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Biomedical subjects

T Doi

Publications and source records attributed to T Doi.

At least 289 records · Page 16Linked to original sources

Application of chemical cytochrome P-450 model systems to studies on drug metabolism. VI. N,N-coupling reaction of N-methylaniline catalyzed by polypeptide-bound porphyrinatoiron(III) and cytochrome P-450.

Polypeptide-bound porphyrinatoiron(III) effectively catalyzed the N,N-coupling reaction of N-methylaniline in the presence of NaBH4/O2/tetramethyl-ammonium hydroxide or cumenehydroperoxide, whereas the corresponding non-bound monomer porphyrinatoiron(III) had little catalytic activity. Rat liver microsomes also catalyzed the N,N-coupling which was inhibited by cytochrome P-450 specific inhibitors, SKF-525A and metyrapone. The polypeptide-bound porphinatoiron(III) appears to be an excellent cytochrome P-450 model for drug metabolism studies.

Aniline Compounds↗

Charged collagen structure mediates the recognition of negatively charged macromolecules by macrophage scavenger receptors.

Macrophage scavenger receptors mediate the recognition of a wide range of negatively charged macromolecules including modified low density lipoproteins (LDL). Truncated bovine receptors lacking residues 330-342, which include the conserved lysine cluster of a collagen-like domain, were unable to degrade modified LDL in spite of their expression on the cell surface. Substitution of lysine 337 into alanine abolished the acetyl-LDL degradation and binding at 37 degrees C, but did not abolish the 4 degrees C binding. In contrast, substitution of more than 2 lysines in this region are needed to abolish the oxidized LDL degradation and 37 degrees C binding. Based on computational modeling of this domain, we propose that a "charged collagen" structure containing a lysine cluster forms a positively charged groove which specifically interacts with negatively charged ligands.

Amino Acid Sequence↗

Localization of hepatitis C viral RNA and capsid protein in human liver.

In the livers of patients whose sera contained antibodies to C100-3 antigen (anti-HCV) and hepatitis C virus (HCV) RNA, the presence of HCV RNA and HCV capsid protein (CP) antigen was demonstrated by in situ hybridization and immunohistochemistry, respectively. It was found that occasional hepatocytes in four of ten livers from patients whose sera were positive for both anti-HCV and HCV RNA hybridized with antisense as well as sense oligonucleotide DNA probes, whereas the probes did not hybridize with livers from patients whose sera were negative for anti-HCV and HCV RNA. Monoclonal antibody against a synthetic oligopeptide with amino acid sequence of HCV CP reacted with occasional hepatocytes in six of 14 livers from patients whose sera contained these HCV markers, but not with livers from patients whose sera were negative for both of them. These results suggest that HCV proliferates within hepatocytes since both antisense and sense probes hybridized with cytoplasm of the hepatocytes and that the virus matures in the cytoplasm as the capsid proteins were also found in the hepatocytes.

Adult↗

Facilitation of beta-adrenoceptor-mediated slow channel responses by hypoxia in guinea pig ventricular myocardium.

The effects of hypoxia on the beta-adrenoceptor-mediated slow channel responses of guinea pig ventricular muscle in a potassium-rich (27 mM) solution containing Ba2+ were examined using microelectrode techniques. Isoproterenol produced a small depolarization of the resting membrane and also induced repetitive discharges of action potentials at higher concentrations, mainly due to a beta-adrenoceptor-mediated increase in the slow channel conductance. Two different threshold concentrations of isoproterenol, one for inducing depolarization and one for inducing automatic activity, were measured to assess myocardial responsiveness to catecholamines. During hypoxia, the electrically triggered slow upstroke action potentials of muscle were gradually depressed and catecholamine-induced membrane responses mediated by the beta-adrenoceptor/slow channel system were enhanced. The enhancement of the catecholamine effects was accelerated by acidosis and reversed by reoxygenation. Methyl xanthine-induced responses, similar to those induced by catecholamines, were also enhanced during hypoxia. It is suggested that not only changes of catecholamine-beta-adrenoceptor interaction, but also changes of intracellular metabolic processes, may be responsible, at least in part, for the enhancement of abnormal automatic activity mediated by the myocardial beta-adrenoceptor/slow channel system under hypoxic conditions.

