RESUMO
We have found mutations in the Menkes disease gene (MNK) which impair, but do not abolish, correct mRNA splicing in patients with less severe clinical phenotypes. In one family, four males aged 2-36 years with a distinctive Menkes variant have a mutation at the +3 position of a splice donor site near the 3' end of the Menkes coding sequence that is associated with exon skipping and a stable mutant transcript. In an unrelated 15-year-old male with typical occipital horn syndrome, a point mutation at the -2 exonic position of a splice donor site in the middle of the gene causes exon-skipping and activation of a cryptic splice acceptor site. In both mutations, maintenance of some normal splicing is demonstrable by RT-PCR, cDNA sequencing and ribonuclease protection.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Transporte/genética , Proteínas de Transporte de Cátions , Síndrome de Ehlers-Danlos/genética , Síndrome dos Cabelos Torcidos/genética , Osso Occipital/anormalidades , Mutação Puntual , Splicing de RNA , Proteínas Recombinantes de Fusão , Adenosina Trifosfatases/química , Adolescente , Animais , Sequência de Bases , Células Cultivadas , Ceruloplasmina/análise , Cobre/sangue , ATPases Transportadoras de Cobre , Análise Mutacional de DNA , Di-Hidroxifenilalanina/sangue , Di-Hidroxifenilalanina/líquido cefalorraquidiano , Síndrome de Ehlers-Danlos/sangue , Síndrome de Ehlers-Danlos/líquido cefalorraquidiano , Síndrome de Ehlers-Danlos/classificação , Éxons , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Síndrome dos Cabelos Torcidos/sangue , Síndrome dos Cabelos Torcidos/líquido cefalorraquidiano , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/sangue , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Camundongos , Camundongos Mutantes Neurológicos , Dados de Sequência Molecular , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Regiões Terminadoras GenéticasRESUMO
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is predominantly caused by alterations of the methyl-CpG-binding protein 2 (MECP2) gene. Disease severity and the presence of comorbidities such as gastrointestinal distress vary widely across affected individuals. The gut microbiome has been implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) as a regulator of disease severity and gastrointestinal comorbidities. Although the gut microbiome has been previously characterized in humans with RTT compared to healthy controls, the impact of MECP2 mutation on the composition of the gut microbiome in animal models where the host and diet can be experimentally controlled remains to be elucidated. By evaluating the microbial community across postnatal development as behavioral symptoms appear and progress, we have identified microbial taxa that are differentially abundant across developmental timepoints in a zinc-finger nuclease rat model of RTT compared to WT. We have additionally identified p105 as a key translational timepoint. Lastly, we have demonstrated that fecal SCFA levels are not altered in RTT rats compared to WT rats across development. Overall, these results represent an important step in translational RTT research.
Assuntos
Microbioma Gastrointestinal/fisiologia , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Síndrome de Rett/microbiologia , Animais , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Feminino , Proteína 2 de Ligação a Metil-CpG/metabolismo , Ratos , Síndrome de Rett/genética , Síndrome de Rett/metabolismoRESUMO
Arylsulfatase A and B have been demonstrated in preparations of human leukocytes. The level of activity of arylsulfatase A is markedly decreased in the preparations from patients with metachromatic leukodystrophy. Acid phosphatase and arylsulfatase B activities were normal. The assay of arylsulfatase A in leukocyte preparations can be useful in the diagnosis of metachromatic leukodystrophy while obviating the difficulties of current methods.
Assuntos
Ensaios Enzimáticos Clínicos , Esclerose Cerebral Difusa de Schilder/diagnóstico , Leucócitos/enzimologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Sulfatases/sangue , Fosfatase Ácida/sangue , Adolescente , Adulto , Cegueira/enzimologia , Catecóis/metabolismo , Criança , Pré-Escolar , Esclerose Cerebral Difusa de Schilder/sangue , Esclerose Cerebral Difusa de Schilder/enzimologia , Feminino , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/enzimologia , Lipidoses/enzimologia , Masculino , Distrofias Musculares/enzimologia , VeiasRESUMO
Medulloblastoma biopsies are heterogenous and might contain normal brain tissue, which limits the usefulness of such tumor material for biochemical analyses. We have, therefore, examined the gangliosides and their metabolism using the medulloblastoma cell lines. Daoy and D341 Med, cultured both in vitro and as xenografts in nude mice. The ganglioside patterns in the Daoy showed a switch from a high GM2, 70% (mol% of total ganglioside sialic acid) and low lactoseries gangliosides (2%) content in monolayer cultures, to a high proportion of lactoseries gangliosides (50%) and virtually no GM2 (1%) in xenografts, but an increased proportion of other a-series gangliosides. The D341 Med showed a similar change regarding the lacto-series gangliosides from 1% in suspension culture to 10% in xenografts. The activity of five glycosyltransferases, GM3, GD3, GM2, GM1 and LA2 synthases, did not parallel the ganglioside patterns and could not account for the noted variations therein. In the Daoy cell line the LA2 synthase as well as the GM2 synthase activity was relatively high in both culture systems, despite the marked difference in the expression of GM2 and the lactoseries gangliosides. These results suggest that environmental factors play a crucial role for the in vivo activity of the glycosyltransferases.
