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Biomedical subjects

K Okajima

Publications and source records attributed to K Okajima.

At least 109 records · Page 6Linked to original sources
PubMed1997

Gabexate mesilate, a synthetic protease inhibitor, prevents compression-induced spinal cord injury by inhibiting activation of leukocytes in rats.

OBJECTIVE: Gabexate mesilate is a synthetic protease inhibitor capable of inhibiting both coagulation and cytokine production by monocytes. To investigate whether gabexate mesilate is useful for the prevention of posttraumatic spinal cord injury, we examined its effect on compression trauma-induced spinal cord injury in rats. DESIGN: Prospective, randomized, blinded, controlled study. SETTING: Research laboratory at a university medical center. SUBJECTS: Male Wistar rats weighing 300 to 350 g. INTERVENTIONS: Spinal cord injury was induced by applying a 20-g weight extradurally to the spinal cord at the level of the 12th thoracic vertebra for 20 mins. Spinal cord injury was evaluated by assessing the motor function of the rats 24 hrs posttrauma. The accumulation of leukocytes and histologic changes in the injured spinal cord tissue also were examined. Rats received gabexate mesilate (10 or 20 mg/kg i.p.) 30 mins before or after the compressive trauma. The effects of heparin or an inactive derivative of activated factor X (a selective inhibitor of thrombin generation) on compressive trauma-induced spinal cord injury also were examined. Leukocytopenia was induced by the administration of nitrogen mustard. MEASUREMENTS AND MAIN RESULTS: The motor disturbances observed following traumatic spinal cord compression, evaluated by Tarlov's score, and the accumulation of leukocytes in the injured tissue, evaluated by measuring tissue myeloperoxidase activity, were markedly reduced by leukocyte depletion induced by nitrogen mustard and by pre- or posttreatment of animals with gabexate mesilate. Neither heparin nor the inactive derivative of activated factor X prevented the motor disturbances and the accumulation of leukocytes. Histologic examination demonstrated that intramedullary hemorrhages observed 24 hrs after trauma at the 12th thoracic vertebra were significantly attenuated by nitrogen mustard-induced leukocytopenia and the administration of gabexate mesilate. CONCLUSIONS: The compression trauma-induced spinal cord injury demonstrated by this model was mainly mediated by leukocytes. Gabexate mesilate prevented spinal cord injury not by inhibiting coagulation, but by inhibiting the activation of leukocytes.

Amino Acid Chloromethyl Ketones↗
PubMed1997

Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production.

We investigated the effect of activated protein C (APC) on pulmonary vascular injury and the increase in tumor necrosis factor (TNF) levels in lipopolysaccharide (LPS)-treated rats to determine whether APC reduces LPS-induced endothelial damage by inhibiting cytokine production. Intravenously administered LPS (5 mg/kg) induced pulmonary vascular injury, as indicated by an increase in the lung wet-to-dry weight ratio. LPS-induced pulmonary vascular injury was prevented by APC but not by active site-blocked factor Xa [dansyl glutamyl-glycyl-arginyl chloromethyl detone-treated activated factor X (DEGR-Xa)], a selective inhibitor of thrombin generation, or inactivated APC [diisopropyl fluorophosphate-treated APC (DIP-APC)]. APC, but not DEGR-Xa or DIP-APC, significantly inhibited the LPS-induced increase in the plasma level of TNF. APC significantly inhibited the production of TNF by LPS-stimulated monocytes in a dose-dependent fashion in vitro, but DIP-APC did not. APC did not inhibit the functions of activated neutrophils in vitro. These findings suggest that APC prevented LPS-induced pulmonary vascular injury by inhibiting TNF production by monocytes and not via its anticoagulant activity. The serine protease activity of APC appears to be essential for inhibition of TNF production.

Amino Acid Chloromethyl Ketones↗
PubMed1997

rhs-TM prevents ET-induced increase in pulmonary vascular permeability through protein C activation.

