Biomedical subjects

Eiji Shimizu

Publications and source records attributed to Eiji Shimizu.

At least 19 recordsLinked to original sources

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↗

PubMed2003

Protective effect of LY379268, a selective group II metabotropic glutamate receptor agonist, on dizocilpine-induced neuropathological changes in rat retrosplenial cortex.

In the present study, we examined the effects of LY379268, the group II metabotropic glutamate receptor (mGluR) agonist, on the neuropathological changes in the rat retrosplenial cortex induced by noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801). Administration of LY379268 (1, 3, 10 mg/kg, i.p.) reduced dizocilpine (0.5 mg/kg, i.p.)-induced neuropathological changes in the retrosplenial cortex, in a dose-dependent manner. Co-administration of LY379268 (10 mg/kg, i.p.) with group II mGluR antagonist LY341495 (5 mg/kg, i.p.) blocked the effects of LY379268. Furthermore, LY379268 (10 mg/kg, i.p.) significantly reduced the expression of heat shock protein HSP-70, a marker of reversible neuronal injury, in the rat retrosplenial cortex after administration of dizocilpine (0.5 mg/kg, i.p.). Moreover, pretreatment with LY379268 (10 mg/kg, i.p.) significantly suppressed the increase in extracellular acetylcholine (ACh) levels in the retrosplenial cortex induced by administration of dizocilpine (0.5 mg/kg, i.p.). These results suggest that LY379268 has a protective effect on the neurotoxicity in the rat retrosplenial cortex after administration of NMDA receptor antagonists such as dizocilpine.

Acetylcholine↗

PubMed2003

Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia are indistinguishable from controls.

Our previous study showed that serum brain-derived neurotrophic factor (BDNF) was significantly decreased in the antidepressant-naive patients with major depressive disorders. However, it was still unclear whether serum BDNF level was altered in drug-naive patients with schizophrenia. Using ELISA, we measured serum BDNF levels in antipsychotic-naive (n=15) and medicated (n=25) patients with schizophrenia, and in age- and sex-matched normal controls (n=40). There were no significant differences in serum BDNF levels among antipsychotic-naive (n=15) and medicated (n=25) patients and normal controls (n=40). Possible factors such as duration of illness, age of onset, Brief Psychiatric Rating Scale scores, and chlorpromazine equivalent dosages of antipsychotics did not reveal any significant correlations with BDNF levels. Our results do not support the view that serum BDNF levels are associated with schizophrenia.

Adult↗

PubMed2003

Increased levels of serum basic fibroblast growth factor in schizophrenia.

Basic fibroblast growth factor (bFGF) is a multifunctional growth factor that has been implicated in a variety of neurodevelopmental processes. The aim of the present study was to examine whether bFGF contributes to the pathophysiology of schizophrenia. Serum bFGF levels in 40 patients with schizophrenia (15 drug-naive and 25 medicated patients) and in 40 age- and sex-matched healthy normal controls were measured. Serum bFGF levels were significantly higher in the medicated patients than in the normal controls. Analysis of partial correlation coefficients showed that the increased bFGF levels might not be attributable to antipsychotic medication. Although there was no significant overall difference in bFGF levels between drug-naive patients and normal controls, the bFGF levels in these patients significantly correlated with the severity of negative symptoms. Furthermore, we found a significant negative correlation between serum bFGF levels and the age of onset in the entire patient group. Our finding of elevated bFGF levels in the serum of patients with schizophrenia, especially in earlier age-of-onset cases considered to have more neurodevelopmental insults, suggests that bFGF abnormalities may be involved in the pathophysiology of schizophrenia.

Adult↗

PubMed2003

Decreased levels of serum brain-derived neurotrophic factor in female patients with eating disorders.

