Linderapyrone: A Wnt signal inhibitor isolated from Lindera umbellata.

Linderapyrone, a Wnt signal inhibitor was isolated from the methanolic extract of the stems and twigs of Lindera umbellata together with epi-(-)-linderol A. Linderapyrone inhibited TCF/ß-catenin transcriptional activity that was evaluated using cell-based TOPFlash luciferase assay system. To evaluate the structure-activity relationship and mechanism, we synthesized linderapyrone and its derivatives from piperitone. As the results of further bioassay for synthesized compounds, we found both of pyrone and monoterpene moieties were necessary for inhibitory effect. cDNA microarray analysis in a linderapyrone derivative treated human colorectal cancer cells showed that this compound downregulates Wnt signaling pathway. Moreover, we successes to synthesize the derivative of linderapyrone that has stronger inhibitory effect than linderapyrone and ICG-001 (positive control).

Identification of high-risk Brugada syndrome patients by combined analysis of late potential and T-wave amplitude variability on ambulatory electrocardiograms.

BACKGROUND: Risk stratification is important in the management of Brugada syndrome (BrS). Late potentials (LPs) and T-wave amplitude variability (TAV) in high-resolution ambulatory electrocardiography (ECG) were retrospectively investigated. METHODS AND RESULTS: One hundred and twenty-seven patients diagnosed with BrS on 12-lead ECG were classified into 3 groups: documented ventricular fibrillation (VF)/asystole (n=19), episodes of syncope alone (n=30), and asymptomatic (n=78). Healthy volunteers were enrolled as controls (n=25). In the BrS patients, LPs showed appreciable circadian periodicity; filtered QRS duration (fQRS) and duration of the terminal low-amplitude signal <40 µV (LAS40) increased, whereas root mean square voltage of the terminal 40 ms of the fQRS (RMS40) decreased at night compared with the day. TAV did not have such a circadian periodicity. LP-positive incidence (night-time) and peak TAV were as follows: VF/asystole>syncope/asymptomatic>control (P<0.001). VF/asystole was discriminated from control at a ratio of 81-84% by night-time LPs (fQRS >116 ms, LAS40 >35 ms, RMS40 <25 µV) or peak TAV (>54 µV); VF/asystole was discriminated from syncope/asymptomatic at a ratio of 60-69%, by night-time LPs (fQRS >122 ms, LAS40 >42 ms, RMS40 <18µV) or peak TAV (>58 µV). Combined analysis of LPs and peak TAV increased the discriminant ratio up to 93% and 77%, respectively. CONCLUSIONS: Analysis of both LPs and TAV (taking circadian periodicity into account) is useful in identification of high-risk BrS patients.

Clinical usefulness of CEA, CA19-9, and CYFRA 21-1 as tumor markers for urothelial bladder carcinoma.

OBJECTIVE: To evaluate the usefulness of measuring serum CEA, CA19-9, and CYFRA 21-1 levels for the diagnosis and monitoring of bladder cancer. MATERIALS AND METHODS: Serum levels of CEA, CA19-9, and CYFRA 21-1 were measured in 85 patients with bladder cancer. The absolute level of each marker and the positive rate were compared with the clinical stage and histological grade of the tumor. Changes of the markers were assessed in patients with or without disease progression, and the correlations between survival and positivity/negativity of these markers were also evaluated. RESULTS: A higher serum level of CYFRA 21-1 was significantly correlated with higher tumor stage (p < 0.01) and higher grade (p < 0.05). In contrast, serum CEA and CA19-9 levels did not differ significantly among each stage and grade. The CYFRA 21-1 level increased significantly along with disease progression (from 7.33 ± 13.3 to 55.9 ± 127 ng/ml, p < 0.01). Patients who were positive for CYFRA 21-1 had significantly worse disease-specific survival (p < 0.0001, log rank test). CONCLUSION: Serum CYFRA 21-1 seems to be a marker of advanced- and high-grade urothelial carcinoma of the bladder. It is useful for monitoring this disease and for predicting the prognosis. In contrast, the clinical usefulness of CEA and CA19-9 as tumor markers was not demonstrated.

Circadian distribution of paroxysmal atrial fibrillation in patients with and without structural heart disease in untreated state.

