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Biomedical subjects

K Inagaki

Publications and source records attributed to K Inagaki.

At least 37 records · Page 2Linked to original sources
PubMed2000

Anti-inflammatory action of a novel peptide, SEK-1005, isolated from a Streptomyces.

The pharmacological activity of a novel cyclic peptide (SEK-1005: C(45)H(70)N(8)0(13)) isolated from Streptomyces nobilis was studied in rats during the development of inflammation. SEK-1005 (0.1-0.5 mg/kg, i.p.) suppressed the passive Arthus reaction and the carrageenin-induced oedema. A steroidal anti-inflammatory drug, prednisolone (10 mg/kg, i.p.), also was effective on both inflammations. However, indomethacin (5 mg/kg, i.p.), a cyclooxygenase inhibitor, was less effective on the passive Arthus reaction. Also interesting was that the SEK-1005 effect showed its maximum level after a 24-h lag period and that its effect, as well as the prednisolone effect, was reduced by the treatment with a protein synthesis inhibitor, cycloheximide. SEK-1005 and prednisolone also showed marked protection against the adjuvant-induced arthritis, but failed to prevent the tuberculin response. These findings indicate that SEK-1005 is a new type of non-steroidal anti-inflammatory agent with an action similar to that of prednisolone.

Animals↗
PubMed2000

Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium.

BACKGROUND: A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts. METHODS AND RESULTS: At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the delta-isoform but not the other isoforms of PKC to the plasma membrane. CONCLUSIONS: The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.

Animals↗
PubMed2000

Roles for the protein tyrosine phosphatase SHP-2 in cytoskeletal organization, cell adhesion and cell migration revealed by overexpression of a dominant negative mutant.

SHP-2, a SRC homology 2 domain-containing protein tyrosine phosphatase, mediates activation of Ras and mitogen-activated protein kinase by various mitogens and cell adhesion. Inhibition of endogenous SHP-2 by overexpression of a catalytically inactive (dominant negative) mutant in Chinese hamster ovary cells or Rat-1 fibroblasts has now been shown to induce a marked change in cell morphology (from elongated to less polarized) that is accompanied by substantial increases in the numbers of actin stress fibers and focal adhesion contacts. Overexpression of the SHP-2 mutant also increased the strength of cell-substratum adhesion and resulted in hyperphosphorylation of SHPS-1, a substrate of SHP-2 that contributes to cell adhesion-induced signaling. Inhibition of SHP-2 also markedly increased the rate of cell attachment to and cell spreading on extracellular matrix proteins such as fibronectin and vitronectin, effects that were accompanied by enhancement of adhesion-induced tyrosine phosphorylation of paxillin and p130Cas. In addition, cell migration mediated by fibronectin or vitronectin, but not that induced by insulin, was impaired by overexpression of the SHP-2 mutant. These results suggest that SHP-2 plays an important role in the control of cell shape by contributing to cytoskeletal organization, and that it is an important regulator of integrin-mediated cell adhesion, spreading, and migration as well as of tyrosine phosphorylation of focal adhesion contact-associated proteins.

Animals↗
PubMed2000

The effect of Kana literacy acquisition on the speech segmentation unit used by Japanese young children.

Three experiments were undertaken to investigate whether young children's segmentation units would change as they learned to read kana letters, which represent morae (subsyllabic rhythmic units). The first 2 experiments used a vocal-motor segmentation task to examine whether 4- to 6-year-olds preferred to segment spoken words containing the special syllables CVN, CVQ, or CV: into syllables or into morae. The third experiment used a target monitoring task for CVN to examine whether children's detection of the target syllable in a series of words would vary depending on the moraic constitution of the target and the moraic-syllabic status of the word initial in which the target was embedded. Results indicated that the children's conscious segmentation of words, except for those having a geminate stop consonant (CVQ), developed from being a mixture of syllable- and mora-based to being predominantly mora-based as they learned to read kana letters. The tendency toward mora-based segmentation was also found in the target monitoring task, which required segmentation at a less conscious level.

Child, Preschool↗
PubMed2000

Treatment for pyothorax-associated lymphoma.

In eight patients with pyothorax-associated lymphoma (PAL), which resulted from artificial pneumothorax for the treatment of pulmonary tuberculosis, seven patients received radiotherapy and five showed no local recurrence. All four patients treated by primary chemotherapy had disease progression. Radiotherapy of 50 Gy with wide margins is recommended to treat PAL.

