Biomedical subjects
Publications and source records attributed to K Inada.
In the presence of IFN-gamma-stimulated vascular endothelial cells which have acquired HLA class II molecules, T cells produced tumor necrosis factors (TNF-alpha and TNF-beta) and IL-2 in response to stimulation with streptococcal pyrogenic exotoxin A.
The value of tumor angiogenesis, EGFR and c-erbB-2 oncoprotein, a long with p 53 protein expression for predicting relapse-free survival was investigated in 110 node-negative breast cancer patients. The grade of neovascularization was assessed by the microvessel density which was obtained by an immunocytochemical staining by factor VIII-related antigen. EGFR, c-erbB-2 oncoprotein and p 53 oncoprotein were also determined by immunocytochemical assay. Univariate analysis showed no statistical significance of EGFR, c-erbB-2 and p53 status as a prognostic indicator. However, the microvessel density was a significant predictor of relapse-free survival. Patients with over 100 counts of factor VIII-RA positive cells per mm2 field in the most active areas of neovascularization showed significantly poorer prognosis compared to those with less than 100 counts (p < 0.005). Multivariate analysis demonstrated that microvessel density was an independent prognostic indicator in node-negative breast cancer patients (p < 0.0005). It was suggested that microvessel density might be of use in selecting the high-risk group in node-negative breast cancer patients needing adjuvant therapies.
To elucidate the interrelationship between active oxygen and polymorphonuclear leukocyte elastase (PMN elastase) in patients with septic adult respiratory distress syndrome (ARDS), we examined the relationship between alpha-tocopherol, which has an antioxidant action, and PMN elastase. Serial blood samples were collected from 16 patients with septic ARDS. Serum levels of alpha-tocopherol were determined by HPLC. PMN elastase was determined by ELISA. The serum alpha-tocopherol level in a nonsurviving group was significantly lower than that in a surviving group at the time that septic ARDS was diagnosed (p = 0.0068). The level of PMN elastase in the nonsurviving group was significantly higher than that in the surviving group (p = 0.0058). A significant negative correlation existed between the serum levels of alpha-tocopherol and those of PMN-elastase (r = -0.659, p = 0.0043). Both the serum alpha-tocopherol level and the PMN elastase level appeared to be good indices of the severity of ARDS. The results suggested that an interaction between active oxygen and PMN elastase may increase the clinical severity of this disease.
We determined the plasma concentrations of interleukin 8 (IL-8), polymorphonuclear leukocyte elastase (PMNE), and endotoxin in patients with septic shock in order to investigate the role of IL-8 and PMNE in the development of septic shock, especially in septic adult respiratory distress syndrome (ARDS). The IL-8 concentration in patients with septic shock was 6.28 +/- 9.00 ng/mL (mean +/- SD, n = 29), which was significantly higher (P < 0.0001) than the concentration in septic patients without shock (0.35 +/- 0.35 ng/mL, n = 40). There was a significant correlation between the IL-8 concentration and the PMNE concentration at the onset of septic shock (r = 0.6916, P < 0.0001). The IL-8 concentration was also significantly correlated with the endotoxin concentration (r = 0.5584, P = 0.0016). There was a significant negative correlation (r = -0.8237, P < 0.0001) between the serum PMNE concentration and the oxygenation index (PaO2/FiO2) at the onset of septic shock. These results indicate that IL-8 and PMNE are produced in large quantities when septic shock occurs, and may play a role in the development of septic ARDS.
To elucidate the role of surgery for MMT, 214 patients during past 34 years were historically divided into the early (1960-1971, n = 80), intermediate (1972-1981, n = 79) and late series (1982-1993, n = 64). The thoracotomy rate for MMT, the rate of thoracotomy after preoperative diagnosis was done, and the number of postoperative survivors were significantly higher in the late series, compared with the early series. The intermediate series located between the early and late series. Nine patients in the late series undergoing chemo-radiation therapies obtained a good result after complete resection of the residual tissue. We conclude that surgical treatment of MMT should be based on accurate preoperative diagnosis and a distinct role for multidisciplinary treatment, especially regarding malignant thymoma, malignant lymphoma and malignant germ cell tumor.
