Biomedical subjects
Jun Nakamura
Publications and source records attributed to Jun Nakamura.
[Delirium tremens].
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[Barbiturate-related disorders].
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[Other sedatives and hypnotics-related disorders].
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Endogenous deoxyribonucleic Acid (DNA) damage in human tissues: a comparison of ethenobases with aldehydic DNA lesions.
Two types of endogenous DNA lesions, ethenobases [1,N(6)-ethenoadenine (epsilonA), 3,N(4)-ethenocytosine (epsilonC)] and aldehydic DNA lesions (ADLs), were measured in several tissues (liver, lung, kidney, colon, colon mucosa, cerebellum, and gray and white matter of the cerebrum) obtained postmortem during autopsy examinations of 12 individuals (6 males, 6 females; ages, 58-87 years). Issues relating to changes in levels of DNA damage with disease and after death were addressed. The extent of DNA damage in autopsy samples was not associated with the length of the postmortem interval and was similar to levels observed in surgery samples, suggesting that endogenous, steady-state levels of etheno adducts and of ADLs are relatively stable during the hours immediately after death. In this limited series of samples, and with a few possible exceptions, the disease status before death was not associated with increased endogenous DNA damage in the affected tissue. DNA ethenobases were lowest in the cerebellum (median molar ratios: epsilonA/A = 1.0 x 10(-8); epsilonC/C = 1.9 x 10(-8)) and highest in the gray matter (epsilonA/A = 2.9 x 10(-8); epsilonC/C = 4.8 x 10(-8)) and white matter (epsilonA/A = 2.4 x 10(-8); epsilonC/C = 5.2 x 10(-8)) of the cerebrum. In other tissues, median values were 1.2-1.9 x 10(-8) for epsilonA/A and 2.0-3.3 x 10(-8) for epsilonC/C. There was a good correlation between the levels of epsilonA and epsilonC (r = 0.80, P < 0.0001). Levels of ADLs were similar in the liver, lung, kidney, and white matter of the cerebrum (median values: 5.7-7.9 ADLs/10(6) nucleotides), higher in the colon (11.3 x 10(-6)) and gray matter of the cerebrum (9.0 x 10(-6)) and lower in the cerebellum (3.7 x 10(-6)). There was no correlation between levels of ethenobases and amounts of ADLs (epsilonA versus ADLs: r = 0.12, P = 0.33; epsilonC versus ADLs: r = 0.024, P = 0.85). Although there was an interindividual variability in the extent of endogenous DNA damage (4-fold for epsilonA and epsilonC, 2-fold for ADLs), which may be determined, in part, by the capacity to repair DNA and may be related to the pathology or treatment of the patients, these results suggest that the cerebrum contains higher endogenous DNA damage than the other tissues. These data are in line with previous studies showing that brain tissues are more susceptible to oxidative stress and lipid peroxidation than other tissues.
[Suicide among psychiatric patients in Fukuoka Prefecture].
To investigate suicide among psychiatric patients in Japan (mainly Fukuoka prefecture), a questionnaire survey was submitted to psychiatrists from departments of psychiatry of university hospitals in Japan, departments of psychiatry of Rosai Hospitals in Japan, psychiatric hospitals in Fukuoka prefecture, psychiatric clinics in Fukuoka prefecture, and departments of psychiatry of general hospitals in Fukuoka prefecture regarding their psychiatric patients who died from suicide (266 females and 267 males). A large proportion of the patients at completed suicide was aged within the thirties to fifties. The majority of patients suffered from either F3 (mood disorders) or F2 (schizophrenia, schizotypal and delusional disorders) categories of the ICD-10 classification. Approximately one-fifth of the patients in Fukuoka prefecture had jobs at the time of completed suicide. The main "occupational risk factors" that were found to be risks for suicide were "failure or overloaded responsibilities in their jobs" and "worsening business situation". The main "other risk factors", i.e., risk factors other than "occupational risk factors" were "worsening psychiatric conditions", "personal life events (e.g., somatic illness or marital discord)" and "life events in other family members (e.g., familial discord or familial problems)". Over 50% of all cases had both "occupational risk factors" and "other risk factors", suggestive of the necessity for multidimensional evaluation and care in the treatment of suicidal patients. Given that numerous males that suffer from psychiatric disorders commit suicide without seeing a psychiatrist, it is important to establish a system to treat them appropriately in order to prevent unnecessary deaths.
