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1.
Sci Rep ; 1: 190, 2011.
Article in English | MEDLINE | ID: mdl-22355705

ABSTRACT

Vacancies and interstitial atoms are primary lattice (point) defects that cause observable microstructural changes, such as the formation of dislocation loops and voids in crystalline solids. These defects' diffusion properties determine the phase stability and environmental resistibility of macroscopic materials under ambient conditions. Although in situ methods have been proposed for measuring the diffusion energy of point defects, direct measurement has been limited. In this study, we propose an alternative in situ method to measure the activation energy for vacancy migration under laser irradiation using a pulsed laser beam from a laser-equipped high-voltage electron microscope (laser-HVEM). We made in situ observations that revealed the formation and growth of vacancy dislocation loops in an austenitic stainless steel during laser irradiation. These loops continued to grow when thermal annealing was performed after laser irradiation at the same temperature. We anticipate that laser-HVEM will provide a new method for investigating lattice defects.

2.
Biol Pharm Bull ; 33(12): 1999-2002, 2010.
Article in English | MEDLINE | ID: mdl-21139240

ABSTRACT

It is widely accepted that selective serotonin reuptake inhibitors (SSRIs) require 2 to 4 weeks of administration before improvements in emotional symptoms of depression are seen. We evaluated whether early monitoring of Hamilton Rating Scale for Depression (HAMD) scores in patients treated with the SSRI fluvoxamine could predict antidepressant response, and also assessed the relationship between the onset of clinical response following the start of fluvoxamine administration and its plasma concentration. Twelve depressed patients (baseline HAMD score ≥15) received an initial dose of fluvoxamine (50 mg/d) followed by an optimized maintenance dose according to their clinical symptoms after 7 d. HAMD scores and plasma drug concentrations were determined at 7 and 28 d after the first administration. There were 7 responders and 5 non-responders on day 28, as evaluated by HAMD scores. The HAMD score for the responders was significantly lower than that for the non-responders on day 7 (mean±S.D., 11.6±6.1 vs. 26.6±6.5, p=0.006). Thus, the reduction in HAMD score on day 7 was clearly divided between responders and non-responders. On day 28, the plasma concentration of fluvoxamine in responders was lower than that in non-responders (14.2±10.5 ng/ml vs. 44.2±28.1 ng/ml, p=0.051). Furthermore, receiver operating characteristic curve analysis conducted on day 28 revealed an upper concentration threshold of 28.2 ng/ml (p=0.042), with none in the responder group above that level. Our results suggest that HAMD score after the first week of treatment with fluvoxamine and the upper threshold of plasma drug concentration could predict whether a patient is a non-responder.


Subject(s)
Antidepressive Agents/therapeutic use , Anxiety Disorders/drug therapy , Depressive Disorder/drug therapy , Feeding and Eating Disorders/drug therapy , Fluvoxamine/therapeutic use , Mood Disorders/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Adult , Antidepressive Agents/blood , Anxiety Disorders/blood , Depressive Disorder/blood , Feeding and Eating Disorders/blood , Female , Fluvoxamine/blood , Humans , Japan , Male , Middle Aged , Mood Disorders/blood , ROC Curve , Selective Serotonin Reuptake Inhibitors/blood , Treatment Outcome
3.
Neurosci Res ; 68(2): 137-41, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20615438

ABSTRACT

MET receptor tyrosine kinase (MET)-mediated signaling has been implicated in multiple aspects of neocortical and cerebellar neuronal growth and maturation. A promoter functional SNP (rs1858830) that disrupts the transcription of MET has been reported to be strongly associated with autism spectrum disorders (ASD) in the Caucasian population. Here, we performed a trio association study of MET with ASD in Japanese subjects (n=126 trios). Based on the HapMap data on the Japanese population, 15 SNPs were chosen for the association study. One SNP located in intron 1, rs38841, showed a nominal association with autism (p=0.044; OR=1.61) when analyzed using the transmission disequilibrium test. To the best of our knowledge, this is the first replication study of the association of MET with autism, in any non-Caucasian population. Association of rs38841 with autism was further confirmed in 252 Caucasian trios from AGRE (p=0.0006). An interesting observation is that all three SNPs of MET (rs1858830, rs38845 and rs38841) shown to be associated with autism in three independent studies including the present one, are located towards the 5'end of the gene at a span of 9.4 kb. Our results provide further evidence for a possible role of MET in the pathogenesis of ASD.


