RESUMO
OBJECTIVE: To describe the epidemiology of pedestrian deaths due to motor vehicle crashes (MVCs) between age groups in New York City (NYC), with a comparison to national data. METHODS: Review of MVC pedestrian deaths in NYC and the US from 1998 to 2002. Data on deaths were obtained from the National Highway Traffic Safety Administration. RESULTS: Almost half (48%) of all MVC deaths in NYC were among pedestrians, compared with 12% nationally. Pedestrian death rates were highest among older age groups (> or =65 years). NYC's older pedestrians were more likely than US older pedestrians to be killed at an intersection, during daytime and on weekdays. CONCLUSION: Older people constitute a major proportion of MVC pedestrian deaths in NYC. Conditions (such as traffic exposure) surrounding pedestrian MVCs may differ by age group. The high burden of MVCs among older pedestrians in NYC highlights the importance of local-level analysis to guide public health planning.
Assuntos
Acidentes de Trânsito/mortalidade , Caminhada/lesões , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Automóveis , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Periodicidade , Distribuição por Sexo , Estados Unidos/epidemiologia , Saúde da População Urbana/estatística & dados numéricosRESUMO
Calcium sensing (CaR) and Group I metabotropic glutamate receptors exhibit overlapping expression patterns in brain, and share common signal transduction pathways. To determine whether CaR and Group I metabotropic glutamate receptors (mGluRs) (mGluR1alpha and mGluR5) can form heterodimers, we immunoprecipitated CaR from bovine brain and observed co-precipitation of mGluR1alpha. CaR and mGluR1alpha co-localize in hippocampal and cerebellar neurons, but are expressed separately in other brain regions. In vitro transfection studies in HEK-293 cells established the specificity and disulfide-linked nature of the CaR:mGluR1alpha (CaR:mGluR5) interactions. CaR:mGluR1alpha (CaR:mGluR5) heterodimers exhibit altered trafficking via Homer 1c when compared with CaR:CaR homodimers. CaR becomes sensitive to glutamate-mediated internalization when present in CaR:mGluR1alpha heterodimers. These results demonstrate cross-family covalent heterodimerization of CaR with Group I mGluRs, and increase the potential role(s) for CaR in modulating neuronal function.
Assuntos
Proteínas de Ligação ao Cálcio/química , Cálcio/metabolismo , Neurônios/metabolismo , Receptores de Glutamato Metabotrópico/química , Animais , Encéfalo/metabolismo , Bovinos , Linhagem Celular , Cerebelo/metabolismo , Dimerização , Dissulfetos , Ensaio de Imunoadsorção Enzimática , Hipocampo/metabolismo , Humanos , Microscopia de Fluorescência , Neurônios/química , Testes de Precipitina , Ligação Proteica , Ratos , TransfecçãoRESUMO
The non-toxic ganglioside binding domain of tetanus toxin (Hc fragment C or TTC) has been studied as a vector for delivering therapeutic proteins to neurons. There is little information on the cellular processing of proteins delivered by linkage to TTC. We have evaluated the cellular handling of a multi-domain hybrid protein containing TTC and both the human enzyme superoxide dismutase and the maltose binding protein from E. coli. Binding, internalization, and cleavage of this protein during prolonged incubation with fetal cortical neurons or cells of the N18-RE-105 line was evaluated by immunoblot analysis, ELISA, and immunocytochemistry. Hybrid proteins were bound and internalized in a manner very similar to TTC. Internalized proteins showed long-term stability within cells, and were degraded into predictable large protein fragments in both cell types. Fragments that were cleaved away from the TTC domain were released into extracellular fluid after internalization. Proteins coupled to TTC share its long-term stability after cellular internalization. After internalization, dissociation of proteins linked to TTC facilitates their release from the cell, but not into other cellular compartments such as the cytosol. TTC linked proteins are probably enclosed within a stable endosomal compartment throughout their cellular lifetime.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Proteínas de Transporte/metabolismo , Proteínas de Escherichia coli , Proteínas de Transporte de Monossacarídeos , Neurônios/efeitos dos fármacos , Proteínas/farmacocinética , Superóxido Dismutase/metabolismo , Toxina Tetânica/farmacologia , Sítios de Ligação , Sistemas de Liberação de Medicamentos , Ensaio de Imunoadsorção Enzimática , Escherichia coli/química , Humanos , Immunoblotting , Imunoconjugados , Imuno-Histoquímica , Proteínas Ligantes de Maltose , Neurônios/enzimologia , Proteínas/administração & dosagem , Proteínas/química , Toxina Tetânica/química , Toxina Tetânica/farmacocinéticaRESUMO
Vacuolation in cellular organelles within the central nervous system is a common manifestation of oxidative injury. We found that the spongiform vacuolation observed in PVC-211 murine leukemia virus (PVC-MuLV) neurodegeneration was associated with oxidative damage as detected by immunoreactivity for 3-nitrotyrosine and protein carbonyl groups. This oxidative injury was present in brain before or concomitant with the appearance of activated microglia, vacuolation, and gliosis that characterize PVC-MuLV neuropathology. Treatment of infected F344 rat pups with the antioxidant vitamin E transiently protected and prolonged the latency of PVC-MuLV neurodegeneration. Taken together, these findings implicate oxidative damage and lipid peroxidation in the pathogenesis of PVC-MuLV neurodegeneration. This animal model may be useful for studies of mechanisms and potential therapies for progressive neurodegeneration following a well-defined insult.
