[Slice patch clamp method for study of synaptic transmission].
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Animals↗
Biomedical subjects
T Manabe
Publications and source records attributed to T Manabe.
[Role of pathology as clinical medicine: experience at Kawasaki Medical School].
The department of Pathology at Kawasaki Medical School was destined, from the outset of its foundation, to be one of clinical departments. To discuss the role of pathology as clinical medicine, the actual state of our department is described here with reference to its organization, principles, and quality assurance program in both surgical pathology service and hospital practice. The department at School also functions as a hospital pathology department and handles 10,000 surgical and 18,000 cytology materials as well as about 180 autopsies per year. Examination of the tissues and organs removed from the patients is wholly entrusted to our department in its full responsibility. All the tissue sections are examined by multiple certified pathologists and reports are returned by the third day. Case reviews are regularly done by peer reviewers and through the conferences held between pathology and relevant clinical departments. The latter conferences serve as a medical audit in the hospital as well. The pathologists sometimes participate in the performance of aspiration cytology, and muscle and nerve biopsy. It is hoped that the description of our experience in surgical pathology will provide some insights on the improvement of the system to concerned readers and cause lively discussion on this matter.
Humans↗
[Undergraduate and postgraduate medical education in pathology department: experience at Kawasaki Medical School].
Described herein is the present status of both undergraduate and postgraduate medical education participated by the department of pathology, Kawasaki Medical School. The department concerns the education of medical students from the second through sixth year. All the subjects taught are more clinically oriented. Resident educational system, composed of two years of junior and four years of senior training period, is well programmed to achieve clinical competence and laboratory management. Many self-learning materials and teaching seminars are provided. In addition, medical museum, which is affiliated to the School, helps learning not only of students and doctors in the hospital but also of laymen and private physicians in the city with many exhibits. It is hoped that the description of our experience will provide some insights on the improvement of the undergraduate and postgraduate education and cause lively discussion on this matter among concerned readers.
Education, Medical, Continuing↗
Loxiglumide (CR1505), a cholecystokinin antagonist, specifically inhibits the growth of human pancreatic cancer lines xenografted into nude mice.
BACKGROUND: Cholecystokinin is thought to be an important factor regulating the growth of human pancreatic cancers. The study was designed to evaluate the effects of the cholecystokinin antagonist loxiglumide (CR1505) on the growth of human pancreatic cancer. METHODS: Human gastrointestinal cancer xenografted tumors (one esophageal, one gastric, two colorectal, two biliary tract, and two pancreatic cancers) were transplanted into nude mice. The mice were given CR1505 at 250 mg/kg daily for 14 days, either subcutaneously or intragastrically, and the tumor volumes before and after treatment were compared. In vitro effects of CR1505 were assessed by measuring the DNA synthesis (3H-thymidine incorporation). RESULTS: CR1505 inhibited the growth of the two pancreatic cancer lines but did not inhibit the growth of the other lines. CR1505 also inhibited in vitro DNA synthesis in the two pancreatic cancer lines at lower concentrations than in the other lines. This pancreatic cancer-specific inhibitory effect of CR1505 was retarded by exogenously administered cholecystokinin in one pancreatic cancer line but was augmented in the other line. The effect of CR1505 was inhibited by oral administration of the trypsin-inhibitor camostate (FOY-305) in both pancreatic cancer lines. CONCLUSIONS: These results suggest that CR1505 may specifically inhibit the growth of human pancreatic cancers and may be suitable for clinical study. However, its antiproliferative effect may not necessarily be dependent on its cholecystokinin-antagonism but may be mediated through the proteolytic enzymes found in the lysosomes of the pancreatic cancer cells.
Animals↗
A case of pancreatic cancer with the sign of Leser-Trélat.
A case of 79-year-old man with pancreatic cancer associated with the sign of Leser-Trélat was presented. Abdominal CT scanning was performed and a pancreatic tail tumor involving the spleen and the greater omentum as well as ascitic retention were detected. Ba-enema study showed the stenosis of the sigmoid colon, suggesting the peritoneal disseminations. Absolute non-curative operation of side-to-side transverso-sigmoidostomy was performed for colonic stenosis, and biopsy of the disseminated omental tumor was performed, which was histologically diagnosed as well differentiated papillary adenocarcinoma compatible with pancreatic cancer. The postoperative course was uneventful and at present the patient was followed at outpatient clinic. To our knowledge, this case is the first report with pancreatic cancer associated with the sign of Leser-Trélat in Japan.