Subject(s)
Child Development Disorders, Pervasive/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide/genetics , Proto-Oncogene Proteins c-met/genetics , Receptors, Growth Factor/genetics , Adolescent , Asian People , Child , Female , Gene Frequency , Humans , Linkage Disequilibrium , Male
4.
Biol Pharm Bull ; 33(2): 285-8, 2010.
Article in English | MEDLINE | ID: mdl-20118554

ABSTRACT

Fluvoxamine is a selective serotonin reuptake inhibitor widely used in the treatment of depression and other psychiatric diseases. The aim of this study was to assess the clinical impact of cigarette smoking on plasma fluvoxamine concentration in Japanese patients, and evaluate whether the cytochrome P450 (CYP) 1A2 and CYP2D6 genotypes have effects on that concentration. Thirty-two Japanese patients receiving fluvoxamine were enrolled. They were maintained on the same daily dose of fluvoxamine (mean + or - S.D., 109.4 + or - 66.2 mg/d) for at least 4 weeks to obtain the steady-state plasma concentration. The steady-state plasma concentration-to-dose (C/D) ratio of fluvoxamine in patients who smoked (n = 6, 11.8 + or - 6.5 ng/ml/dose) was significantly lower than that in non-smoker patients (n = 26, 22.8 + or - 11.2 ng/ml/dose). There was no significant difference for the C/D ratio of fluvoxamine in patients with CYP1A2 -3860G/G, -3860G/A, and -3860A/A between non-smokers and smokers. Among non-smoker patients, the C/D ratios of fluvoxamine in those with one and two mutated alleles of CYP2D6 were 1.6- and 1.4-fold higher, respectively, than those with no mutated alleles, though the differences among those three genotype groups were not significant. Furthermore, stepwise multiple regression analysis revealed that cigarette smoking and daily dose had significant positive correlations with the plasma concentration of fluvoxamine. Our findings suggest that cigarette smoking has a significant impact on the steady-state plasma concentration of fluvoxamine in Japanese patients.


Subject(s)
Asian People/genetics , Cytochrome P-450 CYP2D6/genetics , Fluvoxamine/blood , Smoking/blood , Smoking/genetics , Adult , Aged , Cytochrome P-450 CYP2D6/blood , Female , Genotype , Humans , Male , Middle Aged , Young Adult
5.
Am J Med Genet B Neuropsychiatr Genet ; 150B(7): 967-76, 2009 Oct 05.
Article in English | MEDLINE | ID: mdl-19191256

ABSTRACT

Disrupted-in-Schizophrenia 1 (DISC1) and its molecular cascade have been implicated in the pathophysiology of major psychoses. Previously, we identified pericentrin 2 (PCNT2) and DISC1-binding zinc finger protein (DBZ) as binding partners of DISC1; further, we observed elevated expression of PCNT2 in the postmortem brains and in the lymphocytes of bipolar disorder patients, compared to controls. Here, we examined the association of PCNT2 with schizophrenia in a case-control study of Japanese cohorts. We also examined the association of DBZ with schizophrenia and with bipolar disorder, and compared the mRNA levels of DBZ in the postmortem brains of schizophrenia, bipolar and control samples. DNA from 180 schizophrenia patients 201 controls were used for the association study of PCNT2 and DBZ with schizophrenia. Association of DBZ with bipolar disorder was examined in DNA from 238 bipolar patients and 240 age- and gender-matched controls. We observed significant allelic and genotypic associations of the PCNT2 SNPs, rs2249057, rs2268524, and rs2073380 (Ser/Arg) with schizophrenia; the association of rs2249057 (P = 0.002) withstand multiple testing correction. Several two SNP- and three SNP-haplotypes showed significant associations; the associations of haplotypes involving rs2249057 withstand multiple testing correction. No associations were observed for DBZ with schizophrenia or with bipolar disorder; further, there was no significant difference between the DBZ mRNA levels of control, schizophrenia and bipolar postmortem brains. We suggest a possible role of PCNT2 in the pathogenesis of schizophrenia. Abnormalities of PCNT2, the centrosomal protein essential for microtubule organization, may be suggested to lead to neurodevelopmental abnormalities.


