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Biomedical subjects

T Hirano

Publications and source records attributed to T Hirano.

At least 361 records · Page 20Linked to original sources
PubMed1998

Antitumor activity of tumor necrosis factor alpha conjugated with divinyl ether and maleic anhydride copolymer on solid tumors in mice.

The purpose of this study is to further explore the usefulness of conjugation with functional polymeric modifiers for clinical application of bioactive proteins and to increase the therapeutic efficacy of tumor necrosis factor alpha (TNF-alpha) by conjugation in vivo. We synthesized TNF-alpha conjugated with the copolymer of divinyl ether and maleic anhydride (DIVEMA), which has intrinsic antitumor activity as a synthetic biological response modifier. The synthesis of DIVEMA-TNF-alpha could be controlled by the addition of 2,3-dimethylmaleic anhydride (DMMAn), which binds to or separates from amino groups when the pH is changed. The specific activity of DIVEMA-TNF-alpha (+) synthesized with DMMAn was hardly decreased in vitro. However, DIVEMA-TNF-alpha (-), which is conjugated without blocking by DMMAn, had a markedly diminished specific activity. DIVEMA-TNF-alpha (+) caused a dramatic hemorrhagic necrotic effect on the tumor when compared to native TNF-alpha 24 h after i.v. injection into mice bearing Sarcoma-180 solid tumors. In addition, DIVEMA-TNF-alpha (+) at a dose of only 100 Japan reference units per mouse revealed a dramatic antitumor effect that is approximately 100 times greater than native TNF-alpha and that could induce complete regression in all five mice bearing Meth-A solid tumors without any apparent side effects. Because neither DIVEMA alone nor a mixture of TNF-alpha and DIVEMA caused antitumor activity with i.v. administration, the increase in antitumor potency of TNF-alpha may be caused by the covalent conjugation with DIVEMA. DIVEMA-TNF-alpha at low dose revealed dramatic antitumor potency. Because TNF-alpha injected in vivo is extremely low-dose, concentration of intrinsic TNF-alpha in vivo is not influenced. Therefore, the cytokine network in vivo is not destroyed. These results suggest that DIVEMA is a useful polymeric modifier for conjugation of TNF-alpha to increase its antitumor activity.

Animals↗
PubMed1998

Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma.

Mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) is a key molecule in intracellular signal transducing pathways that transport extracellular stimuli from cell surface to nuclei. MAPK/ERK has been revealed to be involved in the physiological proliferation of mammalian cells and also to potentiate them to transform. However, its role in the outgrowth of human hepatocellular carcinoma (HCC) has yet to be clarified. Therefore, in this study, we investigated the activation of MAPK/ERK and its associated gene expression in HCC. MAPK/ERK was activated in 15 of 26 cases of HCC we examined (58%), and its activity level was significantly higher in HCC than in the adjacent non-cancerous lesions. Besides, MAPK/ERK activation in HCC was positively correlated with protein expression of transcription factor c-Fos. Furthermore, in 25 of 26 cases of HCC which genomic DNA was available, 22 cases without genomic DNA amplification exhibited positive correlation, not only between protein expression of c-Fos and cyclin D1, but also between MAPK/ERK activation and cyclin D1 expression. Concerning the relationship between MAPK/ERK activation and the clinicohistopathological features of HCC, the tumor (HCC) versus non-tumor (non-cancerous counterpart) ratio (T/N) of MAPK/ERK activity was positively correlated with tumor size, but neither with the stage of HCC nor the degree of differentiation of HCC. In conclusion, these findings suggest that MAPK/ERK activation in human HCC may play an important role in multistep hepatocarcinogenesis, especially in the progression of HCC; at least in part, through cyclin D1 up-regulation primarily induced by MAPK/ERK via c-Fos.

Aged↗
PubMed1998

Localization of cortisol receptor in branchial chloride cells in chum salmon fry.

