Antinociceptive effects of ONO-9902, an enkephalinase inhibitor,after visceral stress condition in rats

Purpose

The present study was designed to examine the antinociceptive effects of orally administered ONO-9902, an enkephalinase inhibitor, on both somatic and visceral pain after visceral stress conditions.

Methods

Twenty six male rats were examined. Tail-flick (TF) and colorectal distension (CD) tests were used to determine somatic and visceral antinociceptive effects, respectively. Measurements were performed in rats under immediate post-stress conditions (group ST; n = 14) and in rats nor under stress conditions (group NST; n = 12). In the stressed group, the same device, CD, for visceral antinociceptive effects was used for visceral stress and was applied with an intracolonic pressure of 60 mmHg for 20 min after drug administration. The TF latency and CD threshold were measured before and at 30, 40, 50, 60 and 90 min after administration of ONO-9902 300 mg · kg^?1 or distilled water.

Results

Orally administered ONO-9902 did not produce any changes in the % maximum possible effect (%MPE) in either TF or CD tests in the unstressed group. In the stressed group, %MPE in the CD test increased 18% and 31% at 30 and 40 min, respectively, after oral administration of ONO-9902 compared with the control group (P < 0.05). However, %MPE to TF test did not alter even after the CD-induced stress condition.

Conclusion

These results suggest that ONO-9902 may have analgesic effects on visceral pain but not on somatic pain under immediate post-stress conditions.     

Report on the Computer Software Contest at 38th Congress of the Japan Society of Anesthesiology

We held a computer software contest at 38th Congress of the JSA, held in March, 1991. The aim is to encourage the members of the Society to write softwares and to help distribute them, especially as Freewares. We received 25 entries for the contest; two-thirds of these are for computers of NEC PC9801 series and a third are for Macintosh. We received donations 3 million yen worth of instruments and goods for prizes plus some cash, which as prizes were distributed to those who made entries for the contest.Most of these programs have been registered as freewares at various computer networks, including our Ether-Net, one of the common computer network SIGBBSs among Japanese anesthesiologists.(Suwa K, Miyasaka K, Tanaka Y, et al.: Report on the computer software contest at 38th congress of the Japan society of anesthesiology. J Anesth 5: 441–444, 1991)Executive Committee of the Computer Software Contest at 38th Congress of the Japan Society of Anesthesiology     

Additional Hepatocellular Carcinomas Undetectable before Surgery

The presence of small additional hepatocellular carcinomas (HCCs) undetectable before hepatic resection is a crucial topic for hepatic surgeons. We assessed the incidence of pathologically diagnosed multiple HCCs in 267 patients who underwent hepatic resection for HCC. Ninety-five additional HCC nodules were detected in 72 of the patients (27%). The survival rate of these 72 patients was significant worse than for the 195 with single nodular HCC (p= 0.0013). Twenty-one (22%) were detected before surgery, 29 (31%) during surgery, and 45 (47%) on pathologic examination after surgery. The mean nodule diameters for each group were 2.1, 1.0, and 0.9 cm, respectively (p < 0.0001). None of the 21 nodules detected before surgery was well differentiated, whereas 30 of the 74 nodules in the other two groups were well-differentiated. Although the mean nodule diameter of the well-differentiated HCC group was the smallest, there was no significant difference among the three groups assigned according to tumor differentiation (p= 0.2355). Altogether, 9 of 16 patients with additional nodules detected before surgery (56%) and 49 of 59 with additional nodules detected during or after surgery (88%) had cirrhosis of the liver. The odds ratio for detecting a new HCC nodule during or after surgery in the presence of cirrhosis was 5.444 (p= 0.0087). Improvement in the detection of small additional HCC nodules before and during surgery and meticulous follow-up after surgery are necessary for patients with cirrhosis. For patients without cirrhosis, surgical treatment may be performed according to the results of preoperative imaging studies.     

A cancer-prone case with a background of methylation of p16 tumor suppressor gene.