We investigated the inhibitory effects of a protease inhibitor, FUT-175, on the production of interleukin 8 (IL-8) and polymorphonuclear leukocyte elastase (PMNE) by polymorphonuclear leukocytes (PMN) and vascular endothelial cells. IL-8 production by PMN and vascular endothelial cells stimulated with lipopolysaccharide (LPS) was inhibited by FUT-175. This compound also inhibited PMNE production by PMN following LPS stimulation.
Plasma levels of type II phospholipase A2 (type II PLA2), cytokines and endotoxin were determined in patients with sepsis to investigate their interrelations and their role in the patient's prognosis. Type II PLA2 was measured by radioimmunoassay, tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and IL-8 were each measured by enzyme-linked immunosorbent assay (ELISA). Endotoxin was determined by a method based on an endotoxin-specific synthetic substrate. Plasma levels of type II PLA2 were significantly higher in the patients who died of sepsis than in those who survived the illness. There was a significant correlation between type II PLA2 and TNF-alpha and IL-6. Type II PLA2, TNF-alpha, IL-6, and IL-8 may be useful as indices of disease severity. The results suggest that TNF-alpha and IL-6 stimulate the production of type II PLA2 in the plasma of patients with sepsis.
We evaluated the roles of plasma endothelin-1 and plasma thrombomodulin in the development of disseminated intravascular coagulation (DIC) in patients with sepsis. Plasma endothelin-1 was measured by radioimmunoassay (RIA). Plasma thrombomodulin and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay (ELISA), and serum protein C (protein C) was measured by the synthetic substrate method. Endotoxin was measured by the Endospecy test, a synthetic substrate method. A new perchloric acid method was used for the pretreatment of plasma. Blood levels of endothelin-1 and thrombomodulin were significantly higher in patients with DIC than in those without DIC (p < 0.0001). Endothelin-1 and thrombomodulin levels were positively correlated (r = 0.8645, p = 0.0001), as were endothelin-1 and TNF-alpha levels (r = 0.5441, p = 0.0002). Thrombomodulin and protein C levels were negatively correlated (r = -0.5627, p = 0.0001). Endotoxin was elevated above the normal level 14.3% (6/42) for these patients. TNF-alpha is involved in the production of endothelin-1 and thrombomodulin, which play a role in the pathogenesis of DIC and whose blood levels reflect its severity.
Plasma endotoxin contents of the patients with sepsis or typhoid fever were measured by two sophisticated chromogenic limulus tests; Endospecy and Toxicolor tests. Endospecy test is the endotoxin-specific test and Toxicolor is responsible for both endotoxin and (1,3)-beta-D-glucan. Plasma was pretreated by our new PCA method which resolved the problem as to the detection of a lesser amount of plasma endotoxin when pretreated by the conventional PCA method. Although Toxicolor values have been reported to exceed more than the Endospecy value, under complicated pathophysiological situations, almost all specimens of these patients had a similar value, except in one expired septic shock case. In 18 typhoid fever cases, Salmonella typhi was isolated only from the bile in 5 cases, however endotoxemia occurred in 11 cases (61.1%). Within the first 4 days, the incidence of endotoxemia was higher (10/14, 71.4%). These results suggest that endotoxin assay seemed to be a useful tool for the diagnosis of typhoid fever.
Vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) are known to be angiogenic growth factors in vitro and in vivo. In this study, we have investigated the relationship between VEGF expression and PD-ECGF expression in human breast cancer tissues using immunocytochemical methods. Of 152 primary breast cancers, 84 (55.3%) and 71 (46.7%) were positive for VEGF and PD-ECGF, respectively. Fifty-three (63. 1%) of 84 VEGF-positive tumors had a PD-ECGF-positive phenotype, whereas only 18 (26.5%) of 68 VEGF-negative tumors had a PD-ECGF-positive phenotype. There was a significant correlation between the VEGF expression and PD-ECGF expression (P < 0.01). As a single factor, VEGF expression and PD-ECGF expression were significantly associated with an increase in the microvessel density assessed by the immunocytochemical analysis using antifactor VIII-related antigen mAb. Interestingly, in addition, of 53 tumors with more than 100 microvessel counts/1 mm2, 40 (75.5%) had both VEGF- and PD-ECGF-positive phenotypes. It was found that VEGF and PD-ECGF were frequently coexpressed in highly vascularized tumors with high microvessel counts. It is suggested that VEGF and PD-ECGF might cooperatively function in the neovascularization of human breast cancer.
