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Biomedical subjects

Jun Nakamura

Publications and source records attributed to Jun Nakamura.

At least 19 recordsLinked to original sources
PubMed2004

Apurinic/apyrimidinic endonuclease (APE/REF-1) haploinsufficient mice display tissue-specific differences in DNA polymerase beta-dependent base excision repair.

Apurinic/apyrimidinic (AP) endonuclease (APE) is a multifunctional protein possessing both DNA repair and redox regulatory activities. In base excision repair (BER), APE is responsible for processing spontaneous, chemical, or monofunctional DNA glycosylase-initiated AP sites via its 5'-endonuclease activity and 3'-"end-trimming" activity when processing residues produced as a consequence of bifunctional DNA glycosylases. In this study, we have fully characterized a mammalian model of APE haploinsufficiency by using a mouse containing a heterozygous gene-targeted deletion of the APE gene (Apex(+/-)). Our data indicate that Apex(+/-) mice are indeed APE-haploinsufficient, as exhibited by a 40-50% reduction (p < 0.05) in APE mRNA, protein, and 5'-endonuclease activity in all tissues studied. Based on gene dosage, we expected to see a concomitant reduction in BER activity; however, by using an in vitro G:U mismatch BER assay, we observed tissue-specific alterations in monofunctional glycosylase-initiated BER activity, e.g. liver (35% decrease, p < 0.05), testes (55% increase, p < 0.05), and brain (no significant difference). The observed changes in BER activity correlated tightly with changes in DNA polymerase beta and AP site DNA binding levels. We propose a mechanism of BER that may be influenced by the redox regulatory activity of APE, and we suggest that reduced APE may render a cell/tissue more susceptible to dysregulation of the polymerase beta-dependent BER response to cellular stress.

Animals↗
PubMed2004

Suicide and occupation: further supportive evidence for their relevance.

In recent years, the relationship between occupation and suicide has been extensively investigated, but few definite conclusions regarding the nature of the relationship have been established. In the present study, this relationship was investigated by examining Japanese governmental statistics. First, correlations of suicide rate relative to industry categories were examined individually for primary industry (farmers, fishermen, and forest workers), secondary industry (construction workers, manufacture works, and miners), and tertiary industry (indoor workers) for all of the 47 prefectures of Japan. Second, in the industries that showed a significant correlation with suicide rate, the relationship to other factors was adjusted using possibly confounding factors. As a result, suicide rate was positively correlated with primary industry percentage, but not with secondary or tertiary industry percentages. Multiple regression analysis showed that suicide rate was positively associated with primary industry percentage with significant tendency while it was significantly and negatively associated with annual total sunshine. Limitations are that individual suicide rates according to occupational types were not available and direct correlations with the above variables could not be investigated. The present findings suggest a possibility that occupational factors associated with primary industry may be relevant to suicide, and that, additionally, annual total sunshine may affect suicide independently. Since workers with primary industry are likely to be exposed to sunshine than other workers, they may tend to be more affected by the decrease of annual total sunshine.

Adult↗
PubMed2004

Aging and visual hallucinations in elderly psychiatric outpatients.

Estimates of the reported prevalence of visual hallucinations in the elderly vary from study to study. The aim of the present investigation was to re-evaluate the prevalence of visual hallucinations in elderly psychiatric outpatients and to examine pertinent risk factors. One hundred and twenty-two elderly (> or =60 years old) consecutive outpatients at our university hospital were investigated with a questionnaire regarding visual hallucinations and the Mini-Mental State Examination. Twelve of 122 (10%) patients suffered from visual hallucinations. Although advanced age, lower MMSE scores and dementia were significantly associated with the presence of visual hallucinations, logistic regression analysis revealed that only advanced age showed a tendency to predict the presence of visual hallucinations. In 53 patients with dementia examined separately, only advanced age was significantly associated with visual hallucinations. The present findings suggest that the prevalence of visual hallucinations in the elderly is about 10% and that aging is an important risk factor in the development of visual hallucinations in dementia. Further studies are required in order to investigate the contribution of age-related factors such as lowering visual acuity, bereavement and loneliness to the presence of visual hallucinations.

Aged↗
PubMed2004

Associations between baseline plasma MHPG (3-methoxy-4-hydroxyphenylglycol) levels and clinical responses with respect to milnacipran versus paroxetine treatment.

