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Biomedical subjects

K Iizuka

Publications and source records attributed to K Iizuka.

At least 73 records · Page 4Linked to original sources
PubMed1996

[Outcome of hypopharyngeal cancer].

An analysis of 41 patients with hypopharyngeal cancer treated between April 1985 and March 1996 is presented. Our guidelines for the treatment of hypopharyngeal cancer are a combination of chemotherapy, radiotherapy and surgery. The schedule of combination therapy is as follows: chemotherapy first, preoperative radiotherapy second, and surgery last. The surgery for hypopharyngeal cancer is pharyngolaryngoesophagectomy with radical neck dissection. In many cases free jejunum transplantation was used for reconstruction. The mean age of the patients was 64.8 years, and there were 39 men and 2 women. There were 33 cases of pyriform sinus type, 4 cases of postcricoid type, 3 cases of retropharyngeal type, and 1 case of unclassified type. Histopathologically, there were 40 cases of squamous cell carcinoma and 1 case of anaplastic carcinoma. Five-year total survival rates were 23.0% and 5-year survival rates at each tumor stage were 0% (T-1), 19.9% (T-2), 32.4% (T-3), 0% (T-4). There were no statistically significant differences between tumor stages. Five-year survival rates for each nodal stage were 14.1% (N-0), 54.5% (N-1), 0% (N-2), 0% (N-3). The survival rate for stage N-1 was significantly better (p < 0.05) than that for stage N-2. Five-year survival rates for all stages were 0% (I), 0% (II), 46.3% (III), 0% (IV). The survival rate for stage III was significantly better (p < 0.05) than that for stage IV. Twenty-five patients were operated on with or without chemotherapy and radiotherapy and, 16 patients received nonsurgical treatment. The 5-year cause-specific survival rate for patients who underwent surgery was 57.7% and for patients who underwent nonsurgical treatment was 0%. The survival rate for the radical treatment group was significantly better (p < 0.05) than that for the nonradical treatment group. The 5-year cause-specific survival rate for patients who underwent radical radiotherapy was 0%. That for patients who were treated by chemotherapy was 51.4% and for patients who were not so treated was 20.1%. The results of this study suggest several significant conclusions: 1, Stage is not a good predictor of outcome in hypopharyngeal cancer. 2, Patients undergoing surgery with or without chemotherapy and radiotherapy as the primary treatment enjoyed improved survival. 3, Radical radiotherapy provided poor prognosis. We think that chemotherapy provided some survival benefit.

Adult↗
PubMed1996

[Clinical study of laryngeal cancer].

An analysis of 74 patients with laryngeal cancer treated between February 1985 and July 1995 is presented. Their mean age was 64 years, and the male to female ratio was 14:1. There were 48 cases of the glottic type, 21 cases of the supraglottic type, 2 cases of the subglottic type, and 3 cases of the transglottic type. Histopathologically, there were 72 cases of squamous cell carcinoma and 2 cases of mucoepidermoid carcinoma. Cervical lymph node metastasis was detected in 12 cases (16%). The incidence of cervical lymph node metastasis in supraglottic carcinoma was significantly higher (p < 0.01) than that in glottic carcinoma. There were 12 cases of second primary cancers. The location of the lesions was as follows: lung, 4; esophagus, 2; stomach, 2; prostate, 2; liver, 1; and gingiva, 1. Radical radiotherapy was performed in 52 cases; the local control rate was 98%, and the recurrence rate was 20%. Combined radiotherapy and total laryngectomy or laryngectomy alone was performed in 23 cases, and the recurrence rate was 23%. The recurrence rate for glottic carcinoma after initial therapy was 13%, supraglottic carcinoma 38%, subglottic carcinoma 100% and transglottic carcinoma 33%. Five-year total survival and cause-specific survival rate were 69% and 82%, respectively. Five-year cause-specific survival rates according to subsite were 95% for glottic carcinoma, 69% for supraglottic carcinoma, 0% for subglottic carcinoma, and 50% for transglottic carcinoma. The survival rate in glottic carcinoma was significantly better (p < 0.05) than in supraglottic carcinoma. These results led us to establish the following guidelines for the treatment of laryngeal cancer: for T1 or T2 cases of the glottic type, radiotherapy is recommended first; for T3 or T4 cases of the glottic type, total laryngectomy after radiation therapy is recommended; for T1 or T2N0 cases of the supraglottic type, radiotherapy is recommended first; for T2N(+) or T3 or T4 cases of the supraglottic type, total laryngectomy after radiation therapy is recommended. If cervical lymph node metastasis is presently, neck dissection is necessary.

