Inhibition of tissue factor-factor VIIa by nafamostat mesilate; a reply to the rebuttal.
Explore the source record for details and available documents.
Antithrombins↗
Biomedical subjects
K Okajima
Publications and source records attributed to K Okajima.
Antithrombin III Kumamoto II; a single mutation at Arg393-His increased the affinity of antithrombin III for heparin.
Abnormal antithrombin III (AT III) was found in a 30-year-old woman who suffered from recurrent thrombosis during pregnancy and the postpartum period. Among her family members, only her father had recurrent episodes of deep vein thrombosis of the lower extremities, from his youth. The antithrombin and antifactor Xa heparin cofactor activities of the proposita's plasma were 61% and 42% of normal, respectively. The progressive antithrombin and antifactor Xa activities were also decreased to 55% and 58% of normal, respectively. The immunoreactive level of AT III was within the normal range (23.1 mg/dl). Analysis of the proposita's plasma by crossed immunoelectrophoresis in the presence or absence of heparin and by affinity chromatography on heparin-Sepharose revealed that the proposita's AT III had apparently normal affinity for heparin. Nucleotide sequencing of 7 exons of the proposita's AT III gene amplified by polymerase chain reaction (PCR) disclosed that the second base of codon 393 comprised both G and A, indicating Arg393-His conversion. The base sequences of exons 1, 2, 3a, 3b, 4, and 5 were normal, excluding any other mutation. These findings indicated that the proposita's AT III was a variant of AT III at the thrombin binding site and that the proposita was a heterozygote for the abnormality. Heparin affinity of purified abnormal AT III from the proposita's plasma was demonstrated to be increased upon affinity chromatography using heparin-Sepharose, suggesting that the mutation (Arg393-His) per se could possibly increase the affinity of antithrombin III for heparin. For this variant AT III (Arg393-His), the name AT III Kumamoto II is proposed.
Adult↗
Proximal subtotal gastrectomy for the treatment of carcinoma of the upper third of the stomach: its indications based on lymph node metastasis and perigastric lymphatic flow.
To clarify the indications for a proximal subtotal gastrectomy in the treatment of carcinoma in the upper third of the stomach based on lymph node metastases, 1055 patients in whom either a D2 or greater lymph node removal was performed were reviewed. In the patients in which the lesion was confined to the upper stomach and did not invade beyond the muscularis propria of the stomach wall, no metastases to either the lymph nodes above and below the pylorus or the lymph nodes along the greater curvature were observed. A lymphatic flow study revealed a minimal flow to these nodes from the upper stomach in patients without lymph node metastasis, but in cases with lymph node metastases the lymphatic flow changed. The indications for a proximal subtotal gastrectomy for a carcinoma of upper third of the stomach therefore must fulfill the following two conditions: (1) The deepest layer of cancerous invasion does not extend beyond the muscularis propria of the stomach wall, and (2) No macroscopic evidence of lymph node metastasis can be detected during surgery.
Case-Control Studies↗
Experimental study of liver injury after partial hepatectomy with intermittent or continuous hepatic vascular occlusion. Differences in tolerance to ischemia between normal and cirrhotic livers.
The degree of residual liver injury in normal and cirrhotic rats undergoing 70% hepatectomy with hepatic inflow occlusion was examined. The total duration of clamping was 60 min and animals were divided into 3 groups according to the ischemic modality: a 15-min intermittent clamping group (group I); a 30-min intermittent clamping group (group II), and a 60-min continuous clamping group (group III). In normal liver rats, the survival rates after operation in groups I, II and III were 90, 90 and 30%, respectively, compared to 70, 50 and 38%, respectively, in cirrhotic rats. The serum aspartate aminotransferase (AST) level increased markedly with prolongation of each period of clamping in rats with normal liver, showing higher AST levels than those with cirrhotic liver. The liver tissue adenosine-5'-triphosphate (ATP) levels and energy charge (EC) values decreased with prolongation of each period of clamping. Cirrhotic livers showed lower ATP levels and EC values than normal livers. Although there was no significant difference in the mitochondrial function between normal and cirrhotic livers in the group of the same form of ischemia, phosphorylative efficiency of mitochondria was maintained satisfactorily in normal groups I and II and in the cirrhotic group I. Even though cirrhotic livers showed a smaller necrotic response to ischemia than normal livers, they were more vulnerable to ischemia because of an inability to maintain energy metabolism. Therefore, when performing resection of a cirrhotic liver, a 15-min intermittent clamping method should be adopted.
