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This longitudinal study aimed to investigate the associations between the polymorphisms of guanine nucleotide-binding protein subunit ß-3 (GNB3) C825T and metabolic disturbance in bipolar II disorder (BP-II) patients being treated with valproate (VPA). A 100 BP-II patients received a 12-week course of VPA treatment, and their body weight and metabolic indices were measured. At baseline, the GNB3 C825T polymorphisms were associated with the triglyceride level (P=0.032) in BP-II patients. During the VPA treatment course, the polymorphisms were not only associated with body mass index (BMI) and waist circumference (P-values=0.009 and 0.001, respectively), but also with total cholesterol, triglyceride, low-density lipoprotein and leptin levels (P-values=0.004, 0.002, 0.031 and 0.015, respectively). Patients with the TT genotype had a lower BMI, smaller waist circumference, and lower levels of lipids and leptin than those with the CT or CC genotypes undergoing the VPA treatment course.
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Antimaníacos/efectos adversos , Trastorno Bipolar/tratamiento farmacológico , Dislipidemias/genética , Proteínas de Unión al GTP Heterotriméricas/genética , Obesidad/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Ácido Valproico/efectos adversos , Adulto , Biomarcadores/sangre , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/psicología , Índice de Masa Corporal , Estudios de Casos y Controles , Dislipidemias/sangre , Dislipidemias/inducido químicamente , Dislipidemias/diagnóstico , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Leptina/sangre , Lípidos/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Obesidad/inducido químicamente , Obesidad/diagnóstico , Fenotipo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Circunferencia de la Cintura , Adulto JovenRESUMEN
Long noncoding RNAs (lncRNAs) play important roles in the formation and progression of many types of human malignancies. The aim of our study was to investigate the expression and biological functions of the lncRNA BRAF-activated noncoding RNA (BANCR) in human osteosarcoma. BANCR expression was quantified by real-time PCR in human osteosarcoma cell lines and tissues. We analyzed the association between BANCR levels and clinicopathological factors and patient prognosis. MTT, flow cytometric, and transwell invasion assays were performed to observe the effects of BANCR on MG-63 cell biological behaviors. BANCR overexpression was observed in osteosarcoma cell lines and clinical specimens. Increased BANCR expression was significantly associated with large tumor size, positive distant metastasis, and advanced clinical stage. High BANCR expression in osteosarcoma was an independent predictor of poor survival. Downregulation of BANCR inhibited MG-63 cell proliferation and invasion and promoted cell apoptosis in vitro. These findings suggested that BANCR may act as a tumor promoter in osteosarcoma and could serve as a potential therapeutic target for this disease.
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OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is thought to be involved in the pathophysiology of bipolar disorder (BD) and metabolic syndrome. We investigated the correlation between plasma BDNF with mood symptoms and metabolic indices in patients with BD-II over a 12-week pharmacological intervention. METHOD: Drug-naïve patients with BD-II (n=117) were recruited. Metabolic profiles [cholesterol, triglyceride, HbA1C, fasting serum glucose, body mass index (BMI)] and plasma BDNF wtrun "tblautotrun "tblsctrun "tbl_contere measured at baseline and 2, 8, and 12 weeks after beginning medication. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used. RESULTS: Seventy-six (65.0%) patients completed the intervention. Plasma BDNF levels were significantly associated with BMI (P=9.6E-5), low-density lipoprotein (P=0.034) and total (P=0.001) cholesterol, but not with the Hamilton Depression Rating Scale-17 and Young Mania Rating Scale scores over the 12-week treatment. CONCLUSION: We found initial evidence of a positive correlation between plasma BDNF levels and BMI, low-density lipoprotein and total cholesterol in drug-naïve patients with BD-II. The specific function of BDNF in regulating and maintaining peripheral metabolic health requires additional investigation.