The purpose of this study was to investigate the effects of milnacipran and paroxetine on plasma levels of catecholamine metabolites, and we attempted to elucidate the differences between the mechanisms of these drugs in catecholaminergic neurons. In depressed patients, we investigated the relationships among pretreatment levels of catecholamine metabolites, the changes in plasma catecholamine metabolite levels before and after administration of milnacipran or paroxetine, and clinical response to these drugs. Responders to milnacipran showed lower pretreatment levels of plasma 3-methoxy-4-hydroxyphenylglycol (pMHPG) than did nonresponders to milnacipran; there was also a positive correlation between changes in pMHPG levels and percent improvement of the score on the 17-item Hamilton Rating Scale for Depression (HRSD). On the other hand, responders to paroxetine showed higher pretreatment levels of pMHPG than did nonresponders to paroxetine, and a negative correlation was observed between changes in pMHPG levels and percent improvement of the HRSD score. However, a significant difference was not observed in the pretreatment plasma level of homovanillic acid between responders and nonresponders to treatment with milnacipran or paroxetine. These results suggest that there is an association between baseline pMHPG levels and clinical responses with respect to milnacipran versus paroxetine treatment.

Adult↗
PubMed2003

Quantitation of intracellular NAD(P)H can monitor an imbalance of DNA single strand break repair in base excision repair deficient cells in real time.

DNA single strand breaks (SSBs) are one of the most frequent DNA lesions in genomic DNA generated either by oxidative stress or during the base excision repair pathways. Here we established a new real-time assay to assess an imbalance of DNA SSB repair by indirectly measuring PARP-1 activation through the depletion of intracellular NAD(P)H. A water-soluble tetrazolium salt is used to monitor the amount of NAD(P)H in living cells through its reduction to a yellow colored water-soluble formazan dye. While this assay is not a direct method, it does not require DNA extraction or alkaline treatment, both of which could potentially cause an artifactual induction of SSBs. In addition, it takes only 4 h and requires less than a half million cells to perform this measurement. Using this assay, we demonstrated that the dose- and time-dependent depletion of NAD(P)H in XRCC1-deficient CHO cells exposed to methyl methanesulfonate. This decrease was almost completely blocked by a PARP inhibitor. Furthermore, methyl methanesulfonate reduced NAD(P)H in PARP-1+/+ cells, whereas PARP-1-/- cells were more resistant to the decrease in NAD(P)H. These results indicate that the analysis of intracellular NAD(P)H level using water-soluble tetrazolium salt can assess an imbalance of SSB repair in living cells in real time.

Animals↗
PubMed2003

NAD(P)H: quinone oxidoreductase (NQO1) gene polymorphism and schizophrenia.

NAD(P)H: quinone oxidoreductase (NQO1), an obligate two-electron reductase of quinones, prevents their participation in redox cycling and subsequent generation of reactive oxygen species (ROS). Reduced or negative activity of NQO1 would lead to an excess of neurotoxic compounds of cathecolamine o-quinones and ROS. Recently, there has been increasing evidence that catecholamine o-quinones and ROS might contribute to the development of schizophrenia. We investigated the genetic association between a functional polymorphism (Pro 187Ser) in the human NQO1 gene and schizophrenia (244 Japanese schizophrenic patients and 204 healthy controls). No significant differences in the allelic and genotypic distribution between patients and controls were observed. In addition, our results revealed no association between the genotypes of the polymorphism and any characteristics of patients such as gender, age at onset, family history or current neuroleptic dosage. Our results suggest that the NQO1 gene polymorphism does not confer increased susceptibility for schizophrenia in the present sample.

Adult↗
PubMed2003

Genetic approaches to polydipsia in schizophrenia: a preliminary report of a family study and an association study of an angiotensin-converting enzyme gene polymorphism.

