Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Psychiatry ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591465

RESUMO

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P < 10-52), Latino (Nagelkerke's R2 = 0.089; liability R2 = 0.021; P < 10-58), and European individuals (Nagelkerke's R2 = 0.089; liability R2 = 0.037; P < 10-113), further highlighting the advantages of incorporating data from diverse human populations.

2.
Biol Psychiatry ; 86(2): 110-119, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30686506

RESUMO

BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

3.
Nat Genet ; 49(1): 27-35, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27869829

RESUMO

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.


Assuntos
Variações do Número de Cópias de DNA/genética , Loci Gênicos/genética , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Fatores de Risco
4.
Mol Cell Proteomics ; 11(1): M111.009530, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21976671

RESUMO

Impaired brainstem responses to homeostatic challenges during sleep may result in the sudden infant death syndrome (SIDS). Previously we reported a deficiency of serotonin (5-HT) and its key biosynthetic enzyme, tryptophan hydroxylase (TPH2), in SIDS infants in the medullary 5-HT system that modulates homeostatic responses during sleep. Yet, the underlying basis of the TPH2 and 5-HT deficiency is unknown. In this study, we tested the hypothesis that proteomics would uncover previously unrecognized abnormal levels of proteins related to TPH2 and 5-HT regulation in SIDS cases compared with controls, which could provide novel insight into the basis of their deficiency. We first performed a discovery proteomic analysis of the gigantocellularis of the medullary 5-HT system in the same data set with deficiencies of TPH2 and 5-HT levels. Analysis in 6 SIDS cases and 4 controls revealed a 42-75% reduction in abundance in 5 of the 6 isoforms identified of the 14-3-3 signal transduction family, which is known to influence TPH2 activity (p < 0.07). These findings were corroborated in an additional SIDS and control sample using an orthogonal MS(E)-based quantitative proteomic strategy. To confirm these proteomics results in a larger data set (38 SIDS, 11 controls), we applied Western blot analysis in the gigantocellularis and found that 4/7 14-3-3 isoforms identified were significantly reduced in SIDS cases (p ≤ 0.02), with a 43% reduction in all 14-3-3 isoforms combined (p < 0.001). Abnormalities in 5-HT and TPH2 levels and 5-HT(1A) receptor binding were associated with the 14-3-3 deficits in the same SIDS cases. These data suggest a potential molecular defect in SIDS related to TPH2 regulation, as 14-3-3 is critical in this process.


Assuntos
Proteínas 14-3-3/deficiência , Tronco Encefálico/metabolismo , Serotonina/deficiência , Morte Súbita do Lactente , Triptofano Hidroxilase/deficiência , Cromatografia Líquida , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Espectrometria de Massas , Proteômica
5.
J Neuropathol Exp Neurol ; 70(10): 841-58, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21937910

RESUMO

Despite the key role of γ-aminobutyric acid (GABA) neurons in the modulation of cerebral cortical output, little is known about their development in the human cortex. We analyzed several GABAergic parameters in standardized regions of the cerebral cortex and white matter in a total of 38 human fetuses and infants from 19 gestational weeks to 2.7 postnatal years using immunocytochemistry, Western blotting, tissue autoradiography, and computer-based cellular quantitation. At least 20% of GABAergic neurons in the white matter migrated toward the cortex over late gestation. After term, migration declined and ended within 6 postnatal months. In parallel, the GABAergic neuronal density increased in the cortex over late gestation, also with a peak at term. From midgestation to infancy, the pattern of GABAA receptor binding changed from uniformly low across all cortical layers to high levels concentrated in the middle laminae; glutamic acid decarboxylase (GAD65 and GAD67) levels differentially increased. Thus, the second half of gestation is a period of rapid development of the cortical GABAergic system that continues into early infancy. This period corresponds to the peak window of vulnerability to perinatal hypoxia-ischemia in which GABAergic neurons are potentially developmentally susceptible, including in the preterm infant.