Assuntos
Galactosiltransferases/análise , Glicolipídeos/análise , Meduloblastoma/química , N-Acetilgalactosaminiltransferases , N-Acetilglucosaminiltransferases , Sialiltransferases/análise , Animais , Autorradiografia , Cromatografia em Camada Fina , Ensaio de Imunoadsorção Enzimática , Gangliosídeo Galactosiltransferase , Glucosiltransferases/análise , Humanos , Meduloblastoma/enzimologia , Camundongos , Camundongos Nus , Células Tumorais Cultivadas , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
Rett's syndrome is a progressive disorder in female patients, characterized by autistic behavior, dementia, ataxia, loss of purposeful use of the hands, and seizures. The electroencephalographic (EEG) characteristics of 17 patients with Rett's syndrome, studied between the ages of 1 and 16 years, are reported and correlated with a recently proposed system of clinical staging. Although a specific diagnostic EEG pattern was not seen in these patients, we did observe a progressive deterioration in the EEG, characterized by a slowing of EEG activity, a loss of normal sleep EEG characteristics, and the appearance of multifocal epileptiform abnormalities, followed by a pattern of generalized slow spike-wave activity. These characteristics appear to be typically seen in patients with Rett's syndrome and can be correlated with clinical staging. The EEG may be of benefit in identifying variations or subgroups in patients with Rett's syndrome as a complement to the clinical examination.
Assuntos
Ataxia/fisiopatologia , Transtorno Autístico/fisiopatologia , Demência/fisiopatologia , Eletroencefalografia , Transtornos dos Movimentos/fisiopatologia , Adolescente , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Sono/fisiologia , Vigília/fisiologiaRESUMO
In three patients with Krabbe disease (galactosylceramide lipidosis), CT and MRI patterns progressed with the evolution of the disease. At first, discrete and symmetric dense areas on CT were found in deep gray matter of hemispheres and brainstem, and also in periventricular and capsular white matter. MRI showed decreased T1 values with normal or slightly decreased T2 values in those areas and large symmetric "plaque-like" lesions with high T1 and T2 values in white matter of the centrum semiovale. Later, both CT and MRI revealed diffuse reduction in gray matter and, more profoundly, in white matter mass. These findings may alert clinicians to the possibility of Krabbe disease in infants with progressive encephalopathy.
Assuntos
Leucodistrofia de Células Globoides/diagnóstico , Espectroscopia de Ressonância Magnética , Tomografia Computadorizada por Raios X , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Lactente , Leucodistrofia de Células Globoides/diagnóstico por imagem , MasculinoRESUMO
OBJECTIVE: To evaluate a series of patients with enlarged parietal foramina for associated brain anomalies. BACKGROUND: Enlarged parietal foramina are usually considered a benign calvarial defect. METHODS: Ten patients with enlarged parietal foramina were identified. Seven patients were evaluated with neuroimaging: two by cranial CT and five by CT and/or MRI. Three patients who underwent MRI also underwent MR angiography or MR venography. RESULTS: Six of seven patients had cranial imaging showing a persistent falcine venous sinus. Three of six patients had variations of occipital cortical infolding. One patient had focal encephalomalacia in close proximity to the persistent falcine venous sinus and one had a previously undiagnosed atretic occipital encephalocele. CONCLUSION: This constellation of findings suggests that aberrant vascular evolution during fetal development may affect cerebrovascular, brain, or skull development. Individuals with enlarged parietal foramina (>5 mm) warrant imaging of underlying brain parenchyma and vasculature.