Hepatocyte growth factor (HGF) was first identified as a potent stimulator of hepatocyte growth and DNA synthesis. Later, it was shown that HGF can promote cell motility and cell proliferation in various types of cells, including tumor cells and endothelial cells. We have examined serum concentrations of HGF in breast cancer patients using an ELISA. Of 134 primary breast cancer patients, 49 (36.6%) showed a significant increase in the circulating level of HGF as compared to healthy controls. The increase in the HGF level was significantly associated with axillary lymph node metastases and histological evidence of venous invasion. No significant correlation between serum HGF concentrations and intratumoral HGF concentrations was found; however, the removal of the primary tumor clearly decreased the serum HGF level, suggesting that the elevation of HGF in the serum was tumor related. Twenty-nine (82.9%) of 35 patients with recurrent breast cancer had an increase in the serum HGF level. The HGF level was significantly higher in patients with liver metastases compared to those with other sites of metastases. Postoperative sequential examinations confirmed that the increase in the serum HGF level was associated with the appearance of relapse. In conclusion, the serum HGF level was significantly increased in breast cancer patients. Circulating HGF might play important roles in tumor progression in this malignancy.
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Bcl-2 proto-oncogene is expressed in normal lymphoid tissues and its role has been suggested to involve the selection of B and T cells. Here we report three-color flow cytometric studies on the expression of bcl-2 protein in the thymus and periphery. Bcl-2 was expressed in the majority of T and B cells and down-regulated only in the CD1+, CD3- to low, CD4+8+ thymocytes, and the B cells that are in cell cycle in the tonsil and lymph node. In contrast, the CD2+, CD1-3-4-8-19-, early T cells, and mature single positive cells in the thymus, as well as the tonsilar and lymph node T cells, irrespective of their cell cycle status, expressed bcl-2. These results are consistent with the notion that bcl-2 is down-regulated in the T and B cells that are in the process of generating new antigen receptors and subject to subsequent positive selection.
Nitric oxide (NO) is synthesized by nitric oxide synthase (NOS) from L-arginine (Arg) which has a guanidino group in its molecule. We examined the effect of 23 different Arg analogues on NOS activity in the rat brain. Though homoarginine, epsilon-guanidinocaproic acid and canavanine act as substrates of NOS, production of NO from them was lower than that from Arg. alpha-Guanidinoglutaric acid (2-GGA) and arcaine inhibited NOS activity at levels equal to NG-monomethyl-L-arginine (MeArg), a well known NOS inhibitor. Though almost all previously reported NOS inhibitors were synthesized by substituting the guanidino nitrogen of Arg, the guanidino nitrogens of arcaine and 2-GGA were not substituted. Furthermore, 2-GGA is a known endogenous convulsant in mammals, and arcaine, which was isolated from a marine mollusc, is also a convulsive substance. Hence, 2-GGA and arcaine will be excellent drugs to investigate not only the chemical nature of NOS but also the physiologic function of NO.
OBJECTIVES: The roles of cytokines and endotoxin in hemorrhagic shock, particularly the translocation of endotoxin and bacteria during hemorrhagic shock, were investigated. DESIGN: Prospective study. SETTING: Critical care and emergency center of a university hospital. PATIENTS: Twenty-nine patients with hemorrhagic shock and 20 healthy controls. INTERVENTIONS: Serial blood samples were collected from both study and control patients. Standard resuscitation techniques were used. MEASUREMENTS AND MAIN RESULTS: Plasma levels of endotoxin and various cytokines were determined repeatedly during hemorrhagic shock. Endotoxin was measured using an endotoxin-specific assay in addition to a new perchloric acid method for pretreatment of plasma. Cytokines were measured by commercial enzyme-linked immunosorbent assays. Plasma endotoxin concentrations remained within the normal range for 7 days after admission. Although levels of tumor necrosis factor-alpha and several interleukins increased slightly in some patients, these cytokines did not reach the levels seen in septic shock. CONCLUSIONS: Translocation of bacteria or endotoxin from the gastrointestinal tract into the bloodstream has been noted in animal experiments; however, translocation was not detected in our patients with hemorrhagic shock.
