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Biomedical subjects

K Okajima

Publications and source records attributed to K Okajima.

At least 91 records · Page 5Linked to original sources
PubMed1998

[Correlation between pyrimidine nucleoside phosphorylase (PyNPase)/platelet-derived endothelial cell growth factor and histological prognostic factor, and influences of 5'-deoxy-5-fluorouridine (5'-DFUR) administration on PyNPase levels. 5'-DFUR Joint Research Group in the Osaka Area for Gastric Cancer].

PURPOSE: Pyrimidine nucleoside phosphorylase (PyNPase), among which thymidine phosphorylase (dThdPase) exists mainly in human tumor tissues, is an enzyme to convert 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil. Recently, it was reported that dThdPase was identical to platelet-derived endothelial cell growth factor, angiogenetic factor. Therefore, we expect that there is possibility of dThdPase being a prognostic factor. METHODS: We investigated for a possible correlation between PyNPase activities in tumor tissues and prognostic factors of histological findings, examined the influences of preoperative oral 5'-DFUR administration to PyNPase levels and investigated for a correlation between HPLC methods and ELISA methods in patients with gastric cancer. RESULTS: Higher levels of PyNPase were observed in patients with advanced t,n,v, and ly factors. PyNPase levels decreased by 5'-DFUR in patients with differentiated cases. A high correlation was found between HPLC and ELISA methods. CONCLUSION: This study suggests that we must investigate possibility of PyNPase being a prognostic factor in more detail.

Antineoplastic Agents↗
PubMed1998

Rebamipide prevents indomethacin-induced gastric mucosal lesion formation by inhibiting activation of neutrophils in rats.

Since granulocyte elastase has been shown to be involved in the pathogenesis of gastric mucosal lesion formation induced by nonsteroidal antiinflammatory drugs, inhibition of granulocyte elastase release from neutrophils may be useful in the prevention of these lesions. The objective of this study was to determine whether rebamipide inhibits neutrophil activation in vivo and in vitro. Rebamipide and ONO-5046, a specific granulocyte elastase inhibitor, markedly inhibited indomethacin-induced mucosal injury in rats. Gastric myeloperoxidase activity was significantly increased 3 h after indomethacin administration. This increase was significantly inhibited by rebamipide and ONO-5046. Although cimetidine markedly prevented the indomethacin-induced mucosal lesion formation, it did not reduce the gastric myeloperoxidase activity. Rebamipide inhibited granulocyte elastase release from neutrophils in vitro by inhibiting the increase in intracellular Ca2+ level. Cimetidine did not inhibit granulocyte elastase release from neutrophils. Furthermore, the elevation of intracellular Ca2+ level was not inhibited by cimetidine. Therefore, unlike cimetidine, rebamipide may prevent indomethacin-induced mucosal injury by inhibiting neutrophil activation.

Alanine↗
PubMed1997

Leukocyte depletion and ONO-5046, a specific inhibitor of granulocyte elastase, prevent a stress-induced decrease in gastric prostaglandin I2 in rats.

To examine whether activated leukocytes may impair the endothelial production of prostaglandin (PG) I2, an important cytoprotective agent in gastric mucosa, we investigated the effects of leukocyte depletion and ONO-5046, a specific inhibitor of granulocyte elastase, on the gastric level of this prostaglandin and gastric mucosal injury in rats subjected to water-immersion restraint stress (WIR). Gastric 6-keto-PGF1 alpha was increased after 30 min of WIR, followed by a decrease to below baseline after 6 h of stress. Gastric levels of 6-keto-PGF1 alpha in leukopenic animals or animals pretreated with ONO-5046 after 1 h of stress were significantly higher than those of controls, levels after 6 h of stress were not lower than those preceding stress. Leukocytopenia or ONO-5046 significantly inhibited WIR-induced gastric mucosa lesion formation. Iloprost, a stable derivative of PGI2, prevented stress-induced lesions. These results suggest that activated leukocytes may play an important role in stress-induced gastric mucosal lesion formation by inhibiting production of PGI2.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Effect of human urinary thrombomodulin on endotoxin-induced intravascular coagulation and pulmonary vascular injury in rats.