Subject(s)
Antigens/genetics , Bipolar Disorder/genetics , Carrier Proteins/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation , Genetic Predisposition to Disease , Nerve Tissue Proteins/metabolism , Schizophrenia/genetics , Transcription Factors/genetics , Adult , Alleles , Case-Control Studies , Demography , Female , Genome, Human/genetics , Haplotypes , Humans , Male , Polymorphism, Single Nucleotide/genetics , Protein Binding
6.
Ann N Y Acad Sci ; 1139: 49-56, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18991848

ABSTRACT

Accumulating evidence suggests that genetic factors contribute to the vulnerability to methamphetamine (MAP) abuse and associated psychiatric symptoms. Chronic MAP abuse leads to psychosis, which may be of a transient or a prolonged type. Serotonergic dysfunction has been proposed as one of the contributory factors in the development of MAP psychosis. Our PET studies revealed that the serotonin transporter (5-HTT) density in global brain regions is significantly lower in MAP abusers. In this study, we examined the role of a functional polymorphism in the 5' flanking region of the 5-HTT gene (5-HTTLPR) in the development of MAP psychosis in a Japanese population. We analyzed DNA samples from 166 MAP patients (95 with transient and 71 with prolonged psychosis) and 197 age-, sex-, and geographic-origin-matched healthy controls. Patients were also subdivided according to the presence (n= 119) or absence (n= 148) of spontaneous relapse. We observed significant genotypic association of the 5-HTTLPR polymorphism with MAP psychosis (P= 0.022), particularly in patients who show prolonged psychosis. The frequency of the S allele in patients with prolonged psychosis was significantly higher than that of the controls (P= 0.045); it was further higher in patients with prolonged psychosis with spontaneous relapse (P= 0.004). 5-HTTLPR has been suggested to regulate the transcriptional activity of 5-HTT, with S alleles showing lesser transcriptional efficiency and also lower 5-HT(1A) receptor-binding potential. Prolonged MAP use, combined with the high frequency of 5-HTTLPR S-alleles, may lead to reduced 5-HTT levels and 5-HT(1A) receptor-binding potential in the brain, resulting in the dysfunction of the serotonergic system. Thus, we suggest a possible role for the 5-HTTLPR polymorphism in MAP psychosis.


Subject(s)
Asian People/genetics , Central Nervous System Stimulants/pharmacology , Methamphetamine/pharmacology , Psychoses, Substance-Induced/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Adult , Aged , Drug Users , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Polymorphism, Genetic , Receptor, Serotonin, 5-HT1A/metabolism , Risk Factors , Young Adult
7.
Br J Psychiatry ; 193(4): 316-21, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18827294

ABSTRACT

BACKGROUND: Previous studies have reported the association between advanced paternal age at birth and the risk of autistic-spectrum disorder in offspring, including offspring with intellectual disability. AIMS: To test whether an association between advanced paternal age at birth is found in offspring with high-functioning autistic-spectrum disorder (i.e. offspring without intellectual disability). METHOD: A case-control study was conducted in Japan. The participants consisted of individuals with full-scale IQ>or=70, with a DSM-IV autistic disorder or related diagnosis. Unrelated healthy volunteers were recruited as controls. Parental ages were divided into tertiles (i.e. three age classes). Odds ratios and 95% confidence intervals were estimated using logistic regression analyses, with an adjustment for age, gender and birth order. RESULTS: Eighty-four individuals with autistic-spectrum disorder but without intellectual disability and 208 healthy controls were enrolled. Increased paternal, but not maternal, age was associated with an elevated risk of high-functioning autistic-spectrum disorder. A one-level advance in paternal age class corresponded to a 1.8-fold increase in risk, after adjustment for covariates. CONCLUSIONS: Advanced paternal age is associated with an increased risk for high-functioning autistic-spectrum disorder.