Assuntos
Viroses do Sistema Nervoso Central/patologia , Vírus da Leucemia Murina/patogenicidade , Doenças Neurodegenerativas/patologia , Estresse Oxidativo , Células 3T3 , Animais , Biomarcadores/análise , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Viroses do Sistema Nervoso Central/tratamento farmacológico , Viroses do Sistema Nervoso Central/metabolismo , Viroses do Sistema Nervoso Central/virologia , Suplementos Nutricionais , Camundongos , Microglia/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/dietoterapia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/virologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Vacúolos/patologia , Vitamina E/administração & dosagemRESUMO
The retinal pigment epithelium (RPE) lies at the interface between the neural retina and the choriocapillaries where it forms a blood-retinal barrier. Like endothelial regions of the blood-brain barrier, the development of the RPE barrier is a gradual, multistep process. A culture model of chick RPE was used to study this development. The permeability of the tight junctions that limit diffusion between neighboring RPE cells was measured as the transepithelial electrical resistance (TER). Embryonic day 14 (E14) retinas were used to make a conditioned medium that lowered the permeability of cultured RPE. The TER of cultures prepared from E14 RPE was twice that of E7 RPE. In each culture, retinal conditioned medium increases the TER 2-2.5 fold. The active factors of conditioned medium that affected each culture had different physical properties. The factor that affected E7 was protease-resistant with a Mr<10 kDa, but the factor that affected E14 appeared to be a protein of approximately 49 kDa. Unlike the effect of astrocyte conditioned medium on endothelia, retinal conditioned medium did not act synergistically with cAMP. These data indicate that the chick retina, which lacks astrocytes, uses different diffusible factors to regulate different stages of tight junction development.
Assuntos
Barreira Hematoencefálica/fisiologia , Epitélio Pigmentado Ocular , Agonistas Adrenérgicos/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Catecolaminas/farmacologia , Fracionamento Celular , Células Cultivadas , Embrião de Galinha , Cromatografia em Gel , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/farmacologia , Agonistas de Dopamina/farmacologia , Impedância Elétrica , Endopeptidases/farmacologia , Proteínas do Olho/análise , Proteínas do Olho/metabolismo , Indóis , Epitélio Pigmentado Ocular/crescimento & desenvolvimento , Epitélio Pigmentado Ocular/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Junções Íntimas/metabolismoRESUMO
In normal retinas, the phagocytosis of shed photoreceptor outer segments is mediated in part through a mannose receptor protein located in the apical retinal pigment epithelium membrane. As dystrophic rats of the Royal College of Surgeons have a defect in which the retinal pigment epithelium (RPE) is unable to phagocytize the shed outer segments, it is hypothesized that mannose receptor expression will be lost with the progression of photoreceptor degeneration. Immunohistochemical and molecular techniques have been used to study the developmental expression of the mannose receptor in normal and dystrophic retinal pigment epithelium. By immunofluorescence, the mannose receptor is localized to the retinal pigment epithelium, apical membrane region, beginning around 5 days postnatally in both normal and dystrophic retinas. In immunoblots, bands at 175 kDa are labelled by an anti-mannose receptor antibody in apical membrane samples from both normal and dystrophic RPE at all developmental times sampled. RT-PCR analysis reveals that mannose receptor message is present in normal and dystrophic RPE samples at all developmental time points examined. The present study demonstrates that the expression of the mannose receptor begins prior to outer segment differentiation and the initiation of phagocytosis in both normal and dystrophic RPE. Expression of the mannose receptor continues to be unchanged during the progression of photoreceptor degeneration in the dystrophic retina.
