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Biomedical subjects

A Nagai

Publications and source records attributed to A Nagai.

At least 163 records · Page 9Linked to original sources
PubMed1995

Effect of indomethacin on lung development in postnatal rats: possible role of prostaglandin in alveolar formation.

We administered 1.3 mg ip of indomethacin, a prostaglandin synthetase inhibitor, per 100 g body wt to male rat pups daily on postnatal days 4-13 and examined their lungs on day 14. Indomethacin administration produced abnormal lung structure with diminished alveolar air, increased alveolar duct air, increased mean linear intercept (gas-exchanging wall distance), diminished gas-exchanging surface area and surface-to-volume ratio, increased septal wall thickness, diminished the number of alveolar crests, and increased the number of lamellar bodies in alveolar type II cells. However, this procedure did not alter quantitative lung growth (normal lung weights, volumes, and DNA and protein contents). Tissue prostaglandin content was decreased. The total amount of lung collagen or elastin was unchanged, but when collagen was analyzed into soluble and insoluble components, soluble collagen was increased. Supplementation with 1.0 g of prostaglandin E2 per 100 g body wt to animals treated with indomethacin reduced the abnormalities in pulmonary architecture. We conclude that indomethacin affects lung structure in growing rats and that it is an unusual model in that lung growth is normal, but lung development is abnormal. We also suggest that prostaglandins may play a significant role in alveolar formation in postnatal lung development in rats.

Animals↗
PubMed1995

Effect of erythromycin on endotoxin-induced microvascular leakage in the rat trachea and lungs.

To determine whether the macrolide antibiotic erythromycin prevents microvascular leakage produced by lipopolysaccharide (LPS), we studied tracheae and lungs of pathogen-free rats. Tracheal vascular permeability and neutrophil recruitment were assessed by the percent area occupied by Monastral blue-labeled blood vessels and by myeloperoxidase-containing granulocytes, respectively, in tracheal whole mounts. Pulmonary microvascular leakage was evaluated by lung wet-to-dry (W/D) weight ratio. Inhalation of Escherichia coli LPS (5 mg/kg) caused time-dependent increases in tracheal vascular permeability, neutrophil influx, and lung W/D ratio. These responses were inhibited by pretreatment with oral erythromycin, but not by ampicillin or cefaclor, in a dose-dependent manner: erythromycin at 10 mg/kg daily for 1 wk reduced the area density of Monastral blue-labeled vessels from 6.7 +/- 1.2 to 1.4 +/- 0.3% (p < 0.01), the number of neutrophils (from 365 +/- 51 to 149 +/- 30 cells/mm2, p < 0.01), and lung W/D weight ratio (from 6.76 +/- 0.30 to 5.39 +/- 0.21, p < 0.01). This inhibitory effect of erythromycin was abolished by depletion of circulating neutrophils with cyclophosphamide. These results suggest that LPS causes acute lung injury, microvascular leakage, and neutrophil recruitment in the trachea, and that erythromycin protects against these changes, probably by acting on neutrophils.

Ampicillin↗
PubMed1995

Responsiveness and variability of airflow obstruction in chronic obstructive pulmonary disease. Clinicopathologic correlative studies.

We have studied the relationships between pulmonary lesions and bronchodilator response and variability of FEV1 in 41 patients enrolled in the National Institutes of Health Intermittent Positive Pressure Breathing Trial who died, came to autopsy, and provided adequate tissue to quantitate lesions. The patients had moderate to severe chronic airflow obstruction and various degrees of response to 250 micrograms isoproterenol inhalation. Airway responsiveness was positively correlated with bronchial eosinophilia, bronchial inflammation, and bronchiolar fibrosis, and it was negatively correlated with bronchiolar goblet cell metaplasia and emphysema. Patients with an increase of 190 ml or more in FEV1 after bronchodilator had less bronchial cartilage and less goblet metaplasia in bronchioles. Airway smooth muscle was not related to airway responsiveness and variability. Flow rates were adversely affected by bronchial eosinophilia for given emphysema scores. This study shows the importance of the eosinophil as part of chronic nonspecific lung disease. Lack of airway responsiveness was associated with lesions such as emphysema and goblet cell metaplasia, which by themselves cause severe chronic airflow obstruction. The better-preserved lung function in patients with increased airway responsiveness is attributed to negative correlations with emphysema and positive correlations with bronchial eosinophilia.