Assuntos
Córtex Cerebral , Glutamato Descarboxilase/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Tecido Nervoso/metabolismo , Receptores de GABA/metabolismo , Ácido gama-Aminobutírico/metabolismo , Fatores Etários , Autorradiografia , Contagem de Células/métodos , Movimento Celular , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Pré-Escolar , Período Crítico (Psicologia) , Feminino , Feto , Humanos , Lactente , Recém-Nascido , Masculino , Tecido Nervoso/embriologia , Tecido Nervoso/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia
6.
J Neuropathol Exp Neurol ; 70(9): 799-810, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21865888

RESUMO

γ-Aminobutyric acid (GABA) neurons in the medulla oblongata help regulate homeostasis, in part through interactions with the medullary serotonergic (5-HT) system. Previously, we reported abnormalities in multiple 5-HT markers in the medullary 5-HT system of infants dying from sudden infant death syndrome (SIDS), suggesting that 5-HT dysfunction is involved in its pathogenesis. Here, we tested the hypothesis that markers of GABAA receptors are decreased in the medullary 5-HT system in SIDS cases compared with controls. Using tissue receptor autoradiography with the radioligand H-GABA, we found 25% to 52% reductions in GABAA receptor binding density in 7 of 10 key nuclei sampled of the medullary 5-HT system in the SIDS cases (postconceptional age [PCA] = 51.7 ± 8.3, n = 28) versus age-adjusted controls (PCA = 55.3 ± 13.5, n = 8) (p ≤ 0.04). By Western blotting, there was 46.2% reduction in GABAAα3 subunit levels in the gigantocellularis (component of the medullary 5-HT system) of SIDS cases (PCA = 53.9 ± 8.4, n = 24) versus controls (PCA = 55.3 ± 8.3, n = 8) (56.8% standard in SIDS cases vs 99.35% in controls; p = 0.026). These data suggest that medullary GABAA receptors are abnormal in SIDS infants and that SIDS is a complex disorder of a homeostatic network in the medulla that involves deficits of the GABAergic and 5-HT systems.


Assuntos
Bulbo/metabolismo , Receptores de GABA-A/metabolismo , Serotonina/metabolismo , Morte Súbita do Lactente/patologia , Autorradiografia , Feminino , Humanos , Recém-Nascido , Masculino , Ligação Proteica/fisiologia , Fatores de Risco , Estatística como Assunto
7.
Pediatr Res ; 68(5): 409-13, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20661167

RESUMO

Dysfunction of medullary serotonin (5-HT)-mediated respiratory and autonomic function is postulated to underlie the pathogenesis of the majority of sudden infant death syndrome (SIDS) cases. Several studies have reported an increased frequency of the LL genotype and L allele of the 5-HT transporter (5-HTT) gene promoter polymorphism (5-HTTLPR), which is associated with increased transcriptional activity and 5-HT transport in vitro, in SIDS cases compared with controls. These findings raise the possibility that this polymorphism contributes to or exacerbates existing medullary 5-HT dysfunction in SIDS. In this study, we tested the hypothesis that the frequency of LL genotype and L allele are higher in 179 SIDS cases compared with 139 controls of multiple ethnicities in the San Diego SIDS Dataset. We observed no significant association of genotype or allele with SIDS cases either in the total cohort or on stratification for ethnicity. These observations do not support previous findings that the L allele and/or LL genotype of the 5-HTTLPR are associated with SIDS.


Assuntos
Bases de Dados Factuais , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Morte Súbita do Lactente/genética , California , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , Masculino , Serotonina/metabolismo
8.
JAMA ; 303(5): 430-7, 2010 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-20124538

RESUMO

CONTEXT: Sudden infant death syndrome (SIDS) is postulated to result from abnormalities in brainstem control of autonomic function and breathing during a critical developmental period. Abnormalities of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS. OBJECTIVE: To test the hypothesis that 5-HT receptor abnormalities in infants dying from SIDS are associated with decreased tissue levels of 5-HT, its key biosynthetic enzyme (tryptophan hydroxylase [TPH2]), or both. DESIGN, SETTING, AND PARTICIPANTS: Autopsy study conducted to analyze levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); levels of TPH2; and 5-HT(1A) receptor binding. The data set was accrued between 2004 and 2008 and consisted of 41 infants dying from SIDS (cases), 7 infants with acute death from known causes (controls), and 5 hospitalized infants with chronic hypoxia-ischemia. MAIN OUTCOME MEASURES: Serotonin and metabolite tissue levels in the raphé obscurus and paragigantocellularis lateralis (PGCL); TPH2 levels in the raphé obscurus; and 5-HT(1A) binding density in 5 medullary nuclei that contain 5-HT neurons and 5 medullary nuclei that receive 5-HT projections. RESULTS: Serotonin levels were 26% lower in SIDS cases (n = 35) compared with age-adjusted controls (n = 5) in the raphé obscurus (55.4 [95% confidence interval {CI}, 47.2-63.6] vs 75.5 [95% CI, 54.2-96.8] pmol/mg protein, P = .05) and the PGCL (31.4 [95% CI, 23.7-39.0] vs 40.0 [95% CI, 20.1-60.0] pmol/mg protein, P = .04). There was no evidence of excessive 5-HT degradation assessed by 5-HIAA levels, 5-HIAA:5-HT ratio, or both. In the raphé obscurus, TPH2 levels were 22% lower in the SIDS cases (n = 34) compared with controls (n = 5) (151.2% of standard [95% CI, 137.5%-165.0%] vs 193.9% [95% CI, 158.6%-229.2%], P = .03). 5-HT(1A) receptor binding was 29% to 55% lower in 3 medullary nuclei that receive 5-HT projections. In 4 nuclei, 3 of which contain 5-HT neurons, there was a decrease with age in 5-HT(1A) receptor binding in the SIDS cases but no change in the controls (age x diagnosis interaction). The profile of 5-HT and TPH2 abnormalities differed significantly between the SIDS and hospitalized groups (5-HT in the raphé obscurus: 55.4 [95% CI, 47.2-63.6] vs 85.6 [95% CI, 61.8-109.4] pmol/mg protein, P = .02; 5-HT in the PGCL: 31.4 [95% CI, 23.7-39.0] vs 71.1 [95% CI, 49.0-93.2] pmol/mg protein, P = .002; TPH2 in the raphé obscurus: 151.2% [95% CI, 137.5%-165.0%] vs 102.6% [95% CI, 58.7%-146.4%], P = .04). CONCLUSION: Compared with controls, SIDS was associated with lower 5-HT and TPH2 levels, consistent with a disorder of medullary 5-HT deficiency.