Adult respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) are serious complications of sepsis. Thrombomodulin, an important endothelial anticoagulant, binds thrombin to generate activated protein C (APC). To determine whether thrombomodulin purified from human urine (urinary thrombomodulin, UTM) is useful for the treatment of DIC and ARDS in sepsis, we examined the effect of UTM on endotoxin (ET)-induced coagulation abnormalities and pulmonary vascular injury in rats. Intravenous administration of UTM prevented the ET-induced pulmonary accumulation of leukocytes and the increase in pulmonary vascular permeability, as well as ET-induced histological changes such as leukocyte infiltration and pulmonary interstitial edema. On the other hand, dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, did not prevent these effects of ET. UTM did not prevent ET-induced pulmonary accumulation of leukocytes and pulmonary vascular injury in rats pretreated with DEGR-Xa. Our findings suggest that UTM attenuates ET-induced coagulation abnormalities and pulmonary vascular injury. Furthermore, the latter effect may be dependent on the capacity of UTM to activate protein C.

Amino Acid Chloromethyl Ketones↗
PubMed1997

Plasma levels of soluble E-selectin in patients with disseminated intravascular coagulation.

The plasma level of soluble E-selectin (sE) reflects the activation of endothelial cells induced by cytokines such as tumor necrosis factor-alpha and interleukin-1 in vitro. These cytokines are important in the development of coagulation abnormalities in patients with sepsis. We compared the plasma levels of sE in patients with infections suspected of having disseminated intravascular coagulation (DIC) (n = 33) and in patients with underlying disorders other than infections, including solid tumors (n = 28), obstetric disorders (n = 13), hematologic malignancies (n = 13), and liver disease (n = 9), to clarify the involvement of cytokines in the development of coagulation abnormalities in patients with sepsis. Plasma levels of sE in patients with infection were significantly higher than in patients with the other underlying disorders. The plasma level of sE was also significantly higher in patients with infection with DIC (114.6 +/- 77.9 ng/ml, n = 21) than in patients with infection without DIC (54.5 +/- 53.1 ng/ml, n = 12, P < 0.02). There was no significant difference in sE level between patients with the other underlying disorders with and without DIC. The plasma level of sE was significantly correlated with the serum level of FDP(E) in patients with infection. The plasma level of sE was significantly higher in patients with infection with organ failure compared to patients without organ failure. There was no significant difference between patients with the other underlying disorders with and without organ failure. Plasma levels of tumor necrosis factor-alpha and interleukin-6 were detected in only 12.1% and 20.0% of patients with infections, respectively. These observations strongly suggest that plasma levels of sE reflect the activation of endothelial cells induced by cytokines, which may lead to DIC and organ failure in the presence of sepsis. Furthermore, determination of plasma level of sE may be useful for detecting the endothelial activation induced by cytokines in the pathologic conditions of sepsis, even when plasma levels of cytokines cannot be detected.

Biomarkers↗
PubMed1997

Proliferating cell nuclear antigen expression in the gallbladder with pancreaticobiliary maljunction.

BACKGROUND AND OBJECTIVE: To clarify the histogenesis of cancer of the gallbladder of the patients with pancreaticobiliary maljunction (PBMJ), the proliferating cell activity of the epithelium of gallbladder was examined. METHODS: A total of 21 patients with pancreaticobiliary maljunction [8 with gallbladder cancer (MCA group) and 13 without cancer (M group)] were studied using immunohistochemical staining with a monoclonal antibody to the proliferating cell nuclear antigen (PCNA). The 23 gallbladder cancer patients without PBMJ (CA group) and 10 patients with normal gallbladders (N group) were also examined as controls. RESULTS: The PCNA-positive rates of non-cancerous epithelium of the gallbladder in patients with PBMJ (14.2% in MCA group and 11.6% in M group) were significantly higher than those without PBMJ (3.9% in CA group and 1.5% in N group). CONCLUSION: The high proliferating cell activity of epithelium of the gallbladder may be an explantation for the high incidence of gallbladder cancer in patients with pancreaticobiliary maljunction.

Aged↗
PubMed1997

Pretreatment with activated protein C or active human urinary thrombomodulin attenuates the production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion in rat liver.

