Torsade de pointes (Tdp) is a polymorphic ventricular tachycardia (VT) in which the axis of the QRS complex changes direction after a certain number of complexes as if the complex rotated around the baseline. Tdp is usually associated with QT prolongation, and dispersion of ventricular repolarlization (DR). Experimental models of tdp are usually associated with induction of early after depolarizations (EADs). Several aspects of the pathogenesis of tdp are incompletely understood. The purpose of this article is to propose the directions in research that may increase our current understanding of the factors responsible for tdp.
The most plausible hypotheses requiring further supporting evidence are: 1. The occurrence of tdp requires the presence of DR i.e. tdp does not occur in the absence of DR. 2. EADs appear to play an important role as a trigger to tdp in the animal models, but more evidence are needed at the clinical level. 3. EADs may be responsible for arrhythmias other than tdp. 4. The greater incidence of tdp in the females than in tha males may be attributed to differences in the duration of the QT interval and different morphology of the ST-segment and the T-wave. The above gender differences may be caused by the effects of gonadal hormones which modulate some of the membrane currents flowing during early ventricular repolarization.

View full abstract

The anti-tumor effect of N- [3,4-dimethoxycinnamoyl] -anthranilic acid (tranilast) was examined in experimental pancreatic cancer. Proliferation of PGHAM-1 cells was inhibited by tranilast in a dose-dependent manner, showing a significant difference at a concentration of 25 μg/ml (p<0.05). In colony formation, tranilast reduced the number of colonies at a concentration of 25 μg/ml (p<0.01). DNA synthesis for 12 hours was attenuated dose-dependently and a significant difference was observed at concentrations of greater than 50 μg/ml (p<0.05). From cell cycle analysis, a dose-dependent increase in the distribution of G0-G1 phase was observed. In the dorsal air sac model, the mean angiogenesis indices in PGHAM-1 chambers were 4.17 ± 0.22 (control group) and 2.33 ± 0.84 (treatment group), and in VEGF chambers they were 3.60 ± 0.67 (control group) and 1.92 ± 0.42 (treatment group), In the peritoneal dissemination model, the quantity of sanguineous ascites, the number and the size of diaphragmatic nodules and the microvessel density (MVD) of the metastatic site were reduced by tranilast significantly. In conclusion, the anti-tumor effect of tranilast on proliferation and on tumor-angiogenesis was confirmed in experimental pancreatic cancer.

View full abstract

Gastric signet-ring cell carcinoma comprises a distinct category of gastric cancers and has been reported to have poor prognosis. In an attempt to define genetic changes involved in the pathogenesis of this lesion in an in vivo state, we isolated signet-ring cell carcinoma cells from freshly fixed smears of tumor tissues of 7 primary gastric signet-ring cell carcinomas by laser capture microdissection and applied comparative genomic hybridization (CGH) to screen for DNA sequence copy number changes. Frequent chromosomal gains were detected on 2q, 5p, 7q, 14q and 20q, each in 6/7 cases, on 9q, 12q, 17q, and 19q, each in 5/7 cases, and on 18p in 4/7 cases. Frequent losses were observed on 6p and 17p, each in 5/7 cases, on 6q, and 21p, each in 4/7 cases, and on 3p, 8p and 8q, each in 3/7 cases. Losses on 6p have rarely been observed in conventional types of gastric carcinomas reported in the literature. These data provide the first evidence for the occurrence of specific genomic aberrations in gastric signet-ring cell carcinomas. Our observation of frequent losses on 6p chromosomal arm may provide novel abnormalities of potential significance in gastric signet-ring cell carcinomas, suggesting the involvement of genes residing in this region in the genesis of the disease.

