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Biomedical subjects

S Kojima

Publications and source records attributed to S Kojima.

At least 505 records · Page 28Linked to original sources
PubMed1994

Effect of recombinant human erythropoietin administration on peripheral blood neutrophil counts of premature infants.

To clarify whether administration of recombinant human erythropoietin (rHuEpo) may have toxic effects on neutrophil production in premature infants, 10 low birth weight infants who received rHuEpo, 200 U/kg per week, were studied retrospectively. Treated infants were compared with 10 untreated infants. None of the infants studied had infection antenatally or postnatally. In both groups the neutrophil count remained greater than 5000/mm3 for the first 3 weeks and decreased markedly at approximately 4 weeks. Although reticulocyte counts were significantly elevated in the rHuEpo-treated group, the difference in neutrophil counts between the groups was not significant. In addition, administration of rHuEpo did not exert any significant effect on granulocyte-macrophage colony formation of circulating hematopoietic progenitors in neonates. Thus no evidence was found that administration of rHuEpo has toxic effects on granulopoiesis in premature infants.

Erythropoietin↗
PubMed1994

Physical stability and protein stability of freeze-dried cakes during storage at elevated temperatures.

The relationship between physical stability of freeze-dried cakes and protein stability during storage was studied using beta-galactosidase as a model protein and inositol as an excipient. Amorphous samples freeze-dried from solutions containing the enzyme and various concentrations of inositol in sodium phosphate buffer (50 mM, pH 7.4) were stored for 7 days over P2O5 at 40 to 70 degrees C. Structural collapse and inositol crystallization were observed in some of the samples, depending on the formulation and storage temperature. The physical stability of freeze-dried samples was also studied by differential scanning calorimeter (DSC). Inositol showed a protein-stabilizing effect when its amorphous form was retained during storage, regardless of structural collapse. However, crystallization of inositol during storage removed its stabilizing effect. Addition of water-soluble polymers such as dextran, Ficoll and carboxymethyl cellulose sodium salt (CMC-Na) preserved activity of the enzyme by preventing inositol crystallization.

Aspergillus oryzae↗
PubMed1994

Is stability prediction possible for protein drugs? Denaturation kinetics of beta-galactosidase in solution.

Denaturation and aggregation kinetics of Aspergillus oryzae beta-galactosidase in solution were studied in order to determine whether the stability of protein drugs can be predicted. Denaturation of beta-galactosidase, monitored by measuring enzyme activity, conformed to first-order kinetics, whereas aggregation of the denatured form, monitored by high performance size exclusion chromatography, showed a reaction order higher than 1. Denaturation of beta-galactosidase was irreversible and exhibited a biphasic kinetic pattern which could be explained by assuming that two isoenzymes denatured irreversibly at different rates. Linear Arrhenius plots were obtained for the estimated rate constants, and delta H not equal to and delta S++ to were estimated according to the Eyring equation. The estimated delta H++ was much larger than delta H++ observed in usual chemical reactions. The present study suggests that the denaturation of protein drugs can be analyzed by the Eyring equation in the same manner as chemical degradation, contradicting the general consensus that accelerated testing can not be used to predict the stability of protein formulations.

Enzyme Stability↗
PubMed1994

Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria.

Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle, and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms. In this study, homology probing with mixed primers for the polymerase chain reaction and subsequent sequence analysis were successfully applied to clone cDNA for the flavoprotein (Fp) subunit of human liver complex II. The isolated clone contains an open reading frame of 1,992 nucleotides and encodes a mature protein of 621 amino acids with a molecular weight of 68,011. The amino acid sequence was highly homologous with that of bovine heart Fp (93.2%) and was quite different from the partial sequence of human placental Fp reported previously [Malcovati et al. (1991) in Flavins and Flavoproteins 1990, pp. 727-730], which showed striking homology to that of Bacillus subtilis. To solve this discrepancy, the partial cDNA sequences of the stomach and placental Fp subunits of human complex II were determined in addition to the full length cDNA of liver. The sequence data, sensitivity to thiol reagents and antigenic properties indicated that the major from of FP subunit in human complex II is unique at least among the three tissues analyzed, and is more similar to the Fp subunit of bovine heart than to that of B. subtilis.