Effect of latitude on suicide rates in Japan.
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Effects of lithium addition on daily activity and psychiatric symptoms in schizophrenic inpatients.
Lithium addition to neuroleptic treatment brought about some improvement in 6 schizophrenic inpatients. In 3 of them, however, enhancement of daily activity did not parallel improvement in psychiatric symptoms. This suggests that lithium addition may enhance daily activity independently of psychiatric symptoms, and that lithium effects should also be assessed from the viewpoint of daily activity.
Differences in regional cerebral blood flow during musical and verbal hallucinations.
A 51-year-old male patient suffered from both musical and verbal hallucinations with insight. We performed three single photon emission computed tomographic scans with the patient in different conditions: baseline without hallucinations, musical hallucinations, and verbal hallucinations. Clearly, different patterns of regional cerebral blood flow (rCBF) were observed during musical and verbal hallucinations. The findings suggest that musical and verbal hallucinations are associated with different patterns of rCBF, possibly reflecting the different causes of the two types of hallucinations.
New structure model for the GaAs(001)-c(4x4) surface.
The surface structure of the As-stabilized GaAs(001)-c(4 x 4) surface has been studied. We show that the seemingly established three As-dimer model is incompatible with experimental data and propose here a new structure model which has three Ga-As dimers per c(4 x 4) unit cell. This mixed dimer model, confirmed by the rocking-curve analysis of reflection high-energy electron diffraction and first-principles calculations, resolves disagreements in the interpretation of several previous experiments. A good agreement between the observed scanning tunneling microscopy image and the simulated one further confirms the newly proposed model.
Molecular dosimetry and repair of N(2),3-ethenoguanine in rats exposed to vinyl chloride.
Although the DNA adducts of vinyl chloride (VC) have been well characterized, previous studies have used single concentrations of VC that are well above contemporary human exposures. This study examined the exposure response to VC in male Sprague Dawley rats with respect to the molecular dose of the promutagenic DNA adduct N(2),3-ethenoguanine (N(2),3-epsilonG). Adult rats were exposed by inhalation to 0, 10, 100, or 1100 ppm VC for 1 or 4 weeks (6 h/day, 5 days/week). Weanling rats were similarly exposed for 5 days. The amount of N(2),3-epsilonG in hepatocyte (HEP) and nonparenchymal cell (NPC) fractions obtained from the liver was measured with a sensitive immunoaffinity/gas chromatography/high-resolution mass spectrometry assay. Endogenous N(2),3-epsilonG was present in HEPs and NPCs from all unexposed rats. The exposure response to VC in each group and cell population was supralinear, with a linear increase from 0 to 100 ppm, and a plateau between 100 and 1100 ppm. There was no statistically significant difference in N(2),3-epsilonG concentrations between HEPs and NPCs in any adult exposure group, which suggests that factors other than adduct concentrations contribute to the particular susceptibility of NPCs to VC-induced carcinogenesis. The accumulation of N(2),3-epsilonG with respect to time was nearly linear in rats exposed to 600 ppm VC for 1, 2, 4, or 8 weeks (4 h/day, 5 days/week), and no repair of N(2),3-epsilonG was detected in rats exposed to VC for 4 weeks and allowed to recover for 1 week. N(2),3-epsilonG concentrations in HEPs from weanling rats were 2-3-fold greater than those in adult rats exposed for the same time. Higher adduct concentrations in young rats may contribute to their greater susceptibility to VC-induced hepatic angiosarcoma as well as their particular susceptibility to hepatocellular carcinoma. The molecular dosimetry of N(2),3-epsilonG in liver appears to be a sensitive and informative biomarker of genotoxic effect after exposure to VC. N(2),3-epsilonG was the predominant etheno adduct measured in vivo after exposure to VC, and the saturable nature of VC metabolism was reflected in its molecular dose. The relationships between endogenous N(2),3-epsilonG and that formed by low exposures to VC were demonstrated. Conclusions drawn from these exposures may be more relevant for risk assessment purposes than those drawn from high exposures where activation, detoxication, and repair pathways may be saturated or otherwise perturbed. These data are well suited for consideration in future risk assessments of VC that incorporate nontumor mode of action data.
Atomic structures of the Ge/Si(113)-(2 x 2) surface.
