RESUMEN
Infection of astrocytes with Newcastle disease virus stimulated the production of 1,2-diacylglycerol, and resulted in the kinase-dependent expression of mRNAs encoding tumor necrosis factor (TNF), interferon alpha and beta, and interleukin 6. The half-life of TNF mRNA was significantly decreased in the presence of protein kinase inhibitors H-7 and staurosporine, but not in the presence of HA1004. In contrast to the decay of TNF mRNA, the half-lives of other cytokine mRNAs were only minimally affected by the kinase inhibitors. These data indicated that the stability of TNF mRNA was regulated through a novel, kinase-dependent pathway.
Asunto(s)
Astrocitos/metabolismo , Virus de la Enfermedad de Newcastle/genética , Proteínas Quinasas/metabolismo , ARN Mensajero/metabolismo , Sulfonamidas , Factor de Necrosis Tumoral alfa/genética , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina , Alcaloides/farmacología , Amanitinas/farmacología , Animales , Northern Blotting , Núcleo Celular/metabolismo , Transformación Celular Viral , Células Cultivadas , Diglicéridos/metabolismo , Isoquinolinas/farmacología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas , ARN Mensajero/genética , Ratas , EstaurosporinaRESUMEN
A 32 year old man with symptoms of an upper respiratory infection one week prior presented with mental status changes, diffuse hyperreflexia, and bilateral extensor plantar responses. An MRI scan showed multifocal areas of high signal intensity predominantly in the parietal and occipital white matter, unassociated with mass affect. Despite aggressive treatment, the patient's symptoms rapidly progressed and he was declared brain dead. Post-mortem examination revealed acute hemorrhagic leukoencephalopathy. The clinical and pathologic features of this disorder are reviewed.
Asunto(s)
Cefalea/diagnóstico , Lóbulo Occipital/patología , Adulto , Resultado Fatal , Humanos , Imagen por Resonancia Magnética , Masculino , Escala del Estado MentalRESUMEN
We report an elderly patient with aggressive steroid-refractory giant cell arteritis manifesting as myelopathy and bilateral visual loss while on treatment. Pathologically, spinal cord infarction was observed and was due to extensive necrotizing granulomatous arteritis of spinal arteries. Spinal cord damage in giant cell arteritis is rare. One prior autopsy report of spinal cord infarction in giant cell arteritis did not identify vasculitic changes in the spinal arteries.
Asunto(s)
Arteritis de Células Gigantes/complicaciones , Infarto/complicaciones , Médula Espinal/irrigación sanguínea , Anciano , Arterias/patología , Femenino , Fondo de Ojo , Arteritis de Células Gigantes/patología , Humanos , Imagen por Resonancia Magnética , Arterias Temporales/patologíaRESUMEN
Spinal cord compression caused by extramedullary hematopoiesis is a rare complication of chronic anemic states, most frequently occurring in patients with beta-thalassemia. We report the MR appearance of extramedullary hematopoiesis resulting in cord compression in a patient with a myelodysplastic syndrome, which was isointense with the spinal cord on T1-weighted images and markedly hypointense on fast spin-echo T2-weighted images, and that demonstrated enhancement.
Asunto(s)
Hematopoyesis Extramedular , Síndromes Mielodisplásicos/complicaciones , Compresión de la Médula Espinal/diagnóstico , Compresión de la Médula Espinal/etiología , Anciano , Espacio Epidural , Humanos , Imagen por Resonancia Magnética , Masculino , Médula Espinal/patología , Vértebras Torácicas/patologíaRESUMEN
PURPOSE: Dural arteriovenous fistulas (DAVFs) are acquired arteriovenous shunts located within the dura. The highly variable natural history and symptomatology of DAVFs range from subjective bruit to intracranial hemorrhage and are related to the lesion's pattern of venous drainage and its effect on the drainage of adjacent brain. We examined the prevalence and features of DAVFs in patients with progressive dementia or encephalopathy. METHODS: The records and radiologic studies of 40 consecutive patients with DAVFs treated at our institution were reviewed. RESULTS: Five (12.5%) of 40 consecutive patients with DAVFs had encephalopathy or dementia. In each patient, high flow through the arteriovenous shunt combined with venous outflow obstruction caused impairment of cerebral venous drainage. Hemodynamically, the result was widespread venous hypertension causing diffuse ischemia and progressive dysfunction of brain parenchyma. Results of CT or MR imaging revealed abnormalities in each patient, reflecting the impaired parenchymal venous drainage. Pathologic findings in one patient confirmed the mechanism of cerebral dysfunction as venous hypertension. The hemodynamic mechanism and resulting abnormality appeared identical to that seen in progressive chronic myelopathy resulting from a spinal DAVF (Foix-Alajouanine syndrome). Remission of cognitive symptoms occurred in each patient after embolization. CONCLUSION: Venous hypertensive encephalopathy resulting from a DAVF should be considered a potentially reversible cause of vascular dementia in patients with progressive cognitive deficits.