Bronchi↗
PubMed1995

A specific neutrophil elastase inhibitor (ONO-5046.Na) attenuates LPS-induced acute lung inflammation in the hamster.

We have examined the effect of ONO-5046.Na, a synthetic specific inhibitor of neutrophil elastase, on lipopolysaccharide (LPS)-induced acute lung inflammation. Syrian golden hamsters were injected intraperitoneally with either 300 mg.kg-1 of ONO-5046.Na or saline, 30 min before and 1 h after intratracheal administration of 0.1 mg.kg-1 LPS. Animals were sacrificed 2 and 24 h later and the wet-to-dry lung weight ratio (W/D) was determined. Bronchoalveolar lavage (BAL) was performed, and tissue sections were examined histologically. The effect of ONO-5046.Na on migration of isolated neutrophils was determined. W/D was not significantly different at 2 h, but was increased at 24 h in the LPS-treated animals. This increase was attenuated in the LPS-treated animals injected with ONO-5046.Na. Analysis of BAL fluid revealed that both at 2 and 24 h after LPS administration the total cell number and neutrophil number, albumin concentration, and elastase-like activity were significantly lower in the LPS-treated animals injected with ONO-5046.Na than in those given LPS alone. Histological examination of the lungs of the animals treated with LPS alone showed intra-alveolar haemorrhages and inflammatory cell infiltration 24 h after LPS administration, whereas the lungs of the LPS-treated ONO-5046.Na injected animals were only sparsely infiltrated by inflammatory cells, as indicated by the inflammation score.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Studies on the phenotypic and functional characterization of peripheral blood lymphocytes from patients with early-onset periodontitis.

Juvenile and rapidly progressive periodontitis are grouped under the heading of patients with early-onset periodontitis (EOP). Many studies have investigated host risk factors in the etiology of EOP patients but these remain inconclusive. This study was undertaken to assess the possibility that an abnormality in the systemic lymphocyte subpopulation or function is involved in the etiology of EOP patients. Fourteen (14) patients with juvenile periodontitis (JP), 18 with rapidly progressive periodontitis (RPP), 22 with adult periodontitis (AP), and 33 with a healthy periodontium (HP) participated in this study. Lymphocyte subsets were determined by using panels of monoclonal antibodies (mAbs) and fluorescent flow cytometry. T cell blastogenesis was evaluated by [3H]-thymidine uptake. Pokeweed mitogen induced immunoglobulin G (IgG) and IgM synthesis were detected by sandwich enzyme-linked immunosorbent assay. There were wide distributions of values in all examinations among subjects. No significant difference could be found between the periodontitis patients and HP groups with the exception of a high CD4/CD8 ratio in all patient groups (P < 0.0001) and the depressed percentages of CD3 positive cells noted in the AP patient group (P < 0.0001). These results suggest that the majority of EOP patients do not show significantly different lymphocyte profiles from AP patients and HP subjects, and that lymphocyte cell dysfunctions are not always seen, even in EOP patients.

Adolescent↗
PubMed1995

Clinical and laboratory studies on a patient with early onset periodontitis and her family members. A case report.

Extensive clinical, microbiological, hematological, and immunological studies were performed on a patient with early onset periodontitis (EOP) and two other members of the family. The proband, a 27-year-old female, had early onset periodontitis and a high level of serum rheumatoid factors (RF) with no diagnosable medical disease. Her mother had lost all her teeth at the age of 50 because of advanced periodontitis, while her elder sister was unaffected by periodontitis. Neither the proband's periodontally-affected mother nor her unaffected sister exhibited a detectable level of RF. In this study, we examined: 1) serum immunoglobulin G (IgG) antibody titers against putative periodontal pathogenic bacteria; 2) peripheral neutrophil functions; 3) phenotypic analyses of peripheral lymphocyte subpopulations; and 4) peripheral lymphocyte functions (T cell proliferative activity, ability of cytokine [interleukin (IL)-2, tumor necrosis factor-alpha, interferon-gamma, IL-6 and IL-8] and IgG and IgM productivity). High antibody titers to Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Campylobacter rectus were detected in the sera of the proband, as were high serum antibody titers to P. gingivalis in the mother and to C. rectus in the unaffected sister compared to the non-periodontitis affected subjects. The proband also showed enhanced neutrophil chemotaxis; a high percentage of pan-B cells; and high productivity of IL-6, IgG, and IgM compared to individuals who were not periodontally affected. The mother showed slightly low helper/induced T cells (Th/i) suppressor/cytotoxic T cells (Ts/c) ratios due to the elevated count of Ts/c, and high IFN-gamma productivity compared to control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