Adenocarcinoma, Papillary↗
Serum cathepsin B levels and urinary excretion of cathepsin B in the cancer patients with remote metastasis.
Serum cathepsin B levels and urinary excretion of cathepsin B in the cancer patients without remote metastasis were significantly higher than those in the control non-cancer patients. Moreover, these parameters in the cancer patients with remote (liver or lung) metastasis were significantly higher than those in the cancer patients without remote metastasis. After radical curative operations, these parameters were restored to the control values. These results suggest a possible role of lysosomal enzyme, cathepsin B in the pathogenesis of tumor metastasis, and also suggest that these parameters might be possible indicators for tumor malignancy such as remote metastasis.
Aged↗
Effect of ethanol on pancreatic lysosomes in rats: a possible mechanism for alcoholic pancreatitis.
Four-hour infusion of ethanol (0.5 g/kg.hr) and additional 2-hour infusion of caerulein (0.2 microgram/kg.hr) and secretin (0.2 CU/kg.hr) caused hyperamylasemia, pancreatic edema and pancreatic histological changes such as interstitial edema and acinar cell vacuolization in the rat. Such a combined treatment also induced a redistribution of lysosomal enzyme cathepsin B, from the lysosomal fraction to the zymogen fraction in subcellular fractionation. Only ethanol infusion caused marginal changes in all these parameters. Moreover, 4-hour pre-infusion of ethanol caused a significant increase in pancreatic cathepsin B output stimulated by caerulein (0.2 microgram/kg.hr) and secretin (0.2 CU/kg.hr) compared with the control rats. This pretreatment of ethanol also caused a significant increase in cathepsin B/amylase output ratio. These results indicate that ethanol administration, if combined with exocrine stimulation, causes a colocalization of lysosomal hydrolases with digestive enzymes in the same subcellular compartment as well as in the pancreatic ductal space, and also suggest one possible mechanism for alcoholic pancreatitis both within and outside the acinar cells, since cathepsin B can activate trypsinogen.
Alcoholism↗
A new experimental model for gallstone pancreatitis: short-termed pancreatico-biliary duct obstruction and exocrine stimulation with systemic hypotension in rats.
The effects of short-termed (2 hours) obstruction of pancreatico-biliary duct (PBDO) and exocrine stimulation (IDH) by caerulein infusion (0.2 microgram/kg.hr) with systemic hypotension (SH) (30% reduction of mean arterial pressure for 30 min) on the exocrine pancreas were evaluated in the rat. PBDO and IDH with SH caused more significant rises in portal serum amylase, cathepsin B and malate dehydrogenase levels, and pancreatic water content as well as more significant redistribution of cathepsin B activity from the lysosomal fraction to the zymogen fraction in the subcellular fractionations than only PBDO, or PBDO with IDH, or PBDO with SH group. In addition, more accelerated lysosomal and mitochondrial fragility were observed in the PBDO and IDH with SH group. Moreover, PBDO and IDH with SH caused an activation of larger amount of trypsinogen in the pancreas compared with other groups (PBDO with IDH and PBDO with SH group). These results indicate that present model of short-termed PBDO and exocrine stimulation with systemic hypotension seems to be pertinent model for gallstone pancreatitis in humans, and that redistribution of lysosomal enzymes and subcellular organellar fragility seem to play an important role in the pathogenesis of pancreatic injuries by PBDO, particularly with exocrine stimulation and pancreatic ischaemia, probably via activation of trypsinogen to trypsin by lysosomal enzyme such as cathepsin B.
Animals↗
Human urinary trypsin inhibitor, urinastatin, prevents pancreatic injuries induced by pancreaticobiliary duct obstruction with cerulein stimulation and systemic hypotension in the rat.