Asunto(s)
Fístula Arteriovenosa/complicaciones , Demencia Vascular/etiología , Duramadre/irrigación sanguínea , Malformaciones Arteriovenosas Intracraneales/complicaciones , Anciano , Fístula Arteriovenosa/patología , Fístula Arteriovenosa/terapia , Encefalopatías/etiología , Encefalopatías/patología , Isquemia Encefálica/etiología , Hemorragia Cerebral/etiología , Venas Cerebrales/patología , Circulación Cerebrovascular , Trastornos del Conocimiento/terapia , Demencia Vascular/patología , Embolización Terapéutica , Hemodinámica , Humanos , Hipertensión/complicaciones , Malformaciones Arteriovenosas Intracraneales/patología , Malformaciones Arteriovenosas Intracraneales/terapia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Prevalencia , Flujo Sanguíneo Regional , Estudios Retrospectivos , Enfermedades de la Médula Espinal/etiología , Tomografía Computarizada por Rayos XRESUMEN
Subependymomas are benign intraventricular tumors with an indolent growth pattern, which are usually asymptomatic, and most commonly occur in the fourth and lateral ventricles. When symptomatic, subependymomas often obstruct critical portions of the cerebrospinal fluid (CSF) pathway, causing hydrocephalus, and range from 3 cm to 5 cm in size. We report a case of an unusually massive subependymoma of the lateral ventricles treated with subtotal resection, ventriculoperitoneal shunt, and post-surgical radiation. The clinical course, radiographic and pathologic characteristics of this massive intraventricular subependymoma are discussed, as well as the differential diagnosis of lateral ventricular masses and a review of the literature concerning subependymomas.
Asunto(s)
Neoplasias del Ventrículo Cerebral/diagnóstico , Glioma Subependimario/diagnóstico , Adulto , Humanos , MasculinoRESUMEN
Expansions of unstable trinucleotide repeats cause at least 15 inherited neurologic diseases. Here we review what has been learned of three neuromuscular diseases caused by this type of mutation. X-linked spinal and bulbar muscular atrophy is a motor neuronopathy caused by a CAG repeat expansion in the androgen receptor gene. The mutated protein has an expanded polyglutamine tract, forms intranuclear aggregates, and mediates neurodegeneration through a toxic gain-of-function mechanism. Oculopharyngeal muscular dystrophy is a dominantly inherited myopathy caused by a GCG/polyalanine expansion in the gene encoding poly(A)-binding protein 2. Myotonic dystrophy is a clinically variable multisystem disease caused by a CTG expansion in the 3' untranslated region of the myotonin gene. For each of these disorders, we summarize the clinical and pathologic features and review current understanding of the molecular mechanisms underlying their pathogenesis.
Asunto(s)
Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/patología , Repeticiones de Trinucleótidos , HumanosRESUMEN
Tumor necrosis factor (TNF) is a pleiotropic biomodulator and an important inducer of certain pathophysiologic immune reactions such as granuloma formation, cachexia, and septic shock. The production of TNF by astrocytes, which may figure prominently in the development of immune responses within the central nervous system, is subject to post-transcriptional regulation. We have previously shown that in virus-stimulated astrocytes, inhibition of protein kinase C results in a specific, 10-fold decrease in TNF mRNA half-life. Here we show that the decay of TNF messages induced in the macrophage-like cell line RAW 264.7 by either virus or lipopolysaccharide was subject to similar regulation, and that this pathway influenced the amount of TNF protein released by stimulated cells. Using a modified RNase protection assay, we demonstrate that inhibition of protein kinase C significantly enhanced the rate of poly(A) removal from TNF mRNA, thus facilitating an early event in the process of mRNA degradation.