Amino Acid Sequence↗
PubMed1994

Three novel subtilisin-trypsin inhibitors from Streptomyces: primary structures and inhibitory properties.

Three novel proteinaceous inhibitors, which had been identified as "Streptomyces subtilisin inhibitor-like (SIL) proteins" and exhibited trypsin inhibition in addition to strong inhibition toward subtilisin BPN', were purified from the culture broth of three Streptomyces strains: SIL10 from S. thermotolerans, SIL13 from S. galbus, and SIL14 from S. azureus. Their primary structures were determined by sequence analysis of intact SIL inhibitors and peptides obtained by enzymatic digestions of S-pyridylethylated SIL inhibitors. These inhibitors were composed of about 110 amino acids and existed as dimer proteins. The reactive site was identified as Lys-Gln for all three inhibitors by sequence analysis of their modified forms in which the reactive-site peptide bond was specifically cleaved by subtilisin BPN' under acidic conditions. Thus, their inhibition toward trypsin and subtilisin BPN' was due to the presence of a Lys residue at the P1 site. Inhibitor constants toward subtilisin BPN' and trypsin were also determined. These inhibitors showed relatively high sequence homology to other SSI-family inhibitors possessing a Lys residue at the P1 site, with amino acid replacements on their molecular surface.

Amino Acid Sequence↗
PubMed1994

A new protocol and criteria for quantitative determination of sensitization potencies of chemicals by guinea pig maximization test.

This paper presents precise sensitization test data of 15 chemicals with a wide spectrum of sensitization potencies, and proposes a new protocol and criteria for quantitative evaluation of sensitization potencies of chemicals. The tests were performed according to the design of Magnusson and Kligman, changing the application concentrations for induction as well as for challenge phases. 3-dimensional relationships between mean response (or sensitization rate), induction and challenge concentrations were found in all chemicals tested. The following 2 values are proposed as a quantitative measure of sensitization potency: (a) the minimum induction concentration that induces a positive response; (b) the challenge concentration that induces a mean response approximately equal to 1.0 among the animals applied with the highest concentration for induction. Both values coincided with each other within the range of 1 order of magnitude in every compound except 2. The values varied by 5 orders or more of magnitude among the compounds, showing a wide variation of sensitization potencies among chemicals. A good correlation was found for every chemical between the value of sensitization potency thus obtained and the residual levels in causative products in human cases of allergic contact dermatitis. A new experimental protocol for obtaining values (a) and (b) is proposed.

Allergens↗
PubMed1994

Nature of [Ca2+]i transients during ventricular fibrillation and quinidine treatment in perfused rat hearts.

We studied intracellular Ca2+ concentration ([Ca2+]i) and the electrocardiographic signals during pacing-induced ventricular fibrillation (VF) and quinidine treatment (0.4 mg/min) using surface fluorometry in indo 1-acetoxymethyl ester (AM)-loaded perfused rat hearts. [Ca2+]i was evaluated as the indo 1 fluorescence ratio (F400/F510) and expressed as a percentage of the control amplitude of F400/F510 transients. F400/F510 increased to approximately 250% during 2- (n = 14) or 20-min (n = 9) VF. Quinidine significantly decreased F400/F510 by 60% after 2-min VF; however, this effect was blunted after 20-min VF. After 2-min VF, F400/F510 and left ventricular pressure recovered almost to the control level. However, recovery of F400/F510 and ventricular function was poor after 20-min VF. The relationship between [Ca2+]i and the electrocardiogram (ECG) during VF was evaluated by power spectrum analysis of F400/F510 and ECG signals. During VF (25 +/- 3 Hz) with high irregularity, there were no clear [Ca2+]i transients (n = 110). When the cardiac rhythm (22 +/- 3 Hz) was regular, including ventricular tachycardia, there were recognizable [Ca2+]i signals with dominant frequencies that were the same (n = 2), one-half (n = 12), or one-third (n = 1) of the ECG frequencies. The highest frequency of the [Ca2+]i transients was 19 Hz. During quinidine treatment, the VF rate decreased significantly, and clear [Ca2+]i transients were noted in all records responding to every one or two ECG signals. The conclusions were the following: 1) [Ca2+]i responds to electrical signals rapidly (up to 19 Hz) during VF. This fast [Ca2+]i response is a probable cause of high [Ca2+]i during VF. 2) Quinidine decreased [Ca2+]i after 2-min VF possibly in part by slowing the VF and [Ca2+]i transients rates. 3) 20-min VF caused [Ca2+]i overload and poor functional recovery after defibrillation.