Assuntos
Tronco Encefálico/química , Receptor 5-HT1A de Serotonina/análise , Serotonina/deficiência , Morte Súbita do Lactente , Triptofano Hidroxilase/análise , Autopsia , Estudos de Casos e Controles , Feminino , Humanos , Ácido Hidroxi-Indolacético/análise , Hipóxia , Lactente , Recém-Nascido , Isquemia , Masculino , Fatores de Risco , Serotonina/análise
9.
Brain Pathol ; 18(1): 21-31, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17924983

RESUMO

The high rate of the sudden infant death syndrome (SIDS) in American Indians in the Northern Plains (3.5/1000) may reflect the high incidence of cigarette smoking and alcohol consumption during pregnancy. Nicotine, a neurotoxic component of cigarettes, and alcohol adversely affect nicotinic receptor binding and subsequent cholinergic development in animals. We measured (3)H-nicotine receptor binding in 16 brainstem nuclei in American Indian SIDS (n = 27) and controls (n = 6). In five nuclei related to cardiorespiratory control, (3)H-nicotinic binding decreased with increasing number of drinks (P < 0.03). There were no differences in binding in SIDS compared with controls, except upon stratification of prenatal exposures. In three mesopontine nuclei critical for arousal there were reductions (P < 0.04) in binding in controls exposed to cigarette smoke compared with controls without exposure; there was no difference between SIDS cases with or without exposure. This study suggests that maternal smoking and alcohol affects (3)H-nicotinic binding in the infant brainstem irrespective of the cause of death. It also suggests that SIDS cases are unable to respond to maternal smoking with the "normal" reduction seen in controls. Future studies are needed to establish the role of adverse prenatal exposures in altered brainstem neurochemistry in SIDS.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Tronco Encefálico/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores Nicotínicos/metabolismo , Fumar/efeitos adversos , Morte Súbita do Lactente/patologia , Adulto , Transtornos do Sistema Nervoso Induzidos por Álcool/etnologia , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/patologia , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Tronco Encefálico/patologia , Depressores do Sistema Nervoso Central/efeitos adversos , Fibras Colinérgicas/efeitos dos fármacos , Fibras Colinérgicas/metabolismo , Fibras Colinérgicas/patologia , Estudos de Coortes , Etanol/efeitos adversos , Feminino , Humanos , Índios Norte-Americanos/etnologia , Recém-Nascido , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etnologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Ensaio Radioligante , Receptores Nicotínicos/efeitos dos fármacos , Centro Respiratório/metabolismo , Centro Respiratório/patologia , Fatores de Risco , Morte Súbita do Lactente/etnologia
10.
Pediatr Dev Pathol ; 10(3): 208-23, 2007 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17535090

