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1.
Transl Psychiatry ; 5: e660, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26485544

RESUMO

A genome-wide differential expression of long noncoding RNAs (lncRNAs) was identified in blood specimens of autism spectrum disorder (ASD). A total of 3929 lncRNAs were found to be differentially expressed in ASD peripheral leukocytes, including 2407 that were upregulated and 1522 that were downregulated. Simultaneously, 2591 messenger RNAs (mRNAs), including 1789 upregulated and 821 downregulated, were also identified in ASD leukocytes. Functional pathway analysis of these lncRNAs revealed neurological pathways of the synaptic vesicle cycling, long-term depression and long-term potentiation to be primarily involved. Thirteen synaptic lncRNAs, including nine upregulated and four downregulated, and 19 synaptic mRNAs, including 12 upregulated and seven downregulated, were identified as being differentially expressed in ASD. Our identification of differential expression of synaptic lncRNAs and mRNAs suggested that synaptic vesicle transportation and cycling are important for the delivery of synaptosomal protein(s) between presynaptic and postsynaptic membranes in ASD. Finding of 19 lncRNAs, which are the antisense, bi-directional and intergenic, of HOX genes may lead us to investigate the role of HOX genes involved in the development of ASD. Discovery of the lncRNAs of SHANK2-AS and BDNF-AS, the natural antisense of genes SHANK2 and BDNF, respectively, indicates that in addition to gene mutations, deregulation of lncRNAs on ASD-causing gene loci presents a new approach for exploring possible epigenetic mechanisms underlying ASD. Our study also opened a new avenue for exploring the use of lncRNA(s) as biomarker(s) for the early detection of ASD.


Assuntos
Transtorno do Espectro Autista/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , RNA Longo não Codificante/genética , Pré-Escolar , Feminino , Humanos , Masculino
2.
Transl Psychiatry ; 3: e299, 2013 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-24002085

RESUMO

Autism is a neurodevelopmental disorder associated with social deficits and behavioral abnormalities. Recent evidence suggests that mitochondrial dysfunction and oxidative stress may contribute to the etiology of autism. This is the first study to compare the activities of mitochondrial electron transport chain (ETC) complexes (I-V) and pyruvate dehydrogenase (PDH), as well as mitochondrial DNA (mtDNA) copy number in the frontal cortex tissues from autistic and age-matched control subjects. The activities of complexes I, V and PDH were most affected in autism (n=14) being significantly reduced by 31%, 36% and 35%, respectively. When 99% confidence interval (CI) of control group was taken as a reference range, impaired activities of complexes I, III and V were observed in 43%, 29% and 43% of autistic subjects, respectively. Reduced activities of all five ETC complexes were observed in 14% of autistic cases, and the activities of multiple complexes were decreased in 29% of autistic subjects. These results suggest that defects in complexes I and III (sites of mitochondrial free radical generation) and complex V (adenosine triphosphate synthase) are more prevalent in autism. PDH activity was also reduced in 57% of autistic subjects. The ratios of mtDNA of three mitochondrial genes ND1, ND4 and Cyt B (that encode for subunits of complexes I and III) to nuclear DNA were significantly increased in autism, suggesting a higher mtDNA copy number in autism. Compared with the 95% CI of the control group, 44% of autistic children showed higher copy numbers of all three mitochondrial genes examined. Furthermore, ND4 and Cyt B deletions were observed in 44% and 33% of autistic children, respectively. This study indicates that autism is associated with mitochondrial dysfunction in the brain.


Assuntos
Transtorno Autístico/genética , Variações do Número de Cópias de DNA/genética , DNA Mitocondrial/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Lobo Frontal/metabolismo , Complexo Piruvato Desidrogenase/genética , Adolescente , Transtorno Autístico/enzimologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Lobo Frontal/enzimologia , Humanos , Masculino , Estresse Oxidativo/genética , Complexo Piruvato Desidrogenase/metabolismo , Adulto Jovem
3.
JIMD Rep ; 11: 87-92, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23588842