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Trastorno Bipolar/sangre , Trastorno Bipolar/tratamiento farmacológico , Factor Neurotrófico Derivado del Encéfalo/sangre , Adulto , Afecto/efectos de los fármacos , Trastorno Bipolar/psicología , Índice de Masa Corporal , Colesterol/sangre , Femenino , Fluoxetina/uso terapéutico , Humanos , Modelos Lineales , Lipoproteínas LDL/sangre , Estudios Longitudinales , Lorazepam/uso terapéutico , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/metabolismo , Escalas de Valoración Psiquiátrica , Resultado del Tratamiento , Ácido Valproico/uso terapéuticoRESUMEN
OBJECTIVE: Identification of genetic variants that influence bipolar I disorder (BPD-I) through genome-wide association (GWA) studies is limited in Asian populations. The current study aimed to identify novel common variants for BPD-I in an ethnically homogeneous Taiwanese sample using a multi-stage GWA study design. METHOD: At the discovery stage, 200 BPD-I patients and 200 controls that combined to form 16 pools were genotyped with 1 million markers. Utilizing a newly developed rank-based method, top-ranked markers were selected. After validation with individual genotyping, a fine-mapping association study was conducted to identify associated loci using 240 patients and 240 controls. At the last stage, independent samples were collected (351 cases and 341 controls) for replication. RESULTS: Among the top-ranked markers from the discovery stage, eight genes and 15 individual SNPs were evaluated in the fine-mapping stage. At this stage, rs7619173, which is not in a gene coding region, showed the most significant association (P = 2 ∗ 10(-5)) with BPD-I. Four genes had empirical P-values<0.05, including KCNH7 (P = 0.0047), MYST4 (P = 0.0047), NRXN3 (P = 0.0095), and SEMA3D (P = 0.037). For markers genotyped in replication samples, rs7619173 exhibited a significant association (P(combined) = 2 ∗ 10(-4)) after multiple testing correction, while markers rs11001178 (MYST4) and rs2217887 (NRXN3) showed weak associations (P(combined) = 0.02) with BPD-I. CONCLUSION: A multi-stage GWA design has the potential to uncover the underlying pathogenesis of a complex trait. Findings in the present study highlight three loci that warrant further investigation for bipolar.
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Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad/genética , Histona Acetiltransferasas/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Canales de Potasio Éter-A-Go-Go/genética , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Semaforinas/genética , Taiwán , Adulto JovenRESUMEN
The presence of comorbid anxiety disorders (AD) and bipolar II disorders (BP-II) compounds disability complicates treatment, worsens prognosis, and has been understudied. The genes involved in metabolizing dopamine and encoding dopamine receptors, such as aldehyde dehydrogenase 2 (ALDH2) and dopamine D2 receptor (DRD2) genes, may be important to the pathogenesis of BP-II comorbid with AD. We aimed to clarify ALDH2 and DRD2 genes for predisposition to BP-II comorbid with and without AD. The sample consisted of 335 subjects BP-II without AD, 127 subjects BP-II with AD and 348 healthy subjects as normal control. The genotypes of the ALDH2 and DRD2 Taq-IA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a statistically significant association between DRD2 Taq-I A1/A2 genotype and BP-II with AD (OR=2.231, P=0.021). Moreover, a significant interaction of the DRD2 Taq-I A1/A1 and the ALDH2*1*1 genotypes in BP-II without AD was revealed (OR=5.623, P=0.001) compared with normal control. Our findings support the hypothesis that a unique genetic distinction between BP-II with and without AD, and suggest a novel association between DRD2 Taq-I A1/A2 genotype and BP-II with AD. Our study also provides further evidence that the ALDH2 and DRD2 genes interact in BP-II, particularly BP-II without AD.
