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Biomedical subjects

Eiji Shimizu

Publications and source records attributed to Eiji Shimizu.

At least 19 recordsLinked to original sources
PubMed2005

Association study between brain-derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan.

Several lines of evidence suggest that genetic factors might contribute to drug abuse vulnerability. Recent genomic scans for association demonstrated that the brain-derived neurotrophic factor (BDNF) gene was associated with drug abuse vulnerability. In this study, we analyzed association of two BDNF gene single nucleotide polymorphisms (SNPs), 132C > T (C270T named formerly) in the noncoding region of exon V and 196G > A (val66met) in the coding region of exon XIIIA, with methamphetamine (MAP) abuse in Japan. No significant differences were found in the frequency of the genotype or allele in these two SNPs between MAP abusers and controls (132C > T in exon V: genotype, P = 0.586, allele, P = 0.594; 196G > A (val66met) in exon XIIIA: genotype, P = 0.889, allele, P = 0.713). Furthermore, there was no difference between clinical parameters (e.g., prognosis psychosis, spontaneous relapse, or poly-substance abuse) and the two SNPs of BDNF gene. These results suggest that the two SNPs (132C > T in exon V and 196G > A (val66met) in exon XIIIA) of the BDNF gene may not be associated with Japanese MAP abusers. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.

Adult↗
PubMed2004

Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine.

Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-L-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kg x 4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

Acetylcysteine↗
PubMed2004

Lack of association between angiotensin I-converting enzyme insertion/deletion gene functional polymorphism and panic disorder in humans.

Family and twin studies have indicated that genes influence susceptibility to panic disorder, but the genes involved remain unknown. The neuropeptide angiotensin II has been found to be involved in anxiety and regulation of respiration which are important in the pathophysiology of panic attacks. Assuming that angiotensins may be candidate genes in panic disorder, we analyzed the association between panic disorder and angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) gene functional polymorphism. We recruited 101 patients with panic disorder diagnosed according to DSM-IV criteria, and 184 control subjects in the study. No significant differences in the frequency of the genotype or allele in the polymorphism between patient and control groups were found (genotype, chi(2)=0.56, d.f.=2, P=0.77; allele, chi(2)=0.074, d.f.=1, P=0.78). This study suggests that the ACE I/D gene polymorphism is not directly associated with panic disorder in our Japanese patient group.

Adult↗
PubMed2004

Association between the brain-derived neurotrophic factor 196G/A polymorphism and eating disorders.

Several lines of evidence suggest that genetic factors might contribute to the pathogenesis of eating disorders and that brain-derived neurotrophic factor (BDNF) plays a role in the pathophysiology of eating disorders. To investigate the role of the BDNF gene in the susceptibility to eating disorders, we analyzed the BDNF 196G/A gene polymorphism in female patients with eating disorders and female normal controls. The difference in the genotype frequency between patients (n = 198) and normal controls (n = 222) was statistically significant (P = 0.029). Interestingly, a significant (P = 0.015) difference in the genotype frequency between normal controls and bulimia nervosa patients (n = 101) with binge-purging type was detected. This study suggests that the BDNF 196G/A gene polymorphism might be associated with a susceptibility to eating disorders.

Adolescent↗
PubMed2004

Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers.

Several lines of evidence suggest that increased generation of auto-oxidized dopamine (DA) o-quinone is associated with the neurotoxicity of methamphetamine (MAP) in the brain, and that, as a cellular defenses against DA-derived quinines, glutathione S-transferase (GST) detoxifies auto-oxidized DA o-quinone in the brain. Glutathione S-transferase M1 (GSTM1) of the mu-class of GSTs catalyzes reaction between glutathione and catecholamine o-quinones under physiological conditions. This study was undertaken to investigate the role of the GSTM1 gene deletion polymorphism in the neuropathology of MAP abuse. One hundred fifty-seven MAP abusers and 200 healthy comparison subjects were tested for a genetic polymorphism of GSTM1. The difference in the frequency of deletion (D)/non-deletion (N) alleles between the female abusers and female controls was close to statistical significance (P = 0.071), although there was no statistical difference (P = 0.651) between male abusers and male controls. Furthermore, the number of female abusers with deletion alleles was significantly (P = 0.007, odds ratio: 2.77, 95% CI 1.30-5.89) higher than that of male abusers with deletion alleles. These findings suggest that GSTM1 gene deletion may contribute to a vulnerability to MAP abuse in female subjects, but not in male subjects.