We have previously demonstrated that recombinant human soluble (rhs) thrombomodulin (TM) inhibits the endotoxin (ET)-induced increase in pulmonary vascular permeability by inhibiting leukocyte activation. In the present study, we examined whether rhs-TM could inhibit the ET-induced increase in pulmonary vascular permeability in rats by activating protein C. rhs-TM did not inhibit ET-induced increases in pulmonary vascular permeability when its protein C activation ability was selectively inhibited by a monoclonal antibody (MAb) against rhs-TM (MAb R5G12). Histological examination revealed that neutrophil infiltration in lung tissues after ET administration was significantly reduced by rhs-TM, but infiltration was not reduced by MAb R5G12-pretreated rhs-TM. ET-induced intravascular coagulation was prevented by rhs-TM and by MAb R5G12-pretreated rhs-TM. However, ET-induced coagulation was not prevented by rhs-TM that had been treated with MAb F2H5, which cannot bind thrombin or activate protein C. These observations strongly suggest that rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting pulmonary accumulation of leukocytes through thrombin binding and the subsequent protein C activation and may prevent ET-induced intravascular coagulation through thrombin binding.

Animals↗
PubMed1997

Effect of nafamostat mesilate on pulmonary vascular injury induced by lipopolysaccharide in rats.

Nafamostat mesilate (NM) is a synthetic protease inhibitor that is capable of inhibiting the various coagulation factors such as factor VIIa and thrombin. To determine whether NM may also be useful in treating adult respiratory distress syndrome (ARDS) related in sepsis, we investigated the effect of NM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intraperitoneal administration of NM prevented the pulmonary vascular injury and coagulation abnormalities induced by LPS. DEGR-factor VIIa, a selective inhibitor of factor VIIa, prevented the coagulation abnormalities, but not the pulmonary vascular injury, induced by LPS. NM did not reduce LPS-induced increase in pulmonary accumulation of leukocytes. NM did not inhibit the increase in the plasma concentration of tumor necrosis factor-alpha (TNF-alpha) observed after administration of LPS. NM did not inhibit the function of activated neutrophils in vitro. Plasma values of total serum hemolytic complement (CH50) were markedly decreased after the administration of LPS. NM inhibited the LPS-induced decrease in plasma CH50 values. Findings suggest that NM may reduce the pulmonary vascular injury as well as the coagulation abnormalities induced by LPS. The former effect may be independent of the anticoagulant effect but dependent on the inhibitory effect of the activation of the complement system in rats administered LPS.

Animals↗
PubMed1997

Reduction of spinal cord injury by administration of iloprost, a stable prostacyclin analog.

To investigate whether iloprost, a stable analog of prostacyclin, is useful for the prevention of posttraumatic spinal cord injury, we examined its effects on compression trauma-induced spinal cord injury in rats. Spinal cord injury was induced by applying a 20-g weight for 20 minutes to the spinal cord at the level of T-12, resulting in motor disturbances in the hindlimbs. These motor disturbances, evaluated using Tarlov's index, were markedly attenuated in rats with nitrogen mustard-induced leukocytopenia. Administration of iloprost also attenuated the motor deficits. Histological examination revealed that intramedullary hemorrhages observed 24 hours after trauma were significantly attenuated in leukocytopenic animals and in animals that received iloprost. The accumulation of leukocytes at the site of trauma, evaluated by measuring tissue myeloperoxidase activity, significantly increased with time following the trauma, peaking at 3 hours postinjury. Spinal cord myeloperoxidase activity in sham-operated animals did not increase postoperatively. Leukocyte depletion and administration of iloprost reduced the accumulation of leukocytes in the damaged spinal cord segment 3 hours posttrauma. These findings indicate that iloprost attenuates motor disturbances induced by spinal cord trauma and that its therapeutic efficacy can be partly explained by its inhibition of leukocyte accumulation at the traumatized site.

