Effective and safe use of FK 506: combination treatment with rapamycin or RS-61443 in experimental organ transplantation.
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Biomedical subjects
Publications and source records attributed to K Isono.
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To characterize the action of histamine on ion transport across the airway mucosa, we measured the electrical properties of cultured tracheal epithelium from dogs by Ussing's short-circuited technique in vitro. The addition of histamine to the submucosal side increased short-circuit current (Isc), whereas mucosal addition of histamine had no effect. The histamine-induced increase in Isc was dose-dependent with the maximal increase from the baseline value and EC50 being 4.4 +/- 0.5 microA/cm2 and 10(-6) M, respectively. We also tested the effects of pharmacological blocking agents on the histamine-induced Isc increase. The effect of histamine on Isc was partially inhibited by pretreatment of cells with amiloride, furosemide and diphenylamine carboxylate. Furthermore, the effect of histamine was inhibited by pyrilamine, but not by cimetidine. To determine the contributions of several intracellular second messenger systems to the histamine-induced increase in Isc, we studied the change of Isc by pretreatment of cells with indomethacin, mepacrine and H-7. The increase in Isc produced by histamine was inhibited by indomethacin and mepacrine but not H-7. These results suggest that histamine stimulates both Cl secretion and Na absorption and may affect the subsequent movement of water across the airway epithelium through the activation of submucosal H1-receptor probably involving prostaglandin synthesis.
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The immunoreactivity and affinity of seven kinds of monoclonal antibody raised against human gastric cancer (MKN-45) secreted carcinoembryonic antigen (CEA) were determined with the method of cell binding assay in vitro. Tumor localization and biodistribution of radiolabeled antibodies were performed in athymic mice implanted MKN-45 xenografts. Results obtained were as follows: 1) The affinity constant of CEA-specific three antibodies (1A4, 1B2, 4H11) was the same approximately, whereas the immunoreactivity found to be quite different among them. While CEA-nonspecific four antibodies (7D1, 6C7, 2C3, 5H7) showed the much higher affinity constant than that of the former. 2) In an animal model on tumor localization and biodistribution studies, CEA-specific antibodies obtained more highly tumor targeting and cleared more rapidly from the blood and non-tumor organs than CEA-nonspecific antibodies did, so that tumor to nontumor ratios was increased. 3) In this model system it is the immunoreactivity preparation of antibodies that improved tumor targeting and tumor activity retention, on the other side, the affinity constant of antibodies were associated with rapid clearance from the blood and non tumor sites. In conclusion, this studies would also be beneficial for practical use and clinical application of radiolabeled monoclonal antibodies.
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Hepatic protein synthesis rate (HPS) in human livers were measured to evaluate hepatic functional reserve. HPS of 34 patients who underwent operations were studied and were divided into 4 groups. Normal liver (n = 7), obstructive jaundice (n = 9), liver cirrhosis (n = 8) and other hepatic dysfunction (n = 10). HPS in normal liver was 6.9 +/- 3.0 nmol/mg wet wt./10 min. HPS in obstructive jaundice liver was 17.1 +/- 10.3, and HPS in liver cirrhosis was 47.5 +/- 17.8. There were significant differences among these three groups. HPS correlated well with cholinesterase (r = -0.6533, P less than 0.01) and ICGR15 (r = 0.7315, P less than 0.01). In 15 patients who received hepatectomy, relations between HPS and postoperative complication were studied. There were no complications in patients whose HPS were less than 20 nmol/mg wet wt./10 min. in major hepatic resection and in patient whose HPS were less than 40 in a segmentectomy. Even if HPS were elevated, the operations were safe in subsegmentectomy and partial hepatectomy. So HPS would be one of the good indices to evaluate hepatic functional reserve.
The purpose of this study was to evaluate the reconstruction methods of modified Imanaga procedure and modified Child procedure from a point of fat digestion and absorption in patients who received pancreatoduodenectomy by using 13C-labelled medium chain fat. The 13CO2 abundances were elevated rapidly after oral ingestion of 13C-octanoic acid and 13C-trioctanoin in modified Imanaga procedure group. The peak 13CO2 abundances appeared earlier in modified Imanaga procedure group than in modified Child procedure group. No significant difference was seen between two groups in the percent recovery of 13CO2 in the breath after oral loading of 13C-octanoic acid. But modified Imanaga procedure group showed significantly higher recovery rate of 13CO2 of 13C-trioctanoin when compared to modified Child procedure group. These results suggest that modified Imanaga procedure would have a benefit for fat digestion and absorption after pancreatoduodenectomy.
The patient was 22-year-old male who had suffered from hypermotility during sleep and excessive daytime sleepiness, and 270% in excess body weight. Values of arterial blood gas analysis during sleep were 65mmHg in PaCO2 and 19mmHg in PaO2. He was diagnosed as morbid obesity with Pickwickian syndrome and underwent vertical banded gastroplasty. His body weight decreased from 170kg to 113kg four months after surgery and 107kg one year after surgery. The whole-night polyhypnographic sleep study was performed before and after operation and showed dramatic improvement of apnea index which was calculated by dividing the number of apneas by the total sleep time. We analyzed 199 case reports which had noted symptoms of Pickwickian syndrome between 1963 and 1989 in Japan. In many reported cases, body weight decreased transiently but returned to the level before medical treatment. Under these considerations, gastroplasty is a beneficial surgical treatment for the morbid obesity with Pickwickian syndrome.
