Biomedical subjects
Publications and source records attributed to N Yasuda.
Crystalline 1beta-methyl-2-formyl carbapenem pNB esters were prepared by osmium-mediated oxidative cleavage of the corresponding 2-vinyl derivatives. Reduction of the 2-formyl compounds gave the corresponding 2-hydroxymethyl derivatives, which are key intermediates for the anti-MRS carbapenem candidate (1).
During the summer of 1995, about 20 spot-billed ducks died unnaturally in a pond (Shin-ike) in Nishinomiya, Hyogo Prefecture, Japan. The suspected cause was the sudden appearance of toxic freshwater bloom of cyanobacteria. However, no birds died in a nearby pond (Oo-ike) in which the cyanobacteria was also present. Morphological observation of these cyanobacteria by microscope revealed that they were almost unialgal and were both Microcystis aeruginosa. The lyophilized algal cell powder from Shin-ike contained large amounts of microcystins which showed acute toxicity for mouse, while that from Oo-ike had only a very small amount of microcystin-RR which did not show acute toxicity. Autopsy of one of the birds revealed that the liver was necrotic and severely jaundiced with a dark green color, suggesting the toxicity of the microcystins. These results point to the cause of the unnatural death of spot-billed ducks in Shin-ike as being the sudden appearance of toxic Microcystis aeruginosa. This was due to eutrophication of the pond, following the influx of untreated sewage related to damage from the Great Hanshinn Earthquake of January 1995. This is the first experimental report of toxic cyanobacteria being implicated in the mass death of wild birds in Japan.
The apoptosis-inducing effect of gallic acid (3,4,5-trihydroxybenzoic acid) was investigated in four human lung cancer cell lines, SBC-3 (small cell carcinoma), EBC-1 (squamous cell carcinoma), A549 (adenocarcinoma) and SBC-3/CDDP (cisplatin-resistant subclone of SBC-3). Gallic acid induced apoptosis in a dose-dependent manner as evidenced by analyses of DNA fragmentation, changes in cell morphology and loss of viability. Fifty percent inhibitory concentration (IC50) values of gallic acid on the cell viability of SBC-3, EBC-1 and A549 were around 10, 20 and 60 microg/ml, respectively. The IC50 value for SBC-3/CDDP cells was almost the same as that of SBC-3, suggesting that susceptibility of cells to gallic acid-induced apoptosis is not altered by the acquisition of cisplatin resistance. The apoptotic process was effectively triggered by 30 min exposure to gallic acid. A caspase inhibitor and alpha-tocopherol effectively prevented the gallic acid-induced apoptosis, indicating the involvememt of caspase activation and oxidative processes during the course of apoptosis in gallic acid-treated cancer cells. These findings suggest the possible applicability of gallic acid in lung cancer therapy, especially to circumvent resistance to anti-cancer drugs.
BACKGROUND: Several studies in older people have found a U-shaped or J-shaped association of blood pressure with mortality. The increased mortality associated with the lowest levels of blood pressure in older people have been explained by concurrent illnesses and frailty, but previous studies used blood pressure measured on a single occasion. Such a casual value is different from the long-term average of blood pressure. We investigated the relation between the average level of 5-day consecutive home blood pressure and mortality in older people while adjusting for potential confounding factors including morbidity and frailty at baseline. METHODS: In 1992, 1186 community residents of a rural Japanese town, Kahoku, aged 65 or older, measured their blood pressure in their homes 20 times (four times per day, 5 consecutive days). The mean value of the 20 measurements was used to examine the association between home BP and subsequent 4-year mortality. A proportional hazards model was fitted while adjusting for activities of daily living impairment, medical history, antihypertensive medication, smoking, use of alcohol, and depression. RESULTS: A total of 134 persons died during the four-year follow-up period. There was no significant evidence that frailty is more prevalent in the lowest or highest systolic BP group than in intermediate groups. A U-shaped association between the average level of home systolic blood pressure and mortality was found in men while adjusting for potential confounding factors, including morbidity and frailty. We also showed the U-shaped curve of the association of systolic BP with all cause and noncardiovascular mortality in the whole population and the linear association of systolic BP with cardiovascular mortality. CONCLUSIONS: We showed a U-shaped association between the average level of systolic blood pressure measured at home and mortality in older men while adjusting for potential confounding factors including morbidity and frailty. Not only high home systolic BP, but also low home systolic BP, is an independent risk factor for mortality in older men. The mechanisms underlying the association between BP and mortality differ by levels of systolic BP. Cardiovascular deaths tended to be higher in the highest SBP group, and only noncardiovascular deaths were increased in the lowest SBP group. The latter finding suggests that low SBP may be not only an independent risk of mortality but also an indicator of a subclinical noncardiovascular comorbid condition.