Animals↗
PubMed1997

Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families.

Uridine monophosphate (UMP) synthase is a bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, orotate phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate decarboxylase (ODC). Loss of either enzymatic activity results in hereditary orotic aciduria, a rare autosomal recessive disorder characterized by retarded growth, anemia, and excessive urinary excretion of orotic acid. We have isolated the UMP synthase chromosomal gene from a lambdaEMBL-3 human genomic library and report a single-copy gene spanning approximately 15 kb. The UMP synthase genomic structure encodes six exons ranging in size from 115 bp to 672 bp, and all splicing junctions adhere to the canonical GT/AG rule. Cognate promoter elements implicated in glucocorticoid- and cAMP-mediated regulation as well as in liver-, myeloid-, and lymphocyte-specific expression are located within the 5' flanking sequence. Molecular investigation of UMP synthase deficiency in a Japanese orotic aciduria patient revealed mutations R96G (A-to-G transition; nt 286) and G429R (G-to-C transversion; nt 1285) in one allele and V109G (T-to-G transversion; nt 326) in the other allele. Expression of human UMP synthase cDNAs containing these mutations in pyrimidine auxotrophic Escherichia coli and in recombinant baculovirus-infected Sf21 cells demonstrates impaired activity presumably associated with the urinary orotic acid substrate accumulations observed in vivo. We further establish the identity of two polymorphisms, G213A (v = .26) and 440Gpoly (v = .27) located in exons 3 and 6, respectively, which did not significantly compromise either OPRT or ODC function.

Adult↗
PubMed1997

[Functional MRI using interleaved EPI].

One of main purposes of functional MRI is to identify functional map on human brain. We considered spatial resolution was a important factor and investigated influences of it on signal changes and activated region size. Functional images were acquired with Echo-Planar imaging (EPI) and interleaved EPI (IEPI). IEPI is superior in spatial resolution but inferior in signal to noise ratio (SNR) to EPI. As a result of Student's t-test analysis, activated region sizes of IEPI reduced to less than half those of EPI while IEPI had larger signal increase than EPI. We confirmed that the reduction was caused by low SNR and our estimation analysis could prevent it.

Brain↗
PubMed1997

Effects of plasma kallikrein specific inhibitor and active-site blocked factor VIIa on the pulmonary vascular injury induced by endotoxin in rats.

The acute respiratory distress syndrome (ARDS) is a serious complication of sepsis. To evaluate the role of the coagulation system in the pathogenesis of ARDS in sepsis, we examined the effects of the administration of a synthetic plasma kallikrein specific inhibitor (PKSI) and of active-site blocked factor VIIa (DEGR-VIIa) on the pulmonary vascular injury induced by E. coli endotoxin (ET) in rats. Administration of PKSI prevented the pulmonary vascular injury induced by ET as well as pulmonary histological changes in animals administered ET, but it did not affect the intravascular coagulation. The opposite effect was seen with DEGR-VIIa, which prevented the intravascular coagulation but not the pulmonary vascular injury. PKSI did not inhibit the activation of the complement system induced by ET leading to the activation of neutrophils. Findings suggest that PKSI may prevent the pulmonary vascular injury induced by ET by inhibiting kallikrein, which activates the neutrophils. The intrinsic pathway of coagulation may be more important than the extrinsic pathway in the pulmonary vascular injury produced by ET.

Amino Acid Chloromethyl Ketones↗
PubMed1997

Improvement of tumor oxygenation status by mild temperature hyperthermia alone or in combination with carbogen.