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Aldehído Deshidrogenasa/fisiología , Trastornos de Ansiedad/genética , Trastorno Bipolar/genética , Receptores de Dopamina D2/fisiología , Adulto , Aldehído Deshidrogenasa Mitocondrial , Trastornos de Ansiedad/epidemiología , Trastorno Bipolar/epidemiología , Comorbilidad , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
Many family characteristics were reported to increase the risk of bipolar disorder (BPD). The development of BPD may be mediated through different pathways, involving diverse risk factor profiles. We evaluated the associations of family characteristics to build influential causal-pie models to estimate their contributions on the risk of developing BPD at the population level. We recruited 329 clinically diagnosed BPD patients and 202 healthy controls to collect information in parental psychopathology, parent-child relationship, and conflict within family. Other than logistic regression models, we applied causal-pie models to identify pathways involved with different family factors for BPD. The risk of BPD was significantly increased with parental depression, neurosis, anxiety, paternal substance use problems, and poor relationship with parents. Having a depressed mother further predicted early onset of BPD. Additionally, a greater risk for BPD was observed with higher numbers of paternal/maternal psychopathologies. Three significant risk profiles were identified for BPD, including paternal substance use problems (73.0%), maternal depression (17.6%), and through poor relationship with parents and conflict within the family (6.3%). Our findings demonstrate that different aspects of family characteristics elicit negative impacts on bipolar illness, which can be utilized to target specific factors to design and employ efficient intervention programs.
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Trastorno Bipolar/etiología , Causalidad , Relaciones Familiares , Modelos Psicológicos , Padres/psicología , Adolescente , Adulto , Edad de Inicio , Anciano , Trastorno Bipolar/epidemiología , Trastorno Bipolar/etnología , Composición Familiar/etnología , Conflicto Familiar/etnología , Relaciones Familiares/etnología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Relaciones Padres-Hijo/etnología , Taiwán/epidemiología , Taiwán/etnología , Adulto JovenRESUMEN
BACKGROUND: Reduced P300 event-related potential (ERP) amplitude and latency prolongation have been reported in patients with schizophrenia compared to healthy controls. However, the influence of antipsychotics (and dopamine) on ERP measures are poorly understood and medication confounding remains a possibility. METHOD: We explored ERP differences between 36 drug-naive patients with schizophrenia and 138 healthy controls and examined whether P300 performance was related to dopamine transporter (DAT) availability, both without the confounding effects of medication. We also conducted a random effects meta-analysis of the available literature, synthesizing the results of three comparable published articles and our local study. RESULTS: No overall significant difference was found in mean P300 ERP between patients and controls in latency or in amplitude. There was a significant gender effect, with females showing greater P300 amplitude than males. A difference between patients and controls in P300 latency was evident with ageing, with latency increasing faster in patients. No effect of DAT availability on P300 latency or amplitude was detected. The meta-analysis computed the latency pooled standardized effect size (PSES; Cohen's d) of -0.13 and the amplitude PSES (Cohen's d) of 0.48, with patients showing a significant reduction in amplitude. CONCLUSIONS: Our findings suggest the P300 ERP is not altered in the early stages of schizophrenia before medication is introduced, and the DAT availability does not influence the P300 ERP amplitude or latency. P300 ERP amplitude reduction could be an indicator of the progression of illness and chronicity.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Potenciales Relacionados con Evento P300/fisiología , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Adolescente , Adulto , Envejecimiento/metabolismo , Envejecimiento/fisiología , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Tomografía Computarizada de Emisión de Fotón Único , Adulto JovenRESUMEN
AIMS: To improve prediction efficiency by incorporating complete blood count (CBC) into the TNM system on 5 year disease-specific survival (DSS) for patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: The CBC of 3237 patients undergoing radiotherapy was retrospectively evaluated. In total, 2820 patients treated with non-intensity-modulated radiotherapy (IMRT) were randomly divided into development (1895 patients) and validation cohorts (925 patients). The association of potential risk factors with 5 year DSS was tested by Cox proportional hazards analysis and a prognostic index was created by assigning weighted scores proportional to a regression coefficient to each factor. Each cohort was divided into low, intermediate and high prognostic index. The prognostic index was validated in the validation cohort and compared with the TNM system on prediction of 5 year DSS. Validation was repeated in another independent group of 417 patients treated with IMRT. RESULTS: Eight independent prognostic factors were identified: gender, age, T or N stages, anaemia or thrombocytosis during radiotherapy, continuous reduction in haemoglobin, high neutrophil-lymphocyte ratio before radiotherapy. Each was assigned a number of points. The area under curve (AUC) of the prognostic index was larger than that of Union Internationale Contre le Cancer/American Joint Cancer Committee TNM system 2009 (0.697 versus 0.619, P < 0.001). CONCLUSION: A CBC-based prognostic index was developed and had a higher prediction efficiency on 5 year DSS in NPC than the TNM system alone.