Aged↗
PubMed2000

Acid load during total parenteral nutrition: comparison of hydrochloric acid and acetic acid on plasma acid-base balance.

The effects of hydrochloric acid and acetic acid on the plasma acid-base balance were investigated in four rabbits receiving parenteral nutrition. Hyperchloremic metabolic acidosis was observed only in the animals receiving total parenteral nutrition (TPN) whose pH was adjusted with hydrochloric acid. The observed acidosis was due to an excess of hydrogen ions with chloride ions as judged by the plasma-base excess and urinary net-acid excess and not by the infusion of solution having a high titratable acidity. The hydrogen ion released from the acetic acid added to TPN is consumed by the metabolism of the acetate ion and thus does not contribute to the net hydrogen-ion load. A reduction in the chloride load by using acetic acid to adjust the pH of the TPN solution when it is formulated can be safely achieved and prevents acidosis.

Acetic Acid↗
PubMed2000

Purification and characterization of 3-isopropylmalate dehydrogenase from Thiobacillus thiooxidans.

3-Isopropylmalate dehydrogenase was purified to homogeneity from the acidophilic autotroph Thiobacillus thiooxidans. The native enzyme was a dimer of molecular weight 40,000. The apparent K(m) values for 3-isopropylmalate and NAD+ were estimated to be 0.13 mM and 8.7 mM, respectively. The optimum pH for activity was 9.0 and the optimum temperature was 65 degrees C. The properties of the enzyme were similar to those of the Thiobacillus ferrooxidans enzyme, expect for substrate specificity. T. thiooxidans 3-isopropylmalate dehydrogenase could not utilize malate as a substrate.

Journal Article↗
PubMed2000

Expression and properties of recombinant HbA2 (alpha2delta2) and hybrids containing delta-beta sequences.

Hemoglobin A2 (alpha2delta2), which is present at low concentration (1-2%) in the circulating red cells of normal individuals, has two important features that merit its study, i.e., it inhibits polymerization of sickle HbS and its elevated concentration in some thalassemias is a useful clinical diagnostic. However, reports on its functional properties regarding O2 binding are conflicting. We have attempted to resolve these discrepancies by expressing, for the first time, recombinant hemoglobin A2 and systematically studying its functional properties. The construct expressing HbA2 contains only alpha and delta genes so that the extensive purification required to isolate natural HbA2 is circumvented. Although natural hemoglobin A2 is expressed at low levels in vivo, the amount of recombinant alpha2delta2 expressed in yeast is similar to that found for adult hemoglobin A and for fetal hemoglobin F when the alpha + beta or the alpha + gamma genes, respectively, are present on the construct. Recombinant HbA2 is stable, i.e., not easily oxidized, and it is a cooperative functional hemoglobin with tetramer-dimer dissociation properties like those of adult HbA. However, its intrinsic oxygen affinity and response to the allosteric regulators chloride and 2,3-diphosphoglycerate are lower than the corresponding properties for adult hemoglobin. Molecular modeling studies which attempt to understand these properties of HbA2 are described.

Amino Acid Sequence↗
PubMed2000

The cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts.

A new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury. We investigated the effects of JTV on Ca2+ overload and on functional recovery during ischemia/reperfusion in isolated coronary-perfused rat hearts. After 30 minutes of reperfusion following 30 min of global ischemia, the % recovery of LV developed pressure was improved in a concentration-dependent manner when JTV (0.3-3.0 microM) was administered either 5 min before induction of ischemia or for 5 min at the time of reperfusion only JTV showed a negative inotropic effect only at concentrations above 3.0 microM. In indol-loaded isolated heart preparations, 0.3 microM JTV did not affect the preischemic systolic or diastolic Ca2+ levels of the Ca2+ transient as measured by the ratio of 2-wavelength fluormetry (R405/500). In contrast, it significantly reduced the increase in the ratio in the postischemic reperfusion period (% change of R405/500 from baseline: JTV(-), by 42.7 +/- 3.2%; JTV(+), by 18.4 +/- 9.1%, p < 0.05). In isolated rat ventricular myocytes with a standard patch-clamp method, we further tested the interaction of JTV with the L-type Ca2+ channel (I(Ca)). The % inhibition of the peak current of I(Ca) was 6.2 +/- 0.8% at 0.3 microM (p = n.s.), 22.0 +/- 3.3% at 1.0 microM (p < 0.05), and 59.6 +/- 1.4% at 3.0 microM (p < 0.01). Thus, the marked cardioprotection due to JTV at 0.3 microM may not be solely attributed to its inhibitory effect on the transsarcolemmal Ca2+ influx through I(Ca). In conclusion, JTV519 is a novel pharmacological agent that has been demonstrated for the first time to have clinical potential for the treatment of acute coronary syndrome by its efficacy in administration at the time of reperfusion, by its suppression of reperfusion-related intracellular Ca2+ overload with no significant interaction with I(Ca), and by its subsequent ability of strong myocardial protection.

