GR144053, a fibrinogen receptor antagonist, enhances the suppression of neointima formation by losartan, an angiotensin II receptor antagonist, in the injured carotid artery of hamster

1. The present study investigated the inhibitory effect of losartan, a type 1 angiotensin II (AT1) antagonist, and of combined treatment with losartan and GR144053, a fibrinogen receptor (GPIIb/IIIa) antagonist, on neointima formation subsequent to vascular injury in the hamster carotid artery. Vascular injury was achieved by a roughened-tip 2F catheter and the neointimal area was measured up to 2 weeks inducing the injury. 2. Compared to non-treated hamsters (intimal area (IA/internal elastic laminal area (IELA) ratio = 60.3 +/- 5.9%, n = 12), losartan dissolved in drinking water (1, 3 and 10 mg kg-1 per day, n = 8 each) reduced neointimal area dose-dependently, a significant decrease (IA/IELA = 39.7 +/- 5.6%) being attained with the highest dose when it was administered from 1 day before injury. However, neointima formation was not prevented even with the highest dose of losartan when the administration was started after injury. 3. When the administration of GR144053 (1.0 mg kg-1 per hour) via an implanted osmotic pump was started 30 min before the injury and continued for the next 2 weeks, no suppression of neointima formation was observed, although platelet aggregation evoked ex vivo by adenosine diphosphate (ADP) at the end of treatment period was efficiently inhibited. 4. In separate experiments in which 5-bromo-2-deoxy-Uridine (BrdU) was used to test smooth muscle cell (SMC) proliferation 1 and 7 days after injury, the ratio of SMC proliferation in the injured area was only slightly decreased by losartan when its administration was started after the injury, despite the marked reduction of SMC proliferation when treatment was started before the injury. Treatment with GR144053 as indicated above also significantly decreased the SMC proliferating index 1 day after the injury. 5. To examine the potential benefit of the coadministration of the GPIIb/IIIa antagonist with the AT1 receptor antagonist, GR144053 (1.0 mg kg-1 per hour) was combined with post-injury treatment with losartan (10 mg kg-1 per day). This markedly reduced the proliferation of SMCs and significantly decreased the neointimal area (IA/IELA = 31.2 +/- 4.6%) measured 2 weeks following the catheterization. 6. According to the results of a time-dependent study in which GR144053 was given in combination with post injury treatment with losartan for 1, 3, 7 or 14 days, neointima formation could be reduced by treatment with GR144053 for just 7 days. 7. In conclusion, GR144053, a fibrinogen receptor antagonist, enhanced the inhibitory effect of losartan, an AT1 receptor antagonist, on neointima formation in the damaged carotid artery of hamsters.     

Involvement of antizyme-like regulatory protein in polyamine-caused repression of ornithine decarboxylase in insect-derived Trichoplusia ni 5 cells

BACKGROUND: The diagnosis and classification of oesophageal motility disorders is currently based on assessment of the phasic contractile activity of the oesophagus. Tonic muscular contraction of the oesophageal body (oesophageal tone) has not been well characterised. AIM: To quantify oesophageal tonic activity in healthy subjects and in patients with achalasia. PATIENTS: Oesophageal tone was measured in 14 patients with untreated achalasia and in 14 healthy subjects. In eight patients with achalasia, oesophageal tone was again measured one month after either endoscopic or surgical treatment. METHODS: Tonic wall activity was quantified by means of a flaccid intraoesophageal bag, 5 cm long and of 120 ml maximal capacity, which was placed and maintained 5 cm above the lower oesophageal sphincter and connected to an external electronic barostat. The experimental design included measurement of oesophageal basal tone and compliance as well as the oesophageal tone response to a nitric oxide donor (0.5 ml amyl nitrite inhalation). RESULTS: Oesophageal basal tone, expressed as the intrabag (intraoesophageal) volume at a minimal distending pressure (2 mm Hg), did not differ significantly between patients with achalasia and healthy controls (6.6 (2.5) ml versus 4.1 (0.8) ml, respectively). Oesophageal compliance (volume/pressure relation during intraoesophageal distension) was significantly increased in achalasia (oesophageal extension ratio: 3.2 (0.4) ml/mm Hg versus 1.9 (0.2) ml/mm Hg; p < 0.01). Amyl nitrite inhalation induced oesophageal relaxation both in patients and in controls, but the magnitude of relaxation was greater in the latter (intrabag volume increase: 15.3 (2.4) ml versus 36.2 (7.1) ml; p < 0.01). CONCLUSION: In patients with achalasia, oesophageal tonic activity, and not only phasic activity, is impaired. Although oesophageal compliance is increased, residual oesophageal tone is maintained so that a significant relaxant response may occur after pharmacological stimulation.     

IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice

When LPS is administered to heat-killed Propionibacterium acnes-primed BALB/c nude mice, they develop endotoxin-induced liver injury. As previously reported, this liver injury can be prevented by treatment with an Ab against IL-18, a novel cytokine with the ability to induce IFN-gamma production and up-regulate functional Fas ligand (FasL) expression. To identify the pathologic role of IL-18 in this liver injury, we investigated the hepatic cytokine network and FasL induction after LPS challenge. After LPS challenge to BALB/c nude mice, their livers expressed IL-12 mRNA, followed by the induction of IFN-gamma and FasL mRNA and then by the late elevation of TNF-alpha mRNA, but stably expressed IL-18 mRNA. The TNF-alpha induction curve had two peaks. The first peak was the result of the direct reaction to LPS, and the late peak might have been induced, since P. acnes-elicited Kupffer cells showed one-peak TNF-alpha kinetics in response to LPS stimulation in vitro. LPS-activated P. acnes-elicited Kupffer cells secreted both IL-12 and IL-18, as determined by ELISA and bioassay, respectively. The in vivo administration of anti-IL-18 just before an LPS challenge suppressed not only the induction of IFN-gamma and the late TNF-alpha elevation, but also the FasL induction, resulting in the total prevention of liver injury, whereas such an anti-IL-12 treatment did not. Anti-IFN-gamma treatment reduced the late increase in TNF-alpha, but not FasL, resulting in a partial prevention of the liver injury. The administration of anti-TNF-alpha just before elevation of the late TNF-alpha peak also markedly, but incompletely, suppressed the LPS-induced liver injury. These data suggested that IL-18 activates both TNF-alpha- and FasL-mediated hepatocytotoxic pathways in endotoxin-induced liver injury.     

bor1-1, an Arabidopsis thaliana mutant that requires a high level of boron

Catenins are proteins associated with the cytoplasmic domain of cadherins, a family of transmembrane cell adhesion molecules. The cadherin-catenin adhesion system is involved in morphogenesis during development and in the maintenance of the integrity of different tissue types. Using a gene trap strategy, we have isolated a mouse mutation for the gene encoding the alpha-E-catenin. This form of the alpha-catenin appears frequently coexpressed with E-cadherin in epithelial cell types. The mutation obtained eliminates the carboxyl-terminal third of the protein but nevertheless provokes a complete loss-of-function phenotype. Homozygous mutants show disruption of the trophoblast epithelium (the first differentiated embryonic tissue), and development is consequently blocked at the blastocyst stage. This phenotype parallels the defects observed in E-cadherin mutant embryos. Our results show the requirement of the alpha-E-catenin carboxy terminus for its function and represent evidence of the role of the alpha-E-catenin in vivo, identifying this molecule as the natural partner of the E-cadherin in trophoblast epithelium.     

Effect of resistance exercise training on bone formation and resorption in young male subjects assessed by biomarkers of bone metabolism

We studied the effects of high intensity resistance exercise training on bone metabolism in 17 young adult Oriental males (23-31 years) by measuring sensitive biomarkers of bone formation and resorption. The subjects were assigned to a training group and a sedentary group. The training group followed a weight training program three times per week for 4 months. In the training group, serum osteocalcin concentration and serum bone-specific alkaline phosphatase activity were significantly increased within the first month after the beginning of resistance exercise training, and the elevated levels remained throughout the training period, while there was no significant change in plasma procollagen type-I C-terminal concentration. Urinary deoxypyridinoline excretion was transiently suppressed and returned to the initial value but was never stimulated during the 4 months. These results suggest that the resistance exercise training enhanced bone formation without prior bone resorption. In the sedentary group, there was no significant difference in bone metabolic markers except plasma procollagen type-I C-terminal, which continuously decreased during the experimental period. There were no significant changes in total and regional bone mineral density in either group. In conclusion, (1) resistance exercise training increased markers of bone formation, while it transiently suppressed a marker of bone resorption, and (2) such adaptive changes of bone metabolism to resistance exercise training occurred during the early period of the training, before changes in bone density were observable through densitometry.     

Reversal of multidrug resistance (MDR) by aspidofractinine-type indole alkaloids

A series of indole alkaloids of the aspidofractinine-type was assessed for their potential in reversing MDR in vincristine-resistant KB cells. Of the compounds tested, kopsiflorine, kopsamine, pleiocarpine, 11-methoxykopsilongine, lahadinine A and N-methoxycarbonyl-11,12-methylenedioxy-delta 16,17-kopsinine were found to show appreciable activity.     

Case report: malignant transformation of biliary cystadenoma with mesenchymal stroma: documentation by CT

The object of this cross-sectional study on psychological distress was to reveal such distress among patients treated for colorectal cancer (CRC). Between 1993 and 1996, 95 patients in northern Norway were included in the national study randomising Dukes' B and C CRC patients between adjuvant chemotherapy (ACT: 5-fluorouracil and levamisole) or follow-up following radical surgery. In April 1996, all 82 survivors were mailed the Impact-of-Event Scale (IES), to which 64 patients responded (78%). Less than one-third of the patients reported a moderate to high level of psychological distress. Scores predicting significant stress response syndrome were revealed in 14% of the patients. The mean score on the intrusion and avoidance scales were 6.1 and 7.7, respectively. Such variables as age, sex, tumour location (rectum/colon), Dukes' stage B/C and time of follow up did not significantly influence the scores. Patients receiving ACT reported only a slightly raised level on the intrusion (6.97 vs 5.17) and avoidance (8.48 vs 6.80) scales. This study indicates that ACT in CRC Dukes' B and C is not a stressful happening. All advantages in survival achieved by ACT have to be weighed against the "cost" in terms of physical and psychological side effects. This study indicates the weighting in terms of psychological distress may be minimal.