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Plaquetas/patología , Hemoglobinas/metabolismo , Linfocitos/patología , Neoplasias Nasofaríngeas/sangre , Neutrófilos/patología , Carcinoma , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/radioterapia , Estadificación de Neoplasias , Recuento de Plaquetas , Pronóstico , Modelos de Riesgos Proporcionales , Distribución Aleatoria , Reproducibilidad de los Resultados , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: Prevention or disease-modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson's disease models. EXPERIMENTAL APPROACH: Mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured toxicity in dopaminergic neurons, using dopamine uptake assay and morphological analysis and expression of neurotrophic substances by enzyme-linked immunosorbent assay and real-time RT PCR. KEY RESULTS: In mesencephalic neuron-glia cultures, SAHA displayed dose- and time-dependent prolongation of the survival and protection against neurotoxin-induced neuronal death of dopaminergic neurons. Mechanistic studies revealed that the neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation. CONCLUSION AND IMPLICATIONS: The novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases.
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Neuronas Dopaminérgicas/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Fármacos Neuroprotectores/farmacología , 1-Metil-4-fenilpiridinio/toxicidad , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Femenino , Mesencéfalo/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Embarazo , Ratas , Ratas Endogámicas F344 , VorinostatRESUMEN
Although dysfunction of catechol-O-methyltransferase (COMT)-mediated dopamine transmission is implicated in the etiology of schizophrenia, the human COMT gene has not been associated consistently with schizophrenia. The purpose of this study was to investigate whether the COMT gene is associated with the development of schizophrenia and whether the polymorphisms of this gene influence the psychopathological symptoms in patients with schizophrenia. Fourteen polymorphisms of the COMT gene were analyzed in a case-control study of 876 Han Chinese individuals (434 patients and 442 controls). All participants were screened using a Chinese version of the modified Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) and all patients met the criteria for schizophrenia. Furthermore, pretreatment of psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 224 hospitalized schizophrenia patients, who were drug-naÏve or drug-free, to examine the association between clinical symptomatology and COMT polymorphisms. No significant differences in allele or genotype frequencies were observed between schizophrenia patients and controls, for all variants investigated. Haplotype analysis showed that three haplotype blocks of the COMT gene were not associated with the development of schizophrenia. Moreover, these COMT polymorphisms did not influence the PANSS scores of schizophrenia patients. This study suggests that the COMT gene may not contribute to the risk of schizophrenia and to the psychopathological symptoms of schizophrenia among Han Chinese.
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Pueblo Asiatico/genética , Catecol O-Metiltransferasa/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo Genético/genética , Esquizofrenia/enzimología , Esquizofrenia/genética , Adulto , Pueblo Asiatico/etnología , Estudios de Casos y Controles , China , Femenino , Predisposición Genética a la Enfermedad/etnología , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Esquizofrenia/etnología , Psicología del EsquizofrénicoRESUMEN
Much evidence suggests that dysfunction of dopamine transporter-mediated dopamine transmission may be involved in the pathophysiology of substance abuse and dependence. The aim of this study was to examine whether the dopamine transporter gene (DAT1; SLC6A3) is associated with the development of heroin dependence (HD) and whether DAT1 influences personality traits in patients with HD. Polymorphisms of DAT1 were analyzed in a case-control study of 1046 Han Chinese (615 patients and 431 controls). All participants were screened using a Chinese version of the modified Schedule of Affective Disorder and Schizophrenia-Lifetime and all patients met the criteria for HD. Furthermore, a Chinese version of the Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits in the patient group and examine the association between their personality traits and DAT1 polymorphisms. Of the patient group, 271 completed the TPQ. No statistically significant differences in allele or genotype frequencies of all investigated variants between HD patients and controls were observed. In haplotype analyses, four haplotype blocks of DAT1 were not associated with the development of HD. These DAT1 polymorphisms did not influence novelty seeking and harm avoidance scores in HD patients. This study suggests that the DAT1 gene may not contribute to the risk of HD and specific personality traits in HD among the Han Chinese population.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Dependencia de Heroína/genética , Polimorfismo Genético , Adulto , Pueblo Asiatico , Estudios de Casos y Controles , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Personalidad , TaiwánRESUMEN
Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. Other histone deacetylase inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson's disease.