BACKGROUND: Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays a role in the regulation of eating behavior. Because of its role in eating behavior, which is especially relevant to eating disorders, BDNF is an attractive candidate for investigation of potential biological markers of eating disorders such as bulimia nervosa (BN) and anorexia nervosa (AN). METHODS: We enrolled 18 female patients with BN, 12 female patients with AN, and 21 age-matched female normal control subjects in this study. Eating-related psychopathology and depressive symptoms were evaluated using the Bulimic Investigatory Test, Edinburgh (BITE) and the Hamilton Depression Rating Scale (HDRS). Serum BDNF levels were measured by a sandwich enzyme-linked immunosorbent assay. RESULTS: Serum levels of BDNF in the patients with AN or BN were significantly (p<.0001) decreased compared with those of normal control subjects, and serum BDNF levels in the patients with AN were significantly (p=.027) lower than those in patients with BN. A significant positive correlation (r=.378, p=.006) between serum BDNF levels and body mass index in all of the subjects was detected. Furthermore, there was a significant positive correlation (r=.435, p=.015) between the BITE symptom scale score and HDRS in these patients. CONCLUSIONS: The present study suggests that BDNF may play a role in the pathophysiology of eating disorders.

Adolescent↗

PubMed2003

[Lung cancer].

Explore the source record for details and available documents.

Humans↗

PubMed2003

Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.

BACKGROUND: Because researchers have reported that antidepressants increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels may be used as a putative biological marker for major depressive disorders (MDD). METHODS: We measured serum BDNF in the following three groups: antidepressant-naive patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17), and normal control subjects (n = 50). Patients were evaluated using the Hamilton Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich ELISA method. RESULTS: We found that serum BDNF was significantly lower in the antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean, 30.6 ng/mL; SD, 12.3; p =.001) or in the control group (mean, 27.7 ng/mL; SD, 11.4; p =.002). There was a significant negative correlation (r = -.350, z = -2.003, p =.045) between serum BDNF and HAM-D scores in all patients. In a preliminary examination, reduced BDNF values of three drug-naive patients recovered to basal levels after antidepressant treatment. CONCLUSIONS: Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients.

Adult↗

PubMed2003

Two clusters of serum midkine levels in drug-naive patients with schizophrenia.

Midkine (MK) is a heparin-binding growth factor implicated in various biological phenomena such as development of the hippocampus and anxiety. We evaluated serum MK levels of drug-naive (n=15) and medicated (n=25) patients with schizophrenia, and age- and sex-matched normal controls (n=38). The patients showed two clusters in the levels. Four drug-naive patients (26.7%) and two medicated patients (8.0%) had abnormally high values, but no controls did, there being a significant difference in the numbers (P=0.003, Fisher's exact test). Furthermore, in other patients, the mean MK levels in drug-naive schizophrenia (0.30+/-0.10 ng/ml) were significantly (P=0.018, Fisher's protected least significant difference test) decreased than those in the controls (0.40+/-0.12 ng/ml). These suggest that there are two clusters of serum MK abnormalities in drug-naive patients with schizophrenia.

Adult↗

PubMed2003

Inducible protein knockout reveals temporal requirement of CaMKII reactivation for memory consolidation in the brain.

By integrating convergent protein engineering and rational inhibitor design, we have developed an in vivo conditional protein knockout andor manipulation technology. This method is based on the creation of a specific interaction interface between a modified protein domain and sensitized inhibitors. By introducing this system into genetically modified mice, we can readily manipulate the activity of a targeted protein, such as alpha-Ca(2+)calmodulin-dependent protein kinase II (alphaCAMKII), on the time scale of minutes in specific brain subregions of freely behaving mice. With this inducible and region-specific protein knockout technique, we analyzed the temporal stages of memory consolidation process and revealed the first postlearning week as the critical time window during which a precise level of CaMKII reactivation is essential for the consolidation of long-term memories in the brain.

Amino Acid Sequence↗

PubMed2003

Protective effect of the antipsychotic drug zotepine on dizocilpine-induced neuropathological changes in rat retrosplenial cortex.