Animals↗
PubMed1994

In vitro granulocyte-macrophage colony-stimulating factor production by peripheral blood mononuclear cells in aplastic anemia.

We studied the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by peripheral blood mononuclear cells from 48 patients with aplastic anemia by using an enzyme-linked immunosorbent assay. Detectable concentrations of spontaneous GM-CSF production, ranging from 1.0 to 480 pg/ml (mean +/- SD, 51 +/- 100 pg/ml), were observed in 45 of 48 patients. These concentrations were not significantly different from those observed in normal controls. Phytohemagglutinin-stimulated production of GM-CSF in patients with aplastic anemia, ranged from 1.0 to 2,610 pg/ml (mean +/- SD, 754 +/- 550 pg/ml), which was significantly higher than in normal controls (p < 0.01). The spontaneous production of GM-CSF increased following antilymphocyte globulin (ALG) treatment in 7 of the 11 ALG responders and in 4 of the 14 nonresponders (p = 0.08). The present observations support the hypothesis that ALG functions as an inducer of hematopoietic growth factor in order to restore hematopoiesis.

Adolescent↗
PubMed1994

Biphasic effects of repeated alcohol intake on 24-hour blood pressure in hypertensive patients.

BACKGROUND: The association between alcohol and blood pressure (BP) may be related to the temporal sequencing of alcohol use and BP measurement. We investigated the effects of single and repeated intakes of alcohol on 24-hour BP. METHODS AND RESULTS: Fourteen male habitual drinkers with essential hypertension were placed sequentially on a 4-day control phase: a nonalcoholic drink with the same calories as alcohol was given at dinner (5 PM to 6 PM) and a 7-day drinking phase: alcohol (ethanol, 1 mL/kg) was given at dinner under standardized conditions. Ambulatory BP measurements were performed on day 3 of the control phase and on days 1 and 7 of the alcohol phase. The average 24-hour systolic and diastolic BPs on day 1 were significantly lower than those in the control phase and on day 7. Between 6 PM and midnight, both systolic and diastolic BPs on days 1 and 7 (121 +/- 2/73 +/- 1 and 126 +/- 4/75 +/- 2 mm Hg, respectively) were significantly lower than those in the control phase (139 +/- 4/83 +/- 2 mm Hg). Between midnight and 8 AM (6 to 14 hours after the last drink), both systolic and diastolic BPs on day 7 (138 +/- 4/83 +/- 2 mm Hg) were significantly higher than those in the control phase (131 +/- 4/79 +/- 2 mm Hg) and day 1 (129 +/- 3/77 +/- 1 mm Hg). Between 8 AM and 3 PM, BPs showed no difference among the three phases. CONCLUSIONS: A single intake of alcohol has a depressor effect on BP that lasts for several hours after drinking, while repeated intakes for 7 days have both depressor and pressor effects according to the differences in time intervals after the last drink. This study suggests that the chronic effects of alcohol on BP might be overestimated when based on casual BP measurements alone.

Blood Pressure↗
PubMed1994

Inhibition of carbon tetrachloride-induced hepatotoxicity by neopterins.

We investigated the inhibitory effects of neopterin (NP) and its reduced form, 5,6,7,8-tetrahydroneopterin (NPH4), on carbon tetrachloride (CCl4)-induced hepatotoxicity. In in vivo experiments, intraperitoneal administration of NP or NPH4 significantly inhibited the elevation of plasma alanine aminotransferase activity induced by CCl4 in mice. In in vitro experiments using cultured rat hepatocytes, CCl4 induced in a manner which was both time- and dose-dependent lactate dehydrogenase release, and the addition of NP or NPH4 to the culture-medium significantly inhibited its release from cells. NPH4, but not NP, reacted directly with a stable radical, 1,1-diphenyl-2-picrylhydrazyl. These results suggest that NP and NPH4 inhibit CCl4-induced hepatotoxicity through different mechanisms.