Assuntos
Lectinas Tipo C , Lectinas de Ligação a Manose , Epitélio Pigmentado Ocular/metabolismo , Receptores de Superfície Celular/metabolismo , Degeneração Retiniana/metabolismo , Animais , Sequência de Bases , Southern Blotting , Progressão da Doença , Expressão Gênica , Receptor de Manose , Dados de Sequência Molecular , RNA Mensageiro/genética , Ratos , Ratos Long-Evans , Receptores de Superfície Celular/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Entry of ecotropic murine leukemia virus (MuLV) into host cells is initiated by interaction between the receptor-binding domain of the viral SU protein and the third extracellular domain (TED) of the receptor, cationic amino acid transporter 1 (CAT1). To study the molecular basis for the retrovirus-receptor interaction, mouse CAT1 (mCAT1) was expressed in human 293 cells as a fusion protein with jellyfish green fluorescent protein (GFP). Easily detected by fluorescence microscopy and immunoblot analysis with anti-GFP antibodies, the mCAT1-GFP fusion protein was expressed in an N-glycosylated form on the cell surface and in the Golgi apparatus, retaining the ecotropic receptor function. The system was applied to compare Friend MuLV (F-MuLV) and its neuropathogenic variant, PVC-211 MuLV, which exhibits a unique cellular tropism and host range, for the ability to use various CAT family members as a receptor. The results indicated that F-MuLV and PVC-211 MuLV could infect the cells expressing wild-type mCAT1 at comparable efficiencies and that rat CAT3, but not mCAT2, conferred a low but detectable level of susceptibility to F-MuLV and PVC-211 MuLV. The data also suggested that CAT proteins might be expressed in an oligomeric form. Further application of the system developed in this study may provide useful insights into the entry mechanism of ecotropic MuLV.
Assuntos
Proteínas de Transporte/fisiologia , Vírus da Leucemia Murina/fisiologia , Proteínas de Membrana/fisiologia , Receptores Virais/fisiologia , Replicação Viral , Sequência de Aminoácidos , Sistemas de Transporte de Aminoácidos Básicos , Animais , Gatos , Proteínas de Fluorescência Verde , Humanos , Proteínas Luminescentes , Camundongos , Dados de Sequência Molecular , Ratos , Alinhamento de SequênciaRESUMO
PURPOSE: This study was designed to investigate the presence of the secretory phospholipase A2 receptor in RPE, a protein closely related to the phagocytic mannose receptor. METHODS: Proteins from cultured rat, pig, and human RPE were separated by SDS-PAGE and immunoblotted with a polyclonal guinea pig sPLA2 receptor antibody. RT-PCR was performed on rat and pig RPE samples using primers designed from published rat pancreatic sPLA2 receptor sequences. RESULTS: The sPLA2 receptor protein was not detected in rat, pig, or human RPE by immunoblots. Additionally, message for this receptor was not detected in rat or pig RPE. CONCLUSIONS: With these techniques, these data demonstrate that the sPLA2 receptor is undetectable in the RPE.
Assuntos
Lectinas Tipo C , Lectinas/metabolismo , Lectinas de Ligação a Manose , Fosfolipases A/metabolismo , Epitélio Pigmentado Ocular/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Células Cultivadas , Eletroforese em Gel Bidimensional , Humanos , Immunoblotting , Lectinas/genética , Receptor de Manose , Fosfolipases A2 , Epitélio Pigmentado Ocular/citologia , RNA Mensageiro/metabolismo , Ratos , Receptores de Superfície Celular/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SuínosRESUMO
CONTEXT: Assault injuries and deaths are a major public health problem in New York City but they are poorly understood because there is a dearth of information concerning them. OBJECTIVE: Develop and implement a low-cost, efficient, permanent weapon-related injury surveillance system (WRISS) for the city. DESIGN: WRISS was established, using a hierarchical exclusionary model, to capture all weapon-related (gunshot, stab, blunt instrument trauma) mortality and morbidity. SETTING: The five boroughs of New York City: The Bronx, Brooklyn, Manhattan, Queens, and Staten Island. PARTICIPANTS: NYC Vital Statistics Office, New York State hospital discharge database, Statewide Planning and Research Cooperative Systems (SPARCS), hospital emergency departments, and the police department. MAIN OUTCOME MEASURES: Surveillance system simplicity, acceptability, flexibility, cost. RESULTS: NYC WRISS is a simple surveillance system depending on both existing data sources and active data collection, and is therefore acceptable to providers. It is flexible and has allowed assault injuries without weapons to be added to better reflect domestic assaults. The cost is low, less than $60,000 per year. CONCLUSIONS: NYC WRISS is an efficient, cost-effective surveillance system, particularly suited to big cities with many assault injuries. Its low cost and obvious importance as a public health tool have allowed for its institutionalization, reflected by a permanent health department position, and annual reports alongside the more traditional public health surveillance systems. Analyses of data from 1990 to 1996 have lent new understanding to the decrease in homicides and assaults in New York City during that period.