RESUMO

Homozygous mutations in the gene CLN1 typically result in infantile-onset neuronal ceroid lipofuscinosis, a severe progressive neurological disorder with early death. The gene CLN1 encodes the enzyme palmitoyl protein thioesterase (PPT1), which is involved in lysosomal degradation of S-fatty acylated proteins. Cysteamine bitartrate (Cystagon) has been shown to reduce the storage material in PPT1 deficient cells. We report the results of a 7-year, open label, nonrandomized trial using Cystagon in four individuals with juvenile-onset NCL resulting from milder CLN1 mutations. The Cystagon doses were gradually increased with the goal of achieving 50 mg/kg bodyweight. The disease progression was monitored with parental questionnaires in four treated individuals and five untreated controls with the same CLN1 mutations. Mononuclear leukocytes from the treated individuals were examined for submicroscopic lysosomal storage inclusions. Cystagon treatment resulted in decreased storage material in peripheral leukocytes of the treated individuals. No severe side effects were noted. An allergic rash occurred in one of the individuals that required a dose reduction. The treatment did not result in overall attenuation of the disease progression. Slower progression of the disease was observed in two of the individuals when they were analyzed separately. However, slower progression in these individuals was also observed prior to starting the treatment. This effect may have been due to the higher Cystagon dose achieved in this group, but it could also have been coincidental. The apparent lack of toxicity of Cystagon may warrant further Cystagon trials in infantile NCL, possibly in conjunction with other developing therapies.

4.
J Intellect Disabil Res ; 57(12): 1143-51, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22998578

RESUMO

BACKGROUND: Step ascent and descent can perturb stability increasing the incidence of falls, especially in older individuals with functional limitations and intellectual disabilities, such as those with Down syndrome (DS). The aim of this study was to investigate the biomechanics and motor coordination of step ascent and descent in adults with DS and compare them with a group of healthy individuals, considering movement kinematics and kinetics. METHOD: Fourteen adults with DS and 12 similarly aged adults without DS who were free of known motor problems were quantitatively assessed during ascending and descending a step using an optoelectronic system (BTS SMART-D), force platforms and video recording. Kinematic and kinetic parameters were identified and calculated for each study participant and comparisons were made between the DS and a control group (CG). RESULTS: Despite similar age ranges, subjects in the DS group performed the step ascent and descent movements slower, with longer duration and with a more accentuated range of motion of the trunk and of the ankle joint than those in the CG. Additionally, the double stance phase on the step was substantially longer in the DS group when represented as a percentage of the entire stepping sequence (ascent, double stance on the step and descent). In terms of kinetics, ground force platform data revealed that the DS subjects showed higher instability in the medio-lateral direction during double support phase than similarly aged CG subjects and cannot be attributed to age-associated changes in stability. CONCLUSIONS: These findings help to elucidate the complex biomechanical strategy of people with DS during a step ascent and descent movement task and may have a major role in the multidimensional evaluation and tailored management for them.


Assuntos
Síndrome de Down/fisiopatologia , Marcha/fisiologia , Deficiência Intelectual/fisiopatologia , Atividade Motora/fisiologia , Desempenho Psicomotor/fisiologia , Adulto , Articulação do Tornozelo/fisiologia , Fenômenos Biomecânicos/fisiologia , Feminino , Calcanhar/fisiologia , Humanos , Perna (Membro)/fisiologia , Masculino , Pessoa de Meia-Idade , Equilíbrio Postural/fisiologia , Amplitude de Movimento Articular/fisiologia , Coluna Vertebral/fisiologia , Dedos do Pé/fisiologia
5.
Genes Brain Behav ; 10(8): 834-43, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21848643

RESUMO

Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. A number of studies have shown that the Ras/Raf/ERK1/2 (extracellular signal-regulated kinase) signaling pathway plays important roles in the genesis of neural progenitors, learning and memory. Ras/Raf/ERK1/2 and ERK5 have also been shown to have death-promoting apoptotic roles in neural cells. Recent studies have shown a possible association between neural cell death and autism. In addition, two recent studies reported that a deletion of a locus on chromosome 16, which included the mitogen-activated protein kinase 3 (MAPK3) gene that encodes ERK1, is associated with autism. Most recently, our laboratory detected that Ras/Raf/ERK1/2 signaling activities were significantly enhanced in the brain of BTBR mice that model autism, as they exhibit many autism-like behaviors. We thus hypothesized that Ras/Raf/ERK1/2 signaling and ERK5 could be abnormally regulated in the brain of autistic subjects. In this study, we show that the expression of Ras protein was significantly elevated in the frontal cortex of autistic subjects. C-Raf phosphorylation was increased in the frontal cortex, while both C-Raf and A-Raf activities were enhanced in the cerebellum of autistic subjects. We also detected that both the protein expression and activities of ERK1/2 were significantly upregulated in the frontal cortex of autistic subjects, but not in the cerebellum. Furthermore, we showed that ERK5 protein expression is upregulated in both frontal cortex and cerebellum of autistic subjects. These results suggest that the upregulation of Ras/Raf/ERK1/2 signaling and ERK5 activities mainly found in the frontal cortex of autistic subjects may be critically involved in the pathogenesis of autism.


