Nicorandil is an adenosine triphosphate sensitive K (K-ATP) channel opener and a nitric oxide donor. K-ATP channels and nitric oxide are important factors in ischemic preconditioning, which in turn suppresses reperfusion arrhythmias. The present study sought to evaluate whether nicorandil suppresses ischemic-induced ventricular arrhythmias and enhances sulfonylurea receptors (SUR 2; subunit of K-ATP channel), endothelial nitric oxide (eNOS), and inducible nitric oxide (iNOS) expression in the left ventricle after myocardial infarction without reperfusion. Thirty male Sprague-Dawley rats at 7 weeks of age were separated into three groups, as follows. Acute myocardial infarction was induced in twenty rats by ligating the left main coronary artery. Ten of these twenty rats were continuously administered nicorandil at 3 mg/kg/day i.p. The other ten rats were left untreated. The ten controls were untreated and sham-operated. After coronary ligation, ventricular arrhythmias were evaluated from stored ECG signals. At 24 hours after treatment, eNOS, iNOS, and SUR2 mRNA levels and eNOS, iNOS expression in the left ventricle were determined by reverse transcription polymerase chain reaction (RT-PCR) and by immunohistochemical staining, respectively. Nicorandil suppressed the total number of ventricular arrhythmias from 1 to 2 hours, the total duration of ventricular tachycardia from 2 to 3 hours, and that of ventricular fibrillation from 1 to 2 and from 4 to 5 hours after coronary ligation. Nicorandil improved the survival rate 24 hours after coronary ligation. Levels of SUR2 mRNA increased only in left ventricles treated with nicorandil, particularly in the non-ischemic myocardium. eNOS mRNA was enhanced 2.2-fold in the area at risk in infarcted controls compared to sham-operated rats. In the non-ischemic area and area at risk of rats treated with nicorandil compared to sham-operated rats, eNOS mRNA was enhanced 3.3- and 2.7-fold, respectively. Staining indicated that the highest concentrations of eNOS occurred in the endothelium and myocardium of the non-ischemic area of rats treated with nicorandil. iNOS mRNA was present in both the area at risk and the non-ischemic area only in infarcted rats, and levels thereof were higher in the area at risk than in the non-ischemic area. However, there was no difference in iNOS mRNA levels between nicorandil-treated rats and controls. iNOS exhibited stronger staining in the area at risk than in the non-ischemic area of both nicorandil-treated and infarcted controls, with no differences between these two groups of rats. The mechanisms of protection against lethal ventricular tachyarrhythmia in nicorandil may increase nitric oxide release by upregulated eNOS expression through the opening of K-ATP channels and/or a K-ATP channels opener itself after acute myocardial infarction.

Background In the final step of production of adrenomedullin (AM), an inactive intermediate form of glycine-extended AM (AM-glycine) is converted to the active mature form of adrenomedullin (AM-mature) by enzymatic amidation. Recent studies have revealed that AM-mature and AM-glycine circulate in human plasma. In this study, we investigated the differences of the concentrations of cardiac AM between pressure-overloaded (PO) heart failure (HF) and volume-overloaded (VO)-HF in humans. Methods and results We measured AM-mature and AM-glycine by immunoradiometric assays in pericardial fluid and plasma in 38 patients who underwent valve replacement surgery (PO-HF: aortic stenosis, n = 14; VO-HF: aortic or mitral regurgitation, n = 24). Stable coronary artery disease with normal left ventricular function served as the control (n = 24). Plasma AM-mature (VO-HF: +59%, PO-HF: +65%, P<.05) and AM-glycine (VO-HF: +43%, PO-HF: +50%, P<0.05) were similarly higher in the 2 HF groups than in the control group. Interestingly, pericardial fluid AM-mature was markedly higher than that in plasma (control: +789%, VO-HF: +1050%, PO-HF: +1745%, all P<.001). Pericardial fluid AM-mature was higher in VO-HF (+106%, P<.01) than in controls and they were further increased in PO-HF (+243%, P<.05). Pericardial fluid molecular forms of AM correlated with left ventricular systolic pressure, but not with left ventricular end-diastolic volume index in PO-HF. In contrast, they correlated with left ventricular end-diastolic volume index, but not with left ventricular systolic pressure in VO-HF. Conclusion These results suggest that cardiac AM is differently regulated from plasma AM and that cardiac AM production is upregulated in both types of HF in response to each different stimulus.