OBJECTIVE: The protective effects of human urinary trypsin inhibitor against pancreatic injuries in multifactor-related experimental model of acute pancreatitis were evaluated. DESIGN: Experimental study. MATERIALS AND METHODS: Acute pancreatitis was induced by short-termed (1-hour) pancreatico-biliary duct obstruction with cerulein stimulation (30 minutes; 0.2 microgram/kg per hour) and systemic hypotension (30 minutes; 30% reduction of mean arterial pressure) in rats. In this model, the protective effects of UTI against pancreatic injuries were evaluated at a dose of 10,000 U/kg per hour. RESULTS: In this model, significant increases in portal serum amylase, cathepsin B and malate dehydrogenase levels were observed as compared with the control rats. The redistribution of cathepsin B from the lysosomal to the zymogen fraction and activation of trypsinogen were also observed. Moreover, the increased lysosomal and mitochondrial fragility as well as impaired pancreatic adenylate energy metabolism were noted. The therapeutic administration of human urinary trypsin inhibitor had significant protective effects against these pancreatic injuries. Furthermore, the combined prophylactic and therapeutic administration of human urinary trypsin inhibitor had more significant protective effects than only therapeutic treatment. CONCLUSIONS: These results suggest the importance of timing and of selecting a pertinent protease inhibitor, such as urinary trypsin inhibitor, in the treatment of pancreatitis.
Acute Disease↗
Development of T cells in SCID mice grafted with fetal thymus from AKR mice or F344 rats.
To examine the development of T cells within an allogeneic or xenogeneic environment, we engrafted the fetal thymus from AKR mice or F344 rats under the kidney capsule of SCID mice (mTG and rTG mice). T lymphopoiesis developed in SCID mice 2 months after transplantation, although the ratio of CD4/CD8 in both experimental groups was different from that of normal control. T cells in mTG mice did not show in vitro proliferation or cytotoxicity against either host-type C.B-17 (H-2d) or donor-type AKR (H-2k) cells, while they exerted potent activities against third-party B10 (H-2b) cells. In contrast, T cells in rTG mice exhibited proliferation against both host-type C.B-17 and donor-type F344 rat cells. Consistently, graft-vs.-host disease symptoms developed in these mice and histological examination showed impressive infiltration of lymphocytes into the skin or into the mucosal layers of the stomach. Activated state of T cells in rTG mice was also evidence by the positive expression of interleukin-2 receptor. Taken together, fetal thymus appears to contain progenitor cells which are sufficient for in vivo reconstitution of T lymphopoiesis, but species-specific environment is important for the induction of tolerance. In mTG mice, V beta 6+ T cells reactive to donor Mlsa determinants and V beta 3+ T cells reactive to host Mlsc determinants were deleted, suggesting that tolerance was regulated mainly by clonal deletion. By contrast, V beta 11+ T cells reactive to Mlsf determinants were not deleted possibly due to the lack of their ligands.
Animals↗
Inhibitors of vacuolar-type H(+)-ATPase suppresses proliferation of cultured cells.
We investigated effects of bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase (V-ATPase), and its analogues on proliferation of various cultured cells. The proliferation of the various cell lines was suppressed by adding bafilomycin A1 to the culture medium. This inhibitory effect appeared at a concentration of nanomolar order and was dose dependent. Although the suppression was reversible, the drug exerted not only suppression of the proliferation but also death to some cell lines. Drug concentration required for 50% inhibition of the cell proliferation during 48 h differed markedly depending on cell species and the sensitivity appears to increase by the transformation of the cells. Two derivatives of concanamycin A, an analogue of bafilomycin A1, also inhibited strongly V-ATPase in vitro and in vivo, and simultaneously cell proliferation. Two concanamycin A derivatives which have lost inhibitory effect on V-ATPase lost inhibitory effect on cell proliferation as well. These results suggest that V-ATPase is involved in the machinery maintaining the cell proliferation.
Adenosine Triphosphatases↗
Inhibitory effects of a cholecystokinin antagonist, loxiglumide (CR-1505), on the growth of freshly separated and xenografted human pancreatic cancer.
The effects of cholecystokinin (CCK) and a CCK antagonist, loxiglumide (CR-1505), on four freshly separated and six xenografted human pancreatic cancers, were investigated. The level of DNA synthesis in only one of five tested pancreatic cancers was enhanced by CCK at concentrations of 0.01-10 nM, while in the other four cancers DNA synthesis was not affected. The levels of DNA, RNA, and protein synthesis (by 3H-thymidine, 3H-uridine, and 3H-leucine incorporation tests, respectively) in all the tested cancers were dose-dependently inhibited by loxiglumide at concentrations of 20-2000 microM, and the IC50 of loxiglumide for DNA synthesis in pancreatic cancers was 156 +/- 80 microM (means +/- SD). The in vivo effect of loxiglumide was assessed using a xenografted line (PC-HN) transplanted in nude mice. The in vivo 50% lethal dose of loxiglumide for nude mice was about 500 mg/kg. Death was caused by respiratory failure due to severe congestion of the lung after the administration of a large dose of loxiglumide. The growth of a PC-HN transplanted in the nude mice was significantly inhibited by subcutaneous loxiglumide at 250 mg/kg, twice a day for 28 days, which did not cause death. It is suggested that loxiglumide inhibits the in vivo and in vitro growth of human pancreatic cancer, perhaps independently of its action as a CCK antagonist, and this study also suggests that loxiglumide may be a new type of therapeutic agent to be used for the treatment of human pancreatic cancer.