PURPOSE AND EXPERIMENTAL DESIGN: To date, the presence of p16 gene promoter methylation associated with loss of protein expression has been demonstrated frequently in digestive tract cancers. In this study, we tested for the methylation status of p16 promoter in normal tissue specimens using the methylation-specific PCR technique to examine whether p16 methylation already existed in the background of tumors. RESULTS: Aberrant promoter methylation of p16 gene was detected in 1 of 40 esophageal and 1 of 69 gastric and no colorectal epithelium specimens, and these 2 specimens were derived from the same patient. We also found the same methylation change in both tumor and blood cell DNA. CONCLUSION: These results suggested that the p16 gene was inactivated by methylation in normal background cells of this patient and that other additional factors may promote tumor development in his esophageal and gastric tissues.     

Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance.

PURPOSE: Rituximab has clinical activity in patients with chronic lymphocytic leukemia (CLL) and has a variety of proposed mechanisms, including apoptosis, complement-dependent cell lysis (CDC), and antibody-dependent cellular cytotoxicity (ADCC). Here we examine pretreatment biologic features that promote resistance to apoptosis and CDC in CLL patients and correlate it with clinical outcome to rituximab-based therapy. PATIENTS AND METHODS: Pretreatment samples from 21 CLL patients treated on a prospective, single-agent rituximab trial were examined for quantitative expression of apoptotic and CDC regulatory proteins, and the level of expression of these proteins was correlated with clinical outcome. RESULTS: Of the 21 patents for whom samples were available, 10 attained a partial response and 11 failed to respond to rituximab therapy. The mean pretreatment expression of Bcl-2, Mcl-1, XIAP, and the ratio of Bcl-2/Bax were higher but not statistically increased in nonresponding patients versus those responding to treatment. In contrast, the pretreatment Mcl-1/Bax ratio was significantly elevated (0.82 +/- 0.28 v 0.39 +/- 0.29, P <.016) in nonresponding patients compared with patients responding to rituximab therapy. Although pretreatment expression of CD55 and CD59 was not associated with response to rituximab therapy, significantly higher levels of CD59 were observed in the CLL cells that were not cleared from the blood at completion of therapy than the level observed at baseline levels (P =.02). CONCLUSION: These data indicate that baseline expression of the Mcl-1/Bax ratio, but not CD55 and CD59, predict for clinical response to rituximab therapy in CLL patients. Further study of disrupted apoptosis in CLL as a potential mechanism of resistance to rituximab appears warranted.     

Decrease in serum thyroxine level by phenobarbital in rats is not necessarily dependent on increase in hepatic UDP-glucuronosyltransferase.

We have previously reported that there is a poor correlation between increase in the levels of UDP-glucuronosyltransferases, UGT1A1 and UGT1A6, and decrease in the levels of serum total thyroxine (T4) and free T4 in phenobarbital (PB)-treated rats, although the PB-induced decrease in rats is generally thought to occur through induction of the UDP-glucuronosyltransferase (T4-UDP-GT: UGT1A1 and UGT1A6). In the present study, to clarify a relationship between the decrease in serum T4 level and the increase in the T4-UDP-GT activity by PB in rats, we examined the relationship using Gunn rats, a mutant strain of Wistar rats deficient in UGT1A isoforms. Levels of serum total T4, free T4, and total triiodothyronine (T3) were markedly decreased not only in Wistar rats but also in Gunn rats 1 day after the final administration of PB (80 mg/kg i.p., once daily for 4 days), and no significant difference in magnitude of the decrease between Wistar and Gunn rats was observed. On the other hand, the level and activity of T4-UDP-GT were significantly increased by treatment with PB in Wistar rats but not in Gunn rats. Furthermore, significant decrease in the activity of hepatic type I iodothyronine deiodinase, which mediates the deiodination of T4 and T3, by PB treatment was observed in both Wistar and Gunn rats. In addition, no significant change in the level of serum thyroid-stimulating hormone, the activity of hepatic sulfotransferase, and the binding of [125I]T4 to serum transthyretin and albumin by PB treatment was observed in either Wistar or Gunn rats. In conclusion, the present results demonstrate that the decrease in serum total T4 level by PB in Gunn rats is not dependent on the increase in hepatic T4-UDP-GT activity and suggest that even in Wistar rats, the PB-induced decrease in serum T4 level does not occur only through increase in hepatic T4-UDP-GT.     