Experimental studies have demonstrated that adrenomedullin (AM) has a positive inotropic action and exerts inhibitory effects against ventricular remodelling as an autocrine and paracrine factor. However, there is no clinical evidence for AM acting as a local regulator in the human heart. We measured the levels of various molecular forms of AM, i.e. an active form of mature AM (AM-m), an intermediate inactive form of glycine-extended AM (AM-Gly) and total AM (AMT = AM-m + AM-Gly), in plasma and pericardial fluid using our newly developed immunoradiometric assay in consecutive 67 patients undergoing coronary artery bypass graft surgery. Pericardial fluid and plasma cAMP, atrial natriuretic peptide and brain natriuretic peptide levels were also measured. The relationships between pericardial fluid AM levels and ventricular functions and other hormone levels were analysed. The level of each molecular form of AM in pericardial fluid was closely correlated with that of the other molecular forms of AM in the fluid. However, levels were not correlated with those in plasma. AM-T levels were slightly higher in pericardial fluid than in plasma (+72%; P < 0.05), whereas AM-m levels and AM-m/AM-T ratios were markedly higher in pericardial fluid than in plasma (AM-m, +994%; AM-m/AM-T ratio, +443%; both P < 0.01). AM-m, AM-Gly and AM-T levels in pericardial fluid were correlated with indices of left ventricular function, and with atrial natriuretic peptide and brain natriuretic peptide levels. Interestingly, AM and cAMP levels were positively correlated in plasma, but negatively correlated in pericardial fluid. In addition, AM-m, AM-Gly and AM-T levels in pericardial fluid were higher in patients with acute coronary syndrome than in those with stable ischaemic heart disease (AM-m, +80%; AM-Gly, +96%; AM-T, +83%; all P < 0.01). These results suggest that AM in pericardial fluid reflects cardiac synthesis, and that enhanced cardiac secretion of AM is associated with left ventricular dysfunction, ventricular overload and myocardial ischaemia. Considering that AM has positive inotropic, coronary vasodilatory and anti-remodelling actions, increased cardiac AM may play a compensatory role in the ischaemic and failing myocardium.

We investigated the direct effects of cerivastatin on hypertrophy of cultured rat neonatal myocytes induced by endothelin and the mechanism by which cerivastatin exerts its effects. Endothelin significantly increased [14C]phenylalanine ([14C]Phe) incorporation, atrial natriuretic peptide (ANP) release, ANP mRNA expression and cell size. Cerivastatin significantly reduced the increase in [14C]phenylalanine incorporation, ANP peptide release, ANP mRNA expression and cell size induced by endothelin, but pravastatin did not. Exogenous mevalonate completely prevented the inhibitory effect of cerivastatin on [14C]phenylalanine incorporation, ANP release and cell size. Cotreatment with geranylgeranyl pyrophosphate also attenuated the effect of cerivastatin on [14C]phenylalanine incorporation, but cotreatment with farnesyl pyrophosphate or squalene did not. Furthermore, both Rho inhibitor C3 exoenzyme and Rho-dependent kinase inhibitor, (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide.2HCl (Y27632) significantly decreased [14C]phenylalanine incorporation, ANP secretion, ANP mRNA expression and cell size. Cerivastatin decreased endothelin-induced Rho protein expression, and mevalonate and geranylgeranyl pyrophosphate reversed this effect. These results suggest that cerivastatin directly attenuates cardiac hypertrophy induced by endothelin in cultured rat myocytes partly by inhibition of the Rho pathway.