Assuntos
Vigilância da População/métodos , Violência/estatística & dados numéricos , Ferimentos e Lesões/epidemiologia , Adolescente , Adulto , Análise Custo-Benefício , Coleta de Dados/métodos , Feminino , Humanos , Masculino , Cidade de Nova Iorque/epidemiologia , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Fatores de Risco , Saúde da População Urbana , Ferimentos e Lesões/etiologiaRESUMO
The ability of single doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to induce oxidative stress in hepatic and some extrahepatic tissues of animals is well documented. However, no previous study has examined the ability of TCDD to induce oxidative stress and tissue damage in brain in vivo. In this study the ability of TCDD to induce oxidative stress in brain tissues of mice was studied after subchronic exposures. Groups of female B6C3F1 mice were treated orally with TCDD (0, 0.45, 1.5, 15, and 150 ng/kg/day) for 13 weeks, 5 days/week. The animals were euthanized 3 days after the last treatment and brain tissues were collected. Biomarkers of oxidative stress including production of superoxide anion, lipid peroxidation, and DNA-single-strand breaks (SSB) were determined. TCDD treatment resulted in significant and dose-dependent increases in the production of superoxide anion as assessed by reduction of cytochrome c. Significant increases were also observed in lipid peroxidation and DNA-SSB in those tissues, as assessed by the presence of thiobarbituric acid-reactive substances and the alkaline elution technique, respectively. These results clearly indicate that subchronic exposure to low doses of TCDD can induce oxidative tissue damage in brain tissues which may at least in part play a role in the effects of TCDD on the central nervous system.
Assuntos
Encéfalo/efeitos dos fármacos , DNA de Cadeia Simples/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Animais , Encéfalo/metabolismo , Dano ao DNA , Feminino , Peroxidação de Lipídeos , Camundongos , Estresse Oxidativo , Superóxidos/metabolismoRESUMO
Injuries have long been a leading cause of mortality in urban areas such as New York City. While efforts to address injuries were undertaken by the New York City Department of Health (NYCDOH) starting in the 1940s, it was not until the department received a Capacity Building Grant from the Centers for Disease Control and Prevention (CDC) in 1989 that a more comprehensive program could be developed. The NYCDOH launched several collaborative projects with a variety of organizations and institutions. These efforts indicate that through collaborations, local health departments can increase their effectiveness and better promote their approach to injury prevention.
Assuntos
Redes Comunitárias/organização & administração , Planos de Sistemas de Saúde/organização & administração , Ferimentos e Lesões/prevenção & controle , Redes Comunitárias/tendências , Comportamento Cooperativo , Implementação de Plano de Saúde , Planos de Sistemas de Saúde/tendências , Humanos , Cidade de Nova Iorque/epidemiologia , Vigilância da População/métodos , Estados Unidos , Violência/estatística & dados numéricos , Ferimentos e Lesões/epidemiologiaRESUMO
PVC-211 murine leukemia virus (MuLV) causes neurodegenerative disease following inoculation of neonatal, but not adult, mice and rats. It was previously shown that tropism for brain capillary endothelial cells (CEC) was a determinant of the viral neuropathogenicity. In this study, we demonstrate that host age-dependent replication of PVC-211 MuLV in vivo occurs in CEC in the brain as well as in other organs, such as the liver, kidney, and heart. In contrast, primary explant cultures of CEC derived from brains and livers of adult and neonatal rats could be infected by PVC-211 MuLV, suggesting that the age-dependent susceptibility was abrogated in vitro. Although CEC were generally less susceptible to MuLV-mediated gene transduction than fibroblasts, treatment of CEC with 2-deoxyglucose followed by inoculation of a PVC-211 MuLV-pseudotyped vector in the absence of heparin improved the transduction efficiency. These observations support the possibility that PVC-211 MuLV may be useful for establishing models of CEC gene transduction.