Action Potentials↗

Abnormalities in obese Zuckers: defective control of histaminergic functions.

Histaminergic functions in the hypothalamus of Zucker obese rats were investigated. Blockade of postsynaptic H1-receptor after infusion of chlorpheniramine into the third cerebroventricle (ICV) failed to affect feeding in obese Zuckers, although feeding was potently elicited in Wistar King A control rats. Presynaptic increase in histamine by an H3-receptor antagonist, thioperamide, suppressed feeding in Wistar controls, but not in obese Zuckers. Under high ambient temperature, Wistar controls decreased food intake and maintained their rectal temperature normally. However, obese Zuckers and histamine depleted rats due to alpha-fluoromethyl-histidine (FMH), a specific "suicide" inhibitor of a histamine synthesizing decarboxylase enzyme (HDC), failed to show this decrease in food intake as adaptive behavior. Their rectal temperature concomitantly elevated in response to heated circumstance. ICV infusion of thioperamide increased the blood glucose level in Wistar controls, but not in obese Zuckers. The defect in all these regulatory functions found in obese Zuckers may be derived from an excessive decrease in hypothalamic histamine content due to inactivity of HDC. The histamine-depleted model sufficiently mimicked the abnormalities in obese Zuckers.

Animals↗

Acetylcholine increases intracellular Ca2+ concentration and hyperpolarizes the guinea-pig outer hair cell.

Extracellularly applied acetylcholine (ACh) induced outward currents in isolated outer hair cells of a guinea-pig cochlea. The ACh induced current was carried by K+ ions. The current amplitude was ACh dose dependent with a KD of 12 microM. The ACh induced outward current was reversibly blocked by extracellularly applied atropine (1 microM), d-tubocurarine (d-TC, 1 microM), apamin (1 microM) and strychnine (0.1-10 microM). D-TC (10 microM) not only blocked the ACh induced outward current, but also reduced the amplitude of depolarization induced outward current. ACh induced a rise of intracellular Ca2+ concentration ([Ca2+]i). D-TC (10 microM) reduced but did not totally block the increase of [Ca2+]i. In a low Ca2+ (0.1 mM) extracellular medium, the amplitude of ACh induced current was reduced rapidly and was recovered gradually to the normal level after the extracellular Ca2+ concentration was resumed. It is probable that ACh hyperpolarizes the guinea-pig outer hair cell membrane by activation of a Ca(2+)-activated K+ conductance.

Acetylcholine↗

Pharmacological effects of ibudilast on cerebral circulation: a PET study.

To evaluate the pharmacological effects of ibudilast on cerebral circulation, we examined 5 ischaemic stroke patients, using positron emission tomography, and we measured cerebral blood flow (CBF). Ibudilast loading per os led to a remarkable increase in CBF after 30 min. This CBF elevation was observed in the lesion side as well as in the nonlesion hemisphere. Therefore, we can confirm that ibudilast ameliorates the chronic low perfusion state of CBF in the ischaemic stroke patient.

Aged↗

Kinetics of infectivity are dissociated from PrP accumulation in salivary glands of Creutzfeldt-Jakob disease agent-inoculated mice.

The protease-resistant isoform of prion protein (PrP) has been implicated in the pathogenesis and transmission of Creutzfeldt-Jakob disease (CJD), scrapie and other related diseases, but the relationship between the infectious agent and PrP awaits elucidation. In the present study, we have examined levels of infectivity together with accumulation of the protease-resistant form of PrP (PrPCJD) in various tissues of CJD agent-inoculated mice. Accumulation of PrPCJD occurred only in tissues, including brain, salivary gland and spleen, in which infectivity was readily detectable throughout the course of the experiment. The brain showed the highest levels of both infectivity and PrPCJD accumulation, with well correlated kinetics. On the other hand, the high titres of infectivity detected in salivary gland and spleen early after inoculation of the agent were obviously distinguishable from PrPCJD. Furthermore, in the salivary gland, the kinetics of infectivity and the accumulation of PrPCJD reversed; infectivity declined as PrPCJD accumulated in the tissue. Our findings indicate that PrPCJD accumulation is associated with replication of the agent; however, PrPCJD is unlikely to be the agent itself.