RESUMO

Sudden unexplained death in childhood (SUDC) is the sudden death of a child older than 1 year of age that remains unexplained after review of the clinical history, circumstances of death, and autopsy with appropriate ancillary testing. We report here 5 cases of SUDC in toddlers that we believe define a new entity associated with hippocampal anomalies at autopsy. All of the toddlers died unexpectedly during the night, apparently during sleep. Within 48 hours before death, 2 toddlers had fever, 3 had a minor upper respiratory tract infection, and 3 experienced minor head trauma. There was a history of febrile seizures in 2 (40%) and a family history of febrile seizures in 2 (40%). Hippocampal findings included external asymmetry and 2 or more microdysgenetic features. The incidence of certain microdysgenetic features was substantially increased in the temporal lobes of these 5 cases compared with the temporal lobes of 39 (control) toddlers with the causes of death established at autopsy (P < 0.01). We propose that these 5 cases define a potential subset of SUDC whose sudden death is caused by an unwitnessed seizure arising during sleep in the anomalous hippocampus and producing cardiopulmonary arrest. Precipitating factors may be fever, infection, and/or minor head trauma. Suggested risk factors are a history of febrile seizures and/or a family history of febrile seizures. Future studies are needed to confirm these initial findings and to define the putative links between sudden death, hippocampal anomalies, and febrile seizures in toddlers.


Assuntos
Morte Súbita/etiologia , Hipocampo/anormalidades , Hipocampo/patologia , Autopsia , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Convulsões Febris/fisiopatologia
11.
Auton Neurosci ; 132(1-2): 81-102, 2007 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-17236817

RESUMO

The serotonergic (5-HT) neurons of the medulla oblongata are postulated to comprise a system that modulates homeostatic function in response to metabolic imbalances in the internal milieu in a state-dependent manner. In this study, we define the baseline development of the topography of the human medullary 5-HT system in 30 cases ranging from the embryonic period through infancy. We used immunocytochemical techniques with the PH8 antibody which recognizes the key 5-HT synthetic enzyme, tryptophan hydroxylase, and computer-based methods of cell quantitation. In the infant medulla, 5-HT neurons were distributed in raphé, extra-raphé, and ventral positions that place these neurons adjacent to, or intermingled with, the neurons in the lower cranial nerve nuclei and reticular formation that directly mediate respiration, upper airway reflexes, and autonomic function. Along the ventral and ventrolateral surface, 5-HT neurons formed two lateral and one midline "columns" in the rostrocaudal axis that are homologous in position to chemosensitive 5-HT neurons in rats, and that correspond in part to the classic respiratory chemosensitive fields. Serotonergic neurons comprised a subpopulation of the arcuate nucleus along the ventral surface; their short processes directly abutted the surface, suggesting a role for them in monitoring carbon dioxide levels in the cerebrospinal fluid. The medullary 5-HT system began to form in the embryo, with the raphé primordia appearing as early as 7 weeks (the earliest time-point available). By 10-12 weeks, the lateral tegmental 5-HT neurons clustered into the early primordia of extra-raphé subnuclei. By 20 weeks, the "adult-like" topography of the medullary 5-HT system was in place, with subtle (quantitative) changes occurring thereafter. Thus, protracted changes occur from the prenatal period through infancy. These data provide a foundation for 5-HT neuronal analysis in pediatric brainstem disorders, as proposed in the sudden infant death syndrome.


Assuntos
Bulbo/anatomia & histologia , Bulbo/metabolismo , Vias Neurais/anatomia & histologia , Neurônios/citologia , Serotonina/metabolismo , Adulto , Embrião de Mamíferos , Feto , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Vias Neurais/metabolismo , Neurônios/metabolismo
12.
JAMA ; 296(17): 2124-32, 2006 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17077377

RESUMO

CONTEXT: The serotonergic (5-hydroxytryptamine [5-HT]) neurons in the medulla oblongata project extensively to autonomic and respiratory nuclei in the brainstem and spinal cord and help regulate homeostatic function. Previously, abnormalities in 5-HT receptor binding in the medullae of infants dying from sudden infant death syndrome (SIDS) were identified, suggesting that medullary 5-HT dysfunction may be responsible for a subset of SIDS cases. OBJECTIVE: To investigate cellular defects associated with altered 5-HT receptor binding in the 5-HT pathways of the medulla in SIDS cases. DESIGN, SETTING, AND PARTICIPANTS: Frozen medullae from infants dying from SIDS (cases) or from causes other than SIDS (controls) were obtained from the San Diego Medical Examiner's office between 1997 and 2005. Markers of 5-HT function were compared between SIDS cases and controls, adjusted for postconceptional age and postmortem interval. The number of samples available for each analysis ranged from 16 to 31 for SIDS cases and 6 to 10 for controls. An exploratory analysis of the correlation between markers and 6 recognized risk factors for SIDS was performed. MAIN OUTCOME MEASURES: 5-HT neuron count and density, 5-HT(1A) receptor binding density, and 5-HT transporter (5-HTT) binding density in the medullary 5-HT system; correlation between these markers and 6 recognized risk factors for SIDS. RESULTS: Compared with controls, SIDS cases had a significantly higher 5-HT neuron count (mean [SD], 148.04 [51.96] vs 72.56 [52.36] cells, respectively; P<.001) and 5-HT neuron density (P<.001), as well as a significantly lower density of 5-HT(1A) receptor binding sites (P