Adrenomedullin (AM) has vasodilatory, diuretic and natriuretic actions. Two molecular forms of AM circulate in human plasma: an active, mature form of AM (AM-m) and an intermediate, inactive, glycine-extended form of AM (AM-Gly). In the present study we investigated the pathophysiological significance of the two molecular forms of AM in plasma and urine in patients with acute myocardial infarction. We serially measured venous and arterial plasma levels and urinary excretion of AM-m, AM-Gly and total AM (Am-T; =AM-m+AM-Gly) over 2 weeks using our recently developed immunoradiometric assay in 26 consecutive patients with acute myocardial infarction and in age-matched normal controls, and studied the relationships between AM levels and clinical parameters. Plasma AM-m, AM-Gly and AM-T levels were increased on admission in patients with acute myocardial infarction compared with age-matched normal controls. Levels of AM-m, AM-Gly and AM-T in plasma reached a peak 24 h after the onset of symptoms. Plasma AM-m, AM-Gly and AM-T levels were significantly correlated with plasma levels of brain natriuretic peptide and pulmonary arterial pressure. Plasma AM-Gly levels in the vein were similar to those in the artery, whereas plasma AM-m levels were significantly lower in the artery than in the vein. Urinary excretion of AM-m, AM-Gly and AM-T was also increased on admission, and reached a peak at 12 h after the onset of symptoms. Urinary excretion of AM-m and AM-Gly was significantly correlated with urinary sodium excretion. The AM-m/AM-T ratio was significantly higher in the urine than in the vein or artery. AM-m levels were significantly correlated with AM-Gly levels in both the urine and plasma; however, there were no significant correlations between plasma and urinary AM levels. The results suggest that levels of both molecular forms of AM are increased in the urine as well as in the plasma in the acute phase of myocardial infarction. Since AM exerts potent cardiovascular and renal effects, increased concentrations of AM in plasma and urine in the acute phase of myocardial infarction may be involved in the defence mechanism against further elevations of peripheral and pulmonary vascular resistance and oliguria in acute myocardial infarction.

A noninvasive biochemical testing method for early detection and monitoring the condition of cardiac complications in hemodialysis (HD) patients would be useful and might lead to improved survival. The aim of this study is to clarify the pathophysiological significance of plasma brain natriuretic peptide (BNP) levels in HD patients with and without coronary artery disease (CAD). We measured plasma atrial natriuretic peptide (ANP) and BNP levels on Monday, Wednesday, and Friday before and after HD in 28 consecutive patients who underwent HD three times weekly. In addition, we measured plasma ANP and BNP levels in 21 HD patients with CAD and 27 HD patients without CAD and studied the relationships between BNP levels and cardiac function and clinical variables. Plasma ANP levels significantly decreased after HD on Monday, Wednesday, and Friday, and predialysis plasma ANP levels on Monday were significantly greater than those on other days. Plasma BNP levels did not change after HD on Monday; however, they significantly decreased after HD on Wednesday and FRIDAY: Predialysis plasma BNP levels on Monday were greater than those on other days, and postdialysis plasma BNP levels on Monday were greater than predialysis plasma BNP levels on WEDNESDAY: Plasma BNP levels in HD patients with CAD were significantly greater than those in HD patients without CAD and significantly correlated with left ventricular (LV) ejection fraction (r = -0.69), end-diastolic volume index (r = 0.59), and end-systolic volume index (r = 0.84) determined by left ventriculography. Conversely, plasma BNP levels in HD patients without CAD significantly correlated with LV mass index (r = 0.54) determined by echocardiography and mean systolic blood pressure (r = 0.72) determined by 48-hour ambulatory blood pressure monitoring. These results suggest the following: (1) plasma BNP levels before and after HD in chronic HD patients directly correlate with the degree of body fluid retention, and the day of the week on which the sample is obtained should be considered for its evaluation; (2) plasma BNP levels reflect LV function in HD patients with CAD; and (3) plasma BNP levels reflect LV mass and blood pressure in HD patients without CAD.

To evaluate the malignant potential of synchronous multiple colorectal cancers, we studied clinicopathologically 31 synchronous multiple colorectal cancers resected at our hospital. We also compared the p53 gene mutation rate, replication error (RER) rate, and Ki-67 antigen positivity rate between these cancers and 90 sporadic colorectal cancers. There was no significant difference in lymphoid and venous invasion, hepatic metastasis, or stage of colon cancer between the two types of cancers. The p53 gene mutation rate was lower in synchronous multiple colorectal cancers (p < 0.05). The RER rate and positivity rate for Ki-67 antigen was significantly higher in these cancers (p < 0.05). These results suggest that some synchronous multiple colorectal cancers result from carcinogenesis in which RER genes are involved, as HNPCC does. In the patients with synchronous multiple colorectal cancers, it is clinically important to follow them carefully focusing on multiple metachronous colorectal cancers and multiple organ cancers.