To clarify the involvement of cortisol in functional differentiation of branchial chloride cells, cellular gene expression and localization of cortisol receptor were examined in chum salmon (Oncorhynchus keta) fry in freshwater (FW) and those adapted to seawater (SW) by in situ hybridization and immunocytochemical staining. Sodium-potassium adenosinetriphosphatase (Na+,K(+)-ATPase) activity in the whole gill homogenate was significantly higher in SW fish than in FW fish. There were no significant differences in plasma cortisol levels nor in the expression of cortisol receptor mRNA, examined by Northern blot analysis, between SW and FW fish. The receptor gene expression, examined by in situ hybridization with biotin-labeled synthetic oligonucleotide probe, and specific immunostaining with anticortisol receptor serum were found in two types of chloride cells distributed in the gill filaments and lamellae, which were also labeled with anti-Na+,K(+)-ATPase serum, indicating that cortisol may be one of the important factors regulating chloride cell functions. Gene expression of cortisol receptor in filament chloride cells, which were highly activated in SW-adapted fry, was significantly greater in the fry adapted to SW than in FW-adapted fry, reflecting their specific role in salt secretion in SW. Cortisol receptors were also present in undifferentiated cells in the interlamellar regions adjacent to the central venous sinus, also suggesting the involvement of cortisol in the functional differentiation of chloride cells.

Animals↗
PubMed1998

Experience with kidney transplantation in children and adolescents.

BACKGROUND: Paediatric kidney transplantation has different aspects in adults in terms of underlying primary renal disease, surgical technique, perioperative care and graft prognosis. Significant urological problems are present in a high percentage of paediatric recipients. This study was undertaken to characterize paediatric kidney transplantation as performed at our institutes. METHODS: Twenty-eight patients (age range 4-17 years, 10 girls, 18 boys) were included in this study. We analyzed (1) urologic procedures performed prior to or simultaneously with transplantation, (2) intraoperative changes in haemodynamics, (3) postoperative complications and (4) acute allograft rejection and graft prognosis. RESULTS: Of 4 patients with lower urinary tract abnormalities (neurogenic bladder in 3, posterior urethral valve in 1), 2 underwent augmentation ileocystoplasty prior to transplantation. The Mitrofanoff procedure as a diversion for neourethra was also performed in 2 of the 4 patients. All these 4 patients were managed with clean intermittent catheterization. Central venous pressure changes before and after graft vessel declamping were much greater in patients with body weight below 25 kg than in those above 25 kg. Five surgical complications and 6 infections were encountered postoperatively and hypertension was lasting in 6. Thirteen patients experienced 19 periods of acute allograft rejection. All of the 24 patients in the cyclosporin era (1986-) overcame rejections and they are all alive with good graft function. CONCLUSIONS: As long as proper pretransplant patient evaluation and management, and intensive perioperative care are undertaken, good prognosis of renal allograft can be achieved in young patients.

Adolescent↗
PubMed1998

NADH-diaphorase deficiency identified in a patient with congenital methaemoglobinaemia detected by pulse oximetry.

We report on a young woman with congenital methaemoglobinaemia detected by a pulse oximeter during anaesthesia. Investigation of the patient and her family showed that the methaemoglobinaemia resulted from a recessive deficiency of NADH-diaphorase enzyme. A knowledge of the working principles and limitations of pulse oximetry is essential to determine appropriate management in desaturation episodes during the perioperative period.

Adolescent↗
PubMed1998

Assessment of malignancy of glioma by positron emission tomography with 18F-fluorodeoxyglucose and single photon emission computed tomography with thallium-201 chloride.

The histological diagnosis and proliferative potential measured by bromodeoxyuridine (BrdU) labelling index (LI) were correlated with preoperative CT and contrast-enhanced, MRI, 18F-fluorodeoxyglucose positron emission tomography (PET) and 201T1 single photon emission computed tomography (SPECT) in 43 patients with various grades of glioma. 201T1 SPECT had slightly higher sensitivity to tumours with BrdU LI > or = 5% (showing 10/10) than 18F-FDG PET (7/8 tumours). 18F-FDG PET was better for identifying tumours of BrdU LI < 1% (13/15) than 201T1 SPECT (13/22). Accumulation of 201T1 in the tumour was slightly different from contrast enhancement on CT and/or MRI, and gave "false-positive" results in some low-grade gliomas. However, 201T1 SPECT, which is available in many hospitals and may cost less, provided useful information to supplement that from CT and MRI.