The effects of mild temperature hyperthermia (MTH) on the oxygenation and radioresponse in rodent tumors were investigated. FSall tumors grown in the legs of C3H mice and R3230 AC tumors grown in the legs of Fischer rats were heated with a water bath and the partial pressure of oxygen (pO2) was determined using the microelectrode method. In FSall tumors, the pO2 measured immediately after heating at 41.5 degrees C for 1 hour was markedly higher than that in the control tumors, whereas heating at higher temperatures for 1 hour decreased the tumor oxygenation. In R3230 AC tumors, heating at 41.5 degrees C for 1 hour caused a moderate increase in the pO2 and heating at 42.5 degrees or 43.5 degrees C for 30 minutes markedly increased the pO2. However, heating at 42.5 degrees C or higher temperatures for 1 hour decreased the pO2 in the R3230 AC tumors. The improvement of oxygenation in FSall tumors by heating at 41.5 degrees C for 1 hour increased the radiation-induced cell death in these tumors. The combination of carbogen breathing with MTH was far more potent than carbogen breathing or MTH alone in increasing tumor oxygenation and potentiating the radiation effect in FSall tumors.

Adenocarcinoma↗
PubMed1997

Assessment of intravascular ultrasound-bearing balloon catheter-guided percutaneous transluminal coronary angioplasty and stenting.

To investigate the usefulness of an intravascular ultrasound (IVUS)-bearing balloon catheter, we analyzed results in 17 patients with 19 lesions who underwent percutaneous transluminal coronary angioplasty (PTCA) with IVUS-bearing balloon catheters (group A) and 25 patients with 28 lesions who underwent PTCA without IVUS (group B). The patients had angina pectoris with or without old myocardial infarction. The success rate (less than 50% residual stenosis on coronary angiography) in group A was 17/17 patients (100%) and 19/19 lesions (100%), and that in group B was 21/25 patients (84%) and 24/28 lesions (86%) (NS). The percent stenosis, by coronary angiography, in groups A and B was 71.3% and 76.8% before PTCA (NS) and 4.8% and 22.3% in groups A and B after PTCA (P = 0.005). Complication rates in the two groups were not significantly different, but non-Q myocardial infarction was observed in one patient with a type C lesion (according to the American Heart Association/American College of Cardiology [AHA/ACC] classification) in group A. Postdilation of Wiktor stents was determined by IVUS in four patients. These results suggest that the IVUS-bearing balloon catheter is useful to achieve larger lumen size for optimal PTCA.

Adult↗
PubMed1996

Transient brain activity used in magnetic resonance imaging to detect functional areas.

Functional areas were detected with short stimuli eliciting transient brain activity using the method of 'transient' regions of interest (ROIs) and functional magnetic resonance imaging (fMRI). This method was validated by comparing the results with sustainedly activated areas identified conventionally. Eighty-eight and 89% of the total areas of transient ROIs derived from 0.2 and 2 s stimulation, respectively, were identified at 5-7 s and 5-9 s, respectively, after stimulus onset. Eighty-eight and 76%, respectively, of these areas overlapped 'conventional' ROIs derived from 20 s stimulation. These results suggest that the delineation of transient ROIs, by targeting a period approximately 7 s after transient neural activity, can be useful for fMRI studies of cognitive functions.

Adult↗
PubMed1996

Mild temperature hyperthermia combined with carbogen breathing increases tumor partial pressure of oxygen (pO2) and radiosensitivity.

The partial pressure of oxygen (pO2) of FSaII tumors grown in the leg of C3H mice significantly improved when the tumors were heated by immersing the tumor-bearing legs in a water bath at 41.5 degrees C for 60 min. The tumor pO2 also substantially increased when the tumor-bearing mice breathed carbogen (95% O2:5% CO2). Additionally, mild hyperthermia followed by carbogen breathing further increased the tumor pO2 and increased radiation cytotoxicity as assessed by the in vivo/in vitro excision assay for surviving FSaII cells. It was concluded that mild hyperthermia in combination with carbogen breathing is potentially useful to reoxygenate radioresistant hypoxic cells and improve the radiotherapy of human tumors.

Animals↗
PubMed1996

Multiple early gastric carcinomas. Clinicopathologic features and histogenesis.

