Biomedical subjects
Publications and source records attributed to M Iwai.
We report a case of a patient with life-threatening hemorrhage caused by the presence of acquired factor VIII inhibitors after gastrectomy for signet-ring cell carcinoma of the stomach. Acquired factor VIII inhibitors should be taken into consideration as a cause of acquired bleeding tendency among patients with gastrointestinal malignancies especially when the coagulation tests are unusual.
To study the role of Kupffer cells in the aggravation of liver injury, effects of zymosan on acute liver damage were explored using perfused livers of rats 24 h after intraperitoneal injection of D-galactosamine (800 mg/kg). The leakage of lactate dehydrogenase and aspartate aminotransferase into the effluent was used to indicate acute liver damage. Infusion of zymosan (30 microgram/ml) into the portal vein rapidly increased the leakage of lactate dehydrogenase and aspartate aminotransferase from galactosamine-treated liver with decreased perfusion flow. Pretreatment of animals with gadolinium, which diminished an immunostaining of resident macrophages in the injured liver, significantly attenuated the flow reduction induced by zymosan, whereas it did not affect the increases in enzyme leakage. Infusions of PGF2alpha, PGE2, and leukotriene D4, the eicosanoids mainly produced by Kupffer cells, decreased perfusion flow without rapid augmentation of enzyme leakage from galactosamine-treated liver. These results indicate that zymosan potentiates acute liver damage after galactosamine injection and suggest that certain types of nonparenchymal cells other than Kupffer cells are mainly involved in the action of zymosan.
Human saliva contains a proline-rich polypeptide, salivary peptide P-C, which potentiates insulin release and reduces glucagon release from perfused rat pancreas to decrease blood glucose level. To elucidate the process of secretion into humoral fluid of this peptide morphologically, we investigated ultrastructural localization of P-C in human submandibular gland by immunogold technique with anti-peptide P-C whose specificity to P-C was confirmed by immunoblotting. The labeling with gold particles which represents the distribution of P-C-like-immunoreactivity (P-C-LI) was detected in the secretory granules and rough endoplasmic reticula of the acinar serous cells and in few mucosa cells. P-C-LI was also observed in the lumen of striated duct but not intracellularly in the ductal cells themselves, indicating that P-C is not probably reabsorbed there. These results suggest that salivary peptide P-C is present in acinar serous cells, is secreted into the oral cavity, and may be reabsorbed through the digestive tract to modulate the blood glucose level after feeding.
We investigated the effect of recombinant insulin-like growth factor-I (rhIGF-I) on the expression of glucose transporters, GLUT 2 in the liver and GLUT 4 in the heart, in streptozotocin (STZ)-diabetic rats by the reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. GLUT 2 and its mRNA in the liver was elevated, whereas GLUT 4 and its mRNA in the heart were decreased in STZ-diabetic rats. A two-week treatment with rhIGF-I mostly restored the expression of GLUT 2 and GLUT 4 to normal rat level. We demonstrated that the effect of IGF-I on the expressions of GLUTs was almost the same as that of insulin.
The long-term results of mitral valve repair using artificial polytetrafluorethylene (PTFE) chordae were assessed in 61 consecutive patients with pure mitral regurgitation who underwent mitral valve repair with replacement of elongated or ruptured chordae tendineae between 1992 and 1996. There were 36 men and 25 women aged from 14 to 73 years (mean 52.1 +/- 13.8 years). The patients were followed up for between 1 to 73 months (mean 29.3 +/- 17.6 months). Fifty-five patients underwent mitral valve repair of the anterior leaflet and 6 repair of the posterior leaflet. There were two hospital and two late deaths. Actual survival rate at 5 years was 93.1%. Freedom from cardiac events at 5 years was 87.8%. Two patients required reoperation due to hemolysis. There were three occurrences of non-fatal thromboembolism. Although further investigation is necessary in a large population, expanded PTFE sutures are excellent for chordal replacement during mitral valve repair.
