[Pancreatic mitochondrial fragility and impaired pancreatic energy metabolism induced by cyclosporin A in rats; preliminary report].
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Animals↗
Biomedical subjects
T Manabe
Publications and source records attributed to T Manabe.
[Structure, function and pathophysiology of mucociliary transport system].
There has been growing appreciation of the significant role played by the mucociliary transport system in the body. The mucociliary transport system is an important defense mechanism by which the human body usually maintains its "homeostasis" by protecting the body against invading particles, including bacteria. This system includes two major functional mechanisms; i.e., ciliary transport and mucous secretional systems, each of which is usually complimentary and cooperative. Three hereditary disorders, primary ciliary dyskinesia (immotile-cilia syndrome), cystic fibrosis and Young's syndrome, have been shown to be systemically associated with mucociliary transport failure, leading to male infertility and chronic sinopulmonary infections. Localized mucociliary transport failure, however, is observed in respiratory diseases, especially chronic sinusitis, chronic bronchitis, bronchiectasis and bronchial asthma. We aim, in this review, to draw together those developments in the study of ciliary transport and mucous secretion, the interactions between them and their pathophysiology that can provide a better understanding of the mucociliary transport system of the human body.
Cilia↗
[Post-gastrectomized vitamin B12 deficient anemia with marked leukoerythroblastosis and ringed sideroblasts].
A 77 year-old man, who had received total gastrectomy and splenectomy 11 years ago for gastric cancer was transferred to our hospital because of severe macrocytic anemia. He had been treated with vitamin B1, B2, C and iron preparations for several weeks. Ten days before admission numbness developed in his legs. On physical examination he appeared severely anemic. Laboratory findings revealed severe macrocytic anemia with poikilocytosis, anisocytosis, polychromasia, red cell fragmentation, Howell-Jolly bodies, Cabot rings and marked erythroblastosis (421/100 WBC). Hypersegmented neutrophils and immature granulocytes were also seen in the blood. The bone marrow picture showed marked erythroid hyperplasia, but erythroblasts revealed only slight megaloblastic changes. On bone marrow iron staining all erythroblasts were classified as type III sideroblasts and 15% of them were ringed-form. Serum vitamin B12 was low (44 pg/ml). Methylcobalamin given intramuscularly led to the rapid improvement of all hematological abnormalities including leukoerythroblastosis. Two weeks after vitamin B12 administration, ringed sideroblasts could no longer be detected in the bone marrow. Post-gastrectomy vitamin B12 deficiency anemias combined with erythroblastosis and ringed sideroblasts is a rare condition. Splenectomy is thought to play an important role in the pathogenesis of these conditions.
Aged↗
Automated two-dimensional liquid chromatographic system for mapping proteins in highly complex mixtures.
An automated two-dimensional liquid chromatographic system was developed for systematic protein separations which could serve for analytical mapping and preparative separations of proteins. The system applies the principles of the column-switching technique, and consists of two different columns connected in tandem through an electrical column switching valve, two pumping systems to operate each column independently and a system controller to perform sequential chromatography on the two columns. A protein mixture is applied to the first-dimensional anion-exchange column and is separated by stepwise elution with an increasing sodium chloride concentration. The eluent is introduced directly to the second-dimensional reversed-phase column, and is further separated by gradient elution with an increasing acetonitrile concentration. The two elution stages are synchronized by a computer program. By this system, very complex protein mixtures such as crude cerebellar extracts were resolved reproducibly into ca. 200 peaks within 12 h. The method can be used for the total analysis of proteins in various tissues and cells without complicated premanupulation of samples, and allows the simultaneous analysis of a protein isolated by chromatography. The isolated protein is most suitable for use in the strategy of protein and gene sequence analysis.
Animals↗
Pancreatic lysosomal enzyme secretion via gut-hormone-regulated pathway in rats.