BACKGROUND: Multiple early gastric carcinomas were found in 5-15% of patients with early gastric carcinoma. The goals of this study were to clarify the clinicopathologic features of multiple early gastric carcinomas and to investigate their histogenesis. METHODS: Of 724 patients with early gastric carcinoma, there were 65 with multiple (159) gastric carcinomas. Investigation of the histogenesis of multiple gastric carcinomas was conducted using serial sections of the stomach of 33 patients with multiple early gastric carcinomas (MEGC) and 33 patients with solitary early gastric carcinoma (SEGC). The cancerous and epithelial dysplastic lesions were examined by hematoxylin and eosin staining and immunohistochemical staining of p53 protein with anti-p53 monoclonal antibody (BP53-12). RESULTS: The macroscopically depressed type was common. The flat type was observed only in accessory lesions, most of which were diagnosed postoperatively. There were 126 differentiated type lesions, and 33 poorly differentiated type lesions. In most cases both the main and accessory lesions were differentiated. The average number of epithelial dysplastic lesions (18.3) in the stomach of patients with differentiated MEGC was significantly higher than that in the stomach of patients with differentiated SEGC (7), poorly differentiated MEGC (2.1), and SEGC (2). Moreover, severe dysplastic lesions were frequently observed in the stomach of patients with differentiated MEGC. p53 protein expression was detected in 0.9% of mildly atypical epithelial dysplastic lesions, 3.7% of moderately atypical dysplastic lesions, and 18.2% of severely dysplastic lesions. CONCLUSIONS: In cases of early gastric carcinoma, small depressed type and flat type accessory lesions of multiple gastric carcinomas should be detected preoperatively. Epithelial dysplastic lesions probably are significant in the histogenesis of differentiated multiple gastric carcinomas.

Adenocarcinoma↗
PubMed1996

Pulmonary vascular injury induced by hemorrhagic shock is mediated by P-selectin in rats.

To investigate whether the P-selectin-mediated leukocyte adhesion to the endothelial cells is involved in pulmonary vascular injury after hemorrhagic shock, we examined the effect of an anti-P-selectin monoclonal antibody (MAb PB1.3) on the pulmonary accumulation of leukocytes and the subsequent pulmonary vascular injury observed after hemorrhagic shock in rats. Two hours after hemorrhagic shock, pulmonary accumulation of leukocytes, as evaluated by measuring myeloperoxidase activity, began to increase and peaked after 6 hours. Pulmonary vascular injury, as evaluated by the extravascular leakage of 125I-albumin, was significantly increased 6 hours after hemorrhagic shock. MAb PB1.3 significantly prevented both the pulmonary accumulation of leukocytes and subsequent pulmonary vascular injury. MAb PNB1.6, an anti-P-selectin monoclonal antibody incapable of inhibiting P-selectin-mediated leukocyte adhesion, did not prevent either of these effects. These observations strongly suggest that the pulmonary sequestration of leukocytes and the subsequent pulmonary vascular injury after hemorrhagic shock are mediated by P-selectin.

Animals↗
PubMed1996

Development of an integrated radiotherapy network system.

PURPOSE: To introduce the process of developing an integrated radiotherapy network. METHODS AND MATERIALS: We developed a new radiotherapy treatment-planning system in 1987 that we named the Computer Tomography (CT) simulator. CT images were immediately transported to multiimage monitors and to a planning computer, and treatment planning could be performed with the patient lying on the CT couch. The results of planning were used to guide a laser projector, and radiation fields were projected onto the skin of the patient. Since 1991, an integrated radiotherapy network system has been developed, which consists of a picture archiving and communicating system (PACS), a radiotherapy information database, a CT simulator, and a linear accelerator with a multileaf collimator. RESULTS: Clinical experience has been accumulated in more than 1,000 patients. Based on our 7 years of experience, we have modified several components of our original CT simulator and have developed a second generation CT simulator. A standard protocol has been developed for communication between the CT scanner, treatment planning computer, and radiotherapy apparatus using the Ethernet network. As a result, treatment planning data can be transported to the linear accelerator within 1 min after completion of treatment planning. CONCLUSION: This system enables us to make optimal use of CT information and to devise accurate three-dimensional (3D) treatment-planning programs. Our network also allows for the performance of fully computer-controlled dynamic arc conformal therapy.

