G-proteins (Gi,Go) in the basal ganglia of control and schizophrenic brain

Summary We detected the existence of Gi (the inhibitory G-protein) or Go (a similar G-protein of unknown function) in the striatum of control and schizophrenic brains utilizing pertussis toxin-catalyzed ADP ribosylation. The level of Gi/Go was significantly decreased by 42% in the putamen of the left hemisphere in schizophrenics; caudate head and globus pallidus levels were unchanged. Decreased Gi or Go may underlie enhanced dopamine function in the schizophrenic brain.     

Light microscopy of GTP-binding protein (Go) immunoreactivity within the retina of different vertebrates

To examine species differences in the distribution pattern of guanosine triphosphate (GTP)-binding protein (Go) within the vertebrate retina, paraffin-embedded retinae from a number of vertebrate species, including the goldfish, frog, turtle, chicken, monkey, and human, were immunohistochemically stained with affinity-purified antibody against the alpha-subunit of Go. Go-immunoreactive products were found to be located in the neuropil, but not in the cell bodies of neurons, in the retina of all these species. However, some species differences were observed. In the frog, monkey and human, the inner plexiform layer (IPL) was homogeneously stained with this antibody, but in the goldfish, turtle and chicken, the IPL was heterogeneously stained. In the frog, chicken, turtle and human, the outer plexiform layer (OPL) was densely stained with this antibody, but in the goldfish and monkey, the OPL was rather faintly immunoreactive to the antibody. In the goldfish, monkey and human, the outer nuclear layer (ONL) was not immunoreactive to the Go-antibody, whereas in the frog, turtle and chicken, the ONL was immunoreactive to it. The implications of these species differences in Go localization in the vertebrate retina are discussed.     

CSF levels of diazepam-binding inhibitor correlate with REM latency in schizophrenia,a pilot study

CSF diazepam-binding inhibitor-like immuno-reactivity (DBI-LI) and polysomnography were studied in 28 drug-free male schizophrenic (DSM-III-R) patients. They underwent a three-night polysomnography evaluation and a lumbar puncture. CSF DBI-LI correlated positively with REM latency, the REM latency/2^d nonREM period ratio and stage-4% sleep, and negatively with stage-1% sleep. CSF DBI-LI did not correlate significantly with duration of sleep or sleep latency. CSF DBI-LI during haloperidol treatment did not correlate significantly with sleep EEG measures. The results of this first study of the relationship between endogenous DBI and sleep in humans suggest that physiological effects of DBI other than interactions with the BZD/GABA_A receptor complex may explain its positive effects on sleep. However, the absence of similar sleep data in normal subjects precludes us from establishing a specific relationship between DBI and sleep in schizophrenia.     

Pertussis toxin blocks presynaptic glutamate receptors — a novel ‘glutamateB’ receptor in the lobster neuromuscular synapse

Topical application of L-glutamate to the neuromuscular synapse of the lobster walking leg induced K+-dependent hyperpolarization in the presynaptic membrane. This presynaptic glutamate potential (PGP) was insensitive to Joro spider toxin (JSTX), a spider toxin which specifically blocks the postsynaptic glutamate receptor, but was blocked by pertussis toxin island activating protein (IAP) in a dose-dependent manner. IAP had little effect on the resting conductance channels in pre- and postsynaptic membranes. GTP gamma S, a hydrolysis-resistant analogue of GTP, reduced the PGP supporting the involvement of G-protein in generation of K+ activation. The results suggest that a new type of glutamate receptor exists in the presynaptic membrane in the crustacean neuromuscular synapse.     

Comprehensive dissection of the medial temporal lobe in AD: measurement of hippocampus, amygdala, entorhinal, perirhinal and parahippocampal cortices using MRI

Background Early pathological involvement of specific medial temporal lobe areas is characteristic for Alzheimer’s disease (AD). Objective To determine the extent of regional medial temporal lobe atrophy, including hippocampus, amygdala, and entorhinal, perirhinal, and parahippocampal cortices in mild AD patients and healthy controls, and to compare diagnostic accuracy across volumetric markers. Methods We studied 34 patients with clinically probable AD and 22 healthy elderly control subjects. Regional volumetric measures were obtained from volumetric T1–weighted MRI scans after accounting for global brain atrophy using affine transformation into standard space. Results Volumes of medial temporal lobe structures were significantly smaller in AD patients than in controls with exception of the left entorhinal cortex. The degree of atrophy was comparable between all structures. Diagnostic accuracy (number of correctly allocated cases divided by number of all cases) was highest for the right parahippocampal cortex with 85%, but only slightly lower for the right hippocampus and right entorhinal cortex with 82% and 84%. Using a linear combination of markers, the unilateral volumes of the right hippocampus, parahippocampal cortex and perirhinal cortex yielded an accuracy of 93%. Conclusion Extent of atrophy is similar between the different regions of the medial temporal lobe in mild AD.Volume measurements of medial temporal lobe structures in addition to the hippocampus only yield improved diagnostic accuracy if a combination of these structures is used.     