Assuntos
Bulbo/citologia , Bulbo/metabolismo , Receptores de Serotonina/metabolismo , Morte Súbita do Lactente/etiologia , Morte Súbita do Lactente/patologia , Sítios de Ligação , Contagem de Células , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Neurônios/metabolismo , Polimorfismo Genético , Ligação Proteica , Receptor 5-HT1A de Serotonina/metabolismo , Fatores de Risco , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Morte Súbita do Lactente/genética
13.
J Neuropathol Exp Neurol ; 64(11): 1018-27, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16254496

RESUMO

Autonomic dysfunction is prevalent in girls with Rett syndrome, an X-chromosome-linked disorder of mental retardation resulting from mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). This gene plays a role in regulating neuronal activity-dependent gene expression, including brain-derived neurotrophic factor (BDNF), which is a potent serotonergic (5-HT) neuronal growth factor. We analyzed selected parameters of the 5-HT system of the medulla in autopsied patients with Rett syndrome because of the role of BDNF in 5-HT cell development and because 5-HT plays a key role in modulating autonomic control. 5-HT neurons were identified by immunostaining for tryptophan hydroxylase, the biosynthetic enzyme for 5-HT. We quantitated the number of 5-HT cells in the medulla at 2 standardized levels in 11 Rett and 7 control cases. There was no significant difference in 5-HT cell number between the groups. We analyzed binding to the serotonin transporter (SERT) using the radioligand [(125)I]-RTI-55 with tissue autoradiography in 7 Rett and 5 controls in 9 cardiorespiratory-related nuclei. In the dorsal motor nucleus of the vagus (DMX) (preganglionic parasympathetic outflow), SERT binding for the control cases decreased significantly over time (p = 0.049) but did not change in the Rett cases (p = 0.513). Adjusting for age, binding between the Rett and control cases differed significantly in this nucleus (p = 0.022). There was a marginally significant age versus diagnosis interaction (p = 0.06). Thus, altered 5-HT innervation and/or uptake in the DMX may contribute to abnormal 5-HT modulation of this major autonomic nucleus in patients with Rett syndrome. These data suggest hypotheses concerning 5-HT modulation of vagal function for testing in MeCP2 knockout mice to understand mechanisms underlying autonomic dysfunction in patients with Rett syndrome.


Assuntos
Bulbo/patologia , Neurônios/metabolismo , Síndrome de Rett/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Nervo Vago/fisiopatologia , Adolescente , Adulto , Fatores Etários , Análise de Variância , Autorradiografia/métodos , Contagem de Células/métodos , Criança , Pré-Escolar , Cocaína/análogos & derivados , Cocaína/farmacocinética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Imuno-Histoquímica/métodos , Isótopos de Iodo/farmacocinética , Distribuição Tecidual/efeitos dos fármacos , Triptofano Hidroxilase/metabolismo
14.
J Neuropathol Exp Neurol ; 64(8): 689-94, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16106217

RESUMO

Sudden infant death syndrome (SIDS) is characterized by a sleep-related death in a seemingly healthy infant. Previously, we reported abnormalities in the serotonergic (5-HT) system of the medulla in SIDS cases in 2 independent datasets, including in the Northern Plains American Indians. The medullary 5-HT system is composed of 5-HT neurons in the raphé, extra-raphé, and arcuate nucleus at the ventral surface. This system is thought to modulate respiratory and autonomic function, and thus abnormalities within it could potentially lead to imbalances in sympathetic and parasympathetic tone. We report the case of a full-term American Indian boy who died of SIDS at 2 postnatal weeks, and who had subtle respiratory and autonomic dysfunction measured prospectively on the second postnatal day. Cardiorespiratory assessment of heart rate variability suggested that the ratio of parasympathetic to sympathetic tone was higher than normal in active sleep and lower than normal in quiet sleep in this case. At autopsy, arcuate nucleus hypoplasia and 5-HT receptor-binding abnormalities in the arcuate nucleus and other components of the medullary 5-HT system were found. This case suggests that medullary 5-HT system abnormalities may be able to be identified by such physiological tests before death. Replication of these findings in a large population may lead to the development of predictive cardiorespiratory assessment tools for future screening to identify infants with medullary 5-HT abnormalities and SIDS risk.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Transtornos Respiratórios/fisiopatologia , Serotonina/metabolismo , Morte Súbita do Lactente/patologia , Fatores Etários , Autorradiografia/métodos , Tronco Encefálico/efeitos dos fármacos , Estudos de Coortes , Humanos , Lactente , Dietilamida do Ácido Lisérgico/farmacocinética , Masculino , Nicotina/metabolismo , Mudanças Depois da Morte , Trítio/farmacocinética
15.
Brain Res Brain Res Rev ; 50(1): 169-83, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16043226