Based on scanning tunneling microscopy observations of the epitaxial growth of Ge on Si(113) and first-principles total energy and band calculations, we demonstrate that the Ge/Si(113)-(2 x 2) surface is made up of alternating [1;10]-oriented rows of rebonded atoms and tilted pentamers of five atoms, where each pentamer is stabilized by an interstitial atom at the subsurface. From the existence of stacking defects in rows of tilted pentamers observed at room temperature, we have deduced that at epitaxial temperatures the pentamers frequently change their tilting orientations between two minimum energy states.
Genetic association analysis of 5-HT(6) receptor gene polymorphism (267C/T) with tardive dyskinesia.
Possible involvement of serotonergic (5-hydroxytryptamine: 5-HT) receptors in the pathophysiology of tardive dyskinesia (TD) has been suggested. In the present study, the relationship between the 5-HT(6) receptor gene (HTR6) polymorphisms and TD was studied in 173 Japanese patients with schizophrenia. The 267C/T allele of HTR6 was genotyped using PCR amplification followed by endonuclease digestion. The patients with the three 267C/T genotypes showed no significant difference in gender, age, duration of illness, or current antipsychotic dose. In addition, there were no significant differences in total AIMS scores among patients with the three genotypes. Moreover, no significant differences in genotypes and allele frequencies were observed between subjects with and without TD. These results suggest that the 267C/T polymorphism of HTR6 does not confer increased susceptibility to TD.
Mutations associated with base excision repair deficiency and methylation-induced genotoxic stress.
The long-term effect of exposure to DNA alkylating agents is entwined with the cell's genetic capacity for DNA repair and appropriate DNA damage responses. A unique combination of environmental exposure and deficiency in these responses can lead to genomic instability; this "gene-environment interaction" paradigm is a theme for research on chronic disease etiology. In the present study, we used mouse embryonic fibroblasts with a gene deletion in the base excision repair (BER) enzymes DNA beta-polymerase (beta-pol) and alkyladenine DNA glycosylase (AAG), along with exposure to methyl methanesulfonate (MMS) to study mutagenesis as a function of a particular gene-environment interaction. The beta-pol null cells, defective in BER, exhibit a modest increase in spontaneous mutagenesis compared with wild-type cells. MMS exposure increases mutant frequency in beta-pol null cells, but not in isogenic wild-type cells; UV light exposure or N-methyl-N'-nitro-N-nitrosoguanidine exposure increases mutant frequency similarly in both cell lines. The MMS-induced increase in mutant frequency in beta-pol null cells appears to be caused by DNA lesions that are AAG substrates, because overexpression of AAG in beta-pol null cells eliminates the effect. In contrast, beta-pol/AAG double null cells are slightly more mutable than the beta-pol null cells after MMS exposure. These results illustrate that BER plays a role in protecting mouse embryonic fibroblast cells against methylation-induced mutations and characterize the effect of a particular combination of BER gene defect and environmental exposure.
Substrate regulation of calcium binding in Ca2+-ATPase molecules of the sarcoplasmic reticulum. I. Effect of ATP.
The effect of ATP on calcium binding of the Ca2+-ATPase of the sarcoplasmic reticulum has not been clarified. By comparing the calcium dependence of the ATPase activity and of phosphorylation of the ATPase molecules with that of calcium binding in the absence of ATP, we show the existence of two types of regulatory site of the enzyme molecules at which ATP binding variously improves the calcium binding performance of the molecules depending on the aggregation state of the molecules and pH; the two regulatory sites bind ATP at submillimolar (0.25 mm) and millimolar (5 mm) ATP, respectively. The results are discussed based on a model of two conformational variants (A and B forms) of the chemically equivalent ATPase molecules (Nakamura, J., and Furukohri, T. (1994) J. Biol. Chem. 269, 30818-30821). For example, in the sarcoplasmic reticulum membrane at pH 7.40, submillimolar ATP converted the calcium binding manner of the A form from noncooperative (Hill number (n(H)) of approximately 1) to cooperative (n(H) approximately 2), concurrent with a decrease in the apparent calcium affinity (K(0.5)) from 2-6 to 0.1-0.3 microm. The binding of the A form became almost the same as that of the B form (n(H) approximately 2, K(0.5) approximately 0.2 microm), which was not affected by ATP. Millimolar ATP further decreased the K(0.5) of the cooperative binding of the two forms to approximately 0.05 microm. Regulation of the calcium binding performance by ATP is discussed in terms of monomeric and oligomeric pathway models.