Astrocytoma↗
PubMed1998

Structural changes in blood vessels entering the growth plate during growth in rats.

We observed the structural changes in blood vessels entering the growth plates of the femur and tibia of rats during growth using scanning electron microscopy. The penetrating vessels had blind endings which were bulbous at a time when rats showed rapid skeletal development. With subsequent slowing of development, the density of the vessels decreased and the blind endings became short stumps. These changes were more prominent in the proximal femur than in the distal femur and proximal tibia. The present study indicates an intimate relation between endochondral ossification in the growth plate and the structure of the penetrating vessels.

Animals↗
PubMed1998

Multicentric Castleman's disease associated with renal amyloidosis and pure red cell aplasia.

A 50-year-old man was admitted suffering from severe anemia and renal dysfunction. He had been admitted for the first time at the age of 49, and was diagnosed with multicentric Castleman's disease (MCD) and secondary amyloidosis. At that time, marked erythroid hypoplasia was demonstrated by both aspiration and biopsy of bone marrow. A diagnosis of pure red-cell aplasia (PRCA) was made. Immunosuppressive agents improved his symptoms and laboratory data. We report here a very rare case of PRCA following MCD and amyloidosis, and with reference to the literature, we discuss the relation between MCD and related diseases.

Amyloidosis↗
PubMed1998

Impact of ischemia-reperfusion injury on dimensional changes of hepatic microvessels.

Dimensional alteration of hepatic microvessels was demonstrated during reperfusion after normothermic hepatic ischemia. Using a specially designed cover glass, it was possible to relocate selected sites of observation and microvessels repeatedly throughout the whole reperfusion time. Twenty minutes of hepatic ischemia resulted in a decrease of sinusoidal diameter (mean +/- SEM; 10.0 +/- 0.3 microns at baseline, 8.2 +/- 0.2 microns after ischemia) and diameter of postsinusoidal venules (26.4 +/- 1.2 at baseline, 23.0 +/- 1.0 after ischemia). In the control group (no ischemia induced) no changes of these parameters were observed. Thus, the reduction of hepatic microvascular cross section was present during the early phase of reperfusion. Hepatic dysfunction was characterized by increased serum activity of liver enzymes and reduction of bile flow in the ischemia-exposed animals. It has been suggested that postischemic dimensional microvascular changes are involved in postischemic liver dysfunction.

Animals↗
PubMed1998

Kinetic analysis of the growth rate of the flagellar hook in Salmonella typhimurium by the population balance method.

The growth rate of flagellar hooks in Salmonella typhimurium was analyzed by computer-aided simulation of the length distributions of mutant hooks of uncontrolled length (polyhooks). The wild-type hook has a relatively well-controlled length, with an average of 55 nm and a standard deviation of 6 nm. Mutations in the fliK gene give rise to polyhooks. A histogram of the lengths of polyhooks from a fliK mutant shows a peak at 55 nm with a long monotonic tail extending out to 1 microm. To analyze the growth rate, we employed the population balance method. Regression analysis showed that the histogram could fit a combination of two theoretical curves. In the first phase of growth, the hook starts with a very fast growth rate (40 nm/min), and then the rate exponentially slows until the length reaches 55 nm. In the second phase of growth, where the hook length is over 55 nm, the hook grows at a constant rate of 8 nm/min. Second mutations in either the fliK or flhB genes, as found in pseudorevertants from fliK mutants, give rise to polyhook filaments (phf). The ratio between the numbers of hooks with and without filament was 6:4. The calculated probability of filament attachment to polyhooks was low so that the proportion of hooks that start filament growth was only 2% per minute. The lengths of polyhooks with and without filaments were measured. A histogram of hook length in phf's was the same as that for polyhooks in single-site fliK mutants, against the expectation that the distribution would shift to a shorter average. The role of FliK in hook length control is discussed.

Bacterial Proteins↗
PubMed1998

Individual pharmacodynamics assessed by antilymphocyte action predicts clinical cyclosporine efficacy in psoriasis.

