Promoter hypermethylation of the bone morphogenetic protein-6 gene in malignant lymphoma.

PURPOSE: Bone morphogenetic proteins (BMP), belonging to the transforming growth factor-beta superfamily, are important regulators of cell growth, differentiation, and apoptosis. The biological effects of BMPs on malignant lymphoma, however, remain unknown. Promoter methylation of the BMP-6 gene in lymphomas was investigated. EXPERIMENTAL DESIGN: We investigated BMP-6 promoter methylation and its gene expression in various histologic types of 90 primary lymphomas and 30 lymphoma cell lines. The effect of BMP-6 promoter hypermethylation on clinical outcome was also evaluated. RESULTS: BMP-6 was epigenetically inactivated in subsets of lymphomas. The silencing occurred with high frequency in diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma in association with aberrant BMP-6 promoter methylation. The methylation was observed in 60% (21 of 35) of DLBCL cases and 100% (7 of 7) of DLBCL cell lines, and in 83% (5 of 6) of Burkitt's lymphoma cases and 86% (12 of 14) of Burkitt's lymphoma cell lines. In contrast, other histologic types of primary lymphomas studied had little or no detectable methylation (1 of 49; 2%). The presence of BMP-6 promoter hypermethylation in DLBCL statistically correlated with a decrease in disease-free survival (P = 0.014) and overall survival (P = 0.038). Multivariate analysis showed that the methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.022) and overall survival (P = 0. 046). CONCLUSION: BMP-6 promoter was hypermethylated more often in aggressive types of lymphomas, and the hypermethylation is likely to be related to the histologic type of lymphomas. BMP-6 promoter methylation may be a potential new biomarker of risk prediction in DLBCL.     

Assessing liver function by magnetic resonance imaging two-dimensional phase-shift flow measurement of portal venous blood flow after oral intake of glucose

We have already reported that the ratio of portal venous flow 30 min after oral intake of glucose 75 g to that before intake (PVFR30), measured using pulsed-Doppler ultrasonography (US), correlated significantly with other indicators of liver function and that it could be used to estimate hepatic function before surgery, including liver resection. In this study, to assess the disadvantages of pulsed-Doppler ultrasonography, PVFR30 was measured using two-dimensional (2D) phase-shift (PS) magnetic resonance imaging (MRI). PVFR30 was measured in 17 patients and 7 volunteers: 13 with liver cirrhosis (LC) and 11 without LC (non-LC). Portal venous flow could be measured in all patients without any disturbance of intestinal gas or patient fat, or the high degree of technical skill that Doppler US requires. PVFR30 was significantly lower in the LC group than in the non-LC group. In addition, it correlated significantly with other indicators of liver function, including the indocyanine green clearance test, prothrombin time, hepaplastin test, and cholinesterase activity. These results suggest that PVFR30 measured by 2D PS MRI can be used to estimate liver function, and that this MRI method can be performed more easily than pulsed-Doppler US.     

Diurnal variation of human corneal curvature in young adults

PURPOSE: To elucidate the diurnal variation of human corneal curvature with regard to gender and menstrual cycle. METHODS: Changes in corneal curvature and intraocular pressure (IOP) were measured over 24 hours in 14 young adults using corneal topography and a non-contact tonometer. In study 1, seven males and seven females (after menses) were measured. In study 2, four females out of the seven volunteers who participated in study 1 were measured again during menses. RESULTS: The females after menses showed a remarkable diurnal variation throughout 24 hours. A significant difference between the light-wake periods and dark-sleep periods of 0.83 +/- 0.15 D was found (P < .01). Corneal curvature was significantly flatter during menses than after menses in the light-wake period (P < .05). In the males, no significant diurnal change (0.21 +/- 0.12 D) was measured in corneal curvature. CONCLUSIONS: Diurnal variation of corneal curvature was significant, approximately 0.83 D in young females after menses, and corneal curvature became flatter during menses in young females. Diurnal variation of corneal curvature is an important parameter for planning refractive surgery and contact lens wear.     

Significance of plasminogen-activation system in the formation of macroscopic types and invasion in esophageal carcinoma

BACKGROUND: The roles of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in the formation of macroscopic types and invasion were investigated. MATERIALS AND METHODS: A total of 40 surgically-resected esophageal carcinoma tissues were immunohistochemically stained, and the expression of uPA, PAI-1 and the uPA/PAI-1 ratio, were evaluated. RESULTS: The expression of uPA was significantly stronger in the macroscopically infiltrative type (n = 20: p = 0.0027), whereas PAI-1 was significantly stronger in the localized type (n = 20: p = 0.0005). The uPA/PAI-1 ratio was significantly higher in the infiltrative type (p < 0.0001). A significant correlation was found between the U/P ratio and the depth of tumor invasion (r = 0.511, p = 0.0014). Analysis of tumors of uniform size (4.0-6.0 cm in length), showed that the depth of invasion was significantly greater in the infiltrative type (p = 0.0038). CONCLUSION: The results demonstrated that uPA and PAI-1 play important roles in invasion and formation of macroscopic types of esophageal carcinoma.     