Analysis of Variance↗
PubMed2000

Speciation of protein-binding zinc and copper in human blood serum by chelating resin pre-treatment and inductively coupled plasma mass spectrometry.

A method for the speciation of zinc and copper binding with proteins in human serum was explored by chelating resin (Chelex-100) pre-treatment and inductively coupled plasma mass spectrometry (ICP-MS). It was shown by a SEC (size-exclusion chromatography)-ICP-MS system that albumin-zinc and albumin-copper (loosely-bound species) could be selectively removed from serum by adsorption on the Chelex-100 resin after the chelating resin pre-treatment, while alpha 2-macroglobulin-zinc and ceruloplasmin-copper (firmly-bound species) remained in the serum. The zinc and copper bound with alpha 2-macroglobulin and ceruloplasmin, respectively, were then determined by ICP-MS after batch treatment of the serum samples with the Chelex-100 resin. In addition, the total concentrations of zinc and copper were also determined by ICP-MS after a 20-fold dilution with 0.1 M HNO3. The albumin-zinc and -copper were estimated as the differences between the concentrations of total and firmly-bound species. The present batch pre-treatment method was applied to the speciation analysis of zinc and copper binding with proteins in sera donated from 25 healthy volunteers as well as from a pregnant woman and a myelodysplastic syndrome patient. The observed concentrations of alpha 2-macroglobulin-zinc and ceruloplasmin-copper were in the ranges 109-202 ng ml-1 (12.4-31.3% of total zinc) and 513-880 ng ml-1 (90.6-99.7% of total copper), respectively. The present method is simple (only addition of the chelating resin and centrifugation is required) and reproducible (average RSD = 2% for alpha 2-macroglobulin-zinc and 1% for ceruloplasmin-copper in intra-assay measurements, and 5% for alpha 2-macroglobulin-zinc and 4% for ceruloplasmin-copper in inter-assay measurements), and there is less risk of contamination during separation.

Blood Proteins↗
PubMed2000

Determination of rare earth elements in human blood serum by inductively coupled plasma mass spectrometry after chelating resin preconcentration.

The determination of all rare earth elements (REEs) in human blood serum by inductively coupled plasma mass spectrometry (ICP-MS) was performed with the aid of chelating resin (Chelex 100) preconcentration after acid digestion with HNO3 and HClO4. When chelating resin preconcentration was carried out at room temperature, the recoveries of heavy REEs were lower than those of light REEs because of their stable complex formation with residual organic compounds remaining in the digested serum solution. These problems were overcome by heating the solution at 80 degrees C during the chelating resin preconcentration process. As a result, the recoveries for all REEs were improved to 92-102% in the case of a concentration factor of 4, where the analytical detection limits for REEs were below 0.2 x 10(-12) g ml-1. Consequently, all REEs in individual human blood sera collected from five healthy volunteers could be determined by ICP-MS with good precision. The concentrations of REEs in human blood serum were extremely low, in the range from ca. 1 x 10(-12) g ml-1 of Eu to ca. 230 x 10(-12) g ml-1 of Ce.

Chelating Agents↗
PubMed2000

Crystal structure of the pyridoxal 5'-phosphate dependent L-methionine gamma-lyase from Pseudomonas putida.

L-Methionine gamma-lyase (MGL) catalyzes the pyridoxal 5'-phosphate (PLP) dependent alpha,gamma-elimination of L-methionine. We have determined two crystal structures of MGL from Pseudomonas putida using MAD (multiwavelength anomalous diffraction) and molecular replacement methods. The structures have been refined to an R-factor of 21.1% at 2.0 and 1.7 A resolution using synchrotron radiation diffraction data. A homotetramer with 222 symmetry is built up by non-crystallographic symmetry. Two monomers associate to build the active dimer. The spatial fold of subunits, with three functionally distinct domains and their quarternary arrangement, is similar to those of L-cystathionine beta-lyase and L-cystathionine gamma-synthase from Escherichia coli.

Amino Acid Sequence↗
PubMed2000

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. II. Drug-induced extrapyramidal symptoms].