OBJECTIVES: To determine whether perceived job stress affects mental health in occupational settings. METHODS: A 2 year cohort study was conducted. Initially, a survey including the general health questionnaire (GHQ) and a questionnaire about perceived job stress was carried out. Of 462 workers who initially showed a GHQ score of < or = 7,310 were successfully followed up for 2 years. The 2 year risks of developing mental ill health (a GHQ score > or = 8) were assessed relative to perceived job stress. To control for potential confounding factors, multiple logistic regression analyses were conducted. RESULTS: The overall 2 year risk for developing mental ill health was high at 57.7%. Workers who reported aspects of perceived job stress showed a greater 2 year risk than those without stress. Multiple logistic regression analyses showed that some components of perceived job stress were associated with a higher 2 year risk, among which "not allowed to make mistakes" showed the largest adjusted odds ratio (OR) (95% confidence interval (95% CI) of 2.37 (1.32 to 4.29). "Poor relationship with superior" had a significant effect on mental health only in women, with an adjusted OR (95% CI) of 3.79 (1.65 to 8.73). CONCLUSIONS: Certain specific items of perceived job stress seem to be associated with mental ill health in workers. These could broadly be described as job strain, or job demand items. The type of job stress that predicts mental health may be dependent on the characteristics of the workplace investigated.
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The responsiveness of Mendelian diseases to an increase in the mutation rate is studied by using the concept of the mutation component (MC) of genetic diseases. Algebraic expressions to evaluate MC at any specific generation following either a one-time or a permanent increase in mutation rate are derived and are illustrated with numerical examples. For a one-time increase in mutation rate, the analysis shows that the first generation MC for autosomal dominant diseases is equal to the selection coefficient; this is also true for X-linked diseases (adjusted for the proportion of X-chromosomes in males). For autosomal recessive diseases the first generation MC is substantially smaller than that for autosomal dominants. In subsequent generations MC gradually decays to zero. Under conditions of a permanent increase in the mutation rate, the MC for autosomal dominant, X-linked and completely recessive autosomal disorders progressively increases to reach a value of one at the new equilibrium. For incompletely recessive autosomal disorders, however, the MC at equilibrium can be larger than one. The rates of approach to the new equilibrium are different for the different classes of diseases, dictated by selection and time (in generations) following radiation exposure. The effects of increases in mutation rate on MC are more pronounced for autosomal dominants, followed by X-linked and are far less for autosomal recessives. Even for autosomal dominants, the early generation effects of radiation exposures would not be appreciable unless the heterozygotes have a severely reduced fitness.
A key intermediate for 2-(functionalized-methyl)-1-beta-methylcarbapenems, 3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(2R)- 4-halo-3-oxo-2-butyl]azetidinone, was prepared efficiently from a commercially available carboxylic acid in 3 steps.
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The effects of beta-mercaptoethanol (ME) on the steady-state level of mRNA of the human chorionic gonadotropin-beta subunit (hCG-beta) and the intracellular hormonal dynamics of the product protein were examined in BeWo cells, a choriocarcinoma cell line, using Northern blot analysis and a radioimmunoassay (RIA) specific for hCG-beta. ME reduced both medium and intracellular contents of hCG-beta in a dose-dependent manner, with its minimum effective dose being 0.01 per cent. The highest dose used (0.1 per cent) caused more than 90 per cent inhibition with both parameters, without affecting the cell number and the cell viability as verified by trypan blue exclusion. Significant reductions in both the medium and intracellular contents began to occur 6 h after the onset of incubation with ME. The ME-induced suppressions were reversible. Northern blot analysis showed that ME had no effects on the steady-state level of hCG-beta mRNA. When medium and cell lysates collected from ME-free incubations were incubated with 0.03 per cent ME, there were significant reductions of immunoreactive hCG-beta with both the medium and cell lysates. The magnitude of reduction, however, was much greater with the latter (75 per cent) than with the former (25 per cent). In contrast, the hCG-beta immunoreactivity of the RIA reference preparation was unaffected by incubation with ME. These results suggested that the major target(s) of ME action were the intracellularly located hCG-beta molecule, presumably its intramolecular disulphide bonds. It must also be pointed out that the hCG-beta molecule synthesized and secreted by BeWo cells have some structural deviation from the reference standard molecule of normal trophoblastic origin to explain the differential susceptibility to ME.
