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Biomedical subjects

A Harada

Publications and source records attributed to A Harada.

At least 127 records · Page 7Linked to original sources
PubMed1997

Tumor necrosis factor receptor p55 is essential for intrahepatic granuloma formation and hepatocellular apoptosis in a murine model of bacterium-induced fulminant hepatitis.

Accumulating evidence implicates tumor necrosis factor (TNF) and Fas systems in liver injury, although the interaction between these two systems remains to be investigated. In this study, we examined Propionibacterium acnes-primed TNF receptor p55-deficient (TNFRp55-/-) or Fas-deficient MRL/MpJ Lpr/Lpr mice challenged with lipopolysaccharide (LPS). Priming with P. acnes caused mononuclear cell infiltration into the hepatic lobules and granuloma formation in the livers of TNFRp55 wild-type mice. Subsequent LPS challenge caused massive liver injury and a marked increase in transaminase levels, leading to acute lethality in control wild-type mice. In contrast, the same treatment caused few pathological changes in livers of TNFRp55-/- mice, and all animals survived. P. acnes and subsequent LPS challenge induced granuloma formation and apoptotic changes, respectively, in livers of MRL/MpJ Lpr/Lpr mice. However, liver injury was 50% of that in control MRL/MpJ +/+ mice, suggesting some role of the Fas-Fas ligand system in this liver injury model. On the other hand, an agonistic anti-Fas antibody caused massive apoptosis and hemorrhagic changes of the liver without any priming with P. acnes, leading to death in both TNFRp55-/- and control wild-type mice. These results suggest that TNFRp55 but not Fas was involved in P. acnes-induced granuloma formation as well as subsequent LPS-induced liver injury and that TNFRp55 and Fas independently induced apoptosis of hepatocytes in vivo.

Animals↗
PubMed1997

Effectiveness of fructose-modified chitosan as a scaffold for hepatocyte attachment.

Free amino groups of chitosan, a substance which has previously been shown to be a good scaffold for hepatocyte attachment, were covalently modified with fructose. The modification significantly increased the number of cells that could be attached on the surface of chitosan gel. Rat hepatocytes cultivated on fructose-chitosan behaved similarly to those on unmodified chitosan, i.e., they retained the spherical shape they have in vivo, and released much less lactate dehydrogenase than cells attached on a collagen-coated surface. The modification with fructose did not alter the important characteristics of chitosan for hepatocyte culture: liver-specific functions such as urea synthesis and drug metabolism were stably maintained for 5 d in the hepatocytes cultured on fructose-chitosan. In sharp contrast, hepatocytes attached on a collagen-coated surface underwent a severe morphological change, from spherical to flat, and lost almost all their lidocaine-removal activity within 5d. A very thin fructose-chitosan layer was also applied onto the collagen-coated surfaces of polystyrene plates and a dextran microcarrier by crosslinking free amino groups in the chitosan and collagen with glutaraldehyde to fix the thin layer. Hepatocytes on the fructose-chitosan-coated surface retained their spherical shape, masking the cell-flattening effect of the collagen layer. Perfusion culture was then carried out using a hollow-fiber cartridge in which hepatocytes attached on fructose-chitosan-coated microcarriers were suspended in the extracapillary space: the liver-specific functions were stably maintained during 4d of the culture. A fructose-chitosan-coated surface thus appears to be a very promising scaffold for hepatocyte attachment which can be used in cellular biological studies of liver functions, especially in relation to cytochrome P450, as well as in bioartificial liver support systems.

Animals↗
PubMed1997

Prevention of endotoxemia-induced acute respiratory distress syndrome-like lung injury in rabbits by a monoclonal antibody to IL-8.