Colocalization of CA19-9 and KL-6 to epithelial cells in dilated bronchioles in a patient with idiopathic pulmonary fibrosis complicated by diffuse alveolar damage

A 73-year-old woman with idiopathic pulmonary fibrosis (IPF) had an elevated serum CA19-9 level, but not KL-6. Her condition worsened and she subsequently died and this was associated with a rise in the serum KL-6 level. At autopsy, the lung showed a honeycomb appearance macroscopically and, microscopically, hyaline membrane formation was seen. Immunohistochemical staining revealed partial colocalization of KL-6 and CA19-9 to dilated bronchiolar cells. These features suggest that the mechanisms that cause the synthesis and release of CA19-9 and KL-6 from damaged lung tissue in IPF are likely to differ from those in diffuse alveolar damage. In addition, serum KL-6 levels may reflect the severity of disease more sensitively than CA19-9 levels.     

Current status of radiation therapy--evidence-based medicine (EBM) of radiation therapy. Current management of patients with esophageal cancer

The best management for small mucosal esophageal cancer is generally endoscopic mucosal resection. However, for submucosal cancer and extensive mucosal cancer, either radical surgery or radiation seems to be an equally efficacious option. Radiation therapy concurrent with chemotherapy is more effective than radiation therapy alone for patients with unresectable esophageal cancer. The key drugs are cisplatin and 5-fluorouracil. However, for patients with poor performance status or for aged patients, radiation therapy alone is still a choice of treatment. Surgery has generally been indicated for patients with resectable esophageal cancer. However, outcomes of concurrent chemoradiation therapy may be comparable with those of surgery. Therefore, a prospective randomized study should be performed to determine the best management for patients with resectable esophageal cancer. The usefulness of intra-cavitary irradiation for esophageal cancer has not been clarified. A prospective randomized trial with a large number of patients is necessary to determine the effectiveness of intra-cavitary irradiation. The best management for patients with loco-regionally recurrent esophageal cancer after surgery has not been determined. Intensive therapy should be considered if the site of recurrence is limited and the time interval from surgery to recurrence is long. Chemotherapy is essential in the management of patients with small cell esophageal cancer. However, the best local therapy has not been determined.     

Carnitine affects fatty acid metabolism after cardioplegic arrest in neonatal rabbit hearts

BACKGROUND: Fatty acid (FA) metabolism and the contribution of carnitine to metabolism after cardioplegic arrest still remain unclear, especially in the neonatal heart where beta-oxidation is not a predominant source of adenosine triphosphate. METHODS: FA metabolism and the effects of carnitine administration were evaluated using a newborn (7-day-old) rabbit blood-perfused Langendorff model subjected to cold cardioplegic arrest. The hearts were divided into five groups; (1) perfused with unmodified diluted blood (n = 9), (2) subjected to 180 minutes of cold cardioplegic arrest and reperfused with the blood (n = 9), (3) subjected to the same ischemia and reperfused with the blood containing 40 microM/L (n = 9), (4) 0.5 mM/L (n = 5), and (5) 5 mM/L of carnitine (n = 5). During reperfusion, FA metabolism was assessed by iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid, a fatty acid. The myocardial time-radioactivity curve was then determined and a mathematical compartment analysis of the external detection was used to elucidate FA metabolism in the cardiac myocyte. RESULTS: Cold cardioplegic arrest resulted in significantly impaired FA metabolism following reperfusion. Compartment analysis suggested that FA activation in the cytosol and beta-oxidation were impaired. Carnitine supplementation in groups 3 and 4 improved FA metabolism during reperfusion. In contrast, supplementation in group 5 had no beneficial effect on FA metabolism. CONCLUSIONS: These results suggest that FA metabolism is impaired after cold cardioplegic arrest and that carnitine supplementation may improve aerobic metabolism in neonates after open heart surgery.     

Neurochemistry and neuropharmacology of emesis - the role of serotonin

Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex which is integrated in the medulla oblongata. Emesis caused by cytotoxic drugs and radiation is associated with an increase in the concentration of 5-hydroxytryptamine (5-HT) in the intestinal mucosa and in the brainstem. 5-HT released from enterochromaffin (EC) cells, which synthesize and secrete 5-HT, stimulates the 5-HT(3) receptors on the adjacent vagal afferent nerves. This vagal afferent nerve depolarization may evoke the vomiting reflex. This review describes the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release from EC cells and afferent vagus nerve activity.