Biomedical subjects
Publications and source records attributed to M Oka.
The muscarine receptor agonist SK-946, an aniline derivative with a characteristic bicyclo amine, was found. We describe a new synthetic method for 1-azabicyclo[3.3.0]octane and describe the biological activity of SK-946.
We have studied damage to the tibial articular surface after replacement of the femoral surface in dogs. We inserted pairs of implants made of alumina, titanium and polyvinyl alcohol (PVA) hydrogel on titanium fibre mesh into the femoral condyles. The two hard materials caused marked pathological changes in the articular cartilage and menisci, but the hydrogel composite replacement caused minimal damage. The composite osteochondral device became rapidly attached to host bone by ingrowth into the supporting mesh. We discuss the clinical implications of the possible use of this material in articular resurfacing and joint replacement.
Hemorrhagic adrenal metastasis from lung cancer is extremely rare, although adrenal involvement is common in widely disseminated cancer. We report a case of massive adrenal hemorrhage secondary to metastasis of lung cancer. A 47-year-old female was treated by left upper lobectomy and mediastinal lymph node resection for an adenocarcinoma with intrapulmonary metastasis in the left upper lobe. Eight months later, she presented with right flank and back pain, and abdominal ultrasonography and computed tomography showed a right solitary adrenal tumor with massive hemorrhage. The tumor was not resectable and partially responded to chemotherapy. A massive adrenal hemorrhage, secondary to metastasis of lung cancer, presents with nonspecific clinical signs and symptoms. In lung cancer patients with an acute flank or back pain, hemorrhagic adrenal metastasis should be considered in the differential diagnosis.
A 54-year-old nonsmoker female developed atelectasis of the anterior basal segment of the right lower lobe. A non-pulsating endobronchial tumor was observed bronchoscopically obstructing the right basal bronchus. The tumor was confirmed on arteriography to be a saccular aneurysm of the right bronchial artery. The aneurysm was treated with bronchial artery embolization. Bronchial artery aneurysm, without a predisposing disease, is quite rare, but should be considered as an etiological factor of atelectasis.
Twelve patients with unresectable primary liver cancer (hepatocellular carcinoma and cholangiocarcinoma) and postoperative recurrence of primary liver cancer received continuous arterial or systemic infusion of low-dose CDDP/5-FU. This infusion chemotherapy was continued for five days, discontinued for two days, and repeated four weeks as one course basally. The partial response rate in patients with HCC or CCC treated with intra-arterial infusion was 20% and 33%, respectively. The rate in patients with HCC or CCC treated with systemic infusion was 0% and 33%, respectively. The response rate included decrease of tumor markers in all patients with HCC or CCC was 33% and 67%, respectively. These results suggest that low-dose CDDP/5-FU therapy may be effective in patients with CCC. Severe side effects such as gastro-duodenal ulcer (4 cases) and pseudomembranous colitis (1 case) were observed. The careful management of side effects should be required during this therapy.
A 57-year-old man suffering from gastric cancer with esophageal invasion and liver and paraaortic lymph nodes metastases was treated with continuous 5-FU injection and intra-hepatic arterial infusion of low-dose cisplatin following non-curative surgery. The patient had shown a partial response (PR) in both metastatic lesions with little side effect. In the period following his operation, he was able to sustain a relatively good quality of life and died 16 months after the operation. Continuous injection of 5-FU and low-dose cisplatin infusion could become one of the effective pre-operative chemotherapies for patients with far-advanced gastric cancer when performing a curative resection.
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2-Chloro-4-methylthiobutanoic acid (CMBA, a mutagen from Japanese salted fish) at 15-500 mg/kg body weight induced several-fold increase in replicative DNA synthesis (RDS) (P < 0.05) after 80 min and 17 h, equivocal unscheduled DNA synthesis (UDS) after 80 min and necrosis 80 min after its administration in the stomach pyloric mucosa of F344 and ACI male rats. A positive control, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 50 mg/kg body weight), induced RDS, UDS and erosion. However, the negative control L-methionine (500 mg/kg body weight) did not display any effect. The results suggest possible tumor-initiating and -promoting activity of CMBA but at a lower potency than that of MNNG.