RESUMO

Because the piglet is frequently used as a model for developmental disorders of the medullary serotonergic (5-HT) system in the human infant, this review compares the topography and developmental profile of selected 5-HT markers between humans in the first year of life and piglets in the first 60 days of life. The distribution of tryptophan hydroxylase-immunoreactive 5-HT neurons in the human infant medulla is very similar, but not identical, to that in the piglet. One notable difference is the presence of compact clusters of 5-HT neurons at the ventral surface of the piglet medulla. While it lacks these distinctive clusters, the human infant medulla contains potentially homologous 5-HT neurons scattered along the ventral surface embedded in the arcuate nucleus. Each species shows evidence of age-related changes in the 5-HT system, but the changes are different in nature; in the human infant, statistically significant age-related changes are observed in the proportional distribution of medullary 5-HT cells, while in the piglet, statistically significant age-related changes are observed in the levels of 5-HT receptor binding in certain medullary nuclei. Analyses of 5-HT receptor binding profiles in selected nuclei in the two species suggest that the equivalent postnatal ages for 5-HT development in piglets and human infants are, respectively, 4 days and 1 month, 12 days and 4 months, 30 days and 6 months, and 60 days and 12 months. Collectively, when certain species differences are considered, these data support the use of the piglet as a model for the human infant medullary 5-HT system.


Assuntos
Deficiências do Desenvolvimento/patologia , Bulbo , Neurônios/metabolismo , Serotonina/metabolismo , Animais , Animais Recém-Nascidos , Criança , Pré-Escolar , Deficiências do Desenvolvimento/metabolismo , Modelos Animais de Doenças , Humanos , Bulbo/crescimento & desenvolvimento , Bulbo/metabolismo , Bulbo/patologia , Neurônios/patologia , Suínos
16.
J Exp Biol ; 208(Pt 10): 1963-70, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15879076

RESUMO

During uphill running limb muscles must perform net mechanical work to increase the body's potential energy, while during level running the net mechanical work required is negligible as long as speed is constant. The increased demands for work as running incline increases might be met by an increase in power output at all joints, or only a subset of joints. We used inverse dynamics to determine which joints modulate net work output in humans running uphill. We measured joint kinematics and ground reaction force during moderate speed running at 0 degrees , 6 degrees and 12 degrees inclines. Muscle force, joint power and work per step were determined at the ankle, knee and hip using inverse dynamics calculations. We found that virtually all of the increase in work output with increasing incline resulted from increases in net work done at the hip (-0.25+/-0.23 J kg(-1), level, vs 0.88+/-0.10 J kg(-1), 12 degrees incline), while the knee and ankle performed similar functions at all inclines. The increase in work output at the hip resulted primarily from a large increase in average net muscle moment during stance (2.07+/-17.84 Nm, level, vs 87.30+/-13.89 Nm, 12 degrees incline); joint excursion increased by only 20% (41.22+/-3.41 degrees , level, vs 49.22+/-2.35 degrees , 12 degrees incline). The increase in hip muscle moment and power was associated with a poorer mechanical advantage for producing force against the ground. The increase in hip moment with running incline allows for the production of the power necessary to lift the body. This power may be developed by hip extensors or by transfer of power from muscles at other joints via biarticular muscles.