[Three months oral repeated dose toxicity of T-3761 in rats].

A three months oral repeated dose toxicity study was carried out in rats at dosages of 1,500, 400, 100 and 25 mg/kg. The following results were obtained. 1. There was no dead rat caused by administration of T-3761. Soft feces were observed in male and female rats at 1,500 mg/kg. Body weight gain was slightly suppressed in male rats at 1,500 mg/kg. 2. Crystals which seemed to be test compound in the urinary sediment, were observed in male and female rats at 1,500 and 400 mg/kg. 3. There was no abnormality caused by administration of T-3761 in both hematological and ophthalmological examination. 4. Mild increase in total cholesterol (males and females in 1,500 mg/kg group, females at 400 mg/kg group), phospholipids (males at 1,500 mg/kg group) and A/G ratio (males and females in all treated groups) were observed. However, these biochemical changes were reversible in the recovery period. 5. Dilatation of the cecal lumen was observed in male and/or female rats at 1,500, 400, 100 mg/kg. However, no histological abnormalities were seen in the mucosa of cecum. 6. Blister and erosion were observed at articular cartilage of knee or hip joints in 2 of the 19 rats at 1,500 mg/kg, 1 of the 9 rats at 1,500 mg/kg of recovery study and 3 of the 10 rats at 400 mg/kg of recovery study. 7. No toxic dose level was regarded to be 100 mg/kg/day in this study.

Administration, Oral↗
PubMed1995

[Three months oral repeated dose toxicity of T-3761 in beagle dogs].

A three months oral repeated dose toxicity study was carried out in beagle dogs at dosages of 300, 100, 30 and 10 mg/kg, respectively. The following results were obtained. 1. There was no death of animals during administration at any dose levels. A few to all animals in all T-3761 treated groups complained of pain at the time of extension of limbs. 2. Mild decrease of body weight was observed in 1 of the 10 animals at 300 mg/kg and 1 of the 8 animals at 100 mg/kg, respectively. 3. In urinalysis, crystals which seemed to be the test compound in the urinary sediment, were observed in 5 of the 10 animals at 300 mg/kg and 4 of the 8 animals at 100 mg/kg, respectively. 4. In blood biochemical examination, mild elevation of GPT was observed in 1 of the 10 animals at 300 mg/kg. Increase of A/G ratio was observed in males at 300, 100 and 30 mg/kg, and females at all dose levels. 5. In macroscopic findings at necropsy, blister and erosion were observed at articular cartilage of shoulder, elbow, hip, and/or knee joints in all animals at 300 and 100 mg/kg, 7 of the 8 animals at 30 mg/kg and 1 of the 8 animals at 10 mg/kg. 6. No toxic dose level was less than 10 mg/kg/day in this study.

Administration, Oral↗
PubMed1995

[Utility of polymerase chain reaction for diagnosis of tuberculous pleural effusion].

Polymerase chain reaction (PCR) assay to detect Mycobacterium tuberculosis was done on 14 pleural fluid samples. Eight samples were from patients with pleural effusions suspected to be tuberculous that were smear-negative and culture-negative for acid-fast bacilli, and six samples were from patients with malignant effusions. The DNA extracted from samples was amplified with two different pairs of primers of the 123-bp and the 383-bp target DNAs of the bacilli. Mycobacterial DNA was detected in all eight samples of effusions suspected to be tuberculous, but it was not detected in any malignant effusions. We conclude that PCR assay may be useful for the rapid diagnosis of tuberculous pleural effusions that are smear-negative and culture-negative.