In chronic obstructive pulmonary disease (COPD) which consists of emphysema and chronic bronchitis, alveolar tissue and/or bronchiolar walls are progressively destroyed. This suggests cell death by necrosis and/or apoptosis although no direct evidence of apoptosis has been reported. It was speculated that the apoptosis-related factors are associated with the progression of COPD. Fas/Apo-1 receptor (Fas), Fas ligand (Fas-L) and soluble Fas ligand (sFas-L) are inducers, while soluble Fas (sFas) is an inhibitor of apoptosis. In this study, plasma sFas and sFas-L were measured in 19 COPD patients receiving supplemental O2 (severe COPD) and 20 COPD patients not receiving supplemental O2 (mild/moderate COPD). Twenty-two age- and sex-matched healthy volunteers (healthy controls) and 20 patients receiving supplemental O2 and with level of hypoxaemia similar to severe COPD due to other pulmonary diseases (disease controls) were also examined. Plasma sFas-L was within normal limits in all groups. Plasma sFas levels were similar among healthy controls, disease controls, and mild/moderate COPD patients, but significantly increased in severe COPD (2.6 +/- 1.1, 2.6 +/- 0.2, 2.8 +/- 0.2 and 4.8 +/- 1.0 ng ml-1, respectively). Although PaO2 was lower in severe COPD than in mild/moderate COPD, and PaCO2 was higher in severe COPD than in mild/moderate COPD, they were close between severe COPD and disease controls. Tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and C-reactive protein (CRP) were increased in patients with COPD, but were similar in both severe and mild/moderate COPD patients. We conclude that increased plasma sFas, which is independent of hypoxaemia, and increases in PaCO2, TNF-alpha, IL-6 and inflammation, may be associated with progression of COPD.
BACKGROUND: Although perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) expression is strongly associated with ulcerative colitis, its relationship with the occurrence of pouchitis after restorative proctocolectomy is uncertain. METHODS: Serum p-ANCA was assayed using both indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA) in 49 patients, of whom 25 had, and 24 had not, developed pouchitis. Control sera were obtained from 15 healthy volunteers. RESULTS: By means of indirect immunofluorescence, p-ANCA was detected in 45.8% of patients without and in 48% with pouchitis (NS). Twenty-three (46.9%) of the 49 colitis patients were p-ANCA-positive, compared with none of the 15 controls (P < 0.01). By means of ELISA, p-ANCA positivity was present in 50% of patients without and in 68% with pouchitis (NS). CONCLUSION: Whereas p-ANCA was associated with ulcerative colitis as compared with normal individuals, it was not associated with pouchitis. Thus it is unlikely to be a suitable pre-operative marker to identify those patients who will develop pouchitis.
We have searched the human genome for genes that predispose to rheumatoid arthritis (RA) using fluorescence-based microsatellite marker analysis and affected sib-pair linkage study. A panel of 41 Japanese families, each with at least two affected siblings, was typed for genome-wide 358 polymorphic microsatellite marker loci. Markers were amplified by the PCR using fluorescence-tagged primers and sized based on the difference of CA repeats on DNA. Linkage analysis was made using maximum lod score (MLS). The MLS for D1S214 and D8S556 was 3.27 and 3.33, while the MLS for the HLA-DRB1 region was <3.0. According to detailed analysis by single-point analysis using MAPMAKER/SIBS, the MLS for D1S253 and D1S214 was 3.77 and 3.58. The MLS by multipoint analysis was 6.13 for D1S253. The MLS for D8S556 by single-point analysis was 4.20. The MLS for DXS1232 was 2.35 by single-point analysis, whereas the MLS for the region 2 cM right to DXS1232 and the region between DXS1227 and DXS1200 was 3.03 and 2.93 by multi-point analysis. Three principal chromosome regions of linkage, D1S253/214, D8S556 and DXS1232, have been identified which we call RA1, RA2 and RA3 for RA disease loci.