Substrate regulation of calcium binding in Ca2+-ATPase molecules of the sarcoplasmic reticulum. II. Effect of CTP, GTP, ITP, and UTP.
To examine the effect of CTP, GTP, ITP, and UTP on calcium binding of Ca2+-ATPase molecules of the sarcoplasmic reticulum, the calcium dependence of the Ca2+-activated hydrolysis activities of these NTPs of the enzyme molecules was examined by comparison with that of calcium binding of the molecules in the absence of the NTPs at pH 7.40. In the sarcoplasmic reticulum membrane, CTP, GTP, and ITP did not affect the noncooperative (Hill value (n(H)) of approximately 1, apparent calcium affinity (K(0.5)) of 2-6 microm)) and cooperative (n(H) approximately 2, K(0.5) approximately 0.2 microm) calcium binding of the molecules, whereas UTP caused the molecules to highly cooperatively (n(H) approximately 4) bind calcium ions with a lowered K(0.5) of approximately 0.04 microm. When the enzyme molecules were solubilized with detergent, all of these NTPs reversibly degraded the calcium affinity of the molecule (from K(0.5) = 3-5 to >40 microm), although the effect of the NTPs on the negatively cooperative manner (n(H) approximately 0.5) of calcium binding was not experimentally obtained. Taking into account the first part of this study (Nakamura, J., Tajima, G., Sato, C., Furukohri, T., and Konishi, K. (2002) J. Biol. Chem. 277, 24180-24190) showing the improving effect of ATP on calcium binding of the membranous and solubilized molecules, the results show that ATP is the only intrinsic substrate for the enzyme molecule. This NTP regulation is discussed in terms of the oligomeric structure of the molecules.
Analysis of association between the Gln192Arg polymorphism of the paraoxonase gene and schizophrenia in humans.
An increasing amount of evidence suggests a possible implication of oxidative stress in the pathophysiology of schizophrenia. Oxidized low-density lipoproteins (oxLDL) have been reported to be capable of eliciting neurocytotoxicity. On the other hand, paraoxonase (PON1), an arylesterase, plays a role in protection against oxidative modifications of LDL and is considered to be one of the antioxidant enzymes. Thus, we investigated the genetic association between a functional polymorphism (Gln192Arg) of the human PON1 gene and schizophrenia in 244 patients and 177 controls. No significant association between the polymorphism and schizophrenia was observed. In addition, our results revealed that there was no association between the genotypes of the polymorphism and any demographic characteristics of patients such as gender, age, age at onset, or current neuroleptic dosage. Our results suggest that the Gln192Arg polymorphism of the PON1 gene may not be involved in the susceptibility to schizophrenia.
Coupling of calcium transport with ATP hydrolysis in scallop sarcoplasmic reticulum.
Previously, we showed that incubation of the scallop sarcoplasmic reticulum (SR) with EGTA at above 37 degrees C resulted in the uncoupling of ATP hydrolysis with Ca2+ transport [Nagata et al. (1996) J. Biochem. 119, 1100-1105]. We have extended this study by comparing the kinetic behavior of Ca2+ release and binding to the uncoupled SR with that of intact scallop or rabbit SR. The change in the Ca2+ concentration in the reaction medium, as determined as the absorption of APIII, was followed using a stopped flow system. Intact scallop SR was preincubated with Ca2+ in the presence of a Ca2+ ionophore, A23187, and then ATP was added to initiate the reaction. The Ca2+ level in the medium increased to the maximum level in several seconds, and then slowly decreased to the initial low level. The rising and subsequent slow decay phases could be related to the dissociation and reassociation of Ca2+ with the Ca-ATPase, respectively. When uncoupled scallop SR vesicles were preincubated with CaCl2 in the absence of A23187 and then the reaction was initiated by the addition of ATP, a remarkable amount of Ca2+ was released from the SR vesicles into the cytosolic solution, whereas, with intact scallop or rabbit SR, only a sharp decrease in the Ca2+ level was observed. Based on these findings, we concluded that the heat treatment of scallop SR in EGTA may alter the conformation of the Ca-ATPase, thereby causing Ca2+ to be released from the enzyme, during the catalytic cycle, at the cytoplasmic surface, but not at the lumenal surface of SR vesicles.