Animals↗

Immunohistochemical localization of bone morphogenetic protein (BMP) in calcifying fibrous epulis.

Immunohistochemical detection of bone morphogenetic protein (BMP) in calcifying fibrous epulis was performed to elucidate the biological process of ossification and cemento-ossification. In a total 25 cases, 15 (60%) showed positive BMP staining in bone forming areas. Histopathological features of developing hard tissues were varied, consisting of structures such as woven bone and cemento-osseous formations. BMP immunostaining was limited to osteoblasts and fibrous connective tissue surrounding the bone matrix. BMP was concentrated in the periodontal fibres and in dense fibrous structures in the cemento-osseous masses. On the basis of histopathological and immunohistochemical features, the histogenesis of ossifying and cemento-ossifying processes appear to be of two possible origins; the excessive proliferation of periodontal ligament and a metaplastic process occurring in the connective tissue fibres (non-periodontal in origin), with the former being more common.

Animals↗

[An epidemiological study on chronicity and incidence of hepatocellular carcinoma in the sequence of epidemic hepatitis].

From November 1951 to 1954, 416 patients in Kumayama Town, Okayama Prefecture, suffered from epidemic hepatitis, so-called "Kumayama Hepatitis". The mortality rate was 13.98% in the first one year, and the rate of progress to chronic hepatitis after 10 years was 24.6%. In the present study surveyed in 1991, 720 residents in this area had 13.6% positive anti-HCV (C100-3), significantly higher than in control areas. The rate of positive anti-HBs and abnormal liver functions in the subjects with positive anti-HCV was 42.9% and 40.8%, respectively. In 29 patients with clinically typical "Kumayama Hepatitis", the positivity rate of anti-HA IgG, anti-HBs, and anti-HCV, and the prevalence of abnormal liver function was 82.8%, 41.4%, 34.5%, and 10.3%, respectively. In conclusion, it is suggested that the hepatitis epidemic in Kumayama Town was caused by HAV and superinfected by HCV and/or HBV, then its clinical manifestations became complicated.

Adult↗

Resistance to nitric oxide in Mycobacterium avium complex and its implication in pathogenesis.

Susceptibility of three different strains of Mycobacterium avium complex (MAC), i.e., one strain of M. avium (Mino) and two strains of M. intracellulare (31F093T and KUMS 9007), to nitric oxide (NO) generated by rat alveolar macrophages (M phi) or NO generated chemically by acidification of NO2- was examined in vitro. We also investigated the effects of NO on phagocytosis and superoxide anion (O2-) generation by M phi. The intracellular growth of M. avium Mino was significantly suppressed by NO generated by gamma interferon (IFN-gamma)-stimulated M phi, whereas that of two strains of M. intracellulare (31F093T and KUMS 9007) was not. M. avium Mino was also more susceptible to NO generated chemically by acidification of NO2- than the two M. intracellulare strains. In L-arginine (1 mM)-containing medium, NO release from the M phi assessed by measuring NO2- increased as the concentration of IFN-gamma increased. The enhancing potential of IFN-gamma for NO release became more pronounced when M phi were infected with 31F093T, an NO-resistant strain. A large amount of NO generated by IFN-gamma-stimulated M phi suppressed both phagocytosis and O2- generation by the M phi, especially after infection of the M phi with strain 31F093T. These results indicate that the intracellular growth of MAC is not always inhibited by NO generated by immunologically activated M phi; rather, NO generation induced by infection with an NO-resistant MAC strain suppresses phagocytosis of the M phi, which may allow extracellular spreading of such NO-resistant mycobacteria. Therefore, the pathogenic potential of MAC may be partly attributed to its resistance to NO.

Animals↗

Pronounced enhancement of .NO-dependent antimicrobial action by an .NO-oxidizing agent, imidazolineoxyl N-oxide.

The antimicrobial action of .NO against Cryptococcus neoformans was investigated by using imidazolineoxyl N-oxide, which we recently reported removes .NO via oxidation (T. Akaike, M. Yoshida, Y. Miyamoto, K. Sato, M. Kohno, K. Sasamoto, K. Miyazaki, S. Ueda, and H. Maeda, Biochemistry 32:827-832, 1993). No appreciable fungicidal activity was observed in neutral .NO solutions. Imidazolineoxyl N-oxide induced or enhanced fungicidal action in neutral or acidic .NO solutions, respectively. Our results provide convincing evidence that .NO is not a microbicidal molecular species.