Adult↗
PubMed1996

Elevation of lymphocyte and hematopoietic stem cell numbers in mice transgenic for human granulocyte CSF.

Transgenic mice expressing human granulocyte colony stimulating factor (hG-CSF) were bred to establish an experimental model for studying the biologic function of hG-CSF. The mice produced approximately 1000 pg/ml of hG-CSF in sera and expressed hG-CSF mRNA in all of the tissues examined. Granulocytosis and elevation of hematopoietic precursor number were observed in hematopoietic tissues as expected, but lymphocytosis with 5-fold increase in peripheral blood and 2-fold increase in spleen was also evident. Hematopoietic stem cells capable of reconstituting lethally irradiated recipient mice were abundant in the circulation of these transgenic mice. No disadvantageous tissue damage was observed when various organs were analyzed. As shown in this study, G-CSF has a stimulating effect on lymphopoiesis when it is expressed in a certain condition. The lymphocytosis, as well as the high level of hematopoietic stem cell mobilization into circulation, indicates a wider range of potential G-CSF activity than expected. The mice transgenic for hG-CSF described herein will contribute greatly to the understanding of the regulatory mechanism in hematopoiesis.

Animals↗
PubMed1996

Hepatocyte nuclear factor-4 alpha gene mutations in Japanese non-insulin dependent diabetes mellitus (NIDDM) patients.

A mutation in the hepatocyte nuclear factor-4 alpha (HNF-4 alpha) gene has been recently reported to cause maturity-onset diabetes of the young (MODY) (Yamagata, Furuta, et al., 1996). The mutation can also be a good candidate for the responsible gene of non-insulin dependent diabetes mellitus (NIDDM). The existence of the mutated allele of Q268X (C to T substitution within the exon 7 of HNF-4 alpha gene) was searched in 514 alleles of Japanese NIDDM patients by polymerase chain reaction-restriction fragment length polymorphism analysis. No mutation was found in these patients. The result showed that the Q268X mutation of HNF-4 alpha gene was not frequent among general NIDDM patients and that it cannot serve as the major diabetogenic gene in the Japanese ethnic group.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed1995

Phosphorylation of caldesmon by mitogen-activated protein kinase with no effect on Ca2+ sensitivity in rabbit smooth muscle.

1. Recombinant, activated mitogen-activated protein kinase (3.3 microM; p42mapk) phosphorylated caldesmon in phasic (rabbit portal vein) and tonic (rabbit femoral artery) smooth muscle strips permeabilized with Triton X-100. 2. Phosphorylation of caldesmon by p42mapk neither induced contraction of relaxed smooth muscle nor affected the Ca2+ sensitivity of submaximally contracted permeabilized phasic or tonic smooth muscle.

Animals↗
PubMed1995

Novel monoclonal antibody reactive with thrombin-sensitive 74-kDa glycoproteins present on platelets and megakaryocytes both from mouse and rat.

A monoclonal antibody (designated 1C2) that reacts only with mouse platelets and megakaryocytes among hematopoietic cells was established by immunizing mouse platelets to an Armenian hamster. 1C2 reactive mouse molecule (1C2 antigen) was a surface glycoprotein with molecular weight of 74 kDa. Side by side comparison revealed that 4A5, a rat monoclonal antibody against mouse platelet, immunoprecipitated the identical molecule to 1C2 antigen. Of particular interest, 1C2 also labeled rat tissues with an identical pattern to that of mouse tissues and recognized a 74-kDa protein from rat platelets. Reactivity of 1C2 to mouse and rat platelets decreased when they were treated with thrombin. Following thrombin treatment of mouse platelets, 1C2 reactive 69-kDa protein appeared in the supernatants. Mouse and rat 1C2 antigens purified on 1C2-coated beads were cleaved by thrombin to generate 69-kDa fragments, establishing that 1C2 antigen is a direct substrate for thrombin. 1C2 is the first antibody to platelets and megakaryocytes of mouse and rat whose reactive molecule is well characterized, i.e., substrate for thrombin. 1C2 can be a useful tool in studying megakaryocytopoiesis and thrombopoiesis in rodent systems.