Subject(s)
Autistic Disorder/etiology , Paternal Age , Adolescent , Adult , Case-Control Studies , Child , Child, Preschool , Female , Humans , Intelligence , Male , Maternal Age , Phenotype , Risk Factors , Sex Factors , Young Adult
8.
Int J Neuropsychopharmacol ; 11(8): 1073-84, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18593506

ABSTRACT

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from 249 AGRE trios with autistic probands. Only male probands were selected, since autism is more prevalent among males. The probands of 102 trios had IQ>70, and were considered as high functioning autism (HFA). In transmission disequilibrium test (TDT) analysis, rs2293485 (p=0.034) and rs4717806 (p=0.033) showed nominal associations with HFA; modest haplotype association was also observed. The SNPs that showed associations were related to early developmental abnormalities (ADI-R_D). We further compared STX1A mRNA expression in the lymphocytes of drug-naive HFA patients (n=12) and age- and sex-matched controls (n=13). STX1A expression in the HFA group was significantly higher (p=0.001) than that of controls. Thus, we suggest a possible role of STX1A in the pathogenesis of HFA. During early childhood, there is a period of high brain serotonin synthesis that is disrupted in autistic children; STX1A might influence the serotonergic system during this stage of neurodevelopment, as implied by the association with ADI-R_D.


Subject(s)
Autistic Disorder/genetics , Autistic Disorder/psychology , Syntaxin 1/genetics , Child , DNA Mutational Analysis , Developmental Disabilities/genetics , Exons/genetics , Female , Gene Expression Regulation , Genetic Markers , Genotype , Haplotypes , Humans , Lymphocytes/metabolism , Male , Phenotype , Polymorphism, Single Nucleotide , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Untranslated Regions/genetics , Young Adult
9.
J Neurosci ; 28(22): 5756-61, 2008 May 28.
Article in English | MEDLINE | ID: mdl-18509037

ABSTRACT

Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([(11)C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [(11)C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [(11)C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (>250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.


Subject(s)
Amphetamine-Related Disorders/etiology , Amphetamine-Related Disorders/pathology , Brain/pathology , Central Nervous System Stimulants/adverse effects , Methamphetamine/adverse effects , Microglia/drug effects , Adult , Amphetamine-Related Disorders/diagnostic imaging , Antineoplastic Agents/pharmacokinetics , Brain/diagnostic imaging , Brain Mapping , Carbon Isotopes/pharmacokinetics , Case-Control Studies , Female , Humans , Isoquinolines/pharmacokinetics , Magnetic Resonance Imaging/methods , Male , Microglia/diagnostic imaging , Positron-Emission Tomography/methods , Protein Binding/drug effects
10.
Am J Med Genet B Neuropsychiatr Genet ; 147B(7): 1019-27, 2008 Oct 05.
Article in English | MEDLINE | ID: mdl-18270976

ABSTRACT

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (SERT) modulates serotonin levels, and is a major therapeutic target in autism. Factors that regulate SERT expression might be implicated in the pathophysiology of autism. One candidate SERT regulatory protein is the roundabout axon guidance molecule, ROBO. SerT expression in Drosophila is regulated by robo; it plays a vital role in mammalian neurodevelopment also. Here, we examined the associations of ROBO3 and ROBO4 with autism, in a trio association study using DNA from 252 families recruited to AGRE. Four SNPs of ROBO3 (rs3923890, P = 0.023; rs7925879, P = 0.017; rs4606490, P = 0.033; and rs3802905, P = 0.049) and a single SNP of ROBO4 (rs6590109, P = 0.009) showed associations with autism; the A/A genotype of rs3923890 showed lower ADI-R_A scores, which reflect social interaction. Significant haplotype associations were also observed for ROBO3 and ROBO4. We further compared the mRNA expressions of ROBO1, ROBO2, ROBO3, and ROBO4 in the lymphocytes of 19 drug-naïve autistic patients and 20 age- and sex-matched controls. Expressions of ROBO1 (P = 0.018) and ROBO2 (P = 0.023) were significantly reduced in the autistic group; the possibility of using the altered expressions of ROBO as peripheral markers for autism, may be explored. In conclusion, we suggest a possible role of ROBO in the pathogenesis of autism. Abnormalities of ROBO may lead to autism either by interfering with serotonergic system, or by disrupting neurodevelopment. To the best of our knowledge, this is the first report relating ROBO with autism.