Assuntos
Articulações/fisiologia , Músculo Esquelético/fisiologia , Corrida/fisiologia , Adulto , Análise de Variância , Fenômenos Biomecânicos , Humanos , Masculino , Gravação em Vídeo
17.
J Neuropathol Exp Neurol ; 63(9): 990-9, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15453097

RESUMO

Periventricular leukomalacia (PVL) involves free radical injury to developing oligodendrocytes (OLs), resulting from ischemia/reperfusion, particularly between 24 and 32 gestational weeks. Using immunocytochemistry and Western blots, we tested the hypothesis that this vulnerability to free radical toxicity results, in part, from developmental lack of superoxide dismutases (SOD)-1 and -2, catalase, and glutathione peroxidase (GPx) in the telencephalic white matter of the human fetus. During the period of greatest PVL risk and through term (> or = 37 weeks), expression of both SODs (for conversion of O2- to H2O2) significantly lagged behind that of catalase and GPx (for breakdown of H2O2), which, in contrast, superseded adult levels by 30 gestational weeks. Our data indicate that a developmental "mismatch" in the sequential antioxidant enzyme cascade likely contributes to the vulnerability to free radical toxicity of the immature cerebral white matter, which is "unprepared" for the transition from a hypoxic intrauterine to an oxygen-rich postnatal environment. All enzymes, localized to astrocytes and OLs, had higher-than-adult expression at 2 to 5 postnatal months (peak of myelin sheath synthesis), suggesting an adaptive mechanism to protect against lipid peroxidation during myelin sheath (lipid) synthesis. The previously unrecognized dissociation between the expression of the SODs and that of catalase and GPx in the fetal period has potential implications for future antioxidant therapy in PVL.


Assuntos
Paralisia Cerebral/enzimologia , Leucomalácia Periventricular/enzimologia , Fibras Nervosas Mielinizadas/enzimologia , Traumatismo por Reperfusão/enzimologia , Superóxido Dismutase/metabolismo , Telencéfalo/enzimologia , Idoso , Antioxidantes/metabolismo , Astrócitos/enzimologia , Catalase/metabolismo , Paralisia Cerebral/etiologia , Paralisia Cerebral/prevenção & controle , Pré-Escolar , Feminino , Radicais Livres/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Imunidade Inata/fisiologia , Lactente , Recém-Nascido , Leucomalácia Periventricular/etiologia , Leucomalácia Periventricular/fisiopatologia , Peroxidação de Lipídeos/fisiologia , Pessoa de Meia-Idade , Bainha de Mielina/enzimologia , Fibras Nervosas Mielinizadas/patologia , Trabalho de Parto Prematuro/complicações , Oligodendroglia/enzimologia , Estresse Oxidativo/fisiologia , Gravidez , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/fisiopatologia , Telencéfalo/embriologia , Telencéfalo/crescimento & desenvolvimento
18.
J Comp Neurol ; 472(2): 221-31, 2004 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-15048689

RESUMO

Tissue receptor autoradiography with 3H-lysergic acid diethylamide (3H-LSD), 3H-8-hydroxy-2-[di-N-propylamine] tetralin (3H-8-OH-DPAT), and 125I-RTI-55 was used to map the distribution and developmental profile of 5-HT(1A-1D) and 5-HT2 receptors, 5-HT1A receptors, and the serotonin (5-HT) transporter (SERT), respectively, to nuclei with cardiorespiratory function in the human medulla from midgestation to maturity. The distribution pattern of the 5-HT markers was heterogeneous, with variable densities of binding of each observed both in nuclei with and without 5-HT cell bodies. The highest density of binding for each marker was observed in the raphé nuclei, the site of the highest density of 5-HT cell bodies. A significant reduction in 5-HT receptor binding measured with 3H-LSD was observed between midgestation and infancy, and between infancy and maturity in multiple nuclei, but no changes were observed across infancy. A significant increase in 5-HT1A receptor binding density was observed across infancy in the hypoglossal nucleus (regression slope coefficient = 0.008 +/- 0.002, P = 0.02), and a marginally significant increase was observed in the raphé obscurus (regression slope coefficient = 0.061 +/- 0.026 [mean +/- SEM], P = 0.05). No significant age-related changes in SERT binding were observed at any time. With the exception of the hypoglossal nucleus, where 5-HT1A receptor binding increases while SERT binding remains stable, the medullary 5-HT markers analyzed in the study are essentially "in place" at birth. This study provides important baseline data that serve as a foundation for future work in pediatric 5-HT brainstem disorders, including sudden infant death syndrome.