Assuntos
Transtorno Autístico/enzimologia , Transtorno Autístico/genética , Encéfalo/enzimologia , Genes ras/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 7 Ativada por Mitógeno/genética , Quinases raf/genética , Adolescente , Western Blotting , Cadáver , Cerebelo/enzimologia , Criança , Pré-Escolar , Interpretação Estatística de Dados , Ensaio de Imunoadsorção Enzimática , Feminino , Lobo Frontal/enzimologia , Humanos , Imuno-Histoquímica , Masculino , Microscopia Confocal , Fosforilação , Regulação para Cima/genética
6.
Genes Brain Behav ; 10(5): 615-24, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21595826

RESUMO

Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. BTBR mouse is currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Growing evidence suggests that Ras/Raf/ERK1/2 signaling plays death-promoting apoptotic roles in neural cells. Recent studies showed a possible association between neural cell death and autism. In addition, two studies reported that a deletion of a locus on chromosome 16, which includes the MAPK3 gene that encodes ERK1, is associated with autism. We thus hypothesized that Ras/Raf/ERK1/2 signaling could be abnormally regulated in the brain of BTBR mice that models autism. In this study, we show that expression of Ras protein was significantly elevated in frontal cortex and cerebellum of BTBR mice as compared with B6 mice. The phosphorylations of A-Raf, B-Raf and C-Raf were all significantly increased in frontal cortex of BTBR mice. However, only C-Raf phosphorylation was increased in the cerebellum of BTBR mice. In addition, we further detected that the activities of both MEK1/2 and ERK1/2, which are the downstream kinases of Ras/Raf signaling, were significantly enhanced in the frontal cortex. We also detected that ERK1/2 is significantly over-expressed in frontal cortex of autistic subjects. Our results indicate that Ras/Raf/ERK1/2 signaling is upregulated in the frontal cortex of BTBR mice that model autism. These findings, together with the enhanced ERK1/2 expression in autistic frontal cortex, imply that Ras/Raf/ERK1/2 signaling activities could be increased in autistic brain and involved in the pathogenesis of autism.


Assuntos
Transtorno Autístico/enzimologia , Encéfalo/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Quinases raf/metabolismo , Proteínas ras/metabolismo , Adolescente , Animais , Transtorno Autístico/genética , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Fosforilação , Regulação para Cima , Quinases raf/genética , Proteínas ras/genética
7.
J Intellect Disabil Res ; 55(7): 636-49, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21492292

RESUMO

BACKGROUND: The link between aggression and mental disorders has been the focus of diverse studies in persons with and without intellectual disabilities (ID). Because of discrepancies in the finding of studies in persons with ID to date, and because of differences in research design, instruments used and the population studied, more research is needed. The purpose of this study was to delineate any significant association between certain psychiatric disorders and specific domains of aggressive behaviours in a large sample of persons with ID controlling for sex, age, autism and degree of ID. METHOD: Data from the present study were obtained from 47% of all persons with ID receiving services from New York State agencies, using the Institute for Basic Research - Modified Overt Aggression Scale (IBR-MOAS between 2006 and 2007). The IBR-MOAS was completed by the chief psychologists of 14 agencies based on information from the participants' files. Demographic information obtained included the psychiatric diagnosis made by the treating psychiatrist as well as information on age, sex and degree of ID. Data from 4069 participants were analysed. RESULTS: Impulse control disorder and bipolar disorder were strongly associated with all five domains of aggressive behaviour in the IBR-MOAS. Psychotic disorder was highly associated with four domains except for physical aggression against self (PASLF), which was of borderline significance. Anxiety was most associated with PASLF and verbal aggression against self (VASLF); depression with VASLF; obsessive compulsive disorder with physical aggression against objects (PAOBJ); personality disorders with verbal aggression against others (VAOTH), VASLF and PASLF; and autism with physical aggression against others (PAOTH), PAOBJ and PASLF. Mild to moderate ID was associated with VAOTH and VASLF and severe to profound ID with PAOBJ and PASLF. Female sex was most associated with VASLF. CONCLUSIONS: Impulse control, mood dysregulation and perceived threat appear to underlie most of the aggressive behaviours reported. Psychosis and depression appeared to have been over-diagnosed in persons with mild to moderate ID and under-diagnosed in persons with severe and profound ID. These findings replicate and extend findings from previous studies. The pattern of associations reported can be used as helpful indicators by professionals involved in the treatment of aggressive behaviours in persons with ID.


Assuntos
Agressão , Inquéritos Epidemiológicos/estatística & dados numéricos , Deficiência Intelectual/epidemiologia , Transtornos Mentais/epidemiologia , Violência/estatística & dados numéricos , Adulto , Distribuição por Idade , Idoso , Transtorno Autístico/epidemiologia , Feminino , Humanos , Comportamento Impulsivo/epidemiologia , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/epidemiologia , Transtornos da Personalidade/epidemiologia , Comportamento Autodestrutivo/epidemiologia , Distribuição por Sexo
8.
Comput Aided Surg ; 16(1): 1-10, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21198423

RESUMO

OBJECTIVE: To determine whether robotic stereotactic radiotherapy of 70-75 Gy delivered in five fractions results in an improved therapeutic ratio, compared with three fractions, in the treatment of peripheral non-small-cell lung cancer (NSCLC), in which case doses of up to 85 Gy in five fractions may be feasible. MATERIALS AND METHODS: Between December 2006 and May 2010, 20 patients (9 female, 11 male, aged 65 to 88) were treated using the CyberKnife® Robotic Radiosurgery System for NSCLC with doses ranging from 67 Gy to 75 Gy based on location, histopathological type, grade of histopathological differentiation, tumor diameter/volume, and normal tissue constraints, with the doses being delivered in five fractions over 5 to 8 days. Tumor diameters ranged from 1.5 cm to 3.4 cm (median: 2.5 cm). Patients with Stage I to IV NSCLC were treated, and the results and observations were analyzed for clinical characteristics and outcomes including toxicity. All patients, except one who had refused surgery, had co-morbid conditions that precluded a lobectomy. RESULTS: Twenty patients were followed every three months by positron emission tomography/computed tomography (PET/CT). Mean follow-up was 23 months (range: four to 58 months). Local control was achieved in all treated tumors. Three patients expired, and three developed new regional metastases, none of which was within the planning target volume (PTV). The remainder of the patients demonstrated no evidence of recurrence or continued growth detectable by PET/CT. There was no toxicity above Grade 1. CONCLUSIONS: It is feasible to treat peripheral NSCLC with individualized maximal tolerable doses ranging from 67 Gy to 75 Gy in five fractions chosen on the basis of location, histopathological type, grade of histopathological differentiation, tumor diameter/volume, and normal tissue constraints.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Radiocirurgia/métodos , Cirurgia Assistida por Computador/métodos , Idoso , Idoso de 80 Anos ou mais , Fracionamento da Dose de Radiação , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Radiocirurgia/instrumentação , Robótica , Cirurgia Assistida por Computador/instrumentação , Tomografia Computadorizada por Raios X
9.
Clin Genet ; 79(4): 355-62, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20573161

RESUMO

Autism severity is associated with child and maternal MAOA genotypes. We replicated and extended a previously reported association between autism severity and a functional polymorphism in the monoamine oxidase A (MAOA) promoter region, MAOA-uVNTR, in a sample of 119 males, aged 2-13 years, with autism spectrum disorder from simplex families. We demonstrated that (i) boys with the low activity 3-repeat MAOA allele had more severe sensory behaviors, arousal regulation problems, and aggression, and worse social communication skills than males with the high activity allele; and (ii) problems with aggression, as well as with fears and rituals, were modified by the mothers' genotype. Boys with the 4-repeat high activity allele who had homozygous 4-repeat mothers showed increased severity of these behaviors relative to those born to heterozygous mothers. These findings indicate the importance of considering maternal genotype in examining associations of MAOA and other genes with behavior in male offspring.