Subject(s)
Autistic Disorder/genetics , Genetic Predisposition to Disease , Nerve Tissue Proteins/genetics , Receptors, Immunologic/genetics , Adult , Asian People/genetics , Autistic Disorder/etiology , Case-Control Studies , Family Health , Female , Genotype , Haplotypes , Humans , Lymphocytes , Male , Polymorphism, Single Nucleotide , RNA, Messenger/analysis , Roundabout Proteins
11.
Schizophr Res ; 98(1-3): 148-56, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17936586

ABSTRACT

Reelin, a secretory protease that plays major roles in neurodevelopment and synaptic plasticity, may also play a role in the pathogenesis of schizophrenia. The present study was undertaken to examine whether the expression of two receptors for reelin, very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor type 2 (ApoER2), were abnormal in peripheral blood lymphocytes of schizophrenic patients. In this study, we measured the mRNA levels of VLDLR and ApoER2 in blood lymphocytes from patients with schizophrenia (drug-naive patients (n=20) and medicated patients (n=20)) and age-and gender-matched healthy controls (n=40) using quantitative real-time RT-PCR. Furthermore, we examined the correlation between mRNA levels and clinical variables in patients. Levels of VLDLR mRNA in drug-naive, unmedicated patients with schizophrenia were significantly lower than those of controls. In contrast, levels of ApoER2 mRNA in drug-naive patients did not differ from those of controls, although the levels of ApoER2 mRNA in medicated patients were significantly lower than those of controls. Interestingly, levels of VLDLR mRNA in drug-naive patients showed significant increases with respect to baseline after six months of antipsychotic treatment, whereas levels of ApoER2 mRNA were significantly lower than baseline after six months of treatment. In all patients, there was a negative correlation between VLDLR mRNA levels and the severity of clinical symptoms. Our findings suggest that peripheral VLDLR mRNA levels may serve as a reliable peripheral biological marker of schizophrenia, and that the reelin-VLDLR/ApoER2 signaling pathway plays a role in the pathophysiology of schizophrenia.


Subject(s)
Gene Expression , Lymphocytes/metabolism , Receptors, Cell Surface/genetics , Receptors, LDL/genetics , Receptors, Lipoprotein/genetics , Schizophrenia/genetics , Schizophrenia/physiopathology , Adolescent , Adult , Age Factors , Antipsychotic Agents/pharmacology , Biomarkers/metabolism , Brief Psychiatric Rating Scale , Female , Gene Expression/genetics , Humans , LDL-Receptor Related Proteins , Male , Middle Aged , RNA, Messenger/metabolism , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/physiology , Receptors, LDL/metabolism , Receptors, LDL/physiology , Receptors, Lipoprotein/metabolism , Reelin Protein , Schizophrenia/metabolism , Sex Factors
12.
Biol Psychiatry ; 63(7): 678-85, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-17884020