Adult↗
PubMed2004

Association between brain-derived neurotrophic factor 196 G/A polymorphism and personality traits in healthy subjects.

Several lines of evidence suggest that a certain type of personality or temperament is at risk for developing neuropsychiatric diseases, and that brain-derived neurotrophic factor (BDNF) might be involved in pathophysiology of neuropsychiatric diseases such as mood disorders. Considering the role of BDNF and personality traits in the neuropsychiatric diseases, it is of interest to examine the association between BDNF gene polymorphism and personality test scores. In this study, we examined the association between 196 G/A the polymorphism in the coding region of the BDNF gene and personality traits scores (temperament and character inventory (TCI) and NEO personality inventory (NEO-PI)) in Japanese healthy subjects. We found that female, but not male, subjects with BDNF genotype A/A have high scores in reward dependence on TCI and high scores in extraversion on NEO-PI as compared with other genotypes (G/A or G/G), suggesting an association between reward dependence (or extraversion) personality traits and BDNF genotype in female subjects. Our findings suggest that BDNF 196 A/G polymorphism might be associated with personality traits in female, but not male, healthy subjects.

Adult↗
PubMed2004

Critical role of brain-derived neurotrophic factor in mood disorders.

The purpose of this review is to integrate what is currently known about the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders including major depressive disorder (MDD) and bipolar disorder (BD). We reviewed the pre-clinical and clinical papers demonstrating that BDNF plays a role in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Pre-clinical studies suggest that the expression of BDNF might be a downstream target of antidepressant treatments and mood stabilizers such as lithium and valproate, and that BDNF exerts antidepressant activity in animal models of depression. Furthermore, BDNF protects against stress-induced neuronal damage, and it might affect neurogenesis in the hippocampus, which is thought to be involved in the pathogenesis of mood disorders. Clinical studies have demonstrated that serum levels of BDNF in drug-naive patients with MDD are significantly decreased as compared with normal controls, and that BDNF might be an important agent for therapeutic recovery from MDD. Moreover, recent findings from family-based association studies have suggested that the BDNF gene is a potential risk locus for the development of BD. These findings suggest that BDNF plays a critical role in the pathophysiology of mood disorders and in the activity of therapeutic agents in patients with mood disorders. New agents capable of enhancing BDNF levels may lead aid the development of novel therapeutic drugs for patients with mood disorders.

Animals↗
PubMed2004

Possible role of D-serine in the pathophysiology of Alzheimer's disease.

Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site on the N-methyl-D-aspartate (NMDA) receptor that has been implicated in the pathophysiology of Alzheimer's disease (AD). The purpose of the study was to determine whether serum levels of D- and L-serine in patients with AD are altered as compared with normal controls. Serum levels of D- and L-serine in patients of AD and age- and gender-matched normal controls were determined using a high-performance liquid chromatography (HPLC). Serum levels of D-serine in the patients with AD were slightly (z=-1.77, p=0.078) lower than those of normal controls. In contrast, serum levels of L-serine in the patients were slightly (z=-1.73, p=0.083) higher than those of controls. In addition, the percentage (%) of D-serine in the total (L+D) serine in the patients was significantly (z=-2.36, p=0.018) lower than that of controls. The present study suggests that the reduced activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine may play a role in the pathophysiology of AD.

Aged↗
PubMed2004

Decreased cell proliferation in the dentate gyrus of alpha 7 nicotinic acetylcholine receptor heterozygous mice.

It is suggested that deficits of alpha 7 nicotinic acetylcholine receptors (nAChRs) might be associated with the cognitive impairments of Alzheimer's disease and schizophrenia, and that agonists for alpha 7 nAChR could be useful for treatment of cognitive dysfunction in these diseases. This study was undertaken to examine the role of alpha 7 nAChRs on hippocampal cellular proliferation of adult mice. The number of 5-bromo-2'-deoxyuridine (BrdU)-immunoreactive cells in the granule cell layer (GCL) and hilus of alpha 7 nAChR heterozygous (+/-) mice was significantly decreased as compared with that of wild-type (+/+) mice. In contrast, the number of BrdU-immunoreactive cells in GCL and hilus of alpha 7 nAChR homozygous (-/-) mice was not different from that of wild-type mice. The results suggest that reduced levels of alpha 7 nAChRs may decrease cell proliferation of adult hippocampus.