Assuntos
Encefalopatias/diagnóstico por imagem , Encefalopatias/patologia , Encéfalo/anormalidades , Veias Cerebrais/anormalidades , Osso Parietal/anormalidades , Adulto , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , RadiografiaRESUMO
Comparative study of peripheral nerve biopsies and cultured skin fibroblasts from patients with late infantile and early adult-onset forms of metachromatic leukodystrophy revealed similar pathologic changes in the early stages of nerve degeneration. However, the peripheral nerves in the adult-onset cases eventually reached a more chronically demyelinated fibrotic state than did nerves in the infantile cases. Cultured skin fibroblasts from the adult-onset patients, although clearly abnormal, were able to catabolize sulfatide significantly more effectively than the cultured skin fibroblasts from late infantile patients.
Assuntos
Leucodistrofia Metacromática/patologia , Adolescente , Adulto , Fatores Etários , Células Cultivadas , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Humanos , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/metabolismo , Masculino , Bainha de Mielina/ultraestrutura , Linhagem , Nervo Sural/ultraestruturaRESUMO
Extrapyramidal dysfunction is poorly characterized in Rett's syndrome, a neurodegenerative disorder in girls. We studied the motor and behavioral findings in 32 Rett's syndrome patients, 21 months to 30 years old. In addition to the typical stereotyped movements and scoliosis, other motor disturbances included bruxism, sialorrhea, ocular deviations, parkinsonian findings, dystonia, myoclonus, and athetosis. The types of movement disorders seemed to be age-related, with the hyperkinetic disorders occurring in the younger patients and the bradykinetic disorders occurring more frequently in the older patients.
Assuntos
Doenças dos Gânglios da Base/fisiopatologia , Síndrome de Rett/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Transtornos dos Movimentos/fisiopatologia , Escoliose/fisiopatologiaRESUMO
OBJECTIVE: To examine the developmental profile of myelin basic protein-like material (MBPLM) in urine. If urinary MBPLM exhibits a developmental profile corresponding to that of forebrain myelination, certain inferences should follow deviations from normal. Thus, MBPLM might provide a marker for monitoring the neurodevelopmental status in infants at risk for adverse outcomes. BACKGROUND: MBPLM in different immunochemical forms is detectable in human CSF and urine, presumably a result of myelin basic protein (MBP) catabolism. Urinary MBPLM has been used successfully as a marker of disease status in adults with MS. Urinary MBPLM increases in MS patients changing from a relapsing-remitting to a progressive course, possibly reflecting attempted or failed remyelination. Scant information exists concerning the presence or specific levels of urinary MBPLM during infancy and childhood when myelination is most active. METHODS: MBPLM was assayed in 402 urine specimens from 398 infants and children ranging in age from birth to 17 years according to previously described methods. RESULTS: MBPLM is detectable in urine from newborns, although at substantially lower levels than in adults (157.3 +/- 83.9 ng/mg creatinine). Whether expressed as nanograms per milliliter urine or nanograms per milligram creatinine, MBPLM levels are lower (p < 0.05) from birth through 12 months and greater (p < 0.05) between ages 2 to 8 years than in adults. CONCLUSION: Human urinary MBPLM exhibits a developmental profile that parallels the onset of normal myelination and exceeds normal adult values through early childhood. Thus, urinary MBPLM could serve as a useful marker of myelination in the developing child.
Assuntos
Envelhecimento/urina , Proteína Básica da Mielina/urina , Adolescente , Adulto , Biomarcadores/urina , Criança , Pré-Escolar , Creatinina/urina , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Radioimunoensaio , Valores de Referência , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Benign hereditary chorea (BHC) is an autosomal dominant disorder that can be distinguished from Huntington disease by its early onset, stable or only slightly progressive course, and absence of mental deterioration. The variation in clinical features is such that its very existence has been doubted. The authors recently described the localization of a gene responsible for BHC on chromosome 14q in a large Dutch family. OBJECTIVE: To report results of extensive clinical and linkage analyses for this Dutch family and six other families with BHC. RESULTS: Three of the seven families had linkage to a region on chromosome 14q13.1-q21.1. HOMOG analysis showed odds of 10 x 10(11) in favor of locus heterogeneity. Haplotype analyses for the linked families resulted in a reduction of the critical interval for the BHC gene to 8.4 cM between marker D14S49 and marker D14S278. Clinically, these three families had a homogeneous picture with early-onset chorea, sometimes accompanied by slight ataxia in walking, but without dystonia, myoclonic jerks, or dysarthria. The severity of the choreatic movements tended to abate in adolescence or early adulthood. In the unlinked families, symptoms and signs were more heterogeneous as to age at onset and the occurrence of myoclonic jerks or dystonia. CONCLUSIONS: BHC is a clinically and genetically heterogeneous disorder, with one well-defined clinical syndrome mapping to chromosome 14q.