An atypical antipsychotic drug, zotepine, which is pharmacologically and clinically related to clozapine, has unique therapeutic effects on patients with schizophrenia. It has been demonstrated that clozapine blocks neurotoxicity in the rat retrosplenial cortex induced by administration of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801). We examined whether or not zotepine has the ability to block neurotoxicity in the rat retrosplenial cortex induced by administration of dizocilpine. Female Sprague-Dawley rats were injected intraperitoneally (i.p.) with vehicle (1 mg/kg), zotepine (5, 10 or 20 mg/kg) or clozapine (20 mg/kg). Fifteen minutes later, animals were injected intraperitoneally (i.p.) with vehicle (1 ml/kg) or dizocilpine (0.5 mg/kg). Neuropathological changes (neuronal vacuolization) were assessed 4 h after administration of dizocilpine. Immunohistochemical analysis of heat shock protein HSP-70, a marker of reversible neuronal injury, was performed 24 h after administration of dizocilpine. The pretreatment with zotepine (5, 10 or 20 mg/kg) significantly decreased the number of vacuolized neurons in the rat retrosplenial cortex 4 h after the administration of dizocilpine (0.5 mg/kg), in a dose-dependent manner. The potency of zotepine (20 mg/kg) for dizocilpine-induced neurotoxicity was similar to that of clozapine (20 mg/kg). Furthermore, similar to the case with clozapine (20 mg/kg, i.p.), zotepine (20 mg/kg, i.p.) significantly attenuated the expression of HSP-70 in the rat retrosplenial cortex induced by dizocilpine (0.5 mg/kg, i.p.). The present study suggests that the neuroprotective effects of zotepine- on dizocilpine-induced neurotoxicity are equipotent to those of clozapine. Based on the NMDA receptor hypofunction hypothesis of schizophrenia, the efficacy of zotepine in this study may partly contribute to the unique therapeutic effects of zotepine in patients with schizophrenia.

Animals↗

PubMed2003

Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia.

BACKGROUND: The hypofunction of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been implicated in the pathophysiology of schizophrenia. Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site of the NMDA receptor. The aim of this study was to examine whether serum levels of D- and L-serine in patients with schizophrenia are different from those of healthy controls. METHODS: Forty-two patients with schizophrenia and 42 age- and sex-matched healthy controls were enrolled in this study. Symptoms were assessed using the Brief Psychiatric Rating Scale. Serum levels of total serine and D- and L-serine were measured by high-performance liquid chromatography. RESULTS: Serum levels of D-serine in the patients with schizophrenia were significantly (z = -3.30, P =.001) lower than those of healthy controls. In contrast, serum levels of total (D and L) serine (z = -2.40, P =.02) and L-serine (z = -2.49, P =.01) in the schizophrenic patients were significantly higher than those of controls. In addition, the percentage of D-serine in the total serine in the schizophrenic patients was significantly (z = -4.78, P<.001) lower than that of controls, suggesting that the activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine, may have been reduced in the schizophrenic patients. CONCLUSIONS: Reduced levels of D-serine may play a role in the pathophysiology of schizophrenia, and serum D- and L-serine levels might provide a measurable biological marker for schizophrenia.

Adolescent↗

PubMed2003

Reduction of correlation dimension in human respiration by inhaling a mixture gas of 5% carbon dioxide and 95% oxygen.

In order to investigate the effect of the respiratory control system on deterministic behavior in respiration, we used nonlinear analysis in subjects breathing a mixture gas of 5% carbon dioxide (CO2) and 95% oxygen (O2) (CO2-mixed gas). The respiratory movements during breathing air or CO2-mixed gas in eight healthy volunteers were measured. We estimated the values of the correlation dimension (D2) in respiratory movement using Grassberger-Procaccia algorithm. The respiratory movements during inhaling either air or CO2-mixed gas showed a nonlinear behavior using surrogate data method. The values of D2 in respiratory movement during inhaling CO2-mixed gas (1.77 +/- 0.17) were significantly smaller than those during inhaling air (2.52 +/- 0.60) (P < 0.05). This might be related to a prompt change in the nonlinear signal from the central respiratory chemical system.

Adult↗

PubMed2003

A decrease in interleukin-1 receptor antagonist expression in the prefrontal cortex of schizophrenic patients.