We evaluated the influence of local myocardial ischemia induced by acute coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA) on the ventricular gradients (VG) and investigated whether 2:1 alternans of VG occurs. Twenty-seven patients with angina pectoris, who had one-vessel coronary artery stenosis, were studied. The VG of each consecutive heartbeat before, during, and after PTCA over a 22-second interval was calculated using a microcomputer. The standard deviation and coefficient of variation of magnitude were used as indices of VG variability. Frequency-domain analysis of time series consisting of beat-to-beat VG magnitude for a 22-second interval was also performed by the maximum entropy method. The standard deviation and coefficient of variation of VG magnitude during PTCA were significantly greater than those before and after PTCA (P < .01, P < .01, respectively), and the indices before PTCA were also significantly greater than those after PTCA (P < .05). The maximum power spectrum peaks around 0.5 cycles/beat during PTCA were significantly greater than those after PTCA (P < .01); this suggests that the enhancement of VG alternans is reflected by 2:1 alternans of the action potential in the acute local ischemic myocardium during PTCA.

OBJECTIVES:The relationships between cardiac troponin I, various biochemical markers, and chronic-phase left ventricular ejection fraction (LVEF) after successful direct percutaneous transluminal coronary angioplasty (PTCA) were examined in 36 patients with acute myocardial infarction.METHODS:Biochemical markers were measured on admission, immediately after, and from 6 hours to 9 days after PTCA.RESULTS:The time to peak values were: creatine kinase-MB 9.7 hours, cardiac troponin I 9.8 hours, myoglobin 10.7 hours, creatine kinase 10.6 hours, cardiac troponin T 18.6 hours, and myosin light chain 68.9 hours. Cardiac troponin T, cardiac troponin I and myosin light chain levels were elevated over 9 days after successful direct PTCA. Chronic-phase LVEF inversely correlated with peak values of creatine kinase-MB (r = -0.519, p < 0.01), cardiac troponin T (r = -0.500, p < 0.01), cardiac troponin I (r = -0.441, p < 0.05) and creatine kinase (r = -0.411, p < 0.05). The values of cardiac troponin I, cardiac troponin T, creatine kinase and creatine kinase-MB at each sampling point were significantly inversely related to chronic-phase LVEF. The value of cardiac troponin I at each time point for 7 days correlated well with chronic-phase LVEF.CONCLUSIONS:Cardiac troponin I has high specificity for predicting long-term cardiac function after successful direct PTCA when early values are unavailable.

Colorectal adenoma and early carcinoma are morphologically classified as 2 distinct subtypes: protruded type (PT) and flat type (FT).PT-tumor has been known to develop associated with adenoma-carcinoma sequence including Ki-ras mutation.Progress of colorectal endoscopy technique for last several years has made it feasible to find small flat lesions in the mucosa and such lesions has been admitted as FT tumor.FT tumor may have a potential as an early lesion of invasive carcinoma that has been thought to develop "de novo".Under the hypothesis that different genetic and/or epi-genetic events occur during tumor progressions between PT and FT, we compared frequency of Ki-ras mutation, rate of proliferating cells and apoptotic cells between these 2 types of colorectal tumor.Seventy colorectal adenoma and carcinoma (33 PT, 37 FT) were obtained by endoscopic polypectomy or mucosal resection.They were histologically subclassified as adenoma with low-grade atypia (ALA), adenoma with high grade atypia(AHA), intramucosal carcinoma(IMC), and sub-mucosal invasive carcinoma (SMC).PCR-based dot blot hybridization was performed to detect Ki-ras codon 12 mutations.To detect cell proliferation and apoptosis, immunostaining with Ki-67 and terminal deoxynucleotidyl transferasemediated dUTP nick end labeling (TUNEL) method were performed.The percentage of positive cells were described as Ki-67 labeling index (Ki-LI) and TUNEL labeling index (TUNEL-LI) in each layer (upper 1/3, middle 113, and lower 113) and total.In PT, Ki-ras mutation at codon 12 was detected in 25% of AHA, 37.5% in IMC, and 31.3% in SMC.In FT, it was detected in 0%, 25%, 0%, respectively.In adenoma (ALA and AHA), Ki-LI of upper layer in PT were significantly higher than those in FT(p=0.OO7).Ki-LI of lower layer in FT-SMC were significantly higher than those in PT-SMC(P=0.04).TUNEL-LI of FT-SMC, though not statistically significant, were lower than those of PT-SMC in all of the layers.FT tumors may not need Ki-ras mutation for progression unlike PT tumors do.Higher cell proliferation in the upper layer of PT-adenoma associates with the morphological protuberance of the tumor.Higher cell proliferation rate and tendency of less apoptotic cellsin the lower layer of FT-SMC suggest more aggressive nature in the specific tumor type.Thus, different genetic and epi-genetic events may associate with differences of their morphological features and biological characters between those 2 types of colorectal tumor.