Asunto(s)
Fosfotransferasas/metabolismo , Poli A/metabolismo , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/genética , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina , Amanitinas/farmacología , Animales , Astrocitos/metabolismo , Northern Blotting , Células Cultivadas , Semivida , Isoquinolinas/farmacología , Fosfotransferasas/antagonistas & inhibidores , Piperazinas/farmacología , Procesamiento Proteico-Postraduccional , ARN Mensajero/biosíntesis , ARN Mensajero/efectos de los fármacos , Ratas , Ratas Endogámicas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The human prostate tumor subline 1-LN-PC-3-1A (1-LN) is reproducibly metastatic in adult athymic nude mice. Cells surviving a brief in vitro exposure to ethyl methanesulfonate (EMS) exhibited a profound decrease in capacity for experimental lung metastasis in nude mice. Thirty days after EMS treatment, 1 X 10(6) uncloned EMS-treated 1-LN cells (1-LN-EMS-10) were injected IV into groups of 6 to 8-week-old male athymic nude mice (BALB/cAnBOM). A median of 8.5 colonies/lung was observed among 20 1-LN-EMS-10-injected mice, which was significantly different from the median of 51 colonies/lung produced among 14 1-LN-injected mice (P = 0.0002). This altered phenotype remained stable during 150 days of continuous culture. However, the 1-LN-EMS-10 cells were tumorigenic in 10/10 nude mice injected SC. Single lung tumor colonies recovered from 1-LN-EMS-10-injected mice and reinjected IV into nude mice produced medians of 32-63 colonies/lung. The altered metastatic phenotype resulting from treatment of 1-LN with EMS was reversed by exposure to a noncytotoxic dose of 5-azacytidine, but unaffected by a second exposure to EMS. Collectively these data demonstrate that the metastatic phenotype of these human tumor cells in athymic nude mice can be heritably altered by in vitro exposure to EMS and 5-azacytidine. Analysis of the mechanisms underlying these phenotypic changes may provide insight into parts of the complex process of tumor cell evolution.
Asunto(s)
Azacitidina/farmacología , Metanosulfonato de Etilo/farmacología , Metástasis de la Neoplasia , Neoplasias de la Próstata/patología , Animales , Línea Celular , Humanos , Neoplasias Pulmonares/secundario , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fenotipo , Neoplasias de la Próstata/inmunologíaRESUMEN
The purpose of this study was to determine whether macrophages were directly stimulated by tumor cells to release TNF-alpha. We found that several murine and human tumor cell lines and crude cell membrane vesicles prepared from these tumor cells stimulated pyran copolymer-elicited murine peritoneal macrophages (PEM) to release as much as 362 +/- 69 (mean +/- SE) units of TNF activity per 10(6) PEM in vitro. By contrast, several nontransformed cells, including Con A-stimulated splenic leukocytes and CTLL cloned T lymphocytes, failed to stimulate PEM to release TNF. Antibody and complement-mediated depletion of macrophages abrogated the release of TNF; whereas depletion of NK cells and T lymphocytes did not affect tumor-stimulated TNF release, suggesting that tumor cells directly stimulated PEM to release TNF. Tumor-stimulated TNF release was rapid, peaking in 2 to 3 h with subsequent loss of TNF activity from the medium. In the absence of tumor, PEM contained detectable levels of TNF mRNA, but did not release functionally active TNF. The addition of P815 tumor cell membrane vesicles increased both TNF mRNA levels, peaking at 1 to 2 h, and release of high levels of TNF activity. Confounding effects of endotoxin were excluded by the resistance of tumor-stimulated TNF release to neutralization by polymixin B, and by the equivalent responsiveness of PEM from endotoxin-resistant (C3H/HeJ) and endotoxin-sensitive (C3H/HeN) mice to stimulation by tumor cells. Factors which stimulated PEM to release TNF could be extracted from tumor cell membrane, with 77% of the macrophage-stimulating activity recoverable in aqueous phase. In conclusion, we have demonstrated that some tumor cell lines express specific characteristics which can be recognized by macrophages and which stimulate macrophages to release TNF.