Assuntos
Endotélio Vascular/virologia , Vírus da Leucemia Murina de Friend/fisiologia , Técnicas de Transferência de Genes , Animais , Encéfalo/virologia , Capilares/virologia , Células Cultivadas , Desoxiglucose/farmacologia , Fígado/virologia , Ratos , Ratos Endogâmicos F344RESUMO
The purpose of this study is to present data on the distribution and etiology of nonfatal injuries resulting in hospital discharges in New York City (NYC). Records of all NYC residents discharged for injuries from acute stay hospitals 1990-1992 were tabulated. Injuries from surgical and medical procedures, adverse effects of drugs in therapeutic use, and late effects of injury were excluded. The results indicate that there was a marked geographic variation in rates: higher rates of assaults, self-inflicted injuries, burns, unintentional injuries from firearms, and injuries to bicyclists in disadvantaged neighborhoods. The data show that injuries in NYC have distinctive features that should form the basis for targeted prevention activities.
Assuntos
Ferimentos e Lesões/epidemiologia , Acidentes por Quedas/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Queimaduras/epidemiologia , Criança , Pré-Escolar , Etnicidade , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Grupos Raciais , Fatores Sexuais , Violência/estatística & dados numéricos , Ferimentos e Lesões/etiologiaRESUMO
Poliovirus (PV) is the causal agent of paralytic poliomyelitis. Many survivors of the acute disease, after decades of clinical stability, develop new muscular symptoms called postpolio syndrome. It has been hypothesized that the persistence of PV in the spinal cord is involved in the etiology of this syndrome. To investigate the ability of PV to persist in the spinal cord after the onset of paralysis, we exploited a mouse model in which most animals inoculated with a mouse-adapted mutant survived after the onset of paralysis. Light microscopy and ultrastructural immunohistochemical studies and reverse transcription followed by nested PCR performed on spinal cord from paralyzed mice demonstrated that PV persisted in the mouse spinal cord for at least 12 months after the onset of paralysis. This mouse model provides a new tool for studying poliomyelitis evolution after the onset of paralysis.
Assuntos
Modelos Animais de Doenças , Neurônios Motores/virologia , Poliomielite/virologia , Poliovirus/isolamento & purificação , Animais , Camundongos , Poliomielite/fisiopatologia , Síndrome Pós-Poliomielite/virologia , Medula Espinal/virologiaRESUMO
This comprehensive review of the literature reports on the annual and life-time prevalence of domestic violence against women in the United States. Data on population-based samples, pregnant women, and women treated in emergency rooms are each presented separately, as are the effects of age, marital status, socioeconomic status, race and ethnicity, and alcohol and drug use. Prevalence reports vary across studies, due in part to definitional issues and differences in the populations studied, but this is primarily true for lifetime and not for current prevalence. Prevalence is 0.3% to 4% for severe violence and 8% to 17% for total violence in the past year. Lifetime occurrence is 9% for severe violence and 8% to 22% for total violence. When minor as well as severe acts of physical violence toward women in the general female population are included, prevalence appears to be between 10% and 15% and somewhat higher for some subgroups.
Assuntos
Maus-Tratos Conjugais/estatística & dados numéricos , Adulto , Emergências , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Gravidez , Prevalência , Fatores de Risco , Fatores Socioeconômicos , Transtornos Relacionados ao Uso de Substâncias/complicações , Estados Unidos/epidemiologiaRESUMO
Although a variety of potential sources for reactive oxygen species (ROS) exist in the CNS, brain macrophages, i.e., the microglia, generate large quantities of these reactive species, particularly in response to injury or inflammatory signals. In order to understand how microglia contribute to changes in oxidative status of the CNS and how this might related to disease states, such as Alzheimer disease (AD), we have examined the regulation of superoxide anion and nitric oxide production from rodent and human microglia. Our results indicate that microglia from all species we have studied release superoxide anion, but produce significantly different amounts in response to the same activating agents. Species differences are also found in the ability to generate nitric oxide (NO). In particular, mouse microglia generate large quantities of NO when stimulated, but human and hamster microglia do not produce measurable amounts under the same stimulation conditions. These species differences are important to consider when modeling human disease processes from rodent studies.