Interleukin-1 (IL-1) mediates psychological stress responses by regulating monoamine metabolism and secretion of corticotropin-releasing factor, and is therefore, implicated in various psychiatric diseases. To evaluate the contribution of IL-1 signaling to the brain pathology of schizophrenia, we measured protein and/or mRNA levels for IL-1beta and endogenous IL-1 receptor antagonist (IL-1RA) in the postmortem brain tissues of prefrontal and parietal cortex, putamen, and hypothalamus. Both protein and mRNA levels of IL-1RA were specifically decreased in the prefrontal cortex of schizophrenic patients, whereas IL-1beta levels were not significantly altered in all the regions examined. The IL-1RA decrease was not correlated with the dose of antipsychotics given to patients. There was no influence of this illness on protein levels for IL-1 receptor type 1 in the prefrontal cortex, either. In contrast, IL-1RA serum levels were increased in schizophrenic patients, especially in drug-free patients, as reported previously. These findings suggest that chronic schizophrenia down-regulates IL-1RA production the prefrontal cortex, irrespective of its impact on the periphery. IL-1RA reduction might reflect an immunopathologic trait of the prefrontal region in schizophrenic patients.

Adult↗

PubMed2003

Elevated urinary 8-hydroxydeoxyguanosine, a biomarker of oxidative stress, and lack of association with antioxidant vitamins in chronic obstructive pulmonary disease.

OBJECTIVE: The purpose of this study was to investigate whether patients with COPD are under oxidative stress and to elucidate the relationship between the level of oxidative stress and antioxidant vitamins. METHODOLOGY: Nineteen male patients with COPD and 13 age- matched male control subjects were studied. Urinary 8-hydroxydeoxyguanosine (8-OHdG) concentrations were determined using an enzyme-linked immunosorbent assay kit and corrected for creatinine concentrations. Serum levels of vitamin C, alpha-tocopherol, and beta-carotene were determined by high performance liquid chromatography. RESULTS: The median (interquartile range) 8-OHdG excretion was 8.1 ng/mg (5.3-10.9 ng/mg) in control subjects and 12.2 ng/mg (9.8-15.5 ng/mg) in COPD patients (P < 0.01). Urinary 8-OHdG levels were significantly elevated in ex-smokers in the COPD group compared with ex-smokers in the control group. Urinary 8-OHdG level was negatively correlated with FVC (r = -0.42, P = 0.016), FEV1 (r = -0.49, P = 0.0048), and oxygen tension in arterial blood (r = -0.41, P = 0.0005). No significant differences in antioxidant levels were demonstrated between the two groups. There were no significant correlations between urinary 8-OHdG excretion and the serum concentrations of antioxidant vitamins. CONCLUSION: The burden of oxidative stress was observed to increase in COPD patients as judged by urinary 8-OHdG. A depletion of antioxidant vitamins in serum was not essential for this phenomenon. Elevated urinary 8-OHdG level may not be attributable to smoking status or to antioxidant vitamins in COPD.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2003

Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine therapy.

In this case report, we present genetic differences in two morphine-related gene sequences, UDP-glucuronosyltransferase 2B7 (UGT2B7) and mu opioid receptors (MOR1), in two cancer patients whose clinical responses to morphine were very different [i.e., sensitive (patient 1) and low responder (patient 2)]. In addition, allelic variants in the UGT2B7 gene were analyzed in 46 Japanese individuals. Amplified DNA fragments for the two genes of interest were screened using single strand conformation polymorphism and then sequenced. In the UGT2B7 gene, 12 single nucleotide polymorphisms (SNPs) were newly identified with an allelic frequency ranging from 0.022 to 0.978. Six SNPs in the promoter region (A-1302G, T-1295C, T-1111C, G-899A, A-327G, and T-125C) and two coding SNPs (UGT2B7*2 in exon 2 and C1059G in exon 4) appeared to be consistently linked. Remarkable differences in the nucleotide sequence of UGT2B7 were observed between the two patients; in contrast to patient 1 who had "reference" alleles at almost SNP positions, but a rare ATTGAT*2(AT)C haplotype as homozygosity, patient 2 was a homozygous carrier for the predominant GCCAGC*1(TC)G sequence. Serum morphine and two glucuronide concentrations in patient 2 suggest that the predominant GCCAGC*1G sequence was not associated with a "poor metabolizer" phenotype. In the MOR1 gene, patient 1 had no SNPs, whereas patient 2 was a heterozygous carrier for both the G-1784A and A118G alleles. The present study describes substantial differences in genotype patterns of two genes of interest between the two patients. The results necessitate larger trials to confirm these observations in larger case control studies.