Alanine Transaminase↗
PubMed1994

Protective effects of dithiocarbamates against renal toxicity of cis-diamminedichloroplatinum in rats.

Sodium diethyldithiocarbamate (DDTC), sodium N-benzyl-D-glucamine dithiocarbamate (BGD), sodium N-p-hydroxymethylbenzyl-D-glucamine dithiocarbamate (HBGD), and sodium N-p-carboxybenzyl-D-glucamine dithiocarbamate (CBGD) were evaluated for efficacy as inhibitors of cis-diamminedichloroplatinum (DDP)-induced nephrotoxicity in a rat model. Treatments with 2.0 mmol/kg of BGD, HBGD, and CBGD immediately after DDP (20 mumol/kg) injection effectively prevented the nephrotoxic effects of DDP, but administration of DDTC immediately after DDP injection afforded a small protection. Concurrent treatment with 0.5 or 1.0 mmol/kg of HBGD, or 1.0 mmol/kg of CBGD could prevent DDP-induced renal damage. A significant decrease in weight loss was also observed in these dithiocarbamate-rescued rats. The platinum concentrations in liver and kidney were significantly decreased by BGD, HBGD, and CBGD treatments, respectively. The antitumor efficacy of DDP in the Walker 256 carcinoma-bearing rats was not affected by administration of HBGD (1.0 mmol/kg) or CBGD (1.0 mmol/kg). The results of this study indicated that the injection of HBGD or CBGD to rats treated with DDP can protect against DDP-induced nephrotoxicity more effectively than DDTC or BGD.

Animals↗
PubMed1994

[Postural sway in patients with hereditary ataxia].

Instability of erect stance in patients with autosomal dominant hereditary ataxia was investigated by posturography. Postural sway on a force-measuring platform was measured quantitatively and sway frequencies were analyzed. Thirty patients from 27 families (15 men and 15 women, mean age of 53.1 years (SD 11.1)) were divided into two clinical groups. Twelve patients (group A) had "pure" cerebellar signs with no somatosensory afferent symptoms. Eighteen patients (group B) had sensory disturbances or diminished reflexes of the lower limbs, and a delayed latency of scalp P37 in somatosensory evoked potentials subsequent to tibial nerve stimulation. Postural sway of the patients of both groups was larger than that of normal subjects. Group A patients had a high antero-posterior/lateral sway ratio. Group B patients had increased sway with eyes closed. With respect to sway frequencies, group A patients had a power spectrum peak around 3 Hz. Group B patients had a power spectrum peak around 1 Hz, and twelve of them had another 3 Hz component. Atrophy of the anterior lobe of the cerebellum shown by MRI was more prominent in patients who had the 3 Hz power spectrum peak than in patients lacking the 3 Hz peak. Quantitative posturography was useful to detect disturbances of the anterior lobe of the cerebellum and the spinal ascending system in patients with autosomal dominant hereditary ataxia.

Adult↗
PubMed1994

Effects of chelating agents on tissue distribution and excretion of nickel in mice.