Assuntos
Coreia/genética , Cromossomos Humanos Par 14/genética , Ligação Genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Coreia/diagnóstico , Coreia/epidemiologia , Progressão da Doença , Família , Feminino , Marcadores Genéticos , Testes Genéticos , Genótipo , Grécia/epidemiologia , Haplótipos , Humanos , Internet , Escore Lod , Masculino , Países Baixos/epidemiologia , Remissão Espontânea , Estados Unidos/epidemiologiaRESUMO
In this country, cerebral cysticercosis is not commonly implicated as the etiology of an otherwise uncomplicated seizure disorder occurring during childhood. Nine children with neurologic symptomatology and radiographic (computed tomography) evidence consistent with cerebral cysticercosis have been evaluated. Each patient was born and resided for some period (1 1/2 to 10 years) in an endemic area. Principal symptomatology consisted of a generalized seizure disorder. EEGs were normal in five patients and nonspecific in two. Serologic studies on serum and CSF were negative in 8/9 patients including the single patient requiring surgical intervention for excision of a cysticercal cyst. Cerebral nuclide scanning was not helpful and skull radiography was used to diagnose intracerebral calcifications in six patients. Computed tomography revealed multiple calcifications in six patients and a solitary lesion in one. Five patients had enhancing cystic lesions including three of those with diffuse calcifications. Since the natural history of cerebral cysticercosis presenting in this fashion is benign, symptomatic treatment is often sufficient. Anticonvulsants generally provide adequate seizure control. In one patient, cyst removal was necessary to achieve seizure control. On the basis of this experience, conclusions are (1) that the incidence of cerebral cysticercosis in exposed children is higher than commonly appreciated, and (2) that computed tomography may assist in the establishment of the diagnosis.
Assuntos
Encefalopatias/diagnóstico , Cisticercose/diagnóstico , Adolescente , Encéfalo/diagnóstico por imagem , Encefalopatias/complicações , Calcinose/etiologia , Criança , Cisticercose/complicações , Feminino , Humanos , Masculino , Tomografia Computadorizada por Raios XRESUMO
Congenital cytomegalovirus (CMV) infection is a major public health problem because 30,000 to 40,000 neonates with the infection are born each year in the United States. Although 90% of the congenitally infected infants are asymptomatic at birth, evidence is accumulating that these infants are at risk for audiologic, neurologic, and developmental sequelae. The current study describes the audiologic outcome of 59 infants with asymptomatic congenital CMV infection compared with 26 control infants. Eight of 59 infected infants had congenital sensorineural hearing loss (SNHL) but none of the control subjects did. Longitudinal audiologic assessments revealed that 5 of the 8 infants had further deterioration of their SNHL; a ninth infant with initially normal hearing experienced a unilateral SNHL during the first year of life, with further deterioration subsequently. The frequency of SNHL was similar for infected infants born to mothers with recurrent CMV infections during pregnancy (2 of 9) and for those born to mothers who experienced primary CMV infections (5 of 26). There was a significant difference between the occurrence of hearing loss in infected infants with normal computed tomographic scans (2 of 40) compared with those with either periventricular radiolucencies (4 of 13) or calcifications (1 of 3). Children with SNHL often have no identified cause of the loss; thus, it is likely that many of these children had asymptomatic congenital CMV infection. Given the progressive nature of SNHL associated with asymptomatic congenital CMV infection, longitudinal audiologic assessments are mandatory.
Assuntos
Infecções por Citomegalovirus/congênito , Perda Auditiva Neurossensorial/etiologia , Audiometria , Pré-Escolar , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Lactente , Masculino , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Estudos Prospectivos , Testes SorológicosRESUMO
Necrotizing fasciitis is characterized by necrosis with extension over fascial planes and mixed aerobic-anaerobic etiologies. Necrotizing fasciitis is uncommon in children and seldom involves the head and neck area. An infant who developed necrotizing fasciitis involving the parapharyngeal space is described. Chronic dental pathology was probably the initial focus of infection. The patient had a left hemiparesis due to a right middle cerebral artery infarct. Carotid angiography demonstrated complete occlusion of the right internal carotid artery, probably secondary to inflammatory arteritis or direct compression along its course through the parapharyngeal space. Mixed aerobic-anaerobic etiologies predominate in infections of the potential spaces of the head and neck as was demonstrated in this patient. The patient recovered, but had neurologic sequelae. Prompt and aggressive therapy is necessary in patients with necrotizing fasciitis syndromes in order to avoid such severe complications.