Assuntos
Encéfalo/fisiologia , Microglia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Cricetinae , Humanos , Camundongos , Especificidade da EspécieRESUMO
The most frequent neurological complication of AIDS is a dementia-like syndrome. Power and collaborators (J Virol 1994; 68:4643-4649) have reported an association between the clinical signs of AIDS dementia and the amino acid composition of two positions (305 and 329) within the V3 region of HIV-1 strains amplified from brain tissue. Similarly, we analyzed position 305 in the V3 region of HIV-1 present in the brain or cerebrospinal fluid of 25 nondemented subjects at different clinical stages of HIV-1 infection. Our results are, however, at variance with the findings presented by Power and colleagues. Histidine, found to be common among sequences derived from demented patients, was also present in the majority (16 of 25) of nondemented patients analyzed by us. In the hands of Power and colleagues, sequences derived from nondemented patients contained proline at position 305. None of our patients had proline in this position. We also asked the question whether the presence of a specific amino acid at position 305 of the V3 loop is linked to an increased capacity of HIV-1 isolates to infect primary microglial cells, the major target cell for HIV-1 infection in the brain. Primary HIV-1 isolates derived from blood and cerebrospinal fluid of five patients, two asymptomatic and three AIDS patients, were used to infect microglia cell cultures. Infection was monitored by syncytium formation and by p24 antigen release in the culture supernatant. All but one of the paired blood/CSF isolates replicated in human brain cultures. Replication occurred independently from the amino acid present at position 305 of the V3 region of the viral envelope. Our results indicate that the majority of HIV-1 isolates, even derived during the asymptomatic stage, have the capacity to infect microglial cells. The relevance of viral envelope sequences in determining tropism for microglial cells and development of neurological symptoms remains an open question.
Assuntos
Complexo AIDS Demência/virologia , Síndrome da Imunodeficiência Adquirida/complicações , Proteína gp120 do Envelope de HIV/química , HIV-1/química , Complexo AIDS Demência/sangue , Complexo AIDS Demência/líquido cefalorraquidiano , Adulto , Sequência de Aminoácidos , Células Cultivadas , Células Gigantes/virologia , Proteína do Núcleo p24 do HIV/isolamento & purificação , Humanos , Microglia/virologia , Dados de Sequência MolecularRESUMO
HIV can invade the CNS, where it replicates principally in macrophages. Yet, neurological disease is more often correlated with levels of neurotoxins or tumor necrosis factor alpha than with viral replication or specific viral determinants in brain. In experimental systems, HIV glycoprotein affects functions of uninfected microglia and astrocytes to eventually cause neuronal death. While the cellular basis of cognitive and neurological dysfunction are unravelled in the simian immunodeficiency virus model, the molecular mechanisms of HIV neurotoxicity are being studied in newly developed mouse models.
Assuntos
Sistema Nervoso Central/virologia , HIV/fisiologia , Microglia/virologia , Replicação Viral/fisiologia , AnimaisRESUMO
Microglial cell activation, myelin alteration, and abundant tumor necrosis factor (TNF)-alpha message have been observed in the brains of some human immunodeficiency virus type 1 (HIV-1)-infected and demented patients. We therefore used cultures of purified human microglia and oligodendrocytes derived from adult human brain to examine the role of TNF-alpha in HIV-1 encephalopathy. Human microglia synthesize TNF-alpha message and protein in vitro. When these cells were infected with HIV-1 JrFL and maintained in the presence of TNF-alpha antibodies, soluble TNF-alpha receptors, or the TNF-alpha inhibitor pentoxifylline, viral replication was delayed or strongly inhibited. Both human microglia and oligodendrocytes express the two TNF receptors, TNF-R1, which has been implicated in cytotoxicity, and TNF-R2. While TNF-alpha may enhance HIV-1 replication in an autocrine manner, it is not toxic for microglia. In contrast, recombinant human TNF-alpha causes oligodendrocyte death in a dose-dependent manner. In situ detection of DNA fragmentation in some cells indicated that oligodendrocyte death may occur by apoptosis. Addition of live microglia or medium conditioned by these cells also resulted in 30 to 40% oligodendrocyte death, which was largely prevented by TNF-alpha inhibitors. We propose that TNF-alpha plays a dual role in HIV-1 encephalopathy, enhancing viral replication by activated microglia and damaging oligodendrocytes. Thus, TNF-alpha inhibitors may alleviate some of the neurological manifestations of acquired immunodeficiency syndrome.