Animals↗
PubMed1995

[Polymorphism of 3,9-bis-(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2- c]quinoline-6-one(KCA-098), a new benzofuroquinoline derivative].

Physicochemical properties of polymorphism of 3,9-bis-(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinol ine-6-one (KCA-098) have been investigated. The existence of four crystalline forms (designated as hydrate, I, II and III) was confirmed by X-ray powder diffraction, IR spectroscopy and thermal analysis (DSC and TG). The hydrate was found to be a monohydrate by elemental analysis and water content measurement. DSC measurement found that the hydrate was transformed fo form III at about 93 degrees C, and then to form II at about 152 degrees C, and finally to form I at about 260 degrees C. On the other hand, when suspended in water the forms I, II and III were transformed into hydrate. The transition rate from form III to hydrate was higher than those from form II to hydrate and from form I to hydrate. Form III as a metastable form showed higher solubility than any of form I, II and hydrate.

Chemical Phenomena↗
PubMed1995

Non-phenotypic detection of osteopetrotic (op/op) mutation by using PCR-SSCP analysis.

Mice homozygous for recessive mutation osteopetrosis (op/op) on chromosome 3 provide a unique model to study the mechanism of haematopoiesis in conjunction with bone formation. Based on the DNA sequence data recently reported, we established a PCR-SSCP (polymerase chain reaction--single strand conformation polymorphism) assay which identifies an amplified fragment having an insertional point mutation present in macrophage colony-stimulating factor (M-CSF) gene of op/op mice. With this assay, three genotypes, op/op, +/op, and +/+ can be distinguished. Although heterozygous (+/op) and normal (+/+) mice could not be discriminated phenotypically, we could generate op/op mutant mice starting from a single heterozygous (+/op) mouse using only the PCR-SSCP aided screening method. This assay will permit introduction of the op mutant into any strain to generate a new animal model to study the cytokine network and haematopoiesis.

Animals↗
PubMed1995

Effect of transforming growth factor beta-1 on the intracellular calcium in cardiac fibroblasts.

We attempted to determine the effects of transforming growth factor beta-1 on intracellular Ca2+ concentration changes in the presence of isoproterenol in cardiac fibroblasts. Transforming growth factor beta-1 inhibited the increase of intracellular Ca2+ concentration in the presence of isoproterenol in fibroblasts. It also inhibited the production of cyclic-AMP in fibroblasts in the presence of isoproterenol. Islet-activating protein did not block these reactions of transforming growth factor beta-1. Forskolin did not affect the intracellular calcium concentration change resulting from treatment with transforming growth factor beta-1. Binding of [3H]CGP-12177 was decreased to 47% of control preincubated for 24 hours with transforming growth factor beta-1 in fibroblasts. Scatchard plots suggested a decrease in beta-adrenergic receptor number without specific change in receptor affinity. These results suggested that transforming growth factor beta-1 modulates the signal transduction through beta-adrenergic receptor and intracellular Ca2+ concentration by regulating the number of receptors in fibroblasts.

Animals↗
PubMed1995

Protective effect of an alpha 2-adrenoceptor antagonist, midaglizole, against allergen-provoked late asthmatic responses.

We investigated the effects of midaglizole (MID) on the allergen-provoked early and late asthmatic response (EAR, LAR) in a randomized, single-blind protocol. Four subjects with allergic asthma inhaled the following combinations: (1) allergen alone (control phase); (2) (a) pre- and posttreatment with MID (oral administration of 200 mg), (b) pretreatment with MID (200 mg), or (c) posttreatment with MID (200 mg). MID significantly inhibited the LAR in the three treatment phases (p < 0.05). However, the EAR was not inhibited significantly. These results suggest that MID may participate in the inhibition of the allergen-provoked LAR and may play an important clinical role as an anti-LAR agent.