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Apoptosis/efectos de los fármacos , Dopamina/metabolismo , Inhibidores Enzimáticos/farmacología , Lipopolisacáridos/toxicidad , Neuroglía/efectos de los fármacos , Neuronas/efectos de los fármacos , Ácido Valproico/farmacología , Animales , Animales Recién Nacidos , Encéfalo/citología , Ciclo Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/metabolismo , Etiquetado Corte-Fin in Situ/métodos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Nitritos/metabolismo , Embarazo , Ratas , Ratas Endogámicas F344 , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: Clinical studies have suggested that venlafaxine induces a higher remission rate than paroxetine. However, very few studies have evaluated relapse episodes over treatment periods longer than a few weeks, and the cut-off score of 7 on the Hamilton Rating Scale for Depression (HRSD) often used to define remission is too high. This score is associated with the high rates of social function impairment. We report on a single centre, open-label, prospective 24-week study to investigate the comparative efficacy of acute treatments with venlafaxine and paroxetine, using different definitions of response and remission rates. METHODS: Outpatients satisfying DSM-IV criteria for major depression with a baseline HRSD17 score of at least 16 were eligible. Following baseline evaluations, the patients were assigned to receive venlafaxine 75-225 mg/day with the mean dosage 141.35 +/- 26.98 (SD) mg/day (n = 78), or paroxetine 20 mg/day (n = 92) for 24 weeks. Efficacy was assessed using the mean change in HRSD(17) score from baseline, the response rate and the remission rates based on different criteria for remission (HRSD(17) score < or = 7 or 5). RESULTS: One hundred and seventy patients were evaluated for efficacy; 78 treated with venlafaxine and 92 with paroxetine. Over the treatment period, venlafaxine was comparable with paroxetine on most outcome measures, whereas paroxetine produced significantly higher remission rates at weeks 4, 8, 16, 20 and 24 weeks when the lower cutoff of 5 was used. CONCLUSIONS: Venlafaxine treatment was similar to paroxetine according to the typical efficacy measures for treating outpatients with major depression. However, based on the stricter remission criterion, paroxetine might be superior to venlafaxine.
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Ciclohexanoles/administración & dosificación , Trastorno Depresivo Mayor/tratamiento farmacológico , Paroxetina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Enfermedad Aguda , Adulto , Pueblo Asiatico/genética , China , Trastorno Depresivo Mayor/etnología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Inducción de Remisión , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Clorhidrato de VenlafaxinaRESUMEN
Valproate (VPA), one of the mood stabilizers and antiepileptic drugs, was recently found to inhibit histone deacetylases (HDAC). Increasing reports demonstrate that VPA has neurotrophic effects in diverse cell types including midbrain dopaminergic (DA) neurons. However, the origin and nature of the mediator of the neurotrophic effects are unclear. We have previously demonstrated that VPA prolongs the survival of midbrain DA neurons in lipopolysaccharide (LPS)-treated neuron-glia cultures through the inhibition of the release of pro-inflammatory factors from microglia. In this study, we report that VPA upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) from astrocytes and these effects may play a major role in mediating VPA-induced neurotrophic effects on DA neurons. Moreover, VPA pretreatment protects midbrain DA neurons from LPS or 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson's disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.