Serial changes in mitral regurgitation after anterior mitral valve repair were examined by transesophageal echocardiography (TEE) in 34 of 86 consecutive patients with pure mitral regurgitation who underwent anterior mitral valve repair from 1987 to 1996. The patients were divided into two groups: 15 patients undergoing mitral repair with polytetrafluoroethylene (PTFE; PTFE group) and 19 undergoing conventional mitral repair without PTFE (non-PTFE group). The PTFE group included 11 men and 4 women with a mean age of 52.1 years. They were followed for mean 22.8 +/- 12.0 months. The non-PTFE group included 12 men and 7 women with a mean age of 53.9 years. They were followed for mean 33.9 +/- 20.4 months. Mitral regurgitation jet areas were observed at the time of operation, 1 month after mitral valve repair, and in the late follow-up period. Regurgitation jet areas were 0.7 +/- 0.7, 1.1 +/- 0.9 and 2.5 +/- 2.1 cm2 in the PTFE group, and 1.1 +/- 1.3, 2.4 +/- 1.7, 4.7 +/- 2.9 cm2 in the non-PTFE group. The jet area was significantly smaller in the PTFE group than in the non-PTFE group at 1 month after operation and in the late follow-up period. Moderate to severe regurgitation was observed in two patients (13.3%) in the PTFE group, and eight patients (42.1%) in the non-PTFE group. Mitral valve repair with PTFE showed better results than conventional mitral valve repair without PTFE during the mean follow-up period of 23 months.
We have shown previously that ICRF-193, a catalytic inhibitor of DNA topoisomerase II (topo II), delays cell cycle progression in HeLa S3 cells. We report here that the delay of the transition in M phase is observed when HeLa S3 cells were treated with ICRF-193 during metaphase, but not thereafter. ICRF-193 also delayed the degradation of cyclin B in the transition from M to G1 phase, while in Chinese hamster ovary (CHO) cells the drug did not delay the progression in M phase. Since HeLa S3 and CHO cells are 'stringent' and 'relaxed' in mitotic control, respectively, it is suggested that under topo II inhibition, the M phase checkpoint operates through an inability for chromosome segregation.
The ileal Na+/bile acid cotransporter (IBAT) maintains the reabsorption of bile acids from the intestine in the enterohepatic circulation of bile acids. In the present study, we showed that S-8921 could dose-dependently inhibit the uptake of [3H] taurocholate in the COS7 cell line which constitutively expresses hamster IBAT. The IC50 value of S-8921 against 60 microM of [3H] taurocholate uptake was 66 +/- 8 microM and kinetic analysis revealed that the inhibition by 100 microM of S-8921 was a mixture of competitive and non-competitive types. In vivo administration of S-8921 by its incorporation into diet (0.001-0.1%) caused dose-dependent decrease of serum cholesterol concentrations accompanied by increased fecal excretion of bile acids in hamsters which were not loaded with cholesterol and bile acid. These data suggest that the inhibition of IBAT could decrease serum cholesterol in the non-cholesterol and -bile acid loaded normal condition.
Mutation within the Mitf gene causes, in microphthalmic Mitf(mi)/Mitf(mi) (mi/mi) mice, multiple defects, including white coat color and functional defects in macrophages and osteoclasts. Our previous mating experiments have demonstrated that the mi mutation reduces the numbers of newborns and induces uterine inversion at delivery. The present study was designed to determine the causes of these pregnancy defects. The histology and number of F4/80-positive macrophages were not different between the ovaries of 23-day-old mi/mi and +/+ mice given eCG 48 h earlier. When ovulation was induced in these mice by hCG, the number of ovulated ova was significantly smaller in mi/mi mice than in wild-type (+/+) mice (p < 0.05). When bone marrow cells from +/+ mice were transplanted i.p. into 42 mi/mi female newborns, successful transplantation was observed in 16 of them at 20 days after birth. In one of these, the upper incisors had erupted. The mean number of tubal ova in mi/mi mice significantly increased after transplantation (p < 0.05) and was almost equal to that of +/+ mice. No uterine inversion occurred at 6 deliveries in 5 mi/mi females after bone marrow transplantation, while it occurred at 4 of 5 deliveries in mi/mi females during the same observation period (p < 0.05). These results indicate that bone marrow-derived cells, defective in mi/mi mice, are necessary for normal ovulation and delivery; the findings are consistent with the notion that macrophages play major roles in ovulation.