Aged↗

PubMed2003

Phase II trial of weekly paclitaxel in previously untreated advanced non-small-cell lung cancer.

OBJECTIVE: New effective therapy is desirable for outpatients with advanced non-small-cell lung cancer (NSCLC). 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 chemotherapy-naive NSCLC. METHODS: Patients with pathological or cytological diagnosis of NSCLC, measurable lesions, and no prior therapy were enrolled. We administered weekly infusions of 80 mg/m(2) paclitaxel 3 times in a 4-week cycle. In the absence of progressive disease or intolerable toxicity, we treated each patient for a minimum of four cycles. RESULTS: Of 35 patients enrolled, 17 patients achieved partial response, although no complete responses were observed (response rate 49%; 95% confidence interval 32-66%). The median survival time was 55 weeks (range 6-93 weeks). Grade 3 or 4 leukopenia occurred in only 1 patient (3%). Neurotoxicity was the most frequent adverse effect (grades 1 and 2, 26 and 3%, respectively). Serious toxicity, observed in 2 patients (6%), was interstitial pneumonia, and 1 patient died from sequela. CONCLUSION: Low-dose weekly paclitaxel is a promising therapy for advanced NSCLC with high effectiveness and low toxicity.

Adenocarcinoma↗

PubMed2003

Approximate entropy of human respiratory movement during eye-closed waking and different sleep stages.

STUDY OBJECTIVE: The breath-to-breath variability of respiratory parameters changes with sleep stage. This study investigates any alteration in the approximate entropy (ApEn) of respiratory movement as a gauge of complexity in respiration, by stage of consciousness, in the light of putative brain interactions. PARTICIPANTS: Eight healthy men, who were between the ages of 23 and 29 years, were investigated. MEASUREMENTS AND RESULTS: The signals of chest wall movement and EEG were recorded from 10:30 PM to 6:00 AM. After analog-to-digital conversion, the ApEn of respiratory movement (3 min) and EEG (20 s) were computed. Surrogate data were tested for nonlinearity in the original time series. The most impressive reduction in the ApEn of respiratory movement was associated with stage IV sleep, when the ApEn of the EEG was also statistically significantly decreased. A statistically significant linear relation is found between the ApEn of both variables. Surrogate data indicated that respiratory movement had nonlinear properties during all stages of consciousness that were investigated. CONCLUSION: Respiratory movement and EEG signals are more regular during stage IV sleep than during other stages of consciousness. The change in complexity described by the ApEn of respiration depends in part on the ApEn of the EEG, suggesting the involvement of nonlinear dynamic processes in the coordination between brain and lungs.

Adult↗

PubMed2003

[Cost-effectiveness of weekly paclitaxel for patients with advanced non-small cell lung cancer].

Paclitaxel is known to be efficacious in treating non-small cell lung cancer (NSCLC). We initiated a phase II trial of weekly paclitaxel (W-PTX) therapy in advanced NSCLC, and found that W-PTX was feasible for advanced NSCLC patients. We evaluated the cost of W-PTX from receipts and compared it with a standard cisplatin-vinorelbine (VC) regimen. The aim of this study was to assess the cost of W-PTX therapy. Previously untreated patients with stage IV NSCLC and patients with stage III B/IV NSCLC after at least one previous cisplatin based regimen were eligible if they had preserved organ function for treatment. Paclitaxel was administered at a dose of 80 mg/m2 for 3 consecutive weeks on a 4-week cycle. Patients received at least 1 course of W-PTX in our hospital and then, if possible, were treated on outpatients basis. All patients receiving the VC regimen were treated in the hospital. The mean cost of W-PTX for one month was approximately 699,000 yen per inpatient and 236,000 yen per outpatient. On the other hand, the mean cost of VC for one month was approximately 816,000 yen per patient. Although the cost of W-PTX for inpatient did not differ greatly from the cost of VC, the cost of W-PTX for outpatients was significantly lower than that of VC. The findings of this study suggest that W-PTX is feasible as a cost-effective chemotherapy for patients with advanced NSCLC.

Aged↗