Assuntos
Transtorno Autístico/psicologia , Monoaminoxidase/genética , Polimorfismo Genético , Adolescente , Análise de Variância , Transtorno Autístico/enzimologia , Transtorno Autístico/genética , Criança , Transtornos do Comportamento Infantil/enzimologia , Transtornos do Comportamento Infantil/genética , Transtornos do Comportamento Infantil/psicologia , Pré-Escolar , Genótipo , Humanos , Masculino , Repetições Minissatélites/genética , Regiões Promotoras Genéticas/genética
10.
Neuroscience ; 165(2): 363-70, 2010 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-19854241

RESUMO

Autism is a severe neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior. Recent studies suggest that apoptotic mechanisms may partially contribute to the pathogenesis of this disorder. Cathepsin D is the predominant lysosomal protease and is abundantly expressed in the brain. It plays an important role in regulation of cellular apoptosis and has been shown to mediate apoptosis induced by cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. In this study, we examined the expression levels of cathepsin D in the autistic brain. We found that cathepsin D protein expression was significantly increased in the frontal cortex, in pyramidal and granule cells of the hippocampus, and in cerebellar neurons in autistic subjects as compared to controls. In addition, we found that the expression of the anti-apoptotic protein Bcl-2 was significantly decreased, while caspase-3, a critical executioner of apoptosis, was increased in the cerebellum of autistic subjects. Previously our studies have shown that Bcl-2 expression is decreased and the BDNF-Akt-Bcl-2 pathway is compromised in the frontal cortex of autistic subjects, which suggested that increased apoptosis may be involved in the pathogenesis of autism. Our current finding of decreased Bcl-2 and increased capase-3 in the cerebellum of autistic subjects further supports this suggestion. In addition, the finding of increased cathepsin D in the cerebellum of autistic subjects suggests that, through its regulation of apoptosis, the altered activities of cathepsin D in the autistic brain may play an important role in the pathogenesis of autism.


Assuntos
Transtorno Autístico/metabolismo , Encéfalo/metabolismo , Caspase 3/metabolismo , Catepsina D/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adolescente , Western Blotting , Cerebelo/metabolismo , Criança , Pré-Escolar , Feminino , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Neurônios/metabolismo
11.
Clin Oncol (R Coll Radiol) ; 21(8): 623-31, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19682875

RESUMO

AIMS: To determine the effectiveness of robotic stereotactic radiotherapy with image guidance and real-time respiratory tracking against early stage peripheral lung cancer. MATERIALS AND METHODS: We treated patients with stage I non-small cell lung cancer (NSCLC) with CyberKnife and analysed their clinical characteristics and outcomes. All patients had co-morbid conditions that precluded lobectomy. The clinical target volume (CTV) included the gross tumour volume (GTV) and a 6mm margin in all directions to account for microscopic extension. The planning target volume (PTV) equalled CTV+2mm in all directions for uncertainty. Tumour motion was tracked using a combination of Synchrony and Xsight Spine tracking methods with the aid of a single gold marker implanted in the centre of the tumour, or using the newer Xsight Lung method without markers for selected tumours. A 60-67.5 Gy dose was prescribed to the 60-80% isodose line (median 65%) and given in three to five fractions. Patients were followed every 3 months for a median of 27.5 months (range 24-53 months). RESULTS: Of the 67 patients with NSCLC stage IA or IB treated between January 2004 and December 2008, we report the results of a cohort of 31 with peripheral stage I tumours of 0.6-71 cm(3) volume treated between January 2004 and December 2007 with total doses between 60 and 67.5 Gy in three to five fractions. The median D(max) was 88.2 Gy and the median V(95) of the PTV was 99.6% or 27.9 cm(3). No grade 3 or above toxicity was encountered. Four cases of radiation pneumonitis and one case of oesophagitis were observed. In those patients whose pre- and post-treatment results were available, no change in pulmonary function tests was observed. Actuarial local control was 93.2% for 1 year and 85.8% for up to 4.5 years. One-year overall survival was 93.6% and 83.5% for up to 4.5 years, as projected by Kaplan-Meier analyses. CONCLUSIONS: In this small cohort of patients with stage I peripheral NSCLC, robotic stereotactic radiotherapy seems to be a safe and obviously superior alternative to conventionally fractionated radiotherapy, with results that may be approaching those obtained with lobectomy without the associated morbidity.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Radiocirurgia/instrumentação , Robótica/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radiocirurgia/métodos , Análise de Sobrevida
12.
Neuroscience ; 161(2): 451-8, 2009 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-19328224