难治性精神分裂症和抑郁症患者透明隔腔形态结构的磁共振成像比较研究

目的探索难治性精神分裂症(treatment resistant schizophrenia,TRS)与难治性抑郁症(treatmentresistant depression,TRD)患者透明隔腔(cavum septum pellucidum,CSP)发生率及其形态结构特点。方法采用磁共振成像(magnetic resonance imaging,MRI)技术,对42例TRS、45例TRD患者和30例正常对照进行头部MRI扫描,运用影像学分析软件,对TRS组、TRD组和对照组出现小CSP(冠状面层CSP长度<6毫米)和大CSP(长度≥6毫米)情况有无进行统计,计算各自发生率,并对其长度、最大宽度和体积进行测量,比较三组间差异。结果TRS组、TRD组和对照组小CSP发生率(分别为50.0%、48.9%、50%)的差异无统计学意义(P>0.05);TRS组大CSP发生率(14.3%)均高于TRD组和对照组((均为0%)(P<0.01);TRS组CSP最大宽度分别小于对照组或TRD组,而长度大于对照组或TRD组,均有统计学意义(P<0.05);三组间CSP体积差异无统计学意义(P>0.05)。结论大CSP在TRS患者中发生率显著高于TRD和正常人群,可能为TRS的异常脑结构之一;而小CSP发生率则在三组间无显著差异,其可能为一种正常的结构变异;与TRD患者和正常人群不同,TRS患者有着独特的CSP形状,呈"瘦长"形。     

Morphological and latency abnormalities of the mid-latency auditory evoked responses in schizophrenia: a preliminary report

Introduction: Evoked potential (EP) amplitude and latency abnormalities have been extensively examined in schizophrenia. Morphological abnormalities of the mid-latency auditory evoked responses (MLAERs; P50, N100, P200), on the other hand, received very little attention. Methods: Based on a priori defined set of morphological criteria, the morphology and latency of the MLAERs were blindly compared between stable outpatients with schizophrenia (N=27) and age- and gender-matched healthy control subjects (N=22). The morphology of the MLAERs was considered abnormal if one or more of the components fell outside the expected latency range, if one or more of the components were missing, or if a later occurring component was smaller in amplitude than an earlier occurring one. Results: Of the 27 schizophrenia subjects, 20 had waveforms that were deemed atypical, while only 8 from the control group were classified as atypical (χ²=5.52, p<0.02). The latencies of the P50 and N100 components, identified based on morphology, were significantly prolonged in schizophrenia patients. Conclusions: These preliminary data suggest that morphological abnormalities of the MLAERs in schizophrenia patients are significant and should be taken into consideration when examining the MLAERs of this patient population.     

银杏叶提取物结合氟哌啶醇治疗慢性精神分裂症的双盲对照研究

目的探讨银杏叶提取物结合氟哌啶醇对慢性精神分裂症的治疗作用。方法采用随机、双盲、空白对照法，用银杏叶提取物３６０ｍｇ／ｄ结合氟哌啶醇（０２５ｍｇ／ｋｇ）对１１２例慢性精神分裂症患者进行治疗１２周，在治疗前后评定ＢＰＲＳ、ＳＡＰＳ、ＳＡＮＳ和ＴＥＳＳ量表。结果银杏叶提取物结合氟哌啶醇治疗慢性精神分裂症的疗效比单用氟哌啶醇要好，前者ＢＰＲＳ、ＳＡＰＳ和ＳＡＮＳ量表总分明显降低，而后者仅ＢＰＲＳ量表总分明显降低；同时前者治疗后ＳＡＰＳ量表评分显著低于后者；银杏叶提取物具有减轻氟哌啶醇锥体外系和行为毒性副反应的作用。结论银杏叶提取物可提高抗精神病药治疗慢性精神分裂症的疗效，并减轻抗精神病药副作用。     

Possible association between nonsynonymous polymorphisms of the anaplastic lymphoma kinase (ALK) gene and schizophrenia in a Japanese population

Summary. We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys–1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3–4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.     