BACKGROUND: This study aimed to compare the circadian distribution of the onset, maintenance and termination of paroxysmal atrial fibrillation (PAF) between structural and non-structural heart diseases (SHD and NSHD, respectively) in the untreated state. SUBJECTS AND METHODS: We included 217 patients with 338 PAF (79 SHD patients with 131 episodes; 138 NSHD patients with 207 episodes). The probabilities for the onset, maintenance and termination of PAF for each hour were analyzed using Holter monitoring data and harmonic models being fitted into a cosinusoidal function. RESULTS: The SHD group had a triphasic circadian pattern at the onset with higher peaks at midnight, in the early morning and in the late afternoon (p < 0.05), whereas the NSHD group showed a single peak at midnight (p < 0.01). The probability of maintenance revealed a single peak during midnight (SHD, p < 0.0001; NHD, p < 0.01). The termination showed a peak at noon in the SHD group (p < 0.05), whereas there was a double peak at 10:00 am and 8:00 pm in the NSHD group (p=0.06). RR intervals just after the PAF onset showed marked shortening in the daytime initiation PAF as compared to the nighttime initiation PAF in both SHD and NSHD groups (p < 0.01). CONCLUSION: These observations suggest that the SHD group has very complex onset hours, whereas the NSHD group shows complex termination hours. Reflexly accelerated sympathetic tone just after the PAF onset is suggested in the daytime initiation PAF.

[Intra-arterial chemotherapy for bladder preservation in patients with locally advanced bladder cancer].

PURPOSE: To evaluate intra-arterial chemotherapy for bladder preservation in patients with locally advanced bladder cancer. PATIENTS AND METHODS: A total of 34 patients with locally advanced bladder cancer (T2, n=25; T3, n=9) were treated with intra-arterial chemotherapy. Chemotherapy was consisted of intraarterial administration of cisplatin (100 mg/body), and adriamycin or pirarubicin (50 mg/body) every 4 weeks for two cycles. The response was evaluated by TUR, urine cytology, CT and/or MRI 4 weeks after the treatment. In 4 patients, we combined this treatment with radiotherapy. RESULTS: Among all 34 patients, 12 (35%) patients presented complete response (CR) and 24 patients (70%) presented in objective response (OR). During mean follow up period of 28.7 months, five patients had locally advanced recurrence and one had distant metastasis. The 5-year survival rate was 69.3%. Bladder was conserved in 19 (56%) of all 34 patients. Hematological and gastrointestinal toxicity (more than grade 3) was occurred in 5 and 3 patients. Risk factors on the outcome of this therapy were tumor size >20 mm, multiple tumors and clinical stage > or = cT3. Patients with no or one risk factor had favorable outcomes; the OR rates of 75-100%, the bladder preservation rates of 71-75% and the 5-year cancer specific survival rates of 83%. Whereas patients with two or three risk factors had unfavorable outcomes; the OR rates of 50-58%, the bladder preservation rates of 25-42% and the 3-year cancer specific survival rates of 0-69%. CONCLUSION: The treatment of locally advanced bladder cancer with intra-arterial chemotherapy seems to be good for patients with less risk factor, but not so good for patients with more risk factors.

[Case of malignant mesothelioma presenting as a perineal and intrascrotal mass].

We report here a case of malignant mesothelioma presenting as a perineal and intrascrotal mass. A 42-year-old Japanese male presented with an enlarging mass in the perineum and intrascrotum. Although the initial clinical diagnosis was perineal abscess, angiography revealed a tumor in the perineum and intrascrotum. The tumor was resected, and the pathological examination revealed malignant mesothelioma. Two months after the operation, a hard irregular mass with severe hemorrhage was noticed in the perineum, and was resected. A few weeks after the second operation local recurrence and, inguinal and intrapelvic retroperitoneal lymphadenopathy were found. Radiotherapy to recurrent sites was not effective. The patient died six months after the initiation of therapy. To our knowledge, 24 cases of malignant mesothelioma in the perineum or intrascrotum were reported in Japan and this case was thought to be the 25th case in Japan.

[Two cases of squamous cell carcinoma of upper urinary tract with hypercalcemia].