Animals↗
PubMed2004

Adenosine A1 receptor agonists block the neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine.

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) is known to induce neurotoxicity in rat retrosplenial cortex after systemic administration. The present study was undertaken to examine the effects of adenosine A(1) receptor agonists on the neurotoxicity in rat retrosplenial cortex after administration of dizocilpine. Pretreatment with adenosine A(1) receptor agonists, 2-chloro-N(6)-cyclopentyladenosine (CCPA) (0.1, 0.3, 1, or 3 mg/kg, intraperitoneally (i.p.)), or N(6)-cyclopentyladenosine (CPA) (1, 3, or 10 mg/kg, i.p.), attenuated neurotoxicity by dizocilpine (0.5 mg/kg, i.p), in a dose-dependent manner. Coadministration with adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 3 mg/kg, i.p.) significantly blocked the protective effects of CCPA for dizocilpine-induced neurotoxicity. Furthermore, pretreatment with CCPA (3 mg/kg) attenuated significantly the dizocilpine-induced expression of HSP-70 protein, which is known as a sensitive marker of reversible neuronal damage, and coadministration with DPCPX (3 mg/kg) blocked the inhibitory effects of CCPA for marked expression of HSP-70 protein by administration of dizocilpine. Moreover, pretreatment with CCPA (3 mg/kg, i.p.) significantly suppressed the increase of extracellular acetylcholine (ACh) levels in the retrosplenial cortex by administration of dizocilpine (0.5 mg/kg). In contrast, local perfusion of CCPA (1 microM) into the retrosplenial cortex via the dialysis probe did not alter the ACh levels by administration of dizocilpine (0.5 mg/kg), suggesting that the locus of action of CCPA is not in the retrosplenial cortex. These findings suggest that adenosine A(1) receptors agonists could protect against neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine.

Acetylcholine↗
PubMed2004

Protective effects of N-acetyl-L-cysteine on the reduction of dopamine transporters in the striatum of monkeys treated with methamphetamine.

Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). We undertook the present study to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [11C]beta-CFT. In contrast, the binding of [11C]SCH 23390 to dopamine D1 receptors in the monkey striatum was not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before MAP administration and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.

Acetylcysteine↗
PubMed2004

Cellular immune profile in patients with non-small cell lung cancer after weekly paclitaxel therapy.

Paclitaxel is a new agent for advanced non-small cell lung cancer (NSCLC). Weekly doses may enhance antitumor activity while minimizing toxicity, but little is known about immune recovery. Paclitaxel (80 mg/m2) was administered to 10 patients with NSCLC, weekly during 3-week cycles. Natural killer (NK) activity, CD3-CD16+CD56+ NK cells, and differential counts were monitored. NK activity appeared in all patients after treatment with paclitaxel therapy NK activity showed a 27 +/- 9% decrease (mean +/- SE) on protocol day 8 and a 37 +/- 7% decrease on day 15 (p < 0.05) recovering to 89 +/- 5% of baseline on day 29. With weekly paclitaxel, a decrease in NK cell function persisted through the first cycle but then recovered. Weekly paclitaxel may be less immunosuppressive than agents such as cisplatin.

Adult↗
PubMed2004

MCM2 and Ki-67 expression in human lung adenocarcinoma: prognostic implications.

OBJECTIVE: The expressions of minichromosome maintenance protein 2 (MCM2), Ki-67, and p53 were examined to analyze their pathobiological significance in human lung adenocarcinomas. METHODS: We performed Western blot analysis in six human lung adenocarcinoma cell lines and immunohistochemistry in 145 surgically removed adenocarcinomas to examine the MCM2 expression. Labeling indices (LIs; %) of MCM2, Ki-67, and p53 in the tumor cells were compared with clinicopathological profiles and overall survival rates. RESULTS: MCM2 protein was detected in all cell lines examined, with specific bands. MCM2 LIs were significantly correlated with sex, histological type, differentiation, pathological stage, and LIs of Ki-67 and p53 (p < 0.05). Significantly higher LIs of MCM2 and Ki-67 were noted in the 122 non-pure bronchioloalveolar carcinomas than in the 23 pure bronchioloalveolar carcinomas (p < 0.01), and the prognosis was poorer in the former than in the latter (p < 0.01). Sex, pathological stage, and high LIs of MCM2 and/or Ki-67 were independent prognostic factors (p < 0.05). CONCLUSION: High LIs of MCM2 and/or Ki-67 suggest a poor prognosis in patients with lung adenocarcinoma (non-pure bronchioloalveolar carcinoma).