Base Sequence↗
PubMed1994

Steady-state kinetics of cabbage histidinol dehydrogenase.

Cabbage histidinol dehydrogenase (HDH) oxidizes L-histidinol to L-histidine through two sequential NAD(+)-linked reactions via an alkaline-labile, L-histidinaldehyde intermediate. The kinetic mechanism of the overall reaction as well as the partial reactions involved in the overall catalysis were investigated at pH 7.2 using L-histidinaldehyde as a substrate. Product inhibition patterns conformed to a Bi Uni Uni Bi Ping Pong mechanism as reported for the HDH from Salmonella typhimurium. Thus, the reaction scheme is ordered with the binding of histidinol first and NAD+ second, and histidine is the last product to be released. The intermediate, L-histidinaldehyde, could be a substrate for both the oxidation and the reduction reactions to produce histidine and histidinol, respectively. L-Histidine was not enzymatically reduced in the presence of NADH, indicating that the reaction to oxidize histidinaldehyde is apparently irreversible. L-Histidinaldehyde exhibited a three times greater binding rate constant than histidinol with a considerably small dissociation constant. These results were in agreement with the observation that histidinaldehyde was not released during the overall reaction. The rate of the reduction of histidinaldehyde to histidinol was almost same as that of the overall oxidation reaction. The overall oxidation from histidinol to histidine proceeded about three times slower than the partial oxidation from histidinaldehyde to histidine, suggesting that the first-half forward reaction is the rate-determining step in the total reaction of cabbage HDH.

Alcohol Oxidoreductases↗
PubMed1994

Heat shock protein 60 (GroEL) from Porphyromonas gingivalis: molecular cloning and sequence analysis of its gene and purification of the recombinant protein.

Porphyromonas gingivalis is associated with human periodontal disease. We cloned and sequenced the gene for heat shock protein 60 (GroEL, HSP60) from P. gingivalis FDC381. The identified clone carried a 2.6 kb DNA fragment which contained two open reading frames (ORFs) encoding a 9.6- and a 58.4-kDa protein. The translated amino acid sequence of these ORFs showed a high degree of homology with known sequences for GroES and GroEL from several bacterial species and humans. Escherichia coli carrying this clone expressed a 65-kDa protein which was recognized by anti-Mycobacterium leprae HSP60 monoclonal antibody. We purified the 65-kDa protein by DEAE-sepharose chromatography and hydroxyapatite chromatography. This protein was immunogenic and was recognized by sera from a number of patients with periodontal disease. This immunological reactivity and the existence of molecular mimicry between the P. gingivalis GroEL and other HSP homologs may indicate an important role for this molecule in periodontal lesion.

Amino Acid Sequence↗
PubMed1994

Controlled release of thyrotropin releasing hormone from microspheres: evaluation of release profiles and pharmacokinetics after subcutaneous administration.

The drug-release kinetics of thyrotropin releasing hormone (TRH) containing copoly(dl-lactic/glycolic acid) (PLGA) microspheres were evaluated both in vitro and in vivo. The drug was encapsulated in PLGA using an in-water drying method through a water in oil in water emulsion. The drug release from the PLGA microspheres in vitro correlated well with that in vivo, and pseudo-zero-order release kinetics were observed. The pharmacokinetics of TRH following administration of this controlled-release parenteral dosage form have been also examined in rats. Following a transient increase in the plasma level due to an initial burst, steady-state plasma levels were observed. The duration of drug release estimated from the plasma level was comparable with the results in the in vitro and in vivo release studies. The steady-state plasma levels correlated well with the levels predicted from the pharmacokinetic parameters following a single subcutaneous or intravenous injection of TRH solution. The results of this study confirm the previously reported in vivo sustained release of TRH achieved with this drug-delivery system.

Animals↗
PubMed1994

Pharmacokinetic properties of a novel gastric proton pump inhibitor, (+/-)-2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9- yl)sulfinyl]-1H-benzimidazole sodium salt, in healthy subjects.