N-Benzyl-D-glucaminedithiocarbamate (BGD), diethyldithiocarbamate (DDTC), di-hydroxyethyldithiocarbamate (DHED), trans-1,2-cyclohexanediamine N,N,N',N'-tetra-acetic acid (CDTA), and 2,3-dimercaptosuccinic acid (DMSA) were studied for their relative efficacies in the distribution and excretion of nickel in mice exposed to nickel. Mice were injected intraperitoneally with NiCl2 (5mgNi/kg) and 30 min or 24 hr later, they were injected intraperitoneally with chelating agents (400 mumol/kg). At 30 min after treatment with nickel, these chelating agents all significantly enhanced the fecal excretion of nickel, and DMSA significantly increased the urinary excretion of the metal. At 24 hr after nickel treatment, BGD, DDTC, and DHED significantly increased the fecal excretion of nickel and BGD was the most effective on the fecal excretion of nickel. CDTA and DMSA significantly enhanced the urinary excretion of the metal. At 30 min after nickel treatment, chelating agents other than CDTA effectively depressed nickel concentration in the kidney, lung, and testes. BGD, CDTA, and DMSA significantly reduced the nickel concentration in the liver. However, DDTC and DHED caused the redistribution of nickel to the brain. At 24 hr after nickel treatment, these chelating agents were effective in mobilizing nickel from the kidney, and chelating agents other than DHED were effective in mobilizing nickel from the liver, lung, and testes. These results indicate that the injection of BGD or DMSA at both 30 min and 24 hr after treatment with nickel can remove nickel from the body without redistribution of nickel to other tissues, such as brain, more effectively than DDTC, DHED, and CDTA. Furthermore, the pattern of excretion of nickel after treatment with the chelating agents was related to the partition coefficients of the nickel-chelating agent complexes.

Animals↗
PubMed1994

The association between salt sensitivity of blood pressure and some polymorphic factors.

OBJECTIVE: To examine the association in Japanese subjects between the salt sensitivity of blood pressure and polymorphic factors. DESIGN AND METHODS: One hundred and four patients with essential hypertension were classified as salt-sensitive or non-salt-sensitive depending on their blood pressure response to salt restriction. An insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene was examined by detecting an alu sequence in intron 16. The ACE genotype was classified as II, ID or DD depending on whether each allele had this sequence. The haptoglobin phenotype was determined by the starch-gel electrophoresis method, and was classified as three phenotypes, 1-1, 2-1 or 2-2 form. RESULTS: The response of plasma renin activity to salt restriction was greater in patients with the DD form than in those with other forms, although there were no significant differences in the ratio salt-sensitive: non-salt-sensitive patients among the three ACE genotype groups. However, the ratio was significantly larger in the haptoglobin 2-1 phenotype group than in the 2-2 group. CONCLUSIONS: The salt sensitivity of blood pressure was associated with the haptoglobin phenotype, but was not associated with the ACE genotype. However, the response of plasma renin activity to salt restriction was different according to the ACE genotype.

Adult↗
PubMed1994

[Necessity of cerebral angiography in thunderclap headache patients who show no evidence of subarachnoid hemorrhage: investigation of 350 cases].

PURPOSE: The necessity of cerebral angiography was assessed in patients with thunderclap headache in whom subarachnoid hemorrhage had been ruled out on CT findings and the color of cerebrospinal fluid (CSF). SUBJECTS AND METHODS: The subjects of this study were 350 patients with thunderclap headache in whom subarachnoid hemorrhage was ruled out at our clinic based on CT findings and the color of CSF. The time span from the onset of thunderclap headache to the first visit to our clinic ranged from 1 to 9 days (mean: 2.5 days). The ages of the patients ranged from 22 to 64 years. 147 were male and 203 female. All patients underwent CT angiography. Percutaneous cerebral angiography was also performed in cases in which cerebral aneurysms were suspected on CT angiography or the CSF cell count was elevated (over 10/3mm3 on white blood cells). RESULTS: (1) Of the 350 patients, 162 were suspected to have cerebral aneurysms when examined by CT angiography. When these 162 patients were examined by percutaneous cerebral angiography, cerebral aneurysms were found in 34 patients (9.7%). (2) Four patients had an elevated CSF cell count. Cerebral aneurysms were found in all these patients. (3) Of the 34 patients with cerebral aneurysms, 31 consented to and underwent direct surgery. Localized subarachnoid hemorrhage around their aneurysms was found in seven (22.6%) of these 31 patients intraoperatively. Elevation in CSF cell count was shown in three of these patients. CONCLUSION: Even when CT and CSF studies reveal no abnormalities in the early stage after the onset of thunderclap headache, subarachnoid hemorrhage can not be ruled out. Therefore, cerebral angiography is recommended in patients with thunderclap headache.

Adult↗