Adrenergic alpha-Antagonists↗
PubMed1994

Purification and characterization of the mammalian myosin light chain phosphatase holoenzyme. The differential effects of the holoenzyme and its subunits on smooth muscle.

We have purified to homogeneity from the myofibrillar fraction of pig bladder a mammalian heterotrimeric form of PP-1, SMPP-1M. Purified pig bladder SMPP-1M is similar in composition and substrate specificity to avian gizzard PP-1M reported by Alessi et al. (Alessi, D., Macdougall, L. K., Sola, M. M., Ikebe, M., and Cohen, P. (1992) Eur. J. Biochem. 210, 1023-1035) and consists of the catalytic subunit of PP-1 (37 kDa) and two other equimolar subunits of 130 and 20 kDa. The properties of SMPP-1M and the role of its regulatory subunits in the dephosphorylation of myosin and in the initiation of relaxation were characterized both in vitro and in smooth muscle. We show that the relaxant effect of the catalytic subunit in smooth muscle is markedly potentiated by the addition of the regulatory subunits of SMPP-1M. Our findings demonstrate that SMPP-1M is the major phosphatase dephosphorylating myosin in mammalian smooth muscle and that myosin dephosphorylation is regulated in vivo via targeting subunits that specifically alter the substrate specificity of PP-1C toward myosin.

Animals↗
PubMed1994

Transforming growth factor beta-1 modulates the number of beta-adrenergic receptors in cardiac fibroblasts.

The effects of transforming growth factor beta-1 on concentration of intracellular Ca2+ changes in the presence of isoproterenol were studied in cardiac fibroblasts. Transforming growth factor beta-1 effect on cyclic-AMP production and ligand assay of beta-adrenergic receptors were also examined. Production of cyclic-AMP in fibroblasts preincubated with transforming growth factor beta-1 decreased compared with non-transforming growth factor beta-1-treated fibroblasts in the presence of isoproterenol. An increase of intracellular Ca2+ concentration in the presence of isoproterenol was also inhibited in transforming growth factor beta-1-treated fibroblasts. Islet-activating protein did not restore these reactions of transforming growth factor beta-1. Concentration change of intracellular calcium under the treatment of transforming growth factor beta-1 was unaffected by forskolin addition. Binding of [3H]CGP-12177 was decreased to 47% of control preincubated for 24 h with transforming growth factor beta-1 in fibroblasts. Scatchard plots suggested a decrease in beta-adrenergic receptor number without specific change in receptor affinity. These results suggested that transforming growth factor beta-1 modulates the signal transduction through beta-adrenergic receptor and intracellular Ca2+ concentration by regulating the number of receptor in fibroblasts.

Animals↗
PubMed1994

Introduction of high molecular weight (IgG) proteins into receptor coupled, permeabilized smooth muscle.

The permeability to high molecular weight (IgG, 150 kD) proteins of the plasma membrane of receptor-coupled smooth muscles permeabilized with beta-escin was determined using confocal microscopy of immunofluorescent tracers and measurement of lactate dehydrogenase (LDH, 135-140 kD) leakage. Permeabilized strips of rabbit portal vein and guinea pig ileum were incubated in a relaxing solution containing mouse anti-smooth muscle alpha-actin antibody and immunostained with F(ab')2 labeled with tetramethyl rhodamine isothiocyanate. Confocal light microscopy of Triton X-100 and beta-escin permeabilized cells showed homogeneous staining of the cytoplasm, whereas in alpha-toxin treated and intact preparations only damaged cells at the edges of the strips were stained. Both the Ca(2+)-sensitizing effect of phenylephrine, in rabbit portal vein, and Ca2+ release by carbachol in guinea pig ileum, were retained after permeabilization and the treatment with the primary antibody. During the 30 min permeabilization, 38%, and within the next 75 min an additional approximately 30%, of the total LDH leaked out from the beta-escin-treated group, but not from the alpha-toxin-treated group (3.2%). The responsiveness to agonist and maximum contractility was improved if the preparations were incubated during the introduction of proteins at 4 degrees C, rather than 24 degrees C. Ca(2+)-independent myosin light chain kinase (61 kD) contracted the permeabilized portal vein in the absence of free Ca2+ (pCa < 8). In conclusion, permeabilization with beta-escin allows the transmembrane passage of 150 kD proteins under our experimental conditions that also retain receptor-coupled signal transduction.