By immunocytochemistry we have studied the effect of recombinant human insulin-like growth factor I (rhIGF-I) on expression of renal GLUT-1, -2, and -5 in rats with streptozotocin (STZ)-induced diabetes. In the renal tubules of these rats, expression of GLUT-1 was reduced and that of GLUT-2 was increased. GLUT-1 expression was restored, and GLUT-2 expression was normalized by 2-wk administration of rhIGF-I. We have shown that GLUT-5 was expressed at the brush-border membrane of the proximal convoluted tubules (PCT) of the cortex and at the glomerular mesangial cells (GMC) in normal rat kidney. In the diabetic rats, GLUT-5 expression was increased at both sites, along with an increase of GLUT-2 expression at the basolateral membrane of PCT, and was decreased to normal level at both sites by treatment with rhIGF-I. Thus, like GLUT-2, GLUT-5 is suggested to regulate glucose reabsorption in PCT. The relationship between overexpression of GLUT-5 in GMC and accumulation of sorbitol and advanced glycosylation end products are discussed. Regulation of GLUT expression may play an important role on renal glucose homeostasis.
In a previous study we indicated the involvement of the N-methyl-D-aspartate (NMDA) receptor in the development of morphine dependence as assessed by naloxone-induced rise in norepinephrine release in chronically morphine-treated rats. In the present experiments, we studied (1) the possible role of protein kinases in the increased norepinephrine release occurring after naloxone injection and (2) the effects of NMDA receptor antagonists on chronic morphine exposure-induced changes in protein kinase activity. The naloxone-induced rise in norepinephrine release was attenuated by concomitant administration of a protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H-7) or an NMDA receptor antagonist, (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]-cyclohepten-5, 10-imine hydrogen maleate (dizocilpine, MK-801) with morphine. Both cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), which mediate neurotransmitter release, were clearly activated in the cytosol of the pons/medulla, but not in that of the hippocampus, in chronically morphine-treated rats. This activation of PKA and PKC by chronic morphine treatment was inhibited by infusion of dizocilpine or D(-)-2-amino-5-phosphonopentanoic acid (AP-5), an ionotropic glutamate receptor antagonist, together with morphine. These results suggest that NMDA receptor antagonists inhibit the increase in protein kinase activity produced by chronic morphine treatment, thus suppressing the naloxone-induced rise in norepinephrine release.
Treatment with a combination chemotherapeutic regimen consisting of cyclophosphamide, vincristine, and dacarbazine for malignant paraganglioma with hepatic metastasis is reported. A 51-year-old male presented with tumors in the retroperitoneal space and liver. The patient was diagnosed as having paraganglioma based on elevated levels of serum neuron-specific enolase, urinary catecholamine and vanillylmandelic acid, and on histological findings of the liver specimen. The patient was treated with this combination chemotherapy in repeated 21-day cycles. Temporary improvement in laboratory findings and a 20% reduction in the size of the hepatic masses were observed without severe adverse effects.
A 37-year-old woman underwent an emergency operation at our hospital because of severe abdominal pain and ileus. Most of her small intestine and ascending colon were observed to have become necrotic due to occlusion of her superior mesenteric artery (SMA). Pathological findings of the resected intestine revealed that her SMA was completely thrombosed 2 cm distal from its origin with smooth muscle proliferation. Post-surgical blood analysis of her pre-operative serum was positive for lupus anticoagulant and antinuclear antibodies. She noticed vaginal bleeding due to missed abortion on the 31st day after the operation. We diagnosed her acute abdominal pain to be that of antiphospholipid syndrome associated with her pregnancy.
Patients with antiphospholipid antibody syndrome manifesting as neurological symptoms (one patient with twice repeated cerebral ischemic symptoms in the left parietal and frontal lobes, and the other patient with cerebral infarction of the right temporal lobe) and non-neurological symptoms (one patient with occlusion of the superior mesenteric artery and the other patient with thrombophlebitis) underwent cerebral blood flow (CBF) studies using xenon-enhanced computed tomography. The patients with neurological symptoms had decreased CBF at the affected sites. The patients with non-neurological symptoms had decreased CBF in the left parietal and temporal lobes and/or corona radiata. Subtle preclinical thrombosis may cause chronic cerebral hypoperfusion in patients with antiphospholipid antibody syndrome.