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Anticonvulsivantes/farmacología , Astrocitos/metabolismo , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Factor Neurotrófico Derivado de la Línea Celular Glial/biosíntesis , Mesencéfalo/metabolismo , Neuronas/metabolismo , Ácido Valproico/farmacología , Animales , Astrocitos/citología , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/metabolismo , Comunicación Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Femenino , Humanos , Mesencéfalo/citología , Neuronas/citología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Endogámicas F344 , Regulación hacia Arriba/efectos de los fármacosRESUMEN
A recent study found, in a large sample of Ashkenazi Jews, a highly significant association between schizophrenia and a particular haplotype of three polymorphic sites in the catechol-O-methyl transferase, COMT, gene: an IVS 1 SNP (dbSNP rs737865), the exon 4 functional SNP (Val158Met, dbSNP rs165688), and a downstream SNP (dbSNP rs165599). Subsequently, this haplotype was shown to be associated with lower levels of COMT cDNA derived from normal cortical brain tissue, most likely due to cis-acting element(s). As a first step toward evaluating whether this haplotype may be relevant to schizophrenia in populations other than Ashkenazi Jews, we have studied this haplotype in 38 populations representing all major regions of the world. Adding to our previous data on four polymorphic sites in the COMT gene, including the Val158Met polymorphism, we have typed the IVS 1 rs737865 and 3' rs615599 sites and also included a novel IVS 1 indel polymorphism, yielding seven-site haplotype frequencies for normal individuals in the 38 globally distributed populations, including a sample of Ashkenazi Jews. We report that the schizophrenia-associated haplotype is significantly heterogeneous in populations worldwide. The three-site, schizophrenia-associated haplotype frequencies range from 0% in South America to 37.1% in Southwest Asia, despite the fact that schizophrenia occurs at roughly equal frequency around the world. Assuming that the published associations found between the exon 4 Val158Met SNP and schizophrenia are due to linkage disequilibrium, these new haplotype data support the hypothesis of a relevant cis variant linked to the rs737865 site, possibly just upstream in the P2 promoter driving transcription of the predominant form of COMT in the brain. The previously described HindIII restriction site polymorphism, located within the P2 promoter, varies within all populations and may provide essential information in future studies of schizophrenia.
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Catecol O-Metiltransferasa/genética , Predisposición Genética a la Enfermedad , Variación Genética , Regiones Promotoras Genéticas , Esquizofrenia/genética , Bases de Datos Genéticas , Frecuencia de los Genes , Haplotipos , Humanos , Desequilibrio de LigamientoRESUMEN
In recent studies of the role of the alcohol dehydrogenase genes (ADH) in alcoholism the ADH1B Arg47His polymorphism appears to affect risk via a protective effect associated with the ADH1B*47His. Here we present evidence for an additional effect from outside the Class I ADH genes, presumably from functional variation at the ADH7 gene. The protective effect is restricted to one of two haplotypes identical at ADH1B but differing at an intronic SNP at ADH7 suggesting epistasis or strong linkage disequilibrium (LD).
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Alcohol Deshidrogenasa/genética , Alcoholismo/prevención & control , Epistasis Genética , Haplotipos/genética , Alcoholismo/genética , Femenino , Humanos , Intrones/genética , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
This study examined whether there is evidence for an association between alcoholism with conduct disorder and alleles of the TaqI A and TaqI B polymorphisms, both individually and as haplotypes, at the dopamine D2 receptor gene (DRD2). We studied 182 Han Chinese subjects, including 34 alcoholics with conduct disorder, 63 alcoholics without conduct disorder, and 85 nonalcoholics. Alcohol dependence and conduct disorder were defined according to DSM-III-R criteria. Significant associations were observed between TaqI A and TaqI B at the DRD2 locus, tested individually and as haplotypes, and alcoholism with conduct disorder. Our results suggested that DRD2 might be associated with conduct disorder or a predisposition to both conduct disorder and alcoholism. However, this needs to be further investigated by examining the differences among conduct disorder with alcoholism, conduct disorder only, and controls for the TaqI A and B system at DRD2.