BACKGROUND: Cyclosporine (INN, ciclosporin) use for psoriasis has been proposed and clinically examined. However, individual variation in cyclosporine efficacy is currently observed. To evaluate individual therapeutic potency of cyclosporine, pharmacodynamic approaches were performed with use of peripheral blood mononuclear cells (PBMCs) from patients with psoriasis. METHODS: Cyclosporine effects on PBMC-blastogenesis were examined in 33 patients with psoriasis. The drug concentration that gave 50% inhibition of mitogen-stimulated PBMC proliferation in vitro (IC50, in nanograms per milliliter) was evaluated in each patient. Cyclosporine was administered at an initial dose of 5 mg/kg/day, and the dose was tapered for 16 weeks to 3 mg/kg/day. The recovery rate in the psoriasis area and the severity index (PASI) 16 weeks after cyclosporine therapy began was measured. RESULTS: Cyclosporine IC50 values in 33 patients deviated widely, from 0.1 to 120.6 ng/ml. We classified these patients into two groups on the basis of their PBMC sensitivity to cyclosporine with use of the median cyclosporine IC50 (3.0 ng/ml) of these patients as the cutoff point. The PASI recovery rate after cyclosporine therapy in the patients with high sensitivity was significantly higher than that in the patients with low sensitivity (p < 0.0007). Moreover, a significant negative correlation between the IC50 and the PASI recovery rate was observed in these 33 patients (r = -0.73; p < 0.0001). Blood trough levels and side effects of cyclosporine were not significantly different between the two patient groups. CONCLUSIONS: The results showed that we could use PBMCs to pharmacodynamically predict the patients with a poor response to cyclosporine therapy. These patients may require larger doses of cyclosporine or alternative approaches to treatment. The patients with PBMCs sensitive to cyclosporine should be evaluated for treatment with smaller doses of the drug to avoid serious side effects.

Adult↗
PubMed1998

Triglyceride metabolism in heterozygote of Watanabe heritable hyperlipidemic rabbit.

The present study was conducted in order to examine the role of low-density lipoprotein (LDL)-receptor activity in very-low-density lipoprotein (VLDL) triglyceride metabolism in vivo. Fructose-feeding (10% in drinking water) for 2 weeks resulted in elevated plasma triglyceride in heterozygote of Watanabe heritable hyperlipidemic (WHHL) rabbit (WHHLH) associated with suppressed fractional catabolic rate (FCR) of plasma triglyceride, whereas Japanese white (JW) rabbit with normal LDL receptor activity showed no remarkable change in plasma triglyceride turnover after fructose-feeding, suggesting an involvement of LDL receptor activity on triglyceride metabolism. Thereafter, in order to stimulate cellular LDL receptor activity, fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitor, was administered orally (1.52 +/- 0.26 mg/kg) to fructose-fed WHHLH. Significant suppression of triglyceride secretion rate (TGSR) was observed after treatment. However, since plasma triglyceride level was markedly suppressed, FCR of plasma triglyceride was significantly elevated by fluvastatin. Thus, it is speculated from the present data that LDL receptor activity is significantly involved in VLDL triglyceride metabolism in rabbits.

Animals↗
PubMed1998

High prevalence of small dense LDL in diabetic nephropathy is not directly associated with kidney damage: a possible role of postprandial lipemia.

To determine whether high prevalence of small dense low-density lipoprotein (LDL) in non-insulin-dependent diabetes (NIDDM) with nephropathy is directly associated with kidney damage, we measured LDL particle size by non-denaturing 2-16% gradient polyacrylamide gel electrophoresis in non-diabetic patients with primary renal disease and compared the results to particle size in NIDDM patients with diabetic nephropathy. The average LDL particle diameter was significantly smaller in patients with diabetic nephropathy (245+/-3 A mean +/- SEM) compared to the controls (263+/-1 A), diabetics without nephropathy (257+/-2 A), patients with primary renal disease (254+/-2 A) or non-diabetic patients treated with hemodialysis (HD) (260+/-1 A). The incidence of small LDL (mean diameter is < or =255 A) was remarkably increased in diabetic nephropathy (67%) compared to diabetes without nephropathy (27%), patients with renal disease (24%), HD patients (15%) and controls (10%). LDL size in patients with primary renal disease was significantly smaller than those in controls. However, because there was an excellent correlation between LDL size and plasma triglyceride (TG) levels, when hypertriglyceridemic subjects (TG >1.7 mM) were excluded, no difference of LDL size was observed between the renal disease group (260+/-2 A) and the control group (264+/-1 A). On the other hand, even when hypertriglyceridemic subjects were excluded, LDL size was still smaller in diabetic nephropathy (250+/-4 A). We performed an oral fat load test in normotriglyceridemic subjects (fasting TG <1.7 mM) of control, diabetes with and without nephropathy and primary renal disease. The TG responses in plasma and TG-rich-lipoprotein (TRL) (d <1.006) after the oral fat load were significantly greater in NIDDMs with nephropathy compared to controls or NIDDMs without nephropathy, while such a marked postprandial lipemia was not observed in patients with primary renal disease. In these fasting normotriglyceridemic subjects, LDL size was significantly inversely correlated with postprandial TG responses, which is totally independent from fasting TG levels. These results suggest that high prevalence of small dense LDL in NIDDM patients with nephropathy is not directly associated with kidney damage. Postprandial lipemia may play an important role in reducing LDL particle size in these patients.