View full abstract

Cytochrome P450 2E1 (CYP2E1) is known as a heme-containing enzyme that produces abundant free radicals, and its involvement in carcinogenesis has been suggested in several organs in vivo. In this study, to clarify the involvement of CYP2E1 in liver cancer and its carcinogenesis process, we investigated the expression of CYP2E1 in 42 surgically resected or biopsied specimens of hepatocellular carcinomas (HCC) and 26 cases with other liver lesions immunohistochemically using a newly prepared anti-human CYP2E1 antibody. When intracellular CYP2E1 expression was investigated in three different regions of HCC specimens, the expression in hepatocytes of the peri-tumor region was the highest (p<0.001) compared with those in the tumor and non-peri-tumor regions. Histologically, the expression of CYP2E1 in tumor cells tended to decrease as the cells were less differentiated (p<0.0001) and was the lowest in poorly differentiated HCC (p<0.01). CYP2E1 expression was highest in the pseudo-glandular type and low in the thick trabecular and solid types of HCC (p<0.0001). In mature regenerative nodules of liver cirrhosis, adenomatous hyperplasia (AH) and atypical adenomatous hyperplasia (AAH) to early-HCC, CYP2E1 expression was notably high as compared with other legions. CYP2E1 has a strong free radical-producing ability, and the cell injury and DNA damages by the free radicals are considered to be involved in carcinogenesis. Therefore, our results suggest that the different expression of CYP2E1 in hepatocytes may play important roles in the multistep carcinogenic process and the histogenesis of hepatocellular carcinoma.

View full abstract

Background: Although the pathogeneses of interstitial pneumonia are not well understood, it has been reported that inflammatory cells, especially neutrophils, and their injurious substances play important roles in the progression of interstitial pneumonia. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to inhibit chronic airway inflammation by mechanisms of anti-neutrophil and several other anti-inflammatory activities. The present study was undertaken to investigate the effects and mechanisms of 14-MRMLs (erythromycin: EM; clarithromycin: CAM; roxithromycin: RXM) on an experimental model of bleomycin (BLM) -induced acute lung injury in mice.
Methods: BLM was administered intravenously to ICR mice. For the evaluation of early-phase inflammation, cell populations in broncho-alveolar lavage fluid (BALF) and induction of mRNA of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) and TNF-α tested by RT-PCR in lung tissues were examined at 0 to 13 days after BLM. These parameters were also compared with those of the control (NS alone), 14-MRMLs-untreated (BLM alone) and-pre-treated (BLM+pre 14-MRMLs) groups.
Results: The number of neutrophils, macrophages, and lymphocytes significantly increased in BAL. Neutrophils especially increased with two peaks after BLM administration. 14-MRMLs significantly inhibited both peaks of neutrophil. The increase in number of macrophages in BALF was significantly attenuated by EM and RXM, and slightly attenuated by CAM. Number of lymphocytes in BALF was significantly attenuated by EM and CAM, and slightly attenuated by RXM. Changes in mRNA expression of E-selectin, P-selectin, ICAM-1, VCAM-1, and TNF-α were associated with the number of neutrophils migrating into the airspace. 14-MRMLs clearly inhibited the induction of VCAM-1 mRNA, and tended to attenuate the induction of ICAM-1 and TNF-α mRNA, but did not inhibit the induction of E-selectin and P-selectin mRNA.
Discussion: These findings show that 14-MRMLs clearly attenuated the expression of VCAM-1mRNA, and tended to attenuate the induction of ICAM-1 and TNF-α mRNA, and subsequently inhibited leucocyte, especially neutrophil migration into the airspace during the early phase of BLM-induced lung injury and finally inhibited lung fibrosis. This might be one potent mechanism of the anti-inflammatory effects of 14-MRMLs in BLM-induced acute lung injury. The findings suggest that prophylactic administration of 14-MRMLs may be clinically efficacious in preventing acute exacerbation of interstitial pneumonia and acute lung injury.

View full abstract

The effects of the antidepressant drugs trazodone and imipramine on the circadian rhythm were studied by means of the sleep propensity test (SPT; sleep latency was examined by 35-minute EEG records at 09: 00, 11: 00, 13: 00, 15: 00, 17: 00). The subjects were 11 healthy male volunteers (mean age, 23.6 years old). The drugs were administered 4 times a day with single blind trials using an inactive placebo as a control. The dosages of the drugs were trazodone 50-100 mg/day and imipramine 20-40 mg/day. We discussed the circadian rhythm referring to previous polysomnograhy (PSG) studies using the same drugs and dosages with most of the same subjects. As a result, the mean sleep latency of SPT was the shortest at 09: 00 (p<0.1) with a placebo, at 11: 00 (p<0.05) with trazodone and at 13: 00 (not significantly) with imipramine administration. These results suggested that neither drug affected sleepiness. They affected the circadian rhythm during the daytime (=the day rhythm). They delayed the day rhythm. Delay of the day rhythm was due to trazodone and have been caused by not only trazodon administration itself, but also by the increase of slow-wave sleep obtained in the previous night's PSG study. And the day-rhythm delay was due to imipramine and might have been caused by not only imipramine administration itself, but also by the decrease in the percentage of slow-wave sleep and REM sleep, and an increase in REM latency obtained in the previous night's PSG study. Therefore, we concluded that neither drug affected the tendency toward sleepiness, but did affect the day rhythm in healthy subjects.