We report two cases of squamous cell carcinoma of upper urinary tract with hypercalcemia. Case 1; a 54 year old female with primary squamous cell carcinoma (SCC) of right ureter showed marked hypercalcemia and leukocytosis. High levels of serum parathyroid hormone-related peptide (PTHrP) and granulocyte colony stimulating factor (G-CSF) were detected. Although chemotherapy of cisplatin and 5-fluorouracil with radiotherapy was effective, thereafter recurrence was occurred in renal pelvis, and the patient died 17 months after the initiation of therapy. Case 2; a 54 year old male of primary SCC of right renal pelvis with local lymphadenopathy and anterior mediastinal metastases showed marked hypercalcemia. High levels of PTHrP were detected. Although the patient was administered UFT with palliative radiotherapy to the anterior mediastinum, he died 2 months after the initiation of therapy. To our knowledge, the case 1 is the third case that of the high levels of serum PTHrP and G-CSF simultaneously in squamous cell carcinoma of upper urinary tract.

[A case of adenocarcinoma in female urethral diverticulum].

A 49-year-old woman presented with complaints of dysuria and gross hematuria. Vaginal examination revealed an elastic-soft mass beneath the anterior vaginal wall. Urine cytology was positive. Urethrocystoscopy, magnetic resonance imaging and computed tomographic scan revealed a localized urethral diverticular tumor. Transurethral resection of the tumor was performed and the histopathologic finding was adenocarcinoma. Transvaginal urethral diverticulectomy was performed. Histopathological examination showed that the tumor arose in the urethral diverticulum and the proximal margin was positive. She had local recurrence at six months after the operation, and cystourethrectomy was performed. Six months after the operation, she had no evidence of recurrence. We review 18 cases of urethral diverticular carcinoma in Japan.

Usefulness of Continuous 24-hour Ventricular Late Potential to Predict Prognosis in Patients with Heart Failure.

OBJECTIVES: An estimated 50,000 patients have heart failure (HF) in Japan, and the left ventricular ejection fraction (LVEF) is the typical predictor of prognosis. The identification of a noninvasive marker to predict most high-risk patients is urgently needed. This study aimed to log the continuous ventricular late potential (LP) by using high-resolution ambulatory monitoring in patients with HF with non-sustained ventricular tachycardia, and determine the association between the LP variation and prognosis. METHODS: The 90 hospitalized patients were classified into cardiogenic death (n = 10) and non-death (n = 80) groups. The LVEF, LP, and coefficient of variation (CV) of the filtered QRS (fQRS), and low-amplitude signal < 40 µV for the terminal QRS portion of (LAS40) of both groups were evaluated. The maximum fQRS over 24 h was defined as the maximum fQRS (Max-fQRS). RESULTS: The results were as follows: (1) cardiogenic death occurred in 32% (10/31 patients) with an LVEF ≤ 45% and a Max-fQRS ≤ 114 ms; (2) cardiogenic death occurred in 38% (10/26 patients) with a LAS40-CV ≥ 0.09; and (3) using LVEF, Max-fQRS, and LAS40-CV as the three predictors, the specificity and accuracy were 83% and 82%, respectively, with an odds ratio of 12.3. CONCLUSIONS: LAS40 variations and increases might be new risk indicators of prognosis.

(18)F-Fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of idiopathic retroperitoneal fibrosis associated with mediastinal fibrosis.

A 68-year-old man was admitted to our hospital with left intermittent claudication. Computed tomography showed soft tissue masses surrounding the left iliac artery and in the bilateral pulmonary hilum, and the first FDG PET showed increased FDG uptake by the lesions. Retroperitoneal fibrosis associated with mediastinal fibrosis was most suspected. An open biopsy of the left peri-iliac masses revealed retroperitoneal fibrosis. Corticosteroid treatment was initiated. The second FDG PET under corticosteroid treatment showed no pathological FDG uptake. The third FDG PET after cessation of corticosteroid treatment showed increased FDG uptake in the mediastinum, and so Sairei-to treatment was initiated. The fourth FDG PET under Sairei-to treatment showed no improvement of the pathological FDG uptake, and so low-dose corticosteroid was re-started in combination with Sairei-to treatment. The fifth FDG PET under Sairei-to and corticosteroid treatment showed no pathological FDG uptake. These FDG PET findings suggest the usefulness of FDG PET for the diagnosis and monitoring of retroperitoneal fibrosis associated with mediastinal fibrosis.

Longitudinal analysis of the depressive effects of intravenous amiodarone on depolarization and repolarization: a case report.