We have herein established an endotoxemia-induced acute respiratory distress syndrome (ARDS)-like lung injury administered a sublethal dose of lipopolysaccharide (LPS) intravenously 36 hours after the intratracheal instillation of heat-killed Streptococcus pyogenes (OK-432). At 36 hours after OK-432 priming, a mild infiltration into the lungs, consisting of a small number of neutrophils and macrophages, was observed without destruction of pulmonary architecture. A subsequent challenge with a sublethal dose of LPS induced pathologic changes characteristic of ARDS--such as extensive edema in alveolar lumina, marked infiltration composed of a large number of neutrophils and a few macrophages, fibrin deposit in alveolar space, and destruction of pulmonary architecture--resulting in severe hypoxemia. Concomitantly, LPS challenge after priming with OK-432 induced a marked elevation of IL-8 levels in serum and bronchoalveolar lavage fluid with local IL-8 production in lungs, as revealed by immunohistochemical analysis. An anti-IL-8 antibody treatment almost completely prevented pulmonary edema, destruction of pulmonary architecture, and impairment in gas exchange as well as neutrophil infiltration in lungs; there was also a significant reduction in the rate of acute lethality. These results provide evidence that IL-8 has a pivotal role in the induction of ARDS associated with endotoxemia, probably by recruiting and activating neutrophils locally.

Animals↗
PubMed1997

Regional adjuvant chemotherapy after partial hepatectomy for metastatic colorectal carcinoma.

The prognostic factors after hepatic resection for metastases from colorectal carcinoma were examined, and the results of adjuvant hepatic arterial chemotherapy are presented. Hepatic resection was undertaken in 57 patients with metastatic liver tumor from colorectal cancer. Adjuvant hepatic arterial chemotherapy using 5-fluorouracil, doxorubicin or epirubicin, and mitomycin C was administered to 31 patients. The 3- and 5-year survival rates for the 57 patients were 53% and 23%, respectively. The significant prognostic factors were solitary liver tumor and metachronous liver tumor. However, type of hepatectomy, surgical margin, site of the primary tumor, and histologic differentiation of the carcinoma did not relate to the prognosis. The 3- and 5-year survival rates for the patients given adjuvant arterial chemotherapy were 57% and 57%, respectively, indicating a significantly better survival rate than in the nontreated patients. These results suggest that hepatic arterial chemotherapy is effective treatment in patients with hepatic resection for metastases from colorectal carcinoma. However, recurrence in the lung is relatively high. Further improvement might be achieved by administering hepatic arterial chemotherapy as well as effective systemic chemotherapy.

Adult↗
PubMed1997

Clinical application of a new monoclonal antibody (19B7) against PIVKA-II in the diagnosis of hepatocellular carcinoma and pancreatobiliary malignancies.

OBJECTIVES: A new monoclonal antibody (19B7) against prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) was clinically applied in patients diagnosed with hepatocellular carcinoma and pancreatobiliary malignancies, and the results were compared with those obtained using the conventional monoclonal antibody (MU-3) against PIVKA-II. METHODS: The assays were the standard E-1023 using MU-3, a high sensitivity kit using MU-3 and a highly sensitive avidin-biotin complex method, and a new monoclonal antibody (19B7) kit. RESULTS: The rate of PIVKA-II positivity in patients with hepatocellular carcinoma (n = 182) was 44% with E-1023, 55.5% with the high sensitivity kit, and 58.2% with the new monoclonal antibody kit. Small liver cancers <2 cm in diameter (n = 45) had a positivity rate of 15.6% with E-1023, 26.7% with the high sensitivity kit, and 31.1% with the new monoclonal antibody kit. The incidence of PIVKA-II positivity in patients with pancreatobiliary carcinoma (n = 91) was 29.7% with the high sensitivity kit and 52.7% with the new monoclonal antibody kit. The PIVKA-II ratio (plasma concentration with the high sensitivity kit/plasma concentration with the new monoclonal antibody kit) was calculated as > 1.0 in 89 of the 113 (78.8%) patients with hepatocellular carcinoma with the new monoclonal antibody kit assay level above 0.002 arbitrary units/ml, compared with <1.0 in almost all patients with pancreatobiliary malignancies. CONCLUSIONS: MU-3 has much greater affinity for PIVKA-II in hepatocellular carcinoma than does 19B7, whereas 19B7 has much greater affinity for PIVKA-II in pancreatobiliary malignancies than does MU-3. The new monoclonal antibody, 19B7, is useful for diagnosing hepatocellular carcinoma and can also distinguish patients with hepatocellular carcinoma from those with other pancreatobiliary malignancies when combined with a PIVKA-II assay using the conventional monoclonal antibody, MU-3.

