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Biomedical subjects

M Otsuki

Publications and source records attributed to M Otsuki.

At least 37 records · Page 2Linked to original sources
PubMed2001

Multiple hepatic infarction after transcatheter arterial infusion with SMANCS.

We report a patient with hepatocellular carcinoma who developed multiple hepatic infarction after transcatheter arterial infusion (TAI) with a suspension of styrene maleic acid neocarzinostatin (SMANCS) and Lipiodol (SMANCS/Lipiodol). The parameters of hepatic functional reserve were apparently decreased after the second TAI with SMANCS/Lipiodol, and the patient died of hepatic failure 103 days after the second TAI. The autopsy liver specimen revealed multiple hepatic infarctions associated with peripheral arterial stenosis or occlusion, and portal thrombosis. It is speculated that both the arterial occlusion and the portal thrombosis caused the hepatic infarction, based on a long-term insufficiency of blood supply to the hepatocytes arising from toxic arteritis caused by SMANCS/Lipiodol.

Antineoplastic Agents↗
PubMed2001

Cilostazol represses vascular cell adhesion molecule-1 gene transcription via inhibiting NF-kappaB binding to its recognition sequence.

Cilostazol is a specific inhibitor of cAMP phosphodiesterase, which is used for treatment of ischemic symptoms of peripheral vascular disease. Although cilostazol has antiplatelet and vasodilator properties, its effect on the expression of adhesion molecules in vascular endothelium is not known. In the present investigation, we examined the effect of cilostazol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured vascular endothelial cells. Cilostazol strongly inhibited tumor necrosis factor (TNF)-alpha-induced expression of VCAM-1 protein and its mRNA. In addition, cilostazol reduced TNF-alpha-induced U937 cell adhesion to the vascular endothelial cells. In transient transfection studies, cilostazol inhibited TNF-alpha-induced transcriptional activation of VCAM-1 promoter. Electrophoretic mobility shift assays revealed that cilostazol repressed TNF-alpha-induced increase in binding of the transcription nuclear factor-kappaB (NF-kappaB) to its recognition site of VCAM-1 promoter. Cilostazol, however, failed to prevent nuclear translocation of the NF-kappaB p65 protein. These data indicate that cilostazol repressed VCAM-1 gene transcription in cultured vascular endothelial cells, via inhibiting NF-kappaB binding to its recognition sequence. Since the expression of the adhesion molecule is one of the earliest events occurred in atherogenic process, cilostazol might have the potential to prevent atherosclerosis at least via inhibition of the expression of the adhesion molecule.

Cell Adhesion↗
PubMed2001

Precordial compression without airway management induces lung injury in the rodent cardiac arrest model with central apnea.

To investigate whether the lung injury induced by precordial compression without ventilation or not, in the cardiac-arrest animal model with central apnea. Thirty male Sprague-Dawley rats were anesthetized with halothane. The cardiac arrest was induced by 100 mg/kg ketamine (IV) and accompanied with central apnea. They were allocated to four groups by means of resuscitation. Group A was treated with only precordial compression without the other treatments. In group B with tracheotomy and precordial compression. In group C was performed tracheotomy, oxygenation, and precordial compression. The animals in group D were treated with tracheotomy, oxygen administration, artificial ventilation, and precordial compression. Four minutes after cardiac arrest, the resuscitation was started and continued for 20 min. PaCO(2) in the group without mechanical ventilation increased significantly after the start of the resuscitation. All animals were sacrificed after resuscitation procedure. The wet/dry weight ratio of lung in group A (6.9+/-0.8) was significantly higher than that of the other groups B, C and D (5.9+/-0.6, 5.7+/-0.4 and 5.6+/-0.4, P<0.05 in each). The pathological findings also demonstrated the lung injuries, such as edema, migration, and destruction of structure in group A. The precordial compression alone did not improve CO(2) elimination in the gasping-less cardiac arrest model, as well as maybe inducing more severe lung injury than that with the protective management. This experimental model raises the possibility that chest compressions without airway management might result in lung injury.

Animals↗
PubMed2001

Characterization of premature atherosclerosis of carotid arteries in acromegalic patients.