It has been reported that glomerular cells with apoptosis and positive Fas immunoreactivity are seen in proliferative glomerulonephritis (PGN). Fas induces apoptosis when it binds to Fas ligand (Fas-L) or soluble Fas-L (sFas-L). However, soluble Fas (sFas) blocks apoptosis by inhibiting binding between Fas and Fas-L or sFas-L. That is, Fas, Fas-L, and sFas-L are inducers of apoptosis, but sFas is an inhibitor of apoptosis. We studied the relationship between the plasma levels of sFas and sFas-L in 32 patients with various types of adult chronic glomerulonephritis. Patients with serum creatinine levels >1.5 mg/dl (132.6 micromol/l) were excluded. The plasma levels of sFas-L were within the normal limits in all patients. The plasma levels of sFas in the patients with minimal-change (n = 8) and membranous nephropathy (n = 7) were similar to the age- and sex-matched controls. However, the plasma sFas levels were significantly elevated in patients with mesangial PGN (n = 10) and membranoproliferative glomerulonephritis (n = 7)(3. 4 +/- 0.9 and 3.9 +/- 1.5 ng/ml, respectively) as compared with the age- and sex-matched controls (controls: 2.1 +/- 0.4 and 2.2 +/- 0.6 ng/ml, respectively). In PGN, according to increase of histological grade and decrease of creatinine clearance, the number of TUNEL-positive cells in glomeruli is decreased in spite of an increase of the Fas positivity, and plasma sFas is increased. The degree of proliferative change is determined by the balance between proliferation and apoptosis and/or necrosis. Therefore, increased plasma sFas in PGN may inhibit apoptosis in glomeruli and may be one of the progressing factors in PGN. Thus, we conclude that an increase in plasma sFas levels is important to the protection of apoptosis in PGN.
In order to evaluate factors improving part-time industrial physicians' services, a questionnaire study on occupational safety and health services was conducted on 237 part-time industrial physicians (PIPs) and 628 enterprises in Kochi. PIPs who received physician's fees visited enterprises and consulted with employees about their health conditions, communicated with employers and licensed occupational health supervisors (LOHSs) in enterprises more frequently than PIPs who did not receive physician's fees (p < 0.1-0.001). The rates of performing regular duties related on occupational safety and health, and PIPs' participations in health promotion programs and health consultations with employees among enterprises which paid physician's fees were significantly higher than those among enterprises which did not pay physician's fees (p < 0.05-0.001). Significantly higher rates of health consultation with employees and communications with employers and LOHSs, participation in occupational safety and health committees, recommendations of health promotion programs were found where physicians visited enterprises frequently(p < 0.1-0.01). Although no significant changes in PIPs' occupational safety and health services were observed for hazardous risk factors in enterprises, the rates of performing regular duties on occupational safety and health, and walk-through inspections by LOHSs and PIPs, estimating PIPs' advice and suggestions in enterprises with hazardous risk factors were significantly higher than those in enterprises without hazardous risk factors (p < 0.05-0.001). It is important for PIPs to have a written contract concerning physicians' fees and occupational safety and health services with enterprises and visit enterprises frequently in order to improve PIPs' occupational safety and health services and promote occupational safety and health programs in enterprises.
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This retrospective cohort study describes the mortality pattern after retirement and examines associations of the last job position and work status immediately after retirement with the mortality for male employees who retired from Kochi prefectural government. The subjects include 514 retirees over the 1977-1981 period, who were followed for 9.8 years after retirement, and 721 retirees over the 1982-1986 period, who were followed for 5.8-9.8 years. All subjects were hypothesized to have retired at a normal retirement age. Mortality risk was stable through the follow-up period subdivided into two-year intervals in both cohorts of retirees. In both cohorts, men who did not work immediately after retirement had increased mortality within the first two years of retirement compared with those who worked immediately after retirement. This finding is consistent with the mortality pattern explained by health related selection into working after retirement. The present study does not show a meaningful mortality fluctuation over the post-retirement period among male employees of the local government. Lack of information on ages and health status at retirement of individual subjects hampers discussion about causality of observed associations between two study variables concerning pre- and post-retirement characteristics and post-retirement mortality.
The objective of this study is to clarify clinical characteristics which differentiate bacteriologically positive pulmonary tuberculosis patients from negative ones in Mongolia. The subjects include 338 patients aged 16 years and older who had undergone bacteriological examinations. Of them, 107 patients (31.7%) were confirmed bacteriologically. The proportion of bacteriological positive results increased significantly among patients who had cavities in the roentgenographic examination, cough at diagnosis and the family history of tuberculosis. Addressing these clinical characteristics will contribute to raising not only the sensitivity of the sputum examination, but also the specificity of the roentgenographic examination in the diagnostic process of tuberculosis.