Intravenous amiodarone (AMD) induces multiple antiarrhythmic effects via blocking of Na(+), Ca(2+), and IKr channels, and beta receptors. A patient on chronic dialysis was administered AMD for nonsustained ventricular tachycardia after successful cardiopulmonary resuscitation. QT prolongation occurred 5 h after AMD administration. AMD was withdrawn at 24 h because of prolonged QTc interval (716 ms), which persisted for a further 48 h (661 ms). Ventricular premature contraction (VPC) was significantly decreased at 7h; however, VPC increased again after discontinuing AMD. Depolarization changes induced by the Na(+)-channel blocking action of AMD were analyzed. There was increasing filtered QRS-duration and duration of low-amplitude signals at voltage <40 µV, and decreasing root-mean-square voltage of signals in the last 40 ms of ventricular late potentials (LPs) within 7 h. However after stopping AMD, LPs were reversed. The blood concentration of AMD reached the effective level within 10 min but decreased immediately to an ineffective level. Onset and disappearance of the VPC-inhibiting effect corresponded to the depressive effect on depolarization but not with the increase in the prolonged repolarization effect and blood concentration. Even if the QT interval is sufficiently prolonged, the Na(+)-channel blocking action is required for AMD to induce the antiarrhythmic effect.

Functional formula to determine adequate balloon diameter of simultaneous kissing balloon technique for treatment of bifurcated coronary lesions: clinical validation by volumetric intravascular ultrasound analysis.

BACKGROUND: Final kissing balloon technique (KBT) is known to alter long-term clinical outcomes for treatment of bifurcated coronary lesions. However, determination of adequate diameters of the 2 balloons remains difficult because of lack of a working index. METHODS AND RESULTS: Twenty-one cases of left main (LM)-related bifurcated lesions, treated with Cypher(TM) stents (single/crush stenting) and final KBT, were enrolled. The formula "R(2) = D(1)(2) + D(2)(2)" was used, adjusting balloon diameter (D(1), D(2)) to the downstream branches, to predict the theoretical mean hugging balloon diameter (R) within the main portion. The degree and pattern of stent expansion in the LM and main branch (MB) segments was compared by volumetric intravascular ultrasound assessment. Stents in the LM segments expanded to a greater extent and more asymmetrically than in MB segments (average stent area: 13.2+/-3.1 mm(2) vs 7.6+/-2.1 mm(2), p<0.0001, stent symmetry index: 0.77+/-0.08 vs 0.88+/-0.03, p<0.0001). The actual mean stent diameter significantly correlated with R (p=0.0003, r=0.76). The ratio of actual to theoretical stent expansion was highly consistent between the LM and MB (93.1% vs 93.4%, p=NS). CONCLUSION: The proposed formula may be useful for predicting resultant stent expansion following KBT, despite a more elliptical dilation.

Nifekalant hydrochloride administration during cardiopulmonary resuscitation improves the transmural dispersion of myocardial repolarization: experimental study in a canine model of cardiopulmonary arrest.

BACKGROUND: Because nifekalant hydrochloride (NIF) displayed a superior defibrillating effect on ventricular tachycardia/fibrillation (VT/VF) in cardiopulmonary arrest (CPA) patients, despite some QT prolongation, its effect on transmural dispersion of repolarization (TDR) in the left ventricle (LV) in an animal model of CPA was investigated. METHODS AND RESULTS: Eight beagle dogs were created with a myocardial infarction under anesthesia, and then VT/VF induction by continuous stimulation and cardiopulmonary resuscitation (CPR) were repeated. NIF (0.3 mg/kg) was administered under acidotic conditions (pH 7.26). The QTc interval measured by Y-lead ECG showed no significant prolongation before and after NIF. The activation recovery interval (ARI) measured by 64-lead LV surface mapping showed minimum ARI prolongation (40%) by NIF without maximum ARI prolongation, and as a result the ARI dispersion decreased by 67%. The repolarization time (RPT) with the plunge electrode showed 13-19% prolongation in the subendocardium and subepicardium with CPR, but NIF prolonged the RPT in the middle layer alone (17%), and as a result Plunge-TDR decreased by 82% (n=8, p<0.05). CONCLUSIONS: Administration of NIF during CPR decreased the TDR by RPT prolongation selectively in the middle layer. Because the subendocardial and subepicardial RPTs after CPR were already prolonged before NIF administration, it may have been the reason why the QT-prolonging effect of NIF was not reflected in the body surface ECG.

