Prevention by methylprednisolone of increased circulating tumor necrosis factor-alpha levels and lung injury associated with systemic inflammatory response syndrome due to intraperitoneal hyperthermia

We previously demonstrated that intraperitoneal hyperthermic perfusion (IPHP), which is performed clinically as a treatment for patients with advanced gastrointestinal cancer, can lead to increased serum tumor necrosis factor-alpha (TNF-alpha), systemic inflammatory response syndrome (SIRS), and acute lung injury. Glucocorticoids inhibit the production and actions of TNF-alpha. We investigated whether pretreatment with methylprednisolone (MPS) may modulate serum TNF-alpha and lung injury in patients subjected to IPHP. Serum TNF-alpha was not detected in the patients pretreated with MPS, whereas serum TNF-alpha increased in the control patients (45.7 +/- 8.3 pg/mL, mean +/- SEM) after IPHP. Postoperative lung injury scores were significantly lower in patients pretreated with MPS than in the control patients (P < 0.001). Implications: Pretreatment with methylprednisolone attenuates the increase in circulating tumor necrosis factor-alpha and prevents lung injury in this systemic inflammatory syndrome due to intraperitoneal hyperthermic perfusion.     

Two-dimensional photon counting imaging and spatiotemporal characterization of ultraweak photon emission from a rat's brain in vivo

The process of metabolic reactions within living cells leads to spontaneous ultraweak light emission. The development of a system for highly sensitive imaging and spatiotemporal analysis of ultraweak photon emission from a rat's brain is reported in this paper. The equipment used in this experiment consists of a two-dimensional photon-counting tube with a photocathode measuring 40 mm in diameter, a highly efficient lens system, and an electronic device to record time series of a photoelectron train with spatial information. The sensitivity and ability to extract spatiotemporal information from sequential data of a single photoelectron train were examined. The minimum detectable radiant flux density of the system was experimentally estimated to be 9.9 x 10(-17) W/cm2 with a 1-s observation time. Spontaneous photon emission was demonstrated from an exposed rat's cortex in vivo without adding any chemical agent or employing external excitation. An image of ultraweak photon emission was compared with one obtained after cardiac arrest. The intensity after cardiac arrest was depressed to approximately 60% of before that. The regional properties of time courses of emission intensity were also demonstrated, indicating the potential usefulness for spatiotemporal characterization of photon emission with mapping of physiological information such as oxidative stress. This technology constitutes a novel method, with the potential to extract pathophysiological information from the central nervous system.     

Retention, excretion and translocation of 239Pu in rats following inhalation of 239PuO2 calcined at 1150 and 400 degrees C.

Wistar rats inhaled 239PuO2 particles prepared by the calcination of 239Pu hydroxide at 1150 and 400 degrees C. Lung retention, fecal and urinary excretion, and translocation of 239Pu were compared between the two calcination temperatures. The clearance of 239Pu from the lungs was significantly faster in the rats exposed to 239PuO2 calcined at 400 degrees C (low-temperature group) than those exposed to 239PuO2 calcined at 1150 degrees C (high-temperature group). Both the fecal excretion of 239Pu and the ratio of fecal excretion to urinary excretion was greater in the low-temperature group than in high-temperature group. The amounts of 239Pu translocated from the lungs to the other organs were very small. Even in the liver, which accumulated the largest amount of 239Pu except for the lungs, only 0.13-0.20% of the initial lung burden was retained 1 year after inhalation. The amount of 239Pu deposited in the liver was greater in the high-temperature group than in the low-temperature group both at 1 month and 1 year after the inhalation. These findings clearly suggest that the lung retention of 239Pu in rats is significantly affected by the calcination temperature of 239PuO2.     

Antiulcer effect of lafutidine on indomethacin-induced gastric antral ulcers in refed rats.

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.     

Identification of cytochromes P450 involved in human liver microsomal metabolism of ecabapide, a prokinetic agent

1. In vitro studies identified the hepatic cytochrome P450 (CYP) enzyme(s) involved in the major metabolism of ecabapide in human. 2. Ecabapide mainly underwent N-dealkylation to form M1 and 6-hydroxylation of the benzamide moiety to form M6. 3. The rates of formation of the major metabolites M1 and M6 were significantly correlated with CYP3A-selective testosterone 6beta-hydroxylase activities in 14 different human liver microsomes. The formation of both metabolites was markedly decreased by ketoconazole, miconazole or troleandomycin (TAO), CYP3A-selective inhibitors, and also was inhibited by anti-CYP3A antibodies. 4. These results strongly indicate that CYP3A is the predominant isozyme responsible for the major metabolism of ecabapide in human liver microsomes. 5. Marginal inhibition of the formation of M1 and M6 by nifedipine, a substrate of CYP3A with a Ki > 100 microM, suggested that nifedipne has a limited potential to inhibit the major metabolic pathways of ecabapide.     

Antitumor activity of HO-221, a derivative of benzoylphenylurea against human cancer xenografts in nude mice

HO-221, a derivative of benzoylphenylurea, is a newly developed anticancer drug which was found to show an excellent antitumor effect against transplantable murine tumors by the novel mechanism of action. This study was designed to evaluate the antitumor effect of HO-221 and to establish the optimum regimen, using seven human gastrointestinal and breast cancers xenografted in nude mice. Better antitumor effect of HO-221 by oral administration was observed when it was suspended in larger volume of the vehicle. Moreover, the effect increased by the multiple intermittent administration compared to the single treatment. Best antitumor effect was observed by oral administration of 75 mg/kg (0.1 ml/10 g mouse body weight) repeated twice weekly for a total of eight times or 300 mg/kg (0.2 ml/10 g mouse body weight) repeated once weekly for a total of four times. The antitumor effects of these two regimens were approximately equal except against H-31, the former regimen being more effective. When the tumor growth inhibition rate (IR) over 58% was rated as "effective", the above two regimens were equally effective against 4 of 7 cancers, H-111, H-154, H-143 and H-31. While HO-221 was not effective to a gastric cancer line, H-81, which was most susceptible to the variety of existing anticancer agents, but effective to another gastric cancer line, H-111, which was relatively resistant to conventional cytocidal agents. From the aspect of chemosensitivity spectrum, this drug revealed a rather different pattern compared to other antimetabolites. Although oral administration volume is limited in small animal model, enhancing its antitumor effect may be possible in clinical application by contriving the method of administration. HO-221 is, thus, considered to be a promising drug for further study.     