The pathophysiology of polydipsia in patients with schizophrenia is inadequately understood. This study aims to investigate the genetic influence on polydipsia in schizophrenia, and is comprised of a family study and an association study. First, we screened in-patients in 14 psychiatric hospitals and found a total of 36 pairs of a proband and his/her first-degree relative, both of whom were diagnosed with schizophrenia. Among these pairs, a significant familial concordance of polydipsia was found (Fisher's exact test, two-sided, P = 0.0014; odds ratio, 88.20; 95% confidence interval, 7.31-1064.34). These results indicate that genetic factors may underlie the pathophysiology of polydipsia in patients with schizophrenia. Subsequently, we examined the genetic association between polydipsia/water intoxication and the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism in patients with chronic schizophrenia (polydipsics: n = 65; non-polydipsics: n = 97) because several lines of evidence suggested that ACE might be involved in the development of polydipsia in schizophrenia. The D allele of ACE was found to be associated with a non-significant trend toward an increased risk of polydipsia (P = 0.086). Furthermore, a significant allelic association was found between the D allele of ACE and water intoxication (P = 0.0392). This significance remained after the data were adjusted for confounding variables by regression analysis. These results suggest that the ACE D allele may be a risk factor for polydipsia/water intoxication in patients with schizophrenia.

Adult↗
PubMed2003

Aldehydic DNA lesions induced by catechol estrogens in calf thymus DNA.

The primary purpose of this research is to examine the hypothesis that reactive oxygen species generated by estrogen quinonoids are the main source for the formation of aldehydic DNA lesions (ADL) in genomic DNA. ADL induced by quinonoid metabolites of 17beta-estradiol (E2), e.g. 4-hydroxyestradiol (4-OH-E2), 2-hydroxyestradiol (2-OH-E2), estrogen-3,4-quinones (E2-3,4-Q) and estrogen- 2,3-quinone (E2-2,3-Q), were investigated in calf thymus DNA (CT-DNA) under physiological conditions. The abasic sites resulting from the spontaneous depurination-depyrimidination of the modified bases and the aldehydic base and sugar lesions resulting from the oxidative damage to deoxyribose moieties in the DNA molecules were measured by an aldehyde reactive probe and were estimated as the number of ADL per 106 nucleotides. With the addition of NADPH (100 micro M) and Cu(II) (20 micro M), nanomolar levels (100 nM) of 4-OH-E2 and 2-OH-E2 induced approximately 10-fold increases in the number of ADL over control (P<0.001). In parallel, increases in 8-oxoguanine were detected in DNA exposed to 4-OH-E2 and 2-OH-E2 (100 nM) plus Cu(II) and NADPH. Further investigation indicated that the ADL induced by estrogen catechols plus Cu(II) and NADPH were causally involved in the formation of hydrogen peroxide and Cu(I). Both E2-2,3-Q and E2-3,4-Q alone induced a 2-fold increase in the number of ADL over control (P<0.05) in CT-DNA at high concentrations (1 mM). Neither neutral thermal hydrolysis nor lower ionic strength of the reaction medium induced further increases in the number of ADL in E2-3,4-Q-modified CT-DNA. Conversely, with the inclusion of Cu(II) and NADPH, both E2-3,4-Q and E2-2,3-Q (1 micro M) induced parallel formation of DNA single strand breaks and approximately 20-fold increases in the number of ADL over control (P < 0.001). The data also demonstrated that the ADL induced by estrogen quinones with and without the presence of Cu(II) and NADPH contain 69 and 78% putrescine-excisable ADL in CT-DNA, respectively. Additionally, results of the ADL cleavage assay indicate that the ADL induced by estrogen quinones plus Cu(II) and NADPH in CT-DNA were predominantly T7 exonuclease-excisable (50%) and exonuclease III- excisable (20%) ADL, whereas the intact ADL, and other ADL accounted for 5 and 25%, respectively. These results suggest that the ADL induced by estrogen quinones in CT-DNA are derived from oxidative events rather than depurination/depyrimidination of labile estrogen quinone-DNA adducts. Overall, our results are at variance with the idea that depurination of estrogen quinone-DNA adducts is the major source for the formation of ADL in genomic DNA. We hypothesize that in addition to DNA adducts and oxidized bases, the ADL induced by estrogen quinonoid-mediated oxidative stress may play a role in estrogen-induced carcinogenicity.

Aldehydes↗
PubMed2003

Micromolar concentrations of hydrogen peroxide induce oxidative DNA lesions more efficiently than millimolar concentrations in mammalian cells.