OBJECTIVE: Acromegalic patients have increased mortality from vascular diseases. Although atherosclerotic risk factors such as hypertension, diabetes mellitus and dyslipoproteinaemia are highly associated with acromegaly, the prevalence of premature atherosclerosis in acromegalic patients and its relationship to these risk factors have not been reported. DESIGN: We measured mean intima-media thickness (IMT) of the carotid arteries in 21 acromegalic patients without symptomatic atherosclerotic vascular disease, by ultrasound high-resolution B-mode imaging. In analysis 1, it was compared with the predicted mean IMT based on data from existing risk factors (age, male sex, dyslipoproteinaemia, hypertension, diabetes mellitus, smoking status) in 282 non-acromegalic subjects. In analysis 2, the mean IMT in the 21 acromegalic patients was compared with that in 42 non-acromegalic subjects matched for age, sex and the other atherosclerotic risk factors. We also analysed clinical characteristics between the acromegalic patients with and without the atherosclerosis. RESULTS: Mean IMT in 21 acromegalic patients was 0.92 +/- 0.21 (mean +/- SD) mm. It was significantly (P < 0.05) lower than the mean IMT (1.03 +/- 0.12 mm) predicted from their existing risk factors (analysis 1). It was also less than that in 42 non-acromegalic subjects matched for atherosclerotic risk factors (1.07 +/- 0.37 mm; P < 0.05) (analysis 2). Among the acromegalic patients, 10 patients (48%) had increased mean IMT (> or = 1.1 mm) and/or plaque lesions whereas the other 11 had no such atherosclerotic changes. In the patients without the atherosclerotic changes, plasma insulin-like growth factor-I (IGF-I) concentration was significantly (P < 0.01) higher, and the prevalence of hypertension was significantly (P < 0.05) lower than in those with the atherosclerotic changes. CONCLUSIONS: The extent of carotid atherosclerosis in the acromegalic patients was not higher than that in non-acromegalic subjects, considering their atherosclerotic risk factors. Increased concentration of IGF-I might be involved in the lack of susceptibility to atherosclerosis in some acromegalic patients.

Acromegaly↗
PubMed2001

Fas antigen expression on hepatocytes predicts the short- and long-term response to interferon therapy in patients with chronic hepatitis C.

BACKGROUND: Interaction between Fas antigen on hepatocytes and Fas ligand on cytotoxic T cells induces apoptosis, a major mechanism of hepatitis C virus (HCV) -induced hepatocyte injury. We investigated the usefulness of Fas expression on hepatocytes as a predictor of short-and long-term response to interferon (IFN) therapy in 72 patients with chronic hepatitis C. METHODS: Ten million units of recombinant IFN-alpha2b were administered daily for the first 2 weeks, and three times a week for another 22 weeks. The short-term efficacy of IFN therapy was evaluated after 12-month follow-up from cessation of treatment. We also examined the long-term response to IFN at 56.6 +/- 10.8 (mean +/- s) months after termination of IFN therapy in 55 of 72 patients. RESULTS: Univariate analysis showed that serum HCV-RNA levels, HCV genotype and Fas expression significantly correlated with the short-term efficacy of IFN therapy (P = 0.005, 0.006, and 0.04, respectively). Fas antigen expression did not correlate with serum HCV-RNA levels (P = 0.286), but significantly correlated with HCV genotype (P = 0.003). Multivariate analysis indicated that Fas expression and serum HCV-RNA levels were independent determinants of the short-term response to IFN therapy. Combined together, Fas expression and serum HCV-RNA levels accurately predicted the short-term response to IFN therapy. On the other hand, in 55 patients who were examined the long-term response to IFN, about 60% of Fas-positive patients were HCV-RNA negative, whereas 30% of Fas-negative patients were HCV-RNA negative (P = 0.04). Among Fas-positive patients, the percentage of those with serum ALT levels persistently lower than twice the normal upper limit in long-term study (81.8%; 9/11) was significantly higher than those in short-term study even among patients who failed to show elimination of HCV-RNA (36.4%; 4/11, P = 0.03). CONCLUSION: Our results indicate that Fas expression on hepatocytes is a good predictor of the short-and long-term response to IFN therapy.

Adult↗
PubMed2001

Chronic oral administration of protease inhibitor decreases CCK-A receptor mRNA expression but increases pancreatic growth in rats.