RESUMO

Trisomy of human chromosome 21 (Hsa 21) causes the pathological characteristics of Down syndrome (DS). Little is known about the mechanisms by which trisomy 21 affects the expression of genes on other chromosomes. Using a mouse model of DS, the Ts65Dn mouse, we have performed mRNA and protein measurements to identify genes on chromosomes not syntenic with Hsa 21 whose expression is affected by the presence of three copies of genes between loci Mrpl39 and Znf295 on mouse chromosome 16 (Mmu 16). We report the upregulation of beta-catenin, located on mouse chromosome 9 (Mmu 9) in Ts65Dn brain. Using immunocytochemistry on Ts65Dn and control mouse brain tissue, we observed a striking increase in beta-catenin expression specifically in the endothelial cells lining the cerebral blood vessels of the Ts65Dn mice. Since beta-catenin is involved in cell-cell adhesion, upregulation of this protein in DS may alter adherens protein interactions that are involved in the normal functions of endothelial cells. Elevated beta-catenin might be responsible for altered endothelial cell function/s leading to the impairment of brachial flow velocity observed in DS.


Assuntos
Encéfalo/metabolismo , Síndrome de Down/metabolismo , beta Catenina/biossíntese , Animais , Vasos Sanguíneos/metabolismo , Encéfalo/irrigação sanguínea , Caderinas/biossíntese , Córtex Cerebral/metabolismo , Cromossomos de Mamíferos/genética , Síndrome de Down/genética , Regulação para Baixo , Quinase 3 da Glicogênio Sintase/biossíntese , Glicogênio Sintase Quinase 3 beta , Imuno-Histoquímica , Camundongos , Camundongos Mutantes , Presenilina-1/biossíntese , RNA Mensageiro/biossíntese , Regulação para Cima , alfa Catenina/biossíntese , beta Catenina/genética
13.
Clin Genet ; 75(2): 133-40, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19215247

RESUMO

Miscarriage is the spontaneous loss of an embryo or fetus before the 20th week of pregnancy. Most miscarriages occur before the end of the first trimester (<13 weeks). Although many risk factors relate to this occurrence, genetic factors play the most important role. Chromosomal abnormalities, including both numerical and structural anomalies, underlie the majority of miscarriages. In this study, we employed a comprehensive approach using cytogenetic karyotyping, polymerase chain reaction (PCR)-based genotyping, and microarray-based comparative genomic hybridization (arrayCGH) in combination to analyze chromosomal profiles of 115 first-trimester miscarriages of Chinese women. Seventy cases (61%) were found to have chromosomal anomalies, of which 90% were numerical and 10% were structural. Cytogenetic karyotyping identified 78.6% (55/70), PCR assays 2.9% (2 triploids), and arrayCGH 18.6% (13/70) of the anomalies. In this study, a microdeletion of 108 kb and four microduplications sizing from 300 to 1460 kb were observed. An advantage of using this combination approach is that microsatellite genotyping and arrayCGH can be accomplished in spite of culture failure and maternal cell contamination. In addition, arrayCGH can detect submicroscopic chromosomal anomalies and gene dosage alterations.