Sagittal counter forces (SCF) in the treatment of idiopathic scoliosis: A preliminary report

Background: In patients with idiopathic scoliosis (IS), reduced thoracic kyphosis and reduced lumbar lordosis frequently occur in correlation with the lateral spinal curvature. Normalization of the sagittal profile and hyper-correction of the deviation in frontal and coronal plane are the main issues of the latest concept of bracing. The purpose of this study was to investigate the influence of of sagittal counter forces (SCF) on the scoliotic deformity.

Study design: A case series of four patients with IS treated with two braces designed to improve the sagittal profile (Rigo-System-Chêneau-brace and with a sagittal counter force brace, SCF-brace).

Methods: The short-term effect (30?min) of both braces was evaluated using surface topography (Formetric® surface topography system, Diers International, Wiesbaden).

Results: One patient (Cobb angle 92°) showed no short-term correction in the frontal and coronal planes; others (Cobb angles between 39 and 48°) exhibited valuable correction in frontal and coronal planes. There was no short-term correction in the sagittal plane for either brace.

Conclusion: The application of sagittal counter forces (SCF) seems to have similar short-term effects as 3D correction and should be addressed more in future concepts of scoliosis bracing.     

Changes in region- and cell type-specific expression patterns of neutral amino acid transporter 1 (ASCT-1) in the anterior cingulate cortex and hippocampus in schizophrenia,bipolar disorder and major depression

Summary. Although, the pathogenetic mechanisms of schizophrenia, bipolar disorder, and major depression are not clearly understood, various neurotransmitter systems are reported to have altered expression patterns of their receptor and transporter proteins. Changes in the expression of the neutral amino acid transporter 1 (ASCT-1) protein in the anterior cingulate gyrus and the hippocampus were investigated using immunohistochemistry and western blotting. A significant decrease in ASCT-1 immunoreactivity in neurons in the cingulate cortex as well as astrocytes of the white matter was seen in schizophrenia. In bipolar disorder and major depression, similar results were seen for neurons. In the hippocampus, there was a striking loss of immunoreactivity on astrocytes, neurons and interneurons in multiple regions in schizophrenia and bipolar disorder, while only minor changes were seen in major depression. The altered expression of ASCT-1 in neurons and astrocytes reflects profound changes in glutamatergic neurotransmission and highlights a significant role of astrocytes in the pathophysiology of neurotransmission in these major psychiatric disorders.     

Modelling of the III-IV loop,a domain involved in calcium channel Ca(v)2.1 inactivation,highlights a structural homology with the gamma subunit of G proteins

We have modelled the conformation of the III-IV loop of the Ca(v)2.1 subunit of P/Q calcium channels, a loop that is implicated in fast voltage-dependent inactivation. Change in channel inactivation requires its direct interaction with the I-II loop. This interaction occurs with an affinity in the order of 70 nm. Intracellular injection of a 40-mer III-IV loop-derived peptide produces an increase in the rate of fast inactivation. This alteration in channel kinetic is also accompanied by a hyperpolarizing shift in the steady-state voltage-dependence of inactivation. None of these effects are observed in the presence of a beta subunit, suggesting the existence of a competitive mechanism of action between the beta subunit and the III-IV loop. Amino acid sequence comparison using BLAST reveals that the III-IV loop shares 53% identity with the gamma subunit of G proteins. Because of the pivotal contribution of the III-IV loop to inactivation, an atomic model of the III-IV loop was generated by both homology modelling and molecular mechanics calculations. Using the X-ray structures of the betagamma dimer of the heterotrimeric G-proteins as templates, the III-IV loop is predicted to contain a well-structured alpha-helix at the amino-terminus with both the N- and C-termini having the same orientation in the plane of the inner lipid bilayer. We provide a hypothetical working model in which we propose that the III-IV loop interacts with the I-II loop via its Gbetagamma binding domain.     

Association of minimal thickness of the medial temporal lobe with hippocampal volume, maximal and minimal hippocampal length: volumetric approach with horizontal magnetic resonance imaging scans for evaluation of a diagnostic marker for neuroimaging of Alzheimer's disease