The pharmacokinetics and safety of TY-11345 [(+/-)-2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9- yl)sulfinyl]-1H-benzimidazole sodium salt], a novel gastric proton pump inhibitor, were studied in healthy male volunteers after single (20, 40, and 80 mg) and repeated oral doses (60 mg, once daily for 7 days) as enteric-coated tablet. At the single doses of 20 and 40 mg, intragastric pH was continuously monitored in each of two subjects. No abnormal findings definitely attributable to the test drug were observed throughout the study. In the single-dose study, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve of TY-11345 increased in a dose-proportional manner. The time to reach Cmax was about 3 h after dosing and plasma concentrations declined thereafter with a half-life of about 1 h irrespective of dose. The effect of food intake on the pharmacokinetic parameters of TY-11345, which was evaluated at the dose of 40 mg in a cross-over design, was not significant. TY-11345 was not detected in urine unchanged, while a main metabolite and its conjugate were identified in urine as 32-38% of the dose. An intragastric pH value over 4 was obtained about 3 h after the administration of 40 mg and maintained for more than 5 h, despite the fall of plasma concentration. This effect was less obvious at a dose of 20 mg. In the multiple-dose study, the pharmacokinetics exhibited no substantial difference between the first and last doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Transient neutropenia after intravenous injection of vindesine in patients with lung cancer.

We have found transient circulating neutropenia and pulmonary sequestration of neutrophils after the intravenous injection of vindesine, a microtubule disruptor. Experiment 1 Ten patients with lung cancer were given a bolus intravenous injection of 3 mg.m-2 vindesine (Fildesine(r)). In all patients, total leukocyte and neutrophil counts in the venous blood fell to 65% and 47% of baseline values respectively within 30 min, and returned to baseline values within 6 h. In contrast, the lymphocyte count was stable. Experiment 2 Male Wistar rats were given saline or 0.08 mg.kg-1 vindesine intravenously and were sacrificed after 30 min. Vindesine produced a 58% reduction in the neutrophil count in the systemic circulation and a threefold increase in the neutrophil/erythrocyte ratio in the pulmonary microvasculature. Experiment 3 We studied the effects of vindesine in vitro on neutrophils and lymphocytes isolated from the venous blood of healthy volunteers. Vindesine (10(-5)-10(-8) mol.l-1) reduced neutrophil deformability (filterability) and induced neutrophil polarization, with reversibility of both effects after washout. These effects of vindesine were completely inhibited by cytochalasin B, an actin filament disrupter. Vindesine did not stimulate the neutrophil functions of adherence to polystyrene tubes, chemotaxis, or superoxide anion generation. The filterability and morphology of lymphocytes were not altered by vindesine. Thus, we conclude that a bolus injection of vindesine produces pulmonary sequestration of neutrophils, which produces circulatory neutropenia, and that it is primarily mediated by a decrease in neutrophil deformability that occurs without activation of the cells.

Animals↗
PubMed1994

Analysis of the VNTR locus D1S80 in a Japanese population.

A population study on the VNTR locus D1S80 was carried out in a sample of 377 unrelated Japanese individuals living in and around Gifu Prefecture (central region of Japan). A total of 29 different alleles was distinguished. Alleles 18, 24 and 30 were found to be the 3 most common alleles in this population sample and their frequencies were 0.147, 0.200 and 0.162, respectively. Out of the 435 possible phenotypes, 120 were observed. The observed heterozygosity was 0.88 and the power of discrimination was 0.98. No significant deviations from Hardy-Weinberg equilibrium could be found in this Japanese population sample.

Alleles↗
PubMed1994

Histidinol dehydrogenase loses its catalytic function through the mutation of His261-->Asn due to its inability to ligate the essential Zn.

Histidinol dehydrogenase (HDH), a Zn-metalloenzyme, produces His from histidinol through two successive oxidation reactions with NAD+ as a coenzyme. A mutation, His261-->Asn, caused the complete loss of the Zn, thereby inactivating the enzyme, without significant structural perturbation. The ability to oxidize an intermediate, histidinaldehyde, was restored to about 4% of that of the wild-type enzyme by adding 0.5 mM MnCl2, whereas the histidinol oxidation activity could not be recovered with the mental addition. We concluded that the His residue at position 261 is essential for the ligation of the Zn of cabbage HDH.

Alcohol Oxidoreductases↗