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Neurons arising from neural tube or neural crest do not express epithelial markers from the beginning of their differentiation and neuroblastomas arising from these anlages also do not express epithelial markers. On the other hand, neuroendocrine carcinomas, such as small cell carcinomas of the respiratory tract, express epithelial markers in addition to neuronal or neuroendocrine markers and demonstration of epithelial marker has been regarded as subtle evidence to rule out neuroblastomas. However, this general rule can not be applied to olfactory neuroblastomas. Unlike neurons derives from neural tube or neural crest, developing neurons arising from the anlage of olfactory nerve, i.e., olfactory placode, have keratin during the embryonic stage. Accordingly, it is unnatural for neoplastic neuroblasts of olfactory placodal origin to have keratin as the embryonic phenotype. In addition, neurons arising from this anlage have an epithelial antigen (EA) detected by Ber-EP4 from the beginning of their differentiation, and this antigen is preserved in the olfactory sensory nerve even in the postnatal stage, though it is lost from the neurons migrating from olfactory placode to brain, i.e., luteinizing hormone-releasing hormone producing neurons (LHRH neurons) during post embryonic stage. Therefore, demonstration of this epithelial antigen in the tumor with neurite formation can be regarded as a satisfactory diagnostic evidence of true olfactory neuroblastoma. LHRH also seems to be a useful marker to determine true olfactory placodal origin of the neuroblastoma. Finally, it is concluded that demonstration of epithelial markers could not be regarded as evidence to rule out neuroblastoma developed in the olfactory nerve region.
To investigate the relationship between the modulation of topoisomerase II activity and its phosphorylation state during the cell cycle, a monoclonal antibody against C-terminal peptide (residues 1335-1350) of topoisomerase IIalpha containing a consensus sequence of casein kinase II, TDDE and its phosphorylated threonine were prepared. In an enzyme-linked immunosorbent assay, the antibody, named PT1342, recognized the immunogenic phosphopeptide but not the non-phosphorylated form of the peptide. The PT1342 antibody reacted only with a 170-kDa protein from HeLa cells and recognized anti-topoisomerase IIalpha immunoprecipitants. Furthermore, the antibody did not react with the human topoisomerase IIalpha mutated at codon 1342 from threonine to alanine, showing that PT1342 was directed against the phosphorylated threonine 1342. To examine the level of phosphorylation of threonine 1342 of topoisomerase IIalpha through the cell cycle, HeLa cells were stained simultaneously for phosphorylated topoisomerase IIalpha and DNA and analyzed by flow cytometry. Cells in the G2-M phase contained about double the PT1341-reacted topoisomerase IIalpha than did cells in G1 or S phases. The antibody stained the nuclei in interphase and mitotic chromosomes and its periphery, as seen with anti-topoisomerase IIalpha antibody. Thus, threonine 1342 in topoisomerase IIalpha is phosphorylated throughout the cell cycle.
BACKGROUND/AIMS: Our previous study indicated that the amount of connexin32, the major gap-junctional protein of rat liver, is transiently reduced in acute liver injury after single administration of hepatotoxic chemicals. This study was designed to examine alteration in the expression of connexin32 in chronic liver injury, unassociated with hepatocyte proliferation. METHODS: Rats were injected with carbon tetrachloride (CCI4, 0.5 ml/kg) twice a week for 12 weeks. After cessation of CCI4 injection, hepatic contents of connexin32 and its mRNA levels were measured by immunoblotting as well as immunohistochemical examination and by Northern-blot analysis. RESULTS: The plasma alanine-aminotransferase activity was increased from 30 U/I to about 1000 U/l after 12 weeks of CCI4 injections, but recovered nearly to normal level in 7 days after cessation of the injection. Liver specimens 12 days after the last CCI4 injection appeared cirrhotic with a marked increase in fibrosis. Connexin32 contents in these livers decreased to about 37% of controls. The significant decrease in connexin32 content was sustained for at least 30 days and recovered to the control level by 60 days. The alteration of connexin32 content in chronically injured liver was confirmed immunohistochemically. The level of connexin32-mRNA, however, was not reduced, but rather increased by chronic injection of CCI4. CONCLUSION: The results suggest that intercellular communication is disturbed in chronic liver injury, lasting even after recovery from the acute phase of injury. Since the mRNA levels of connexin32 were sustained, the prolonged decrease in connexin32 contents in these livers might be due to a post-transcriptional change that causes decrease in protein synthesis or a derangement of post-translational controls.