Adenine Nucleotides↗
[A possible mechanism of interstitial pneumonia during interferon therapy with sho-saiko-to].
Interstitial pneumonia has been reported to be a side effect of treatment with interferon, and Sho-saiko-to (Xiao-Chai-Hu-Tang) may enhance this side effect. It is well known that activated neutrophils are important mediators of pulmonary fibrosis, so we studied the effects of interferon and Sho-saiko-to on neutrophil activation. Homogenized lung myeloperoxidase (MPO) activity was assayed after intraperitoneal injection of interferon with or without pretreatment with Sho-saiko-to. Although Sho-saiko-to alone did not change the lung MPO content, MPO in the lung was significantly increased by interferon administration. The increase was enhanced further by pretreatment with Sho-saiko-to. When the accumulated neutrophils are activated by some cytokines, such as TNF alpha or IL-1 beta from monocytes/macrophages, they may damage lung tissue. We therefore studied the effects of Sho-saiko-to and interferon on TNF alpha production in freshly isolated human monocytes. Sho-saiko-to increased the production of TNF alpha, but interferon did not. In addition, Sho-saiko-to significantly increased the production of TNF alpha by monocytes stimulated by lipopolysaccharide. Taken together, these data indicate that interferon causes neutrophils to accumulate in the lung. Sho-saiko-to alone may not injure lung tissue, but it increases the effect of interferon. When stimulated by some antigen, Sho-saiko-to may overstimulate the neutrophils. Granulocytes elastase and oxygen radicals released from activated neutrophils may damage lung tissue. The fibroblasts that repair the damaged tissue may increase the risk of pulmonary fibrosis.
Animals↗
Endothelial cell injury induced by plasmin in vitro.
We investigated the effect of plasmin on the integrity and function of endothelial cells to elucidate the mechanism by which bleeding or rethrombosis may be induced in thrombolytic therapy. When incubated with cultured human umbilical vein endothelial cells (HUVECs), plasmin increased the endothelial permeability to serum albumin 10 minutes after the incubation. Plasmin damaged the cell membranes 30 minutes after the incubation, detached the cells from the matrix 3 hours after the incubation, and finally induced cell lysis. Such damaging effects on HUVECs were not observed with plasminogen or plasmin pretreated with aprotinin and alpha 2-plasmin inhibitor, suggesting that the catalytic function of plasmin plays an important role in inducing this damage. Sulfur 35-labeled glycosaminoglycans (35S-GAGs) of HUVECs were decreased 1 hour after the incubation of plasmin with HUVECs, and the thrombomodulin (TM) activity of HUVECs measured by protein C activation capacity was decreased 6 hours after the incubation. Neither 35S-GAGs nor the TM activity of HUVECs was decreased after the incubation of plasmin pretreated with aprotinin and alpha 2-plasmin inhibitor. These findings suggest that the nonthrombogenic properties of endothelial cells can be damaged by the proteolytic action of plasmin. Our findings, taken together, suggest that plasmin damages the endothelial barrier function, endothelial cell integrity, and nonthrombogenic properties. These damaging effects of plasmin on endothelial cells may be related to the pathophysiology of bleeding or rethrombosis observed in patients undergoing high-dose thrombolytic therapy for thrombosis.
Cell Membrane Permeability↗
[Combination therapy of high dose 5'-DFUR+MMC for advanced or recurrent gastric cancer. 5'-DFUR Joint Research Group in the Osaka District for Gastric Cancer].
We conducted multi-center clinical trials of 'Treatment with high dose 5'-DFUR+MMC' in order to evaluate the effects, the possibility for outpatient treatment and the survival effects in patients with advanced or recurrent gastric cancer. The treatment schedule was as follow; 5'-DFUR 1,600 mg/body/day was given orally for five consecutive days every week and MMC 6 mg/m2 was injected intravenously once every four weeks. Forty-eight patients were enrolled and 34 cases were evaluated for anti-tumor responses. The overall response rate was 29.4% (10/34 cases). Side effects were mainly diarrhea, but outpatient treatment was possible in most cases. The median survival period was 249 days, which is longer than with other treatments. This result suggests that this combination chemotherapy is useful in patients with advanced or recurrent gastric cancers.
Adult↗
[Detection of chromosomal aberration using fluorescence in situ hybridization on breast cancer].