Anti-Infective Agents↗

Quantitative hepatitis C virus RNA and liver histology in chronic hepatitis C patients treated with interferon alfa.

Seventy patients with hepatitis C virus (HCV) infection received alpha interferon at doses ranging from 3 to 10 million units (MU) daily for eight weeks, three times weekly for 12-24 weeks, or daily and three times weekly for 12-24 weeks. The efficacy of interferon was closely related to the initial blood HCV-RNA values in that these were lower in those who responded completely and partially compared with non-responders. Continuous reductions in HCV-RNA and improvements in the histology activity index score were seen in those who responded completely. In contrast, most of the partial and non-responders remained HCV-RNA positive.

Drug Evaluation↗

[Digit preference in birth weight data of obstetric facilities].

An investigation on instrumentation of birth weight in obstetric facilities was made in the northern part of Fukuoka Prefecture from March 1989 to January 1991. A distribution of 3000 cases from 100 facilities was analyzed for the purpose of clarifying the reliability of the data. The following results were obtained. 1) Birth weights measured by analogue scales (1530 cases) showed digit preference in all distributions of the whole, the lower three digits and the lower two digits. But those measured by digital scales (1470 cases) did not show any distortion in these three distributions. 2) There were significant differences among mean birth weights calculated from the intact data, and 50g-, 100g- and 500g-interval frequency histograms in analogue scales (p < 0.01). But in digital scales there were no significant differences among mean birth weights. Rounding error was supposed to be one of the main causes of this discrepancy. Digital scales are superior to other types of scales because they do not show distribution distortion of the data. The reliability of the birth weight data is different among the types of scales. We have to consider which type of scale is used when we refer to annual changes or differences among areas in mean birth weights.

Biometry↗

[Secular changes of the mean birth weight in Japan during the past 20 years (single births, 1969-88)].

Using vital statistics (1981-1988) of the Japanese government, the mean birth weight (MBW) classified by sex was calculated from a birth weight distribution of the single births with 500g intervals for all Japan, prefectures and regions. These MBWs were linked with the MBW of 1969-1980 in our previous reports (Ref. 1) 2)). The MBWs of single births for twenty years (1969-1988) were investigated and it was pointed out that the MBWs classified by area (all Japan, prefectures and regions) were on the decrease recently and that the areal differences of the MBW were becoming large. For all Japan a secular change in the MBW was discussed for the term of a standard deviation, a skewness, a kurtosis, and relative frequencies of less than 2500g (weight class 1), those from 2500g to 3999g (weight class 2) and those of 4000g or more (weight class 3). These investigations revealed that birth weights of Japan have had a tendency to have a small standard deviation, a negative skewness, and a large kurtosis. Weight class 1 decreased until 1976 and increased after this year. Weight class 2 was on the increase up to 1988, and weight class 3 increased until 1973 and decreased afterward, as if it were accompanied by the MBW. For the purpose of confirming the contribution of each weight class to the annual change of the MBW, an analytical method for the weight frequency distribution was proposed as follows. Let M, M', pi and pi' represent the MBW of a given year (year A), the MBW of an another year (year B), the relative frequency of the i-th weight class in year A and that in year B, respectively. Suppose that M(i)'' represents the MBW when only the i-th weight class has pi as a relative frequency even in year B. Then, as the result of a fairly simple calculation, the difference between the MBW in year A and that in year B, M'-M, is obtained as follows; M'-M = sigma (1-pi') (M'-M(i)''). Therefore, the amount (1-pi') (M'-M(i)'') is able to be considered as a share of the i-th weight class in relation to the difference of M'-M. Accordingly, the share proportioned to the summation of the absolute amount [formula: see text] may represent the degree of the contribution of the i-th weight class to the difference, M'-M.(ABSTRACT TRUNCATED AT 400 WORDS)

Birth Weight↗

[Correction of the mean birth weight calculated from a frequency distribution (Japan, single births, 1969-88)].