Actins↗
PubMed1994

[Research and development of ozagrel, a highly selective inhibitor of TXA2 synthase].

Highly selective inhibitors of thromboxane (TX) A2 synthase were noted as a therapeutic agent for ischemic heart diseases, thromboembolic disorders, cerebral circulatory disorders, and asthma. The 1-substituted imidazoles and beta-substituted pyridines showed high inhibitory potency on TXA2 synthase. The structure-activity relationships of the imidazole and pyridine derivatives as inhibitors of TXA2 synthase were investigated. Introduction of various substituents into the carboxy-bearing side chain of 1-(7-carboxyheptyl) imidazole and beta-(7-carboxyheptyl) pyridine was found to increase the inhibitory potency. The length of the side chains with the phenylene group was optimum in the region of 8.5 to 10 A for the inhibitory potency on TXA2 synthase. Among the tested imidazole and pyridine derivatives, (E)-4-(1-imidazolylmethyl)cinnamic acid (44) and (E)-3-[4-(3-pyridylmethyl)phenyl]-2-methylacrylic acid (56) showed the highest potency (IC50 = 1.1 x 10(-8) and 3 x 10(-9) M). The inhibition by these derivatives was highly selective for TXA2 synthase, since other enzymes which are involved in the arachidonic acid cascade, such as fatty acid cyclooxygenase, 5-lipoxygenase, prostacyclin (PGI2) synthase, and PGE2 isomerase were not affected. On the basis of the results obtained from the pharmacological, physicochemical and toxicological studies on the two compounds (44 and 56), (E)-4-(1-imidazolylmethyl) cinnamic acid (44; OKY-046, ozagrel) was selected as the best compound of highly selective inhibitors of TXA2 synthase. The pharmacological properties of ozagrel are as follows. The inhibition of TXA2 synthase by ozagrel was more effective on human and rabbit enzymes than those of other species. Ozagrel increased 6-keto-PGF1 alpha, one of stable metabolites of PGI2, in various isolated cells and tissues perhaps via accumulated PG endoperoxides resulted by the inhibition of TXA2 synthase. Such an increase in PGI2 production by ozagrel was also observed in various experimental animals. We obtained the suggestion that, by the reduction of TXA2 production and increment of PGI2 production, ozagrel inhibits the spasms of basilar artery and the decreases in regional cerebral blood flow in dogs which received autologous blood into cisterna magna, and inhibits the decreases in motor function and regional cerebral blood flow, and the formation of infarcted area in the animals of cerebral ischemic treatment. It was also suggested that ozagrel inhibits leukotriene-, platelet-activating factor-, and antigen-induced bronchoconstriction in guinea-pigs and inhibits the induction of airway hyperresponsiveness by various stimuli in several species of animals by both mechanisms. The summarized results of ADME, toxicological, and clinical studies were also described.

Animals↗
PubMed1994

[Role of calpain on hypoxic myocyte injury].

The calcium-activated neutral protease, calpain, was tested for its proteolytic effects to degrade the cell membrane spectrin-like protein, fodrin, during hypoxia. Cardiac myocytes, isolated from neonatal rat hearts, were incubated under hypoxic conditions for 6 hours. The cell death during hypoxia rose to 80% after 6 hours. Extracellular protease activity was much more elevated during hypoxia, than in aerobic states at 6 hours. Intracellular protease activity was also elevated in hypoxia. These protease activities were markedly inhibited by the cysteine protease inhibitor E-64 and the calpain specific inhibitor, calpastatin. Hypoxic cell death was also suppressed by E-64. Cell membrane proteins prepared from hypoxic myocytes were examined with electroblots stained for fodrin by the peroxidase method. A 125 kilodalton immunoreactive degradation product of fodrin was found under hypoxic conditions. Treatment with E-64 inhibited both the appearance of this degradation band and the decrease in the content of fodrin. These observations indicate that calpain is activated during hypoxia and that it is related to cell membrane protein degradation, especially in fodrin. The data also suggest that protease inhibitor E-64 treatment may be beneficial in protection against hypoxic myocyte injury.

Animals↗