ABSTRACT

BACKGROUND: DISC1 has been suggested as a causative gene for psychoses in a large Scottish kindred. PCNT2 has recently been identified as an interacting partner of DISC1. In this study, we investigated the role of PCNT2 in bipolar disorder, by gene expression analysis and genetic association study. METHODS: By TaqMan real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), we examined the messenger RNA (mRNA) levels of PCNT2 in the postmortem prefrontal cortex of bipolar disorder (n = 34), schizophrenia (n = 31), and control subjects (n = 32), obtained from Stanley Array Collection. We also compared the mRNA levels of PCNT2 in the peripheral blood lymphocytes of bipolar disorder (n = 21), schizophrenia (n = 21), depression (n = 33), and control subjects (n = 57). For the association study, 23 single nucleotide polymorphisms (SNPs) were analyzed in 285 bipolar disorder patients and 287 age-and gender-matched control subjects, all of Japanese origin. The genotypes were determined by TaqMan assay. RESULTS: Significantly higher expression of PCNT2 was observed in the brain samples of bipolar group, compared with the control (p = .001) and schizophrenia (p = .018) groups. In the peripheral blood lymphocytes also, a significantly higher expression of PCNT2 was observed in the bipolar group, compared with the control subjects (p = .043). However, none of the SNPs analyzed in our study showed a significant association with bipolar disorder; a weak tendency toward association was observed for two intronic SNPs. CONCLUSIONS: Our findings suggest that elevated levels of PCNT2 might be implicated in the pathophysiology of bipolar disorder.


Subject(s)
Antigens/genetics , Bipolar Disorder/genetics , Gene Expression/genetics , Adult , Antigens/metabolism , Binding Sites , Bipolar Disorder/metabolism , Bipolar Disorder/physiopathology , Chromosomes, Human, Pair 21/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Genetic Predisposition to Disease , Humans , Lymphocytes/metabolism , Male , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Prefrontal Cortex/metabolism , RNA/analysis , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
13.
Biochem Biophys Res Commun ; 360(4): 715-20, 2007 Sep 07.
Article in English | MEDLINE | ID: mdl-17626784

ABSTRACT

Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. Growth factors have been found to play a key role in the cellular differentiation and proliferation of the central and peripheral nervous systems. Epidermal growth factor (EGF) is detected in several regions of the developing and adult brain, where, it enhances the differentiation, maturation, and survival of a variety of neurons. Transforming growth factor-beta (TGFbeta) isoforms play an important role in neuronal survival, and the hepatocyte growth factor (HGF) has been shown to exhibit neurotrophic activity. We examined the association of EGF, TGFbeta1, and HGF genes with autism, in a trio association study, using DNA samples from families recruited to the Autism Genetic Resource Exchange; 252 trios with a male offspring scored for autism were selected for the study. Transmission disequilibrium test revealed significant haplotypic association of EGF with autism. No significant SNP or haplotypic associations were observed for TGFbeta1 or HGF. Given the role of EGF in brain and neuronal development, we suggest a possible role of EGF in the pathogenesis of autism.


Subject(s)
Autistic Disorder/genetics , Epidermal Growth Factor/genetics , Haplotypes , Hepatocyte Growth Factor/genetics , Polymorphism, Single Nucleotide , Transforming Growth Factor beta1/genetics , Humans , Linkage Disequilibrium
14.
Biol Psychiatry ; 62(9): 1056-8, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17509538

ABSTRACT

BACKGROUND: Accumulating evidence suggests that the immune system plays a role in the pathophysiology of autism, and that the adhesion molecules play an important role in the process of inflammation. This study was undertaken to determine whether serum levels of the adhesion molecules in subjects with high-functioning autism are altered as compared with those of normal controls. METHODS: Seventeen male subjects with high-functioning autism and 22 male age-matched unrelated healthy control subjects were enrolled. Serum levels of the soluble forms of platelet-endothelial adhesion molecule (PECAM-1), intracellular adhesion molecule (ICAM-1), and vascular cell adhesion molecule (VCAM-1) were measured. RESULTS: Levels of PECAM-1, but not ICAM-1, in the subjects with autism were significantly lower than those of control subjects. VCAM-1 showed a weak trend for a lowered level. There was a negative correlation between serum levels of PECAM-1 and head circumference at birth in the autistic subjects. CONCLUSIONS: These results suggest that PECAM-1 plays a role in the pathophysiology of high-functioning autism.