Hand-arm vibration syndrome and its prevalence in the present status of private forestry enterprises in Japan

Summary Currently there are no limitations on age of employment on private forestries in Japan. Hence, it was hypothesized that in these kind of enterprises, elderly chain saw operators, or those with long-term exposure, might be at higher risk of developing hand-arm vibration syndrome (HAVS). We consequently investigated the prevalence of HAVS in 447 chain saw workers on private forestries in Gifu Prefecture, Japan, with particular reference to age and exposure period. Of this population, 43 (9.6%) had signs and symptoms of vibration-induced white finger (VWF), and among these workers the severity of finger blanching was significantly correlated (P < 0.01) with the exposure period. Classification of all subjects by exposure period showed that workers with 30 years' exposure had higher prevalences of VWF (20.9%) and numbness of the hands (25.4%) compared to other groups. Significant differences (P < 0.01) were found between the functional capacities of workers with VWF and those of control subjects. We concluded that (a) the elderly chain saw operators and those with longer exposure should be moved to other jobs with a lower or no risk of exposure to vibration, and (b) the results of screening tests, even without cold water immersion (which we did not employ, in order to protect workers' hands), could be helpful for the identification of workers with VWF.     

Use of tactile stiffness to detect fatigue in the latissimus dorsi muscle

In clinical settings, no method has been established to examine the fatigue of a latissimus dorsi muscle (LDM) preconditioned for cardiomyoplasty. We examined the feasibility of measuring muscle stiffness (tactile stiffness) to evaluate muscle fatigue in situ using our tactile sensor. We stimulated canine LDM with burst pacing and monitored both stiffness and tension to determine their relationship. In both dissected LDM and LDM in situ, the decrements of these parameters during burst pacing were compared between preconditioned and unconditioned LDM. In measurement in situ, the sensor probe was placed on the LDM through a small incision. Strong statistical correlation was shown between stiffness and tension (r = 0.935). In decrements of stiffness in situ, there were statistically significant differences between preconditioned and unconditioned LDM. Our tactile sensor system can provide an efficient method for evaluating fatigue of muscles in situ without measuring muscle tension.     

A 5 year follow-up study on the relationship between changes in serum lipids and blood pressure, and changes in exercise habits in subjects 30 years of age

A 5 year follow-up study was conducted to investigate the relationships between %changes in serum lipids and blood pressure and corresponding changes in exercise habits in the middle-aged. The subjects were 152 males and 169 females who received a health check-up at 30-years-old during the period between 1990-1992 and then at 35-years-old during the period between 1995-1997. The results are as follows: 1. In multiple regression analysis, % delta toriglyceroid (TG) and % delta AI(atherogenic index) ratio were associated significantly with changes in exercise habits in males (P < 0.05) and % delta high density lipoprotein cholesterol (HDLC) was associated with changes in exercise habits in females (P < 0.05). % delta TG and % delta HDLC were affected by changes in exercise habits adjusted for BMI, smoking, and drinking. But changes in TC and blood pressure were not affected by changes in exercise habits. 2. In males, % delta TG was significantly lower in those subjects who started their exercise habit than in the no exercise group and than in those within the ceased exercise group who ceased their exercise during the study period (P < 0.05). % delta AI was significantly lower in the started exercise group than in the no exercise group. Also, the continued exercise group had a significantly (P < 0.05) lower % delta AI as compared to the ceased exercise group. In females, % delta TG was significantly lower in the started exercise group than in the no exercise group (P < 0.05). % delta HDLC was higher significantly in the continued exercise group than in the ceased exercise group (P < 0.05). From the results obtained, it is recommended that the no exercise subjects should have exercise more than once time per week and those with more than 1 time per week maintain their exercise habits.     

Increased Sensitivity to Long-term 5-Fluorouracil Exposure of Human Colon Cancer HT-29 Cells Resistant to Short-term Exposure

A 5-fluorouracil (5-FU)-resistant subline of human colon cancer HT-29 cells was developed by repeated 1-h exposure in vitro to 5-FU. This subline (HT-29/5-FU/S) had 8-fold resistance to 5-FU in a 1-h exposure assay. However, it had rather increased sensitivity to 5-FU when assayed after a continuous 96-h exposure to it. Significantly less 5-fluorouridine-5'-triphosphate was produced in the resistant cells, leading to a lower level of 5-FU incorporation into the cellular RNA. The reduced activity of orotate phosphoribosyltransferase might explain these results. In contrast, the HT-29/5-FU/S cells were more sensitive to the inhibition of in situ thymidylate synthase (TS) by 5-FU than were the parent cells. The lower in situ TS activity may have made HT-29/5-FU/S cells more sensitive to TS inhibition by 5-FU as compared with the parent cells. The fact that HT-29/5-FU/S was more resistant to short-term 5-FU exposure but more sensitive to long-term exposure than the parent line confirmed the existence of different modes of action of 5-FU, depending on the exposure time.