Interaction analysis between 5-HTTLPR and TNFA -238/-308 polymorphisms in schizophrenia.

This study investigated the potential interaction between the polymorphisms of serotonin transporter gene (SLC6A4, a 44 base pair insertion/deletion in the promoter region, 5-HTTLPR) and tumor necrosis factor-alpha gene (TNFA; -238G/A and -308G/A polymorphisms) on the development of schizophrenia, as well as the interaction of the three polymorphisms in relation to symptomatology, family history, onset age and antipsychotic treatment response. Genomic DNA analyses with polymerase chain reaction (PCR) was used for the genotyping. One hundred and fifty-two (152) patients with schizophrenia and 152 normal controls participated in the study. Any associations between the individual polymorphism and schizophrenia were not found. However, marginal association between subjects with both TNFA -238 A allele (genotype AA plus AG) and 5-HTTLPR s allele (ss plus sl) and presence of family history was found (p = 0.023; p = 0.026). The subjects with TNFA -308 AG genotype showed higher change in PANSS total score (p = 0.028). No significant interaction effect between 5-HTTLPR and TNFA -238/-308 polymorphisms either on the development of schizophrenia or on antipsychotics treatment response and psychopathology was found, although a significant interaction effect for subjects carrying TNFA -238 AG and -308 AA genotypes on a positive family history was observed (p = 0.017). These results suggest that the interaction effects between 5-HTTLPR and TNFA -238/-308 polymorphisms gives no significant contribution to the susceptibility to schizophrenia, and is not associated with clinical variables, antipsychotic treatment response and psychopathological features, except for family history of disease, at least in the Korean population.

Identification of antibodies to heat shock proteins 90 kDa and 70 kDa in patients with schizophrenia.

OBJECTIVES: Recent reports of antibodies to heat shock proteins 60kDa (HSP60) and HSP70 suggested that antibodies to the heat shock protein that plays a protective role against environmental stresses in a cell might be related to the pathogenesis of schizophrenia, although the antibody to HSP90 had not yet been identified in patients with schizophrenia. In this study, we tried to elucidate the specific involvement of the autoimmunity to HSPs in the pathogenesis and development of schizophrenia. METHODS: Antibodies to HSP90 and HSP70 in 90 patients with schizophrenia and in 83 normal controls were measured by enzyme-linked immunosorbent assay (ELISA) coupled with the avidin-biotin system. In the patients, the association between antibody levels and clinical variables were sought. In addition, changes in antibody levels after treatment with antipsychotic medication were investigated. RESULTS: Eighteen (20.0%) of the 90 patients showed 'high' levels of antibody to HSP90 above a cutoff value, and 28 (31.1%) of those showed 'high' antibody levels to HSP70. On the other hand, only four (4.8%) of the normal controls showed 'high' HSP90 antibody levels, and one (1.2%) of these showed 'high' antibody level to HSP70. The distribution of elevated HSP90 antibody was significantly associated with that of elevated HSP70 antibody in the patients with schizophrenia. The patients with 'high' levels of antibody to HSP70 showed higher initial Brief Psychiatric Rating Scale (BPRS) scores and showed greater clinical improvement than those with 'low' levels, while the patients with 'high' levels of antibody to HSP90 did not. The frequency of patients with high levels of antibody to HSP70 was decreased significantly after 6 weeks of antipsychotic treatment, while the frequency of patients with high levels of antibody to HSP90 was not. CONCLUSIONS: Our results presented the presence of abnormal immune reactivity involving antibody to HSP90 and antibody to HSP70 in a subset of patients with schizophrenia. Differential patterns of distribution, of the association with clinical symptom severity, and of the changes of levels with treatment suggested the possibility that these two antibodies might be involved specifically in the pathogenesis of schizophrenia.

Antimalarial simplified 3-aryltrioxanes: synthesis and preclinical efficacy/toxicity testing in rodents.

A streamlined five-step chemical synthesis of rationally designed, simplified 3-aryltrioxane 8a is described. A noteworthy feature of this synthetic scheme is use of air rather than expensive molecular oxygen as the source of the pharmacologically critical peroxide unit in trioxane 8a. This simplified acetal trioxane carboxylic acid 8a is thermally stable, and it is hydrolytically stable in water even at 40 degrees C and pH 7.4 for at least 7 days. Preclinical evaluation of this water-soluble synthetic trioxane 8a in rodents shows it to have at least as good a therapeutic index (efficacy/toxicity) as that of water-soluble semisynthetic trioxane artelinic acid (5).

An estimation of the first positive Lyapunov exponent of the EEG in patients with schizophrenia.