A 3-D volumetric study of the medial temporal lobe (MTL) was performed to evaluate how a minimum thickness of the MTL (mtMTL), a visually estimated measure, is associated with other MTL measures, maximal and minimal hippocampal length (max-HL, min-HL) and hippocampal volume, all measured with a 3-D device, Neurolucida, in 33 patients with Alzheimer's disease (AD), seven patients with mild cognitive impairment (MCI), and 20 age-matched controls. Cognitive impairment was evaluated with Mini-Mental State examination (MMSE). The T1-weighted horizontal magnetic resonance imaging (MRI) scans with slices 5 mm thick were analyzed with Neurolucida and the mtMTL was measured with visual estimation. The MTL was divided into the amygdala and hippocampus. Max-HL on both sides was longer in controls than in AD and MCI, whereas min-HL and mtMTL were longer in controls than in AD, and no difference was observed between MCI and controls. Similarly hippocampal volume was larger in controls than in AD, and no differences were seen within the MCI and controls. No difference in amygdala and midbrain volumes was observed among AD, MCI and controls. Correlation of MMSE score with min-HL and mtMTL was higher than that with max-HL. Although hippocampal and MTL measures examined here failed to show significant difference between AD and MCI, max-HL could be a diagnostic neuroimaging sign of AD. The high correlation of MMSE with mtMTL as well as with min-HL compared with that with max-HL, also will support neuroimaging diagnosis of AD.     

Arg(184)His mutant GTP cyclohydrolase I, causing recessive hyperphenylalaninemia, is responsible for dopa-responsive dystonia with parkinsonism: a case report.

We describe a 54-year-old man with dominant adult-onset dopa-responsive dystonia (DRD) with parkinsonism caused by an Arg184His mutation in guanosine 5'-triphosphate cyclohydrolase I (GCH-I). This is the first mutation in the GCH-I gene that has been proven to be responsible for both recessive and dominant phenotypes.     

Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia.

BACKGROUND: Neurocognitive deficits are recognized as a cardinal feature of schizophrenia, but the determinants of these deficits remain unknown. Recent reports have suggested that a functional polymorphism, Val(158)Met in exon III of the catechol-O-methyltransferase gene, shares approximately 4% variance with performance on the Wisconsin Card Sorting Test. These findings led to suggestions that the catechol-O-methyltransferase polymorphism may exert its effects by modulating prefrontal dopamine function, but few other neurocognitive measures have been examined, leaving open questions about phenotypic specificity. METHODS: We examined the effects of the catechol-O-methyltransferase Val(158)Met polymorphism in 58 individuals with chronic schizophrenia who completed a battery of 15 neurocognitive tests, which were reduced to four reliable neurocognitive domain scores. We examined the effects of genotype on these four domains and on global neurocognitive ability. RESULTS: The Met allele was associated with better performance in the Processing Speed and Attention domain, but not with other domain scores measuring executive and visuoperceptual functions, declarative verbal learning and memory, simple motor ability, or global neurocognitive function. Genotype shared approximately 11% of variance with Processing Speed and Attention scores, and approximately 2% of variance with Wisconsin Card Sorting Test scores. CONCLUSIONS: The findings provide independent support for the hypothesis that the catechol-O-methyltransferase Val(158)Met polymorphism influences neurocognitive function in schizophrenia, and suggest that the functional effects may be expressed on measures of Processing Speed and Attention. This information may prompt reconsideration of the "prefrontal dopamine" hypothesis and invites examination of a broader range of effects in efforts to refine the neurocognitive phenotype that is most relevant to variation in catechol-O-methyltransferase expression.     

Proton magnetic resonance spectroscopy (1H-MRS) of hippocampus, basal ganglia, and vermis of cerebellum in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome)

OBJECTIVE: Whether patients with schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome, GS) have specific changes in brain metabolism was examined in this study. METHOD: This study applied proton magnetic resonance spectroscopy (1H-MRS) to the hippocampus, basal ganglia, and vermis of the cerebellum of schizophrenic patients with GS (n=15) or without GS (n=15), all diagnosed according to DSM-IV criteria, and healthy subjects (n=15). RESULTS: In the hippocampus, schizophrenic patients with GS showed a significant decrease of N-acetyl aspartate/creatine-phosphocreatinine (NAA/Cr) and myoinositol/creatine-phosphocreatinine (mI/Cr) ratios compared to healthy subjects and schizophrenic patients without GS, while schizophrenic patients without GS showed only a significant decrease of NAA/Cr compared to healthy subjects. In the basal ganglia, schizophrenic patients with GS showed a significant decrease of ml/Cr compared to schizophrenic patients without GS and healthy subjects, and schizophrenic patients with GS showed a significant decrease of NAA/Cr compared to healthy subjects. In the vermis of the cerebellum, schizophrenic patients with GS showed only a significant decrease of ml/Cr compared to healthy subjects, although schizophrenic patients without GS did not show a significant decrease of ml/Cr compared to healthy subjects. CONCLUSION: The findings suggest that schizophrenia with GS is a more severe sub-type with regard to brain metabolism.