Assuntos
Aborto Espontâneo/genética , Hibridização Genômica Comparativa , Genótipo , Repetições de Microssatélites/genética , Primeiro Trimestre da Gravidez/genética , Diagnóstico Pré-Natal/métodos , Aborto Espontâneo/diagnóstico , Citogenética , Feminino , Humanos , Cariotipagem , Gravidez
14.
CNS Spectr ; 13(6): 515-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18567976

RESUMO

Genetic factors are known to contribute to the development of schizophrenia and related psychoses. Cytogenetic abnormalities have been occasionally found in patients with psychotic disorders and, thus, have helped identify candidate gene contributors for these conditions. The individual described here first presented with mental retardation and anxiety disorder in his mid-childhood. In his early 20s, the patient started exhibiting various psychotic manifestations, including delusions and hallucinations. His psychotic symptoms were difficult to control with psychotropic medications. The family history was negative for psychiatric disorders. This patient was found to have a 6.2 megabase deletion of the terminal portion of the short arm of chromosome 12 that was characterized using fluorescence in situ hybridization and microarray comparative genomic hybridization analysis. The maternal chromosomes were normal, but the paternal chromosomes could not be tested. To-date such a chromosomal abnormality has not been described in association with schizophrenia/psychosis. This case suggests that psychosis-associated gene(s) may be located in the terminal region of the short arm of chromosome 12.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 12/genética , Deficiência Intelectual/genética , Transtornos Psicóticos/genética , Adolescente , Adulto , Criança , Mapeamento Cromossômico , Seguimentos , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Transtornos Psicóticos/diagnóstico
15.
Clin Genet ; 64(3): 190-7, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12919132

RESUMO

A functional polymorphism (the upstream variable-number tandem repeat region, or uVNTR) in the monoamine oxidase A (MAOA) promoter region has been reported to be associated with behavioral abnormalities as well as increased serotonergic responsivity. We examined the relation between MAOA-uVNTR alleles and the phenotypic expression of autism in 41 males younger than 12.6 years of age. Children with the low-activity MAOA allele had both lower intelligence quotients (IQ) and more severe autistic behavior than children with the high-activity allele. In follow-up testing of 34 of the males at the 1-year time-point, those with the low-activity allele showed a worsening in IQ but no change in the severity of their autistic behavior. We conclude that functional MAOA-uVNTR alleles may act as a genetic modifier of the severity of autism in males.


Assuntos
Transtorno Autístico/genética , Repetições Minissatélites , Monoaminoxidase/genética , Regiões Promotoras Genéticas/genética , Atividades Cotidianas , Adaptação Psicológica , Alelos , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Cognição , Feminino , Seguimentos , Genética Comportamental , Genótipo , Humanos , Testes de Inteligência , Testes de Linguagem , Estudos Longitudinais , Masculino , Monoaminoxidase/fisiologia , Testes Psicológicos , Índice de Gravidade de Doença , Fatores Sexuais
17.
J Am Dent Assoc ; 132(2): 204-9, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11217594

RESUMO

BACKGROUND: Health care is being changed dramatically by the marriage of computers and telecommunications. Implications for hospitals and physicians already have received extensive media attention, but comparatively little has been said about the impact of information technology on dentistry. This article illustrates how the digital transformation will likely affect dentists and their patients. CONCLUSIONS: Based on recent experiences of hospitals and medical practices, dentists can expect to encounter revolutionary changes as a result of the digital transformation. The Internet, the World Wide Web and other developments of the information revolution will redefine patient care, referral relationships, practice management, quality, professional organizations and competition. PRACTICE IMPLICATIONS: To respond proactively to the digital transformation of oral health care, dentists must become familiar with its technologies and concepts. They must learn what new information technology can do for them and their patients and then develop creative applications that promote the profession and their approaches to care.


Assuntos
Assistência Odontológica/tendências , Aplicações da Informática Médica , Segurança Computacional , Sistemas Computacionais/economia , Registros Odontológicos , Humanos , Internet , Administração da Prática Odontológica , Telemedicina , Interface Usuário-Computador
18.
Am J Med Genet ; 98(3): 224-9, 2001 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-11169559