We studied the complexity of the electroencephalogram (EEG) in schizophrenic patients by estimating the first Lyapunov exponent (L1), which might serve as an indicator of the specific brain function in schizophrenia. We recorded the EEG from 25 schizophrenic patients (12 male, 13 female; age=25.1+/-7.0 years) fulfilling DSM-IV criteria and 15 healthy controls (9 male, 6 female; age=27. 8+/-4.2 years) at 16 electrodes, different from previous studies which recorded the EEGs at limited electrodes. We employed a method with an optimal embedding dimension to calculate the L1s. For limited noisy data, this algorithm was strikingly faster and more accurate than previous ones. Our results showed that the schizophrenic patients had lower values of the L1 at the left inferior frontal and anterior temporal regions compared with normal controls. These results for L1 in non-linear analysis have some differences from those for power ratios in linear analysis. These suggest that the non-linear analysis of the EEGs such as the estimation of the L1 might be a useful tool in analyzing EEG data to explore the neurodynamics of the brains of schizophrenic patients.

Psychological stress may induce increased humoral and decreased cellular immunity.

Stress alters immune function and affects different immune cell populations in different ways. The authors examined whether psychological stress has different effects on the production of macrophage, T-helper 1(Th1) cell, and T-helper 2(Th2) cell-derived cytokines. Forty-two college students were recruited and their blood was sampled on the day they were to take a stressful academic examination and again 4 weeks after the examination. The stress from the academic examination significantly increased IL-1 beta, IL-6, and IL-10 and decreased IFN-gamma production. These findings suggest that examination stress may increase Th2 cell-mediated humoral immunity and macrophage activities and may decrease Th1 cell-mediated cellular immunity.

Nonlinear analysis of the EEG of schizophrenics with optimal embedding dimension.

We estimated the correlation dimensions of EEGs in patients with schizophrenia to investigate the dynamical properties underlying the EEG. We employed a new method, proposed by Kennel et al. (Kennel MB, Brown R, Abarbanel HDI. Determining embedding dimension for phase-space reconstruction using a geometrical construction. Phys Rev A 1992;45:3403-11), to calculate the correlation dimension D2. That method determined the proper minimum embedding dimension by looking at the behaviour of nearest neighbours under a change in the embedding dimension d from d to d + 1. We demonstrated that for limited noisy data, our algorithm was strikingly faster and more accurate than previous ones. We estimated the D2 of EEGs from 16 channels in patients with schizophrenia according to DSM-IV whereas previous studies, which estimated chaoticity of EEG in schizophrenia, recorded EEG only in a limited number of channels. Schizophrenic patients had a lower correlation dimension in the left inferior frontal and anterior temporal regions compared with controls. Our finding of decreased left frontal and temporal chaotic activity in schizophrenics is in line with the findings of a hypofrontality and hypotemporality reported in previous clinical studies such as EEG, blood flow, brain MRI and positron emission tomography studies in schizophrenia. This result suggests that chaos analysis may be a useful tool in analysing EEG data to explore the brain mechanism of schizophrenia.

Observation of metabolic changes in chronic schizophrenia after neuroleptic treatment by in vivo hydrogen magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES: The authors investigate: (1) whether there is a lateral effect of hydrogen (1H) magnetic resonance (MR) spectroscopy observable metabolite ratios between the right and the left prefrontal lobe in chronic schizophrenia; (2) whether there is a change of proton metabolite ratios in chronic schizophrenia after neuroleptic treatment; (3) whether there is a relation between changes in 1H MR spectra and the clinical assessment of Brief Psychiatric Rating Scale (BPRS); and (4) to investigate a hypofrontality hypothesis in schizophrenia in terms of neurochemical aspects. METHODS: Localized in vivo 1H MR spectroscopy was used to measure the metabolite levels in the prefrontal lobes of control persons (n = 20) and of chronic patients before and after neuroleptic treatment (n = 34). The MR spectra of 8 cm3 voxels were compared with clinical assessment of BPRS in each subject. RESULTS: No significant metabolic lateral effect was established in both schizophrenia and control groups (P > 0.05). After neuroleptic treatment, chronic schizophrenic patients generally demonstrated a decrease of the complex of gamma-aminobutyric acid (GABA) and glutamate (Glu) containing (GABA + Glu)/creatine (Cr) ratio. CONCLUSIONS: The current follow-up 1H MR spectroscopy study shows a significant correlation between alterations of (GABA + Glu)/Cr ratio and BPRS, and supports a hypofrontality hypothesis in chronic schizophrenia. The reduction of (GABA + Glu)/Cr ratio after neuroleptic treatment may implicate the recovery of normal neuronal function in neurotransmitters. In vivo 1H MR spectroscopy may be a useful modality in follow-up evaluation of neuroleptic treatment in chronic schizophrenia.

Reliability of the ICD-10 diagnostic criteria for research in mental disorders in the Republic of Korea.