The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers.

PURPOSE: Recent studies reported that clinical responsiveness to gefitinib was associated with somatic mutation of epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers (NSCLC). Here, we investigated the relationship between EGFR mutation and clinicopathologic features. EXPERIMENTAL DESIGN: EGFR mutational status of 120 NSCLCs was determined mainly in EGFR exons 18 to 21 by direct sequence and correlated with clinicopathologic parameters. RESULTS: EGFR mutations were present in 38 cases (32%) and the majority of mutations were in-frame deletions of exon 19 (19 cases) and a missense mutation in exon 21 (18 cases). EGFR mutations were frequently associated with adenocarcinoma (P < 0.0001), never smoker (P < 0.0001), and female gender (P = 0.0001). Of interest, increasing smoke exposure was inversely related to the rate of EGFR mutation (P < 0.0001). Multivariate analysis showed that smoking and histology were independent variables. Furthermore, gender difference was observed for the mutational location (P = 0.01) dominance of exon 19 for males and exon 21 for females. Twenty-one cases were treated with gefitinib and found that EGFR mutation was significantly related to gefitinib responsiveness (P = 0.002). In addition, median survival times of patients with and without EGFR mutations treated with gefitinib were 25.1 and 14.0 months, respectively. Patients with EGFR mutations had approximately 2-fold survival advantage; however, the difference was not significant. CONCLUSIONS: We show that EGFR mutations were significantly related to histology and smoke exposure and were a strong predictive factor for gefitinib responsiveness in NSCLC.     

Role of SCOX in determination of Drosophila melanogaster lifespan

In man, COX (cytochrome c oxidase) deficiency is reported to be related to mutation of the SCO2 (synthesis of cytochrome c oxidase 2) gene, which encodes one of the copper-donor chaperones involved in the assembly of mitochondrial cytochrome c oxidase. Such COX deficiency due to the genetic condition leads to heart disease and the Leigh syndrome and is frequently fatal in childhood. Synthesis of cytochrome c oxidase X (SCOX) is a Drosophila orthologue of human SCO2. Here, we generated SCOX-knockdown flies and the full length SCOX transgenic flies to investigate the in vivo roles of SCOX. Our results demonstrated knockdown of SCOX gene in all cells and tissues to be associated with lethality at larval or pupal stages and this correlated with a decrease in ATP level. In contrast, the full length SCOX transgenic flies showed a longer lifespan than wild type flies and control flies carrying Act5C-GAL4 alone and this correlated with an increase in ATP level. Finally, when cultured on paraquat-added medium, full length SCOX transgenic flies also exhibited an elongated lifespan. Therefore, we hypothesized that SCOX plays an important role in ATP production and consumption, which helps to prevent production of mitochondrial reactive oxygen species and/or impairment of mitochondrial activity under oxidative stress.     

Laterality of vestibular evoked myogenic potentials

To clarify the laterality of acoustically evoked vestibulocollic reflexes with a short latency (vestibular evoked myogenic potentials, VEMPs), responses on the bilateral sternocleidomastoid muscles (SCMs) to unilateral acoustic stimulation were studied. Twenty-one healthy volunteers were enrolled. Surface electrodes were placed on the upper half of each SCM (active) and on the lateral end of the upper sternum (reference). Clicks and 500-Hz tone-bursts (95 dB nHL) were used. All subjects showed positive-negative biphasic responses on the ipsilateral SCM by clicks and tone-bursts. Click-stimulation of 41 of the 42 ears did not evoke any response on the contralateral SCM. However, in one ear, positive-negative biphasic responses were evoked on the contralateral SCM. Recordings on the contralateral SCM by tonebursts showed no response in 32 ears, small positive-nega-tive biphasic responses in four ears, and small negative-positive biphasic responses in six ears. These findings show that VEMPs are ipsilateral-dominant, basically consistent with the hypothesis that they are of saccular origin.