To explore the secretory profiles of lysosomal enzyme in pancreatic juice, we stimulated the secretion of lysosomal enzyme by intravenous pancreatic secretagogues and intraduodenal instillation of liquid meals in rats. Lysosomal hydrolases, such as cathepsin B, are secreted from the apices of pancreatic acinar cells via a hormone-regulated pathway, as in the secretion of pancreatic digestive enzymes. The intravenous infusion of the cholecystokinin analogue caerulein, or the intraduodenal administration of nutrients results in a closely related secretion of both amylase and cathepsin B from the apices of acinar cells, suggesting that they are discharged from the same presecretory compartment (zymogen granules). Lysosomal enzymes appear to enter into the secretory compartment as a result of malsorting, but the cause of this anomaly is not known. We found small amounts of lysosomal enzymes colocalized with digestive enzymes within zymogen granules in normal acinar cells and in normal pancreatic juice, suggesting some physiological roles of lysosomal enzymes in pancreatic ducts. Furthermore, lysosomal enzymes appear to play important roles in the pathogenesis of pancreatic disease, such as pancreatitis, from both inside and outside the pancreas, since cathepsin B can probably activate trypsinogen.
Amylases↗
Role of free radical scavengers in pancreatic carcinomas of hamsters.
The involvement of free radicals in the carcinogenic mechanism has been suggested, however, little is known about the role of free radicals in the pancreatic cancer. In this study, the effects of active oxygen on the carcinogenesis of the tumor were examined by measuring the levels of scavengers in pancreatic cancer of Syrian golden hamsters. Pancreatic cancer was induced by di-iso-propanol nitrosamine (500 mg/kg body weight/week x 24 weeks). Activities of superoxide dismutase (SOD), catalase, glutathion peroxide (GSH-Px) and malon dialdehyde (MDA) in the tumor and border zone were compared with those in the non-tumor region and control normal tissue. Activities of SOD and catalase in the tumor and border zone were significantly lowered than those in non-tumor region and normal tissue. GSH-Px levels were significantly higher in the tumor than those in the non-tumor region and normal tissue. MDA levels also tended to be high in the tumor. These results suggest that the development of cancer in pancreatic tissue is related to a reduction of SOD and catalase. GSH-Px and MDA are suggested to be involved in the reactions of free radicals.
Animals↗
A new synthetic protease inhibitor, E-3123, reduces organelle fragility of acinar cells in rat caerulein pancreatitis.
The present study investigated the protective effect of a new potent synthetic protease inhibitor, E-3123 (4-guanidinobenzoate methanesulfonate) on the exocrine pancreas in the caerulein induced experimental pancreatitis both in-vivo and in-vitro at 3 different doses (1, 2, and 5 mg/kg.hr). This protease inhibitor prevented hyperamylasemia, pancreatic edema, congestion of amylase, and both amylase and lactic dehydrogenase (LDH) discharge from dispersed acini, as well as cathepsin B leakage from lysosomes and malate dehydrogenase (MDH) leakage from mitochondria in a dose-dependent manner, particularly in doses of 2 and 5 mg/kg.hr. Furthermore, the combined prophylactic and therapeutic use of this agent seems to be very effective in preventing caerulein induced pancreatitis. These results indicate that E-3123 plays its protective roles against pancreatitis in the subcellular compartment: lysosomes, mitochondria, cellular or organella membranes. It is hoped that such a low molecular weight protease inhibitor as E-3123 will be clinically useful in the treatment of acute pancreatitis.
Acute Disease↗
[Effect of synthetic protease inhibitor on the oncogenesis of pancreatic cancer in hamsters: study on pancreatic endocrine cells and free radicals].
In order to study the effect of synthetic trypsin inhibitor on the oncogenesis of pancreatic cancer, the histology, the kinetics of the B, A and D cells in the islets of Langerhans and activities of free radical scavengers, superoxide dismutase (SOD), glutathion peroxide (GSH-Px) and malon dialdehyde (MDA) in the tumor bearing tissues were measured in hamsters with pancreatic cancer induced by di-iso-propanol nitrosamine (DIPN) with or without camostat (FOY-305). In DIPN group (DIPN alone), the tubular adenocarcinoma was found in 80%, however, in FOY group (DIPN+FOY-305), papillary adenocarcinoma was found in 91%. In both DIPN and FOY groups, the number of B cells was decreased at 8 weeks and the number of A and D cells was decreased at 16 weeks. Activities of SOD in the tumor and borderzone in DIPN group were significantly lower than those in non-tumor region and normal tissue. However, activities of SOD in the tumor and borderzone in FOY group were higher than those in DIPN group. GSH-Px and MDH levels were significantly higher in FOY group suggesting the involvement in the reaction of free radicals. These results suggest that trypsin inhibitors have a prophylactic effect on the development of pancreatic cancer.