The interrater reliability, confidence and ease of use of ICD-10 diagnostic criteria for research were assessed in the Republic of Korea as part of the field trials of World Health Organization collaborative study. A total of 279 patients were diagnosed according to the ICD-10 diagnostic criteria for research. Interrater reliability, calculated by kappa statistics, was found to be between 0.74 and 0.91 on 2-character categories and between 0.64 and 0.90 on 3-character categories except schizotypal disorder (F21). On the 4-character categories, the agreement in the affective states between raters was lower. The reasons are discussed based on cultural differences.

1H magnetic resonance spectroscopy characterization of neuronal dysfunction in drug-naive, chronic schizophrenia.

RATIONALE AND OBJECTIVES: We investigated the proton metabolism of right prefrontal white matter in drug-naive, chronic schizophrenic patients (n = 23), compared with healthy normal control subjects (n = 10), by using localized, water-suppressed in vivo 1H magnetic resonance (MR) spectroscopy. METHODS: All 1H MR spectroscopy examinations were performed on a 1.5-T MR imaging/MR spectroscopy system by using a point-resolved spectroscopy pulse sequence for localized volumes of 2 x 2 x 2 cm3. Proton metabolite ratios relative to creatine (Cr) were obtained using a Marquart algorithm. RESULTS: Drug-naive, chronic schizophrenic patients demonstrated a decrease in the N-acetylaspartate (NAA):Cr and choline (Cho):Cr ratios and an increase of the complex of gamma-aminobutyric acid (GABA) and glutamate (Glu)-containing ratio [(GABA + Glu):Cr] as compared with normal control subjects. CONCLUSION: Results suggest that the reduction of NAA and Cho may indicate neuronal dysfunction and that the elevation of GABA and Glu may play a role in chronic schizophrenia. 1H MR spectroscopy may be a useful modality in research and in the clinical evaluation of chronic schizophrenic patients.

Possible involvement of supersensitivity in cerebral ?-adrenergic and dopaminergic receptors in the occurrence of sensitization to d-methamphetamine in mice.

Behavioral sensitization of mice (male STD-ddy) to d-methamphetamine (MAP) and its correlation with the neurochemical alterations in cerebral catecholaminergic systems were investigated following the repeated administration of MAP (5 mg/kg, i.p. x 2/day, 5 days). MAP-pretreated mice showed an enhancement in MAP-stimulated locomotor activity following the readministration of MAP (0.625 mg/kg). The metabolic turnovers of cerebral norepinephrine (NE) and dopamine (DA) showed a significant decrease in these sensitized mice. The activities of tyrosine hydroxylase. DOPA decarboxylase, monoamine oxidase and catechol-O-methyltransferase, however, showed no change under the same experimental conditions. On the other hand, the repeated MAP pretreatment induced the enhancement of the specific bindings of [(3)H]dihydroalprenolol and [(3)H]spiperone to cerebral synaptic membrane, which resulted from the increase of B(max) values. Furthermore, pretreatments of mice with propranolol (10 mg/kg) and haloperidol (0.1 mg/kg) inhibited the development of behavioral sensitization to MAP. These results suggest that the supersensitivity in cerebral ?-adrenergic and dopaminergic receptors may be involved in behavioral sensitization to MAP.

Mianserin-induced restless legs syndrome.

Restless legs syndrome was observed in three patients receiving mianserin. The symptoms resolved when the treatment was discontinued or reduced.

Preferential release of newly synthesized [(3)H]GABA from striatal slices to preloaded [(3)H]GABA.

The release of [(3)H]GABA which is newly synthesized from [(3)H]l-glutamic acid (GLU) has been examined using striatal slices obtained from the rat brain. It was found that 8-10% of [(3)H]GLU transported was converted to [(3)H]GABA during the incubation of striatal slices in the presence of nipecotic acid (5 x 10(?5) M). Nipecotic acid was added to the medium in order to prevent possible reuptake of [(3)H]GABA released during its synthesis, and it was found to have no significant effect on the formation of [(3)H]GABA from [(3)H]GLU as well as on the uptake of [(3)H]GLU. The application of high potassium (60 mM) stimulation exhibited a significant enhancement of the release of this newly synthesized [(3)H]GABA in a Ca(2+) dependent manner. Kinetic analysis revealed that the evoked release of newly synthesized [(3)H]GABA was approximately two times greater than that of previously-loaded [(3)H]GABA, whereas no significant difference was observed in the spontaneous release. An immobilization stress in water failed to affect the release of newly synthesized [(3)H]GABA from striatal slices despite the occurrence of a significant enhancement of GABA formation in this structure. These results suggest that newly synthesized GABA may be preferentially released from its nerve terminals in response to the excitation of neurons at least in the striatum as compared with previously accumulated GABA.