Of 342 breast cancer patients radically operated on in the Second Department of Surgery, School of Medicine, Chiba University during 1965-1988, treatment for 75 recurrent patients were evaluated by the initial modes of recurrence. The modes of recurrence were classified into distant metastases, local lymph node recurrence (axillary, parasternal and supraclavicular nodes) and chest wall recurrence according to the General Rules for Clinical and Pathological Recording of Breast Cancer. Of 75 recurrent patients, distant metastases were seen as common as 77.3%, followed by recurrences of local lymph nodes (14.7%) and chest wall (8.0%). The number of patients in each mode of recurrence increased in relation to increase in the size of tumor and the number of metastatic lymph nodes at the time of the first operation. Histologically, scirrhous carcinoma was most common in chest wall recurrence. 2-year disease-free survival rates of distant metastases, local lymph node recurrence and chest wall recurrence were 44.6%, 24.2% and 16.7%, respectively. 5-year survival of bone metastasis with chemo-endocrine therapy was as significantly favorable as 60%, compared to chemo- or radiotherapy alone (p less than 0.01). However, 5-year survival of lung metastasis with or without endocrine therapy revealed no significant difference. Local lymph node recurrence with the combination of resection, radio- and/or chemotherapy produced a trend toward showing more favorable survival than that without resection.
We studied the effect of loperamide on electrical properties of canine cultured tracheal epithelium by Ussing's short-circuited technique. Addition of loperamide to the mucosal bath decreased the short-circuit current, transepithelial potential difference and conductance, whereas submucosal loperamide had no effect. This inhibitory effect was attenuated by furosemide, diphenylamine-2-carboxylate and Cl(-)-free medium but not by amiloride or naloxone. Thus, loperamide may selectively inhibit Cl- secretion across airway epithelium through a non-opiate-dependent mechanism.
Ras gene is one of the oncogenes most commonly detected in human cancers and consists of three families (H-ras, K-ras, N-ras) that are converted to active oncogenes by point mutations occurring in codon 12, 13, or 61. The authors analyzed mutations of these codons in 12 extrahepatic bile duct carcinomas, nine gallbladder carcinomas, and 20 pancreatic tumors (18 pancreatic adenocarcinomas and two islet cell tumors) by a method to directly sequence nucleotides, using polymerase chain reaction and a direct sequencing method. Point mutations at K-ras codon 12 were found in all of 18 pancreatic adenocarcinomas and in one bile duct carcinoma, but there were no mutations in the remaining 11 bile duct carcinomas, in all of 9 gallbladder carcinomas, or in two islet cell tumors. A very high incidence of ras gene mutations may be used clinically for the diagnosis of debatable cases of pancreatic adenocarcinoma.
The genes for two large subunit proteins, YmL8 and YmL20, of the mitochondrial ribosome of Saccharomyces cerevisiae were cloned by hybridization with synthetic oligonucleotide mixtures corresponding to their N-terminal amino acid sequences. They were termed MRP-L8 and MRP-L20, respectively, and their nucleotide sequences were determined using a DNA sequencer. The MRP-L8 gene was found to encode a 26.8-kDa protein whose deduced amino acid sequence has a high degree of similarity to ribosomal protein L17 of Escherichia coli. The gene MRP-L20 was found to encode a 22.3-kDa protein with a presequence consisting of 18 amino acid residues. By Southern blot hybridization to the yeast chromosomes separated by field-inversion gel electrophoresis, the MRP-L8 and MRP-L20 genes were located on chromosomes X and XI, respectively. Gene disruption experiments indicate that their products, YmL8 and YmL20 proteins, are essential for the mitochondrial function and the absence of these proteins causes instability of the mitochondrial DNA.
The effect of calcitonin gene-related peptide (CGRP) on parasympathetic contraction of rabbit airway smooth muscle was studied under isometric conditions in vitro. CGRP (10(-7) M) did not contract tracheal smooth muscle, but it potentiated the contractile response to electrical field stimulation (EFS) in a dose-dependent manner, the maximal increase from the baseline response being 14.4 +/- 6.2%. In contrast, the contractile responses to exogenously administered acetylcholine were not altered by this peptide. The CGRP-induced potentiation of the contractile responses to EFS was further augmented by physostigmine (123.1%), but not influenced by phentolamine, propranolol, indomethacin, or thiorphan, an enkephalinase inhibitor. These results suggest that CGRP augments the neurally mediated contraction of rabbit airway smooth muscle probably through a prejunctional mechanism and that this effect may not be modulated by tissue enkephalinase.
During the period between 1965 and the end of 1988, 560 patients with esophageal cancer were surgically treated in our University hospital. In an attempt to improve patient survival, three-field lymphadenectomy of the bilateral neck, mediastinum and abdomen was performed in 117 patients treated since 1983. The present study was undertaken to reveal the substantial rate of lymph node metastasis in esophageal cancer and to decide if three-field lymphadenectomy is mandatory or not for surgery of esophageal cancer. Despite the increased radicality of the operation, the mortality and morbidity rates decreased in the 1980's compared to the earlier periods, the operative death being 12.5 per cent in the 1960's, vs. 2.0 per cent in the 1980's. Moreover, the mortality rate of the patients receiving the three-field lymphadenectomy was as low as 2.6 per cent. The metastatic rate of cervical nodes in the patients receiving three-field lymphadenectomy was 32.5 per cent, while that of mediastinal and abdominal nodes was 47.0 per cent and 46.0 per cent respectively. The metastatic rate in the mediastinum was high in the bilateral recurrent nerve lymph nodes, bifurcation nodes and paraesophageal nodes, while in the abdomen, it was high in the bilateral paracardial nodes. Recurrent nerve paralysis, which had been rarely seen was observed in 12.0 per cent of the patients. Metastasis from esophageal cancer is often seen in the cervical nodes, however, the clinical importance of three-field lymphadenectomy will be decided by the data of patient survival in the near future.