Animals↗
Role of pancreatic blood flow and vasoactive substances in the development of canine acute pancreatitis.
To study the role of pancreatic blood flow and vasoactive substances in the development of acute pancreatitis, we measured portal vein blood levels of bradykinin, prostaglandin E2 (PGE2), histamine, serotonin, and pancreatic enzymes, and with an electromagnetic blood flowmeter we recorded gastroduodenal arterial flow (GDAF), superior mesenteric arterial flow (SMAF), and mean arterial blood pressure for 6 hr in dogs with acute hemorrhagic necrotizing pancreatitis induced by the retrograde injection of autologous bile (0.5 ml/kg) into the pancreatic duct. GDAF and SMAF decreased immediately in the early phase of acute pancreatitis (-17.8 +/- 6.1%** at 10 min and -15.8 +/- 7.1%* at 20 min; *P < 0.05, **P < 0.01); portal bradykinin concentration increased quickly (3.2 +/- 1.2 pM at 0 time, 16.2 +/- 5.2 pM* at 5 min, 30.4 +/- 4.8** pM** at 10 min, and 39.6 +/- 15.1 pM* at 20 min). Portal PGE2 concentration increased gradually after the induction of acute pancreatitis, and differences from the control group were significant at 20, 30, and 180 min (1426 +/- 175 pM at 0 time, 1956 +/- 273 pM* at 20 min, 2148 +/- 265 pM** at 30 min, and 3369 +/- 686 pM* at 180 min). Portal histamine and serotonin concentrations increased somewhat, but not significantly. These findings suggest that the injection of bile into the pancreatic duct causes the pancreas to quickly release a large amount of bradykinin into the portal vein, which immediately reduces the pancreatic blood flow in the early phase, thus accelerating the progress of acute pancreatitis.
Acute Disease↗
Connectin, giant elastic protein, in giant sarcomeres of crayfish claw muscle.
In the giant sarcomeres (sarcomere length, 10 microns at rest) of crayfish claw muscle, 3000 kDa connectin-like protein but not projectin (mini-titin) appears to be responsible for passive tension generation. Proteolysis of crayfish connectin in skinned fibres was parallel with disappearance of resting tension. Immunofluorescence observations using the antiserum to crayfish connectin showed that crayfish connectin linked the A band to the Z line in a giant sarcomere. It appears that crayfish connectin exerts a centering force on the A band in a sarcomere. Very thin filaments in the I band were visualized after the actin filaments had been removed by the treatment with plasma gelsolin. Crayfish connectin was partially purified and its rotary shadowed image was a very long filament. Projectin was localized on the A band of crayfish giant sarcomeres and remained unmoved during stretch or contraction. However, on dissolution of myosin filaments, projectin moved to the Z line together with crayfish connectin. It seems that projectin binds to connectin on the myosin filament. In regular size of sarcomeres (sarcomere lengths, 3-4 microns at rest) of crayfish stretcher muscle, projectin linked the A band to the Z line, as in insect flight muscle.
Animals↗
Effect of urinary trypsin inhibitor on pancreatic cellular and lysosomal fragility in cerulein-induced acute pancreatitis in rats.
We evaluated the protective effect and the mechanism of action of the trypsin inhibitor, urinastatin, extracted from human urine, in experimental acute pancreatitis induced by a supramaximal dose of cerulein (5 micrograms/kg/hr for 3.5 hr). Urinastatin in a dose of 10,000 units/kg/hr was given by three different methods of continuous infusion: (1) 2 hr before and during cerulein infusion, (2) only during cerulein infusion, and (3) starting 1 hr after the beginning of cerulein infusion and continued for 3.5 hr. In protocol 1 and 2 urinastatin was significantly more protective than in 3. In protocol 1 urinastatin was very protective in all parameters tested (serum amylase level, pancreatic water and amylase content, distribution of lysosomal enzymes, cellular and lysosomal fragility). These results suggest that the administration of urinastatin before and during cerulein infusion may suppress the pathogenesis and evolution of pancreatitis by inhibiting the chain reaction of pancreatic enzyme activation closely related to redistribution of lysosomal enzyme and lysosomal fragility.