Animals↗
[Effect of oxygen free radicals on the rat pancreas in vivo].
Many reports concerning the involvement of active oxygen free radicals in the pathogenesis and progression of acute pancreatitis have been published. In this study, the direct toxic effect of active oxygen free radicals on the rat pancreas was evaluated in vivo. Superoxide anions, generated via the xanthine/xanthine oxidase (X/XO) system, and hydrogen peroxide (H2O2) were used. After continuous arterial injection of X/XO into the celiac artery hemorrhage and extensive edema developed. However, additional continuous injection of superoxide dismutase (SOD) into the external jugular vein completely suppressed the hemorrhage and relieved the edema. When hydrogen peroxide (100 microM/Kg/hour) was injected continuously through the celiac artery made hemorrhage and edema were recognized in the pancreas, both of which were suppressed by continuous injection of catalase (10 mg/Kg/hour) or gabexate mesilate (10 mg/Kg/hour) into the external jugular vein. The amylase and lipase levels in the intraperitoneal fluid rose to more than 10 times the preoperative values 5 hours after drug administration. These levels were lowered to 2 times the preoperative values by the continuous venous injection of SOD or catalase (which are specific scavengers of superoxide anions or hydrogen peroxide, respectively) or by gabexate mesilate. On the other hand, serum amylase and lipase levels remained almost constant throughout the entire experiment. Thus, the administration of active oxygen free radicals caused acute pancreatitis, which was suppressed by the systemic administration of specific scavengers for each free radical. Active oxygen free radicals were shown to have a direct, toxic effect on the pancreas.
Acute Disease↗
[Effect of short-term-ischemia and reperfusion on the rat pancreas].
In order to examine the toxic effects on the pancreas of oxygen free radicals which are generated at reperfusion after ischemia, a short term-ischemia/reperfusion model was prepared in rats. Both the anterior mesenteric artery and the celiac artery were ligated and then released to restore blood flow. In a group where the anterior mesenteric and the celiac arteries were ligated for 60 minutes, the serum levels of amylase and lipase rose 7 and 6 times, respectively, 7 hours after reperfusion. In a group ligated for 30 minutes, both levels remained unchanged. Histologically, vacuolization of the pancreatic acinar cells was observed, only in a group rats ischemic for 7 hours. In rats ligated for 60 minutes with a continuous venous infusion of superoxide dismutase (SOD) (3600 U/Kg/hour), the secretion of amylase and lipase decreased to 25 percent of that in the non-injected group. These results confirm that the oxygen free radicals, which are generated by the short term-ischemia/reperfusion method, injure the pancreas. This may lead to pancreatitis with hyperamylasemia and hyperlipasemia. Pretreatment with an active oxygen scavenger, SOD, markedly reduces the rise in serum amylase and lipase levels. This suggests that active oxygen free radicals are involved in the pathogenesis of acute pancreatitis.
Acute Disease↗
Changes of A, B and D cells in Langerhans islets in pancreatic cancers of hamsters.
In order to clarify the effect of pancreatic hormones on the oncogenesis of pancreatic cancer, the kinetics of the B, A and D cells in the islets of Langerhans were studied in hamsters with pancreatic cancer induced by di-iso-propanol nitrosamine (DIPN). Tumors appeared histologically 8 weeks and duct adenocarcinomas became evident 12 weeks after the administration of DIPN. Although the area of the islets did not change in 8 to 16 weeks, the numbers of B cells was decreased 8 weeks after the administration of DIPN and of A and D cells was decreased at 16 weeks. The area occupied by B cells in proportion to the number of islet cells showed a significant decrease 8 weeks after the administration of DIPN. Since insulin has been reported to have a trophic effect on the exocrine pancreas, our findings suggest that pancreatic B cells start to decrease at the same time that pancreatic cancer begins to form. Thus, insulin appears to play an important role locally in the oncogenesis of pancreatic cancer in acinar cells.