Asunto(s)
Alcoholismo/complicaciones , Alcoholismo/genética , Trastorno de la Conducta/complicaciones , Trastorno de la Conducta/genética , Receptores de Dopamina D2/genética , Adulto , Alelos , Desoxirribonucleasas de Localización Especificada Tipo II , Femenino , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
The purpose of this article is to explore assaultive behavior of psychiatric in-patients in a hospital and to examine the interplay of patient, environmental, and staff factors related to assault. The present study was carried out prospectively using standardized instruments applied in four acute wards in one hospital. A log system was used to record the occurrence of assaults. The results showed 595 episodes of assault from 238 patients in 7 months. Forty one nurses participated in the study. To further examine the differences between assaultive and non-assaultive patients, and assaulted and non-assaulted nurses, a logistic regression analysis was used. The results indicated that patient factors (diagnosis, history of assault, time since admission, and history of smoking), environmental factors (patient/nurse ratio and spatial density), and staff factors (age, length of work experience, training program received in prevention and management of assaults) are contributing variables to assaultive behavior. The present study examined a wider range of variables than have been included in many previous studies. This reinforces the necessary complexity of models likely to prove useful in predicting assaults among psychiatric inpatients.
Asunto(s)
Pacientes Internos , Trastornos Mentales , Violencia , Adolescente , Adulto , Anciano , Trastorno Bipolar , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , EsquizofreniaRESUMEN
Two dinucleotide short tandem-repeat polymorphisms (STRPs) and a polymorphic Alu element spanning a 22-kb region of the PLAT locus on chromosome 8p12-q11.2 were typed in 1,287-1,420 individuals originating from 30 geographically diverse human populations, as well as in 29 great apes. These data were analyzed as haplotypes consisting of each of the dinucleotide repeats and the flanking Alu insertion/deletion polymorphism. The global pattern of STRP/Alu haplotype variation and linkage disequilibrium (LD) is informative for the reconstruction of human evolutionary history. Sub-Saharan African populations have high levels of haplotype diversity within and between populations, relative to non-Africans, and have highly divergent patterns of LD. Non-African populations have both a subset of the haplotype diversity present in Africa and a distinct pattern of LD. The pattern of haplotype variation and LD observed at the PLAT locus suggests a recent common ancestry of non-African populations, from a small population originating in eastern Africa. These data indicate that, throughout much of modern human history, sub-Saharan Africa has maintained both a large effective population size and a high level of population substructure. Additionally, Papua New Guinean and Micronesian populations have rare haplotypes observed otherwise only in African populations, suggesting ancient gene flow from Africa into Papua New Guinea, as well as gene flow between Melanesian and Micronesian populations.
Asunto(s)
Elementos Alu/genética , Cromosomas Humanos Par 8/genética , Variación Genética/genética , Haplotipos/genética , Filogenia , Polimorfismo Genético/genética , Secuencias Repetidas en Tándem/genética , África del Sur del Sahara/etnología , Alelos , Animales , Repeticiones de Dinucleótido/genética , Evolución Molecular , Frecuencia de los Genes , Hominidae/genética , Humanos , Desequilibrio de Ligamiento , Micronesia , Papúa Nueva Guinea , Eliminación de Secuencia/genéticaRESUMEN
Because defects in the phenylalanine hydroxylase gene (PAH) cause phenylketonuria (PKU), PAH was studied for normal polymorphisms and linkage disequilibrium soon after the gene was cloned. Studies in the 1980s concentrated on European populations in which PKU was common and showed that haplotype-frequency variation exists between some regions of the world. In European populations, linkage disequilibrium generally was found not to exist between RFLPs at opposite ends of the gene but was found to exist among the RFLPs clustered at each end. We have now undertaken the first global survey of normal variation and disequilibrium across the PAH gene. Four well-mapped single-nucleotide polymorphisms (SNPs) spanning approximately 75 kb, two near each end of the gene, were selected to allow linkage disequilibrium across most of the gene to be examined. These SNPs were studied as PCR-RFLP markers in samples of, on average, 50 individuals for each of 29 populations, including, for the first time, multiple populations from Africa and from the Americas. All four sites are polymorphic in all 29 populations. Although all but 5 of the 16 possible haplotypes reach frequencies >5% somewhere in the world, no haplotype was seen in all populations. Overall linkage disequilibrium is highly significant in all populations, but disequilibrium between the opposite ends is significant only in Native American populations and in one African population. This study demonstrates that the physical extent of linkage disequilibrium can differ substantially among populations from different regions of the world, because of both ancient genetic drift in the ancestor common to a large regional group of modern populations and recent genetic drift affecting individual populations.