Asunto(s)
Activación de Macrófagos , Macrófagos/fisiología , Neoplasias Experimentales/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Northern Blotting , Membrana Celular/análisis , Membrana Celular/inmunología , Relación Dosis-Respuesta Inmunológica , Expresión Génica , Humanos , Hylobates , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos , Neoplasias Experimentales/análisis , Polimixina B/farmacología , ARN Mensajero/genética , Tasa de Secreción/efectos de los fármacos , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Three related human prostate carcinoma cell lines, PC-3, 1-LN-PC-3-1A (1-LN), and 1-LN-PC-3-1A clone 4 (clone 4) were compared in terms of relative metastatic capacity in adult and young male nude mice. Only 1-LN produced lung metastases after intravenous injection into both 6- to 8-week-old and 4-week-old nude mice, as well as in mice injected intraperitoneally. The extent of the phenotypic diversity exhibited by these human prostate tumor lines was influenced by inherent dissemination ability, age of the host, and route of injection. These lines provide a useful system for the analysis of the biology of human tumor metastasis in nude mice.
Asunto(s)
Neoplasias de la Próstata/patología , Animales , Línea Celular , Humanos , Inyecciones Intraperitoneales , Neoplasias Renales/secundario , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Linfoma/secundario , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , Trasplante de Neoplasias , FenotipoRESUMEN
Rat astrocytes, immunologically competent glial cells of the central nervous system (CNS), released a variety of cytokines after activation. Lipopolysaccharide-stimulated astrocytes produced tumor necrosis factor (TNF) as demonstrated by Northern blot analysis using a mouse TNF probe and by functional assay. Biological activity of rat astrocyte-derived TNF was neutralized by rabbit antiserum against recombinant murine TNF. Stimulation of astrocytes by lipopolysaccharide also activated the interleukin 1 and interleukin 6 genes. We have also investigated whether a neurotropic paramyxovirus, Newcastle disease virus, triggers cytokine production by astrocytes. This virus induced astrocytes to produce TNF, lymphotoxin, interleukin 6, and alpha- and beta-interferons. Thus, stimulation by endotoxin and virus activated distinct, yet overlapping, sets of cytokine genes. We propose that astrocytes and the cytokines they produce may play a significant role in the pathogenesis of immunologically and/or virally mediated CNS disease, in CNS intercellular communication, and in the interactions between the nervous and immune systems.
Asunto(s)
Astrocitos/metabolismo , Factores Biológicos/biosíntesis , Transformación Celular Viral , Lipopolisacáridos/farmacología , Virus de la Enfermedad de Newcastle/genética , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Astrocitos/efectos de los fármacos , Factores Biológicos/genética , Línea Celular , Células Cultivadas , Citocinas , Femenino , Interferones/biosíntesis , Interferones/genética , Interleucina-6 , Interleucinas/biosíntesis , Interleucinas/genética , Cinética , Macrófagos/fisiología , ARN Mensajero/genética , Ratas , Ratas Endogámicas , Transcripción Genética/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Androgens are known to alter the morphology, survival, and axonal regeneration of lower motor neurons in vivo. To understand better the molecular mechanisms of androgen action in neurons, we created a model system by stably expressing the human androgen receptor (AR) in motor neuron hybrid cells. Motor neuron hybrid cells express markers consistent with anterior horn cells and can be differentiated into a neuronal phenotype. When differentiated in the presence of androgen, AR-expressing cells, but not control cells, exhibit a dose-dependent change in morphology: androgen-treated cells develop larger cell bodies and broader neuritic processes while continuing to express neuronal markers. In addition, androgen promotes the survival of AR-expressing cells, but not control cells, under low-serum conditions. Our results demonstrate a direct trophic effect of androgens on lower motor neurons, mediated through the AR expressed in this population of neurons.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Células Híbridas/citología , Neuronas Motoras/citología , Neuronas Motoras/efectos de los fármacos , Testosterona/farmacología , Biomarcadores , Supervivencia Celular/efectos de los fármacos , Colina O-Acetiltransferasa/genética , Medios de Cultivo , ADN Complementario , Regulación Enzimológica de la Expresión Génica , Humanos , Células Híbridas/química , Células Híbridas/enzimología , Proteínas Asociadas a Microtúbulos/genética , Degeneración Nerviosa , Proteínas de Neurofilamentos/genética , Fenotipo , Receptores Androgénicos/fisiología , TransfecciónRESUMEN
Androgens, like other steroid hormones, exert profound effects on cell growth and survival by modulating the expression of target genes. In vertebrates, androgens play a critical role downstream of the testis determination pathway, influencing the expression of sexually dimorphic traits. Among cells of the nervous system, motor neurons respond to trophic effects of androgen stimulation, with a subpopulation of spinal motor neurons exhibiting sexually dimorphic survival. To study the mechanisms of androgen action in these cells, we performed a subtractive screen for genes upregulated by androgen in a motor neuron cell line. We show androgen-inducible expression of two RNA-binding proteins that are the mammalian homologues of invertebrate sex determination genes. Androgens upregulate the expression of tra-2alpha, an enhancer of RNA splicing homologous to Drosophila tra-2, and promote redistribution of the protein from a diffuse to a speckled pattern within the nucleus. Similarly, androgens upregulate the expression of a novel gene homologous to Caenorhabditis elegans fox-1. These data indicate that androgens exert their effects, in part, by modulating the expression and function of genes involved in RNA processing, and identify homologues of invertebrate sex determination genes as androgen-responsive genes in mammals.