Adult↗
PubMed1997

Prevention of cerebral edema and infarct in cerebral reperfusion injury by an antibody to interleukin-8.

Reperfusion after a transient ischemia is a frequently encountered clinical condition that often causes greater tissue damage than persistent ischemia itself. Reperfusion to rabbit brain, after a transient focal ischemia, induced neutrophil infiltration and aggregation--neither of which were observed in rabbit brain rendered ischemic alone for the same time interval--thereby leading to severe brain edema and infarct. Brain tissue levels of interleukin-8 (IL-8), a potent neutrophil chemotactic cytokine (chemokine), increased significantly at 6 hours after reperfusion, but without a noticeable elevation of plasma IL-8 levels. Moreover, we detected IL-8 protein immunohistologically in the vascular wall and, to a lesser degree, in infiltrated neutrophils, suggesting a local production of IL-8 in reperfused brain tissues. Furthermore, a neutralizing anti-IL-8 antibody significantly reduced brain edema and infarct size in comparison to rabbits receiving a control antibody. These results implicate locally produced IL-8 as a pivotal mediator of cerebral reperfusion and suggest that IL-8 is a novel target for the intervention of this injury.

Animals↗
PubMed1996

The valine catabolic pathway in human liver: effect of cirrhosis on enzyme activities.

The activities of key enzymes in the valine catabolic pathway--branched-chain aminotransferase, branched-chain alpha-keto acid dehydrogenase complex, methacrylyl (MC)-coenzyme A (CoA) hydratase (crotonase), and 3-hydroxyisobutyryl-CoA (HIB-CoA) hydrolase--were measured in normal and cirrhotic human livers. Unlike rat liver, which does not contain branched-chain aminotransferase, the aminotransferase activity in the normal liver was measurable and is increased somewhat in cirrhosis of the human liver. The total activity of branched-chain alpha-keto acid dehydrogenase complex in the normal human liver was approximately 1% of that in rat liver, and 20% to 30% of the complex was in the active form in both normal and cirrhotic livers. Only the actual activity of the enzyme was significantly decreased by cirrhosis. These results suggest that human liver is less active than rat liver in the catabolism of branched-chain amino and alpha-keto acids. Activities of MC-CoA hydratase and HIB-CoA hydrolase in human liver were very high compared with that of branched-chain alpha-keto acid dehydrogenase complex, suggesting an important role for these enzymes in catabolism of a potentially toxic compound, MC-CoA, formed as an intermediate in the catabolism of valine and isobutyrate. Cirrhosis resulted in a significant decrease in HIB-CoA hydrolase activity but had no effect on the citrate synthase activity, suggesting that the decrease in HIB-CoA hydrolase activity does not reflect a general decrease in mitochondria but that it may contribute to cellular damage that culminates in liver failure.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1996

Detection of mouse IL-8 receptor homologue expression on peripheral blood leukocytes and mature myeloid lineage cells in bone marrow.