Subject(s)
Autistic Disorder/blood , Head/pathology , Parturition , Platelet Endothelial Cell Adhesion Molecule-1/blood , Adolescent , Adult , Analysis of Variance , Cephalometry , Enzyme-Linked Immunosorbent Assay/methods , Humans , Intercellular Adhesion Molecule-1/metabolism , Male , Severity of Illness Index , Vascular Cell Adhesion Molecule-1/blood
15.
Biochem Biophys Res Commun ; 356(1): 200-6, 2007 Apr 27.
Article in English | MEDLINE | ID: mdl-17349978

ABSTRACT

Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. Brain-derived neurotrophic factor (BDNF) plays a critical role in the pathogenesis of autism. In this study, we examined the SNP- and haplotypic-association of BDNF with autism in a trios-based association study (the Autism Genetic Resource Exchange). We also examined the expression of BDNF mRNA in the peripheral blood lymphocytes of drug-naïve autism patients and control subjects. In the TDT of autism trios, the SNP haplotype combinations showed significant associations in the autism group. BDNF expression in the drug-naïve autistic group was found to be significantly higher than in the control group. We suggest that BDNF has a possible role in the pathogenesis of autism through its neurotrophic effects on the serotonergic system.


Subject(s)
Autistic Disorder/genetics , Brain-Derived Neurotrophic Factor/genetics , Polymorphism, Single Nucleotide , Adult , Child , Female , Gene Expression , Gene Frequency , Genotype , Haplotypes , Humans , Linkage Disequilibrium , Lymphocytes/metabolism , Male , Nuclear Family , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods
16.
Prog Neuropsychopharmacol Biol Psychiatry ; 31(1): 187-90, 2007 Jan 30.
Article in English | MEDLINE | ID: mdl-17030376

ABSTRACT

BACKGROUND: The neurobiological basis for autism remains poorly understood. Given the key role of transforming growth factor-beta1 (TGF-beta1) in brain development, we hypothesized that TGF-beta1 plays a role in the pathophysiology of autism. In this study, we studied whether serum levels of TGF-beta1 are altered in patients with autism. METHODS: We measured serum levels of TGF-beta1 in 19 male adult patients with autism and 21 age-matched male healthy subjects using enzyme-linked immunosorbent assay (ELISA). RESULTS: The serum levels (7.34+/-5.21 ng/mL (mean+/-S.D.)) of TGF-beta1 in the patients with autism were significantly (z=-5.106, p<0.001) lower than those (14.48+/-1.64 ng/mL (mean+/-S.D.)) of normal controls. However, there were no marked or significant correlations between serum TGF-beta1 levels and other clinical variables, including Autism Diagnostic Interview-Revised (ADI-R) scores, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), aggression, Theory of Mind, and Intellectual Quotient (IQ) in patients. CONCLUSIONS: These findings suggest that decreased levels of TGF-beta1 may be implicated in the pathophysiology of autism.


Subject(s)
Autistic Disorder/blood , Transforming Growth Factor beta1/blood , Adolescent , Adult , Aggression/psychology , Compulsive Personality Disorder , Enzyme-Linked Immunosorbent Assay , Humans , Intelligence Tests , Male , Psychiatric Status Rating Scales
17.
Schizophr Res ; 89(1-3): 154-60, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17049815

ABSTRACT

OBJECTIVE: Numerous studies have linked schizophrenia with altered immune function. The selectin family of adhesion molecules plays a prominent role in immune/inflammatory responses. To further study the immunological processes in the pathophysiology of schizophrenia, we determined the serum levels of selectins in patients with schizophrenia. For specificity, we also investigated selectin levels in patients with major depression. METHOD: We studied 23 unmedicated patients with schizophrenia, 17 unmedicated patients with major depression, and 36 healthy subjects. The serum levels of three types of soluble-form selectin (sE-, sL- and sP-selectin) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum sL-selectin levels were significantly higher in patients with schizophrenia than in either control subjects (p=0.005) or patients with major depression (p=0.02). No significant difference was found with regard to the level of either serum sE-selectin or sP-selectin. CONCLUSION: Elevated sL-selectin levels in patients with schizophrenia may represent immune system dysfunction and may be involved in the pathogenesis of the illness.