Assuntos
Arteriopatias Oclusivas/complicações , Doenças das Artérias Carótidas/complicações , Fasciite/complicações , Hemiplegia/complicações , Doença Aguda , Arteriopatias Oclusivas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Artéria Carótida Interna/diagnóstico por imagem , Fasciite/diagnóstico por imagem , Fasciite/patologia , Feminino , Hemiplegia/diagnóstico por imagem , Humanos , Lactente , Pescoço , Necrose , Tomografia Computadorizada por Raios XRESUMO
The Texas Rett Syndrome Registry maintains the largest population-based registry of cases and potential cases of Rett syndrome in the world. The most precise estimate of the prevalence of Rett syndrome of 1 per 22800 (0.44/10000) females aged 2 through 18 years of age was generated from this Registry. In addition, the first prevalence figures for black and Hispanic female cases were estimated. Registry cases are actively ascertained from multiple sources. Registry staff identify presumptive cases from review of information provided to the Registry by the parent or guardian. Preliminary diagnostic evaluation includes standardized review of medical records and videotape of key behaviors. Diagnosis is confirmed at clinical evaluation. The active surveillance system is monitored with the two-source capture-recapture methodology and case ascertainment is projected. The 1990 prevalence estimate of Rett syndrome indicates that the syndrome occurs less frequently than previously estimated. Until a biologic marker for Rett syndrome is identified or a standard definition for an incident case of Rett syndrome is designated, the prevalence of Rett syndrome will remain a major investigative issue of its epidemiology, and the Registry will be an important, systematic mean to gather case material for clinical and laboratory studies providing the foundation for the development of preventive interventions.
Assuntos
Bases de Dados Factuais/normas , Vigilância da População , Sistema de Registros/normas , Síndrome de Rett/epidemiologia , Adolescente , Comportamento do Adolescente , Biomarcadores/análise , Criança , Comportamento Infantil , Pré-Escolar , Etnicidade , Estudos de Avaliação como Assunto , Feminino , Previsões , Humanos , Incidência , Crescimento Demográfico , Prevalência , Grupos Raciais , Reprodutibilidade dos Testes , Projetos de Pesquisa/normas , Síndrome de Rett/diagnóstico , Síndrome de Rett/mortalidade , Fatores de Risco , Taxa de Sobrevida , Texas/epidemiologia , Gravação de VideoteipeRESUMO
Rett syndrome is a neurodegenerative disorder that occurs exclusively in females. The syndrome is sporadic in most cases with the exception of a few familial cases with an inheritance pattern through maternal lines. These observations raised the possibility that Rett syndrome may be due to an X-linked dominant mutation which is lethal in the male. To evaluate this hypothesis, we have systematically performed high-resolution chromosome analysis on 28 patients with Rett syndrome searching for deletions and/or translocations. In one patient, a de novo balanced translocation was observed with the chromosome constitution of 46,X,t(X;3) (p22.11;q13.31). This finding supports the hypothesis of an X-linked dominant mutation and suggests that the Rett gene might map to distal Xp21 or proximal Xp22.
Assuntos
Cromossomos Humanos Par 3 , Síndrome de Rett/genética , Translocação Genética , Cromossomo X , Pré-Escolar , Bandeamento Cromossômico , Feminino , HumanosRESUMO
To delineate further the clinical spectrum of Menkes disease, an X-linked recessive disorder of copper transport, we studied 4 related males, ranging in age from 4-38 years, with a unique phenotype that combines manifestations of classical and mild Menkes disease and occipital horn syndrome (OHS). The propositus, and 18-year-old man, was evaluated following an intracerebral hemorrhage at age 15 years and was noted to have marked hypotonia, motor delay with mental retardation, bladder diverticula, failure to thrive, and diarrhea from infancy; seizures from age 3 years; and abnormal hair (pili torti) and face, cutis laxa, and multiple joint dislocations. Radiographic abnormalities included occipital exostoses, tortuous cerebral blood vessels with multiple branch occlusions, and hammer-shaped clavicles. Biochemical studies demonstrated reduced copper and ceruloplasmin levels in serum, and abnormal plasma catecholamine ratios. We reported previously the molecular defect in this family, a splice-site mutation that predicts formation of approximately 20% of the normal Menkes gene product [Kaler et al., 1994: Nat Genet 18:195-202]. Here, we detail the clinical course and physical features and radiographic findings in these 4 individuals, and compare their phenotype with classical and mild Menkes and OHS. Unusual Menkes disease variants such as this may escape recognition due to anomalies that appear inconsistent with the diagnosis, particularly prolonged survival and later onset of seizures. Males with mental retardation and connective tissue abnormalities should be evaluated for biochemical evidence of defective copper transport.