Aged↗
PubMed1998

A selective inhibitor of intestinal ACAT, EAB309 suppresses both intestinal and hepatic cholesterol output and stimulates chylomicron removal.

The effect of a novel inhibitor of acylcoenzyme A:cholesterol acyltransferase (EC 2.3.1.26, ACAT), EAB309 (EAB) on plasma lipid metabolism was studied in cholesterol-fed rats. Orally administered EAB was not detected in the portal vein or the liver but distributed exclusively in the intestine, suggesting that this agent selectively inhibits intestinal ACAT. The rats were fed with either a cholesterol-diet or a cholesterol-diet containing 0.005% EAB (w/w) ad. libium for three weeks. ACAT activity in intestinal microsomes was significantly inhibited in EAB-treated rats. Hepatic ACAT activity was also decreased in EAB-treated rats, however, this was attenuated by the addition of excess cholesterol to the liver microsome, indicating that substrate availability is tightly associated with this enzyme's activity and the inhibition of hepatic ACAT by EAB is not direct. Incorporation of [3H]-cholesterol to cholesteryl ester (CE) in mesenteric lymph were markedly suppressed by EAB treatment. Chylomicrons (CMs) were doubly labeled with [3H]-vitamin A and [14C]-triglyceride (TG) in EAB-treated or non-treated rats and injected into normal chow-fed rats. The CMs from EAB-treated rats were cleared faster from the plasma and taken up more by the liver compared with the CMs from non-treated rats. The content of CE in newly secreted VLDL was remarkably decreased by EAB treatment without affecting TG output. These results demonstrate that EAB, a novel inhibitor of intestinal ACAT, significantly suppresses both intestinal and hepatic CE output and stimulates CM removal. This suggests that the inhibition of intestinal ACAT can subsequently suppress hepatic ACAT by decreased CE delivery from the intestine to the liver.

Animals↗
PubMed1998

Tacrolimus-induced apoptosis and its prevention by interleukins in mitogen-activated human peripheral-blood mononuclear cells.

The present study demonstrated that tacrolimus (FK506) induced apoptosis in mitogen-activated human PBMCs and that several interleukins (ILs) prevented the apoptosis. Mitogen-activated PBMCs obtained from healthy subjects treated with 1 ng/ml of FK506 exhibited a DNA-ladder structure in agarose-gel electrophoresis. Moreover, in quantitative analysis of fragmented DNA using cell death detection ELISA, 1 ng/ml of FK506 induced maximal apoptotic induction, whereas > 10 ng/ml of glucocorticoids (GCs) or cyclosporine (CsA) was required to achieve maximal induction of apoptosis in PBMCs. FK506-induced apoptosis was efficiently attenuated by co-addition of ILs including IL-1beta (2 ng/ml), IL-2 (5 ng/ml) and IL-4 (40 ng/ml) into culture. The results showed that FK506 induces apoptosis in mitogen-activated PBMCs at concentrations which exhibited sufficient suppression of PBMC-blastogenesis. The data also suggested that cytokine networks including those via IL-1beta and IL-4 in addition to IL-2 prevent FK506-induced apoptosis.

Apoptosis↗