Interleukin-8 (IL-8) exhibits activities on bone marrow progenitor cells such as regulation of their growth and their mobilization into peripheral blood. In order to clarify the molecular mechanism of the effects of IL-8 on mouse bone marrow cells, we examined the cellular distribution of mouse IL-8 receptor homologue by an immunofluorescence analysis. Peripheral blood Gr-1+ mature granulocytes, and a substantial portion of NK1.1+ natural killer cells in peripheral blood and spleen were stained positively with anti-mouse IL-8 receptor homologue antibody, whereas CD4+, CD8+, or B220+ lymphocytes in peripheral blood and spleen, and thymocytes were not. Moreover, a small portion of ER-MP20+ monocytes in peripheral blood but neither peritoneal resident nor bone marrow macrophages were stained with anti-IL-8 receptor homologue antibody. In bone marrow, mature granulocytes and to a lesser degree, metamyelocytes and myelocytes expressed IL-8 receptor homologue. Moreover, lineage marker (Lin)-c-kit+ bone marrow progenitor cells started to express IL-8 receptor homologue only 5 days after in vitro culture with IL-3 and stem cell factor when metamyelocytes and myelocytes appeared. These results indicated that myeloid lineage cells express a substantial number of IL-8 receptor homologues only at the stage of myelocytes.

Animals↗
PubMed1996

Doxorubicin-induced disturbance of the energy metabolism after hepatectomy.

This study was designed to clarify effects of gamma-glutamylcysteine ethyl ester, a prodrug of glutathione, on doxorubicin-induced changes in liver energy metabolism after hepatectomy. Rats were divided into two major groups dependent on whether hepatectomy had been performed. Rats undergoing hepatectomy were subdivided into three groups: the control group, 70% of the liver was resected; the doxorubicin group, after hepatectomy 2 mg/kg body weight doxorubicin was administered intraperitoneally; and the doxorubicin + gamma-glutamylcysteine group, 30 min before hepatectomy 50 mg/kg body weight of gamma-glutamylcysteine ethyl ester was injected intravenously and other procedures were performed as in the doxorubicin group. In the group not undergoing hepatectomy, 2 mg/kg body weight doxorubicin was administered intraperitoneally after a sham operation. Rats in each group were sacrificed 24, 72, and 120 hr after hepatectomy or sham operation, and the remnant liver was isolated. Liver mitochondrial function, adenine nucleotide concentrations, and glutathione and glutathione peroxidase activities were determined. Doxorubicin did not show any significant effects on parameters measured in rats not undergoing hepatectomy. Liver mitochondrial function was increased significantly 24 hr after hepatectomy, and significant decreases in adenine nucleotide concentrations were observed 24 and 72 hr after hepatectomy. Doxorubicin inhibited the increase in mitochondrial function associated with hepatectomy and delayed recovery of liver adenine nucleotide concentrations. Significant increases in tissue glutathione concentrations were observed 24 and 72 hr after hepatectomy. These significant increases in glutathione concentrations were not observed in rats treated with doxorubicin 72 hr after hepatectomy. Furthermore, doxorubicin decreased glutathione peroxidase activity after hepatectomy. Administration of gamma-glutamylcysteine ethyl ester lessened these doxorubicin-induced changes. These results indicate that changes in the glutathione redox system might be involved in the doxorubicin-induced deterioration of the remnant liver energy metabolism. Clinical application of gamma-glutamylcysteine ethyl ester might be expected.

Adenosine Triphosphate↗
PubMed1996

Mitochondrial glutathione redox and energy producing function during liver ischemia and reperfusion.

The glutathione in mitochondria is thought to play a crucial role in protecting mitochondria against ischemia-reperfusion-induced injury. However, little is known about the mitochondrial redox system. This study was conducted to clarify changes of mitochondrial glutathione redox during liver ischemia and reperfusion and its role on energy producing function. Rats were divided into three groups each of which were treated respectively with saline (Control), buthionine sulfoximine (BSO), which induces a rapid decrease in tissue glutathione concentrations, and gamma-glutamylcysteine ethyl ester (GCE), which conversely induces a rapid increase in tissue glutathione concentrations before induction of ischemia. Liver ischemia was induced for 120 min, and blood reflow was subsequently restored for 60 min. Total and mitochondrial glutathione concentrations, mitochondrial respiratory function, and tissue adenine nucleotide were determined after both the ischemic and the reperfusion periods. In all groups, concentrations of the reduced form of glutathione (GSH) gradually decreased during ischemia and reperfusion. On the other hand, significant increases in mitochondrial GSH were apparent after reperfusion despite significant decreases during ischemia in the control and GCE groups. Total and mitochondrial GSH in the BSO and GCE groups were significantly lower and higher, respectively, compared with the control throughout the experiment. Recovery of the mitochondrial energy producing function and cellular adenine nucleotide after reperfusion were dependent on GSH concentrations. We conclude that mitochondrial GSH concentrations dramatically change in a different manner from cytosolic concentrations after reperfusion, and that recovery of the mitochondrial energy-producing function might be closely associated with mitochondrial GSH concentrations.