View full abstract

There are few studies on the many complications that disrupt the rehabilitation of patients with cervical cord injuries and their subsequent health-economic benefits. I particularly focused on the treatment of urinary tract infection and decubitus ulcers because these are very frequently encountered complications in a clinical setting. I examined how these complications affect the progress of rehabilitation and facilitate a patient's return to society. The subjects included ninety-eight cervical cord injury patients with tetraplegia who were discharged from the Rehabilitation Center for Severely Disabled Persons from 1995 to 2000. I retrospectively investigated these ninety-eight subjects regarding ninety-six items from clinical records, among which twenty items were selected because they are considered to be closely associated with outcome, such as age, sex, length of stay, medical expense, urinary tract infection, and decubitus ulcer. Moreover, I examined the influence that urinary tract infection and decubitus ulcer had on other items. The average length of stay and total medical expenses per patient were 1,174.4 ± 559.9 days and 13,563,128.4 ± 6,351,078.1 yen, respectively. Urinary tract infection and decubitus ulcer occurred at a rate of 97% in patients with cervical cord injury undergoing chronic stage rehabilitation, and these complications caused a two-fold prolongation of the length of stay and a three-fold increase in medical expenses compared with patients without complications. It is important to fully recognize that these complications produce many expenses as well as those for the medical treatment of cervical cord injury.

View full abstract

We describe an unusual case of extreme hepatic left lobar atrophy with hilar cholangiocarcinoma. A 67-year-old woman was referred to Nippon Medical School with obstructive jaundice. On admission, computed tomography revealed dilated intrahepatic bile ducts and a defect in the area drained by the left side of the middle hepatic vein. A Spiegel lobe was demonstrated, but the left lobe could not be detected to the left side of the gallbladder. Percutaneous transhepatic cholangiography was performed and demonstrated obstruction of the intrahepatic bile duct at the hepatic hilum. A drainage catheter was left in place. Angiography revealed that the left hepatic artery was present, but there was narrowing of the left portal vein. A diagnosis of agenesis of the left hepatic lobe with hilar cholangiocarcinoma was made. At surgery, the left lobe appeared extremely atrophic without atrophy of the Spiegel lobe. The right anterior branches of the hepatic artery and portal vein had been invaded by carcinoma, so a left trisegmentectomy was performed. Final pathology was advanced hilar cholangiocarcinoma with invasion of the hepatic parenchyma, portal vein, and nervous system. The left lobe was atrophic without hepatolithiasis. The left portal vein was narrow distal to the Spiegel branch. The serum total bilirubin concentration was elevated postoperatively, and the patient was treated for hepatic failure. The patient died of pneumonia without recurrence 7 months after surgery.
This rare case of extreme hepatic left lobar atrophy with hilar cholangiocarcinoma was successfully treated by left trisegmentectomy. Preoperative portal embolization was unnecessary because the left lobe was already atrophic.

View full abstract

We report a case of a huge chronic expanding hematoma completely removed by surgery. A 71-year-old man was found to have a 3-cm-diameter round nodule in the posterior mediastinum seven years previously. He was not administered any treatment because he did not have any other serious symptoms. There was nothing in his history that could be related to his present condition, such as thoracic surgical treatment or tuberculosis. The massive tumor in the left pleural cavity grew, compressing the left lung and heart gradually in the past seven years. Cytological examination of a needle biopsy specimen showed only erythrocytes with a few infiltrating inflammatory cells. Moreover, his preoperative histopathological analysis did not reveal any significant findings. Therefore, he underwent complete resection of the hematoma including the fibrous capsule and left lower lobectomy. Severance of abundant new vascularizations caused massive bleeding. The postoperative course was uneventful. There was no recurrence in the two years. In cases of gradual growth of a mass without indications of malignancy, we should consider the existence of a chronic expanding hematoma even in patients without a history of thoracic operation or tuberculosis.

View full abstract