We investigated the role of anticoagulant in the ischemia/reperfusion injury of the liver, using activated protein C (APC), active human urinary thrombomodulin (UTM), and factor Xa blocked at the active site (DEGR-Xa). Liver ischemia was induced in male Wistar rats by occlusion of the portal vein with a microvascular clip for 30 minutes. Each anticoagulant was injected intravenously 10 minutes before clamping the portal vein. Serum concentrations of cytokine-induced neutrophil chemoattractant (CINC) were determined by enzyme-linked immunosorbent assay. The serum levels of CINC increased significantly following reperfusion, reaching a peak in 6 hours, and then decreasing gradually to control levels by 24 hours. CINC levels in rats pretreated with APC (500 U/kg), UTM (3,000 TMU/kg), or DEGR-Xa (10 mg/kg) peaked 3 hours following reperfusion and decreased rapidly to baseline level within 6 and 12 hours, respectively. These peak values were significantly lower than those observed in untreated rats (P < .01). Expression of CINC transcripts in liver tissue of untreated rats was evaluated by Northern blot analysis and peaked 3 hours following reperfusion. Pretreatment with these anticoagulants significantly decreased the expression of CINC messenger RNA transcripts as compared with untreated animals. Myeloperoxidase activity and the number of neutrophils accumulated into the liver 24 hours following ischemia/reperfusion were also significantly decreased in animals pretreated with these anticoagulants. In addition, correlations between the peak values of liver enzymes and serum CINC levels were found to be significant (P < .001). The inactive derivative of factor Xa, a selective inhibitor of thrombin generation, inhibited ischemia/reperfusion-induced increases in the serum concentration and messenger RNA transcript quantities of CINC. The inactive factor Xa also reduced hepatic accumulation of neutrophils after ischemia/reperfusion. These results indicate that the release of CINC is likely related to the hepatic microcirculation disturbance induced by microthrombotic occlusion following ischemia/reperfusion.

Animals↗
PubMed1997

Surgery for gastric cancer in patients with cirrhosis.

To clarify the therapeutic strategies for gastric cancer surgery in the presence of cirrhosis, 39 patients with gastric cancer accompanied by liver cirrhosis were reviewed. Severe postoperative complications developed in 10 patients (25.6%), and there were 4 (10.3%) hospital deaths. 1 (2.6%) of which occurred within 1 month. Although extended lymph node dissection of D2 or more was adopted for low-risk patients, 3 of 19 patients who underwent such extensive operations, most of which involved complete lymph node dissection in the hepatoduodenal ligament, died. Conversely, only 1 of 20 patients who underwent limited lymph node dissection of D1 or less died. Postoperative massive ascites developed in 6 patients, 3 of whom died. The cumulative 5-year survival rate following curative resection was 63.7% for patients with early gastric cancer, and 13.9% for those with advanced gastric cancer. The most frequent cause of death was cirrhosis-related, such as hepatic failure or hepatoma. In conclusion, extensive lymph node dissection for patients with gastric cancer accompanied by cirrhosis carried a risk of postoperative fatal massive ascites as lymphorrhea. Thus, lymph node dissection in the hepatoduodenal ligament should be avoided, except in patients with evident metastases, and as a rule, aggressive surgery should not be performed in cirrhotic patients.

Adult↗
PubMed1997

Distant lymph node metastasis of early gastric cancer.

Among 601 patients with early gastric cancer (EGC), the clinicopathological findings of 5 patients (invasion of the mucosal layer in 2 and of the submucosal layer in 3) with distant lymph node metastasis according to TNM classification (third- or fourth-tier lymph node metastasis according to the Japanese classification) were investigated. The proliferating-cell nuclear antigen (PCNA) expression of EGC was also examined immunohistologically. The sites of distant metastasis were the nodes at the root of the mesentery, in the hepatoduodenal ligament, and the paraaortic nodes. While the PCNA-positive rate of EGC with distant lymph node metastasis (35.4%) was significantly higher than that of EGC without lymph node metastasis (14.7% P = 0.01), it was similar to that of EGC with perigastric lymph node metastasis. The cumulative survival rate of the EGC patients with distant lymph node metastasis (5-year survival rate 20.0%) was significantly lower than that without lymph node metastasis (88.2%, P < 0.0001), first-tier lymph node metastasis (76.9%, P < 0.04), or second-tier lymph node metastasis (77.1%, P < 0.04). Thus, although the prognosis of EGC patients with distant lymph node metastasis was poor, a dissection of the distant lymph nodes should be performed when metastasis is suspected.