Subject(s)
L-Selectin/blood , Schizophrenia/immunology , Adult , Depressive Disorder, Major/immunology , E-Selectin/blood , Female , Humans , Leukocytes/immunology , Male , Middle Aged , P-Selectin/blood , Reference Values , Schizophrenia/diagnosis
18.
Prog Neuropsychopharmacol Biol Psychiatry ; 31(2): 412-5, 2007 Mar 30.
Article in English | MEDLINE | ID: mdl-17157424

ABSTRACT

BACKGROUND: The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a role in the pathophysiology of autism. In this study, we studied whether serum HGF levels are altered in subjects with high-functioning autism. METHODS: Using an enzyme-linked immunosorbent assay (ELISA), we measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects. RESULTS: The serum levels (503.5+/-160.5 pg/mL (mean+/-SD)) of HGF in the subjects with high-functioning autism were significantly (Mann-Whitney U=34.0, p<0.001) lower than those (817.6+/-232.4 pg/mL (mean+/-SD)) of control subjects. However, there were no correlations between serum HGF levels and clinical variables in the patients. CONCLUSIONS: This study suggests that reduced HGF levels may play a role in the pathophysiology of high-functioning autism.


Subject(s)
Autistic Disorder/blood , Hepatocyte Growth Factor/blood , Adult , Case-Control Studies , Enzyme-Linked Immunosorbent Assay/methods , Humans , Male , Psychological Tests , Statistics, Nonparametric
19.
Biol Psychiatry ; 62(3): 267-9, 2007 Aug 01.
Article in English | MEDLINE | ID: mdl-17123472

ABSTRACT

BACKGROUND: The neurobiological basis for autism remains poorly understood. Given the role of growth factors in brain development, we hypothesized that epidermal growth factor (EGF) may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of EGF are altered in adult subjects with high-functioning autism. METHODS: We measured serum levels of EGF in the 17 male subjects with high-functioning autism and 18 age-matched healthy male subjects. RESULTS: The serum levels of EGF in the subjects with high-functioning autism (72.4 +/- 102.8 pg/mL [mean +/- SD]) were significantly lower (Mann-Whitney U = 22.0, p < .001) than those of normal control subjects (322.3 +/- 122.0 pg/mL [mean +/- SD]). However, there were no correlations between serum EGF levels and clinical variables in the subjects with autism. CONCLUSIONS: This study suggests that decreased levels of EGF might be implicated in the pathophysiology of high-functioning autism.


Subject(s)
Autistic Disorder/blood , Epidermal Growth Factor/blood , Adult , Case-Control Studies , Humans , Male , Matched-Pair Analysis , Reference Values , Severity of Illness Index
20.
Prog Neuropsychopharmacol Biol Psychiatry ; 30(8): 1472-7, 2006 Dec 30.
Article in English | MEDLINE | ID: mdl-16863675

ABSTRACT

BACKGROUND: Precise mechanisms underlying the pathophysiology of autism are currently unknown. Given the major role of glutamate in brain development, we have hypothesized that glutamatergic neurotransmission plays a role in the pathophysiology of autism. In this study, we studied whether amino acids (glutamate, glutamine, glycine, D-serine, and L-serine) related to glutamatergic neurotransmission are altered in serum of adult patients with autism. METHODS: We measured serum levels of amino acids in 18 male adult patients with autism and age-matched 19 male healthy subjects using high-performance liquid chromatography. RESULTS: Serum levels (mean = 89.2 microM, S.D. = 21.5) of glutamate in the patients with autism were significantly (t = -4.48, df = 35, p < 0.001) higher than those (mean = 61.1 microM, S.D. = 16.5) of normal controls. In contrast, serum levels of other amino acids (glutamine, glycine, d-serine, l-serine) in the patients with autism did not differ from those of normal controls. There was a positive correlation (r = 0.523, p = 0.026) between serum glutamate levels and Autism Diagnostic Interview-Revised (ADI-R) social scores in patients. CONCLUSIONS: The present study suggests that an abnormality in glutamatergic neurotransmission may play a role in the pathophysiology of autism.


Subject(s)
Autistic Disorder/blood , Glutamic Acid/blood , Adolescent , Adult , Autistic Disorder/diagnosis , Autistic Disorder/psychology , Humans , Male , Medical History Taking , Psychological Tests , Reference Values
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