It is well-known that chronic oral administration of trypsin inhibitors induces pancreatic hypertrophy and hyperplasia via stimulation of endogenous cholecystokinin (CCK) release. Because the growth-promoting effect of CCK on the pancreas is specifically mediated by the CCK-A receptor, we examined the plasma CCK concentrations, the expression of CCK mRNA in the intestine and CCK-A receptor mRNA in the pancreas, and pancreatic growth in rats after chronic oral administration of synthetic protease inhibitor (PI). PI at a dose of 100 mg/kg body weight was administered via an orogastric tube once daily for 20 days. Plasma CCK concentrations at 24 hours after the first PI administration were significantly higher than those in randomly fed rats (6.57 +/- 0.67 pmol/L vs 4.31 +/- 0.51 pmol/L; p < 0.001), and further increased to 14.24 +/- 1.63 pmol/L after PI for 10 days and decreased to 10.05 +/- 0.72 pmol/L after 15 days of PI administration. Treatment with PI for 20 days significantly increased the pancreatic weight, and the total pancreatic protein and DNA content by 190%, 290%, and 170%, respectively, when compared to the control rats. Chronic oral administration of PI, however, reduced CCK-A receptor mRNA expression in the pancreas by 60%. These findings suggest that chronic oral administration of PI induces an elevation of endogenous CCK release and stimulates pancreatic growth, but down-regulates the biosynthesis of CCK-A receptor at the transcriptional level in the pancreas.

Administration, Oral↗
PubMed2001

Role of TGF-beta1, extracellular matrix, and matrix metalloproteinase in the healing process of the pancreas after induction of acute necrotizing pancreatitis using arginine in rats.

INTRODUCTION: Pancreatic tissues are almost completely restored to normal after an attack of acute pancreatitis, once the cause of the disease is removed. Transforming growth factor (TGF)-beta and extracellular matrix (ECM) are known to play an important role in the process of wound healing in pathologic diseases. Tissue repair is a process regulated by a balance between synthesis and degradation of ECM. AIMS: To elucidate the role of TGF-beta, ECM, and matrix metalloproteinase (MMP) in the process of regeneration occurring after acute necrotizing pancreatitis. METHODOLOGY: Acute necrotizing pancreatitis was induced by intraperitoneal injection of 500 mg/100 g body weight of L-arginine in male Wistar rats. Expression of TGF-beta1 and ECM messenger RNA (mRNA) was determined by Northern blot analysis, and that of MMP-1 and MMP-2 mRNA was examined by the reverse transcription polymerase chain reaction (RT-PCR). Immunoreactivity for ECM components, TGF-beta1, and MMP-2 in the pancreas was assessed by using a monoclonal antibody. RESULTS: TGF-beta1 mRNA expression reached a peak value on day 2.5, with a decrease on day 3, and reached the control level on day 7. Procollagen types III and IV and fibronectin mRNA reached a peak value on day 2.5, whereas the expression level of procollagen type I mRNA was maximal on day 3, and gradually decreased to control levels by day 7. MMP-2 mRNA was significantly elevated on day 3, and peaked on day 5, whereas MMP-1 mRNA levels did not change throughout the observation period. Immunoreactivity for MMP-2 was observed around disrupted acinar cells and interstitial spaces on day 3, and maximally on day 7. Immunoreactivity for fibronectin was detected around disrupted acinar cells and interstitial spaces. On day 7, it was less than on day 5 around disrupted acinar cells and interstitial spaces, whereas in the regenerated acinar cells, it was undetected. CONCLUSION: Our results show that TGF-beta1 mRNA expression peaked earlier than that of ECM mRNA. Furthermore, increased level of the MMP-2 transcript was followed by disappearance of fibronectin. Our findings suggest that TGF-beta1 plays an important role in ECM production in the early phase of acute pancreatitis, and that MMP-2 is involved in the subsequent healing process.

Animals↗
PubMed2001

Troglitazone stimulates pancreatic growth in congenitally CCK-A receptor-deficient OLETF rats.