Can nifekalant hydrochloride be used as a first-line drug for cardiopulmonary arrest (CPA)? : comparative study of out-of-hospital CPA with acidosis and in-hospital CPA without acidosis.

BACKGROUND: Early defibrillation of ventricular tachycardia and fibrillation (VT/VF) is an urgent and most important method of resuscitation for survival in cardiopulmonary arrest (CPA). We have previously reported that nifekalant (NIF), a specific I(Kr) blocker developed in Japan, is effective for lidocaine (LID) resistant VT/VF in out-of-hospital CPA (OHCPA). However, little is known about the differences in the effect of NIF on OHCPA with acidosis and in-hospital CPA (IHCPA) without acidosis. METHODS AND RESULTS: The present study enrolled 91 cases of DC shock resistant VT/VF among 892 cases of CPA that occurred between June 2000 and May 2003. NIF was used (0.15-0.3 mg/kg) after LID according to the cardiopulmonary resuscitation (CPR) algorithm of Tokai University. The defibrillation rate was higher in the NIF group for both OHCPA and IHCPA than for LID alone, and the VT/VF rate reduction effect could be maintained even with acidosis. However, sinus bradycardia in OHCPA, and torsades de pointes in IHCPA were occasionally observed. These differences in adverse effects might be related to the amount of epinephrine, serum potassium levels, serum pH, and interaction with LID. CONCLUSIONS: NIF had a favorable defibrillating effect in both CPA groups, and it shows promise of becoming a first-line drug for CPR.

Quantitative analysis of thymidine phosphorylase and dihydropyrimidine dehydrogenase in renal cell carcinoma.

OBJECTIVE: The purpose of the present study was to clarify the clinicopathological significance of both thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) in renal cell carcinoma (RCC) based on a quantitative analysis of RCC patients. METHODS: Levels of TP and DPD in RCC and/or uninvolved renal tissues from 65 RCC patients were measured by enzyme-linked immunosorbent assay. RESULTS: The TP level and TP/DPD ratio were significantly higher in RCC than in adjacent uninvolved renal tissues (p < 0.0001). There was no significant difference in DPD levels between RCC and uninvolved renal tissues. The ratio of the highest to the lowest level was 623 in TP level, 28.9 in DPD level, and 985 in TP/DPD ratio. In the univariate analysis, patient's age (p = 0.04), tumor stage (p < 0.0001), tumor size (p = 0.007), TP expression (p = 0.03), and DPD expression (p = 0.04) were significantly associated with increased risk of death. Multivariate analysis showed that patient's age, tumor stage, and TP expression were independent prognostic factors. CONCLUSIONS: TP and DPD in RCC provide prognostic information although DPD was not an independent prognostic factor. The present finding of a wide range in these enzyme expressions in RCC suggests that a certain subpopulation with a high TP/DPD ratio has potential responsiveness to fluoropyrimidines, especially 5'-deoxy-5-fluorouridine and capecitabine.

Forced expression of cytidine deaminase confers sensitivity to capecitabine.

OBJECTIVE: Cytidine deaminase (CDD) is involved in the metabolism of new pyrimidine analogues, capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) and gemcitabine (2',2'-difluorodeoxycytidine). The purpose of the present study was to directly examine the role of CDD in tumor cells themselves in mediating the sensitivity to capecitabine compared with gemcitabine. METHODS: The human bladder cancer cell line T24 was transfected with human CDD2 cDNA by the lipofectin method. RESULTS: Transfection of CDD2 cDNA did not change the levels of thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidylate synthase (TS) but increased the CDD activity significantly (p < 0.01). Forced expression of CDD made T24 sensitive to 5'-deoxy-5-fluorocytidine (5'DFCR) in vitro and capecitabine in vivo, but resistant to gemcitabine both in vitro and in vivo. Tetrahydrouridine, a specific CDD inhibitor, abrogated the changes in the in vitro sensitivity to 5'DFCR and gemcitabine by transfection of CDD2 cDNA. Transfection of CDD2 cDNA resulted in a significant increase in cellular 5-fluorouracil level (p < 0.01) and inhibition of TS activity (p < 0.01) after treatment with 5'DFCR in vitro. CONCLUSIONS: The present study clearly showed direct evidence for the contribution of CDD in tumor cells themselves to the sensitivities to capecitabine and gemcitabine.