The relationship between interphase cytogenetics and prognostic factors, especially the grade of nuclear atypism, nuclear DNA content, histological lymph node metastasis and clinical data was examined in 48 primary breast cancer specimens (touch preparation). Using fluorescence in situ hybridization (FISH) with a chromosome-specific DNA probe, the copy number of pericentrometric sequences on chromosome 17 was examined within the interphase nuclei in touch preparations from the tumor. The copy number of chromosome 17 was correlated with the increase in the grade of nuclear atypism, tumor size, histological lymph node metastasis and nuclear DNA content. In the diploid type of nuclear DNA content, the copy number of chromosome 17 was correlated with the increase in the grade of nuclear atypism and histological lymph node metastasis. In conclusion, the numerical chromosomal aberrations detected by FISH were found in the DNA diploid cases by FCM. The detection of numerical chromosomal aberrations by FISH provide important information about the prognostic factors.
Breast Neoplasms↗
Clinical results of breast-conservation therapy using a CT simulator.
The CT simulator is a real-time, CT-linked, 3-D treatment planning system which consists of a CT scanner, a multi-image display, a treatment planning device with real-time visual optimization, and a laser beam projector. The clinical benefit of this system was evaluated in breast cancer patients undergoing breast-conserving therapy. Between December 1987 and March 1993, 244 breasts in 243 patients underwent breast-conserving therapy at Kyoto University Hospital. Clinically, there were 159 stage I and 85 stage II tumors. Pathological staging showed 216 stage I, 24 stage II, and 4 stage III tumors. All except 10 tumors were invasive ductal carcinomas. Eleven tumors were margin-positive by histopathological examinations. As surgical treatment, quadrantectomy or wide excision with complete axillary dissection was performed. Radiation therapy consisted of 50 Gy delivered to the whole breast by opposed tangential fields over 5 weeks using 60Co gamma rays. For patients with a positive margin, boost electron irradiation was given to a total of 10 Gy. We used the CT simulator for individualized optimization of the tangential fields. Prompt and accurate determination of the tangential portals was possible by using the simulator to determine various parameters, including the beam angle and head rotation angle. During follow-up for 2-66 months (median: 20 months), unrelated death occurred in 2 patients and distant metastases developed in 5 (bone 4, lung 1). However, neither local recurrence nor symptomatic radiation pneumonitis has since occurred. The cumulative survival rate and the disease-free survival rate at five years were 95.2% and 91.8%, respectively. The CT simulator appears to be a useful tool for individualized optimization of tangential irradiation fields in breast-conserving therapy.
Adult↗
Timing of transplantation and donor selection in living related liver transplantation for fulminant Wilson's disease.
Explore the source record for details and available documents.
ABO Blood-Group System↗
Recombinant human soluble thrombomodulin reduces endotoxin-induced pulmonary vascular injury via protein C activation in rats.
Adult respiratory distress syndrome (ARDS) is a serious complication of disseminated intravascular coagulation (DIC) or multiple organ failure. To determine whether recombinant soluble human thrombomodulin (rsTM) may be useful in treating ARDS due to sepsis, we investigated the effect of rsTM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intravenous administration of rsTM prevented the increase in pulmonary vascular permeability induced by LPS. Neither heparin plus antithrombin III (AT III) nor dansyl Glu Gly Arg chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, prevented LPS-induced vascular injury. The agents rsTM, heparin plus AT III, and DEGR-Xa all significantly inhibited the LPS-induced intravascular coagulation. Recombinant soluble TM pretreated with a monoclonal antibody (moAb) that inhibits protein C activation by rsTM did not prevent the LPS-induced vascular injury; in contrast, rsTM pretreated with a moAb that does not affect thrombin binding or protein C activation by rsTM prevented vascular injury. Administration of activated protein C (APC) also prevented vascular injury. LPS-induced pulmonary vascular injury was significantly reduced in rats with leukopenia induced by nitrogen mustard and by ONO-5046, a potent inhibitor of granulocyte elastase. Results suggest that rsTM prevents LPS-induced pulmonary vascular injury via protein C activation and that the APC-induced prevention of vascular injury is independent of its anticoagulant activity, but dependent on its ability to inhibit leukocyte activation.
Animals↗
[Antithrombin III (AT III)].
Explore the source record for details and available documents.
Antithrombin III↗
Preliminary Results of Quadrantectomy and Radiation Therapy for Breast Cancer.