Reactive oxygen species produce oxidized bases, deoxyribose lesions and DNA strand breaks in mammalian cells. Previously, we demonstrated that aldehydic DNA lesions (ADLs) were induced in mammalian cells by 10 mM hydrogen peroxide (H2O2). Interestingly, a bimodal H2O2 dose-response relationship in cell toxicity has been reported for Escherichia coli deficient in DNA repair as well as Chinese hamster ovary (CHO) cells. Furthermore, it has been demonstrated that H2O2 causes single-strand breaks in purified DNA in the presence of iron and induces mitochondrial DNA damage in CHO cells with a biphasic dose-response curve. Here we show that H2O2 produces ADLs at concentrations as low as 0.06 mM in HeLa cells and that lower concentrations of H2O2 were much more efficient at inducing ADLs than higher concentrations. This dose-response curve is strikingly similar to that for cell killing effects in E.coli deficient in DNA repair exposed to H2O2. Interestingly, serial treatment of submillimolar levels of H2O2 induced a massive accumulation of ADLs. The toxicity arising from H2O2 determined by intracellular NAD(P)H in cells correlated well with the formation of ADLs. The addition of dipyridyl, an iron (II)-specific chelator, significantly protected against DNA damage and cell toxicity from submillimolar, but not millimolar, amounts of H2O2. These results suggest that ADLs induced by submillimolar levels of H2O2 may be due to a Fenton-type reaction between H2O2 and intracellular iron ions in mammalian cells.

2,2'-Dipyridyl↗
PubMed2003

Schneiderian first-rank symptoms associated with fluvoxamine treatment: a case report.

This communication describes a patient who developed Schneiderian first-rank symptoms in the course of treatment with fluvoxamine. The patient, a 28-year-old man suffering from panic disorder, developed several first-rank symptoms during fluvoxamine administration. These symptoms abated 1 week after fluvoxamine treatment was discontinued and haloperidol was started. Although haloperidol was discontinued, no further hallucinations or delusions occurred. This finding suggests that fluvoxamine can precipitate Schneiderian first-rank symptoms in some susceptible patients.

Adult↗
PubMed2003

A perspective on molecular genetic studies of tardive dyskinesia: one clue for individualized antipsychotic drug therapy.

Interindividual genetic profile differences related to antipsychotic drug therapy may be determined based on molecular genetic studies of the pathogenesis of schizophrenia and studies of antipsychotic drug responses (therapeutic as well as adverse responses). In the present article, we review molecular genetic studies of tardive dyskinesia (TD), which is a representative adverse response to antipsychotic drugs. Such studies have been performed to explore the gene-associated pharmacokinetic and pharmacodynamic processes of antipsychotic drugs. Positive associations between several genes and TD have been reported. The accumulation of results from such studies will hopefully lead to individualized antipsychotic drug therapies that involve the application of new genomic techniques, including DNA microarrays. Subsequently, antipsychotic drugs may in the future be prescribed for smaller subgroups of patients who have been classified as having a particular genetic profile.

Antipsychotic Agents↗
PubMed2003

Characteristics of repeatedly secluded elderly female schizophrenic inpatients.

The purpose of the present study was to determine the characteristics of repeatedly secluded female inpatients. Fifty female inpatients in a typical mental hospital were retrospectively investigated from the viewpoint of their recent history of seclusion, age, psychiatric symptoms rated by the Positive and Negative Syndrome Scale, doses of antipsychotics, and serum prolactin levels. The patients were divided into three groups (none, once, twice or more) by the frequency of seclusion in the most recent year. The three groups were significantly different in terms of positive symptoms, general psychopathological symptoms and serum prolactin levels. Unexpectedly, the seclusion frequency was negatively associated with serum prolactin levels. The present findings suggest that repeatedly secluded female inpatients suffered from relatively low prolactin levels as well as more positive and psychopathological symptoms. Further prospective studies are warranted to confirm these findings and to investigate whether low prolactin levels are useful in predicting the risk of frequent seclusion in female inpatients.

Aged↗
PubMed2003

Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes and male alcohol use disorders in Khon Kaen, north-east Thailand.