Assuntos
Síndrome de Ehlers-Danlos/fisiopatologia , Síndrome dos Cabelos Torcidos/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Ehlers-Danlos/diagnóstico por imagem , Síndrome de Ehlers-Danlos/genética , Exostose/diagnóstico por imagem , Humanos , Lactente , Masculino , Síndrome dos Cabelos Torcidos/diagnóstico por imagem , Síndrome dos Cabelos Torcidos/genética , Osso Occipital/diagnóstico por imagem , Linhagem , Fenótipo , RadiografiaRESUMO
Few registries are available for evaluating population differences for rare, newly, or ill-defined pediatric neurologic disorders. The purpose of this article is to present standard methodologies for establishing a population-based registry and evaluating the completeness of a registry's case ascertainment. The Texas Rett Syndrome Registry (TRSR) is used as a model. The combination of health care and education resources has identified approx. 89-100% of the Rett syndrome cases in Texas. Cases reported by non-physician sources, although older on average (10.7 vs 7.7 years of age), did not differ by other demographic characteristics from those reported by physicians. Non-physician health and education professionals participated with the TRSR at a significantly higher rate than physicians, 89 and 37% (p < 0.05), respectively. Capture-recapture techniques, both two-sample and log-linear modeling, were used to quantitatively evaluate case ascertainment. Standardized national and international population-based registries could be the basis of an initiative to identify the etiology and perhaps preventive measures for pediatric neurologic disorders.
Assuntos
Doenças do Sistema Nervoso/epidemiologia , Vigilância da População/métodos , Sistema de Registros , Criança , Humanos , Modelos Lineares , Modelos Estatísticos , Síndrome de Rett/epidemiologia , Texas/epidemiologiaRESUMO
We extend our findings showing dose-dependent cocaine inhibition of differentiation in NGF-stimulated PC-12 cells without affecting cell viability by demonstrating that neurite extension is severely limited after 24 h, maximal effect is reached at 36 h and recovery is only partial. Cocaine metabolites lack these effects. A similar process may occur following human prenatal exposure, perhaps through cocaine-induced changes in gene expression or other intracellular signalling events.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Cocaína/farmacologia , Fatores de Crescimento Neural/farmacologia , Células PC12/efeitos dos fármacos , Animais , Ratos , Fatores de TempoRESUMO
In utero cocaine exposure can adversely affect CNS development. Previous studies showed that cocaine inhibits neuronal differentiation in a dose-dependent fashion in nerve growth factor (NGF)-stimulated PC12 cells. Cocaine binds with high affinity to several neurotransmitter transporters, resulting in elevated neurotransmitter levels in nerve endings. To determine if cocaine inhibits neurite outgrowth through the effects of these neurotransmitters, we applied dopamine, norepinephrine, serotonin, and acetylcholine to NGF-induced PC12 cells. Dopamine was the only neurotransmitter to inhibit neurite outgrowth significantly in a dose-dependent pattern without affecting cell viability. Norepinephrine and acetylcholine did not affect neurite outgrowth, while serotonin enhanced it. Furthermore, GBR 12909, a potent dopamine transporter (DAT) inhibitor, yielded similar effects. We then showed PC12 cells express D(1) and D(2) receptors and DAT proteins. Dopamine uptake measured over time was significantly blocked by cocaine and GBR 12909 which may result in elevated extracellular dopamine. The role of dopamine receptors in PC12 differentiation was further examined by using D(1) and D(2) specific receptor agonists. Only the D(1) agonist, SKF-38393, had a significant dose-dependent inhibitory effect. In addition, a D(1) antagonist produced significant recovery of neurite outgrowth in cocaine-treated cells. These findings suggest that cocaine inhibitory effects on neuronal differentiation are mediated through its binding to the dopamine transporter, resulting in increased dopamine level in the synapses. Subsequently, up regulation of D(1) receptors alters NGF signaling pathways.