Between November 1987 and December 1992, a total of 200 breast carcinomas in 199 patients were treated by definitive radiation therapy following quadrantectomy and level III axillary dissection. One patient with sumultaneous bilateral breast cancers was excluded and 198 patients with breast cancer were enrolled in this study. There were 9 Stage 0, 117 Stage I and 72 Stage II tumors by the UICC tumor classification system (1987). Histological examination revealed that 9 tumors were non-invasive carcinomas and 189 were invasive carcinomas. For radiation therapy, a total of 50 Gy was delivered to the ipsilateral breast using &sup60;Co gamma rays. In three cases with level III lymph node involvement, the ipsilateral supraclavicular and parasternal regions were also irradiated. Boost irradiation was given to 8 of 12 margin-positive patients, and 2 of 24 patients in whom tumor cells were present within 5 mm from the margin. We used a CT simulator for the treatment planning of radiation therapy in 196 tumors. During follow-up for 16-77 months (median: 35 months), 2 patients died of unrelated causes and 6 developed distant metastasis (4 to bone and 2 to lung). Local recurrence was noted in 1 patient. Acute reactions to radiation therapy included moist desquamation involving the tip of the breast and the axilla in 14 and 5 patients, respectively, as well as bright erythema in 7 patients. Late reactions included arm edema in 12 patients, patchy depigmentation at the tip of the breast in 5 patients, moderate telangiectasia in 1 patient, and symptomatic radiationpneumonitis in 1 patient. The actuarial overall survival, cause-specific survival, disease-free survival, and relapse-free survival rates at 5 years were 97.2%, 100%, 93.5%, and 93.0%, respectively. This excellent locoregional control, together with a highly acceptable toxicity strongly suggests the usefulness of quadrantectomy and radiation therapy for Japanese women with breast cancer. The possible indications include clinical Stage 0 and, I breast cancer, and clinical Stage II cancer in patients with relatively large breasts and with the primary tumor not located close to the nipple.
Journal Article↗
Esophageal cancer treated with radiotherapy: impact of total treatment time and fractionation.
PURPOSE: Local control rate and survival rate of esophageal cancer treated with radical radiation therapy (RT) were analyzed with special respect to total treatment time and fractionation. METHODS AND MATERIALS: Between 1979 and 1992, 88 patients with Stages I-III esophageal cancer were treated radically with RT at Kyoto University Hospital and Wakayama Red Cross Hospital. Of the 88 patients, 52 patients were treated with conventional fractionation (1.7-2.0 Gy/day, five times/week), and the remaining 36 patients were treated with accelerated hyperfractionation (AHF). In 1989, we started AHF regimen for esophageal cancer. Daily fractionations were 2.0 Gy and 1.2 Gy (field-in-field), or 1.5 Gy and 1.5 Gy at 5- to 6-h interval. Most of the patients treated with AHF received the total radiation dose of 64-68 Gy. Twenty-seven patients were treated with intraluminal brachytherapy (IBT) as boost therapy following external RT. Fourteen patients were treated with IBT following AHF. RESULTS: The median of treatment time of AHF was approximately 2 weeks shorter than that of conventional fractionation. Local control rate at 1 year were 47% for AHF, which was significantly higher than that for conventional fractionation (22%, p < 0.05). The improvement of local control by AHF was responsible for a trend to an improved cause-specific survival (p = 0.07). Local control rates at 1 year were plotted as a function of total treatment time. The slope of the linear regression line was -2.3 +/- 0.5% per day (p < 0.025) for patients treated with external RT alone, indicating a 2.3% per day loss in local control. Pretreatment and treatment parameters were evaluated in a multivariate analysis for the end point of local control. T stage (T1, 2 vs. T3, 4; p = 0.003) and fractionation schedule (p = 0.03) were independent of prognostic significance. Patients could tolerate the AHF well, although esophageal stenosis was noted frequently as a late toxicity. CONCLUSION: Accelerated hyperfractionation was the most important treatment-related variable in this patient population. Total treatment time may have a significant impact on the treatment outcome for esophageal cancer.
Adenocarcinoma↗
Three-dimensional treatment planning for maxillary cancer using a CT simulator.