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In cardiac tissues, angiotensin II causes inotropic and chronotropic effects on the heart. It is indicated that the mechanism of the inotropic effect of angiotensin II is attributed to an increase in cytosolic free calcium ([Ca2+]i) in cardiomyocytes. However, increased [Ca2+]i should be restored to a physiological level because cumulative elevation in [Ca2+]i leads to irreversible injury in cardiomyocytes. Whereas it is known that angiotensin II causes the increase in [Ca2+]i in cardiac cells, little is known about the mechanisms of decrease in [Ca2+]i in cardiomyocytes upon angiotensin II stimulation. In the present study, we examined the effect of angiotensin II on Ca2+ efflux from freshly isolated adult rat cardiomyocytes. Angiotensin II stimulated the efflux of 45Ca2+ from the cells in a concentration-dependent manner (10(-7)-10(-5) M). The 45Ca2+ efflux from the cells was inhibited by type 1 angiotensin II receptor inhibitor. The angiotensin II-stimulated 45Ca2+ efflux was not affected by deprivation of the extracellular Ca2+, but was dependent on the presence of extracellular Na+. These results indicate that angiotensin II stimulates extracellular Na(+)-dependent 45Ca2+ efflux from freshly isolated adult rat cardiomyocytes, probably through its stimulatory effect on the plasma membrane type 1 angiotensin II receptors which may couple to Na+/Ca2+ exchange.
The effect of flavoxate hydrochloride (flavoxate), an anti-pollakiurea agent, on cyclic AMP (cAMP) formation was investigated in the rat brain and a possible involvement of brain G proteins in the action of flavoxate on the bladder function was subsequently examined. Flavoxate (10(-8)-10(-5) M) inhibited cAMP formation in a concentration-dependent manner, an action which was completely abolished by pretreating the membranes with pertussis toxin (PTX). The inhibitory effect of flavoxate was also completely antagonized by combined treatment with any two antagonists for adenosine A1 (8-cyclopentyl-1,3-dipropylxanthine), dopamine D2 (sulpiride) or adrenergic alpha 2 (yohimbine) receptors, although each antagonist alone did not significantly block the flavoxate-induced inhibition of cAMP formation. Radioligand binding studies indicated that flavoxate at micro- or submicromolar concentrations has affinity for Gi-coupled receptors such as A1, D2 and alpha 2 receptors. Therefore, flavoxate may inhibit cAMP formation by the stimulation of A1, D2 and alpha 2 receptors. To clarify the involvement of brain Gi proteins in the flavoxate-induced inhibition of the micturition reflex, the effect of pretreatment with PTX (i.c.v.) on the flavoxate-induced inhibition of isovolumetric rhythmic bladder contractions was examined in rats. Flavoxate (3 mg/kg, i.v.) completely abolished rhythmic bladder contractions in vehicle-pretreated rats, but not in PTX-pretreated rats. These findings suggest that signal transduction via Gi-coupled receptors is involved, at least in part, in the inhibition of the micturition reflex by flavoxate in rats. These results also provide the first evidence suggesting a negative role of brain PTX-sensitive G proteins in the micturition reflex.
Serum levels of interleukin 6 (IL-6) are correlated with the disease status and prognosis in cancer patients. IL-6 is also an important mediator of experimental cancer cachexia. We investigated the production of IL-6 and IL-6 receptors and expression of IL-6 mRNA by esophageal squamous carcinoma cells using immunohistochemical staining and in situ reverse transcription-PCR. We also measured levels of serum IL-6 using an ELISA in 50 patients with esophageal squamous cell carcinoma (ESCC) to determine the correlation between serum levels of IL-6 and clinicopathological factors IL-6 mRNA was expressed in the primary tumor. Esophageal squamous carcinoma cells produced both IL-6 and IL-6 receptor. IL-6 concentrations were significantly higher in the primary tumor than in the normal epithelium. The incidences of weight loss, tumor invasion to adjacent organs, and noncurative resection were significantly higher in ESCC patients with serum levels of IL-6 > or = 7 pg/ml (n = 13, group C) compared with patients with serum levels <7 pg/ml and > or = 3 pg/ml (n = 14, group B) and <3 pg/ml (n = 23, group A). Tumor size and C-reactive protein levels were significantly higher and albumin levels were significantly lower in group C. Results suggest that IL-6, which is produced by tumor cells, may be related to various disease parameters as well as to the nutritional status in patients with ESCC.
Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are two factors considered to be involved in the morphogenesis of several organs. To understand the role of HGF and KGF in the stomach development, we analyzed changes in the levels of expression of the genes for the two growth factors and their receptors in the fetal rat stomach by competitive RT-PCR. Resembling our previous results for HGF, the expression of the genes for KGF and its receptor was observed in the mesenchyme and epithelium of 16.5 day fetal stomach, respectively, indicating the possibility that KGF mediates the epithelial-mesenchymal interaction in the early stage of stomach development. The developmental profile of the expression of the genes for the two growth factors and their receptors were different, indicating a difference in their roles; the genes for HGF and c-met, the receptor for HGF, are expressed mainly during the morphogenetic period, while the genes for KGF and its receptor mainly after the morphogenetic period. Thus, it is probable that HGF controls the proliferation of epithelial cells during the morphogenetic process. The expression of the genes for KGF and its receptor is not correlated with epithelial proliferation during morphogenesis, but it does appear to be linked with epithelial differentiation. These results, together with the absence of significant mitogenic effect of KGF on the epithelial cells of the fetal rat glandular stomach in vitro, suggest a role for KGF as a differentiation factor. In addition, the expression profile of the genes for KGF and its receptor towards the end of fetal period appears to be closely correlated with that of mesenchymal cell proliferation, suggesting another role for the growth factor that is not regulated by the epithelial-mesenchymal interaction.
N-Terminally truncated DNA polymerase from Thermus thermophilus (delta Tth polymerase) lacking 5'-3' exonuclease activity was used for DNA sequencing and polymerase chain reaction (PCR). In contrast to the high background of the sequencing ladder observed with the wild-type Tth polymerase, delta Tth polymerase gave readable sequencing patterns which extend up to more than 500 bases from the primer site on cycle sequencing and automated sequencing. The delta Tth polymerase was used for the standard and mutagenic PCR, and net amplification of the DNA and the mutations accumulated during PCR were analyzed. Under mutagenic PCR, the mutation rates were 7.0 x 10(-4) (Tth) and 8.3 x 10(-4) (delta Tth) per nucleotide per cycle of amplification, which were 4-9 times higher than the rates under standard PCR.
Topoisomerase I-targeting anticancer agents such as 7-ethyl-10-[4-(1-piperidyl)-1-piperidyl]carbonyloxy-camptothecin (CPT-11) and 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D- glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-di one (NB-506) have been developed and show strong antitumor activity against various cancers. We examined the interaction of these drugs and cisplatin (CDDP), and biochemical mechanisms of synergism between them. Interaction of drugs in human small cell lung cancer cells, SBC-3, was analyzed using the isobologram method. Combinations of CDDP with NB-506, CPT-11, and an active metabolite of CPT-11, 7-ethyl-10-hydroxy-CPT (SN-38), showed synergistic effects. Formation of DNA interstrand cross-links (ICLs) on the cells was analyzed using an alkaline elution assay and increased ICLs were observed by simultaneous exposure to CDDP (1.5 microM) and NB-506 (10 nM) compared with that in response to CDDP alone. DNA repair after ICL formation induced by 3-h exposure to CDDP (1.5 microM) was reduced by NB-506 (10 nM) exposure. On the other hand, a higher concentration of CDDP (150 microM) enhanced the topoisomerase I inhibitory activity of NB-506 and SN-38 determined by relaxation of supercoiled Escherichia coli DNA. These biological interactions might result in synergistic interactions between CDDP and NB-506 or SN-38. Topoisomerase I inhibitors and CDDP may be a key regimen for cancer chemotherapy and merit further examination.
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To improve the safety and speed of the peritoneal dissection, we developed a saline ballooning method in which a dull needle is inserted lateral to the inferior epigastric vessels under direct laparoscopic visualization to a tissue plane just superficial to the peritoneum. Then, saline solution is injected. As a result, the peritoneum is easily separated from the spermatic cord and inferior epigastric vessels. Furthermore, bleeding is minimized during dissection of the peritoneum.