Adenosine Triphosphate↗
PubMed1996

Use of Blocking Antibodies as Probes for in Vivo Functions of Chemokines

Leukocyte infiltration into an inflammatory site is one of the pathological hallmarks of inflammatory reaction. Locally produced chemotactic factors are presumed to mediate the sequence of events leading to tissue injury associated with the infiltration of leukocytes. Chemotactic cytokines (chemokines) have been identified as being produced by various types of cells upon stimulation with inflammatory stimuli and exhibit a variety of effects on leukocytes in vitro and in vivo. Administration of highly specific neutralizing antibodies against these chemokines in several types of animal inflammation models clearly suggests important roles of these chemokines in recruiting and activating specific types of leukocytes at the inflammatory sites. Anti-IL-8 Ab treatment prevented neutrophil-dependent tissue damage as well as neutrophil infiltration in lipopolysaccharide (LPS)-induced dermatitis, LPS/IL-1-induced arthritis, lung reperfusion injury, and acute immune complex type glomerulonephritis in rabbits. Moreover, anti-MCP-1 Ab and anti-RANTES Ab inhibited macrophage infiltration in IgA immune complex alveolitis in rats and influx of lung macrophages in a murine model of endotoxemia, respectively. The use of anti-MIP-1alpha Ab also revealed that MIP-1alpha mediates eosinophil infiltration in allergic, granulomatous reactions in vivo.

Journal Article↗
PubMed1996

Transient hepatofugal portal blood flow after hepatectomy in a patient with cirrhosis: report of a case.

We report herein the case of a 60-year-old man who developed hepatic failure with simultaneous transient hepatofugal portal blood flow after undergoing hepatectomy for hepatocellular carcinoma accompanied by cirrhosis with a splenorenal shunt. The transient hepatofugal portal blood flow was detected by color Doppler ultrasonography. Following this case report, the possibility of a relationship between hepatofugal portal blood flow, portal-systemic shunts, and postoperative hepatic failure is discussed.

Carcinoma, Hepatocellular↗
PubMed1996

Extrapancreatic nerve plexus invasion by carcinoma of the head of the pancreas. Diagnosis with intraportal endovascular ultrasonography.

CONCLUSION: The intraportal endovascular ultrasonography (IPEUS) could diagnose the second portion of the extrapancreatic nerve plexus invasion and provide precise information in operative strategy. But, the first portion was not visualized clearly owing to poor tissue penetration of the ultrasound beam, which may have reduced diagnostic accuracy. Improvement of the scanning area is expected to make intraportal endovascular US even more useful. BACKGROUND: Pancreatic cancer easily invades the retroperitoneal tissue, especially the extrapancreatic nerve plexus. We evaluated the extrapancreatic nerve plexus invasion of the pancreatic cancer with IPEUS. IPEUS was performed intraoperatively in 20 consecutive resected cases with carcinoma of the head of the pancreas. METHODS: IPEUS was performed with an 8-French, 20 MHz intravascular ultrasound catheter. IPEUS visualized the inferior pancreaticoduodenal artery (IPDA) in the extrapancreatic nerve plexus. The high-echoic area around the IPDA corresponds to the second portion of the extrapancreatic nerve plexus. The sonographic criterion for detection of the extrapancreatic nerve plexus invasion is low-echoic infiltration around the IPDA. RESULTS: Extrapancreatic nerve plexus invasion was confirmed with resected specimens in 10 patients. The IPDA could not be visualized in two patients. In 18 patients, the diagnostic accuracy of invasion was evaluated. For diagnosis of extrapancreatic nerve plexus invasion with intraportal endovascular US, the sensitivity, specificity, and overall accuracy were 87.5, 90, and 88.7%, respectively.