PURPOSE: The results of three-dimensional treatment planning using a computed tomography simulator were evaluated in patients with maxillary cancer. METHODS AND MATERIALS: Treatment planning was done in 25 patients using an x-ray simulator and plain x-ray films (1979-1982, group 1) in 34 patients using an x-ray simulator and computed tomography films (1983-1987, group 2), in 24 patients using a computed tomography simulator (1988-1992, group 3). The number of patients with Stage IV disease increased in the order of group 1 to group 3. RESULTS: The average radiation field was smallest in group 3 (66.5 cm2) followed by group 2 (67.4 cm2) and group 1 (72.9 cm2). A radiation dose of more than 30 Gy to the lens of the effected side was delivered to 13% of group 3, 44% of group 2, and 44% of group 1. The dose to the lens on the uneffected side was zero in 56% of group 1, 74% of group 2, and 96% of group 3. A long-term decrease in visual activity on the effected side occurred in 11% of group 3, 32% of group 2, and 44% of group 1. However, a significant increase in survival was only noted between groups 1 and 2, because the three population of patients were different. CONCLUSION: The three-dimensional treatment planning results in a better treatment than two-dimensional treatment planning as measured by complication rates and field sizes.
Aged↗
Effect of nafamostat mesilate, a synthetic protease inhibitor, on tissue factor-factor VIIa complex activity.
Nafamostat mesilate (NM), a synthetic protease inhibitor, is frequently used for the treatment of disseminated intravascular coagulation (DIC) in Japan. NM inhibits several proteases which may be importantly involved in the pathophysiology of DIC. Since tissue factor (TF) plays a critical role in DIC associated with septicemia, inhibition of the extrinsic pathway of coagulation by coagulation inhibitors may be useful for the treatment of DIC. NM inhibited extrinsic pathway activity (TF-F.VIIa mediated-F.Xa generation) in a concentration dependent manner; the IC50 was 1.0 x 10(-7) M. F.Xa was not inhibited by NM at the concentrations used in the experiment, suggesting that NM might inhibit TF-F.VIIa complex activity. When incubated with TF-F.VIIa complex, NM inhibited the complex activity with an IC50 of 1.5 x 10(-7) M, the same value that found for inhibition of extrinsic pathway activity. A Lineweaver-Bulk's plot of the inhibition demonstrated that NM inhibited TF-F.VIIa complex in a competitive fashion, with an inhibition constant (Ki) of 2.0 x 10(-7) M. These findings suggested that NM may be a potent inhibitor of TF-F.VIIa complex and the therapeutic effect of NM in DIC patients could be partly explained by inhibition of the extrinsic pathway of the coagulation system.
Amino Acid Sequence↗
Direct evidence for systemic fibrinogenolysis in patients with acquired alpha 2-plasmin inhibitor deficiency.
To examine whether or not acquired alpha 2-plasmin inhibitor deficiency is associated with systemic fibrinogenolysis, we analyzed the fibrin and fibrinogen degradation products in eight patients with this condition in various disease states. The underlying disease was gastric cancer in three patients, metastatic prostatic cancer in two, acute promyelocytic leukemia in two, and abdominal aortic aneurysm in one patient. In all eight patients, the alpha 2-plasmin inhibitor level was reduced to less than 50% of normal, and plasmin-alpha 2-plasmin inhibitor complex levels were increased. Immunoblotting of serum using an antifibrinogen antibody detected a 250 kDa protein (corresponding to fragments X or DY) in all eight patients. Fragment Y and D monomer were detected in seven of the eight patients, indicating the occurrence of systemic fibrinogenolysis. However, they were not detected in one patient with metastatic prostatic cancer. To determine whether or not fibrinogen degradation was also occurring in the patient without fragment Y, we characterized the 250 kDa protein in all eight patients. The protein was found to be fragment X in the metastatic prostatic cancer patient without fragment Y, while it was fragment DY in the other seven patients. Thus, systemic fibrinogenolysis was present in all eight patients. In the two patients with metastatic prostatic cancer, the level of alpha 2-plasmin inhibitor gradually increased with the reduction of tumor size by treatment. Fragment X, fragment Y, and D monomer were not detected when the alpha 2-plasmin inhibitor level exceeded 60% of normal in both patients. In the other six patients fragment Y and D monomer also disappeared when the alpha 2-plasmin inhibitor level exceeded 60% of normal. These findings suggest that systemic fibrinogenolysis only occurs when the plasma levels of alpha 2-plasmin inhibitor falls below 60% of normal due to activation of the fibrinolytic system by various pathological conditions.
Adult↗