Animals↗
[Changes of lysosomal and digestive enzymes in rat caerulein pancreatitis].
We evaluated the changes of lysosomal and digestive enzymes in the exocrine pancreas after caerulein induced acute pancreatitis in rats. The serum amylase levels and water content as well as pancreatic amylase and cathepsin B contents increased significantly in the early stage (0-12 h) after caerulein was administered, however, returned to the normal levels at 36 h. In the early stage, colocalization of lysosomal enzyme and digestive enzyme was found. Histologically, in the early stage, there were remarkable changes such as acinar cell vacuolization and interstitial edema, but these changes disappeared at 36 h. Furthermore, amylase and cathepsin B outputs decreased significantly in the early stage (12 h) but at 24 h, these increased significantly. LDH discharge from dispersed acini and cathepsin B leakage from lysosomes also increased in the early stage (0-12 h), but these values returned to the normal levels at 36 h. These results indicate that exocrine pancreas needs about 36 h to recover from the caerulein induced acute pancreatitis, and in this recovering process, secretion of colocalized digestive enzyme and lysosomal enzyme seem to play an important role.
Acute Disease↗
Effect of partial hepatectomy on glucose-stimulated insulin release from perfused rat pancreas.
To investigate the functional reserve of the endocrine pancreas both in the early and in the recovering stage after partial hepatectomy, we evaluated the changes in the secretion of insulin in response to a glucose load in isolated perfused rat pancreas 4 and 7 d after about 70% hepatectomy in rats. Insulin responses to a high glucose load (16.7 mM) were significantly higher in the first stimulation phase (first 10 min (p less than 0.01 at 4 and 7 d), and the second stimulation phase (second 20 min) (p less than 0.01 at 4 and 7 d), after hepatectomy. These results indicate that in the regenerating stage after hepatectomy, the sensitivity of islet B-cells to a glucose load is increased to support the increased glucose metabolism in this stage. Thus, this insulin hypersecretion from B-cells seems to be among the adaptations of the endocrine pancreas after hepatectomy.
Animals↗
Protective effects of gabexate mesilate (FOY) against impaired pancreatic energy metabolism in rat acute pancreatitis induced by caerulein.
A supramaximal dose of caerulein (5 micrograms/kg.hr for 3.5 hours) caused edematous acute pancreatitis in rats, characterized by portal hyperamylasemia (32 +/- 3 U/ml) and pancreatic edema (pancreatic water content, 86 +/- 2%) [control group: amylase, 8 +/- 1 U/ml; water content, 74 +/- 2%]. In this model, increased portal levels of malate dehydrogenase (148 +/- 25 U/ml), increased mitochondrial fragility and impaired pancreatic energy charge level (0.77 +/- 0.05) were also observed [control group: malate dehydrogenase, 54 +/- 11 U/ml; energy charge level, 0.94 +/- 0.03]. Administration of gabexate mesilate, FOY, in a dose of 50 mg/kg.hr for 2 hours before and during the caerulein infusion had a significant protective effect against these pancreatic injuries (portal amylase level, 11 +/- 2 U/ml; MDH level, 72 +/- 19 U/ml; E.C., 0.89 +/- 0.02; water content, 76 +/- 2%). FOY in a dose of 20 mg/kg.hr was partially protective. These results indicate that subcellular organelle fragility and malfunction are closely related to the pathogenesis of acute pancreatitis and suggest the usefulness of FOY in the treatment of this disease.
Acute Disease↗
Venous bypass grafting for celiac occlusion in radical pancreaticoduodenectomy.