Acute Disease↗
The fibrosing process in so-called organized diffuse alveolar damage. An immunohistochemical study of the change from hyaline membrane to membranous fibrosis.
On the assumption that some cases of organized diffuse alveolar damage (DAD) result from organization of hyaline membrane, we collected nine autopsy cases of DAD in various stages of the fibrosing process from hyaline membrane to membranous fibrosis and studied changes in the basement membrane and epithelial cells immunohistochemically. In the majority of cases, the following sequence of events was assumed: the hyaline membrane is first formed at the tip of the alveolar septum, a part of the alveolar duct wall where epithelial cells have disappeared. With time it elongates and completely covers alveolar mouths. In the organizing stage, fibroblasts start to permeate through the alveolar duct walls to replace the hyaline membrane completely and to form membranous fibrous tissue. In a few cases, however, fibrous tissue will fill alveolar spaces to form intraluminal diffuse fibrosis. Alveolar epithelial cells and the basement membrane of the alveolar walls are well preserved until the end of the organizing stage when the basement membrane becomes distorted. We believe that membranous fibrosis represents a form of "alveolar duct damage" and that it differs from diffuse fibrosis, which is indicative of diffuse alveolar damage in the true sense.
Adult↗
Nuclear DNA content as a prognostic predictor in carcinoma of the pancreas.
Eighty-six patients with carcinoma of the pancreas were studied retrospectively. Paraffin-embedded specimens and flow cytometry were used to evaluate the accuracy of the measurement of nuclear DNA as a predictor of the postoperative prognosis. From the series of 86 patients, 72 with a diagnosis of tubular adenocarcinoma (Japanese classification) were selected, and their DNA ploidy pattern and clinical and pathological features were correlated; 52.3% of the 86 patients and 52.8% of the 72 tubular adenocarcinoma patients showed DNA aneuploidy. Histological examinations of the tubular adenocarcinomas showed 42.9% DNA aneuploidy in well differentiated, 56.8% in moderately differentiated, and 71.4% in poorly differentiated types. The DNA ploidy showed a statistically significant positive correlation with the T category. The presence or absence of retroperitoneal invasion was thought to be the most important prognostic factor. Cumulative survival rates showed that the prognosis for patients with retroperitoneal invasion and DNA aneuploidy was significantly worse than for those with DNA diploidy or those without retroperitoneal invasion.
Adenocarcinoma↗
Modulation of synaptic transmission and long-term potentiation: effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus.
1. Whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs) were made from guinea pig hippocampal CA1 pyramidal cells. The sensitivity of paired pulse facilitation (PPF) and EPSC variance to changes in synaptic transmission was investigated and the results were compared with the changes in these parameters evoked by long-term potentiation (LTP). 2. Presynaptic manipulations, such as activation of presynaptic gamma-aminobutyric acid-B receptors by baclofen, blockade of presynaptic adenosine receptors by theophylline, blockade of presynaptic potassium channels by cesium, and increasing the Ca(2+)-Mg2+ ratio in the external recording solution, each reliably changed PPF in a fashion reciprocal to the change in the EPSC amplitude. However, recruitment of additional synaptic release sites by increasing stimulus strength and antagonism of non-N-methyl-D-aspartate (NMDA) glutamate receptors by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) failed to alter PPF. 3. Presynaptic manipulations including increased stimulus strength gave the predicted changes in the value of mean 2/variance (M2/sigma 2). Moreover, postsynaptic manipulations that altered EPSC amplitude, including blockade of non-NMDA receptors by CNQX, or changing the holding potential of the postsynaptic cell, gave little change in M2/sigma 2, as would be predicted for manipulations resulting in a uniform postsynaptic change. 4. LTP caused no change in PPF, whereas the presynaptic manipulations, which caused a similar amount of potentiation to that induced by LTP, significantly decreased PPF. On the other hand, LTP did increase M2/sigma 2, although the increase was less than that predicted for a purely presynaptic mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
6-Cyano-7-nitroquinoxaline-2,3-dione↗