Adenocarcinoma↗
PubMed1997

Role of granulocyte elastase in indomethacin-induced gastric mucosal lesion formation in rats.

To investigate whether granulocyte elastase may be involved in indomethacin-induced gastric mucosal injury, we examined the effects of the granulocyte elastase inhibitors ONO-5046 and L-658,758 on gastric mucosal lesion formation in rats given indomethacin. Both gastric mucosal lesion formation and gastric mucosal vascular damage were markedly attenuated in animals with leukocytopenia and in those given granulocyte elastase inhibitors. The administration of indomethacin significantly increased gastric myeloperoxidase activity, a measure of leukocyte accumulation, 3 hours after the administration of indomethacin compared with activity in animals receiving saline solution. The administration of ONO-5046 or L-658,758 significantly prevented this increase. Histologic examinations revealed submucosal edema and marked infiltration by leukocytes, as well as widespread necrosis with loss of surface epithelium. ONO-5046 and L-658,758 markedly prevented these histologic changes. Although cimetidine significantly prevented mucosal lesion formation, it did not inhibit either granulocyte elastase release from activated neutrophils in vitro or gastric accumulation of leukocytes in vivo. These results suggest that granulocyte elastase as well as gastric acid may play an important role in the pathologic process by which indomethacin induces gastric mucosal lesions.

Animals↗
PubMed1997

Novel role of prostacyclin in stress-induced gastric mucosal lesion formation in rats.

We investigated the novel role of prostacyclin (PGI2) in gastric mucosal lesion formation induced by stress in rats. Gastric 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) levels were significantly increased 30 minutes after water-immersion restraint stress (WIR). Subcutaneous indomethacin (IM) (5 mg/kg) inhibited this increase but significantly exacerbated gastric mucosal lesion formation in rats subjected to WIR. Although gastric myeloperoxidase (MPO) activity was not increased by WIR, it significantly increased with time after WIR in animals pretreated with IM. NS-398, a selective inhibitor of cyclooxygenase-2, did not inhibit the WIR-induced increase in gastric 6-keto-PGF1alpha. Neither the gastric lesion index nor gastric MPO activity were affected in animals pretreated with NS-398 and subjected to WIR. WIR-induced mucosal lesion formation was significantly inhibited in animals given iloprost, a stable analog of PGI2, and in those with nitrogen mustard-induced leukocytopenia. Iloprost prevented the gastric leukocyte accumulation and exacerbation of gastric mucosal lesions induced by IM in animals subjected to WIR. These IM-induced events also were prevented in animals subjected to WIR with nitrogen mustard-induced leukocytopenia. These observations implicate leukocytes in the process leading to gastric mucosal lesions induced by WIR. The increase in WIR-induced gastric PGI2 synthesis, mainly mediated by cyclooxygenase-1, appears important in preventing lesion formation, not only by maintaining gastric mucosal blood flow but also by inhibiting leukocyte activation.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Role of neutrophils in spinal cord injury in the rat.

Activated neutrophils are thought to be involved in tissue injury through the release of various inflammatory mediators. To understand the role of neutrophils in spinal cord injury, the effects of nitrogen mustard-induced leukocyte depletion and the administration of an anti-P-selectin monoclonal antibody on motor disturbances observed following spinal cord compression were examined in rats. Spinal cord injury was induced by applying a 20-g weight for 20 min at the level of the 12th thoracic vertebra, resulting in motor disturbances of the hindlimbs 24 h postcompression. Motor disturbances, evaluated using Tarlov's index, an inclined-plane test and climbing ability, were markedly attenuated in rats with nitrogen mustard-induced leukocytopenia. Administration of the anti-P-selectin monoclonal antibody, by which adhesion of activated neutrophils to endothelial cells may be inhibited, also attenuated motor disturbances. Histological examination revealed that intramedullary hemorrhages observed 24 h after compression at the 12th thoracic vertebra of the spinal cord were significantly attenuated in leukocytopenic animals and those which received the anti-P-selectin monoclonal antibody. The accumulation of neutrophils at the site of compression, as evaluated by measuring the tissue myeloperoxidase activity, significantly increased with time following the compression, peaking at 3 h postcompression. Spinal cord myeloperoxidase activity did not increase in sham-operated animals. Leukocyte depletion and administration of the anti-P-selectin monoclonal antibody both reduced the accumulation of neutrophils in the damaged spinal cord segment 3 h postcompression. These observations strongly suggest that activated neutrophils play an important role in compression-induced thoracic spinal cord injury and that a P-selectin-mediated interaction between activated neutrophils and endothelial cells may be a critical step in endothelial cell injury leading to spinal cord injury.