A case-control study on the relationship between alcohol dehydrogenase-2 (ADH2), aldehyde dehydrogenase-2 (ALDH2) and male probable alcohol use disorders (AUD) was performed in Khon Kaen, north-east Thailand. One hundred and fifty-three paired cases (probable AUD) and controls (non-probable AUD) were sampled from villagers aged 18-65 years using the modified Michigan Alcoholism Screening Test - Thai version, controls being matched for gender, age (+/- 4 years) and village. All of the cases and 86.9% of the controls were current drinkers. The percentage of ADH2*1/1 among cases was 47.1%, being significantly larger than the 29.4% among controls, and yielding a univariate odds ratio (OR) of 2.421* (95% confidence interval (CI) = 1.419-4.132) for developing probable AUD. The ALDH2*1/1 proportion among cases, 92.8%, was comparable to the 92.2% among controls, yielding a univariate OR of 1.100 (95%CI = 0.757-1.599). Multivariate analysis based on a conditional logistic regression model and a hierarchically well-formulated model strategy revealed that: (i) the OR of developing probable AUD due to 1 g increment of daily ethanol drinking was 1.110* among farmers (95%CI = 1.054-1.170); (ii) OR due to 1 g increment of daily ethanol drinking was 1.329* among non-farmers (95%CI = 1.109-1.593); (iii) OR due to either ADH2*1/1 or ALDH2*1/1 was insignificant; and (iv) the daily amount of smoking is independently associated with probable AUD. The present findings suggest that one of the genetic factors that may be related to probable AUD among Thai males living in the north-east is the ADH2 gene.

Adult↗
PubMed2003

Plasma levels of homovanillic acid and the response to risperidone in first episode untreated acute schizophrenia.

We have previously reported that risperidone might improve negative symptoms in schizophrenia by influencing noradrenergic neurons. In the present study, we focused on the clinical efficacy and mechanisms of risperidone towards positive symptoms in the acute phase of schizophrenia. Thirty-four patients meeting DSM-IV criteria for schizophrenia and treated with risperidone alone were evaluated regarding their clinical improvement using the Positive and Negative Syndrome Scale (PANSS) before and 2 weeks after risperidone administration, and blood samples were also drawn at the same times. Plasma concentrations of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol were analysed by high-performance liquid chromatography with electrochemical detection. Plasma HVA levels in the responders to the risperidone treatment (more than 50% improvement in scores of positive symptoms in PANSS) were higher than those of non-responders before risperidone administration. Furthermore, there was a negative trend between changes in plasma HVA levels and improvement of total scores for positive symptoms in PANSS. These results suggest that higher levels of plasma HVA before risperidone administration might be a predictor of a good response to risperidone treatment, and the influence of risperidone on dopaminergic activity might be associated with its efficacy in treating symptoms of schizophrenia in the acute phase.

Acute Disease↗
PubMed2003

Perinatal development of the rat kidney: apoptosis and epidermal growth factor.

Localization of apoptotic cells in the kidney of perinatal rats was examined by the terminal deoxynucleotidyl transferase-mediated d-UTP-biotin nick end labeling (TUNEL) method and electron microscopy. Perinatal changes in the percentage of kidney cells with DNA fragmentation were determined by flow cytometric analysis. Through observation of two successive sections, the relationship between the localization of the epidermal growth factor receptor (EGFR) positive cells and TUNEL positive cells in the kidney was determined. From fetal day 18 to neonatal day 5, TUNEL positive cells were noted in immature glomeruli, collecting ducts and interstitium. Electron microscopically, chromatin condensed nuclei and apoptotic bodies were seen in the same tissue component as the TUNEL positive cells. The percentage of DNA fragmented cells significantly increased from fetal days 18 to 20 and significantly decreased from fetal days 20 to 22, while they still remained low in the neonatal period. The TUNEL positive cells in immature glomeruli and collecting ducts were not reactive to the EGFR antibody. The TUNEL positive cells were not observed in the proximal tubular cells, which were positive to EGFR antibody. These results indicate that apoptotic cells are present in the kidney throughout the perinatal period in the rat and that EGF plays an important role in perinatal development of the rat kidney.

Animals↗
PubMed2003

Higher plasma 5-hydroxyindoleacetic acid levels are associated with SSRI-induced nausea.

We investigated the association between selective serotonin reuptake inhibitors (SSRIs; paroxetine or fluvoxamine) and nausea with regard to plasma 5-hydroxyindoleacetic acid (p5-HIAA) levels. Forty-eight patients meeting the DSM-IV criteria for major depressive disorder and treated with paroxetine or fluvoxamine participated in this study. p5-HIAA levels after SSRI administration were significantly higher in the nausea group than those in the nonnausea group (nausea group: 8.0 +/- 4.6 ng/ml; nonnausea group: 3.6 +/- 2.2 ng/ml; p < 0.01). On the other hand, no significant difference was found between the nausea and nonnausea group in terms of p5-HIAA levels before each drug administration. These results suggest that SSRI-induced nausea is associated with serotonergic hyperactivity in the gastrointestinal tract.

Acetophenones↗