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2004

Phase II study of weekly paclitaxel in patients with non-small cell lung cancer who have failed previous treatments.

OBJECTIVE: New effective therapy is desirable for patients with non-small cell lung cancer (NSCLC) who have failed previous treatments. Fractionated administration of paclitaxel may be less toxic and more active against NSCLC. The aim of this study was to evaluate the activity and toxicity of weekly paclitaxel therapy for NSCLC in a second-line setting. METHODS: Patients with pathological or cytological diagnosis of NSCLC, measurable lesions, and one or more prior therapies were enrolled. We administered weekly infusions of 80 mg/m2 paclitaxel 3 times in a 4-week cycle. In the absence of progressive disease or intolerable toxicity, each patient was treated for a minimum of 4 cycles. RESULTS: Of 39 patients enrolled, 1 patient achieved complete response and 11 patients achieved partial response (response rate, 31%: 95% confidence interval, 17-48%). The median survival time was 43 weeks (range, 7-128 weeks). Grade 3 or 4 leukopenia occurred in only 7 patients (18%). Neurotoxicity was the most frequent adverse effect (grades 1 and 2.26 and 5%, respectively). Although all patients recovered rapidly with corticosteroid treatment, drug-induced pneumonitis was observed in 3 patients (8%). CONCLUSION: Low-dose weekly paclitaxel is a promising therapy with high effectiveness for advanced NSCLC in patients with NSCLC who have failed previous treatments.

Adult↗
PubMed2004

Epstein-Barr virus-infected malignant T/NK-cell lymphoma in a patient with hypersensitivity to mosquito bites.

We report an autopsy case of Epstein-Barr virus (EBV)-infected malignant lymphoma in a young male who had hypersensitivity to mosquito bites. The autopsy revealed multiple confluent lymphoma lesions in the lungs, and on the right leg irregular-shaped skin ulcers were seen. The left pleural effusion also contained a large number of lymphoma cells. The lymphoma cells were determined as T/NK-cell type cells by immunohistochemistry. EBV DNA was detected most intensively in the lungs and EBV-encoded small RNAs-positive lymphoma cells were also observed in the lungs at a high frequency. EBV latent membrane protein-1 expression and a high Ki-67 labeling indices were noted in the lymphoma cells of the lung lesions. These findings indicate that the development of the malignant lymphoma was associated with the proliferation of EBV-infected lymphoma cells, and the cells that infiltrated the whole the body, especially the lungs, caused the patient's death.

Adolescent↗
PubMed2004

ERK activation and subsequent RB phosphorylation are important determinants of the sensitivity to paclitaxel in lung adenocarcinoma cells.

Paclitaxel is used frequently in the treatment of advanced non-small cell lung cancer. This study was carried out in order to determine the role of extracellular signal-regulated kinases (ERK) and retinoblastoma protein (pRB) in the governing mechanism resistance to paclitaxel using two lung adenocarcinoma cell lines with differing sensitivities. In paclitaxel-sensitive Ma-10 cells, treatment with paclitaxel induced pRB phosphorylation at Ser795 and ERK activation. In contrast, in paclitaxel-resistant Ma-31 cells, paclitaxel dephosphorylated pRB at Ser795 without affecting ERK activity. A specific ERK inhibitor, PD98059, blocked paclitaxel-induced ERK activation and pRB phosphorylation at Ser795 in Ma-10 cells. Furthermore, PD98059 inhibited cell cycle progression during paclitaxel treatment, the accumulation of sub-G1 population, and the cytotoxic effect by paclitaxel in Ma-10 cells, suggesting that ERK activation by paclitaxel, subsequent pRB phosphorylation, and the cell cycle progression during paclitaxel treatment are important determinants of sensitivity to paclitaxel. These observations raise the possibility that the promotion of cell cycle during the exposure of lung cancer cells to paclitaxel may sensitize resistant cells to paclitaxel.

Adenocarcinoma↗