Assuntos
Proteínas de Transporte/metabolismo , Bulbo/crescimento & desenvolvimento , Bulbo/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso/metabolismo , Receptores de Serotonina/metabolismo , Feto/metabolismo , Humanos , Lactente , Recém-Nascido , Bulbo/embriologia , Ligação Proteica/fisiologia , Serotoninérgicos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina
19.
Auton Neurosci ; 110(2): 65-80, 2004 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-15046730

RESUMO

The anatomy of the 5-HT system in the medulla oblongata is well defined in several vertebrate species, but not in the piglet. A detailed map and developmental profile of this system is particularly important in the piglet because this species increasingly is used as a model for physiological studies of medullary homeostatic control and its disorders in human infancy, especially the sudden infant death syndrome. Tryptophan hydroxylase immunohistochemistry was used to identify 5-HT cells and map their distribution in the medullae of piglets between postnatal days 4 and 30, the putative comparable period to early human infancy. Tritiated (3H)-lysergic acid diethylamide (LSD) binding to 5-HT1A-D and 5-HT2 receptors and 3H-8-hydroxy-2-[di-N-propylamine]tetralin (8-OH-DPAT) binding to 5-HT1A receptors were used to quantify and map the distribution of these serotonin receptors between 4 and 60 postnatal days. The distribution of 5-HT cells was similar to that observed in other vertebrate species, with cell bodies in and lateral to the caudal raphé. Tritiated-LSD and 3H-8-OH-DPAT binding both showed significant age-related changes in select raphé and extra-raphé subnuclei. Taken together, these findings suggest that while the medullary 5-HT cells are topographically in place at birth in the piglet, changes in 5-HT neurotransmission take place during the first 30 days of life, as reflected by changes in patterns of receptor binding. Therefore, the first 30 days of life represent a critical period in the development of the 5-HT system and the homeostatic functions it mediates.


Assuntos
Bulbo/citologia , Bulbo/crescimento & desenvolvimento , Núcleos da Rafe/citologia , Núcleos da Rafe/crescimento & desenvolvimento , Serotonina/metabolismo , Sus scrofa/anatomia & histologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacocinética , Envelhecimento/metabolismo , Animais , Animais Recém-Nascidos , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Vasos Sanguíneos/inervação , Diferenciação Celular/fisiologia , Tamanho Celular/fisiologia , Dendritos/metabolismo , Dendritos/ultraestrutura , Imuno-Histoquímica , Dietilamida do Ácido Lisérgico/metabolismo , Dietilamida do Ácido Lisérgico/farmacocinética , Bulbo/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Ensaio Radioligante , Núcleos da Rafe/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Sus scrofa/crescimento & desenvolvimento , Transmissão Sináptica/fisiologia , Triptofano Hidroxilase/metabolismo
20.
J Neuropathol Exp Neurol ; 62(11): 1178-91, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14656075

RESUMO

The rate of the sudden infant death syndrome (SIDS) among American Indian infants in the Northern Plains is almost 6 times higher than in U.S. white infants. In a study of infant mortality among Northern Plains Indians, we tested the hypothesis that receptor binding abnormalities to the neurotransmitter serotonin (5-HT) in SIDS cases, compared with autopsied controls, occur in regions of the medulla oblongata that contain 5-HT neurons and that are critical for the regulation of cardiorespiration and central chemosensitivity during sleep, i.e. the medullary 5-HT system. Tritiated-lysergic acid diethylamide binding to 5-HT(1A-D) and 5-HT2 receptors was measured in 19 brainstem nuclei in 23 SIDS and 6 control infants using tissue receptor autoradiography. Binding in the arcuate nucleus, a part of the medullary 5-HT system along the ventral surface, in the SIDS infants (mean age-adjusted binding 7.1 +/- 0.8 fmol/mg tissue, n = 23) was significantly lower than in controls (mean age-adjusted binding 13.1 +/- 1.6 fmol/mg tissue, n = 5) (p = 0.003). Binding also demonstrated significant diagnosis x age interactions (p < 0.04) in 4 other nuclei that are components of the 5-HT system. These data suggest that medullary 5-HT dysfunction can lead to sleep-related, sudden death in affected SIDS infants, and confirm the same binding abnormalities reported by us in a larger dataset of non-American Indian SIDS and control infants. This study also links 5-HT abnormalities in the arcuate nucleus with exposure to adverse prenatal exposures, i.e. cigarette smoking (p = 0.011) and alcohol (p = 0.075), during the periconceptional period or throughout pregnancy. Prenatal exposure to cigarette smoke and/or alcohol may contribute to abnormal fetal medullary 5-HT development in SIDS infants.


Assuntos
Tronco Encefálico/anormalidades , Serotonina/metabolismo , Morte Súbita do Lactente/patologia , Fatores Etários , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Autorradiografia , Sítios de Ligação , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Estudos de Casos e Controles , Etanol/efeitos adversos , Feminino , Humanos , Índios Norte-Americanos/etnologia , Lactente , Recém-Nascido , Entrevistas como Assunto , Dietilamida do Ácido Lisérgico/farmacocinética , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Fumaça/efeitos adversos , Morte Súbita do Lactente/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA