-PLS)大量療法では反応せず.肝炎後重症再生不良性貧血と診断. Antithymocyte globulin (ATG)・cyclosporin (CyA)・m-PSL・granulocyte colony-stimulating factor (G-CSF)併用療法を行い寛解を得た.現在治療薬なしで寛解を維持している.

Short-chain fatty acids (SCFAs), acetate, propionate and butyrate, are the major anions in the lumen of the large intestine. One of the G protein coupled receptors, GPR43, was recently described as a receptor for SCFAs. To understand pharmacological role of butyrate through GPR43, we analyzed cell shape, GPR43 mRNA expression and mitogen-activated protein (MAP) kinase activation in rat hepatic stem-like (HSL) cells. RT-PCR demonstrated that GPR43 mRNA was expressed in HSL cells and the expression level was not affected by butyrate treatment. Western blot analysis revealed that ERK phosphorylation was enhanced 10 min after sodium butyrate treatment then decreased to the initial level after 24 h. In contrast, Ark phosphorylation was not detected. The results obtained were contrary to our intention, because much cell death was observed after sodium butyrate treatment.

Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and an associated molecule, placenta growth factor (PlGF), are thought to be important for normal and malignant hematopoiesis. This study examined mRNA expression of VEGF, PlGF and receptors for these molecules in AML cells and identified the disease-specific patterns of expression. AML M3 having t(15;17) abnormality showed highest expression of VEGF and VEGF receptor type 1 (VEGFR1), suggesting the autocrine pathway of VEGF-VEGFR1. Then, t(8;21) AML demonstrated augmented expression of VEGF and VEGF receptor type 2 (VEGFR2), suggesting VEGF-VEGFR2 autocrine pathway. Then, addition of VEGFR2 kinase inhibitor in Kasumi-1, a t(8;21) AML cell line, resulted in marked inhibition of cell growth, although growth inhibitory effect of R2 kinase inhibitor to HL-60 was marginal. In addition, cell cycle analysis study showed S-phase cell population reduction by R2 kinase inhibitor in Kasumi-1, but not in HL-60. This observation is thought to be the rationale for novel molecular target therapy directed to angiogenic molecules.

A global real-time quantitative/reverse transcription-polymerase chain reaction technique for detecting the expression of six 14q32 chromosomal translocation-associated proto-oncogenes in marrow plasma cells was established and applied to myeloma specimens. This technique is an alternative method of detecting 14q32 rearrangements and allows investigation of the relationship between proto-oncogene expression and clinical features.

Hematopoietic cells and endothelial cells are mutually correlated in their development and growth. Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietins (Angs), are thought to be associated with leukemia cell growth. In this study, we examined if the Angs–Tie2 autocrine pathway works in primary AML cells or not by using soluble Tie2-Fc, which inhibits Angs from binding to Tie2 receptor. After 48 h of culture with Tie2-Fc, nine AML cells from 19 examined samples were not influenced by Tie2-Fc (group A), while AML cells from remaining 10 patients demonstrated remarkable reduction of cell number by Tie2-Fc treatment (group B). Tie2 receptor, upon binding to Angs, are known to activate phosphatidyl-inositol 3 kinase (PI3 kinase). Then, we examined the effect of LY294002, a potent PI3 kinase inhibitor, on primary AML cells. Cell number reduction effect by the treatment of LY294002 was much more prominent in cells of group B than of group A. In addition, extent of cell number reduction by Tie2-Fc and LY294002 was quite well correlated. These observations demonstrated that cells from a part of AML were dependent on autocrine Angs–Tie2 pathway. This notion was further supported by the study of two AML cell lines, KG-1 and HL-60: the growth of KG-1 was suppressed by Tie2-Fc, and also by anti-Tie2 antibody, which inhibits receptor–ligand interaction, while that of HL-60 was not suppressed by Tie2-Fc or anti-Tie2 antibody. Our results will help to explore the angiogenesis-oriented or endothelial cell-mediated therapy for leukemia. The Hematology Journal (2004) 5, 353–360. doi:10.1038/sj.thj.6200410

MUM1(multiple myeloma oncogene 1)/IRF4(interferon regulatory factor 4) is a transcription regulatory factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas/leukemias and has been reported to predict an unfavorable outcome in some lymphoma subtypes including diffuse large B-cell lymphoma (DLBCL) and B-cell chronic lymphocytic leukemia (B-CLL). To elucidate its role in B-cell malignancies, we prepared stably MUM1-expressing Ba/F3 cells, which proliferated at a higher rate than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the Monokine induced by interferon-gamma (MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1 in inducible MUM1 expressing system. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed in chromatin immunoprecipitation assay. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and its receptor CXCR3 was also coexpressed in B-CLL cell lines that were positive for MUM1. Interestingly, treatment with neutralizing antibodies against MIG and its receptor, CXCR3, partially inhibited the proliferation of two MUM1-expressing B-CLL cell lines. These results suggest that MUM1 plays certain roles in the progression of B-cell lymphomas/leukemias by regulating the expression of various genes including MIG.