Recently the mean birth weight (MBW) of Japan is on the decrease. This phenomenon started in 1976 and continues up to the present as of 1988. Various factors accounting for this phenomenon have been considered and discussed by several researchers. They were interested in social, cultural and economic factors as well as factors influencing community health status. Although the above factors seem to be important, one problem connected with calculation of MBW is worth discussing. The MBW was calculated from a frequency distribution because of a limitation of the source material. The accuracy of calculation of statistics from a frequency distribution depends on the assumption that few frequencies fall on boundaries, but birth weight measurements are apt to fall on figures having 0 at the end because of the properties of weighing scales. Suppose that the exact weight of an infant is 2996g. If his weight is read to the nearest figure having 0 at the end by rounding, it is recorded as 3000g on the birth certificate. Then, in a frequency distribution whose class interval is 500g, his weight is treated as 3250g in calculation of the mean. But some improvements of the methods of weighing, for example, utilization of a scale displaying a digital value of weight may result in a greater chance that his weight is recorded as 2996g. Then, in the same frequency distribution, his weight is treated as 2750g in calculation of the mean. Therefore, an improvement of the method of weighing produces the phenomenon that MBW decreases even if all the original birth weights did not change. Exact relative frequency, recorded as just 2500g, that is mentioned secondarily in the Vital Statistics of Japan has been decreasing consistently since 1969. This year is the oldest in the above source having frequency distributions of single birth infants. This fact shows that methods of weighing have been improved as the years pass. In this paper we tried to correct MBW by using the relative frequency recorded as exactly 2500g. Two kinds of widths where rounding would be executed were estimated from a frequency polygon. We obtained the following results. 1) The correction equation is represented as ld approximately; where l is a class interval (500g in this paper) and d is calculated by d = Q/(pa + pa+1 + Z) as a mean value in a certain sense and by d = 2Q/(pa + pa+1 + Z) as a maximum value.(ABSTRACT TRUNCATED AT 400 WORDS)

Birth Weight↗

[Analysis of geographical differences in the seasonal variation of mean birth weight in Japan (1974-1983)].

Geographical differences in the seasonal variation in mean birth weight (MBW) were examined by a traditional time series analysis based on the birth data of 47 different prefectures in Japan for the period from January 1974 to December 1983. The general pattern on the seasonality in MBW has two peaks in spring and autumn, and two troughs in summer and winter. There is a general trend in the seasonality with the autumn-peak-dominant pattern observed in the northern part of Japan (Hokkaido, Tohoku, Kita-Kanto) giving way to the spring-peak-dominant pattern in the southwest. Another interesting finding is that there is high statistical significance as a general tendency, in the seasonality among immensely populated prefectures such as Tokyo, Kanagawa, Aichi, Osaka, and Fukuoka, while in the case of scarcely populated rural prefectures, the time series fluctuates almost randomly. Some socio-cultural and biometerological hypotheses were evaluated to explain these results.

Birth Weight↗

The signal-averaged electrocardiogram of P wave in patients with documented atrial fibrillation or flutter and in patients with left or right atrial overload without atrial fibrillation.

To evaluate the significance of the signal-averaged P wave in various pathological conditions of the atrium, signal-averaged electrocardiograms and echocardiograms were studied in the following 4 groups: (1) 10 normal subjects (control group), (2) 24 patients with paroxysmal atrial fibrillation or flutter (AF) (AF group), (3) 12 patients with left atrial overload without AF (LA group), and (4) 10 patients with right atrial overload without AF (RA group). Original P wave durations showed no significant difference among the 4 groups. Filtered P wave durations (F-PDs) in the AF and LA groups were significantly longer than that in the control group. F-PD correlated significantly with left atrial dimension (LAD). F-PD in AF patients with LAD shorter than 40 mm was significantly longer than that in the control group, but there was no significant difference in F-PD between AF patients with LAD longer than 40 mm and the LA group. Root mean square voltages of original P waves were significantly higher in the LA and RA groups than that in the control group, but in AF patients it did not differ from that in the control group. In conclusion, the signal-averaged P wave is useful to predict atrial fibrillation, but prolongation of F-PD is seen not only in patients with AF but also in patients with LA overload.

Atrial Fibrillation↗