Asunto(s)
Andrógenos/farmacología , Proteínas de Caenorhabditis elegans , Proteínas de Drosophila , Proteínas de Unión al ARN/genética , Ribonucleoproteínas/genética , Procesos de Determinación del Sexo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular , Cartilla de ADN/genética , Humanos , Masculino , Metribolona/farmacología , Ratones , Datos de Secuencia Molecular , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/metabolismo , Procesamiento Postranscripcional del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Homología de Secuencia de Aminoácido , Congéneres de la Testosterona/farmacología , Transfección , Regulación hacia Arriba/efectos de los fármacosRESUMEN
We conducted cognitive, imaging, and neuropathological studies on a patient with Pick's disease. The patient was impaired at interpreting sentences with complex grammatical constructions, differing significantly from control subjects and patients with Alzheimer's disease (AD). Evaluation of regional brain functioning at rest, with positron emission tomography, revealed reduced left frontal activity compared with control subjects and AD patients. Autopsy demonstrated the classic pathology of Pick's disease, including massive neuron loss and gliosis in the frontal and cingulate cortex as well as numerous tau-positive hippocampal Pick bodies. The abnormal tau proteins were phosphorylated at the same amino acid residues as AD paired helical filament tau (PHFtau), but they exhibited a unique migration profile on western blot. Our observations support the hypothesis that a distinct variety of hyperphosphorylated tau in Pick's disease compromises the long-term viability of selectively vulnerable populations of neurons in frontal cortices that contribute to sentence processing.
Asunto(s)
Corteza Cerebral/patología , Demencia/diagnóstico , Anciano , Amígdala del Cerebelo/patología , Atrofia , Circulación Cerebrovascular , Trastornos del Conocimiento/diagnóstico , Demencia/fisiopatología , Giro Dentado/patología , Resultado Fatal , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Microscopía Electrónica , Neurofibrillas/ultraestructura , Neuronas/patología , Tomografía Computarizada de Emisión , Proteínas tau/análisisRESUMEN
A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas de la Membrana/genética , Mutagénesis Insercional , Paraparesia Espástica/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Sustitución de Aminoácidos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Codón/genética , Femenino , Humanos , Masculino , Michigan , Persona de Mediana Edad , Pruebas Neuropsicológicas , Paraparesia Espástica/complicaciones , Paraparesia Espástica/diagnóstico por imagen , Presenilina-1 , Tomografía Computarizada de EmisiónRESUMEN
Neuronal intranuclear inclusion disease (NIID) is a multisystem neurodegenerative disorder characterized by large intranuclear aggregates in neurons of the central and peripheral nervous system. These ubiquitinated intranuclear inclusions are morphologically similar to the intraneuronal aggregates that have been identified in the CAG/polyglutamine expansion diseases. As rare aggregates in NIID contain a polyglutamine epitope, we further investigated the relationship between this disease and the CAG/polyglutamine expansion diseases. Here, we show that ataxin 1 and ataxin 3 proteins are recruited into aggregates in NIID in the absence of a CAG expansion in the SCA1 and SCA3 genes. These data support an association of NIID with the polyglutamine disorders and provide evidence of in vivo recruitment of proteins with polyglutamine tracts into intraneuronal aggregates.