A 26-year-old female was admitted to our hospital because of lasting retrosternal burning pain and back pain after taking a doxycycline tablet. It was taken with little water just going to bed 5 days ago. Esophagoscopy revealed circular ulcers with clot in the lower esophagus in 3cm length (34cm from incisors) . She was diagnosed as doxycycline-induced esophageal ulcers by endoscopic findings and course, and treated with H2-receptor antagonist under nothing by mouth. On the 15th day after the onset, endoscopy showed marked improvement. The follow-up esophagoscopy performed 3 month later showed disapperance of the ulcers with scars. There have been several reports of solitary ulcer induced by doxycycline tablet. However very few cases of circular ulcers caused by the tablet have been reported.

A 62-year-old woman presented with nephrotic syndrome and severe anemia although the renal function was not impaired. Renal biopsy revealed the histology of membranoproliferative glomerulonephritis, and the proteinuria was resistant to steroid therapy. Iron deficiency, bleeding and other causes of anemia were ruled out, however, her serum erythropoietin level was inappropriately low. The anemia was rapidly corrected by administration of recombinant human erythropoietin. It is suggested that inappropriately low erythropoietin level, in part at least, accounts for the anemia in nephrotic syndrome. It is proposed that erythropoietin therapy should be taken into consideration for severe anemia in nephrotic syndrome even when the renal function is not impaired.

Purpose: The main purpose of this study was to determine influential factors related to minor leukoencephalopathy (LEP) caused by moderate-dose methotrexate (MTX) and prophylactic cranial radiotherapy (CRT) in childhood hematopoietic malignancies, We also compared the incidence of LEP following this treatment to that reported in the literature following treatment with high-dose MTX alone.Methods and Materials: Thirty-eight pediatric patients of hematopoietic malignancies (37 acute lymphoblastic leukemias, 1 non-Hodgkin lymphoma) who were given CRT (18-24 Gy) as well as prophylactic intrathecal and per os MTX were studied for leukoencephalopathy by magnetic resonance (MR) imaging, All the patients were free from grave neuropsychiatric disturbances, The data were examined to elucidate the influential ones of five factors (patients' age, doses of intrathecal and per os MTX, dose of CRT, interval between treatment, and MR study) to develop LFP using multiple regression analysis, To compare the effect of moderate-dose MTX and prophylactic CRT on LEP to that of high-dose MTX alone, we conducted literature review.Results: Seven out of 38 patients (18%) developed LEP, From multiple regression analysis and partial correlation coefficients, the age and CRT dose seemed influential in the subsequent development of LEP, The incidence of LEP following treatment with moderate-dose MTX and prophylactic CRT appears to be less than that reported in the literature following treatment with intravenous high-dose MTX, However, even moderate-dose MTX in combination with CRT can result in a significant incidence of MR-detectable LEP, particularly in children 6 years of age or younger receiving 24 Gy.Conclusion: Leukoencephalopathy was caused by moderate-dose MTX and prophylactic CRT in pediatric patients, probably less frequently than by high-dose MTX treatment alone, The influential factors were patient's age and CRT dose.