Adult↗
PubMed1996

Atrial activation during chronic atrial fibrillation in patients with isolated mitral valve disease.

BACKGROUND: A computerized 32-channel mapping system has been developed to investigate the characteristics of the atrial activation sequence. The system is capable of displaying sequential atrial maps and provides a rapid and dynamic means of verifying the activation sequence of atrial fibrillation. METHODS: Using this system, we performed intraoperative atrial activation mapping in 10 patients with chronic atrial fibrillation who were undergoing isolated mitral valve operations. RESULTS: Regular and repetitive activation (cycle length ranged from 131 to 228 milliseconds) originated in the left atrium in all 10 patients. Two patterns of repetitive activation in 2 patients and three patterns in 1 patient appeared alternately during the observation period in the left atrium. In contrast to the repetitive activation in the left atrium, the activation sequence of the right atrium was extremely complex and chaotic. In 7 of the 10 patients, the same pattern of right atrial activation was never repeated during the observation period. In 2 patients, revolution of repetitive activation in the right atrium sporadically appeared, but the pattern of activation immediately deteriorated to a complex and chaotic pattern. In 1 patient, repetitive activation emerged from the low lateral portion of the right atrium. Because our mapping technique was limited by the number of available atrial electrodes, discrete reentrant circuits or ectopic foci could not be demonstrated in the present study. However, the activation sequences during chronic atrial fibrillation suggested that (1) the left atrium would act as an electrical driving chamber for atrial fibrillation in the majority of the patients and (2) atrial activation patterns are different in each case. CONCLUSIONS: Computerized intraoperative mapping should guide surgeons in determining the appropriate surgical procedure and facilitate operation for chronic atrial fibrillation associated with mitral valve disease.

Adult↗
PubMed1996

Interleukin 8 as a novel target for intervention therapy in acute inflammatory diseases.

Aberrant production of interleukin 8 (IL-8) has been shown in various human inflammatory diseases. Recent investigations in animal models using either blocking antibodies against IL-8 or disruption of the gene encoding the IL-8 receptor have revealed the involvement of IL-8 in the recruitment of neutrophils and in neutrophil-associated tissue injury in acute inflammation. These studies suggest that IL-8 is a novel target to alleviate acute inflammation. This review describes the properties of IL-8 and discusses different therapeutic approaches to target IL-8, particularly the use of humanized monoclonal antibodies against IL-8 and inhibition of IL-8 gene transcription.

Animals↗
PubMed1996

Localization of monocyte chemotactic and activating factor (MCAF/MCP-1) in psoriasis.

The monocyte chemotactic protein-1 (MCAF) also termed MCP-1, a strong chemotactic factor towards monocytes, is produced by several cell types present in the skin. The in situ presence of MCAF/MCP-1 protein in the skin has, however, not yet been established. Using immunohistochemical techniques we have investigated the distribution of MCAF in skin from patients with different types of psoriasis and normal healthy volunteers. We report the novel finding that psoriasis has strong positive immunostaining for MCAF located to all the layers of the epidermis, except the stratum granulosum, in pustular, guttate and chronic plaque psoriasis. In the dermis, infiltrating cells in the perivascular aggregates and the blood vessels stained positive for MCAF. No significant differences were observed between the different subtypes of psoriasis except that strongly positive infiltrating cells were observed in the epidermal pustules in pustular psoriasis. In normals positive staining was observed in all the layers of the epidermis and in a few perivascular cells and blood vessels in the dermis. Where present in normal and diseased skin, eccrine ducts of sweat glands and sebaceous glands stained positive for MCAF. Arrector pili muscles were in all cases negative. These findings are consistent with a role for MCAF in attracting inflammatory cells, including monocytes, into the skin in psoriasis.

Chemokine CCL2↗