We examined the effect of troglitazone treatment on pancreatic growth in the CCK-A receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model for type 2 diabetes mellitus. A troglitazone-rich diet (0.2%) was given from 12 to 28 wk of age or from 12 or 28 wk of age to 72 wk of age. Fasting serum glucose concentrations in control OLETF rats increased progressively with age, which was almost completely prevented by troglitazone treatment. Insulin levels in serum and pancreatic content in the control rat markedly increased at 28 wk of age but significantly decreased at 72 wk of age compared with those at 12 wk of age, whereas those in troglitazone-treated rats were nearly the same at all ages and were similar to those in control rats at 12 wk of age. Pancreatic wet weight in control rats decreased with age irrespective of whether they were hyperinsulinemic (28 wk old) or hypoinsulinemic (72 wk old). Troglitazone treatment significantly increased pancreatic wet weight and protein, DNA, and enzyme contents compared with those in the control rats. Moreover, troglitazone treatment completely prevented or reversed histological alterations such as fibrosis, fatty replacement, and inflammatory cell infiltration. Our results indicate that troglitazone stimulates pancreatic growth in the congenitally CCK-A receptor-deficient OLETF rat not only by reducing insulin resistance and potentiating insulin action but also by suppressing inflammatory changes in the pancreas.

Aging↗
PubMed2001

Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells.

-It has been shown that ovarian steroid hormones can reduce the incidence of cardiovascular disease in postmenopausal women. As hormone replacement therapy for postmenopausal women, progestins are added to estrogens to eliminate the increased risk of endometrial cancer. However, the effects of progestins on the atherogenic process have not been well understood. In the present study, we examined the effects of progestins on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Immunocytochemical analysis revealed the presence of progesterone receptors in HUVECs. Progesterone clearly inhibited tumor necrosis factor-alpha-activated expression of VCAM-1 protein and its mRNA in HUVECs. Synthetic progesterone receptor agonist R5020 also inhibited the tumor necrosis factor-alpha-activated VCAM-1 expression, whereas medroxyprogesterone acetate (MPA) failed to do so. Electrophoretic mobility shift assays demonstrated that progesterone, but not MPA, inhibited DNA binding of the transcription nuclear factor-kappaB, which is critical for the inducible expression of VCAM-1. Because the expression of VCAM-1 is one of the earliest events that occurs in the atherogenic process, this adhesion molecule might be a target molecule for progesterone on vascular walls. The contrasting effects of progesterone and MPA seem clinically important, inasmuch as MPA is a widely used progestin in the regimen of hormone replacement therapy.

Endothelium, Vascular↗
PubMed2001

PPARalpha and GR differentially down-regulate the expression of nuclear factor-kappaB-responsive genes in vascular endothelial cells.

The antiinflammatory action of glucocorticoids is mediated partly by the inhibition of the expression of several cytokines and adhesion molecules. Some activators for nuclear receptors other than the GR have also been shown to inhibit the expression of these inflammatory molecules, although their molecular mechanisms remain unidentified. We therefore examined the effects of the PPARalpha activator fenofibrate and the GR activator dexamethasone on TNFalpha-stimulated expression of IL-6 and vascular cell adhesion molecule-1 in vascular endothelial cells. Both fenofibrate and dexamethasone reduced TNFalpha-induced IL-6 production in human vascular endothelial cells, but only fenofibrate reduced TNFalpha-stimulated vascular cell adhesion molecule-1 expression in these cells. Transient transfection of bovine aortic endothelial cells with an IL-6 promoter construct or a vascular cell adhesion molecule-1 promoter construct revealed that fenofibrate inhibited TNFalpha-induced IL-6 promoter as well as vascular cell adhesion molecule-1 promoter activities, whereas dexamethasone inhibited only the former. EMSA demonstrated that both fenofibrate and dexamethasone reduced nuclear factor-kappaB binding to its recognition site on the IL-6 promoter, but only fenofibrate reduced such binding to the vascular cell adhesion molecule-1 promoter. Thus, down-regulation of nuclear factor-kappaB activity by PPARalpha occurs in both the IL-6 and vascular cell adhesion molecule-1 genes, whereas that by GR occurs only in the IL-6 gene in vascular endothelial cells. These results strongly suggest the existence of a target gene-specific mechanism for the nuclear receptor-mediated down-regulation of nuclear factor-kappaB activity.

Biological Transport↗