RESUMO

The prevalence of fragile X syndrome (FXS) is approximately 7% in Thai boys with developmental delay of unknown cause. To determine if FXS might have a specific haplotype association, we analyzed 125 unrelated control subjects and 25 unrelated FXS patients using 3 microsatellites, DXS548, FRAXAC1 and FRAXE, and two single nucleotide polymorphisms, ATL1 and IVS10. FRAXAC1 and DXS548 are located approximately 7 kb and approximately 150 kb proximal to the CGG-FMR1 whereas ATL1, IVS10 and FRAXE are located approximately 5.6 kb, approximately 24.5 kb and approximately 600 kb distal to the CGG-FMR1. We found 40 haplotypes in the control group and 14 haplotypes in the FXS group. Of 14 haplotypes in the FXS group, 6 haplotypes were not found in the control group suggesting possible new mutations or admixture of immigrant haplotypes. We observed that most diverse haplotypes came from different FRAXE alleles. For this reason, we analyzed haplotypes composed from the remaining markers alone (DXS548-FRAXAC1-ATL1-IVS10). We found 2 major haplotypes (20-18-G-T and 20-19-A-C) with no significant haplotype differences between the control group (67/125 of 20-18-G-T and 25/125 of 20-19-A-C) and FXS group (16/25 of 20-18-G-T and 6/25 of 20-19-A-C). The other haplotypes found were 33/125 in the control group and 3/25 in the FXS group. The two major haplotypes associated FXS in Thai subjects were the two most common haplotypes in the normal Thai subjects. We could not prove, therefore, that there were founder effects at the FRAXA locus in Thailand. We could not, however, exclude it completely. These findings apparently contrast with most other reports on FXS founder effects in various ethnic groups.


Assuntos
Síndrome do Cromossomo X Frágil/genética , Haplótipos , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA , Alelos , Southern Blotting , DNA/genética , Proteína do X Frágil da Deficiência Intelectual , Frequência do Gene , Humanos , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único , Tailândia , Repetições de Trinucleotídeos/genética
19.
Neurogenetics ; 3(1): 41-4, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11085596

RESUMO

The lysosomal storage of lipofuscins is the common pathological feature that characterizes the infantile, late-infantile, juvenile (Batten's disease), and Finnish-variant neuronal ceroid lipofuscinosis (INCL, LINCL, JNCL and FNCL), which are due to mutations in the genes CLN1, CLN2, CLN3, and CLN5, respectively. The CLN1 and CLN2 genes encode lysosomal enzymes, but the CLN3 and CLN5 genes encode membrane-spanning proteins. Why deficiencies of lysosomal enzymes and membrane-spanning proteins produce similar clinical phenotypes and pathological changes is still unanswered. We hypothesize that CLN-encoded proteins may comprise a functional pathogenic pathway, in which protein associations may play important roles. To test this hypothesis, we studied protein-protein interactions among the CLN1-, CLN2-, and CLN3-encoded proteins using a yeast two-hybrid system. Our results provided no evidence that CLN-encoded proteins interact with each other. This suggests there may be unidentified components in NCL pathogenesis.


Assuntos
Proteínas de Membrana/genética , Lipofuscinoses Ceroides Neuronais/genética , Mapeamento Cromossômico , Clonagem Molecular , Humanos , Lisossomos/enzimologia , Proteínas de Membrana/metabolismo , Fases de Leitura Aberta , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tripeptidil-Peptidase 1
20.
Neuroscience ; 100(2): 423-9, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11008180

RESUMO

The Fmr1 gene knockout mouse is a model for the human Fragile X mental retardation syndrome. Fmr1 knockout mice with a C57BL/6-129/OlaHsd hybrid background have been reported to have only a very mild deficiency in learning the Morris water maze task. We compared the effect of this knockout mutation on learning in mice with either an FVB/N-129/OlaHsd hybrid background or a C57BL/6 background. When FVB-129 mice were tested in a cross-shaped water maze task, the knockout mice showed a pronounced deficiency in their ability to learn the position of a hidden escape platform in comparison to normal littermates. In contrast, knockout mice with a C57BL/6 background learned the maze just as well as their normal littermates. Fear conditioning did not reveal differences between knockout and normal mice in either background. These results show that silencing the Fmr1 gene clearly interfered with learning a specific visuospatial task in FVB/N-129 hybrid mice but not in C57BL/6 mice. The strain dependence may model the influence of genetic background in the human Fragile X syndrome.


Assuntos
Síndrome do Cromossomo X Frágil/genética , Deficiências da Aprendizagem/genética , Aprendizagem em Labirinto/fisiologia , Camundongos Knockout/genética , Animais , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Especificidade da Espécie
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