Animals↗
PubMed1997

Rebamipide attenuates indomethacin-induced gastric mucosal lesion formation by inhibiting activation of leukocytes in rats.

Granulocyte elastase released from activated leukocytes plays an important role in leukocyte infiltration. Since activated leukocytes have been shown to be involved in the pathogenesis of gastric mucosal lesion formation induced by nonsteroidal antiinflammatory drugs, inhibition of granulocyte elastase release from activated leukocytes may be useful in the prevention of these lesions. Rebamipide, a novel antiulcer agent, inhibited granulocyte elastase release from activated neutrophils in vitro. Rebamipide and ONO-5046, a granulocyte elastase inhibitor, markedly inhibited gastric mucosal lesion formation in rats. Gastric myeloperoxidase activity was significantly increased 3 hr after indomethacin administration. This increase was significantly inhibited by rebamipide and ONO-5046. Cimetidine did not inhibit granulocyte elastase release from activated neutrophils. Although cimetidine markedly prevented the indomethacin-induced gastric mucosal lesion formation, it did not reduce the gastric myeloperoxidase activity. Therefore, unlike cimetidine, rebamipide may prevent indomethacin-induced gastric mucosal lesion formation by inhibiting neutrophil activation.

Alanine↗
PubMed1997

Mutations in the human Jagged1 gene are responsible for Alagille syndrome.

Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by intrahepatic cholestasis and abnormalities of heart, eye and vertebrae, as well as a characteristic facial appearance. Identification of rare AGS patients with cytogenetic deletions has allowed mapping of the gene of 20p12. We have generated a cloned contig of the critical region and used fluorescent in situ hybridization on cells from patients with submicroscopic deletions to narrow the candidate region to only 250 kb. Within this region we identified JAG1, the human homologue of rat Jagged1, which encodes a ligand for the Notch receptor. Cell-cell Jagged/Notch interactions are known to be critical for determination of cell fates in early development, making this an attractive candidate gene for a developmental disorder in humans. Determining the complete exon-intron structure of JAG1 allowed detailed mutational analysis of DNA samples from non-deletion AGS patients, revealing three frame-shift mutations, two splice donor mutations and one mutation abolishing RNA expression from the altered allele. We conclude that AGS is caused by haploinsufficiency of JAG1.

Alagille Syndrome↗
PubMed1997

Antithrombin III (AT III) prevents LPS-induced pulmonary vascular injury: novel biological activity of AT III.

Acute respiratory distress syndrome (ARDS) adversely affects the outcome of patients with disseminated intravascular coagulation (DIC) associated with sepsis. To determine whether antithrombin III (AT III) is useful for the treatment of ARDS in sepsis, we evaluated the effect of AT III on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. Although the intravenous administration of AT III (250 U/kg) prevented LPS-induced pulmonary accumulation of leukocytes, increases in pulmonary vascular permeability, and coagulation abnormalities, inactivated factor Xa, a selective inhibitor of thrombin generation, did not prevent such events other than the coagulation abnormalities. AT III promotes the endothelial release of prostacyclin by interacting with cell surface glycosaminoglycans in vivo. Trp49-modified AT III, which lacks affinity for heparin, did not prevent LPS-induced pulmonary vascular injury. Plasma levels of 6-keto-prostaglandin F1alpha were markedly increased in rats after the administration of LPS and significantly decreased in the LPS-treated rats administered Trp49-modified AT III, but not altered in those LPS-treated rats receiving AT III. Preventive effects of AT III were not observed in rats pretreated with indomethacin, which inhibits prostacyclin biosynthesis. Prostacyclin prevents LPS-induced pulmonary vascular injury by inhibiting leukocyte accumulation in the lungs. These observations strongly suggest that AT III prevents pulmonary vascular injury induced by LPS by promoting the endothelial release of prostacyclin, a potent inhibitor of leukocyte activation.

6-Ketoprostaglandin F1 alpha↗