OBJECTIVES: The purpose of this study was to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms (complaints) of patients. This time, we focused and studied on drug-induced extrapyramidal symptoms. METHODS: We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information Systems) since 1987, and the case reports of adverse drug reaction accumulated in the CARPIS database to be total about 16,000. We studied for 180 cases of drug-induced extrapyramidal symptoms cumulated in CARPIS database. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. We estimated 180 cases using these evaluation scores. RESULTS: We could estimate 178 cases (98.9%) in 180 cases to be drug-induced extrapyramidal symptoms using these evaluation scores. The validity of these evaluation scores were sensitivity = 98.9%, specificity = 98.0% and predictive value of positive test = 98.9%. The positive likelihood ratio was 49.5 and the negative likelihood ratio was 0.01. CONCLUSIONS: This study confirmed the validity of our evaluation scores. We reported the evaluation scores about drug-induced liver diseases before. Therefore, to apply these evaluation scores onto the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. III. Drug-induced leucopenia].

OBJECTIVES: The purpose of this study was to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms (complaints) of patients. This time, we carried out this study focusing on drug-induced leucopenia. METHODS: We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) since 1987, and the total number of case reports of adverse drug reaction accumulated in the CARPIS database amounts to about 16,000. Using the date obtained from 139 cases of drug-induced leucopenia accumulated in the CARPIS database, we investigated a relationship between leucopenia and patients. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. RESULTS: We could estimate 91 cases (65.5%) in 139 cases to be drug-induced leucopenia by the use of these evaluation scores. The validity of this evaluation scores was estimated to be as follows; sensitivity = 65.5%, specificity = 80.0% and predictive value of positive test (PVP) = 82.0%. The positive likelihood (LR) ratio was 3.3 and negative likelihood ratio 0.43. CONCLUSIONS: In this study, PVP and LR values were not good, because among the symptoms of leucopenia a very few specific symptoms could be detected. But we reported previous by the evaluation scores about drug-induced liver disorders. Therefore, in order to apply these evaluation scores to the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions. In the future, we plan to examine other adverse reactions which adds the data to this form.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. IV. Drug eruptions].

OBJECTIVES: The purpose of this study is to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms (complaints) of patients. This time, we focused and studied on drug eruptions. METHODS: We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) since 1987, and the case reports of adverse drug reactions accumulated in the CARPIS database to be total about 20,000. We studied 1473 cases of drug eruptions cumulated in CARPIS database. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. We estimated 1473 cases using this evaluation scores. RESULTS: We could estimate 1455 cases (98.8%) in 1473 cases to be drug eruptions using this evaluation scores. The validity of this evaluation scores were sensitivity = 98.8%, specificity = 91.0% and predictive value of positive test = 99.4%. The positive likelihood ratio was 11.0 and negative likelihood ratio was 0.01. CONCLUSIONS: This study confirmed the validity of our evaluation scores. We reported the evaluation scores about drug-induced liver diseases, drug-induced extra-pyramidal symptoms and drug-induced leukopenia before. In order to apply these evaluation scores to the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. V. Drug-induced gastrointestinal system disorders].

OBJECTIVES: The purpose of this study was to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms (complaints) of patients. This time, we focused and studied on drug-induced gastrointestinal system disorders. METHODS: We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) since 1987. We studied 224 cases of drug-induced Gastrointestinal System Disorders (stomach or colon disorders: 148, esophagus disorders: 31, pancreas disorders: 45) cumulated in the CARPIS database. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. We estimated 224 cases using these evaluation scores. RESULTS: We could estimate 137 cases (92.6%) in 148 cases to be stomach or colon disorders by the use of these evaluation scores. The validity of this evaluation scores was estimated to be as follows: Sensitivity = 92.6%, Specificity = 95.0% and Predictive Value of Positive Test (PVP) = 96.5%. The positive likelihood ratio (LR) was 18.5 and negative likelihood ratio was 0.08. On the other hand, in the case of esophagus disorders, PVP was 84.8% and LR was 18.1. In the case of pancreas disorders, PVP was 90.7% and LR was 21.7. CONCLUSIONS: In this study, PVP and LR values were good. We thought that these evaluation scores could pick up the drug-induced gastrointestinal system disorders efficiently. We reported previously the evaluation scores about drug-induced liver disorders, extra-pyramidal symptoms, leukopenia and eruption before. In order to apply these evaluation scores onto the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions. As a result, the adverse reactions symptoms of each one defined more.

Adverse Drug Reaction Reporting Systems↗