The capacity of human T cell subsets, CD4+ or CD8+ T cells, to produce tumour necrosis factors (TNF-alpha and TNF-beta) upon stimulation with toxic shock syndrome toxin-1 (TSST-1) and the requirement for MHC class II molecules on accessory cells (AC) in the response were investigated. The capacity of CD4+ T cells was much higher than that of CD8+ T cells in TSST-1-induced production of TNF-alpha and TNF-beta. The expression of MHC class II molecules on AC was required in the response.
A clinical Phase I study of E5, edobacomab, an anti-endotoxin monoclonal IgM antibody was carried out to evaluate its efficacy, safety and pharmacokinetics and in parallel, explore an optimum dosage in the treatment of patients with gram-negative sepsis (incl. those suspected). A total of 10 patients were administered a dose of 1 mg/kg, 2 mg/kg or 4 mg/kg of E5 by infusion over one hour. 1. Peak blood levels after an intravenous dose of 1 mg/kg, 2 mg/kg and 4 mg/kg of E5 were 9.9, 11.5 and 35.6 micrograms/ml, respectively and the half-lives of elimination were 8.7, 11.7 and 10.8 hours, respectively, about the same at all dose levels. The area under the blood concentration-time curve (AUC) were 129.8, 200.8 and 574.4 micrograms.hr/ml, respectively, showing an increase in proportion with the dosage. 2. Urinary E5 concentration was not detectable in all the patients and renal excretion of unchanged E5 was not observed. 3. Out of the 8 patients with a positive pre-treatment endotoxin level with a value of above 9.8 pg/ml, those who showed its reduction to a level of below 9.8 pg/ml within one hour after dosing of E5 were 0 of 2 patients (0%) at a dose of 1 mg/kg, 3 of 3 (100%) at a dose of 2 mg/kg and 1 of 3 (33.3%) at a dose of 4 mg/kg. 4. The clinical efficacy following a single intravenous dose of E5 was rated as being "good" or "excellent" for 3 of 3 patients (100%) at a dose of 1 mg/kg, 4 of 4 (100%) at a dose of 2 mg/kg and 2 of 3 (66.7%) at a dose of 4 mg/kg. 5. As for antipyretic effect as assessed by the mean value of temperature, a fall in fever to the level of 36 degrees C was noted from 12 hours after administration of E5 in the patients treated with 2 mg/kg. The degree of improvement in WBC, platelet count and CRP was also more evident in this 2 mg/kg group. 6. The safety was rated as "no problem in safety" for all 10 patients. No adverse reaction and clinical laboratory abnormalities suspected of their relation to E5 was observed. 7. Positive antibody (HAMA) response to E5 was observed in 2 of the 10 patients. In one patient (4 mg/kg) of them, response because negative 9 weeks later and in the other patient (1 mg/kg) it tended to decrease.(ABSTRACT TRUNCATED AT 400 WORDS)
A study was carried out to investigate the efficacy of therapy with recombinant human granulocyte colony-stimulating factor (rhG-CSF) in 24 patients with granulocytopenia and sepsis who had failed to respond to antibiotics. The mean leukocyte count at the start of the study was 911 +/- 334/microliter. Patients were injected subcutaneously with 75 micrograms rhG-CSF once daily for a mean of 5.2 days. The plasma G-CSF concentration was measured by ELISA. The leukocyte count increased approximately 9-fold after 1 week in 19 patients and the percentage of granulocytes rose from 46.2% to 78.9%. These 19 patients survived, while the 5 patients with no leukocyte response to rhG-CSF died. High plasma G-CSF levels were found in patients with granulocytopenia. Plasma G-CSF levels decreased as levels of granulocyte increased in survivors. A high plasma G-CSF concentration persisted in the 5 non-responding patients resulting in a fatal outcome. This study suggests that rhG-CSF both increased the leukocyte count and was a useful therapeutic manoeuvre for sepsis.