Computer Communication Networks↗
PubMed1996

Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats.

We investigated the effect of activated protein C (APC) on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats to investigate the possible usefulness of APC as a treatment for adult respiratory distress syndrome. Intravenously administered LPS (5 mg/kg) significantly increased pulmonary vascular permeability. APC prevented the LPS-induced increase in pulmonary vascular permeability observed at 6 hours. Heparin plus antithrombin III (ATIII) and active site-blocked factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, inhibited LPS-induced coagulopathy but did not prevent LPS-induced pulmonary vascular injury. LPS-induced pulmonary vascular injury was significantly attenuated in rats with nitrogen mustard-induced leukocytopenia and in rats treated with ONO-5046, a potent granulocyte elastase inhibitor. Administration of LPS also increased pulmonary accumulation of leukocytes, as evaluated by measurement of myeloperoxidase activity in the lungs. APC significantly reduced LPS-induced increases in pulmonary accumulation of leukocytes at 1 hour. Neither ATIII plus heparin nor DEGR-Xa inhibited leukocyte accumulation. Active site-blocked APC (DIP-APC) prevented neither the LPS-induced pulmonary accumulation of leukocytes nor the LPS-induced increase in pulmonary vascular permeability. These results suggest that the mechanism of APC inhibition of LPS-induced pulmonary vascular injury was independent of its anticoagulant activity and was related to its ability to inhibit accumulation of leukocytes. In addition, these findings suggest that the serine protease activity of APC may be essential to its inhibitory effect on LPS-induced pulmonary accumulation of leukocytes and subsequent pulmonary vascular injury.

Amino Acid Chloromethyl Ketones↗
PubMed1996

Determination of plasma soluble fibrin using a new ELISA method in patients with disseminated intravascular coagulation.

We measured plasma levels of soluble fibrin (SF) in 98 patients suspected of having disseminated intravascular coagulation (DIC) using a newly developed enzyme-linked immunosorbent assay (ELISA) and investigated the correlations between SF determinations and measurements of other hemostatic molecular markers to determine the diagnostic usefulness of determinations of SF. Patients were classified into four groups according to their clinical and laboratory findings: overt DIC (n =33), subclinical DIC (n =23) hypercoagulability (n =22), and non-DIC (n =20). SF levels were significantly higher in patients with overt DIC compared with the other three groups and were significantly higher in the subclinical DIC and hypercoagulability groups compared with the non-DIC patients. SF levels increased significantly with each increase in the clinical stage. Although levels of thrombin-antithrombin III complex (TAT), prothrombin fragment 1 + 2 (PF 1+2), cross-linked fibrin degradation products (XDP), and plasmin-antiplasmin complex (PAP) were significantly increased in patients with overt DIC compared with non-DIC patients, the values of these hemostatic molecular markers did not consistently show an increase in association with advances in the disease stage. Plasma levels of SF in patients with overt DIC showed a positive correlation with levels of TAT, XDP,and FDP(E), but not with PF1+2 and PAP. Analysis of receiver-operating characteristic curves showed that the sensitivity and specificity of SF were similar to those of XDP for diagnosis of DIC. The sensitivity and specificity of SF for diagnosis of overt DIC were both above 90% when the cut-off value was set at 65 mu g/ml.plasma levels of SF were also increased in patients with extravascular fibrin formation without DIC. Our findings suggest that measurement of plasma levels of SF by this ELISA method is useful for the diagnosis of DIC and the evaluation of the patient's clinical status.

Amino Acid Sequence↗