Radical pancreaticoduodenectomy was performed for cancer of the head of the pancreas in a 65-year-old male patient with congenital celiac occlusion. Preoperative angiography revealed that the arterial flow to the liver, spleen, and stomach was supplied via the pancreaticoduodenal arcade and that the dorsal pancreatic artery arose from the superior mesenteric artery. In order to perform radical pancreatectomy with sufficient clearance of lymph nodes and soft tissues around the pancreas, the celiac arterial circulation was reconstructed. The restoration of flow was effected via a saphenous vein graft between the common hepatic artery and the aorta. Postoperative angiography demonstrated patency of the graft. The patient's postoperative course was uneventful.
Adult↗
Role of L3T4+ and Lyt-2+ T cell subsets in protective immune responses of mice against infection with a low or high virulent strain of Toxoplasma gondii.
In order to elucidate the role of T cell subsets in protective immunity against infection with high virulent and low virulent strains of Toxoplasma gondii, monoclonal antibodies specific for T cell subsets were injected into mice before immunization or challenge infection. Treatment of mice with monoclonal antibody to either L3T4+ or Lyt-2+ T cells before they were immunized with Toxoplasma cell homogenate prepared from high virulent RH strain tachyzoites markedly reduced survival after mice were challenged with low virulent bradyzoites of the Beverley strain. Thus, induction of protective immunity against bradyzoites of the Beverley strain requires the presence of both L3T4+ and Lyt-2+ T cells. In contrast, mice injected with living bradyzoites of the low virulent Beverley strain after immunization with Toxoplasma cell homogenate acquired protective immunity against high virulent tachyzoites of the RH strain. Lyt-2+ T cells alone appear to be final effector cells for protection against the challenge with high virulent RH strain tachyzoites, since treatment of the bradyzoite-immune mice with anti-Lyt-2 antibody, but not anti-L3T4 antibody, before challenge significantly increased mortality.
Animals↗
Necrotizing fasciitis rapidly diagnosed by aspiration cytology.
A case of necrotizing fasciitis caused by beta-hemolytic streptococci is reported. A 66-year-old man was admitted because of pain and swelling in the right buttock. Rapid application of aspiration cytology made it possible to diagnose necrotizing fasciitis with bacterial infection. Unfortunately, however, the patient died of cardiac arrest due to hyperpotassemia 11 h after admission. Mortality from this disease is most often related to failure in recognizing it early. Rapid diagnosis and early treatment is mandatory in order to save the patients' life. We emphasize the usefulness of rapid aspiration cytology, despite the unfortunate outcome in the present case.
Aged↗
Membrane currents recorded from sexually dimorphic motoneurones of the bulbocavernosus muscle in neonatal rats.
1. The electrophysiological properties were compared between sexually dimorphic motoneurones in the spinal nucleus of the bulbocavernosus (SNB) and those innervating hindlimb muscles by the whole-cell recording technique in thin slices of the neonatal rat spinal cord. 2. The mean duration of action potentials in SNB motoneurones was significantly longer than that in hindlimb motoneurones. 3. The spike duration of motoneurones was inversely related to the magnitude of transient K+ currents (IA), and in this relation, there was a continuous gradation between SNB and hindlimb motoneurones. 4. The mean duration of spike after-hyperpolarization (AHP) in female SNB motoneurones was significantly longer than that in male SNB motoneurones. 5. In both SNB and hindlimb motoneurones, sustained, Ca(2+)-dependent K+ currents (IAHP) appear to be responsible for the generation of AHP. When IAHP was recorded as a tail current following an identical depolarizing pulse, the magnitude and time course of IAHP were relatively uniform, regardless of the type of motoneurone. 6. In both SNB and hindlimb motoneurones, voltage-gated Ca2+ currents showed an initial transient phase followed by a sustained phase. The mean magnitude of sustained Ca2+ currents was larger in female SNB motoneurones than in male SNB motoneurones, whereas the mean magnitude of transient Ca2+ currents showed no significant different between male and female SNB motoneurones. 7. It is concluded that SNB and hindlimb motoneurones cannot be classified into two distinct neurone types in terms of their electrophysiological properties. 8. It is suggested that the predominant occurrence of natural cell death in female SNB motoneurones during early development may be due in part to high densities of sustained Ca2+ channels in these neurones.
Action Potentials↗